Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF INVENTION
CHRONOTHERAPEUTIC DILTIAZEM FORMULATIONS AND THE
ADMINISTRATION THEREOF
FIELD OF INVENTION
This invention relates to once daily preparations comprising Diltiazem and
pharmaceutically acceptable salts thereof, such as the hydrochloride salt,
suitable
for evening administration to patients suffering hypertension and/or angina.
This invention also relates to a method for evening administration of such
once
daily preparations to patients for the treatment of the patients' hypertension
and/or angina.
BACKGROUND OF THE INVENTION
Diltiazem, a benzothiazepine, is an orally active calcium channel blocker
(calcium-antagonist) with relatively high selectivity for vascular smooth
muscle
that is effective in the treatment of hypertension and angina pectoris. Today,
persons having these conditions take prescribed once daily preparations of
Diltiazem generally to maintain constant levels of the drug in the body over a
24-
hour period. Until recently the timing of the taking of the medicine wasn't
considered an important consideration by the medical community. Doctors
generally did not take into account the natural circadian variation in the
body's
physiological functions. Researchers have now found that the timing of the
taking of a medicine can affect the way the human body responds to the
medicine. The science of treating the human body taking into account the
natural circadian variation is Chronotherapeutics. Chronotherapeutics relies
on
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the practice of delivering the correct amount of medication to the correct
site of
action at the most appropriate time period for the particular disease or
condition.
In man, blood pressure does not remain constant during day and night. Early in
the morning blood pressure begins to rise from the low levels reached during
sleep. Increases in blood pressure are accompanied by increases in heart rate
caused by the chemicals generated by the body and delivered into the blood
stream. Epidemiological studies have indicated that the greatest incidence of
heart problems such as stroke, heart attack, myocardial ischemia and sudden
cardiac death occur during the early morning waking hours when the blood
pressure is rising in response to the natural circadian rhythm. After normally
rising in the morning, blood pressure remains elevated during the day until
generally early evening when it starts to fall to its lowest level during
sleep.
In one study, evening medication with Diltiazem for treatment of hypertension
for effect the next morning has been stated to be more efficacious than other
dosage schedules. Administration Time - Dependent Effects of Diltiazem on The
24-
Hour Blood Pressure Profile of Essential Hypertension Patients, Isao Kohno et
al.
(Chronobiology International 14(1), 71-84, (1997.) In the report of the study,
Herbesser RTM (200mg) was identified as the Diltiazem preparation. Herbesser
RTM is a Diltiazem formulation comprising a mixture of immediate release
diltiazem - containing microspheres and sustained release diltiazem -
containing
coated microspheres. According to the report, following a single dose (200 mg)
administration, the time of peak plasma diltiazem concentration occurred at
12.5
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hours after administration. The peak plasma diltiazem concentration Cmax in
the persons studied was 107mg/ml. Following multiple dosages of 200 mg
Diltiazem given over 7 days, the time of peak plasma diltiazem concentration
(Cmax) was at 10 hours after administration. Cmax was 154 mg/ml.
However a careful review of the report shows inconsistencies which cannot
support the authors' conclusions. Particularly at page 80, the best results
shown
in the graph are with respect to morning treatment with this formulation.
Moreover at page 82, the authors themselves acknowledge the study cannot lead
to reliable conclusions "because the number of patients was too small".
Further,
an immediate release portion of the dosage in the order of 15% is not
desirable
for evening administration. When the blood pressure is naturally at its
lowest,
not only is there no need for further reduction at that time, but such
reduction
can harm the patient. Particularly, if the blood pressure is reduced below a
minimum the patient is put at a greater risk for cardiovascular accidents
including stroke. Further, the 15% immediate release diltiazem is no longer
available when needed.
In A comparative study of the steady-state pharmacokinetics of immediate-
release and
controlled-release diltiazem tablets, O. R. Leeuwenkamp et al., Eur. J. Clin.
Pharmacol (1994) 46:243-247, controlled release properties and relative
systemic
availabilities of two dosages of the same controlled release diltiazem tablet
formulation were studied by comparing them as steady state with those of an
immediate release formulation. In the testing, the diltiazem plasma
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concentration increased slowly from about 6 hours after the evening dose of
both
CR tablets (Diltiazem CR 90mg and Diltiazem CR 120 mg) resulting in relatively
high plasma concentrations in the early morning hours. The clinicians
concluded
that twice-daily treatment with diltiazem CR tablets can replace thrice-daily
treatment with a conventional diltiazem IR tablet. According to the clinicians
"The early morning rise of the diltiazem plasma concentration, which might
lead
to a lower incidence of ischemic events, may be an important clinical
advantage
of both CR tablets."
On April 22, 1998, Searle Canada announced that its Chronovera (controlled
onset extended-release verapamil) a high blood pressure medication was now
available in Canada. Chronovera was, according to Searle Canada, specifically
designed to work with the body's natural circadian variations and was designed
to be taken once-a-day just before bedtime. Chronovera provided 24-hour
blood pressure control but was designed to deliver peak concentrations of
verapamil in the morning when the blood pressure, heart rate and incidence of
cardiovascular events were highest. According to Searle Canada, simply
changing the time you take the drug your physician has prescribed will not
provide the same safety and effectiveness that is designed specially for
chronotherapy using verapamil. According to Searle Canada, its Chronovera is
unlike traditional medications including extended-release (XL) and sustained-
release (SR) formulations which are usually prescribed in doses that maintain
relatively constant levels of the drug in the body over a 24-hour period or
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attempt to maintain relatively constant levels of the drug in the body over a
24-
hour period. According to Searle Canada, the prior formulations do not take
into
account the natural circadian variations in the body's physiological
functions.
Sustained-release, once-daily diltiazem formulations have been taught which
may be considered the traditional medication (according to Searle Canada).
They
appear not to give the benefits meant to be achieved by chronotherapy.
For example, in Pharmacokinetic Properties and Antihypertensive Efficacy of
Once-
Daily Diltiazem, J. G. Kelly et al., Journal of Cardio-Vascular Pharmacology,
17:6:957-963, (1991), the controlled-release formulation of diltiazem released
a
proportion of the diltiazem relatively rapidly with the remainder released
over a
period extending to 24-hours. During in vitro dissolution testing 15% of the
diltiazem in the dosage form was released in the first two hours, 54% was
released in the first six hours, 89% in the first 13 hours and all of the
remainder
was released between 13 and 24 hours after administration. The diltiazem
capsules contained either 120 mg or 240 mg of diltiazem. It should be noted
that
no difference is shown between the placebo and dosages in the article at wake-
up
(between 5:00 a.m. and 8:00 a.m.).
U.S. Patent 4,960,596 discloses slow release 12 hour diltiazem formulations
whose
dissolution, when measured in accordance with United States Pharmacopoeia 21,
purports to be within broad limits (between 5% and 35% after one hour, between
15% and 40% after two hours, between 20% and 50% after three hours, between
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30% and 75% after four hours, between 40% and 80% after six hours and between
55% and 95% after eight hours). The examples in the patent, however, provide
more specific range limitations specifying range limitations for the
formulations
exemplified such as at column 4, lines 8-10 and column 5, lines 60-62. In the
first
series of examples the release into aqueous medium was measured using the
method of USP No. 21 of 10%-20% after one hour, 30%-35% after four hours and
60%-75% after eight hours. In the later examples, the release into aqueous
medium was measured using the method of USP No. 21 at 15%-35% after one
hour, 55 %-75 % after four hours, 75 %-95 % after eight hours. These
formulations
were, however, twice a day (b.i.d.) formulations.
A series of patents have issued to Elan Corporation p.l.c. involving
controlled
absorption diltiazem pellet formulations for oral administration in which each
pellet has a core comprising diltiazem or a pharmaceutically acceptable salt
thereof in association with a specified organic acid covered by an outer
membrane which permits release of diltiazem from aqueous medium in
accordance with U.S. Pharmacopoeia XX (Paddle Method) in buffered media at
pH 1.5, pH 4.0 and pH 7Ø These are U.S. Patent 4,721,619; 4,891,230;
4,894,240;
4,917,899; 5,002,776; 5,219,621; 5,336,504; 5,364,620 and 5,616,345.
In U.S. Patent 4,721,619, dissolution rates of the pellets of examples are
found at
column 4, lines 41-49 and column 5, lines 5-12. The formulations, however are
for 12 hour. The formulations of U.S. Patents 4,891,230 are also for
administration every 12 hours.
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U.S. Patent 4,894,240 purports to provide formulations for once-daily
administration and specifies a general dissolution pattern at column 2, lines
43-52
and a more restricted dissolution pattern at column 3, lines 3-12. The
dissolution
rates are determined according to U.S. Pharmacopoeia XXI in 0.05M KC1 at pH
7.0 and at 100 r.p.m. The examples of the patent, however, provide a more
limited dissolution pattern under U.S. Pharmacopoeia XXI (Paddle Method) at
column 7, lines 30-34 and 47-51, at colunm 8, lines 16-20, 32-36 and 49-53 and
at
column 8, line 66 - column. 9, line 5. Similar examples are provided at
columns 9,
10, 11 and 12. Nothing is taught with respect to formulations suitable as
chronotherapeutics.
U.S. Patents 4,917,899, 5,364,620 and 5,616,345 are to the same effect. So are
the
remaining Elan patents. Nothing in these patents teach formulations suitable
as
chronotherapeutics.
U.S. Patent 5,529,790 purports to teach a delayed sustained-release
pharmaceutical preparation in which a water-soluble drug core is surrounded by
a hydratable diffusion barrier which delays drug release for about two to ten
hours. While diltiazem hydrochloride dissolution patterns were provided in
accordance with the U.S.P. basket dissolution method specified, no Cmax or the
timing of the maximum blood levels is provided. The dissolution rates of the
active are not appropriate for a suitable chronotherapeutic (see also U.S.
Patents
5,376,384 and 5,478,573).
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U.S. Patent 5,288,505 and 5,529,791 relate to extended-release galenical
formulations of diltiazem or pharmaceutically acceptable salts thereof which
comprise beads in which the active ingredient is in association with a wetting
agent and which beads are coated by a microporous membrane. The Cmax of
some formulations given in the patents provide for a Cmax after about 8-12
hours. Where the dosing of the formulations of the patents yields maximum
diltiazem blood plasma levels (Cmax) of about 145 ng/ml, the Cmax is at about
or less than 8 hours.
The applicants are also aware of a formulation marketed under the trade mark
TiazacTM a diltiazem HCl 24-hour sustained-release formulation based on
teachings of U.S. Patent 5,529,791 and 5,288,505.
Following chronic administration of Tiazac (240 mg once daily), the average
peak
plasma Diltiazem concentration (Cmax) is 183 ng/ml (multiple dosage) which
occurred after about 7 hours past dose administration. TiazacTM provides a
bioavailability of approximately 59% of the total Diltiazem in the first 12
hours
and 41% in the second 12 hours (after 12 hours, 59%; after 16 hours 77% and
after
hours 90%).
In an article entitled Effect of Morning Versus Evening Dosing of Diltiazem on
Myocardial Ischemia Detected by Ambulatory Electrocardiographic Monitoring in
20 Chronic Stable Angio Pectoris, PRA KASH, C. Deedwanian et al., The American
Journal of Cardiology, Vol. 80, Aug. 15, 1997, p. 421-425, the authors compare
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a.m. and p.m. dosing without using an appropriate dosage form for p.m. The
Tmax is achieved between 2-6 hours at steady state.
In an article The Influence of Time Administration on the Pharmacokinetics of
a Once A
Day Diltiazem Formulation: Morning Against Bedtime, Jean Thiffault et al.,
Biopharmaceutics & Drug Disposition, Vol. 17, 107 - 115 (1996), the once-a-day
diltiazem formulation given at 2200 hours for seven days gave according to the
article "significantly higher plasma concentrations of diltiazem in the early
morning hours when the incidence of cardiovascular events is higher". The
diltiazem dosages comprise 240 mg taken at 10:00 p.m. (22:00 hours) and
maximum concentrations (Cmax) were achieved of 120 ng/ml after about six -
eight hours of dosing. Unfortunately, the proposed system covers only the
period from 2:00 a.m. to 8:00 a.m. To be a true chronotherapeutic, the time
period covered should be between about 6:00 a.m. and noon. Moreover, this
formulation when given at night leads to significantly lower bioavailability
than
if given in the morning.
It is therefore an object of this invention to provide diltiazem preparations
suitable for once-a-day administration in the evening for providing effective
dosage amounts in the blood of diltiazem in the morning when blood pressure
begins to rise from the low levels reached during sleep, so as to be suitable
as a
chronotherapeutic preparation.
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It is a further object of this invention to provide a method of administration
of the
diltiazem preparations suitable as a chronotherapeutic so as to be effective
in the
morning at a time when the patient has most need of the diltiazem preparation.
Further and other objects of the invention will be realized by those skilled
in the
art from the following summary of the invention and detailed description of
embodiments thereof.
SUMMARY OF THE INVENTION
According to one aspect of the invention, there is provided a controlled-
release
Galenical preparation (such as a tablet and a capsule) of pharmaceutically
acceptable Diltiazem including the pharmaceutically acceptable salts thereof,
such as the hydrochloride salt, suitable for evening dosing every 24 hours
containing from about 120 mg to about 540 mg or more (as desired) of the form
of Diltiazem associated with excipients to provide controlled (sustained)
release
of the form of Diltiazem for providing a Cmax of Diltiazem in the blood at
between about 10 hours and about 15 hours (preferably about 11 - about 13
hours) after administration, the preparation comprising the form of Diltiazem
in
oral sustained-release dosage form in which the Diltiazem is adapted to be
released after administration over a prolonged period of time and the
preparation is adapted to release the Diltiazem
(i) into an aqueous medium at the following rates measured using the
method of United States Pharmacopoeia No. XXIII (at 100 rpm in 900 ml of
water):
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(a) between about 1% and about 15% after about 2 hours,
preferably between about 4% and about 8% after 2 hours;
(b) between about 7% and about 35% after about 4 hours
preferably between about 16% and about 21% after 4 hours;
(c) between about 30% and about 58% after about 8 hours
preferably between about 44% and about 52% after 8 hours;
(d) between about 55% and about 80% after about 14 hours
preferably between about 69% and about 76% after about 14 hours;
and
(e) in excess of about 75% after about 24 hours and preferably
more than about 85 % after 30 hours.
and/or (ii) into a buffered medium (such as, for example, phosphate buffer
(U.S.P.)) having a pH between about 5.5 and about 6.5, preferably about 5.8 at
the
following rates measured using the method of United States Pharmacopoeia No.
XXIII at 100 rpm in 900m1 of the buffered medium:
(a) between about 1% and about 25% after about 2 hours,
preferably between about 4% and about 15% after 2 hours;
(b) between about 7% and about 45% after about 4 hours
preferably between about 16% and about 30% after 4 hours;
(c) between about 30% and about 68% after about 8 hours
preferably between about 44% and about 62% after 8 hours;
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(d) in excess of about 75% after about 24 hours and preferably
more than 80% after 24 hours.
Preferably no initial retard or delay is built into the preparation retarding
/delaying release of Diltiazem from the preparation. Preferably the release
rate
from the preparation of the Diltiazem is less than about 15% of the total
active
per hour during dissolution. The preparation may be a diffusion controlled
preparation such as, for example, a preparation incorporating the use of
microgranules found, for example, in capsules and tablets; tablets; and coated
tablets.
The preparation may comprise a plurality of microgranules or pellets, each
microgranule comprising a central core or bead containing the form of
diltiazem
coated with a microporous membrane. The microgranules or pellets may be
included in a capsule which dissolves when swallowed to release the
microgranules or pellets. The preparation may also comprise a tablet in which
the microgranules have been compressed to form the tablet. When compressed
into tablet form, wax placebo beads (as known by persons skilled in the art)
are
preferably included to absorb the shock placed on the microgranules (core and
membrane) during the tableting process. By doing so, the integrity of the
microgranules containing the Diltiazem active remains intact and the release
rate
from the preparation is not affected. The tablet may also be coated or
uncoated.
The preparation may also comprise a sustained-release tablet coating from
which
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preparation the Diltiazem is released. In this regard, the sustained release
coating may be applied (sprayed onto) to each tablet.
Where the preparation comprises microgranules or pellets (for example) in the
capsule or tablet (made, for example, by compressing the microgranules (with
preferably wax placebo beads)), the central core may comprise Diltiazem or a
pharmaceutically acceptable salt thereof associated with a wetting agent. The
Diltiazem may be mixed (in whole or in part) with the wetting agent or may not
be mixed with the wetting agent. The wetting agent assists to maintain the
solubility of the Diltiazem. in each microgranule, ensuring that the
solubility of
the Diltiazem is unaffected by the pH of the gastrointestinal tract or other
adverse conditions which each of the microgranules of the preparation will
meet
in the gastrointestinal tract.
If the Diltiazem and/or pharmaceutically acceptable salt is not mixed with the
wetting agent then the microporous membrane should comprise with suitable
adjuvants, a water-dispersible or water-soluble polymer (such as HPMC) and a
water-, acid- and base-insoluble polymer of a neutral acrylic polymer such as
Eudragit NE30D (a neutral copolymer of acrylic acid ethyl ester and acrylic
acid
methyl ester) which hydrates the microgranule (including core). If the
composition comprises a mixture of the Diltiazem and/or pharmaceutically
acceptable salt with the wetting agent, the microporous membrane is preferably
the same. However, it may also comprise any suitable membrane which gives to
the preparation the required dissolution characteristics.
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In this regard, the preferred microporous membrane comprises Eudragit NE30D
and hydroxypropylmethylcellulose. This membrane will hydrate the core within
the microporous membrane which, for example, may contain diltiazem
surrounding a neutral pellet of sugar. The Eudragit NE30D in the membrane
expands when it encounters gastrointestinal fluid to greater than 365% of its
original size (elongation). This expandability of the membrane gives it the
ability
to hydrate the membrane and core. The mechanism of release is postulated to be
that the membrane will swell while the fluids penetrate and hydrate the core
and
dissolve the diltiazem and wetting agent. This mechanism is, it is thought,
driven by the concentration gradient through the membrane (high concentration
inside and low concentration outside).
When Eudragit RS and Eudragit RL are combined to form the microporous
membrane, the membrane can expand only very little before breakage or
fracturing. The reason is that Eudragit RS expands minimally (about 6%)
before the membrane material breaks or fractures changing its release
mechanism from the core. Thus, the mechanism of release from this membrane is
thought to be by "wasliing" the diltiazem through pores created when a
plasticizer incorporated in the membrane is released in the gastrointestinal
fluid.
The diltiazem at the outer surface of the core would be washed from the core
through the pores of the microporous membrane, then the diltiazem next
presenting itself to the fluids after "washing" of the uppermost (outermost)
diltiazem, and so on.
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Instead of the wetting agent, any other suitable dissolution agent may be used
to
assist the release of the Diltiazem from the preparation. For example, instead
of
the preferred surface active (wetting) agent (surfactant), an organic acid
(such as
adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic
acid,
tartaric acid and the like) may be incorporated in the core. In this regard,
the
presence of the organic acid in the core permits the diltiazem in the core to
dissolve when the composition passes into the higher pH regions of the
gastrointestinal tract of the intestine at which pH diltiazem is much less
soluble.
One of the membranes which may be used (though not preferred) is the
combination of Eudragit(J RS and Eudragit RL disclosed in U.S. Patent
4,721,619. (See column 1, lines 55-68 and column 2, lines 44-68.) The '619
patent
also mentions the use of hydroxypropylmethylcellulose as a water-soluble
membrane. The mechanism of release in this case is not by hydration of the
core
but rather by "washing" the Diltiazem through the pores created in the
membrane (for example when the plasticizer in the membrane is released in the
gastrointestinal fluid).
The Diltiazem may be present in the core in, for example, the hydrochloride
salt
form, in which event no dissolution agent may be required in the core.
Suitable preparations such as capsules of the microgranules making up the
total
Diltiazem active present, may comprise, in the core, Diltiazem hydrochloride
between about 50% and about 85% (% w/w of the total preparation (for
example, about 69% to about 73%)), a wetting agent (such as sucrose stearate)
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between about 2% and about 25% (% w/w of the total preparation) (for example
about 7% to about 8%) together with suitable adjuvants in the core, and in the
membrane between about 0.1% and about 2% of the total preparation of water-
soluble and/or water-dispersible polymer such as hydroxypropylmethylcellulose
(for example about 0.3% to about 0.6%), and between about 5% and about 20% (%
w/w of the preparation) of a neutral copolymer of acrylic acid ethyl ester and
acrylic acid methyl ester (such as Eudragit NE30D) (for example about 7% to
about 11%).
The microgranules may also be compressed into tablets using suitable
excipients.
The percentages may be as described above. The tablets may be manufactured,
as discussed above, using the microgranules with wax placebo beads and
compressing the combination into tablets in the presence of, for example,
hydrogenated vegetable oil, sodium starch glycolate and silicone dioxide which
have been blended with the microgranules and wax placebo beads before
tableting. The tablets may then be coated or uncoated.
According to another aspect of the invention, there is provided a controlled-
release Galenical preparation (such as a tablet and a capsule) of
pharmaceutically
acceptable Diltiazem including the pharmaceutically acceptable salts thereof,
such as the hydrochloride salt, suitable for evening dosing every 24 hours
containing from about 120 mg to about 540 mg or more (as desired) of the form
of Diltiazem associated with excipients to provide controlled (sustained)
release
of the form of Diltiazem for providing a Cmax of Diltiazem in the blood at
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between about 10 hours and about 15 hours (preferably about 11 - about 13
hours) after administration, the preparation comprising the form of Diltiazem
in
oral sustained-release dosage form in which the Diltiazem is adapted to be
released after administration over a prolonged period of time and exhibits
when
given to humans
(i) a higher bioavailability when given at night compared to when given in
the morning without food according to FDA guidelines or criteria and
(ii) bioequivalence when given in the morning with food (such as a
standardized FDA breakfast) and without food according to the same FDA
guidelines or criteria.
The FDA guidelines are those entitled:
"GUIDANCE
ORAL EXTENDED (CONTROLLED) RELEASE DOSAGE FORMS IN VIVO
BIOEQUIVALENCE AND IN VITRO DISSOLUTION TESTING" prepared under
21 CFR 10.90(b)(9) by Shrikant V. Dighe, Ph.D., Director, Division of
Bioequivalence Office of Generic Drugs dated 9/3/93 and concurred by Roger L.
Williams, M.D., Director, Office of Generic Drugs, Center for Drug Development
Research dated 9/4/93 which is incorporated herein by reference; and
"GUIDANCE
STATISTICAL PROCEDURES FOR BIOEQUIVALENCE STUDIES USING A
STANDARD TWO-TREATMENT CROSSOVER DESIGN" prepared under 21
CFR 10.90(b)(9) by Mei-Ling Chem, Ph.D., Division of Bioequivalence Review
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Branch II dated 6/12/92 and Rabindra Patnaik, Ph.D., Division of
Bioequivalence
Review Branch II dated 6/26/92, approved by Shrikant V. Dighe, Ph.D.,
Director,
Division of Bioequivalence dated 6/29/92 and concurred by Roger L. Williams,
M.D., Director, Office of Generic Drugs dated 6/29/92 which is incorporated
herein by reference.
In small part the said "GUIDANCE" documents provide as follows:
Pharmacokinetic Analysis of Data: Calculation of area under the plasma
concentration-time curve to the last quantifiable concentration (AUCat)
and to infinity (AUCo-.), Cmaxr and Tmax should be performed according to
standard techniques.
Statistical Analysis of Pharmacokinetic Data: The log transformed AUC
and C,r,x data should be analyzed statistically using analysis of variance.
These two parameters for the test product should be shown to be within
80-125% of the reference product using the 90% confidence interval. See
also Division of Bioequivalence Guidance Statistical Procedures for
Bioequivalence Studies Using a Standard Two-Treatment Crossover
Design.
Statistical Analysis of Pharmacokinetic Data: The log transformed AUC
and Cmax data should be analyzed statistically using analysis of variance.
These two parameters for the test product should be shown to be within
80-125% of the reference product using the 90% confidence interval.
Fluctuation for the test product should be evaluated for comparability
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with that for the reference product. For further information on statistical
analysis, see the Division of Bioequivalence Guidance Statistical
procedures for Bioequivalence Studies Using a Standard Two-Treatment
Crossover Design.
2. Multiple Dose Studies
At a minimum, the following pharmacokinetic parameters for the
substance(s) of interest should be measured in a multiple dose
bioequivalence study:
a. Area under the plasma/blood concentration - time curve
from time zero to time ti over a dosing interval at steady state
(AUCo-t), where T is the dosing interval.
b. Peak drug concentration (Cmax) and the time to peak drug
concentration (Tmax), obtained directly from the data without
interpolation, after the last dose is administered.
c. Drug concentrations at the end of each dosing interval
during steady state (Cmin).
d. Average drug concentration at steady state (Cav), where Cav -
AUCat/T=
e. Degree of fluctuation (CF) at steady state, where DF = 100%
X (Cmax' Cmin)/Cav.
Evidence of attainment of steady state for the test and reference
products should be submitted in the bioequivalence study report.
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B. Statistical Analysis
Parametric (normal-theory) general linear model procedures are
recommended for the analysis of pharmacokinetic data derived
from in vivo bioequivalence studies. An analysis of variance
(ANOVA) should be performed on the pharmacokinetic
parameters AUC and CmaX using General Linear Models (GLM)
procedures of SAS (4) or an equivalent program. Appropriate
statistical models pertaining to the design of the bioequivalence
study should be employed. For example, for a conventional two-
treatment, two-period, two-sequence (2 x 2) randomized crossover
study design, the statistical model often includes factors accounting
for the following sources of variation:
1. Sequence (sometimes called Group or Order)
2. Subjects, nested in sequences
3. Period (or Phase)
4. Treatment (sometimes called Drug or Formulation)
The sequence effect should be tested using the [subject
(sequence)]mean square from the ANOVA as an error term. All
other main effects should be tested against the residual error (error
mean square) from the ANOVA. The LSMEANS statement should
be used to calculate least squares means for treatments. The
ESTIMATE statement in SAS should be used to obtain estimates for
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the adjusted differences between treatment means and the standard
error associated with these differences.
The two one-sided hypotheses at the a= 0.05 level of significance
should be tested for AUC and C.X by constructing the 90%
confidence interval for the ratio between the test and reference
averages.
III. LOGARITHMIC TRANSFORMATION OF
PHARMACOKINETIC DATA
A. Statistical Assumptions
The assumptions underlying the ANOVA are (5):
1. Randomization of samples
2. Homogeneity of variances
3. Additivity (linearity) of the statistical model
4. Independency and normality of residuals
In bioequivalence studies, these assumptions can be
interpreted as follows:
1. The subjects chosen for the study should be randomly
assigned to the sequences of the study.
2. The variances associated with the two treatments, as
well as between the sequence groups, should be equal
or at least comparable.
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3. The main effects of the statistical model, such as
subject, sequence, period and treatment effect for a
standard 2 x 2 crossover study, should be additive.
There should be no interactions between these effects.
4. The residuals of the model should be independently
and normally distributed. In other words, data from
bioequivalence studies should have a normal
distribution.
If these assumptions are not met, additional steps should be
taken prior to the ANOVA including data transformation to
improve the fit of the assumptions or use of a nonparametric
statistical test in place of ANOVA. However, the normality
and constant variance assumptions in the ANOVA model
are known to be relatively robust, i.e., small or moderate
departure from each (or both) of these assumptions will not
have a significant effect on the final result.
B. Rationale for Log Transformation
1. Clinical Rationale
In a meeting in September 1991, the Generic Drugs Advisory
Comniittee (GDAC) concluded that the primary comparison
of interest in a bioequivalence study was the ratio rather
than the difference between average parameter data from
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the test and reference formulations. Using log
transformation, the general linear statistical model employed
in the analysis of bioequivalence data allows inferences
about the difference between the two means on the log scale,
which can then be retransformed into inferences about the
ratio of the two averages (means or medians) on the original
scale. Log transformation thus achieves the general
comparison based on the ratio rather than the difference (6).
2. Pharmacokinetic Rationale
Westlake (7,8) observed that a multiplicative model is
postulated for pharmacokinetic parameters in
bioavailability/bioequivalence studies, i.e., AUC and Cmax
(but not T,,,ax). Assuming that elimination of the drug is first
order and only occurs from the central compartment, the
following equation holds after an extravascular route of
administration:
AUCa, = FD/CL
= FD/(VKe)
where F is the fraction absorbed, D is the administered dose,
and FD is the amount of drug absorbed. CL is the clearance
of a given subject which is the product of the apparent
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volume of distribution (V) and the elimination rate constant
(Ke).2
The tise of AUC as a measure of the amount of drug
absorbed thus involves a multiplicative term (CL) which
might be regarded as a function of the subject. For this
reason, Westlake contends that the subject effect is not
additive if the data is analyzed on the original scale of
measurement.
Logarithmic transformation of the AUC data will bring the
CL (VKe) term into the equation in an additive fashion.
1nAUCo, =1nF+1nD-1nV-1nK3
Similar arguments were given for C,,,ax. The following
equation applies for a drug exhibiting one compartmental
characteristics:
Ccnax = (FD/ V) x e-Ke x Tmax
where again F, D and V are introduced into the model in a
multiplicative manner. However, after logarithmic
transformation, the equation becomes
1nCmax=lnF+1ND-INV-KeTmax
Log transformation of the Cmax data also results in the
additive treatment of the V term.
3. Statistical Rationale
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Logar:ithmic transformation of the data from bioequivalence
studies can be used to circumvent the use of estimates of the
reference product average for computation of the confidence
interval for the ratio of product averages. This is an
advantage for the cases where a least squares estimate for
the reference product mean is not well defined. Standard
parametric methods are ill-suited to making inferences about
the ratio of two averages, though some valid methods do
exist (9). Log transformation changes the problem to one of
making inferences about the difference (on the log scale) of
two averages, for which the standard methods are well
suited.
Many biological data correspond more closely to a log-
normal distribution than to a normal distribution. The
plasma concentration data including the derived parameters
AUC and C,T,aX tend to be skewed, and their variances tend
to increase with the means. Log transformation is likely to
remedy this situation and make the variances independent
of the mean. In addition, frequency distributions skewed to
the left (with a long tail to the right) are often made more
symmetrical by log transformation.
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This argument is actually less persuasive than the argument
based on the additivity of the statistical model because it is
based largely on the between-subject distribution of AUC
and C,T,ax values. For crossover studies, it is largely the
within-subject distribution of values that determines the
validity and efficiency of the standard parametric methods
of analysis.
Despite the arguments regarding the effect of log
transformation on normality of bioequivalence data, the
division of Bioequivalence recognizes that the limited
sample size (20-30 subjects) in a bioequivalence study
precludes a reliable determination of the underlying normal
distribution of the data set either with or without log
transformation.
C. General Procedures
Based on the arguments in the preceding section, the
Division of Bioequivalence recommends that the
pharmacokinetic parameters AUC and Cmax be log
transformed. Firms are not encouraged to test for normality
of data distribution after log transformation, nor should they
employ normality of data distribution as a justification for
carrying out the statistical analysis on the original scale.
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Robustness of a balanced study to nonnormality of the data
plus use of log transformation will be adequate in most
cases.
If a firm believes that the data of a particular bioequivalence
study should be statistically analyzed on the original scale
rather than the log scale, justification based upon a sound
scientific rationale, as well as the statistical methods to be
used, ought to be submitted to and reviewed by the Division
of Bioequivalence.
2Note that a more general equation can be written for any
multi-compartmental model as AUCo, = FD/ (VapkZ) where
Vap is the volume of distribution relating drug concentration
in plasma or blood to the amount of drug in the body during
the terminal exponential phase, and XZ is the terminal slope
of the concentration-time curve.
Thus according to another aspect of the invention, the results of biostudies
employing a formulation according to an embodiment of the invention,
clearly show that when given at different times (P.M. or A.M. dosing) and
under different conditions (with and without food) though they achieve
their maximum bioavailability at the same Tn-,a,,, when the formulation is
given at night (no food) a higher bioavailability (for example a
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significantly higher bioavailability exceeding 25% (Cn,aX) is attained than
when given in the morning without food (according to FDA guidelines)
and bioequivalence when given with food or without food in the morning
according to the FDA guidelines.
According to another aspect of the invention, a method of treatment of a
patient's
hypertension and/or angina is provided comprising administration of a
preparation of Diltiazem described above, to the patient in the evening for
example at about 7:00 - about 11:00 p.m. for effective treatment of the
patient's
hypertension and/or angina the next morning, for example between about 6:00
a.m. and about noon.
According to another embodiment of the invention a method of treatment of a
patient's hypertension and/or angina is provided comprising administration of
a
preparation which exhibits a higher bioavailability (exceeding, for example,
25%)
when given at night compared to when given in the morning without food
according to FDA guidelines or criteria and bioequivalence when given with
food (for example given a standardized FDA breakfast) and without food
according to the same FDA guidelines or criteria.
Thus a 24-hour diltiazem preparation is provided wherein the Cmax of diltiazem
in the blood is provided from about 10-15 hours after administration of a
single
dosage to a patient or about 9-15 hours after multiple dosages over a number
of
days and displays the dissolution pattern described above determined according
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to USP 23, page 1791 using Apparatus 1. Apparatus 1 is described as consisting
of the following:
a covered vessel made of glass or other inert, transparent
materiall; a motor; a metallic drive shaft; and a cylindrical basket.
The vessel is partially immersed in a suitable water bath of any
convenient size that permits holding the temperature inside the
vessel at 37 0.5 during the test and keeping the bath fluid in
constant, smooth motion. No part of the assembly, including the
environment in which the assembly is placed, contributes
significant motion, agitation, or vibration beyond that due to the
smoothly rotating stirring element. Apparatus that permits
observation of the specimen and stirring element during the test
is preferable. The vessel is cylindrical, with a hemispherical
bottom. It is 160 to 175 mm high, its inside diameter is 98 to 106
mm, and its nominal capacity is 1000 mL. Its sides are flanged at
the top. A fitted cover may be used to retard evaporation.2 The
shaft is positioned so that its axis is not more than 2 mm at any
point from the vertical axis of the vessel and rotates smoothly and
without significant wobble. A speed-regulating device is used
that allows the shaft rotation speed to be selected and maintained
at the rate specified in the individual monograph, within 4%.
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Shaft and basket components of the stirring element are
fabricated of stainless steel, type 316 or equivalent, to the
specifications shown in Figure 1. Unless otherwise specified in
the individual monograph, use 40-mesh cloth. A basket having a
gold coating 0.0001 inch (2.5 m) thick may be used. The dosage
unit is placed in a dry basket at the beginning of each test. The
distance between the inside bottom of the vessel and the basket is
maintained at 25 2 mm during the test.
I The materials should not sorb, react, or interfere with the specimen
being tested.
2 If a cover is used, it provides sufficient openings to allow ready
insertion of the thermometer and withdrawal of specimens.
(taken from USP 23)
According to another aspect of the invention, where the preparations comprise
cores wherein the diltiazem is in association with a wetting agent, the
wetting
agent may be selected from:
sugars;
saccharose, mannitol, sorbitol;
lecithins;
C12 to C2o fatty acid esters of saccarose, commercialized under the name of
sucroesters (Gattefosse, France) or under the name of crodesters (Croda,
U.K.) such as sucrose stearate marketed under the trade name of
Crodesta ;
xylose esters or xylites;
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polyoxyethylenic glycerrides;
esters of fatty acids and polyoxyethylene (Brijs, Renex and Eumulgines ,
Henkel, RFA);
sorbitan fatty acid esters (Span , Atlas, U.S.A.);
polyglycides-glycerides and polyglycides-alcohols esters (Gelucires,
Gattefosse, France)
Metal salts such as NaCl or sodium lauryl sulphate
The microporous membrane may be of any suitable material or combination of
materials known in the art. Where the wetting agent is in association with the
diltiazem in the core and not mixed therewith, the microporous membrane
should comprise a water-soluble or water dispersible polymer or copolymer such
as hydroxypropylmethylcellulose and a water-, acid- and base-insoluble polymer
such as a neutral copolymer of acrylic acid ethyl ester and acrylic acid
methyl
ester such as Eudragit NE30D. This enables the bead to be hydrated by the
introduction of intestinal fluids into the bead hydrating the bead and
therefore
mixing the diltiazem and the wetting agent. The membrane itself, because of
the
fluids passing through the membrane, will swell. This membrane acts
differently
from membranes which do not swell. These other non-hydratable or swellable
membranes may be made-up, for example, of water-soluble or water-dispersible
polymers or copolymers and a water-, acid- and base-insoluble polymer such as
Eudragit RS which swell less easily (owing to the reduced content in
quaternary ammonium groups) and are only slightly permeable to active
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ingredients. This membrane is best suited for coating cores of Diltiazem mixed
with a wetting agent or organic acid.
Among materials which may be used to make the microporous membranes, may
be mentioned particularly polyacrylates and polymethacrylates of the Eudragit
type, ethyl celluloses such as Ethocels from Dow U.S.A. and Aquacoat of FMC
U.S.A., hydroxypropylmethylcellulose, hydroxyethylcellulose and
hydroxypropylcellulose.
Additionally, adjuvants may be put in the formulation as required such as
plastifying agents (plasticizer), pigments, fillers, lubricants and anti-
foaming
agents. For example talc and/or magnesium stearate may be used as a lubricant,
dibutyl sebecate as plasticizer, titanium dioxide as a pigment, Tween 80 as
an
emulsifier and silicone oil as an anti-foaming agent.
The amount of the microporous membrane is adjusted to provide the sustained
release characteristics described.
Thus embodiments of the invention have higher bioavailability (greater AUC
and Cmax at the same time (T)) when given at night than given in the morning
without food according to the FDA guidelines discussed previously and are
bioequivalent when given in the morning with food to formulation given in the
morning without food according to the FDA guidance.
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DETAILED DESCRIPTION OF EMBODIMENTS
The invention will now be illustrated with reference to the following examples
and with reference to the following Figures:
Figure 1: is a graph illustrating the Diltiazem Concentration (ng/mL) in the
blood after a specified pei=iod after a single dose of a 300 mg Diltiazem
capsule
preparation made according to an embodiment of the invention.
Figure 2: is a graph illustrating the Diltiazem Concentration (ng/mL) in the
blood over a 24-hour period after giving multiple doses of the same 300 mg
Diltiazem capsules referred to with respect to Figure 1 but over a number of
days.
Figure 3: is a graph illustrating dissolution profiles generated according to
USP
23 using Apparatus 1(baskets) at 100 r.p.m. in 900 ml of water for capsule
preparations made according to embodiments of the invention (120 mg, 180 mg,
240 mg and 300 mg of Diltiazem active).
Figure 4: illustrates the dissolution profile of a 120 mg capsule preparation
of
Diltiazem HCl in water according to USP 23 (Apparatus 1 - baskets) according
to
an embodiment of the invention.
Figure 5: illustrates the dissolution profile of a 120 mg capsule preparation
of
Diltiazem HCl in gastric fluid according to USP 23 (Apparatus 1 - baskets)
according to an embodiment of the invention.
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Figure 6: illustrates the dissolution profile of a 120 mg capsule preparation
of
Diltiazem HCl in intestinal fluid according to USP 23 (Apparatus 1 - baskets)
according to an embodiment of the invention.
Figure 7: is a graphic comparison of the blood level concentrations of a
preparation (240 mg) made according to an embodiment of the invention and
Dilacor (240 mg), a 24-hour oral sustained release dosage form of Diltiazem.
Figure 8: is a graphic comparison of the blood level concentrations of a
preparation (240 mg)made according to an embodiment of the invention and
Tiazac (240 mg), a 24-hour oral sustained-release dosage form of Diltiazem.
Figure 9: illustrates graphically the Mean Diltiazem Concentration when
administration of the same dosage form, is given in the P.M., in the A.M. with
food and in the A.M. with :fasting (without food) by 29 persons.
Figure 10: illustrates graphically the Mean Diltiazem Concentration when the
dosage form is an open capsule sprinkled on applesauce and swallowed and the
dosage form is swallowed intact by 30 persons.
Preparations were manufactured according to the percentages and constituents
set out below:
Component % W/W
(1) Diltiazem hydrochloride 69 - 73
(2) Microcrystalline cellulose (Avicel ph101) 8- 9.5
(3) Povidone K30 1-2
(4) Sucrose stearate (Crodesta F150) 7-8
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(5) Magnesium stearate NF 0.5 - 2.5
(6) Talc USP 0.5 - 5.0
(7) Titanium dioxide (USP) 0.15 - 0.3
(8) Hydroxypropylmethylcellulose 2910 0.3 - 0.6
(9) Polysorbate 80 (tween) 0.01- 0.025
(10) Simeticone C emulsion USP (dry of 30%) 0.01- 0.015
(11) Eudragit NE30 D (dry of 30%) 7-11
(12) Purified water USP 0
Two Examples of preparations given the above percentages were made as 120
mg and 180 mg strengths of Diltiazem (as the HC1 salt) in capsule form.
Example 2 Example 3
Strength Strength
120 mg capsule 180 mg capsule
(1) 120.00 (1) 180.00
(2) 13.63 -16.18 (2) 20.44 - 24.27
(3) 1.7 - 3.41 (3) 2.56 - 5.11
(4) 11.92 -13.63 (4) 17.88 - 20.44
(5) 0.852 - 4.26 (5) 1.278 - 6.388
(6) 0.852 - 8.52 (6) 1.278 - 12.78
(7) 0.256 - 0.511 (7) 0.383 - 0.767
(8) 0.511-1.02 (8) 0.7665 - 1.533
(9) 0.0170 - 0.0426 (9) 0.0256 - 0.0639
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(10) 0.017 - 0.0256 (10) 0.0255 - 0.383
(11) 11.92 - 18.74 (11) 17.886 - 28.106
(12) 0 (12) 0
240 mg, 300 mg, 360 mg and 420 mg strength preparations in capsule form of
Diltiazem (as the HCl salt) were also prepared having the same percentages.
They provide the release patterns shown in Figure 3. The dissolution profiles
of
all of the strengths were generated from biobatches of capsules using
Apparatus
1 (baskets) at 100 RPM in 900 ml of water in accordance with USP 23.
Less than 20% of the formulation is dissolved after about four hours (for
example
between about 16%-21%) with less than about 10% dissolved in the first two
hours (for example between about 4% - about 8%). Less than about 50% is
released after 8 hours (for example between about 44%-52%). Less than about
73% is released after 14 hours (for example 69%-76%). Preferably in excess of
about 85% is released after 24 hours.
Specifically, samples of 120 mg capsules of Diltiazem HCl (made according to
the
embodiment of the invention) had the following dissolution profile:
Percent Dissolved - Time Elapsed
2h (%) 4h (%) 8h (%) 14h (%) 24h (%)
5 8 19 19 49 49 72 72 88 88
4 5 16 14 32 44 76 69 93 86
5 6 18 16 50 49 72 73 88 90
7 6 21 17 54 48 76 72 92 87
5 8 17 19 51 50 74 74 92 91
6 7 18 19 52 52 74 75 90 92
Mean (%) 6 18 50 73 90
RSD 21.3 10.5 5.1 2.7 2.6
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Samples of 180 mg capsules of Diltiazem HCl (made according to an
embodiment of the invention) had the following dissolution profiles:
Percent Dissolved - Time Elapsed
Lapsed 2h (%) 4h (%) 8h (%) 14h (%) 24h (%)
Time
_ 8 7 21 20 52 52 76 73 91 89
6 7 19 20 52 51 76 73 93 90
5 6 16 18 48 50 72 72 89 90
6 7 19 18 52 49 76 72 98 88
7 7 20 19 51 51 73 74 91 91
8 7 20 21 51 51 74 73 92 91
Mean (%) 7 19 51 74 91
RSD 12.8 7.4 2.5 2.1 1.7
Samples of 240 mg capsules of Diltiazem HCl (made according to an
embodiment of the invention) had the following dissolution profiles:
Percent Dissolved - Time Elapsed
2h (%) 4h (%) 8h (%) 14h (%) 24h (%)
6 4 19 16 46 48 73 71 86 86
6 5 18 15 48 45 70 68 85 84
5 5 18 17 49 49 71 72 86 88
4 7 16 18 46 48 68 71 83 87
6 4 18 15 49 50 70 68 84 84
6 6 18 17 48 48 70 71 85 86
Mean (%) 5 17 48 70 85
RSD 18.5 7.7 2.9 2.3 1.7
Samples of Diltiazem HCl capsules 300 mg (made according to an embodiment
of the invention) had the following dissolution profile:
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Pe:rcent Dissolved - Time Elapsed
2h(%) 4h(%) 8h(%) 14h(%) 24h(%)
3 4 16 16 46 45 68 67 83 83
6 5 17 16 49 45 73 67 90 83
6 5 16 16 46 46 69 68 84 84
5 16 16 46 46 69 69 83 87
6 4 17 15 46 45 68 68 82 86
5 5 17 17 46 47 69 70 84 87
Mean (%) 5 16 46 69 85
RSD 13.2 3.8 2.4 2.3 2.8
Additionally, the following Dissolution Profiles were obtained for the samples
of
5 120 mg Diltiazem HCl Capsules:
Medium: Water
Hour Diltiazem HCl Capsules Range RSD
% Dissolved
(Average of 12 ca sules [%]
2 6 4-8 17.6
4 18 14 - 21 9.8
8 50 44 - 54 5.1
14 73 69 - 76 2.8
24 90 86 - 93 2.5
Medium: Gastric Fluid
Hour Diltiazem 1-iCl Capsules Range RSD
% Dissolved
(Average of 12 ca sules [%]
2 5 3-6 18.8
4 16 14 -18 9.0
8 49 47 - 52 3.5
14 73 71-75 1.8
24 87 85 - 89 1.5
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Medium: Intestinal Fluid
Hour Diltiazem HCl Capsules Range RSD
% Dissolved
(Average of 12 ca sules [%]
2 5 3-7 26.0
4 17 14 - 20 12.0
8 43 40 - 47 6.1
14 64 53 - 69 8.1
24 78 65 - 85 8.1
Other Dissolution Profiles were determined of
embodiments of the invention
(Medium - USP Water)
Apparatus: USP #1 (baskets) at 100 rpm
Diltiazem 120 mg Capsules
TIME [h] 2 4 8 14 24
vessell 5% 19 49 72 88
vessel 2 4 16 52 76 93
vessel 3 5 18 50 72 88
vessel 4 7 21 54 76 92
vessel5 5 17 51 74 92
vessel 6 6 18 52 74 90
vessel 7 8 19 49 72 88
vessel 8 14 44 69 86
vessel 9 16 49 73 90
vessel 10 6 17 48 72 87
vessel 11 8 19 50 74 91
vessel 12 7 19 52 75 92
MEAN 6% 18 50 73 90
SD 1.3 1.9 2.6 2.0 2.3
RSD 21.3 10.5 5.1 2.7 2.6
RANGE 4-8 14-21 44 - 54 69-76 86-93
(Medium - Gastric)
Apparatus: USP #1 (baskets) at 100 rpm
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Diltiazem 120 mg Capsules
TIME [h] 2 4 8 14 24
vessel 1 3 14 51 74 88
vessel 2 6 17 48 72 85
vessel 3 5 17 49 72 85
vessel 4 5 15 48 72 87
vessel 5 4 47 71 86
vessel 6 6 18 50 72 86
vessel 7 15 49 73 88
vessel 8 4 14 48 71 86
vessel9 5 17 51 74 88
vessel 10 6 18 52 74 88
vessel 11 6 18 75 89
vessel 12 5 17 50 73 87
MEAN 5 16 49 73 87
SD 0.9 1.5 1.7 1.3 1.3
RSD 19.0 9.0 3.5 1.8 1.5
RANGE 3-6 14-18 47-52 71-75 85-89
(Medium - Intestinal)
Apparatus: USP #1 (baskets) at 100 rpm
Diltiazem 120 mg Capsules
TIME [h] 2 4 8 14 24
vessel 1 7 19 45 67 81
vessel 2 4 14 40 64 79
vessel 3 7 20 47 69 83
vessel 4 5 19 46 68 83
vessel 5 17 41 58 69
vessel 6 17 45 69 83
vessel 7 4 17 40 53 65
vessel 8 5 17 42 65 78
vessel 9 5 58 73
vessel 10 5 17 47 68 85
vessel 11 4 15 44 64 81
vessel 12 4 15 43 64 81
MEAN 5 17 43 64 78
SD 1.2 2.0 2.7 5.2 6.4
RSD 25.9 13.0 6.1 8.1 8.1
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RANGE 3- 7 114 - 20 140 - 47 153 - 69 165 - 85
Briefly, the dosages in Examples 1 (120 mg) and 2 (180 mg), the 240 mg, 300
mg,
360 mg and 420 mg dosages were manufactured by mixing the core (bead)
ingredients (diltiazem, microcrystalline cellulose, povidone, sucrose
stearate) by
introducing the components into a planetary mixer and granulating same and
mixing with purified water. The plastic mass was then extruded to provide an
extrudate. The extrudate was subsequently spheronized to produce diltiazem
spheres in admixture with the wetting agent. The spheres (cores) were dried in
an oven and sieved to the appropriate size cores or beads.
The membrane was prepared by mixing the hydroxypropylmethylcellulose,
titanium dioxide, talc, magnesium stearate, Polysorbate 80 and Simethacone C
emulsion and thereafter combined with the Eudragit NE30D and water. The
spheronized cores were coated with the appropriate thickness of membrane by
spraying the cores, coating same. Thus the cores (beads) were coated with the
coating suspension to produce the microgranules or pellets. The microgranules
or pellets were then dried.
In more detail the process combines Diltiazem Hydrochloride USP,
Microcrystalline cellulose NF (Avicel PH 101), Povidone K30 USP and Sucrose
Stearate (Crodesta F160) as follows:
The following were screened through a 1.9 mm screen and added to a mixer
bowl:
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Diltiazem
Avicel PH 101
Povidone K30.
To remove large agglomerates, the Crodesta 7.98 kg was screened through a 1.0
- 1.2 mm screen and added to the same mixing bowl. The items were then
blended in an AMF blender at 50 RPM. 1 kg of the above dry blend was set aside
to be used as dusting powder (Diltiazem Dusting Powder). The remainder of the
blend was continued to be blended at 50 rpm until adequately granulated. The
granulated material was then loaded into the hopper of an extruder (such as
EXDCS100 or EXDS 60). The granulation was extruded and without breaking up
the extrudate, the extrudate was collected. The extrudate was then spheronized
into the cores (beads) of the desired size and were dusted as desired by the
Diltiazem Dusting Powder set aside. The beads were then dried by spreading
them on trays and drying in an oven set at about 57 C. The Drying Temp. was in
the order of 55-60 C for about 12 hours (in the order of 12-16 hours). The
dried
cores (beads) were sieved to collect those of appropriate size (0.7 - 1.4 mm).
A Eudragit NE30D and hydroxypropylmethylcellulose coating suspension,
was made. The following:
Magnesium Stearate NF
Talc USP
Titanium Dioxide USP
Hydroxypropylmethylcellulose 2910 USP (Pharmacoat 606)
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Polysorbate 80 NF (Tween 80)
Simethicone C Emulsion USP
and pure water were combined within a Silverson Mixer. Water was first mixed
with Polysorbate 80 and the Simethicone. The HPMC was then added, then
titanium dioxide, then talc and then the Magnesium Stearate. The mixture was
stored for 2 hours. The Eudragit NE30D was screened through a 0.310 mm
sieve and added to the mixture.
The beads were then coated with the suspension by using an AerocoaterTM and
spraying the beads (which have been preheated to 26 C)with the coating
suspension to achieve the desired thickness (about 0.05 mm). The beads were
then dried by spreading on trays and drying at 40-45 C for 10 -12 hours.
Diltiazem HCl 300 mg capsules made according to an embodiment of the
invention were tested in a single dose study to determine their
bioavailability,
their Cmax and Tmax, their rate and extent of absorption. Blood sampling for
drug content analysis was carried out at 0.0 (predrug) 1, 2, 3, 4, 5, 6, 8,
10, 12, 14,
16, 18, 24, 30, 36, 42 and 48 hours post-drug. Vital sign and 12 - Lead ECG
monitoring were conducted at 0 (predrug) 2, 6, 8 and 12 hours post-drug. The
following was determined from the plasma study:
Mean Pharmacokinetic Parameters for Plasma Diltiazem
(n = 41)
Parameter 1 x 300 mg
Mean (%CV)
AUC 0-t) n .hr/mL) 2703.83 (36.26)
AUC 0-inf. (n .hr/mL 2786.95 (36.39)
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Cmax (ng/mL) 146.33 (38.43)
Tmax (hours) 13.17 (14.79)
tl/z (hours) 6.96 (17.56)
K,1(hour-1) 0.102 (15.983)
Mean Plasma Diltiazem Concentrations (ng/mL)
(n = 41)
SAMPLE TIME 1 x 300 mg
(HOURS)
0.00 0.00 0.00
1.00 0.76 2.20
2.00 4.92 3.87
3.00 10.97 5.92
4.00 20.01 10.77
5.00 33.46 18.39
6.00 70.21 37.03
8.00 95.43 41.50
10.00 110.16 47.43
12.00 132.84 52.04
14.00 139.54 55.11
16.00 126.35 50.23
18.00 105.74 40.86
24.00 62.84 24.20
30.00 43.92 16.94
36.00 25.67 11.46
42.00 13.40 7.37
48.00 7.50 4.46
Mean Pharmacokinetic Parameters for Plasma Diltiazem
(n = 36)
Parameter Geometric Mean
Arithmetic Mean (C.V.)
1x300m
AUC (0-t hours)(ng.hr/mL) 2682.87
2872.06 (38.44)
AUC (0-x)(ng.hr/mL) 1955.92
2075.00 (35.63)
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AUC (0-infinity)(ng.hr/mL) 2847.57
3055.19 (39.05)
CmaX (ng/mL) 134.96
144.00 (37.17)
TmaX (hours)** 13.00 (2.92)
tl/z (hours)* 8.69 (22.85)
Kei hour-1)* 0.084 (22.860)
* These are arithmetic means (CV%).
** This is median ( S.D.).
With reference to Figures 1 and 2, it is clear the 300 mg capsule preparation
made
according to an embodiment of the invention provides the appropriate Diltiazem
blood levels at the appropriate time to be suitable for administration as a
chronotherapeutic - being given in the evening to provide effective
concentrations of Diltiazem the following morning. This suitability is
illustrated
with reference to Figures 7 and 8. In Figure 7, the 240 mg Diltiazem
preparation
made according to the embodiment of the invention provides elevated blood
levels that are effective all morning for effective treatment of the patient
with
Diltiazem. However, the Dilacor formulation (given either in the evening or
the
following morning) does not protect the patient from 6:00 a.m. - noon, the
more
dangerous period.
The same is true with Figure 8. Tiazac given in the morning, does not provide
the protection. Further, peak plasma concentrations for Tiazac are achieved
after
about 7 hours after dose administration.
A 3-way single-dose study was undertaken using the same formulation (420 mg
capsule) administered in the P.M. (10:00 P.M.) without food, and in the A.M.
dosing with and without food.
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3-Way Single-Dose Study
A: Formulation According to Embodiment of Invention - Fasting (AM Dosing)
B: Formulation According to Embodiment of Invention - Fed (AM Dosing)
C: Formulation According to Embodiment of Invention - (PM Dosing)
N=29
The results illustrated in Figures 9A and Figure 9B were found whose mean were
graphically illustrated in Figure 9.
A 2-way single-dose fasting study was undertaken using the same formulation
(420 mg capsule) administered in the following manners - capsule intact and
capsule opened and sprinkled on applesauce and ingested.
2-Way Single Dose Fasting Study
A: Formulation According to Embodiment of Inventions - Open Capsule
Sprinkled on Applesauce
B: Formulation According to Embodiment of Inventions - Capsule Intact
N=30 (FINAL DATA)
The results illustrated in Figures 10A,10B and 10C were found whose mean were
graphically illustrated in Figure 10.
The preparations according to embodiments may also be made as tablets. The
tablets may be made as compressed tablets in the desired strengths (for
example
120 mg - 540 mg or more Diltiazem) incorporating the microgranules. The
tablets may even be scored to permit division into smaller doses.
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Tablets may be made as follows using the microgranules or pellets, wax placebo
beads and hydrogenated vegetable oil, sodium starch glycolate and silicone
dioxide as follows:
The microgranules of Diltiazem may be the following:
Magnesium Stearate
Talc
Titanium Dioxide
Hydroxypropylmethyl-Cellulose 2910
Polysorbate 80
Simethicone Emulsion
Eudragit NE30D
Diltiazem Hydrochloride
Microcrystalline Cellulose
Povidone K30
Sucrose Stearate
Purified Water
The wax placebo beads may be the following:
Microcrystalline Wax NF
Pregelatinized Starch
Sodium Starch Glycolate
Titanium Dioxide
Carbon Dioxide
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The microgranules, wax placebo beads, hydrogenated vegetable oil, sodium
starch glycolate and silicone dioxide may be combined and compressed into the
desired strengths of tablets, for example 240 mg, 300 mg and 360 mg tablets.
Briefly, to form the microgranules, Diltiazem HCI, Microcrystalline Cellulose,
Povidone 30, Sucrose Stearate may be mixed to form a "dry blend". A 1 kg
portion of the dry blend may be removed and stored in a separate labeled
container as the Dusting Powder, for use in subsequent manufacturing steps (if
desired). Following the removal of the Dusting Powder, Purified Water is added
to the dry blend and mixed to create a plastic mass. The plastic mass is
extruded
through a 1.0 mm screen to form a spaghetti like extrudate. This extrudate is
then spheronized into beads. During the spheronization process Dusting
Powder is added to dry the beads and provide them with a smooth aspect (if
required). The addition of Dusting Powder also prevents the newly spheronized
beads from sticking together. The spheronized beads are tray dried for 12 - 16
hours and sieved to select beads that are larger than 0.7 mm and smaller than
1.4
mm in diameter.
The beads are loaded into a preheated (40 - 45 C) fluid bed Aerocoater.
Coating
suspension is applied at an amount of 10% by spray coating. The resulting
Diltiazem Microgranules (coated beads) are dried for between 10 - 12 hours and
the dried coated beads are sieved to select coated beads that are larger than
0.7
mm and smaller than 1.7 mm in diameter.
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For the manufacture of the placebo wax beads, Microcrystalline Wax,
Pregelatinized Maize Starch, Sodium Starch Glycolate and Titanium Dioxide are
mixed in a high shear mixer and heated to 64 C (jacket temperature 70 C). The
resulting melt is cooled by the addition of liquid CO2 to form the solid
starters of
the pellets. The pellet starters are mixed and the size is increased by the
gradual
turning of the impeller for a fixed timeperiod (mixing time is directly
related to
the impeller speed and the time to reach a temperature of 57 2 C). The
resulting beads are sieved to select beads larger than 0.7 mm and smaller than
1.4
mm in diameter.
For manufacturing the Diltiazem chronotherapeutic tablets, the placebo wax
beads and the microgranules of Diltiazem are blended at a ratio of about 2:3
(placebo wax beads: microgranules of Diltiazem) with Hydrogenated Vegetable
Oil (lubricant), Sodium Starch Glycolate (disintegrant) and Silicone Dioxide
(lubricant) added. The blend is tableted under low pressure (approximately 6 -
8
Sc) to form the compressed Diltiazem Tablets.
In the compressed tablets, the placebo wax beads serve to absorb the shock
placed on the microgranules of Diltiazem during the tableting process. By
doing
so the integrity of the microgranules remains in tact and the release rate of
the
diltiazem is not affected.
As many changes can be made to the embodiments of the invention without
departing from the scope thereof, it is intended that all material contained
herein
be determined as illustrative of the invention and not in a limiting sense.
