RU2801279C1 - Pharmaceutical composition of antidiabetic action in solid dosage form in the form of tablets - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to the production of antidiabetic agents. A solid dosage form of prolonged action made in the form of tablets with antidiabetic activity containing gliclazide and microencapsulated dry extracts of Galega officinalis, licorice and peppermint, as well as polyethylene glycol 6000, at a certain ratio of components, is proposed.

EFFECT: proposed dosage form is characterized by a prolonged release of gliclazide and pharmacologically active substances contained in dry extracts, provides an increase in the effectiveness and safety of the treatment of diabetes mellitus by controlling the release rate of gliclazide and maintaining its uniform concentration in the blood, as well as smoothing out side effects by plant components of the composition.

1 cl, 3 tbl

Description

The invention relates to the pharmaceutical industry, medicine, pharmacology and for the production of antidiabetic agents.

Diabetes mellitus among endocrine diseases is widespread throughout the world. According to the World Health Organization, about 1/2 of the population of industrialized countries suffer from diabetes mellitus, and this disease is on the rise (Abstract 4I th EASD Meeting Athens Greece / A. Stirbanetal.-2005. 10-15 Sept.107.American Diabetes Association Standards of melical care in diabetes//Diabetes Care.-2007.-Vol. 30; Suppl, Sl-S-103. Does autonomic neuropathy play a role in erythropoietin regulation in nonproteinuric type 2 diabetic patients?/ V. Spallone et al // Diabetes Med/-2004; 21:1174-1180).

The adequacy of diabetes therapy remains the most pressing issue, since it has been established that hyperglycemia is the starting point of many pathogenetic mechanisms that contribute to the development of vascular complications. To date, the task of developing new drugs for the treatment and prevention of diabetes mellitus, which could help to level the side effects of synthetic drugs and enhance their hypoglycemic effect, remains relevant. In the treatment of diabetes, in addition to synthetic drugs, an important place is occupied by herbal medicines. The advantage of medicinal plants over synthetic drugs in the treatment of diabetes is that they interfere more physiologically with the metabolism of carbohydrates and lipids, are less toxic (Ernst, E. “Herbalmedicines: balancingbenefitsandrisks”. 2007, NovartisFound.Symp. 282: 154-67 ; discussion 167-72,212-8. PMID 17913230. Nuraliev, Yu, N. Medicinal plants / Yu. N. Nuraliev.-Dushanbe: Maorif, 1989-p.232-235).

Known medicinal plants with a pronounced hypoglycemic effect. These include.

Galega officinalis is a perennial herbaceous plant belonging to the genus Goat's Rue, their legume family. Galega fruits are beans containing 5-7 greenish-yellow seeds. After the seeds ripen, the beans remain on the plant, do not fall off, do not crack, but simply dry out. In folk medicine, preparations based on galega (infusions, decoctions, extracts, teas) are used to treat diabetes mellitus (Pastushenkov L.V., Pastushenkov A.L., Pastushenkov V.L. "Medicinal plants. Use in folk medicine and everyday life", St. Petersburg, BHV-Petersburg, 2012-70 p.). The rich chemical composition of this plant is effective with the right dosage. The stems and seeds contain the alkaloid galegin, which is structurally related to metformin and was used in the 1950s as an antidiabetic agent (Metformin-lifebeginsat 50: A symposiumheldontheoccasionofthe 43rd Annual Meetingof the European Association for the Study of Diabetes, Amsterdam, The Netherlands, September 2007 (English) // The British Journal of Diabetes&VascularDisease (English) Russian : journal / Campbell IW. - 2007. - Vol. 7. - P. 247-252. - doi: 10.1177/14746514070070051001. Bailey CJ, Day C. Metformin: its botanical background // Practical Diabetes International, 2004 , vol. 21, no. sainfoin: gallega officinalis and metformin: the Edinburgh connection (English) // JR Coll Physicians Edinb (English) Russian : journal - 2005. - October (vol. 35, no. 3) - P. 258-260 .-PMID 16402501).

Licorice - The main active ingredient of the licorice root is glycyrrhizic acid and its salts. Licorice root is used for various diseases, mainly for diseases of the upper respiratory tract. Licorice root in diabetes can be used as an additional component in the process of drug therapy for diabetes. Tea based on licorice helps to normalize the level of cholesterol and sugars in the blood plasma. The use of such tea effectively resists the development of diabetes mellitus and atherosclerosis as one of the accompanying ailments. Licorice contains compounds that effectively control blood sugar levels. Amorphrutins are able to effectively lower sugar without causing side effects. Taking decoctions and infusions based on this plant material helps to strengthen the protective properties of the body, lowers cholesterol levels, and helps restore the functioning of the human endocrine system. The last quality of decoctions and tinctures from this plant is of particular importance in the presence of developing type 2 diabetes mellitus in the body. The use of licorice will reduce the likelihood that unpleasant complications of type 2 diabetes will develop. The use of licorice by a person suffering from diabetes helps to bring the body into tone, allows you to get rid of a depressive state and improves the quality of life of a patient with diabetes mellitus (https://mkkmz. ru/lechenie/koren-solodki-pri-diabete.html).

Peppermint is a cultivated plant. It is used for a number of diseases: viral and bacterial nature, proceeding according to the type of acute respiratory infections, as well as tuberculosis; of cardio-vascular system; nervous system; digestive system, diseases of the oral cavity; skin and mucous membranes. In folk medicine, it is included in antidiabetic collections (http://zdravotvet.ru/myata-perechnaya-lechebnye-svojstva-i-protivopokazaniya-maslo-otvar-nastoj/).

Of the synthetic hypoglycemic drugs, gliclazide has proven itself well. It increases insulin secretion by pancreatic beta cells and improves glucose utilization. Stimulates the activity of muscle glycogen synthetase. It is effective in metabolic, latent diabetes mellitus, in patients with exogenous constitutional obesity. Normalizes the glycemic profile after a few days of treatment. Reduces the time interval from the moment of ingestion to the onset of insulin secretion, restores the early peak of insulin secretion and reduces food-induced hyperglycemia. Improves hematological parameters, rheological properties of blood, hemostasis and microcirculation system. Prevents the development of microvasculitis, including lesions of the retina. Suppresses platelet aggregation, significantly increases the relative disaggregation index, increases heparin and fibrinolytic activity, increases heparin tolerance. It exhibits antioxidant properties, improves the vascularization of the conjunctiva, ensures continuous blood flow in microvessels, and eliminates signs of microstagnation. Reduces proteinuria in diabetic nephropathy (https://www.rlsnet.ru/mnn_index_id_39.htm).

An important biopharmaceutical factor influencing the final pharmacological effect is the dosage form, which can avoid unwanted side effects.

Synthetic drugs for the treatment of type II diabetes mellitus are widely known and used in medicine: metformin and its combinations with glimepiride, empagliflozin, glibenclamide, gliclazide, sitagliptin, saxagliptin (https://www.rlsnet.ru/fg_index_id_292.htm).

A composition is known that has a multicomponent mechanism of antidiabetic action, made in the form of capsules containing a mixture of dry aqueous extracts of forest hymnema 80 mg, elecampane high 100 mg, grape ridges 40 mg (RF Patent 2289419), which can be used to normalize sugar levels in the prediabetic period , to normalize metabolism, etc.

The closest in action is the invention Pharmaceutical antidiabetic composition of prolonged action (RF patent 2465896). According to this invention, the drug for the treatment of diabetes mellitus based on metformin is in the form of coated tablets with a modified release profile. In addition to metformin, the composition contains the following excipients: polyacrylate, hydroxypropyl methylcellulose, filler, glidant, lubricant.

Known substances that are used as film formers in the production of microcapsules. So, for example, microcapsules of sedative preparations are obtained using gelatin (RF patent 2632304), with carrageenan in the presence of a surfactant E472, rosemary microcapsules (RF patent 2550929) and antioxidant microcapsules (RF patent 2557950) are obtained. To block the unpleasant organoleptic properties of the active substance, microencapsulation is used from waterproof neutral methyl or ethyl esters of polymethacrylic acid or quaternary ammonium compounds of polymethacrylic acid or ethylcellulose (RF patent 2110255). Preparations of the cephalosporin group are encapsulated in konjac gum in toluene (RF patent 2525158), to obtain microcapsules containing phospholipid micelles, a method has been developed for obtaining shells based on chitosan and alginic acid salts (RF patent 2411077). To obtain microcapsules of amino acids, I use sodium alginate in butanol in the presence of E472 (RF patent 2565408), and for encapsulation of furacillin, tetracycline, dibazol and metronidazole, aqueous solutions of sodium alginate and guar gum (RF patent 2582274). Also known is a method of obtaining microcapsules of dry extract of Jerusalem artichoke in pectin (RF patent 2555824) and a method of obtaining biopag-D microcapsules in pectin (RF patent 2561586).

The objective of our invention is to create a pharmaceutical composition with an antidiabetic effect of a complex composition, made in the form of tablets obtained by pressing microencapsulated dry plant extracts obtained by spray drying, as well as the use of modern excipients that slow down the release by creating a hydrophilic matrix of swelling hydrocolloids and improve technological properties - tablet mass (flowability and compressibility). The main active ingredients in the proposed composition is gliclazide, as well as dry extracts of galega officinalis, licorice root, peppermint, which play an auxiliary role in normalizing the level of sugars and cholesterol in the blood plasma.

The technical solution of the task lies in the fact that the composition of the proposed drug as additional means that enhance the hypoglycemic effect of gliclazide and soften its side effects includes microcapsules of dry extracts of Galega officinalis, licorice root, peppermint, in which polyethylene glycol 6000 (PEG 6000) with an average molecular weight in the range of 5400-6600 and polyvinylpyrrolidone with a molecular weight of 81-97 thousand (plasdon K-90).

Microcapsules of dry extracts are obtained by the following method.

When microencapsulating dry plant extracts of galega, licorice and mint, the method of dispersion in the liquid:liquid system is used, and the melt of the solid dispersion of dry extracts in polyethylene glycol 6000 is used as the dispersed phase, and vaseline oil is used as the dispersion medium. To obtain microcapsules, 10 parts of PEG 6000 are melted in a water bath at a temperature of 70°C, then dry extracts are alternately added to the melt: galega - 5 parts by weight, licorice - 7 parts by weight and mint - 3 parts by weight, mixed until smooth. The obtained solid dispersion of the extracts is fed into a reactor with a propeller stirrer, containing vaseline oil as a dispersion medium, heated to a temperature of 60°C. Continue dispersion at agitator speed of 900 rpm. Then the contents of the reactor are rapidly cooled to 15°C by supplying cold water into the jacket, and stirring is continued until the microcapsules solidify. The resulting microcapsules are washed with hexane or petroleum ether, dried to remove the smell of the solvent at room temperature in a fume hood, then calibrated through a 0.5 mm sieve.

To obtain tablets, microcapsules are mixed with a calculated amount of gliclazide substance and excipients that slow down the release by creating a hydrophilic matrix of swelling hydrocolloids and improve the technological properties of the tablet mass (flowability and compressibility). Tablets are pressed from the resulting mass.

The proposed composition is characterized by a prolonged release of gliclazide and pharmacologically active substances contained in dry extracts and provides a supportive antidiabetic effect.

The technical result is achieved by the fact that the solid dosage form, which has an antidiabetic effect, contains the active substance of gliclazide, microencapsulated dry plant extracts of galega, licorice and mint, obtained by spray drying, and excipients with the following content of components in g / table. and wt.%:

Gliclazide 0.0600 11.58

Dry extract of Galega officinalis herb 0.0500 9.65

Dry extract of licorice root 0.0700 13.51

Dry extract of peppermint herb 0.0300 5.79

Polyethylene glycol 6000 0.1500 28.96

Hypromellose 0.0700 13.51

Microcrystalline cellulose (MKTs-102) 0.0680 13.12

Plasdon K-90 0.018 3.48

Silicon dioxide colloidal 0.0010 0.20

Magnesium stearate 0.00100.20

Total 0.5180 100.00

The choice of the composition of the tablets was carried out on the basis of the studies below. For the study, 5 formulations of tablets were proposed, in which various swelling matrices of hydrocolloids were modeled for the purpose of prolongation (Table 1).

Biconvex tablets with a diameter of 10 mm (compositions No. 1 and 4) and 12 mm (compositions No. 2,3,5) were obtained from the indicated ingredients on a RTM-12 tablet machine. The choice of the optimal composition of excipients that provide the specified release parameters and technological quality of tablets was carried out on the basis of weighted average estimates of indicators regulated by OFS 1.4.1.0015 "Pills" OFS 1.4.2.0011.15 "Crushing strength of tablets", as well as FS.3.1.0019.18 " Gliclazide, tablets" according to the "Dissolution" test of the Global Fund of the XIV edition.

Experiment conditions:

Paddle mixer 100 rpm

Dissolution medium: phosphate buffer, pH 7.4

Dissolution medium volume - 900 ml

Temperature 37±0.5°С

Detection: spectrophotometry at 226 and 290nm

Sample selection:

2 hours - release from 15 to 35%

4 hours - from 30 to 55%

12 hours - not less than 75%.

The results of the analysis are shown in table 2.

The evaluation of the compositions was carried out on the basis of a set of indicators given in a single scoring system. The maximum score for each indicator is assumed to be 100, given that the quality is optimized when approaching this score.

The scoring of each indicator K _i was determined by the formula:

where: x is the natural value of the technological indicator;

х _н ,х _в - upper and lower limits of its permissible values;

Based on the results obtained, the arithmetic mean score for each composition was calculated. The results of calculating the arithmetic mean scores of technological indicators of model tablets are presented in Table 3, in which the results of the analysis that go beyond the permissible values were evaluated with a zero score.

Thus, the maximum score belongs to composition No. 5.

The essence of the claimed invention is as follows.

The original composition of the synthetic drug gliclazide and dry extracts of plants used in official and traditional medicine as antidiabetic agents for the treatment and prevention of diabetes mellitus.

The use of a technological method for obtaining microcapsules makes it possible to obtain a drug with a prolonged action, to increase the stability of dry extracts. The main distinguishing feature of the claimed composition is the use of the chemotherapeutic agent gliclazide in combination with microcapsules of dry extracts of galega officinalis, licorice root, peppermint, which normalize blood sugar and cholesterol levels and potentiate the hypoglycemic effect.

The use of modern excipients in the claimed amounts makes it possible to obtain a solid dosage form - tablets that are stable during storage and provide prolonged release of gliclazide, which fully complies with the requirements of the State Pharmacopoeia of the Russian Federation of the XIV edition.

Thanks to the pharmaceutical composition developed by us, the effectiveness and safety of the treatment of diabetes mellitus increases, as side effects on the body are reduced by controlling the release rate of gliclazide and maintaining its uniform concentration in the blood, as well as smoothing out side effects with herbal components of the composition. The ease of use of the medicinal product is increased, since fewer doses per day are required compared to the conventional dosage form. The claimed composition is stable during storage and meets the requirements and quality standards applicable to tablets of the State Pharmacopoeia of Russia.

Table 1 - Model tablet formulations Components Composition No. (g/tab) 1 2 3 4 5 medicinal substances Gliclazide 0.06 0.06 0.06 0.06 0.06 Galega herb dry extract 0.05 0.05 0.05 0.05 0.05 Dry licorice root extract 0.07 0.07 0.07 0.07 0.07 Dry mint extract 0.03 0.03 0.03 0.03 0.03 Excipients Framework-forming substances Dibasic calcium phosphate 0.07 0.06 0.07 Cellulose microcrystalline (MKTs-102) 0.068 Cellulose microcrystalline "Avicel-PH-103" 0.068 Polyethylene glycol 6000 0.170 0.150 Swellable hydrocolloids Hypromellose 0.070 0.070 Hydroxyethylcellulose 0.06 sodium alginate 0.08 Chitosan 0.12 Binding prolongators PlasdonK-30 0.02 Plasdon K-90 0.02 0.017 0.018 Lubricants and Glidants Magnesium stearate 0.001 0.001 0.001 0.001 calcium stearate 0.001 Silicon dioxide colloidal 0.001 0.001 0.001 0.001 Total 0.382 0.541 0.599 0.387 0.518

Table 2 - Results of the analysis of model tablets according to the "Dissolution" test and strength (X _cf. , n=3) No. p / p Name of indicator Interv. opt.value No. of the model prescription of tablets 1 2 3 4 5 1 Dissolution in 2 hours (%) 15-35 42 37 47 19 26 2 Dissolution in 4 hours (%) 30-55 64 58 72 36 46 3 Dissolution in 12 hours (%) 75 - 95 92 86 84 87 88 4 Strength mod.tabletok (N) 40-100 47 68 66 56 54

Table 3 - The results of calculating the arithmetic mean scores of technological indicators of model tablets composition number Quality indicators (points) K ₁ K ₂ K ₃ K ₄ 1 0 0 85 11.67 24.17 2 0 0 55 46.67 25.41 3 0 0 45 43.33 22.08 4 20 thirty 60 26.67 34.16 5 55 64 65 23 51.75

Note: K1 - scoring % dissolution in 2 hours;

K2 - scoring % dissolution in 4 hours;

K3 - scoring % dissolution in 12 hours;

K4 - scoring of the strength of model tablets.

Claims (12)

Solid dosage form, prolonged action, made in the form of tablets, with antidiabetic activity, characterized in that it contains gliclazide and microencapsulated dry extracts of Galega officinalis, licorice and peppermint as an active ingredient, and polyethylene glycol 6000 is used to obtain microcapsules in the following ratio components, g/table. and wt.%: Gliclazide………………………………………....0.0600……….11.58 Dry extract of Galega officinalis herb... . ..0.0500….….….9.65 Dry extract of licorice root……………….…0.0700……......13.51 Dry extract of peppermint herb…………0.0300…….…..5.79 Polyethylene glycol 6000………………….…..….0.1500………28.96 Hypromellose………………………………………0.0700………13.51 Microcrystalline cellulose (MKTs-102) …0.0680………13.12 Plasdon K-90……………….…………………..…...0.018………..3.48 Colloidal silicon dioxide……………………0.0010………..0.20 Magnesium stearate……………….…………………….0.0010………..0.20 Total……….……………………………………….0.5180……...100.00