RU2449779C1 - Dragee with oximethyluracyl and netylmicine for treatment of infectious intestinal diseases - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine. Claimed medication in form of dragee as active substances contains oximethyluracyl and netylmicine, as auxiliary substances for core covering it contains potato starch 1500, aerocyl, mixture of 10% water solution of potato starch, 3% water solution of Kollidon 90F povidone and 5% alcohol-acetone solution of acetylphthalylcellulose (APC) in ratio 1:1:1 as moisturiser 1; 3% water solution of Kollidone 90F povidone as moisturiser 2; 5% alcohol acetone APC solution as moisturiser 3; mixture of 64% of sugar syrup and 1% water solution of kollidone 25 in ratio 5:1 as moisturiser 4 with specified ratio of components.

EFFECT: invention ensures obtaining novel medication, possessing anti-inflammatory and antimicrobial activity, with even distribution and complete solubility in intestine in 2 hours, with retard action during 1 hour.

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Description

The present invention relates to medicine, namely to pharmacy, and can be used to treat infectious inflammatory bowel diseases.

Known X-ray contrast diagnostic tool used for fluoroscopy - "X-ray contrast diagnostic system with barium sulfate" (Urazlina OI "Development and study of radiopaque and diagnostic and treatment systems with chloramphenicol used for stenosis of the small intestine" Diss. ... Ph.D. Pharmaceutical Sciences Ufa, 1998, P.78-82), with the following ratios of ingredients: barium sulfate for fluoroscopy up to 2.0; alcohol-acetone solution AFC - 5%; solution of NMPE in hexane 10% 1-3 layers; Sulfacrylate medical glue 1-2 layers.

The closest analogue of the invention in terms of composition and achieved result is a radiopaque diagnostic tool used for fluoroscopy - “Medicinal radiopaque diagnostic system with barium sulfate and oxymethyluracil in the form of a sphere” containing oxymethyluracil - 0.25 g per sphere, barium sulfate for x-ray and potato starch (4: 1) or (6: 1) to a mass of a sphere of 2.0; alcohol-acetone solution of acetylphthalyl cellulose - 5%; a solution of NMPE in hexane 10% - 1-3 layers; Sulfacrylate medical glue - 1-2 layers (RF patent No. 2275197, 2006). The use of the invention allows to have a therapeutic effect in the diagnosis of the intestine with a given time disintegration and controlled release of active substances, increases convenience and hygiene.

However, this tool has the following disadvantages. The tool is able to detect stenotic areas of the small intestine and have a therapeutic effect on the intestinal area only due to oxymethyluracil, while not providing both antimicrobial and anti-inflammatory, stimulating tissue regeneration and prolonged (retard) action, it breaks down in the intestine after 2, 4, 6 hours.

The objective of the invention is to expand the arsenal of funds for the treatment of infectious diseases of the intestine.

The technical result when using the invention is to obtain a new domestic drug in the form of a dragee containing oxymethyluracil and netilmicin, having anti-inflammatory and antimicrobial effects, with a uniform distribution in the intestine, controlled release of active substances for 1 hour, convenient to use, with a prolongation effect ( retard), providing complete dissolution of the dragee with oxymethyluracil and netilmicin after 2 hours.

The indicated technical result is achieved in that the therapeutic agent in the form of a dragee with solubility in the intestine after 2 hours, with a retard action for 1 hour, is characterized in that it consists of a kernel, which is a sugar grain, onto which successively layers of potato starch are applied 1500 s a solution of 10% aqueous solution of potato starch, 3% aqueous solution of Collidone 90F povidone and 5% alcohol-acetone solution of acetylphthalyl cellulose (AFC) in a ratio of 1: 1: 1 as a humidifier 1 to a dragee diameter of 3 mm, not a layer tilmicin and 2-3 layers of humidifier 1 to a diameter of 4 mm, a layer of potato starch 1500 and aerosil with a humidifier 1 to a diameter of 6 mm, a layer of oxymethyluracil (crushed and sifted through sieve No. 61) with a humidifier 1 to a diameter of 7 mm, 2-3 layers solution of 3% Collidone 90F povidone as a humidifier 2, 2 layers of netilmicin with a humidifier 1, a layer of humidifier 2, a layer of oxymethyluracil with a humidifier 1 to a diameter of 7.5 mm, a layer of potato starch 1500 and aerosil to a diameter of 8.5 mm, 2-3 layer of a solution of AFC 5% as a humidifier 3, 2-3 layers of a 64% solution of sugar syrup and 1% in one solution of collidone 25 in a ratio of 5: 1 as a humidifier 4 to a dragee diameter of 8.5-9 mm in the following ratio of components, per dragee:

Oxymethyluracil 0.250 g Netilmicin 0,200 g Aerosil A-380 0.0030 g Potato starch 1500 To a mass of 0.52-0.55 g

The invention is illustrated by the following figures: figure 1 shows a structural diagram of a dragee with oxymethyluracil and netilmicin;

figure 2 - photo pills with oxymethyluracil and netilmicin;

figure 3 - kinetics of the release of oxymethyluracil and netilmicin from tablets in example 1;

figure 4 - kinetics of the release of oxymethyluracil and netilmicin from tablets in example 2.

The proposed tablets are intended for treatment at the localization site, since two active substances, oxymethyluracil and netilmicin, are simultaneously released. Dragees contain the active substance netilmicin, which has a wide spectrum of activity against gram-negative microorganisms: Escherichia coli, Klebsiella spp., Enterobacter spp., Serratia spp., Shigella spp., Salmonella spp., Proteus spp., Citrobacter sp., Proteus spp. (indole positive and indole negative), Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Pseudomonas aeruginosa and Neisseria gonorrhoeae and some gram-positive microorganisms, in particular Staphylococcus spp. (strains producing and not producing penicillinase, as well as penicillin-resistant strains); and oxymethyluracil having anti-inflammatory, immunomodulating and accelerating regeneration action; provides a prolonged effect of the drug complex due to surface-active properties. In general, dragees containing oxymethyluracil and netilmicin are intended for the treatment of infectious and inflammatory bowel diseases with a retard action, have a mechanism for the release of oxymethyluracil and netilmicin, delayed up to 2 hours of passage through the small intestine and then evenly extended - for 1 hour, since the release time of the active substances programmed. In this case, the dragee is multi-layered: the layers of active substances alternate with layers of experimentally selected excipients that interfere with the release of oxymethyluracil and netilmicin until they are destroyed by various factors in the gastrointestinal tract, namely pH, enzyme composition and temperature. The controlled release of active substances is due to the multilayer dragee, that is, the time of their entry into the biophase is lengthened, in turn, the controlled release directly depends on the amount of released active substances - oxymethyluracil and netilmicin and on the parameters that affect the release process.

All components that make up the complex tablets are approved for medical use. Oxymethyluracil (VFS 42-2730-96). Netilmicin P-8-242 No. 009143 02/17/97. Kollidon F90 povidone (ND 42-8482-98) is used as a prolonging and film-forming substance (manufactured by the German company BASF). Collidone F90 forms a matrix, as a hydrophilic component regulates the release of drugs, improves the bioavailability of active substances. Kollidon 25 (ND 42-8482-98) is used as a film-forming substance (manufactured by the German company BASF). Kollidon 25 is used as a coating of dragees. Aerosil A-380 (GOST 14922-77) mixes well with water and organic liquids, is used as a thickener, is hygroscopic, and easily absorbs (absorbs) moisture during storage, as carriers of active substances (medicine, perfumery). Sugar (GOST 21-94). Acetylphthalyl cellulose (FS 42-1263-79). Acetone (GOST 2603). Ethyl alcohol 95% (FS 42-3072-94). Potato starch (GOST 7699).

As a result of experimental studies, it was found that AFC, collidone F90 and potato starch due to increased adhesion to surfaces provide reliable fixation of layers of potato starch (up to a mass of 0.52-0.55 g) and aerosil (0.003 g), and 3% water povidone collidone solution 90F regulates, provides prolonged retard release, improves the bioavailability of oxymethyluracil and netilmicin, which subsequently roll up and take the form of dragees, 5% AFC solution provides an enteric coating. The combination of sugar syrup 64% and collidone 25 (5: 1) provides a glossy, durable sugar coating (collidon 25 prevents cracking of the sugar coating in dragees with loss of moisture during drying). Shaping dragees with a retard release provides convenience and hygiene of use, storage stability. The above components in the above ratios make it possible to obtain a new composition of the dosage form that has stability and is controlled by a predetermined time disintegration after 2 hours with controlled retard release of oxymethyluracil and netilmicin for 1 hour, which have anti-inflammatory effects in the small intestine, antimicrobial, immunomodulating and accelerating effects.

Receive the proposed integrated tablets as follows.

1st stage. Growth of a layer of potato starch with a humidifier solution 1: AFC 5%, 3% solution of collidone 90F, potato starch 10% in a ratio (1: 1: 1) on sugar grains (kernels) up to a dragee diameter of 3 mm in a pelletizing boiler. Loading 25 cores, rotation speed 72 rpm, tilt angle 90 °, forced supply of warm air for drying. The kernels are evenly moistened with a pre-prepared solution of a binder - humidifier 1.

2 stage. Application of 1 layer of netilmicin (100 mg per 1 tablet) and, moistening 2-3 times with moisturizer 1, diameter 4 mm, the tablet is dried.

3 stage. Knurling of a layer of potato starch and aerosil with a humidifier 1, after which the dragee is dried, diameter 6 mm.

4 stage. Then apply the 1st layer of oxymethyluracil (150 mg per 1 tablet oxymethyluracil pre-crushed and sieved through a No. 61 sieve) with a humidifier 1 and periodically dried with warm air, dragee diameter 7 mm.

5 stage. Then apply a layer of a solution of collidone 90F povidone - 3% - 2-3 layers (moisturizer 2).

6th stage. Application of 2 layers of netilmicin (100 mg per 1 tablet) with a moisturizer 1 - 2-3 times, after which the tablets are dried.

7th stage. Cover with a layer of humidifier 2 and then apply the 2nd layer of oxymethyluracil (100 mg per 1 tablet) with moisturizer 1, diameter 7.5 mm.

Dried dragees were standardized by screening from dust and weighing, loaded into a coating pan to continue the process. Oxymethyluracil powder was applied in several doses to moistened dragees during periodic drying with warm air.

8 stage. Application of a filler layer - potato starch and aerosil to a dragee diameter of 8.5 mm; dragee is periodically dried with warm air.

9th stage. Applying layers of an AFC solution of 5% - 2-3 layers (humidifier 3), dragees are dried.

10 stage. Application of a sugar coating layer with a solution of collidone 25 1% (moisturizer 4) - 2-3 layers, the dragee is dried, the diameter of the dragee is 8.5-9 mm.

11 stage. The quality of the obtained dragees with oxymethyluracil and netilmicin is assessed by the following indicators: appearance, authenticity and quantitative content of oxymethyluracil and netilmicin in the dragee, average weight, diameter, integrity and strength, the time of their disintegration in artificial digestive juices, and the rate of release of oxymethyluracil and netilmicin from the dosage form. In a multilayer dosage form, the layers of active substances alternate with layers of auxiliary substances that interfere with the release of oxymethyluracil and netilmicin under the influence of gastrointestinal tract factors, while creating a predetermined and controlled release with a prolongation effect. Finished products are packaged in NS-1 glass jars with a pull-on closure lid. Banks are packed in group or shipping containers in accordance with GOST 17768-90, OST 64-071-89 and RD 00001910-6-92.

The resulting dragees of regular spherical shape, with a diameter of 7.5-8.5 mm, with a smooth and even surface of uniform white color or with a slightly yellowish tint, referred to in further studies as dragees "Immureg-netilmicin" (Figure 1, figure 2).

Example 1. Composition on 1 dragee weighing 0.52-0.55 g: oxymethyluracil - 0.25; netilmicin - 0.2; Aerosil 0.003; potato starch; humectant 1: 10% potato starch solution; 3% aqueous solution of Collidone 90F povidone; alcohol-acetone solution of acetylphthalyl cellulose 5% (1: 1: 1) - 10-15 layers; humidifier 2: 3% aqueous solution of Collidone 90F povidone - 2-3 layers; humidifier 3: alcohol-acetone solution of acetylphthalyl cellulose 5% - 2-3 layers; humectant 4: sugar syrup solution 64%; collidone solution 25 1% (5: 1) 2-3 layers. Dragees dissolve after 2 hours, the release of oxymethyluracil and netilmicin is prolonged - retard - within 1 hour (Figure 3).

Example 2. Composition on 1 dragee weighing 0.52-0.55 g: oxymethyluracil - 0.25; netilmicin - 0.2; Aerosil 0.003; potato starch; humectant 1: 10% potato starch solution; 3% aqueous solution of Collidone 90F povidone; (1: 1) - 10-15 layers; humidifier 2: 3% aqueous solution of Collidone 90F povidone - 2-3 layers; humectant 4: sugar syrup solution 64%; collidone solution 25 1% (5: 1) 2-3 layers. Dragees are made in a similar manner, but there is no enteric coating. Dragee dissolves after 15 minutes, dragee does not dissolve in the intestine, but dissolves in the stomach (Figure 4).

Example 3. Composition on 1 dragee weighing 0.52-0.55 g: oxymethyluracil - 0.25; netilmicin - 0.2; Aerosil 0.003; potato starch; humectant 1: 10% potato starch solution; alcohol-acetone solution of acetylphthalyl cellulose 5% (1: 1) - 10-15 layers; humidifier 3: alcohol-acetone solution of acetylphthalyl cellulose 5% - 2-3 layers; humectant 4: sugar syrup solution 64%; collidone solution 25 1% (5: 1) 2-3 layers. A dragee is made in a similar manner, but there is no 3% aqueous solution of Collidone 90F povidone. Dragee dissolves after 1.5 hours, the release of oxymethyluracil and netilmicin begins 1 hour after ingestion and lasts for 30 minutes, however, early dissolution of the dragee (after 1.5 hours) does not allow local therapeutic effect of oxymethyluracil and netilmicin to be achieved with organ therapy abdominal cavity after 2 hours.

Example 4. Composition on 1 dragee weighing 0.52-0.55 g: oxymethyluracil - 0.25; netilmicin - 0.2; Aerosil 0.003; potato starch; humectant 1: 10% potato starch solution; 3% aqueous solution of Collidone 90F povidone; alcohol-acetone solution of acetylphthalyl cellulose 5% (1: 1: 1) - 10-15 layers; humidifier 2: 3% aqueous solution of Collidone 90F povidone - 2-3 layers; humidifier 3: alcohol-acetone solution of acetylphthalyl cellulose 5% - 2-3 layers; humectant 4: solution of sugar syrup 64% 2-3 layers. Dragees dissolve after 2 hours, the release of oxymethyluracil and netilmicin is prolonged - retard - within 1 hour. Dragees are made in the same way, but the coating is made with 64% sugar syrup without 25 1% collidone solution, as a result of which cracks are noted on their surface when drying the dragee, which is explained by moisture loss during drying, sugar crystals and an uneven coating appear. The solubility of the dragee after 2 hours, the release of oxymethyluracil and netilmicin was prolonged for 1 hour.

Example 5. Composition on 1 dragee weighing 0.52-0.55 g: oxymethyluracil - 0.25; netilmicin - 0.2; Aerosil 0.003; potato starch; humidifier 1: 3% aqueous solution of Collidone 90F povidone; alcohol-acetone solution of acetylphthalyl cellulose 5% (1: 1) - 10-15 layers; humidifier 2: 3% aqueous solution of Collidone 90F povidone - 2-3 layers; humidifier 3: alcohol-acetone solution of acetylphthalyl cellulose 5% - 2-3 layers; humectant 4: sugar syrup solution 64%; collidone solution 25 1% (5: 1) 2-3 layers. Dragees are made in a similar manner, but difficulties are noted in the layering of active and auxiliary substances, poor adhesion. Dragee dissolves unsatisfactorily, complete dissolution after 1.5-2 hours.

From the above examples it is seen that the optimal from the point of view of solubility and treatment effectiveness is the composition of the complex tablets, described in example 1.

Clinical trials have shown that the amount of drug used for a given ratio of components, and the prolonged release of oxymethyluracil and netilmicin are the same in the studied patients. This makes it possible for the doctor, in practical medicine - in abdominal surgery, depending on the form and severity of the disease, to individually recommend the necessary amount of complex dragees with a controlled dissolution time for self-treatment of the intestine, which makes the dragee claimed a promising dosage form in practical surgery. After conducting full-scale clinical trials and developing quality control methods for the developed dragees, it is planned to draw up a pharmacopeia article.

Claims (1)

A medicinal product in the form of dragees with solubility in the intestine after 2 hours, with a retard action for 1 hour, characterized in that it consists of a kernel, which is a sugar grain, on which successively layers of 1500 potato starch with a mixture of 10% aqueous a solution of potato starch, 3% aqueous solution of Collidone 90F povidone and 5% alcohol-acetone solution of acetylphthalyl cellulose (AFC) in a ratio of 1: 1: 1 as a humidifier 1 to a dragee diameter of 3 mm, a layer of netilmicin and 2-3 layers humidifier 1 to diameter 4 mm, a layer of potato starch 1500 and aerosil with a humidifier 1 to a diameter of 6 mm, a layer of oxymethyluracil (crushed and sieved through a No. 61 sieve) with a humidifier 1 to a diameter of 7 mm, 2-3 layers of a solution of 3% Povidone Collidone 90F as humidifier 2, 2 layers of netilmicin with a humidifier 1, a layer of humidifier 2, a layer of oxymethyluracil with a humidifier 1 up to a diameter of 7.5 mm, a layer of potato starch 1500 and aerosil up to a diameter of 8.5 mm, 2-3 layers of an AFC solution of 5% as a humidifier 3, 2-3 layers of a 64% solution of sugar syrup and 1% aqueous solution of collidone and 25 in a ratio of 5: 1 as a humidifier 4 to a dragee diameter of 8.5-9 mm in the following ratio of components, in 1 dragee:
Oxymethyluracil 0.250 g Netilmicin 0,200 g Aerosil A-380 0.0030 g Potato starch 1500 To a mass of 0.52-0.55 g

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