Method for diabetes treatment

FIELD: medicine, endocrinology, in particular treatment of diabetus mellitus type 2 in patient didn't use anti-diabetic drugs.

SUBSTANCE: claimed method includes simultaneous administration of metformine in daily dose of 160-750 mg and gliburide in daily dose of 0.5-15 mg. Gliburide has grain-size classification wherein min.10 % particles have size less than 2 mum and max.10 % particles have size more than 60 mum.

EFFECT: treatment of improved effectiveness with decreased drug doses and reduced side effects.

24 cl, 10 dwg, 4 ex, 4 tbl

 

The scope to which the invention relates.

This invention relates to a method for the treatment of type 2 diabetes in patients who were not taking drugs previously (not treated), using the drug with a low (small) dose, which includes Metformin and gliburid. A drug with a low dose, at least almost equivalent in their effectiveness in the treatment of type 2 diabetes compared with preparations containing higher doses of Metformin and/or gliburida, but gives significantly fewer side effects.

Background of invention

Biguanides antihyperglycemic agent Metformin, described in U.S. Patent 3174901, currently available in the United States in the form of its hydrochloric acid salt (GlucophageT), Bristol-Myers Squibb Company.

Diagnosis and treatment of diabetes mellitus type 2 changes very quickly. Currently it is generally accepted that an important glycemic control (the control of glucose in the blood). The goal of treatment of diabetes is currently the achievement and maintenance of blood glucose as much as possible close to normal to prevent long-term microvascular and arterial complications caused by the high content of glucose in the blood. Diagnosis of diabetes has undergone significant changes, as is evident from new installations ADA for the diagnosis and classification. The choice of oral is therapeutic agents for the treatment of diabetes mellitus type 2, until recently, was very limited. Until 1995 the basis of oral diabetic agents in the USA amounted to sulfonylureas. Sulfonylureas act on one mechanism of hyperglycemia by reducing insulin secretion by the beta cell. From 1995 to "anti-diabetic equipment" for the treatment of hyperglycemia added three new classes of agents. Metformin, biguanide, acts on additional mechanisms of hyperglycemia by inhibiting the production of glucose in the liver and by increasing peripheral glucose uptake and thereby reduce resistance to insulin; preparations of thiazolidinediones, such as troglitazone, rosiglitazone and pioglitazone, reduce peripheral resistance (vessels) to insulin; alpha-glucosidase inhibitors such as acarbose and miglitol, help to regulate the movement of glucose after a meal by reducing the absorption of carbohydrates from food. All these agents are indicated for monotherapy, and some of them are shown to work normally after it was found that monotherapy is not sufficient.

In 1995 Metformin added to sulfonylurea in the treatment of patients who failed to achieve glycemic control with monotherapy with sulfonylureas, and it was found that the two agents have a significant effect on glycemic control or reduction of hemoglobin Alc. Razlichnimi action if the target of hyperglycemia are positive and make joint use of attractive and sustainable. Prescription data show that about 60% of the Metformin is used in combination with sulfonylurea.

Examples of combination products (combinations) of Metformin and sulfonylurea - gliburida (also known as glibenclamide) described in the following links:

(1) In the International application WO 97/17975, published may 22, 1997 (Barelli et al., Institute Gentili S.P.A.), and U.S. Patent 5922769 issued Barelli et al.) (hereinafter Barelli et al.), described the combination of glibenclamide and Metformin in a weight ratio of 1:100, so that the daily dose is 15 mg of glibenclamide and 1500 mg of Metformin for the treatment from the initial stages to the most severe cases of diabetes, in particular in cases of secondary failure combination glibenclamide-Metformin HCl) in a weight ratio higher 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 (Treatment of NIDDM patients with secondary failure gliburida: comparison of additions gliburida Metformin or NPH insulin at night), Diabete & Metabolisme, 1991, 17, 232-234, describe the application of a combination of 1.5 g/day of Metformin and 15 mg/day gliburida for the treatment of NIDDM patients with acquired deficiency treatment 15 mg/day gliburida.

(3) Higginbotham et al., Double-Blind Trial of Metformin in therapy of Non-Ketotic Diabetes (Double-blind study of Metformin in the treatment of necatoriasis diabetes) The Medical Journal of Austraia, August 11, 1979, 154-156, describes the treatment of patients with diabetes who have received 10-20 mg/day glyburide with 500 mg Metformin twice a day. Higginbotham et al. they conclude that "in selected patients with diabetes, the condition of some insufficiently controlled with sulfonylurea, significant improvement in diabetic control can be achieved by adding a small dose of Metformin 500 mg twice a day."

(4) the Patent application U.S. 09/353141, filed July 14, 1999 (based on European application 98401781.4 filed July 15, 1998), describes drugs that contain Metformin and gliburid in which gliburid has a particular particle size, as described below.

References that describe the combination of Metformin and glipizide, include the following:

(1) Treatment combination of glipizide/Metformin decreases the binding of low density lipoprotein with arterial proteoglycans with NIDDM, Edwards et al., Diabetes, (46, Suppl. 1, 45A, 1997).

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

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

(4) Sensitivity to insulin is increased after monotherapy with glipizide and combination with Metformin, Cefalu et al., Diabetologia, (39, uppl. 1, A231, 1996).

(5) the Combined treatment of NIDDM patients using Metformin/sulfonylurea if glycemic control from mediocre to bad, Reaven et al., J. Clin. Endocrinol. Metab. (74, No. 5, 1020-26,1992).

(6) treatment with the combination of glipizide/Metformin in NIDDM, Hollenbeck et al., Diabetes, (39, Suppl. 1, 108A, 1990).

(7) Treatment of oral antidiabetic combination with sulfonylureas Metformin, Haupt et al., Med. Welt. (40, No. 5, 118-23, 1989).

(8) Change lipemic paintings diabetic patients after treatment with the combination of glipizide and Metformin, Ferlito et al., PROGR. MED. (Roma) 31/6 (289-301) 1975.

(9) the Results obtained using 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 agent are described in the following papers (links):

(1) U.S. Patent 5631224 owned by Efendic et al., describes the combination of Metformin with GLP-1 (7-36) amidon or GLP-1 (7-37) or its fragment.

(2) the international application WO 98/57634 (SKB) describes a method of treating diabetes using a combination of thiazolidinedione and Metformin. Thiazolidinedione can be troglitazone, ciglitazone, pioglitazone or englitazone and can be used in dosages of 2 to 12 mg per day, whereas Metformin can be used in daily doses up to 3000 mg per day as single dose 500 mg (e.g., 2-3 times per day) or 850 mg (2 R is for a day), in one example, the dosage of Metformin is 500 mg to 5 times a day".

(3) U.S. Patent 5965584 (Takeda) described the combination of thiazolidinediones enhancer (amp) insulin sensitivity (such as pioglitazone) and Metformin.

None of the above works (links) does not include the use of diabetic combinations containing Metformin as first-line treatment for treatment-naïve medicine patients.

Several combinations of Metformin and gliburida (glibenclamide) permanent makeup available currently outside the United States. They include (1) a combination of 400 mg of Metformin/2.5 mg glibenclamide (Bi-Euglucon company Boehringer in Argentina and Bi-Euglucon M in Italy; Glibomet company Guidotti/Menarini in the Dominican Republic and in Italy; Normell firm HMR in Greece and Suguan-M company Hoechst in Italy; Glucored Sun Pharma in India; Benclamet company Monsanto (Searle) in India; Glibomet company Guidotti in Lebanon; Glibomet company Berlin-Chemie/Menarini in the Slovak Republic and Bi-Euglucon company Roche Uruguay); (2) combination 500 mg of Metformin/5 mg glibenclamide (Glucored Sun Pharma in India; Benclamet company Monsanto (Searle) in India; Duotrol company in India USV; and Bi-Euglucon M5 firms Lakeside (Roche) in Mexico); (3) a combination of 500 mg of Metformin/2.5 mg glibenclamide (Glucomide company Molteni in Italy; Bi-Euglucon M company Lakeside (Roche) in Mexico and Dublex company Szabo in Uruguay); and (4) 1 g of Metformin/5 mg glibenclamide (Sil-Norborad company Silanes in Mexico).

an explanation of the GlucophageT (Metformin company Bristol Myers Squibb) in the Directory of the doctor in 1999 under the "Indications and usage" indicates what Glucophage (glucophage) can be used in conjunction with a sulfonylurea. Next, under "Dosage and application" "Concomitant oral therapy with glucophage and sulfonylurea States that "If patients do not respond to therapy with the maximum dose of glucophage (monotherapy) for the time up to four weeks, you should consider the gradual addition of an oral sulfonylurea while continuing receiving the maximum dose of glucophage... When joint (concomitant) therapy using glucophage and sulfonylurea given control of glucose in the blood can be achieved by adjusting the dose of each drug. However, you should try to make efforts to determine the most effective dose of each drug substance to achieve this goal." The recommended regimen is applied glucophage: initial dose of 500 mg twice daily or 850 mg once a day when the increment of increasing doses of 500 mg weekly or 850 mg every two weeks up to a total amount of 2000 mg per day.

Inserts in packages bi-euglucon M (Bi-Euglucon M) and shuana M (Suguan M) in Italy (400 mg Metformin/2.5 mg glibenclamide) indicate that these combinations of drugs used in cases of primary or acquired resistance to sulfonylureas [i.e. as the e of the preparation of the second or third row] and that applies dosage 1/2 tablet per day with a gradual increase in the dose of 1/2 tablet in accordance with the glycemic changes to 4 tablets a day.

Refills in packs of glibomet (Glibomet 400 mg of Metformin/2.5 mg glibenclamide) and glycolide (Glycomide, 500 mg of Metformin/2.5 mg glibenclamide) in Italy indicate that these combinations of drugs used to treat type 2 diabetes, unregulated or not able to be regulated only through diet or by diet and sulfonylureas [i.e. therapy first-or second-line].

In the liner in the package glibomet (Glibomet in Italy indicated daily dose of 2 tablets, ie 800 mg of Metformin and 5 mg of glibenclamide, up to 2 grams of Metformin. The liner in the package glucoside (Glycomide) in Italy indicates a daily dose of 2 capsules, ie 1000 mg of Metformin, up to 2 grams of Metformin and 5 mg of glibenclamide.

Description of the invention

According to this invention created a method of treatment of diabetes, mainly type 2 diabetes, in a patient who previously medicines, which includes a step of introducing a sick man, who had not drugs as first-line therapy a therapeutically effective pharmaceutical drug with a low (small) dose, which contains a combination of Metformin and gliburida. The above combination preferably provides at least equivalent efficacy in the treatment of diabetes in patients not treated with RA is her drug, in comparison with the combinations of Metformin and gliburida used in higher doses required in conventional medical practice for first-line therapy in the treatment of diabetes, but with significantly fewer side effects.

In one aspect of the method according to the invention, the daily dose received Metformin is less than 800 mg

It should be understood that the drug low dose used according to the method according to the invention, includes an initial low dose of active ingredients of a medicinal product, which is below the initial dose of such drugs commonly prescribed in generally accepted medical practice in the first-line therapy in the treatment of diabetes. That is, the above pharmaceutical drug low dose contains a small dose of Metformin, as defined below in this description, or a low dose of Metformin and low dose gliburida, as described later in this description.

According to this invention, the effectiveness of first-line therapy in the treatment of diabetes in patients who were not taking drugs previously achieved by the use of a pharmaceutical preparation with a low dose, with the initial dose of Metformin is only about one-fifth the initial daily dose of Metformin used in conventional medical practice as first-line therapy for the treatment of di is beta (i.e. the initial dose is only 160 mg of Metformin per day), up to a daily maintenance dose of Metformin used in common medical practice in the treatment of first-or second-line treatment of diabetes (i.e. up to 2000 mg of Metformin a day). Preferably the maximum daily maintenance dose of Metformin is about two thirds of the daily maintenance dose of Metformin used in conventional medical practice as first-line therapy in the treatment of diabetes.

In the process according to the invention, the initial dose of Metformin is only about 25-60% of the starting daily dosage of Metformin employed in generally accepted medical practice for first-line therapy in the treatment of diabetes (i.e. initial daily dose of Metformin is 160-500 mg, preferably 250-500 mg). If necessary, the initial daily dose can be increased up to a daily maintenance dose of 40-60% of the maintenance dose used in conventional medical practice as first-line therapy in the treatment of diabetes (i.e. daily maintenance dose 320-2000 mg, preferably 320-1200 mg).

According to the method according to the invention the pharmaceutical preparation with a low dose preferably used in first-line therapy with this daily dose to ensure less is 800 mg of Metformin per day, preferably no more than about 750 mg of Metformin per day, more preferably no more than about 600 mg of Metformin per day, and with an initial dose of about 160-500 mg per day, preferably 250-500 mg per day, as a one-time (single or divided doses of one to four tablets a day.

Gliburid used as initial daily dose constituting only about one-fifth the initial daily dose used in conventional medical practice as first-line therapy in the treatment of diabetes (i.e. minimum initial dose 0.5 mg). If necessary, the dose can be increased up to the value of the daily maintenance dose gliburida used in common medical practice in the treatment of first-or second-line treatment of diabetes (i.e. up to a maximum of 15 mg gliburida in the day). Preferably the maximum daily dose gliburida two-thirds of the daily maintenance dose gliburida used in conventional medical practice as first-line therapy in the treatment of diabetes (i.e. up to a maximum of 2.5-10 mg gliburida in the day).

Gliburid preferably take with initial daily dose constituting only about 20-60% of the initial daily dose gliburida used in common medical practice for first-line therapy in the treatment of diabetes (i.e. the minimum initial dose with what is only 0.5-3.5 mg, more preferably 1.25 mg or 2.5 mg). Dose gliburida can bring to daily maintenance dose of about 40-100%, preferably about 40-60% of the daily maintenance dose gliburida used in conventional medical practice as first-line therapy in the treatment of diabetes (i.e. the maximum daily dose of 2-1,5 mg, preferably the maximum daily dose of 2.5-10 mg).

The above daily dose gliburida can be used as a single or divided doses one to four times per day.

Metformin and gliburid can be prepared in the form of a single pill that can be applied in the form of single or multiple (split) doses 1-4 times a day.

The term "combination (combination drug) with a low dose, the drug low dose" or "pharmaceutical drug with low-dose"used in this description, the preferred drug belongs to the drug, which includes as an initial daily dose of 250 mg of Metformin 1.25 mg gliburida or 500 mg of Metformin and 2.5 mg gliburida.

To date a combination of drugs Metformin and gliburida usually, with a few exceptions, was used as drugs (for treatment) of the second row in the treatment of type 2 diabetes. Daily dose taken in normal medical practice for the treatment of the second row, use jsousa permanent makeup is a combination of drugs Metformin and gliburida amount to 3-4 pills, each of which contains 400-500 mg of Metformin and 2-2,5 mg gliburida or about 1200-2000 mg of Metformin and 6-10 mg gliburida daily.

As indicated above glibomet (Glibomet) and glycolide (Glucomide) (a combination of drugs Metformin and gliburida permanent makeup), manufactured in Italy, these combinations can be used as first-line therapy (patients who had not drugs) at a daily dose of 800-1000 mg to 2 grams of Metformin and 5 mg of glibenclamide (gliburida).

The above dose may be covered by a concept (term) "dose prescribed in conventional medical practice in the treatment of first-or second-line treatment for diabetes". In some refractory (resistant) cases of diabetes can be displayed up to 15 mg gliburida.

As indicated above relative to the bi-euglucon M (Bi-Euglucon M) company Boehringer and shuana M (Suguan M) company Hoechst (a combination of drugs Metformin and glibenclamide permanent makeup), manufactured in Italy, these combination drugs are used as second-line therapy in daily doses ranging from 1/2 tablet, that is, 200 mg of Metformin and 1.25 mg of glyburide. The initial or starting small (low) dose used in order to determine whether the patient carry drugs. In addition, apparently, is unknown for the marijuana clinical studies on first-line therapy, which confirm the use of these initial doses. These initial dose is gradually increased - 1/2 tablet at a time - up to 4 tablets per day to achieve effective dose. Therefore, the initial or starting dose of 1/2 tablet or 200 mg of Metformin and 1.25 mg of glyburide is not considered in this description as "dose, as prescribed in conventional medical practice for treating diabetes".

It has been unexpectedly discovered that the use of Metformin and gliburida in this invention has the following advantages. Metformin low dose is an insulin sensitizer and reduces insulin resistance in liver, muscle and pancreas. Combined with reduced dose of the drug Metformin-gliburid behaves in the pancreas as a sensitizer glucose; it reduces the toxicity of glucose in the pancreas and enhances the function of the pancreas.

In addition, according to this invention proposes a method of treatment of diabetes, mainly type 2 diabetes not treated patient (person), which includes a step of introducing not taking medications to a patient in need of treatment as first-line therapy with an initial low dose of a pharmaceutical preparation, which contains a combination of Metformin and gliburida.

This nachalnoy low-dose combination drug preferably provides, at least almost equivalent efficacy in the treatment of diabetes not previously treated preparations of patients in comparison with the combined drugs Metformin and gliburida used in doses (including the initial dose)prescribed in the usual medical practice for first-line therapy in the treatment of diabetes, but with significantly fewer side effects.

Initial daily dose of Metformin is only 20% of the initial daily dose of Metformin used in common medical practice for first-line therapy in the treatment of diabetes, preferably, the initial dose is about 160-500 mg, more preferably the initial dose is 250 mg or 500 mg

The initial dose gliburida is only 20% of the initial daily dose gliburida used in common medical practice for first-line therapy in the treatment of diabetes, preferably the initial daily dose of 0.625 about 5 mg, more preferably the initial dose is 1.25 mg or 2.5 mg

In addition, according to this invention is the method of lowering glucose in plasma shock, lowering resistance to insulin, lowering hemoglobin Alc, increasing the level of insulin after a meal and/or decrease the amplitude changes of glucose after a meal at h the rights, a patient with diabetes, which includes a step of introduction as first-line therapy for patients not treated previously, drugs, pharmaceutical drug with a low dose, which contains a combination of Metformin and gliburida.

In the process according to the invention using the preferred initial low dose of a pharmaceutical product containing Metformin and gliburid, for the treatment of patients with diabetes who were not taking drugs previously, the effectiveness in the treatment of patients who were not taking drugs previously, at least equivalent, and the frequency of side effects (adverse effects on the gastrointestinal tract and hypoglycemia) unexpectedly and significantly lower compared with patients receiving higher doses of Metformin and gliburida (i.e. the initial dose prescribed in generally accepted medical practice for treating diabetes). That is, although the effectiveness in the treatment of diabetes in patients who were not taking drugs previously determined by the decrease of level of haemoglobin Andlc(HbA1ccompared with the baseline in time, the decrease of glucose in the plasma of fasting (FPG), increased levels of insulin after a meal and decrease the amplitude changes of glucose after a meal (PPG), almost equivalent to the above patients when applied pharmaceutical prep the rata low dose used in this description, and pharmaceutical drug at much higher doses, frequency of hypoglycemia and gastrointestinal side effects in patients who were not taking drugs previously treated with significantly higher daily doses significantly higher than in patients treated with the pharmaceutical drug with a low dose.

The most preferred dose for use according to this description, up to 250 mg of Metformin/1.25 mg gliburida and 500 mg of Metformin/2.5 mg gliburida.

Pharmaceutical drug Metformin and gliburida with a low dose is used as the primary (initial) therapy, which is a Supplement to diet and exercise to improve glycemic control in patients with diabetes mellitus type 2.

ADA recommends as a goal (task) treatment HbAlc<7% (ADA. Diabetes Care 21 [Suppl. 1]: S23-S31, 1998) to reduce the risk of complications of diabetes mellitus type 2, including cardiovascular disease and microvascular complications.

The preferred dose combination Metformin-gliburid should be individualized, based on both efficacy and tolerability. It is preferable to give during the meal, and should begin with small doses, gradually increasing. In the ideal case, the response to therapy should be evaluated using HbAlc(glycosylamine the th hemoglobin), which is the best indicator of long-term glycemic control than FPG alone. The goal of therapy (therapeutic goal, goal) of all patients with type 2 diabetes should be improved glycemic control, including levels of FPG, glucose in plasma after a meal and HbAlcto normal or as close to normal level. Patients check ("titrated") to achieve ADA-target - HbAlc<7%, following the recommendations of the ADA to change (increase) the dose up to the maximum recommended dose (ADA. Diabetes Care 21 [Suppl. 1]: S23-S31, 1998).

As the primary therapy is most preferred is the initial (starting) dose combined drug Metformin-gliburid 250/1,25 mg once a day during meals. For patients in whom the baseline (background) line HbAlc>9% or fasting glucose >200 mg/DL, the recommended initial dose 250/1,25 mg twice a day, preferably at Breakfast and dinner. The dose should preferably be done with increment 250/1,25 mg every two weeks until the minimum effective dose required to achieve adequate glycemic control. For patients requiring additional glycemic control, the dose 250/1,25 mg can be replaced by 500/2,5 mg

The preferred formulation of Metformin-gliburid with a low dose is given below.

Table 1
The nature of productThe amount of ingredient mg per tablet 250/1,25 or 500/2,5 or 500/5,0
Ingredient
Metformin hydrochloride250,0 or 500.0
Gliburidof 1.25 or 2.5 or 5.0
Sodium-cross carmellose3,0-15,0
Microcrystalline cellulose15,0-60,0
Polyvinylpyrrolidone3,0-20
Magnesium stearate0,3-7,5
Film coating*of 4.5 to 12.0
* Used manufactured composition for film coating, such as Opadry (use, UK).

Especially preferred are the following formulation Metformin-gliburid low dose:

Table 2
The nature of productThe amount of ingredient mg per tablet
250/1,25500/2,5500/5,0
Ingredient
Metformin hydrochloride*251,25502,50502,50
Gliburid1,25 2,55,0
Sodium crosscarmellose7,01414
Microcrystalline cellulose28,2556,5054,0
Polyvinylpyrrolidone10,02020
Magnesium stearate2,254,504,50
Film coating**6,0to 12.0to 12.0
* Contains of 99.5 wt.% Metformin Hcl and 0.5 wt.% stearate Mg

** Applied industrial composition for film coating, such as Opadry (use, UK).

Pharmaceutical drug with a low dose that contains a combination of Metformin-gliburid, preferably prepared according to the methods described in Application for U.S. Patent No. 09/353141, filed July 14, 1999, which claims the priority of European application No. 98401781.4 filed July 15, 1998, and this application for U.S. Patent is entered in this description by reference.

Preferred pharmaceutical drug low dose used in the method according to the invention in the form of solid oral forms, such as tablet preferably contains a combination of Metformin-gliburid described in Application for U.S. Patent No. 09/353141 filed 14 EULA year, and as such contains gliburid, the bioavailability of which is comparable to the bioavailability gliburida dealt with separately Metformin and gliburida. This is achieved by (performed) through the use of gliburida with a specified particle size distribution. That is, the drug Metformin-gliburid contains a combination of Metformin and gliburida in which the particle size gliburida is such that a maximum of 10% of the particles less than 2 microns and a maximum of 10% of the particles larger than 60 μm. The preferred particle size gliburida is such that a maximum of 10% of the particles less than 3 microns and a maximum of 10% of particles larger than 40 microns. This specific interval of particle size gliburida (particle size distribution) can be obtained by sieving or grinding in vostokstrojj mill.

In the second variant of the invention the solid oral dosage form with low-dose contains a combination of Metformin and gliburida in which the particle size gliburida is such that a maximum of 25% of the particles less than 11 microns and a maximum of 25% of the particles larger than 46 microns.

Preferably 50% of the particles less than 23 microns.

Most preferred is the combination of Metformin and gliburida in which the granulometric composition gliburida is such that a particle size of about 25% lower (podkrkonosi) fraction of not more than 6 μm, the particle size is about 50% lower fraction of 7-10 microns and a particle size of about 75% lower fra is tion does not exceed 23 microns.

Detailed description of the invention

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

The term "Metformin", as used herein, refers to Metformin or its pharmaceutically acceptable salts, such as hydrochloric acid salt (hydrochloride), Metformin fumarate (2:1) and Metformin (2:1) succinate as described in Patent application U.S. 09/262526 filed March 4, 1999; the hydrobromide, p-chlorophenoxyacetate or embonate and other known salts of Metformin and mono - and dibasic carboxylic acids, including salts described in U.S. Patent 3174901, all these salts in General are called "Metformin". Preferably, Metformin, used in this invention, represented a hydrochloric acid salt of Metformin hydrochloride, namely Sol "Metformin hydrochloride", issued under the title GlucophageT (trademark of Bristol-Myers Squibb).

The expression "substantially weakened (lower, lower) side effect", as used herein, refers to a less frequent occurrence (lower prevalence) cases of hypoglycemia and unpleasant gastro-intestinal conditions, including diarrhea, nausea/vomiting and/or abdominal pain observed in the reception of a pharmaceutical product with a low dose of u-naïve patients is offering patients compared with patients taking the same active ingredients in the pharmaceutical preparation according to the invention, but in higher doses.

The expression "at least, almost (substantially) equivalent efficiency", in the treatment of type 2 diabetes, as used herein, refers to the efficiency with which pharmaceutical drug low (low, low) dose in the treatment-naïve drugs patients reduces and/or maintains the level of hemoglobin Andlc(glycosylated hemoglobin) at 7% or less, reduces insulin resistance (increasing the level of insulin after a meal) and/or reduces the amplitude of the change (increase) of glucose after a meal (PPG) compared to patients taking the same active ingredients in the pharmaceutical preparation according to the invention, but in higher doses.

The expression "amplitude changes in the content of postprandial (after eating)"used in this description, refers to the difference between glucose after a meal (PPG) and fasting (FPG).

Pharmaceutical drug low dose containing Metformin in combination with gliburid, can be administered orally in the same dosage form or in separate oral dosage form or by injection.

I believe that the use of Metformin in Combi is then with gliburid gives higher antihyperglycemics results than those which could be achieved when using each of these drugs individually, and higher than the total additive antihyperglycemics effect caused by the drug.

Metformin is used in a weight ratio with gliburid in the range from about 1000:1 to 10:1, preferably from about 400:1 to 50:1, more preferably about 200:1-100:1.

When implementing the method according to this invention used in the pharmaceutical formulation (drug) or a composition with a low dose containing Metformin and gliburid in combination with a pharmaceutical carrier or diluent. Pharmaceutical drug with a low dose can be prepared using suitable solid or liquid carriers or diluents and pharmaceutical additives, according to the specified method of administration). Pharmaceutical drug with a low (small) dose, you can enter a mammal, including humans, monkeys, dogs, etc. orally, for example in the form of tablets, capsules, granules or powders, or it may be administered parenterally in the form of injectable preparations. The dose for patients not treated previously preparations, such as described above, and may be given as a single dose or multiple (separate) doses 1-4 times a day.

The above dosage forms can also clusterability physiologically acceptable carrier, excipient, lubricant, buffer, antibacterial agent, a filler (such as mannitol), antioxidants (ascorbic acid or sodium bisulfite), etc.

Enter the dose should be carefully adjusted according to age, weight and condition of the patient, and the method of administration, dosage form and the desired result.

Combined drug Metformin or its salt and gliburida can be prepared separately or, if possible, in the form of a single drug, using appropriate technology.

Various formulations (drugs) according to the invention can, optionally, include one or more filler or excipient in an amount of about 0-90 wt.% and preferably about 1-80 wt.%, such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate and/or derivatives of cellulose, such as wood cellulose and microcrystalline cellulose.

In addition to or instead of the fillers may be present in one or more binders in an amount of about 0-35% and preferably about 0.5-30% by weight of the composition. Examples of such binders which are suitable for use in this invention include polyvinylpyrrolidone (molecular weight in the range of about 5000-80000, preferably up to about 40000), lactose, KRA is small, such as corn starch, modified corn starch, sugar, Arabian gum, etc. and fine powders (less than 500 microns), the binder is a wax, such as palm wax (Carnauba wax), paraffin, spermaceti, polyethylene or microcrystalline wax.

If the composition should be in the form of tablets, it contains one or more lubricant for tableting in an amount of about 0.2 to 8% and preferably about 0.5-2% by weight of the composition, such as magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, palm wax (Carnauba wax), etc. Other suitable ingredients, which, if necessary, may be present include preservatives, stabilizers, antiadhesive or silicon fluidity improvers or substances that promote ingestion, such as silicon dioxide trademark Syloid as well as dyes FD & C.

Tablets may also include a coating layer, which can be from 0 to about 15% by weight of the composition of the tablets. The coating layer, which is located on an external solid phase containing particles of the solid phase, enclosed in it, may be any conventional composition for coating and may include one or more film-forming or binder, such as a hydrophilic polymer such as hypromellose and/or hydro is one polymer, such as a neutral polymer of esters of methacrylic acid, ethylcellulose, cellulose acetate, copolymers of polyvinyl alcohol and maleic anhydride, polymers β-pinene, glycerol esters of wood resins and the like, and one or more plasticizer, such as triethylcitrate, diethylphthalate, castor oil, etc. In the composition as the core tablet and the coating may include aluminum lacquer to give a color.

The binders are applied from a solvent system consisting of one or more solvents, including water, alcohols such as methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones, such as acetone or ethylmethylketone, chlorinated hydrocarbons such as methylene chloride, dichloroethane and 1,1,1-trichloroethane.

If you use the dye, it is used together with the compositions of the foaming agent, plasticizer and solvent.

The final dosage form is a compressed tablet, a hard gelatin capsule, preferably a tablet. Tablet, if necessary, may have a film coating. The total number of medicinal substances on the standard dose should be such that the size of the dosage form was convenient for patients.

Pharmaceutical preparation in the form of tablets can be obtained by a method described in the Patent application U.S. 09/35341, filed July 14, 1999, which involves the following stages:

a) formation of granules by wet granulation of a mixture of Metformin and gliburida;

b) mixing the granules with the addition of for tabletting and thinner and

c) tableting obtained with this mixture.

The mixture used for the formation of granules, includes binder for granulation. The binder for granulation is preferably polyvinylpyrrolidone, such as, for example, polyvinylpyrrolidone with a molecular weight of 45,000. Polyvinylpyrrolidone can be used in 2-4% of the final weight of the tablets.

After the granulation phase of pellets can sift and dry.

Then the granules are mixed with the diluent and additive for tableting. The diluent may be a conventional filler, usually used for the preparation of tablets, such as microcrystalline cellulose. Teletrauma additive may be a conventional material such as magnesium stearate.

Received this tablet can then optionally be coated with polymer - hydrophilic cellulose and talc. Polymer - hydrophilic cellulose - preferably represents 2-hypromellose.

Description of figures

Figures 1 and 2 represent a column graph depicting the change in hemoglobin Alc (HbAlc), depending on the Chi is La tablets of combination drugs Metformin/gliburid permanent makeup, used in first-line therapy compared with monotherapy separate gliburid and Metformin.

In Figures 3, 4 and 5 column graph depicting the change in HbAlc in time when receiving combination drugs Metformin/gliburid constant composition used in the first-line therapy, compared with the same indicator monotherapy gliburid and Metformin.

Figure 6 is a bar chart which shows the change in the content of plasma glucose fasting (FPG) depending on the number of tablets of combination drugs Metformin/gliburid constant composition used in the first-line therapy compared with monotherapy separate gliburid and Metformin.

Figure 7 is a bar chart, which shows the initial insulin levels and insulin levels after a meal when receiving combination drugs Metformin/gliburid constant composition used in the first-line therapy compared with monotherapy separate gliburid and Metformin.

Figures 8A and 8B represent a column graph depicting the change in the amplitude of the PPG at the initial (baseline) and after 20 weeks of receiving combination drugs Metformin/gliburid constant composition used in the first-line therapy compared with monotherapy of the Department is Ino the gliburid and Metformin.

Figure 9 is a bar chart that shows how many people reported symptoms of hyperglycemia when receiving combination drugs Metformin/gliburid constant composition used in the first-line therapy, compared with the same indicator in monotherapy separate gliburid and Metformin.

Figure 10 is a bar chart depicting the frequency of side effects in the gastrointestinal tract of patients when receiving combination drugs Metformin/gliburid constant composition used in the first-line therapy compared with monotherapy separate gliburid and Metformin.

The following examples represent preferred variants of the invention.

Examples 1-3

Tablets containing combination Metformin/gliburid receive, as described below.

The tablet formulation of Metformin hydrochloride - gliburid 250 mg/1.25 mg, 500 mg/2.5 mg and 500 mg/5 mg

Table 3
IngredientExample 1Example 2Example 3
Quantity per tablet (mg)
250 mg/1.25 mg500 mg/2.5 mg500 mg/5 mg
Metformin hydrochloride*251,25555,0 502,50
Gliburid1,252,55
Sodium-cross carmellose7,014,014,0
Microcrystalline cellulose10,020,020,0
Polyvinylpyrrolidone28,2556,554,0
Magnesium stearate2,254,54,5
Film coating**61212
* Contains of 99.5 wt.% Metformin HCl and 0.5 wt.% stearate Mg

** Apply a film coating based on a receiver array.

Tablets of Metformin hydrochloride - gliburida 250 mg/1.25 mg, 500 mg/2.5 mg and 500 mg/5 mg, pressed from the same granulate. A pill with a lower dose (efficiency) is pressed out half of the weight of the tablets tablets Metformin hydrochloride gliburid 500 mg/2,5 mg Tablets for clinical application cover film hydroxypropylmethylcellulose (receiver array). Film coating is not functional and is done for aesthetic purposes. Film coating of clinical product is transparent.

Process for the production of clinical dosage forms is as follows:

Sodium crosscarmellose and glibo the ID is dispersed together and then mixed with Metformin hydrochloride/magnesium stearate (of 99.5:0.5 wt.%) in the mixer with high shear. The resulting dry mixture is granulated in a mixer with a high shear with an aqueous solution of povidone and dried in a fluidized bed dryer at about 60°to achieve a certain moisture content, determined by the weight loss during drying. The dried granulate is milled in the mill sieving and mixed with microcrystalline cellulose in a drum mixer. Magnesium stearate is introduced as lubricants, using a drum mixer to obtain the final mixture for extrusion.

The resulting mixture is pressed into tablets scheduled weight, based on the definition in the process, the moisture content in the appropriate media for tableting. Theoretical weight of the tablet (on the basis of their composition formulas are not corrected for moisture content) is 300 mg tablets composition 250 mg/1.25 mg and 600 mg tablets composition 500 mg/2,5 mg

Tablet cover film cover in perforated form to cover with appropriate water non-functional film coating system on the basis of the receiver array to the desired weight of the film coating. The typical contents of a film coatings on tablets is 2 wt.%.

In vivo evaluation of a prototype composite tabletas the bathrooms drugs are reduced to the determination of the distribution of particle size (grain size), required (scheduled) for use in the clinical program to achieve the bioavailability of the combined product comparable with Micronesia. The distribution of particle size for any party gliburida describes three total (cumulative) criteria size: 25% lower fraction (podkrkonosi), 50% lower fraction (also known as srednevekovoi granulometric composition, MMPS) and 75% lower fractions. The clinical program includes a total of six batches (lots) of medicinal substances gliburida with 25% lower fraction in the range of 4-7 microns, 50% of the bottom fraction in the range of 8-14 µm, and 75% lower faction within 17-26 μm. All six series (parties) gliburida synthesized by one firm, Profarmaco, with four of them crushed on the micron mill at the company Profarmaco. Distribution received four parties granulometric composition are presented in detail in the following table.

Data on particle size distribution of a batch of drug substance gliburida used in the clinical program

Table 4
The batch numberA particle size ofA(value equivalent to the diameter of the sphere in microns)
25% lower fraction50% lower fraction75% lower fraction
15921
25921
34818
45918
AndParticle size is determined by the method of laser scattering, the reference method #CRM 8532 (#SM 248533)

Suggested data (specifications) of particle size distribution include three total size criterion described above interval for valid srednevekovogo particle size distribution (50% bottom fraction) and the upper limit for the lower quartile (75% of the bottom fraction). Specifications particle size distribution set for gliburida come from particle size distribution gliburida used in studies of the bioavailability of experience with various clinical batches, close composition distribution of the particle size (particle size distribution) industrial gliburida and precision particle size distribution method. Criteria of particle size (particle size distribution), described below, confirmed the reproducibility of the dissolution gliburida and bioavailability from a tablet Metformin hydrochloride gliburid.

25% lower fractions of size not more than 6 m is m

50% lower fractions of size not more than 7 to 10 µm

75% lower fraction of not more than 23 μm.

Example 4

A. SUMMARY (ESSENCE) 5 CLINICAL PROTOCOLS

(1) Purpose (goal)

The following study was undertaken in order to compare glycemic control with the use of 2 different doses of combined drug Metformin/gliburid constant composition (described in Examples 1 and 2) compared with placebo in naïve drugs (not held treatment, primary) patients with diabetes mellitus type 2 with diet and exercise do not provide adequate glycemic control. 2 doses of varying strength estimate the combined drug of constant composition containing Metformin 250 mg and gliburid 1.25 mg and 500 mg of Metformin 2.5 mg gliburida. Glycemic control (glucose) are estimated with the help of hemoglobin Alc (HbAlc), the gold standard for determining prolonged glycemic control. Comparing the average value of the change in HbAlcrelative to the baseline (background) after 20 weeks of treatment (4 weeks constant dose once a day for 4 weeks ascent changing the dose and 12 weeks constant dose). Phase (period) continue treatment for another 12 weeks to assess the duration of action.

The contribution of individual components of the combined preparation is the constant composition appreciate comparing the glycemic Express the performance of the combined product and monotherapeutic treatment after 4 weeks of constant single dose. Glycemic control is achieved at the same frequency of hypoglycemia in the case of combined preparations of permanent staff compared with one sulfonylurea or tends to decrease gastrointestinal side effects compared to one with Metformin. Glycemic control is achieved with reduced side effects compared with each agent separately. Estimated trends in levels of hypoglycemia, gastrointestinal symptoms, and lactate.

2. Space research and the number of subjects

To study selected primary (not earlier treatment) subjects or those who did not take oral antihyperglycemics medicines within 2 months prior to screening. Approximately 100 areas of study, located in the United States were recruited to a maximum of 800 people. Select both men and women aged from 30 to 78 years with established diabetes mellitus type 2 as specified in the history of the disease impaired glucose tolerance or with the change of glucose on an empty stomach, with inadequate glycemic control despite diet and exercise is.

(3) the Program and duration of study

This study takes 34 weeks, is a multicenter, random, placebo-controlled, double control (blind, parallel study with, if necessary, extended open-label treatment phase.

(4) the measurement Result

Analysis of the measurement results for the Periods b and C perform after getting all the data in a 32-week period randomly selected treatment.

The main (primary) variable indicator of effectiveness is the deviation from the baseline HbAlcin the case of two combination therapies compared to placebo after 20 weeks arbitrary treatment.

Secondary outcomes include the following:

The frequency of adverse reactions, particularly hypoglycemia and gastrointestinal adverse reactions with the different methods of treatment are compared in 20 and 32 weeks arbitrary (randomized) treatment.

- Number and proportion of subjects who have achieved the reaction of glucose to therapy, assess with the different methods of treatment after 20 and 32 weeks arbitrary treatment.

- Reduction of glucose on an empty stomach and in 2 hours after eating appreciate with the different methods of treatment in 20 and 32 weeks arbitrary treatment.

C. RATIONALE

Metformin and sulfonylureas, such as the gliburid, are well-known and effective combination treatment for diabetes type 2. Both drug substances exhibit Energeticheskiy effect, reducing the combined use of glucose. Each medicinal substance can be used alone as first-line therapy. They can be used in combination with each other, if monotherapy with any of them is insufficient. Currently there are no data on the use of combination with low-dose as first-line therapy.

It was expected that treatment tablets combined drug permanent makeup will improve glycemic control with first-line therapy in patients with diabetes mellitus type 2 with poor control with diet and exercise. It was expected that glycemic control can be achieved at lower doses than used in monotherapy, and at a comparable or lower potential side effects of the individual agents and the ease of use.

This is an arbitrary (randomized, double-blind, placebo-controlled study of patients with diabetes type 2 diabetes with inadequate glycemic control provided by diet and exercise, carried out to test the following hypotheses:

1. Receive the combined drug metf the pmin/gliburid with a constant dose over a period of 20 weeks (4 weeks with a constant dose once a day in the reporting Period, and 16 weeks of treatment during Period (C) patients with diabetes mellitus type 2 with insufficient glycaemic control through diet and exercise will cause a significant reduction in HbAlccompared with placebo.

2. Receiving a fixed dose combination drug Metformin/gliburid for 32 weeks in patients with diabetes mellitus type 2 with insufficient glycemic control through diet and exercise is well tolerated.

C. TASK

(1) Basic(primary)

To compare, after 20 weeks of oral administration, the tablets combined drug Metformin/gliburid with two different doses (Examples 1 and 2), which is titrated to assess glycemic control in reducing HbAlcwith the effect of placebo.

(2) Secondary (includes the following)

1. To evaluate the safety and tolerability of different treatments after 20 and 32 weeks arbitrary treatment. It is possible to achieve glycemic control with a similar frequency of hypoglycemia in the case of combined preparations of permanent staff compared with one sulfonylurea or by reducing the number of gastrointestinal side effects compared to one with Metformin.

2. To evaluate after 20 weeks and after 32 weeks the proportion of patients with response to therapy glycemic control with oral use of combined drug Metformin/gliburid for each scheme are compared with the susceptibility to treatment dealt with monotherapy with Metformin, monotherapy gliburid and in those receiving placebo. Therapeutic response (response to treatment, response to treatment) of glucose in plasma is defined as FPG<126 mg/DL (according to current ADA standards for FPG). Therapeutic response for HbAlcdefined as HbAlc<7%.

3. To evaluate after 20 weeks and after 32 weeks the reduction of glucose on an empty stomach and in 2 hours after a meal and insulin levels after oral administration of combined drug Metformin/gliburid each constant composition with reduced glucose on an empty stomach and in 2 hours after a meal and insulin levels obtained with monotherapy with Metformin monotherapy gliburid and when receiving a placebo.

4. To estimate the length of lower levels of HbAlcafter 32 weeks of taking the combined drug Metformin/gliburid permanent makeup.

5. To evaluate long-lasting safety and efficacy of combination drugs Metformin/gliburid permanent makeup.

D. PROGRAM of STUDY

This is a multicenter, random, five areas in parallel groups, double-blind (control), placebo-controlled study antihyperglycemic activity tablets combined drug Metformin/gliburid permanent makeup as first-line therapy of diabetes on what Abete type 2 with insufficient glycemic control (HbA lc<7%) in the diet and in the presence of physical activity. Patients either had not taken drugs before, or did not take oral therapeutics for 2 months before screening. About 100 U.S. points select a maximum of 800 patients with diabetes mellitus with insufficient glycaemic control, defined as HbAlc7-11%when diet and in the presence of physical activity. The minimum number of patients required to achieve the main (primary) result is a total of 500 patients and 100 patients for one direction. However, the set continued up to 6 months in order to take the maximum of 150 patients at one direction with the aim to obtain additional information about the security. The program included 3 the following period:

(1) the Period And a two - week diet and placebo

Introductory stage

This initial phase includes instruction in enough calories, supporting the weight, reasonable diet in diabetes, consistent with the ADA standards, or a balanced diet containing 55% carbohydrate, 20% protein and 25% fats. The portability of taking multiple capsules and tablets estimate using a placebo. Home meter glucose give together with instructions to use them.

(2) Period - 4-week stage, double blind testing with a constant dose given to the th once a day

The period begins In stage random, double-blind, parallel quadrilateral idling of the study (treatment). Selected patients randomizer (arbitrarily referred to one of the five areas of research that include placebo, monotherapy gliburid, monotherapy with Metformin and two combined drug Metformin/gliburid permanent makeup with different values ("force") dose (Examples 1 and 2). During the 4-week period mode single daily reception of patients, so that the contribution of the individual components of the combined product can be estimated using the glycemic Express settings.

This 4-week stage disposable daily administration of a constant dose illustrates the contribution of the individual components of the combined drug of constant composition with rapid indicators. Glycemic control assessed by the content of fructosamine and glucose on an empty stomach.

(3) the Period of 28-week double-blind phase (control) titration and receiving a constant dose.

The period is an extension phase of a randomized, double-blind (control) treatment. Patients check ("titrated", analyze) on glycemic control during the first four weeks, then the dose remain constant over the 24-week is eriod treatment. The analysis on the primary outcome, change in comparison with baseline HbAlcin the case of treatment with 2 combined preparations (Examples 1 and 2) relative to placebo, carried out on a 16-week period, i.e. after 20 weeks, randomized, double-blind treatment. The analysis carried out in this period, as this is sufficient time for stabilization of the level of HbAlcand for security reasons, as it was expected that in the case of a large number of patients receiving placebo, you will need to stop randomized medical study due to inadequate glycemic control with increasing duration of the experiment. Patients, not stopping randomized study drug due to lack of efficacy, continue to take regular doses of a total of 24 weeks to assess the duration of effectiveness and to collect additional data on safety and tolerability. The study is blind, and sick, who have ceased to take randomly drawn their share in the study of the drug, due to its lack of efficiency, had the right to start a long-term open-label phase of treatment is a combination drug of constant composition.

This 28-week phase includes an initial 4-week titration period with the aim of increasing g is iceiceice control with subsequent 24-week phase with a constant dose. The analysis to obtain the primary, the primary result is performed on a 16-week period, Patients With. check to stop taking randomly drawn their share in the course of the study drug due to its lack of glycemic control, starting with a visit to C1 until C. The lack of effectiveness of the test in patients during the visit S and all follow-up visits until the end of randomized treatment. The purpose of random drug for research remains blind. In patients continuing to take arbitrarily inherited preparation for the study, the stage of receiving a constant dose lasts a total of 28 weeks, which allows to estimate the duration of effectiveness (duration) and to collect additional data on safety and tolerability. Patients tested to the termination of the experimental treatment due to lack likemichael control during or after a visit to C1 (week 0, Period).

DOSAGE

Investigated in this experiment drugs (for research) are defined as placebo, gliburid, Metformin, Metformin/gliburid 250/1,25 mg and Metformin/gliburid 500/2,5 mg. To implement blind experiment this study includes Quad-idling program. Patients who meet the criterion for inclusion in PR the program and do not have any symptoms for exclusion from the program, meet glycemic criteria Period And choose to participate in the Period A.

Period And

This period is blind with placebo, for the purpose of testing, as tolerated by the ingestion of numerous capsules and tablets, in addition to the evaluation of consistency with "quadruple" idling program. Patients receive kits containing four bottles with placebo, corresponding to the drug for research.

Week 0 (Visit A1) - Patients are instructed to take 1 capsule or tablet from each bottle during the first Breakfast.

Week 1 (Visit A8) - Patients are instructed to take 1 capsule or tablet from each bottle at Breakfast and one capsule or tablet from each bottle during dinner.

Period

Upon completion blind introductory phase (Period A) "qualified" patients starting treatment in accordance with a randomized double-blind phase (Period). During the visit A15/B1 patients randomly divided into two groups, receiving once during Breakfast placebo, gliburid 2.5 mg, Metformin 500 mg, Metformin/gliburid 250/1,25 mg or Metformin/gliburid 500/2,5 mg Once daily dose remains constant in total for 4 weeks.

The period

Upon completion of the 4-week stage with a single constant daily dose (Period) patients remain the same with the directly randomised (arbitrarily assigned) therapy during 28-week treatment phase: titration/constant dose (Period). The effect of drug therapy check ("titrated") during visits C1, C15 and C. Dose of drugs given during the first meal in the morning and at dinner time. Achieved maximum potential dose contains 10 mg gliburida, 2000 mg of Metformin, 1000/5 mg drug Metformin/gliburid and 2000/10 mg drug Metformin/gliburid. After a 4-week "segment titration during the Period From patients continue to receive a constant dose of the test drug to the rest of the time Period C.

If achieved adequate (sufficient) glycemic control or the maximum dose, the number of medicinal substances do not increase, only decrease in the case of documented hypoglycemia.

RESULTS

The results obtained in the above studies indicate that taking the drug Metformin/gliburid with a low dose (250/1,25) according to the invention is achieved glycemic control, at least almost equivalent glycemic control while taking the drug with a high dose of Metformin/gliburida (500/2,5), as evidenced by the following:

(1) response to therapy (therapeutic response) hemoglobin Alc, namely a decrease in HbAlcbelow 7% (from an average baseline of 8.2%) on 20-th week (Figures 1, 2 and 3), on the 20th and 32nd weeks and at the last visit (Figures 4 and 5),

(2) response to therapy with is the actual content of the plasma glucose fasting (FPG), namely, the decrease in FPG less than 126 mg/DL after 20 weeks (from the base level of about 175 mg/DL), (as shown in Figures 6),

(3) therapeutic response levels of insulin after a meal, such as increased levels of insulin after a meal before 19-25 mkme/ml (microlibrary units/ml) (Figure 7),

(4) therapeutic response amplitude changes of glucose after a meal (PPG) (which represents the difference of glucose levels after eating and fasting plasma), namely the reduction of the deviation of the glucose level after a meal at the 20th week to 17.7 for the combined drug ("combo") 500/2 .5 mg and to 20.8 for "combo" 250/1,25 mg, compared with 15.2 for Metformin, 6,8 for gliburida (Figures 8A and 8B).

At the same time the above results, characterizing the efficiency in the study of the preparation according to the invention with a low dose (Example 1), are achieved with a lower incidence of side effects (Figures 9 and 10).

As can be seen in Figure 9, the frequency of hypoglycemia in the application of the preparation according to the invention with a low dose (Example 1) is less than 1/3 of the frequency of hypoglycemia in the case of a drug with a high dose of the previous prior art (Example 2)used in generally accepted medical practice for treating diabetes.

As can be seen in Figure 10, the frequency of gastrointestinal side effects when using the drug according to the invention with a low dose (Example 1) which is less than 20% of the frequency of these effects in the case of a drug with a high dose (Example 2), used in generally accepted medical practice for treating diabetes.

Next follows a discussion of the above results.

Discussion of results

For the development of clinical type 2 diabetes takes time and requires many physiological disorders that are already present by the time most patients are diagnosed as diabetes. The choice of oral therapeutics for the treatment of type 2 diabetes a few years ago was very limited. In addition, it is assumed that with the gradual development of the disease over time, all oral antihyperglycemics tools become less effective, resulting in insufficient for the patient's glycemic control.

Combination therapy has traditionally been shown as second-line therapy if it is detected that the treatment of one primary agent is ineffective, called the "primary failure" (failure), or after the original effective agents are ineffective to maintain control of glucose levels what is called "secondary failure" (failure). It is not proved that the transition from one unsuccessful monotherapy to an alternative monotherapy is effective to achieve glycemic control; it was shown that only adding the second is of Ghent with great mechanism of action leads to improved glycemic control. If we take into account that the combination of resistance to insulin and a relative insufficiency of insulin secretion is the pathophysiological basis of type 2 diabetes, it should be expected that combinations of agents have great therapeutic opportunities. That is, as clinical experience and pathophysiological signs confirm the application of the combined treatment at an earlier stage of the disease.

Although the combination drug Metformin and gliburida permanent makeup is not new and, as discussed above, outside of the United States issued its various forms for the treatment of first and second line, the combined therapeutic drug with a low or moderate dose as first-line therapy in case of not taking drugs previously (primary) patients earlier in extensive controlled clinical studies have not been studied. Treatment to achieve almost normal glycemia, with HbAlc<7%recommended by the ADA, is a challenge for any antihyperglycemic therapy. However, with prolonged disease diabetes and the development of the disease one agent may not provide the performance needed for the implementation of the main task, even in the case of patients with newly diagnosed diabetes. The data presented in this description, prove that com is nirovany drug (product) Metformin/gliburid constant composition with a low dose is safe and provides effective content antihyperglycemics substances, necessary in order to achieve in the treatment of most naïve treatment of patients recommended by the ADA glycemic goals.

As a first-line therapy only recipe combined drug Metformin/gliburid ratio Metformin/gliburid = 200:1 evaluate, using two doses of various forces, low dose (Metformin/gliburid 250/1,25 mg) and high dose (Metformin/gliburid 500/2 .5 mg). Two doses of the different forces combined drug Metformin/gliburid permanent makeup compare double (double) blind study with placebo, monotherapy with gliburida and monotherapy with Metformin. The average final dose achieved in each direction (using each tool), make up approximately 5.3 mg gliburida, 1307 mg of Metformin, 557/2,78 mg of combined drug Metformin/gliburid constant composition with a low dose (250/1,25 mg) and 818/4,1 mg of combined drug permanent makeup with medium dose (500/2 .5 mg). When used as first-line therapy combined drug Metformin/gliburid permanent makeup gives a statistically significant improvement in glycemic control compared with Metformin, gliburid or placebo. Intermediate open label data treatment confirm the clinical usefulness of treatment with combined drug posto the frame structure more "glycemic diverse population of patients and for a longer time.

Security

As a first-line therapy assess two doses of the various forces Metformin/gliburida; force low dose (250/1,25 mg) and medium dose (500/2 .5 mg) compared with placebo, gliburid and Metformin. On the stage, double-blind study diarrhea is the most common reverse effect (AE) in those patients who are exposed to monotherapy with Metformin or combination therapy. It is important, however, that the frequency of gastrointestinal AE lower in the group receiving combined product of constant composition with a low dose than in the Metformin-alone (as seen in Figure 10). Termination (experiment) due to AE also occurs less frequently in the group receiving combined product of constant composition with a low dose, compared with any other active drugs. Termination (experiment) due to inadequate glycemic control is most rare in both groups, a combination drug of constant composition, and severe hypoglycemia was not observed in this study. The frequency of complaints on cases of hypoglycemia higher in the group receiving combined product of constant composition with an average dose, whereas in the group with low dose observed lower frequency (hypoglycemia)than in the case of gliburid-monotherapy (Figure 9). Weak the increase of lactate levels observed in all groups, take Metformin, but in this study not reported one case of lactic acidosis.

At the stage of "open label" study of patients can be directly included in the number of examinees, if glycemic indices they are not suitable for the double-blind phase. Patients can be included in the open label phase, if they prematurely stopped the experiment on "double-blind" stage due to lack of glycemic control or after they completed the double-blind phase. "Open label phase of the study schedule AE similar graphics AE, observed at "double-blind" stage, the most frequent AE occur in systems of the same composition. In the group receiving combination drug with a low dose, is also the most favorable in relation to the overall security of the graph compared to the group receiving high dose.

As in patients with newly diagnosed diabetes, and in patients with low (inadequate) full control chart safety and tolerability observed in the "double-blind" studies, such as expected on the basis of clinical experience with the use of Metformin and gliburida In this clinical program, no new or unexpected events or laboratory abnormalities not observed. Interim analyses lengthy "open label" additionally on the confirm favorable safety profile, observed short-term stages of the study. In particular, in the case of combined drug with a low dose schedule safety/tolerability the most favourable in comparison with other schemes used in this program.

Efficiency

Double-blind therapy, the first row shows a statistically significant mean decrease in hemoglobin Andlc(HbAlc) 1.3% compared with placebo in both groups receiving combined product of constant composition, the average decrease compared to the baseline of about 1.5%. Although all groups receiving active drug, acceptable glycemic control in both groups, a combination drug of constant composition achieves a higher average reduction level HbAlccompared with Metformin therapy or gliburid therapy. Duration antihyperglycemics actions observed in all active treatment groups (gliburid, Metformin, Metformin/gliburid 250/1,25 mg, Metformin/gliburid 500/2 .5 mg)that can be seen on the average level of HbAlcsince weeks 20 (6,64%, 6,79%, 6,68%, 6,44%) up to a week 32 (6,78%, 6,96%, 6,87%, 6,68%) or double-blind therapy below therapeutic target of 7% (Figures 3 and 4).

Intermediate data "open label" first-line therapy demonstrate that the right near St is only selected patients average HbA lc(baseline) is 10.6% and for patients with appropriate data, the average reduction level HbAlcthe 3.5% is achieved when the magnitude of 7.1% after 26 weeks. Of patients directly admitted to participate in open-label therapy, 87% receive an average dose of 500/2 .5 mg combined drug permanent makeup as initial therapy, and by the time of the interim Protocol average dose combined drug permanent makeup Metformin/gliburid is 1569/7,85 mg In patients fit for open-label treatment phase data, completing the double-blind phase of treatment and continuing it on the open-label phase, the average value of the HbAlc3,5% on the baseline is 8,32. In all patients, prolechivshis 13 weeks, achieved average reduction level HbAlc1,76% with an average value of HbAlc6,56%. Among patients completing the double-blind phase of the study and continuing treatment in the open-label phase, 78% received low-dose (250/1,25 mg) and 22% had received high dose (500/2 .5 mg) combined drug permanent makeup as initial therapy. The average dose of combined drug permanent makeup Metformin/gliburid is 696/3,48 mg.

No clinically significant example increased or reduced effect is not observed in any of the subpopulations (age, who, race) in terms of deviations (reaction) HbAlcfrom the baseline in any double-blind test with a combination drug Metformin/gliburid permanent makeup as first-line therapy.

In this clinical program also considers the content of glucose as an indicator quick (Express) glycemic control. The results of FPG in double-blind tests are consistent with the HbAlc. As a first-line therapy statistically and clinically significant higher mean values reduce the level of FPG are achieved in both groups treated with combined product of constant composition, compared with placebo and Metformin (Figure 6). There is an earlier response to treatment is a combination drug of constant composition; differences in the experimental groups become apparent at week 2, double-blind therapy, the time when "subjects" are still going through the initial "titration" and get half of the potential maximum dose. This early reaction of resistant populations of patients at half of the maximum dose for monotherapy demonstrates the advantage of combination therapy for the patient and application of combined drug at an earlier stage of the disease.

Hemoglobin Andlcis a common standard criterion fully what about the glycemic control and he is a glycemic marker, which, as found, correlated with long-term complications. Although the content of glucose in plasma fasting, modern standard, is more quickly testable, more convenient marker, it does not give optimal estimates of circadian blood glucose control. Shown and it is intuitively clear that the concentration of glucose in plasma after a meal is the best indicator of diabetic control than FPG, when type 2 diabetes; this figure is also better correlated with HbAlc. Hyperglycemia after eating an early indicator of metabolic disorders that can be detected by the type 2 diabetes and it contributes to the dysfunction of beta cells. Shows the important link between glucose levels after eating and cardiovascular disease. If normal glycemia is aimed at the prevention of late complications of diabetes, monitoring and lowering blood glucose levels after a meal is a reasonable strategy to improve metabolic functions and establish full control over glucose levels.

As a first-line therapy is a statistically significant higher average absolute reduction of glucose after a meal (63-65 mg/DL) was observed in both groups receiving combined product of constant composition, compared with the placebo group. Also get a higher average value is I reduce the absolute PPG compared with monotherapy gliburid (16-18 mg/DL) and Metformin (18-20 mg/DL) (Figure 8A and 8B). The deviation of the glucose levels within two hours from the baseline fasting in both groups receiving lower dose of 22.5 mg/DL) and high dose (23.9 mg/DL) combined drug permanent makeup is only 56-59% of the placebo (of 40.3 mg/DL), 59-63% of gliburida (38,2 mg/DL) and 75-81% of the Metformin (29,5 mg/DL). The deviation brighter than an absolute value demonstrates that gliburid similar to placebo, Metformin better reduces glucose levels after a meal than gliburid and placebo, and that combined drug with a low dose of the most effective in reducing the amplitude level of glucose after a meal. As there is no published clinical data on combination therapy in a population of primary (not received prior treatment) patients, these results provide new insights on the discussion of the impact of the choice of method of treatment at this stage of the disease. Indeed, the results cannot be predicted on the basis of the changes observed in the population during many studies of therapy of the second row.

In a study of first-line therapy are evaluated insulin levels fasting and after a meal (Figure 7). There is a statistically significant increase in response to insulin in the presence of glucose load in both groups receiving combined product of constant composition (24-28,8 mkme/ml), compared with placebo. There is more the one amplification reaction of insulin in the presence of glucose load group, receiving low-dose combined drug of constant composition (14.6 mkme/ml), compared with gliburid-monotherapy and a more significant increase in the insulin response in the presence of glucose load in both groups receiving combined product of constant composition (21-25,8 mkme/ml)in comparison with Metformin-monotherapy. If we consider the average doses of active drug substances in a group of subjects (experimental group), the reaction of insulin cannot be explained by the influence of one sulfonylurea in combination therapy. These clinical data support preclinical study with isolated insularity podgeludognoi cancer, when it was suggested that Metformin prevents hyperglycemic hyposensitization of insulation. The combination of normal and suitable elevated reaction of insulin with a corresponding large decrease in the amplitude (variance) of glucose suggests that the combination increases the effectiveness of the pancreas in response to glucose load, while maintaining the function of beta cells and improving insulin sensitivity.

A major challenge in the care of patients with type 2 diabetes, in addition to the energetic treatment of high blood pressure and high lipid content is determining how close to normal the possession of glucose (blood glucose level), or achieving a therapeutic glycemic goals. There is a stronger reaction to the combined product of constant composition, which is expressed in the fact that more patients achieve therapeutic goals and a more significant reduction in the absolute value of the HbAlc. As a first-line therapy combined product of constant composition leads to a greater number of "subjects" (66-71%) reaches glycemic goals HbAlcJ 7% compared with 60% in the case of monotherapy with sulfonylurea, 50% when Metformin is used alone and 20% in those receiving placebo after 20 weeks of double-blind therapy. Approximately 28% of patients in each group receiving combined product of constant composition, HbAlcdecreases compared to the baseline of more than 2.0%, compared to 16-17% in each group exposed to monotherapy, and 3% in the placebo group. It should be noted that these objectives are achieved not by simply increasing total doses of drugs, but at lower doses of additional components. The average final dose of each therapeutic agent of the first series is about: gliburid 5.3 mg, Metformin 1307 mg, a combination drug with a low dose of 557/2,78 mg, and a combination drug with an average dose 818/4,1 mg In the event of a change in HbAlcwith the number of tablets picture observed when combined vannoy therapy, there is nothing unexpected in terms of pathophysiology. This indicates that there is a clear reaction to the "object" at all doses, and that the need for higher doses correlated with higher baseline (background) HbAlc. A similar picture can be detected for gliburida up to a total dose of 7.5 mg; Metformin does not show a clear pattern.

The presented data confirm that the combination drug Metformin/gliburid as agent of the first number of most likely causes of the patient for therapeutic purposes, regardless of how high background (baseline) HbAlc. For both the combined preparations with a constant dose average reduction compared with baseline HbAlchigher for patients with higher levels of background (baseline). This phenomenon is not observed in the case gliburida, Metformin, or placebo, and we do not think that this may be the case another monotherapy. This demonstrates the contribution of the components necessary for achieving a therapeutic glycemic goals when the background (basic) level HbAlcabove 9%. It is shown that when alone there is a sloping part of the curve glycemic response to background levels HbAlc<9%, while the combined "fixed" therapy there are additional incremental lowered what I HbA lcfor background HbAlclevels <9%.

All patients included in the "open" phase of first-line therapy with appropriate data for at least two time points, the average value of the HbAlcat the baseline is 9.45%. At weeks 13, 26 and 39 approximately 50-55% of patients the level of HbAlcreaches less than 7%, and even 30% of it is <8%. This speed of response and the magnitude of the changes at the top level HbAlccan be expected with combination therapy, but she is rarely seen with monotherapy using antihyperglycemic agents. The fundamental question is, at what initial antihyperglycemics treatment will be achieved glycemic target HbAlc<7% the largest number of patients. These data make it even more necessary reassessment of modern views on the treatment of type 2 diabetes and switching to the use of combination therapy at an earlier stage of the disease.

Weight gain usually occurs if all antihyperglycemic agents other than Metformin (monotherapy). With improved glycemic control really expected to increase weight because the calories rather remain than are lost due to poor metabolic control. In the clinical program, as well as glycemic control improved, minimally the earlier weight gain, approximately 1-2 kg, observed in the case of "fixed" combination therapy; it is comparable to the weight gain of 2 kg observed in monotherapy using gliburida as first-line therapy. During double-blind therapy after the initial minimum increase in weight remains stable and does not increase with time.

Generally not observed clinically or statistically significant difference between any groups of subjects in terms of changes of lipid profile in plasma. As the most severe patients were excluded from placebo-controlled trials, the smaller the change of the reaction (response) to treatment could not be detected. The population of patients with first-line therapy had inadequate glycemic control, but diet and exercise helped to bring the average value of the HbAlcto 8.2%. Patients receiving combined product of constant composition, lipid profile in plasma has no side effects (total cholesterol, LDL, HDL and triglycerides) or significant differences compared with placebo or gliburid - and Metformin-monotherapy.

Better understanding the relationship between diabetic control and speed of the distant complications, we can say that the goal of care for diabetes at present is to achieve and maintain as much as possible to normal glycemia (RRD is the tier glucose). Targeting many violations with agents with sinergeticheskim or additional (complementary) mechanisms of action, intuitively seek to achieve a therapeutic glycemic goals. A deeper understanding of the nature of type 2 diabetes suggests that current perspectives on treatment, allowing the "violation" to occur before applying more aggressive treatment should be reconsidered. Earlier application of the combined drug with a low dose, particularly when using lower doses, gives better portability, therefore, is, apparently, an important therapeutic method if the goal is achievable and the mode is maintained. Combination drug being evaluated in this study allows the use of lower doses and use one common form.

Combined product of constant composition Metformin/gliburid low dose is safe and effective for achieving and maintaining glycemic control in patients with type 2 diabetes whose diet and exercise do not provide adequate likemichael control. The use of combination therapy at earlier stages of the disease (diabetes), apparently, is clinically successful alternative to classic view on the treatment of admitting failure (audace) sequential therapy before how to make more intense, but clinically important treatment strategy. Although this short-term study, this is not considered, the strategy to achieve as close as possible to normal strategic goals, apparently, affects slow down the development of diabetes and delays the start of late complications of diabetes. The population of patients resistant to monotherapy, combination drug Metformin and gliburida permanent makeup causes clinically significant improvement in glycemic control in the absence of signs, and adverse metabolic effects of or relating to security. No clinically significant hypoglycemia, adverse effect on the lipids in the plasma, and after a limited early increase in weight over time becomes constant. The synergistic combination of Metformin and a sulfonylurea is established, fixed combination of Metformin and gliburida effectively improves glycemic control and is a reasonable choice in antihyperglycemics "outfit". It is assumed that the fixed combination simplifies dosing, more convenient and, therefore, treatment is more flexible.

Low dose (250/1,25 mg) combined drug permanent makeup may be the initial dose as first-line therapy is the primary (not received prior treatment) patients. Then it should be correct ("chitravati"), as indicated, to achieve HbAlc<7%.

GENERAL CONCLUSIONS

Data on safety and efficacy in this clinical program evaluating combined drug Metformin/gliburid permanent makeup ("fixed") as first-line therapy for patients with type 2 diabetes, agree to the following:

- The percentage of patients who stop treatment due to hyperglycemia, lower in the case of "fixed" combination Metformin/gliburid compared with Metformin, gliburid and placebo.

- Hypoglycemia and symptoms of hypoglycemia occur less frequently when used as first-line therapy (Figure 9) drug Metformin/gliburid 250/1,25 mg compared to form Metformin/gliburid 500/2 .5 mg and gliburid.

The frequency of gastrointestinal disorders (side effects)caused by a combination drug of constant composition, the lowest in the case of use as first-line therapy Metformin/gliburida 250/1,25 mg compared to Metformin/gliburid 500/2 .5 mg and Metformin (Figure 10).

- Patients who are receiving long-time open-label "fixed" combination Metformin/gliburid there are no new and unexpected adverse events or laboratory abnormalities.

Significantly higher efficiency of the combined preparation is the permanent makeup Metformin/gliburid any active substance, that proved to be a more significant decrease in all glycemic parameters (HbAlcthe content of glucose after a meal, glucose on an empty stomach and the contents of fructosamine), compared with placebo, gliburid and Metformin.

- Energeticheskiy effect of combined drug with a low dose, aimed at many metabolic disorders, leads to the enhancement of the function of beta cells and improve insulin sensitivity, as shown by the concentration of glucose in plasma after a meal and amplitude (variance) of the content of insulin, and increased metabolic function and improve glycemic control.

- Greater number of patients receiving combination drug Metformin/gliburid permanent makeup, reach glycemic therapeutic targets HbAlcJ 7%.

Effective blood glucose lowering to appropriate therapeutic purposes, for any basic (initial) values HbAlccompared with treatment with placebo, gliburid and Metformin. It was shown that when used as initial therapy gliburid and Metformin have a flat area (plateau) glycemic response to cases of initial levels (baseline) HbAlc>9%, whereas in the case of therapy "fixed" combination Metformin/gliburid there are additional incremental pangeni the levels of HbA lcfor levels baseline HbAlc>9%.

- Limited early weight gain at the same time (in parallel) with improved glycemic control compared with monotherapy gliburid; however, weight over time remains constant.

Therapy with combined drug of constant composition (fixed combination) no adverse effects on lipid profile (total cholesterol, LDL, HDL and triglycerides), with no significant differences from placebo or gliburid - and Metformin-monotherapy.

- Fit the efficacy and tolerability of combined drug permanent makeup Metformin/gliburid 250/1,25 mg confirms the possibility of its use as the starting dose in the first-line therapy.

The above results clearly show that treatment of diabetes through medication Metformin/gliburid low dose according to the invention (250/1,25 mg), at least equivalent in efficacy to treatment with medicines with a higher dosage (500/2 .5 mg), but gives a more mild side effects.

1. A method of treating type 2 diabetes in a patient person, not who had anti-diabetic drugs, which is the introduction of combined drug Metformin and gliburida, and the daily dose of injected Metformin is 160-750 mg, gliburida - ,5-15 mg, and granulometric composition gliburida is that the size of a maximum of 10% of the particles less than 2 microns, and the size of a maximum of 10% of the particles is more than 60 μm.

2. The method according to claim 1, wherein the initial dose of Metformin is about one fifth of the initial daily dose of Metformin used in common medical practice in the treatment of diabetes in patients not treated previously antidiabetic drugs.

3. The method according to claim 1, wherein the initial dose gliburida is about one fifth of the initial daily dose gliburida used in common medical practice in the treatment of diabetes.

4. The method according to claim 1, wherein the combination drug Metformin and gliburida prepared in the form of a single dosage form.

5. The method according to claim 1, wherein Metformin is used in a weight ratio with gliburid in the range of 400:1-50:1.

6. The method according to claim 5, wherein Metformin is used in a weight ratio with gliburid in the range of 200:1-100:1.

7. The method according to claim 1, wherein Metformin is administered in the amount of 125-750 mg, one to four times per day, provided that the maximum daily dose of Metformin is from 225 to 750 mg per day, and gliburid enter in the amount of 0.75 to 5 mg, one to four times per day, up to a maximum of 15 mg per day.

8. The method according to claim 1, wherein Metformin is administered in the amount of 250-500 mg, and gliburid of 1.2-5 mg

9. The method according to claim 1, in which the combined product contains 250 mg of Metformin 1.25 mg gliburida.

10. The method according to claim 1, in which the combined product contains 500 mg of Metformin and 2.5 mg gliburida.

11. The method according to claim 1, in which the combined product contains 500 mg of Metformin and 5 mg gliburida.

12. The method according to claim 1, wherein the dose of Metformin/gliburida 250/1,25 mg administered once a day or twice a day.

13. The method according to item 12, wherein the dose of Metformin/gliburida 250/1,25 mg administered to patients with baseline (background) HbA1c>9% or fasting glucose >200 mg/DL twice a day, increasing, if necessary, dose increments 250/1,25 mg every two weeks until the minimum effective daily dose necessary to achieve adequate glycemic control.

14. A method of treating type 2 diabetes in a patient person, not who had anti-diabetic drugs, which consists in the introduction of combined drug Metformin and gliburida, with the initial dose is 250 mg of Metformin 1.25 mg gliburida and granulometric composition gliburida is that the size of a maximum of 10% of the particles less than 2 microns, and the size of a maximum of 10% of the particles is more than 60 μm.

15. A method of treating type 2 diabetes in a patient person who previously antidiabetic drugs containing the I in the introduction of combined drug Metformin and gliburida, if this initial dose is 250 mg of Metformin 1.25 mg gliburida twice a day or 500 mg of Metformin and 2.5 mg gliburida once a day, and granulometric composition gliburida is that the size of a maximum of 10% of the particles less than 2 microns, and the size of a maximum of 10% of the particles is more than 60 μm.

16. A method of treating type 2 diabetes in a patient person, not who had anti-diabetic drugs, which consists in the introduction of combined drug Metformin and gliburida, with the initial dose is 500 mg of Metformin and 5 mg gliburida and granulometric composition gliburida is that the size of a maximum of 10% of the particles less than 2 microns, and the size of a maximum of 10% of the particles is more than 60 μm.

17. A method of treating type 2 diabetes in a patient person, not who had anti-diabetic drugs, which consists in the introduction of combined drug Metformin and gliburida, with granulometric composition gliburida is that the size of a maximum of 10% of the particles less than 2 microns, and the size of a maximum of 10% of the particles is more than 60 μm.

18. The method according to 17, wherein a maximum of 10% gliburida are particles smaller than 3 μm, and a maximum of 10% of the particles are particles larger than 40 microns.

19. The method according to 17, wherein a maximum of 25% gliburida comprise a particle size of less than 11 μm, and max the minimum is 25% of the particles larger than 46 microns.

20. The method according to 17, at which 50% of particles gliburida have a size of less than 23 micron.

21. The method according to 17, in which 25% gliburida amount of particles not larger than 6 µm, 50% 7-10 µm, and 75% not more than 23 μm.

22. The method according to 17, wherein the initial dose is 250 mg of Metformin 1.25 mg gliburida or 500 mg of Metformin and 2.5 mg gliburida.

23. A method of reducing the level of glucose in human blood, a patient with hyperglycemia treated previously antidiabetic drugs, which is the introduction of combined drug Metformin and gliburida, and the daily dose of injected Metformin is 160-175 mg, gliburida - 0.5 to 15 mg, and granulometric composition gliburida is that the size of a maximum of 10% of the particles less than 2 microns, and the size of a maximum of 10% of the particles is more than 60 μm.

24. A method of reducing resistance to insulin, and/or lowering of hemoglobin A1cand/or increase insulin levels after eating, and/or decrease the amplitude changes of glucose after a meal in a patient person, not who had anti-diabetic drugs, which is the introduction of combined drug Metformin and gliburida, and the daily dose of injected Metformin is 160-175 mg, and granulometric composition gliburida is that the size of a maximum of 10% of the particles are less than 2 m is m, and the size of a maximum of 10% of the particles is more than 60 μm.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of diphenylazathedinone of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another (0-C30)-alkylene-L wherein one or some C-atoms of alkylene residue can be substituted with -O-, -(C=O)- or -NH- and, except for, R1-R6 can represent hydrogen atom (H), fluorine atom (F), and L represents compound of the formula: , and their pharmaceutically tolerated salts also. Compounds of the formula (I) elicit hypolipidemic effect and can be used in therapeutic aims. Also, invention describes a medicinal agent and its using.

EFFECT: valuable medicinal properties of compounds.

7 cl, 31 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used for stabilization of homeostasis and arresting pathological processes in the body. Invention proposes a pharmaceutical composition as powder with particles size from 250 to 400 mcm comprising the following components by the first variant, wt.-%: carbon, 10.01-53.02; oxygen, 30.10-53.10; potassium, 0.26-1.99, and calcium, 0.20-31.37, and comprising the following components by the second variant, wt.-%: calcium, 0.35-31.20; carbon, 10.99-50.21; oxygen, 34.55-51.03; sulfur, 0.73-14.81, and phosphorus, 0.08-3.30. Invention provides compensation of trace elements unbalance that causes and accompanies many diseases, possibility for stabilization of trace element homeostasis and arresting pathological processes of different etiology.

EFFECT: improved and valuable medicinal properties of composition.

12 cl, 13 ex

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition made mainly as solid medicinal formulations and comprising therapeutically effective amount of gliclazide and the special additive in the amount 4.65-6.70 mass. p. per mass unit of active substance. The additive comprises hydroxypropylmethylcellulose, microcrystalline cellulose, aerosil and stearate taken in the following ratio of components, mass. p. per 1 m. p. of active substance: hydroxypropylmethylcellulose, 2.50-3.50; microcrystalline cellulose, 2.12-3.00; aerosil, 0.01-0.05, and stearate, 0.02-0.15. Proposed pharmaceutical composition provides the sustained-release of gliclazide and high bioavailability of active substance, a simple method for its preparing as compared with solid medicinal formulation of gliclazide known from the prior art.

EFFECT: improved and valuable properties of composition.

3 cl, 2 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical preparation based on angiotensin-converting enzyme inhibitor, its using in prophylaxis of insult, diabetes and/or congestive cardiac insufficiency and corresponding methods for its using in patient with maintenance heart function and subjected for risk of cardiovascular attack due to previous history of ischemic disease, insult or peripheral arterial disease. In particular, inhibitor of angiotensin-converting enzyme can be chosen from ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. Invention promotes to reducing the total lethality of patients group in case of cardiovascular diseases, cardiac attacks and insults, the necessity for carrying out procedures for revascularization (such as surgery operation for coronary shunt, angioplasty with using balloon and so on) and diabetic complication are diminished.

EFFECT: improved and valuable medicinal properties of preparations.

19 cl, 1 ex

FIELD: medicine, cardiology, endocrinology.

SUBSTANCE: method involves administration of amlodipine in the dose 5 mg, once in the same time and metformin in the dose 500 mg, 2 times per 24 h in patients at the background of individually selected hypocaloric diet. Treatment is carried out for 8 weeks, not less. Method provides optimization of intravascular activity of platelets due to correction of primary homeostasis and the level of their antioxidant protection. Invention can be used for rapid optimization of functions of platelets at metabolic syndrome.

EFFECT: improved and enhanced method for optimization.

2 ex

FIELD: organic chemistry, medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to new derivatives of acylphenylurea of the formula (I) and to their physiologically acceptable salts possessing property of glycogen phosphorylase inhibitors. In compound of the formula (I) A means phenyl and phenyl residue can be substituted three times with fluorine (F), chlorine (Cl), bromine (Br) atoms, -CF3, -NO2, -O-(C1-C6)-alkyl, -SO2-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R1 means hydrogen atom (H), (C1-C6)-alkyl; R2 means H, (C1-C6(-alkyl, -CO-(C1-C6)-alkyl; 3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -O(C1-C6)-alkyl, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, -COOH, -COO-(C1-C6)-alkyl; X means oxygen (O), sulfur (S) atom; R7 means (C1-C10)-alkylene-COOH, (C1-C10)-alkylene-COO-(C1-C6)-alkyl, (C1-C10)-alkylene-NH2, (C1-C10)-alkylene-NH-(C1-C6)-alkyl, (C1-C10)-alkylene-N-[(C1-C6)-alkyl]2, (C1-C10)-alkylene-B wherein B means piperidinyl or furyl. Also, invention relates to a pharmaceutical composition and a method for preparing the pharmaceutical composition. Proposed compounds can be used for preparing pharmaceutical composition useful for declining level of blood glucose and for treatment of diabetes mellitus type II.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

7 cl, 2 sch, 2 tbl, 1 ex

FIELD: medicine, endocrinology.

SUBSTANCE: treatment involves prescription to patient light water as drinking water with the total mineralization 200-500 mg/l, the deuterium content 100 ppm, not above, and the oxygen-18 content 1800 ppm, not above, on the background of dietetic therapy and insulin therapy or intake of hypoglycemic preparations in the daily dose 1000-1500 ml. The first intake is carried out before eating in the morning in the dose 200-250 ml and the remaining amount for a day, 30-40 min before eating or in breaks of eating every day. The curative course is from 28 to 45 days. Method provides declining the blood glucose content and to improve metabolic processes.

EFFECT: improved treatment method.

2 ex

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to O-arylglucoside inhibitors of SGLT2 of the formula (I): wherein Y means compounds of formulae: A means -O(CH2)m, sulfur atom (S), -NH(CH2)m or -(CH2)n wherein n = 0-3; m = 0-2; R1-R6 are determined above, and to a pharmaceutical composition based on thereof, and to methods for treatment of diabetes mellitus type 2, and micro- and macrovascular diabetic complications.

EFFECT: valuable medicinal properties of inhibitors.

15 cl, 1 tbl, 99 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition made mainly as solid medicinal formulations and comprising therapeutically effective amount of gliclazide and the special additive in the amount 4.65-6.70 mass. p. per mass unit of active substance. The additive comprises hydroxypropylmethylcellulose, microcrystalline cellulose, aerosil and stearate taken in the following ratio of components, mass. p. per 1 m. p. of active substance: hydroxypropylmethylcellulose, 2.50-3.50; microcrystalline cellulose, 2.12-3.00; aerosil, 0.01-0.05, and stearate, 0.02-0.15. Proposed pharmaceutical composition provides the sustained-release of gliclazide and high bioavailability of active substance, a simple method for its preparing as compared with solid medicinal formulation of gliclazide known from the prior art.

EFFECT: improved and valuable properties of composition.

3 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying substituted benzenesulfonylureas and -thioureas of the formula (I) for preparing a medicinal agent used for treatment and prophylaxis of disturbances in vegetative nervous system. In particular, invention relates to treatment and prophylaxis of disturbances associated with vagus nerve, for example, in cardiovascular diseases, and to applying compounds of the formula (I) in combination with beta-receptor blocking agents. Also, invention relates to products and pharmaceutical compositions that comprise at least one substance among compounds of the formula (I) and at least one beta-receptor blocking agent, and to new compounds also. Invention provides enhancing effectiveness in treatment.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

22 cl, 2 tbl, 6 ex

FIELD: pharmaceutical agents, in particular glyburide containing composition.

SUBSTANCE: claimed composition contains 5-chloro-N-[2-[4-[[(cyclohexylamino) carbonyl]amino]sulfonyl]ethyl]-2-methoxybenzamide, known under generic name as glyburide, and has the next grain-size classification (%): undersize of 3-11 mum - 25; undersize of 6-23 mum - 50 %, and undersize of 15-46 mum - 75 %. Such grain-size classification affords the ability to increase glyburide dissolution rate and provide reproducible biological availability of glyburide.

EFFECT: pharmaceutical composition useful for treatment of II- type diabetes.

11 cl, 2 tbl, 6 ex

The invention relates to medicine, specifically to a solid dosage form for oral administration comprising a combination of Metformin and glibenclamide in which the particle size of glibenclamide provides bioavailability of glibenclamide, comparable to the bioavailability of glibenclamide provided by the introduction of Metformin and glibenclamide in separate tablets

The invention relates to the derivatives of benzosulfimide formula (I):

< / BR>
where X represents a nitro-group, a cyano or halogen; Y1represents a secondary or tertiary amino group; Y2represents nitrogen or NH group; Z represents oxygen, sulfur, -N-CN or CH-NO2; and R1and R2that may be the same or different, are each independently saturated or unsaturated linear or branched alkyl group containing from 2 to 12 carbon atoms, saturated or unsaturated alicyclic group containing from 3 to 12 carbon atoms, phenyl, unsubstituted or substituted by one or more substituents, which represents a1-C4alkyl group, nitro, cyano, trifluoromethyl, carboxy and halogen, benzyl group or phenylethylene group, or Y1means tertiary amino group and R1form a morpholine or homopiperazin and Y2represents nitrogen and R2forms homopiperazin, except for derivatives, for which X is a nitro-group, Y1represents a secondary amino group (-NH-), Y2represent the group, includes m-toluyl, phenyl and cyclooctyl, and with the exception of N-[(2-cyclooctylamino-5-cyanobenzoyl)sulfonyl] N'-Isopropylamine, or its pharmacologically acceptable salt

The invention relates to new substituted benzosulfimide or timesaving formula I and their pharmaceutically acceptable salts, method of production thereof, containing pharmaceutical composition and method of reception

The invention relates to new substituted benzosulfimide or-thiourea of the formula I and their pharmaceutically acceptable salts, possess antiarrhythmic activity and activity to prevent sudden, caused by arrhythmia death from cardiac arrest, the way they are received, containing pharmaceutical composition and method of reception

The invention relates to medicine, specifically to medicinal drug with anti-diabetic action

FIELD: medicine, pediatric gastroenterology.

SUBSTANCE: the present innovation deals with selecting children with functional dyspepsia at helicobacteriosis for the purpose to carry out anti-helicobacter therapy. So, one should detect the following signs in a child: hypertrophic gastropathy in gastric antral department, relapses of dyspepsia symptoms during 1 yr and more, despite treatment by applying antacids and anti-secretory preparations, inheritance on ulcerous disease, previously observed erosions in gastroduodenal area; and in case of any of the above-mentioned signs in a child it is necessary to fulfill anti-helicobacter therapy, and in case of the absence of the above-mentioned signs this therapy should not be carried out. This innovation provides differentiated approach to therapy, it, also, enables to avoid groundless medicinal loading upon a child and decrease financial expenses for the treatment.

EFFECT: higher efficiency of individualization.

4 ex

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