Pharmaceutical composition comprising a combination of metformin and glibenclamide

Description of the invention

The present invention relates to the use of metformin and glyburide for the preparation of a pharmaceutical composition containing a low dose composition of these substances. The prepared composition finds use in the treatment of type 2 diabetes mellitus in drug naïve patients. The low dose formulation has at least substantially equivalent efficacy in the treatment of type 2 diabetes compared to formulations containing higher doses of metformin and / or glyburide, but has significantly reduced side effects.

The biguanide antihyperglycemic agent metformin as disclosed in US Pat. US Am. No. US-3,174,901 is currently sold in St. US Am. in the form of the hydrochloride salt (Glucophage®, Bristol-Myers Squibb Company).

Diagnosis and management of type 2 diabetes are rapidly changing. It is now widely accepted that the type of blood glucose control is important. Currently, the goal of diabetes treatment is to achieve and maintain blood glucose levels as close to normal as possible in order to prevent progressive microvascular and macrovascular complications due to elevated blood glucose levels. The diagnosis of diabetes has changed significantly, as evidenced by the new ADA guidelines for diagnosis and classification. Until recently, oral therapeutic options for treating type 2 diabetes were very limited. Prior to 1995, sulfonylureas were the primary oral antidiabetic agents in St. US Am. Sulfonylureas act on one mechanism for elevated blood glucose levels by increasing insulin secretion from the beta cell. Since 1995, three new classes of agents for reducing elevated blood glucose levels have been added to the antidiabetic arsenal of medical tools. Metformin, a biguanide, acts on additional mechanisms of elevated blood glucose levels by inhibiting hepatic glucose production and increasing peripheral glucose uptake, thereby reducing insulin resistance; thiazolidinediones such as troglitazone, rosiglitazone and pioglitazone reduce peripheral insulin resistance; and alpha-glucosidase inhibitors such as acarbose and miglitol help to control postprandial glucose spikes by delaying the absorption of carbohydrates from the diet. All of these agents are indicated for monotherapy and some are indicated for use in combination therapy, generally when monotherapy is considered insufficient.

In 1995, metformin was added to sulfonylurea therapy in patients who had not achieved blood glucose control on sulfonylurea monotherapy, and the two agents were found to significantly affect blood glucose control or lower hemoglobin-A1c. The different mechanisms of action to address elevated blood glucose levels are complementary making administration of the combination beneficial and a rational method of treatment. Prescription data reveal that approximately 60% of metformin is used in combination with a sulfonylurea.

Examples of combinations of metformin and glyburide sulfonylurea (also known as glibenclamide) are disclosed in the following references:

(1) Application WO 97/17975 published May 22, 1997 (Barelli et al., Istituto Gentili SPA) and US Patent 5,922,769 to Barelli et al. (below as Barelli et al.) discloses the combination of glibenclamide and metformin in a weight ratio of 1: 100 to allow a daily dosage of 15 mg glibenclamide and 1500 mg metformin, used in the onset of diabetes in the most severe cases, especially in cases of secondary treatment failure with the combination of glibenclamide metformin hydrochloride in a weight ratio greater than 1: 100.

(2) Vigneri et al., Treatment of NIDDM Patients with 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 the use of combination 1 , 5 g / day metformin and 15 mg / day glyburide for the treatment of NIDDM patients with secondary treatment failure 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, Aug.11, 1979, 154-156, discloses treatment of diabetic patients who received between 10 mg and 20 mg per day of glibenclamide with 500 mg of metformin twice daily. Higginbotham et al. state that in some diabetics who are not adequately controlled by sulfonylurea treatment, a significant improvement in diabetes control may be achieved by additionally administering metformin at a low dose of 500 mg twice daily.

PL 199 278 B1 (4) US patent application no. US Am. 09/353141, filed Jul 14, 1999 (based on European Application No. 98401781.4, filed Jul 15, 1998) discloses formulations containing metformin and glyburide in which the glyburide has a specific particle size as described below.

References that disclose metformin and glipizide combinations include the following:

(1) Combination of glipizide / metformin treatment reduces Iow density lipoprotein binding to arterial proteglycans in DIDDM, Edwards et al., Diabetes, (46, Suplement 1, 45A, 1997).

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

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

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

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

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

(7) Orał Antidiabetic Combination Therapy with 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 with a combination of glipizide and metformin, Ferlito et al., PROGR. MED. (Roma) 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 combinations of metformin and a second antidiabetic agent are disclosed in the following references.

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

(2) Application WO 98/57634 (SKB) discloses a method of treating diabetes mellitus using a combination of a thiazolidenedione and metformin. The thiazolidenedione can be troglitazone, ciglitazone, pioglitazone or englitazone, and can be used in daily doses of 2 to 12 mg, while metformin can be used in daily doses of up to 3,000 mg per day, in 500 mg (e.g. 2 up to 3 times a day) or 850 mg (2 times a day) unit doses, one example of a metformin dosage is the administration of 500 mg 5 times a day.

(3) EP 0749751A2 (Takeda) discloses a combination of a thiazolidenedione insulin sensitiser (such as pioglitazone) and metformin.

None of the above references suggest the use of antidiabetic combinations containing metformin as first approach in drug naïve patients.

Several fixed combination metformin and glyburide (glibenclamide) combinations are sold outside of St. US Am. These include (1) combinations of 400 mg metformin / 2.5 mg glibenclamide (Boehringer, Bi-Euglucon in Argentina and Bi-Euglicon M in Italy; Guidotti / Menarini, Glibomet in the Dominican Republic and Italy; HMR, Normell in Greece and Hoechst, Suguan-M in Italy; Sun Pharma, Glucored in India; Monsanto (Searle), Benclamet in India; Guidotti, Glibomet in Lebanon; Berlin Chemie / Menarini, Glibomet in Slovakia, and Roche, Bi-Euglucon in Uruguay); (2) combinations of 500 mg metformin / 5 mg glibenclamide (Sun Pharma, Glucored in India; Monsanto (Searle), Benclamet in India, USV, Duotrol in India, and Lakeside (Roche), Bi-Euglucon M5 in Mexico); (3) combinations of 500 mg metformin / 2.5 mg glibenclamide (Molteni, Glucomide in Italy, Lakeside (Roche), Bi-Euglucon M in Mexico and Szabo, Dublex in Uruguay); and (4) 1 g metformin / 5 mg glibenclamide (Silans, Sil-Norboral in Mexico).

The designation for Glucophage® (metformin from Bristol-Myers Squibb), in Physicians' Desk Reference 1999, in the section "Indications and Use" indicates that Glucophage can be used in conjunction with a sulfonylurea. In addition, the "Dosage and Administration" section of Concominant Glucophage and Orał Sulfonylurea Therapy states that "If patients do not respond after four weeks of administration of the maximum dose of Glucophage monotherapy, gradual addition of oral doses of sulfonylurea should be considered while continuing with the maximum dose of Glucophage ... With the combined treatment of Glucophase and sulfonylurea4

By adjusting the dose of each drug, the desired blood glucose control can be achieved. However, efforts 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 followed by increments of 500 mg a week or 850 mg every 2 weeks up to a total of 2,000 mg per day.

The package insert 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 sulfonylurea resistance [i.e. in the second or third treatment approach] and that a dose of 1/2 tablet per day is used, increasing by 1/2 tablet according to changes in blood glucose up to 4 tablets per day.

The package insert 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 to treat type 2 diabetes that is not controlled or it cannot be controlled only by diet or diet and the sulfonylurea [i.e. in the first therapeutic approach of the second therapeutic approach].

The leaflets inside the Glibomet packs in Italy indicate a daily dosage of 2 tablets, i.e. 800 mg metformin and 5 mg glibenclamide, up to 2 g metformin. The package insert of Glucomide in Italy indicates a daily dosage of 2 capsules, i.e. 1000 mg of metformin, up to 2 g of metformin, and 5 mg of glibenclamide.

The invention relates to the use of metformin and glyburide for the preparation of a pharmaceutical composition containing a low dose of a combination of metformin and glyburide, which contains 250 mg metformin / 1.25 mg glyburide, the glyburide particle size distribution being such that at most

10% of the particles are less than 2 µm and at most 10% of the particles are greater than 60 µm for the treatment of drug naïve type 2 diabetes mellitus, where metformin is administered at a daily dose of less than 800 mg.

Preferably, a low dose combination of metformin and glyburide is used in the use of the invention that is at least as effective in treating diabetes in drug naïve patients but exhibits significantly reduced side effects, as is the combination of metformin and glyburide used in significantly higher daily doses prescribed in commonly accepted medical practice for the first therapeutic approach in the treatment of diabetes mellitus.

Preferably, the use according to the invention uses the starting daily amount of metformin that is only about one fifth of the starting daily amount of metformin used in conventional medical practice in the first line of therapy for the treatment of diabetes mellitus.

Preferably, in the use according to the invention, a maintenance daily dose of metformin is used which is even equivalent to that used in conventional medical practice in the first or second therapeutic approach for the treatment of diabetes.

Preferably, in the practice of the invention, a starting daily dose of glyburide is used that is only about one fifth of the starting daily dose of glyburide used in conventional medical practice for the first line of therapy for the treatment of diabetes mellitus.

Preferably, in the use of the invention, a maintenance daily dose of glyburide is used which is even equivalent to that used in conventional medical practice for the first approach or second treatment for the treatment of diabetes mellitus.

Preferably, in the use of the invention, a combination of low-dose metformin and glyburide formulated as a single dosage form is used.

Preferably, in the use according to the invention, metformin and glyburide are used in a weight ratio of 200: 1 to each other.

Preferably, in the use of the invention, metformin is used in an amount ranging from about 250 to about 500 mg, and glyburide is administered in an amount ranging from about 1.25 to about 5 mg.

Preferably, in the use according to the invention, a metformin / glyburide dose of 250 mg / 1.25 mg is administered once a day or twice a day.

Preferably, in the use according to the invention, a metformin / glyburide dose of 250 mg / 1.25 mg is used in patients with a baseline HbA1c> 9% or a fasting glucose level> 200 mg / dL twice daily, increasing the dose by 250 mg as necessary. / 1.25 mg every 2 weeks, up to the minimum effective daily dose necessary to obtain adequate blood glucose control.

Preferably, in the use according to the invention, metformin is used in the daily dose used in commonly accepted medical practice for the first approach or second treatment for the treatment of diabetes mellitus.

Preferably, in the use according to the invention, the glyburide is used in the daily dose used in common medical practice in the first or second therapeutic approach for the treatment of diabetes mellitus.

Preferably, a low dose combination of 250 mg metformin and 1.25 mg glyburide is used in the use of the invention, which is at least substantially as effective as a formulation containing 500 mg metformin and 2.5 mg glyburide in treating diabetes by reducing hemoglobin A1c. , reducing insulin resistance, increasing insulin levels after a meal, and / or reducing the glucose spike after a meal, while the harmful side effects of hypoglycaemia and gastrointestinal side effects are significantly reduced.

Preferably, in the use according to the invention, metformin and glyburide are administered at a starting daily dose of 250 mg metformin and 1.25 mg glyburide.

Preferably, in the use according to the invention, metformin and glyburide are administered at a starting daily dose of 250 mg metformin and 1.25 mg glyburide twice daily, or 500 mg metformin and 2.5 mg glyburide once daily.

Preferably, in the use according to the invention, metformin and glyburide are administered at a starting daily dose of 500 mg metformin and 5 mg glyburide.

Preferably, in the use of the invention, the glyburide is in such a form that the bioavailability of the glyburide is comparable to that of the glyburide obtained with the separate administration of metformin and glyburide.

Preferably, in the use according to the invention, a glyburide with a particle size distribution such that at most 10% is less than 3 µm and at most 10% is greater than 40 µm.

Preferably, in the use according to the invention, a glyburide is used with a particle size distribution such that at most 25% are less than 11 µm and at most 25% are greater than 46 µm.

Preferably, in the use of the invention, 50% of the glyburide particles are less than 23 µm.

Preferably, in the use of the present invention, the glyburide has a particle size distribution such that 25% has an undershot size of not more than 6 µm, about 50% has an undershot size of not more than 7 µm, and about 75% has an undershot size of not more than 23 µm.

Preferably, in the use according to the invention, the combination is administered at a starting daily dose of 250 mg metformin / 1.25 mg glyburide or 500 mg metformin / 2.5 mg glyburide.

Preferably, in the use of the invention, the significantly reduced side effects include hypoglycaemia and / or gastrointestinal side effects of diarrhea, nausea / vomiting and / or abdominal pain.

Preferably, in the use of the invention, the incidence of hypoglycaemia in naïve patients with a low dose metformin-glyburide combination is 1/3 or less than in patients treated with a double dose of metformin-glyburide of the low dose metformin-glyburide combination.

Advantageously, in the use of the invention, the occurrence of gastrointestinal side effects in naïve patients with a low dose metformin-glyburide combination is 20% lower than in patients treated with double the amount of metformin and glyburide of the metformin-glyburide combination. low dose.

Preferably, the use of metformin and glyburide for the preparation of a low dose pharmaceutical composition which comprises 250 mg metformin / 1.25 mg glyburide, wherein the glyburide particle size distribution is such that at most 10% of the particles are less than 2 µm and at most 10% of the particles are above 60 µm in size for the manufacture of a drug for lowering blood glucose in a hyperglycemic human patient who is naïve to treatment. as a first therapeutic approach, with metformin administered in a daily dose of less than 800 mg.

Preferably, the use of metformin and glyburide for the preparation of a pharmaceutical composition containing a low dose of a combination of metformin and glyburide which contains 250 mg metformin / 1.25 mg

Of glyburide, wherein the particle size distribution of the glyburide is such that at most 10% of the particles are less than 2 Pm and at most 10% of the particles are greater than 60 Pm, to reduce insulin resistance and / or reduce hemoglobin A1c and / or increasing postprandial insulin levels and / or reducing postprandial glucose spike in a naïve human patient as a first treatment approach. wherein metformin is administered in a daily dose of less than 800 mg.

It should be understood that a low-dose formulation initially comprises a "small dose of one of the active ingredients of an antidiabetic drug, ie a lower dose than the dose of such drug prescribed in commonly accepted medical practice in the first approach of therapeutic treatment of diabetes mellitus. Thus, the above low dose pharmaceutical formulation contains a low dose of metformin and a low dose of glyburide as described below.

According to the present invention, efficacy in a first approach in treating diabetes in drug naïve patients is achieved by using a low dose pharmaceutical formulation wherein the metformin dose used is one fifth of the initial daily dose prescribed in conventional medical practice for the first approach. therapeutic in the treatment of diabetes, and this dose is as high as 160 mg of metformin per day, up to the maintenance daily dose of metformin used in common medical practice in the first or second treatment of diabetes (which is up to 800 mg of metformin per day). Preferably, the maximum daily dose of metformin is about two-thirds of the maintenance daily dose of metformin used in conventional medical practice in the first line of therapy for the treatment of diabetes mellitus.

In the practice of the invention, the starting daily dose of metformin is only from about 25% to about 60% of the starting daily dose of metformin used in conventional medical practice in the first line of treatment for diabetes treatment (i.e. the starting daily dose of 160 to 500 mg metformin, preferably 250 or 500 mg of metformin).

The low dose pharmaceutical preparation is preferably used in the first treatment approach at a daily dose 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, with the starting dose being from about 160 mg. to about 500 mg per day, preferably 250 mg per day or 500 mg per day, in single or divided doses in the amount of one to six tablets per day.

The glyburide is used at a starting daily dose of only about one fifth of the starting daily dose of glyburide used in conventional medical practice in first approach or second treatment for diabetes treatment (i.e. minimum daily starting dose of only 0.5 mg). When necessary, the starting dose of glyburide can be gradually increased up to the maintenance daily dose of glyburide as used in conventional medical practice for first or second treatment of diabetes (ie, up to a maximum of 15 mg of glyburide per day). Preferably, the maximum daily dose of glyburide is about two-thirds of the daily maintenance amount of glyburide as used in conventional medical practice for the first line of treatment for the treatment of diabetes (ie, up to a maximum of 2.5 to 10 mg of glyburide per day).

The glyburide is preferably used in a starting daily dose of only about 20% to about 60% of the starting daily dose of glyburide used in conventional medical practice in the first line of treatment for diabetes treatment (i.e. the minimum starting dose is only 0.5 mg to 3.5 mg). mg, more preferably 1.25 mg or 2.5 mg). The glyburide dose can be gradually increased up to the maintenance daily dose of about 40 to about 100%, preferably from about 40 to about 60% of the daily maintenance dose of glyburide used in conventional medical practice in the first line of therapy for diabetes treatment (i.e., maximum daily dose of 2). to 15 mg preferably of a maximum daily dose of 2.5 to 10 mg).

The above daily dose of glyburide may be administered in single or divided doses of one to four tablets per day.

Metformin and glyburide can be combined into a single tablet, which can be used in single or divided doses from one to four times daily.

As used herein, the term "low dose combination," low dose formulation or "low dose pharmaceutical formulation" refers to a formulation which starts with a daily dose of 250 mg metformin and 1.25 mg glyburide.

PL 199 278 B1

So far, combinations of metformin and glyburide have been used normally, with a few exceptions, as a second therapeutic approach in the treatment of type 2 diabetes. to 4 tablets and containing 400 to 500 mg of metformin and 2 to 2.5 mg of glyburide, or approximately 1200 to 2000 mg of metformin and 6 to 10 mg of glyburide, daily.

As indicated above for Glibomet and Glucomide (fixed combination metformin and glyburide combinations) sold in Italy, these combinations can be used as a first treatment approach (naive patients) at a daily dose of 800 to 1000 mg to 2 grams of metformin and 5 mg of glibenclamide (glyburide).

The above dosages may be included within the term of those prescribed in common medical practice for the first approach to therapy or the second approach for the treatment of diabetes mellitus. In some refractory cases of diabetes, up to 15 mg of glyburide may be indicated.

As indicated above for Bi-Euglucon M. from Boehringer and Suguan M from Hoechst (fixed combination metformin and glibenclamide combinations) sold in Italy, these combinations are used as a second treatment approach at the starting daily dose for 1/2 tablet equivalent to 200 mg metformin and 1.25 mg glibenclamide. Initial or starting low doses are used to determine if a patient is tolerating these medications. In addition, no first-approach clinical trial results have been disclosed to support the use of such starting doses. The starting dose is gradually increased from 1/2 tablet at the beginning to 4 tablets a day until an effective dose is obtained. Thus, the starting or starting daily dose for 1/2 tablet or 200 mg of metformin and 1.25 mg of glibenclamide is not taken here as "the dose prescribed in common medical practice for the treatment of diabetes mellitus.

It has been surprisingly found that the use of a combination of metformin and glyburide according to the present invention has the following advantages. Low-dose metformin is an insulin sensitiser and reduces insulin resistance in the liver, muscles and pancreas. The low dose metforminaglyburide combination acts as a glucose sensitizer in the pancreas; reduces the toxicity of glucose in the pancreas and improves the work of the pancreas.

Thus, the use of the invention relates to the preparation of a drug naive human patient for the treatment of diabetes, particularly type 2 diabetes, which comprises the step of administering to a drug naive human patient in need of treatment. , as a first therapeutic approach, a low dose pharmaceutical starting material formulation that contains a combination of metformin and glyburide. The initial low dose combination preferably provides at least the same efficacy in treating diabetes in naïve patients as the metformin and glyburide combinations used at the doses (including starting doses) prescribed in common practice in the first approach to treatment of diabetes mellitus, but shows significantly reduced side effects.

The starting daily dose of metformin is only 20% of the starting daily dose of metformin used in conventional medical practice, in the first line of therapeutic treatment of diabetes mellitus, preferably a starting daily dose of from about 160 to about 500 mg.

The starting daily dose of glyburide is only 20% of the starting daily amount of glyburide used in conventional medical practice, in the first line of therapeutic treatment of diabetes mellitus, preferably a starting daily dose of from about 0.625 to about 5 mg.

In addition, the present invention relates to a method of reducing fasting blood glucose, reducing insulin resistance, reducing hemoglobin A1c, increasing postprandial insulin, and / or reducing postprandial glucose spike in a human diabetic patient who includes, as a first therapeutic approach, the step of administering a drug to a human patient, a low dose pharmaceutical preparation according to the invention which comprises a combination of metformin and glyburide.

Practical use of the preferred low dose starting pharmaceutical formulation containing metformin and glyburide for the treatment of diabetes in naïve patients, the efficacy of treating patients, treatment naïve is at least the same and the incidence of side effects (gastrointestinal and hypoglycemia) is unexpectedly substantially and significantly reduced compared to patients on higher daily doses of metformin and glyburide (i.e. the doses prescribed in the commonly used8

In this practice for the treatment of diabetes mellitus). Thus, while efficacy in treating naïve patients as measured by decreasing hemoglobin A1c (HbA1c) from baseline over time, reducing fasting blood glucose (FPG), increasing postprandial insulin and reduction of the postprandial glucose jump (PPG), is in fact the same in the above-described patients with the use of a pharmaceutical preparation with a low dose and much higher daily doses, the incidence of hypoglycaemia and gastrointestinal side effects in naïve patients treated with much higher daily doses is significantly higher than in patients treated with a low-dose pharmaceutical preparation.

A low-dose pharmaceutical preparation consisting of metformin and glyburide is used as initial treatment, i.e. as an adjunct to diet and exercise to improve blood glucose control in patients with type 2 diabetes.

The ADA recommends reducing HbA1c <7% as a treatment target (ADA. Diabetes Care 21 [Supplement 1]: pp. 23-31, 1998), which has the effect of reducing the risk of complications of type 2 diabetes, including coronary heart disease and microvascular complications.

The dosage of the preferred metformin-glyburide combination should be individualized based on both efficacy and tolerability. Preferably it is given with meals and should be started with a low dose and gradually increased. Optimally, response to treatment should be assessed using HbA1c (glycosylated hemoglobin), which is a better indicator of progress in blood glucose control than FPG alone. The therapeutic goal in all patients with type 2 diabetes is to improve blood glucose control, including FPG, postprandial glucose and HbA1c levels, to normal or as close to normal as possible. Patients should be titrated to achieve the ADA HbA1c <7% of the dosing recommendations up to the maximum recommended dose. (ADA. Diabetes Care 21 [Supplement 1]: S23 - S32, 1998).

As initial treatment, the preferred starting dose of the metformin-glyburide combination is 250 / 1.25 mg once daily, given with a meal. For patients with a baseline HbA1c> 9% or a fasting glucose level> 200 mg / dL, the recommended starting dose is preferably 250 / 1.25 mg twice daily in the morning and evening with meals. The dose should preferably be increased by 250 / 1.25 mg every 2 weeks, up to the minimum effective dose necessary to obtain adequate blood glucose control. For patients requiring additional blood glucose control, the 250 mg / 1.25 mg dose may be replaced by 500 / 2.5 mg.

A preferred low dose metformin-glyburide formulation is provided below.

<td>Product identity</td><td>The amount of ingredient in mg per tablet 250 / 1.25 or 500 / 2.5 or 500 / 5.0</td>

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

<td>Metformin hydrochloride</td><td>250.0 or 500.0</td>

<td>Glyburyd</td><td>1.25 or 2.5 or 5</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> 3,0-20</td>

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

<td>Sheath*</td><td> 4,5-12,0</td>

* a commercially available coating composition such as Opadry (Colorcon, UK)

PL 199 278 B1

Particularly preferred low dose metformin-glyburide formulations are as follows:

<td>Product identity</td><td colspan="3">The amount of ingredient, mg per tablet 250 / 1.25 500 / 2.5 500 / 5.0</td>

<td>Ingredient</td><td colspan="3"></td>

<td>Metformin hydrochloride *</td><td> 251,25</td><td> 502,50</td><td> 502,50</td>

<td>Glyburyd</td><td> 1,25</td><td> 2,5</td><td> 5,0</td>

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

<td>Microcrystalline cellulose</td><td> 28,25</td><td> 56,50</td><td> 54,0</td>

<td>Polyvinylpyrrolidone</td><td> 10,0</td><td> 20</td><td> 20</td>

<td>Magnesium stearate</td><td> 2,25</td><td> 4,50</td><td> 4,50</td>

<td>Sheath**</td><td> 6</td><td> 12,0</td><td> 12,0</td>

* contains 99.5% metformin EC1 and 0.5% Mg stearate (by weight) ** a commercially available coating composition such as Opadry (Colorcon, UK)

A low dose pharmaceutical formulation containing a metformin-glyburide combination is preferably formulated as disclosed in US 09/353141 filed July 14, 1999 based on priority European Application No. 98401781.4 filed July 15, 1998.

A preferred low-dose pharmaceutical formulation used in the method of the invention in the form of an oral solid form such as a tablet comprises a metformin-glyburide combination as disclosed in US patent application. US Am. No. 09/353141, filed Jul 14, 1999, and as such contains glyburide which shows a glyburide bioavailability comparable to that obtained when metformin and glyburide are administered separately. This effect is achieved by using a glyburide with a predetermined particle size distribution. Thus, a metformin-glyburide formulation comprises a combination of metformin and glyburide, wherein the glyburide particle size is such that at most 10% of the particles are less than 2 µm and at most 10% of the particles are greater than 60 µm. Preferably, the particle size of the glyburide is such that at most 10% of the particles are less than 3 Pm and at most 10% of the particles are greater than 40 Pm. This specific range of glyburide size can be obtained either by sieving or by pneumatic milling.

In a second embodiment, a low dose solid oral dosage form comprises a combination of metformin and a glyburide wherein the glyburide particle size is such that at most 25% of the particles are less than 11 µm and at most 25% of the particles are greater than 46 µm.

Preferably, 50% of the particles are less than 23 µm in size.

The combination of metformin and glyburide is most preferred when the glyburide has a particle size distribution such that about 25% has an undersize of no more than 6 µm, about 50% is an undersize of no greater than 6 µm, and about 75% has an undersize of no greater than 23 µm .

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

The term "metformin as used herein" refers to metformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride, metformin fumarate (2: 1) and metformin succinate (2: 1) disclosed in US Application Serial No. 09/262526 filed March 4, 1999, hydrobromide, p- chlorophenoxyacetate or pamoate, and other known salts of metformin with mono and dibasic carboxylic acids, including those disclosed in US Patent 3,174,901, all salts being collectively included in the term metformin. Preferably, metformin as used herein is metformin hydrochloride, marketed as Glucophage® (tradename Bristol-Myers Squibb Company).

The term "significantly reduced side effects" as used herein refers to the reduced occurrence of hypoglycemia and gastrointestinal adverse events including diarrhea, nausea / vomiting and / or abdominal pain, using a low-dose pharmaceutical formulation in naïve patients compared to to patients who have been administered the same active substances as in the pharmaceutical preparation according to the invention, but in higher doses.

PL 199 278 B1

The term "at least as effective in treating type 2 diabetes mellitus as used herein refers to the efficacy of a low-dose pharmaceutical formulation in treating naïve patients to reduce and / or maintain hemoglobin A1c (glycosylhemoglobin) at 7% or less. reducing insulin resistance (by increasing insulin levels after a meal) and / or reducing the postprandial glucose excursion (PPG), compared to patients treated with the same active substances as in the pharmaceutical preparation according to the invention, but in higher doses.

The term "postprandial jump" as used herein refers to the difference between the postprandial blood glucose (PPG) and the fasting (FPG) blood glucose.

A low dose pharmaceutical preparation containing metformin in combination with glyburide can be administered orally in the same dosage form or in separate oral dosage forms or by injection.

The combination of metformin and glyburide is believed to produce a greater antihyperglycaemic effect than either drug alone and greater than the combined additive antihyperglycaemic effect of these drugs.

In practicing the invention, a low-dose pharmaceutical formulation or composition is employed containing metformin and glyburide in association with a pharmaceutical excipient or diluent. The low-dose pharmaceutical preparation may be formulated using conventional solid or liquid excipients or diluents and pharmaceutical additives of the type appropriate to the desired mode of administration. The low-dose pharmaceutical preparation can be administered to mammals, including humans, monkeys, dogs and the like, by the oral route, e.g., in the form of tablets, capsules, granules or powder, or it can be administered parenterally in the form of injectable preparations. The dose for drug naïve patients is as described above and may be administered in a single dose or in the form of divided doses 1-4 times daily.

The above dosage forms may also contain the necessary physiologically acceptable carriers, excipients, lubricants, buffers, antibacterials, bulking agents (such as mannitol), antioxidants (ascorbic acid or sodium bisulfite), or the like.

The administered dose should be carefully titrated to the age, weight and condition of the patient, as well as the route of administration, dosage form and regimen, and the desired result.

The combination of metformin or a salt thereof and glyburide can be formulated as separate or, where possible, as a single preparation using conventional formulation methods.

The various formulations of the invention may optionally contain one or more fillers or excipients in an amount ranging from about 0 to about 90% by weight and preferably from 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 in addition to or in place of the fillers in an amount ranging from about 0 to about 35%, and preferably from about 0.5 to about 30%, by weight of the composition. Examples of such binders that are suitable for use herein include polyvinylpyrrolidone (molecular weight from about 5,000 to about 80,000 and preferably about 40,000), lactose, starches such as corn starch, modified corn starch, sugars, gum arabic, etc., and a binder. waxes in a finely powdered form (less than 500 microns), such as carnauba wax, paraffin, spermaceti, polyethylene or microcrystalline wax.

When the composition is to be in the form of a tablet, it will contain one or more tablet lubricants in an amount ranging from about 0.2 to about 8% and 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 etc. Other typical ingredients that may optionally be present include silica based preservatives, stabilizers, anti-adherent or flow improvers, or glidants such as Syloid type silicon dioxide, as well as FD&amp;C dyes.

Tablets may also include a coating layer which may be from 0 to about 15% by weight of the tablet composition. The coating layer that is applied to the outer solid phase containing embedded particles of the inner solid phase may contain any conventional coating formulations and one or more shell formers or binders such as a hydrophilic polymer such as hydroxypropyl methyl cellulose and / or a hydrophobic polymer such as acid esters. methacrylic, neutral polymer, ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, β-pinene polymers, glyceryl esters and wood resins and the like, and one or more plasticizers such as

Triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butyl phthalate, castor oil, etc. Both the tablet core and the coating formulations can contain aluminum pigments to provide color.

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

When a dye is used, it is applied together with the composition of the shell-forming material, plasticizer and solvent.

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

A low dose pharmaceutical formulation in the form of a tablet can be prepared as disclosed in US Patent Application No. US Am. 09/353141, filed July 14, 1999, which includes the stages:

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

b) mixing the granules with a tabletting aid and diluent, and

c) pressing the blend so obtained into tablets.

The mixture used to form the granules includes a granulation binder. The granulating binder is preferably polyvinylpyrrolidone, such as e.g. polyvinylpyrrolidone with a molecular weight of 45,000. Polyvinylpyrrolidone may be used in an amount of 2 to 4% by weight based on the final weight of the tablet.

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

The granules are then mixed with a diluent and tabletting aid. The diluent can be a conventional filler usually used in tablet preparation, such as microcrystalline cellulose. The tabletting aid can be a conventional material such as magnesium stearate.

The tablets thus obtained can then optionally be coated with a hydrophilic cellulose polymer and talc. The hydrophilic cellulose polymer is preferably 2-hydroxypropyl methylcellulose.

Description of the drawings

Figures 1 and 2 are bar graphs that depict the change in hemoglobin A1c (HbA1c) levels for the number of fixed dose metformin / glyburide tablets used in the first approach compared to glyburide and metformin monotherapy alone.

Figures 3, 4 and 5 are bar graphs that depict the change in HbA1c levels over time for the fixed ratio metformin / glyburide combination used in the first approach compared to glyburide and metformin monotherapy.

Figure 6 is a bar graph that shows the change in fasting blood glucose (FPG) for the number of fixed dose metformin / glyburide tablets used in the first approach compared to glyburide and metformin monotherapy.

Figure 7 is a bar graph that shows baseline and postprandial insulin levels for fixed metformin / glyburide combination in first approach compared to glyburide and metformin monotherapy.

Figures 8A and 8B are bar graphs that depict the change in PPG jump at baseline and after 20 weeks of treatment with the fixed metformin / glyburide combination used in the first approach compared to glyburide and metformin monotherapy alone.

Figure 9 is a bar graph that shows hypoglycemic symptoms in patients on fixed metformin / glyburide combinations used in the first approach compared to glyburide and metformin monotherapy.

Figure 10 is a bar graph that shows the frequency of gastrointestinal adverse events in patients on fixed metformin / glyburide combinations used in the first approach compared to glyburide and metformin monotherapy alone.

The following examples illustrate the invention.

Examples 1 to 3

Metformin / glyburide combination tablets were prepared as described below.

PL 199 278 B1

Tablets composition metformin hydrochloride glyburide 250 mg / 1.25 mg, 500 mg / 2.5 mg and 500 mg / 5 mg

<td></td><td>Example 1</td><td>Example 2</td><td>Example 3</td>

<td>Ingredient</td><td colspan="3">Amount per tablet (mg) 250 mg / 1.25 mg 500 mg / 2.5 mg 500 mg / 5 mg</td>

<td>Metformin hydrochloride *</td><td> 251,25</td><td> 502,50</td><td> 502,50</td>

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

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

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

<td>Microcrystalline cellulose</td><td> 28,25</td><td> 56,5</td><td> 54,0</td>

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

<td>Sheath**</td><td> 6</td><td> 12</td><td> 12</td>

* contains 99.5% metformin HCl and 0.5% Mg stearate (by weight) ** a coating based on HPMC is used.

Metformin hydrochloride-glyburide tablets, 250 mg / 1.25 mg, 500 mg / 2.5 mg and 500 mg / 5 mg, were pressed from the same granulate. The lower dose tablet was pressed from half the weight of the metformin hydrochloride-glyburide 500 mg / 2.5 mg tablet. Tablets manufactured for clinical use are coated with a hydroxypropyl methylcellulose (HPMC) coating. The shell had no function, only an aesthetic one. The coating applied to the clinical product was clear.

The manufacturing process for clinical products was as follows:

Croscarmellose sodium and glyburide were suspended together and then mixed with metformin hydrochloride / magnesium stearate (99.5%: 0.5% by weight) in a high shear mixer. The resulting dry blend was granulated in a high shear mixer using an aqueous solution of povidone and dried in a fluid bed dryer at approximately 60 ° C to achieve the specified moisture content, determined by loss of drying. The size of the dried granulate was reduced using screening milling and mixed with microcrystalline cellulose using a tumble mixer. Magnesium stearate was added as a lubricant using a tumble blender to obtain the final extrusion blend.

The resulting blend was pressed into tablets with a target weight based on in-process moisture content determinations on a suitable tablet press. The theoretical tablet weight (based on the benchmark composition without moisture correction) was 300 mg for the amount of 250 mg / 1.25 mg and 600 mg for the amount of 500 / 2.5 mg.

The tablets were coated in a perforated coater using a suitable aqueous coating system based on neutral HPMC until the required amount of coating was applied. A typical amount of coating applied to tablets is 2% by weight.

In vivo evaluations of prototype combination tablet formulations identified a particle size distribution intended for use in a clinical program to achieve comparable bioavailability to Micronase from the combination product. The particle size distribution of any batch of glyburide was described by three cumulative size criteria: 25% undersize, 50% underscore (also known as mass median particle size, MMPS), and 75% underscore. The clinical program consisted of a total of six lots of active ingredient glyburide where 25% had an undersize ranging between 4-7 µm, 50% had an undersize ranging between 8-14 µm and 75% had an undersize ranging between 17-26 µm . All six lots of glyburide were produced by the same supplier, Profarmaco, and four were micronized by Profarmaco. The particle size distributions of the four batches produced are detailed in the table below.

PL 199 278 B1

Particle size data for the lot of glyburide active used in the clinical program

<td rowspan="2">Lot number</td><td colspan="3">Particle sizeA (units are equivalent to the sphere diameters in μιτι)</td>

<td>Under-screen dimension for 25%</td><td>Under-screen dimension for 50%</td><td>Under-screen dimension for 75%</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>

^AND Particle size measured by laser light scattering method, reference to #CRM 8532 method (#SM 248533)

The proposed particle size specification included the three aggregate size criteria described above with a range for an acceptable median mass particle size (50% undersize) and an upper limit for the lower quartile (25% undersieve) and the upper quartile (75% undersieve). The particle size specification established for glyburide was based on the size of the glyburide particles used in bioavailability studies, experiments with various clinical batches, well-defined properties of the size distribution of commercially available glyburide and the precision of the particle size measurement method. The particle size criteria described below ensured the reproducibility of glyburide release and bioavailability from metformin hydrochloride-glyburide tablets.

25% has a screen size of no more than 6 μm

50% has an under-screen size of 7-10 μm

75% of the screen has a screen size of no more than 23 μm

Example 4

A. Summary of 5 Clinical Protocols (1) Purpose

The following study was conducted to compare blood glucose control of 2 doses of different strengths of fixed combination metformin / glyburide (described in Examples 1 and 2) versus placebo in naïve patients with type 2 diabetes. who had inadequate blood glucose control with diet and exercise. The dose strengths of the fixed combination product were evaluated as containing 250 mg metformin with 1.25 mg glyburide and 500 mg metformin with 2.5 mg glyburide. Blood glucose control was assessed using hemoglobin-A1c (HbA1c), the gold standard of progression in blood glucose control. The mean change from baseline in HbA1c over a 20-week treatment period was compared (the same daily dose administered once for 4 weeks, the next 4 weeks of tapering, and the same dose for 12 weeks). The treatment phase was continued for another 12 weeks to assess the durability of the effect.

The contribution of the individual components of the fixed combination product was assessed compared to the short term blood glucose parameters of the combination product and monotherapy after 4 weeks of administration of the same dose once daily. Blood glucose control was achieved with similar levels of hypoglycemia using the fixed dose combination dose compared to sulfonylurea alone or with a trend towards reduced gastrointestinal side effects compared to metformin alone. Blood glucose control was achieved with a trend toward reduced adverse events compared to any of the agents alone. Trends in hypoglycemia, gastrointestinal symptoms, and lactate levels were assessed.

(2) Study population and study sites

Appropriate patients included those naïve or those who had not received oral antihyperglycemic therapy for 2 months prior to classification. From the approximately 100 study sites distributed throughout the US, up to approximately 800 patients were selected. Appropriate patients included both men and women between 30 and 78 years of age with known type 2 diabetes mellitus, a history of impaired glucose tolerance or impaired fasting glucose levels who showed insufficient blood glucose control through diet and exercise.

(3) Study Design and Duration

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

(4) Endpoint measurements

Analysis of the endpoint measurements for Periods B and C was performed after all data from the 32-week randomized treatment period had been collected.

The primary efficacy endpoint parameter was the change from baseline in HbA1c of the two combination therapies versus placebo after 20 weeks of randomized treatment.

Secondary endpoints included the following:

The incidence of adverse events, especially hypoglycaemia and gastrointestinal side effects, was compared among treatment groups after 20 and 32 weeks of randomized treatment.

The number and proportion of patients showing a therapeutic glucose response were assessed among treatment groups following 20 and 32 weeks of randomized treatment.

Fasting and 2-hour postprandial glucose and insulin reductions were assessed among treatment groups following 20 and 32 weeks of randomized treatment.

B. Rationale

Metformin and a sulfonylurea such as glyburide are a known and effective combination in the treatment of type 2 diabetes. These two drugs showed a synergistic glucose lowering effect when used in combination. Either of these drugs can be used alone as a monotherapy in the first approach. They can also be used in combination with each other if monotherapy with either of them is insufficient. Currently, there are no data available on the use of low dose combination therapy in first line treatment.

Treatment with the fixed dose combination tablet was expected to improve blood glucose control as first approach in type 2 diabetic patients with insufficient diet and exercise control. Blood glucose control was expected to be achieved at lower dosages than monotherapy, with comparable or less potential side effects of the individual agents, and ease of administration.

This randomized, double-blind, placebo-controlled study in type 2 diabetic patients who have insufficient blood glucose control with diet and exercise tested the following hypotheses:

1. Administration of a fixed dose combination metformin / glyburide product for 20 weeks (the same dose once daily for 4 weeks in Period B and for 16 weeks of treatment in Period C) in patients with type 2 diabetes mellitus who have inadequate blood glucose control with diet and exercise will significantly reduce HbA1c compared with placebo.

2. The administration of a fixed dose combination of metformin / glyburide for 32 weeks in patients with type 2 diabetes mellitus who have inadequate blood glucose control with diet and exercise will be well tolerated.

C. Test Guideline (1) Primary

A comparison, after 20 weeks of oral administration, of the effect of 2 doses of different strengths (Examples 1 and 2) of a fixed dose combination metformin / glyburide tablet that was administered gradually to control blood glucose on the reduction in HbA1c relative to placebo.

(2) Secondary (which included the following)

1. Assessment of safety and tolerability among treatment groups after 20 and 32 weeks of randomized treatment. Blood glucose control can be achieved to a similar level in hypoglycemia with the fixed dose combination compared to sulfonylurea alone or reduced gastrointestinal side effects compared to metformin alone.

2. Assessment at 20 weeks and assessment at 32 weeks of the proportion of patients with an oral blood glucose control therapeutic response for each metformin / glyburide combination regimen compared to the therapeutic response achieved with the metformin monotherapy, glyburide monotherapy and placebo regimens. The therapeutic response for plasma glucose levels is defined as FPG &lt;126 mg / dL (based on current ADA guidelines for FPG). The therapeutic response for HbA1c is defined as HbA1c &lt;7%.

3. Assessment at 20 weeks and assessment at 32 weeks of reduction in fasting glucose and glucose and insulin levels 2 hours postprandial after oral administration of each fixed combination metformin / glyburide regimen compared to a reduction in fasting glucose and glucose and insulin levels 2 hours after meals obtained with metformin monotherapy, glyburide monotherapy and placebo.

4. Assessment of the sustained reduction in HbA1c levels after 32 weeks of dosing with fixed combination metformin / glyburide.

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

D. Study plan

This was a multicentre, randomized, five-group, parallel-group, double-blind, placebo-controlled study of fixed dose combination metformin / glyburide antihyperglycaemic activity in first line treatment in type 2 diabetic patients with insufficient glucose control. in the blood (HbA1c &lt;7%) through diet and exercise. Patients included naïve or naïve to oral antihyperglycaemic therapy for 2 months prior to classification. From the approximately 100 study sites, a maximum of approximately 800 patients with type 2 diabetes mellitus who had insufficient blood glucose control defined as an HbA1c of between 7-11% with diet and exercise were selected. The minimum number of patients required to achieve the primary endpoint was a total of 500 or 100 patients per group. However, selection continued for up to 6 months to create groups of up to 150 patients, providing additional safety data. The plan covered the following 3 periods:

(1) Period A - two weeks - diet and placebo

Introductory phase

This initial phase included dietary recommendations for a low calorie, weight-maintaining ADA balanced diet for diabetics or a balanced diet of approximately 55% carbohydrate, 20% protein and 25% fat.

The tolerance of repeated administration of capsules and tablets was assessed with placebo. Home use glucometers were distributed along with the instruction manual.

(2) Period B - four weeks - once daily double-blind administration

Steady dose phase

Period B began a randomized, double-blind, parallel quadruplet treatment phase. Appropriate patients were randomized into 1 of 5 study groups that included placebo, glyburide monotherapy, metformin monotherapy, and two different strengths of fixed combination metformin / glyburide.

(Examples 1 and 2). Patients were dosed once daily for a 4-week period so that the contribution of the individual components of the combination product could be assessed by short term blood glucose parameters.

This 4-week, once-daily dosing phase illustrated the contribution of the individual components of the fixed combination product using short term blood glucose parameters. Blood glucose control was assessed with fructosamine and under fasting conditions.

(3) Period C - 28 weeks - Double-blind dose escalation and steady-state phase

Period C was a continuation of the randomized double-blind treatment phase. Patients were gradually titrated to control their blood glucose levels for the first four weeks and thereafter the dose was maintained at treatment levels for 24 weeks. Primary endpoint analysis, change in HbA1c from baseline for the two combination therapies (Examples 1 and 2) relative to placebo, was assessed at week 16 of Period C, ie after 20 weeks of randomized double-blind treatment. This was done at this time as it was suitable for stabilization of HbA1c and for safety reasons as it was expected that a large number of placebo treated patients might have to discontinue the randomized trial of the drug due to insufficient blood glucose control with prolongation16

The duration of treatment. Patients who did not discontinue the randomized study of the drug due to lack of efficacy were kept at the same doses for a total of 24 weeks to assess the durability of the effect and to gather additional safety and tolerability data. The study remained classified, and those patients who discontinued the randomized study of the drug due to ineffectiveness were able to enter the long-term, open-label treatment phase with the fixed combination product.

This 28-week phase initially consisted of a 4-week dose tapering phase to improve blood glucose control followed by a 24-week steady-dose phase. Primary endpoint analysis was assessed at week 16 of Period C. Patients were assessed for discontinuation of the randomized drug study due to lack of blood glucose control from visit C1 through to C85. Patients were assessed for ineffectiveness at visit C113 and all subsequent visits until the end of the randomized treatment. The evaluation of the randomized study of the drug remained classified. Patients who remained in the randomized study of the drug then progressed to the steady-state dose phase for a total of 28 weeks in order to be able to assess the durability of the effect and gather additional safety and tolerability data. Patients were assessed for drug discontinuation due to lack of blood glucose control at or after Visit C1 (Week 0, Period C).

Dosage

The study drugs in this study were defined as placebo, glyburide, metformin, metformin / glyburide 250 / 1.25 mg, and metformin / glyburide 500 / 2.5 mg. For the sake of confidentiality, this study was conducted according to a quadruple secret design. Subjects meeting the inclusion criteria, but not any of the exclusion criteria, and meeting the blood glucose criteria for Period A were eligible for enrollment through Period A.

Period A:

This period was a single-blind, placebo-controlled trial allowing the testing of a patient's tolerance to repeated capsule and tablet intake in addition to a compliance assessment with a quadruple design study. Patients received kits containing four placebo bottles appropriate for study drug.

Week 0 (Visit A1) - Patients were instructed to take 1 capsule or tablet from each bottle with their first morning meal.

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

Period B:

Following completion of the single-blind lead-in phase (Period A), enrolled patients began treatment in the randomized, double-blind phase (Period B). At visit A15 / B1, patients were randomized to dosing once daily with breakfast of placebo, 2.5 mg glyburide, 500 mg metformin, metformin / glyburide 250 / 1.25 mg, or metformin / glyburide 500 / 2.5 mg. The once daily doses remained the same for a total of 4 weeks.

Period C:

Following completion of the 4-week dose titration phase once daily (Period B), the same randomized treatment was continued for patients in the 28-week titration / steady-state phase (Period C). Study medication was titrated at visits C1, C15, and C29. The drug was administered with the first morning meal and the evening meal. Potential maximum doses achieved were glyburide 10 mg, metformin 2000 mg, metformin / glyburide 1000/5 mg, metformin / glyburide 2000/10 mg. Following the 4-week tapering period in Period C, patients continued treatment at the constant dose of study drug for the remainder of Period C.

Immediately after obtaining adequate blood glucose control or the maximum dose, the study of the drug was not extended, but only shortened in the event of documented hypoglycaemia.

Results

The results obtained from the above studies indicate that the low dose metformin-glyburide formulation (250 / 1.25) of the invention provides blood glucose control at least substantially equivalent to the high dose metformin-glyburide formulation (500 / 2.5). what they prove:

(1) a therapeutic response for hemoglobin A1c, namely a decrease in HbA1c levels to less than 7% (from the mean baseline 8.2%) at week 20 (Figures 1, 2 and 3) at weeks 20 and 32 and on final visit (Figs. 4 and 5) (2) therapeutic fasting blood glucose (FPG) response, namely reduction of FPG to below 126 mg / dL after 20 weeks (from baseline by approximately 175 mg / dL) ( as shown in Fig. 6) (3) therapeutic response to postprandial insulin levels, namely increasing the postprandial insulin level by 19-25 uu / ml (international micro-units / ml) (Fig. 7) (4) therapeutic response to postprandial glucose spike (PPG) ) (i.e. difference between postprandial and fasting plasma glucose), namely a reduction in the postprandial glucose jump at week 20 by 17.7 for the 500 / 2.5 mg combination and 20.8 for the 250 / 1.25 mg combination versus 15 , 2 for metformin, 6.8 for glyburide. (Figures 8A and 8B).

At the same time, the above efficacy results using the low dose formulation of the invention (Example 1) were obtained with reduced incidence of side effects (Figures 9 and 10).

As can be seen in Fig. 9, the occurrence of hypoglycemia with the low-dose formulation of the invention (Example 1) is about 1/3 lower than that with the high-dose formulation of the present invention (Example 2) used in common medical practice for the treatment of diabetes. .

As can be seen in Fig. 10, the occurrence of gastrointestinal side effects with the low-dose formulation of the invention (Example 1) is 20% lower than with the high-dose formulation (Example 2) used in common medical practice for the treatment of diabetes.

The above results are discussed below.

Discussion of the results

Progress in clinical type 2 diabetes requires time and the presence of many physiological defects that occur before diagnosis is made in most diabetic patients. Oral therapeutic options for treating type 2 diabetes, until a few years ago, were very limited. Moreover, it can be expected that as the disease continues to progress over time, all oral antihyperglycemic therapies will become less effective, leading to insufficient control of the patient's blood glucose.

The traditional indication for combination therapy is the second approach when initial treatment with a single agent is judged to be ineffective, which is called "primary treatment failure, or after initially effective measures have become ineffective in maintaining glucose control, what we call" secondary. treatment failure. Switching from one ineffective monotherapy to an alternative monotherapy has not been proven to be effective in achieving blood glucose control; only the addition of a second agent with a different mechanism of action has been shown to achieve better blood glucose control. Knowing that the combination of insulin resistance and relative insulin secretion deficiency is the pathophysiological basis of type 2 diabetes, it is expected that combinations of agents will have greater therapeutic potential. Thus, both clinical studies and pathophysiological evidence justify the use of combination therapy earlier in the disease process.

While the fixed combination of metformin and glyburide is not a new concept and, as discussed above, various forms are available outside the US in first and second treatment approaches, the use of low or moderate dose combination therapy as the first therapeutic approach for treatment in naïve patients have never been studied in large, controlled clinical trials. Treatment leading to a constant blood glucose, HbA1c &lt;7% as recommended by the ADA, is the goal of any antihyperglycaemic therapy. However, depending on the duration of diabetes and the progression of the disease, a single agent may not provide the efficacy necessary to achieve this goal even in recently diagnosed patients. The data presented in this report prove that the fixed-dose, low-dose combination metformin / glyburide product is safe and provides the effective antihyperglycaemic activity necessary to achieve the blood glucose recommended by the ADA in most naïve patients.

As a first approach, a single formulation of a fixed combination metformin / glyburide 200: 1 combination metformin / glyburide was evaluated using two different strengths, a low dose (metformin / glyburide 250 / 1.25 mg) and a medium dose (metformin / glyburide 500 / 2.5 mg).

PL 199 278 B1

The two dose strengths of the fixed combination metformin / glyburide product were compared in a double-blind study to placebo, glyburide monotherapy and metformin monotherapy. The mean final doses achieved in each treatment group were approximately 5.3 mg glyburide, 1,307 mg metformin, 557 / 2.78 mg for the low dose (250 / 1.25 mg) fixed combination metformin / glyburide and 818/4. 1 mg for the medium dose (500 / 2.5 mg) of the fixed combination. Using fixed combination metformin / glyburide treatment as the first treatment approach resulted in statistically significant improvements in blood glucose control compared to metformin, glyburide or placebo. The temporary open label treatment data confirmed the clinical utility of the established combination therapy in a more "blood glucose heterogeneous" patient population and over a longer period of time.

Security

Two dose strengths of metformin / glyburide were evaluated as a first treatment approach; low dose (250 / 1.25 mg) and medium dose (500 / 2.5 mg) compared to placebo, glyburide and metformin. In the double-blind phase of this study, diarrhea was the most common adverse event (AE) in those patients who remained on either monotherapy or combination therapy with metformin. However, the incidence of GI AE was lower in the low dose fixed combination group than in the metformin monotherapy group (as seen in Figure 10). Discontinuation due to AE was also the lowest in the low dose fixed combination group compared to any other active treatment. Discontinuation of the study due to lack of blood glucose control was lowest in both fixed combination groups, and severe hypoglycaemia was not observed in this study. The frequency of patient reporting of hypoglycemia was highest in the fixed dose medium dose combination treatment group, while the low dose group showed a lower incidence than glyburide monotherapy (Fig. 9). Mild increases in lactate levels were seen in all metformin groups, but there were no cases of lactic acidosis in this study.

In the open label phase, patients were eligible directly if they did not meet blood glucose criteria for entry into the double-blind study. Patients could also enter the open label phase if they prematurely discontinued the double-blind phase due to lack of blood glucose control, or after completion of the double-blind phase. In the open label phase, the AE profile was similar to that observed in the double-blind phase of the study, with AE being the most common in the same body systems. The low dose combination group again demonstrated a favorable overall safety profile compared to the medium dose group.

In both recently diagnosed patients and in insufficiently controlled patients, the overall pattern of safety and tolerability observed in the double-blind study was consistent with that expected from clinical trials with metformin and glyburide. No new or unexpected events or abnormalities have been observed in this clinical program. Interim analyzes of long-term open-label trials confirmed the favorable safety profile observed in the short-term study phase. In particular, the low dose fixed combination showed a favorable safety / tolerability profile when compared to the other regimens used in this program.

Effectiveness

The double-blind first-approach study showed a statistically significant mean reduction in hemoglobin A1c (HbA1c) of 1.3% compared to placebo for both fixed combination treatment groups and a mean reduction from baseline of approximately 1.5%. While all active treatment groups achieved acceptable blood glucose control, higher mean reductions in HbA1c were achieved for both treatment groups on the fixed combination treatment groups compared to metformin and glyburide treatments. Persistence of the antihyperglycaemic effect was observed in all active treatment groups (glyburide, metformin, metformin / glyburide 250 / 1.25 mg, metformin / glyburide 500 / 2.5 mg) as evidenced by maintenance of mean HbA1c levels at week 20 (6.64 %, 6.79%, 6.68%, 6.44%) at week 32 (6.78%, 6.96%, 6.87%, 6.68%) of double-blind treatment below therapeutic target 7 % (Figs. 3 and 4).

Temporary data from an open-label first approach show that for directly eligible patients, the mean HbA1c at baseline was 10.6% and for a subgroup of patients with available data, a mean 3.5% reduction in HbA1c was achieved with mean HbA1c 7.1% for 26 weeks. Of the patients directly eligible for open-label treatment, 87% received the mean fixed dose combination of 500 / 2.5 mg as initial treatment and during interim follow-up, the mean fixed dose combination dose was 1569 / 7.85 mg metformin / glyburide. For patients with available open-label data who completed the double-blind treatment phase and entered the open-label treatment phase, the mean HbA1c at baseline was 8.32%. For all patients who reached the 13th week of treatment, there was a mean reduction of 1.76% in HbA1c with a mean HbA1c of 6.56%. Of the patients who completed the double-blind treatment phase and entered the open-label treatment phase, 78% received the fixed low dose combination (250 / 1.25 mg) and 22% received the medium dose (500 / 2.5 mg) as an initial treatment. The mean dose of the fixed combination therapy metformin / glyburide was 696 / 3.48 mg.

There were no clinically meaningful patterns of greater or lesser effect in any subgroups of the population (age, gender, race) on the HbA1c response from baseline in any double-blind study with fixed combination metformin / glyburide in first line treatment.

This clinical program also assessed fasting blood glucose as a parameter of short-term blood glucose control. The FPG results in the double-blind study were consistent with the HbA1c results. The first approach resulted in statistically and clinically significant greater mean reductions in FPG for both treatment groups on the fixed combination treatment compared to placebo and metformin (Fig. 6). An early response to treatment with fixed combination combination was observed; the differences among the treatment groups were evident through 2 weeks of double-blind treatment, while patients were still undergoing the initial dose titration and only receiving one-second of the potential maximum dose. This early response at one-half of the maximum dose in the monotherapy insensitive patient population outweighs the benefit of combination therapy for the patient and using combination therapy earlier in the disease process.

Hemoglobin A1c is the dominant standard of measure of overall blood glucose control and is a blood glucose marker known to be associated with long-term complications. Although fasting blood glucose, the current standard in the diagnosis of diabetes, is a faster, more convenient marker, it does not provide an optimal assessment of 24-hour blood glucose control. It has been shown and intuitively understood that non-fasting blood glucose is a better marker of diabetic control than FPG in type 2 diabetes; it also correlates better with HbA1c. Elevated postprandial blood glucose is an early marker of the metabolic defects found in type 2 diabetes and contributes to beta cell dysfunction. An important association has been demonstrated between postprandial glucose levels and cardiovascular disease. If normal blood glucose is the goal of preventing the long-term complications of diabetes, monitoring and lowering postprandial glucose is a rational strategy for improving metabolic function and achieving overall glucose control.

In the first approach, statistically significant greater mean reductions in absolute postprandial glucose (63-65 mg / dL) were observed for both fixed combination treatment groups than for the placebo groups. Greater mean reductions in absolute PPG were also achieved compared to glyburide (16-18 mg / dL) and metformin (18-20 mg / dL) monotherapy (Figures 8A and 8B). The 2-hour postprandial glucose jump from baseline in fasting for both treatment groups on the fixed-dose low (22.5 mg / dL) and medium dose (23.9 mg / dL) combination was only 56% -59% of placebo (40.3 mg / dL), 59% -63% glyburide (38.2 mg / dL), and 75% -81% metformin (29.5 mg / dL). The jump score rather than the absolute value demonstrates that glyburide is similar to placebo, that metformin produced a greater fall in postprandial glucose than glyburide and placebo, and that the low-dose combination was the most potent in reducing the postprandial glucose jump. As there are no published clinical trial data for combination therapy in a naïve patient population, these results provide new insight into understanding the impact of treatment options at this stage of the disease. Indeed, the results cannot be predicted from the changes observed in many studies of the second treatment approach.

Insulin levels were assessed under fasting and fed conditions in the first treatment approach study (Fig. 7). There was a statistically significant increase in insulin response in the presence of glucose for both fixed combination treatment groups (24-28.8 μίυ / ml) compared to

PL 199 278 B1 with placebo. Greater increases in glucose response in the presence of glucose were observed for the low dose fixed combination treatment group (14.6 μ ^^) compared to glyburide monotherapy, and greater increases in glucose response were observed for both fixed dose combination treatment groups (21-25.8 ^ u / ml) compared to metformin monotherapy. When considering mean doses of active ingredient per treatment group, the insulin response cannot be explained by the presence of the sulfonylurea component alone when using fixed combination therapy. These clinical data support preclinical studies on isolated pancreatic islet cells that suggested that metformin prevents hyperglycemic islet cell desensitization. The combination of the physiological and correspondingly increased insulin response with a correspondingly greater reduction in the glucose excursion suggests that the combination improves the pancreatic effectiveness in responding to glucose, preserving beta-cell function and improving insulin sensitivity.

The primary goal in managing patients with type 2 diabetes, in addition to aggressively treating elevated blood pressure and lipid levels, is to get as close to normal blood glucose levels as possible or to achieve therapeutically determined blood glucose levels. There was a greater response to treatment with the fixed combination in terms of achieving a more therapeutic effect in patients and a greater reduction in absolute HbA1c levels. in the first approach, patients treated with a fixed combination (66% -71%) more often achieved the target blood glucose level HbA_1c &lt;7% versus 60% for sulphonylurea monotherapy, 50% for metformin monotherapy and 20% for placebo after 20 weeks of double-blind treatment. Approximately 28% of patients in each fixed combination group showed a reduction in HbA1c from baseline of greater than 2.0% compared to 16-17% of each monotherapy group and 3% of placebo. It should be noted that these goals were not achieved by simply increasing the total doses of the drugs, but by reducing the doses of the complementary ingredients. The mean final doses achieved in each treatment group in the first approach were approximately 5.3 mg glyburide, 1,307 mg metformin, 557 / 2.78 mg fixed dose low dose combination and 818 / 4.1 mg fixed medium dose fixed combination . For the change in HbA1c from the number of tablets, the pattern observed with fixed combination treatment was not unexpected from a pathophysiological point of view. It indicates that there is a clear target response to all dose levels and that the need for higher doses correlates with a higher HbA1c baseline. A similar pattern can be established for glyburide up to a total dose of 7.5 mg; no clear pattern was observed for metformin treatment.

The data presented support the use of a low dose fixed combination metformin / glyburide as the most likely first treatment approach to achieve a patient's therapeutic target, regardless of his baseline HbA1c. For both fixed combinations, the mean reduction from baseline in HbA1c is greater for patients with higher baseline levels. This phenomenon has not been observed with glyburide, metformin or placebo and is not expected to occur with other monotherapies. This indicates the component component required to achieve the therapeutic blood glucose level when baseline HbA1c is above 9%. Monotherapy has been shown to flatten the blood glucose response for baseline HbA1c levels &lt;9%, while treatment with the fixed combination combination provides additional incremental HbA1c reduction for baseline HbA1c levels &lt;9%.

For all patients enrolled in the open-label first approach treatment phase with data available from at least two time points, the mean HbA1c at baseline was 9.45%. At weeks 13, 26 and 39, approximately 50-55% of patients achieved HbA1c below 7% and an additional 30% achieved HbA1c &lt;8%. This degree of response and magnitude of change in HbA1c decline can be expected with combination therapy, but is rarely seen with monotherapy with antihyperglycaemic agents. The crucial question is which initial antihyperglycaemic therapy will achieve the target blood glucose level of HbA1c &lt;7% in the greatest number of patients. This intensifies the need to re-evaluate current treatment models for type 2 diabetes and focus on the use of combination therapy earlier in the disease process.

Weight gain is typically seen with all antihyperglycaemic agents other than metformin monotherapy. With improved blood glucose control, weight gain is generally expected as calories are stored rather than lost due to poor metabolic control. In this clinical program, as glucose control

Blood pressure was improved, minimal early weight gain of approximately 1-2 kg was observed with fixed combination treatment; this can be compared to the 2 kg weight gain seen with glyburide monotherapy in the first approach. In double-blind treatment, after the initial minimal gain, body weight remained the same and did not increase over time.

Overall, there were no clinically or statistically significant differences between any of the treatment groups in altering the plasma lipid profile. Since the most severely ill patients were excluded from the placebo-controlled trial, smaller changes in response to treatment might not be detectable. The first approach patient population had insufficient blood glucose control, but diet and exercise alone allowed the mean HbA1c to be increased to 8.2%. Patients treated with the fixed combination did not experience any adverse events in the plasma lipid profile (total cholesterol, LDL, HDL, and triglycerides) or significant differences from placebo or glyburide or metformin monotherapy.

A better understanding of the relationship between diabetes control and the severity of long-term complications is motivating the current approach to achieving and maintaining blood glucose levels as close as possible. Targeting multiple defects through the use of agents with synergistic or complementary mechanisms of action intuitively makes sense to achieve a therapeutic target blood glucose level. A better understanding of the natural history of type 2 diabetes suggests that current treatment models likely to lead to "treatment failure before a more aggressive strategy" should be re-evaluated. Earlier application of low-dose combination therapy, especially when lower doses are more tolerable, therefore appears to be an important therapeutic approach if the goal is achieved and compliance is maintained. The fixed ratio combination evaluated in this study allows lower dosages and ease of use in unit form.

Low dose fixed combination metformin / glyburide treatment is safe and effective to maintain blood glucose control in patients with type 2 diabetes who are inadequately controlled with diet and exercise. The use of combination therapy earlier in progressive diabetic disease appears to be a clinical alternative to classical treatment models with a high probability of treatment failure in the pre-stage prior to a more aggressive, but clinically valid, treatment strategy. Although it was not investigated in this short-term study, the strategy to get blood glucose levels as close as possible to normal is likely to slow the progression of diabetes and delay the onset of long-term diabetic complications. Administration of a monotherapy-insensitive patient population of a fixed combination of metformin and glyburide was associated with clinically meaningful improvements in blood glucose control with no proven adverse metabolic effects or safety concerns. There was no clinically significant hypoglycaemia, no negative effects on plasma lipids, and limited early weight gain, and weight did not change over time. The synergism of the combination of metformin and sulfonylurea is established; the fixed combination of metformin and glyburide is effective in improving blood glucose control and is a rational choice from the antihyperglycemic arsenal of medical tools. Fixed combination is believed to simplify dosing, is more convenient, and therefore may lead to better treatment compliance.

A fixed dose low dose combination (250 / 1.25 mg) would be the initial starting dose in treatment naïve patients. Then it should be gradually increased until HbA1c &lt;7%.

Summary

Safety and efficacy data from the evaluation of this fixed dose combination metformin / glyburide clinical program as a first-line treatment in patients with type 2 diabetes support the following:

The percentage of patients who discontinued treatment due to elevated blood glucose levels was lower with the fixed combination metformin / glyburide compared to metformin, glyburide, and placebo.

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Hypoglycaemia and symptoms of hypoglycaemia, in the first approach (Fig. 9), were less frequent with the metformin / glyburide 250 / 1.25 mg combination compared to the metformin / glyburide 500 / 2.5 mg combination and glyburide.

In the first approach, the incidence of gastrointestinal adverse events associated with the fixed combination was lowest for metformin / glyburide 250 / 1.25 mg compared to metformin / glyburide 500 / 2.5 mg and metformin (Fig. 10). .

There were no new or unexpected adverse events or abnormalities in patients who received fixed combination metformin / glyburide in long-term open label treatment.

Significantly better efficacy of fixed combination metformin / glyburide at any dose, as demonstrated by greater reductions in all blood glucose parameters (HbA1c, postprandial glucose, fasting glucose and fructosamine) compared to placebo, glyburide and metformin treatment.

The synergistic effect of the low dose combination targeting multiple metabolic defects, improved beta cell function and insulin sensitivity, as demonstrated by postprandial spikes in plasma glucose and insulin levels, improved metabolism and blood glucose control.

Patients treated with fixed combination metformin / glyburide were more likely to achieve the therapeutic target blood glucose HbA_1c &lt; 7%.

Effective in lowering blood glucose to a therapeutic target for any HbA1c baseline compared to placebo, glyburide and metformin treatment. Glyburide and metformin as initial therapy were found to flatten the blood glucose response for baseline HbA1c levels&gt; 9%, while treatment with fixed combination metformin / glyburide further incrementally reduced HbA1c for baseline HbA1c levels&gt; 9%.

Limited early weight gain parallel to improved blood glucose control, comparable to glyburide monotherapy; however, body weight did not change with time.

No adverse events for fixed combination combinations in lipid profile (total cholesterol, LDL, HDL, and triglycerides) or significant differences from placebo or glyburide or metformin monotherapy.

The favorable efficacy and tolerability of the fixed-ratio 250 / 1.25 mg metformin / glyburide combination justifies its use as the initial starting dose in the first approach.

The above results clearly show that the treatment of diabetes with the low dose metformin / glyburide formulation (250 mg / 1.25 mg) of the present invention is at least as effective as with the higher dose dosage forms (500 mg / 2.5 mg). ) while ultimately associated with reduced side effects.