U.S. patent application number 09/726193 was filed with the patent office on 2001-09-27 for controlled release metformin formulations.
This patent application is currently assigned to Andrx Corporation. Invention is credited to Chen, Chih-Ming, Cheng, Xiu Xiu, Chou, Joseph, Jan, Steve.
Application Number | 20010024659 09/726193 |
Document ID | / |
Family ID | 21937256 |
Filed Date | 2001-09-27 |
United States Patent
Application |
20010024659 |
Kind Code |
A1 |
Chen, Chih-Ming ; et
al. |
September 27, 2001 |
Controlled release metformin formulations
Abstract
Sustained release pharmaceutical formulations comprising an
antihyperglycemic drug or a pharmaceutically acceptable salt
thereof are disclosed. The formulations provide therapeutic plasma
levels of the antihyperglycemic drug to a human patient over a 24
hour period after administration.
Inventors: |
Chen, Chih-Ming; (Davie,
FL) ; Cheng, Xiu Xiu; (Davie, FL) ; Jan,
Steve; (Coral Springs, FL) ; Chou, Joseph;
(Manassas, VA) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Assignee: |
Andrx Corporation
4001 SW 47th Avenue
Fort Lauderdale
FL
33314
|
Family ID: |
21937256 |
Appl. No.: |
09/726193 |
Filed: |
November 29, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09726193 |
Nov 29, 2000 |
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09594637 |
Jun 15, 2000 |
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|
09594637 |
Jun 15, 2000 |
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09045330 |
Mar 20, 1998 |
|
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6099859 |
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Current U.S.
Class: |
424/457 ;
514/635 |
Current CPC
Class: |
A61K 9/282 20130101;
A61K 31/155 20130101; A61K 9/2866 20130101; A61K 9/0004 20130101;
A61K 9/2886 20130101; A61K 9/2072 20130101; A61P 3/10 20180101 |
Class at
Publication: |
424/457 ;
514/635 |
International
Class: |
A61K 009/52; A61K
031/155 |
Claims
We claim:
1. A sustained release pharmaceutical formulation comprising an
antihyperglycemic drug or a pharmaceutically acceptable salt
thereof, wherein said formulation provides therapeutic plasma
levels of said antihyperglycemic drug to a human patient over a 24
hour period after administration to said patient.
2. The sustained release pharmaceutical formulation of claim 1
wherein said administration is with or shortly after the evening
meal.
3. The sustained release pharmaceutical formulation of claim 1
wherein the bioavailability of the antihyperglycemic drug is
increased by the presence of food.
4. The sustained release pharmaceutical formulation of claim 1
wherein said formulation provides a T.sub.max of the
antihyperglycemic drug which occurs at a time from about 8 hours to
about 12 hours after administration to said human patient.
5. The sustained release pharmaceutical formulation of claim 1
wherein said antihyperglycemic drug is metformin.
6. A sustained release pharmaceutical formulation comprising a dose
of metformin or a pharmaceutically acceptable salt thereof suitable
for once daily dosing, said formulation providing a T.sub.max of
the metformin which occurs at a time from about 8 hours to about 12
hours after administration to a human patient.
7. The sustained release pharmaceutical formulation of claim 6
wherein said administration is with or shortly after the evening
meal.
8. A sustained release pharmaceutical formulation comprising
metformin or a pharmaceutically acceptable salt thereof, said
formulation suitable for once daily dosing and providing a peak of
a mean plasma concentration/time curve of metformin at a time from
about 4 hours to about 10 hours after administration.
9. A sustained release pharmaceutical formulation comprising a dose
of metformin or a pharmaceutically acceptable salt thereof suitable
for once daily dosing, said formulation when administered with or
after a meal to a human patient, providing a C.sub.max of metformin
from about 52.8% to about 75.1% of the C.sub.max provided by an
equivalent dose of metformin in an immediate release reference
formulation.
10. The sustained release pharmaceutical formulation of claim 9
wherein said formulation provides a T.sub.max of the metformin
which occurs at a time from about 8 hours to about 12 hours after
administration to said human patient.
11. The sustained release pharmaceutical formulation of claim 9
wherein the bioavailability of the drug is increased by the
presence of food.
12. A sustained release pharmaceutical formulation comprising a
dose of metformin or a pharmaceutically acceptable salt thereof
suitable for once daily dosing, said formulation when administered
with or after a meal to a human patient, providing a T.sub.max of
metformin from about 182% to about 200% of the T.sub.max provided
by an equivalent dose of metformin in an immediate release
reference formulation.
13. The sustained release pharmaceutical formulation of claim 12
wherein said formulation provides a T.sub.max of the metformin
which occurs at a time from about 8 hours to about 12 hours after
administration to said human patient.
14. The sustained release pharmaceutical formulation of claim 12
wherein the bioavailability of the metformin is increased by the
presence of food.
15. A sustained release pharmaceutical formulation comprising a
dose of metformin or a pharmaceutically acceptable salt thereof
suitable for once daily dosing, said formulation when administered
in the fasted state to a human patient, providing a T.sub.max of
metformin from about 173% to about 215% of the T.sub.max provided
by an equivalent dose of metformin in an immediate release
reference formulation.
16. The sustained release pharmaceutical formulation of claim 15
wherein said formulation provides a T.sub.max of the metformin
which occurs at a time from about 8 hours to about 12 hours after
administration to a human patient.
17. The sustained release pharmaceutical formulation of claim 15
wherein the bioavailability of the metformin is increased by the
presence of food.
18. A sustained release pharmaceutical formulation comprising a
dose of metformin or a pharmaceutically acceptable salt thereof
suitable for once daily dosing, said formulation upon
administration to a human patient, providing a width at 50% of the
height of a mean plasma concentration/time curve from about 6 hours
to about 12 hours.
19. The sustained release pharmaceutical formulation of claim 18
wherein said formulation provides a T.sub.max of the metformin
which occurs at a time from about 8 hours to about 12 hours after
administration.
20. The sustained release pharmaceutical formulation of claim 18
wherein the bioavailability of the metformin is increased by the
presence of food.
21. A sustained release pharmaceutical formulation comprising a
dose of metformin or a pharmaceutically acceptable salt thereof
suitable for once daily dosing, wherein a single administration of
said formulation provides a lower mean fluctuation index in the
plasma than a single administration of a substantially equal dose
of an immediate release composition of metformin.
22. The sustained release pharmaceutical formulation of claim 21
wherein said formulation provides a T.sub.max of the metformin
which occurs at a time from about 8 hours to about 12 hours after
administration to a human patient.
23. The sustained release pharmaceutical formulation of claim 21
wherein the bioavailability of the metformin is increased by the
presence of food.
24. A sustained release pharmaceutical formulation comprising a
dose of metformin or a pharmaceutically acceptable salt thereof
that exhibits the following dissolution profile when tested in a
USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal
fluid (pH 7.5 phosphate buffer) and at 37.degree. C.: after 2 hours
0-25% of the metformin or salt thereof is released; after 4 hours
10-45% of the metformin or salt thereof is released; after 8 hours
30-90% of the metformin or salt thereof is released; after 12 hours
not less than 50% of the metformin or salt thereof is released;
after 16 hours not less than 60% of the metformin or salt thereof
is released; and after 20 hours not less than 70% of the metformin
or salt thereof is released.
25. The sustained release pharmaceutical formulation of claim 24
wherein after administration to a human patient, said formulation
provides a bioavailability of metformin which is increased by the
presence of food.
26. The sustained release pharmaceutical formulation of claim 24
wherein after administration to a human patient, said formulation
provides a T.sub.max of metformin which occurs at a time from about
8 hours to about 12 hours after said administration.
27. A sustained release pharmaceutical formulation comprising a
dose of metformin or a pharmaceutically acceptable salt thereof
that exhibits the following dissolution profile when tested in a
USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal
fluid (pH 7.5 phosphate buffer) and at 37.degree. C.: after 2 hours
0-15% of the metformin or salt thereof is released; after 4 hours
20-40% of the metformin or salt thereof is released; after 8 hours
45-90% of the metformin or salt thereof is released; after 12 hours
not less than 60% of the metformin or salt thereof is released;
after 16 hours not less than 70% of the metformin or salt thereof
is released; and after 20 hours not less than 80% of the metformin
or salt thereof is released.
28. The sustained release pharmaceutical formulation of claim 27
wherein after administration to a human patient, said formulation
provides a bioavailability of metformin which is increased by the
presence of food.
29. The sustained release pharmaceutical formulation of claim 27
wherein after administration to a human patient, said formulation
provides a T.sub.max of metformin which occurs at a time from about
8 hours to about 12 hours after said administration.
Description
[0001] The present application is a continuation of U.S. Ser. No.
09/594,637 filed Jun. 15, 00 which is a continuation of U.S. Ser.
No. 09/045,330 filed Mar. 20, 1998, now issued as U.S. Pat. No.
6,099,859, the enclosures of which are hereby incorporated by
reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to controlled release unit
dose formulations containing an antihyperglycemic drug. More
specifically, the present invention relates to an oral dosage form
comprising a biguanide such as metformin or buformin or a
pharmaceutically acceptable salt thereof such as metformin
hydrochloride or the metformin salts described in U.S. Pat. Nos.
3,957,853 and 4,080,472 which are incorporated herein by
reference.
[0003] In the prior art, many techniques have been used to provide
controlled and extended-release pharmaceutical dosage forms in
order to maintain therapeutic serum levels of medicaments and to
minimize the effects of missed doses of drugs caused by a lack of
patient compliance.
[0004] In the prior art are extended release tablets which have an
osmotically active drug core surrounded by a semipermeable
membrane. These tablets function by allowing a fluid such as
gastric or intestinal fluid to permeate the coating membrane and
dissolve the active ingredient so it can be released through a
passageway in the coating membrane or if the active ingredient is
insoluble in the permeating fluid, pushed through the passageway by
an expanding agent such as a hydrogel. Some representative examples
of these osmotic tablet systems can be found in U.S. Pat. Nos.
3,845,770, 3,916,899, 4,034,758, 4,077,407 and 4,783,337. U.S. Pat.
No. 3,952,741 teaches an osmotic device wherein the active agent is
released from a core surrounded by a semipermeable membrane only
after sufficient pressure has developed within the membrane to
burst or rupture the membrane at a weak portion of the
membrane.
[0005] The basic osmotic device described in the above cited
patents have been refined over time in an effort to provide greater
control of the release of the active ingredient. For example U.S.
Pat. Nos. 4,777,049 and 4,851,229 describe an osmotic dosage form
comprising a semipermeable wall surrounding a core. The core
contains an active ingredient and a modulating agent wherein the
modulating agent causes the active ingredient to be released
through a passageway in the semipermeable membrane in a pulsed
manner. Further refinements have included modifications to the
semipermeable membrane surrounding the active core such as varying
the proportions of the components that form the membrane, i.e U.S.
Pat. Nos. 5,178,867, 4,587,117 and 4,522,625 or increasing the
number of coatings surrounding the active core, i.e U.S. Pat. No.
5,650,170 and 4,892,739.
[0006] Although vast amounts of research has been performed on
controlled or sustained release compositions and in particular on
osmotic dosage forms, very little research has been performed in
the area of controlled or sustained release compositions that
employ antihyperglycemic drugs.
[0007] The limited work on controlled or sustained release
formulations that employ antihyperglycemic drugs such as metformin
hydrochloride has been limited to the combination of the
antihyperglycemic drug and an expanding or gelling agent to control
the release of the drug from the dosage form. This limited research
is exemplified by the teachings of WO 96/08243 and by the
GLUCOPHAGE.RTM. product which is a commercially available product
from Bristol-Myers Squibb Co. containing metformin HCl.
[0008] It is reported in the 50th Edition of the Physicians' Desk
Reference, copyright 1996, p. 753, that food decreases the extent
and slightly delays the absorption of metformin delivered by the
GLUCOPHAGE.RTM. dosage form. This decrease is shown by
approximately a 40% lower peak concentration and a 25% lower AUC in
plasma and a 35 minute prolongation of time to peak plasma
concentration following administration of a single GLUCOPHAGE.RTM.
tablet containing 850 mg of metformin HCl with food compared to the
similar tablet administered under fasting conditions.
[0009] It is an object of the present invention to provide a
controlled or sustained release formulation for an
antihyperglycemic drug wherein the bioavailability of the drug is
not decreased by the presence of food.
[0010] It is a further object of the present invention to provide a
controlled or sustained release formulation for an
antihyperglycemic drug that does not employ an expanding
polymer.
[0011] It is also a further object of the present invention to
provide a controlled or sustained release formulation for an
antihyperglycemic drug that can provide continuous and
non-pulsating therapeutic levels of an antihyperglycemic drug to an
animal or human in need of such treatment over a twelve hour to
twenty-four hour period.
[0012] It is an additional object of the present invention to
provide a controlled or sustained release formulation for an
antihyperglycemic drug that obtains peak plasma levels
approximately 8-12 hours after administration.
[0013] It is also an object of this invention to provide a
controlled or sustained release pharmaceutical tablet having only a
homogeneous osmotic core wherein the osmotic core component may be
made using ordinary tablet compression techniques.
SUMMARY OF THE INVENTION
[0014] The foregoing objectives are met by a controlled release
dosage form comprising:
[0015] (a) a core comprising:
[0016] (i) an antihyperglycemic drug;
[0017] (ii) optionally a binding agent; and
[0018] (iii) optionally an absorption enhancer;
[0019] (b) a semipermeable membrane coating surrounding the core;
and
[0020] (c) at least one passageway in the semipermeable
membrane.
[0021] The dosage form of the present invention can provide
therapeutic levels of the antihyperglycemic drug for twelve to
twenty-four hour periods and does not exhibit a decrease in
bioavailability if taken with food. In fact, a slight increase in
the bioavailability of the antihypoglycemic drug is observed when
the controlled release dosage form of the present invention is
administered with food. In a preferred embodiment, the dosage form
will be administered once a day, ideally with or after a meal and
most preferably with or after the evening meal, and provide
therapeutic levels of the drug throughout the day with peak plasma
levels being obtained between 8-12 hours after administration.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 is a graph which depicts the dissolution profile in
simulated intestinal fluid (pH 7.5 phosphate buffer) and simulated
gastric fluid (SGF) of the formulation described in Example 1 as
tested according to the procedure described in United States
Pharmacopeia XXIII, Apparatus 2@75 rpm.
[0023] FIG. 2 is a graph which depicts the dissolution profile in
simulated intestinal fluid (pH 7.5 phosphate buffer) and simulated
gastric fluid (SGF) of the formulation described in Example 2 as
tested according to the procedure described in United States
Pharmacopeia XXIII, Apparatus 2@75 rpm.
[0024] FIG. 3 is a graph which depicts the dissolution profile in
simulated intestinal fluid (pH 7.5 phosphate buffer) and simulated
gastric fluid (SGF) of the formulation described in Example 3 as
tested according to the procedure described in United States
Pharmacopeia XXIII, Apparatus 2@75 rpm.
[0025] FIG. 4 is a graph depicting the in vivo metformin plasma
profile of the formulation described in Example 1 and the in vivo
metformin plasma profile of the commercially available metformin
HCl product GLUCOPHAGE.RTM. under fasting conditions.
[0026] FIG. 5 is a graph depicting the in vivo metformin plasma
profile of the formulation described in Example 2 and the in vivo
metformin plasma profile of the commercially available metformin
HCl product GLUCOPHAGE.RTM. under fasting conditions.
[0027] FIG. 6 is a graph depicting the in vivo metformin plasma
profile of the formulation described in Example 2 and the in vivo
metformin plasma profile of the commercially available metformin
HCl product GLUCOPHAGE.RTM. under fed conditions.
[0028] FIG. 7 is a graph depicting the in vivo metformin plasma
profile of the formulation described in Example 3 and the in vivo
metformin plasma profile of the commercially available metformin
HCl product GLUCOPHAGE.RTM. under fed conditions (after
breakfast).
[0029] FIG. 8 is a graph depicting the in vivo metformin plasma
profile of the formulation described in Example 3 and the in vivo
metformin plasma profile of the commercially available metformin
HCl product GLUCOPHAGE.RTM. under fed conditions (after
dinner).
DETAILED DESCRIPTION OF THE INVENTION
[0030] The term antihyperglycemic drugs as used in this
specification refers to drugs that are useful in controlling or
managing noninsulin-dependent diabetes mellitus (NIDDM).
Preferably, the antihyperglycemic drug is a biguanide such as
metformin or buformin or a pharmaceutically acceptable salt thereof
such as metformin hydrochloride.
[0031] The binding agent may be any conventionally known
pharmaceutically acceptable binder such as polyvinyl pyrrolidone,
hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose,
polymethacrylate, waxes and the like. Mixtures of the
aforementioned binding agents may also be used. The preferred
binding agents are water soluble such as polyvinyl pyrrolidone
having a weight average molecular weight of 25,000 to 3,000,000.
The binding agent comprises approximately about 0 to about 40% of
the total weight of the core and preferably about 3% to about 15%
of the total weight of the core.
[0032] The core may optionally comprise an absorption enhancer. The
absorption enhancer can be any type of absorption enhancer commonly
known in the art such as a fatty acid, a surfactant, a chelating
agent, a bile salt or mixtures thereof. Examples of some preferred
absorption enhancers are fatty acids such as capric acid, oleic
acid and their monoglycerides, surfactants such as sodium lauryl
sulfate, sodium taurocholate and polysorbate 80, chelating agents
such as citric acid, phytic acid, ethylenediamine tetraacetic acid
(EDTA) and ethylene glycol-bis(.beta.-aminoethyl
ether)-N,N,N,N-tetraacetic acid (EGTA). The core comprises
approximately 0 to about 20% of the absorption enhancer based on
the total weight of the core and most preferably about 2% to about
10% of the total weight of the core.
[0033] The core of the present invention which comprises the
antihyperglycemic drug, the binder which preferably is a
pharmaceutically acceptable water soluble polymer and the
absorption enhancer is preferably formed by wet granulating the
core ingredients and compressing the granules with the addition of
a lubricant into a tablet on a rotary press. The core may also be
formed by dry granulating the core ingredients and compressing the
granules with the addition of a lubricant into tablets or by direct
compression.
[0034] Other commonly known excipients may also be included into
the core such as lubricants, pigments or dyes.
[0035] The homogeneous core is coated with a semipermeable
membrane; preferably a modified polymeric membrane to form the
controlled release tablet of the invention. The semipermeable
membrane is permeable to the passage of an external fluid such as
water and biological fluids and is impermeable to the passage of
the antihyperglycemic drug in the core. Materials that are useful
in forming the semipermeable membrane are cellulose esters,
cellulose diesters, cellulose triesters, cellulose ethers,
cellulose ester-ether, cellulose acylate, cellulose diacylate,
cellulose triacylate, cellulose acetate, cellulose diacetate,
cellulose triacetate, cellulose acetate propionate, and cellulose
acetate butyrate. Other suitable polymers are described in U.S.
Pat. Nos. 3,845,770, 3;916,899, 4,008,719, 4,036,228 and 4,11210
which are incorporated herein by reference. The most preferred
semipermeable membrane material is cellulose acetate comprising an
acetyl content of 39.3 to 40.3%, commercially available from
Eastman Fine Chemicals.
[0036] In an alternative embodiment, the semipermeable membrane can
be formed from the above-described polymers and a flux enhancing
agent. The flux enhancing agent increases the volume of fluid
imbibed into the core to enable the dosage form to dispense
substantially all of the antihyperglycemic drug through the
passageway and/or the porous membrane. The flux enhancing agent can
be a water soluble material or an enteric material. Some examples
of the preferred materials that are useful as flux enhancers are
sodium chloride, potassium chloride, sucrose, sorbitol, mannitol,
polyethylene glycol (PEG), propylene glycol, hydroxypropyl
cellulose, hydroxypropyl methycellulose, hydroxypropyl
methycellulose phthalate, cellulose acetate phthalate, polyvinyl
alcohols, methacrylic acid copolymers and mixtures thereof. The
preferred flux enhancer is PEG 400.
[0037] The flux enhancer may also be a drug that is water soluble
such as metformin br its pharmaceutically acceptable salts or a
drug that is soluble under intestinal conditions. If the flux
enhancer is a drug, the present dosage form has the added advantage
of providing an immediate release of the drug which is selected as
the flux enhancer.
[0038] The flux enhancing agent comprises approximately 0 to about
40% of the total weight of the coating, most preferably about 2% to
about 20% of the total weight of the coating. The flux enhancing
agent dissolves or leaches from the semipermeable membrane to form
paths in the semipermeable membrane for the fluid to enter the core
and dissolve the active ingredient.
[0039] The semipermeable membrane may also be formed with commonly
known excipients such a plasticizer. Some commonly known
plasticizers include adipate, azelate, enzoate, citrate, stearate,
isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl
tri-n-butyl citrate, citric acid esters, and those described in the
Encyclopedia of Polymer Science and Technology, Vol. 10 (1969),
published by John Wiley & Sons. The preferred plasticizers are
triacetin, acetylated monoglyceride, grape seed oil, olive oil,
sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin
sorbitol, diethyloxalate, diethylmalate, diethylfumarate,
dibutylsuccinate, diethylmalonate, dioctylphthalate,
dibutylsebacate, triethylcitrate, tributylcitrate,
glyceroltributyrate, and the like. Depending on the particular
plasticizer, amounts of from 0 to about 25%, and preferably about
2% to about 15% of the plasticizer can be used based upon the total
weight of the coating.
[0040] As used herein the term passageway includes an aperture,
orifice, bore, hole, weaken area or an erodible element such as a
gelatin plug that erodes to form an osmotic passageway for the
release of the antihyperglycemic drug from the dosage form. A
detailed description of the passageway can be found in United
States Patents such as U.S. Pat. Nos. 3,845,770, 3,916,899,
4,034,758, 4,077,407, 4,783,337 and 5,071,607.
[0041] Generally, the membrane coating around the core will
comprise from about 1% to about 5% and preferably about 2% to about
3% based on the total weight of the core and coating.
[0042] In an alternative embodiment, the dosage form of the present
invention may also comprise an effective amount of the
antihyperglycemic drug that is available for immediate release. The
effective amount of antihyperglycemic drug for immediate release
may be coated onto the semipermeable membrane of the dosage form or
it may be incorporated into the semipermeable membrane.
[0043] In a preferred embodiment the dosage form will have the
following composition:
1 Preferred Most Preferred CORE: drug 50-98% 75-95% binder 0-40%
3-15% absorption enhancer 0-20% 2-10% COATING: semipermeable
polymer 50-99% 75-95% flux enhancer 0-40% 2-20% plasticizer 0-25%
2-15%
[0044] The dosage forms prepared according to the present invention
should exhibit the following dissolution profile when tested in a
USP type 2 apparatus at 75 rpms in 900 ml of simulated intestinal
fluid (pH 7.5 phosphate buffer) and at 37.degree. C.:
2 Time (hours) Preferred Most Preferred 2 0-25% 0-15% 4 10-45%
20-40% 8 30-90% 45-90% 12 NTL 50% NTL 60% 16 NTL 60% NTL 70% 20 NTL
70% NTL 80%
[0045] NTL=NOT LESS THAN
[0046] In the preparation of the tablets of the invention, various
conventional well known solvents may be used to prepare the
granules and apply the external coating to the tablets of the
invention. In addition, various diluents, excipients, lubricants,
dyes, pigments, dispersants etc. which are disclosed in Remington's
Pharmaceutical Sciences, 1995 Edition may be used to optimize the
formulations of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
EXAMPLE 1
[0047] A controlled release tablet containing 850 mg of metformin
HCl and having the following formula is prepared as follows:
3 I Core metformin HCl 90.54% povidone.sup.1, USP 4.38% sodium
tribasic phosphate 4.58% magnesium stearate 0.5% .sup.1approximate
molecular weight = 50,000; dynamic viscosity (10% w/v solution at
20.degree. C.) = 5.5-8.5 m Pa s.
[0048] (a) Granulation
[0049] The metformin HCl is delumped by passing it through a 40
mesh screen and collecting it in a clean, polyethylene-lined
container. The povidone, K-30, and sodium tribasic phosphate are
dissolved in purified water. The delumped metformin HCl is then
added to a top-spray fluidized bed granulator and granulated by
spraying the binding solution of povidone and sodium tribasic
phosphate under the following conditions: inlet air temperature of
50-70.degree. C.; atomization air pressure of 1-3 bars; and spray
rate of 10-100 ml/min.
[0050] Once the binding solution is depleted, the granules are
dried in the granulator until the loss on drying is less than 2%.
The dried granules are passed through a Comil equipped with the
equivalent of an 18 mesh screen.
[0051] (b) Tableting
[0052] The magnesium stearate is passed through a 40 mesh stainless
steel screen and blended with the metformin HCl granules for
approximately five (5) minutes. After blending, the granules are
compressed on a rotary press fitted with {fraction (15/32)}" round
standard concave punches (plain lower punch, upper punch with an
approximately 1 mm indentation pin).
[0053] (c) Seal Coating (Optional)
[0054] The core tablet is seal coated with an Opadry material or
other suitable water-soluble material by first dissolving the
Opadry material, preferably Opadry Clear, in purified water. The
Opadry solution is then sprayed onto the core tablet using a pan
coater under the following conditions: exhaust air temperature of
38-42.degree. C.; atomization pressure of 28-40 psi; and spay rate
of 10-15 ml/min. The core tablet is coated with the sealing
solution until a theoretical coating level of approximately 2% is
obtained.
4 II Sustained Release Coating cellulose acetate (398-10).sup.2 85%
triacetin 5% PEG 400 10% .sup.2acetyl content 39.3-40.3%
[0055] (d) Sustained Release Coating
[0056] The cellulose acetate is dissolved in acetone while stirring
with a homogenizer. The polyethylene glycol 400 and triacetin are
added to the cellulose acetate solution and stirred until a clear
solution is obtained. The clear coating solution is then sprayed
onto the seal coated tablets in a fluidized bed coater employing
the following conditions: product temperature of 16-22.degree. C.;
atomization pressure of approximately 3 bars; and spray rate of
120-150 ml/min. The sealed core tablet is coated until a
theoretical coating level of approximately 3% is obtained.
[0057] The resulting tablet is tested in simulated intestinal fluid
(pH 7.5) and simulated gastric fluid (SGF) according to the
procedure described in United States Pharmacopeia XXIII, Apparatus
2@75 rpm and found to have the following release profile:
5 TIME (hours) % Released (SGF) % Released (pH 7.5) 2 9 12 4 27 32
8 62 82 12 82 100 16 88 105 20 92 108
[0058] The release profile in pH 7.5 and SGF of the sustained
release product prepared in this Example is shown in FIG. 1.
[0059] FIG. 4 depicts the in vivo metformin plasma profile of the
sustained release product prepared in this Example. Also shown in
FIG. 4 is the in vivo metformin plasma profile of GLUCOPHAGE.RTM.,
a commercially available pharmaceutical product containing the drug
metformin HCl.
EXAMPLE 2
[0060] A controlled release tablet containing 850 mg of metformin
HCl and having the following formula is prepared as follows:
6 I Core metformin HCl 88.555% povidone.sup.3, USP 6.368% sodium
lauryl sulfate 4.577% magnesium stearate 0.5% .sup.3approximate
molecular weight = 1,000,000, dynamic viscosity (10% w/v solution
at 20.degree. C.) = 300-700 m Pa s.
[0061] (a) Granulation
[0062] The metformin HCl and sodium lauryl sulfate are delumped by
passing them through a 40 mesh screen and collecting them in a
clean, polyethylene-lined container. The povidone, K-90F, is
dissolved in purified water. The delumped metformin HCl and sodium
lauryl sulfate are then added to a top-spray fluidized bed
granulator and granulated by spraying with the binding solution of
povidone under the following conditions: inlet air temperature of
50-70.degree. C.; atomization air pressure of 1-3 bars; and spray
rate of 10-100 ml/min.
[0063] Once the binding solution is depleted, the granules are
dried in the granulator until the loss on drying is less than 2%.
The dried granules are passed through a Comil equipped with the
equivalent of an 18 mesh screen.
[0064] (b) Tableting
[0065] The magnesium stearate is passed through a 40 mesh stainless
steel screen and blended with the metformin HCl granules for
approximately five (5) minutes. After blending, the coated granules
are compressed on a rotary press fitted with {fraction (15/32)}"
round standard concave punches (plain lower punch, upper punch with
an approximately 1 mm indentation pin).
[0066] (c) Seal Coating (Optional)
[0067] The core tablet is seal coated with an Opadry material or
other suitable water-soluble material by first dissolving the
Opadry material, preferably Opadry Clear in purified water. The
Opadry solution is then sprayed onto the core tablet using a pan
coater under the following conditions: exhaust air temperature of
38-42.degree. C.; atomization pressure of 28-40 psi; and spay rate
of 10-15 ml/min. The core tablet is coated with the sealing
solution until a theoretical coating level of approximately 2% is
obtained.
7 II Sustained Release Coating cellulose acetate (398-10).sup.4 85%
triacetin 5% PEG 400 10% .sup.4acetyl content 39.3-40.3%
[0068] (d) Sustained Release Coating
[0069] The cellulose acetate is dissolved in acetone while stirring
with a homogenizer. The polyethylene glycol 400 and triacetin are
added to the cellulose acetate solution and stirred until a clear
solution is obtained. The clear coating solution is then sprayed
onto the seal coated tablets in a fluidized bed coater employing
the following conditions: product temperature of 16-22.degree. C.;
atomization pressure of approximately 3 bars; and spray rate of
120-150 ml/min. The sealed core tablet is coated until a
theoretical coating level of approximately 3% is obtained.
[0070] The resulting tablet is tested in simulated intestinal fluid
(pH 7.5) and simulated gastric fluid (SGF) according to the
procedure described in United States Pharmacopeia XXIII, Apparatus
2@75 rpm and found to have the following release profile:
8 TIME (hours) % Released (SGF) % Released (pH 7.5) 2 13 12 4 29 27
8 55 52 12 72 71 16 81 83 20 87 91
[0071] The release profile in pH 7.5 and SGF of the sustained
release product prepared in this Example is shown in FIG. 2.
[0072] FIG. 5 depicts the in vivo metformin plasma profile of the
sustained release product prepared in this Example under fasting
conditions. FIG. 5 also shows the in vivo metformin plasma profile
of the GLUCOPHAGE.RTM. product under fasting conditions.
[0073] FIG. 6 depicts the in vivo metformin plasma profile of the
sustained release product prepared in this Example under fed
conditions. FIG. 6 also shows the in vivo metformin plasma profile
of the GLUCOPHAGE.RTM. product under fed conditions.
[0074] FIGS. 5 and 6 clearly show that the dosage forms prepared in
accordance with the present invention exhibit consistent
bioavailability under both fed and fasting conditions while the
GLUOPHAGE.RTM. product's bioavailability decreases in the presence
of food.
EXAMPLE 3
[0075] A controlled release tablet containing 850 mg of metformin
HCl and having the same formula as in Example 2 is prepared as
described in Example 2 except that an additional hole was drilled
on the plain side of the coated tablet. The additional hole had a
diameter of approximately 1 mm.
[0076] The resulting tablet is tested in simulated intestinal fluid
(pH 7.5) and simulated gastric fluid (SGF) according to the
procedure described in United States Pharmacopeia XXIII, Apparatus
2@75 rpm and found to have the following release profile:
9 TIME (hours) % Released (SGF) % Released (pH 7.5) 2 13 14 4 27 28
8 50 63 12 67 84 16 84 95 20 97 102
[0077] The release profile in pH 7.5 and SGF of the sustained
release product prepared in this Example is shown in FIG. 3.
[0078] FIG. 7 depicts the in vivo metformin plasma profile of the
sustained release product prepared in this Example when
administered shortly after breakfast. FIG. 7 also shows the in vivo
metformin plasma profile of the GLUCOPHAGE.RTM. product
administered shortly after breakfast.
[0079] FIG. 8 depicts the in vivo metformin plasma profile of the
sustained release product prepared in this Example when
administered shortly after dinner. FIG. 8 also shows the in vivo
metformin plasma profile of the GLUCOPHAGE.RTM. product
administered shortly after dinner.
[0080] Table 1 is a summary of the bioavailability comparision
data, test/reference ratio, shown in FIGS. 4-8 wherein the
GLUCOPHAGE.RTM. product is the reference product in a two way
crossover biostudy with n=6.
10 TABLE 1 Formula FIG. Study AUC Cmax Tmax Ex. 1 4 Fasting 0.202
0.12 2.15 Ex. 2 5 Fasting 0.369 0.214 1.73 Ex. 2 6 Fed (bkft) 0.628
0.305 1.94 Ex. 3 7 Fed (bkft) 0.797 0.528 1.82 Ex. 3 8 Fed (dinner)
0.850 0.751 2.00 bkft = breakfast
[0081] The results reported in Table 1 and FIGS. 4-8 show that
dosage forms prepared in accordance with the present invention
exhibit an increase in the bioavailability of the antihyperglycemic
drug in the presence of food, especially when taken with or shortly
after the evening meal.
[0082] While certain preferred and alternative embodiments of the
invention have been set forth for purposes of disclosing the
invention, modifications to the disclosed embodiments may occur to
those who are skilled in the art. Accordingly, the appended claims
are intended to cover all embodiments of the invention and
modifications thereof which do not depart from the spirit and scope
of the invention.
* * * * *