Low-dose antidiabetic pharmaceutical formulation

Field of the Invention

The present invention relates to a low dose composition for the treatment of type 2 diabetes in low-dose patients, which includes metformin (preferably in reduced amounts relative to standard treatment practice) and another antidiabetic agent such as a sulfonylurea such as glyburide; this formulation has at least substantially equivalent efficacy to previous antidiabetic formulations containing metformin, but has significantly reduced side effects, and to the method of treating diabetes using such formulations.

Origin of the Invention

The biguanidic antihyperglycemic agent metformin described in U.S. Pat. 3174901, currently sold in the United States by Bristol-Myers Souuibb in the form of its hydrochloride (Glucophage®).

The diagnosis and treatment of type 2 diabetes is rapidly undergoing increasing changes. It is now widely accepted that glycemic control is of great importance. The goal of today's therapy is to achieve and maintain as close to normal glycemic control as possible to prevent long-term microvascular and macrovascular complications of high blood glucose levels. Diagnosis of diabetes has undergone significant changes, as evidenced by new ADA diagnostic and classification principles. The choice of oral medication for the treatment of type 2 diabetes has been very limited so far. Prior to 1995, sulfonylureas were the major oral diabetic agents in the United States. Sulfonylureas act through a single mechanism of hyperglycemia to increase beta-cell secretion of insulin. Since 1995, three new classes of agents have contributed to the control of hyperglycemia in diabetes mellitus. Metformin (biguanide) acts via a complementary mechanism of hyperglycaemia, by inhibiting hepatic glucose production and potentiating peripheral glucose utilization, and therefore reducing insulin resistance; thiazolidinediones such as troglitazone, rosiglitazone, and pioglitazone reduce peripheral insulin resistance; and alpha-glucosidase inhibitors such as acarbose and miglitol help control fasting glucose by delaying the intake of dietary carbohydrate. All of these agents have been proposed for monotherapy, and some have been suggested for use in combination therapy, usually after monotherapy has been found to be insufficient.

1995 Metformin was added to sulfonylurea therapy in patients who failed to achieve glycemic control with sulfonylurea monotherapy in the year 2000, and both agents were found to have significant effects on glycemic control or hemoglobin-A1c reduction. The different mechanisms of action on hyperglycemia are complementary, and therefore the use of the combination is a very attractive and rational course of action. Recipe data show that about 60% of metformin is used in combination with a sulphonylurea.

Examples of combinations of metformin and sulfonylurea glyburide (also called glibenclamide) are described in the following sources:

(1) WO 97/17975, published July 1997. May 22 (Barelli et al., Istituto Gentili SPA) (hereinafter Barelli et al.) Describe a combination of glibenclamide and metformin in a 1: 100 weight ratio to provide a daily dose of 15 mg of glibenclamide and 1500 mg of metformin for use in the onset of diabetes, particularly secondary resistance when treated with a combination of glibenclamidometformin HCl greater than 1: 100 by weight.

(2) Vigneri et al., Treatment of NIDDM Patients with Secondary Failure to Glyburide: Comparison of Addition of Either Metformin or Bed-time NPH Insulin to Glyburide, Diabetes & Metabolism, 17, 232-234, 1991, 1.5. g / day metformin and 15 mg / day glyburide for the treatment of NIDDM in patients with secondary resistance to 15 mg / day glyburide.

(3) Higinbotham et al., Double Blind Trial of Metformin in Non-Ketotic Diabetes Therapy, August 11, 1979, pp. 154-156, describes the treatment of diabetic patients who have already received 10 mg. up to 20 mg daily glibenclamide, 500 mg metformin twice daily. Higginbotham et al. concludes that "for some diabetics with poorly controlled sulphonylurea therapy, a significant improvement in diabetic control may be achieved by the addition of a low dose of 500 mg metformin twice daily."

(4) In U.S. Application Ser. No. No. 09 / 353,141 filed March 1999 July 14 (based on European Application No. 98401781.4, filed July 15, 1998) describes compositions containing metformin and glyburide in which the glyburide is of a particular particle size as described below.

References describing combinations of metformin and glipizide include:

(1) Combination of glipizide / metformin treatment requires low density lipoprotein binding to arterial proteoglycans in DIDDIM, Edwards et al., Diabetes, (46, Suppl.1,45A, 1997).

(2) Combination of glipizide / metformin treatment normalizes glucose and improves insulin sensitivity in hyperinsulinemia moderately well controlled. Cefalu et al., Diabetes, (45, Suppl. 2, 201 A, 1996).

(3) Effects of a combination of glipizide / metformin treatment on oxidation of LDL in NIDDIM, Crouse et al., Circulation, (94, No.8, Suppl., 1508, 1996).

(4) Insulin sensitivity is improved after glipizide monotherapy and combination with metformin, Cefalu et al., Diabetologia, (39, Suppl. 1, A231, 1996).

(5) Combined Metformin-Sulfonylurea Treatment of Patients with NIDDM in Fair to Poor Glycemic Control, Reaven et al., J. Clin. Endocrin. Metab. (74, No.5,1020-26,1992).

(6) Combination of Glipizide / Metformin Treatment in NIDDM, Hollenbecket et al., Diabetes, (39, Suppl.1,108A, 1990).

(7) Weather Antidiabetic Combination Therapy with Sulfonylureas and Metformin, Haupt et al., Med. Weit. (40, No.5,118-23 1989).

(8) Variations on the lipemic pattern in diabetic subjects after treatment with a combination of glipizide and metformin, Ferlito et al., App. Med. (Rome) 31/6 (289-301) 1975.

(9) Results with a combination of glipizide and dimethylbiguanide in 40 cases of diabetes, Parodi et al., Gazz. Med. Ital., 132/5 (226-235), 1973.

Other derivatives of metformin and another antidiabetic agent are described in the following references:

(1) U.S. Patent No.5631224 to Efendic et al. describes the combination of metformin with GLP-1 (7-36) amide or GLP-1 (7-37) or a fragment thereof.

(2) WO 98/57634 (SKB) describes a method of treating diabetes using a combination of thiazolidinedione and metformin. Thiazolidinedione can be troglitazone, ciglitazone, pioglitazone or englitazone and can be used in a dose range of 2 to 12 mg / day, whereas the daily dose of metformin is' up to 3,000 mg / day in 500 mg unit (eg 2 to 3 times daily) or At doses of 850 mg (twice daily); one example of a dose of metformin is 500 mg up to 5 times a day ”.

(3) EP 0749751A2 (Takeda) describes a combination of a thiazolidinedione insulin sensitizer (such as pioglitazone) and metformin.

Neither of the above references suggests the use of metformin-containing diabetic combinations for first-line treatment of low-dose patients.

Several defined combinations of metformin and glyburide (glibenclamide) are now marketed outside the United States. Such combinations are: (1) 400 mg metformin / 2.5 mg glibenclamide combinations (Boehringer's Bi-Euglucon in Argentina and Bi-Euglikon M in Italy; Guidotti / Menarini's Glibomet in the Dominican Republic and Italy; HMR's Normell in Greece and Hoechst Suguan-M in Italy; Sun Pharma's Glucored in India; Monsanto (Searle) Benclamet in India; Guidotti's Glibomet in Lebanon; Berlin Chemie / MenariniO Glibomet in the Slovak Republic and Roche's B-Euglucon in Uruguay); (2) 500 mg metformin / 5 mg glibenclamide combinations (Sun Pharma's Glucored in India; Monsanto's (Searle's) Benclamet in India, USV's Duotrol in India and Lakeside's (Roche) B-Euglucon in Mexico); (3) 500 mg metformin / 2.5 mg glibenclamide combinations (Molteni's Glucomide in Italy, Lakeside's (Roche) Bi-Euglucon M in Mexico and Szabo Dublex in Uruguay); and (4) 1 g metformin / 5 mg glibenclamide (Silanes' Sil-Norboral in Mexico).

The Glucophage® (Bristol-Myers Sowib Metformin) label, Physicians Desk Reference 1999, section "Indications and Uses" states that Glucophge may be used in combination with a sulphonylurea.

In addition, under “Dosage and Administration”, “Simultaneous Glucophage and Oral Sulfonylurea Therapy” is indicated when “if patients fail to respond to the maximum dose of Glucophage monotherapy for four weeks, Consideration should be given to whether or not the addition of oral sulfonylureas should be gradual, with continued administration of the maximum dose of Glucophage. However, efforts must be made to determine the maximum effective dose of each drug to achieve this goal. ” The recommended dosing regimen for Glucophage is an initial dose of 500 mg twice daily or 850 mg once daily in increments of 500 mg weekly or 850 mg every 2 weeks until a total of 2000 mg daily is achieved.

The Italian B-Euglucon M and Suguan M (400 mg metformin / 2.5 mg glibenclamide) leaflets state that these combinations are used in cases of primary or secondary resistance to sulphonylureas (as second or third line therapy) and that 1 / Dose of 2 tablets a day, increments of 1/2 tablet once a day according to glycemic changes to 4 tablets a day.

The Italian Glibomet (400 mg metformin / 2.5 mg glibenclamide) and Glucomide (500 mg metformin / 2.5 mg glibenclamide) leaflets indicate that these combinations are used for type 2 diabetes, ⁵which is out of control or cannot be controlled by diet alone ⁴or diet and sulphonylureas (for first-line therapy or second-line therapy).

The Italian Glibomet leaflet states the daily dose of 2 tablets of 800 mg metformin and 5 mg glibenclamide up to 2 grams of metformin. The Glucomide Italian leaflet states the daily dose of 2 capsules, which is 1000 mg metformin to 2 grams metformin and 5 mg glibenclamide.

Description of the Invention

The present invention provides a low dose pharmaceutical composition comprising a combination of metformin and at least one other antidiabetic agent, preferably glyburide; this combination has at least substantially equivalent efficacy in the treatment of low-dose patients (first-line therapy) as the combination of metformin and another antidiabetic agent used at significantly higher doses than generally accepted in medical practice for the treatment of first-line diabetes. However, the use of the low dose pharmaceutical composition of the present invention has significantly reduced side effects compared to the same combination used at the higher doses usually administered.

It is to be understood that the low dose compositions of the present invention include a "low dose" of at least one of the active ingredients of the antidiabetic drug, that is, a lower dose than the generally accepted medical practice for first line diabetes therapy. Thus, the aforementioned low dose pharmaceutical composition will comprise a low dose of metformin as described above or a low dose of another antidiabetic agent as described above or a low dose of both metformin and another antidiabetic agent as described above.

According to the present invention, the efficacy of first-line therapy in the treatment of diabetes in low-dose patients is achieved by the use of a low-dose composition wherein the daily dose of metformin can be as conventionally used in medical practice for first-line diabetes. within the starting daily dose, which is about 1/5 of the initial daily dose commonly used in medical practice for first-line treatment of diabetes, to a daily maintenance dose of about 2/3 of the daily maintenance dose for first-line diabetes.

Preferably, in a low dose composition of the present invention, the daily dose of metformin ranges from an initial daily dose of only 25-60% of the initial commonly used daily dose of diabetes in first-line therapy to a daily maintenance dose of approximately 40-60% of the maintenance dose. doses are used daily for first-line therapy to treat diabetes.

Thus, in fact, the low dose composition of the present invention will be used in first-line therapy at daily doses of less than about 800 mg metformin per day, preferably no more than about 750 mg metformin per day, more preferably no more than about 600 mg metformin per day. and preferably (initial dose) from about 160 to about 225 mg / day as a single dose or in divided doses 1 to 4 times daily

Other antidiabetic agent (preferably sulfonylurea,

A desirable glyburide) can be used in daily doses that are commonly prescribed for the treatment of diabetes in first-line therapy, and preferably within a starting daily dose of about 1/10 of the initial daily dose of another antidiabetic agent commonly used in diabetes practice. treated as first-line therapy, up to a daily maintenance dose of approximately 2/3 of the maintenance dose of the other antidiabetic agent, commonly used in first-line therapy for the treatment of diabetes.

Preferably, the other antidiabetic agent is administered in daily doses ranging from an initial daily dose of only 20-60% of the initial daily dose of such an antidiabetic agent in first-line therapy for diabetes to a daily maintenance dose of approximately 40-60% of the maintenance dose of such other antidiabetic agent commonly used in first-line therapy for the treatment of diabetes.

The aforementioned daily dose of another antidiabetic agent (preferably glyburide) ranges from the initial daily dose of such an antidiabetic agent (e.g., 0.1-1.5 mg glyburide) to the maximum maintenance daily dose of commonly used medical practice in first line therapy for the treatment of diabetes. In the case of glyburide, it is desirable that the daily dose should be up to 2/3 of the daily dose for first line therapy in diabetes accepted medical practice, i.e. up to about 4.5 mg, preferably up to about 3.75 mg of glyburide per day, as a single dose or in divided doses of 1-4 tablets per day.

As used herein, the term "low dose combination", "low dose composition" or "low dose pharmaceutical composition" as used to describe a preferred composition of the invention means a composition comprising an initial dose of metformin of about 1/5 of the initial first-line therapy for diabetes, up to about 2/3 of the metformin maintenance daily dose usually for first-line diabetes. The aforementioned daily doses of metformin include the initial daily doses of metformin (for example, only 160 mg) and the metformin doses determined by titration to a maximum maintenance dose of less than about 800 mg / day, preferably less than 750 mg / day, and another antidiabetic agent is used. in the quantities indicated here.

To date, combinations of metformin with another antidiabetic drug such as a sulfonylurea such as glyburide, with few exceptions, have been commonly used as second-line therapy for the treatment of type 2 diabetes. In commonly accepted medical practice, daily doses for such second-line therapy using defined combinations of metformin and glyburide are 3 to 4 tablets containing 400 to 500 mg metformin and 2 to 2.5 mg glyburide, or about 1,200 to 2,000 mg of metformin and 6 to 10 mg of glyburide per day

As noted above for Glibomet and Glucomide (fixed combinations of metformin and glyburide) commercially available in Italy, these combinations can be used as first line therapy (in low-dose patients) at doses of 800-1000 mg up to 2 grams of metformin and 5 mg glibenclamide (glyburide) daily. This daily dose is referred to herein as the "generally accepted dose in the first line of medical practice: first line therapy for the treatment of diabetes" or "previous dose" or "previous daily dose:

The above dosages may be encompassed by the term¹ Doses used in standard medical practice for first-line therapy for the treatment of diabetes.

As noted above for Boehringer's BiEuglucon M and Hoechst's Suguan M (fixed combinations of metformin and glibenclamide), these combinations can be used as second-line therapy starting with 1/2 tablet, that is 200 mg metformin and 1, 25 mg glibenclamide. Initial or initial low doses are used to determine if the patient is able to carry these drugs, and these doses are gradually increased from 1/2 tablet to 4 tablets per day until an effective dose is reached. Starting or starting 1/2 tablets or 200 mg metformin and 1.25 mg daily glibenclamide are not considered by Boehringer and Hoechst and physicians who prescribe these drugs as "commonly prescribed medical practice for the treatment of diabetes".

Unexpectedly, the combination of metformin and glyburide in accordance with the present invention has been found to provide the following benefits. Low-dose metformin is an insulin sensitizer and reduces insulin resistance in the liver, muscle and pancreas. The low-dose metformin-glyburide combination acts on the pancreas as a glucose sensitiser; it reduces pancreatic toxicity and improves pancreatic function.

The present invention further provides a method of treating diabetes, in particular type 2 diabetes, in low-dose patients, comprising administering therapeutically effective low-dose formulations of the present invention comprising metformin and at least one other antidiabetic agent (preferably glyburide) at doses as herein described. the composition provides at least substantially the same efficacy in the treatment of diabetes in low-dose patients as for metformin and said other antidiabetic agent, used in generally accepted medical practice dosages for first line therapy for the treatment of diabetes but with substantially reduced side effects, for the treatment of a low dose drug requiring first line therapy.

In addition, the present invention provides a method for reducing fasting plasma glucose, reducing insulin resistance, hemoglobin^JA method of lowering A1c, increasing fasting insulin and / or fasting glucose in a diabetic patient, comprising administering to a patient in a low dose pharmaceutical composition of the present invention a metformin / other anti-diabetic agent, preferably glyburide. this low dose pharmaceutical composition would be administered as first-line therapy and that the patient-to-person would be a low-drug patient.

In the practice of the present invention, using the most suitable low dose pharmaceutical composition of the present invention comprising metformin and glyburide for the treatment of diabetes in low drug patients, it has been found that treatment efficacy in low drug patients is at least substantially the same with side effects. gastrointestinal side effects and hypoglycaemia) are surprisingly severe and substantially reduced compared to patients, previously treated daily doses of metformin and glyburide commonly accepted in medical practice for the treatment of diabetes. Thus, since treatment efficacy in low-dose patients, as measured by a decrease in hemoglobin Aic compared to baseline over time, a decrease in fasting plasma glucose (FPG), a rise in fasting insulin and a decrease in fasting glucose (PPG) are the same as in the patients described above using the low dose pharmaceutical composition of the present invention and previous daily doses or prior combinations, the extent of hypoglycaemia in the treatment of low dose patients with previous doses is more than 3 times higher than in patients treated with the low dose pharmaceutical composition of the present invention, and the extent of gastrointestinal side effects in patients with treatment , treated with a low dose pharmaceutical composition of the present invention.

Preferred daily doses of the metformin plus glyburide combination will be from about 175 to about 600 mg metformin, preferably from about 200 mg to about 500 mg metformin, more preferably from about 250 to about 400 mg metformin and from about 0.5 to about 4.5 mg glyburide, preferably from about 0.625 to about 3.75 mg of glyburide, and more preferably from about 1 to about 1.5 mg of glyburide.

Detailed Description of the Invention

As used herein, the term "diabetes" refers to type 2 (or type II) diabetes or non-insulin dependent diabetes mellitus (NIDDM).

As used herein, the term "metformin" refers to metformin or a pharmaceutically acceptable salt thereof, such as hydrochloride, metformin (2: 1) fumarate, and metformin (2: 1) succinate, as described in U.S. Ser. No. 09/262526, filed December 1999 March 4, hydrobromide, pchlorophenoxyacetate or embonate, and other salts of known mono- and dibasic carboxylic acids, including those described in U.S. Pat. 3174901; all of which are called metformin. Preferably, the metformin used herein is metformin hydrochloride, namely, metformin marketed as Microphage® (a trademark of Bristol-Myers Squibb).

As used herein, the term substantially reduced side effects refers to reduced volume of hypoglycaemia and gastrointestinal adverse effects, including diarrhea, nausea / vomiting, and / or abdominal pain resulting from the use of a low dose pharmaceutical composition of the invention in low dose patients as compared to patients the same active components of the composition of the present invention, but in higher doses, as is common practice in the treatment of diabetes.

The term "at least substantially equivalent efficacy" as used herein in treating type 2 diabetes refers to reducing the efficacy of the low dose formulation of the present invention and / or maintaining hemoglobin A_1c (glycosylated hemoglobin) of 7% or less, to reduce insulin resistance (by increasing fasting insulin) and / or increase fasting glucose (PPG) in low-dose patients compared to patients treated with the same active components of the composition of the present invention, but at higher doses than conventional medical practice for the treatment of diabetes.

As used herein, the term "fasting change" refers to the difference between fasting glucose (PPG) and fasting plasma glucose (FGP).

the low dose composition of the present invention will contain metformin for use in combination with another antidiabetic agent (also referred to herein as "another antidiabetic agent"), which may be administered orally in the same dosage form or in separate dosage forms or injections.

The other antidiabetic agent may be one or more of the following: <sulfonylurea, glucosidase inhibitor, thiazolidinedione, insulin sensitizer, glucagon-like peptide-1 (GLP-1), insulin, PPAR α / γ double antagonist, meglitinide and / or aP2 inhibitor. .

The use of metformin in combination with another antidiabetic agent according to the present invention is expected to produce antihyperglycemic effects that are greater than those achievable with each of these drugs individually and greater than the combined total antihyperglycaemic effects of these drugs.

Preferably, the other antidiabetic agent is a sulfonylurea such as glyburide (also known as glibenclamide), glimepride (described in U.S. Patent No. 4,379,785), gliprid, glipizide, gliclazide or chloropropamide, and / or other known sulfonylureas or other antihyperglycemic agents. acts on the ATP-dependent β-cell channel; better is glyburide. The sulfonylurea can be administered in the same oral dosage form with metformin or in a separate oral dosage form.

Metformin with a sulfonylurea will be used in a weight ratio of from about 1000: 1 to about 10: 1, preferably from about 400: 1 to about 100: 1, more preferably from about 250: 1 to about 150: 1, and most preferably 200: 1.

The oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (described in U.S. Patent No. 4904769), vaglibose, miglitol (described in U.S. Patent No.4639436), which may be administered in a single oral dosage form or in the same dosage form as metformin.

Metformin with a glucosidase inhibitor will be used in a weight ratio of about 0.01: 1 to about 100: 1, preferably about 0.5: 1 to about 50: 1.

Another antidiabetic agent may be a meglitinide, such as repaglinide (Prondin®, NovoNordisk) or nataglinide (Starlex®, Novartis), which may be administered alone or in the same dosage form; with metformin in dosage form:

Metformin with meglitinide will be used in a weight ratio of about 0.01: 1 to about 500: 1, preferably about 0.5: 1 to about 300: 1.

Metformin can be used in combination with a thiazolidinedione oral antidiabetic agent or other insulin sensitizers (which affect insulin sensitivity in NIDDM patients) such as troglitazone (Varner-Labert's Rezulin® described in U.S. Patent 4,572,912 to Rosiglitazone, SKB-Avandia). pioglitazone (Takeda-Lilly-Actos®), Mitsubishi's MCC-555 (described in U.S. Patent No.5594016), Glaxo-Welcome GL-262570, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325), Pfizer), which may be administered alone or in the same dosage form as metformin.

Metformin with thiazolidinedione will be used in a weight ratio of about 0.01: 1 to about 100: 1, preferably about 0.5: 1 to about 5: 1.

Thiazolidinedione in an amount less than about 150 mg oral antidiabetic agent can be incorporated into a single tablet containing metformin.

Another anti-diabetic agent may be an aP2 inhibitor such as that described in U.S. Patent Application Serial No. 60/100677 filed December 1998. and No.60 / 127745, filed September 17, 1999, April 5th, the descriptions of which are incorporated herein by reference. The dosages used are indicated in these applications.

The aP2 inhibitor metformin will be used in a weight ratio of about 0.01: 1 to about 100: 1, preferably about 0.5: 1 to about 2: 1. aP2 inhibitor and metformin may be administered in the same or separate dosage forms.

Metformin may also be used in combination with a non-oral antihyperglycemic agent such as insulin or glucagon-like peptide-1 (GLP-1) such as GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-1 (7-37) (as described in U.S. Patent No.5614492 to Habener, the disclosure of which is incorporated by reference), which may be administered by injection or transdermal or oral devices.

If available, a sulphonylurea such as glyburide, glimepride, glipyride, glipizide, chlorpropamide or gliclazide, thiazolidinedione such as troglitazone, rosiglitazone or pioglitazone, a glucosoxidase inhibitor acarbose or miglitol, may be used as a compositions, and compositions, amounts, and dosages specified in the Physicians' Desk Reference.

If present, GLP-1 peptides may be administered orally, orally or parenterally as described in U.S. Pat. 55346701 (TheraTech), 5614492 and 5631224, which are hereby incorporated by reference.

Metformin can be used in combination with another antidiabetic agent which may be a PPAR α / γ dual antagonist such as the N-benzyldioxothiazolidylbenzamide derivative such as described in WO 96/38428 5- (2,4-Dioxothiazolidin-5-ylmethyl) -2-methoxy-N - [4- (trifluoromethyl) benzyl] benzamide (KRP-297), WO 98/05531 (Ligand Pharmaceuticals, Ine.), Which describes 2- (4- [2,4-difluorophenyl] -1-heptylureido) ethyl] phenoxy ) -2-methylbutyric acid, and WO 97/25042 and WO 96/04260 (SKB), containing benzoxazole and pyridine derivatives having the formula:

R °

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or a pharmaceutically acceptable salt thereof, and / or a pharmaceutically acceptable solvate thereof, wherein R 0 represents 2-benzoxazolyl or 2-pyridyl and R¹ represents CH 2 OCH 3 or CF 3 such as (S) -3- [4- [2- [N- (2-benzoxazolyl) -N-methylamino) ethoxy] phenyl] -2- (2-methoxyethoxy) propanoic acid or (S) -3- [4- [2 [N- (2-Benzoxazolyl) -N-methylamino) ethoxy] phenyl] -2- (2,2,2-trifluoroethoxy) propanoic acid or a pharmaceutically acceptable salt thereof and / or a pharmaceutically acceptable salt thereof insulted. The dosages used are given in the literature cited above.

Metformin with a PPAR α / γ dual antagonist will be used in a weight ratio of about 0.01: 1 to about 100: 1, preferably about 0.5: 1 to about 5: 1.

When metformin is used in combination with a PPAR α / γ dual antagonist, the combination may be used in an oral dosage form such as a tablet or capsule, as will be understood by those skilled in the art.

Low-dose combinations of metformin and glyburide and, if appropriate, an insulin sensitizer such as glitazone such as rosiglitazone, pioglitazone or troglitazone are preferred.

In the practice of the present invention, a low dose pharmaceutical composition containing metformin and at least one other antidiabetic agent will be used together with a pharmaceutical solvent or diluent. The low dose pharmaceutical composition may be formulated using conventional solid or liquid diluents or diluents and the pharmaceutical additives suitable for the intended route of administration, the low dose composition of the present invention may be administered orally to mammals, including humans, monkeys, dogs, etc. in the form of granules or powders, or as parenteral injection preparations. Doses for low-dose patients are described above, which can be given as a single dose or as a single dose 1 to 4 times a day.

The dosage forms described above may also contain the required physiologically acceptable carrier, excipient, ointment, buffer, antimicrobial agent, bulking agent (such as mannitol), antioxidants (ascorbic acid or sodium bisulfite) or the like.

The dose administered should be carefully adjusted according to the age, weight and condition of the patient, and the route of administration, dosage form and regimen and the result to be achieved.

The combination of metformin or a salt thereof and another antidiabetic agent may be formulated alone or, if possible, in a single dosage form, using conventional formulation techniques.

The various compositions of the present invention may also include one or more excipients or excipients in an amount of from about 0 to about ^yabout 90% by weight, preferably about 1 to about 80% by weight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate, and / or cellulose derivatives such as wood cellulose and microcrystalline cellulose.

One or more binders may be present as a supplement to, or in place of, the excipients in an amount of from about 0 to about 35%, preferably from about 0.5 to about 30% by weight of the composition. Examples of suitable binders for use in the present invention are polyvinylpyrrolidone (molecular weight from about 5000 to about 80,000, preferably about 40,000), lactose, starches such as corn starch, modified corn starch, sugars, acacia, and the like. a finely divided (less than 500 microns) wax binder such as carnauba wax, paraffin wax, spermaceti, polyethylene or microcrystalline wax.

When the composition is to be in tablet form, it will contain one or more tableting lubricants in an amount of from about 0.2 to about 8%, preferably from about 0.5 to about 2% by weight of the composition, such as magnesium stearate, stearic acid , palmitic acid, calcium stearate, talc, carnauba wax and the like. Other common ingredients which may also be in the form of a dosage form include preservatives, stabilizers, anti-caking agents or silica-type anti-skid conditioners or glidants such as Syloid silica as well as FD&amp;C pigments.

The tablets of the present invention may also comprise a coating layer which may comprise from 0 to about 15% by weight of the tablet composition. The coating applied on the outer solid phase containing the inner solid phase particles may be any conventional coating composition and may consist of one or more film-forming materials or binders, such as a hydrophilic polymer such as hydroxypropyl methylcellulose, and / or hydrophobic polymer as neutral polymer of methacrylic acid ester, ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, β-pinene polymers, resin glyceryl esters and the like, and one or more plasticizers such as triethyl citrate, diethyl phthalate, propylene glycol, glycerol, butyl phthalate, castor oil and the like. Both the core of the tablet and the coating composition may contain aluminum paint.

The film-forming substances are applied to the tablet from a solvent system containing one or more solvents including water, alcohols such as methyl aclohol, ethyl alcohol or isopropyl alcohol, ketones such as acetone ethyl methyl ketone chlorinated hydrocarbons such as methylene chloride dichloroethane and 1. , 1,1-trichloroethane.

When pigments are used, the pigments will be applied together with the film-forming material, the plasticizer and the solvent compositions.

The finished dosage form is either a compressed tablet or a hard gelatin capsule, preferably a tablet. This tablet may be film-coated. The total amount of the drug in the dosage form will be such that the size of the dosage form is convenient for patients.

When the pharmaceutical composition of the present invention contains a combination of metformin and glyburide, the composition will be administered to provide between about 55 and about 500 mg of metformin one to four times daily, at least 160 mg of metformin per day, and most less than about

800 mg, preferably up to about 750 mg metformin per day. Preferably, glyburide is administered from about 0.5 to about 3.75 mg once to four times daily, up to a maximum of 4.5 mg daily.

A preferred low dose formulation of the present invention is metformin and glyburide and is used as a primary therapy, that is, as a nutritional supplement and used for glycemic control in patients with type 2 diabetes.

The ADA recommends that HbAi be treated for therapeutic purposes_c &lt;7% (ADA. Diabetes Care 21 [Suppl.1]: S23-S31, 1998) to reduce the risk of complications of type 2 diabetes, including coronary heart disease and microvascular complications.

The dosage of the most preferred metformin-glyburide combination of the present invention should be individualized based on efficacy and delivery. It is best to take it with meals and start with a low dose, gradually increasing it. Ideally, response to treatment should be assessed by determination of HbAi_c (glycosylated hemoglobin), which is a better indicator of long-term glycemic control than FPG alone. Improving glycemic control, including FPG, fasting glucose and HbAi, should be the therapeutic goal in all patients with type 2 diabetes_c quantities reaching normal or as close to normal as possible. Patients should be titrated to achieve the ADA target of HbAi_c &lt;7%, according to dosing recommendations up to the maximum recommended dose (ADA, Diabetes Care 21 [Suppl.1]: S23S31, 1998).

As the initial treatment, the preferred starting dose of the metformin-glyburide combination of the present invention is 250 / 1.25 mg once daily with food. In patients with baseline HbAi_c &gt; 9% or fasting glucose&gt; 200mg / dl, the best recommended starting dose is 250 / 1.25 mg twice daily in the morning and evening with meals. It is best to increase the dose by increments of 250 / 1.25 mg every 2 weeks to the minimum effective dose required to achieve adequate glycemic control. In patients requiring additional glycemic control, the dose of 250 mg / 1.25 mg may be increased to 500 / 2.5 mg. However, as indicated, the preferred maximum daily dose of metformin is 600-750 mg and the preferred maximum daily dose of glyburide is 3.75 mg.

The low dose pharmaceutical composition of metformin-glyburide of the present invention will preferably be formulated according to the instructions described in U.S. Ser. No. 09/353141, filed December 1999 July 14, which declares priority under European Application No.98401781.4_r filed in 1998 July 15; The U.S. application is attached as a reference.

The preferred low dose metformin-glyburide formulations are given below.

<td>Product Identity</td><td>Ingredient amount, mg / tablet 250 / 1.25</td>

<td>The Ingredient</td><td></td>

<td>Metformin hydrochloride</td><td> 250,0</td>

<td>Gliburid</td><td> 1,25</td>

<td>Croscarmellose sodium</td><td> 3,0-15,0</td>

<td>Microcrystalline cellulose</td><td> 15,0-60,0</td>

<td>Polyvinylpyrrolidone</td><td> 3,0-18,0</td>

<td>Magnesium stearate</td><td> 0,3-7,5</td>

<td>Film coating *</td><td> 4,5-12,0</td>

uses a commercially available film coating such as Opadry (Colorcon, UK.

Particularly suitable low dose metformin-glyburide formulations are:

<td>Product Identity</td><td>Ingredient amount, mg / tablet 250 / 1.25</td>

<td>The Ingredient</td><td></td>

<td>Metformin hydrochloride</td><td> 250,0</td>

<td>Gliburid</td><td> 1,25</td>

<td>Croscarmellose sodium</td><td> 7,0</td>

<td>Microcrystalline cellulose</td><td> 28,25</td>

<td>Polyvinylpyrrolidone</td><td> 10,0</td>

<td>Magnesium stearate</td><td> 0,6-6,0</td>

<td>Film coating *</td><td> 4,5-12,0</td>

uses a commercially available film coating such as Opadry (Colorcon, UK.

Preferably, the low dose pharmaceutical compositions of the present invention in the form of a solid oral dosage form comprise a combination of metfomnine and glyburide in which the glyburide has a particle size such that at most 10% of the fine particles are larger than 60 µιτι. Preferably, the glyburide has a particle size such that at most 10% of the fine particles are less than 3 pm and at most 10% of the fine particles are greater than 40 pm. This particular range of particle sizes can be obtained by sieving or grinding in an air-jet mill.

In another embodiment, the low dose solid oral dosage form of the present invention will comprise a combination of metformin and glyburide wherein the glyburide has a particle size such that at most 25% of the fine particles are less than 11 µm and at most 25% of the fine particles are larger than 46 µm.

Ideally, 50% of the fine particles should be smaller than 23 μίτι.

Most preferred is a combination of metformin and glyburide, in which the particle size distribution of glyburide is such that approximately 25% of the values ​​are at least 6 pm, approximately 50% of the values ​​are at 7-10 pm and about 75% of the values ​​are at most 23 pm.

A low dose pharmaceutical composition of the present invention in tablet form may be prepared by a process comprising the steps of:

(a) Granular metformin and glyburide granules,

(b) mixing the granules with tableting additives and diluents; and

c) tableting the resulting mixture into tablets.

The mixture used to obtain the granules has a granulation binder. Preferably, the granulation binder is a polyvinylpyrrolidone such as, for example, a polyvinylpyrrolidone having a molecular weight of 45,000. The polyvinylpyrrolidone may be used in an amount of 2% to 4% by weight relative to the final tablet weight.

After the granulation step, the granules can be sieved and dried.

The granules are then mixed with the diluent and the tableting additives. The diluent may be a conventional excipient such as microcrystalline cellulose for tablet production. The tableting agent may be a conventional substance such as magnesium stearate.

The tablets thus obtained may then, if necessary, be coated with a hydrophilic cellulose polymer and talc. The preferred hydrophilic cellulose polymer is 2-hydroxypropylmethyl cellulose.

Description of the drawings

Figures 1 and 2 are bar graphs showing hemoglobin A1c (HbA_1c) change from the number of tablets in the fixed combination of metformin / glyburide used in first line therapy compared to monotherapy, glyburide or metformin.

Figures 3, 4 and 5 are bar graphs depicting HbA- |_C change from time to time with fixed metformin / glyburide combinations used in first line therapy versus monotherapy with glyburide or metformin.

Figure 6 is a bar graph depicting the change in fasting plasma glucose (FPG) from the number of tablets of fixed metformin / glyburide combinations used in first line therapy versus monotherapy with either glyburide or metformin.

Fig. 7 is a bar graph showing baseline and fasting insulin levels under fixed metformin / glyburide combinations used in first line therapy versus monotherapy with either glyburide or metformin.

Figures 8A and 8B are bar graphs showing the change from baseline in PPG at 20 weeks for the fixed metformin / glyburide combinations used in first line therapy versus monotherapy with either glyburide or metformin.

Figure 9 is a bar graph depicting hypoglycemic symptoms in subjects exposed to fixed metformin / glyburide combinations used in first line therapy versus monotherapy with either glyburide or metformin.

FIG. 10 is a bar graph depicting the frequency of gastrointestinal side effects in subjects exposed to fixed metformin / glyburide combinations used in first line therapy versus monotherapy with either glyburide or metformin.

The following examples represent preferred embodiments of the invention.

and 2 examples

Metformin / glyburide containing tablets may be prepared as described below.

Metformin hydrochloride-glyburide combination tablets

250mg / 1.25mg and 500mg / 2.5mg Example_2 Example

<td rowspan="2">The Ingredient</td><td colspan="2">Amount per tablet (mg)</td>

<td>250 mg / 1.25 mg</td><td>500 mg / 2.5 mg</td>

<td>Metformin hydrochloride</td><td> 250,0</td><td> 500,0</td>

<td>Gliburid</td><td> 1,25</td><td> 2,5</td>

<td>Croscarmellose sodium</td><td> 7,00</td><td> 14,0</td>

<td>Povidon</td><td> 10,00</td><td> 20,0</td>

<td>Microcrystalline cellulose</td><td> 28,25</td><td> 56,5</td>

<td>Magnesium stearate</td><td> 2,25</td><td> 4,5</td>

<td>Film coating *</td><td> 6</td><td> 12</td>

HPMC based film coating is used

Metformin hydrochloride / glyburide tableted products, 250 mg / 1.25 mg and 500 mg / 2.5 mg, were compressed from the same granulation. The lower dose tablet was compressed in half of the metformin hydrochloride 500 mg / 2.5 mg tablet weight. The tablets made for clinical purposes were film coated using hydroxypropylmethyl cellulose (HPMC) film coating. This film coating was non-functional and applied for aesthetic purposes. The film coating applied to the clinical product was transparent.

The manufacturing process for clinical products was as follows:

Croscarmellose sodium and glyburide were dispersed together, then mixed with au metformin hydrochloride / magnesium stearate (99.5%; 0.5% w / w) in a high shear mixer. The resulting dry mixture was granulated in a high shear mixer with povidone aqueous solution and dried in a "fluid bed" dryer at about 60 ° C to achieve a specific moisture content determined by drying loss. The dried granulate is crushed in a screening mill and mixed with microcrystalline cellulose using a mixer. Using this mixer, magnesium stearate is added and the final blend is obtained.

The final mixture, using a suitable press, is pressed into tablets of the desired mass, which has been adjusted based on the moisture settings during the process. The theoretical tablet weight (based on the composition regardless of moisture) was 300 mg for a 250 mg / 1.25 mg dose tablet and 600 mg for a 500 mg / 2.5 mg dose tablet.

The tablets were film-coated on a perforated coating plate using an appropriate non-functional film-coating system on an HPMC basis until the required thickness was applied. A typical amount of film coating applied to the tablets was 2% by weight.

In an in vivo evaluation of tablet formulation for the prototype combination tablet, particle size distribution was identified for use in the clinical program to achieve bioavailability of the combination product from Micronase. The particle size distribution for any batch of glyburide was described by three cumulative size criteria: 25% fines,% fines (also known as mass average particle size, MMPS) and 75% fines. The clinical program included a total of six batches of glyburide drug substance with 25% fine material with particles within 4-7 pm, 50% fine material with particles within 8-14 pm and 75% fine material with particles within 17-26 pm . All six batches of glyburide were synthesized by Profarmac of the same dealer; four of them were micronized by Profarmaco. The particle size distribution of the four batches produced is detailed in the table below.

Batch size data of glyburide drug substance used in the clinical program

<td rowspan="2">Party No.</td><td colspan="3">Particle size^A (units are equivalent to the diameter of the sphere, pm)</td>

<td>25% fine material</td><td>50% fine material</td><td>75% fine material</td>

<td> 1</td><td> 5</td><td> 9</td><td> 21</td>

<td> 2</td><td> 5</td><td> 9</td><td> 21</td>

<td> 3</td><td> 4</td><td> 8</td><td> 18</td>

<td> 4</td><td> 5</td><td> 9</td><td> 18</td>

^A Particle size measured by laser light scattering, Method Reference #CRM 8532 (#SM 248533)

The proposed particle size specification includes the three cumulative size criteria described above: acceptable bulk average particle size (50% for fine material), lower quarter upper limit (25% for fine material), and upper quarter (75% for fine material). This particle size specification for glyburide was based on bioavailability studies from the experience of various clinical batches due to the very close size distribution of industrially produced glyburide and the precision of the particle size determination method. The particle size criteria described below provided reproducibility of the results of glyburide dissolution and bioavailability from metformin hydrochloride-glyburide tablets.

% fine material has a particle size value of no more than 6 pm;

% fine particle size value: 7 to 10 μην,% fine particle size value not more than μιη.

example

A. SUMMARY OF THE 5 CLINICAL PROTOCOLS (1) Purpose

This study was conducted to compare the glycemic control of 2 meteredin / glyburide fixed dose combination products (described in Examples 1 and 2) with placebo in low-dose patients with type 2 diabetes who had insufficient glycemic control on diet and exercise. The fixed dose combination combinations studied included 250 mg metformin with 1.25 mg glyburide and 500 mg metformin with 2.5 mg glyburide. Glycemic control was monitored using hemoglobin A1c (HbA_1c) - long-term measurement of glycemic control with a gold standard. The mean HbAi was compared_c change from baseline after 20 weeks of treatment (4 weeks stable dose once daily, 4 weeks dose titration, and 12 weeks stable dose). The treatment phase was continued for an additional 12 weeks to assess the duration of efficacy.

The contribution of the individual components of the fixed combination product was evaluated by comparing the short-term glycemic parameters of the combination product with monotherapy after a 4-week stable period with once daily dosing. Glycemic control was achieved with similar degrees of hypoglycaemia using fixed dose combinations versus one sulfonylurea or a decrease in gastrointestinal side effects compared to one metformin. Glycemic control was achieved with a decreasing tendency for gastrointestinal side effects compared to any single agent. The tendency to change hypoglycaemia, gastrointestinal symptoms and lactate levels was assessed.

(²) Research sites and subjects

Selected subjects had little or no oral antihyperglycaemic therapy for 2 months prior to screening. Approximately 100 locations in the US were recruited and a maximum of approximately 800 subjects were selected. The subjects selected were both males and females between the ages of 30 and 78 years with diagnosed type 2 diabetes, reduced glucose transport, or fasting glucose, who had insufficient glycemic control with food and exercise.

(2) Study Design and Duration This study was a 34-week, multicenter, randomized, placebo-controlled, double-blind, parallel study, with a long-term, open label treatment phase, as appropriate. ⁴ (4) Measures of consequences

Analysis of endpoint measures in periods B and C was performed after all data from a 32-week randomized treatment period were available.

The major consequence - the change in efficiency - was HbAi_c change from baseline in two combinations compared with placebo after 20 weeks of randomized treatment.

Secondary consequences included:

- The incidence of adverse events, in particular hypoglycaemia and gastrointestinal side effects, was compared between treatment groups after 20 and 32 weeks of randomized treatment.

- The number and proportion of subjects who achieved a therapeutic response to glucose were evaluated between treatment arms after 20 and 32 weeks of randomized treatment. - A reduction in fasting glucose and 2 hours after a meal between treatment groups was observed after 20 and 32 weeks of randomized treatment.

B. JUSTIFICATION

Metformin and a sulfonylurea such as glyburide are known and effective in the treatment of type 2 diabetes. These two drugs have shown synergistic effects on glucose lowering when used in combination. Each of these drugs can be used alone as first-line therapy. They can also be used in combination with each other if monotherapy with each of these drugs is inadequate. There is currently no data available on low-dose combination therapy for first-line use.

It was expected that treatment with a fixed dose combination tablet would improve glycemic control in first-line therapy for subjects with type 2 diabetes who do not achieve adequate control over diet and exercise. It was expected that glycemic control would be achieved at lower doses than monotherapy, with comparable or less pronounced side effects than the effects of the individual agents, and that the combination would be convenient.

This randomized double-blind study, controlled by placebo in subjects with type 2 diabetes who did not achieve adequate glycemic control through diet and exercise, tested the following hypotheses:

1. Administration of a fixed dose metformin / glyburide combination product over 20 weeks (4 weeks steady-state once daily in period B and 16 weeks in treatment period C) in subjects with type 2 diabetes who have not achieved adequate glycemic control through diet and exercise will provide significant HbA_1c reduction compared to placebo.

2. The use of a fixed dose metformin / glyburide combination product over 32 weeks in subjects with type 2 diabetes mellitus who have not achieved adequate glycemic control through diet and exercise will be well transmissible.

C. OBJECTIVES (1) The overriding objective

Comparison of the effect of 2 metered dose fixed metformin / glyburide combination tablets (Examples 1 and 2) on glycemic control after 20 weeks of oral administration to HbAi_c reduction with placebo.

(2) Secondary objectives (include)

1. assess safety and tolerability between treatments after 20 and 32 weeks of randomized therapy. Glycemic control can be achieved with similar levels of hypoglycaemia, with fixed dose combinations compared to one sulfonylurea, or with reduced gastrointestinal side effects compared to one metformin.

2. To determine the proportion of subjects responding to glycemic control at each oral metformin / glyburide combination regimen after 20 weeks compared with the therapeutic response in metformin monotherapy, glyburide monotherapy and placebo regimens. The therapeutic plasma glucose response will be determined as FPG &lt;126 mg / dl (based on current ADA references to FPG). Therapeutic HbAi_c the response will be defined as HbA_1c &lt; 7 %.

3. Measured at 20 weeks and measured at 32 weeks, fasting and 2 hours postprandial glucose and insulin after each oral metformin / glyburide regimen compared to fasting glucose and 2 hours postprandial insulin levels obtained from metformin monotherapy, glyburide monotherapy, and placebo.

4. Evaluate HbAi_c duration of depression following 32 weeks of fixed metformin / glyburide combination product.

5. To evaluate the long-term safety and efficacy of fixed metformin / glyburide combination products.

D. INVESTIGATION PLAN

This was a multicentre, randomized, five-treatment arm, equivalent group, double-blind, placebo-controlled study of metformin / glyburide fixed tablets as first-line therapy in subjects with type 2 diabetes mellitus who did not achieve adequate glycemic control (HbAi_c&lt;7%) diet and exercise. Patients had little or no oral antihyperglycaemic therapy for 2 months prior to screening. the trial included about 100 US locations to a maximum of 800 patients with type 2 diabetes who did not achieve adequate glycemic control as defined by HbAi_c between 7 and 11%, diet and exercise. The minimum number of patients required to achieve the most important outcome is 500 patients or 100 patients per treatment group. However, it took up to 6 months to recruit at least 150 patients for each treatment group for additional safety information. The plan covered three periods:

(1) Period A - Two-Week Diet and Placebo Introductory Phase This initial phase includes instructions on a eucalyptic, weight-bearing diabetic diet that meets ADA guidelines, or a balanced diet of approximately 55% carbohydrate, 20% protein, and 25% fat. Transmission of multiple capsules and tablets was controlled by placebo. Glucose meters were distributed to the home with instructions for their use.

(2) Period B is the 4-week double-blind, once-daily stable dose phase

Period B began a randomized, double-blind, parallel, four-part simulation treatment phase. Selected patients were randomized to one of 5 treatment arms in the placebo, glyburide monotherapy, metformin monotherapy and two different dose fixed metformin / glyburide combination products (Examples 1 and 2). Subjects were dosed once daily for 4 weeks so that the contribution of the individual components of the product-combination could be assessed by short-term glycemic parameters.

This 4-week period, at a constant single daily dose, showed the contribution of the individual components of the product-combination using short-term glycemic parameters. Glycemic control was evaluated by glucosamine and fasting glucose.

(3) Period C - 28-week double-blind titration and stable dose phase

Period C was a continuation of the randomized, double-blind treatment phase. Subjects were titrated to glycemic control for the first four weeks, followed by a steady-state 24-week treatment regimen. Analysis of baseline HbAic change from baseline in two combination therapies (Examples 1 and 2) was performed at Week 16 of Period C, which was followed by 20 weeks of randomized double-blind treatment. This was done at this time because of the time needed to stabilize HbAic and, for safety reasons, to prevent a large number of placebo-treated patients from discontinuing randomized treatment due to inadequate glycemic control as the duration of treatment increases. Subjects who were not discontinued from the randomized trial due to lack of efficacy were left on a constant dose for a total of 24 weeks to evaluate duration of efficacy and to collect additional safety and drug data. The study remained blinded, and subjects who discontinued randomized drug trials due to lack of efficacy were offered the initiation of a long-term open label treatment phase with a fixed combination product.

This 28-week phase included an initial 4-week titration step to improve glycemic control, followed by a 24-week steady-state phase. Critical data analysis was conducted at week 16 of period C. Subjects were evaluated for discontinuation of the randomized drug trial due to lack of glycemic control starting at C1 visit to C85. Subjects were assessed for lack of efficacy at C113 visit and all follow-up visits until the end of the randomized treatment. The randomized drug trial remained blind. Subjects who remained in the randomized drug study continued the steady-state phase for a total of 28 weeks to assess duration of efficacy and to collect additional safety and drug data. Subjects were assessed for drug discontinuation due to lack of glycemic control during Visit C1 (week C, period 0).

DOSAGE

The drugs tested in this experiment were labeled: placebo, glyburide, metformin, metformin / glyburide 250 / 1.25 mg, and metformin / glyburide 500 / 2.5 mg. To maintain blindness, a four-part training plan was used in this experiment. Patients who met the criteria for belonging, who did not meet the exclusion criteria, and who met the glycemic control of period A were selected for enrollment in period A.

Period A:

This period was a single blind, placebo, introductory study to determine whether patients tolerated swallowing of many capsules and tablets, as well as an assessment of compliance with the four-line study plan. Patients received kits containing four vials of placebo corresponding to the study drug.

Zero week (Visit A1) - Subjects were instructed to take 1 capsule or tablet from each vial with their first meal in the morning.

Week A8 (Visit A8) - Subjects were instructed to take 1 capsule or tablet from each vial with the first meal of the day and a second capsule or tablet from each vial with the evening meal.

Period B:

At the end of the introductory phase of single blindness (period A), the acquired experience subjects began the randomized, double-blind treatment phase (period B). During the A15 / B1 visit, subjects were randomized to receive placebo, glyburide 2.5 mg, metformin 500 mg, metformin / glyburide 250 / 1.25 mg or metformin / glyburide 500 / 2.5 mg once daily with breakfast. The single daily dose was constant for a total of 4 weeks.

Period C:

After the 4-week steady-state daily single dose phase (Period B), subjects continued the same randomized treatment in the 28-week titration / steady-state treatment phase (Period C). Study drugs were titrated at C1, C15 and C21 visits. The dose was given with the first morning meal and with the evening meal. The effective maximum doses achieved were: glyburide 10 mg, metformin 2000 mg, metformin / glyburide 1000/5 mg, metformin / glyburide 2000/10 mg. After a 4-week titration period in C, subjects continued to receive the study drug at a constant dose for the remainder of C.

When sufficient glycemic control or maximum dose was achieved, the study drug was not increased and only decreased if hypoglycaemia was recorded.

RESULTS

The results of the studies described above show that the low-dose metformin-glyburide (250 / 1.25) combination of the present invention achieved glycemic control at least substantially equivalent to that obtained with the high-dose metformin-glyburide (500 / 2.5) combination, confirmed by:

(1) therapeutic response of hemoglobin A1c, namely HbAi_c decrease below 7% (from 8.2% of baseline) at week 20 (Figures 1, 2 and 3), week 20 and 32 and at final visit (Figures 4 and 5);

(2) a therapeutic response to fasting plasma glucose (FPG), namely a decrease in FPG to less than 126 mg / dl after 20 weeks (from about 175 mg / dl baseline) (as shown in Figure 6);

(3) a fasting insulin response to insulin levels, namely, an increase in fasting insulin levels from 19 to 25 plU / ml (microvascular units / ml);

(4) fasting glucose (PPG) (the difference between fasting plasma glucose and fasting plasma glucose), namely a 17.7 reduction in fasting glucose over 20 weeks after treatment with the 500 / 2.5 mg combination and 20.8 after treatment with the combination 250 / 1.25 compared with 15.2 for metformin and 6.8 for glyburide (Figs. 8A and 8B).

At the same time, the above efficacy results using the low dose composition of the present invention (Example 1) were achieved with reduced side effects (Figs. 9 and 10).

As can be seen from Figure 9, the extent of hypoglycemia using the low dose composition of the present invention (Example 1) is less than about 1/3 of the hypoglycemia resulting from the prior high dose composition (Example 2) used in generally accepted medical practice for diabetes.

As can be seen from FIG. 10, the amount of gastrointestinal side effects of the low dose composition of the invention (Example 1) is 20% less than the number of cases resulting from the high dose combination (Example 2) used in generally accepted medical practice for the treatment of diabetes.

The results described above are discussed below.

Discussion of results

Progression to clinical type 2 diabetes takes time and requires the presence of many physiological deficiencies that most individuals should have when diagnosing diabetes. The choice of oral medication for type 2 diabetes has been very limited until the last few years. In addition, as the disease progresses over time, any oral antihyperglycaemic therapy is expected to be less effective and the patient's glycemic control to be insufficient.

Traditionally, second-line therapy is appropriate for combination therapies where initial single agent therapy is found to be ineffective, so-called "primary failure", or after initially effective agents are no longer effective in maintaining glucose control, so-called " secondary failure. The switch from one unsuccessful monotherapy to another monotherapy was not found to be effective in achieving glycemic control; only the addition of a second agent with a different mechanism of action has been shown to achieve improved glycemic control. If, for example, insulin resistance and relative insulin secretion deficiency are the pathophysiological basis of type 2 diabetes, the combination of agents can be expected to have a greater therapeutic potential. Thus, both clinical experience and pathophysiological data support combination therapy in the early phase of the disease process.

Although the fixed combination of metformin and glyburide is not a novel idea and, as mentioned above, its various forms of first- and second-line therapies are available outside the US, the use of combination therapies for low- to medium-dose first-line therapy in low-dose patients has not been studied extensively. in controlled clinical trials. The purpose of antihyperglycaemic therapy is to achieve treatment up to an almost euglycemic level, HbAi_c &lt;7% as recommended by ADA. However, depending on the duration of diabetes and the progression of the disease, one agent may not provide the required efficacy to reach even the newly diagnosed patients at the target level. The data presented in this summary indicates that the low dose fixed metformin / glyburide combination product is safe and has the effective antihyperglycemic potency required to achieve low ADA-recommended glycemic control in most low-dose patients.

As a first-line therapy, one fixed combination of metformin / glyburide in a 200: 1 metformin / glyburide ratio was evaluated using two different doses - low dose (metformin / glyburide 250 / 1.25 mg) and medium dose (metformin / glyburide 500). / 2.5 mg). The product of two different fixed dose metformin / glyburide combinations was compared in a double-blind trial with placebo, glyburide monotherapy and metformin monotherapy. The mean final doses achieved in each treatment group were approximately 5.3 mg glyburide, 1307 mg metformin, 557 / 2.78 mg low-dose (250 / 1.25 mg) metformin / glyburide fixed combination and 818 / 4.1 mg average dose (500 / 2.5 mg) fixed combination. When used as first-line therapy, the fixed, metformin / glyburide combination achieved a statistically significant improvement in glycemic control compared to metformin, glyburide, or placebo. Transient open label treatment data confirmed the clinical benefit of fixed combination therapy in most patients with a "glycemic" population and over a relatively long period.

Security

As first-line therapy, two doses of metformin / glyburide of varying strength were evaluated; low dose (250 / 1.25 mg) and medium dose (500 / 2.5 mg) were compared with placebo, glyburide and metformin. In the double-blind phase of this study, diarrhea was the most frequently reported adverse event (AE) in subjects receiving metformin monotherapy or combination therapy. Importantly, however, the extent of gastrointestinal AE in subjects in the low-dose fixed combination group was lower than in the metformin monotherapy group (as seen in Figure 10). Discontinuations due to AEs were also less frequent in the low dose fixed combination group than in any other active treatment. Discontinuation due to lack of glycemic control was lowest in both fixed combination groups, and severe hypoglycaemia was not observed in this study. The number of subjects reporting a hypoglycaemic episode was highest in the medium-dose fixed combination treatment group, whereas in the low-dose group, such events were less frequent than in glyburide monotherapy (Fig.9). A slight increase in lactate levels was observed in all metformin groups, but no lactic acidosis was observed in this study.

Subjects in the open label phase of this study were eligible for direct entry if they did not meet the glycemic criterion in the double-blind phase. Subjects were also able to enter the open label phase if they discontinued prematurely the double-blind phase due to lack of glycemic control or after they completed the double-blind phase. In the open-label phase of this study, the AE image was similar to that seen in the double-blind phase, with AEs occurring most frequently in systems of the same species. The low dose combination group again showed the most appropriate overall safety picture compared to the medium dose group.

In both newly diagnosed subjects and under-controlled subjects, the overall picture of safety and tolerability observed in double-blind studies was as expected from clinical experience with metformin and glyburide. No new or unexpected cases or laboratory abnormalities were observed in this clinical program. Analyzes from time to time in long-term open label studies confirm the favorable safety picture observed in the short term study phase. More specifically, the low dose fixed combination exhibited a favorable safety / tolerability picture compared to other regimens used in this program.

Efficiency

Double-blind first-line therapy showed a statistically significant mean of 1.3% hemoglobin Ai_c (HbAi_c) compared to placebo for both fixed combination treatment groups and a mean reduction of approximately 1.5% from baseline. Although all active therapy groups achieved acceptable glycemic control, higher mean HbA-i_c reductions were achieved in both fixed combination treatment groups compared to metformin therapy and glyburide therapy. The maintenance of antihyperglycaemia was observed in all active treatment groups (glyburide, metformin, metformin / glyburide 250 / 1.25 mg, metformin / glyburide 500 / 2.5 mg) as evidenced by the_c quantities retention from week 20 (6.64%, 6.79%, 6.68%, 6.44%) to week 32 (6.76%, 6.96%, 6.87%, 6.68%) in double-blind therapy below the therapeutic target of 7% (Figs. 3 and 4).

Transient open-label first-line therapy data suggest direct admission of subjects to HbAi_c baselines were at 10.6%, and an average of 3.5% HbAi was achieved for the group of subjects with available data_c decrease, for mean HbAi_c at 7.1% over 26 weeks. Of the subjects directly enrolled in the open label group, 87% received an average dose of 500 / 2.5 mg fixed combination as initial treatment and at the time of the interim report; the average fixed dose combination therapy was metformin / glyburide 1569 / 7.85 mg. For subjects with available open-label data, who entered the double-blind treatment phase and continued treatment in the open-label phase, the mean HbA_1c at baseline was 8.32%. All subjects achieved a mean HbAi of 1.76% after 13 weeks of treatment_c decrease with mean HbAic at 6.56%. Of subjects who completed the double-blind treatment phase and continued treatment in the open label phase, 78% received a low dose (250 / 1.25 mg) low dose combination and 22% received a medium dose (500 / 2.5 mg) fixed combination. The mean dose of fixed combination therapy was 696 / 3.48 mg metformin / glyburide.

No clinically relevant events with greater or lesser effects were observed in any of the subpopulations (age, gender, race) in response to HbA-i._c compared with baseline in either of the double-blind studies using the fixed metformin / glyburide combination as first-line therapy.

This clinical program also evaluated fasting plasma glucose as a parameter for short-term glycemic control.

FPG results in double-blind studies coincided with HbAi_c results. As first-line therapy, statistically and clinically significant greater mean reductions in FPG were achieved in both fixed-combination treatment groups compared to placebo and metformin (Fig.6). An early response to fixed combination therapy was observed; differences between groups occurred at week 2 in double-blind therapy while subjects were still in the initial titration phase and received only half of the potentially maximum dose. This early response at half the maximum dose in the monotherapy population of non-responders demonstrates the benefit of combination therapy in such patients and suggests the use of combination therapy at the onset of the disease.

Hemoglobin A_1c is the most common standard measure of total glycemic control and is an indicator of glycemia that has been found to be associated with long-term complications. Although fasting plasma glucose, the current standard for diabetes diagnosis, is a faster, more convenient indicator, it does not provide an optimal assessment of daily glycemic control. It has been shown and intuitively understood that fasting plasma glucose in type 2 diabetes is a better indicator of diabetes control than FPG; it also correlates better with HbAi_c. Fasting hyperglycaemia is an early indicator of metabolic defects in type 2 diabetes and contributes to beta-cell dysfunction. An important association between fasting glucose and cardiovascular disease has been shown. While normal glycemia is the goal of preventing long-term complications of diabetes, controlling and reducing fasting glucose is a rational strategy for improving metabolic function and achieving overall glucose control.

As first-line therapy, a statistically significant greater mean reduction in total fasting glucose (63-65 mg / dl) was observed in both fixed-combination treatment groups compared to placebo. A greater mean reduction in absolute PPG was also achieved compared to glyburide (16-18 mg / dl) and metformin (18-20 mg / dl) monotherapy (Figs. 8A and 8B). Changes from baseline in fasting glucose over two hours to low dose (22.5 mg / dl) and medium (23.9 mg / dl) fixed combination groups were only 56% -59% of those on placebo (40.3 mg). / dl), 59% -63% from glyburide (38.2 mg / dl), and 75% -81% from metformin (29.5 mg / dl). Evaluation of change rather than absolute value indicates that glyburide is similar to placebo, that metformin provides better fasting glucose than glyburide and placebo, and that a low dose combination is most effective in reducing fasting glucose. In the absence of published clinical data on combination therapy in low-dose patients, these results provide new insights into the contribution of selected therapies at this stage of the disease. In fact, these results could not be predicted from the changes observed in most studies in the second-line therapy population.

Insulin levels were evaluated in first line therapy in the fasting and postprandial study (Fig.7). There was a statistically significant increase (24-28.8 μΐυ / ml) in insulin response to fasting glucose in both fixed combination therapy groups compared to placebo. A greater increase in insulin response to fasting glucose was observed in the low dose fixed combination treatment group (14.6 μΐυ / ml) compared to glyburide monotherapy and a greater increase in the insulin response to fasting glucose was observed in both fixed dose treatment groups (21-25, 8 μΐυ / ml) as compared to metformin monotherapy. When considering average doses of active therapy in treatment groups, the insulin response cannot be explained by the sulfonylurea component alone in fixed combination therapy. These clinical data support preclinical work on isolated pancreatic islet cells, where metformin has been shown to prevent hyperglycemic desensitization of these islet cells. The combination of a physiological and intrinsic increased insulin response with a correspondingly greater reduction in glucose response suggests that this combination improves pancreatic efficiency in responding to glucose load, protecting beta-cell function, and improving insulin sensitivity.

In addition to the aggressive treatment of high blood pressure and lipids, the primary goal of treatment for patients with type 2 diabetes is to achieve near-normal glycemic levels or to achieve glycemic therapeutic targets.

A greater response to fixed combination therapy was observed in terms of the greater number of subjects achieving therapeutic targets and higher absolute HbAi_cin terms of quantity reduction. In first-line therapy, a higher proportion of subjects using fixed combination therapy (66% -71%) achieved HbAi_c &lt;7% glycemic target compared to 60% for sulphonylurea monotherapy, 50% for metformin monotherapy and 20% for placebo monotherapy after 20 weeks of double-blind treatment. Approximately 28% of subjects in each fixed combination group had more than 2.0% reduction in HbAi_c compared with baseline versus 16% -17% of subjects in each monotherapy group and 3%:

in the placebo group. Notably, these goals were not achieved simply by higher total doses of the drug but by lower doses of the combination components. The mean final doses achieved in each first-line treatment were approximately 5.3 mg glyburide, 1307 mg metformin, 557 / 2.78 mg low-dose fixed combination and 818 / 4.1 mg mid-dose fixed dose combination. When on HbAi_c the change from the number of pills observed in fixed combination therapy is not unexpected from a pathophysiological point of view. It shows that there is a clear target response at all doses and that the need for higher doses correlates with higher HbAi_c baseline. A similar image can be detected with glyburide up to a total dose of 7.5 mg; no clear picture was observed with metformin therapy.

The data presented suggest that the low-dose metformin / glyburide combination as a first-line agent will bring the patient to the therapeutic target, regardless of the size of his baseline HbAi._c.

Mean fixed reduction from basal HbA for both fixed combination therapies_1c lines are larger for subjects with higher baseline levels. This phenomenon has not been observed with glyburide, metformin and placebo and is not expected to occur._xso that it would be the case with other monotherapies. This indicates the components required to achieve therapeutic glycemic targets when HbAi_c baseline is greater than 9% contribution. Monotherapy has been shown to resolve to a glycemic response area at &lt;9% HbA_1c for baseline levels, while fixed combination therapy has additional incremental HbAi_c reduction at &lt;9% HbA_1c for baseline levels.

Mean HbAi of all subjects enrolled in the open label first-line treatment phase with data available with at least two time points_c the baseline was 9.45%. After 13, 26 39 weeks, about 50-55% of subjects achieved less than 7% HbAi_c level and another 30% of subjects achieved HbA_1c &lt;8% level of such response rate and HbA_1c a decrease in magnitude could have been expected in combination therapy but is rare in monotherapy with antihyperglycaemic agents. The primary endpoint of what the initial antihyperglycaemic treatment should achieve is HbAi_c &lt;7% in the majority of patients. These data reinforce the need for a review of current treatment models for type 2 diabetes and suggest shifting the use of combination therapies toward a closer disease process.

Weight gain is usually monitored with all antihyperglycaemic agents except metformin Improving glycemic control is a way of gaining weight because poor metabolic control keeps calories rather than losing weight. In this clinical program, with the use of fixed combination therapy with improved glycemic control, a minimum weight gain of approximately 1-2 kg was observed at baseline; it is comparable to the 2 kg gain seen with first-line glyburide monotherapy. In double-blind therapy, weight remained constant after the initial minimum gain and did not increase over time.

Overall, there were no clinically or statistically significant differences in plasma lipid change between any treatment group. All of the most severe patients were excluded from the placebo-controlled trial and minor changes in response to treatment may have gone unnoticed. The first-line patient population had inadequate glycemic control, but diet and exercise helped to correct mean HbAi_c to 8.2%. Subjects receiving fixed combination therapy showed no significant effects on plasma lipid profile (total cholesterol, LDL, HDL, and triglycerides) or significant differences compared with placebo or glyburide or metformin monotherapy.

By better understanding the relationship between diabetes control and the rate of long-term complications, today the goal of diabetes management is to achieve and maintain glycemia as close to normal as possible. By acting on multiple defective agents with synergistic or complementary mechanisms of action, one can intuitively expect to achieve the therapeutic goal of glycemia. The improved understanding of the onset of type 2 diabetes suggests that current treatment models that allow for "failure" should be reviewed before initiating a more aggressive treatment strategy. Therefore, the early use of low dose combination therapy, especially when low doses provide better tolerability, seems to be an important therapeutic strategy for achieving and maintaining the goal. The fixed combination evaluated in this study allows the use of lower doses and is easy to use as a whole.

Low-dose fixed metformin / glyburide therapy is safe and effective in achieving and maintaining glycemic control in patients with type 2 diabetes who lack glycemic control through diet and exercise. The use of combination therapy at the onset of diabetes progression appears to be a clinical alternative to classical treatment models that lead to failure of stepwise therapy prior to the use of a more aggressive but clinically signaling treatment strategy. Although not evaluated in this short-term study, the strategy of achieving as close to normal glycaemia as possible is likely to contribute to slowing the progression of diabetes and delaying the onset of long-term diabetes complications. The population of monotherapy refractory patients who received a fixed combination of metformin and glyburide had clinically highly improved glycemic control and no adverse metabolic effects or worsening of safety. There was no clinically significant hypoglycemia, no negative contribution to plasma lipids, and only a small initial weight gain, which continued to be stable. Synergism between metformin and sulfonylurea is established; a fixed combination of metformin and glyburide is effective in improving glycemic control and is a rational choice in anti-hyperglycemic armament. A fixed combination is believed to simplify dosing and is therefore more convenient and therefore leads to a greater desire for treatment.

A fixed combination of low dose (250 / 1.25 mg) could be the initial starting dose for first-line therapy in low-dose patients. It should then be titrated as indicated to achieve HbA_1c &lt; 7%.

OVERALL CONCLUSIONS

The safety and efficacy data obtained from this clinical program evaluating the fixed combination of metformin / glyburide as first-line therapy in patients with type 2 diabetes confirm that:

• The percentage of subjects who discontinued hyperglycaemia treatment was lower for the fixed metformin / glyburide combination compared to metformin, glyburide, and placebo.

• Hypoglycaemia and hypoglycaemic symptoms on first line therapy (Figure 9) occurred less frequently with metformin / glyburide 250 / 1.25 mg compared to metformin / glyburide 500 / 2.5 mg and glyburide.

• As first-line therapy, the fixed combination gastrointestinal adverse events were the lowest for metformin / glyburide 250 / 1.25 mg compared to metformin / glyburide 500 / 2.5 mg and glyburide (Fig. 10). .

• No new or unexpected adverse events or laboratory abnormalities were observed in subjects receiving long-term open label fixed metformin / glyburide combination.

• There is a marked improvement in the efficacy of the fixed metformin / glyburide combination at any strength, as evidenced by greater reductions in total glycemic parameters (HbAic, fasting glucose, fasting glucose and fructosamine) compared with placebo, glyburide and metformin therapy.

• The synergistic effect of the low dose combination, targets multiple metabolic defects, improving beta cell function and insulin sensitivity, as evidenced by changes in plasma glucose and fasting insulin levels, resulting in improved metabolic function and glycemic control.

• More patients on fixed metformin / glyburide combination therapy achieved HbAi_c &lt;7% therapeutic glycemic target.

, · There is an effective reduction of glycemia to therapeutic goals at all times

HbAic baseline versus placebo, glyburide, and metformin therapy.

As initial therapy, glyburide and metformin were shown to reach the glycemic control response area at baseline of HbAic&gt; 9%, whereas fixed metformin / glyburide combination therapy provided additional incremental HbA_1c decreases at HbAic&gt; 9% baseline.

• Limited initial weight gain, in parallel with improved glycemic control, is comparable to glyburide monotherapy; however, weight remains unchanged over time.

• No adverse effects on lipid imaging (total cholesterol, LDL, HDL and triglycerides) or significant differences from placebo or glyburide or metformin monotherapy were observed with fixed combination therapy.

• Proper efficacy and tolerability of the fixed metformin / glyburide 250 / 1.25 mg combination supports its use as an initial dose in first line therapy.

The above results clearly demonstrate that the low-dose metformin / glyburide formulation (250 mg / 1.25 mg) of the present invention is at least equivalent in efficacy to the higher dose form (500 mg / 2.5 mg) but has fewer side effects. .