Note: Descriptions are shown in the official language in which they were submitted.
CA 02503155 2005-04-21
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SUSTAINED-RELEASE TRAMADOL FORMULATIONS
WITH 24-HOUR EFFICACY
FIELD OF THE INVENTION
[0001]This invention relates to a novel once daily oral pharmaceutical
composition
for controlled release of tramadol or a salt thereof.
BACKGROUND OF THE INVENTION
Tramadol Pharmaceutical Formulations
[0002]Tramadol hydrochloride (HCi) was developed by Grunenthal GmbH, Germany.
It has been marketed in Germany since 1977 (eg. TramaIT""), and in the United
States as Ultram~ since 1995. The efficacy and safety profile of tramadol HCI
make
it highly suitable as a long-term treatment for chronic pain.
[0003]Tramadol HCI is a synthetic, centrally acting analgesic that has been
shown to
be effective in a variety of acute and chronic pain states. In particular,
tramadol HCI,
in both immediate and slow-release formulations, in conjunction with non-
steroidal
anti-inflammatory drugs (NSAIDs) (Roth SH. "Efficacy and safety of tramadol
HCI in
breakthrough musculoskeletal pain attributed to osteoarthritis". J. Rheumatol
1998;
25:1358-1363. Wilder-Smith CH et al. "Treatment of severe pain from
osteoarthritis
with slow-release tramadol or dihydrocodeine in combination with NSAID's: a
randomized study comparing analgesia, antinociception and gastrointestinal
effects".
Pain 2001; 91:23-31.), has been demonstrated to reduce pain attributed to
osteoarthritis (OA). After oral administration, tramadol HCI is rapidly and
almost
completely absorbed, and it is extensively metabolized. The major metabolic
pathways appear to be N- and O- demethylation and glucuronidation or
sulfonation in
the liver. Only one metabolite, mono-O-desmethyltramadol (M1), is
pharmacologically active, which has an approximate 200-fold higher affinity
for the ,u-
opioid receptor than racemic tramadol (DeJong R. "Comment on the hypoalgesic
effect of tramadol in relation to CYP2D6" (comment) Pain Dig 1997; 7:245;
Kogel B.
et al "Involvement of metabolites in the analgesic action of tramadol" Proc.
9t" World
Congress on Pain, Vienna, 1999). In healthy humans, tramadol is demethylated
by
the polymorphic enzyme cytochrome P450 2D6 (CYP2D6) to the M1 metabolite.
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[0004]The mechanism of action of tramadol HCI is not completely understood.
Animal models indicate that the drug (and its active M1 metabolite) acts as an
opiate
agonist, apparently by selective activity at the ,u-receptor. In addition to.
opiate
agonist activity, tramadol HCI inhibits re-uptake of certain monoamines
(norepinephrine, serotonin) which appears to contribute to the drug's
analgesic effect.
The antinociceptic effect of tramadol HCI is only partially antagonized by
naloxone in
some tests in animals and humans. In addition, because of the drug's opiate
agonist
activity, it has been suggested that tramadol HCI may produce dependence;
however, its abuse potential appears to be low, and tramadol HCI is not
"subject to
control" under the United States Federal Controlled Substances Act of 1970 as
a
scheduled drug.
[0005] Immediate release formulations of tramadol HCI are well known in the
art.
Such formulations, however, require frequent dosing in order to provide
effective pain
relief. Lack of compliance with high frequency dosing regimens can result in
inconsistent plasma drug concentrations and accordingly less consistent
analgesia.
Twice daily formulations are available and are desirable over immediate
release
formulations as they provide longer periods of analgesia after administration
and
require less frequent dosing. A once daily formulation is even more desirable
for
increased effectiveness, safety and convenience.
[0006]A critical factor influencing the rate of absorption, and thereby the
safety and
efficacy, of an active pharmaceutical ingredient by the body following oral
administration in a tablet or other solid dosage form is the rate of release
of the active
pharmaceutical ingredient from that dosage form post ingestion.
[0007] It is thus the ability of the dosage form components to control the
release rate
that constitutes the basis for the so-called controlled-release, extended-
release,
sustained-release or prolonged-action pharmaceutical preparations that are
designed
to produce slow, uniform release and absorption of active pharmaceutical
ingredients
over a period of hours, days, weeks or months. The advantages of such
controlled-
release formulations include: a reduction in the required administration
frequency of
the drug as compared to conventional immediate release dosage forms, often
resulting in improved patient compliance; the maintenance of a stable
concentration
of the drug in the body and thereby a sustained therapeutic effect over a set
period of
time; and a decreased incidence and intensity of undesired side effects of the
active
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agent caused by the high plasma concentrations that occur after administration
of
immediate-release dosage forms.
[0008] Many materials have been proposed and developed as matrices for the
controlled release of active pharmaceutical ingredients. These include, for
example,
polymeric materials such as polyvinyl chloride, polyethylene amides, ethyl
cellulose,
silicone and poly (hydroxymethyl methacrylate). See e.g., U.S. Patent No.
3,087,860
to Endicott et al.; U.S. Patent No. 2,987,445 to Levesque et al.; Salomon et
al.
Pharm. Acta Helv., 55, 174-182 (1980); Korsmeyer, Diffusion Controlled
Systems:
Hydrogels, Chap. 2, pp 15-37 in Polymers for Controlled Drug Delivery, Ed
Tarcha,
CRC Press, Boca Raton, Fla. USA (1991 ); and Buri et aG, Pharm. Acta Helv. 55,
189-
197 (1980).
[0009] High amylose starch has also been used for controlled-release purposes
and,
in particular, recent advances have been made using cross-linked high amylose
starch. For example, United States Patent No. 6,284,273 (Lenaerts ef al.),
which
issued September 4, 2001, and No. 6,419,957 (Lenaerts et al.), which issued
July 16,
2002, teach a solid controlled release oral pharmaceutical dosage unit in the
form of
tablets comprising a dry powder of a pharmaceutical product and a dry powder
of
cross-linked high amylose starch, wherein said cross-linked high amylose
starch is a
matrix comprising a mixture of about 10-60% by weight of amylopectin and about
40-
90% amylose. United States Patent No. 6,607,748 (Lenaerts et al.) which issued
on
August 19, 2003 describes a process for making a cross-linked high amylose
starch
which is known under the name Contramid~.
Extended Release Formulations Known in the Art
[0010] Extended and controlled release formulations relating to tramadol HCI
have
been suggested, examples being described in: United States Patent Application
Publication No. 2003!0143270, (Deboeck et al.) published July 31, 2003; United
States Patent No. 6,254,887 (Miller et al.) issued July 3, 2001; United States
Patent
Application Publication No. 2001/0036477 (Miller et al.) published November 1,
2001;
United States Patent No. 6,326,027 (Miller et al.) issued December 4, 2001;
and
United States Patent No. 5,591,452 (Miller et an issued January 7, 1997; and
European Patent No. 1 190 712 (Vanderbist) published March 27, 2002.
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[0011]Although there are some controlled release tramadol HCI formulations on
the
market which purport to be once-daily formulations, none of these has
successfully
replaced twice-daily tramadol HCI formulations.
[0012]Articles have been published in which comparative data between putative
"once-daily" tramadol HCI formulations and immediate release tramadol HCI
formulations are presented: Adler et al., "A Comparison of Once-Daily Tramadol
with
Normal Release Tramadol in the Treatment of Pain in Osteoarthritis," The
Journal of
Rheumatology (2002) 29(10): 2195-2199; and Bodalia et al., "A Comparison of
the
Pharmacokinetics, Clinical Efficacy, and Tolerability of Once-Daily Tramadol
Tablets
with Normal Release Tramadol Capsules," Journal of Pain and Symptom
Management (2003) 25(2): 142-149.
Adverse Events from Administration of Tramadol HCI
[0013]The most frequently reported side effects of tramadol observed in
clinical trials
in the United States are constipation, nausea, dizziness/vertigo, headache,
somnolence and vomiting. These are typical adverse effects of opiate drugs.
Seizures and anaphylactoid reactions have also been reported, though the
estimated
incidence of seizures in patients receiving tramadol HCI is less than 1
(Kazmierczak, R., and Coley, K.: "Doctor letters on prescribing: evaluation of
the use
of tramadol HCL" Formulary 32: 977-978, 1997).
[0014]Adler et al., supra, reports on the results of a clinical study
comparing a once
daily tramadol formulation to immediate release tramadol in the treatment of~
pain in
osteoarthritis. The authors report similar adverse event profiles for
individuals in both
treatment groups. Table 2 of Adler et al. indicates that a greater percentage
of
people who were in the once daily treatment group withdrew due to adverse
events
than did those in the other treatment group.
[0015] In Bodalia et al., supra, the authors report comparable tolerability
with a 150
mg once daily dose, a 200 mg once daily dose and three doses of a 50 mg normal
release tramadol formulation. This article does not however include any
information
on how to make the formulations which are purported to be "once daily" nor
does the
article disclose any pharmacokinetic data after a single dose.
[0016]Citation or identification of any reference in this section shall not be
construed
as an admission that such reference is available as prior art to the present
invention.
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SUMMARY OF THE INVENTION
[0017]An object of the present invention is to provide an improved sustained-
release
tramadol formulation with 24-hour effective analgesia.
[0018] In accordance with one aspect of the present invention, there is
provided a
once daily oral pharmaceutical composition for controlled release of tramadol
or a
salt thereof, in which the composition, upon initial administration, provides
an onset of
analgesic effect within 2 hours, which analgesic effect continues for at least
24 hours
after administration.
[0019] In accordance with another aspect of the present invention, there is
provided a
once daily oral pharmaceutical composition for controlled release of tramadol
or a
salt thereof, wherein the composition, upon initial administration of one
dose,
provides a mean plasma concentration of at least 100 nglmL within 2 hours of
administration and continues to provide a mean plasma concentration of at
least 100
ng/mL for at least 22 hours after administration.
[0020] In an embodiment of the present invention, there is provided a once
daily oral
pharmaceutical composition for controlled release of tramadol or a salt
thereof,
wherein the composition, upon initial administration of one dose, provides a
mean
plasma concentration of at least 100 ng/mL within 2 hours of administration
and
continues to provide a mean plasma concentration of at least 100 ng/mL for at
least
22 hours after administration and wherein the mean maximum plasma
concentration
(Cm~) is less than 2.2 times the mean plasma concentration obtained 24 hours
after
administration (C24n).
[0021]The term "~,Z" is the apparent terminal elimination rate constant,
determined by
the slope of the regression during the log-linear phase.
[0022]The term "AUCo_-rmax" is the mean area under the plasma concentration-
time
curve from time 0 to Tmax and is used as an indicator of the rate of drug
absorption, or
metabolite formation. It is calculated as the arithmetic mean of the area
under the
plasma concentration-time curve from time 0 to Tmax calculated for each
individual
participating in the bioavailability study.
[0023]The term "AUCo-~" is the mean area under the plasma concentration-time
curve extrapolated to infinity. It is calculated as the arithmetic mean of the
area under
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the plasma concentration-time curve from time 0 extrapolated to infinity,
calculated
for each individual participating in the bioavailability study.
[0024]The term "analgesic effect" is defined for the purposes of the present
invention
as providing a mean blood plasma concentration of at feast about 100 ng/mL of
tramadol.
[0025]The term "C'max" is the maximum observed plasma concentration,
calculated
as the mean of the individual maximum blood plasma concentrations.
[0026] The term "controlled release" is defined for purposes of the present
invention
as a method of oral drug delivery where the rate of release of the active
pharmaceutical ingredient from the formulation is not solely dependent on the
concentration of active pharmaceutical ingredient remaining in the formulation
and/or
the solubility of the active pharmaceutical ingredient in the medium
surrounding the
formulation, and where the time course and/or location of release of an active
ingredient from a pharmaceutical formulation are chosen to accomplish
therapeutic or
convenience objectives not offered by conventional dosage forms.
[0027]The term "half-life" is the apparent terminal elimination half-life.
[002]The term "HVD" is the half value duration, that is, the time during which
tramadol concentrations are above one half the C'm~. This parameter is an
indicator
of the shape of the plasma concentration time curve.
[0029]The term "immediate release" is defined for purposes of the present
invention
as the release of an active ingredient from a pharmaceutical formulation where
the
rate of release of the active pharmaceutical ingredient from the
pharmaceutical
formulation is not retarded by means of a controlled release matrix and where
the
components of the pharmaceutical formulation are designed such that, upon
ingestion, maximum exposure of said active pharmaceutical ingredient to body
tissues occurs in the minimum period of time.
[0030]The term "initial administration" is defined for purposes of the present
invention
as the first single dose of a formulation containing an active ingredient
administered
to a patient or subject or the first dose administered to a patient or subject
after a
suitable washout period.
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[0031]The term "MRT" is the mean residence time, which is an estimate of the
average time that a tramadol molecule resides in the body following oral
administration.
[0032]The term "mean maximum plasma concentration" (CmaX) is defined for the
purposes of the present invention as the maximum mean plasma concentration.
[0033]The term "mean plasma concentration" is defined for purposes of the
present
invention as the arithmetic mean blood plasma concentration. 0026a]
[0034]The term "tmax" is the time at which CmaX is achieved.
[0035]The term "TmaX " is the time at which the maximum blood plasma
concentration
is observed for each individual participating in the bioavailability study.
[0036]The term "Rstart" is the time at which plasma concentrations begin to
decline
in a log-linear fashion, that is, the time at which either drug absorption or
metabolite
formation is complete.
[0037]The word "tramadol", as used herein shall refer to tramadol, its
stereoisomers
and its pharmaceutically acceptable salts.
[0038]The term "steady state" is defined for purposes of the present invention
as the
state, following multiple dose administration, where the rate of drug
elimination
matches the rate of input and the plasma drug concentrations at a given time
within a
dosing interval are approximately the same from one dosing interval to
another.
BRIEF DESCRIPTION OF THE FIGURES
[0039]Various features and advantages of the present invention will become
clear
from the more detailed description given below with reference to the
accompanying
drawings, in which:
[0040] Figure 1: Flow diagram showing manufacturing process for tablets.
[0041]Figure 2: Dissolution profiles of formulations A, B and C: In vitro
performance
of formulations A, B and C: under USP Type 1 Conditions; sodium phosphate
buffer,
50 mM, pH 6.8, 100 rpm. 6 tablets were tested per time point.
[0042] Figure 3: Mean tramadol plasma concentrations following single-dose
administration of (i) a 100 mg dose of the inventive controlled release
composition
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WO 2004/037222 PCT/CA2003/001638
(~), (ii) a 200 mg dose of the inventive controlled release composition (~),
and (iii) a
300 mg dose of the inventive controlled release composition (~).
[0043] Figure 4: Mean O-desmethyltramadol plasma concentrations of following
single dose administration of either 100 mg (~), 200 mg (O), and 300 mg (D)
strength tramadol formulations (A, B, and C, respectively).
[0044] Figure 5: Mean tramadol plasma concentrations following single-dose
administration of (i) 2 x 200 mg doses of the inventive controlled release
composition
(~); and (ii) Topalgic~ LP 200 mg BID ql2h (~).
[0045] Figure 6: Mean O-desmethyltramadol plasma concentrations following
single-dose administration of (i) 2 x 200 mg doses of the inventive controlled
release
composition (~); and (ii) Topalgic~ LP 200 mg BID ql2h (~).
[0046] Figure 7: Mean steady-state tramadol and O-desmethyltramadol plasma
concentration following administration of (i) a 200 mg dose of the inventive
controlled
release composition (~ & o); and (ii) Topalgic~ LP 100 mg BID ql2h (~ & d). ,
DETAILED DESCRIPTION OF THE INVENTION
CORE
[0047]The core of a tablet of the invention includes at least one active
ingredient and
a matrix, these components associated in such a way that release of the
pharmaceutical ingredient from the matrix is controlled. In a specific
embodiment,
the matrix of the core is a cross-linked high amylose starch known under the
name
Contramid~, and described most recently in U.S. Patent No. 6,607,748 (Lenaerts
et
al.), which issued August 19, 2003. A preferred formulation in the context of
this
invention is provided in the specification of U.S. Patent No. 6,607,748.
[0048] Preferably, the core is formed by admixing the ingredients (in granular
or
powder form) and then compressing the mixture to form the core over which the
coat
is subsequently formed. The weight of the core can be any percentage of the
weight
of the total composition between 10% and 80%. The preferred percentage
depends,
upon other things, the total dosage of the pharmaceutical agent. In a
particular
embodiment described further below, a tablet contains 100 mg tramadol
hydrochloride and the core is about 26% of the total weight of the tablet. In
another
embodiment, a tablet contains 200 mg tramadol hydrochloride and the core makes
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up about 33% of the total weight of the tablet. In yet another embodiment, a
tablet
contains 300 mg tramadol hydrochloride, and the core contributes 33% to the
total
weight of the tablet.
Active Agent in the Core
[0049)An active pharmaceutical ingredient is present in the core of the
composition
of the present invention. A suitable pharmaceutical ingredient of the present
invention is any such ingredient that is desired to be delivered in a
sustained-release
dosage form. A comprehensive list of suitable pharmaceutical agents can be
found
in The Merck Index, 12'" Ed. Preferably, the pharmaceutical ingredient is, but
not
limited to, isonicotinic acid hydrazide, sodium salicylate, pseudoephedrine
hydrochloride, pseudoephedrine sulfate, acetaminophen or diclofenac sodium,
verapamil, glipizide, nifedipine, felodipine, betahistine, albuterol,
acrivastine,
omeprazole, misoprostol, tramadol~, oxybutynin, trimebutine, ciprofloxacin,
and salts
thereof. In addition, the pharmaceutical agent can be an antifungal agent,
such as
ketoconazole, or an analgesic agent such as acetylsalicylic acid,
acetaminophen,
paracetamol, ibuprofen, ketoprofen, indomethacin, diflunisal, naproxen,
ketorolac,
diclofenac, tolmetin, sulindac, phenacetin, piroxicam, mefamanic acid,
dextromethorphan, other non-steroidal anti-inflammatory drugs including
salicylates,
pharmaceutically acceptable salts thereof or mixtures thereof. Pro-drugs are
part of
the invention.
(0050]The solubility of the pharmaceutical agent in aqueous solution can be a
wide
variety of values. The aqueous solubility of the pharmaceutical agent can be
less
than 10-3 g/L, more than 10-3 g/L, more than 10-2 g/L, more than 10-1 g/L,
more than
1 g/L, more than 10 g/L, more than 100 g/L, more than 500 g/L, more than 1000
g/L,
or more than 2000 g/L. Preferably, the solubility is more than 100 g/L. More
preferably, the solubility is more than 500 g/L. Most preferably, the
solubility is more
than 1000 g/L.
[0051]The pharmaceutical agent can meet a variety of dosage requirement. For
example, the dosage requirement of the pharmaceutical agent can be less, than
1
mg/dosage unit, more than 1 mg/dosage unit, more than 10 mg/dosage unit, more
than 100 mg/dosage unit, more than 200 mg/dosage unit, more than 300 mg/dosage
unit, more than 400 mg/dosage unit, more than 500 mg/dosage unit, or more than
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a
1000 mg/dosage unit. Preferably, the pharmaceutical agent is more than
50 mg/dosage unit. More preferably, the pharmaceutical agent is 100 mgldosage
unit, or more, e.g. 150 mg/dosage unit, or 200 mg/dosage unit, or 250
mg/dosage
unit, or 300 mg/dosage unit, or more.
[0052] Particular embodiments include a core containing tramadol hydrochloride
in
which the core contains between about 10% and 90% of the total tramadol
present in
the tablet, e.g. about 45 mg of a 100 mg strength tablet (45% of the tablet
total), or
about 90 of a 200 mg strength tablet (45% of the tablet total), or about 151
mg of a
300 mg strength tablet (50% of the tablet total).
Matrix of the Core
[0053]The release from the formulation of an active pharmaceutical ingredient
located in the core is slower than the release of an active pharmaceutical
ingredient
located in the matrix of the coat. A preferred matrix of the core is cross-
linked high
amylose starch, known under the name Contramid~ and described in U.S. Patent
No.
6,607,748. In particular embodiments, the matrix makes up between about 10%
and
about 90% by weight of the core i.e., the ratio of the matrix of the core to
the active
ingredient of the core (w/w) is between about 0.1 and about 10, or between
about 0.2
and about 9, or between about 0.2 and about 8, or between about 0.3 and about
7, or
between about 0.4 and about 6, or between about 0.5 and about 5, or between
about
0.6 and about 4, or between about 0.7 and about 4 or between about 1 and about
4,
or between about 1 and about 3 and about 1.5 and about 2.5. In one particular
embodiment, the core totals about 90 mg, of which about 44 mg is Contramid~,
and
45 mg is tramadol hydrochloride. In this case, Contramid~ thus makes up about
49
weight percent of the core.
Optional Components
[0054]The core composition of the present invention may optionally include a
pharmaceutically acceptable carrier or vehicle. Such carriers or vehicles are
known
to those skilled in the art and are found, for example, in Reminatons's
Pharmaceutical Sciences, 14t" Ed. (1970). Examples of such carriers or
vehicles
include lactose, starch, dicalcium phosphate, calcium sulfate, kaolin,
mannitol and
powdered sugar. Additionally, when required, suitable binders, lubricants, and
CA 02503155 2005-04-21
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disintegrating agents can be included. If desired, dyes, as well as sweetening
or
flavoring agents can be included.
[0055]The core composition of the present invention may optionally include
accessory ingredients including, but not limited to dispersing agents such as
microcrystalline cellulose, starch, cross-linked starch, cross-linked
polyvinyl
pyrrolidone), and sodium carboxymethyl cellulose; flavoring agents; coloring
agents;
binders; preservatives; surfactants and the like.
[0056]The core can, optionally, also include one or more suitable binders
known to
one of ordinary skilled in the art.
[0057]Suitable forms of microcrystalline cellulose, for example, MCC-PH101~,
MCC-
102, MCC-105, etc.
[0058]Suitable lubricants, such as those known to the skilled person, may also
be
included. For example, magnesium stearate, vegetable oil, talc, sodium-stearyl
fumarate, calcium stearate, stearic acid, etc.
[0059]Suitable glidants, known in the art, may also be included. Examples bf
such
glidants include, but are not limited to talc, colloidal silicon dioxide, etc.
Proportion
[0060]The active agent is present at levels ranging from about 1 to about 90
wt.% of
the total weight of the core, preferably from about 10 to about 70 wt.% of the
total
composition of the core, more preferably from about 20 to about 60 wt.% of the
total
composition of the core, and probably most often between about 30 to about 50
wt.%
of the total composition of the core.
[0061]Of course, the total amount of all components is 100 wt.%, and those of
ordinary skill in the art can vary the amounts within the stated ranges to
achieve
useful compositions.
COAT
[0062]The coat of the dosage form includes a physical mixture of polyvinyl
acetate
and polyvinylpyrrolidone and the active pharmaceutical ingredients) of the
coat. The
coat can also include a cross-linked high amylose starch, e.g., Contramid~,
and other
optional components. In a preferred embodiment, the coat is formed ~ by dry
compression. The weight of the coat can be any percentage of the weight of the
total
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composition between about 10% and about 90%, but is preferably in the higher
part
of this range. The coat thus usually makes up between about 20% to about 90%,
(w/w) of a tablet of the invention, or about 25% to about 90%, or about 30% to
about
85%, or about 35 % to about 85%, or about 40% to about 85%, or about 45% to
about 85%, or about 45% to about 90%, or about 50% to about 90% or about 50%
to
about 85 %, or about 55% to about 90%, or about 55% to about 85%, or about 55%
to about 80%, or about 60% to about 90%, or about 60% to about 85%, or about
60%
to about 80%, or about 60% to about 75%, or about 65% to about 90%, or about
65%
to about 85%, or about 65% to about 80%, or about 65% to about 75%, or about
65%
or about 70% or about 75%.
The coat often includes an optional binding agent.
Polyvinyl Acetate and Polyvinylpyrrolidone of the Coat
[0063]The weight percentage of the polyvinyl acetate/polyvinylpyrrolidone
mixture in
the coat can be anywhere within a wide range of values. Depending on the
solubility
in water of the active ingredient in the coat, the amount of the polyvinyl
acetate/polyvinylpyrrolidone mixture in the coat can be adjusted. United
States
Patent Publication No. 2001/0038852 describes ways in which such adjustments
can
be made. For example, for active ingredients that are soluble to extremely
soluble in
water, polyvinyl acetatelpolyvinylpyrrolidone mixture can be about 20 to about
80 wt.% of the coat, preferably about 30 to about 65 wt.%, or about 40 to
about
55 wt.%. In a particular embodiment described below, KollidonTM SR makes up
about 45% by weight of a coat that is about 31 % by weight tramadol
hydrochloride
and about 23% xanthan gum. For active ingredients that are sparingly soluble
to
slightly soluble in water, the amount of polyvinyl
acetatelpolyvinylpyrrolidone mixture
is often lower, as described in United States Patent Publication No.
2001/0038852.
[0064]The weight ratio of polyvinyl acetate to polyvinylpyrrolidone in the
polyvinyl
acetate/polyvinylpyrrolidone mixture can be a wide range of values.
Preferably, such
ratio is between about 6:4 and 9:1; more likely between about 7:3 and 6:1,
even
more preferably about 8:2.
(0065]The molecular weight of the polyvinyl acetate component in the polyvinyl
acetate/polyvinylpyrrolidone mixture can be a wide range of values.
Preferably, the
average molecular weight of the polyvinyl acetate is about 100 to about
10,000,000;
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or about 1,000 to about 1,000,000; or about 10,000 to about 1,000,000; or
about
100,000 to about 1,000,000; or about 450,000.
[0066]The molecular weight of the polyvinylpyrrolidone component in the
polyvinyl
acetatelpolyvinylpyrrolidone mixture can be a wide range of values. The
average
molecular weight of the polyvinylpyrrolidone can be from about 100 to about
10,000,000; or about 1,000 to about 1,000,000; or about 5,000 to about
500,000; or
about 10,000 to about 100,000; or about 50,000.
[0067]The polyvinyl acetate and polyvinylpyrrolidone mixture can be prepared
by a
variety of processes including simply mixing powders of polyvinylpyrrolidone
and
polyvinyl acetate. In a preferred embodiment, such mixture is spray dried
powder of
a colloidal dispersion of polyvinyl acetate and polyvinylpyrrolidone solution.
Optionally, sodium lauryl sulfate is used as a stabilizer in order to prevent
agglomeration during spray drying process and/or colloidal silica is used to
improve
the flow properties of the polyvinyl acetate/polyvinylpyrrolidone mixture.
Optionally,
polyvinyl acetate and polyvinylpyrrolidone can be formed in a random or a
block
copolymer.
Optional Components
[0068] Suitable binding agents for the present invention include, but are not
limited to,
plant extracts, gums, synthetic or natural polysaccharides, polypeptides,
alginates,
synthetic polymers, or a mixture thereof.
[0069]Suitable plant extracts to be used as gelling agents include, but are
not limited
to, agar, ispaghula, psyllium, cydonia, ceratonia or a mixture thereof.
[0070]Suitable gums to be used as gelling agents include, but are not limited
to,
xanthan gum, guar gum, acacia gum, ghatti gum, karaya gum, tragacanth gum or a
mixture thereof.
[0071]Suitable synthetics or natural hydrophilic polysaccharides to be used as
gelling
agents include, but are not limited to, hydroxyalkylcelluloses, cellulose
ethers,
cellulose esters, nitrocelluloses, dextrin, agar, carrageenan, pectin,
furcellaran, starch
or starch derivatives, cross-linked high amylose starch, or a mixture thereof.
[0072] Suitable polypeptides to be used as gelling agents include, but are not
limited
to, gelatin, collagen, polygeline or a mixture thereof.
13
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
[0073]Suitable alginates to be used as gelling agents include, but are not
limited to,
alginic acid, propylene glycol alginate, sodium alginate or a mixture thereof.
[0074] Suitable synthetic polymers to be used as gelling agents include, but
are not
limited to, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl pyrrolidone,
polyethelene
oxide, polyethylene glycols, copolymers of ethylene oxide and propylene oxide
and
their copolymers or a mixture thereof.
[0075] In a preferred embodiment, the gelling agent is a gum such as xanthan
gum,
guar gum, acacia gum, ghatti gum, karaya gum, tragacanth gum or a mixture
thereof,
PEO 7,000,000 and HPMC K100 M.
[0076] In a most preferred embodiment, the gelling agent is xanthan gum.
Active agent of the Coat
[0077]A suitable active pharmaceutical ingredient of the present invention is
any
active agent that it is desired to be delivered in a sustained-release dosage
form. A
comprehensive list of suitable pharmaceutical agents can be found in The Merck
Index, 12th Ed. Preferably, the pharmaceutical agent is, but not limited to,
isonicotinic
acid hydrazide, sodium salicylate, pseudoephedrine hydrochloride,
pseudoephedrine
sulfate, acetaminophen or diclofenac sodium, verapamil, glipizide, nifedipine,
felodipine, betahistine, albuterol, acrivastine, omeprazole, misoprostol,
tramadol~,
oxybutynin, trimebutine, ciprofloxacin, and salts thereof. In addition, the
pharmaceutical agent can be an antifungal agent, such as ketoconazole, or an
analgesic agent such as acetylsalicylic acid, acetaminophen, paracetamol,
ibuprofen,
ketoprofen, indomethacin, diflunisal, naproxen, ketorolac, diclofenac,
tolmetin,
sulindac, phenacetin, piroxicam, mefamanic acid, dextromethorphan, other
non-steroidal anti-inflammatory drugs including salicylates, pharmaceutically
acceptable salts thereof or mixtures thereof.
[0078]The solubility of the pharmaceutical agent in aqueous solution can be a
wide
variety of values. The aqueous solubility of the pharmaceutical agent can ~be
less
than 10-3 g/L, more than 10-3 g/L, more than 102 g/L, more than 10-1 g/L, more
than
1 g/L, more than 10 g/L, more than 100 glL, more than 500 g/L, more than 1000
g/L,
or more than 2000 g/L. Preferably, the solubility is more than 100 g/L. More
preferably, the solubility is more than 500 g/L. or even 1000 g/L.
14
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
[0079]The pharmaceutical agent can meet a variety of dosage requirements. For
example, the dosage requirement of the pharmaceutical agent can be less than
1 mg/dosage unit, more than 1 mg/dosage unit, more than 10 mg/dosage unit,
more
than 100 mg/dosage unit, more than 200 mg/dosage unit, more than 300 mg/dosage
unit, more than 400 mg/dosage unit, more than 500 mg/dosage unit, or more than
1000 mgldosage unit. Preferably, the pharmaceutical agent is more than
50 mg/dosage unit. More preferably, the pharmaceutical agent is more than
100 mg/dosage unit. Most preferably, the pharmaceutical agent is more than
200 mg/dosage unit.
[0080]The coat can be between about 5% and about 90% by weight active
pharmaceutical ingredient, or between about 5% and about 80% by weight api, or
between about 10% and about 70% by weight api, or between about 10% and about
60% by weight api, or between about 15% and about 50% by weight api, or
between
about 15% and about 45% by weight api, or between about 15% and about 40% by
weight api, or between about 20% and about 35% by weight api, or between about
20% and about 30% by weight api.
[0081] In particular embodiments, described further below, the weight of
tramadol
from a 100 mg tramadol tablet is about 21 % by weight of the coat. The weight
of
tramadol from a 200 mg tablet is about 31 % by weight of the coat. The weight
of
tramadol from a 300 mg tablet is about 30% by weight of the coat.
ROUTES OF ADMINISTRATION
[0082]The tablet composition of the present invention can be administered
through,
but not limited to, a number of routes such as oral, sublingual, and rectal.
The
preferred route of administration of the compositions of the present invention
is oral.
[0083] Compositions of the present invention that are suitable for oral
administration
may be presented as discrete units such as tablets or granules. Preferably,
the
compositions of the present invention are presented in a tablet form. Such
tablets
may be conventionally formed by compression or molding. Compressed tablets may
be prepared by compressing in a suitable machine the mixture of one or more
components described above. Molded tablets may be made by molding in a
suitable
machine the above components, which can be optionally moistened with an inert
liquid diluent. The tablets may optionally be coated and/or have other
identifying
indicia visible to the consumer. A tablet can also be in a variety of forms,
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
e.g., uncoated , dry coated, or film coated, etc. A tablet can also be in a
variety of
shapes (e.g., oval, sphere, etc.) and sizes. A comprehensive discussion of
tablets
can be found in references such as The Theory and Practice of Industrial
Ph~armacy
by Lachman et al., 3rd Ed. (Lea & Febiger, 1986).
Dissolution Profile of Sustained-Release Composition
[0084]The active agent of the composition exhibits the following in vitro
dissolution
profile when measured with a USP Type I apparatus in 50 mM phosphate, pH 6.8,
and stirring between 50 and 150 rpm:
an average rate of between 10% and 30% per hour of the agent is released
between
0 and 2 hours when tested in vitro using a USP Type I apparatus in 50 mM
phosphate, pH 6.8, and stirring between 50 and 150 rpm; or
between 10% and 40% of the agent is released from the formulation between 0
and
about 2 hours of measurement, between about 30% and 60% of the agent is
released from the formulation between 2 and about 7 hours of the measurement,
between about 50% and 80% of the agent is released from the formulation
between
7 and about 12 hours of measurement, and between about 80% and 100% of the
agent is released from the formulation after about 20 hours of measurement; or
more
preferably
between 15% and 35% of the agent is released from the formulation between at 2
hours of measurement, between about 40% and 60% of the agent is released from
the formulation between at 7 hours of the measurement, between about 60% and
80% of the agent is released from the formulation at 12 hours of measurement,
and
between about 85% and 100% of the agent is released from the formulation after
about 20 hours of measurement, or
between 20% and 40% of the agent is released from the formulation between at 2
hours of measurement, between about 40% and 60% of the agent is released from
the formulation between at 7 hours of the measurement, between about 60% and
80% of the agent is released from the formulation at 12 hours of measurement,
and
16
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
between about 85% and 100% of the agent is released from the formulation after
about 20 hours of measurement.
[0085]The present invention will be more readily understood by referring to
the
following examples which are given to illustrate the invention rather than to
limit its
scope.
EXAMPLES
[0086]The cross-linked high amylose starch used in the these examples is made
by
a process comprising the sfieps of crosslinking and chemically modifying,
followed by
gelatinization and drying. Such process is described in more detail in U.S.
Patent
No. 6,607,748 (Lenaerts et al.), which issued August 19, 2003, and known in
the
marketplace under the name Contramid~. and described in Examples 1 and 2.
Example 1
A. Cross-Linking
[0087] High amyiose starch (30.0 kg) containing about 70% w/w of amylose (CI
AmyloGel 03003) is placed in a reactor. To this reactor is added water (55.0 1
)
containing sodium hydroxide (30.0 g) and sodium sulfate (2.40 kg). The
resulting
slurry is heated to a temperature of 30°C. Phosphorus oxychloride (22.5
g) is added
to the reaction mixture which is reacted for one hour.
B. Chemical Modification, Hydroxyproylation
[0088] The crude reaction mixture from Part A is transferred into a
hydroxypropylation reactor. The reaction mixture is heated to 40°C.
over 30 minutes
and the reaction is purged with nitrogen. After a full purge, propylene oxide
(1.80 kg)
is added. The reaction mixture is kept at 40°C. for 20 hours. The
reaction mixture is
neutralized with 0.1 N H2S04 (1:2 v/v) to a pH of 5.5. The starch slurry is
washed with
a basket-centrifuge at a speed of 1200 rpm. The obtained starch cake is re-
slurrified
in 35 i of water and centrifuged a second time. The resulting starch cake is
dried in a
flash dryer at an inlet temperature of 160°C. and an outlet temperature
of 60°C.
C. Gelatiniaation
[0089]The modified granular starch cake is diluted in demineralized water in
order to
form a slurry at a concentration of about 8% calculated on dry substance. The
resulting slurry has a relative density of 1.032 kgh compared to water. The pH
of the
17
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
modified starch slurry is adjusted to 6Ø The slurry is then heated to
160°C, by direct
steam injection (Schlick Model 825). The temperature variation is not higher
than
~1 °C. The slurry is held in a holding column for a period of 4 minutes
at a
temperature of 160°C. and a pressure of about 5.5 bar. The pressGre is
then
reduced to atmospheric by passing through a flash. The slurry is then
contained at
95°C. in a hold tank.
D. Spray-Drying
[0090]The drying of the slurry from Part C is carried out using a Niro FSD 4
spray
drying tower equipped with a 0.8 mm nozzle and fed at 10 I/hour. The inlet
temperature is fixed at 300°C. and the outlet temperature of
120°C. The obtained
powder is a controlled release excipient with the following properties:
Properties
Moisture Content 4.5%
Bulk Density 150 g/I
Packed Density 210 g/I
pH 5.4
Particle Size Peak Value 50,um
(Laser Particle Sizer-Sympatec)
Example 2
A. Cross-Linking
[0091]High amylose starch (30.0 kg) containing about 70% w/w of amylose (CI
AmyloGel 03003) is placed in a reactor. To this reactor is added water (55.01
)
containing sodium hydroxide (30.0 g) and sodium sulfate (2.40 kg). The
resulting
slurry is heated to a temperature of 30°C. Sodium trimetaphosphate (45
g) is added
to the reaction mixture which is reacted for one hour.
B. Chemical Modification, Hydroxyproylation
[0092]The crude reaction mixture from Part A is transferred into a
hydroxypropylation
reactor. The reaction mixture is heated to 40°C. over 30 minutes and
the reaction is
purged with nitrogen. After a full purge, propylene oxide (1.80 kg) is added.
The
reaction mixture is kept at 40°C. for 20 hours. The reaction mixture is
neutralized
with 0.1 N H2S04 (1:2 v/v) to a pH of 5.5. The starch slurry is washed with a
basket-
centrifuge at a speed of 1200 rpm. The obtained starch cake is re-slurrified
in 35 I of
18
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
water and centrifuged a second time. The resulting starch cake is dried in a
flash
dryer at an inlet temperature of 160°C. and an outlet temperature of
60° C.
C. Gelatinization
[0093]The modified granular starch cake is diluted in demineralized water in
order to
form a slurry at a concentration of about 8% calculated on dry substance. The
resulting slurry has a relative density of 1.032 kg/I compared to water. The
pH of the
modified starch slurry is adjusted to 6Ø The slurry is the heated to
160°C. by direct
steam injection (Schlick Model 825). The temperature variation is not higher
than
~1 °C. The slurry is held in a holding column for a period of 4 minutes
at a
temperature of 160°C. and a pressure of about 5.5 bar. The pressure is
then
reduced to atmospheric by passing through a flash. The slurry is then
contained at
95°C. in a hold tank.
D. Spray-Drying
[0094]The slurry from Part C is carried out using a Niro FSD 4 spray-drying
tower
equipped with a 0.8 mm nozzle and fed at 10 I/hour. The inlet temperature is
fixed at
300°C. and the outlet temperature of 120°C. The obtained powder
is a controlled
release excipient with the following properties:
Properties
Moisture Content 5.2%
Bulk Density 103 g/I
Packed Density 155 g/I
pH 5.3
Particle Size Peak Value 70 Nm
(Laser Particle Sizer-Sympatec)
[0095] Lubritab~ is a product sold by Penwest Pharmaceuticals Co. (Cedar
Rapids,
IA, USA). KollidonTM SR is a product produced by BASF (Germany). EncompressT""
is a dicalcium phosphate dihydrate which can be purchased from Mendell
(Patterson,
NY). Tramadol hydrochloride can be obtained from Chemagis Ltd., 3 Hashlosha
Street, P.O. Box 9091, 61090, Tel Aviv, Israel. Methods of synthesis and
purification
of tramadol are described in, for example, U.S. Patent Nos., 3,652,589,
5,414,129,
5,672,755, 5,874,620, 5,877,351, and 6,169,205.
19
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
Manufacturing Procedure
[0096]Tablets of the invention can be manufactured according to the process
set out
generally in the flow chart of Figure 1, and described in more detail below.
[0097]Weighing: Raw materials are dispensed into clearly labeled containers.
[0098]Core Pre-Blend: Blend a portion of the Contramid~ and Colloidal Silicon
Dioxide and pass through #30 mesh screen into a suitable container.
[0099]Core Blend: Place a portion of the Contramid~ into a blender. Pass
Tramadol Hydrochloride through a #30 mesh screen and add to blender. Rinse
container with a portion of Contramid~ and add to blender. Sieve Hydrogenated
Vegetable Oil Type I through a #30 mesh screen and add to the blender. Add the
Core Pre-Blend into the blender. Add the remaining Contramid~ into the
blender,
and blend all ingredients. Sieve the Magnesium Stearate through a #30 mesh
screen and add blend with other ingredients. Dispense blend in suitable
container
and identify as Core Blend.
[00100] Dry Coated Pre-Blend: Blend a portion of the Xanthan Gum and all of
the Colloidal Silicon Dioxide and pass through #30 mesh screen.
[00101] Dry Coated Blend: Place a portion of the Kollidon~ SR into a blender.
Pass Tramadol Hydrochloride through Kason Separator with a #30 mesh screen
into
suitable container and add to blender. Rinse container with remaining xanthan
gum
and add to blender. Sieve Hydrogenated Vegetable Oil Type 1 through a #30 mesh
screen and add to the blender. Place Dry Coated Pre-Blend and the remainder of
the Kollidon~ SR into the blender, and blend with all ingredients. Sieve the
magnesium stearate through a #30 mesh screen and blend with other ingredients.
Dispense granulation in suitable container and identify as Dry Coated Blend.
[00102] Compression: Use a Manesty Dry-Cota press to produce
compression-coated tablets.
Example 3
[00103] Formulations A, B, and C, as shown in Table 1, were manufactured
according to the process set out above.
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
..
d
'- 00 tc~ a0 ~ ~ O ~ ~ O ~t ~ ~ fir., I~ W N ~
r O r N d' r N O d' CV ~ C9 pp O r d' N ~ I~
r r r
(~
O
O
O o N O ~ N ~ p ~ N ~ ~ O tOn, p ~_ (O_O~ ~ N ~ N O O
M ~ O O O r M O '~h N r O r ~ r O O O ~ T r
O CO M
tn CO ~ N Lf~ c~? O O ~ tn GO tn ~ C~ O
O O O O_ . CO 00 ~ p~ p r _ d.
O CO 'r O r ~ r O Cp cO M r ~ N ~ d' r M CO 00
M r r
O r CO
O M ~ N ~ O ~ N ~ ~ O l~ O O ~ ~ N ~ r O p
o LO ~ ~ p ~ ~ CO O due' N r O O ~ ~ O O O M T '_
r
O
U
c E
L
a
In .due' ~ Or r O tf7 ~ M 000 CO P'J COO p0 d' N ~ ~ M
~'M O O Or CpON N '-dM' lMOrr CpOM
d' O O
i
O
(~ In N ~ O r O dN' ~ O O O ~ dN. d' O CO N
~VOOOO~ NO~ NOOO NT OOO~ ~O
C
O
H
N O
L
O
C
O ~ a~
O
U
-c .fl .~ ~ .Q +. I-
o .c ~ ~ ~ y ~ ~ ~ J o ~ ~ "°
Q. '~ ~ a~ ~ 'N o a~ ~ 'N a ~ a~ ~ t-°
> ~~ o > ~ o >
'~ cn _ >, ~ ~ ~ ~ _ o '° ~ cn ~ E ~
o t-
o ~ ~ .~ Q ~ c c a~ y a -°c ~ ~ 'cn c c a
o ~ c ~ U ~ U ~ ~ ° ~ ~ V ~ c~ ~ c ~ ~ m
~ o '° ~ ~ O ~ ~ = o ~ -° ~ O ~ ~ O __ c~ .o c~ o
r I- U Z fn ~ U N E- ~ Y X Z ~ U M I- U Z fn ~ Y X V
~1
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
Dissolution profiles of formulations A, B and C are shown in Figure 2.
Tramadol Once Dail~i Formulation
[00104] The present invention relates to a controlled release tablet
composition
which provides analgesic effect within 2 hours of oral administration and
lasts for at
least 24 hours after administration.
[00105] The 200 mg dose of the inventive controlled release composition
surprisingly provides a rapid onset of analgesic effect within 2 hours after
oral
administration, and a mean tramadol plasma concentration between 100 ng/mL and
200 ng/mL for at least 24 hours after a single dose.
[00106] Furthermore, at steady-state, the mean tramadol plasma concentration
remains between 100 ng/mL and 350 ng/mL. The inventive controlled release
compositions have surprisingly been shown to provide full clinical effect for
at least
24 hours after oral administration.
Bioavailability Studies
[00107] An object of the present invention is to provide flexible dosing
options
for patients with different analgesic requirements, with a once daily
formulation.
[00108] One embodiment of the present invention is to provide a once daily
formulation which upon initial ingestion of a dose of 100 mg would provide the
desired early onset of action but achieve mean tramadol plasma concentrations
of at
least 45 ng/mL between 2 and 24 hours.
[00109] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose of 200 mg would provide the
desired early onset of action but achieve mean tramadol plasma concentrations
of at
least 100 nglmL between 2 and 24 hours.
[00110] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose of 300 mg would provide the
desired early onset of action but achieve mean tramadol plasma concentrations
of at
least 150 ng/mL between 2 and 24 hours.
[00111] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose of 400 mg would provide the
desired early onset of action but achieve mean tramadol plasma concentrations
of at
feast 180 ng/mL between 2 and 24 hours.
22
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
[00112] further embodiment of the present invention is to provide a once daily
formulation which upon initial ingestion of a dose would provide a C'max to
dose ratio
of from about 0.90 to about 1Ø
[00113] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a tramadol
plasma
concentration which rises steadily until peak tramadol concentrations are
attained at
a TmaX of about 4 hours to about 6 hours. Preferably, the Tmax occurs at about
5 hours
to about 5.5 hours.
[00114] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a tramadol
plasma
concentration which, after Tm~, declines in a slow but steady manner,
reflecting
continuing absorption in addition to elimination processes. Preferably, the
decline in
the tramadol plasma concentration after Tmax occurs in a log-linear fashion
with a
mean apparent terminal elimination half-life of between about 5.5 hours and
about
6.5 hours.
[00115] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a tramadol
plasma
concentration which, after Tm~, declines in a slow but steady manner,
reflecting
continuing absorption in addition to elimination processes, and which
absorption
continues for at least 20 hours from the time when absorption of the ingested
dose
begins.
[00116] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose provides a tramadol plasma
concentration which, after Tm~, declines in a log-linear fashion with an
apparent
terminal elimination rate constant (~,Z) of about 0.12 h-1.
[00117] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a mean
residence
time (MRT) of tramadol ranging from about 15 hours to about 18 hours.
[00118] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a half value
duration
(HVD) of tramadol which ranges from about 22.5 hours to about 25.4 hours.
[00119] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a C'maX to
AUCo_
23
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
ratio of from about 0.04 h'1 to about 0.06 h-1. Preferably, the C'max to
AUCo_~ ratio is
from about 0.04 h-1 to about 0.05 h-1. The ratio C'm~/AUCo_~ is used for
evaluating
the rate of drug absorption.
[00120] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a mean
AUCo_24 with
respect to the tramadol plasma concentration which increases proportionally
with
dose over the range of dosage strengths of 100 mg to 300 mg of the controlled
release composition.
[00121] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose of 100 mg would provide a
mean
AUCo_Tmax of from about 610 ng~h/mL to about 630 ng~h/mL.
[00122] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose of 200 mg would provide a
mean
AUCo_Tm~ of from about 910 ng~h/mL to about 920 ng~h/mL.
[00123] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose of 300 mg would provide a
mean
AUCo-Tmax of from about 1570 ng~h/mL to about 1590 ng~h/mL.
[00124] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose provides a mean ratio of
AUCo_2~/AUCo_~ of tramadol plasma concentration which ranges between about 70%
and about 85%. Preferably, the mean ratio of AUCo_2~/AUCo_~ of tramadol plasma
concentration ranges between about 74% and about 80%. As a result, about 15%
to
about 30% of the administered dose is still circulating in the plasma 24 hours
post-
dose, depending on the dose administered.
[00125] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a ratio of
the C'maX to
the dose released to the blood plasma in the first 24 hours (AUCo_2~/AUCo_~
multiplied
by the dose) of from about 1.10 to about 1.35. Preferably the ratio is from
about 1.15
to about 1.31.
[00126] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose, would provide a ratio of
the C'maX
/Tm~ to the dose administered of from about 0.10 to about 0.20. Preferably the
ratio
is from about 0.12 to about 0.19.
24
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
[00127] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a slope in
ng/ml-hr
following the peak blood plasma concentration level, which does not exceed a
factor
of about 0.035 of the total dose administered in mg. Preferably, the factor is
about
0.03.
[00128] Tramadol pharmacokinetic parameters of the controlled release
composition are presented in Table 2.
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
W O N O r O r
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~sn:.
.
v
p Q ~c.
a
U
(~ r ~ ~ o
rn ~
v c
J ' O C9 o
'
~ E~: Nn V~'r trON mM
;
,
l1'::.:..'J
.
co m m cm n m
~. m c~
,. . O lO O M V
N C9
E N ~
~~ ~
~Ul.' O t N r V N
U
W C,,-
.
" .CD cD ~D ~D
c0 N N UJ N Cn
UJ (~
~ E E
C V'
.C L t
.C ~C
~,,. a a a a
~
o in
-. 0 0 0 0
~ ~ O M O'
' r N V
Q ".
.
O O O
. ~pj'..: O N c9 N
r
E
N
.
E c
''
~ ~
v
26
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
[00129] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a ratio of
the C'maX
calculated with respect to the blood plasma concentration of O-
desmethyltramadol, to
the dose of tramadol of from about 0.19 to about 0.22. Preferably the ratio is
from
about 0.20 to 0.21.
[00130] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide .an O-
desmethyltramadol plasma concentration which rises steadily until peak
tramadol
concentrations are attained at a Tmax of about 8 hours to about 16 hours.
[00131 J A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide an O-
desmethyltramadol plasma concentration which, after Tmax, declines in a slow
but
steady manner, reflecting continuing tramadol absorption and subsequent
metabolite
formation in addition to elimination processes. Preferably, the decline in the
O-
desmethyltramadol plasma concentration occurs in a log-linear fashion with a
mean
apparent terminal elimination half-life of between about 6.7 hours and about
8.1
hours.
[00132] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide the formation
of
metabolite for at least 18 hours.
[00133] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would, after TmaX, provide
a decline
in the O-desmethyltramadol plasma concentration in a log-linear fashion with
an
apparent terminal elimination rate constant (~,Z) of about 0.1 h''.
[00134] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a half value
duration
(HVD) of O-desmethyltramadol which ranges from about 25.6 hours to about 28.1
hours.
[00135] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a C'max to
AUCo.
ratio calculated with respect to the O-desmethyltramadol plasma concentration,
of
about 0.04 h'1. The ratio C'maX/AUCo-~ is used for evaluating the rate of
metabolite
formation.
27
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
[00136] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a mean
AUCo_2a
calculated with respect to the O-desmethyltramadol plasma concentration, which
increases proportionally with dose over the range of dosage strengths of 100
mg to
300 mg of the controlled release composition.
[00137] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose of 100 mg would provide a
mean
AUCo_Tmax with respect to the O-desmethyltramadol plasma concentration of from
about 175 ng~h/mL to about 180 ng~h/mL.
[00138] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose of 200 mg would provide a
mean
AUCo_Tmax with respect to the O-desmethyltramadol plasma concentration of from
about 530 ng~h/mL to about 550 ng~h/mL.
[00139] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose of 300 mg would provide a
mean
AUCo--rmaX with respect to the O-desmethyltramadol plasma concentration of
from
about 580 ng~h/mL to about 590 ng~h/mL.
[00140] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose provides a mean ratio of
AUCo-2a/AUCo_~ of O-desmethyltramadol plasma concentration which ranges
between about 65% and about 80%. Preferably, the mean ratio of AUCo_2alAUCo_~
of
O-desmethyltramadol plasma concentration ranges between about 68% and about
75%. As a result, about 25% to about 32% of the active metabolite is still
circulating
in the plasma 24 hours post-dose.
[00141] A further embodiment of the present invention is to provide a once
daily
formulation which upon initial ingestion of a dose would provide a ratio of
the C'ma~
calculated with respect to the O-desmethyltramadol plasma concentration, to,
the O-
desmethyltramadol blood plasma concentration in the first 24 hours
(AUCo_2~/AUCo_~
multiplied by the dose of tramadol) of from about 0.0025 to about 0.0035.
Preferably
the ratio is from about 0.0027 to about 0.0031.
[00142] O-desmethyltramadol pharmacokinetic parameters of the controlled
release composition are presented in Table 3.
28
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
' ~ ~ M a0 ~ O c0
n I~ I~O c~Or ~ O
,
o
Q
..;
J M r ~ N O M W i
': t
p
V
.i
Q'.'
0 0~ ~ o r
N N tfJN tO Z Z
Z
~a
W tO0a~0.~ N r~-
v cDr c0r I~N o0CV
-'
r N r O a0tD t~Ln
m o0
L
N
O r O O O
v
~
', 0 O O O O O O O
U .
~' m ~ m ~ ~ m ~
o o o o o 0 0 0
' o , o co d d o d
0
f~
.
U
.
v ~ o~o'~ z z
3 w ,- m m
U-
.,
a
.:.
G
.;:
c~
O M ~ ~ 0 n
U t a
.. O 0
~ N
.
.
'
,
~ a
...
O
,
.
_ _ CO~t~O r ~ a00r M C0~
.J
, O ~ ~ O
~ ~ ~ ,
U:" d,
::
U .~,
d
~ :o
;
-
Q a E E E E
:
:
,
,
.
~
~ N'; r .t" L L
U.'.;:;
N
~
o a
in, c a u a v a c
n ~ ~ n
m.v o 0 0 00
m N c0 V'
-
~ O O O O
N p3 N
'
E
G
O
.
~ .
-,
"~
.~.
h
29
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
Example 4
(i) Dose Proportionality - Single Dose
[00143] A bioavailability study was conducted to assess the dose-
proportionality
between three dosage strengths (100 mg, 200 mg and 300 mg). This study was
conducted with a suitable washout period between each administration. The
doses
were taken by 27 healthy human volunteers under fasting conditions.
[00144] Figure 3 depicts the mean plasma concentration time-profiles of
tramadol obtained in the subjects after the administration of the inventive
controlled
release composition (dosed at 100 mg, 200 mg and 300 mg of tramadol HCI). The
data used to create Figure 3 is included in Table 4.
Table 4
Mean (~SD) Tramadol Plasma Concentrations (na/mL~
100 mg 200 mg 300 mg
dose dose dose
Time of the of the of the
inventive inventiveinventive
controlledcontrolledcontrolled
release release release
com ositioncom ositioncom osition
0 0 0 0
1 41.814.1 82.524.i 110.236.7
2 60.0 t 129.2 168.6
14.6 t 25.7 52.1
3 69.2 20.2156.5 218.1
t 37.0 82.3
4 72.5 21.8164.0 242.0 t
44.9 96.2
5 81.7 t 177.2 277.1 t
24.2 61.8 153.8
6 77.9 24.7169.2 260.3 t
58.1 134.8
8 83.0 t 164.1 243.6 ~
25.6 52.7 127.1
10 81.O t 157.8 219.81
24.7 57.8 101.6
12 84.4 t 156.4 223.4 t
25.3 t 55.9 85.1
16 73.0 24.1152.8 209.9
42.0 70.2
56.4 19.4121.0 185.7 t
t 34.4 62.7
24 47.2 20.9101.6 157.0
38.2 60.4
26.8 t 56.4 99.9 t
15.0 28.3 50.3
36 13.2 t 29.1 t 55.9 t
9.4 18.7 37.9
48 3.73.5 8.56.7 15.713.1
15 [00145] The results from this study indicated that the 100 mg, 200 mg and
300
mg formulations of the inventive controlled release composition are dose
proportional
with respect to the rate and extent of absorption of tramadol and the rate and
extent
of formation of O-desmethyltramadol.
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
[00146] Bioavailability studies were conducted in order to characterize the
pharmacokinetic properties of the inventive controlled release composition and
to
demonstrate similar exposure of the drug and/or its active metabolite when
compared
to a reference product.
Example 5
(ii) Comparison to a Twice-Daily Formulation - Single Dose
[00147] The 2 x 200 mg dosage of the inventive controlled release composition
was compared to the twice daily formulation, Topalgic~ LP (200 mg) tablets
manufactured by Laboratoires Hoechst Houde in a comparative bioavailability
study
after administration under fasting conditions in 24 healthy human volunteers.
[00148] The pharmacokinetic results from the inventive controlled release
composition were compared to those obtained following twice daily
administration (at
12-hour intervals) of the reference formulation in order to assess
bioequivalence
between the test and the reference product. Based on calculation of the 90%
confidence interval of the test versus reference ratios of geometric means,
the extent
of exposure (determined by assessment of AUCo_~ and AUCo_~ of tramadol
following
dose normalization) was within the conventional bioequivalence interval of 80-
125%
for the log-transformed parameters. Thus the inventive controlled release
composition and the twice daily formulation were found to be bioequivalent in
terms
of the overall exposure to tramadol. Results for tramadol AUCo_~ are presented
in
Table 5,
Table 5
Comparison of AUCo_~ (Single-dose versus twice-daily formulation)
Treatment Arithmetic Mean Geometric Mean Ratio
SD
n ~h/mL 90% Confidence Interval
2 x 200 mg dose g332 3767
of the
inventive controlled 103 (98 - 109)
release composition
1 x 200 mg
8887 3124
TopaIgicQ LP BID
[00149] Figure 5 depicts the arithmetic mean plasma concentration time-course
profiles of tramadol obtained after the administration of the inventive
controlled
31
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
release composition once a day and of the reference product in one day at 12-
hour
intervals in the 24 healthy volunteers. The data used to create Figure 5 is
included in
Table 6.
Table 6
Mean Tramadol Plasma Concentrations (na/mL)
Test Reference
formulation formulation
Conc. Conc.
2x200 mg dose
of the inventive
Timecom osition Time 200 m BID
0 0 0 0
1 138.49 58.621 101.93
43.72
2 257.56 81.202 226.89
72.90
3 350.21 166.4.23 296.35
99.46
4 373.93 124.334 318.22 t
91.27
5 427.66 t 166.905 330.88
98.68
6 424.72 176.206 281.67 t
85.95
9 408.61 196.289 236.39
87.89
12 357.88 162.4812 167.41
65.49
16 312.70 153.3413 181.96
70.51
20 243.94 117.9314 284.67
126.76
24 184.96 102.9015 378.82
136.23
30 99.78 61.60 16 396.87
146.56
36 51.01 43.33 17 388.83
142.32
48 0 18 396.38 140.65
21 331.81 121.52
24 275.00
110.61
30 118.69
64.92
36 54.04 39.07
48 0
[00~ 50] Figure 6 depicts the arithmetic mean plasma concentration time-course
profiles of O-desmethyltramadol obtained after the administration of the
inventive
controlled release composition once-a-day and of the reference product in one
day at
12-hour intervals in the 24 healthy volunteers. The data used to create Figure
6 is
included in Table 7.
32
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
Table 7
Mean ~SD) O-desmethyltramadol Plasma Concentrations (na/mL)
Test Reference
formulation formulation
Conc. Conc.
2x200 mg dose
of the inventive
Timecom osition Time 200 m BID
0 0 0 0
1 29.82117.0 1 17.71 14.6
2 57.8 17.0 2 48.3 17.5
3 76.331.6 3 66.225.9
4 84.9 t 30.9 4 74.3 26.2
98.0 41.4 5 80.64 29.2
6 100.641.7 6 74.326.1
9 99.9 t 41.7 9 68.1 24.6
12 96.52 38.8 12 56.6 +_
22.1
16 83.9 32.6 13 59.1 23.8
20 68.2 28.8 14 75.1 32.6
24 57.6 t 28.0 15 92.6 38.0
30 33.2 t 20.0 16 96.7 37.0
36 0 17 97.0 34.5
48 0 18 100.4 33.6
21 93.0 32.4
24 83.3 37.8
30 44.4 21.6
36 18.1 16.8
48 0
5 Example 6
(iii) Comparison to a Twice Daily Formulation - Steady State
[00151 ] The 200 mg dosage of the inventive controlled release composition was
compared to the twice daily formulation, Topalgic~ LP (100 mg) tablets,
manufactured by Laboratoires Hoechst Houde, in a comparative bioavailability
study
after multiple administration under fasting conditions in 26 healthy human
volunteers.
[00152] The results from this study indicated that the inventive controlled
release composition is equivalent to the reference product with respect to the
rate
and extent of absorption of tramadol and the rate and extent of formation of O-
desmethyltramadol. The comparative bioavailability of the two products was
assessed on the basis of the confidence interval for the primary variable
AUCSS for
33
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
tramadol and O-desmethyltramadol in relation to the conventional
bioequivalence
range of 80% to 125%. Results for tramadol AUCSS are presented in Table 8.
Table 8
Comparison of AUCSS,~Once-a-d y versus twice-daily formulation)
Treatment Arithmetic Mean Geometric Mean Ratio
~ SD
(ng~h/mL) (90% Confidence Interval)
200 mg dose of 5185 1460
the
inventive controlled 92.4 (87.5 - 97.5)
release composition
Topalgic~ LP 5538 t 1214
100 mg
BID
[00153] Figure 7 depicts the arithmetic mean plasma concentration time-course
profiles of tramadol and O-desmethyltramadol following administration of a 200
mg
dose of the inventive controlled release composition once a day and of the
reference
product {Topalgic~ LP 100 mg BID) in one day at 12 hour intervals. The data
used
to create Figure 7 is included in Table 9.
34
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
Table 9
Mean (~SD) Tramadol and O-desmethyltramadol Plasma Concentrations (n lq mL)
Test
formulation Reference
(200 formulation
mg 100
dose m
of BID
the
inventive
controlled
release
com
osition
Time Tramadol Metabolite Time Tramadol Metabolite
0 113.3 37.6 t 9.0 0 157.8 t 49.1 t 10.7
48.8 48.8
1 195.4 t 49.9 t 13.91 220.2 58.1 t 12.9
58.4 61.1
2 249.5 58.9 t 14.42 251.6 t 63.1 14.6
61.0 60.9
3 285.0 t 65.4 16.3 2.5 282.7 t 68.0 t 14.7
66.0 65.3
4 290.6 t 66.2 t 16.03 290.8 t 69.4 t 15.6
65.5 59.7
298.9 t 67.3 t 16.73.5 290.9 69.6 t 15.7
81.1 70.6
6 280.0 67.7 17.5 4 297.3171.371.3 15.3
70.7
9 244.9 t 63.9 16.8 4.5 305.2 72.8 t 15.6
58.4 75.2
12 226.0 59.8 t 17.25 281.8 .65.569.1 15.7
70.2
16 209.4 t 57.3 14.8 6 262.8 t 67.4 t 17.3
73.4 55.5
20 161.5 47.9 t 12.17 243.9 64.9 t 15.2
68.9 60.2
24 119.9 37.1 8.9 9 198.0 t 57.0 t 12.8
59.1 54.4
12 154.6147.846.2110.5
13 203.5 t 53.2 t 12.8
55.4
14 260.7 t 63.7 15.0
54.2
14.5 307.259.9 72.216.5
15 303.7 73.2 t 17.1
60.5
15.5 290.7 71.3 16.8
54.3
16 289.0 72.1 15.6
54.6
16.5 276.4 72.1 16.8
53.2
17 267.6 71.6 16.8
55.2
18 244.6158.468.2 15.0
19 237.1 66.4 14.8
59.4
21 201.5 57.9 12.0
52.7
24 156.9 49.6 t 10.1
49.9
[00154] The present invention is not limited in scope by the specific
5 embodiments disclosed in these examples which are intended to illustrate the
most
preferred embodiments of the invention. Indeed, various modifications of the
invention or other embodiments which are functionally equivalent to those
shown and
described herein will become apparent to those sleilled in the art and are
intended to
be.covered by the appended claims.
[00155] A number of references have been cited, the entire disclosures of
which
are incorporated herein by reference.
[00156] Although various examples of combined elements of the invention have
been described, it will also be understood that these are not intended to be
exhaustive and features of one embodiment may be combined with those of
another,
CA 02503155 2005-04-21
WO 2004/037222 PCT/CA2003/001638
and such other combinations are contemplated to be within the scope of the
invention disclosed herein.
36
