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Publication numberUS20010024659 A1
Publication typeApplication
Application numberUS 09/726,193
Publication dateSep 27, 2001
Filing dateNov 29, 2000
Priority dateMar 20, 1998
Also published asCA2324493A1, CA2324493C, CN1158999C, CN1308520A, DE69941115D1, EP1063971A1, EP1063971A4, EP1063971B1, EP2087889A2, EP2087889A3, US6099859, US6495162, US7919116, US8475841, US20020064556, US20070154548, US20110195119, WO1999047125A1
Publication number09726193, 726193, US 2001/0024659 A1, US 2001/024659 A1, US 20010024659 A1, US 20010024659A1, US 2001024659 A1, US 2001024659A1, US-A1-20010024659, US-A1-2001024659, US2001/0024659A1, US2001/024659A1, US20010024659 A1, US20010024659A1, US2001024659 A1, US2001024659A1
InventorsChih-Ming Chen, Xiu Cheng, Steve Jan, Joseph Chou
Original AssigneeAndrx Corporation
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Controlled release metformin formulations
US 20010024659 A1
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.
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Claims(29)
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 Tmax 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 Tmax 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 Cmax of metformin from about 52.8% to about 75.1% of the Cmax 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 Tmax 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 Tmax of metformin from about 182% to about 200% of the Tmax 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 Tmax 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 Tmax of metformin from about 173% to about 215% of the Tmax 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 Tmax 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 Tmax 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 Tmax 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° 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 Tmax 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° 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 Tmax 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 GLUCOPHAGEŽ 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 GLUCOPHAGEŽ 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 GLUCOPHAGEŽ 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 GLUCOPHAGEŽ 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 GLUCOPHAGEŽ 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 GLUCOPHAGEŽ 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 GLUCOPHAGEŽ 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 GLUCOPHAGEŽ 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(β-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:

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° C.:

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:

I Core
metformin HCl 90.54%
povidone1, USP  4.38%
sodium tribasic phosphate  4.58%
magnesium stearate  0.5%

[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° 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° 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.

II Sustained Release Coating
cellulose acetate (398-10)2 85%
triacetin  5%
PEG 400 10%

[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° 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:

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 GLUCOPHAGEŽ, 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:

I Core
metformin HCl 88.555%
povidone3, USP  6.368%
sodium lauryl sulfate  4.577%
magnesium stearate  0.5%

[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° 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° 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.

II Sustained Release Coating
cellulose acetate (398-10)4 85%
triacetin  5%
PEG 400 10%

[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° 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:

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 GLUCOPHAGEŽ 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 GLUCOPHAGEŽ 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 GLUOPHAGEŽ 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:

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 GLUCOPHAGEŽ 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 GLUCOPHAGEŽ 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 GLUCOPHAGEŽ product is the reference product in a two way crossover biostudy with n=6.

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

[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.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US6407128Dec 3, 2001Jun 18, 2002Elan Pharmaceuticals, Inc.Method for increasing the bioavailability of metaxalone
US6455557Nov 28, 2001Sep 24, 2002Elan Pharmaceuticals, Inc.Method of reducing somnolence in patients treated with tizanidine
US6683102Mar 25, 2002Jan 27, 2004Elan Pharmaceuticals, Inc.Methods of using metaxalone in the treatment of musculoskeletal conditions
US7588779May 27, 2005Sep 15, 2009Andrx Labs, Llctime-release dosage forms contains antihyperglycemic drug metformin and angiotensin antagonist selected from the group consisting of valsartan, losartan, candesartan, eprosartan, irbesartan, olmesartan, tasosartan, and telmisartan
US7714006Jul 15, 2005May 11, 2010King Pharmaceuticals Research & Development, Inc.reducing the effect of a patient's age on the oral bioavailability by taking metaxalone with food; sedatives for treating muscular disorders
US8039019Aug 5, 2009Oct 18, 2011Andrx Labs, LlcPharmaceutical formulation containing a biguanide and an angiotensin antagonist
US8309125Jul 14, 2010Nov 13, 2012Watson Pharmaceuticals, Inc.Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US8470368Jun 2, 2011Jun 25, 2013Watson Pharmaceuticals, Inc.Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
US8668931May 8, 2013Mar 11, 2014Actavis, Inc.Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative
EP1460998A2 *Dec 4, 2002Sep 29, 2004Biovail Laboratories IncorporatedExtended release pharmaceutical tablet of metformin
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Classifications
U.S. Classification424/457, 514/635
International ClassificationA61P3/10, A61K9/22, A61K9/20, A61K31/155, A61K9/52, A61K9/28, A61K9/00
Cooperative ClassificationA61K31/155, A61K9/2886, A61K9/2072, A61K9/2866, A61K9/0004, A61K9/282
European ClassificationA61K9/28H6F2, A61K31/155, A61K9/00L4, A61K9/20K, A61K9/28H4
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