LV12910B - Pharmaceutical composition comprising a combination of metformin and glibenclamide - Google Patents

Description

Field of the Invention

The present invention relates to a method for treating type 2 diabetes in drug naive patients, employing a low dose formulation which includes metformin and glyburide. The low dose formulation has at least substantially equivalent efficacy in treating type 2 diabetes as compared to formulations containing higher doses of metformin and/or glyburide, but with substantially reduced side effects.

Background of the Invention

The biguanide antihyperglycemic aģent metformin disclosed in U.S. Patent No. 3,174,901 is currently marketed in the U.S. in the form of its hydrochloride salt (Glucophage®), Bristol-Myers Squibb Company).

The diagnosis and management of type 2 diabetes mellitus is rapidly undergoing progressive changes. It is now widely accepted that glycemic control makes a difference. The goal of diabetes therapy today is to achieve and maintain as near normai glycemia as possible to prevent the long-term microvascular and macrovascular complications of an elevated blood glucose. The diagnosis of diabetes has undergone significant changes as evidenced by the hew ADA diagnostic and classification guidelines. Oral therapeutic options for the treatment of type 2 diabetes mellitus, until recently, have been severely limited. Prior to 1995, sulfonyl ureas had been the mainstay of oral diabetes aģents in the United States. Sulfonyl ureas target one mechanism of hyperglycemia by augmenting insulin secretion from the beta celi. Since 1995, three new classes of aģents have been added to the anti-diabetes armamentarium for the management of hyperglycemia. Metformin, a biguanide, targets additional mechanisms of hyperglycemia by inhibiting hepatic glucose production and enhancing peripheral glucose uptake and thereby reduce insulin resistance; thiazolidinediones such as troglitazone, rosiglitazone and pioglitazone decrease peripheral insulin resistance; and alpha-glucosidase inhibitors such as acarbose and migl'itol help control postprandial glucose excursion by delaying absorption of dietary carbohydrate. These aģents are ali indicated as monotherapy and some are indicated for use in combination therapy, generally, after monotherapy has been found to be inadequate.

In 1995, metformin vvas added to sulfonyl urea therapy in patients vvho had not aehieved glycemic control vvith sulfonyl urea monotherapy and the tvvo aģents vvere found to have a remarkable effect on glycemic control or lovvering of hemoglobin-Alc. The different mechanisms of action in targeting hyperglycemia are complimentary and make combination use attractive and a rational course of action. Prescription data reveals approximately 60% of metformin use is in combination vvith a sulfonyl urea.

Examples of combinations of metformin and the sulfonyl urea glyburide (also referred to as glibenclamide) are disclosed in the follovving references.

(1) W0 97/17975 published May 22, 1997, (Barelli et al, Istituto Gentili S.P.A.) and U.S. Patent No. 5,922,769 to Barelli et al (hereinafter Barelli et al) discloses a combination of glibenclamide and metformin in a 1:100 vveight ratio, so as to allovv a daily dosage of 15 mg glibenclamide and 1500 mg metformin, used for the onset of diabetes to the most severe cases, particular in cases of secondary failure to a combination of glibenclamide-metformin HCl in a vveight ratio higher than 1:100.

(2) Vigneri et al, Treatment of NIDDM Patients vvith Secondary Failure to Glyburide: Comparison of the Addition of Either Metformin or Bed-Time NPH Insulin to Glyburide, Diabete & Metabolisme, 1991, 17, 232-234, disclose use of a combination of 1.5 g/day metformin and 15 mg/day glyburide to treat NIDDM patients vvith secondary failure to 15 mg/day glyburide.

(3) Higginbotham et al, Double-Blind Trial of Metformin in the Therapy of Non-Ketotic Diabetes, The Medical Journal of Australia, August 11, 1979, 154-156, discloses treatment of diabetic patients, vvho vvere already receiving from 10 mg to 20 mg per day of glibenclamide, vvith 500 mg metformin tvvice a day. Higginbotham et al conclude that in selected diabetics whose condition is inadequately controlled vvith sulphonylurea therapy, significant improvement in diabetic control can be obtained by the addition of metformin in a lovv dose of 500 mg tvvice a day.

(4) U.S. application Serial No. 09/353,141, filed July 14, 1999 (based on European application No. 98401781.4, filed July 15, 1998) discloses formulations containing metformin and glyburide vvhere the glyburide is of a particular particle size as described hereinafter.

References vvhich disclose combinations of metformin and glipizide include the follovving:

(1) Combination of glipizide/metformin treatment reduces lovv density lipoprotein binding to arterial proteglycans in DIDDM, Edvvards et al, Diabetes, (46,

Suppl. 1, 45A, 1997).

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

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

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

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

(6) Combination of Glipizide/Metformin Treatment in NIDDM, Hollenbeck et al, Diabetes, (39, Suppl. 1,

108A, 1990).

(7) Oral Antidiabetic Combination Therapy vvith Sulfonyl ureas and Metformin, Haupt et al, Med. Welt.

(40, No. 5, 118-23, 1989).

(8) Variation of the lipemic pattern in diabetic subjects after treatment vvith a combination of glipizide and metformin, Ferlito et al, PROGR. MED. (Roma) 31/6 (289-301) 1975.

(9) Results vvith a combination of glipizide and dimethylbiguanide in 40 cases of diabetes, Parodi et al, GAZZ. MED. ITAL. 132/5 (226-235) 1973.

Other combinations of metformin and another antidiabetic aģent are disclosed in the follovving references.

(1) U.S. Patent No. 5,631,224 to Efendic et al discloses a combination of metformin vvith GLP-l (7-36) amide or GLP-l(7-37) or a fragment thereof.

(2) W0 98/57634 (SKB) discloses a method for treating diabetes employing a combination of a thiazolidenedione and metformin. The thiazolidenedione may be troglitazone, ciglitazone, pioglitazone or englitazone, and may be employed in dosages of 2 to 12 mg per day vvhile the metformin may be employed in daily dosages of up to 3000 mg per day, in unit doses of 500 mg (for example, 2 to 3 times per day) or 850 mg (2 times per day), one example of a dosage for metformin is 500 mg building to 5 times per day.

(3) U.S. Patent No. 5,965,584 (Takeda) discloses a combination of a thiazolidenedione insulin sensitivity enhancer (such as pioglitazone) and metformin.

None of the above references suggests employing diabetic combinations containing metformin for first line treatment of drug naive patients.

Several fixed combinations of metformin and glyburide (glibenclamide) are presently being marketed outside the U.S. These inelude (1) combinations of 400 mg metformin/2.5 mg glibenclamide (Boehringer's BiEuglucon in Argentīna, and Bi-Euglicon M in Italy; Guidotti/Menarini's Glibomet in the Dominican Republic and Italy; HMR' s Normell in Greece and Hoechst's Suguan-M in Italy; Sun Pharma's Glucored in India; Monsanto's (Searle's) Benclamet in India; Guidotti's Glibomet in Liban; Berlin Chemie/Menarini's Glibomet in the Slovak Rep., and Roche's Bi-Euglucon in Uruguay); (2) combinations of 500 mg metformin/5 mg glibenclamide (Sun Pharma's Glucored in India; Monsanto's (Searle's) Benclamet in India, USV's Duotrol in India; and Lakeside's (Roche) Bi-Euglucon M5 in Mexico); (3) combinations of 500 mg metformin/2.5 mg glibenclamide (Molteni's Glucomide in Italy, Lakeside's (Roche) BiEuglucon M in Mexico and Szabo's Dublex in Uruguay); and (4) 1 g metformin/5mg glibenclamide (Silanes Sil-Norboral in Mexico).

The labelling for Glucophage® (Bristol-Myers Squibb's metformin), in the Physicians' Desk Reference 1999, under Indications and Use, indicates that Glucophage may be used concomitantly with a sulfonylurea. It is further indicated under Dosage and Administration Concomitant Glucophage and Oral Sulfonylurea Therapy that If patients have not respended to four weeks of the maximum dose of Glucophage monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Glucophage at the maximum dose.... With concomitant Glucophase and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the maximum effective dose of each drug to achieve this goal. The recommended dosing schedule for Glucophage is a starting dose of 500 mg twice a day or 850 mg once a day with dosage increases in increments of 500 mg weekly or 850 mg every 2 weeks up to a total of 2000 mg per day.

Package inserts for Bi-Euglucon M and Suguan M in Italy (400 mg metformin/2.5 mg glibenclamide) indicate that these drug combinations are used in cases of primary or secondary resistance to sulfonyl ureas [that is as second or third line therapy] and that a dosage of b tablet per day increasing tablet at a time according to glycemic variations up to 4 tablets per day are employed.

Package inserts for Glibomet (400 mg metformin/2.5 mg glibenclamide) and Glucomide (500 mg metformin/2.5 mg glibenclamide) in Italy indicate that these drug combinations are used for treating type 2 diabetes which is non-controllable or cannot be controlled with only diet or with diet and sulfonyl urea [that is as first line therapy or second line therapy] .

The package insert for Glibomet in Italy indicates a daily dosage of 2 tablets, that is 800 mg metformin and 5 mg glibenclamide, up to 2 grams metformin. The package insert for Glucomide in Italy indicates a daily dosage of 2 capsules, that is 1000 mg metformin up to 2 grams metformin, and 5 mg glibenclamide.

Description of the Invention

In accordance with the present invention, a method is provided for treating diabetes, especially type 2 diabetes, in a drug naive human patient, which includes the step of administering to a drug naive human patient in need of treatment, as first line therapy, a therapeutically effective low dose pharmaceutical formulation vvhich includes a combination of metformin and glyburide. The above combination will preferably provide at least substantially equivalent efficacy in treating diabetes in drug naive patients as do combinations of metformin and glyburide employed in higher dosages, such as prescribed in generally accepted medical practice for first line therapy treating diabetes, but with substantially reduced side effects.

In one aspect of the method of the invention, the daily dosage of metformin administered will bē less than 800 mg.

It is to be understood that the low dose formulation employed in the method of the invention will include a starting low dose of the active antidiabetes drug components, that is a lower starting dosage than the starting dosage for such drug prescribed in generally accepted medical practice in first line therapy of treating diabetes. Thus, the above low dose pharmaceutical formulation will include a low dose of metformin and a low dose of glyburide as defined hereinafter.

In accordance with the present invention, efficacy in first line therapy in treating diabetes in drug naive patients is achieved employing the low dose pharmaceutical formulation wherein the starting daily dosage of metformin is as low as about one-fifth of the starting daily dosage of metformin employed in generally accepted medical practice for first line therapy for treating diabetes (that is a starting daily dosage of as low as 160 mg metformin per day) , up to a daily maintenance dosage of metformin employed in generally accepted medical practice for first line or second line therapy for treating diabetes (that is up to 2000 mg metformin per day) . Preferably, the maximum daily maintenance dosage of metformin will be about two-thirds of the daily maintenance dosage of metformin employed in generally accepted medical practice for first line therapy for treating diabetes.

In carrying out the method of the invention, the starting daily dosage of metformin vvill be as lovv as from about 25% up to about 60% of the starting daily dosage of metformin employed in generally accepted medical practice for first line therapy for treating diabetes (that is a starting daily dosage from 160 to 500 mg metformin, preferably 250 or 500 mg metformin) . Where necessary, the starting dosage may be titrated up to a daily maintenance dosage of from about 40 to about 100%, preferably from about 40 to about 60% of the maintenance dosage employed in generally accepted medical practice for first line therapy for treating diabetes (that is a daily maintenance dosage from 320 to 2000 mg, preferably from 320 to 1200 mg).

In the method of the invention, the low dose pharmaceutical formulation vvill preferably be employed in first line therapy in a daily dosage to provide 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 a starting dosage of from about 160 to about 500 mg per day, preferably 250 mg per day or 500 mg per day, in single or divided doses of one to four tablets daily.

The glyburide is employed in a starting daily dosage as lovv as about one-fifth of the starting daily dosage of glyburide employed in generally accepted medical practice for first line or second line therapy for treating diabetes (that is a minimum starting daily dosage as lovv as 0.5 mg) . Where necessary, the starting dosage of glyburide may be titrated up to a daily maintenance dosage of glyburide employed in generally accepted medical practice for first or second line therapy for treating diabetes (that is up to a maximum of 15 mg glyburide per day) . Preferably, the maximum daily dosage of glyburide vvill be about tvvo-thirds of the daily maintenance dosage of glyburide employed in generally accepted medical practice for first line therapy for treating diabetes (that is up to a maximum of 2.5 to 10 mg glyburide per day).

The glyburide will preferably be employed in a starting daily dosage as low as about 20% up to about 60% of the starting daily dosage of glyburide employed in generally accepted medical practice for first line therapy for treating diabetes (that is a minimum starting dosage as low as 0.5 mg to 3.5 mg, more preferably 1.25 mg or 2.5 mg) . The glyburide may be titrated up to a daily maintenance dosage of about 40 to about 100%, preferably from about 40 to about 60% of the daily maintenance dosage of glyburide employed in generally accepted medical practice for first line therapy for treating diabetes (that is a maximum daily dosage of 2 to 15 mg preferably a maximum daily dosage of 2.5 to 10 mg) .

The above daily dosage of glyburide may be employed in single or divided doses of one to four tablets daily.

The metformin and glyburide may be formulated in a single tablet which may be employed in single or divided doses of one to four times daily.

The term low dose combination, low dose formulation or low dose pharmaceutical formulation as employed herein, in a most preferred formulation, refers to a formulation which includes as a starting daily dosage 250 mg metformin, and 1.25 mg glyburide, or 500 mg metformin and 2.5 mg glyburide.

Until now, combinations of metformin and glyburide, have normally been used with few exceptions, as second line therapy in treating type 2 diabetes. Generally accepted medical practice daily dosages for such second line therapy employing fixed combinations of metformin and glyburide range from 3 to 4 tablets containing 400 to 500 mg metformin and 2 to 2.5 mg glyburide, or about 1200 to 2000 mg metformin and 6 to 10 mg glyburide, daily.

As indicated above with respect to Glibomet and . Glucomide (fixed combinations of metformin and glyburide) marketed in Italy, these combinations may be employed as first line therapy (drug naive patients) in a daily dosage of 800 to 1000 mg up to 2 grams metformin and 5 mg glibenclamide (glyburide).

The above dosages may be ineluded vvithin the term dosages as prescribed in generally accepted medical practice for first line therapy or second line therapy in treating diabetes. In some refractory cases of diabetes, up to 15 mg glyburide may be indicated.

As indicated above vvith respect to Boehringer's BiEuglucon M and Hoechst's Suguan M (fixed combinations of metformin and glibenclamide) marketed in Italy, these combinations are employed as second line therapy in a daily dosage starting at tablet, that is, 200 mg metformin and 1.25 mg glibenclamide. The initial or starting lovv doses are employed to determine if the patient can tolerate the drugs. Furthermore, there apparently is no knovvn clinical first line therapy study available vvhich supports use of these starting doses. These starting doses are gradually titrated upwardly tablet at a time up to 4 tablets per day until an efficacious dosage is aehieved. Thus, the initial or starting daily dosage of h tablet or 200 mg metformin and

1.25 mg glibenclamide is not considered herein as dosages as prescribed in generally accepted medical practice for treating diabetes.

Surprisingly, it has been found that use of the combination of metformin and glyburide in accordance vvith the present invention affords the follovving benefits.

The low dose metformin is an insulin sensitizer and decreases insulin resistance at the liver, muscle and panereas. The lovv dose metformin-glyburide combination acts on the panereas as a glucose sensitizer; it decreases glucose toxicity at the panereas and improves function of the panereas.

In addition, in accordance vvith the present invention, a method is provided for treating diabetes, especially type 2 diabetes, in a drug naive human patient, vvhich includes the step of administering to a drug naive human patient in need of treatment, as first line therapy, a starting lovv dose pharmaceutical formulation vvhich includes a combination of metformin and glyburide. The starting lovv dose combination preferably provides at least substantially equivalent efficacy in treating diabetes in drug naive patients as do combinations of metformin and glyburide employed in dosages (including starting dosages) prescribed in generally accepted medical practice for first line therapy treating diabetes, but vvith substantially reduced side effects.

The starting daily dosage of metformin is as lovv as 20% of the starting daily dosage of metformin employed in generally accepted medical practice for first line therapy for treating diabetes, preferably a starting daily dosage from about 160 to about 500 mg, more preferably a starting daily dosage of 250 mg or 500 mg.

The starting daily dosage of glyburide is as lovv as

20% of the starting daily dosage of glyburide employed in generally accepted medical practice for first line therapy for treating diabetes, preferably a starting daily dosage from about 0.625 to about 5 mg, more preferably a starting daily dosage of 1.25 mg or 2.5 mg.

In addition, in accordance vvith the present invention, a method is provided for decreasing fasting plasma glucose, decreasing insulin resistance, decreasing hemoglobin Alc, increasing post-prandial insulin and/or decreasing post-prandial glucose excursion in a human diabetic patient, vvhich includes the step of administering as first line therapy to a drug naive human patient a lovv dose pharmaceutical formulation vvhich includes a combination of metformin and glyburide.

In carrying out the method of the invention employing the preferred starting lovv dose pharmaceutical formulation containing metformin and glyburide, to treat drug naive patients for diabetes, the efficacy in treating drug naive patients is at least substantially equivalent and incidence of side effects (gastrointestinal side effects and hypoglycemia) is surprisingly significantly and substantially reduced as compared to patients on higher daily dosages of metformin and glyburide (that is in starting dosages prescribed in generally accepted medical practice for treating diabetes) . Thus, vvhile efficacy in treating drug naive patients as measured by decrease in hemoglobin A_lc (HbA_ic) from baseline over time, decrease in fasting plasma glucose (FPG), increase in post-prandial insulin Ievels, and dēcrease in post-prandial glucose (PPG) excursion, are essentially substantially equivalent in the abovedescribed patients vvhen employing the lovv dose pharmaceutical formulation employed herein and substantially higher daily dosages, incidence of hypoglycemia and gastrointestinal side effects ih drug naive patients treated vvith substantially higher daily dosages are substantially greater than in patients treated vvith the lovv dose pharmaceutical formulation.

Most preferred dosages for use herein are 250 mg metformin/1.25 mg glyburide, and 500 mg metformin/2.5 mg glyburide.

The lovv dose pharmaceutical formulation of metformin and glyburide is employed as initial therapy that is as an adjunct to diet and exercise to improve glycemic control in patients vvith type 2 diabetes mellitus.

The ADA recommends a treatment goal of HbAi_c < 7% (ADA. Diabetes Care 21 [Suppl. 1]: S23 - S31, 1998) in order to reduce the risk of complications of type 2 diabetes mellitus, including coronary heart disease and microvascular complications.

Dosage of the preferred metformin-glyburide combination must be individualized on the basis of both effectiveness and tolerance. It is preferably given vvith meals and should be started at a lovv dose, vvith gradual dose escalation. Ideally, the response to therapy should be evaluated using HbA_lc (glycosylated hemoglobin) vvhich is a better indicator of long-term glycemic control than FPG alone. The therapeutic goal in all patients vvith type 2 diabetes mellitus should be to improve glycemic control, including FPG, postprandial glucose and HbA_lc Ievels, to normai or as near normai as possible.

Patients should be titrated to achieve the ADA goal of HbAi_c < 7% follovving the dosing recommendations up to the maximum recommended'dose. (ADA. Diabetes Care 21 [Suppl. 1]: S23 - S32, 1998).

As initiai therapy, the most preferred starting dose of the metformin-glyburide combination is 250/1.25 mg once a day, given vvith a meal. For patients vvith a baseline HbA_ic > 9% or a fasting glucose > 200 mg/dL, a recommended starting dose of 250/1.25 mg tvvice daily vvith the morning and evening meal may be preferred. Dosage increases should preferably be made in increments of 250/1.25 mg, every 2 vveeks, up to the minimum effective dose necessary to achieve adequate glycemic control. For those patients requiring additional glycemic control, the 250 mg/1.25 mg dosage may be svvitched to 500/2.5 mg.

The preferred lovv dose metformin-glyburide formulation are set out belovv.

Product identity	Amount of ingredient, mg per tablet 250/1,25 or 500/2.5 or 500/5.0
Ingredient
Metformin hydrochloride	250.0 or 500.0
Glyburide	1.25 or 2.5 or 5
Croscarmellose sodium	3.0-15.0
Microcrystailine cellulose	15.0-60.0
Polyvinyl pyrrolidone	3.0-20
Magnesium stearate	0.3-7.5
Film coat*	4.5-12.0

*a commercially available film coat composition is used, such as Opadry (Colorcon, UK) .

The especially preferred lovv dose metformin5 glyburide formulations are as follovvs:

Product identity	Amount of ingredient, mg per tablet
250/1.25	500/2.5	500/5.0
Ingredient
Metformin hydrochloride*	251.25	502.50	502.50
Glyburide	1.25	2.5	5.0
Croscarmellose sodium	7.0	14	14
Microcrystalline cellulose	28.25	56.50	54.0
Polyvinyl pyrrolidone	10.0	20	20
Magnesium stearate	2.25	4.50	4.50
Film coat**	6	12.0	12.0

♦contains 99.5% metformin HCI and 0.5% Mg stearate (w/w) **a commercially available film coat composition is used, such as Opadry (Colorcon, UK) .

The lovv dose pharmaceutical formulation containing the metformin-glyburide combination, vvill preferably be formulated according to the teachings disclosed in U.S. application Serial No. 09/353,141, filed July 14, 1999, vvhich claims priority from European application No.

98401781.4 filed July 15, 1998, vvhich U.S. application is incorporated herein by reference.

The preferred low dose pharmaceutical formulation employed in the method of the invention in the form of a solid oral form such as a tablet will contain the metformin-glyburide combination as disclosed in U.S. Application Serial No. 09/353,141, filed July 14, 1999, and as such will include glyburide which has a glyburide bioavailability comparable to the glyburide availability obtained with a separate administration of metformin and glyburide. This is accomplished by employing glyburide in a predetermined particle size distribution. Thus, the metformin-glyburide formulation will contain a combination of metformin and glyburide in vvhich the size of the glyburide is such that at most 10% of the pārticies are less than 2 pm and at most 10% of the pārticies are greater than 60 pm. Preferably, the size of the glyburide is such that at most 10% of the pārticies are less than 3 pm and at most 10% of the pārticies are greater than 40 pm. This specific size range of glyburide may be obtained by sieving or air jet milling.

In a second embodiment, the low dose solid oral dosage form will contain a combination of metformin and glyburide in which the size of glyburide is such that at most 25% of the pārticies are less than 11 pm and at most 25% of the pārticies are greater than 46 pm.

Preferably, 50% of pārticies are less than 23 pm.

Most preferred are a combination of metformin and glyburide, where the glyburide has a particle size distribution of about 25% undersize value not more than 6 pm, about 50% undersize value 7 to 10 pm and about 75% undersize value not more than 23 pm.

Detailed Description of the Invention

The term diabetes as employed herein, refers to type 2 (or Type II) .diabetes or non-insulin dependent diabetes mellitus (NIDDM).

The term metformin as employed herein refers to metformin or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, the metformin (2:1) fumarate salt, and the metformin (2:1) succinate salt as disclosed in U.S. application Serial No. 09/262,526 filed March 4, 1999, the hydrobromide salt, the p-chlorophenoxy acetate or the embonate, and other known metformin salts of mono and dibasic carboxylic acids including those disclosed in U.S. Patent No. 3,174,901, ali of which salts are collectivēly referred to as metformin. It is preferred that the metformin employed herein be the metformin hydrochloride salt, namely, that marketed as Glucophage® (trademark of Bristol-Myers Squibb Company).

The term substantially reduced side effects as employed herein refers to reduced incidence of hypoglycemia and gastrointestinal adverse events including diarrhea, nausea/vomiting and/or abdominal pain, occurring with use of the low dose pharmaceutical formulation in drug naive patients as compared to patients on the same active components in the pharmaceutical formulation of the invention but at higher dosages.

The term at least substantially equivalent efficacy in treating type 2 diabetes as employed herein refers to the effectiveness of the low dose pharmaceutical formulation in treating drug naive patients to reduce and/or maintain hemoglobin A_lc (glycosylated hemoglobin) at 7% or less, to decrease insulin resistance (by inereasing post-prandial insulin Ievel) and/or to decrease post-prandial glucose (PPG) excursion, as compared to patients treated with the same active components in the pharmaceutical formulation of the invention but at higher dosages.

The term post-prandial excursion as employeč herein refers to the difference between post-prandial glucose (PPG) and fasting plasma glucose (FPG).

The lovv dose pharmaceutical formulation containing metformin in combination vvith glyburide may be administered orally in the same dosage form or in separate oral dosage forms or by injection.

It is believed that the use of metformin in combination vvith glyburide producēs antihyperglycemic results greater than that possible from each of these medicaments alone and greater than the combined additive anti-hyperglycemic effects produced by these medicaments.

Metformin vvill be employed in a vveight ratio to the glyburide in the range from about 1000:1 to about 10:1, preferably from about 400:1 to about 50:1, more preferably from about 200:1 to about 100:1.

In carrying out method of the present invention, a low dose pharmaceutical formulation or composition vvill be employed containing metformin and glyburide in association vvith a pharmaceutical vehicle or diluent.

The lovv dose pharmaceutical formulation can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration. The lovv dose pharmaceutical formulation can be administered to mammalian species including humāns, monkeys, dogs, etc., by an oral route, for example, in the form of tablets, capsules, granules or povvders, or it can be administered by a parenteral route in the form of injectable preparations. The dose for drug naive patients is as described above, vvhich can be administered in a single dose or divided doses, from 1-4 times per day.

The above dosage forms may also include the necessary physiologically acceptable carrier material, excipient, lubricant, buffer, antibacterial, bulking aģent (such as mannitol) , anti-oxidants (ascorbic acid or sodium bisulfite) or the like.

The dose administered must be carefully adjusted according to the age, vveight, and condition of the patient, as well as the route of administration, dosage form and regimen, and the desired result.

The combination of the metformin or salt thereof and glyburide may be formulated separately or, vvhere possible, in a single formulation employing conventional formulation procedures.

The various formulations of the invention may optionally include one or more fillers or excipients in an amount vvithin the range of from about 0 to about 90% by vveight and preferably from about 1 to about 80% by vveight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate and/or cellulose derivatives such as vvood cellulose and microcrystalline cellulose.

One or more binders may be present in addition to or in lieu of the fillers in an amount vvithin the range of from about 0 to about 35% and preferably from about 0.5 to about 30% by vveight of the composition. Examples of such binders vvhich are suitable for use herein include polyvinylpyrrolidone (molecular vveight ranging from about 5000 to about 80,000 and preferably about 40,000), lactose, starches such as corn starch, modified corn starch, sugars, gum acacia and the like as vvell as a vvax binder in finely povvdered form (less than 500 microns) such as camauba vvax, paraffin, spermaceti, polyethylenes or microcrystalline wax.

Where the composition is to be in the form of a tablet, it vvill include one or more tableting lubricants in an amount vvithin the range of from about 0.2 to about 8% and preferably from about 0.5 to about 2% by vveight of the composition, such as magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax and the like. Other conventional ingredients vvhich may optionally be present include preservatives, stabiiizers, anti-adherents or silica flovv conditioners or glidants, such as Syloid brand Silicon dioxide as vvell as FD&C colors.

Tablets may also include a coating layer which may comprise from 0 to about 15% by weight of the tablet composition. The coating layer which is applied over the outer solid phase containing pārticies of inner solid phase embedded therein may comprise any conventional coating formulations and will include one or more filmformers or binders, such as a hydrophilic polymer like hydroxypropylmethylcellulose, and/or a hydrophobic polymer like methacrylic acid esters neutral polymer, ethyl celiulose, celiulose acetate, polyvinyl alcoholmaleic anhydride copolymers, β-pinene polymers, glyceryl esters of wood resins and the like and one or more plasticizers, such as triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butyl phthalate, castor oil and the like. Both core tablets as well as coating formulations may contain aluminum lakes to provide color.

The film formers are applied from a solvent system containing one or more solvents including water, alcohols like methyl alcohoi, ethyl alcohoi or isopropyl alcohoi, ketones like acetone, or ethylmethyl ketone, chlorinated hydrocarbons like methylene chloride, dichloroethane, and 1,1,1-trichloroethane.

Where a color is employed, the color will be applied together with the film former, plasticizer and solvent compositions.

The finished dosage form is either a compressed tablet or a hard gelatin capsule, preferably a tablet.

The tablet may be optionally film coated. The total amount of drug per dosage unit would be such as to offer a dosage form of convenient size for patients.

The low dose pharmaceutical formulation in the form of a tablet may be obtained by a process as disclosed in U.S. Application Serial No. 09/353,141, filed July 14, 1999, which includes the steps of

a) forming granules by wet granulation of a mixture of metformin and glyburide

b) biending the granules vvith a tabletting aid and diluent, and

c) tabletting the biend thus obtained into tablets.

The mixture used for forming the granules includes a granulating binder. The granulating binder is preferably a polyvinylpyrrolidone such as, for example, a polyvinylpyrrolidone having a molecular vveight of 45,000. The polyvinylpyrrolidone may be used in a proportion of 2 to 4% by vveight vvith respect to the final tabiet.

After the granulating step, the granules may be sieved and dried.

The granules are then blended vvith a diluent and tableting aid. The diluent may be a conventional filler usually used for making tablets, such as microcrystalline cellulose. The tabletting aid may be a conventional material, such as magnesium stearate.

The tablets thus obtained may then optionally be coated vvith a hydrophilic cellulose polymer and talc.

The hydrophilic cellulose polymer is preferably 2hydroxypropyl methylcellulose.

Description of the Figurēs Figurēs 1 and 2 are bar graphs vvhich depict change in hemoglobin Alc (HbAlc) by number of tablets of fixed combinations of metformin/glyburide used in first line therapy versus monotherapy vvith each of glyburide and metformin.

Figurēs 3, 4 and 5 are bar graphs vvhich depict change in HbAlc over time of fixed combinations of metformin/glyburide used in first line therapy versus monotherapy vvith each of glyburide and metformin.

Figurē 6 is a bar graph vvhich depicts change in fasting plasma glucose (FPG) by number of tablets of fixed combinations of metformin/glyburide used in first line therapy versus monotherapy vvith each of glyburide and metformin.

Figurē 7 is a bar graph vvhich depicts baseline and post-prandial insulin Ievels of fixed combinations of metformin/glyburide in first line therapy versus monotherapy vvith glyburide and metformin.

Figurēs 8A and 8B are bar graphs vvhich depict change in PPG excursion at baseline and after 20 vveeks of fixed combinations of metformin/glyburide used in first line therapy versus monotherapy vvith each of glyburide and metformin.

Figurē 9 is a bar graph vvhich depicts hypoglycemic symptoms in subjeets on fixed combinations of metformin/glyburide used in first line therapy versus monotherapy vvith each of glyburide and metformin.

Figurē 10 is a bar graph vvhich depicts freguency of gastrointestinal adverse effects in subjeets on fixed combinations of metformin/glyburide used in first line therapy versus monotherapy vvith each of glyburide and metformin.

The follovving Examples represent preferred embodiments of the invention.

Examples 1 to 3

Tablets containing metformin/glyburide combinations vvere prepared as described belovv.

Composition of Metformin Hydrochloride-Glyburide Tablets

250mg/l.25mg, 500mg/2.5mg and 500mg/5mg

Example 1 Example 2 Example 3

INGREDIENT	QUANTITY PER TABLET (mg)
250mg/1.25mg	500mg/2.5mg	5 0 Omg/5mg
Metformin Hydrochloride*	251.25	502.50	502.50
Glyburide	1.25	2.5	5
Croscarmellose Sodium	7.00	14.0	14.0
Povidone	10.00	20.0	20.0
Microcrystailine Cellulose	28.25	5S.5	54.0
Magnesium Stearate	2.25	4.5	4.5
Fiim Coat**	6	12	12

♦contains 99.5% metformin HCI and 0.5% Mg stearate (w/w) **HPMC based fiim coat used.

The metformin hydrochloride-glyburide tablet products, 250 mg/1.25 mg and 500 mg/2.5 mg and 500 mg/5 mg, vvere compressed from the same granuiation. The lovver strength tablet vvas compressed at half the vveight of the metformin hydrochloride-glyburide 500 mg/2.5 mg tablet. Tablets manufactured for clinical use vvere film-coated vvith a hydroxypropylmethylcellulose (HPMC) fiim coat.

The fiim coat vvas non-functional and vvas applied for aesthetic purposes. The fiim coat applied to the clinical product vvas clear.

The manufacturing process for clinical products proceeded as follovvs:

Croscarmellose sodium and glyburide vvere dispersed together follovved by blending vvith the metformin hydrochloride/magnesium stearate (99.5%: 0.5% vv/vv) in a high shear mixer. The resultant dry mix vvas granulated in a high shear mixer vvith an aqueous povidone solution and dried in a fluid bed dryer at approximately 60 °C to achieve a specified moisture content, determined by loss on drying. The dried granuiation vvas reduced vvith a screening mill and mixed vvith the microcrystalline cellulose using a tumble mixer. Magnesium stearate vvas incorporated as a lubricant using a tumble mixer to producē the final compression blend.

The resultant blend was compressed into tablets, to a target vveight that vvas adjusted based on in-process moisture content determinations, on a suitable tablet press. The theoretical tablet vveight (based on formula composition vvith no adjustment for moisture content) vvas 300 mg for the 250 mg/1.25 mg strength and 600 mg for the 500/2.5 mg strength products.

The tablets vvere film-coated in a perforated coating pan vvith an appropriate aqueous non-functional HPMC based film coating system until the reguired amount of film coat had been applied. The typical Ievel of film coat applied to the tablets vvas 2%

In vivo evaluations of prototype combination tablet formulations identified the particle size distribution targeted for use in the clinical program to achieve comparable bioavailability to Micronase from the combination product. The particle size distribution of any glyburide lot vvas described by three cumulative size criteria: 25% undersize, 50% undersize (also knovvn as the mass median particle size, MMPS) and 75% undersize values. The clinical program involved a total of six glyburide drug substance lots vvith the 25% undersize value ranging betvveen 4-7 pm, the 50% undersize value ranging betvveen 8-14 pm and the 75% undersize value ranging betvveen 17-26 pm. Ali six lots of glyburide vvere synthersized by the same vendor, Profarmaco, vvith four of them being micronised by Profarmaco. The particle size distributions of the four lots produced are detailed in the follovving table.

Particle Size Data for Glyburide Drug Substance

Batches Used In Clinical Program

Batch Number	Particle Sizex (units are eguivalent sphere diameters in μη)
25% Undersize	50% Undersize	75% Undersize
1	5	9	21
2	5	9	21
3	4	8	18
4	5	9	18

Particle size measured by laser light scattering, method reference #CEM 8532 (#SM 248533)

The proposed particle size specification included the three cumulative size criteria described above vvith a range for acceptable mass median particle size (50% undersize) and an upper limit for the lovver quartile (25% undersize) , and the upper quartile (75% undersize). The particle size specification established for glyburide had been based on the particle size of glyburide used in bioavailability studies, the experience of various clinical lots, the closely matching nature of the size distributions of commercially produced glyburide and the particle size method precision. The particle size criteria described belovv assured reproducibility of glyburide dissolution and bioavailability from metformin hydrochloride-glyburide tablets.

25% undersize value not more than 6 pin 50% undersize value 7-10 pm

75% undersize value not more than 23 pm

Example 4

A. STJMMARY OF 5 CLINICAL PROTOCOLS (1) Purpose

The follovving study vvas conducted to compare glycemic control of 2 dosage strengths of a fixed combination metformin/glyburide product (described in Examples 1 and 2) versus placebo in drug naive patients vvith type 2 diabetes mellitus vvho have had inadequate glycemic control vvith diet and exercise. The dosage strengths of fixed combination product evaluated ineluded metformin 250 mg vvith glyburide 1.25 mg, and metformin 500 mg vvith glyburide 2.5 mg. Glycemic control vvas assessed using Hemoglobin Alc (HbA_lc) , the gold-Standard measure of long-term glycemic control. Mean change from baseline in HbAi_c follovving a 20 vveek treatment period (4 vveeks stable once daily dose, 4 vveek titration and 12 vveeks stable dose) vvere compared. The treatment phase continued for an additional 12 vveeks to assess durability of efficacy.

Contribution of the individual components of the fixed combination product vvere assessed by comparison of short term glycemic parameters of the combination product and monotherapy arms after 4 vveeks of stable once daily dosing. Glycemic control vvas aehieved vvith similar incidence of hypoglycemia vvith the fixed dose combinations as compared vvith sulfonyl urea alone or trends tovvards decreased gastrointestinal side effects as compared vvith metformin alone. Glycemic control vvas aehieved vvith trends tovvard decreased adverse events as compared vvith either aģent alone. Trends in hypoglycemia, gastrointestinal symptoms and lactate Ievels vvere assessed.

(2) Study sites and Subject Population

Eligible subjects vvere drug naive or have had no oral antihyperglycemic therapy for the 2 months prior to screening. Approximately 100 study sites located in the USA were recruited up to a maximum of approximately 800 subjects. Eligible subjects included both males and females between 30 and 78 years of age with established type 2 diabetes mellitus, history of impaired glucose tolerance or impaired fasting glucose who have inadequate glycemic control with diet and exercise.

(3) Study Design and Duration

This study was a 34 week, multicenter, randomized, placebo-controlled, double-blind, parallel study with an optional long-term, open-label treatment phase.

(4) Outcome Measures

Analysis of outcome measures for Periods B and C was performed after ali data was made available from the 32 week randomized treatment period.

The primary outcome variable for efficacy was the change from baseline in HbA_lc of the two combination therapies relative to placebo following 20 weeks of randomized treatment.

Secondary outcomes included the following:

Incidence of adverse events, particularly hypoglycemia and gastrointestinal side effects, was compared among treatment arms after 20 and 32 weeks of randomized therapy.

The number and proportion of subjects achieving a therapeutic glucose response were assessed among treatment arms following 20 and 32 weeks of randomized therapy.

The reduetion in fasting and 2-hour postprandial glucose and insulin were assessed among treatment arms following 20 and 32 weeks of randomized therapy.

Β. RATIONALE

Metformin and sulfonyl ureas, such as glyburide, are a known and effective combination in the treatment of type 2 diabetes mellitus. The two drugs have demonstrated a synergistic effect on glucose lowering when used in combination. Either drug can be used alone as first line monotherapy. They may also be used in combination with each other if monotherapy of either is inadequate. No data currently exists on the use of low dose combination thērapy for first line use.

Treatment with a fixed dose combination tablet was expected to improve glycemic control as first line therapy in subjects with type 2 diabetes mellitus with inadequate control on diet and exercise. Glycemic control was expected to be achieved at lower doses than monotherapy with comparable or less potential side effects of the individual aģents and with ease of administration.

This randomized double-blind, placebo-controlled study in subjects with type 2 diabetes mellitus who have inadequate glycemic control on diet and exercise tested the following hypotheses:

1. Administration of a fixed dose metformin/ glyburide combination product for 20 weeks (4 weeks stable once daily dosing in Period B and 16 weeks of treatment in Period C) in subjects with type 2 diabetes mellitus who have inadequate glycemic control on diet and exercise will producē significant reductions in HbAic compared to placebo.

2. Administration of a fixed dose metformin/ glyburide combination product for 32 weeks in subjects with type 2 diabetes mellitus who have inadequate glycemic control on diet and exercise will be well tolerated.

- 27 C. OBJECTIVES (1) Primary

To compare, after 20 vveeks of oral administration, the effect of 2 dosage strengths (Examples 1 and 2) of a fixed combination metformin/glyburide tablet that has been titrated for glycemic control on the reduction in HbAi_c Ievel versus placebo.

(2) Secondary (included the follovving)

1. To assess safety and tolerability among treatment arms after 20 and 32 vveeks of randomized therapy. Glycemic control may be achieved vvith a similar incidence in hypoglycemia vvith the fixed dose combinations as compared vvith sulfonyl urea alone or decreased gastrointestinal side effects as compared vvith metformin alone.

2. To assess after 20 vveeks and assess after 32 vveeks, the proportion of subjects vvith a therapeutic response in glycemic control of oral administration of each metformin/glyburide combination regimen vvhen compared to the therapeutic response achieved vvith metformin monotherapy, glyburide monotherapy and placebo regimens. Therapeutic plasma glucose response vvill be defined as a FPG < 126 mg/dL (based on current ADA guidelines for FPG). Therapeutic response for HbA_lc vvill be defined as HbAi_c < 7%.

3. To assess after 20 vveeks and assess after 32 vveeks, the reductions in fasting glucose and 2hour postprandial glucose and insulin Ievels follovving the oral administration of each fixed combination metformin/glyburide regimen vvith the reduction in fasting glucose and 2-hour postprandial glucose and insulin Ievel achieved vvith metformin monotherapy, glyburide monotherapy and placebo.

4. To assess the durability of reductions in HbA_lc Ievels after 32 vveeks of administration of f ixed combination metformin/glyburide product.

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

D. STUDY DESIGN

This vvas a multicenter, randomized, five-arm, parallel group, double-blind, placebo controlled trial of the antihyperglycemic activity of a fixed combination metformin/glyburide tablet as first line therapy in subjects vvith type 2 diabetes mellitus vvho have inadequate glycemic control (HbAi_c < 7%) , vvith diet and exercise. Patients vvere drug naive or had no oral antihyperglycemic therapy for the 2 months prior to screening. Approximately 100 US sites enrolled up to a maximum of 800 patients vvith type 2 diabetes mellitus vvho had inadequate glycemic control defined as an HbAx_c betvveen 7-11% on diet and exercise. The minimum number of patients required to achieve the primary outcome vvas a total of 500 patients or 100 patients per arm. Hovvever, recruitment continued for up to 6 months to recruit up to a maximum of 150 patients per arm to provide additional safety information. The design included 3 periods as follovvs:

(1) Period A - Tvvo Week Dietary and Placebo

Lead-in Phase

This initial phase included dietary instruction on a eucaloric, vveight maintaining diabetes prudent diet consistent vvith ADA guidelines or a balanced diet of approximately 55% carbohydrates, 20% protein and 25% fat.'

Tolerability of the administration of multiple capsules and tablets were assessed with placebo. Home glucose meters were dispensed vvith instruction on their use.

(2) Period B-4 Week Double-blind Once Daily

Stable Dose Phase

Period B began the randomized, double-blind, parallel quadruple dummy treatment phase. Eligible patients vvere randomized to 1 of 5 study arms vvhich included placebo, glyburide monotherapy, metformin monotherapy, and tvvo different dose strengths of fixed combination metformin/glyburide product (Examples 1 and 2) . Subjeets vvere maintained on once daily dosing for a 4 vveek period so that the contribution of the individual components of the combination product can be assessed by short term glycemic parameters.

This 4 vveek phase at stable once daily dosing illustrated the contribution of the individual components of the fixed combination product using short term glycemic parameters. Glycemic control vvas assessed vvith fruetosamine and fasting glucose.

(3) Period C - 28 Week Double-blind Titration and

Stable Dose Phase

Period C vvas the continuation of the randomized, double-blind treatment phase. Subjeets vvere titrated for glycemic control over the first four vveeks then dose vvas maintained for a 24 vveek stable dose treatment segment. Analysis for the primary outeome, the change from baseline in HbA_lc of the tvvo combination therapies (Examples 1 and 2) relative to placebo, vvas assessed at vveek 16 of Period C vvhich vvas after 20 vveeks of randomized, double-blind treatment. This vvas done at this time as there had been adequate time for stabilization of HbA_Xc and for safety reasons as it vvas anticipated that a high number of placebo treated patients may have had to discontinue randomized study medication due to insufficient glycemic control as treatment duration was extended. Subjects not discontinuing randomized study drug due to lack of efficacy remained on stable doses for a total of 24 weeks to evaluate durability of efficacy and gather additional safety and tolerability data. The study remained blinded and those subjects who discontinued randomized study drug due to lack of efficacy were eligible to begin the longterm, open-label treatment phase with fixed combination product.

This 28 week phase included an initial 4 week titration segment to improve glycemic control followed by a 24 week stable dose phase. Analysis for the primary outcome was assessed at the 16^th week of Period C.

Subjects were evaluated for discontinuation of randomized study drug due to lack of glycemic control beginning at visit Cl through C85. Subjects were evaluated for lack of efficacy at visit C113 and ali subseguent visits until the end of randomized treatment. The assignment of randomized study drug remained blinded. Subjects who remained on randomized study drug continued the stable dose phase for a total of 28 weeks to allow evaluation of durability of efficacy and to gather additional safety and tolerability data. Subjects were evaluated for discontinuation of study medication due to lack of glycemic control on or after Visit Cl (Week 0, Period C) .

DOSING

Study drugs for this study were defined as: placebo, glyburide, metformin, metformin/glyburide 250/1.25 mg and metformin/glyburide 500/2.5 mg. For blinding purposes this study incorporated a quadrupledummy design. Patients meeting the inclusion criterion without meeting any exclusion criterion, satisfying the Period A glycemic criteria, were eligible for enrollment into Period A.

Period Α:

This period vvas a single-blind placebo lead-in to tēst patient tolerability of ingesting multiple capsules and tablets in addition to evaluating compliance vvith the quadruple dummy design. Patients received kits containing four bottles of placebo corresponding to study drug.

Week 0 (Visit Al) - Subjects were instructed to take 1 capsule or tablet from each bottle vvith their first meal of the morning.

Week 1 (Visit A8) - Subjects vvere instructed to take 1 capsule or tablet from each bottle vvith their first meal of the day and a second capsule or tablet from each bottle vvith their evening meal.

Period B:

Follovving completion of the single-blind lead-in phase (Period A), gualifying subjects commenced therapy in the randomized, double-blind treatment phase (Period

B) . At visit A15/B1 subjects vvere randomized to once daily dosing vvith breakfast of placebo, glyburide 2.5 mg, metformin 500 mg, metformin/glyburide 250/1.25 mg or metformin/glyburide 500/2.5 mg. Once daily dosing remained stable for a total of 4 vveeks.

Period C:

Follovving completion of the 4 vveek stable once daily dose phase (Period B) subjects continued the same randomized therapy in the 28 vveek titration/stable dose treatment phase (Period C) . Study medication vvas titrated at visits Cl, C15 and C29. Medication vvas dosed vvith the first morning meal and vvith the evening meal. Potential maximal doses achieved included glyburide 10 mg, metformin 2000 mg, metformin/glyburide 1000/5 mg, metformin/glyburide .2000/10 mg. After the 4 vveek titration segment in Period C, subjects continued on a stable dose of study medication for the remainder of

Period C.

Once adequate glycemic control had been aehieved or maximum dose had been attained, study drug vvas not increased and vvas only reduced vvith documented hypoglycemia.

RESULTS

The results obtained from the above studies indicate that the lovv dose metformin-glyburide (250/1.25) formulation of the invention aehieved glycetnic control at least essentially equivalent to the high dose metforminglyburide (500/2.5) formulation as evidenced by (1) a therapeutic response for hemoglobin Alc, namely, a reduction in HbAlc of belovv 7% (from a mean baseline of 8.2%) at vveek 20 (Figurēs 1, 2 and 3), at vveeks 20 and 32 and final visit (Figurēs 4 and 5) (2) a therapeutic response for fasting plasma glucose (FPG), namely, a reduction in FPG to less than 126 mg/dL after 20 vveeks (from a baseline of about 175 mg/dL) , (as shovvn in Figurēs 6) (3) a therapeutic response for post-prandial insulin Ievels, namely an increase in post-prandial insulin of 19-25 piu/mL (microintemational units/mL) (Figurē 7) (4) a therapeutic response for post-prandial glucose excursion (PPG) (that is the difference betvveen post-prandial glucose and fast plasma glucose), namely, a decrease in post-prandial glucose excursion at vveek 20 of 17.7 for the 500/2.5 mg combo and 20.8 for the 250/1.25 mg combo versus 15.2 for metformin, 6.8 for glyburide. (Figurēs 8A and 8B).

At the same time, the above efficacy results employing the lovv dose formulation of the invention (Example 1) were achieved with reduced incidence of side effects (Figurēs 9 and 10).

As seen in Figurē 9, the incidence of hypoglycemia employing the low dose formulation of the invention (Example 1) is less than about 1/3 of that occurring using the prior art high dose formulation (Example 2) employed in generally accepted medical practice for treating diabetes.

As seen in Figurē 10, the incidence of gastrointestinal side effects employing the lovv dose formulation of the invention (Example 1) is less than 20% of that occurring using the high dose formulation (Example 2) employed in generally accepted medical practice for treating diabetes.

A discussion of the above results follovvs.

Discussion of Results

The progression to clinical type 2 diabetes takes time and requires the presence of multiple physiologic defects vvhich are already present by the time most individuāls are diagnosed vvith diabetes. Oral therapeutic options for the treatment of type 2 diabetes, until the last fevv years, have been severely limited. Further, vvith continued disease progression over time, ali oral antihyperglycemic therapies are expected to become less effective leading to inadequate glycemic control for the patient.

Combination therapy has traditionally been indicated for second line use if initial single aģent therapy is found to be ineffective, called primary failure, or after initially effective aģents are found to be ineffective at maintaining glucose control, called secondary failure. Svvitching from one monotherapy that is failing to an alternative monotherapy has not been proven to be effective in achieving glycemic control;

only the addition of a second aģent with a different mechanism of action has been shown to achieve improved glycemic control. Given that a combination of insulin resistance and relative deficiency of insulin secretion is the pathophysiological basis of type 2 diabetes, it is expected that combinations of aģents offer greater therapeutic potential. Thus, both clinical experience and pathophysiologic evidence support the use of combination therapy earlier in the disease process.

While a fixed combination of metformin and glyburide is not a novel concept, and, as discussed above, different forms of it are available outside the U.S. for first and second line therapy, the use of combination therapy, low or moderate dose, as first line treatment in drug naive patients has never been studied in large controiled clinical trials. Treating to a near euglycemic target, an HbA_lc < 7% as recommended by the ADA, is the goal with any antihyperglycemic therapy. However, depending upon the duration of diabetes and the progression of the disease, a single aģent may not provide the efficacy necessary to bring even newly diagnosed patients to their target goal. The data presented in this summary provides evidence that a low dose fixed combination metformin/glyburide product is safe and provides the efficient antihyperglycemic potency necessary to bring most drug naive patients to the ADA's recommended glycemic target.

As first line therapy, a single formulation of fixed combination metformin/glyburide in ratio of a 200:1 metformin/glyburide was evaluated using two different dose strengths, a low dose (metformin/glyburide 250/1.25 mg) and a medium dose (metformin/glyburide 500/2.5 mg) . The two dose strengths of fixed combination metformin/glyburide product were compared in a doubleblind study to placebo, glyburidē monotherapy and metformin monotherapy. Mean final doses achieved in each treatment arm were approximately 5.3 mg of glyburide,

1307 mg of metformin, 557/2.78 mg of low dose (250/1.25 mg) metformin/glyburide fixed combination and 818/4.1 mg of medium dose (500/2.5 mg) fixed combination. When used as first line therapy, fixed combination metformin/glyburide treatment achieved statistically significant improvement in glycemic control compared to metformin, glyburide or placebo. The interim open-label treatment data confirmed the clinical utility of fixed combination therapy in a more glycemically diverse patient population and for a longer period of time.

Safety

As first line therapy use, two dose strengths of metformin/glyburide were evaluated; a lovv-dose (250/1.25 mg) and a medium dose (500/2.5 mg) strength were compared vvith placebo, glyburide and metformin. In the doubleblind phase of this study, diarrhea vvas the most frequently-occurring adverse effects (AE) in those subjects vvho vvere on metformin mono- or combination therapy. Importantly, hovvever, the incidence of gastrointestinal AEs vvas lovver in the lovv dose fixed combination group than in the metformin monotherapy group (as seen in Figurē 10). Discontinuations due to AEs also occurred vvith the lovvest frequency in the lovv dose fixed combination group compared to any of the other active treatments. Discontinuations due to lack of glycemic control vvere lovvest in both the fixed combination groups, and severe hypoglycemia vvas not observed in this study. The frequency of subjects reporting an episode of hypoglycemia vvas highest in the medium dose fixed combination treatment group, vvhile the lovv dose group had a lovver incidence than glyburide monotherapy (Figurē 9) . Mild increase in lactate Ievels vvere observed in all metformin groups, but no cases of lactic acidosis vvere reported in this study.

In the open-label phase of the study, subjects could be directly enrolled if they did not meet the glycemic criteria for entry into the double blind study. Subjects could also enter the open-label phase if they discontinued prematurely from the double-blind phase due to lack of glycemic control, or after they completed the double-blind phase. In the open-phase of the study, the AE profilē vvas similar to that observed in the doubleblind phase, vvith the most frequently-occurring AEs in the same body systems. The lovv dose combination group again displayed a favorable overall safety profilē compared to the medium dose group.

In both the nevvly-diagnosed subjects as vvell as inadequately-controlled subjects, the overall pattem of safety and tolerabilifcy observed in the double-blind studies vvas as expected from the ciinicai experience vvith metformin and glyburide. No nevv or unexpected events or laboratory abnormalities vvere observed i’n this ciinicai program. Interim analyses of the long-term open-label extensions support the favorable safety profilē observed in the short-term phase of the studies. In particular, the lovv dose fixed combination shovved a favorable safety/tolerability profilē vvhen compared to the other regimens used in this program.

Efficacy

Double-blind, first line therapy demonstrated a statistically significant mean decrease in HemoglobinA_lc (HbAi_c) of 1.3% from placebo for both fixed combination treatment groups and a mean decrease from baseline of approximately 1.5%. While ali active therapy treatment groups achieved acceptable glycemic control, greater mean decreases in HbAi_c for both fixed combination treatment groups vvere achieved vvhen compared to metformin therapy of glyburide therapy. Antihyperglycemic durability vvas observed vvith ali active treatment groups (glyburide, metformin, metformin/glyburide 250/1.25 mg, metformin/glyburide 500/2.5 mg) as evidenced by the maintenance of the mean HbAi_c Ievels from Week 20 (6.64%,

6.79%, 6.68%, 6.44%) to Week 32 (6.78%, 6.96%, 6.87%,

6.68%) of double-blind therapy belovv the therapeutic target of 7% (Figurēs 3 and 4).

Interim open-label first line therapy data demonstrate that for subjects directly enrolled, the mean HbAi_c at baseline vvas 10.6%, and for the subset of subjects vvith available data, a mean decrease of 3.5% in HbAi_c was aehieved vvith a mean HbAi_c of 7.1% through 26 vveeks. Of the subjects directly enrolled into open-label therapy, 87% received the medium dose 500/2.5 mg fixed combination as initial therapy and at the time of the interim report, the mean dose of fixed combination therapy vvas metformin/glyburide 1569/7.85 mg. For subjects vvith available open-label data completing the double-blind treatment phase and continuing into the open-label treatment phase, the mean HbAi_c at baseline vvas 8.32%. For ali subjects reaching 13 vveeks of therapy, a mean decrease of 1.76% in HbAi_c vvas aehieved vvith the mean HbAi_c of 6.56%. Of the subjects completing the doubleblind treatment phase and continuing into the open-label treatment phase, 78% received the lovv dose (250/1.25 mg) and 22% received the medium dose (500/2.5 mg) fixed combination as initial therapy. The mean dose of fixed combination therapy vvas metformin/glyburide 696/3.48 mg.

No clinically significant pattems of greater or reduced effect vvere apparent in any of the subpopulations (age, gender, race) vvith respect to response in HbAic from baseline in either double-blind trial vvith fixed combination metformin/glyburide as first line therapy.

This clinical program also assessed fasting plasma glucose as a parameters of short term glycemic control. FPG results in double-blind studies vvere consistent vvith the HbA_lc results. As first line therapy, statistically and clinically significant larger mean decreases in FPG for both fixed combination treatment groups compared to placebo and metformin vvere aehieved (Figurē 6) . An early response to fixed combination therapy vvas observed; differences among treatment groups vvere apparent by Week 2 of double-blind therapy as a time vvhen subjeets vvere stili undergoing initiai titration and vvere receiving only one-half potential maximum dosing. This early response at one-half maximum dosing in a monotherapy refractory patient population demonstrates the benefit of combination therapy for the patient and using combination therapy earlier in the disease process.

HemoglobinA_lc is the prevailing Standard measure of overail glyoemic control and it is the glycemic marker found to be correlated vvith long term complications. Although, fasting plasma glucose, the current Standard for the diagnosis of diabetes, is a faster, more convenient marker, it does not provide an optimal assessment of circadian glycemic control. It has been shovvn, and intuitively understood, that non-fasting plasma glucose is a better marker of diabetic control than FPG in type 2 diabetes; it also correlates better vvith HbAi_c. Postprandial hyperglycemia is an early marker of the metabolic defects found in type 2 diabetes and contributes to beta celi dysfunction. An important association betvveen postprandial glucose Ievels and cardiovascular disease has been demonstrated. If normai glycemia is the goal in preventing long term complications of diabetes then monitoring and lovvering postprandial glucose is a rational strategy in improving metabolic function and achieving overail glucose control.

As first line therapy, statistically significant larger mean decreases in absolute postprandial glucose (63-65 mg/dL) vvere observed for both fixed combination treatment groups than the placebo group. Larger mean decreases in absolute PPG vvere also achieved compared vvith gyburide (16-18 mg/dL) and metformin (18-20 mg/dL) monotherapy (Figurēs 8A and 8B) . The 2-hour postprandial glucose excursion from a fasting baseline for both the lovv dose (22.5 mg/dL) and medium dose (23.9 mg/dL) fixed combination treatment groups was only 56%-59% of placebo (40.3 mg/dL), 59%-63% of glyburide (38.2 mg/dL) and 75%81% of metformin (29.5 mg/dL), Evaluating the excursion rather than the absolute value demonstrates that glyburide is similar to placebo, metformin achieves better postprandial glucose lowering than glyburide and placebo, and that the low dose combination is the most powerful in lowering postprandial glucose excursion. As there is no published clinical data with combination therapy studied in a drug naive patient population, these results add new insight to understanding of the impact of treatment options at this stage of the disease. īndeed, the results could not have been predicted from the changes observed in the much studies second line therapy population.

Insulin Ievels were evaluated in the fasting and postprandial state in the first line therapy study (Figurē 7). There was a statistically significant increase in insulin response in the presence of a glucose load for both fixed combination treatment groups (24-28.8 piu/mL) compared to placebo. A larger increase in insulin response in the presence of a glucose load for the low dose fixed combination (14.6 piu/mL) treatment group was observed when compared to glyburide monotherapy and a larger increase in insulin response in the presence of a glucose load for both fixed combination (21-25.8 piu/mL) treatment groups was observed when compared to metformin monotherapy. When considering the mean doses of active therapy per treatment group, the insulin response cannot be explained by the sulfonylurea component alone with fixed combination therapy. This clinical data supports preclinical work with isolated pancreatic islet celis where it has been suggested that metformin prevents the hyperglycemic desensitization of the islet celis. The combination of the physiologic and appropriate increased insulin response with a corresponding larger decrease in glucose excursion suggests that the combination is improving the efficiency of the pancreas in responding to a glucose load, preserving beta celi function and improving insulin sensitivity.

The essential goal in the management of patients vvith type 2 diabetes, in addition to aggressively treating elevated blood pressure and lipid Ievels, is aehieving as near normai glycemic Ievels as possible or aehieving glycemic therapeutic targets. There vvas a greater response to fixed combination therapy vvith respect to greater frequencies of subjeets aehieving therapeutic targets and greater decreases in absolute HbAic. As first line therapy, a higher frequency of subjeets on fixed combination therapy (66%-71%) aehieved a glycemic target of an HbAi_c A 7% compared vvith 60% of sulfonylurea monotherapy, 50% of metformin monotherapy and 20% of placebo follovving 20 vveeks of double-blind therapy. Approximately 28% of subjeets in each fixed combination group had decreases in HbA_lc from baseline greater than 2.0%, compared vvith 16%-17% of each monotherapy group and 3% of placebo. Of note, is that these targets vvere not aehieved vvith simply higher total doses of medication, but vvith lovver doses of the complementary components. Mean final doses aehieved in each first line therapy treatment arm vvere approximately glyburide 5.3 mg, metformin 1307 mg, lovv dose fixed combination 557/2.78 mg and medium dose fixed combination 818/4.1 mg. For the change in HbAi_c by number of tablets, the pattern observed vvith fixed combination therapy is not unexpected from a pathophysiologic vievvpoint. It indicates that there is a clear response to target at ali dose Ievels and that the need for higher doses correlates vvith a higher baseline HbAi_c. A similar pattern can be detected for glyburide up to a total dose 7.5 mg; no clear pattern vvas observed vvith metformin therapy.

The data presented supports lovv dose fixed combination metformin/glyburide as the first line aģent most likely to bring a patient to therapeutic target, no matter how high their baseline HbAi_c. For both fixed combination therapies, the mean decrease from baseline HbAi_c is larger for subjects with higher baseline Ievels.

This phenomenon was not observed with glyburide, metformin or placebo and is not expected to be seen with other monotherapies. This demonstrates the contribution of components necessary for achieving therapeutic glycemic targets when baseline HbAi_c Ievel is greater than

9%. Monotherapy was shown to have a plateauing of glycemic response for baseline HbA_lc Ievels < 9% while fixed combination therapy had additional incremental decreases in HbA_lc for baseline HbA_lc Ievels < 9%.

For ali subjects enrolled into the open-label first line treatment phase with available data for at least two time points, the mean HbA_lc at baseline was 9.45%. By Weeks 13, 26 and 39 approximately 50-55% of subjects had achieved an HbA_lc of less than 7% and an additional 30% had achieved an HbAi_c < 8%. This response rāte and magnitude of change in HbAi_c lowering can be expected with combination therapy but is rarely seen with monotherapy antihyperglycemic aģents. The fundamental issue is what initial antihyperglycemic treatment will achieve the glycemic target of an HbA_ic < 7% in the greatest proportion of patients. This data strengthens the need for the reevaluation of current type 2 diabetes treatment paradigms and to shift to the use of combination therapy sooner in the disease process.

Weight gain is typically observed with ali antihyperglycemic aģents other than metformin monotherapy. With improved glycemic control, a weight gain is actually expected as calories are conserved rather than lost due to poor metabolic control. In this clinical program, as glycemic control improved, minimal early weight gain of approximately 1-2 kg was observed with fixed combination therapy; this was comparable to the 2 kg weight gain observed with first line glyburide monotherapy. In double-blind therapy, after the initial minimal gain, vveight remained stable and did not continue to increase vvith time.

Overall there vvere no clinically or statistically significant differences betvveen any of the treatment groups vvith respect to changes in the piasma lipid profilē. As the most severe patients vvere excluded from the placebo controlled trial, smaller changes in response to therapy might be undetectable. The first line therapy patient popuiation had inadequate glycemic control but diet and exercise has already succeeded in bringing the mean HbA_lc to 8.2%. In subjects treated vvith fixed combination therapy, there vvas no adverse effect on the piasma lipid profilē (total cholesteroi, LDL, HDL, and triglycerides) or significant differences compared vvith placebo or either glyburide and metformin monotherapy.

With better understanding of the relationship betvveen diabetes control and long-term complication rāte the goal of diabetes management today is to achieve and maintain as near normai glycemia as possible. Targeting multiple defects using aģents vvith synergistic or complementary mechanisms of action intuitively makes sense to achieve a therapeutic glycemic target. Improved understanding of the natūrai history of type 2 diabetes suggests that current treatment paradigms of allovving failure to occur prior to implementing a more aggressive treatment strategy should be reassessed. Earlier use of lovv dose combination therapy, particularly vvhen the use of lovver doses results in better tolerability, therefore appears to be an important therapeutic approach if targets are to be achieved and compliance maintained. The fixed combination evaluated in this study allovvs for lovver dosing and the ease of use in a single entity.

Lovv dose fixed combination metformin/glyburide therapy is safe and effective in achieving and maintaining glycemic control in patients vvith type 2 diabetes vvho have inadequate glycemic control vvith diet and exercise. The use of combination therapy earlier in the diabetes disease progression appears to be a clinically sound altemative to the classic treatment paradigms of allowing failure of step wise therapy before instituting a more aggressive, but clinically sound, treatment strategy. Though not evaluated in this shortterm study, the strategy to achieve as near normai glycemic targets as possible is likely to have an impact in slowing the progression of the diabetes disease process and delay the onset of long-term diabetes complications. Given a refractory monotherapy patient population the fixed combination of metformin and glyburide was associated with a clinically significant improvement in glycemic control vvithout evidence of detrimental metabolic effects or safety concems. There vvas no clinically significant hypoglycemia, no negative impact in plasma lipids and a limited early vveight gain follovved by stable vveight vvith time. The synergism of the metformin and sulfonylurea combination is an established one; a fixed combination of metformin and glyburide is effective in improving glycemic control and is a rationale choice in the antihyperglycemic armamentarium. It is assumed that a fixed combination simplifies dosing, is more convenient and therefore may lead to better compliance vvith therapy.

The lovv dose (250/1.25 mg) fixed combination vvould be the initial starting dose as first line therapy in drug naive subjects. This should then be titrated as indicated to achieve a HbA_lc <7%.

OVERALL CONCLUSIONS

The safety and efficacy data presented from this clinical program assessing fixed combination metformin/glyburide as first line therapy in patients vvith type 2 diabetes confirm the follovving:

• The percentages of subjects who discontinue from therapy because of hyperglycemia were lower for fixed combination metformin/glyburide compared with metformin, glyburide, and placebo.

• Hypoglycemia and symptoms of hypoglycemia, as first line therapy (Figure 9), occurred less often with metformin/glyburide 250/1.25 mg compared to metformin/glyburide 500/2.5 mg and glyburide.

• As first line therapy, the incidence of gastrointestinal adverse events associated with fixed combination was lowest for metformin/glyburide 250/1.25 mg compared with metformin/glyburide 500/2.5 mg and metformin (Figure 10) .

• No new or unexpected adverse events or laboratory abnormalities occurred in subjects who received longterm open-label fixed combination metformin/glyburide.

• Significantly better efficacy of fixed combination metformin/glyburide at any dose strength as evidenced by greater reductions of ali glycemic parameters (HbAx_c, postprandial glucose, fasting glucose and fructosamine) compared to placebo, glyburinde and metformin therapy, • A synergistic effect of the low dose combination in targeting multiple metabolic defects to improve beta celi function and insulin sensitivity, as evidenced by postprandial plasma glucose and insulin excursions, to achieve improved metabolic function and glycemic control.

• A higher frequency of patients on fixed combination metformin/glyburide therapy achieved a glycemic therapeutic target of an HbAi_c 7%.

• Efficient glycemic lowering to therapeutic targets for any baseline HbAi_c compared with placebo, glyburide and metformin therapy. As initial therapy, glyburide and metformin were shown to have a plateauing of glycemic response for baseline HbAi_c Ievels > 9% while fixed combination metformin/glyburide therapy had additional incremental decreases in HbA_lc for baseline HbA_lc Ievels > 9%.

. · Limited early weight gain paralleling improved glycemic control, comparable to glyburide monotherapy; however, weight remained stable with time.

• No adverse effect of the fixed combinacion therapies on the lipid profilē (total cholesterol, LDL, HDL, and triglycerides) or significant differences from placebo or either glyburide and metformin monotherapy.

• The favorable efficacy and tolerability of fixed combination metformin/glyburidē 250/1.25 mg supports its use as the initial starting dose in first line therapy.

The above results clearly show that treating diabetes with the low dose metformin/glyburide formulation of the invention (250 mg/1.25 mg) is at least equivalent in efficacy to the higher dosage form (500 mg/ 2.5 mg), while resulting in reduced side effects.

Claims (36)

1. Use of a pharmaceutical composition for first line treatment of type 2 diabetes, in a drug naive human patient, which comprises administering to a drug naive human patient in need of treatment, as first line therapy, a lovv dose of a combination of metformin and glyburide.

2. The use of the pharmaceutical composition as defined in Claim 1 vvherein the daily dosage of metformin administered is less than 800 mg.

3. The use of the pharmaceutical composition as defined in Claim 1 vvherein the lovv dose combination of metformin and glyburide provides at least substantially equivalent efficacy in treating diabetes in drug naive patients, but vvith substantially reduced side effects, as do combinations of metformin and said glyburide employed in substantially higher daily dosages as prescribed in generally accepted medical practice for first line therapy in treating diabetes.

4. The use of the pharmaceutical composition as defined in Claim 1 vvherein the starting daily dosage of metformin is as lovv as about one-fifth of the starting daily dosage of metformin employed in generally accepted medical practice for first line therapy for treating diabetes.

5. The use of the pharmaceutical composition as defined in Claim 4 vvherein the daily maintenance dosage of metformin employed is up to that employed in generally accepted medical practice for first line or second line therapy for treating diabetes.

6. The use of the pharmaceutical composition as defined in Claim 1 vvherein the starting daily dosage of glyburide is as lovv as about one-fifth of the starting daily dosage of glyburide employed in generally accepted medical practice for first line therapy for treating diabetes.

7. The use of the pharmaceutical composition as defined in Claim 6 vvherein the daily maintenance dosage or glyburide employed is up to that employed in generally accepted medical practice for first line therapy or second line therapy for treating diabetes.

8. The use of the pharmaceutical composition as defined in Claim 1 vvherein the metformin is. administered in a daily dosage in an amount vvithin the range from about 160 mg to about 750 mg, and the glyburide is administered in a daily dosage in an amount vvithin the range from about 0.5 to about 15 mg.

9. The use of the pharmaceutical composition as defined in Claim 1 vvherein the lovv dose combination of metformin and glyburide is formulated as a single dosage form.

10. The use of the pharmaceutical composition as defined in Claim 1 vvherein the metformin is employed in a vveight ratio to glyburide vvithin the range from about 400:1 to about 50:1.

11. The use of the pharmaceutical composition as defined in Claim 1 vvherein the metformin and glyburide are employed in a vveight ratio to each other of about 200:1 or 100:1.

12. The use of the pharmaceutical composition as defined in Claim 1 vvherein the metformin is administered in an amount vvithin the range from about 125 to about 750 mg, one to four times daily, provided that the maximum daily dosage for metformin is about 750 mg per day, but more than about 225 mg, and the glyburide is administered in an amount vvithin the range from about 0.75 to about 5 mg, one to four times daily, up to a maximum of 15 mg per day.

13. The use of the pharmaceutical composition as defined in Claim 1 vvherein the metformin is administered in an amount vvithin the range from about 250 to about 500 mg, and the glyburide is administered in an amount vvithin the range from about 1.25 to about 5 mg.

14. The use of the pharmaceutical composition as defined in Claim 1 vvherein the metformin/glyburide combination contains of 250 mg metformin/1.25 mg glyburide.

15. The use of the pharmaceutical composition as defined in Claim 1 vvherein the metformin/glyburide combination contains 500 mg metformin/2.5 mg glyburide.

16. The use of the pharmaceutical composition as defined in Claim 1 vvherein the metformin/glyburide combination contains 500 mg metformin/5 mg glyburide.

17. The use of the pharmaceutical composition as defined in Claim 1 vvherein a metformin/glyburide 250/ mg/1.25 mg dosage is administered once a day or tvvice a day.

18. The use of the pharmaceutical composition as defined in Claim 19 vvherein the metformin/glyburide 250 mg/1.25 mg dosage is administered to patients vvith a baseline HbA_lc > 9% or a fasting glucose > 200'mg/dL tvvice daily, vvith dosage increases, vvhere necessary, in increments of 250 mg/1.25 mg every 2 vveeks, up to the minimum effective daily dose necessary to achieve adequate glycemic control.

19. The use of the pharmaceutical composition as defined in Claim 1 vvherein said metformin is employed in a daily dose as employed in generally accepted medical practice for first line therapy or second line therapy for treating diabetes.

20. The use of the pharmaceutical composition as defined in Claim 1 vvherein glyburide is employed in a daily dose as employed in generally accepted medical practice for first line therapy or second line therapy for treating diabetes.

21. The use of the pharmaceutical composition as defined in Claim 1 vvherein the lovv dose combination comprising 250 mg metformin and 1.25 mg glyburide characterized in that it has at least substantially equivalent efficacy to a formulation comprising 500 mg metformin and 2.5 mg glyburide in treating diabetes vvith respect to decrease in hemoglobin Ai_c, decrease in insulin resistance, increase in post-prandial insulin Ievels and/or decrease in post-prandial glucose excursion, vvhile providing substantially reduced incidence of adverse side effects vvhich are hypoglycemia and gastrointestinal side effects.

22. Use of the pharmaceutical composition for first line treatment of type 2 diabetes, in a drug naive human patient, vvhich comprises administering to a drug naive human patient in need of treatment, as first line therapy, a lovv dose of a combination of metformin and glyburide vvherein the starting daily dosage is 250 mg metformin and

1.25 mg glyburide.

23. Use of the pharmaceutical composition for first line treatment of type 2 diabetes, in a drug naive human patient, vvhich comprises administering to a drug naive human patient in need of treatment, as first line therapy, a therapeutically effective lovv dose of a combination of metformin and glyburide vvherein the starting daily dosage is 250 mg metformin and 1.25 mg glyburide tvvice a day or 500 mg metformin and 2.5 mg glyburide once a day.

24. Use of the pharmaceutical composition for first line treatment of type 2 diabetes, in a drug naive human patient, vvhich comprises administering to a drug naive human patient in need of treatment, as first line therapy, a therapeutically effective lovv dose of a combination of metformin and glyburide vvherein the starting daily dosage is 500 mg metformin and 5 mg glyburide.

25. Use of the pharmaceutical composition for first line treatment of type 2 diabetes, in a drug naive human patient, vvhich comprises administering to a drug naive human patient in need of treatment, as first line therapy, a therapeutically effective lovv dose of a combination of metformin and glyburide vvherein the glyburide is such that the glyburide bioavailability is comparable to the glyburide bioavailability obtained vvith . a separate administration of metformin and glyburide.

26. The use of the pharmaceutical composition as defined in Claim 25 vvhere in the combination of metformin and glyburide the particle size distribution of the glyburide is such that at most 10% of the pārticies are less than 2 pm and at most 10% of the pārticies are greater than 60μτη.

27. The use of the pharmaceutical composition as defined in Claim 25 vvherein the glyburide has a particle size distribution such that at most 10% are less than 3 pm and at most 10% are greater than 40 pm.

28. The use of the pharmaceutical composition as defined in Claim 25 vvherein the glyburide has a particle size distribution such that at most 25% are less than 11 um and at most 25% are greater than 46 pm.

29. The use of the pharmaceutical composition as defined in Claim 25 vvherein 50% of the glyburide patients are less than 23 um.

30. The use of the pharmaceutical composition as defined in Claim 25 vvherein the glyburide has a particle size distribution of about 25% undersize value not more than 6 μτη, about 50% undersize value 7 to 10 um and about 75% undersize value not more than 23 um.

31. The use of the pharmaceutical composition as defined in Claim 25 vvherein the starting daily dosage is 250 mg metformin/l.25 mg glyburide or 500 mg metformin/2.5 mg glyburide.

32. The use of the pharmaceutical composition as defined in Claim 3 vvherein the substantially reduced side effects are hypoglycemia and/or gastrointestinal side effects vvhich are diarrhea, nausea/vomiting and/or abdominal pain.

33. The use of the pharmaceutical composition as defined in Claim 32 vvherein the incidence of hypoglycemia in drug naive patients resulting from use of the lovv dose metformin-glyburide combination is 1/3 or less than in patients treated vvith double the metformin-glyburide present in the lovv dose metformin-glyburide.

34. The use of the pharmaceutical composition as defined in Claim 32 vvherein the incidence of gastrointestinal side effects in drug naive patients resulting from use of the lovv dose metformin-glyburide combination is 20% less than in patients treated vvith tvvice the amount of each of the metformin-glyburide present in the lovv dose metformin-glyburide.

35. Use of the pharmaceutical composition for lovvering blood glucose in a hyperglycemic human patient, vvhich comprises administering to a drug naive human patient in need of treatment, as first line therapy, a therapeutically effective amount of a lovv dose pharmaceutical formulation as defined in Claim 1.

36. Use of the pharmaceutical composition for decreasing insulin resistance and/or decreasing hemoglobinAic and/or inereasing postprandial insulin Ievels and/or decreasing post-prandial glucose excursion, in a human patient, which comprises administering to a drug naive human patient in need of treatment as first line therapy a pharmaceutical formulation as defined in