Note: Descriptions are shown in the official language in which they were submitted.
CA 02481739 2009-12-17
SUSTAINED RELEASE OF GUAI + E NESIN COMBINATION DRUGS
Cross-Reference to Related Applications
(001) This application is a continuation-in-part of United States patent
application
number U.S. 2004/0018233 which was filed on April 4, 2003 and United States
patent application number U.S. 2004/0022851 which was filed on April 4, 2003
both of which are a continuation-in-part of United States patent no. 6,955,821
which is a continuation-in-part of United States patent no. 6,372,252 which
was
filed on April 28, 2000 and issued on April 16, 2002.
BACKGROUND OF THE INVENTION
1002] The invention is directed to a modified release formulation for oral
administration comprising combinations of guaifenesin and optionally at least
one additional drug and methods of manufacture thereof. In particular, the
invention is directed to a sustained release formulation which maintains a
therapeutically effective blood concentration of guaifenesin and optionally
the
additional drug for a duration of about twelve hours. The invention further
relates to combinations which demonstrate a maximum serum concentration
equivalent to an immediate release tablet, while maintaining therapeutically
effective blood concentration for about twelve hours.
(003] Sustained release pharmaceutical formulations provide a significant
advantage over immediate release formulations to both clinicians. and their
patients. Sustained release dosage forms provide for fewer daily dose
administrations than their immediate release counterparts. For example, a
standard dosage regimen for a 400 mg immediate release drug with a short half-
life, such as guaifenesin, requires administration three times within twelve
hours
to maintain adequate bioavailability to achieve the desired therapeutic
effect.
This results in a series of three serum concentration profiles in the patient
showing a rapid increase of drug followed by a similar rapid decrease. As a
result, patients are provided with only a short window of the appropriate
blood
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concentration of the medicament for optimum therapy. A 1200 mg sustained
release dosage form, on the other hand, may require administration once every
twelve hours to achieve therapeutic effect. Sustained release dosage forms
generally control the rate of drug absorption, to avoid excessive drug
absorption
while maintaining effective blood concentration of the drug to provide a
patient
with a consistent therapeutic effect over an extended duration of time.
[0041 Besides reducing the frequency of dosing and providing a more consistent
therapeutic effect, sustained release dosage forms generally help reduce side
effects caused by a drug. Because sustained release dosage forms deliver the
drug in slow, incremental amounts versus the cyclic high and low
concentrations
of immediate release formulations, it is easier for a patient's body to digest
the
drug, thereby avoiding undesirable side-effects. For patients who self-
administer
therapies, sustained release dosage forms generally result in greater
compliance
due to the lower frequency of dosing, lower quantity of dosage units to be
consumed, and reduced undesired side-effects.
[005] Generally, sustained release formulations contain drug particles mixed
with
or covered by a polymer material, or blend of materials, which is resistant to
degradation or disintegration in the stomach and/or in the intestine for a
selected
period of time. Release of the drug may occur by leeching, erosion, rupture,
diffusion or similar actions depending upon the nature of the polymer material
or
polymer blend used.
[006] Conventionally, pharmaceutical manufacturers have used hydrophilic
hydrocolloid gelling polymers such as hydroxypropyl methylcellulose
(hydroxypropyl methylcellulose is also known as hypromellose and is used
interchangeably throughout the application), hydroxypropyl cellulose, or
Pullulan to formulate sustained release tablets or capsules. These polymers
first
form a gel when exposed to an aqueous environment of low pH thereby slowly
diffusing the active medicament that is contained within the polymer matrix.
When the gel enters a higher pH environment such as that found in the
intestines,
however, it dissolves resulting in a less controlled drug release. To provide
better sustained release properties in higher pH environments, some
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pharmaceutical manufacturers use polymers which dissolve only at higher pHs,
such as acrylic resins, acrylic latex dispersions, cellulose acetate
phthalate, and
hydroxypropyl methylcellulose phthalate, either alone or in combination with
hydrophilic polymers.
[007] Generally, these formulations are prepared by combining the medicament
with a finely divided powder of the hydrophilic polymer, or the hydrophilic
and
water-insoluble polymers. These ingredients are mixed and granulated with
water or an organic solvent and the granulation is dried. The dry granulation
is
then usually further blended with various pharmaceutical additives and
compressed into tablets.
[008] Although these types of formulations have been successfully used to
manufacture dosage forms that demonstrate sustained release properties, these
formulations generally do not have the desired release profile or serum
concentration of medicament over an extended period of time. These sustained
release formulations generally result in a delay in the appearance of drug in
the
blood stream, thereby delaying therapeutic effect. Additionally, when the drug
does appear, its maximum serum concentration (Cmax) is lower than the
maximum concentration required for the most effective therapeutic result.
Furthermore, most formulations that claim twelve hour potency release almost
all of their drug within six to eight hours, making the formulation less
therapeutically effective towards the end of the twelve hour period. To
prevent
blood serum concentrations of drug from falling below a therapeutically
effective level (Crain) at extended time periods, many manufacturers increase
the
drug strength of the dosage form. The increase in drug strength, however,
results in a concomitant increase in side-effects.
[009] Other pharmaceutical manufacturers have made tablets and capsules
containing a combination of an immediate release formulation and a sustained
release formulation to improve the release profile of certain sustained
release
dosage forms. Although this solution improves the Cmax and length of time
before the drug appears in the blood stream in some formulations, the extended
therapeutic effect is not improved.
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[010] Furthermore, medicaments have different solubility properties and pH
dependencies, which affect dissolution rate and bioavailability.
Bioavailability
can also be affected by a number of factors such as the amounts and types of
adjuvants used, the granulation process, compression forces (in tablet
manufacturing), surface area available for dissolution and environmental
factors
such as agitation in the stomach and the presence or absence of food. Due to
these numerous factors, specific formulations play an important role in the
preparation of prolonged action solid dosage forms, particularly in the
preparation of solid dosage forms that achieve appropriate bioavailability for
optimum therapeutic effect.
[011] Guaifenesin, 3-(2-methoxyphenoxy)-1,2-propanediol, is an expectorant
that
increases respiratory tract fluid secretions and helps to loosen phlegm. By
reducing the viscosity of secretions, guaifenesin increases the efficiency of
a
cough reflex and of ciliary action in removing accumulated secretions from
trachea and bronchi. Guaifenesin is readily absorbed from the intestinal tract
and is rapidly metabolized and excreted in urine. Guaifenesin has a typical
plasma half-life of approximately one hour. The rapid metabolism and excretion
of guaifenesin provides only a short window of therapeutic effectiveness when
immediate release dosage is used.
[012] Pseudoephedrine hydrochloride is an orally active sympathomimetic amine
and exerts a decongestant action on the nasal mucosa. Pseudoephedrine produces
peripheral effects similar to those of ephedrine and central effects similar
to, but
less intense than, amphetamines. It has the potential for excitatory effects.
At the
recommended oral dose, it has little or no pressor effect in normotensive
adults.
Pseudoephedrine has been shown to have a mean elimination half-life of 4-6
hours.
[013] Dextromethorphan acts centrally to elevate the threshold for coughing.
It has
no analgesic or addictive properties. The major circulating metabolite is
dextrorphan.
[014] The need exists for a sustained release dosage form of guaifenesin alone
and
in combinations, which are capable of sustaining therapeutic effective for
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extended periods of time. Further the need exists for sustained release dosage
forms of guaifenesin alone and in combination which results in a C...
equivalent
to that of an immediate release formulation, appears in the blood stream as
quickly as an immediate release formulation, and sustains the therapeutic
effect.
[015] SUMMARY OF THE INVENTION
The invention relates to strategies and designs in formulations of modified
release guaifenesin and guaifenesin combination dosage forms. This invention
provides sustained release pharmaceutical formulation comprising guaifenesin
and at least one additional drug. The sustained release formulation (SR) may
comprise a combination of at least one hydrophilic polymer and at least one
water-insoluble polymer. The total weight ratio of hydrophilic polymer to
water-insoluble polymer may be in a range of about one-to-one (1:1) to about
nine-to-one (9:1), more preferably in a range of about three-to-two (3:2) to
about
six-to-one (6:1), and most preferably in a range of about two-to-one (2:1) to
about four-to-one (4:1). When a tablet comprising the sustained release
formulation is exposed to an aqueous medium of low pH, such as that found in
the stomach, the polymer combination gels causing guaifenesin and the drug(s)
to diffuse from the gel. When the tablet passes to the intestines where an
aqueous medium of higher pH is present, the gel begins to dissolve, thereby
releasing guaifenesin and/or the drug(s) in controlled amounts. The tablet is
capable of releasing therapeutically effective amounts of guaifenesin over an
extended period, e.g. twelve or more hours and at least one additional drug
immediately, over an extended period, or both.
[016] This invention also encompasses a modified release composition which
comprises two portions (e.g. a bi-layer tablet, or capsule), an immediate
release
formulation (IR) and a sustained release formulation (SR). Each formulation
comprises a specific quantity of guaifenesin and may optionally contain at
least
one additional drug. The immediate release formulation is formulated to
dissolve in aqueous acidic medium, such as that found in the stomach, to
quickly
release guaifenesin contained within the portion, and optionally quickly
release
the at least one additional drug. The sustained release portion may comprise a
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combination of hydrophilic polymer and a water-insoluble polymer in a ratio
range of about one-to-one (1:1) to about nine-to-one (9:1), more preferably a
range of about three-to-two (3:2) to about six-to-one (6:1), and most
preferably
from about two-to-one (2:1) to about four-to-one (4:1). Likewise, the
sustained
release portion may also contain the additional drug(s).
[017] The invention also relates to sustained release preparations of the type
described above in the form of capsules having beads or granules of both
immediate release formulation and beads or granules of sustained release
formulation. The beads may comprise a mixture of discrete beads each having
only one of the SR or IR formulations or may comprise beads containing both
SR and JR formulations associated in a single bead, or combinations of the
foregoing. Alternatively, the sustained release formulation may comprise a
core
that is coated by a layer of the immediate release formulation to form a
single
tablet. For purpose of illustration only, the invention will be described in
detail
in the context of the bi-layered tablet embodiment. It should be understood
that
for either the immediate release and/or the sustained release portion the
guaifenesin and optionally the additional drug may be mixed within the same
matrix portion or comprise separate release portions which are then either
compressed or mixed for capsules (e.g. comprise separate beads or granules)
etc.
[018] A bi-layer tablet demonstrates a maximum serum concentration (Cma,,) and
time of availability in the blood stream that are equivalent to an immediate
release tablet. The bi-layer tablet also provides sustained release of
guaifenesin
over about a twelve hour period from one dose. The bi-layer tablet further
maintains serum concentration levels of guaifenesin at a therapeutically
effective
level for about a twelve hour period without an increase in dosage strength.
As
the bi-layer tablet may also contain at least one additional drug, the
additional
drug can be formulated within the sustained release formulation, immediate
release formulation, or both. In one embodiment, the bi-layer tablet maintains
serum concentration levels of at least one additional drug at a
therapeutically
effective level for about a twelve hour period without an increase in dosage
strength.
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[019] In another embodiment, the tablets and capsules of the invention provide
a
Cmiõ which is above the necessary therapeutically effective level for a period
of
hours, more preferably 12 or more hours. In a more preferred embodiment, a
tablet or capsule of the invention provides the above describe Cmin
characteristics
and provides the necessary Cmax to mimic an immediate release product to
obtain
symptom relief. In a more preferred embodiment, the delivery system provides
the above describe Cmin characteristics and provides the necessary Cmax to
mimic
an immediate release product to obtain symptom relief within a substantially
similar Tmax period to an immediate release profile.
[020] In another embodiment of the invention, the delivery system provides a
Cmax
which does not result in an equivalent C,,,ax of an immediate release product
but
does provide a Cmax which is therapeutically effect to relieve systems while
reducing the likelihood of side effects due to an increased Cmax.
[021] The invention also relates to methods of manufacturing sustained release
formulations and bi-layer tablets. An example of a manufacturing method for a
sustained release formulation comprises mixing a hydrophilic polymer and
active ingredients in a mixer, adding water to the mixture and continuing to
mix
and chop, drying the mixture to obtain hydrophilic polymer encapsulated
granules, milling and screening the resulting granulation, and blending it
with
various pharmaceutical additives, additional hydrophilic polymer, and water
insoluble polymer. The formulation may then be tableted and may further be
film coated with a protective coating which rapidly dissolves or disperses in
gastric juices.
[022] An example of a bi-layer tablet manufacturing method comprises blending
a
quantity of guaifenesin and optionally, at least one drug with various
excipients,
colorants, and/or other pharmaceutical additives to form an immediate release
formulation, separately blending another quantity of guaifenesin and
optionally
at least one drug with a hydrophilic polymer, a water-insoluble polymer, and
various excipients, colorants, and/or other pharmaceutical additives to form a
sustained release formulation, and compressing a quantity of the immediate
release formulation with a quantity of the sustained release formulation to
form a
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bi-layer tablet. The tablet may then optionally be coated with a protective
coating which rapidly dissolves or disperses in gastric juices.
[023] Other objects, advantages and embodiments of the invention are described
below and will be obvious from this description and practice of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[024] Figure 1 is a flow diagram depicting steps in a wet granulation method
for
manufacturing the sustained release formulation.
[025] Figure 2 is a flow diagram depicting steps in a dry granulation method
for
manufacturing the sustained release formulation.
[026] Figure 3 is a flow diagram depicting steps in a method for manufacturing
the
bi-layer tablet.
[027] Figure 4 is a graph demonstrating the dissolution profiles of tablets
comprising two different sustained release formulations.
[028] Figure 5 is a graph demonstrating the dissolution profiles of a
commercially
available immediate release dosage form and two sustained release dosage forms
of guaifenesin.
[029] Figure 6 is a graph demonstrating the plasma concentration of
guaifenesin
over time in healthy human volunteers who were dosed with three different
guaifenesin formulations; a commercial immediate release formulation, and two
different sustained release formulations (Lot 7B-32 and Lot 7B-3 1).
[030] Figure 7 is a graph demonstrating the plasma concentration of
guaifenesin
over time in healthy human volunteers from a commercially available immediate
release tablet, a non-layered modified release tablet of the invention, and
two bi-
layered modified release tablets of the invention (one comprising 600 mg of
immediate release formulation and 600 mg of sustained release formulation and
the other one comprising 400 mg of immediate release formulation and 800 mg
of sustained release formulation).
[031] Figure 8 is a graph demonstrating the dissolution profiles of four
sustained
release tablets: one tablet is non-layered, comprising 1200 mg of sustained
release formulation; another tablet is bi-layered, comprising 600 mg of
sustained
release formulation and 600 mg of immediate release formulation; another
tablet
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is bi-layered, comprising 800 mg of sustained release formulation and 400 mg
of
immediate release formulation; and yet another tablet is bi-layered comprising
1000 mg of sustained release formulation and 200 mg of immediate release
formulation.
[032] Figure 9 is a graph demonstrating the plasma concentration of
guaifenesin
over an averaged 12 hour interval (taken from 11 twelve hour intervals over
5.5
days) in healthy human volunteers from an immediate release tablet and a bi-
layered modified release tablet of the invention.
[033] Figure 10 is a graph demonstrating the plasma concentration of
guaifenesin
over time (the last twelve hour interval of the 11 twelve hour intervals
described
above) in healthy human volunteers from an immediate release tablet and a bi-
layered modified release tablet of the invention.
[034] Figure 11 is a graph demonstrating the averaged plasma concentration of
guaifenesin over a 16 hour period in 27 healthy human volunteers from 600 mg
bi-layered modified release tablets of the invention administered to fasting
volunteers, 1200 mg bi-layered modified release tablets of the invention
administered to fasting volunteers, and 1200 mg bi-layered modified release
tablets of the invention administered to volunteers who had been fed a high
fat
meal.
[035] Figure 12 is a graph demonstrating the dissolution profile of
dextromethorphan HBr as measured by three different batches of a 1200 mg
guaifenesin - 60 mg dextromethorphan tablet over a 12 hour period as measured
by the weight percentage of dextromethorphan HBr dissolved over time.
[036] Figure 13 is a graph demonstrating the plasma concentration of
guaifenesin
following the administration of 1200 mg guaifenesin and 60 mg
dextromethorphan HBr to volunteers separately and in formulations of the
invention.
[037] Figure 14 is a graph demonstrating the plasma concentrations of
dextromethorphan HBr following the administration of 1200 mg guaifenesin and
60 mg dextromethorphan HBr to volunteers in three different formulations.
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[038] Figure 15 is a graph demonstrating the plasma concentrations of the
metabolite dextrorphan following the administration of 1200 mg guaifenesin and
60 mg dextromethorphan HBr to volunteers in three different formulations.
[039] Figure 16 is a graph demonstrating the dissolution profile of
pseudoephedrine HCl in three different batches of a 1200 mg guaifenesin - 120
mg pseudoephedrine HCl tablet formulation over a 12 hour period as measured
by the percent pseudoephedrine HCl dissolved over time.
[040] Figure 17 is a graph demonstrating the plasma concentration of
guaifenesin
following the administration of 1200 mg guaifenesin and 120 mg
pseudoephedrine HCl to volunteers separately and in formulations of the
invention.
[041] Figure 18 is a graph demonstrating the plasma concentration of
pseudoephedrine HCl following the administration of 1200 mg guaifenesin and
120 mg pseudoephedrine HCl to volunteers in three different formulations.
[042] Figure 19 is a graph demonstrating the plasma concentration of three
different 1200 mg guaifenesin dosages in groups A, B, and C of example 12.
[043] Figure 20 is a graph demonstrating the plasma concentration of three
different 120 mg pseudoephedrine dosages in groups A, B, and C of example 12.
[044] Figure 21 is a graph demonstrating the plasma concentration of three
different 1200 mg guaifenesin dosages for treatments A, B, and C of example
13.
[045] Figure 20 is a graph demonstrating the plasma concentration of three
different 120 mg pseudoephedrine dosages for treatments A, B, and C of
example 13.
[046] Figure 21 depicts guaifenesin concentrations of various formulations and
dosage strength.
[047] Figure 22 depicts pseudoephedrine plasma concentrations following
administration of two different dose strengths of pseudoephedrine, as well as,
different formulations.
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[048] Figure 23 depicts guaifenesin concentrations following administration of
1200 mg of guaifenesin with 120 mg pseudoephedrine hydrochloride in two
different formulations following a high-fat meal.
[049] Figure 24 depicts pseudoephedrine concentrations following
administration
of 1200 mg of guaifenesin with 120 mg pseudoephedrine hydrochloride in two
different formulations following a high-fat meal.
[050] Figure 25 depicts steady-state guaifenesin plasma concentrations
following
administration of 11 doses of 120 mg pseudoephedrine with 1200 mg of
guaifenesin in two different formulations.
[051] Figure 26 depicts steady-state pseudoephedrine plasma concentrations
following administration of 11 doses of 120 mg pseudoephedrine with 1200 mg
of guaifenesin in two different formulations.
[052] Figure 27 depicts guaifenesin plasma concentrations following
administration of 1200 mg of guaifenesin with and without the co-
administration
of 120 mg of pseudoephedrine.
[053] Figure 28 depicts pseudoephedrine plasma concentrations following
administration of 120 mg of pseudoephedrine with and without the co-
administration of 1200 mg of guaifenesin.
[054] Figure 29 depicts guaifenesin plasma concentrations following
administration of an experimental 1200 mg guaifenesin-120 mg
pseudoephedrine formulation to volunteers under fed and fasted conditions.
[055] Figure 30 depicts pseudoephedrine plasma concentrations following
administration of an experimental 1200 mg guaifenesin-120 mg
pseudoephedrine formulation to volunteers under fed and fasted conditions.
[056] Figure 31 depicts guaifenesin dissolution profiles for various batches
associated with the studies.
[057] Figure 32 depicts pseudoephedrine dissolution profiles for various
batches
associated with the studies.
[058] Figure 33 depicts guaifenesin plasma concentrations following the
administration of 1200 mg guaifenesin with or without the co-administration of
60 mg dextromethorphan hydrobromide.
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[059] Figure 34 depicts mean dextromethorphan plasma concentrations following
the administration of dextromethorphan hydrobromide in different formulations,
doses and dosing regimens.
[060] Figure 35 depicts plasma guaifenesin concentrations following the
administration of 1200 mg guaifenesin along with 60 dextromethorphan
hydrobromide in three different formulations.
[061] Figure 36 depicts dextromethorphan plasma concentrations following the
administration of 60 mg dextromethorphan hydrobromide at three different
rates.
[062] Figure 37 depicts plasma guaifenesin concentrations following the
administration of 1200 mg guaifenesin and 60 mg dextromethorphan in an
experimental formulation under fed and fasted conditions.
[063] Figure 38 depicts plasma dextromethorphan concentrations following the
administration of 60 mg dextromethorphan hydrobromide and 1200 mg
guaifenesin in the fed and fasted conditions.
[064] Figure 39 depicts steady-state plasma concentrations of guaifenesin
following the multiple dose administration of 1200 mg guaifenesin in different
formulations.
[065] Figure 40 depicts mean steady-state guaifenesin plasma concentration-
time
profiles.
[066] Figure 41 depicts steady-state plasma concentrations of dextromethorphan
following the multiple dose administration of 60 mg dextromethorphan
hydrobromide in different formulations and/or different dosage rates.
[067] Figure 42 depicts dextromethorphan plasma concentrations following the
administration of 60 mg dextromethorphan hydrobromide in different
formulations and dosage rate.
[068] Figure 43 depicts a process flow diagram for the manufacture of
guaifenesin
DC (95%).
[069] Figure 44 depicts a process flow diagram for a
guaifenesin/pseudoephedrine
product (1200/120 mg) tablets.
[070] Figure 45 depicts a process flow diagram for guaifenesin/pseudoephedrine
product (600/60 mg) tablets.
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DETAILED DESCRIPTION OF THE INVENTION
[071] The invention relates to sustained release formulations of guaifenesin.
In a
preferred embodiment, the formulations also comprise at least one additional
drug in immediate release form, sustained release form, or both. Each
formulation comprises a specific quantity of guaifenesin and may optionally
contain at least one additional drug. The immediate release formulation is
formulated to dissolve in aqueous acidic medium, such as that found in the
stomach, to provide rapid release of the guaifenesin and optionally the at
least
one additional drug. In a preferred embodiment, the sustained release
formulation comprises a combination of a hydrophilic polymer and a water-
insoluble polymer in a ratio range of about one-to-one (1:1) to about nine-to-
one
(9:1), more preferably a range of about three-to-two (3:2) to about six-to-one
(6:1), and most preferably in a range of about two-to-one (2:1) to about four-
to-
one (4:1).
[072] In a preferred embodiment the hydrophilic polymers are selected from
acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum,
methylcellulose, hydroxomethylcellulose, hydroxypropyl methylcellulose,
hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose, agar,
pectin, carrageen, alginates, carboxypolymethylene, gelatin, casein, zein,
bentonite, magnesium aluminum silicate, polysaccharides, and modified starch
derivatives. In a more preferred embodiment the hydrophilic polymers are
selected from cellulose ethers. In a most preferred embodiment the hydrophilic
polymers are selected from hydroxypropyl methylcelluloses such as Methocel
(EIOM). Preferred total amounts of the hydrophilic polymer include more than
0.5% and less than 10% by weight for a 1200 mg tablet. More preferably
hydrophilic polymer amounts includes more than 1.0% and less than 7.0%, more
than 2% and less than 6.0%. These amounts include the hydrophilic polymer in
the Guaifenesin DC described below. The hydrophilic polymer added separately
to form the release-delaying matrix is preferably from about 0.5% to 4.0% and
more preferably from about 1.0% to 2.0%. It should be recognized that these
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amounts may be proportionally present in a 600 mg tablet or any desired
formulation strength.
[073] In a preferred embodiment the water-insoluble polymers are selected from
polyacrylic acids, acrylic resins, acrylic latex dispersions, cellulose
acetate
phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose
phthalate.
In a more preferred embodiment the water-insoluble polymers are selected from
acrylic resins. In a most preferred embodiment the water-insoluble polymers
are
selected from CarbomerTM acrylic resins such as CarbomerTM 934P. Preferred
amounts of the water-insoluble polymer include more than about 0.5% and less
than about 2.5% by weight for a 1200 mg tablet. More preferably hydrophilic
polymer amounts includes more than about .75% and less than about 1.5%, and
most preferably more than about .9% and less than 1.25%. It should be
recognized that these amounts may be proportionally present in a 600 mg tablet
or any desired formulation strength.
[074] The invention also relates to sustained release preparations of the type
described above in the form of bi-layered tablets or capsules having a
combination of beads or granules of immediate release formulation and beads or
granules of sustained release formulation. Alternatively, the sustained
release
formulation may comprise a core that is coated by a layer of immediate release
formulation to form a single tablet. For purpose of illustration only, the
invention will be described in detail in the context of the bi-layered tablet
embodiment. When the embodiment is a bi-layered tablet, the tablet is made of
two portions: one portion comprising a sustained release formulation and a
second portion comprising an immediate release formulation. In a preferred
embodiment, the at least one additional drug can be present within the
sustained
release formulation, the immediate release formulation, or both depending upon
the desired effect.
[075] For instance, a preferred embodiment of the present invention has the
following ingredients and proportions in the sustained release layer
(mg/tablet):
1052.6 mg Guaifenesin DC (95%) [1000.0 mg of Guaifenesin, LISP and 52.6 mg
of hydroxypropyl methylcellulose, LISP]; 120.0 mg Pseudoephedrine HCL,
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USP; 30.0 mg hydroxypropyl methylcellulose, USP [MethocelTM E10M, USP];
15.0 mg CarbomerTM 934P, NF [CarbopolTM 974P]; 0.4 mg FD&C Red #40
Aluminum Lake (14-16%); and 10.0 mg magnesium stearate, NF for a total
sustained release weight of 1228.0 mg. In a preferred embodiment the immediate
release layer has the following proportions: 210.5 mg Guaifenesin DC (95%)
[200.0 mg of guaifenesin, USP and 10.5 mg of hydroxypropyl methylcellulose,
USP]; 117.5 mg of microcrystalline cellulose, NF [AvicelTm PH102]; 30.0 mg of
sodium starch glycolate, NF [EXPLOTABTM] ; and 1.0 mg magnesium stearate,
NF for a total immediate release weight of 359.0 mg.
[0761 In another preferred embodiment a 1200 mg Guaifenesin/120 mg
Pseudoephedrine Tablet has the following ingredients and proportions:
Component Amount Representative Representative
(mg/tablet) Batch (kg)' Batch (kg)'
1R Laver SR Layer
Guaifenesin DC (95%) 1263.1 280.00 947.376
Hydroxypropyl methylcellulose (MethocePT's) 30.0 N/A 27.000
Pseudoephedrine hydrochloride 120.0 N/A 108.0
Microcrystalline cellulose 117.50 156.28 N/A
Sodium starch glycolate 30.0 39.90 N/A
CarbomerTr' 934P 15.0 N/A 13.500
Magnesium stearate 11.0 1.33 9.000
FD&C Red #40 Aluminum Lake 0,4 N/A 0.360
(14-16%)
Water, purified N/A3 N/A.' N/A3
Total Weight 1587.0 477.51 1105.236
Based on batch size of 900.000 tablets
2 Guaifenesin direct compression used in the manufacturing process consists of
95% Guaifenesin,
USP, 5% hydroxpropyl methylcellulose, USP (MethocelTM F1OM) granulated with
Purified water, USP
(49.21 Kg).
3 Water is removed during processing of Guaifenesin DC 95%.
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[077] In another preferred embodiment a 600 mg Guaifenesin/60 mg
Pseudoephedrine Tablet has the following ingredients and proportions:
Component Amount Representative Representative
(mg/tablet) Batch (kg)' Batch (kg)'
IR Layer SR Layer
Guaifenesin DC (95%)2 631.55 280.00 947.376
Hydroxypropyl methylcellulose 15.0 N/A 27.000
(Methocel TM)
Pseudoephedrine hydrochloride, USP 60.0 N/A 108.0
Microcrystalline cellulose 58.75 156.28 N/A
Sodium starch glycolate 15.0 39.90 N/A
Carbomer 934P 7.5 N/A 13.500
Magnesium stearate 5.50 1.33 9.000
D&C Yellow #6 Aluminum Lake 0.8 N/A 1.440
(15-18%)
Water, purified N/A3 N/A3 N/A3
Total Weight 794.1 477.51 1106.316
1 Based on batch size of 1,800,000 tablets
guaifenesin direct compression used in the manufacturing process consists of
95% guaifenesin,
2 USP, 5% hydroxpropyl methylcellulose, USP (MethocelTM E1OM) granulated with
purified water,
USP (49.21 Kg).
3 Water is removed during processing of Guaifenesin DC 95%.
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[078] In another example, a 1200 mg Guaifenesin/120 mg Pseudoephedrine Tablet
may also have the following properties:
Description 1200 mg bi-layer tablet
Average Tablet Weight 1587.0 mg 3% (1539.4 mg - 1634.6 mg)
Tablet Thickness 0.321" - 0.341"
Tablet Hardness 25-45 SCU
Friability NMT 0.8%
Loss on Drying NMT 2.0%
(moisture) NMT 31.74 mg/unit dose
Assay-guaifenesin 1140.0 - 1260.0 mg/tablet
(95.0 - 105.0%)
Assay-Pseudoephedrine 116.6 to 128.4 mg/tablet
hydrochloride (93.0 - 107.0%)
Guaifenesin The retention time of the peak obtained from the Assay
Identification A preparation matches that of the Standard preparation.
Guaifenesin (Identification B) A deep-cherry red to purpose color is produced.
Pseudoephedrine hydrochloride The retention time of the peak obtained from the
Assay
Identification A preparation matches that of the Standard preparation.
Pseudoephedrine hydrochloride The IR spectrum matches that of the standard in
the 2510 cm -1
Identification B to 2400 range cm 1.
Dose Uniformity %RSD NMT 6.0% (%RSD NMT 7.8% for Level II)
All individual values between 85.0 - 115.0%
(For Level II, one value is allowed outside 85.0 - 115.0%, but
none outside 75.0 - 125.0%)
Dissolution: 1 Hour: NMT 45%
Guaifenesin 2 Hour: 36 - 56%
6Hour:61 -81%
12 Hour: NLT 85%
Dissolution: 1 Hour: NMT 53%
Pseudoephedrine hydrochloride 2 Hour: 48 - 68%
6 Hour: NLT 75%
12 Hour: NLT 85%
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[079] In another example, a 600 mg Guaifenesin/60 mg Pseudoephedrine Tablet
may also have the following properties:
Description 600 mg bi-layer tablet
Average Tablet Weight 794.1 mg 3% (766.4 mg - 821.8 mg)
Tablet Thickness 0.247" - 0.262"
Tablet Hardness 17 - 32 SCU
Friability NMT 0.8%
Loss on Drying NMT 2.0%
(moisture) NMT 15.88 mg/unit dose
Assay-Guaifenesin 570.0 - 630.0 mg/tablet(95.0 - 105.0%)
Assay-Pseudoephedrine 58.2 to 61.8 mg/tablet
hydrochloride (93.0 - 107.0%)
Guaifenesin The retention time of the peak obtained from the Assay
Identification A preparation matches that of the Standard preparation.
Guaifenesin A deep-cherry red to purpose color is produced.
Identification B
Pseudoephedrine hydrochloride The retention time of the peak obtained from the
Assay
Identification A preparation matches that of the Standard preparation.
Pseudoephedrine hydrochloride The IR spectrum matches that of the standard in
the 2510 cm 1
Identification B to 2400 range cm 1.
Dose Uniformity %RSD NMT 6.0% (%RSD NMT 7.8% for Level II)
All individual values between 85.0 - 115.0%
(For Level II, one value is allowed outside 85.0 - 115.0%, but
none outside 75.0 - 125.0%)
Dissolution: 1 Hour: NMT 48%
Guaifenesin 2 Hour: 41 - 61%
6 Hour: 73 - 93%
12 Hour: NLT 90%
Dissolution: 1 Hour: NMT 58%
Pseudoephedrine hydrochloride 2 Hour: 56 - 76%
6 Hour: NLT 80%
12 Hour: NLT 85%
[080] In one embodiment, the 1200/60 mg guaifenesin/dextromethorphan weight
specification is 1530.4 mg -j- 3.0%, corresponding to a range of 1484.5 -
1576.3
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mg. For the 600/30 mg tablet, the weight specification is 765.2 mg 3.0%,
corresponding to a range of 742.2 - 788.2 mg. This specification range of
3.0% of the theoretical weight is similar to the guaifenesin alone 1200 mg and
600 mg tablets, respectively.
[081] The proposed hardness and thickness specifications for the 1200/60 mg
guaifenesin/dextromethorphan tablet are 15-65 SCU and 0.310" - 0.340",
respectively. Tablets pressed at 527 tpm at the minimum hardness parameter
(12LB86A) ranged from 0.329" - 0.334" and 17-23 SCU. The friability ranged
from 0.20-0.33%. Tablets pressed at 737 tpm at the minimum hardness
parameter (12LB86B) ranged from 0.331" - 0.335" and 15-24 SCU. The
friability ranged from 0.20-0.39%. Dissolution testing was performed for each
test condition (527 tpm and 737 tpm) within one hour of compression. No
significant difference was seen in the release profile between the test
samples
and the pilot batches.
[082] Further tablets pressed as thin and as hard as the press would allow at
speeds
of 527 tpm (12LB86C) and 737 tpm (12LB86D) provided a thickness range of
0.303" - 0.312" with a corresponding initial hardness range of 39-47 SCU at
527
tpm. The friability ranged from 0.07-0.13%. A thickness range of 0.304" -
0.313" was obtained with a corresponding initial hardness range of 38-47 SCU
at
737 tpm. The friability ranged from 0.06-0.13%. Historically, it has been
noted
that these tablets harden during the first few days after compression.
Therefore,
these `hard' tablets were tested for dissolution at least 5 days after
compression.
The hardness range on the fifth day after compression was 52-60 SCU for the
tablets pressed at 527 tpm. The hardness range on the fifth day after
compression was 48-56 SCU for the tablets pressed at 737 tpm. Again, the
dissolution profile for the test samples corresponded closely with that seen
in the
pilot batches. Additionally, a tablet hardness range of 60-79 SCU was reported
for PBO1-H30 at the 3-month real-time stability time point. No significant
difference in the dissolution profile from "To" was noted.
[083] The proposed hardness and thickness specifications for the 600/30 mg
guaifenesin/dextromethorphan tablet were 15-65 SCU and 0.220" - 0.260"
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respectively. Tablets pressed at the minimum hardness parameter at 527 tpm
(12LB85A) ranged from 0.257" - 0.260" and 8-13 SCU. The friability ranged
from 0.13-0.26%. Tablets pressed at the minimum hardness parameter at 840
tpm (12LB85B) ranged from 0.258" - 0.261" and 8-13 SCU. The friability
ranged from 0.13-0.26%. Dissolution testing was performed for each test
condition (527 tpm and 840 tpm) within one hour of compression. No
significant difference was seen in the release profile between the test
samples
and the pilot batches.
[084] Tablets were then pressed as thin and as hard as the press would allow.
A
range of 0.232" - 0.241" was obtained at compression with a corresponding
hardness ranging from 25-30 SCU at 527 tpm (12LB85C). The friability ranged
from 0.13-0.78%. The hardness on the seventh day after compression ranged
from 28-34 SCU. A range of 0.230" - 0.241" was obtained at compression with
a corresponding hardness ranging from 23-30 SCU at 840 tpm (12LB85D). The
friability ranged from 0.00-0.13%. The hardness on the seventh day after
compression ranged from 28-33 SCU. Again, the dissolution profile for the test
samples (seven days after compression) corresponded closely with that seen in
the pilot batches. Additionally, a tablet hardness range of 37-51 SCU was
reported for lot PBO1-H54 at the 3-month real-time stability time point. No
significant difference in the dissolution profile from "To" was noted.
[085] The preferred 1200 mg guaifenesin/60 mg dextromethorphan tablets have an
average tablet thickness of 0.305" - 0.335", an average tablet hardness of 25 -
35 SCU (in process), and average tablet hardness 20 - 79 SCU (at time of
release).
[086] The preferred 600 mg guaifenesin/30 mg dextromethorphan tablets have an
average tablet thickness of 0.230" - 0.260", an average tablet hardness of 20 -
30 SCU (in process), and an average tablet hardness of 10 - 51 SCU (at time of
release through expiration date).
[087] The specification of NMT 0.8% set for the friability of both
guaifenesin/dextromethorphan tablet strengths is based on the limit
established
with the guaifenesin alone tablets. The specification for Loss on Drying is
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comparable to guaifenesin alone, i.e. NMT 2.0%. The moisture limit is 2.0% of
the total theoretical tablet weight, recorded in mg/unit dose.
[088] The range for the specification for guaifenesin is based on the labeled
amount, 1200 mg or 600 mg 4.0%. For the 1200/60 mg
guaifenesin/dextromethorphan tablet, the range is 1152.0 - 1248.0 mg per
tablet.
For the 600/30 mg guaifenesin/dextromethorphan tablet, the range is 576.0 -
624.0 mg per tablet. The range for the specification for dextromethorphan HBr
is based on the labeled amount, 60 mg or 30 mg 4.0%. For the 1200/60 mg
tablet, the range is 57.6 - 62.4 mg per tablet. For the 600/30 mg tablet, the
range
is 28.8 - 31.2 mg per tablet.
[089] Other embodiments of the invention, include a SCU that is preferably
less
than 43, more preferably less than 41, more preferably less than 38, , more
preferably less than 37, and more preferably between 32 and 35. SCU is also
preferably greater than 21, more preferably greater than 24, more preferably
greater than 28, and more preferably greater than 31.
[090] The weight of 10 bi-layer guaifenesin/pseudoephedrine tablets (1200
mg/120
mg) is preferably less than 16.4g, more preferably less than 16.35g, more
preferably less than 16.29g, more preferably less than 16.22g, more preferably
less than 16.16g, more preferably less than 16.10g, more preferably less than
16.04g, and more preferably between 15.71g and 16.03g. The weight of 10 bi-
layer tablets is also preferably greater than 15.35g, more preferably greater
than
15.40g, more preferably greater than 15.46g, more preferably greater than
15.53g, more preferably greater than 15.59g, more preferably greater than
15.65g.
[091] Other embodiments and characteristics of the invention are described in
further detail below.
Sustained Release Formulation
[092] In one embodiment of the invention, a sustained release formulation
comprises guaifenesin and optionally at least one drug both mixed with a
polymer blend which comprises at least one hydrophilic polymer and at least
one
water-insoluble polymer. In a further embodiment, the sustained release
21
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formulation may comprise a combination of guaifenesin and at least one
additional drug, wherein the additional drug may be selected from, but is not
limited to, an antitussive such as dextromethorphan hydrobromide, codeine,
hydrocodone, a decongestant such as phenylephrine hydrochloride,
phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride or
ephedrine, an antihistamine such as chlorpheniramine maleate, brompheniramine
maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate,
phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, and
clemastine fumerate, an analgesic such as Aspirin""i, ibuprofen, naprosin, and
acetaminophen, or . combinations thereof. Preferably, the drug is
dextromethorphan hydrobromide, pseudoephedrine hydrochloride, or a
combination thereof.
[093] The sustained release matrix utilizes polymers as described below to
achieve
the required delay release profile in vivo. To obtain the release profile
proper
mixing and formulation is required. For instance, too much hydrophilic polymer
will result in too quick of a release and not allow for 12 hour relief while
too
much hydrophobic polymer will result in inadequate Cn,. for relief of
symptoms. Therefore, the selection of polymers, the amounts utilized in total
and the amount utilized in comparison to each other provide a matrix which is
then formulated according to the below methods to provide the appropriate
release profile.
[094] Hydrophilic polymers suitable for use in the sustained release
formulation
include: one or more natural or partially or totally synthetic hydrophilic
gums
such as acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum,
modified cellulosic substances such as methylcellulose,
hydroxomethylcellulose,
hydroxypropyl methylcellulose; hydroxypropyl cellulose, hydroxyethylcellulose,
carboxymethylcellulose; proteinaceous substances such as agar, pectin,
carrageen, and alginates; and other hydrophilic polymers such as
carboxypolymethylene, gelatin, casein, zein, bentonite, magnesium aluminum
silicate, polysaccharides, modified starch derivatives, and other hydrophilic
polymers known to those of skill in the art or a combination of such polymers.
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[095] These hydrophilic polymers gel and dissolve slowly in aqueous acidic
media
thereby allowing the guaifenesin and at least one drug to diffuse from the gel
in
the stomach. When the gel reaches the intestines, where the guaifenesin and
the
drug are fairly absorbable, it dissolves in controlled quantities in the
higher pH
medium to allow sustained release of guaifenesin and at least one drug
throughout the digestive tract. Preferred hydrophilic polymers are the
hydroxypropyl methylcelluloses such as those manufactured by The Dow
Chemical Company and known as MethocelTM ethers. In one preferred
embodiment of a sustained release formulation the hydrophilic polymer is a
MethocelTM ether known as MethocelTM E 1 OM.
[096] Water-insoluble polymers, which are suitable for use in the sustained
release
formulation, are polymers which generally do not dissolve in solutions of a pH
below 5, and dissolve more slowly in basic solutions than the hydrophilic
polymer. Because the polymer is insoluble in low pH environments such as
those found in gastric fluid, it aids in retarding drug release in those
regions.
Likewise, because the polymer dissolves more slowly in solutions of higher pH
than hydrophilic polymers, it aids in retarding drug release throughout the
intestines. This overall delayed release results in a more uniform serum
concentration of guaifenesin.
[097] The water-insoluble polymers suitable for use in this invention include
for
example: polyacrylic acids, acrylic resins, acrylic latex dispersions,
cellulose
acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose
phthalate, and other polymers common to those of skill in the art. In a
preferred
embodiment, a sustained release formulation comprises the acrylic resin
CarbopolTM 974P supplied by BF Goodrich.
[0981 A sustained release formulation of the invention may further comprise
pharmaceutical additives including, but not limited to: lubricants such as
magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid,
hydrogenated vegetable oils, talc, polyethylene glycol, and mineral oil;
colorants; binders such as sucrose, lactose, gelatin, starch paste, acacia,
tragacanth, povidone polyethylene glycol, Pullulan and corn syrup; glidants
such
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as colloidal silicon dioxide and talc; surface active agents such as sodium
lauryl
sulfate, dioctyl sodium sulfosuccinate, triethanolamine, polyoxyethylene
sorbitan, poloxalkol, and quarternary ammonium salts; preservatives and
stabilizers; excipients such as lactose, mannitol, glucose, fructose, xylose,
galactose, sucrose, maltose, xylitol, sorbitol, chloride, sulfate and
phosphate salts
of potassium, sodium, and magnesium; and/or any other pharmaceutical
additives known to those of skill in the art. Colorants include, but are not
limited to, Emerald Green Lake, FD&C Red No. 40, FD&C Yellow No. 6, D&C
Yellow No. 10, or FD&C Blue No. 1 and other various certified color additives
(See 21 CFR, Part 74). In one preferred embodiment, a sustained release
formulation further comprises magnesium stearate and Emerald Green Lake. In
another preferred embodiment, a sustained release formulation further
comprises
magnesium stearate and FD&C Blue No. 1 Aluminum Lake Dye.
[099] In another embodiment the modified release formulation comprises at
least
two drugs, one of which is guaifenesin, at least one hydrophilic polymer, at
least
one water-insoluble polymer, and at least one pharmaceutical additive which
permits dissolution of drugs in a therapeutically effective profile for an
extended
period of time. It is preferred that the drug profile provides a
therapeutically
effective profile for greater than 10 hours, more preferably greater than 12
hours,
and most preferably greater than 14 hours. In a preferred embodiment, a
modified release formulation comprises from about 75% to about 95%
guaifenesin by weight, from about 1% to about 15% by weight of an additional
drug, from about 0.5% to about 10% hydroxypropyl methylcellulose, from about
0.5% to about 2.5% acrylic resin, from about 0.4% to about 1.5% magnesium
stearate, and from about 0.01% to about 1% colorant by weight. In a more
preferred embodiment, a modified release formulation comprises from about
75% to about 80% guaifenesin by weight, from about 3% to about 10% by
weight of an additional drug, from about 3% to about 6% hydroxypropyl
methylcellulose, from about 1% to about 1.5% acrylic resin, from about 0.7% to
about 1% magnesium stearate, and from about 0.03% to about 0.13% colorant by
weight.
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[0100] The sustained release formulation controls the release of guaifenesin
and
optionally at least one additional drug into the digestive tract over an
extended
period of time resulting in an improved profile when compared to immediate
release combinations. guaifenesin solubility is effected by the pH of the
environment in which it is present (i.e. stomach versus intestinal tract). In
a
more acidic environment, such as the stomach, guaifenesin is less soluble
while
in a higher pH environment, such as the intestines, guaifenesin is readily
soluble.
The pH changes throughout the digestive tract effect the dissolution rate of
guaifenesin and are partially determinate of the concentrations of guaifenesin
attained in the blood and tissues.
[0101] To maintain a blood concentration of guaifenesin which provides good
therapeutic effect, the release, or dissolution, of guaifenesin from a
formulation
matrix is preferably retarded and/or controlled through the intestines. The
hydrophilic and water-insoluble polymers of the sustained release formulation
gel when exposed to media of low pH. This gel matrix allows the sustained
release drugs, e.g. guaifenesin alone or in combination with a second drug to
diffuse at a controlled rate when exposed to a higher pH environment.
[0102] When using drugs approved by the Food and Drug Administration (FDA),
the sustained release formulation may be formulated to mimic the blood serum
profile of guaifenesin and optionally the additional drug(s) as described in
the
clinical documents filed with the FDA or as required by the FDA. In other
words, the sustained release formulation releases at least one additional drug
at a
similar rate to the commercially available formulation, thereby providing a
therapeutically effective amount of the additional drug.
[0103] In a preferred embodiment, a sustained release formulation comprises a
hydrophilic polymer and a water-insoluble polymer in a ratio of about one-to-
one (1:1) to about nine-to-one (9:1), more preferably the range is about three-
to-
two (3:2) to about six-to-one (6:1), and most preferably the range of
hydrophilic
polymer to water-insoluble polymer is about two-to-one (2:1) to about four-to-
one (4:1). In another embodiment, the sustained release formulation comprises
not more than about 10% hydrophilic polymer, preferably, not more than 6%,
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and in a more preferred embodiment, the sustained release formulation also
comprises not more than 2.5% of the water-insoluble polymer by weight. In
another preferred embodiment, the water- hydrophilic polymer is hydroxypropyl
methylcellulose and the water-insoluble polymer is acrylic resin. The ratios
result in a serum concentration profile of guaifenesin that provides an
optimal
therapeutic concentration for about twelve hours.
[0104] A sustained release formulation may be manufactured according to any
appropriate method known to those of skill in the art of pharmaceutical
manufacture. In one embodiment, guaifenesin and a hydrophilic polymer may
be mixed in a mixer with an aliquot of water to form a wet granulation. The
granulation may be dried to obtain hydrophilic polymer encapsulated granules
of
guaifenesin. The resulting granulation may be milled, screened, and then
blended with various pharmaceutical additives, water insoluble polymer, and
additional hydrophilic polymer. The formulation may then tableted and may
further be film coated with a protective coating which rapidly dissolves or
disperses in gastric juices.
[0105] In a preferred embodiment the method of preparing a sustained release
formulation comprises loading approximately 126 kg of guaifenesin and about 2
kg of Methocel ElOM into a high shear mixer. The Methocel E10M and
guaifenesin may be mixed for about seven minutes at a mixing speed of about
150 RPM and a chopper speed of about 2000 RPM. The mixing and chopping
speeds may then be increased to about 200 RPM and 3000 RPM respectively for
about five minutes while about 49 kg of water are added to the mixer contents.
The mixer may be run for two additional minutes to complete granulation. In a
further preferred embodiment, the shut off for the mixer load is set to 21
kilowatts.
[0106] The wet granulation may be emptied into a fluid bed bowl and placed
into a
fluid bed dryer set to a dryer air flow of 900 CFM and an inlet temperature of
about 50 C to about 55 C until the outlet temperature increases at a rate of 1
C
per minute. The air flow may then be decreased to 600 CFM, and the inlet
temperature may be decreased to 43 C until the granulation is dried to a
moisture
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content of no more than 0.5%. In another preferred embodiment, the outlet
temperature is set to a cut-off of 48 C. In yet another preferred embodiment,
an
agitator in the fluid bed bowl may be run intermittently during drying. The
dried
granulation may be passed through a mill fitted with a suitable screen size so
that
not more than about 30% of the resulting granulation comes through a 100 mesh
screen and not more than about 10% of the resulting granulation is retained on
a
mesh screen. In one preferred embodiment, the dried granulation may be
passed through a mill fitted with a 0.109" size screen at a mill speed of
about
500 to about 1500 RPM and a screw feed rate of about 35 to about 45 RPM.
The resulting screened granulation is about 95% guaifenesin and is called G
Guaifenesin DC (Direct Compressed) herein after. Screened granulation may be
transferred to a 10 cubic foot V blender, combined with about another 0.6 kg
of
Methocel E1OM, about 0.3 kg of a colorant such as Emerald Green Lake or
FD&C BLUE No. 1, about 0.7 kg of magnesium stearate, and about 1.3 kg of
Carbopol 974P. The combination may be blended for about three minutes.
[0107] In another preferred embodiment the method of preparing a sustained
release
formulation comprises loading about 101 kg to about 150 kg of guaifenesin,
about 4.5 kg to about 18 kg of the additional drug, about 4.5 kg to about 5 kg
of
Methocel E10M, about 1.5 kg to about 2.25 kg of Carbopol0 974P, and about
40 g to about 240 g of colorant into a high shear mixer. If at this time water
is to
be added, then about 1 kg to about 1.5 kg of magnesium stearate is added as
well. The ingredients may be mixed for about ten to about 12 minutes at a
mixing speed of about 150 RPM and a chopper speed of about 2000 RPM. The
mixing and chopping speeds may then be increased to about 200 RPM and 3000
RPM, respectively, for about five minutes while optionally about 29 kg of
water
are added to the mixer contents. If no water is added, then from about 1 kg to
about 1.5 kg of magnesium stearate can be added at this time. The mixer may be
run for ten additional minutes to complete granulation. In a further preferred
embodiment, the shut off for the mixer load is set to 21 kilowatts.
[0108] The wet granulation may be emptied into a fluid bed bowl and placed
into a
fluid bed dryer set to a dryer air flow of 900 CFM and an inlet temperature of
27
CA 02481739 2009-12-17
about 38 C to about 48 C until the outlet temperature increases at a rate of
VC
per minute. The air flow may then be decreased to 600 CFM, and the inlet
temperature may be decreased to 43 C until the granulation is dried to a
moisture content of no more than 0.5%. In another preferred embodiment, the
outlet temperature is set to a cut-off of 48 C. In yet another preferred
embodiment, an agitator in the fluid bed bowl may be run intermittently during
drying. The dried granulation may be passed through a mill fitted with a
suitable
screen size so that not more than about 30% of the resulting granulation comes
through a 100 mesh screen and not more than about 10% of the resulting
granulation is retained on a 10 mesh screen. In one preferred embodiment, the
dried granulation may be passed through a mill fitted with a size screen of
about
0.109" to about 0.125" at a mill speed of about 500 to about 1500 RPM and a
screw feed rate of about 35 to about 45 RPM.
[0109] The resulting formulations may further be compressed on a tablet
compressor machine using tooling to form tablets. The tablets may be any
appropriate weight, size, and shape depending on the desired dosage strength
of
tablet. In one embodiment, these tablets may further be loaded into a coating
pan and film coated with OpadryTM Y-S-3-714 (supplied by Colorcon, Inc.) and
air dried in the pan.
[0110] In another embodiment, the method of preparing a sustained release
formulation comprises blending the drugs, hydrophilic polymer, water insoluble
polymer, and any pharmaceutical additives. The resulting blend may then be
compressed into tablets and, if desired, film coated with a protective coating
which rapidly dissolves or disperses in gastric juices. In a preferred
embodiment
of such a method, about 126 kg of Guaifenesin DC (about 95% purity), about 2.6
kg of Methoce]TM ElOM, about 1.3 kg of CarbopolTM 974P and about 0.333 kg of
a colorant such as Emerald Green Lake or FD&C BLUE No. 1 may be loaded into
a 10 cubic foot V Blender. The ingredients may be blended for about 20 minutes
at which time about 0.6 kg of magnesium stearate may be added to the blended
ingredients. This mixture may be blended for about another 10 minutes. The
resulting formulation may further be compressed on a tablet compressor machine
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using tooling to form tablets. The tablets may be any appropriate weight,
size,
and shape depending on the desired dosage strength of the tablet. These
tablets
may further be loaded into a coating pan and film coated with Opadry Y-S-3-714
(supplied by Colorcon, Inc.) and air dried in the pan.
[0111] One embodiment of the invention uses the following general methods of
manufacturing. To make the Guaifenesin DC (95%) intermediate granulation is
conducted. The granulator is charged with purified water USP. The guaifenesin
USP is added into the granulator. Next the hydroxypropyl methylcellulose USP
(Methocel El OM) is added. The guaifenesin intermediate is dried with the air
inlet temperature set about 5 C, until the air outlet temperature reached
approximately 44 C. A sample may then be taken for in-process control testing
(moisture analysis). After the material reaches the target moisture level,
discharge the blend and proceed to milling. The dried granulation is then
added
to the milling machine and the milling process initiated. Again a sample may
be
taken for in-process control testing (moisture and sieve analysis). The milled
material is collected into tared fiber drums, double-lined with plastic bags
and
containing a desiccant pouch between the inner and outer plastic bags, then
transferred to blending. The batches are blended in a 60-cu. foot blender for
at
least 10 minutes. Again, a sample may be taken for in-process control testing
(description, moisture, blend assay and sieve analysis). The final sieve
analysis
for milled Guaifenesin DC preferably will be as follows: not more than about 2
to 10% retained on a 10-mesh screen (2.00 mm), not less than about 50 to 60%
retained on the 20-mesh through 100-mesh screens (150 gm), not less than about
4 to 6% will pass through a 100-mesh screen, and not more than about 15-20%
will pass through a 140-mesh screen (106 m). When at least 50%, and
preferably at least 60% of the Guaifenesin DC has a particle size in the range
of
from about 2 mm to about 150 gm, this facilitates both processability and
achievement of the desired in vivo release profiles for the single entity and
combination drugs described herein. The final Guaifenesin DC (95%)
granulation is collected into tared fiber drums, double-lined with double-
lined
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with plastic bags and containing a desiccant pouch between the inner and outer
plastic bags.
[0112] In one embodiment the immediate release layer is produced according to
the
following general procedures. The released components, Guaifenesin DC (95%)
and microcrystalline cellulose, NF (Avicel PH102), are weighed and blended
in a PK V-blender for about 20 minutes. Then sodium starch glycolate, NF
(Explotab ), is added to the blender and blend for about 10 minutes. Next
magnesium stearate, NF, is added to the blender and blended for approximately
an additional 10 minutes. Sample may then be taken for in-process control
testing (description, blend assay and sieve analysis).
[0113] In one embodiment the sustained release layer is produced according to
the
following general procedures. The released components, Guaifenesin DC (95%)
and pseudoephedrine HCI, USP, previously screened through a No. 20 screen,
are weighed and blended for ten minutes with hydroxypropyl methylcellulose,
USP (Methocel EIOM), Carbomer 934P and the appropriate colorant (FD & C
Red No. 40 aluminum lake dye for 1200 mg guaifenesin/120 mg
pseudoephedrine HCl tablets or FD & C Yellow No. 6 aluminum lake dye for
600 mg guaifenesin/60 mg pseudoephedrine HCl tablets). Next, an additional
amount of Guaifenesin DC (95%), previously screened through a No. 10 screen,
is added and blended for about ten minutes. Then magnesium stearate, NF,
previously screened through a No. 20 screen, is added and blended for about
ten
minutes. Again, samples may be taken for in-process control testing
(description,
sieve analysis, and blend assay for both guaifenesin and pseudoephedrine HC1).
Tablet Compression involved loading each blend (IR and SR) into its respective
hopper on the bi-layer tablet compressor and then compressed according to the
described parameters.
[0114] In another embodiment 1200 mg guaifenesin and 60 mg dextromethorphan
HBr tablets are manufactured using the following protocol. The manufacturing
process yields 600,000 tablets per batch for the 1200 mg guaifenesin and 60 mg
dextromethorphan HBr or 1,200,000 tablets for 600 mg guaifenesin and 30 mg
dextromethorphan HBr tablets. The components for the immediate release layer
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(IR layer) for both strength tablets are identical. The components for the
sustained release layer (SR layer) for both strength tablets are also
identical.
[0115] For the SR layer (for 1200 mg guaifenesin and 60 mg dextromethorphan
HBr
tablets), the guaifenesin and dextromethorphan HBr (previously screened
through a 20-mesh screen), are granulated together with CarbomerTM 934P,
hydroxypropyl methylcellulose (MethocelTM E1OM), and FD&C blue #1,
aluminum lake (11 - 13%) using purified water as the granulating fluid in a
Day
mixer. The wet mass is evenly spread onto paper-lined trays and dried in a
drying oven set at 109 10 F for approximately 25 hours until the average
moisture is not more than 1.5%. The process for the SR layer for 600 mg
guaifenesin and 30 mg dextromethorphan HBr tablets is identical to the process
for the 1200 mg guaifenesin and 60 mg dextromethorphan HBr extended release
tablets with the exception of the dye used. The dye used in the half strength
tablet is D&C yellow #10, aluminum lake (14 - 18%) while the dye in the full
strength tablet is FD&C Blue #1, aluminum lake (11-13%). The dried
granulation is milled using a Fitzpatrick Mill fitted with a 0.125" round-hole
screen, knives forward at a "fast" speed. The granulation is fed into the mill
using an automatic feeder. The six sublots (112.04 kg per sublot, granulated,
dried, and milled as described above) are then blended together in a 60-cu.
foot
blender with magnesium stearate for ten minutes.
[0116] For the IR layer, the guaifenesin and dextromethorphan HBr (previously
screened through a 20-mesh screen), are granulated together with sodium starch
glycolate (ExplotabTM), microcrystalline cellulose (AvicelTM PH102), and
hydroxypropyl methylcellulose (MethoceiTM El OM) using purified water as the
granulating fluid in a Day mixer. The wet mass is evenly spread onto paper-
lined trays and dried in a drying oven set at 109 10 F for approximately 26
hours until the average moisture is not more than 2.0%. The IR layer process
is
the same for both tablet strengths. The dried granulation is passed through a
Sweco equipped with 10-mesh screen. The granulation retained on the 10-mesh
screen is milled using a Fitzpatrick Mill fitted with a 0.125" round-hole
screen,
knives forward at a "medium" speed. The granulation is fed into the mill using
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an automatic feeder. The milled material is later blended with the material
that
passed through the 10-mesh screen. The three sublots (95.52 kg per sublot,
granulated, dried, and milled as described above) are then blended together in
a
60 cu.-foot blender with magnesium stearate for ten minutes. Each blend is
then
loaded into their respective hoppers and compressed into bi-layer tablets.
[0117] Tablets comprising a sustained release formulation were prepared and
tested
for both in vitro and in vivo release characteristics as described in Examples
1, 2,
and 3 below. In the in vitro testing, the dissolution rates of these tablets
were
compared against modified release tablets formulated without acrylic resin
(Example 1), and three commercially available tablets, one being an immediate
release formulation and the other two being modified release formulations.
Tablets comprising the sustained release formulation demonstrated a slower,
more controlled release of guaifenesin over a twelve hour period than any of
the
other tablets (see e.g., Example 1 and 2, and Figures 4 and 5).
[0118] In the in vivo testing, serum concentrations of subjects taking tablets
comprising the sustained release formulation were compared with serum
concentrations of subjects taking immediate release guaifenesin tablets and
modified release guaifenesin tablets formulated without acrylic resin (see
Example 3 and Figure 6). Tablets comprising the sustained release formulation
demonstrated improved sustained release and therapeutic concentration over an
extended time period compared to the other two formulations. Additionally, in
the subjects taking tablets comprising the sustained release formulation, it
took
longer for guaifenesin to appear in the blood stream and the maximum
guaifenesin serum concentration (Cmax) was less than half that of the subjects
who took the immediate release tablets.
Modified Release Formulation
[0119] To improve the Cmax and guaifenesin appearance speed in patients while
maintaining therapeutic effect for about twelve hours, a portion of a
sustained
release formulation as described above may be combined with a portion of an
immediate release formulation in a modified release product. In a preferred
embodiment, at least one additional drug can be present within the sustained
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release formulation, the immediate release formulation, or both depending upon
the desired effect. When using drugs approved by the Food and Drug
Administration (FDA), the sustained release formulation, immediate release
formulation, or both may be formulated to mimic the blood serum profile of the
additional drug as described in the clinical documents filed with the FDA or
as
required by the FDA. In other words, the sustained and/or immediate release
formulations of the modified release formulation may release the at least one
additional drug at a similar rate to the commercially available formulation,
thereby providing a therapeutically effective amount of the additional drug.
[0120] The modified release formulation can be in the form of bi-layered
tablets,
capsules having a combination of beads or granules of immediate release
formulation and sustained release formulation, or a tablet wherein the
sustained
release formulation comprises a core that is coated by a layer of the
immediate
release formulation. For purpose of illustration only, the invention will be
described in detail in the context of the bi-layered tablet embodiment.
[0121] The immediate release formulation may comprise guaifenesin and various
pharmaceutical additives such as lubricants, colorants, binders, glidants,
surface
active agents, preservatives, stabilizers, as described above and/or any other
pharmaceutical additives known to those of skill in the art. In one
embodiment,
the immediate release layer comprises at least one drug. In another
embodiment,
the immediate release layer comprises at least two drugs. In a more preferred
embodiment, an immediate release formulation comprises guaifenesin,
microcrystalline cellulose, sodium starch glycolate, and magnesium stearate.
In
another more preferred embodiment, an immediate release formulation
comprises guaifenesin, at least one additional drug, microcrystalline
cellulose,
hydroxypropyl methylcellulose, sodium starch glycolate, and magnesium
stearate. In yet another preferred embodiment, an immediate release
formulation
may comprise about 47% to about 58% guaifenesin, about 32% to about 42%
microcrystalline cellulose, about 3% to about 8% sodium starch glycolate, and
about 0.3% to about 0.5% magnesium stearate by weight. In yet another
preferred embodiment, an immediate release formulation comprises about 47%
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to about 58% guaifenesin, about 3% to about 5% of at least one additional
drug,
about 32% to about 42% microcrystalline cellulose, about 2% to about 5%
hydroxypropyl methylcellulose, about 3% to about 8% sodium starch glycolate,
and about 0.3% to about 0.5% magnesium stearate by weight.
[01221 The bi-layer tablet may be manufactured according to any method known
to
those of skill in the art. The resulting tablet comprises the two portions
compressed against one another so that the face of each portion is exposed as
either the top or bottom of the tablet, or the resulting tablet may comprise
the
sustained release portion in the center coated by the immediate release
portion so
that only the immediate release portion is exposed. In a preferred embodiment,
a
bi-layer tablet comprises the two portions compressed against one another so
that
the face of each portion is exposed.
[0123] In a preferred method of manufacturing the bi-layer tablets, a
sustained
release formulation is prepared according to either a wet granulation or dry
granulation method as described above. The immediate release formulation may
be prepared by simply blending the guaifenesin with any pharmaceutical
additives. If at least one additional drug is present, then water may be added
to
the formulation, as described above. In a further preferred embodiment,
appropriate quantities of Guaifenesin DC, microcrystalline cellulose, and
sodium
starch glycolate are blended in a 10 cubic foot blender for about twenty
minutes.
An appropriate quantity of magnesium stearate is then added to the ingredients
and blended for about ten more minutes to make an immediate release
formulation. Portions of the sustained release formulation and immediate
release
formulation are then compressed by a tablet compressor machine capable of
forming bi-layer tablets. In one embodiment, these tablets may further be
coated
with a protective film which rapidly disintegrated or dissolves in gastric
juices.
[0124] The tablets may be made with any ratio of guaifenesin to at least one
additional drug which results in a blood profile demonstrating appropriate
therapeutic effect over extended time periods. As discussed above, the
additional drug may be present in an amount sufficient to mimic the blood
serum
profile of the commercially available formulation of the drug and not to
exceed
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the maximum dose approved by the FDA for the treatment, prevention, or
amelioration of a particular illness or disease. In one embodiment, the ratio
of
total guaifenesin to at least one additional drug is about 1:1 to about 30:1,
more
preferably about 1:1 to 25:1, and more preferably about 20:1 by weight.
Alternatively, the ratio is about 2:1 to about 15:1 by weight, and more
preferably, the ratio of guaifenesin to at least one additional drug is about
8:1 to
about 12:1 by weight. When present in the immediate release layer, the amount
of the at least one additional drug should be sufficient to match the drug
release
profile of the additional drug within the sustained release profile.
[0125] In a preferred embodiment, the tablets are made with any ratio of
guaifenesin
to pseudoephedrine which results in a blood profile demonstrating appropriate
therapeutic effect over extended time periods. As discussed above, the
pseudoephedrine is present in an amount sufficient to mimic the blood serum
profile of the commercially available formulation of the drug and not to
exceed
the maximum dose approved by the FDA for the treatment, prevention, or
amelioration of a particular illness or disease. In one embodiment, the ratio
of
total guaifenesin to pseudoephedrine is about 1:1 to about 30:1, more
preferably
about 1:1 to 25:1, and more preferably about 20:1 by weight. Alternatively,
the
ratio of guaifenesin to pseudoephedrine is about 8:1 to about 12:1 by weight.
In
another embodiment the pseudoephedrine is only present in the immediate
release layer.
[0126] In a preferred embodiment, the tablets are made with any ratio of
guaifenesin
to dextromethorphan which results in a blood profile demonstrating appropriate
therapeutic effect over extended time periods. As discussed above, the
dextromethorphan is present in an amount sufficient to mimic the blood serum
profile of the commercially available formulation of the drug and not to
exceed
the maximum dose approved by the FDA for the treatment, prevention, or
amelioration of a particular illness or disease. In one embodiment, the ratio
of
total guaifenesin to dextromethorphan is about 1:1 to about 30:1, more
preferably about 1:1 to 25:1, and more preferably about 20:1 by weight.
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Alternatively, the ratio of guaifenesin to dextromethorphan is about 8:1 to
about
12:1 by weight.
[0127] The tablets may be made with any ratio of sustained release to
immediate
release formulation which results in a blood profile demonstrating appropriate
therapeutic effect over extended time periods. In one embodiment, the bi-layer
tablets comprise guaifenesin distributed within the sustained release
formulation
and the immediate release formulation wherein the ratio of guaifenesin in the
SR
to guaifenesin in the IR is about 1:1 to about 20:1, more preferably about 1:1
to
about 1:15 by weight, preferably the ratio is about 3:2 to about 11:1, and
more
preferably, the ratio of guaifenesin distributed within the sustained release
formulation and the immediate release formulation is about 5:1 to about 9:1 by
weight, respectively. For example, in a 1200 mg bi-layer modified release
guaifenesin tablet, there may be about 200 mg of guaifenesin in the immediate
release layer and about 1000 mg of guaifenesin in the sustained release layer.
[0128] The tablets may be made with at least one additional drug only within
the
sustained release formulation or with the additional drug only in the
immediate
release formulation. Optionally, the tablets may be made with at least one
additional drug distributed within the sustained release formulation and the
immediate release formulation. In one embodiment, the bi-layer tablets
comprise an additional drug distributed within the sustained release
formulation
and immediate release formulation wherein the ratio of additional drug in the
SR
to additional drug in the IR is about 1:1 to about 20:1, more preferably about
1:1
to about 1:15 by weight, preferably the ratio is about 3:2 to about 9:1, and
more
preferably the ratio is about 3:1 to about 4:1 by weight, respectively.
Alternatively the weight ratio for the additional drug is sustained release
portion
to immediate release portion is about 4:1 to about 1:1, more preferably about
1:1
to about 2:1.
[0129] In one preferred embodiment of manufacturing a 1200 mg bi-layer
sustained
release guaifenesin tablet, about 105 kg of Guaifenesin DC, about 2.5 kg of
Methocel E 10M, about 1.25 kg of Carbopol 974P, and about 0.333 kg of
Emerald Green Lake or FD&C Blue No. 1 in a 10 cubic foot P.K. blender for
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about twenty minutes. About 0.6 kg of magnesium stearate may then be added
and blending continued for about another ten minutes to prepare the sustained
release formulation. Approximately 21 kg of Guaifenesin DC, approximately
11.75 kg of microcrystalline cellulose, and approximately 3 kg of sodium
starch
glycolate may be blended in a 3 cubic foot P.K. blender for about twenty
minutes. Approximately 0.1 kg of magnesium stearate may then be added and
blending continued for about another ten minutes to prepare the immediate
release formulation. The two formulations may then be compressed to make bi-
layer tablets wherein about 75% of each tablet may be sustained release
formulation and about 25% of each tablet may be immediate release formulation.
The tablets may be any dosage strength, size, or shape. In a preferred
embodiment, 1200 mg tablets are round and about 5/8 inch in diameter, about
0.28 inch - 0.31 inch in thickness, weigh about 1.46 grams and have a hardness
range of about 15-40 SCU. In another preferred embodiment, 600 mg tablets are
round and about 1/2 inch in diameter, about 0.218 inch - 0.230 inch in
thickness,
weigh about 0.729 grams and have a hardness range of about 12-30 SCU.
[0130] In another preferred embodiment of manufacturing a 1200 mg bi-layer
sustained release guaifenesin tablet, about 101 kg of Guaifenesin DC, about
4.5
kg of at least one additional drug such as dextromethorphan, about 5 kg of
Methocel E10M, about 1.5 kg of Carbopol 974P, and about 0.04 kg of FD&C
Blue No. 1 are blended in a 10 cubic foot Day mixer for about twelve minutes.
Thereafter, about 29 kg of water is added and the mixture is blended for an
additional 10 minutes, followed by drying. About 1 kg of magnesium stearate
may then be added and blending continued for about another ten minutes to
prepare the sustained release formulation. About 45.6 kg of GUAIFENESIN,
about 3.6 kg of at least one additional drug such as dextromethorphan, about
40.32 kg of microcrystalline cellulose, and approximately 3 kg of sodium
starch
glycolate are blended in a 3 cubic foot Day mixer for about 12 minutes.
Thereafter, about 36 kg of water is added and the mixture is blended for an
additional 10 minutes, followed by drying. About 0.48 kg of magnesium
stearate may then be added and blending continued for about another ten
minutes
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to prepare the immediate release formulation. The two formulations may then be
compressed to make bi-layer tablets wherein about 75% of each tablet may be
sustained release formulation and about 25% of each tablet may be immediate
release formulation. The tablets may be any dosage strength, size, or shape.
In a
preferred embodiment, 1200 mg tablets are round and about 5/8 inch in
diameter, about 0.31 inch - 0.34 inch in thickness, weigh about 15.3 grams and
have a hardness range of about 15-35 SCU. In another preferred embodiment,
600 mg tablets are round and about 1/2 inch in diameter, about 0.22 inch -
0.26
inch in thickness, weigh about 7.65 grams and have a hardness range of about
15-65 SCU.
[0131] The immediate release portion of the bi-layer tablet is formulated to
dissolve
in aqueous media of low pH, such as that found in the stomach, to quickly
release the guaifenesin contained within the portion. This results in rapid
bioavailability of a high concentration of guaifenesin. As demonstrated in
Example 6 and Figures 9 and 10 below, the immediate release portion of the bi-
layer tablet results in a maximum serum concentration (Cmax) and time of
maximum serum concentration (Tmax) equivalent to the Cmax obtained when the
first of three doses of a standard immediate release formulation having one
third
the amount of guaifenesin is dosed every four hours over a 12 hour period.
[0132] The sustained release portion gels when exposed to media of low pH
allowing the sustained release portion of the tablet to be passed into the
intestinal
tract. In the intestines, the gelled sustained release portion is exposed to a
higher
pH environment, causing the gel to slowly dissolve, thereby allowing
guaifenesin to diffuse and dissolve out of the gelled matrix. This results in
controlled bioavailability over an extended time period (i.e. eight to twelve
or
more hours) causing the tablet to provide extended therapeutic effect. As
shown
in Example 6 and Figures 9 and 10, the half-life of the modified release bi-
layer
tablet is increased to more than 3 hours and the tablet has an AUCiõ f (the
area
under a plasma concentration versus time curve from time 0 to infinity) of
greater than 8000 hr-ng/mL.
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[0133] As demonstrated in Example 7 and Figure 11, the bi-layer tablets of the
invention had a further surprising result in that a 600 mg tablet had a Tmax
equivalent to that of a 1200 mg and a Cmax and AUCinf approximately half of a
1200 mg tablet. Thus, without adjusting or changing the composition of the
sustained release formulation or bi-layer tablet, a lower dosage strength
guaifenesin tablet of the invention exhibits a plasma concentration profile
that is
approximately directly proportional to that of a higher dosage strength
guaifenesin tablet. As further demonstrated in Example 7 and Figure 11, the bi-
layer tablets resulted in that the Cmax and AUCiõf of a 1200 mg tablet
administered to volunteers who had been fasting and the Cmax and AUCinf of a
1200 mg tablet administered to volunteers who had consumed a high fat meal
were approximately equivalent. Thus, a bi-layer tablet of the invention
demonstrates a reduced food effect, being approximately equally effective when
administered to a patient on an empty or full stomach. Similar results were
obtained for combination formulations for instance as described in Examples 8-
21.
[0134] Several combination formulations were also compared to commercial drugs
for bioavailability. For instance, Example 8 shows three batches of the 1200
mg
guaifenesin/ 60 mg dextromethorphan HBr which were dissolved to determine
the amount of dextromethorphan HBr released over time. Generally, the
formulations had 1200 mg of guaifenesin and 60 mg dextromethorphan HBr and
were studied over a 12 hour period. The released amount of dextromethorphan
HBr was determined as a weight percent of dissolved dextromethorphan in
contrast to the total weight of dextromethorphan prior to dissolution. After 1
hour about 46% to 47% of the dextromethorphan had dissolved. After 2 hours
the about 59% to 60% had dissolved, after 6 hours 73% to 76% had dissolved,
and after 12 hours about 86% to 89% by weight of the dextromethorphan had
dissolved. Thus, the formulations of the invention reproducibly release
dextromethorphan over time. (see, Figure 12). While, example 9, for instance
demonstrates the in vivo bioavailability of a sustained release guaifenesin
with
dextromethorphan.
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[0135] Various combination guaifenesin/pseudoephedrine compositions were also
examined to determine their dissolution rates and bioavailability. Examples 10
and 11, provide a formulations of guaifenesin and pseudoephedrine in the
sustained release portion of a bi-layered tablet. Results demonstrated that
combining the drugs into a single tablet according to methods of the invention
did not effect their dissolution profile or their in vivo release profile.
[0136] The two prototype lots of example 12 showed similar in vitro release to
market MucinexTM and Sudafed . In particular, Formulation B (lot PB01-K61)
produced optimal bioavailability for both guaifenesin and pseudoephedrine and
was therefore used in subsequent bioavailability studies.
[0137] Example 13 compared combination products for guaifenesin/
pseudoephedrine HCL) of 1200/120 mg strength, Formulation B(lot PBO1-
M65A2) and of 600/60 mg strength, Formulation C(lot PB01-A12A) to
commercial MucinexTM and Sudafed 12 Hour. The 1200/120 mg strength
showed bioequivalence for ratios of both Cmax and AUCinf with a 90%
confidence interval, which is contained in the 80-125% range. Further, the
600/60 mg strength demonstrated proportional dosage pharmacokinetics.
[0138] Example 14 compared reference MucinexTM and Sudafed 12 Hour to a
1200/120 mg strength test formulation (lot PB01-M65A3) for steady-state
bioavailability in an 11 day twice-daily dose regime. The test formulation was
bioequivalent (within the 80-125% range with a 90% confidence interval) when
compared to the reference formulation. Therefore, for both guaifenesin and
pseudoephedrine, the steady state for Cmax and AUCSS were bioequivalent.
[0139] Examples 15 and 17 compared the effect of a high fat meal for both
reference formulations and combination formulations of the invention. The test
formulation (lot PBO1-M65) was not bioequivalent with regard to Cmax for
guaifenesin but was for the pseudoephedrine portion when compared to the
reference. However, the AUC;nf was bioequivalent for both guaifenesin and
pseudoephedrine within the 80-125% range.
[0140] Example 16 compared single-dose relative bioavailability and
interaction
potential of guaifenesin and pseudoephedrine administered as MucinexTM and
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Sudafed 12 Hour alone or in combination. The results demonstrate that the
pharmacokinetics of guaifenesin and pseudoephedrine are unaffected with regard
to both AUCinf and Cmax in the presence or absence of one another (ratios
within
80-125%). This further confirms the results of the other examples which
demonstrate bioequivalence for the combination formulations of the invention.
[0141] Example IS compared the bioavailability of guaifenesin and
dextromethorphan from an experimental formulation containing both guaifenesin
and dextromethorphan as compared to reference guaifenesin and
dextromethorphan. The pharmacokinetics of guaifenesin and dextromethorphan
were not affected by the presence of the other component and the
pharmacokinetics of dextromethorphan were linear over the range studied.
[0142] Example 19 compared the relative bioavailability of guaifenesin and
dextromethorphan from an experimental formulation, containing both
guaifenesin and dextromethorphan, as compared to reference guaifenesin and
dextromethorphan. The guaifenesin in the experimental tablet was clearly
bioequivalent to that of the Reference, Mucinex, in terms of Cmax AUCo_t or
AUCinf. Dextromethorphan hydrobromide in the experimental tablet was also
found to be bioequivalent to both 30 mg dextromethorphan hydrobromide every
6 hours, and 20 mg every 4 hours, in terms of Cmax, AUCo_t or AUCinf.
[0143] Example 20 compared the relative bioavailability of guaifenesin and
dextromethorphan from an experimental formulation containing both guaifenesin
and dextromethorphan following the consumption of a high fat meal as
compared to following an overnight fast. There was no food effect on the
absorption of guaifenesin from the experimental tablet. There was an effect of
food on the rate of absorption of dextromethorphan from the experimental
tablet
formulation (a small increase in the rate of absorption) but not on the extent
of
absorption.
[0144] Example 21 compared the relative bioavailability of guaifenesin and
dextromethorphan from an experimental formulation containing both guaifenesin
and dextromethorphan, as compared to reference guaifenesin and
dextromethorphan products. The guaifenesin in the experimental tablet was
41
CA 02481739 2009-12-17
bioequivalent to that of the Reference, Mucinex, in terms of C,,. and AUCSS
within 80% to 125%. Dextromethorphan hydrobromide in the experimental
tablet was bioequivalent to both 30 mg dextromethorphan hydrobromide every 6
hours, and 20 mg every 4 hours, in terms of Cmax and AUCSs within 80% to
125%.
[01451 These studies demonstrate the compositions of the invention provide
systemic levels of drug over a 12-hour period. Additionally, the studies
demonstrate the bioequivalence of the combination formulations.
Comparison to FDA Approved Drugs
[01461 When using drugs approved by the Food and Drug Administration (FDA),
the sustained release formulation alone or in combination with an immediate
release component may be formulated to mimic the blood serum profile of
guaifenesin and optionally the additional drug(s) as described in the clinical
documents filed with the FDA or as required by the FDA. For instance, a single
dose 400 mg immediate release tablet has a C,x ax of 2,463 1033, a T,,,ax of
.5, an
AUC0.12, 8,382 * 3,282, an AUC;,,f 8,529 t 3,362, and a T112 of 0.78 0.09.
Alternatively, multiple doses of a 400 mg immediate release tablet has a C,,,
of
2,278 791, a Tmax of .5, an AUCQ.12 7,751 f 2,697, Cmino 112 52, and a
C,,,;,,12
137 -1 98. Preferably, the formulations result in a maximum serum
concentration
(Cm x) and/or time of maximum serum concentration (T,ogx) equivalent to the C,
obtained when the first of three doses of a standard immediate release
formulation having one third the amount of guaifenesin is dosed every four
hours over a 12 hour period. In other words, the sustained release formulation
releases both the guaifenesin and at least one additional drug at a similar
rate to
the commercially available formulation, thereby providing a therapeutically
effective amount of both drugs. Alternatively, the parameters may be
calculated
through any of the following or combinations thereof: C., Cm,n, Twa,,, AUCiõ#,
AUCt1_t, AUCSS and T112. Unless otherwise specified, all reference to AUC04 in
the specification and claims shall refer to data which corresponds to a time
(t) of
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24 hours. The parameters may also be calculated from in vivo studies such as
those presented herein where equivalence is determined from the mean and an
80-125% range with a 90% confidence level and/or one standard deviation from
the mean. Alternatively, the parameters may also be calculated from in vivo
studies such as those presented herein where equivalence is determined from
the
median and an 80-125% range with a 90% confidence level and/or one standard
deviation from the median. Due to the extreme variability for
dextromethorphan,
as recognized by the FDA and the inherent variability of measuring plasma
serum levels at the picogram level the equivalence is determined from the mean
and a 50-150% range, more preferably the equivalence is determined from the
mean and a 60-140% range, and most preferably the equivalence is determined
from the mean and a 80-125% range with a 90% confidence level. Figures 31
and 32 demonstrate specification ranges for various batch compositions of the
invention.
[0147] Additionally the Cmax for either guaifenesin, the additional drug(s) or
both is
preferably between 80% and 125% of the FDA approved mean, more preferably
between 90% and 115%, and most preferably between 95% and 115%. These
ranges do not have to adjust commensurately, that is to say the mean may for
instance preferably be between 90% and 125% of the FDA mean depending on
the formulation. Alternatively, the low end of the Cmax for guaifenesin is
preferably greater than 640 ng/mL, more preferably 700 ng/mL, more preferably
800 ng/mL, more preferably 900 ng/mL, more preferably 1000 ng/mL, more
preferably 1100 ng/mL, and most preferably 1250 ng/mL depending on the
formulation. The high end of the Cmax for guaifenesin is preferably less than
3750 ng/mL, more preferably 3500 ng/mL, more preferably 3250 ng/mL, more
preferably 3000 ng/mL, more preferably 2750 ng/mL, and most preferably 2500
ng/mL depending on the formulation. For a 1200 mg tablet the range is
preferably between 1000 ng/mL and 3750 ng/mL, 1200 ng/mL and 3500 ng/mL,
1350 ng/mL and 3000 ng/mL, and 1450 ng/mL and 2750 ng/mL. For a 600 mg
tablet the range is preferably between 320 ng/mL and 1875 ng/mL, 400 ng/mL
and 1500 ng/mL, 500 ng/mL and 1375 ng/mL, and 625 ng/mL and 1250 ng/mL.
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[0148] Alternatively, the low end of the Cmax for pseudoephedrine is
preferably
greater than 150 ng/mL, more preferably 175 ng/mL, more preferably 200
ng/mL, and most preferably 250 ng/mL depending on the formulation. The high
end of the Cmax for pseudoephedrine is preferably less than 500 ng/mL, more
preferably 450 ng/mL, more preferably 400 ng/mL, and most preferably 375
ng/mL depending on the formulation. For a 120 mg tablet the range is
preferably
between 150 ng/mL and 500 ng/mL, 175 ng/mL and 500 ng/mL, 200 ng/mL and
450 ng/mL, 250 ng/mL and 400 ng/mL, and 300 ng/mL and 375 ng/mL. For a 60
mg tablet the range is preferably between 75 ng/mL and 250 ng/mL, 88 ng/mL
and 250 ng/mL, 100 ng/mL and 225 ng/mL, 125 ng/mL and 200 ng/mL, and 150
ng/mL and 188 ng/mL.
[0149] Alternatively, the low end of the Cm for dextromethorphan is preferably
greater than 3840 pg/mL, more preferably 5,500 pg/mL, more preferably 6,600
pg/mL, more preferably 7,000 pg/mL, more preferably 7,700 pg/mL, more
preferably 8,000 pg/mL, more preferably 8,800 pg/mL, more preferably 9,900
pg/mL, and most preferably 10,000 pg/mL depending on the formulation. The
high end of the Cmax for dextromethorphan is preferably less than 22,500
pg/mL,
more preferably 16,500 pg/mL, more preferably 15,400 pg/mL, more preferably
14,300 pg/mL, more preferably 13,200 pg/mL, and most preferably 12,100
pg/mL depending on the formulation. For a 60 mg tablet the range is preferably
between 9,600 pg/mL and 15,000 pg/mL, 10,800 pg/mL and 13,500 pg/mL,
10,800 pg/mL and 12,000 pg/mL, and 12,000 pg/mL and 13,500 pg/mL. For a
30 mg tablet the range is preferably between 7,200 pg/mL and 11,250 pg/mL,
8,100 pg/mL and 10,125 pg/mL, 8,100 pg/mL and 9,000 pg/mL, and 9,000
pg/mL and 10,125 pg/mL. In an alternative embodiment the low end of the Cm
for dextromethorphan is preferably greater than 1300 pg/mL, more preferably
1,550 pg/mL, more preferably 1,860 pg/mL, more preferably 2,170 pg/mL, more
preferably 2,480 pg/mL, and most preferably 2,790 pg/mL depending on the
formulation. The high end of the Cmax for dextromethorphan is preferably less
than 5,400 pg/mL, more preferably 4,650 pg/mL, more preferably 4,350 pg/mL,
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more preferably 4,000 pg/mL, more preferably 3,750 pg/mL, and most
preferably 3,400 pg/mL depending on the formulation.
[0150] The Cmin is another aspect which is often not met by various extended
release
drugs found on the market. Formulations of the invention provide a Cmin which
maintains it therapeutic effectiveness for a period of at least 10 hours, more
preferably 12 hours and most preferably 14 or more hours. Additionally the
Cmin
for either guaifenesin, the additional drug(s) or both is preferably between
80%
and 125% of the FDA approved mean, more preferably between 90% and
115%, and most preferably between 95% and 115%. These ranges do not have to
adjust commensurately, that is to say the mean may for instance preferably be
between 90% and 125% of the FDA mean depending on the formulation.
Alternatively, the low end of the Cmin for guaifenesin is preferably greater
than
40 ng/mL, more preferably 50 ng/mL, more preferably 60 ng/mL, and most
preferably 70 ng/mL depending on the formulation. The high end of the Cmin for
guaifenesin is preferably less than 200 ng/mL, more preferably 175 ng/mL, more
preferably 150 ng/mL, and most preferably 125 ng/mL depending on the
formulation. The Cmin range for either a 1200 or a 600 mg tablet may be
selected
from 50 ng/mL and 150 ng/mL, 50 ng/mL and 125 ng/mL, 60 ng/mL, 125
ng/mL, 70 ng/mL and 125 ng/mL, 80 ng/mL and 125 ng/mL, between 35 ng/mL
and 75 ng/mL, 40 ng/mL and 70 ng/mL, 45 ng/mL and 65 ng/mL, and 50 ng/mL
and 60 ng/mL.
[0151] Alternatively, the low end of the Cmin for pseudoephedrine is
preferably
greater than 75 ng/mL, more preferably 100 ng/mL, more preferably 125 ng/mL,
and most preferably 150 ng/mL depending on the formulation. The high end of
the Cmin for pseudoephedrine is preferably less than 300 ng/mL, more
preferably
250 ng/mL, more preferably 225 ng/mL, and most preferably 200 ng/mL
depending on the formulation. The Cmin range for either a 120 mg or 60 mg
tablet may be selected from 75 ng/mL and 300 ng/mL, 100 ng/mL and 250
ng/mL, 125 ng/mL and 225 ng/mL, 150 ng/mL and 200 ng/mL.
[0152] Alternatively, the low end of the Cmin for dextromethorphan is
preferably
greater than 1,250 pg/mL, more preferably 1,500 pg/mL, more preferably 1,700
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pg/mL, more preferably 2,000 pg/mL, and most preferably 2,250 pg/mL.
Alternatively, the high end of the Cmin for dextromethorphan is preferably
less
than 3,750 pg/mL, more preferably 3,500 pg/mL, more preferably 3,250 pg/mL,
more preferably 3,000 pg/mL, and most preferably 2,750 pg/mL depending on
the formulation. Alternatively, the Cmin range for a 60 mg tablet may be
selected
from 7,200 pg/mL and 11,250 pg/mL, 8,100 pg/mL and 10,125 pg/mL, 8,100
pg/mL and 9,000 pg/mL, and 9,000 pg/mL and 10,125 pg/mL. The Cmin range
for a 30 mg tablet may be selected from 5,400 pg/mL and 8,400 pg/mL, 6,075
pg/mL and 7,600 pg/mL, 6,075 pg/mL and 6,750 pg/mL, and 6,750 pg/mL and
7,600 pg/mL. In another embodiment the low end of the Cmin for.
dextromethorphan is preferably greater than 1,050 pg/mL, more preferably 1,250
pg/mL, more preferably 1,450 pg/mL, more preferably 1,650 pg/mL, and most
preferably 1,850 pg/mL. The high end of the C,,,in for dextromethorphan is
preferably less than 3,150 pg/mL, more preferably 2,950 pg/mL, more preferably
2,700 pg/mL, more preferably 2,500 pg/mL, and most preferably 2,300 pg/mL
depending on the formulation.
[0153] Formulations of the invention provide a Tmax for either guaifenesin,
the
additional drug(s) or both which is preferably between 80% and 125% of the
FDA approved mean, more preferably between 90% and 115%, and most
preferably between 95% and 115%. These ranges do not have to adjust
commensurately, that is to say the mean may for instance preferably be between
90% and 125% of the FDA mean depending on the formulation. Alternatively,
the low end of the Tmax for guaifenesin is preferably greater than 0.6 hours,
more
preferably 0.8 hours, more preferably 0.9 hours, more preferably 1.0 hours,
and
most preferably 1.1 hours depending on the formulation. The high end of the
Tmax for guaifenesin is preferably less than 3.0 hours, more preferably 2.5
hours,
more preferably 2.25 hours, and most preferably 2 hours depending on the
formulation. The Tmax range may also be selected from between 0.6 hours and
3.0 hours, 0.8 hours and 2.5 hours, 0.9 hours and 2.25 hours, 1.0 hours and 2
hours, and 1.1 hours and 2 hours.
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[0154] Alternatively, the low end of the Tmax for pseudoephedrine is
preferably
greater than 3.75 hours, more preferably 4.0 hours, more preferably 4.25
hours,
more preferably 4.5 hours, and most preferably 4.75 hours depending on the
formulation. The high end of the Tmax for pseudoephedrine is preferably less
than
9.0 hours, more preferably 8.5 hours, more preferably 8.0 hours, and most
preferably 7.5 hours depending on the formulation. The Tmax range may also be
selected from between 3.75 hours and 9.0 hours, 4.0 hours and 8.5 hours, 4.25
hours and 8.0 hours, 4.5 hours and 7.5 hours, and 4.75 hours and 7.5 hours.
[0155] Alternatively, the low end of the Tmax for dextromethorphan is
preferably
greater than 3.3 hours, more preferably 3.9 hours, more preferably 4.6 hours,
more preferably 5.2 hours, and most preferably 5.85 hours depending on the
formulation. The high end of the Tmax for dextromethorphan is preferably less
than 10.6 hours, more preferably 9.8 hours, more preferably 9.1 hours, more
preferably 8.8 hours, more preferably 8.5 hours, more preferably 7.8 hours and
most preferably 7.2 hours depending on the formulation. The Tmax range may
also be selected from between 6.2 hours and 9.7 hours, 6.7 hours and 8.8
hours,
6.7 hours and 7.75 hours, and 7.75 hours and 8.8 hours for a 60 mg tablet. The
Tn,ax range may also be selected from between 4.6 hours and 7.25 hours, 5.2
hours and 6.5 hours, 5.2 hours and 5.8 hours, and 5.8 hours and 6.5 hours for
a
30 mg tablet.
[0156] Formulations of the invention provide a AUCiõf for either guaifenesin,
the
additional drug(s) or both which is preferably between 80% and 125% of the
FDA approved mean, more preferably between 90% and 115%, and most
preferably between 95% and 115%. These ranges do not have to adjust
commensurately, that is to say the mean may for instance preferably be between
90% and 125% of the FDA mean depending on the formulation. Alternatively,
the low end of the AUC;nf for guaifenesin is preferably greater than 4,000 hr-
ng/mL, more preferably 5,000 hr-ng/mL, more preferably 5,500 hr-ng/mL, and
most preferably 6,000 hr-ng/mL depending on the formulation. The high end of
the AUCinf for guaifenesin is preferably less than 12,500 hr-ng/mL, more
preferably 10,000 hr-ng/mL, more preferably 9,500 hr-ng/mL, and most
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preferably 9,000 hr-ng/mL depending on the formulation. For a 1200 mg tablet
the AUCiõ f range may be selected from between 4,000 hr-ng/mL and 12,500 hr-
ng/mL, 5,000 hr-ng/mL and 10,000 hr-ng/mL, 5,500 hr-ng/mL and 9,500 hr-
ng/mL, and 6,000 hr-ng/mL and 9,000 hr-ng/mL. For a 600 mg tablet the AUCinf
range may be selected from between 2,000 hr-ng/mL and 6,250 hr-ng/mL, 2,500
hr-ng/mL and 5,000 hr-ng/mL, 2,250 hr-ng/mL and 4,750 hr-ng/mL, and 3,000
hr-ng/mL and 4,500 hr-ng/niL.
[0157] Alternatively, the low end of the AUCinf for pseudoephedrine is
preferably
greater than 2,500 hr-ng/mL, more preferably 2,800 hr-ng/mL, more preferably
3,500 hr-ng/mL, and most preferably 3,750 hr-ng/mL depending on the
formulation. The high end of the AUCinf for pseudoephedrine is preferably less
than 6,000 hr-ng/mL, more preferably 5,800 hr-ng/mL, more preferably 5,500
hr-ng/mL, and most preferably 5,000 hr-ng/mL depending on the formulation.
For a 120 mg tablet the AUCinf may be selected from between 2,500 hr-ng/mL
and 6,000 hr-ng/mL, 2,800 hr-ng/mL and 5,800 hr-ng/mL, 3,500 hr-ng/mL and
5,500 hr-ng/mL, and 3,750 hr-ng/mL and 5,000 hr-ng/mL. For a 60 mg tablet the
AUC1nf may be selected from between 1,250 hr-ng/mL and 3,000 hr-ng/mL,
1,400 hr-ng/mL and 2,900 hr-ng/mL, 1,750 hr-ng/mL and 2,750 hr-ng/mL, and
1,875 hr-ng/mL and 2,500 hr-ng/mL.
[0158] Alternatively, the low end of the AUCinf for dextromethorphan is
preferably
greater than 55,200 hr-ng/mL, more preferably 145,000 hr-ng/mL, more
preferably 174,000 hr-ng/mL, more preferably 192,000 hr-ng/mL, more
preferably 203,000 hr-ng/mL, more preferably 216,000 hr-ng/mL, more
preferably 232,000 hr-ng/mL, more preferably 240,000 hr-ng/mL, and most
preferably 261,000 hr-ng/mL depending on the formulation. The high end of the
AUCinf for dextromethorphan is preferably less than 587,500 hr-ng/mL, more
preferably 435,000 hr-ng/mL, more preferably 405,000 hr-ng/mL, more
preferably 400,000 hr-ng/mL, more preferably 377,000 hr-ng/mL, more
preferably 360,000 hr-ng/mL, more preferably 348,000 hr-ng/mL, and most
preferably 320,000 hr-ng/mL depending on the formulation. For a 60 mg tablet
the AUC1nf may be selected from between 256,000 hr-ng/mL and 400,000 hr-
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ng/mL, 288,000 hr-ng/mL and 360,000 hr-ng/mL, 288,000 pg/mL and 320,000
hr-ng/mL, and 320,000 hr-ng/mL and 360,000 hr-ng/mL. For a 30 mg tablet the
AUCinf may be selected from between 192,000 hr-ng/mL and 300,000 hr-ng/mL,
216,000 hr-ng/mL and 270,000 hr-ng/mL, 216,000 hr-ng/mL and 240,000 hr-
ng/mL, and 240,000 hr-ng/mL and 270,000 hr-ng/mL. In another embodiment
the low end of the AUCinf for dextromethorphan is preferably greater than
15,000 hr-ng/mL, more preferably 18,000 hr-ng/mL, more preferably 21,000 hr-
ng/mL, more preferably 24,000 hr-ng/mL, and most preferably 27,000 hr-ng/mL
depending on the formulation. The high end of the AUCinf for dextromethorphan
is preferably less than 46,900 hr-ng/mL, more preferably 45,000 hr-ng/mL, more
preferably 42,000 hr-ng/mL, more preferably 39,000 hr-ng/mL, more preferably
36,000 hr-ng/mL, and most preferably 33,000 hr-ng/mL depending on the
formulation.
[0159] Formulations of the invention provide a AUCO-t for either guaifenesin,
the
additional drug(s) or both which is preferably between 80% and 125% of the
FDA approved mean, more preferably between 90% and 115%, and most
preferably between 95% and 115%. These ranges do not have to adjust
commensurately, that is to say the mean may for instance preferably be between
90% and 125% of the FDA mean depending on the formulation. Alternatively,
the low end of the AUCO-t for guaifenesin is preferably greater than 3,200 hr-
ng/mL, more preferably 3,700 hr-ng/mL, more preferably 4,000 hr-ng/mL, and
most preferably 4,500 hr-ng/mL depending on the formulation. The high end of
the AUCO-t for guaifenesin is preferably less than 11,250 hr-ng/mL, more
preferably 10,500 hr-ng/mL, more preferably 9,500 hr-ng/mL, more preferably
9,000 hr-ng/mL, and most preferably 8,500 hr-ng/mL depending on the
formulation. For a 1200 mg tablet the AUCO-t may be selected from between
3,200 hr-ng/mL and 11,250 hr-ng/mL, 3,700 hr-ng/mL and 10,500 hr-ng/mL,
4,000 hr-ng/mL and 9,500 hr-ng/mL, 4,250 hr-ng/mL and 9,000 hr-ng/mL, and
4,500 hr-ng/mL and 8,500 hr-ng/mL. For a 600 mg tablet the AUCO-t may be
selected from between 1,600 hr-ng/mL and 5,625 hr-ng/mL, 1,850 hr-ng/mL and
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5,250 hr-ng/mL, 2,000 hr-ng/mL and 4,750 hr-ng/mL, 2,125 hr-ng/mL and 4,500
hr-ng/mL, and 2,250 hr-ng/mL and 4,250 hr-ng/mL.
[0160] Alternatively, the low end of the AUCO-t for pseudoephedrine is
preferably
greater than 2,000 hr-ng/mL, more preferably 2,200 hr-ng/mL, more preferably
2,500 hr-ng/mL, and most preferably 2,800 hr-ng/mL depending on the
formulation. The high end of the AUCO-t for pseudoephedrine is preferably less
than 6,000 hr-ng/mL, more preferably 5,750 hr-ng/mL, more preferably 5,500
hr-ng/mL, more preferably 5,250 hr-ng/mL, and most preferably 5,000 hr-ng/mL
depending on the formulation. For a 120 mg tablet the AUCO-t may be selected
from between 2,000 hr-ng/mL and 6,000 hr-ng/mL, 2,200 hr-ng/mL and 5,750
hr-ng/mL, 2,500 hr-ng/mL and 5,500 hr-ng/mL, 2,700 hr-ng/mL and 5,250 hr-
ng/mL, and 2,800 hr-ng/mL and 5,000 hr-ng/mL. For a 60 mg tablet the AUCO-t
may be selected from between 1,000 hr-ng/mL and 3,000 hr-ng/mL, 1,100 hr-
ng/mL and 2,875 hr-ng/mL, 1,250 hr-ng/mL and 2,750 hr-ng/mL, 1,350 hr-
ng/mL and 2,625 hr-ng/mL, and 1,400 hr-ng/mL and 2,500 hr-ng/mL.
[0161] Alternatively, the low end of the AUCO-t for dextromethorphan is
preferably
greater than 59,000 hr-ng/mL, more preferably 119,000 hr-ng/mL, more
preferably 143,000 hr-ng/mL, more preferably 162,000 hr-ng/mL, more
preferably 166,000 hr-ng/mL, more preferably 182,000 hr-ng/mL, more
preferably 190,000 hr-ng/mL, more preferably 202,000 hr-ng/mL, and most
preferably 214,000 hr-ng/mL depending on the formulation. The high end of the
AUCo_t for dextromethorphan is preferably less than 475,000 hr-ng/mL, more
preferably 360,000 hr-ng/mL, more preferably 337,500 hr-ng/mL, more
preferably 333,000 hr-ng/mL, more preferably 309,000 hr-ng/mL, more
preferably 300,000 hr-ng/mL, more preferably 286,000 hr-ng/mL, more
preferably 270,000 hr-ng/mL, and most preferably 262,000 hr-ng/mL depending
on the formulation. For a 60 mg tablet the AUCO-t may be selected from between
216,000 hr-ng/mL and 337,500 hr-ng/mL, 243,000 hr-ng/mL and 300,000 hr-
ng/mL, 243,000 hr-ng/mL and 270,000 hr-ng/mL, and 270,000 hr-ng/mL and
300,000 hr-ng/mL. For a 30 mg tablet the AUCo_t may be selected from between
162,000 hr-ng/mL and 250,000 hr-ng/mL, 182,000 hr-ng/mL and 230,000 hr-
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ng/mL, 182,000 hr-ng/mL and 202,000 hr-ng/mL, and 202,000 hr-ng/mL and
230,000 hr-ng/mL. In another embodiment the low end of the AUC0_t for
dextromethorphan is preferably greater than 15,000 hr-ng/mL, more preferably
18,000 hr-ng/mL, more preferably 21,000 hr-ng/mL, more preferably 24,000 hr-
ng/mL, and most preferably 27,000 hr-ng/mL depending on the formulation. The
high end of the AUCo_t for dextromethorphan is preferably less than 47,300 hr-
ng/mL, more preferably 45,000 hr-ng/mL, more preferably 42,000 hr-ng/mL,
more preferably 39,000 hr-ng/mL, more preferably 36,000 hr-ng/mL, and most
preferably 33,000 hr-ng/mL depending on the formulation.
[0162] Formulations of the invention provide a AUCSS for either guaifenesin,
the
additional drug(s) or both which is preferably between 80% and 125% of the
FDA approved mean, more preferably between 90% and 115%, and most
preferably between 95% and 115%. These ranges do not have to adjust
commensurately, that is to say the mean may for instance preferably be between
90% and 125% of the FDA mean depending on the formulation. Alternatively,
the low end of the AUCSS for guaifenesin is preferably greater than 5000 hr-
ng/mL, more preferably 5600 hr-ng/mL, more preferably 6000 hr-ng/mL, and
most preferably 6500 hr-ng/mL depending on the formulation. The high end of
the AUCSS for guaifenesin is preferably less than 9000 hr-ng/mL, more
preferably 8750 hr-ng/mL, more preferably 8250 hr-ng/mL, and most preferably
8000 hr-ng/mL depending on the formulation. The AUCSS for a 1200 mg tablet
may be selected from between 5000 hr-ng/mL and 9000 hr-ng/mL, 5600 hr-
ng/mL and 8750 hr-ng/mL, 6000 hr-ng/mL and 8000 hr-ng/mL, and 6500 hr-
ng/mL and 8250 hr-ng/mL. The AUCSS for a 600 mg tablet may be selected from
between 2,500 hr-ng/mL and 4,500 hr-ng/m]L, 2,800 hr-ng/mL and 4,375 hr-
ng/mL, 3,000 hr-ng/mL and 4,000 hr-ng/mL, and 3,250 hr-ng/mL and 4,125 hr-
ng/mL.
[0163] Alternatively, the low end of the AUCSS for pseudoephedrine is
preferably
greater than 2,100 hr-ng/mL, more preferably 2,400 hr-ng/mL, more preferably
2,650 hr-ng/mL, and most preferably 2,800 hr-ng/mL depending on the
formulation. The high end of the AUCSS for pseudoephedrine is preferably less
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than 5,500 hr-ng/mL, more preferably 5,000 hr-ng/mL, more preferably 4,500
hr-ng/mL, and most preferably 4,000 hr-ng/mL depending on the formulation.
The AUCSS for a 120 mg tablet may be selected from between 2,100 hr-ng/mL
and 5,500 hr-ng/mL, 2,400 hr-ng/mL and 5,000 hr-ng/mL, 2,650 hr-ng/mL and
4,500 hr-ng/mL, and 2,800 hr-ng/mL 4,000 hr-ng/mL. The AUCSS for a 60 mg
tablet may be selected from between 1,050 hr-ng/mL and 2,250 hr-ng/mL, 1,200
hr-ng/mL and 2,500 hr-ng/mL, 1,325 hr-ng/mL and 2,250 hr-ng/mL, and 1,400
hr-ng/mL 2,000 hr-ng/mL.
[0164] Alternatively, the low end of the AUCSS for dextromethorphan is
preferably
greater than 87,750 hr-ng/mL, more preferably 105,000 hr-ng/mL, more
preferably 120,000 hr-ng/mL, more preferably 132,000 hr-ng/mL, more
preferably 140,000 hr-ng/mL, and most preferably 158,000 hr-ng/mL depending
on the formulation. The high end of the AUCSS for dextromethorphan is
preferably less than 263,000 hr-ng/mL, more preferably 245,000 hr-ng/mL, more
preferably 228,000 hr-ng/mL, more preferably 220,000 hr-ng/mL, more
preferably 210,000 hr-ng/mL, more preferably 197,000 hr-ng/mL, and most
preferably 193,000 hr-ng/mL depending on the formulation. The AUCSS for a 60
mg tablet may be selected from between 140,000 hr-ng/mL and 220,000 hr-
ng/mL, 157,500 hr-ng/mL and 197,000 hr-ng/mL, 157,500 hr-ng/mL and
175,000 hr-ng/mL, and 175,000 hr-ng/mL and 197,000 hr-ng/mL. The AUCSS for
a 30 mg tablet may be selected from between 105,000 hr-ng/n-iL and 165,000 hr-
ng/mL, 120,000 hr-ng/mL and 149,000 hr-ng/mL, 120,000 hr-ng/mL and
132,000 hr-ng/mL, and 132,000 hr-ng/mL and 149,000 hr-ng/mL. In another
embodiment the low end of the AUCSS for dextromethorphan is preferably
greater than 19,000 hr-ng/mL, more preferably 22,800 hr-ng/mL, more
preferably 26,600 hr-ng/mL, more preferably 30,500 hr-ng/mL, and most
preferably 34,000 hr-ng/mL depending on the formulation. The high end of the
AUCSS for dextromethorphan is preferably less than 57,000 hr-ng/mL, more
preferably 53,000 hr-ng/mL, more preferably 49,500 hr-ng/mL, more preferably
45,600 hr-ng/mL, and most preferably 41,800 hr-ng/mL depending on the
formulation.
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[0165] Formulations of the invention provide a TI/2 for either guaifenesin,
the
additional drug(s) or both which is preferably between 80% and 125% of the
FDA approved mean, more preferably between 90% and 115%, and most
preferably between 95% and 115%. These ranges do not have to adjust
commensurately, that is to say the mean may for instance preferably be between
90% and 125% of the FDA mean depending on the formulation. Alternatively,
the low end of the T1/2 for guaifenesin is preferably greater than 0.7 hours,
more
preferably 0.9 hours, more preferably 1.1 hours, more preferably 1.3 hours,
and
most preferably 1.4 hours depending on the formulation. The high end of the
TI/2
for guaifenesin is preferably less than 7.25 hours, more preferably 6.0 hours,
more preferably 5.0 hours, and most preferably 3.5 hours depending on the
formulation. The TI/2 for a 1200 mg tablet may be selected from between 0.7
hours and 7.25 hours, 0.9 hours and 6.0 hours, 1.1 hours and 5.0 hours, 1.3
hours
and 3.5 hours, and 1.4 hours and 3.5 hours. The TI/2 for a 600 mg tablet may
be
selected from between 0.35 hours and 3.63 hours, 0.45 hours and 3.0 hours, .55
hours and 2.5 hours, .65 hours and 1.75 hours, and .70 hours and 1.75 hours.
[0166] Alternatively, the low end of the TI/2 for pseudoephedrine is
preferably
greater than 3.2 hours, more preferably 3.6 hours, more preferably 4.0 hours,
more preferably 4.2 hours, and most preferably 4.5 hours depending on the
formulation. The high end of the T1/2 for pseudoephedrine is preferably less
than
8.0 hours, more preferably 7.5 hours, more preferably 7.0 hours, and most
preferably 6.25 hours depending on the formulation. The TI/2 for a 120 mg
tablet
may be selected from between 3.2 hours and 8.0 hours, 3.6 hours and 7.5 hours,
4.0 hours and 7.0 hours, 4.2 hours and 6.25 hours, and 4.5 hours and 6.25
hours.
The TI/2 for a 60 mg tablet may be selected from between 1.60 hours and 4.0
hours, 1.80 hours and 3.75 hours, 2.0 hours and 3.5 hours, 2.1 hours and 3.13
hours, and 2.25 hours and 3.13 hours.
[0167] Alternatively, the low end of the T1/2 for dextromethorphan is
preferably
greater than 4.6 hours, more preferably 5.6 hours, more preferably 6.5 hours,
more preferably 7.0 hours, more preferably 7.4 hours, more preferably 7.9
hours,
more preferably 8.4 hours, and most preferably 8.8 hours depending on the
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formulation. The high end of the T1/2 for dextromethorphan is preferably less
than 15.75 hours, 14.7 hours, more preferably 13.0 hours, more preferably 13.0
hours, more preferably 12.1 hours, more preferably 11.75 hours, more
preferably
11.2 hours, and most preferably 10.2 hours depending on the formulation. The
T1/2 for a 60 mg tablet may be selected from between 9.4 hours and 14.7 hours,
10.6 hours and 13.2 hours, 10.6 hours and 11.75 hours, and 11.75 hours and
13.2
hours. The T112 for a 60 mg tablet may be selected from between 7.0 hours and
11.0 hours, 7.9 hours and 9.9 hours, 7.9 hours and 8.8 hours, and 8.8 hours
and
9.9 hours.
[0168] Examples of other sustained release/immediate release formulations with
and
without additional drugs are discussed further in the examples which follow.
EXAMPLES
[0169] The invention is further defined by reference to the following examples
describing in detail the compositions and methods of the invention. It will be
apparent to those skilled in the art that many modifications, both to
materials and
methods, may be practiced without departing from the purpose and interest of
this invention.
[0170] For the in vivo study portions, the following general procedures were
used
for sample analysis unless otherwise indicated. Blood samples (5-10 mLs with
sodium heparin as anticoagulant) were taken prior to dosing and at specific
intervals after dosing. All blood samples were chilled and centrifuged within
30
minutes of being drawn. The plasma was separated, transferred to a
polypropylene tube, frozen at -20 C or below and stored frozen until being
shipped for drug analysis. The plasma samples were then analyzed by a fully
validated HPLC method. This resulting plasma concentration v. time data was
subjected to pharmacokinetic analysis using non-compartmental analysis with
Winnonlin 1.5.
[0171] When necessary, volunteers were then given at least a seven day washout
period (where no guaifenesin was administered to them under the study) prior
to
being crossed-over to the next treatment group. Generally, the subjects
weighed
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within 15% of their Ideal Body Weight as defined by the 1983 Metropolitan Life
chart.
Example 1
[01721 A batch of sustained release guaifenesin tablets, LotNo. 7LB-31FC, with
the
following composition was prepared:
Components Weight per Tablet
Guaifenesin DC 1260 mg
Methocel ElOM 30 mg
Emerald Green Lake 4 mg
Magnesium Stearate 6.8 mg
Opadry Y-S-3-7413 13.01 mg
[01731 Another batch of sustained release guaifenesin tablets, Lot No. 7LB-
32FC,
with the following composition was prepared:
Components Weight per Tablet
Guaifenesin DC 1260 mg
Methocel ElOM 30 mg
Carbopol 974P 15 mg
Emerald Green Lake 4 mg
Magnesium Stearate 6.8 mg
Opadry Y-S-3-7413 13.16 mg
[01741 Six tablets from Lot 7LB-31FC and six tablets from Lot 7LB-32FC were
tested for in vitro guaifenesin release using an Acid/Base dissolution
(slightly
modified USP 23/NF 18 <711> Drug Release using Apparatus 2). Six
dissolution vessels of a USP calibrated Hanson dissolution bath, equipped with
shafts and paddles, and were filled with 675 mL of 0.1N hydrochloric acid at
37.0 C. The bath and vessels were maintained at a temperature of 37.0 0.5 C
throughout the 12 hour dissolution test. The paddles were set to rotate at 50
RPM and slowly lowered into the vessels. One tablet of lot 7LB-31 was then
dropped into each vessel.
[0175] At the one hour and two hour intervals of testing, 5 mL samples of
dissolution solution were withdrawn from each vessel and filtered through a 10
micron polyethylene filter into glass HPLC vials. Immediately after the two
hour samples were withdrawn, 225 mL of 0.2M sodium phosphate tribasic was
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added to each vessel to increase the solution pH to about 6.8. The dissolution
was run for ten additional hours, 2.0 mL samples being withdrawn from each
vessel at the four, eight, 10, and 12 hour intervals. The filtered samples
were
then run on an HPLC to determine percent guaifenesin released.
[0176] The same dissolution testing procedure was performed for lot 7LB-32 FC.
The lots gave dissolution profiles shown below and depicted in Figure 4.
Lot 7LB-31
Vessel 1 hr. 2 hr. 4 hr. 8 hr. 10 hr. 12 hr.
No.
1 26 38 55 77 84 88
2 27 39 54 75 81 86
3 22 37 50 73 78 85
4 23 33 47 64 73 79
25 36 52 75 81 86
6 24 35 49 74 81 87
Average 24.5 36.3 51.2 73.0 79.7 85.2
Lot 7LB-32FC
Vessel 1 hr. 2 hr. 4 hr. 8 hr. 10 hr. 12 hr.
No.
1 25 36 42 54 59 64.0
2 24 35 42 55 61 66
3 26 38 45 59 65 69
4 24 35 42 54 60 65
5 24 36 43 54 59 64
6 23 34 38 50 55 59
Average 24.3 35.7 42.0 54.3 59.8 64.5
[0177] Both formulations demonstrated sustained release of guaifenesin over a
12
hour period. Lot 7LB-32FC demonstrated identical release properties to Lot
7LB-31FC in O.1N HCI. In buffered solution, however, Lot 7LB-32FC, the lot
comprising a 2:1 ratio of Methocel ElOM to Carbopol 974P, demonstrated a
statistically slower release than Lot 7LB-31FC, comprising Methocel El OM and
no Carbopol 974P. A slower release rate in vitro translates to a slower, more
controlled release with longer drug action in vivo - a favorable
characteristic for
pharmaceutical products containing a high concentration of an active
ingredient
with a short half-life (e.g. guaifenesin).
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Example 2
[0178] A dissolution study was run to compare dissolution profiles of lots 7LB-
32FC and 7LB-31FC with currently available guaifenesin dosage forms. One
immediate release tablet, ORGANIDIN NR, and two sustained release tablets,
HUMIBID L.A. and DURATUSS, were subjected to the same dissolution study
as described for lots 7LB-31FC and 7LB-32FC in Example 1 above. The
following is a summary of the results which are also depicted in Figure 5.
Organidin NR Humibid LA Duratuss
% guaifenesin released % guaifenesin released % guaifenesin released
1 hr. 100 36 24
2 hr. 103 51 35
4 hr. 104 72 47
8 hr. 103 91 75
hr. 103 96 86
12 hr. 105 100 92
[0179] The immediate release Organidin released 100% of guaifenesin content
within the first hour of dissolution. The two commercial sustained release
dosage forms demonstrated a slower release of guaifenesin. However, both the
Humibid LA and Duratuss released guaifenesin more rapidly than either Lot
7LB-31FC or 7LB-32FC, particularly after the eight hour interval. Both
Humibid LA and Duratuss would, therefore, exhibit a faster rate of release and
thus a shorter lived therapeutic effect in vivo.
Example 3
[0180] The in vivo behavior of sustained release tablets of Lot 7LB-31FC and
Lot
7LB-32FC from Example 1 were compared to the in vivo behavior of an
immediate release formulation (Organidin NR). The open-label study involved 9
healthy volunteers averaging 38 11.01 years of age with a range of 23 years
to
55 years of age. The subjects weighed 175.56 24.22 lbs. with a range of 143
to
210 lbs. One subject was female and the remainder was male. Each subject
received either one 1200 mg dose of 7LB-31FC, 7LB-32FC or a commercial 400
mg immediate release tablet (every four hours for 3 doses).
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[0181] The results of the pharmacokinetic parameters analysis are described
below
and depicted in Figure 6.
Subject Formulation Tmax Cmax AUCO_12 T1/2 AUCinf
(hr.) (ng/mL) (hr-ng/mL) (hrs.) (hr-ng/mL)
1 7LB-31FC 2.00 827.02 4817.20 4.64 6339.25
2 7LB-31FC 1.50 834.65 4695.89 2.71 5291.71
3 7LB-31FC 1.50 802.44 4142.14 3.44 4728.33
4 7LB-32FC 0.75 625.48 3034.31 5.78 5134.35
7LB-32FC 1.00 1052.00 5872.46 5.99 8298.33
6 7LB-32FC 2.00 1372.00 7924.35 5.53 9557.78
7 Organidin NR 0.50 2140.00 6921.94 0.86 7009.68
8 Organidin NR 4.25 18.17.00 6598.26 0.73 6674.65
9 Organidin NR 0.50 2831.00 9389.76 0.81 9570.91
Mean 7LB-31FC 1.67 821.37 4551.74 3.59 5453.10
Mean 7LB-32FC 1.25 1016.49 5610.37 5.77 7663.49
Mean Organidin NR 1.75 2262.67 7636.65 0.80 7751.74
Ratio (%) 7LB-31FC/IR 95.43 36.30 59.60 448.27 70.35
Ratio (%) 7LB-32FC/IR 71.43 44.92 73.47 718.92 98.86
[0182] Subjects given the 1200 mg formulation 7LB-32FC reached maximum
plasma guaifenesin concentrations of 1016 ng/mL in 1.25 hours and had an
AUCiõf of 7663 hr-ng/mL. The subjects given formulation 7LB-31FC reached
maximum plasma guaifenesin concentrations of 821 ng/mL in 1.67 hours and
had an AUC;,,f of 5453 hr-ng/mL. The subjects given the immediate release
formulation, Organidin NR, reached maximum plasma guaifenesin
concentrations of 2263 ng/mL in 1.75 hours (2 subjects peaked at 0.5 hours
after
the first dose and the third peaked at 0.25 hours after the second dose at 4
hours)
and had an AUCinf of 7752 hr-ng/mL. The two controlled release formulations
demonstrated sustained release in that their half-lives were longer, 5.77
hours for
the 7LB-32FC and 3.59 hours for the 7LB-31 FC compared to 0.8 hours for the
immediate release formulation, Organidin NR.
[0183] Both formulations 7LB-32FC (with both Methocel ElOM and Carbopol
974P) and 7LB-31FC (with Methocel EIOM only) control the release of
guaifenesin from the tablet compared to the immediate release Organidin NR.
Formulation 7LB-32FC, the formulation containing a 6:1 ratio of Methocel
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MOM to Carbopol 974P, had the longest half life at 5.77 hours with the largest
AUCiõ f between the two sustained release formulation. However, both sustained
release formulations have a Cmax less than half of the Cmax of the immediate
release Organidin NR.
Example 4
[0184] Three different sustained release tablet lots of guaifenesin alone were
prepared: i) Formulation I - 1200 mg SR; ii) Formulation II - 400 mg JR and
800
mg SR; and iii) Formulation III - 600 mg IR and 600 mg SR.
Non-layered tablet (sustained release)
Formulation I
Components Weight per Tablet
Guaifenesin DC 1260 mg
Methocel ElOM 40 mg
Carbopol 974P 20 mg
Emerald Green Lake 4 mg
Magnesium Stearate 6.8 mg
Bi-layered tablets (sustained release and immediate release)
Immediate release layer
Formulation II Formulation III
Components Weight per Tablet Weight per Tablet
Guaifenesin DC 421 mg 630.8 mg
Microcrystalline Cellulose 40 mg 353 mg
(Avicel)
Sodium Starch Glycolate 60 mg 90.1 mg
(Explotab)
Magnesium Stearate 2 mg 3 mg
Sustained release layer
Formulation II Formulation III
Components Weight per Tablet Weight per Tablet
Guaifenesin DC 842 mg 630.8 mg
Methocel E I OM 27 mg 40 mg
Carbopol 974P 13.5 mg 20 mg
Emerald Green Lake 3 mg 4 mg
Magnesium Stearate 4.5 mg 6.8 mg
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[0185] The in vivo behavior of each of the three sustained release tablets and
a
commercial immediate release formulation (Organidin NR) were compared. The
open-label study involved 15 healthy volunteers averaging 31.67 11.89 years
of age with a range of 20 years to 51 years of age. The subjects weighed
162.00
25.05 lbs. with a range of 123 to 212 lbs. All 15 subjects were administered
400 mg of the immediate release formulation every 4 hours for a total of 12
hours in on one day. On another day, 5 subjects were administered Sustained
Formulation I, another 5 subjects were administered Sustained Formulation II,
and yet another 5 subjects were administered Sustained Formulation III.
[0186] The results of the pharmacokinetic parameters analysis are described
below
and depicted in Figure 7.
Formulation Tmax Cmax AUCO-12 T112 AUCinf
(hr.) (ng/mL) (hr-ng/niL) (hrs.) (hr-ng/mL)
Mean Organidin NR 0.90 2609.40 8768.40 1.28 9082.78
Mean Formulation I 2.30 1631.40 5549.30 2.88 6044.93
Mean Formulation II 2.30 2415.40 7304.38 1.48 7509.78
Mean Formulation III 1.95 2938.00 8904.62 2.05 9161.03
[0187] Sustained Formulations II and III exhibited a Cmax more comparable to
the
immediate release formulation and an increased AUC1'If from that of the non-
layered Sustained Formulation I. The half-lives of both Sustained Formulation
II
and III were reduced from the half-life of Sustained Formulation I. These bi-
layer tablets, however, showed an improved serum concentration of guaifenesin
and an increased overall concentration with time.
Example 5
[0188] A dissolution study was run to compare dissolution profiles of
Formulation I,
Formulation II and Formulation III prepared as defined in Example 4 above, and
Formulation IV, a bi-layer tablet lot with 200 mg IR and 1000 mg SR prepared
with the following composition:
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Immediate release laver
Formulation IV
Components Weight per Tablet
Guaifenesin DC 211 mg
Microcrystalline Cellulose 118 mg
(Avicel)
Sodium Starch Glycolate 30 mg
(Explotab)
Magnesium Stearate 1 mg
Sustained release layer
Formulation IV
Components Weight per Tablet
Guaifenesin DC 1053 mg
Methocel E l OM 25 mg
Carbopol 974P 12.5 mg
Emerald Green Lake 3.3 mg
Magnesium Stearate 5.7 mg
The following is a summary of the results which are also depicted in Figure 8.
Formulation I Formulation II Formulation III Formulation IV
% released % released % released % released
1 hr. 22 45 38 29
2 hr. 34 54 46 38
4 hr. 43 65 56 48
6 hr. 50 70 61 53
8 hr. 58 73 66 60
hr. 62 78 70 66
12 hr. 66 81 75 71
[0189] Formulation I, the non bi-layered tablet, demonstrated the slowest
release of
guaifenesin. Formulation II and Formulation III had the fastest rates of
release
and would, therefore, exhibit a faster rate of release and thus a shorter
lived
therapeutic effect in vivo. Formulation IV has a rate of release which was
faster
than Formulation I, comprising no immediate release blend, but slower than
Formulation II and Formulation III, both comprising more immediate release
blend than Formulation IV.
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Example 6
[0190] The in vivo behavior of Formulation IV bi-layered tablets, prepared as
described above in Example 5, was compared to an immediate release
formulation (Organidin NR). The open-label, multiple dose, randomized, 2-way
crossover study involved 26 healthy volunteers averaging 31.31 9.81 years of
age with a range of 19 years to 50 years of age. The subjects weighed 166.77
29.83 lbs. The subjects were placed into one of two treatment groups. Group 1
received Formulation IV tablet with 240 mL of water after an overnight fast
every 12 hours for 5 days and a single dose on day 6. Group 2 received 400 mg
of Organidin NR (2 x 200 mg tablets) with 240 mL of water every 4 hours for 5
days and one 400 mg dose every four hours for a total of 3 doses on day 6.
[0191] Blood samples (5 mL with sodium heparin as anticoagulant) were taken
prior
to dosing on days 1, 4, 5, and 6. On Day 1, additional blood samples (5 mL
with
sodium heparin as anticoagulant) were also obtained at 0.5, 0.75, 1, 1.5, 2,
3, 4,
4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10. 11, and 12 hours after the
initial
dose. On Day 6, additional blood samples (5 mL with sodium heparin as
anticoagulant) were also obtained at 0.5, 0.75, 1, 1.5, 2, 3, 4, 4.5, 4.75, 5,
5.5, 6,
7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, and 24 hours after the initial
dose.
[0192] The results of the pharmacokinetic parameters analysis are below.
Averaged Testing - 11 Twelve-Hour Intervals
Formulation Tmax Cmax AUCo_12 T1/2 AUCinf
(hr.) (ng/mL) (hr-ng/mL) (hrs.) (hr-ng/mL)
Mean Organidin NR 1.69 2463.20 8381.93 0.78 8528.51
Mean Formulation IV 1.05 2111.38 7875.68 3.31 8686.08
The results of the testing are depicted in Figure 9.
Steady State Testing
Formulation Tmax Cmax AUCo-12 T1n AUCInf
(hr.) (ng/mL) (hr-ng/mL) (hrs.) (hr-ng/mL)
Mean Organidin NR 2.03 2278.20 7751.23 0.88 7962.14
Mean Formulation IV 0.86 2349.6 8202.47 3.61 9259.24
[0193] The results of the testing are depicted in Figure 10.
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[0194] The 200/1000 mg bi-layered tablet exhibited a Cmax and a AUC;,,f
equivalent
to that of the immediate release blend, a short Tmax and an extended half-
life.
Thus, a bi-layered tablet with 200 mg guaifenesin in the immediate release
formulation and 1000 mg of guaifenesin in the sustained release formulation
results in a tablet which delivers a high serum concentration in a short
period of
time, yet maintains an effective concentration of guaifenesin in the blood
stream
for a full twelve hours.
Example 7
[0195] A study was performed to examine the relative bioavailability of two
different dosage strengths of modified release guaifenesin formulations of the
invention as well as the effect of food on the relative bioavailability of a
guaifenesin formulation of the invention in normal, healthy male and/or female
volunteers. Two batches of guaifenesin bi-layer tablets, one 600 mg and one
1200 mg, were prepared.
Immediate release layer
600 mg Tablet 1200 mg Tablet
Components Weight per 200,000 Tablets Weight per 100,000 Tablets
Guaifenesin DC 21.05 kg 21.05 kg
Microcrystalline Cellulose 11.75 kg 11.75 kg
(Avicel PH102)
Sodium Starch Glycolate 3.00 kg 3.00 kg
(Explotab)
Magnesium Stearate 0.10 kg 0.10 kg
Sustained release lamer
600 mg Tablet 1200 mg Tablet
Components Weight per 200,000 Tablets Weight per 100,000 Tablets
Guaifenesin DC 105.27 kg 105.27 kg
Hydroxypropyl Methyl 2.50 kg 2.50 kg
Cellulose (Methocel ElOM)
Carbomer (Carbopol 974P) 1.25 kg 1.25 kg
FD&C Blue No. 1 0.33 kg 0.33 kg
Aluminum Lake Dye
Magnesium Stearate 0.57 kg 0.57 kg
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[0196] The 600 mg and 1200 mg tablets were similarly prepared, the with the
exception of the number of tablets produced from the amount of materials used.
[0197] The in vivo behaviors of a 600 mg tablet administered to volunteers in
the
fasting state (about 10 hours pre-dose until about 4 hours after dosing), the
1200
mg tablet administered to volunteers in the fasting state (about 10 hours pre-
dose
until about 4 hours after dosing), and the 1200 mg tablet administered to
volunteers after a high fat meal (consumed within 30 minutes of dosing) were
compared. The open-label study involved 27 healthy volunteers between the
ages of 18 and 55. The 27 volunteers were divided into 3 treatment groups, 9
receiving the 600 mg tablet, 9 receiving the 1200 mg tablet while fasting, and
9
receiving a 1200 mg tablet after consuming a high fat meal for Period 1 of the
trial. After completion of Period 1, the volunteers were crossed-over for
Period
2 (e.g. so that the 9 volunteers who had been receiving the 600 mg tablet in
Period 1 received the 1200 mg tablet while fasting in Period 2). After
completion of Period 2, the volunteers were crossed-over again into their 3rd
and
final treatment group (i.e. the 9 volunteers who received the 1200 mg tablet
while fasting in Period 2 and the 600 mg tablet while fasting in Period 1
received
the 1200 mg tablet after consumption of a high fat meal in Period 3). Each
volunteer was administered one dose of the appropriate tablet and then
monitored over a 16 hour period.
[0198] Blood samples were taken about one hour prior to dosing and at specific
intervals up to 16 hours after dosing (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6,
8, 10,
12, 14, and 16 hours). The results of the pharmacokinetic parameters analysis
are described below and in Figure 11.
Formulation Tmax Cmax AUCO_12 T112 AUCiõ f
(hr.) (ng/mL) (hr-ng/mL) (hrs.) (hr-ng/mL)
Mean 600 m Fasted 0.81 1074.26 3623.03 2.33 3676.23
Mean 1200 m Fasted 0.94 1948.62 7483.20 3.33 7912.61
Mean 1200 mg Fed 2.18 1988.08 7424.20 0.91. 7425.29
[0199] The 600 mg tablet demonstrated a serum profile approximately directly
proportional to the serum profile of the 1200 mg tablet. The Cmax of the 600
mg
tablet was about 55% that of the 1200 mg tablet. The AUCO_12 of the 600 mg
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tablet was about 48% that of the 1200 mg tablet and the AUCi,,f of the 600 mg
tablet was about 46% that of the 1200 mg. improved serum concentration of
guaifenesin and an increased overall concentration with time, their half-life
was
compromised.
[0200] The 1200 mg tablet demonstrated that the bi-layer tablets of the
invention
greatly reduce the food effect in bioavailability and serum concentration of
guaifenesin. The Cmax of the 1200 mg tablet administered after a high fat meal
(fed tablet) was about 102% of the Cma. of the 1200 mg tablet administered
after
fasting (fasted tablet). The AUC0.12 of the 1200 mg fed tablet was about 99%
that of the fasted tablet and the AUC;,,f of the 1200 mg fed tablet was about
94%
that of the fasted tablet.
Example 8
[0201] In an example of a combination drug formulation, two batches of
guaifenesin/dextromethorphan HBr bi-layer tablets were prepared: i) 600 mg/ 30
mg dextromethorphan and ii) 1200 mg/ 60 mg. In the 30 mg dextromethorphan
tablet 7.5 mg was within the immediate release layer and 22.5 mg within the
sustained release layer. The 60 mg dextromethorphan tablet comprised double
the dextromethorphan respectively.
[0202] Sustained release layer
600 mg/ 30 mg 1200 mg/ 60 mg
Components Weight per 200,000 tablets Weight per 100,000 tablets
(kg) (kg)
Guaifenesin, USP 101.00 101.00
Dextromethorphan HBr 4.50 4.50
Carbopol 974P, NF 1.50 5.00
Microcrystalline Cellulose 5.00 1.50
(Methocel E I OM)
D&C Yellow No. 10 0.04 0.04
Aluminum Lake (14-18%)
Magnesium Stearate 1.00 1.0
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Immediate release layer
600 mg-1 30 mg 1200 mg-/ 60 mg
Components Weight per 480,000 tablets Weight per 240,000 tablets
(kg) (kg)
Guaifenesin, USP 45.60 45.60
Dextromethorphan HBr 3.60 3.60
Sodium Starch Glycolate, 3.60 3.60
NF (Explotab)
Microcrystalline Cellulose 40.32 40.32
(Avicel PH102)
Methocel E10M, USP 2.40 2.40
Magnesium Stearate, NF 0.48 0.48
[0203] The following is a summary of 1200 mg guaifenesin/ 60 mg
dextromethorphan HBr Dissolution Rate for three different batches also
depicted
in Figure 12.
PB01-H30 (clinical batch) PB01-H43 PBO1-H44
% released % released % released
1 hr 46 47 47
2 hr 59 60 61
6 hr 73 74 76
12 hr 86 87 89
[0204] The in vivo behavior of the 1200 mg guaifenesin and 60 mg tablet was
studied by measuring the plasma concentration of guaifenesin,
dextromethorphan HBr, and the metabolite dextrorphan. Figures 13-15 illustrate
the plasma concentration for each drug or metabolite in two formulations,
Formulation B and Formulation C, during a 24 hour period. Immediately after
administration the plasma concentration of guaifenesin peaks in about an hour,
followed by a gradual plasma concentration decrease over 24 hours.
Immediately after administration, guaifenesin plasma concentration never
decreased to less than 200 ng/mL over 12 hours. Thereafter, guaifenesin plasma
concentration gradually decreased over the next 12 hours. Plasma concentration
of dextromethorphan HBr peaks at about 6 hours at about 12 ng/mL and the
concentration is maintained for the following 19 hours.
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[0205] Formulations B and C of Figure 13, exhibited guaifenesin release
profiles
similar to the reference formulation. The reference formulation for Figure 13
was Formulation IV of Example 5. Formulation B comprised 77% guaifenesin
by weight, 3.8% by weight dextromethorphan, 9.1% by weight microcrystalline
cellulose, 1.9% by weight Methocel E10M, and 0.9% Carbopol 974P.
Formulation C comprised 76.5% by weight guaifenesin, 3.8% by weight
dextromethorphan, 9.7% by weight microcrystalline cellulose, 1.9% by weight
Methocel ElOM, and 0.9% by weight Carbopol 974P. Formulations B and C
exhibited similar behavior and had a guaifenesin release profile similar to
the
reference formulation. Accordingly, the combination formulations of the
invention did not interfere with the release of guaifenesin. In particular,
after 12
hours Formulation C released a greater dose of guaifenesin than the reference
formulation.
[0206] Formulations B and C of Figure 13 were compared against a reference
consisting of an extended release formulation of dextromethorphan
commercially available under the name Delsym sold by Celltech. The
comparison was carried out to determine the behavior of guaifenesin-
dextromethorphan formulations of the invention as compared to separately
administered combination formulations of dextromethorphan. Formulations B
and C had longer dextromethorphan release profiles than the reference, as
shown
in Figure 14. Additionally, the combined formulations of the inventions had no
detrimental effect upon the release profile of dextromethorphan.
[0207] Another method to monitor dextromethorphan plasma concentrations is to
measure the plasma concentration of the metabolite dextrorphan. The plasma
concentration of dextrorphan metabolite of the reference formulation and
Formulations B and C of Figure 14 were plotted in Figure 15. Generally, the
formulations exhibited similar dextrorphan concentrations, with Formula C
exhibiting the highest dextrorphan concentration after 12 hours. Figure 15
demonstrates that the formulations of the invention containing guaifenesin do
not inhibit the release of dextromethorphan, as determined by measuring the
presence of the metabolite dextrorphan.
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Example 9
[0208] A study was performed to examine the relative bioavailability of a
sustained
release guaifenesin with dextromethorphan formulation of the invention with
normal, healthy male and/or female volunteers. A batch of guaifenesin and
dextromethorphan bi-layer tablet, 1200 mg, was prepared according to the
composition described above for Example 8.
[0209] The in vivo behaviors of the 1200 mg tablet administered to volunteers
in the
fasting state (about 10 hours pre-dose until about 4 hours after dosing) was
determined. The open-label study involved 29 healthy volunteers between the
ages of 18 and 55. The 29 volunteers were divided into two treatment groups
half receiving the 1200 mg tablet while fasting for Period 1 of the trial.
Each
volunteer was administered one dose of the appropriate tablet and then
monitored over a 16 hour period.
[0210] Blood samples (7 mL with sodium heparin as anticoagulant) were taken
about one hour prior to dosing and at specific intervals up to 16 hours after
dosing (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 16 hours).
The
results of the pharmacokinetic parameters analysis for guaifenesin include a
T,T,ax
of 1.48 hr, Cmax (ng/mL) of 2196, AUCO_12 (hr-ng/mL) of 8702, T112 of 1.32
hrs.,
and an AUCiõf (hr-ng/mL) of 8732.5. The results of the pharmacokinetic
parameters analysis for dextromethorphan include a Tmax of, 5.0 hrs, Cmax
(pg/mL) of 5157, AUCO_12 (hr-pg/mL) of 74209, T112 of 7.93 hrs., and an AUCinf
(hr-pg/mL) of 75016.
Example 10
[0211] In another example of a combination formulation, two batches of
guaifenesin-pseudoephedrine HCl bi-layer tablets, one 600 mg and one 1200 mg,
were prepared in the following amounts.
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Sustained release layer
600 mg-/ 60 mg 1200 mg/ 120
Ing
Components Weight per 300,000 tablets Weight per 150,000 tablets
(kg) (kg)
Guaifenesin DC (95%) 157.90 157.89
Pseudoephedrine HC1 18.0 18.00
Hydroxypropyl 4.50 4.50
Methylcellulose (Methocel
El OM)
Carbopol 974P, NF 2.25 2.25
FD&C Yellow No. 6 0.24 0.06
Aluminum Lake (15-18%)
Magnesium Stearate 1.50 1.50
Immediate release layer
600 mg/ 60 mg 1200 mg/ 120
mg
Components Weight per 300,000 tablets Weight per 150,000 tablets
(kg) (kg)
Guaifenesin DC (95%) 39.476 39.476
Microcrystalline Cellulose 22.028 22.028
(Avicel PHI 02)
Sodium Starch Glycolate 5.626 5.626
Magnesium Stearate, NF 0.188 0.188
[0212] The following is a summary of 1200 mg guaifenesin/ 120 mg
pseudoephedrine dissolution rates also depicted in Figure 16.
PB01-M65 PB01-M68 PB01-M71
(clinical batch) % released % released
% released
1 hr 45 44 43
2 hr 60 59 58
6 hr 89 87 82
12 hr 97 98 96
[0213] The in vivo behavior of the 1200 mg guaifenesin and 120 mg
pseudoephedrine tablet was studied by measuring the plasma concentration of
guaifenesin, and pseudoephedrine HC1. The three batches of the 1200 mg
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guaifenesin/ 120 mg pseudoephedrine HC1 formulation were dissolved to
determine the amount of pseudoephedrine HCI released over time. Generally,
the formulations had 1200 mg of guaifenesin and 120 mg pseudoephedrine HC1
and were studied over a 12 hour period. The released amount of
pseudoephedrine HCl was determined as a weight percent of dissolved
pseudoephedrine HCI in contrast to the total weight of pseudoephedrine HC1
prior to dissolution. After 1 hour about 43% to 45% of the pseudoephedrine HCI
had dissolved. After 2 hours the about 58% to 60% dissolved, after 6 hours 82%
to 89% had dissolved, and after 12 hours about 96% to 97% by weight of the
pseudoephedrine HCI had dissolved. (See Figure 16).
[0214] Three formulations of guaifenesin, two containing an additional drug,
pseudoephedrine, were compared to determine whether an additional drug
affects the release profile of guaifenesin. Figures 17-18 illustrate the
plasma
concentration for each drug (Formulation B and Formulation C) during a 24 hour
period. Immediately after administration the plasma concentration of
guaifenesin peaks in about an hour, followed by a gradual plasma concentration
decrease over 24 hours. Immediately after administration, guaifenesin plasma
concentration never decreased below 200 ng/mL over 12 hours. Thereafter,
guaifenesin plasma concentration gradually decreased over the next 12 hours.
Plasma concentration of pseudoephedrine HCI peaked at about 6 hours and
gradually decreased over the next 18 hours. The plasma concentration of
pseudoephedrine HCI never decreased to less than 50 ng/mL after 30 minutes of
administration.
[0215] In Figure 17, the reference formulation included formulation IV of
Example
and a separate Sudafed 12 hour formulation available from Pfizer Inc. 201
Tabor Road, Morris Plains, New Jersey, 07950. The reference formulation was
compared to Formulation B and Formulation C of the invention. Formulation B
comprised a sustained release formulation having 86% by weight Guaifenesin
DC, 9.8% by weight pseudoephedrine HCI, 2.4% by weight hydroxypropyl
methylcellulose, and 1.2% by weight Carbopol 974P, and an immediate release
formulation having 52% by weight Guaifenesin DC and 39% by weight
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microcrystalline cellulose by weight. Formulation C comprised 77% by weight
Guaifenesin DC, 7.7% by weight pseudoephedrine, 9% by weight
microcrystalline cellulose, 1.8% by weight Methocel ElOM, and 0.9% by weight
Carbopol 974P. Formulations B and C exhibited similar behavior to separately
administered formulations, thus demonstrating that formulations of the
invention
did not interfere with the profile release of pseudoephedrine.
[0216] The plasma concentration for pseudoephedrine HCl was studied to
determine
whether the formulations of the invention interfered with the release profile
of
pseudoephedrine. The pseudoephedrine plasma concentrations for the
formulations of Figure 17 were plotted over a 24 hour period. As illustrated
in
Figure 18, Formulations B and C of Figure 17 exhibited higher pseudoephedrine
concentrations than the reference formulation. Thus, the combined formulations
of the invention release pseudoephedrine in comparable or better release
profiles
than formulations containing pseudoephedrine alone.
Example 11
[0217] A study was performed to examine the relative bioavailability of
sustained
release guaifenesin with pseudoephedrine formulations of the invention in
normal, volunteers. A batch of guaifenesin and pseudoephedrine bi-layer
tablets,
1200 mg, was prepared according to the composition described above for
Example 10.
[0218] The in vivo behaviors of a 1200 mg tablet administered to volunteers in
the
fasting state (about 10 hours pre-dose until about 4 hours after dosing) were
compared. The open-label study involved 29 healthy volunteers between the
ages of 18 and 55. The 29 volunteers were divided into two treatment groups,
half receiving the 1200 mg tablet while fasting for Period 1 of the trial.
Each
volunteer was administered one dose of the appropriate tablet and then
monitored over a 16 hour period.
[0219] Blood samples (7 mL with sodium heparin as anticoagulant) were taken
about one hour prior to dosing and at specific intervals up to 16 hours after
dosing (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 16 hours).
The
results of the pharmacokinetic parameters analysis for guaifenesin include a
Tmax
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of 1.48 hr, Cmax (ng/mL) of 2196, AUCO_12 (hr-ng/mL) of 8702, T112 of 1.32
hrs.,
and an AUCinf (hr-ng/mL) of 8732.5. The results of the pharmacokinetic
parameters analysis for pseudoephedrine include a Tmax of 6 hrs, Cmax (ng/mL)
of
300, AUCO.12 (hr-ng/mL) of 4201, T1/2 of 5.98 hrs., and an AUCinf (hr-ng/mL)
of
4709.
Example 12
[0220] Guaifenesin and pseudoephedrine sustained release formulations were
compared to commercial controlled release guaifenesin and pseudoephedrine
products in healthy volunteers in an open label, single dose, randomized, 3-
way
crossover study in 15 subjects.
[0221] The subjects were randomized and placed into one of three treatment
groups.
Group A was given Formulation A, one 1200 mg controlled release guaifenesin
product (Mucinex) plus a 120 mg controlled release pseudoephedrine
hydrochloride product (Sudafed- 12 Hour) with 240 mL of water after an
overnight fast. Group B received Formulation B (lot PBOl-K61), an
experimental controlled release tablet containing 1200 mpg guaifenesin and 120
mg of pseudoephedrine hydrochloride with 240 mL of water after an overnight
fast. Group C received Formulation C (lotCBOO-O1A), another experimental
controlled release tablet containing 1200 mg guaifenesin and 120 mg
pseudoephedrine hydrochloride with 240 mL of water after an overnight fast.
There was at least a 7-day washout between doses.
[0222] The volunteers averaged 26.4 10.57 years of age (Mean Standard
Deviation) with a range of 18 years to 50 years of age. They were 66.93 4.37
inches tall with a range of 60 to 74 inches. They weighed 160.87 26.22
pounds
with a range of 118 to 222 pounds. Seven were male (47%) and eight female
(53%). Ten (67%) of the subjects had a large frame size, three (20%) had a
medium frame and two (13%) had a small frame. Thirteen volunteers (87%)
were Caucasian and two (13%) were Multiracial. Blood (10 mL, sodium heparin
anticoagulant) was obtained at the following times: Pre dose, 0.5, 0.75, 1,
1.5, 2,
3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post dose.
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[0223] Subjects given 1200 mg of guaifenesin as guaifenesin ER (reference)
reached a CmaX of 1847 ng/mL in 0.78 hours and had an AUCinf of 7302 hr-
ng/mL. Subjects given 1200 mg guaifenesin as Formulation B reached a CmaX of
1784 ng/mL (103% of that of the reference) in 0.82 hour (113% of that of the
reference) and had an AUCinf of 7602 hr-ng/mL (109% of that of the reference).
Subjects given 1200 mg guaifenesin as Formulation C reached a CmaX of 1154
ng/mL (65% of that of the reference) in 1.22 hours (179% of that of the
reference) and had an AUCinf of 7128 hr-ng/mL (100% of that of the reference).
[0224] Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed-12 Hour
(reference) reached a CmaX of 300 ng/mL (mean standard deviation) in 6 hours
and had an AUCinf of 4710 hr-ng/mL. Subjects given 120 mg pseudoephedrine
hydrochloride as Formulation B reached a CmaX of 285 ng/mL (99% of that of the
reference) in 6 hours (101% of that of the reference) and had an AUCinf of
4449
hr-ng/mL (100% of that of the reference). Subjects given 120 mg
pseudoephedrine hydrochloride as Formulation C reached a CmaX of 256 ng/mL
(86% of that of the reference) in 8 hours (151% of that of the reference) and
had
an AUCinf of 4444 hr-ng/mL (97% of that of the reference).
[0225] The plasma concentrations of guaifenesin are depicted in Figure 19. The
resulting pharmacokinetic data is shown in Tables 1 through 4. The maximum
plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex
were 1847 686.6 ng/mL and occurred in 0.78 0.28 hours. The resulting area
under the plasma concentration vs. time curve (AUCinf was 7302 2866.4 hr-
ng/mL. The maximum plasma concentrations of guaifenesin following a 1200
mg oral dose as Formulation B were 1784 549.9 ng/mL (102.93% 36.57% of
that of the reference formulation) and occurred in 0.82 0.27 hours (112.78%
43.29% that of the reference formulation). The resulting AUCinf was 7602
2492.8 hr-ng/mL (108.67% 23.93% of that of the reference formulation). The
maximum plasma concentrations of guaifenesin following a 1200 mg oral dose
as Formulation C were 1154 523.3 ng/mL (64.56% 28.03% of that of the
reference formulation) and occurred in 1.22 0.45 hours (178.9% 100.64%
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that of the reference formulation). The resulting AUCInf was 7128 3166.0 hr
ng/mL(99.81% 34.23% of that of the reference formulation).
Table 1. Guaifenesin Pharmacokinetic Variables Following the Administration of
1200 mg Guaifenesin as Mucinex along with Sudafed 12 Hour to Normal
Volunteers
Subject Cmax Tmax AUC0_t AUC;nf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 1847 0.78 7143 7302 3.60 188.98
Median 1530 0.75 5776 5863 3.21 204.68
Standard 686.63 0.28 2793.41 2866.39 2.05 74.55
Deviation
Standard 183.51 0.08 746.57 766.08 0.55 19.92
Error
% CV 37.18 35.92 39.11 39.26 56.94 39.45
Maximum 1847 0.78 7143 7302 3.60 188.98
Minimum 1530 0.75 5776 5863 3.21 204.68
Table 2. Guaifenesin Pharmacokinetic Variables Following the Administration of
1200 mg Guaifenesin and 120 mg Pseudoephedrine Hydrochloride as Formulation
B to Normal Volunteers
Subject Cmax Tmax AUC0_t AUCInf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 1784 0.82 7557 7602 1.59 172.56
Median 1730 0.75 7297 7349 1.35 163.30
Standard 549.90 0.27 2487.33 2492.75 0.59 49.49
Deviation
Standard 146.97 0.07 664.77 666.22 0.16 13.23
Error
% CV 30.82 33.67 32.91 32.79 37.09 28.68
Maximum 1800 0.75 5818 5842 1.35 205.42
Minimum 1120 0.5 49521, 4979 1.14 241.01
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Table 3. Guaifenesin Pharmacokinetic Variables Following the Administration of
1200 mg Guaifenesin and 120 mg Pseudoephedrine Hydrochloride as Formulation C
to Normal Volunteers
Subject Cmax Tmax AUCo-t AUCiõ f Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 1154 1.22 6989 7128 2.40 202.57
Median 1050 1.00 6291 6314 2.38 190.05
Standard 523.29 0.45 3078.23 3165.98 1.06 89.63
Deviation
Standard 139.86 0.12 822.69 846.14 0.28 23.96
Error
% CV 45.35 37.14 44.04 44.41 44.30 44.25
Maximum 612 0.75 3157 3205 1.25 374.38
Minimum 781 0.75 4902 4949 2.49 242.46
Table 4. Ratio of Guaifenesin Pharmacokinetic Variables Following the
Administration of 1200 mg Guaifenesin and 120 mg Pseudoephedrine
Hydrochloride as Formulation B Compared to that of the Reference Formulation
to
Normal Volunteers (%)
Subject Cmax Tmax AUCo-t AUCiõ f Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 102.93 112.78 110.31 108.67 66.51 95.42
Median 90.59 100.00 102.28 100.45 50.76 99.55
Standard 36.57 43.29 23.94 23.93 65.61 16.90
Deviation
Standard 9.77 11.57 6.40 6.40 17.53 4.52
Error
% CV 35.53 38.38 21.70 22.02 98.64 17.72
Maximum 165.14 75 122.87 121.60 83.97 82.24
Minimum 80 50 87.60 84.93 17.70 117.75
[0226] The plasma concentrations of pseudoephedrine are depicted in Figure 20.
The resulting pharmacokinetic data is shown in Tables 5 through 9. The
maximum plasma concentrations of pseudoephedrine following a 120 mg oral
dose as Sudafed-12 Hour (reference) were 300.3 91.44 ng/mL and occurred in
6 1.69 hours. The resulting AUCinf was 4710 1394.5 hr-ng/mL. The
maximum plasma concentrations of pseudoephedrine following a 120 mg oral
dose as Formulation B were 285.3 53.28 ng/mL (99.3 1% 20.39% of that of
the reference formulation) and occurred in 5.80 2.40 hours (101.11%
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41.77% of that of the reference formulation). The resulting AUC;,,f was 4449
1079.6 hr-ng/mL (99.87% 26.40% of that of the reference formulation). The
maximum plasma concentrations of pseudoephedrine following a 120 mg oral
dose as Formulation C were 256.4 80.7 ng/mL (86.37% 14.38% of that of
the reference formulation) and occurred in 8.27 2.71 hours (5 1.11% 73.25%
of that of the reference formulation). The resulting AUC;,,f was 4444 1212.1
hr-ng/mL (96.78% 17.90% of that of the reference formulation).
Table 5. Pseudoephedrine Pharmacokinetic Variables Following the
Administration
of 120 mg Pseudoephedrine Hydrochloride as Sudafed-12 Hour along with 1200 mg
Guaifenesin as Mucinex to Normal Volunteers
Subject Cmax Tmax AUCo_t AUC,,,f Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 300.27 6.00 4201.62 4709.88 5.98 22.93
Median 287.00 6.00 4042.53 4601.31 5.19 21.37
Standard 91.44 1.69 1182.92 1394.49 1.68 7.77
Deviation
Standard 24.44 0.45 316.15 372.69 0.45 2.08
Error
CV 30.45 28.17 28.15 29.61 28.01 33.87
Maximum 523 8 6518.45 7137.33 10.18 38.94
Minimum 183 4 2419.97 2524.37 4.29 13.77
Table 6. Pseudoephedrine Pharmacokinetic Variables Following the
Administration
of 120 mg Pseudoephedrine Hydrochloride and 1200 mg Guaifenesin as
Formulation B to Normal Volunteers
Subject Cmax Tmax AUCo_t AUC,,,f Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) n /mL)
Mean 285.33 5.80 4080.27 4448.85 5.40 23.41
Median 269.00 6.00 3985.05 4463.18 5.21 22.03
Standard 53.28 2.40 946.92 1079.61 1.01 6.06
Deviation
Standard 14.24 0.64 253.07 288.54 0.27 1.62
Error
CV 18.67 41.32 23.21 24.27 18.64 25.88
Maximum 387 10 6003.14 6799.07 7.44 37.40
Minimum 215 2 2381.18 2628.19 3.85 14.46
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Table 7. Pseudoephedrine Pharmacokinetic Variables Following the
Administration
of 120 mg Pseudoephedrine Hydrochloride and 1200 mg Guaifenesin as
Formulation C to Normal Volunteers
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 256.40 8.27 4008.32 4444.09 5.39 23.85
Median 226.00 10.00 3888.93 4266.92 5.15 23.04
Standard 80.71 2.71 1084.90 1212.13 1.10 7.16
Deviation
Standard 21.57 0.72 289.95 323.96 0.29 1.91
Error
% CV 31.48 32.80 27.07 27.28 20.41 30.03
Maximum 448 10 6200.18 6756.67 8.66 40.05
Minimum 162 2 2360.01 2454.79 4.09 14.55
Table 8. Ratio of Pseudoephedrine Pharmacokinetic Variables Following the
Administration of 120 mg Pseudoephedrine Hydrochloride and 1200 mg
Guaifenesin as Formulation B Compared to that of the Reference Formulation to
Normal Volunteers (%)
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 99.31 101.11 101.58 99.87 93.38 109.24
Median 94.74 100.00 104.95 101.63 90.66 98.40
Standard 20.39 41.77 24.96 26.40 17.54 40.60
Deviation
Standard 5.45 11.16 6.67 7.06 4.69 10.85
Error
% CV 20.53 41.31 24.57 26.44 18.79 37.13
Maximum 140.40 200 139.07 144.72 120.84 234.43
Minimum 65.97 25 50.46 42.66 60.12 69.10
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Table 9. Ratio of Pseudoephedrine Pharmacokinetic Variables Following the
Administration of 120 mg Pseudoephedrine Hydrochloride and 1200 mg
Guaifenesin as Formulation C Compared to that of the Reference Formulation to
Normal Volunteers (%)
Subject Cmax Tmax AUC0_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 86.37 151.11 96.79 96.78 93.98 107.04
Median 85.66 133.33 98.75 99.37 96.77 100.63
Standard 14.38 73.25 14.24 17.90 21.06 22.01
Deviation
Standard 3.84 19.58 3.80 4.78 5.63 5.88
Error
CV 16.65 48.48 14.71 18.49 22.41 20.56
Maximum 115.30 250 126.82 132.10 129.45 153.94
Minimum 62.60 50 75.98 64.96 51.20 75.70
[0227] The data indicates that both formulations produce optimum guaifenesin
bioavailability (although Formulation B appears to more closely match the
reference) and Formulation B produces optimal pseudoephedrine bioavailability.
Example 13
[0228] The bioavailability of a sustained release combination formulation of
1200
mg guaifenesin and 120 mg Pseudoephedrine Hydrochloride was used to
examine the dose proportionality of Pseudoephedrine normal volunteers
compared to reference guaifenesin and Pseudoephedrine Hydrochloride in an
open label, single dose, randomized, 3-way crossover study with 36 subjects.
The example also demonstrates the dose proportionality of pseudoephedrine.
[0229] The subjects were randomized and placed into one of three treatment
groups.
Group I received Treatment A, a 1200 controlled release guaifenesin product
(Mucinex) plus a 120 mg controlled release pseudoephedrine product (Sudafed0
12 Hour) with 240 mL of water after an overnight fast (Reference). Group 2
received Treatment B(PBO1-M65A2), an experimental controlled release
formulation containing 1200 mg guaifenesin and 120 mg pseudoephedrine
hydrochloride with 240 mL of water after an overnight fast (test). Group 3
received Treatment C(PBO1-Al2A), an experimental controlled release
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formulation containing 600 mg guaifenesin and 60 mg pseudoephedrine with
240 mL of water after an overnight fast.
[0230] The volunteers averaged 23.06 7.05 years of age (Mean Standard
Deviation) with a range of 18 years to 48 years of age. They were 70.58 3.08
inches tall with a range of 64 to 75 inches. They weighed 167.42 26.14
pounds
with a range of 114 to 229 pounds. Twenty-four were male (67%) and twelve
female (33%). Sixteen (44%) of the subjects had a large frame size, thirteen
(36%) had a medium frame and seven (19%) had a small frame. Thirty-two
volunteers (89%) were Caucasian, three (8%) were Black and one (3%)
Multiracial. Blood (10 mL, sodium heparin anticoagulant) was obtained at the
following times: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16
and 24
hours post dose (the total blood loss for guaifenesin and pseudoephedrine
analysis will be 450 mL).
[0231] Subjects given 1200 mg of guaifenesin as Mucinex and 120 mg
pseudoephedrine hydrochloride as Sudafed 12 Hour (Treatment A, Reference)
reached a Cmax of 1940 ng/mL in 0.77 hours and had an AUCInf of 8061 hr-
ng/mL. Subjects given 1200 mg guaifenesin and 120 mg pseudoephedrine
hydrochloride as Treatment B (Test) reached a Cmax of 1813 ng/mL (98% of that
of the reference) in 1.04 hour (140% of that of the reference) and had an
AUC0__
of 8124 hr ng/mL (101% of that of the reference). Subjects given 600 mg
guaifenesin and 60 mg pseudoephedrine hydrochloride as Treatment C reached a
Cmax of 920 ng/mL (54% of that of the reference) in 0.99 hours (116% of that
of
the reference) and had an AUC;nf of 3565 hr-ng/mL (46% of that of the
reference).
[0232] Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed 12 Hour
and 1200 mg guaifenesin as Mucinex (Treatment A, Reference) reached a mean
Cmax of 250 ng/mL in 6 hours and had an AUCxnf of 3847 hr-ng/mL. Subjects
given 120 mg pseudoephedrine and 1200 mg guaifenesin as an experimental
formulation (Treatment B, Test) reached a of 263 ng/mL (107% of that of the
reference) in 5 hours (85% of that of the reference) and had an AUC;nf of 3884
hr-ng/mL (103% of that of the reference). Subjects given 60 mg
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pseudoephedrine hydrochloride and 600 mg guaifenesin in an experimental
formulation (Treatment C) reached a Cmax of 141 ng/mL (54% of that of
Formulation B) in 5 hours (100% of that of Formulation B) and had an AUCinf of
1968 hr-ng/mL (50% of that of Formulation B).
[0233] Blood (10 mL, sodium heparin anticoagulant) was obtained at the
following
times: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours
post
dose. Bioequivalence was examined between the test (Treatment B - guaifenesin
or pseudoephedrine hydrochloride experimental formulation) and the reference
(Treatment A - guaifenesin or pseudoephedrine hydrochloride reference
formulations) groups. The dose response relationship was also examined
between the test (Treatment B- guaifenesin or pseudoephedrine hydrochloride
experimental formulation) and the reference (Treatment C - guaifenesin or
pseudoephedrine hydrochloride reference formulations) groups.
[0234] The plasma concentrations of guaifenesin is depicted in Figure 21. The
resulting pharmacokinetic data is shown in Tables 10 through 14. The maximum
plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex
and 120 mg pseudoephedrine hydrochloride as Sudafed 12 Hour were 1940
889 ng/mL and occurred in 0.77 0.22 hours. The resulting area under the
plasma concentration vs. time curve (AUCinf was 8061 3329 hr-ng/mL. The
maximum plasma concentrations of guaifenesin following a 1200 mg oral dose
as Treatment B were 1813 900 ng/mL (98.1% 35.8% of that of the reference
formulation) and occurred in 1.04 0.49 hours (140% 65.3% that of the
reference formulation). The resulting AUCinf was 8124 3677 hr-ng/mL (101%
19.3% of that of the reference formulation). The maximum plasma
concentrations of guaifenesin following a 600 mg oral dose as Treatment C were
920 481 ng/mL (54.3% 20.2% of that of the reference formulation) and
occurred in 0.99 0.46 hours (116% 78.7% that of the reference
formulation).
The resulting AUCinf was 3565 1442 hr-ng/mL (45.6% 10.2% of that of the
reference formulation).
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Table 10. Guaifenesin Pharmacokinetic Variables Following the Administration
of
1200 mg guaifenesin Mucinex along with Sudafed 12 Hour to Normal Volunteers
(%)
Subject Cmax Tmax AUCo_t AUCinf Half- Clearance
(ng/mL) (hr) (hr- (hr- life (L/hr)
ng/mL) ng/mL) (hr)
Mean 1847 0.78 7143 7302 3.60 188.98
Median 1530 0.75 5776 5863 3.21 204.68
Standard 686.63 0.28 2793.41 2866.39 2.05 74.55
Deviation
Standard 183.51 0.08 746.57 766.08 0.55 19.92
Error
% CV 37.18 35.92 39.11 39.26 56.94 39.45
Maximum 1847 0.78 7143 7302 3.60 188.98
Minimum 1530 0.75 5776 5863 3.21 204.68
Table 11. Guaifenesin Pharmacokinetic Variables Following the Administration
of
1200 mg guaifenesin and 120 mg Pseudoephedrine Hydrochloride as an
Ex erimental Formulation to Normal Volunteers (Treatment B, Test)
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 1813 1.04 8002 8124 2.21 175
Median 1530 0.75 7036 7083 1.99 169
Standard 900 0.49 3677 3677 1.19 68.2
Deviation
Standard 154 0.08 631 631 0.20 11.7
Error
% CV 49.6 46.9 45.9 45.3 53.9 38.9
Table 12. Guaifenesin Pharmacokinetic Variables Following the Administration
of
600 mg Guaifenesin and 60 mg Pseudoephedrine Hydrochloride to Normal
Volunteers (Treatment C)
Subject Cmax Tmax AUCO_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) n /mL)
Mean 920 0.99 3529 3565 1.76 192
Median 721 0.75 3078 3098 1.47 194
Standard 481 0.46 1437 1442 0.92 66.5
Deviation
Standard 81.3 0.08 243 244 0.16 11.2
Error
% CV 52.3 46.0 40.7 40.4 52.4 34.5
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Table 13. Ratio of Guaifenesin Pharmacokinetic Variables Following the
Administration of 1200 mg Guaifenesin and 120 mg Pseudoephedrine
Hydrochloride as Formulation B Compared to that of the Reference Formulation
(Treatment A) to Normal Volunteers (%)
Subject Cmax Tmax AUCo_t AUCiõ f Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 98.1 140 104 101 66.2 103
Median 96.8 133 106 100 53.1 99.5
Standard 35.8 65.3 20.3 19.3 42.0 24.2
Deviation
Standard 6.14 11.2 3.48 3.31 7.20 4.16
Error
% CV 36.5 46.5 19.5 19.1 63.4 23.5
Table 14. Ratio of Guaifenesin Pharmacokinetic Variables Following the
Administration of 600 mg Guaifenesin and 60 mg Pseudoephedrine Hydrochloride
(Treatment C) Compared to that of (Treatment B) to Normal Volunteers (%)
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (Lfhr)
ng/mL)
n /mL)
Mean 54.3 116 45.9 45.6 97.0 114
Median 48.8 100 43.9 44.0 86.1 114
Standard 20.2 78.7 10.6 10.2 61.6 23.2
Deviation
Standard 3.47 13.50 1.82 1.75 10.57 3.98
Error
% CV 37.3 67.9 23.1 22.4 63.5 20.3
[0235] The plasma concentrations of pseudoephedrine are depicted in Figure 22.
The resulting pharmacokinetic data is shown in Tables 15 through 19. The
maximum plasma concentrations of pseudoephedrine following a 120 mg oral
dose as Sudafed 12 Hour and 1200 mg guaifenesin as Mucinex (Treatment A,
Reference) were 250 53.4 ng/mL and occurred in 6.29 1.76 hours. The
resulting AUCinf was 3847 910 hr-ng/mL. The maximum plasma
concentrations of pseudoephedrine following a 120 mg oral dose as an
experimental formulation (Treatment B) were 263 58.5 ng/mL (107% 18.9%
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of that of the reference formulation) and occurred in 5.11 1.78 hours (85.2%
31.5% of that of the reference formulation). The resulting AUCinf was 3884
911 hr-ng/mL (103% 20.2% of that of the reference formulation). The
maximum plasma concentrations of pseudoephedrine following a 60 mg oral
dose as an experimental formulation (Treatment C) were 141 30.3 ng/mL
(53.5% 6.52% of that of Formulation B) and occurred in 4.94 1.60 hours
(99.5% 25.9% of that of Formulation B). The resulting AUCinf was 1968 477
hr-ng/mL (50.5% 8.77% of that of Formulation B).
Table 15. Pseudoephedrine Pharmacokinetic Parameters Following the
Administration of 120 mg Pseudoephedrine Hydrochloride as Sudafed 12 Hour
and 1200 mg Guaifenesin as Mucinex to Normal Volunteers (Treatment A)
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 250 6.29 3479 3847 5.75 27.1
Median 252 6 3381 3652 5.42 26.9
Standard 53.4 1.76 805 910 1.02 7.11
Deviation
Standard 9.16 0.30 138 156 0.18 1.22
Error
% CV 21.3 28.0 23.2 23.7 17.8 26.2
Table 16. Pseudoephedrine Pharmacokinetic Following the Administration 120 mg
Pseudoephedrine Hydrochloride and 1200 mg Guaifenesin in an Experimental
Formulation to Normal Volunteers (Treatment B)
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 263 5.11 3591 3884 5.22 26.7
Median 257 4.00 3507 3824 5.19 25.7
Standard 58.5 1.78 824 911 0.89 6.23
Deviation
Standard 10.0 0.31 141 156 0.15 1.07
Error
% CV 22.3 34.8 23.0 23.5 16.9 23.3
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Table 17. Pseudoephedrine Pharmacokinetic Parameters Following the
Administration of 60 mg Pseudoephedrine Hydrochloride and 600 mg Guaifenesin
in an Experimental Formulation to Normal Volunteers (Treatment C)
Subject Cmax Tmax AUCo_t AUC,~f Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 141 4.94 1781 1968 5.57 26.5
Median 134 4.00 1696 1855 5.38 26.5
Standard 30.3 1.60 445 477 1.02 6.58
Deviation
Standard 5.12 0.27 75.1 80.6 0.17 1.11
Error
% CV 21.5 32.4 25.0 24.2 18.4 24.9
Table 18. Ratio of the Pseudoephedrine Pharmacokinetic Parameters Following
the
Administration of 120 mg Pseudoephedrine Hydrochloride and 1200 mg
Guaifenesin as an Experimental Formulation (Treatment B) Compared to that
Following the Administration of 120 mg Pseudoephedrine Hydrochloride as
Sudafed0 12 Hour and 120 m Guaifenesin as Mucinex (Treatment A) (%)
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 107 85.2 105 103 92.1 101
Median 106 75.0 102 101 93.7 98.7
Standard 18.9 31.5 19.39 20.16 15.19 22.03
Deviation
Standard 3.24 5.41 3.33 3.46 2.61 3.78
Error
% CV 17.7 37.0 18.4 19.5 16.5 21.8
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Table 19. Ratio of Pseudoephedrine Pharmacokinetic Parameters Following the
Administration of 60 mg Pseudoephedrine Hydrochloride and 600 mg Guaifenesin
as an Experimental Formulation (Treatment C) Relative to that Following the
Administration of 120 mg Pseudoephedrine Hydrochloride and 1200 mg
Guaifenesin in an Experimental Formulation (Treatment B) (%)
Subject Cmax Tmax AUC0_t AUC;nf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 53.5 99.5 49.1 50.5 108 102
Median 52.6 100 46.7 48.0 105 104
Standard 6.52 25.9 7.80 8.77 17.4 16.2
Deviation
Standard 1.12 4.44 1.34 1.50 2.98 2.78
Error
% CV 12.2 26.0 15.9 17.4 16.2 15.9
[0236] In conclusion, the experimental formulation containing 1200 mg
guaifenesin
and 120 mg pseudoephedrine hydrochloride is bioequivalent to the reference
formulations given is separate doses. In addition the pharmacokinetics of
guaifenesin and pseudoephedrine are linear over the range studied.
Example 14
[0237] The effects of a high fat meal on the bioavailability of a combination
formulation were tested. The bioavailability of a 1200 mg guaifenesin and 120
mg Pseudoephedrine Hydrochloride formulation volunteers was compared to
reference drug bioavailability in an open-label, single-dose, randomized, 2-
way-
crossover study using 36 subjects.
[0238] The subjects were randomized and placed into one of two treatment
groups.
Group 1 received a 1200-mg controlled-release guaifenesin product (Mucinex)
and 120 mg pseudoephedrine hydrochloride (Sudafed 12 Hour) with 240 mL
of water, 30 minutes after the beginning of the consumption of a high-fat
breakfast (Reference). Group 2 received an experimental formulation containing
1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL
of water, 30 minutes after the beginning of the consumption of a high-fat
breakfast (Test)(PB01-M65A3).
[0239] Blood (10 mL, sodium heparin anticoagulant) was obtained at the
following
times: Pre dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours
post
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dose (the total blood loss for guaifenesin and pseudoephedrine analysis was
300
mL).
[0240] Subjects given 1200 mg of guaifenesin as Mucinex (Reference) reached a
Cmax of 2207 ng/mL in 1.85 hours and had an AUCiõ f of 8067 hr-ng/mL. Subjects
given 1200 mg guaifenesin as an experimental formulation (Treatment B)
reached a of 1649 ng/mL (79% of that of the Reference) in 1.84 hour (118% of
that of the Reference) and had an AUCiõ f of 7663 hr-ng/mL (93% of that of the
Reference).
[0241] Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed 12 Hour
(Reference) reached a Cmax of 268 ng/mL in 6.38 hours and had an AUCif of
3636 hr-ng/mL. Subjects given 120 mg pseudoephedrine hydrochloride as an
experimental formulation (Treatment B) reached a Cmax of 274 ng/mL (103% of
that of the Reference) in 4.80 hours (76.5% of that of the Reference) and had
an
AUCiõ fof 3528 hr-ng/mL (96.5% of that of the Reference).
[0242] Additionally, bioequivalence data was examined between the Test group
(Treatment B - 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride
as an experimental formulation) and the Reference group (Treatment A - the
reference 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride
formulations).
[0243] The plasma concentrations of guaifenesin are depicted in Figure 23. The
resulting pharmacokinetic data are shown in Tables 20 through 22. The
maximum plasma concentrations of guaifenesin following a 1200 mg oral dose
as Mucinex were 2207 952 ng/mL and occurred in 1.85 1.06 hours. The
resulting area under the plasma concentration vs. time curve (AUCiõ f was 8067
2663 hr-ng/mL. The maximum plasma concentrations of guaifenesin following a
1200-mg oral dose as an experimental formulation (Treatment B) was 1649
690 ng/mL (79% 31.5% of the Reference formulation) and occurred in 1.84
0.818 hours (118% 68.8% of the Reference formulation). The resulting AUCiõ f
was 7663 2864 hr-ng/mL (93% 17.6% of that of the Reference formulation).
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Table 20. guaifenesin Pharmacokinetic Parameters Following the Administration
of
1200 mg Guaifenesin as Mucinex Along with 120 mg Pseudoephedrine
Hydrochloride as Sudafed0 12 Hour to Normal Volunteers Following the
Consumption of a High Fat Meal (Treatment A, Reference)
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 2207 1.85 8049 8067 1.22 168
Median 2140 1.50 8160 8196 0.983 146
Standard 952 1.06 2666 2663 0.621 64.4
Deviation
Standard 166 0.184 464 464 0.108 11.2
Error
% CV 43.2 57.2 33.1 33.0 51.1 38.3
Table 21. Guaifenesin Pharmacokinetic Parameters Following the Administration
of
1200 mg Guaifenesin and 120 mg Pseudoephedrine Hydrochloride in an
Experimental Formulation to Normal Volunteers Following the Consumption of a
High-Fat Meal (Treatment B, Test)
Subject Cmax Tmax AUCo_t AUCiõf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 1649 1.84 7611 7663 1.40 181
Median 1580 2.00 7474 7485 1.07 160
Standard 690 0.818 2816 2864 0.793 77.6
Deviation
Standard 118 0.140 483 491 0.136 13.3
Error
% CV 41.9 44.4 37.0 37.4 56.6 42.9
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Table 22. Ratio of Guaifenesin Pharmacokinetic Parameters Following the
Administration of 1200 mg Guaifenesin and 120 mg Pseudoephedrine
Hydrochloride in an Experimental Formulation Compared to those of Treatment A
(Reference) to Normal Volunteers Following the Consumption of a High-Fat Meal
(%)
Subject Cmax Tmax AUCe-t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 79 118 93 93 135 109.9
Median 73 100 91 91 99 109.8
Standard 31.5 68.8 17.5 17.6 97.1 16.8
Deviation
Standard 5.57 12.2 3.09 3.12 17.2 2.96
Error
% CV 39.8 58.3 18.8 18.9 72.0 15.3
[0244] The plasma concentrations- of pseudoephedrine are depicted in Figure
24.
The resulting pharmacokinetic data are shown in Tables 23 through 25. The
maximum plasma concentrations of pseudoephedrine following a 120 mg oral
dose as Sudafed 12 Hour (Reference) was 268 69.7 ng/mL and occurred in
6.38 1.26 hours. The resulting AUCinf was 3636 940 hr-ng/mL. The
maximum plasma concentrations of pseudoephedrine following a 120 mg oral
dose as an experimental formulation (Treatment B) was 274 72.3 ng/mL
(103% 10.3% of that of the Reference formulation) and occurred in 4.80
1.28 hours (76.5% 23.1% of that of the Reference formulation). The resulting
AUCinf was 3528 962 hr-ng/mL (96.5% 11.7% of that of the Reference
formulation).
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Table 23. Pseudoephedrine Pharmacokinetic Parameters Following the
Administration of 120 mg Pseudoephedrine Hydrochloride as Sudafed0 12 Hour
Along with 1200 mg Guaifenesin as Mucinex to Normal Volunteers Following the
Consumption of a High-Fat Meal (Treatment A, Reference)
Subject Cmax Tmax AUC0_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 268 6.38 3362 3636 5.28 28.8
Median 249 6.00 3238 3545 4.97 27.7
Standard 69.7 1.26 847 940 1.08 7.55
Deviation
Standard 12.1 0.219 147 164 0.188 1.31
Error
% CV 26.03 19.67 25.18 25.86 20.42 26.19
Table 24. Pseudoephedrine Pharmacokinetic Parameters Following the
Administration of 120 mg of Pseudoephedrine Hydrochloride and 1200 mg
Guaifenesin in an Experimental Formulation to Normal Volunteers Following the
Consumption of a High-Fat Meal (Treatment B, Test)
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 274 4.80 3273 3528 5.26 30.0
Median 268 4.00 3198 3448 5.31 28.5
Standard 72.3 1.28 876 962 1.02 8.48
Deviation
Standard 12.2 0.216 148 163 0.172 1.43
Error
% CV 26.4 26.6 26.8 27.3 19.4 28.3
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Table 25. Ratio of Pseudoephedrine Pharmacokinetic Parameters Following the
Administration of 120 mg Pseudoephedrine Hydrochloride and 1200 mg
Guaifenesin in an Experimental Formulation Compared to those of Treatment A
(Reference) to Normal Volunteers Following the Consumption of a High-Fat Meal
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 103 76.5 96.5 96.5 101 105
Median 103 66.7 95.7 94.2 99.5 106
Standard 10.3 23.1 10.6 11.7 17.9 12.6
Deviation
Standard 1.82 4.09 1.88 2.06 3.17 2.23
Error
% CV 10.0 30.3 11.0 12.1 17.7 12.0
[0245] The rate of absorption of guaifenesin from the experimental
formulation, as
assessed by Cmax is not bioequivalent to the test formulation in the presence
of a
high fat meal with a 95% confidence interval between 67.9% and 81.8%. The
extent of absorption of guaifenesin from the experimental tablet, as assessed
by
AUCi,,f is equivalent to the test formulation in the presence of a high fat
meal.
[0246] In conclusion, the rate of guaifenesin absorption from the experimental
formulation is not bioequivalent to the Reference formulations; whereas the
extent of guaifenesin absorption is bioequivalent to the Reference formulation
in
the presence of a high-fat meal. The rate and extent of pseudoephedrine
absorption from the experimental formulation are bioequivalent to the
Reference
formulation in the presence of a high-fat meal.
Example 15
[0247] A combination guaifenesin and Pseudoephedrine formulation was tested
for
steady state pharmacokinetics as compared to references in an open-label,
multiple-dose, randomized, 2-way-crossover study using 36 subjects. The
subjects were randomly placed into one of two treatment groups. Group 1
received a 1200 mg controlled-release guaifenesin product (Mucinex) plus a 120
mg controlled-release pseudoephedrine product (Sudafed 12 Hour) with 240
mL of water after an overnight fast and again 12 hours later for 11 doses
(Reference). Group 2 received an experimental controlled-release formulation
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comprising 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride
with 240 mL of water after an overnight fast and again 12 hours later for 11
doses (Test)(PBO1-M65).
[0248] Blood (10 mL, sodium heparin anticoagulant) was obtained at the
following
times: Pre dose blood sample before the AM dose on Days 1, 4, 5 and 6. On Day
6 additional blood samples (5 mL, sodium heparin anticoagulant) were also
obtained at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours
after the
last dose (total blood loss for guaifenesin determination was 380 mL).
[0249] The subjects given 1200 mg guaifenesin, as Mucinex every 12 hours for
11
doses, reached a maximum steady-state plasma guaifenesin concentration of
1960 ng/mL at 0.81 hours after the last dose (120.81 hours after the first
dose).
The mean AUCSS was 7209 hr-ng/mL and the mean Cmin was 52 ng/mL.. Those
subjects given 1200 mg guaifenesin, as an experimental formulation every 12
hours for 11 doses, reached a maximum steady-state plasma guaifenesin
concentration of 1983 ng/mL (103% of the Reference formulation) at 0.96 hours
after the last dose (120.96 hours after the first dose, 100% of that of the
Reference formulation). The mean AUCSS was 8183 hr-ng/mL (114% of that of
the Reference formulation) and the mean Cm;n was 117 ng/mL.
[0250] At steady state, the subjects given 120 mg pseudoephedrine
hydrochloride,
as Sudafed 12 Hour, every 12 hours for 11 doses, reached a steady-state
maximum plasma pseudoephedrine concentration of 361 ng/mL at 4.89 hours
after the last dose (124.89 hours after the first dose). The mean AUCSS was
3528
hr-ng/mL and the mean Cmin was 182 ng/mL. Those subjects, when given the
120 mg pseudoephedrine hydrochloride as an experimental formulation, reached
a steady-state maximum plasma pseudoephedrine concentration of 365 ng/mL
(103% of that of the Reference) 4.10 hours after the last dose (124.10 hours
after
the first dose, 99.4% of that of the Reference). The mean AUCSS was 3550 hr-
ng/mL (102% of that of the Reference) and the mean Cm;,, was 173 ng/mL.
[0251] The mean plasma concentrations of guaifenesin are depicted in Figure
25.
The resulting pharmacokinetic data are shown in Tables 26 through 28. At
steady state, the subjects given 1200 mg guaifenesin every 12 hours, as
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Reference Mucinex for 11 doses, reached a steady-state maximum plasma
guaifenesin concentration of 1960 859 ng/mL (Mean Standard Deviation) in
0.81 hours 0.305 hour after the last dose (120.81 hours after the first
dose) and
the steady-state AUC (AUCSS) was 7209 3746 hr-ng/mL. At steady state, the
subjects given 1200 mg guaifenesin every 12 hours, as an experimental tablet
formulation for 11 doses, reached a steady-state maximum plasma guaifenesin
concentration of 1983 1019 ng/mL (103% 29.6% of the Reference Mucinex)
in 0.96 hours 0.645 hour after the last dose (120.96 hours after the first
dose,
100% 0.494%). The AUCSS was 8183 5141 hr-ng/mL (114% 27.0%).
Table 26. Guaifenesin Steady-State Pharmacokinetic Parameters Following the
Administration of 11 Doses of 1200 mg guaifenesin as Mucinex and 120 mg
Pseudoephedrine Hydrochloride as Sudafed 12 Hour to Normal Volunteers -
Treatment A (Reference)
Subject AUCss Cmin Cmax Tmax CAVERAGE
(hr-ng/mL) (ng/mL) (ng/mL) (hr) (ng/mL
Mean 7209 52.0 1960 120.81 604
Median 6554 28.3 1850 120.75 547
Standard 3746 48.1 859 0.305 311
Deviation
Standard 633 8.13 145 0.052 52.6
Error
% CV 52.0 92.5 43.8 0.253 51.5
Table 27. guaifenesin Steady-State Pharmacokinetic Parameters Following the
Administration of 11 Doses of 1200 mg guaifenesin and 120 mg Pseudoephedrine
Hydrochloride in an Experimental Formulation to Normal Volunteers - Treatment
B (Test)
Subject AUCss Cmin Cmax Tmax CAVERAGE
(hr-ng/mL) (ng/mL) (ng/mL) (hr) (ng/mL
Mean 8183 117 1983 120.96 686
Median 6769 100 1750 120.75 564
Standard 5141 87.2 1019 0.645 431
Deviation
Standard 869 14.7 172 0.109 72.8
Error
% CV 62.8 74.5 51.4 0.533 62.7
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Table 28. Ratio of Guaifenesin Steady-State Pharmacokinetic Parameters
Following the Administration of 11 Doses of 1200 mg Guaifenesin and 120 mg
Pseudoephedrine Hydrochloride in an Experimental Formulation Compared to
Reference Formulations to Normal Volunteers (%)
Subject AUCss Cmin Cmax Tmax CAVERAGE
Mean 114 550 103 100 114
Median 116 261 104 100 113
Standard 27.0 712 29.6 0.494 26.4
Deviation
Standard 4.57 120 5.01 0.084 4.46
Error
% CV 23.7 129 28.6 0.494 23.2
[0252] The mean plasma concentration of Pseudoephedrine are shown in Figure
26.
The resulting pharmacokinetic data are shown in Tables 29 through 31. At
steady state, the subjects given 120 mg pseudoephedrine hydrochloride, as
Sudafed0 12 Hour, every 12 hours for 11 doses, reached a steady-state
maximum plasma pseudoephedrine concentration of 361 77.7 ng/mL in 4.89
hours 2.14 hour after the last dose (124.89 hours after the first dose). The
AUCS, was 3528 862 hr-ng/mL. At steady state, the subjects given 120 mg
pseudoephedrine hydrochloride every 12 hours, as an experimental tablet
formulation for 11 doses, reached a steady-state maximum plasma
pseudoephedrine concentration of 365 83.3 ng/mL (103% 2 1.4% of the
Reference Sudafed 12-Hour) in 4.10 hours 1.85 hours after the last dose
(124.10 hours after the first dose, 99.4% 2.09%). The AUCSS was 3550 898
hr-ng/mL (102% 19.6%).
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Table 29. Pseudoephedrine Steady-State Pharmacokinetic Parameters Following
the Administration of 11 Doses of 120 mg Pseudoephedrine Hydrochloride as
Sudafed0 12 Hour and 1200 mg Guaifenesin as Mucinex to Normal Volunteers -
Treatment A (Reference)
Subject AUCss Cmin Cmax Tmax CAVERAGE
(hr-ng/mL) (ng/mL) (ng/mL) (hr) (ng/mL
Mean 3528 182 361 124.89 294
Median 3462 164 362 124.00 288
Standard 862 66.4 77.7 2.14 71.9
Deviation
Standard 146 11.2 13.1 0.361 12.1
Error
% CV 24.4 36.5 21.5 1.71 24.4
Table 30. Pseudoephedrine Steady-State Pharmacokinetic Parameters Following
the Administration of 11 Doses of 120 mg Pseudoephedrine Hydrochloride and
1200 mg Guaifenesin in an Experimental Formulation to Normal Volunteers -
Treatment B (Test)
Subject AUCSS Cmin Cmax Tmax CAVERAGE
(hr-ng/mL) (ng/mL) (ng/mL) (hr) (ng/mL
Mean 3550 173 365 124.10 296
Median 3399 170 350 124.00 283
Standard 898 55.2 83.3 1.85 74.8
Deviation
Standard 152 9.34 14.1 0.313 12.7
Error
% CV 25.3 32.0 22.8 1.49 25.3
Table 31. Ratio of Pseudoephedrine Steady-State Pharmacokinetic Parameters
Following the Administration of 11 Doses of 120 mg Pseudoephedrine
Hydrochloride and 1200 mg Guaifenesin in an Experimental Formulation
Compared to Reference Formulations to Normal Volunteers (%)
Subject AUCss Cmin Cmax Tmax CAVERAGE
Mean 102 100 103 99.4 102
Median 99.6 102 100 99.2 100
Standard 19.6 28.0 21.4 2.09 19.6
Deviation
Standard 3.31 4.73 3.62 0.354 3.31
Error
% CV 19.1 27.9 20.8 2.11 19.1
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[0253] In conclusion, the experimental tablet formulation was bioequivalent to
the
Reference formulations at steady state. The experimental formulation is
bioequivalent to the Reference formulations in terms of both Cmax and AUCSS
for
guaifenesin and pseudoephedrine hydrochloride.
Example 16
[0254] In another study drug interaction potential for combination drugs was
examined. The interaction potential for 1200 mg guaifenesin and 120 mg
Pseudoephedrine Hydrochloride was compared to reference in an open label,
single dose, randomized, 3-way crossover study using 36 subjects.
[0255] The subjects were randomized and placed into one of three treatment
groups.
group A received a 1200 mg controlled release guaifenesin product (Mucinex)
with 240 mL of room-temperature water after an overnight fast. Group B
received a 120 mg controlled release pseudoephedrine product (Sudafed 12
Hour) with 240 mL of room-temperature water after an overnight fast. Group C
received a 1200 mg guaifenesin product (Mucinex) and 120 mg pseudoephedrine
hydrochloride (Sudafed 12 Hour) with 240 mL of room-temperature water
after an overnight fast.
[0256] Blood (10 mL, sodium heparin anticoagulant) was obtained at the
following
times: Pre dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours
post
dose (the total blood loss for guaifenesin and pseudoephedrine analysis was-
450
mL).
[0257] Subjects given 1200 mg of guaifenesin as Mucinex (Treatment A,
Reference)
reached a Cmax of 2009 ng/mL in 0.89 hours and had an AUC;nf of 8138 hr-
ng/mL. Subjects given 1200 mg guaifenesin as Mucinex along with 120 mg
Pseudoephedrine hydrochloride as Sudafed 12 Hour (Treatment C, Test)
reached a Cmax of 1989 ng/mL (102% of that of the reference) in 0.84 hour
(104% of that of the reference) and had an AUC;nf of 8052 hr-ng/mL (100% of
that of the reference).
[0258] Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed 12 Hour
(Treatment B, Reference) reached a Cmax of 296 ng/mL in 6 hours and had an
AUC;nf of 4505 hr ng/mL. Subjects given 120 mg pseudoephedrine
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hydrochloride as Sudafed 12 Hour, along with 1200 mg guaifenesin as
Mucinex (Treatment C, Test) reached a C of 289 ng/mL (98% of that of the
reference) in 6 hours (101% of that of the reference) and had an AUCinf of
4396
hr-ng/mL (98% of that of the reference).
[0259] The plasma concentrations of guaifenesin are depicted in Figure 27. The
resulting pharmacokinetic data is shown in Tables 38 through 41. The maximum
plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex
(Treatment A, Reference) were 2009 819.2 ng/mL and occurred in 0.89 0.42
hours. The resulting area under the plasma concentration vs. time curve
(AUCinf
was 8138 3253 hr-ng/mL. The maximum plasma concentrations of guaifenesin
following a 1200 mg oral dose as Mucinex along with 120 mg pseudoephedrine
hydrochloride (Treatment C, Test) were 1989 863 ng/mL (102.33% 31.40%
of that of the reference formulation) and occurred in 0.84 0.31 hours
(103.94%
35.38% that of the reference formulation). The resulting AUCinf was 8052
3344 hr-ng/mL (100.06% 18.09% of that of the reference formulation).
Table 38. Guaifenesin Pharmacokinetic Parameters Following the Administration
of
1200 mg Guaifenesin to Normal Volunteers (Treatment A)
Subject Cmax Tmax AUC0_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
n /mL) n /mL)
Mean 2009 0.89 7921 8138 4.00 172.13
Median 1695 0.75 7063.8 7284.17 2.82 164.87
Standard 819.22 0.42 3196.53 3253.39 5.58 70.19
Deviation
Standard 138.47 0.07 540.31 549.92 0.94 11.87
Error
% CV 40.77 46.79 40.35 39.98 139.48 40.78
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Table 39. Guaifenesin Pharmacokinetic Parameters Following the Administration
of
1200 mg Guaifenesin Along with 120 mg Pseudoephedrine Hydrochloride to
Normal Volunteers (Treatment C)
Subject Cmax Tmax AUC0_t AUCiõ f Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 1989 0.84 7923 8052 3.41 175.45
Median 1770 0.75 6689 6745 3.33 177.93
Standard 863.36 0.31 3337 3344 1.72 71.07
Deviation
Standard 145.93 0.05 564.04 565.25 0.29 12.01
Error
% CV 43.41 36.37 42.12 41.53 50.56 40.51
Table 40. Ratio of Guaifenesin Pharmacokinetic Parameters Following the
Administration of 1200 mg Guaifenesin Along with 120 mg Pseudoephedrine
Hydrochloride Compared to 1200 mg Guaifenesin Alone to Normal Volunteers (%)
Subject Cmax Tmax AUCo_t AUCiõ f Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 102.33 103.94 100.87 100.06 128.38 103.47
Median 95.79 100 103.14 101.71 107.41 98.32
Standard 31.40 35.38 18.01 18.09 79.38 20.60
Deviation
Standard 5.31 5.98 3.05 3.06 13.42 3.48
Error
% CV 30.69 34.04 17.86 18.08 61.83 19.91
Table 41. Pseudoephedrine Pharmacokinetic Parameters Following the
Administration of 120 mg Pseudoephedrine Hydrochloride to Normal Volunteers
(Treatment B)
Subject Cmax Tmax AUCo_t AUCif Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 295.8 6.17 4024 4505 6.05 23.66
Median 297.5 6 3823 4430 5.81 22.20
Standard 73.25 1.92 1047 1250 1.44 7.24
Deviation
Standard 12.38 0.32 177 211 0.24 1.22
Error
% CV 24.76 31.13 26.02 27.75 23.83 30.60
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[0260] The plasma concentrations of pseudoephedrine are depicted in Figure 28.
The resulting pharmacokinetic data is shown in Tables 42 through 43. The
maximum plasma concentrations of pseudoephedrine following a 120 mg oral
dose as Sudafed 12 Hour (Treatment B, Reference) were 295.8 73.25 ng/mL
and occurred in 6.17 1.92 hours. The resulting AUCinf was 4505 1250 hr-
ng/mL. The maximum plasma concentrations of pseudoephedrine following a
120 mg oral dose as Sudafed 12 Hour along with 1200 mg guaifenesin as
Mucinex (Treatment C, Test) were 289.3 77.61 ng/mL (98.41% 12.77% of
that of the reference formulation) and occurred in 5.75 1.54 hours (100.74%
38.65% of that of the reference .formulation). The resulting AUC1f was 4396
1347 hr-ng/mL (98.40% 15.24% of that of the reference formulation).
Table 42. Pseudoephedrine Pharmacokinetic Following the Administration of 120
mg Pseudoephedrine Hydrochloride Along with 1200 mg guaifenesin to Normal
Volunteers (Treatment C)
Subject Cmax Tmax AUCo_t AUCiõ f Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 289.33 5.75 3925 4396 6.04 24.30
Median 286 6 3932 4247 5.63 23.16
Standard 77.61 1.54 1089 1347 1.38 6.95
Deviation
Standard 13.12 0.26 184 228 0.23 1.17
Error
% CV 26.82 26.74 27.75 30.65 22.79 28.60
Table 43. Ratio of Pseudoephedrine Pharmacokinetic Parameters Following the
Administration of 120 mg Along with 1200 mg Guaifenesin Hydrochloride
Compared to 120 mg Pseudoephedrine one to Normal Volunteers (%)
Subject Cmax Tmax AUC0_t AUCiõf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
n /mL) ng/mL)
Mean 98.41 100.74 98.22 98.40 103.30 103.99
Median 98.40 100 96.90 97.91 97.46 102.14
Standard 12.77 38.65 13.15 15.24 30.44 15.96
Deviation
Standard 2.16 6.53 2.22 2.58 5.14 2.70
Error
% CV 12.97 38.36 13.39 15.49 29.47 15.35
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[0261] In conclusion, the pharmacokinetics of guaifenesin and pseudoephedrine
hydrochloride are unaffected by the presence or absence of one another.
Example 17
[0262] In another experiment the effect of a high-fat on the bioavailability
of an of
the combination of 1200 mg guaifenesin and 120 mg Pseudoephedrine
Hydrochloride in normal healthy volunteers was again compared to reference
drug in an open-label, single-dose, randomized, 2-way- crossover study using
36
subjects.
[0263] The subjects were randomized and placed into one of two treatment
groups.
Each treatment group was fasted overnight. Treatment A received an
experimental formulation containing 1200 mg guaifenesin and 120 mg
pseudoephedrine hydrochloride with 240 mL of water (Reference). Treatment B
received an experimental controlled-release formulation containing 1200 mg
guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water,
30 minutes after the beginning of the consumption of a high-fat breakfast
(Test).
[02641 Blood (10 mL, sodium heparin anticoagulant) was obtained at the
following
times: Pre dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours
post
dose (the total blood loss for guaifenesin and pseudoephedrine analysis was
300
mL). Subjects given 1200 mg of guaifenesin and 120 mg pseudoephedrine
hydrochloride as an experimental formulation following an overnight fast
(Treatment A, Reference) reached a plasma guaifenesin Cmax of 1857 ng/mL in
1.06 hours and had an AUCinf of 8142 hr-ng/mL. Subjects given 1200 mg
guaifenesin and 120 mg pseudoephedrine hydrochloride as an experimental
formulation after the consumption of a high-fat meal (Treatment B, Test)
reached a plasma guaifenesin Cmax of 1364 ng/mL (79.3% of that of the
Reference) in 2.06 hour (238% of that of the Reference) and had an AUCinf of
7469 hr-ng/mL (94.1% of that of the Reference).
[0265] Subjects given 120 mg pseudoephedrine hydrochloride as an experimental
formulation after an overnight fast (Treatment A, Reference) reached a plasma
pseudoephedrine Cmax of 283 ng/mL in 4.6 hours and had an AUCinf of 3746 hr-
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ng/mL. Subjects given 120 mg pseudoephedrine hydrochloride as an
experimental formulation following the consumption of a high-fat meal
(Treatment B, Test) reached a plasma pseudoephedrine Cmax of 301 ng/mL
(108% of that of the Reference) in 5.77 hours (137% of that of the Reference)
and had an AUCInf of 3660 hr-ng/mL (99% of that of the Reference).
[0266] The plasma concentrations of guaifenesin are depicted in Figure 29. The
resulting pharmacokinetic data are shown in Tables 44 through 46. The
maximum plasma concentrations of guaifenesin following 1200 mg guaifenesin
and 120 mg pseudoephedrine hydrochloride after an overnight fast were 1857
838 ng/mL (Mean Standard Deviation) and occurred in 1.06 0.582 hours.
The resulting area under the plasma concentration vs. time curve (AUCjnf was
8142 3500 hr-ng/mL. The maximum plasma concentrations of guaifenesin,
following 1200 mg oral guaifenesin and 120 mg pseudoephedrine hydrochloride
as an experimental formulation following the consumption of a high-fat meal
(Treatment B, Test), were 1364 691 ng/mL (79.3% 34.7% of that of the
Reference formulation) and occurred in 2.06 1.16 hours (23 8% 157% that of
the Reference formulation). The resulting AUCinf was 7469 3217 hr-ng/mL
(94.1 % 23.1 % of that of the Reference formulation).
Table 44. Guaifenesin Pharmacokinetic Parameters Following the Administration
of
1200 mg Guaifenesin and 120 mg Pseudoephedrine Hydrochloride in an
Experimental Formulation to Normal Volunteers After an Overnight Fast
(Treatment
A, Reference)
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 1857 1.06 8091 8142 1.82 18.0
Median 1830 0.750 8228 8244 1.68 14.6
Standard 838 0.582 3501 3500 0.702 8.46
Deviation
Standard 144 0.100 600 600 0.120 1.45
Error
% CV 45 55.0 43.3 43.0 38.6 47.0
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Table 45. Guaifenesin Pharmacokinetic Parameters Following the Administration
of
1200 mg Guaifenesin and 120 mg Pseudoephedrine Hydrochloride in an
Experimental Formulation to Normal Volunteers After the Consumption of a High-
Fat Meal (Treatment B, Test)
Subject Cmax Tmax AUC0_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 1364 2.06 7403 7469 1.39 18.9
Median 1190 2.00 6842 6857 1.12 17.5
Standard 691 1.16 3185 3217 0.833 7.80
Deviation
Standard 119 0.200 546 552 0.143 1.34
Error
% CV 50.7 56.6 43.0 43.1 60.0 41.2
Table 46. Ratio of Guaifenesin Pharmacokinetic Parameters Following the
Administration of 1200 mg Guaifenesin and 120 mg Pseudoephedrine
Hydrochloride in an Experimental Formulation Following the Consumption of a
High-Fat Meal (Treatment B, Test) Compared to that After an Overnight Fast
(Treatment A, Reference) to Normal Volunteers (%)
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
n /mL) ng/mL)
Mean 79.3 238 94.0 94.1 87.2 112
Median 71.4 200 89.7 89.6 68.1 112
Standard 34.7 157 23.4 23.1 53.2 24.5
Deviation
Standard 6.04 27.4 4.07 4.02 9.27 4.26
Error
% CV 43.8 66.1 24.8 24.6 61.1 21.9
[0267] The plasma concentrations of pseudoephedrine are depicted in Figure 45.
The resulting pharmacokinetic data are shown in Tables 47 through 49. The
maximum plasma concentrations of pseudoephedrine following a 120 mg
pseudoephedrine hydrochloride and 1200 mg guaifenesin, in an experimental
formulation after an overnight fast (Treatment A, Reference), were 283 79.6
ng/mL and occurred in 4.60 1.56 hours. The resulting AUCinf was 3746 997
hr-ng/mL. The maximum plasma concentrations of pseudoephedrine following
120 mg pseudoephedrine hydrochloride and 1200 mg guaifenesin, in an
experimental formulation following the consumption of a high-fat meal
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(Treatment B, Test), were 301 80.4 ng/mL (108% 18.5% of that of the
Reference formulation) and occurred in 5.77 1.78 hours (137% 6 1.9% of
that of the Reference formulation). The resulting AUCinf was 3660 963 hr-
ng/mL (99.0% 20.1 % of that of the Reference formulation).
Table 47. Pseudoephedrine Pharmacokinetic Parameters Following the
Administration of 120 mg of Pseudoephedrine Hydrochloride and 1200 Guaifenesin
in an Experimental Formulation to Normal Volunteers After an Overnight Fast
(Treatment A, Reference)
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 283 4.60 3477 3746 5.01 28.2
Median 266 4.00 3374 3552 4.94 27.7
Standard 79.6 1.56 884 997 1.06 8.03
Deviation
Standard 13.7 0.267 152 171 0.182 1.38
Error
% CV 28.2 33.8 25.4 26.6 21.2 28.5
Table 48. Pseudoephedrine Pharmacokinetic Parameters Following the
Administration of 120 mg of Pseudoephedrine Hydrochloride and 1200 mg
guaifenesin in an Experimental Formulation to Normal Volunteers After
Consumption of a High-Fat Meal (Treatment B, Test)
Subject Cmax Tmax AUCo_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 301 5.77 3403 3660 4.64 28.8
Median 292 6.00 3152 3455 4.45 28.5
Standard 80.4 1.78 915 963 1.05 7.91
Deviation
Standard 13.8 0.306 157 165 0.180 1.36
Error
% CV 26.7 30.9 26.9 26.3 22.6 27.5
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Table 49. Ratio of Pseudoephedrine Pharmacokinetic Parameters Following the
Administration of 120 mg Pseudoephedrine Hydrochloride and 1200 mg guaifenesin
in an Experimental Formulation After the Consumption of a High-Fat Meal
(Treatment B, Test) Compared to that After an Overnight Fast (Treatment A,
Reference) to Normal Volunteers (%)
Subject Cmax Tmax AUC0_t AUCinf Half-life Clearance
(ng/mL) (hr) (hr- (hr- (hr) (L/hr)
ng/mL) ng/mL)
Mean 108 137 98.9 99.0 93.7 105
Median 109 133 96.9 95.9 88.4 104
Standard 18.5 61.9 20.8 20.1 17.1 20.2
Deviation
Standard 3.22 10.8 3.62 3.50 2.97 3.52
Error
% CV 17.1 45.2 21.0 20.3 18.2 19.3
[0268] The rate of absorption of guaifenesin from the experimental
formulation, as
assessed by Cmax is not bioequivalent to the Test formulation in the presence
of a
high-fat meal. The extent of absorption of guaifenesin from the experimental
tablet, as assessed by AUCiõf, is equivalent to the Test formulation in the
presence of a high-fat meal.
[0269] The rate and extent of pseudoephedrine absorption from the experimental
formulation was bioequivalent to the Reference formulation in the presence of
a
high-fat meal.
[0270] In conclusion, the rate of guaifenesin absorption from the experimental
formulation is not bioequivalent to the Reference formulation; whereas the
extent of guaifenesin absorption is bioequivalent to the Reference formulation
in
the presence of a high-fat meal. The rate and extent of pseudoephedrine
absorption from the experimental formulation are bioequivalent to the
Reference
formulation in the presence of a high-fat meal.
Example 18
[0271] In another experiment the relative bioavailability of guaifenesin and
dextromethorphan from an experimental modified release formulation containing
both guaifenesin and dextromethorphan was compared to reference guaifenesin
and dextromethorphan products in normal volunteers was determined in a 36
subject open-label, randomized, 4-way crossover study.
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[0272] The subjects were randomized and placed into one of four treatment
groups.
Group 1 received an experimental combination tablet containing 1200 mg of
controlled-release guaifenesin and 60 mg of controlled-release
dextromethorphan hydrobromide (Treatment A) with 240 mL of water, after an
overnight fast. Group 2 received a reference controlled-release tablet
containing
1200 mg guaifenesin (Mucinex, Treatment B) with 240 mL of water, after an
overnight fast. Group 3 received 60 mg of dextromethorphan hydrobromide in a
reference immediate-release liquid formulation according to 2 different dosing
regimes (one half of the volunteers received 30 mg of dextromethorphan and a
second 30 mg dose 6 hours later [Treatment C], while the other half received
20
mg dextromethorphan every 4 hours for three doses [Treatment D]) with 240 mL
of water, after an overnight fast. Group 4 received 30 mg of dextromethorphan
hydrobromide in a reference immediate-release liquid formulation according to
2
different dosing regimes (one half of the volunteers received 15 mg of
dextromethorphan and a second 15 mg dose 6 hours later [Treatment E], while
the other half received 10 mg dextromethorphan every 4 hours for three doses
[Treatment F]) with 240 mL of water, after an overnight fast. Those subjects
that received 30 mg dextromethorphan hydrobromide in one treatment period
received 15 mg dextromethorphan in another treatment period; similarly, those
that received 20 mg dextromethorphan in one treatment period received 10 mg
dextromethorphan in a subsequent treatment period. In this experiment there
was a 14-day washout between doses.
[0273] Blood (7 mL, sodium heparin anticoagulant) was obtained at the
following
times: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14,
16, 24, 36,
48, 72 and 96 hours post dose (the total blood loss for guaifenesin and
dextromethorphan analysis was to be 644 mL).
[0274] Subjects given 1200 mg of guaifenesin as Mucinex (reference, Treatment
B)
reached a mean Ca, of 2145 ng/mL in 0.9 hours and had a mean AUCinf of 8953
hr-ng/mL. Subjects given 1200 mg guaifenesin as an experimental formulation,
also containing 60 mg dextromethorphan hydrobromide (Treatment A), reached
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a mean guaifenesin Cmax of 2176 ng/mL in 1.4 hours and had a mean AUCiõf of
8766 hr-ng/mL.
[0275] Subjects given 60 mg dextromethorphan hydrobromide along with 1200 mg
guaifenesin in an experimental formulation (Treatment A) reached a mean
dextromethorphan Cmax of 4834 pg/mL in 5 hours and had a mean AUCiaf of
68851 hr-pg/mL. Subjects given 60 mg dextromethorphan hydrobromide as 30
mg every 6 hours (Treatment C) reached a mean dextromethorphan Cmax of 4711
pg/mL in 8.3 hours and had a mean AUC;,,f of 82655 hr-pg/mL. Subjects given
60 mg dextromethorphan hydrobromide as 20 mg every 4 hours (Treatment D)
reached a mean dextromethorphan Cmax of 3344 pg/mL in 7 hours and had a
mean AUCiõf of 44683 hr-pg/mL. Subjects given 30 mg dextromethorphan
hydrobromide as 15 mg every 6 hours (Treatment E) reached a mean
dextromethorphan Cmax of 2180 pg/mL in 8 hours and had a mean AUCiõ f of
40324 hr-pg/mL. Subjects given 30 mg dextromethorphan hydrobromide as 10
mg every 4 hours (Treatment F) reached a mean dextromethorphan Cmax of 1286
pg/mL in 7.7 hours and had a mean AUC1õf of 20114 hr-pg/mL.
[0276] The plasma concentrations of guaifenesin is shown in Figure 33. The
resulting pharmacokinetic data is shown in Tables 50 through 52. Subjects
given 1200 mg of guaifenesin as Mucinex (Treatment B) reached a mean Cmax of
2145 997 ng/mL (Mean Standard Deviation) in 0.91 0.5 hours and had an
AUCiõ f of 8953 4272 hr-ng/mL. Subjects given 1200 mg guaifenesin as an
experimental formulation also containing 60 mg dextromethorphan (Treatment
A) reached a mean guaifenesin Cr,,,,, of 2176 1320 ng/mL (101.36% 29.88%
of that of Mucinex) in 1.44 0.67 hour (178.57% 82.70% of that of Mucinex)
and had an AUCiõ f of 8761 4755 hr-ng/mL (99.57% 24.27% of that of
Mucinex). These data indicate that the pharmacokinetics of guaifenesin are not
affected by the presence of dextromethorphan.
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Table 50 Guaifenesin Pharmacokinetic Parameters Following the Administration
of 1200 mg
Guaifenesin
along with 60 mg Dextromethor han Hydrobromide to Normal Volunteers -
Treatment A
Subject Cmax Tmax AUCo, AUC;,,f Half Life Clearance
(ng/mL) (hr) (hr n /mL) (hr*ng/mL) (hr) (L/hr)
Mean 2176 1.44 8732 8761 1.31 179
Median 1830 1.50 7579 7734 1.08 155
Standard
Deviation 1320 0.67 4761 4755 1.12 93.93
Standard
Error 237.15 0.12 855 854 0.20 16.87
%CV 60.67 46.88 54.52 54.27 85.67 52.59
Table 51 Guaifenesin Pharmacokinetic Parameters Following the Administration
of 1200 mg
Guaifenesin alone to Normal Volunteers - Treatment B
Subject Cmax Tmax AUC0_t AUC11 f Half Life Clearance
(ng/mL) (hr) (hrl*ng/mL) (hr*ng/mL) (hr) (L/hr)
Mean 2145 0.91 8657 8953 4.79 171
Median 1915 0.75 8346 8826 3.03 136
Standard
Deviation 997 0.50 4268 4272 4.85 94.28
Standard
Error 179 0.09 766 767 0.87 16.93
%CV 46.49 54.97 49.29 47.71 101.41 55.17
Table 52 Ratio of the Guaifenesin Pharmacokinetic Parameters Following the
Administration of
1200 mg Guaifenesin in an Experimental Tablet along with 60 mg
Dextromethorphan
Hydrobromide Com ared to Guaifenesin Alone (%)
Subject Cmax Tmax AUC0_t AUC17 f Half Life Clearance
Mean 101.36 178.57 102.78 99.57 47.71 106.07
Median 100.00 200.00 98.64 95.57 34.50 104.64
Standard
Deviation 29.88 82.70 23.27 24.27 39.04 25.35
Standard
Error 5.46 15.10 4.25 4.43 7.13 4.63
%CV 29.48 46.31 22.64 24.37 81.83 23.90
[0277] The plasma concentrations of dextromethorphan is shown in Figure 34.
The
resulting pharmacokinetic data is shown in Tables 53 through 61. Subjects
given 60 mg dextromethorphan hydrobromide as an experimental formulation
also containing 1200 mg guaifenesin (Treatment A) reached a mean
dextromethorphan Cmax of 4834 6182 pg/mL in 5.06 0.93 hours and had an
AUC;,,f of 68851 112906 hr-pg/mL. Subjects given 60 mg dextromethorphan
hydrobromide as 30 mg every 6 hours (Treatment C) reached a mean
dextromethorphan Cmax of 4711 6124 pg/mL (141.85% 82.73% of that of the
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experimental tablet, Treatment A) in 8.31 1.58 hours (62.07% 23.12% of
that of Treatment A) and had an AUCinf of 82655 123509 hr-pg/mL (108%
44.44% of that of Treatment A). Subjects given 60 mg dextromethorphan
hydrobromide as 20 mg every 4 hours (Treatment D) reached a mean
dextromethorphan Cmax of 3130 2355 pg/mL (100.31% 37.06% of that of the
reference) in 7.01 1.93 hours (80.02% 22.83% of that of Treatment A) and
had an AUCinf of 44683 37119 hr-pg/mL (82.77% 22.93% of that of
Treatment A). These results indicate that the tablet is not bioequivalent to
either
dextromethorphan dosing regimen, but is equivalent to the range generated by
these two dosing regimens. These data also indicate that the pharmacokinetics
of dextromethorphan are not affected by the presence of guaifenesin.
[0278] Subjects given 30 mg dextromethorphan hydrobromide as 15 mg every 6
hours (Treatment E) reached a mean dextromethorphan Cmax of 2180 2650
pg/mL (53.89% 17.62% of that of Treatment C) in 8.03 2.52 hours (96.08%
24.88% of that of Treatment C) and had an AUCinf of 40324 62644 hr-
pg/mL (5 1.73% 16.77% of that of Treatment Q. Subjects given 30 mg
dextromethorphan hydrobromide as 10 mg every 4 hours (Treatment F) reached
a mean dextromethorphan Cmax of 1286 903 pg/mL (53.41% 12.82% of that
of Treatment D) in 7.73 2.43 hours (142.42% 67.86% of that of Treatment
D) and had an AUCinf of 6945 16158 hr-pg/mL (54.32% 16.37% of that of
Treatment D). These data suggest that the pharmacokinetics of
dextromethorphan are linear over the range studied.
Table 53 Dextromethorphan Pharmacokinetic Parameters Following the
Administration of an
Experimental Tablet Formulation Containing 60 mg Dextromethorphan Hydrobromide
and 1200 mg
Guaifenesin to Normal Volunteers - Treatment A
Subject Cmax Tmax AUCo_, AUC11f Half Life Clearance
(pg/ -) (hr) (hr*pg/mL) (hr*pg/mL) (hr) LL/hr)
Mean 4834 5.06 68189 68851 7.73 1697
Median 2550 5.00 27821 28088 6.94 1088
Standard
Deviation 6182 0.929 112242 112906 1.78 1585
Standard
Error 1129 0.170 20493 20614 0.33 289
%CV 127.88 18.34 164.61 163.99 23.04 93.39
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Table 54 Dextromethorphan Pharmacokinetic Parameters Following the
Administration of 60 mg
Dextromethorphan Hydrobromide as Two Doses of 30 mg Six Hours Apart to Normal
Volunteers -
Treatment C
Subject Cmax Tmax AUCo_, AUC;,,f Half Life Clearance
(pg/mL) (hr) (hr*pg/mL) (hrk g/mL) (hr) (L/hr)
Mean 4711 8.31 82279 82655 7.46 1291
Median 1665 8.50 23483 23860 6.76 999
Standard
Deviation 6124 1.58 123157 123509 1.94 1078
Standard
Error 1581 0.41 31799 31890 0.50 278
%CV 129.99 19.01 149.68 149.43 25.97 83.45
Table 55 Dextromethorphan Pharmacokinetic Parameters Following the
Administration of 60 mg
Dextromethorphan Hydrobromide as Three Doses of 20 mg Four Hours Apart to
Normal Volunteers -
Treatment D
Subject Cmax Tmax AUCo_, AUC;,,f Half Life Clearance
(P /mL) (hr) (hr*Pg/mL) (hr*pg/mL) (hr) (L/hr)
Mean 3130 7.01 44287 44683 7.04 1335
Median 2720 6.00 26142 26321 6.60 1124
Standard
Deviation 2355 1.93 36759 37119 1.57 1098
Standard
Error 630 0.515 9824 9920 0.44 293
%CV 75.26 27.50 83.00 83.07 22.32 82.26
Table 56 Dextromethorphan Pharmacokinetic Parameters Following the
Administration of 30 mg
Dextromethorphan Hydrobromide as Two Doses of 15 mg Six Hours Apart to Normal
Volunteers -
Treatment E
Subject Cmax Tmax AUCo_t AUC;,,f Half Life Clearance
(Pg/mL) (hr) (hr*pg/mL) (hr*pg/mL) (hr) (L/h)
Mean 2180 8.03 39746 40324 7.32 2940
Median 1180 9.00 16061 16226 6.48 2735
Standard
Deviation 2650 2.52 61502 62644 2.28 2234
Standard
Error 684 0.65 15880 16175 0.59 577
%CV 121.59 31.37 154.74 155.35 31.13 75.98
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Table 57 Dextromethorphan Pharmacokinetic Parameters Following the
Administration of 30 mg
Dextromethorphan Hydrobromide as Three Doses of 10 mg Four Hours Apart to
Normal Volunteers -
Treatment F
Subject Cmax Tmax AUCo-t AUCinf Half Life Clearance
(g/mL) (hr) (hr*pg/mL) (hr*pg/mL) (hr) (L/hr)
Mean 1286 7.73 19833 20114 7.44 3894
Median 795 6.00 12940 13170 6.95 2860
Standard
Deviation 903 2.43 16162 16158 2.02 3274
Standard
Error 241 0.650 4319 4318 0.54 875
%CV 70.19 31.47 81.49 80.33 27.18 84.09
Table 58 Ratio of Dextromethorphan Pharmacokinetic Parameters Following the
Administration of
60 mg Dextromethorphan Hydrobromide as Treatment A Compared to Two Doses of 30
mg Six
Hours Apart (Treatment C) in Normal Volunteers %
Subject Cmax Tmax AUCo-t AUCinf Half Life Clearance
Mean 141.85 62.07 106.81 108.00 107.71 122.40
Median 121.79 59.03 95.92 96.02 108.89 107.97
Standard
Deviation 82.73 23.12 43.92 44.44 9.65 60.31
Standard
Error 21.36 5.97 11.34 11.47 2.49 15.57
%CV 58.32 37.25 41.12 41.15 8.96 49.28
Table 59 Ratio of Dextromethorphan Pharmacokinetic Parameters Following the
Administration of
60 mg Dextromethorphan Hydrobromide as Treatment A Compared to Three Doses of
20 mg Four
Hours Apart (Treatment D) in Normal Volunteers %
Subject Cmax Tmax AUCo-t AUCinf Half Life Clearance
Mean 100.31 80.02 83.01 82.77 107.26 164.60
Median 94.35 83.33 77.49 77.84 101.62 158.65
Standard
Deviation 37.06 22.83 23.39 22.93 16.71 88.09
Standard
Error 10.70 6.59 6.75 6.62 4.82 25.43
%CV 36.94 28.53 28.18 27.71 15.57 53.52
Table 60 Ratio of Dextromethorphan Pharmacokinetic Parameters Following the
Administration of
30 mg Dextromethorphan Hydrobromide as Two Doses of 15 mg Six Hours Apart
(Treatment E)
Compared to 60 mg Dextromethorphan Hydrobromide as Two Doses of 30 mg Six
Hours Apart
(Treatment C) (%)
Subject Cmax Tmax AUCo-t AUCinf Half Life Clearance
Mean 53.89 96.08 51.35 51.73 98.33 278.94
Median 57.20 100.00 50.70 50.64 103.29 214.90
Standard
Deviation 17.62 24.88 16.64 16.77 14.88 172.08
Standard
Error 4.55 6.42 4.30 4.33 3.84 44.43
%CV 32.70 25.89 32.40 32.42 15.14 61.69
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Table 61 Ratio of Dextromethorphan Pharmacokinetic Parameters Following the
Administration of
30 mg Dextromethorphan Hydrobromide as Three Doses of 10 mg Four Hours Apart
(Treatment F)
Compared to 60 mg Dextromethorphan Hydrobromide as Three Doses of 20 mg Four
Hours Apart
(Treatment D) (%)
Subject Cmax Tmax AUCa, AUC;,,f Half Life Clearance
Mean 53.41 142.42 54.28 54.32 103.46 313.85
Median 56.73 166.67 52.75 52.23 89.13 255.28
Standard
Deviation 12.82 67.86 16.26 16.37 35.81 143.22
Standard
Error 6.41 33.93 8.13 8.19 17.91 71.61
%CV 24.00 47.65 29.95 30.14 34.62 45.63
[0279] In conclusion, the pharmacokinetics of guaifenesin and dextromethorphan
are not affected by the presence of the other component and the
pharmacokinetics of dextromethorphan are linear over the range studied.
Example 19
[0280] In another experiment the relative bioavailability of guaifenesin and
dextromethorphan from an experimental modified release formulation,
containing both guaifenesin and dextromethorphan was compared to reference
guaifenesin and dextromethorphan was determined in normal volunteers in a 36
subject open-label, single-dose, randomized, 3-way-crossover study.
[02811 The subjects were randomized and placed into one of three treatment
groups.
Group 1 received a 1200-mg controlled-release guaifenesin product (Mucinex)
plus 60 mg of dextromethorphan hydrobromide (administered as 30 mg every 6
hours), with 240 mL of water after an overnight fast (Reference). Group 2
received a 1200-mg controlled-release guaifenesin product (Mucinex) plus 60
mg of dextromethorphan hydrobromide (administered as 20 mg every 4 hours),
with 240 mL of water after an overnight fast (Reference). Group 3 received an
experimental controlled-release tablet containing 1200 mg guaifenesin and 60
mg of dextromethorphan hydrobromide, with 240 mL of water after an overnight
fast (Test). In this experiment there was a 14-day washout between doses.
[0282] Blood (7 mL sodium heparin anticoagulant) was obtained at the following
times: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 4.5, 4.75, 5, 5.5, 6, 6.5, 6.75,
7, 7.5, 8,
9, 10, 11, 12, 14, 16, 24, 36, 48, 72 and 96 hours post dose (the total blood
loss
for guaifenesin and dextromethorphan analysis was 609 mL). Subjects given
1200 mg of guaifenesin as Mucinex, along with 60 mg dextromethorphan
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hydrobromide as two 30-mg doses 6 hours apart (Treatment A, Reference),
reached a mean plasma guaifenesin Cmax of 1743 ng/mL in 1.25 hours and had
an AUCinf, of 7836 hr-ng/mL. Subjects given 1200 mg of guaifenesin as
Mucinex, along with 60 mg dextromethorphan hydrobromide as three 20-mg
doses 4 hours apart (Treatment B, Reference), reached a mean plasma
guaifenesin Cmax of 1783 ng/mL in 1.27 hours and had an AUCinf of 7616 hr-
ng/mL. Subjects given 1200 mg guaifenesin as an experimental formulation,
also containing 60 mg dextromethorphan hydrobromide (Treatment C, Test),
reached a mean plasma guaifenesin Cmax of 1710 ng/mL in 1.55 hour and had an
AUCinf of 7102 hr-ng/mL.
[0283] Subjects given 1200 mg guaifenesin as Mucinex, along with 60 mg
dextromethorphan hydrobromide as 30 mg Vick's Formula 44 Cough Medicine
and a second 30-mg dextromethorphan hydrobromide dose 6 hours later
(Treatment A, Reference), reached a mean plasma dextromethorphan Cmax of
7946 pg/mL in 8.32 hours and had an AUCinf of 294267 hr-pg/mL. Subjects
given 1200 mg guaifenesin as Mucinex, along with 60 mg dextromethorphan
hydrobromide as 20 mg Vick's Formula 44 Cough Medicine, a second 20-mg
dextromethorphan hydrobromide dose 4 hours later and a third 20-mg
dextromethorphan hydrobromide dose 4 hours after that (Treatment B,
Reference), reached a mean plasma dextromethorphan C,,,ax of 8598 pg/mL in
8.90 hours and had an AUCinf of 339447 hr-pg/mL. Subjects given 1200 mg
guaifenesin along with 60 mg dextromethorphan hydrobromide in an
experimental formulation (Treatment C, Test), reached a mean plasma
dextromethorphan Cmax of 7483 pg/mL in 6.30 hours and had an AUCinf of
316592 hr-pg/mL.
[0284] The plasma concentrations of guaifenesin are shown in Figure 35. The
resulting pharmacokinetic data are shown in Tables 62 through 64. Subjects
given 1200 mg of guaifenesin as Mucinex, along with 60 mg dextromethorphan
hydrobromide as two 30-mg doses 6 hours apart (Treatment A, Reference),
reached a mean plasma guaifenesin Cmax of 1743 903 ng/mL (Mean Standard
Deviation) in 1.25 0.660 hours and had an AUCinf of 7836 3616 hr-ng/mL.
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Subjects given 1200 mg of guaifenesin as Mucinex, along with 60 mg
dextromethorphan hydrobromide as three 20-mg doses 4 hours apart (Treatment
B, Reference), reached a mean plasma guaifenesin Cmax of 1783 808 ng/mL in
1.27 0.833 hours and had an AUCiõ f of 7616 3398 hr-ng/mL. Subjects given
1200 mg guaifenesin as an experimental formulation, also containing 60 mg
dextromethorphan hydrobromide (Treatment C, Test), reached a mean plasma
guaifenesin Cn, of 1710 807 ng/mL in 1.55 0.789 hour and had an AUCinf
of 7102 2807 hr-ng/mL.
Table 62 Guaifenesin Pharmacokinetic Parameters Following the Administration
of 1200 mg
Guaifenesin
as Mucinex along with 60 mg Dextromethorphan Hydrobromide as 30 mg Vick's
Formula 44 Cough Medicine and a Second 30-mg Dextromethorphan Hydrobromide
Dose 6 Hours
Later to Normal Volunteers - Treatment A (Reference)
Subject Cmax Tmax AUCo_t AUGnf Half Life Clearance
(n /mL) (hr) (hr*ng/mL) (hr*ng/mL) (hr) (L/hr)
Mean 1743 1.25 7730 7836 2.60 192
Median 1545 1.00 6854 6956 2.27 173
Standard 903 0.660 3578 3616 1.37 109
Deviation
Standard 147 0.107 580 587 0.221 17.7
Error
% CV 51.8 52.7 46.3 46.1 52.4 57.0
Table 63 Guaifenesin Pharmacokinetic Parameters Following the Administration
of 1200 mg
Guaifenesin
as Mucinex along with 60 mg Dextromethorphan Hydrobromide as 20 mg Vick's
Formula 44 Cough Medicine, a Second 20-mg Dextromethorphan Hydrobromide Dose 4
Hours
Later and a Third 20-mg Dextromethorphan Hydrobromide Dose 4 hours After That
to
Normal Volunteers - Treatment B (Reference)
Subject Cmax Tmax AUCo_t AUC;,,f Half Life Clearance
(ng/mL) (hr) (hr*ng/mL) (hr*ng/mL) (hr) (L/hr)
Mean 1783 1.27 7477 7616 3.19 191
Median 1615 1.00 6948 7268 2.77 165
Standard 808 0.833 3369 3398 1.81 90.1
Deviation
Standard 137 0.141 570 574 0.307 15.2
Error
% CV 45.3 65.5 45.1 44.6 56.9 47.2
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Table 64 Guaifenesin Pharmacokinetic Parameters Following the Administration
of 1200 mg
Guaifenesin
along with 60 mg Dextromethorphan Hydrobromide in an Experimental Formulation
to
Normal Volunteers - Treatment C (Test)
Subject Cmax Tmax AUCo_t AUC;nf Half Life Clearance
(ng/mL) (hr) (hr*n /niL) (hr*ng/mL) (hr) (L/hr)
Mean 1710 1.55 7082 7102 1.24 201
Median 1525 1.50 6847 6899 1.05 174
Standard 807 0.789 2805 2807 0.501 100
Deviation
Standard 141 0.137 488 489 0.087 17.4
Error
% CV 47.2 51.0 39.6 39.5 40.5 49.8
[0285] The plasma concentrations of dextromethorphan are shown in Figure 36.
The resulting pharmacokinetic data are shown in Tables 65 through 67. Subjects
given 1200 mg guaifenesin as Mucinex, along with 60 mg dextromethorphan
hydrobromide as 30 mg Vick's Formula 44 Cough Medicine and a second 30-
mg dextromethorphan hydrobromide dose 6 hours later (Treatment A,
Reference), reached a mean plasma dextromethorphan Cmax of 7946 12386
pg/mL in 8.32 2.88 hours and had an AUCinf of 294267 724235 hr-pg/mL.
Subjects given 1200 mg guaifenesin as Mucinex, along with 60 mg
dextromethorphan hydrobromide as 20 mg Vick's Formula 44 Cough Medicine,
a second 20-mg dextromethorphan hydrobromide dose 4 hours later and a third
20-mg dextromethorphan hydrobromide dose 4 hours after that (Treatment B,
Reference), reached a mean plasma dextromethorphan Cmax of 8598 13559
pg/mL in 8.90 3.62 hours and had an AUCinf of 339447 850232 hr-pg/mL.
Subjects given 60 mg dextromethorphan hydrobromide, along with 1200 mg
guaifenesin in an experimental formulation (Treatment C, Test), reached a mean
plasma dextromethorphan Cmax of 7483 12332 pg/mL in 6.30 2.64 hours and
had an AUCinf of 316592 796975 hr-pg/mL.
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Table 65 Dextromethorphan Pharmacokinetic Parameters Following the
Administration of 1200 mg
Guaifenesin
as Mucinex Along with 60 mg Dextromethorphan Hydrobromide as 30 mg Vick's
Formula 44 Cough Medicine and a Second 30-mg Dextromethorphan Hydrobromide
Dose 6 Hours
Later to Normal Volunteers - Treatment A (Reference)
Subject Cmax Tmax AUC0_t AUC;,,f Half Life Clearance
(g/mL) (hr) (hr*p /mL) (hr*pg/mL) (hr) (L/hr)
Mean 7946 8.32 248123 294267 10.9 2044
Median 2375 8.00 31290 31544 7.57 1394
Standard 12386 2.88 575122 724235 9.42 2153
Deviation
Standard 2009 0.468 93297 117486 1.53 349
Error
% CV 156 34.7 232 246 86.2 105
Table 66 Dextromethorphan Pharmacokinetic Parameters Following the
Administration of 1200 mg
Guaifenesin
as Mucinex along with 60 mg Dextromethorphan Hydrobromide as 20 mg Vick's
Formula 44 Cough Medicine and a Second 20-mg Dextromethorphan Hydrobromide
Dose 4 Hours
Later and a Third 20-mg Dextromethorphan Hydrobromide Dose 4 Hours After That
to Normal
Volunteers - Treatment B (Reference)
Subject Cmax Tmax AUCo_t AUC;,,f Half Life Clearance
(p /mL) (hr) (hr*pg/ ) (hr*pg/mL) (hr) (Lmr)
Mean 8598 8.90 271074 339447 11.3 1920
Median 2470 7.75 31698 31978 7.11 1374
Standard 13559 3.62 641451 850232 11.4 1655
Deviation
Standard 2292 0.612 108425 143715 1.93 280
Error
% CV 158 40.7 237 250 101 86.2
Table 67 Dextromethorphan Pharmacokinetic Parameters Following the
Administration of 1200 mg
Guaifenesin
and 60 mg Dextromethorphan Hydrobromide in an Experimental Formulation to
Normal
Volunteers - Treatment C (Test)
Subject Cmax Tmax AUCo_t AUC;,,f Half Life Clearance
(pg/mL) (hr) (hr*pg/mL) (hr*p /mL) (hr) (L/hr)
Mean 7483 6.30 253196 316592 12.6 2756
Median 2550 5.50 24730 24981 8.64 1760
Standard 12332 2.64 604557 796975 11.5 3530
Deviation
Standard 2115 0.453 105240 138735 2.00 614
Error
% CV 165 42.00 239 252 91.7 128
[0286] Dextromethorphan hydrobromide is widely recognized as a highly variable
drug and therefore one can consider confidence interval width of 70% to 143%
as bioequivalent rather than the classical 80% to 125%. In conclusion,
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guaifenesin in the experimental tablet is clearly bioequivalent to that of the
Reference, Mucinex, in terms of Cmax, AUCo_t or AUCinf as the 90% confidence
intervals are all contained within 80% to 125%. Dextromethorphan
hydrobromide in the experimental tablet can be considered bioequivalent to
both
30 mg dextromethorphan hydrobromide every 6 hours, and 20 mg every 4 hours,
in terms of Cmax, AUCo_t or AUCinf as the 90% confidence intervals are
contained
within 70% to 143%.
Example 20
[0287] To determine the relative bioavailability of guaifenesin and
dextromethorphan from an experimental modified release formulation containing
both guaifenesin and dextromethorphan following the consumption of a high fat
meal was compared to following an overnight fast in normal volunteers an open
label, single dose, randomized, 2-way crossover study was conducted in 36
subjects.
[0288] The subjects were randomized and placed into one of two treatment
groups.
Treatment A received a 1200 mg guaifenesin and 60 mg dextromethorphan
hydrobromide with 240 mL of water after an overnight fast (Reference).
Treatment B received a 1200 mg guaifenesin and dextromethorphan
hydrobromide experimental tablet with 240 mL of water within 30 minutes after
the beginning of the consumption of a high fat meal (Test). There was a 14 day
washout between doses.
[0289] Blood (7 mL, sodium heparin anticoagulant) was obtained at the
following
times: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24, 36,
48, 72
and 96 hours post dose (the total blood loss for guaifenesin and
dextromethorphan analysis will be 280 mL). Subjects given 1200 mg of
guaifenesin and 60 mg dextromethorphan hydrobromide in an experimental
formulation following an overnight fast (Treatment A, Reference) reached a
mean Cma, of 2030 ng/mL in 1.61 hours and had an AUCinf of 8128 hr-ng/mL.
Subjects given 1200 mg of guaifenesin and 60 mg dextromethorphan
hydrobromide following the consumption of a high fat meal (Treatment B, Test)
reached a mean Cmax of 1825 ng/mL (98.0% of that of Treatment A) in 2.93
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hours (248% of that of Treatment A) and had an AUC;,,f of 7093 hr-ng/mL
(92.9% of that of Treatment A).
[0290] Subjects given 60 mg dextromethorphan hydrobromide and 1200 mg
guaifenesin in an experimental formulation following an overnight fast
(Treatment A, Reference) reached a mean dextromethorphan Cmax of 10722
pg/mL in 6.23 hours and had an AUCinf of 466518 hr-pg/mL. Subjects given 60
mg dextromethorphan hydrobromide and 1200 mg guaifenesin in an
experimental formulation after the consumption of a high fat meal (Treatment
B,
Test) reached a mean dextromethorphan Cmax of 12757 pg/mL (132% of that of
Treatment A) in 5.74 hours (104% of that of Treatment A) and had an AUCinf of
472064 hr-pg/mL (117% of that of Treatment A).
[0291] The plasma concentrations of guaifenesin is shown in Figure 37. The
resulting pharmacokinetic data is shown in Tables 68 through 70. Subjects
given 1200 mg of guaifenesin and 60 mg dextromethorphan hydrobromide in an
experimental formulation following an overnight fast (Treatment A, Reference)
reached a mean Cmax of 2030 882 ng/mL (Mean Standard Deviation) in 1.61
1.15 hours and had an AUCinf of 8128 3497 hr-ng/mL. Subjects given 1200
mg of guaifenesin and 60 mg dextromethorphan hydrobromide in an
experimental formulation after the consumption of a high fat meal (Treatment
B,
Test) reached a mean Cmax of 1825 789 ng/mL (98.0% 40.3% of that of
Treatment A) in 2.93 1.44 hours (248% 164% of that of Treatment A) and
had an AUCinf of 7093 2787 hr-ng/mL (92.9% 23.6% of that of Treatment
A).
Table 68 Guaifenesin Pharmacolinetic Parameters Following the Administration
of 1200 mg
Guaifenesin
and 60 mg Dextromethorphan Hydrobromide in an Experimental Formulation to
Normal
Volunteers Following an Overnight Fast - Treatment A (Reference)
Subject Cmax Tmax AUCo_, AUC;,,f Half Life Clearance
(ng/mL) (hr) (hr'"ng/mL) (hr*ng/mL) (hr) (L/hr)
Mean 2030 1.61 8107 8128 1.15 172
Median 1760 1.5 777 7789 1.04 154
Std. Dev. 882 1.15 3485 3497 0.356 65.7
Std. Err. 151 0.198 598 600 0.0611 11.3
% CV 43.4 71.4 43.0 43.0 30.97 38.1
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Table 69 Guaifenesin Pharmacokinetic Parameters Following the Administration
of 1200 mg
Guaifenesin
and 60 mg Dextromethorphan Hydrobromide in an Experimental Formulation to
Normal Volunteers
After
the Consumption of a High Fat Meal - Treatment B (Test)
Subject Cmax Tmax AUCa, AUC;,,f Half Life Clearance
(ng/mL) (hr) (hr*ng/mL) (hr'*n /mL) (hr) (L/hr)
Mean 1825 2.93 7077 7093 0.849 190
Median 1520 3 6201 6228 0.854 193
Std.Dev. 789 1.44 2788 2787 0.115 60.6
Std. Err. 133 0.243 471 471 0.0194 10.2
% CV 43.2 49.1 39.4 39.3 13.5 31.9
Table 70 Ratio of Guaifenesin Pharmacokinetic Parameters Following the
Administration of 1200
mg
Guaifenesin and 60 mg Dextromethorphan Hydrobromide After the Consumption of a
High Fat Meal
Compared to that Following an Overnight Fast (%)
Subject Cmax Tmax AUClast AUCtot thalf Clearance
Mean 98.0 248 92.9 92.9 79.5 114
Median 89.8 250 88.9 88.3 79.5 113
Std. Dev. 40.3 163.7 23.7 23.6 19.4 26.8
Std. Err. 6.92 28.1 4.07 4.05 3.33 4.60
% CV 41.1 66.0 25.6 25.4 24.4 23.5
[0292] The plasma concentrations of dextromethorphan is shown in Figure 38.
The
resulting pharmacokinetic data is shown in Tables 71 to 73. Subjects given 60
mg dextromethorphan hydrobromide and 1200 mg guaifenesin in an
experimental formulation following an overnight fast (Treatment A, Reference)
reached a mean dextromethorphan Cmax of 10722 15966 pg/mL in 6.23 3.55
hours and had an AUCif of 466518 987204 hr-pg/mL. Subjects given 60 mg
dextromethorphan hydrobromide and 1200 mg guaifenesin in an experimental
formulation after the consumption of a high fat meal (Treatment B, Test)
reached
a mean dextromethorphan Cmax of 12757 17914 pg/mL (132% 69.8% of that
of Treatment A) in 5.74 2.27 hours (104% 43.4% of that of Treatment A)
and had an AUCiõ f of 472064 977485 hr-pg/mL (117% 61.5% of that of
Treatment A).
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Table 71 Dextromethorphan Pharmacokinetic Parameters Following the
Administration of 60 mg
Dextromethorphan Hydrobromide and 1200 mg Guaifenesin in an Experimental
Formulation to
Normal Volunteers Following an Overnight Fast - Treatment A (Reference)
Subject Cmax Tmax AUCo_, AUC;,,f Half Life Clearance
(pg/mL) (hr) (hr*pg/mL) (hr*pg/mL) (hr) (L/hr)
Mean 10722 6.23 372897 466518 13.8 2343
Median 3020 6.0 33799 34134 8.52 1287
Std. Dev. 15966 3.55 753127 987204 12.8 3352
Std. Err. 2738 0.609 129160 169304 2.19 575
% CV 149 57.0 202 212 92.7 143
Table 72 Dextromethorphan Pharmacokinetic Parameters Following the
Administration of 60 mg
Dextromethorphan Hydrobromide and 1200 mg Guaifenesin to Normal Volunteers
After the
Cons Consumption of a High Fat Meal - Treatment B (Test)
Subject Cmax Tmax AUCo_t AUCinf Half Life Clearance
(p /mL) (hr) (hr*pg/mL) (hr*pg/mL) (hr) (L/hr)
Mean 12757 5.74 381391 472064 13.5 2246
Median 3470 5 37515 37808 7.98 1174
Std. Dev. 17914 2.27 753249 977485 13.3 2905
Std. Err. 3028 0.384 127322 165225 2.3 491
% CV 140 39.6 198 207 98.5 129
Table 73 Ratio of Dextromethorphan Pharmacokinetic Parameters Following the
Administration of
60 mg Dextromethorphan Hydrobromide and 1200 mg Guaifenesin After the
Consumption of a High
Fat
Meal Compared to that Following an Overnight Fast (%)
Subject Cmax Tmax AUCo_, AUC;,,f Half Life Clearance
Mean 132 104 118 117 98.6 100
Median 124 100 106 106 100 94.4
Std. Dev. 69.8 43.4 62.2 61.5 18.8 35.6
Std. Err. 12.0 7.5 10.7 10.5 3.22 6.10
% CV 52.8 41.9 52.8 52.6 19.0 35.7
[0293] In conclusion, there is no food effect on the absorption of guaifenesin
from
the experimental tablet. There is an effect of food on the rate of absorption
of
dextromethorphan from the experimental tablet formulation (a small increase in
the rate of absorption) but not on the extent of absorption.
Example 21
[0294] To determine the relative bioavailability of guaifenesin and
dextromethorphan from an experimental modified release formulation containing
both guaifenesin and dextromethorphan was compared to reference guaifenesin
and dextromethorphan products in normal volunteers an open-label, multiple-
dose, randomized, 3-way-crossover study was conducted in 36 subjects.
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[0295] The subjects were randomized and placed into one of three treatment
groups.
Group 1 received a 1200-mg controlled-release guaifenesin product (Mucinex)
plus 60 mg of dextromethorphan hydrobromide (administered as 30 mg every 6
hours) with 240 mL of water after an overnight fast, and again 12 hours later
for
11 twelve-hour dosing periods (Treatment A, Reference). Group 2 received a
1200-mg controlled-release guaifenesin product (Mucinex) plus 60 mg of
dextromethorphan hydrobromide (administered as 20 mg every 4 hours) with
240 mL of water after an overnight fast, and again 12 hours later for 11
twelve-
hour dosing periods (Treatment B, Reference). Group 3 received an
experimental controlled-release tablet containing 1200 mg guaifenesin and 60
mg of dextromethorphan hydrobromide with 240 mL of water after an overnight
fast, and again 12 hours later for 11 twelve-hour dosing periods (Treatment C,
Test). There was a 14-day washout between doses.
[0296] Blood (7 mL, sodium heparin anticoagulant) was obtained at the
following
times: Day 1 Pre-AM dose, Day 4 Pre-AM dose and Day 5 Pre-AM dose for all
three treatment groups. On Day 6 Treatment A subjects were bled at: Pre-Dose,
0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 6.5, 6.75, 7, 7.5, 8, 9, 10, 11, 12, 14, 16,
24, 36, 48,
72, and 96 hours post dose. Treatment B subjects were bled at: Pre-dose, 0.5,
0.75, 1, 1.5, 2, 3, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11,
12, 14, 16,
24, 36, 48, 72 and 96 hours post dose. On Day 6, Treatment C subjects were
bled at: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 24,
36, 48, 72
and 96 hours post dose (the total blood loss for guaifenesin and
dextromethorphan analysis was 588 mL).
[0297] Subjects given 1200 mg of guaifenesin as Mucinex, along with 60 mg
dextromethorphan hydrobromide as two 30-mg doses 6 hours apart (Treatment
A, Reference), reached a mean steady-state plasma guaifenesin Cmax of 1935
ng/mL in 1.27 hours after the last dose (121 hours after the first dose); had
a Cmin
of 75.5 ng/mL, a CAVE of 631 ng/mL and an AUCsteady state of 7540 hr-ng/mL.
Subjects given 1200 mg of guaifenesin as Mucinex, along with 60 mg
dextromethorphan hydrobromide as three 20-mg doses 4 hours apart (Treatment
B, Reference), reached a mean steady-state plasma guaifenesin Cmax of 1938
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ng/mL in 0.850 hours after the last dose (121 hours after the first dose), had
a
Crain of 59.6 ng/mL, a CAVE of 618 ng/mL and an AUCSteady state of 7403 hr-
ng/mL. Subjects given 1200 mg guaifenesin as an experimental formulation,
also containing 60 mg dextromethorphan hydrobromide (Treatment C, Test),
reached a mean steady-state plasma guaifenesin Cmax of 1780 ng/mL in 1.35
hours after the last dose (121 hours after the first dose), had a Crain of
18.2
ng/mL, a CAVE of 601 ng/mL and an AUCSteady state of 7138 hr-ng/mL.
[0298] Subjects given 60 mg dextromethorphan hydrobromide as 30 mg Vick's
Formula 44 Cough Medicine along with 1200 mg guaifenesin as Mucinex and a
second 30-mg dextromethorphan.hydrobromide dose 6 hours later (Treatment A,
Reference), reached a mean steady-state plasma dextromethorphan Cmax of
17960 pg/mL in 5.03 hours after the last dose (125 hours after the first
dose), had
a Cmin of 11949 pg/mL, a CAVE of 15167 pg/mL and an AUCSteady state of 181904
hr-pg/mL. Subjects given 60 mg dextromethorphan hydrobromide as three 20-
mg doses of Vick's Formula 44 Cough Medicine four hours apart, along with
1200 mg of guaifenesin as Mucinex (Treatment B, Reference), reached a mean
steady-state plasma dextromethorphan Cmax of 17251 pg/mL in 5.91 hours after
the last dose (126 hours after the first dose), had a Cmin of 11018 pg/mL, a
CAVE
of 14097 pg/mL and an AUCSteady state of 169160 hr-pg/mL. Subjects given 60
mg dextromethorphan hydrobromide and 1200 mg guaifenesin as an
experimental formulation (Treatment C, Test), reached a mean steady-state
plasma dextromethorphan Cmax of 17213 pg/mL in 5.10 hours after the last dose
(125 hours after the first dose), had a Cn,in of 10978 pg/mL, a CAVE of 14609
pg/mL and an AUCSteady state of 175309 hr-pg/mL.
[0299] The plasma concentrations of guaifenesin are shown in figures 39 and
40.
The resulting pharmacokinetic data are shown in Tables 74 through 76. Subjects
given 1200 mg of guaifenesin as Mucinex, along with 60 mg dextromethorphan
hydrobromide as two 30-mg doses 6 hours apart (Treatment A, Reference),
reached a mean steady-state plasma guaifenesin Cmax of 1935 746 ng/mL at
121 0.854 hours after the first dose (1.27 hours after the last dose), had a
Cmin
of 75.5 73.9 ng/mL, a CAVE of 631 212 ng/mL and an AUCSteady state of 7540
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2570 hr-ng/mL. Subjects given 1200 mg of guaifenesin as Mucinex, along with
60 mg dextromethorphan hydrobromide as three 20-mg doses 4 hours apart
(Treatment B, Reference), reached a mean steady-state plasma guaifenesin Cmax
of 1938 637 ng/mL at 121 0.463 hours after the first dose (0.850 hours
after
the last dose), had a Cmin of 59.6 51.9 ng/mL, a CAVE of 618 205 ng/mL and
an AUCSteady State of 7403 2474 hr-ng/mL. Subjects given 1200 mg guaifenesin
as an experimental formulation, also containing 60 mg dextromethorphan
hydrobromide (Treatment C, Test), reached a mean steady-state plasma
guaifenesin Cmax of 1780 633 ng/mL at 121 0.864 hours after the first dose
(1.35 hours after the last dose), had a Cmin of 18.2 18.3 ng/mL, a CAVE of
601
189 ng/mL and an AUCSteady State of 7138 2268 hr-ng/mL.
Table 74 Steady-State Guaifenesin Pharmacokinetic Parameters Following the
Administration of
1200 mg Guaifenesin as Mucinex Every 12 Hours for 11 Doses and 60 mg
Dextromethorphan
Hydrobromide as 30 mg Vick's Formula 44 Every 6 Hours for 22 Doses to Normal
Volunteers
(Treatment A, Reference)
Subject AUC,, Crain Cmax T.. Caverage %Ptf %Swing LZ T112
(hr- (ng/mL) (ng/mL) (hr) (ng/mL) (%) (%) (hr 1) (hr)
ng/mL
Mean 7540 75.5 1935 122 631 296 5828 0.270 3.11
Median 7366 59.0 1910 121 614 297 2962 0.226 3.07
Std. 2570 73.9 746 0.854 212 56.2 6702 0.151 1.26
%CV
Dev.
Std. 441 12.7 128 0.146 36.4 9.64 1149 0.026 0.217
Error
34.1 97.9 38.6 0.704 33.7 19.0 115 55.8 4076]
Table 75 Steady-State Guaifenesin Pharmacokinetic Parameters Following the
Administration of
1200 mg Guaifenesin as Mucinex Every 12 Hours for 11 Doses and 60 mg
Dextromethorphan
Hydrobromide as 20 mg Vick's Formula 44 Every 4 Hours for 22 Doses to Normal
Volunteers
(Treatment B, Reference)
Subject AUC,, Cmin Cmax Tmax Caverage %Ptf %Swing LZ T112
(hr- (ng/mL) (nglmL) (hr) (ng/mL) (%) (%) (hr-1) (hr)
ng/mL
Mean 7403 59.6 1938 121 618 313 7215 0.269 3.22
Median 7230 36.1 1910 121 603 294 3173 0.227 3.05
Std. 2474 51.9 637 0.463 205 72 8948 0.164 1.36
Dev.
Std. 424 8.90 109 0.079 35.2 12.4 1535 0.028 0.232
Error
% CV 33.4 87.1 32.9 0.383 33.2 23.2 124 61.0 42.1
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Table 76 Steady-State Guaifenesin Pharmacokinetic Parameters Following the
Administration of
1200 mg Guaifenesin and 60 mg Dextromethorphan Hydrobroniide in an
Experimental Formulation
Every 12 Hours for 11 Doses to Normal Volunteers (Treatment C, Reference)
Subject AUC,, Cmin Cmax Tmax Caverage %Ptf %Swing LZ TU2
(hr- (ng/mL) (ng/mL) (hr) (ng/mL) (%) (%) (hr t) (hr)
ng/mL
Mean 7138 18.2 1780 121 601 292 14215 0.431 1.91
Median 6992 13.7 1770 121 583 291 10240 0.414 1.67
Std. 2268 18.3 633 0.864 189 45.2 11362 0.177 0.832
Dev.
Std. 395 3.18 110 0.150 32.8 7.88 1978 0.031 0.145
Error
% CV 31.8 101 35.6 0.712 31.4 15.5 79.9 41.1 43.6
[0300] The plasma concentrations of dextromethorphan are shown in figures 41
and
42. The resulting pharmacokinetic data are shown in Tables 77 through 79.
Subjects given 60 mg dextromethorphan hydrobromide as 30 mg Vick's
Formula 44 Cough Medicine, along with 1200 mg guaifenesin as Mucinex and a
second 30-mg dextromethorphan hydrobromide dose 6 hours later (Treatment A,
Reference), reached a mean steady-state plasma dextromethorphan Cmax of
17960 37537 pg/mL at 125 2.94 hours after the first dose (5.03 hours after
the last dose), had a Cmin of 11949 28101 pg/mL, a CAVE of 15167 33349
pg/mL and an AUCsteady state of 181904 400226 hr-pg/mL. Subjects given 60
mg dextromethorphan hydrobromide as three 20-mg doses of Vick's Formula 44
Cough Medicine 4 hours apart, along with 1200 mg of guaifenesin as Mucinex
(Treatment B, Reference), reached a mean steady-state plasma
dextromethorphan Cmax of 17251 39562 pg/mL, at 126 1.73 hours after the
first dose (5.91 hours after the last dose), had a C1ttjn of 11018 26007
pg/mL, a
CAVE of 14097 33537 pg/mL and an AUCsteady state of 169160 402449 hr-pg/mL.
Subjects given 60 mg dextromethorphan hydrobromide and 1200 mg guaifenesin
as an experimental formulation (Treatment C, Test), reached a mean steady-
state
plasma dextromethorphan Cmax of 17213 33703 pg/mL at 125 1.62 hours
(5.10 hours after the last dose), had a Cm;n of 10978 24713 pg/mL, a CAVE of
14609 30804 pg/mL and an AUCSteady state of 175309 369653 hr-pg/mL.
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Table 77 Steady-State Dextromethorphan Pharmacokinetic Parameters Following
the Administration
of 1200 mg Guaifenesin as Mucinex Every 12 Hours for 11 Doses and 60 mg
Dextromethorphan
Hydrobromide as 30 mg Vick's Formula 44 Every 6 Hours for 22 Doses to Normal
Volunteers
(Treatment A, Reference)
Subject AUC,, Cmin Cmax Tmax Caverage %Ptf %Swing LZ TI/2
(hr- (pg/mL) (pg/mL) (hr) (Pg/mL) (%) (%) (br') (hr)
pg/mL
Mean 181904 11949 17960 125 15167 56.4 80.0 0.108 8.67
Median 39400 2270 4100 124 3312 53.1 73.1 0.113 6.13
Std. 400226 28101 37537 2.94 33349 19.7 37.7 0.045 8.50
Dev.
Std. 68638 4819 6438 0.503 5719 3.38 6.47 0.008 1.46
Error
% CV 220 235 209 2.35 220 35.0 47.2 41.4 98.1
Table 78 Steady-State Dextromethorphan Pharmacokinetic Parameters Following
the Administration
of
1200 mg Guaifenesin as Mucinex Every 12 Hours for 11 Doses and 60 mg
Dextromethorphan
Hydrobromide as 20 mg Vick's Formula 44 Every 4 Hours for 22 Doses to Normal
Volunteers
(Treatment B, Reference)
Subject AUC,, Cmin Cmax Tmax Caverage %Ptf %Swing Lz T112
(hr- (pg/mL) (pg/mL) (hr) (pg/mL) (%) (%) (hr1) (hr)
pg/mL
Mean 169160 11018 17251 126 14097 57.2 78.4 0.090 11.8
Median 36778 2280 4250 126 3065 58.7 75.6 0.075 9.27
Std. 402449 26007 39562 1.73 33537 19.0 32.1 0.054 9.54
Dev.
Std. 69019 4460 6785 0.297 5752 3.26 5.51 0.009 1.64
Error
% CV 238 236 229 1.38 238 33.2 41.0 59.7 80.9
Table 79 Steady-State Dextromethorphan Pharmacokinetic Parameters Following
the Administration
of
1200 mg Guaifenesin and 60 mg Dextromethorphan Hydrobromide in an Experimental
Formulation Every 12 Hours for 11 Doses to Normal Volunteers (Treatment C,
Reference)
Subject AUC,, Cmin Cmax Tmax Caverage %Ptf %Swing LZ T1/2
(hr- (pg/mL) (pg/mL) (hr) (pg/mL) (%) (%) (hr ) (hr)
pg/mL
Mean 175309 10978 17213 125 14609 74.0 129 0.112 7.84
Median 37663 1855 4355 125 3139 73.4 126 0.113 6.12
Std. 369653 24713 33703 1.62 30804 23.2 56.3 0.042 5.71
Dev.
Std. 64348 4302 5867 0.282 5362 4.04 9.80 0.007 0.994
Error
% CV 211 225 196 1.30 211 31.4 43.6 37.6 72.8
[0301] In conclusion, guaifenesin in the experimental tablet is bioequivalent
to that
of the Reference, Mucinex, in terms of Cmax and AUCSS, as the 90% confidence
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intervals are all contained within 80% to 125%. Dextromethorphan
hydrobromide in the experimental tablet is bioequivalent to both 30 mg
dextromethorphan hydrobromide every 6 hours, and 20 mg every 4 hours, in
terms of Cmax and AUCSS, as the 90% confidence intervals are contained within
80% to 125%.
[0302] Other embodiments and uses of the invention will be apparent to those
of
skill in the art from consideration of the specification and practice of the
invention disclosed herein. The specification and examples should be
considered exemplary only with the true scope and spirit of the invention
indicated by the following claims. As will be easily understood by those of
skill
in the art, variations and modifications of each of the disclosed embodiments
can
be easily made within the scope of this invention as defined by the following
claims.
124
