FIELD OF INVENTION

The present invention is related to oral extended release dosage forms comprising metformin or its pharmaceutically acceptable salts, and mixtures thereof.

More particularly, the present invention is related to oral extended release dosage forms comprising metformin or its pharmaceutically acceptable salts, and mixtures thereof, wherein said dosage forms provide extended absorption and availability of metformin in the body.

In particular, the present invention is related to oral extended release dosage forms comprising metformin or pharmaceutically acceptable salts, and mixtures thereof, wherein said dosage forms provide plasma concentration of metformin even after 24 hours in fed conditions within the therapeutic range.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Metformin (Structure I), a member of the biguanide class of oral anti-hyperglycemics, which is chemically known as (N, N-dimethylimidodicarbon imidiodiamide), is well known for its use in the management of non-insulin-dependent diabetes mellitus (type 2 diabetes).

There are many extended or controlled release formulations of metformin available in the United States and other countries; for example, FORTAMET™ (Andrx Labs), GLUCOPHAGE XR™ (Bristol Myers Squibb), and GLUMETZA™ (Depomed Inc.). All the above marketed dosage forms are

indicated for once or twice a day administration and further they all provide plasma concentrations till the maximum period of 24hrs or even less.

In the prior art, many techniques have been used to provide controlled and extended-release pharmaceutical dosage forms in order to maintain therapeutic levels of medicaments.

US 6099859 discloses metformin dosage forms which can provide therapeutic levels for twelve to twenty-four hour period only.

US 2001/0024659 discloses sustained release pharmaceutical formulations comprising an anti-hyperglycemic drug or a pharmaceutically acceptable salt that provide therapeutic plasma levels of the anti-hyperglycemic drug to a human patient over a 24 hour period after administration.

Similarly, US 2007/0154548, US 2006/0008523, US 2006/0008524, US 2006/0008525, US 2006/0008526, US 2006/0034922; all disclose sustained or controlled release pharmaceutical formulations comprising anti-hyperglycemic drug or a pharmaceutically acceptable salt wherein the dosage form in all the above prior arts provide therapeutic levels for a period of twelve to twenty-four hour only.

Gluconeogenesis is well known to those skilled in the art to be maximum at night. Hence, the concentration of the anti-hyperglycemic drug should be at the therapeutic level at the time when human patients are manufacturing glucose at highest levels.
Currently available extended release metformin products do not control the glucose levels after morning breakfast. Hence there is need for a dosage form which provides sufficient blood concentrations in the day time also. This concentration of metformin will be able to control the blood glucose levels during the day time also.

Thus, the present invention provides oral extended release pharmaceutical dosage forms comprising metformin or pharmaceutically acceptable salts which provide sufficient levels of metformin, effectively reducing night time surge in the glucose levels and further controlling the levels even in the morning thereafter.

This and other such needs are addressed by the present invention.

SUMMARY AND OBJECTIVE OF THE INVENTION

The present invention is related to oral extended release dosage forms comprising metformin or its pharmaceutically acceptable salts, and mixtures thereof.

In particular, the present invention is related to oral extended release pharmaceutical dosage forms comprising metformin or its pharmaceutically acceptable salts, and mixtures thereof, wherein said dosage forms provide extended absorption and availability of metformin in the body.

More particularly, the present invention is related to oral extended release pharmaceutical dosage forms comprising metformin or pharmaceutically acceptable salts, and mixtures thereof, wherein said dosage forms provide plasma concentration of metformin even after 24 hours in fed conditions within the therapeutic range.

More particularly, the present invention is related to osmotic delivery system comprising metformin which is designed to provide effective plasma concentration at 24 hours and beyond, post dosing in fed-conditions.

It is an object of the present invention to provide a controlled or extended release of an anti-hyperglycemic drug which provides effective control of blood glucose levels in humans.

It is a further object of the present invention to provide formulations for treating human patients with non-insulin-dependent diabetes mellitus which

provides advantages over the state-of-the-art, and which may be administered on a once-a-day basis by itself or together with other anti-diabetic agents.

It is a further object of the present invention to provide a controlled or extended release formulation of an anti-hyperglycemic drug wherein the bioavailability of the drug is not decreased by the presence of food.

It is also a further object of the present invention to provide a controlled or extended release formulation of an anti-hyperglycemic drug that can provide continuous and non-pulsating therapeutic levels of the drug to an animal or human in need of such treatment over a 24 hour period and beyond that.

It is also an object of this invention to provide a controlled or extended release pharmaceutical formulation having an osmotic delivery system, designed to provide effective plasma concentration of metformin at 24 hours and beyond, post dosing in fed-conditions.

It is also an object of this invention to provide a controlled or extended release pharmaceutical formulation having an osmotic delivery system, having a dosing schedule preferably l000mg once in 40 hours.

It is further an object of this invention to provide a controlled or extended release pharmaceutical formulation having an osmotic delivery system, having a dosing schedule preferably l000mg once in 36 hours.

It is further an object of this invention to provide a controlled or extended release pharmaceutical formulation having an osmotic delivery system, having a dosing schedule preferably l000mg once in 30 hours.

In accordance with the above-mentioned objects and others, the present invention provides a controlled or extended release oral dosage form comprising metformin or a pharmaceutically acceptable salt thereof, which is suitable for providing once-a-day administration of the drug, wherein the dosage form provides an extended absorption and plasma profiles beyond 24 hours post dosing

in fed conditions, to effectively control the glucose level in the body. The dosage form comprises a drug and a membrane. More preferably, the dosage form comprises an osmotic tablet.

In preferred embodiments, the controlled or extended release oral dosage form of the present invention is an osmotic tablet comprising: (a) a core comprising: (i) metformin; (ii) a binding agent; and (iii) an absorption enhancer; (b) optionally a seal coat; (c) a membrane coating surrounding the core; and (d) at least one passageway in the membrane coat.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a plot of plasma concentration of metformin HC1 vs. time resulting from extended or controlled release tablets after dosing at fed conditions in normal healthy human volunteers (n=14).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an osmotic tablet comprising metformin or a pharmaceutically acceptable salt thereof, which is suitable for providing once-a-day administration of the drug, wherein said tablet provides an extended absorption, availability and plasma profiles at 24 hours and beyond that post dosing in fed conditions, to effectively control the glucose level in the body.

The present invention also provides an osmotic tablet comprising metformin or a pharmaceutically acceptable salt thereof, which is suitable for providing once-a-day administration of the drug, wherein said tablet provides an extended absorption, availability and plasma profiles at 30 hours and beyond that post dosing in fed conditions, to effectively control the glucose level in the body.

The present invention further provides an osmotic tablet comprising metformin or a pharmaceutically acceptable salt thereof, which is suitable for providing once-a-day administration of the drug, wherein said tablet provides an

extended absorption, availability and plasma profiles at 36 hours and beyond that post dosing in fed conditions, to effectively control the glucose level in the body.

In the context of the present invention, the term "metformin" as it is used herein means metformin base or any pharmaceutically acceptable salt for e.g., metformin hydrochloride and other pharmaceutically acceptable salts.

The term "Cmax" is the highest plasma concentration of the drug attained within the dosing interval, i.e., about 24 hours.

The term "Tmax" is the time period which elapses after administration of the dosage form at which the plasma concentration of the drug attains the highest level/value within the dosing interval (i.e., about 24 hours).

The term "AUC" as used herein, means area under the plasma concentration-time curve, as calculated by the trapezoidal rule over the complete 24-hour interval.

The term "single dose" means that the human patient has received a single dose of the drug formulation.

The term "multiple dose" means that the human patient has received at least two doses of the drug formulation in accordance with the dosing interval for that formulate on (e.g., on a once-a-day basis).

The term "mean", when preceding a pharmacokinetic value (e.g. mean Tmax) represents the arithmetic or geometric mean value of the pharmacokinetic value taken from a population of patients.

The dosage forms of the present invention, when administered on a once-a-day basis, can contain, e.g., from about 500 mg to about 2000 mg of metformin. Such daily dose may be contained in one dosage form of the invention, or may be contained in more than one such dosage form.

In certain embodiments, the controlled-release metformin dosage forms of the present invention can provide a mean Cmax of metformin from about 500 to about 975 ng/ml with 1000 mg metformin hydrochloride included therein.

In certain embodiments, the controlled-release metformin dosage forms of the present invention can provide a mean Tmax at from about 7 to about 15 hours after oral administration.

In certain embodiments, the controlled-release metformin dosage forms of the present invention can provide a mean AUC0-iast of metformin from about 7,500 to about 17,500 ng.hr/ml with 1000 mg metformin hydrochloride included therein.

In certain embodiments, the controlled-release metformin dosage forms of the present invention provide a mean AUC0-inf of metformin from about 8,500 to about 20,500 ng.hr/ml with 1000 mg metformin hydrochloride included therein.

In certain embodiments of the invention, the once daily administration of the metformin can provide a mean AUC0-24hr from about 80% to about 120%, wherein the daily dose of the reference standard is equal to the once-a day dose of metformin administered in the controlled-release oral dosage form of the present invention.

In an alternate embodiment, the dosage form of the present invention can include a further anti-diabetic agent in addition to the biguanide. For example, the dosage form can include a sulfonylurea such as glipizide, glyburide (glibenclamide), chloropropamide, tolbutamide, acetohexamide and tolazamide, troglitazone, rosiglitazone pioglitazone darglitazone, acarbose, miglitol, or pharmaceutically acceptable salts thereof.

The dosage form of the invention provides plasma concentration of metformin after 24 hours more than l00ng/ml when taken at l000mg dose in fed condition after dinner.

The designed osmotic drug delivery system when taken at dinner time provides Tmax after oral administration, such that the level of drug is greatest at the time when human patients are manufacturing glucose at highest levels. Thus the dosage form having Tmax in the range of 6 to 13 hours provides sufficient levels of metformin, effectively reducing night time surge in the glucose levels.
The designed osmotic drug delivery comprises;
(a) an immediate release core comprising:
(i) 50-98% of metformin;
(ii) 0-40% of a binding agent;
(iii) 0-20% of an absorption enhancer; and

(b) a semi-permeable membrane coating covering said core wherein the

membrane is permeable to the passage of water and biological fluids and is
impermeable to the passage of the anti-hyperglycemic drug wherein said coating
comprises less than 50% of a polymer; 0-40% of a flux enhancer; 0-25% of a
plasticizer; optionally anti-tacking agents and other pigments; and
(c) at least one passageway in the semi-permeable membrane for the release of
anti-hyperglycemic drug.
Alternatively, the designed osmotic drug delivery comprises
(a) a non-immediate release core comprising:
(i) 50-98% of metformin;
(ii) 0-40% of a binding agent;
(iii) 0-20% of an absorption enhancer; and

(b) a semi-permeable membrane coating covering said core wherein the
membrane is permeable to the passage of water and biological fluids and is
impermeable to the passage of the anti-hyperglycemic drug wherein said coating
comprises less than 50% of a polymer; 0-40% of a flux enhancer; 0-25% of a
plasticizer; optionally anti-tacking agents and other pigments; and
(c) at least one passageway in the semi-permeable membrane for the release of thebanti-hyperglycemic drug.

The excipients used in the tablet of present invention are preferably selected among, but is not limited to hydroxyalkylcellulose (e.g., hydroxypropyl cellulose, hydroxy propyl methyl cellulose); polyalkylene oxide (e.g., poly(ethylene) oxide, poly(methylene oxide), poly(butylene oxide), and poly(hexylene oxide); poly(hydroxy alkyl methacrylate); poly(vinyl)alcohol, Carbopol®, Eudragit®, ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, polymethyl methacrylate, polyethyl methacrylate, polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl methacrylate, poly isodecyl methacrylate, polylauryl methacrylate, polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate, polyisobutyl acrylate, polyoctadecyl acrylate, polyvinyl isobutyl ether, polyvinyl acetate, polyvinyl chloride, polyurethane or a mixture thereof; polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose, polyethyleneglycol, hydroxypropylcellulose, sodiumcarboxymethylcellulose, carboxymethylcellulose calcium, ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propyleneglycol alginate, alginic acid, polyvinylalcohol, carbomer, potassium pectate, potassium pectinate and mixtures thereof.

Other pharmaceutically acceptable excipients which can optionally be used in the preparation of the particles, granules, pellets, beads, mini-tablets, tablets or final dosage form according to the invention may include, but are not limited to diluents such as microcrystalline cellulose (MCC), silicified MCC,

lactose, starch, pregelatinized starch, mannitol, sorbitol, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like; binders such as PVP, cellulose derivatives such as hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, carboxy methyl cellulose sodium, starch and the likes; disintegrants such as crospovidone, sodium starch glycolate, starch and its derivatives, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose and the like; glidant and lubricants such as colloidal silicon dioxide, talc, stearic acid and its salts and the like; plasticizers such as diethylphthalate, triacetin, tributyl sebacate, or polyethylene glycol and the like; anti-foaming agents such as dimethicone, simethicone and the like; surfactants such as sodium dodecyl sulfate, and the like; anti-tacking agents such as talc, fumed silica, magnesium stearate and the like; pigments such as titanium dioxide, edible lake pigments and the like.

In certain embodiments, the core tablet matrix can be prepared by dry granulation processes or alternatively, certain embodiments can be prepared by wet granulation processes which are well known in the art. In certain preferred embodiments, the core tablet matrix may be prepared from a mixture prepared by dry blending at least one pharmaceutically acceptable excipient with a granulation consisting essentially of metformin (preferably prepared by wet granulation).
The core tablet of the present invention can be optionally coated with a pharmaceutically acceptable film-coating. The film coat may contain a pigment and/or a barrier agent, such as hydroxypropyl methylcellulose. An example of a suitable material which may be used for such a coating is hydroxypropyl methylcellulose (e.g., Opadry™, commercially available from Colorcon). The coating may be applied using a coating pan or a fluidized bed using an organic, aqueous or a mixture of an organic and aqueous solvent. Aqueous solvents are preferred for the over-coating procedures. The film coat preferably does not affect the release of drug from the dosage form.

The core tablet is coated with a semi-permeable membrane, preferably a modified polymeric membrane to form the controlled release tablet of the invention. The semi-permeable membrane is permeable to the passage of an external fluid such as water and biological fluids and is impermeable to the passage of the anti-hyperglycemic drug in the core. Materials that are useful in forming the semi-permeable 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. The most preferred semi-permeable membrane material is cellulose acetate.

In a certain embodiment, the semi-permeable membrane can be formed from the above-described polymers and a flux enhancing agent. The flux enhancing agent can be a water soluble material or any other suitable material. Some examples of the preferred materials that are useful as flux enhancers are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof.

The semi-permeable membrane may also be formed with commonly known excipients such a plasticizer. Some commonly known plasticizers include citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and the like.

The semi-permeable membrane coating is layered over the core tablet using conventional coating machines, for example, pan coaters, rotary drum-type coaters, Wurster-type fluidizing coaters and fluidizing coaters may be employed in said method of the invention.

As used herein the term passageway includes an aperture, orifice, bore, hole, which forms an osmotic passageway for the release of the anti-hyperglycemic drug from the dosage form.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Example 1;

Brief manufacturing procedure:

Metformin HC1 and sodium lauryl sulphate is mixed together and sifted through # 40 mesh and loaded in to bowel of top spray granulator and granulated using solution of povidone in water and resulting granules are dried at 60°C to get LOD about 1.5%. The dried granules are lubricated with magnesium stearate. The resulting blend is compressed using suitable tooling, and seal coated using aqueous solution of Opadry®, to get weight build up of 2.0-3.0% w/w. The semi-

permeable coating is done to get weight buildup of 4.0 - 7.0%w/w. Each tablet is mechanically drilled with 0.5 mm diameter driller.
Dissolution Profile:

Dissolution profile is generated in 1000 mL of pH 6.8 Phosphate Buffer, USP Type 1,1000 rpm

Example 2:

Brief manufacturing procedure:

Metformin HC1 and Sodium lauryl sulphate is mixed together and sifted through #40 mesh, and granulated using solution of ethyl cellulose in dichloromethane and resulting granules are dried at 60°C to get LOD about 1.5%. The dried granule is blended with microcrystalline cellulose, colloidal silicon dioxide and glyceryl behenate. The resulting blend is compressed using suitable tooling, and seal coated using aqueous solution of Opadry®, to get weight build up of 2.0-3.0% w/w. The semi-permeable coating is done to get weight buildup of 4.0-7.0%w/w. Each tablet is mechanically drilled with 0.5mm diameter driller.

Dissolution Profile:

Dissolution profile is generated in 1000 mL of pH 6.8 Phosphate Buffer, USP Type I, 1000 rpm.

Example 3:

Brief manufacturing procedure:

Metformin HC1 and sodium lauryl sulphate is mixed together and sifted through #40 mesh, and granulated using solution of Eudragit® RL30D and resulting granules are dried at 60°C to get LOD about 1.5%. The dried granules are blended with microcrystalline cellulose, colloidal silicon dioxide, glyceryl behenate and magnesium stearate. The resulting blend is compressed using suitable tooling, and seal coated using aqueous solution of Opadry®, to get weight build up of 2.0-3.0% w/w. The semi-permeable coating is done to get weight buildup of 4.0-7.0%w/w. Each tablet is mechanically drilled with 0.5mm diameter driller.

Dissolution Profile:

Dissolution profile is generated in 1000 mL of pH 6.8 Phosphate Buffer, USP Typel, 1000 rpm

Example 4:

Brief manufacturing procedure:

Metformin HC1 and sodium lauryl sulphate is mixed together and sifted through # 40 mesh, and granulated using solution of Eudragit® EPO in isopropyl alcohol and resulting granules are dried at 60°C to get LOD about 1.5%. The dried granules are blended with microcrystalline cellulose, colloidal silicon dioxide, glyceryl behenate and magnesium stearate. The resulting blend is compressed using suitable tooling, and seal coated using aqueous solution of Opadry®, to get weight build up of 2.0-3.0% w/w. The semi-permeable coating is done to get weight buildup of 4.0-7.0%w/w. Each tablet is mechanically drilled with 0.5mm diameter driller.

Dissolution Profile:
Dissolution profile is generated in 1000 mL of pH 6.8 Phosphate Buffer, USP Typel, l000rpm

Bio Study:

The dosage form of example 2 is dosed in healthy human volunteers under fed conditions (n=14).

The mean plasma profile of the study is depicted in figure 1.

WE CLAIM:
1. An oral controlled release dosage form comprising an effective amount of metformin or a pharmaceutically acceptable salt thereof, wherein after oral administration of a l000mg single dose of said metformin in the dosage form post-dinner provides:

i. a time to maximum plasma concentration (Tmax) of metformin at from 7 to 15 hours;

ii. a maximum plasma concentration (Cmax) in the range of 500-975 ng/ml;

iii. a mean area under the curve (AUCo-iast) in the range of 7500-17500 ng-hr/ml;

iv. a mean area under the curve (AUCo-a) in the range of 8500-20500 ng.hr/ml.

2. The oral controlled release dosage form according to claim 1, wherein after oral administration of a 1000mg single dose of metformin in the dosage form post-dinner provides a mean time to maximum plasma concentration (Tmax) of metformin at from 10 to 12 hours after administration.

3. The oral controlled release dosage form according to claim 1, wherein after oral administration of a 1000mg single dose of metformin in the dosage form post-dinner provides a mean plasma concentration (Cmax) 773 ± 203 ng/ml of metformin.

4. The oral controlled release dosage form according to claim 1, wherein after oral administration of a 1000mg single dose of metformin in the dosage form post-dinner provides a mean area under the curve (AUC0-iast) of 11524 ±4616 ng.hr/ml of metformin.
5. The oral controlled release dosage form according to claim 1, wherein after oral administration of a 1000mg single dose of metformin in the dosage form post-dinner provides a mean area under the curve (AUC0-a) of 12696 ± 4429 ng.hr/ml of metformin.

6. An oral controlled release dosage form comprising:
i. a core comprising of:

a) 50-98% of metformin;
b) 0-40% of a binding agent;
c) 0-20% of an absorption enhancer; and

ii. a semi-permeable membrane coating covering said core, wherein said coating comprises:
a) 10-45% of a polymer;
b) 0-40% of a flux enhancer;
c) 0-25% of a plasticizer;

d) optionally anti-tacking agents and other pigments; and iii. at least one passageway in the semi-permeable membrane for the
release of metformin.

7. The oral controlled release dosage form according to claim 6, wherein said binding agent is selected from a group consisting of polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, acrylic acid derivatives, polymethacrylates, waxes, gelatin, glyceryl behenate, polyacrylamides, polyvinyl alcohol or mixtures thereof.

8. The oral controlled release dosage form according to claim 6, wherein said absorption enhancer is selected from a group consisting of sodium lauryl sulfate, sodium taurocholate, glyceryl behenate, polyethylene glycol and polysorbate 80.

9. The oral controlled release dosage form according to claim 6, wherein said polymer used for semi-permeable membrane is cellulose acetate.

10. The oral controlled release dosage form according to claim 6, wherein said flux enhancer is selected from the group consisting of sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof.
11. The oral controlled release dosage form according to claim 6, wherein said plasticizer is selected from the group consisting of triethyl citrate, tri-

n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, polyethylene glycol, propylene glycol and mixtures thereof.

12. The oral controlled release dosage form according to claim 6, wherein said anti-tacking agent and other pigments are selected from the group consisting of talc, titanium dioxide, fumed silica, aluminium lakes and mixtures thereof.

13. The oral controlled release dosage form according to claim 1 or 6, wherein said dosage form is an osmotic tablet.

14. The oral controlled release dosage form according to claim 1, wherein said osmotic tablet provides a plasma concentration of atleast l00ng/ml of metformin after 24 hours, after oral administration of a l000mg single dose of said metformin in the dosage form post-dinner.

15. The oral controlled release dosage form according to claim 1, wherein said osmotic tablet is scheduled for oral dosing once in 40 hour in fed state post-dinner.

16. The oral controlled release dosage form according to claim 1, wherein said osmotic tablet is scheduled for oral dosing once in 36 hour in fed state post-dinner.

17. The oral controlled release dosage form according to claim 1, wherein said osmotic tablet is scheduled for oral dosing once in 30 hour in fed state post-dinner.

18. The oral controlled release dosage form according to claim 1, further include a second drug intended for the treatment of diabetes mellitus.

19. The oral controlled release dosage form according to claim 18, wherein said second drug is selected from a group consisting of glipizide, glyburide, chloropropamide, tolbutamide, acetohexamide, tolazamide, troglitazone, rosiglitazone pioglitazone darglitazone, acarbose, miglitol, or their pharmaceutically acceptable salts thereof.

20. The oral controlled release dosage form according to claim 1, used in the treatment of non-insulin-dependent diabetes mellitus.