RU2380097C1 - Solid unit dosage form for pancreatic diabetes - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to solid unit dosage form for pancreatic diabetes. The solid unit dosage form for pancreatic diabetes contains as an active substance a combination of taurine, butadion, metformin, Riboxinum, arginine and gliclazide, as well as targeted additives in the certain ratio.

EFFECT: drug is effective for pancreatic diabetes.

4 cl, 2 tbl, 3 ex

Description

The invention relates to medicine, in particular to a dosage form for oral administration intended for the treatment of non-insulin-dependent and non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (type II diabetes mellitus) is characterized by relative insulin deficiency, which occurs due to the resistance of peripheral tissues to insulin, and normal or even increased secretion of insulin into the blood. The treatment of relative insulin deficiency does not require the use of insulin preparations. Compensation for impaired carbohydrate metabolism is achieved by oral hypoglycemic agents.

Insulin-dependent diabetes mellitus (type I diabetes mellitus) is characterized by insufficient insulin production by the cells of the pancreatic islets of Langerhans, i.e. absolute insulin deficiency. Insulin injections are used to treat insulin-dependent diabetes mellitus.

A known method of treatment with oral hypoglycemic agents, including the use of sulfonylurea derivatives and biguanides individually and in combination [A. Okorokov Treatment of diseases of internal organs. M .: Honey. Literature, 2002, 596 pp.]. The method is based on the fact that the mechanism of action of sulfanylurea derivatives involves binding to specific receptors located on the membranes of β-cells, which leads to an increase in the intracellular content of cAMP by stimulating adenylate cyclase and inhibiting phosphodiesterase [Sherstnev M.P. Adenylcyclase system for the regulation of the chemiluminescent response of phagocytes. Q. chemiluminescence, 1990, v. 1, No. 1, 1-7]. In this work, a theoretical analysis and experimental study of the regulatory action of the adenylate cyclase system in relation to the generation of free radicals, which are of key importance in the pathogenesis of diabetes mellitus, [Vladimirov Yu.A., Sherstnev MP Chemiluminescence of animal cells. M .: VINITI, 1989, 176 pp.]. An increase in cAMP leads to an increase in the calcium content in the cytoplasm of β-cells [Sherstnev MP Calcium-dependent and calcium-independent ways of generating chemiluminescence of cells. For example, chemiluminescence, 1991, v. 1, No. 2, 1-4], which stimulates the secretion of endogenous insulin by them. Cyclic nucleotides have the universal function of intracellular messengers, which provides a positive trophic effect on β-cells.

The composition of the new stable pharmaceutical composition with a hypoglycemic effect was developed on the basis of pharmacotherapeutic data on the pharmacological effects and mechanisms of action of metformin, glyclazide, butadione, taurine and arginine. Each of the drugs contributes its positive hypoglycemic effect to the combined drug.

Sulfonylurea derivatives increase the number of insulin receptors in insulin-dependent tissues and thus increase their cell sensitivity to insulin. There is a normalization of the postreceptor mechanism of the action of insulin on glucose metabolism inside the cell and on its transport to the cell. Recent studies have established that the most promising drug from the group of sulfonylurea derivatives is the second-generation drug gliclazide. Gliclazide enhances insulin secretion by pancreatic beta cells and improves glucose utilization. Possessing the pharmacological action inherent in other sulfonylurea derivatives, glyclazide has several advantages, in particular, does not lead to an increase in body weight, and also has anti-atherogenic properties.

Biguanides are known to potentiate the effects of insulin. From the whole group of biguanides, we chose metformin, because it does not cause hypoglycemic reactions [Mashkovsky M.D. Medicines M .: Medicine, 1993, t.1, s.662-663]. Metformin lowers blood glucose levels in patients with diabetes mellitus and increases their glucose tolerance. In addition, the use of metformin is not accompanied by lactic acidosis, and this also was the rationale for its appointment among all other biguanides.

The pyrazolone derivative, butadione, is an effective inhibitor of prostaglandin synthesis, thus increasing the intracellular level of cAMP, the main regulator of metabolic processes in the cell [Sherstnev MP Adenylcyclase system for the regulation of the chemiluminescent response of phagocytes. Q. chemiluminescence, 1990, v. 1, No. 1, 1-7]. Butadion has an insulin-sensitizing effect, anti-inflammatory effect and reduces the intensity of free radical processes in the pancreas, leading to irreversible damage to beta cells, and reduces its edema.

Taurine has osmoregulatory and membrane protective properties, regulates the exchange of Ca ²⁺ and K ⁺ ions. Depending on the status of the cell membrane, it increases or decreases its rigidity by changing the phospholipid composition and the ratio of phospholipids and cholesterol. It improves the metabolic processes in the liver; in diabetes, it lowers the level of sugar, as well as the concentration of triglycerides in the blood. It has the properties of a neurotransmitter and neuromodulator.

It is known that the dietary supplement arginine amino acid normalizes lipid and carbohydrate metabolism in the human body and reduces the number of cases of resistance to hypoglycemic treatment of type II diabetes mellitus. Previously, we showed that the combination of a number of medicinal plants with anti-inflammatory properties, in combination with amino acids, in particular arginine, in balms leads to a decrease in blood sugar [Sherstnev MP, Yakovlev S.A. Herbal balms based on medicinal herbs. In the book: Energy-informational visualization of a nosological diagnosis. M.: Intern. Acad. energoinform. Sciences, 2000, part III, 101-102; Sherstnev M.P., Yakovlev S.A. Herbal balms based on medicinal herbs. In the book: Spiritual and folk healing in ecology and medicine. M .: III Intern. Cong., 2000, 131-133]. Arginine exhibits antioxidant properties, as well as potentiates the effects of butadione and normalizes metabolism in beta cells, helping to restore their function, which gives long-term remission in the treatment of diabetes.

These drugs, when combined, complement the hypoglycemic effect of each other, which allows to increase the effectiveness of treatment with minimal doses of drugs. By combining six drugs, it is possible to avoid side effects of each of them by reducing their concentration in the drug. This combination avoids resistance to hypoglycemic treatment.

Derivatives of sulfonylureas and biguanides and butadione with prolonged use have a number of side effects, in particular they have cardiotoxic and hepatotoxic effects. Riboxin was introduced to reduce the side effects of these drugs. Riboxin is a purine derivative that is regarded as a precursor to ATP. It is an anabolic substance and has a positive effect on metabolic processes in myocardial cells, improves coronary circulation, and has an antihypoxic effect. Riboxin helps with coronary heart disease, it is prescribed for the treatment of myocardial infarction, with myocardial dystrophy, as well as with liver diseases (hepatitis, cirrhosis).

Recently, patents have appeared that use combinations of various drugs with a hypoglycemic effect, for example, an insulin-sensitizing substance (thiazolidinedione derivatives), sulfonylureas and biguanide derivatives. So, for the treatment of diabetes, a triple combination is used: an insulin-sensitizing substance (derivative of thiazolidinedione), an agent that stimulates the secretion of insulin (derivative of sulfonylurea), and a biguanide hypoglycemic agent [Eurasian patent No. 003021, 2002]. Their use in one composition is proposed. The patent indicates the possible dosage limits of individual drugs.

Thus, there is currently a wide range of different oral glycemic agents and their combinations.

However, currently known combinations of oral hypoglycemic agents alone are not effective enough and have side effects, when they are used, resistance often develops - lack of sensitivity to treatment - and the effectiveness of combination therapy may decrease over the years.

The closest in technical essence to the claimed object is a solid dosage form for oral administration containing a combination of metformin and glycazide [RF patent No. 2333760, 2008]. The patent states that tablets can be prepared by a process comprising the following operations:

a) the formation of granules by wet granulation of a mixture of metformin and gliclazide;

b) mixing the granules with a tabletting additive and diluent;

C) tableting the mixture to obtain tablets.

No information was found on the combination drug for the treatment of diabetes mellitus based on metformin, gliclazide, butadione, taurine and arginine as active substances.

The objective of the invention is the creation of a dosage form for the treatment of diabetes mellitus, including as an active ingredient a combination of taurine, butadione, metformin, riboxin, arginine and glycazide.

As excipients, various pharmaceutically acceptable excipients have been tested, such as microcrystalline cellulose, sorbitol, lactose; corn starch, potato starch, various polyvinylpyrrolidones were tested as binders; disintegrants, for example sodium glycolate starch, polyvinylpyrrolidone; tabletting lubricants, for example stearic acid, its magnesium and calcium salts.

The problem is solved in a dosage form containing a combination of therapeutically effective amounts of taurine, butadione, metformin, riboxin, arginine and glyclazide in a ratio of 3: 3: 2: 2: 1: 1 to 30: 25: 15: 10: 5: 1 and target additives, in which it contains sorbitol, polyvinylpyrrolidone, stearic acid salt and croscarmellose sodium in the following ratio, wt.%:

taurine 15.0-50.0 butadione 14.0-40.0 metformin 6.0-30.0 riboxin 6.0-30.0 arginine 4.0-20.0 gliclazide 0.9-4.0 sorbitol 2.0-8.0 polyvinylpyrrolidone 1,5-4,5 stearic acid and / or stearic acid salt 0.2-1.0 croscarmellose sodium 0.5-2.0

The proposed pharmaceutical composition is made in the form of a solid dosage form, mainly in the form of tablets. Sorbitol gives a pleasant taste, its use allows to achieve high mechanical strength of the tablets with a small time of their disintegration. Polyvinylpyrrolidone is mainly used as polyvinylpyrrolidone of the type Kollidon 25 (povidone), it is not only a binding ingredient, but also improves the disintegration of the tablets and the dissolution of active ingredients. Croscarmellose sodium provides a layered release of the active substances upon dissolution of the solid dosage form. As the salt of stearic acid, magnesium and / or calcium salts are used.

The proposed ratio of active substances and target additives is found experimentally and is optimal. The solid dosage form obtained according to the invention meets all the requirements of the State Pharmacopoeia of the XIth ed., Has a shelf life of 2 years (see table 1).

Table 1 Quality indicators Quality Standards Examples one 2 four The average weight of the tablet, g from 0.598 to 0.662 0.650 0.598 0.635 Disintegration, min No more than 15 eleven 10 9 Dissolution%
Taurina
Riboxin
Butadione
Arginine
Metformin
Glyclazide in 45 min
not less than 75
not less than 75
not less than 75
not less than 75
not less than 75
not less than 70 one hundred
99
98
95
96
98 99
98
99
95
97
95 one hundred
99
95
97
99
99 Content, g
Taurina
Riboxin
Butadione
Arginine
Metformin
Glyclazide from 0.150 to 0.250
from 0.100 to 0.200
from 0.050 to 0.150
from 0.050 to 0.150
from 0.020 to 0.080
from 0.005 to 0.015 0,203
0.150
0,100
0,100
0,050
0.006 0.195
0.127
0,092
0,092
0,042
0.007 0.212
0.160
0,120
0,120
0,060
0.015 Foreign impurities,%
Dicyandiamide
The amount of impurities from gliclazide no more than 0,04
no more than 1,0 missing 0.3 missing 0.2 0.02
0.3 Shelf life 2 years 2 years 2 years 2 years

The preparation of tablets is carried out by wet granulation. The following examples illustrate the invention (see table 2).

table 2 No. p / p Indicators Examples g one 2 3 one The ratio of active substances in the tablet 40: 30: 20: 20: 10: 1 30: 25: 15: 10: 5: 1 3: 3: 2: 2: 1: 1 2 Taurine 200,0 300,0 15.0 3 Butadion 150.0 250,0 15.0 four Metformin 100.0 150.0 10.0 5 Riboxin 100.0 100.0 10.0 6 Arginine 50,0 50,0 5,0 7 Gliclazide 5,0 10.0 5,0 8 Sorbitol 26.0 25.0 5.3 9 Polyvinylpyrrolidone 18.0 17.4 3,7 10 Stearic acid and / or its salts 2.97 2.85 1.3 eleven Croscarmellose sodium 7.1 5.7 2,8

Example 1. (The ratio of taurine, butadione, metformin, riboxin, arginine and gliclazide 40: 30: 20: 20: 10: 1). The preparation of tablets is carried out according to example 1 on the basis of 5.0 g of gliclazide (in terms of 100% substance), 200.0 g of taurine (in terms of 100% substance), 150.0 g of butadione, 100.0 g of metformin, 100, 0 g of riboxin, 50.0 g of arginine, 26.0 g of sorbitol, 18.0 g of polyvinylpyrrolidone, 2.97 g of calcium stearate and 7.1 g of croscarmellose sodium. Get 1000 tablets of the combined preparation of metformin, riboxin, butadione, arginine, hydroxychloroquine and gliclazide with an average weight of 0.659 g. The resulting tablets meet all the requirements of the State Pharmacopoeia XI ed. and have a shelf life of 2 years (see tables 1 and 2).

Example 2. (The ratio of taurine, butadione, metformin, riboxin, arginine and gliclazide 30: 25: 15: 10: 5: 1). Pre-sieved powders of gliclazide in an amount of 10.0 g (in terms of 100% substance) and croscarmellose sodium in an amount of 5.7 g are mixed, the mixture is loaded into an MP 2 Multigel laboratory mixer, the sieved substance of taurine in an amount of 300 is also loaded there, 0 g (in terms of 100% substance), butadione in an amount of 250.0 g (in terms of 100% substance), metformin hydrochloride in an amount of 150.0 g (in terms of 100% substance), riboxin in an amount of 100.0 g (in terms of 100% substance), arginine in an amount of 50.0 g (in terms of 100% substance). A 30% solution of polyvinylpyrrolidone in an amount of 58.0 g (17.4 g of dry matter) is added to the mixture, mixed until the moisture distribution in the mass is uniform, wet granulation is carried out, the granulate is dried at a temperature of 45 ± 5 ° C to a residual moisture of 1-3 % The dried granules are ground, 25.0 g of sorbitol, 2.85 g of magnesium stearate are added, mixed until the components are evenly distributed and the tablet mixture is transferred in an amount of 638.55 g to the tabletting step. Get 1000 tablets with an average weight of 0.639 g that meet all the requirements of the Gosfarmakopeyi XI ed. and having a shelf life of 2 years (see tables 1 and 2).

Example 3. (The ratio of taurine, butadione, metformin, riboxin, arginine and gliclazide 3: 3: 2: 2: 1: 1). The preparation of tablets is carried out according to example 1 on the basis of 5.0 g of gliclazide (in terms of 100% substance), 5.0 g of arginine, 10.0 g of metformin (in terms of 100% substance), 10.0 g of riboxin, 15, 0 g of butadione, 15.0 g of taurine, 5.3 g of sorbitol, 3.7 g of polyvinylpyrrolidone, 1.3 g of calcium stearate and 2.8 g of croscarmellose sodium. Get 1000 tablets of the combined preparation of metformin, riboxin, butadione, arginine, hydroxychloroquine and glycazide with an average weight of 0.373 g. The resulting tablets meet all the requirements of the State Pharmacopoeia XI ed. and have a shelf life of 2 years (see tables 1 and 2).

     A preliminary preclinical study of the proposed solid dosage form for the treatment of diabetes mellitus, which includes a combination of taurine, butadione, metformin, riboxin, arginine and glyclazide as an active ingredient, showed that it lowers the concentration of glucose in the blood, increases glucose tolerance, increases the secretion of insulin beta pancreatic cells and improves glucose utilization. It exhibits antioxidant properties. The drug lowers blood sugar and urine, reduces the amplitude of glycemic fluctuations, improves the general condition of patients: eliminates dry mouth, thirst, fatigue, leg pain, and also prevents the development of diabetic vascular complications. The purpose of the drug allowed to reduce the daily dose of insulin by 4-9 units.

Acute toxicity was studied on nonlinear white male mice weighing 17-21, the average lethal dose (LD _5o) taurine, butadiona, metformin riboksina, arginine, gliclazide and their combination do not have significant differences, and to refer them to low-toxic substances and class III danger.

A subchronic experiment was conducted on non-linear male rats weighing 180-220 g. The studied drug was administered intragastrically once daily for 30 days at doses of 100 mg / kg and 500 mg / kg according to metformin, five times the single therapeutic dose for rats and 35 times for a person.

As a result of the experiment, it was found that the combination of taurine, butadione, metformin, riboxin, arginine and gliclazide in the studied doses did not cause significant changes in the integral parameters in the experimental animals (weight gain, behavioral reactions, food, water intake), cellular composition and parameters of blood coagulation, excretory, absorption, protein synthesizing liver function, the level of cholesterol in blood serum, the functional state of the cardiovascular, excretory and nerve Noah systems. The combination of taurine, butadione, metformin, riboxin, arginine and glyclazide in the studied doses had a hypoglycemic effect. The above effect is associated with the specific action of the components of the drug.

The drug in the studied doses did not cause structural disorders in organs and tissues, did not have a local irritant effect.

In accordance with the obtained pharmacological and toxicological data, the claimed solid dosage form for the treatment of diabetes mellitus, comprising, as an active ingredient, a combination of therapeutically effective amounts of taurine, butadione, metformin, riboxin, arginine and gliclazide in a ratio of 3-40: 3-30: 2- 20: 2-20: 1-10: 1, and as target additives - sorbitol, polyvinylpyrrolidone, stearic acid and / or stearic acid salt and croscarmellose sodium, was recommended for clinical trials.

Claims (4)

1. A solid dosage form for the treatment of diabetes mellitus containing, as an active ingredient, a combination of therapeutically effective amounts of taurine, butadione, metformin, riboxin, arginine and glycazide in a ratio of 3-40: 3-30: 2-20: 2-20: 1 -10: 1 and target additives, in which it contains sorbitol, polyvinylpyrrolidone, stearic acid and / or a salt of stearic acid and croscarmellose sodium in the following ratio, wt.%:
taurine 15.0-50.0 butadione 14.0-40.0 metformin 6.0-30.0 riboxin 6.0-30.0 arginine 4.0-20.0 gliclazide 0.9-4.0 sorbitol 2.0-8.0 polyvinylpyrrolidone 1,5-4,5 stearic acid and / or stearic acid salt 0.2-1.0 croscarmellose sodium 0.5-2.0 2. The solid dosage form according to claim 1, where as polyvinylpyrrolidone it contains mainly collidone 25 (povidone). 3. The solid dosage form according to claim 1 or 2, wherein, as the stearic acid salt, it contains magnesium and / or calcium salts. 4. The solid dosage form according to claim 1, where it is made in the form of a solid dosage form, mainly in the form of a tablet.