Anti-diabetic preparation and method for treatment of diabetes mellitus

FIELD: medicine, endocrinology.

SUBSTANCE: invention elates to a method for treatment of diabetes mellitus type 2, method for declining the glucose content in patient blood and method for reducing resistance to insulin, diminishing the hemoglobin A1c content, enhancing the insulin level after eating, and reducing the amplitude change content ("mobility") of glucose in diabetic patients. Method involves administration of metformin to patient in the low dose (160-750 mg) in combination with the second anti-diabetic agent chosen from the group including glucose oxidase inhibitor, glucagons-like peptide-1 (GLP-1), insulin, α/β-double agonist of PRAP other than thiazolidinedione, meglitimide and inhibitor aP2 wherein the second anti-diabetic agent is administrated as a daily dose in interval between the initial daily dose comprising 20-60% of the initial daily dose of this anti-diabetic agent used in usual medicinal practice in therapy of the first order in treatment of diabetes mellitus up to the daily supporting dose comprising 40-60% of the daily supporting dose of this anti-diabetic agent used in usual medicinal practice as therapy of the first order in treatment of diabetes mellitus. Invention provides the effectiveness in treatment of diabetes mellitus that is equivalent practically to effectiveness of treatment by using combination of metformin and other indicated anti-diabetic agent used in doses prescribing in usual medicinal practice but with significantly less adverse effects.

EFFECT: improved method for treatment of diabetes mellitus.

7 cl, 10 dwg, 4 tbl, 3 ex

 

The scope to which the invention relates.

This invention relates to a pharmaceutical preparation with a small (low) dose of medicinal substance for the treatment of type 2 diabetes have not been subjected to the action of drugs for patients, which contains Metformin (preferably used in smaller quantities in comparison with commonly accepted in medical practice) and another antidiabetic agent, such as, for example, sulfonylurea, gliburid, and the drug treatment of type 2 diabetes is almost equivalent known from the prior art anti-diabetic medications containing Metformin, but has significantly reduced side effects, and to a method of treatment of diabetes with these drugs.

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 microcosm the East 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 therapeutics 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 be used together, usually after it was found that monotherapy is not sufficient.

In 1995 metform the nom complements the sulfonylurea in the treatment of patients, have 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. Different mechanisms of action in case 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) - are 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.) (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 is 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 non-katolicheskogo diabetes) The Medical Journal of Australia, 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 increases the sensitivity to and Sulina in moderately controlled hyperinsulinemia. Cefalu et al., Diabetes, (45, Suppl. 2, 201 A, 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, Suppl. 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 the 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 times daily), in one example, the dosage of Metformin is 500 mg to 5 times a day".

(3) In European patent application EP A (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 f is my 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).

Explanation GlucophageT (Metformin company Bristol Myers Squibb) in the Directory of the doctor in 1999 under the "Indications and usage" indicates that 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 a gradual add - 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 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, irregular or unable 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 it is proposed to use in the treatment of diabetes and related diseases drug smalol (low) dose of medicinal substance, which contains a combination of Metformin and at least one anti-diabetic agent, and this combination ensures the effectiveness of the treatment of diabetes in patients who were not taking drugs previously (first-line treatment, primary treatment), at least equivalent efficacy of combination therapy of Metformin and another antidiabetic agent, is used in much higher doses prescribed in generally accepted medical practice for first line treatment of diabetes. However, the application of a pharmaceutical preparation with a reduced dose according to the invention leads to a significant reduction of side effects compared with the combination of those agents, but in higher doses usually prescribed.

It should be understood that contains a lower dose of the agent preparation according to the invention contains a lower dose of at least one active antidiabetic component that this dose is lower than the dose of such drugs commonly prescribed in generally accepted medical practice as first-line treatment for diabetes. Therefore, the above pharmaceutical drug low (low) dose contains a small dose of Metformin, as defined below in this description, or low-dose (low, micro) dose as Metformin and the other as tudiabetes.com agent, as defined below in this specification.

Daily dose of Metformin in the treatment methods according to this invention, component from 160 to 750 mg, lies in the interval between the initial daily dose of about 25-60% of the starting daily dosage of Metformin employed in generally accepted medical practice for first-line therapy in treating diabetes, up to a daily maintenance dose of about 40-60% of the maintenance dose used in conventional medical practice as first-line therapy in the treatment of diabetes.

Thus, the daily dose of the pharmaceutical preparation according to the invention in a first-line therapy is to get no more than 750 mg of Metformin per day, more preferably not more than 600 mg of Metformin per day, and the minimum (initial dose) is 160 mg per day as single dose or divided doses (multiple doses) in the form of one to four tablets daily.

As a second antidiabetic agent according to the invention can be used glucosidase inhibitor, glucagonomas peptide 1 (GLP-1), insulin, α/β dual agonist PRAP, other than thiazolidinedione, meglitinide and inhibitor ar, and the daily dose of Metformin is 160-750 mg.

Daily dose of the second anti-diabetic agent may be equal to a daily dose prescribed in generally accepted the medical practice as first-line therapy in the treatment of diabetes, and preferably is in the range which includes the initial daily dose of approximately one-tenth the initial daily dose of the other antidiabetic agent employed in generally accepted medical practice as first-line therapy for treating diabetes, up to a daily maintenance dose, which constitutes two-thirds of the daily maintenance dose of the other antidiabetic agent employed in generally accepted medical practice as first-line therapy in the treatment of diabetes.

The other antidiabetic agent is preferably used in the form of a daily dose in the interval between the initial daily dose of about 20-60% of the initial daily dose of the other antidiabetic agent employed in generally accepted medical practice for first-line therapy in treating diabetes, up to a daily maintenance dose of about 40-60% of daily maintenance doses doses of the other antidiabetic agent employed in generally accepted medical practice as first-line therapy in the treatment of diabetes.

The above daily dose of another anti-diabetic agent includes from the initial daily dose of such anti-diabetic agent (for example, 0.1 to 1.5 mg gliburida) supports up to a maximum daily dose prescribed in generally accepted medical is some practice as first-line therapy in the treatment of diabetes.

The term "a combined preparation (combination) low (low, low) dose, the drug is low (low, low) dose" or "pharmaceutical drug low (low, low) dose used in this description and in the preferred preparation according to the invention refers to medicine that contains Metformin from initial daily dose of about one-fifth of the starting daily dosage of Metformin prescribed in generally accepted medical practice as first-line therapy for treating diabetes, up to about two thirds of the daily maintenance dose of Metformin prescribed in generally accepted medical practice as first-line therapy in the treatment of diabetes. The above daily dose of Metformin includes an initial daily dose of Metformin (for example, 160 mg) and the dose of Metformin, titrated to maximum support daily dose, less than 750 mg of Metformin a day and another antidiabetic agent used in the quantities presented in this description.

To date a combination of drugs (combination) of Metformin and other antidiabetic drugs, such as sulfonylureas, such as gliburid was used, with a few exceptions, the quality of medicines (treatment) of the second row in the treatment of diabetes 2 TEPAV generally accepted medical practice daily dose of these second-line drugs, use constant Metformin, are 3-4 tablets containing 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 combination drugs 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). This daily dose of this description is called the "dose prescribed (prescription) in generally accepted medical practice as first-line therapy for treating diabetes", or dose combination drugs previous techniques", or "daily dose of the previous techniques".

The above dose may be part of the expression ("term") "dose, as prescribed in generally accepted medical practice as first-line therapy for treating diabetes".

As indicated above for 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 12 pills, that is, 200 mg of Metformin and 1.25 mg of glyburide. The initial or starting a low dose is used to determine whether the patient tolerate the drugs, and these doses are gradually increased with 1 / 2 tablets up to 4 tablets per day to achieve effective dose. The initial or starting daily dose of 1/2 tablet or 200 mg of Metformin and 1.25 mg of glyburide, was not considered by the firms and Boehringer Hoechst and doctors, predjamski these medicinal substances in the form of doses, as prescribed in generally accepted medical practice (conventional dose) for the treatment of diabetes".

It has been unexpectedly discovered that the use of Metformin and a second anti-diabetic agent in a reduced dose according to 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 behaves in the pancreas as a sensitizer glucose; it reduces the toxicity of glucose in the pancreas and enhances the function of the pancreas.

According to this invention proposes a method of treatment of diabetes, mainly type 2 diabetes, have not treated the patient (person), which is the introduction to the patient of Metformin in combination with at least one the m other antidiabetic agent, selected from the group comprising an inhibitor of glucosidase, glucagonomas peptide 1 (GLP-1), insulin, α/β dual agonist PRAP, other than thiazolidinedione, meglitinide and inhibitor ar, and the daily dose of Metformin is 160-750 mg.

In addition, according to the present invention proposes a method of lowering glucose levels in the blood of a sick person suffering from hyperglycemia, which is the introduction to the patient of Metformin in combination with at least one other antidiabetic agent selected from the group comprising an inhibitor of glucosidase, glucagonomas peptide 1 (GLP-1), insulin, α/β dual agonist PRAP, other than thiazolidinedione, meglitinide and inhibitor ar, and the daily dose of Metformin is 160-750 mg.

In addition, according to this invention proposes a method of reducing resistance to insulin, and/or lowering of hemoglobin A1Cand/or increase insulin levels after eating, and/or decrease the amplitude of changes in the content ("mobility") glucose in patients with diabetes, which is the introduction to the patient of Metformin in combination with at least one other antidiabetic agent selected from the group comprising an inhibitor of glucosidase, glucagonomas peptide 1 (GLP-1), insulin, α/β dual agonist PRAP, other than thiazolidinedione, meglitinide and inhibit the R ar, moreover, the daily dose of Metformin is 160-750 mg. Preferably, the pharmaceutical preparation with a low dose was used as first-line therapy and have not previously taken drugs (not treated).

In the process according to the invention, using a preferred pharmaceutical preparation with a low dose according to the invention, containing Metformin and gliburid, for the treatment of diabetes patients naïve drugs, it was found that the effectiveness of treatment-naïve drugs (not previously subjected to treatment) patients at least equivalent, and cases (frequency) side effects (gastro-intestinal disorders and hypoglycemia) were found, which is a surprise, substantially significantly less compared to patients treated with daily doses of Metformin and gliburida in accordance with the previous technique (i.e. the doses prescribed in generally accepted medical practice for treating diabetes). That is, although the effectiveness of treatment of primary (not previously treated) patients, as measured by the decrease with time of hemoglobin A1Ccompared with the baseline, the decrease of plasma glucose fasting (FPG), increased levels of insulin after a meal and a decrease in the change (increase) of glucose after a meal (PPG), almost foundations of the Ohm equivalent efficacy in patients above, receiving pharmaceutical drug low dose according to the invention, and in patients receiving daily doses according to the prior art, or a combination of drugs previous techniques, the incidence of hypoglycaemia in primary patients receiving daily doses according to the prior art, more than 3 times higher than in patients receiving pharmaceutical drug with a low (low) dose according to the invention, and the frequency of side effects with disorders of the gastrointestinal tract in patients with primary (not held previously treatment-naïve drugs) patients treated with daily doses of the previous prior art, more than 20% higher than in patients treated with a pharmaceutical preparation with a low dose according to the invention.

The preferred daily dose combination of Metformin and gliburida in the range of about 175-600 mg of Metformin, more preferably about 200-500 mg of Metformin, even more preferably about 250-400 mg of Metformin and about 0.5-4.5 mg gliburida, preferably about of 0.625 3.75 mg gliburida and more preferably about 1-1,5 mg gliburida.

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 "meth the pmin", 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 when taking pharmaceutical drug low dose according to the invention in naïve drugs patients compared with patients taking the same active ingredients in the pharmaceutical preparation according to the invention, but in higher doses, as prescribed in obseryations practice for the treatment of diabetes.

The expression "at least almost (substantially) equivalent efficacy in the treatment of type 2 diabetes, as used herein, refers to the efficiency with which pharmaceutical drug low (low, low) dose according to the invention in the treatment-naïve drugs patients reduces and/or maintains the level of hemoglobin And1C(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, as prescribed in generally accepted medical practice for treating diabetes.

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

Pharmaceutical drug low dose according to the invention contains Metformin used in combination with another antidiabetic agent (also referred to in this description of "other antihyperglycemic agent"), which can be used orally in the same dosage form or in separate per the General dosage forms or enter by injection.

The use of Metformin in combination with another antidiabetic agent according to this invention gives a higher antihyperglycemics results than those obtained would result from the application of each of these drugs individually, and higher than the total additive antihyperglycemics effect given to these medicinal substances.

Oral antidiabetic agent may be a glucosidase inhibitor such as acarbose (described in U.S. Patent 4904769), voglibose, miglitol (described in U.S. Patent 4639436), which can be administered in separate oral dosage form or in the form of a single, shared with Metformin dosage forms.

Metformin can be used in a weight ratio with the glucosidase inhibitor is about 0,01:1-100:1, preferably about 0.5:1-50:1.

The other antidiabetic agent may also be meglitinide, such as Repaglinide (ProdinT. NovoNordisk) or nateglinide (StarlexT, Novartis), which can be applied in the form of a separate oral dosage form or in the form of a single, shared with Metformin dosage forms.

Metformin can be used in a weight ratio with meglitinides in the approximate range of 0.01:1-500:1, preferably about 0.5:1-300:1.

Thiazolidinedione in amounts less than about 150 mg oral antidiabetic what about the agent, you can enter in one tablet with Metformin.

The other antidiabetic agent may be an inhibitor ar, such as described in Provisional applications U.S. Patent No. 60/100677, filed September 17, 1998, and No. 60/127745 filed April 5, 1999.

Metformin can be used in a weight ratio with the inhibitor or 0,01:1-100:1, preferably about 0.5:1-2:1. Inhibitor ar, Metformin can be in the form of one common or separate dosage forms.

Metformin can also be used in combination with non-oral antihyperglycemic agent such as insulin or the like peptide-1 (GLP-I), such as GLP-1 (1-36) amide, GLP-1 (7-36) amide, GLP-i (7-37) (as described in U.S. Patent 5614492), which can be introduced by injection or transdermal, or transbukkalno method.

If there are GLP-1 peptides can be applied in the form of oral cheek drugs, you can enter the nasal or parenteral, as described in U.S. Patent 5346701 (TheraTech), 5614492 and 5631224 entered in this description as a reference.

Metformin can also be used in combination with another antidiabetic agent, which can be α/β dual agonist PRAP, such as a derivative of N-benzyloxyacetaldehyde disclosed in International application WO 96/38428, such as 5-(2,4-dioxothiazolidine-5-ylmethyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide (KRP-297) in the International application WO 98/553 1 (Ligand Pharmaceutical, Inc.), which describes 2-(4-[2,4-differenl]-1-heptylene)ethyl]phenoxy)-2-methyl-butyric acid, and in International applications WO 97/25042 and WO 96/04260 (SKB), which stated benzoxazolone and pyridine derivatives, structure

or their pharmaceutically acceptable salt, and/or their pharmaceutically acceptable MES, where ROis a 2-benzoxazolyl or 2-pyridyl, a R' denotes CH2OCH3or CF3for example, (S)-3-[4-[2-N-(benzoxazolyl)-N-methylamino)ethoxy]phenyl]-2-(2-methoxyethoxy)propanoic acid or (S)-3-[4-[2-N-(benzoxazolyl)-N-methylamino)ethoxy]phenyl]-2-(2,2,2-triptoreline)propanoic acid; or their pharmaceutically acceptable salt, and/or their pharmaceutically acceptable MES. The applied dosages are presented in the above references.

Metformin is used in a weight ratio of from α/β dual agonist PRAP 0,01:1-100:1, preferably about 0.5:1-5:1.

If Metformin is used in combination with α/β dual agonist PRAP, combined preparation can be applied in the form of an oral dosage form such as a tablet or capsule that is obvious to experts in the field of technology.

Preferred are containing low dose combination drugs Metformin and gliburida and, if necessary, insulin sensitizer is, such as glitazone, for example, rosiglitazone, pioglitazone or troglitazone.

When implementing the present invention is applied pharmaceutical preparation or composition with low dose containing Metformin and at least one (other) anti-diabetic agent, together with a pharmaceutical carrier or diluent. Pharmaceutical drug with a low dose can be prepared using conventional solid or liquid carriers or diluents and pharmaceutical additives corresponding to the method of application. Pharmaceutical drug low dose according to the invention it is possible to enter a mammal, including humans, monkeys, dogs, etc. through the mouth, for example, in the form of tablets, capsules, granules or powders, or it may be administered parenterally in injectable form. The dose for patients not previously treated preparations described above and entered as a single dose or in separate doses 1-4 times a day.

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

Enter the dose should be carefully selected in accordance with age, weight and condition of the patient, and in accordance with the method of application, lekarz the governmental form and regimen and the expected result.

The combination of Metformin or its salt and other anti-diabetic agent can be prepared as separate preparations or, if possible, in a single (combined) of the drug using conventional technological methods.

Various preparations according to the invention can, optionally, include one or more filler or excipient, 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 an amount of about 0-90 wt.% and preferably about 1-80 wt.%.

In addition to the fillers, or instead may contain one or more binders in amounts 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 and preferably about 40,000), lactose, starches such as corn starch, modified corn starch, sugar, Arabian gum, etc. and a binder based wax in the form of a fine powder (less than 500 microns), such as palm wax (Carnauba wax), paraffin, spermaceti, polyethylene or microcrystallization.

If the composition should be in the form of tablets, it includes one or more lubricant for tableting, such as magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, Carnauba wax and the like, and preferably about 0.5-2% by weight of the composition.

Other conventional ingredients which may optionally present in the composition)include preservatives, stabilizers, antiadhesive or fluidity improvers silicon dioxide or substances that promote ingestion, such as silicon dioxide trademark Syloid, as well as dyes FD & C.

Tablets according to the invention can also include a coating layer, which can be from 0 to about 15% by weight of the composition of the tablets. Coating (sheath)is deposited on the external solid phase containing particles contained in it internal solid phase, may be of any conventional formulation for coatings and may include one or more film-forming or binding agents, such as hydrophilic polymer such as hypromellose and/or hydrophobic 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 plasticizers, such as triethyltin is at, diethylphthalate, castor oil, etc. the Recipe as the kernel(core) of the tablet and the shell may contain aluminum lacquer to give a color.

The film obtained from the 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 kopmoziciya foaming agent, plasticizer and solvent.

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

If a pharmaceutical product with a small dose according to the invention contains a combination of Metformin and gliburida take medication to provide about 55-500 mg Metformin one to four times a day, with at least 160 mg of Metformin a day and maximum of less than about 800 mg, preferably up to about 750 mg of Metformin a day. Gliburid preferably taken in an amount of about 0.5 to 375 mg one to four times per day for a maximum of about 4.5 mg per day.

Preferred pharmaceutical preparation with a low (low) dose contains Metformin and gliburid and used as initial therapy, which together with diet and exercise improves glycemic control in patients with diabetes mellitus type 2.

The ADA recommends that as the target treatment level HbA1c<7% (ADA. Diabetes Care 21 [Suppl. 1]: S23-S31, 1998)to reduce the risk of complications of diabetes mellitus type 2, including coronary heart disease and microvascular complications.

The preferred dosage of the combination of Metformin-gliburid according to the invention should be individualized based on both efficacy and tolerability. The drug is preferably take with meals and should be started with low doses, gradually increasing. In the ideal case, the response to treatment should be assessed using HbA1c(glycosylated hemoglobin), which is the best indicator for long-term glycemic control than FPG one. The task of therapy for all patients with diabetes mellitus type 2 is improved glycemic control (glucose), including FPG levels, glucose levels after eating and HbA1cto normal or to possibly closer to normal levels. Patients check in order to achieve the objectives of the ADA - HbA1c<7% after recommended doses up to maximilianeum dose. (The ADA. Diabetes Care 21 [Suppl. 1]: S23-S31, 1998).

As initial therapy preferred starting dose combination Metformin-gliburid according to the invention is 250/1,25 mg once daily with a meal. For patients with a baseline HbA1c>9% or fasting glucose >200 mg/DL, the recommended starting (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 needing additional glycemic control, the dose 250/1,25 mg can immediately be raised to 500/2,5 mg. However, as indicated, the preferred maximum daily dose for Metformin is 600 to 750 mg, and the preferred maximum daily dose for gliburida is 3.75 mg

Pharmaceutical drug with a low dose that contains a combination of Metformin-gliburid, according to this invention is preferably prepared according to recommendations (methods)described in the application for U.S. Patent 09/353141, filed July 14, 1999, which claims the priority of European application 98401781.4 filed July 15, 1998, application for U.S. Patent is entered in this description by reference.

Preferred drug Metformin-gliburida with low the th dose according to the invention are presented below.

The nature of productThe amount of ingredient mg per tablet 250/1,25
Ingredient
Metformin hydrochloride250,0
Gliburid1,25
Sodium crosscarmellose3,0-15,0
Microcrystalline cellulose15,0-60,0
Polyvinylpyrrolidone3,0-18,0
Magnesium stearate0,3-7,5
Film coating*of 4.5 to 12.0
* Used in industrial composition for film coating, such as Opadry (use, UK).

Especially preferred are the following drugs Metformin-gliburida low dose:

The nature of productThe amount of ingredient mg per tablet 250/1,25
Ingredient
Metformin hydrochloride250,0
Gliburid1,25
Sodium crosscarmellose7,0
Microcrystalline cellulose28,25
Polyvinylpyrrolidone10,0
Magnesium stearate of 0.6 to 6.0
Film coating*of 4.5 to 12.0
* Used in industrial composition for film coating, such as Opadry (use, UK).

Pharmaceutical drug low dose according to the invention in the form of solid oral forms, such as tablet preferably contains a combination of Metformin and gliburida. in which a maximum of 10% of the particles gliburida have a size less than 2 microns and a maximum of 10% of the particles gliburida have a particle size greater 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. Particles gliburida the amount in this particular interval can be obtained by sieving or grinding on vostokstrojj mill.

In the second variant of the invention the solid oral dosage form with a low dose according to the invention 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.

The most preferred combination of Metformin and gliburida in which the distribution of particles gliburida in size such that about 25% of the screening material is not more than 6 μm, about 50% of the screening material has a size of 7-10 microns and about 75% of the material has a size which is not more than 23 μm.

Pharmaceutical drug low dose according to the invention in tablet form can be obtained by a process comprising the 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 diluent, and

c) tableting obtained with this mixture.

The mixture used to produce pellets, includes the following 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 - preferred is-2-hypromellose.

Description of the drawings

Figures 1 and 2 represent a column graph izobrajaya the change in hemoglobin A1c (HbA1c) depending on the number of tablets of combination drugs Metformin/gliburid permanent makeup, used in first-line therapy compared with monotherapy separate gliburid and Metformin.

Figure 3, 4 and 5 column graph depicting the change in HbA1c 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.

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.

Fig.7 is a column chart, which depicts 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.

Figa and 8B are bar graphs 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 separately gliburid the m and Metformin.

Fig.9 is a column 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 and 2

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

The tablet formulation of Metformin hydrochloride - gliburid

250 mg/1.25 mg and 500 mg/2.5 mg

IngredientQuantity per tablet (mg)
250 mg/1.25 mg500 mg/2.5 mg
Metformin hydrochloride250,0500,0
Gliburid1,252,5
Sodium crosscarmellose7,014,0
Microcrystalline cellulose10,020,0
Polyvinylpyrrolidone28,2556,5
Magnesium stearate2,254,5
Film coating*612
* Apply a film coating based on a receiver array.

Products for tablets Metformin hydrochloride gliburid, 250 mg/1.25 mg and 500 mg/2.5 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 gliburid 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 the dryer with pseudouridines layer at about 60°to achieve a certain moisture content, redesenho 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 course of 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 prototype combined tablet preparations are to determine 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 the mi) 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

Room

party
A 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 scattering the Oia laser radiation, 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 fraction of not more than 6 μm

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

75% lower fraction of not more than 23 μm.

Example 3

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 postoyanno the composition described in Examples 1 and 2) compared with placebo in naïve drugs (not held treatment, primary diabetes mellitus type 2 with diet and exercise does 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) estimated using hemoglobin A1c (HbA1c), the gold standard for determining prolonged glycemic control. Comparing the average value of the change in HbA1crelative 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 the individual components of the combined drug of constant composition assessed by 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. The Glik the systematic 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.

(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 HbAsub> 1cin 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 gliburid are known and effective combination treatment for diabetes type 2. Both drug substances exhibit synergistically 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.

Writing the axle, what 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 Metformin/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 glycemic control with diet and exercise will cause a significant reduction in HbA1ccompared 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 with diet and exercise well the case is designed.

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 HBA1cwith 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, through 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 Metformin monotherapy, 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 HbA1cdefined as HbA1c<7%.

3. To estimate h is cut to 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 HbA1cafter 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 type 2 diabetes with inadequate glycemic control (HbA1c<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 ill the x diabetes mellitus with insufficient glycaemic control defined as HbA1c7-11%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 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 the 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 treatment period. The analysis on the primary outcome, change in comparison with baseline HbA1cin 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 HbA1cand for security reasons, so the spacecraft is expected 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 randomized stopping the 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 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 to improve glycemic 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 of primavista 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 the program and not have any symptoms for exclusion from the program, meet glycemic criteria Period And choose to participate in the Period A.

Period:

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 LAF is she with placebo, appropriate drug for the study.

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 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 A1c, a reducing level HbA1cbelow 7% (from an average baseline of 8.2%) on 20-th week (figure 1, 2 and 3), on the 20th and 32nd weeks and at the last visit (figure 4 and 5);

(2) the response to therapy of glucose in the plasma of fasting (FPG), namely the decrease in FPG lower than 126 mg/DL after 20 weeks (from the base level of about 175 mg/DL), (as shown in Fig.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) (Fig.7);

(4) terapeutiche the Kaya 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 (figa 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 Fig.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) 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. You the PR 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 the addition of a second agent with an excellent 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 is zabolevaniya.

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 HbA1c<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 proves that the combination drug (product) Metformin/gliburid constant composition with a low dose is safe and provides effective content antihyperglycemics substances required 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/g is ibored 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 "openlabel" data treatment confirm the clinical usefulness of treatment with combined drug permanent makeup 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, glebo the home 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 hipoglicemia higher in the group receiving combined preparation of a permanent structure with an average dose, whereas in the group with low dose observed lower frequency (hypoglycemia)than in the case of gliburid-monotherapy (Fig.9). A weak increase in the levels of lactate was observed in all groups receiving Metformin, but in this study not reported one case of lactic acidosis.

At the stage of "open label" study of patients can p is yamo be 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 confirm the favorable safety profile observed in short-term stages of the study. In particular, in the case of combined drug with a low dose schedule security/re is eimaste most favorable in comparison with other schemes, used in this program.

Efficiency

Double-blind therapy, the first row shows a statistically significant mean decrease in hemoglobin And1c(HbA1c) 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 HbA1ccompared 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 HbA1csince 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% (figure 3 and 4).

Intermediate data open-label, first-line therapy demonstrate that directly selected patients average HbA1C(baseline) is 10.6% and for patients with appropriate data, the average reduction level HbA1cthe 3.5% is achieved when the magnitude of 7.1% after 26 weeks. the C patients directly enrolled to participate in the 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 HbA1C3,5% on the baseline is 8,32. In all patients, prolechivshis 13 weeks, achieved average reduction level HbA1C1,76% with an average value of HbA1C6,56%. 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, gender, race) in terms of deviations (reaction) HBA1Cfrom the baseline in any double-blind test with a combination drug Metformin/gliburid constant composition is 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 HbA1C. 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 (Fig.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 And1Cis a common standard criterion of complete glycemic control and he is a glycemic marker, which is found to be correlated with long-term complications. Although the content of glucose in plasma fasting, modern standard, b is the more quickly check 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 HbA1C. 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 values for the reduction of absolute PPG compared with monotherapy gliburid (16-18 mg/DL) and Metformin (18-20 mg/DL) (figa and 8B). The deviation of the glucose levels within two hours from the gas line on an empty stomach in both groups, receiving a low 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 (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 a more significant increase in the insulin response in the presence of glucose load, receive the her low dose combined drug of constant composition (14.6 mkme/ml), compared to 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 glucose (blood glucose level) or achieving glycemic, therapeuti the mini-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 HbA1c.As a first-line therapy combined product of constant composition leads to a greater number of "subjects" (66-71%) reaches glycemic goals HbA1cJ 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, HBA1Cdecreases compared to the baseline of more than 2.0% compared to 16-17% in each group undergoing 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 HbA1Cwith the number of tablets picture observed in combination therapy, is not unexpected from the point of the vision is the 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) HbA1C. 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) HbA1C. For both the combined preparations with a constant dose average reduction compared with baseline HbA1Chigher 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 HbA1Cabove 9%. It is shown that when alone there is a sloping part of the curve glycemic response to background levels HbA1C<9%, while the combined "fixed" therapy there are additional incremental lowering of HbA1Cfor background HbA1Clevels <9%.

In the 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 HbA1Cat the baseline is 9.45%. At weeks 13, 26 and 39 approximately 50-55% of patients the level of HbA1Creaches less than 7%, and even 30% of it is <8%. This speed of response and the magnitude of the changes at the top level HbA1Ccan 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 HbA1C<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, the minimum earlier weight gain of 1-2 kg is observed in the case of "tirovannoj" 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 statisticheski significant difference between any groups of subjects in terms of changes of lipid profile in plasma. As most tirilye 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 HbA1Cto 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 (glucose). Targeting many violations with agents with synergistic the sky 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 (fail) sequential therapy before you can take more intense, but clinically important treatment strategy. Although this short is sovremennom the study is not considered, the strategy to achieve as close as possible to normal strategic goals, apparently, affects slow 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 in primary (not received prior treatment) patients. Then it should be correct ("chitravati"), as indicated, to achieve HbA1c<7%.

OVERALL THE FINDINGS

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, confirm 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 (Fig.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 of the permanent composition of Metformin/gliburid any active substance that proved more significant is the first decrease in all glycemic parameters (HbA 1Cthe 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 HbA1CJ 7%.

Effective blood glucose lowering to appropriate therapeutic purposes, for any basic (initial) values HbA1Ccompared 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) HbA1C>9%, whereas in the case of therapy "fixed" combination Metformin/gliburid there are additional incremental lowering levels of HbA1Cfor levels baseline HbA1C>9%.

- Limited early led the increase of weight at the same time (in parallel) with improved glycemic control, compared with monotherapy gliburid, but the 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 who previously antidiabetic drugs, which consists in the introduction to the patient of Metformin in combination with at least one other antidiabetic agent selected from the group comprising an inhibitor of glucosidase, glucagonomas peptide 1 (GLP-1), insulin, α/β dual agonist PRAP, other than thiazolidinedione, meglitinide and inhibitor ar, and the daily dose of metfo the mine is 160-750 mg, and the second anti-diabetic agent is administered in a daily dose in the interval between the initial daily dose comprising 20-60% of initial daily dose of this anti-diabetic agent used in generally accepted medical practice for first-line therapy in treating diabetes, up to a daily maintenance dose, which constitutes 40-60% of daily maintenance doses of this anti-diabetic agent used in conventional medical practice as first-line therapy in the treatment of diabetes.

2. The method according to claim 1, in which another anti-diabetic agent is selected from a glucosidase inhibitor, glucagonoma peptide 1 (GLP-1), insulin, α/β dual agonist PRAP.

3. The method according to claim 1, in which another anti-diabetic agent selected from acarbose or insulin.

4. A method of reducing glucose in the blood of a sick person suffering from hyperglycemia, which is the introduction to the patient of Metformin in combination with at least one other antidiabetic agent selected from the group comprising an inhibitor of glucosidase, glucagonomas peptide 1 (GLP-1), insulin, α/β dual agonist PRAP, other than thiazolidinedione, meglitinide and inhibitor ar, and the daily dose of Metformin is 160-750 mg, and the second anti-diabetic agent is administered in a daily dose in the interval between starting the th daily dose, part of 20-60% of the initial daily dose of this anti-diabetic agent used in generally accepted medical practice for first-line therapy in treating diabetes, up to a daily maintenance dose, which constitutes 40-60% of daily maintenance doses of this anti-diabetic agent used in conventional medical practice as first-line therapy in the treatment of diabetes.

5. The method according to claim 4, in which the drug is used as first-line therapy for patients who were not taking drugs previously.

6. The method according to claim 4, in which the first 4 days of treatment Metformin is administered in an amount of from 160 to 400 mg

7. The method of reducing resistance to insulin, and/or lowering of hemoglobin A1cand/or increase insulin levels after eating, and/or decrease the amplitude of changes in the content ("mobility") glucose in patients with diabetes, which consists in the introduction to the patient of Metformin in combination with at least one other antidiabetic agent selected from the group comprising an inhibitor of glucosidase, glucagonomas peptide 1 (GLP-1), insulin, α/β dual agonist PRAP, other than thiazolidinedione, meglitinide and inhibitor ar, and the daily dose of Metformin is 160-750 mg, and the second anti-diabetic agent is administered in the form of daily doses in the interval between the initial daily dose comprising 20-60% of the t initial daily dose of this anti-diabetic agent, used in generally accepted medical practice for first-line therapy in treating diabetes, up to a daily maintenance dose, which constitutes 40-60% of daily maintenance doses of this anti-diabetic agent used in conventional medical practice as first-line therapy in the treatment of diabetes.



 

Same patents:

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

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: medicine, endocrinology, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to nateglynide-containing preparation used in treatment of diabetes mellitus that comprises nateglynide as an active component and a carrier wherein nateglynide in amorphous form and indicated carrier represents hydrophilic material. Amorphous property of crystalline nateglynide is provided by the following methods: 1) by dissolving nateglynide crystals in pharmacologically acceptable solvent in common with hydrophilic materials taken among the group consisting of water-soluble polymers, water-swelling polymers, sugar alcohols and salts followed by granulation in fluidized layer, granulation by stirring at high rate, drying by spraying and process for coat applying for granulation of amorphous nateglynide; 2) by mixing nateglynide crystals with hydrophilic materials taken among the group of water-soluble polymers, water-swelling polymers, sugar alcohols and salts and the following application of the high shift force to the prepared mixture; 3) by mixing nateglynide crystals with hydrophilic materials taken among the group of water-soluble polymers, water-swelling polymers, sugar alcohols and salts and the following plasticizing the prepared mixture in melt by heating and milling at cooling; 4) by dissolving nateglynide crystals in pharmacologically acceptable liquid additives wherein liquid additives represent water-soluble polymers that are liquid at 37°C. Using amorphous nateglynide allows preparing the nateglynide preparation with immediate release wherein the dissolving rate of medicinal agents is high and without crystalline transition during preparing or preserving preparations.

EFFECT: valuable pharmaceutical properties of preparation.

6 cl, 3 tbl, 9 dwg

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for preparing an antibacterial agent. Method involves mixing active components - ampicillin trihydrate and oxacillin sodium salt, and starch as a vehicle and filling gelatin capsules with the prepared mixture. Method involves separate mixing each active component with half of potato starch and following their combination, addition of lactose and powdering with aerosil. Then the prepared dry mixture is added into gelatin capsules that are covered preliminary by gelatinized potato starch layer from the interior of capsule and dried with inert gas at the rate of gas feeding 3-5 m/s. Method provides simplifying preparing capsulated preparations due to facility filling capsules and to enhance stability of the preparation in storing.

EFFECT: improved preparing method, improved properties of preparation.

1 tbl

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a new pharmaceutical composition comprising benzamide derivative and one or some additives taken among the following substances: 1) mixture of polyethylene glycol and surface-active substance; 2) amino acid or inorganic acid salt, and 3) propylene carbonate. The composition comprises benzamide derivative taken in the amount from 0.001 to 1000 mg per a single dosing formulation. The composition shows the enhanced solubility and absorption capacity in oral route of administration.

EFFECT: improved medicinal and pharmaceutical properties of composition.

9 cl, 4 tbl, 1 dwg, 5 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with peroral liquid compositions which could be designed into gelatinous capsules. The suggested pharmaceutical composition includes a pharmaceutically active agent, a solubilizing agent and, not obligatory, a surface-active substance and a plastifying agent. The pharmaceutically active agent has got, at least, one acidic fragment, preferrably, that of carbonic acid being chosen out of the group of non steroid antiphlogistic preparations being acid-soluble at acid : dissolved substance ratio being from 3:1 to 10000:1. New compositions provide increased rates and degrees of absorption of pharmaceutically active agent and minimize side effects caused by such active substances.

EFFECT: higher efficiency of application.

42 cl, 39 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with cyclosporin-containing and practically oil-free compositions being of immunosuppressive action. The composition contains a hydrophilic surface-active substance, a lipophilic component, a lipophilic surface-active substance and ethanol. As a hydrophilic surface-active substance this composition contains ether of fatty acid and polyoxyethylene sorbitane and product of either natural or hydrogenised castor oil and ethylenoxide; as a lipophilic component and lipophilic surface-active substance it contains ether of fatty acid and sorbitane. The suggested composition has been designed as a gelatinous capsule with solid covering. The present innovation solves the problem dealing with stability of galena compositions with cyclosporin: at treating with water the composition develops practically stable microemulsion.

EFFECT: higher efficiency of application.

11 cl, 2 ex

FIELD: medicine.

SUBSTANCE: means is manufactured as capsule containing dibunol and 15% oil extraction of propolis.

EFFECT: enhanced effectiveness of treatment; prolonged regenerating and antibacterial action.

2 cl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition for oral administration in treatment or prophylaxis of obesity or hyperlipidemia. The composition comprises orlistat and at least one ester of fatty acids and polyols. Melting point of fatty acid ester exceeds the body temperature and polyol is taken among group including glycerol, sugars, derivatives of sugars and their mixtures. Also, invention relates to a method for preparing above described composition and to a method for treatment or prophylaxis of obesity. Invention enhances effectiveness and activity of orlistat by reducing variability of effectiveness and/or activity of orlistat between patients and frequency and severity of adverse effects.

EFFECT: improved and valuable pharmaceutical properties of compositions.

24 cl, 1 tbl, 10 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal agent made as a gelatin capsule. A medicinal agent as gelatin capsule consists of cycloserine and accessory additives wherein calcium phosphate dihydrate, aerosil and calcium stearate taken in the definite components are used as accessory additives. Also, gelatin capsule comprises additionally glutamic acid, gelatin and water, Invention provides rapid and complete release of agent in intake and the development of a medicinal formulation reducing toxicity of an active substance and eliciting stability in storage.

EFFECT: improved and valuable pharmaceutical and medicinal properties of agent.

1 tbl, 1 ex

FIELD: medicine, gastroenterology, phytotherapy, pharmacy.

SUBSTANCE: invention relates to solid medicinal formulations, namely capsules "Gastrobiol-TSD". Gelatin capsule contain the natural pharmacologically active component - sea-buckthorn oil concentrate, cyclodextrin, vitamin U and magnesium oxide taken in the definite ratio of components given in the invention description. Invention provides preparing a medicinal formulation eliciting an anti-ulcer, analgetic and protective effect on mucosa effect being with minimal risk for development of adverse effect.

EFFECT: valuable medicinal properties of preparation.

1 tbl, 1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition as a capsule for oral administration that comprises testosterone undecanoate as an active component dissolved in pharmaceutically acceptable liquid carrier wherein liquid carrier involves at least 50 wt.-% of castor oil. Using castor oil as a liquid carrier in combination with testosterone undecanoate as androgen provides preparing a solution that can contain about 200-250 mg of testosterone undecanoate/ml that represents the new achievement for testosterone solution for oral administration. Solution can contain lipophilic surface-active substance, such as lauryl glycol also. The composition shows good absorption in human body and elicits higher activity as compared with the known composition of undecanoate.

EFFECT: improved and valuable properties of composition.

7 cl, 1 ex

FIELD: medicine.

SUBSTANCE: claimed method includes blending of active base and auxiliary ingredients to form tablet corn, representing composition of sugar powder, monocrystalline cellulose, vinylpyrrolidone and calcium stearate; humidifying of obtained mixture; drying of obtained granules; dry granulation through granulator with standardized holes; pelletization of standardized granules to produce tablet corn; and coating. Mixture is humidified with 5-7 % starch mucilage in starch mucilage/humidifying mixture mass ratio of 1:25-30, wherein mixture is blending with starch mucilage for homogeneous distribution wet in whole mass.

EFFECT: tablets with increased hardness and enhanced pharmacological activity.

2 cl, 2 ex

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