RU2276985C1 - Pharmaceutical composition for treating the cases of pancreas diseases and digestion disorders related to hepatic diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: composition comprises pancreatine as active ingredient, lactose, calcium stearate, filler and coating capsule soluble in intestine composed of acetylphthalyl cellulose, titanium dioxide, binding agent and acid red and sliding. Potato starch is used is used as filler. Nucleus additionally has sugar invention in 1 : (1.8-2) proportion to lactose, Copolyvidon. The coating capsule has polyethyleneoxide as binding agent.

EFFECT: high stability in acid medium; enhanced effectiveness of treatment.

4 tbl

Description

The invention relates to medicine, namely to a pharmaceutical composition for treating pancreatic diseases and digestive disorders associated with liver disease.

In intestinal disorders of a non-infectious nature, the key part of therapy is the correction of digestive processes in the intestine, which is achieved by taking enzyme preparations.

Enzymatic preparations that improve digestion include preparations containing individual enzymes or enzyme complexes of the gastrointestinal tract.

Various dosage forms containing pancreatin are known — capsules, granules, tablets. Japanese Patent No. 4-257525 describes the preparation of granules containing pancreatin, lactose, disintegration agent, silica, binding agents. US Pat. No. 5,378,462 describes a composition comprising panreatin, polyethylene glycol and liquid paraffin. British Patent No. 1561613 describes capsules containing pancreatin, a swelling and alkaline agent.

A medicament is known (RF patent No. 2068698) for the treatment of patients with decreased exocrine pancreatic function, containing pancreatin, oraz, lyophilized bile, as well as excipients. The disadvantages of this tool are the large size and weight of the tablets. In order for the enzyme preparation to act on food, it is necessary that both the food and the tablet are in the place of digestion of the food (intestine). Due to the large size of the tablets, it is difficult for the tablets to pass through the pyloric sphincter, which separates the stomach from the intestine.

Enzyme preparations should have a membrane that protects enzymes from inactivation in the stomach and digestion of gastric juice (the main components of enzyme preparations, lipase and trypsin, are quickly inactivated in an acidic environment: lipase - at pH less than 4.0, trypsin - at pH less than 3.0) . These drugs should provide rapid release of enzymes in the upper small intestine. The lipase content should be quite high - up to 30,000 units per dose, due to the fact that in exocrine pancreatic insufficiency, the digestion of fats is disturbed in the first place.

A drug is known (RF patent No. 2172170) for improving digestion, containing an enzyme, stabilizing additives, excipients and a polymer shell. As an enzyme, the drug contains pancreatin, as stabilizing additives - magnesium oxide and calcium carbonate, as an auxiliary substance, an interpolymer complex of polymethacrylic acid with polyethylene glycol or polypropylene glycol is used. This product is coated with the same complex. The use of an interpolymer complex makes the product expensive and uneconomical on an industrial scale. In addition, this shell slows down the release of the active substance.

A drug is known (RF patent No. 2201763) that affects tissue metabolism in the form of a coated tablet. The core contains pancreatin, hemicellulose, bovine bile extract, polyvinylpyrrolidone, calcium stearate and sodium chloride. The shell includes sodium chloride, acetylphthalyl cellulose, ethyl vanillin, castor oil, calcium carbonate, talc, gelatin, glucose syrup, gum arabic, nipagin, nipazole, titanium dioxide, capol, sucrose. The disadvantage of this tool is: the multicomponent composition of the shell, which significantly complicates the process of manufacturing tablets and increases the price of the drug.

Known enzyme preparation "Ponzym forte" in the form of a coated tablet (US Pat. RF No. 2225724). The core contains pancreatin, microcrystalline cellulose, aerosil, magnesium stearate and sodium starch glycolate. The shell includes Eudragit E-100 polymer, polyethylene glycol, citric acid, propylene glycol, liquid paraffin, carmuazine, indigo carmine, hydroxypropyl methyl cellulose, Opadru PINK suspension.

The closest technical solution, selected as a prototype, is a pharmaceutical composition for the treatment of pancreatic diseases and digestive disorders associated with liver disease, containing the active substance pancreatin, milk sugar, calcium stearate, a filler and having an enteric coating, consisting of cellulose acetate, titanium dioxide, binder, acid red and sliding (US Pat. RF No. 2207847).

A common disadvantage of known drugs is the relatively low stability in an acidic environment and the complexity of the composition.

The aim of this invention is to provide a pharmaceutical composition for the treatment of pancreatic diseases and digestive disorders associated with liver disease with higher stability in an acidic environment and, consequently, higher efficiency, and the creation of a simple composition using available raw materials.

This goal is achieved through the use of a pharmaceutical composition for the treatment of pancreatic diseases and digestive disorders associated with liver disease, containing the active substance pancreatin, milk sugar, calcium stearate, a filler and having an enteric coating consisting of acetylphthalyl cellulose, titanium dioxide, a binder, acid red and rolling. In this case, potato starch is used as a filler and the core additionally contains sugar taken in the ratio 1: (1.8-2) to milk sugar, copolyvidone, and the shell as a binder contains polyethylene oxide in the following ratio of ingredients, g:

composition of the tablet - core:

pancreatin 0.05-0.103 sugar 0.05-0.062 milk sugar 0.1-0.124 copolyvidone 0.001-0.0013 calcium stearate 0.003-0.0033 potato starch the rest is up to 100%

The shell contains these ingredients in the following ratio, g:

tablet shell composition:

cellulose acetate 0.01-0.014 titanium dioxide 0,00058-0,00061 polyethylene oxide 0.00270-0.00284 acid red 0.000048-0.000051 moving 0.002499-0.006672

The shell preferably contains as a moving talc.

The claimed ratio of ingredients is optimal, found experimentally and provides the necessary quality of the composition.

A method of obtaining a pharmaceutical composition includes mixing pancreatin powder with excipients (a mixture of sugar with milk sugar, copovilidone, potato starch, calcium stearate), moisturizing, keeping in a sealed container, drying, granulating, dusting, tabletting and applying a film coating.

Table 1 shows the compositions of the proposed composition.

Table 1. Options Pat. No. 2207847, g. prototype Examples, g (tablet weight 0.34 g) one 2 3 four Kernel (0.32 g) Pancreatin 0.1 0.05 0,075 0.1 0.103 Milk sugar 0.202 0.1 0.12 0.108 0.124 Sugar 0.05 0.06 0,0596 0,062 Calcium stearate 0.0032 0.003 0.0031 0.0032 0.0033 Cellulose 0.0148 Copovilidone (Collidone V-64) 0.001 0.0011 0.0012 0.0013 Potato starch 0.116 0,0608 0,048 0.0264 Shell (0.02 g) Acetylphthalyl cellulose 0.01884 0.01 0.012 0.013 0.014 Titanium dioxide 0.001 0,00058 0,00059 0,0006 0,00061 Twin 80 0.00006 Acid red 0.0001 0,000048 0,000049 0.00005 0,000051 Polyethylene oxide 0.00270 0,00274 0,00276 0,00284 Talc 0,006672 0,003621 0.00359 0,002499

The resulting compositions were tested for stability of 0.1 N. a solution of hydrochloric acid (pH 1.2; 37 ° C) when incubated for 120 minutes The research results are presented in table 2.

Table 2. Example Residual activity,% proteolytic amylolytic one one hundred 87 2 97 84 3 98 85 Prototype 89 73

Preliminary studies on the compatibility of the enzyme substance with excipients of various classes showed that their nomenclature is very limited. In order to preserve the high biological activity of the enzyme substance in a tablet dosage form, studies were carried out on the effect of various auxiliary substances on it in a number of excipients and substances that ensure disintegration of tablets in the upper intestinal tract and at the same time improve the technological qualities of the tablet mass.

As a result of studies, it was found that excipients in the composition with the enzyme can change the activity of the latter. It retains the activity of the enzyme talc, calcium stearate, a mixture of sugar with milk sugar as much as possible.

In the process of selecting excipients, in addition to the compatibility property with the enzyme, their influence on the technological properties of tablet masses was evaluated. Talc and calcium stearate reduce the friction force between the contacting surfaces of the particles. As a result, the flowability of the mass was maintained for 30 days during exposure in an environment with a relative humidity of 90%. Tablet masses, including selected excipients, are technological. In the process of tabletting, they do not stick to the press tool, uniformly enter the matrix, form tablet cores with a flat surface and solid edges without jagged spots. A mixture of sugars in the claimed ratio improved the quality of the tablets. The test results are summarized in table 3.

Table 3. Indicators Examples prototype one 2 3 The strength of the cores, N 79 90 85 83 Disintegration of cores, min eleven fifteen 13 eleven Pancreatin activity, U / g 250 310 400 450

In pancreatin, disaccharides are used, which partially serve as a substrate for the action of the amylase of the drug and cannot increase the activity of enzymes. A mixture of sugar with milk sugar plays the role of a stabilizer of biologically active substances, forms the basis of the drug, providing some protection for biologically active substances in the first stages of advancement along the gastrointestinal tract. In order to study the effect of a sugar mixture on the stability of pancreatic enzymes during drying of the preparation, pancreatin with various sugar contents was prepared. The results of the experiment are shown in table 4.

Table 4. Enzyme activity The amount of sugar mixture in the preparation Sugar / Milk sugar 0 / 0,1 0.06 / 0.12 0.05 / 0.1 0.15 / 0 Amylases mg / g min 5140 7300 7388 8350 Protease, mg / g min 244 483 423 375

The ingredients that make up the tablet core and shell of the claimed composition are known, however, it is their specified set and quantitative ratio that provide a tablet form of the composition with high desired pharmacological and technological properties. The effect of the interaction of the active substance of the tablet core with auxiliary substances is not obvious, when the latter not only maintain a high activity of the enzyme substance, but also enhance it. All this allows us to conclude that the invention meets the criterion of "inventive step".

Claims (1)

A pharmaceutical composition for the treatment of pancreatic and digestive disorders associated with liver disease, containing the active substance pancreatin, milk sugar, calcium stearate, a filler and an enteric coating consisting of acetylphthalyl cellulose, titanium dioxide, a binder, acid red and a sliding, the fact that potato starch is used as a filler and the core additionally contains sugar taken in a ratio of 1: (1.8-2) to milk sugar, copolividone, and the boll as a binder contains polyethylene oxide, the moving one is talc, in the following ratio of ingredients, g: core composition: Pancreatin 0.05-0.103 Sugar 0.05-0.062 Milk sugar 0.1-0.124 Copolyvidone 0.001-0.0013 Calcium stearate 0.003-0.0033 Potato starch 0.0264-0.116 shell composition: Acetylphthalyl cellulose 0.01-0.014 Titanium dioxide 0,00058-0,00061 Polyethylene oxide 0.00270-0.00284 Acid red 0.000048-0.000051 Sliding - Talc 0.002499-0.006672