WO2006092711A2

WO2006092711A2 - Extended release tablets of metformin and glipizide

Info

Publication number: WO2006092711A2
Application number: PCT/IB2006/000437
Authority: WO
Inventors: Amit Kumar Kesarwani; Manish Chawla; Rajeev Singh Raghuvanshi; Ashok Kumar Rampal
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2005-03-02
Filing date: 2006-03-01
Publication date: 2006-09-08
Also published as: WO2006092711A3

Abstract

The present invention relates to extended release tablet containing metformin and glipizide for treating patients with non-insulin dependent diabetes mellitus (NIDDM) on a once-a-day basis. The extended release tablet provides therapeutically effective plasma levels of metformin as well as glipizide for a period of at least 12 hours, particularly 24 hours.

Description

EXTENDED RELEASE TABLETS OF METFORMIN AND GLIPIZIDE

Field of the Invention

Background of the Invention

Biguanides, especially metformin, control the blood glucose by inhibiting hepatic glucose production, reducing intestinal absorption of glucose and enhancing peripheral glucose uptake. Biguanides lower both basal and post-prandial plasma glucose and thus improve glucose tolerance in. patients. On the other hand, sulfonylureas, particularly glipizide, help in controlling or managing NIDDM by stimulating the release of endogenous insulin from the beta cells of the pancreas.

Biguanide monotherapy has been used as a first line treatment in diabetic patients but may be supplemented with other drugs when secondaiy failure of the therapy occurs.

Administration of a biguanide with a sulfonylurea provides optimum glycemic control where monotherapy of each is inadequate. A combination therapy of a biguanide and a sulfonylurea has a synergistic effect on glucose control since both agents act by different but complementary mechanisms. Other advantages of fixed dose combinations include: 1. They provide a simple regimen due to lesser dosage, resulting in improved patient compliance and convenience.

2. They provide a reduction in overall cost of therapy by combining two or more drugs in one dosage form relative to the cost of the individual administration of the individual dosage forms. Bristol Myers Squibb Company is currently marketing a combination of metformin and glipizide under the brand name Metaglip™. Thus, the concomitant use of metformin and glipizide is known and has been found to be more effective in lowering blood glucose levels than either metformin or glipizide when used alone in patients with Type 2 diabetes (NIDDM).

Extended release dosage forms for metformin alone and glipizide alone have been commercially available. Glipizide extended release formulations are available as osmotic dosage forms (Glucotrol XL™) and monolithic dosage forms (Glipizide ER). These dosage forms exhibit an initial lag in the release of glipizide.

A number of extended release metformin formulations are currently marketed. However, no such formulation is available that contains extended release metformin in combination with an extended release glipizide in one single dosage form so as to achieve once-a-day administration.

Our co-pending application describes various ways of combining metformin and glipizide, i.e., monolithic matrix dosage forms, bi- or multilayered tablets, multiparticulates, etc. Another co-pending application describes a layered tablet comprising a layer containing a portion of biguanide and another layer containing a combination of sulfonylurea and biguanide.

Summary of the Invention

It is one of the aspects to provide an extended release tablet of metformin and glipizide wherein the tablet when administered once daily under fed conditions exhibits area under the plasma concentration time curves (AUC) for metformin and glipizide comparable to that exhibited by immediate release formulation of metformin and glipizide administered twice daily on same total daily dose basis.

It is another aspect to provide an extended release tablet of metformin and glipizide wherein the tablet when administered once daily under fed conditions exhibits mean maximum plasma concentrations (C_max) of metformin and glipizide comparable to the C_max exhibited by immediate release formulation of metformin and glipizide administered twice daily.

It is another aspect to provide an extended release tablet of metformin and glipizide wherein the tablet when administered once daily under fed conditions exhibits median time to maximum plasma concentration (T_max) of metformin 1.5 to 4.5 times the T_maχ exhibited for metformin by an immediate release formulation and exhibits median time to maximum plasma concentration (T_max) of glipizide 1.5 to 5 times the T_max exhibited for glipizide by an immediate release formulation. It is yet another aspect to provide an extended release tablet of metformin and glipizide wherein the tablet exhibits a T_max of metformin which occurs at a time 4 hours to about 10 hours and exhibits a T_max of glipizide which occurs at a time 5 hours to about 18 hours after administration to a human patient.

In another general aspect, there is provided an extended release layered tablet comprising: a layer comprising metformin, rate-controlling polymer and pharmaceutically acceptable excipients, and another layer comprising glipizide, metformin, rate-controlling polymer and pharmaceutically acceptable excipients. Such a tablet may have one or more of the following pharmacokinetic characteristics: (a) the tablet when administered once daily under fed condition exhibits area under the plasma- concentration time curves (AUC) for metformin and glipizide comparable to that exhibited by immediate release formulation of metformin and glipizide administered twice daily on same total daily dose basis, (b) the tablet when administered once daily under fed conditions exhibits mean maximum plasma concentrations (C_max) of metformin and glipizide comparable to the C_max exhibited by immediate release formulation of metformin and glipizide administered twice daily, and (c) the tablet when administered once daily under fed conditions exhibits median time to maximum plasma concentration (T_max) of metformin 1.5 to 4.5 times the T_max exhibited for metformin by an immediate release formulation and exhibits median time to maximum plasma concentration (T_max) of glipizide 1.5 to 5.0 times the T_max exhibited for glipizide by an immediate release formulation.

Accordingly, in one general aspect there is provided an extended release layered tablet of metformin and glipizide wherein the tablet when administered once daily under fed conditions exhibits area under the plasma-concentration time curves (AUC) and mean maximum plasma concentrations (C_max) of metformin and glipizide comparable to the AUC and C_max exhibited by immediate release formulation of metformin and glipizide administered twice daily; and exhibits median time to maximum plasma concentration (T_max) of metformin 1.5 to 4.5 times the T_max exhibited for metformin by an immediate release formulation and median time to maximum plasma concentration (T_max) of glipizide 1.5 to 5.0 times the T_max exhibited for glipizide by an immediate release formulation.

Embodiments of the tablet may include one or more of the following features. For example, the tablet may be a layered tablet that includes a first layer and a second layer. The first layer includes metformin, one or more rate-controlling polymers and pharmaceutically acceptable excipients. The second layer includes glipizide, metformin, one or more rate- controlling polymers and pharmaceutically acceptable excipients.

The metformin may constitute about 20% to about 80% by weight of the tablet. The glipizide may constitute about 0.05% to about 10% by weight of the tablet. The rate controlling polymers may be one or more of hydrophilic polymers, hydrophobic polymers or a combination thereof. The one or more rate-controlling polymers . comprise about 5% to about 60% w/w of the tablet.

The hydrophilic polymers may be one or more of cellulose derivatives comprising hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose or combinations thereof; polyvinylpyrrolidone, vinyl acetate/ vinyl - pyrrolidone copolymer, microcrystalline cellulose, polysaccharides, polyalkylene glycols, starch and derivatives thereof.

The hydrophobic polymers may be one or more of ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, waxes, shellac and hydrogenated vegetable oils. The layers may be prepared by one or more of dry granulation, wet granulation or direct compression. The glipizide layer may further include an alkalizing agent. The tablet may further include one or both of an outer protective coating layer or a separating layer between first and second layers. The tablet may exhibit a T_max of metformin which occurs at a time 4 hours to about 10 hours and exhibits a T_max of glipizide which occurs at a time 5 hours to about 18 hours after administration of the tablet to a human patient.

In another general aspect there is provided an extended release tablet of metformin and glipizide which exhibits an in vitro dissolution profile for glipizide, when measured in the USP paddle type apparatus, at 50 rpm, at a temperature of 37D0.5DC in 900 ml of simulated intestinal fluid, as follows: from about 5% to about 40% by weight after 2 hours, from about 20% to about 75% by weight after 4 hours, not less than 50% by weight after 12 hours, and wherein the tablet when administered once daily under fed conditions exhibits a median time to maximum plasma concentration (T_max) of glipizide that is 1.5 to 5.0 times the Tm_ax exhibited by an immediate release formulation.

The metformin may constitute about 20% to about 80% by weight of the tablet. The glipizide may constitute about 0.05% to about 10% by weight of the tablet. The rate controlling polymers may be one or more of hydrophilic polymers, hydrophobic polymers or a combination thereof. The one or more rate-controlling polymers comprise about 5% to about 60% w/w of the tablet.

The hydrophilic polymers may be one or more of cellulose derivatives comprising hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose or combinations thereof; polyvinylpyrrolidone, vinyl acetate/ vinyl pyrrolidone copolymer, microcrystalline cellulose, polysaccharides, polyalkylene glycols, starch and derivatives thereof. The hydrophobic polymers may be one or more of ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, waxes, shellac and hydrogenated vegetable oils.

The layers may be prepared by one or more of dry granulation, wet granulation or direct compression. The glipizide layer may further include an alkalizing agent. The tablet may further include one or both of an outer protective coating layer or a separating layer between first and second layers.

The tablet may exhibit a T_max of metformin which occurs at a time 4 hours to about 10 hours and exhibits a T_max of glipizide which occurs at a time 5 hours to about 18 hours after administration of the tablet to a human patient.

In another general aspect there is provided a method of treating non-insulin dependent diabetes mellitus in a patient in need thereof. The method includes administering a tablet that includes a combination of metformin and glipizide. The tablet when administered once daily under fed conditions exhibits a median time to maximum plasma concentration (T_max) of metformin that is 1.5 to 4.5 times the T_max exhibited for metformin by an immediate release formulation; and exhibits a median time to maximum plasma concentration (T_max) of glipizide that is 1.5 to 5.0 times the T_max exhibited for glipizide by an immediate release formulation. Embodiments of the method may include one or more of the features described above. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Detailed Description Figure 1 is a graph of the mean plasma concentration-time profile for metformin in the test and reference products.

Figure 2 is a graph of the mean plasma concentration-time profile for glipizide in the test and reference products.

Detailed Description To achieve the clinical advantage of a combination of a controlled release sulfonylurea and a controlled release biguanide that provides a synergistic effect in the treatment of NIDDM, the individual commercially available products have been administered together. However, no such combinations exist for the simultaneous controlled delivery of a biguanide along with a sulfonylurea in a single dosage form for ready administration. The availability of a dosage form that can provide therapeutic levels of a sulfonylurea and a biguanide from the same unit-dose composition over a period of 12-24 hours would be extremely advantageous in clinical practice for glycemic control in the treatment of NIDDM. Such a dosage form could then be administered once-a-day and provide both increased convenience and improved patient compliance resulting from both the avoidance of missed doses through patient forgetfulness and a reduced dosing frequency. There is also the possibility of a significant reduction in the doses of the drug substances used in combination because of a synergistic action between the two active substances. Such a reduction in dose strengths of the either or both of the active substances could additionally provide a reduction in toxicity.

As used herein, the area under the concentration time curve for the test product (T) is said to be comparable to that of the reference product (R) when the T/R ratio of the geometric means based on log-transformed data falls within 70% to 150% for the AUC (area under the concentration) time curve. As used herein, the C_max for the test product is said to be comparable to that of the reference product when the T/R ratio of the geometric means based on log-transformed data fall within 70% to 150% for C_max (peak concentration).

Metformin as used herein means base per se or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt may be hydrochloride, fumarate, hydrobromide, succinate or embonate. The daily effective dose of metformin may range from 500 mg to 2550 mg, and particularly the dose may be a single dose of 250 mg to 1000 mg. Metformin may be present in an amount ranging from about 20% to about 80% by weight of the tablet. The daily effective dose of glipizide may range from 2.5 mg to 20 mg, and particularly the dose may be about 2.5 mg to about 10 mg, once a day. Glipizide may be present in an amount ranging from about 0.05% to about 10% by weight of the tablet.

The rate-controlling polymers may be hydrophilic, hydrophobic or a combination thereof. These polymers comprise 5% to 60% w/w of the tablet. Hydrophilic polymers of the present invention include cellulose derivatives such as hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose or combinations thereof; polyvinyl pyrrolidone, vinyl acetate/ vinyl pyrrolidone copolymer, microcrystalline cellulose and other polysaccharides, polyalkylene glycols, and starch and derivatives thereof.

The hydrophobic polymers may be selected from ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, copolymers of acrylic or methacrylic acid esters, waxes, shellac, and hydrogenated vegetable oils. The blends for each layer may be prepared by any pharmaceutically acceptable technique that achieves uniform blending, e.g., dry granulation, wet granulation and direct compression. The blend for each layer may also contain other pharmaceutically acceptable excipients that act in one or more capacities as diluents, binders, lubricants, glidants, colorants or flavoring agents.

Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, mannitol, starch, sorbitol, sucrose, dextrose, maltodextrin or mixtures thereof.

Suitable binders may be selected from polyvinyl pyrrolidone, vinyl acetate/ vinyl pyrrolidone copolymer, microcrystalline cellulose, lactose, starches, gums, waxes, gelatin, polymers or mixtures thereof.

Suitable lubricants include colloidal silicon dioxide, talc, stearic acid, magnesium stearate, magnesium silicate, sodium benzoate, polyethylene glycol, sodium lauryl sulphate, fumaric acid, zinc stearate, paraffin, glyceryl behenate or mixtures thereof.

Suitable glidants may be selected from talc and colloidal silicon dioxide.

An alkalizing agent may be provided as part of glipizide layer so that the incorporated active agent attains optimal dissolution and release from the matrix. It will ensure substantially complete release of glipizide from the matrix and thus bioavailability. Suitable alkalizing excipients include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, ammonia, tertiary sodium phosphate, basic amino acids as diethanolamine, ethylenediamine, N-methylglucamine, 6 N-methyl-glucamine or L- lysine and/or mixtures thereof. The alkalizing agent may be added to the glipizide extragranularly.

The two blends comprising metformin and glipizide may then be compressed and combined to form a layered tablet employing conventional layered tabletting equipment. Alternatively, the two blends may be compressed in such a manner that one layer of granules/blend envelopes the second layer of granules on all the sides except the top surface to produce inlay tablets.

Other conventional ingredients that optionally may be present in any of the layers include preservatives, stabilizers, colorants, anti-adherents and antioxidants. The layered tablet may also include an outer protective coating layer or a separating layer between the two drug layers. The protective coating layer or the separating layer may include one or more film-formers or binders, such as a hydrophilic polymer like hydroxypropyl methyl cellulose and a hydrophobic polymer like ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, acrylic copolymers, glyceryl esters of wood resins or mixtures thereof and enteric polymer like polyacrylate material, cellulose acetate phthalate, cellulose phthalate hydroxy propyl methyl ether, polyvinyl acetate phthalate, hydroxy propyl methyl cellulose acetate succinate, cellulose acetate trimellitate, or shellac, and one or more plasticizers, such as polyethylene glycol, triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butyl phthalate and castor oil.

The film formers are applied from a solvent system containing one or more solvents including water, alcohols like methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones like acetone, or ethylmethyl ketone, chlorinated hydrocarbons like methylene chloride, dichloroethane, and 1,1,1-trichloroethane. The following examples are provided merely to illustrate various aspects of the present inventions. These examples are for illustration only and should not be construed as limiting the scope of the invention.

EXAMPLE 1

Metformin Hydrochloride 500 mg + Glipizide 5 mg

Procedure: Layer I

1. Metformin hydrochloride was blended with hydroxypropyl methylcellulose and granulated with an aqueous solution of polyvinyl pyriOlidone.

2. The wet mass was dried and milled to size.

3. The milled granules were lubricated with magnesium stearate and talc. Layer II

4. Metformin hydrochloride, glipizide and colorant were blended with hydroxypropyl methylcellulose and granulated with an aqueous solution of polyvinyl pyrrolidone.

5. The wet mass was dried and milled to size.

6. Sized granules were blended with magnesium oxide, talc and magnesium stearate.

The two layers were compressed over each other to form a layered tablet. EXAMPLE 2 Metformin Hydrochloride 500 mg + Glipizide 2.5 mg

Procedure: Similar to the procedure of Example 1.

EXAMPLE 3 Metformin Hydrochloride 250 mg + Glipizide 2.5 mg

Procedure: Similar to the procedure of Example 1.

Tables 1 and 2 provide the in- vitro release profiles of metformin and glipizide, respectively, from layered tablets prepared by the compositions and processes illustrated by Examples 1-3 in simulated intestinal fluid (phosphate buffer pH 6.8), 900 ml, USP Apparatus 2 at 50 rpm.

Table 1: Release profile of metformin from tablets prepared as per Examples 1-3 in simulated intestinal fluid (Phosphate buffer pH 6.8), 900 ml, USP 2 at 50 rpm.

Table 2: Release profile of glipizide from tablets prepared as per Examples 1-3 in simulated intestinal fluid (Phosphate buffer pH 6.8), 900 ml, USP 2 at 50 rpm.

Pharmacokinetic studies under fed conditions:

A single fixed dose combination of Metformin ER 500 mg and Glipizide ER 5 mg tablet of Example 1 was compared with the rwice-a-day administration of a single fixed dose combination of metformin hydrochloride 250 mg and glipizide 2.5 mg tablets (Metaglip™ tablets; Bristol Myers Squibb Company) under fed conditions.

Values for various pharmacokinetic parameters, including observed T_max, C_max, AUCo-t and AUCo-oc, were calculated using standard non-compartmental methods and are provided in Tables 3 and 4. A comparison of the test and reference products is provided in the form of the ratio of test to reference and is shown in Tables 5 and 6. Figure 1 depicts the mean plasma concentration-time profile for metformin and Figure 2 depicts the mean plasma concentration- time profile for glipizide. These results demonstrate a median time to maximum plasma concentration (T_max) of metformin that is 1.5 to 4.5 times the T_max exhibited for metformin by an immediate release formulation and median time to maximum plasma concentration (T_max) of glipizide that is 1.5 to 5.0 times the T_max exhibited for glipizide by an immediate release formulation.

Reference R: Metaglip™ (Metformin hydrochloride 250 mg and Glipizide 2.5 mg) tablets, Mfd. By Bristol Myers Squibb

Test T: Metformin ER + Glipizide ER tablets (Example 1)

Table 3: Summary of pharmacokinetic parameters for metformin

Table 4: Summary of pharmacokinetic parameters for glipizide

The results as indicated by ratio of test to reference are shown in Tables 5 and 6. These results indicate the test product to be comparable to the reference product with respect to the area under the concentration (AUC) time curve and the C_max (peak concentration).

Table 5: Summary of pharmacokinetic parameters for metformin

Table 6: Summary of pharmacokinetic parameters for glipizide

Parameters

Product / Statistics Cπiax AUC (o-t) AUC (o-oc )

(ng/ml) (ng.hr /ml) (ng.hr /ml)

Ratio % (T/R) 103.52 98.95 99.67

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention.

Claims

We Claim: 1. An extended release layered tablet of metformin and glipizide wherein the tablet when administered once daily under fed conditions exhibits area under the plasma-concentration time curves (AUC) and mean maximum plasma concentrations (C_max) of metformin and glipizide comparable to the AUC and C_max exhibited by an immediate release formulation of metformin and glipizide administered twice daily; and exhibits median time to maximum plasma concentration (T_max) of metformin that is 1.5 to 4.5 times the T_max exhibited for metformin by an immediate release formulation and median time to maximum plasma concentration (T_max) of glipizide that is 1.5 to 5.0 times the T_max exhibited for glipizide by an immediate release formulation.

2. The tablet according to claim 1, wherein the tablet is a layered tablet comprising: a first layer comprising metformin, one or more rate-controlling polymers and pharmaceutically acceptable excipients, and a second layer comprising glipizide, metformin, one or more rate-controlling polymers and pharmaceutically acceptable excipients.

3. The tablet according to claim 1, wherein the metformin comprises about 20% to about 80% by weight of the tablet.

4. The tablet according to claim 1, wherein the glipizide comprises about 0.05% to about 10% by weight of the tablet.

5. The tablet according to claim 2, wherein the rate controlling polymers comprise one or more of hydrophilic polymers, hydrophobic polymers or a combination thereof.

6. The tablet according to claim 5, wherein the hydrophilic polymers comprise one or more of cellulose derivatives comprising hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose or combinations thereof; polyvinylpyrrolidone, vinyl acetate/ vinyl pyrrolidone copolymer, microcrystalline cellulose, polysaccharides, polyalkylene glycols, starch and derivatives thereof.

7. The tablet according to claim 5, wherein hydrophobic polymers comprise one or more of ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, waxes, shellac and hydrogenated vegetable oils.

8. The tablet according to claim 2, wherein the one or more rate-controlling polymers comprise about 5% to about 60% w/w of the tablet.

9. The tablet according to claim 2, wherein the layers are prepared by one or more of dry granulation, wet granulation or direct compression.

10. The tablet according to claim 2, wherein the glipizide layer further comprises an alkalizing agent.

11. The tablet according to claim 3 , wherein the tablet further comprises one or both of an outer protective coating layer or a separating layer between first and second layers.

12. The tablet according to claim 1 , wherein the tablet exhibits a T_max of metformin which occurs at a time 4 hours to about 10 hours and exhibits a T_max of glipizide which occurs at a time 5 hours to about 18 hours after administration to a human patient.

13. An extended release tablet of metformin and glipizide which exhibits an in vitro dissolution profile for glipizide, when measured in the USP paddle type apparatus, at 50 rpm, at a temperature of 37+0.5°C in 900 ml of simulated intestinal fluid: - from about 5% to about 40% by weight after 2 hours, - from about 20% to about 75% by weight after 4 hours, - not less than 50% by weight after 12 hours, and wherein the tablet when administered once daily under fed conditions exhibits a median time to maximum plasma concentration (T_max) of glipizide that is 1.5 to 5.0 times the T_max exhibited by an immediate release formulation.

14. The tablet according to claim 13, wherein the tablet is a layered tablet comprising: a first layer comprising metformin, one or more rate-controlling polymers and pharmaceutically acceptable excipients, and a second layer comprising glipizide, metformin, one or more rate-controlling polymers and pharmaceutically acceptable excipients;

15. The tablet according to claim 13, wherein the metformin comprises about 20% to about 80% by weight of the tablet.

16. The tablet according to claim 13, wherein the glipizide comprises about 0.05% to about 10% by weight of the tablet.

17. The tablet according to claim 14, wherein the rate controlling polymers comprise one or more of hydrophilic polymers, hydrophobic polymers or a combination thereof.

18. The tablet according to claim 17, wherein the hydrophilic polymers comprise one or more of cellulose derivatives comprising hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose or combinations thereof; polyvinylpyrrolidone, vinyl acetate/ vinyl pyrrolidone copolymer, microcrystalline cellulose, polysaccharides, polyalkylene glycols, starch and derivatives thereof.

19. The tablet according to claim 17, wherein the hydrophobic polymers comprise one or more of ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters, waxes, shellac and hydrogenated vegetable oils.

20. The tablet according to claim 14, wherein the one or more rate-controlling polymers comprise about 5% to about 60% w/w of the tablet.

21. The tablet according to claim 14, wherein the layers are prepared by one or more of dry granulation, wet granulation or direct compression.

22. The tablet according to claim 14, wherein the glipizide layer further comprises an alkalizing agent.

23. The tablet according to claim 14, wherein the tablet further comprises one or both of an outer protective coating layer or a separating layer between first and second layers.

24. The tablet according to claim 13, wherein the tablet exhibits a T_max of metformin which occurs at a time 4 hours to about 10 hours and exhibits a T_max of glipizide which occurs at a time 5 hours to about 18 hours after administration to a human patient.

25. A method of treating non-insulin dependent diabetes mellitus in a patient in need thereof, the method comprising administering a tablet comprising a combination of metformin and glipizide, wherein the tablet when administered once daily under fed conditions exhibits a median time to maximum plasma concentration (T_max) of metformin that is 1.5 to 4.5 times the T_max exhibited for metformin by an immediate release formulation; and exhibits a median time to maximum plasma concentration (T_max) of glipizide that is 1.5 to 5.0 times the T_max exhibited for glipizide by an immediate release formulation.