RU2453308C1 - Oxymethyluracyl and mebeverine hydrochloride pill for functional gastrointestinal diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine. The presented therapeutic agent in the form of a pill contains oxymethyluracyl and mebeverine hydrochloride as active substances, as core-coating excipients - mixed potato starch and lactic sugar in relation 1:1; mixed 5% alcohol-acetone acetyl phthalylcellulose (APC), 10% aqueous potato starch and 0.1% aqueous styrene maleic anhydride copolymer (SMAC) in relation 1:1:1 as a humidifier 1; mixed 3% aqueous Kollidon 90F, povidone and 0.1% aqueous SMAC in relation 1:1 as a humidifier 2; 5% APC as a humidifier 3; mixed 64% sugar syrup and 1% Kollidon 25 in relation 5:1 as a humidifier 4 in certain proportions.

EFFECT: invention provides preparing the new therapeutic agent possessing anti-inflammatory, recycling, antispasmodic and antioxidant actions, with uniform distribution and complete enteric solubility in 2 hours, with retard action during 1 hour.

4 dwg, 2 tbl, 5 ex

Description

The present invention relates to medicine, namely to pharmacy, and can be used to treat functional diseases of the gastrointestinal tract.

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. ... Candidate of 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 the Solvay Pharma Duspatalin therapeutic agent, which is a prolonged-action capsule that contains mebeverine microspheres coated with two layers (Vidal Handbook. Medicinal Products in Russia. 2009. Issue 15. AstraFarmService. Page B-567-568). The outer layer is acid resistant, and the inner one consists of a drug of prolonged action. This structure allows mebeverin to be released throughout the gastrointestinal tract (GIT), including the colon, which is very important in the treatment of symptoms of irritable bowel syndrome. Duspatalin (mebeverin), contains one capsule: 200 mg of mebeverin hydrochloride as the active ingredient, excipients: magnesium stearate, methyl methacrylate and ethyl acrylate copolymer (2: 1), talc, hypromellose, methacrylic acid and ethacrylate copolymer (1 : 1), triacetin, and the hard gelatin capsule contains: gelatin, titanium dioxide (E171); ink composition: shellac (E904), black iron oxide (E172), soy lecithin (E 322), antifoam. Mebeverin is a myotropic antispasmodic with a selective effect on the smooth muscles of the gastrointestinal tract: relieves spasm and hyperactivity of the smooth muscles. A feature of the drug is that smooth muscle contractions are not completely suppressed, due to which normal peristalsis after suppression of hypermotility is maintained. The use of "Duspatalin" is not accompanied by the development of reflex intestinal hypotension.

The use of the drug allows you to have a therapeutic effect in the symptomatic treatment of pain, spasms, dysfunction and discomfort in the intestine associated with irritable bowel syndrome, symptomatic treatment of spasms of the gastrointestinal tract (including those caused by organic diseases).

However, this tool has the following disadvantages. The tool is able to exert a symptomatic therapeutic effect on the intestinal area only due to mebeverin, while not simultaneously providing an anti-inflammatory, stimulating tissue regeneration effect, the drug releases mebeverin in the intestine prolonged up to 16 hours.

The objective of the invention is to expand the arsenal of therapeutic agents for the treatment of functional diseases of the gastrointestinal tract.

The technical result when using the invention is to obtain a new domestic drug in the form of dragees containing oxymethyluracil and mebeverine hydrochloride, which has anti-inflammatory, regenerating, antispasmodic and antioxidant effects, with uniform distribution in the intestine, with the release of active substances for 15 minutes or controlled release of active ingredients substances within 1 hour, complete dissolution of the dragee 2 hours after administration, convenient to use AI, with the effect of prolongation (retard).

The specified technical result is achieved by the fact that the therapeutic agent in the form of dragees with solubility in the intestine after 2 hours, with a retard action for 1 hour, is characterized by the fact that it consists of a kernel, which is a sugar grain, on which layers of potato starch and milk sugar in a ratio of 1: 1 with a humidifier solution of 1: 5% alcohol-acetone solution of acetylphthalyl cellulose (AFC), 10% aqueous solution of potato starch and 0.1% aqueous solution of styrene-maleic anhydride copolymer (CCM ) in a ratio of 1: 1: 1 to a dragee diameter of 3 mm, a layer of mebeverine hydrochloride and 2-3 layers of a humidifier 1 to a diameter of 4 mm, a starch layer of potato and milk sugar in a ratio of 1: 1 with a humidifier 1 to a diameter of 4.5 mm, a layer of oxymethyluracil with a humidifier 1 to a diameter of 5 mm, 2-3 layers of a 3% aqueous solution of Collidone 90F povidone and a 0.1% aqueous solution of CCMA in a ratio of 1: 1 as a humidifier; 2 layers of mebeverine hydrochloride with a humidifier 1 to a diameter of 5, 5 mm, humidifier layer 2, oxymethyluracil layer with humidifier 1 to a diameter of 6 mm, potato starch layer of sugar and milk in a ratio of 1: 1 to about 8 mm diameter, 2-3 layers CAP solution of 5% as a humectant 3; 2-3 layers of 64% solution of sugar syrup and 1% aqueous 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 in 1 dragee:

Oxymethyluracil 0.250 g Mebeverina hydrochloride 0,200 g A mixture of potato starch and 1: 1 milk sugar to a mass of 0.56-0.60 g

The invention is illustrated by the following illustrations: figure 1 shows a structural diagram of a dragee with oxymethyluracil and mebeverine hydrochloride; figure 2 - photo dragee with oxymethyluracil and mebeverine hydrochloride; figure 3 - kinetics of the release of oxymethyluracil and mebeverin hydrochloride from pills in example 1; figure 4 - kinetics of the release of oxymethyluracil and mebeverin hydrochloride from pills in example 2; in table 1 - indicators of chemiluminescence in a model system that generates reactive oxygen species (ROS) when adding drugs according to example 1; in table 2 - indicators of chemiluminescence in the model system of lipid peroxidation (LP) with the addition of drugs according to example 1.

The proposed tablets are intended for treatment at the localization site, since two active substances, oxymethyluracil and mebeverin hydrochloride, are simultaneously released. Dragees contain the active substance mebeverine hydrochloride, which has an antispasmodic effect, it is a myotropic antispasmodic that has a direct effect on the smooth muscles of the gastrointestinal tract (mainly the large intestine), and eliminates spasm without affecting normal intestinal motility, and oxymethyluracil, which has anti-inflammatory and inflammatory action; provide a prolonged effect of the drug complex due to surface-active properties. In the process of research dragees with mebeverine hydrochloride and oxymethyluracil, an over-action was revealed - the total antioxidant effect. In general, dragees containing oxymethyluracil and mebeverine hydrochloride are intended for functional diseases of the gastrointestinal tract with a retard action, have a mechanism for the release of oxymethyluracil and mebeverin hydrochloride is delayed up to 2 hours of passage through the small intestine and then evenly extended - for 1 hour, because the time release of active substances is programmed. In this case, the dragee is multi-layered: the layers of active substances alternate with layers of experimentally selected auxiliary substances that prevent the release of oxymethyluracil and mebeverine hydrochloride until it is destroyed by various factors in the digestive 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 active substances released - oxymethyluracil and mebeverine hydrochloride and on parameters that affect the release process.

All components that make up the complex tablets are approved for medical use. Oxymethyluracil (VFS 42-2730-96). Mebeverina hydrochloride 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. The styrene copolymer with maleic anhydride or the modified Plastigel styromal a rare crosslinked water-swelling polymer (patent No. 2135187, 1996), (TU 6-01-02274010913-01) - a copolymerization of styrene with maleic anhydride, modified with ammonia, is a white powder . The appearance of a 1% solution of styrene copolymer in water is a transparent or slightly turbid liquid - a gel. Soluble in water - swells, soluble in glycerin, alcohol. Milk sugar (lactose) (TU 9229-128-04610209-2003). 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, SSMA and potato starch due to increased adhesion to surfaces provide reliable fixation of the starch layers of potato and milk sugar (1: 1) (to a weight of 0.56-0.60 g), and 3% povidone collidone aqueous solution 90F in combination with CCMA 0.1% (1: 1) regulates, provides prolonged retard release, improves the bioavailability of oxymethyluracil and mebeverin hydrochloride, which subsequently roll up and take the form of dragees, 5% AFC solution provides 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 mebeverine hydrochloride for 1 hour, which have anti-inflammatory action in the intestine, immunomodulating, accelerating regeneration and antioxidant.

Receive the proposed integrated tablets as follows.

1st stage. Growing a layer of starch of potato and milk sugar (1: 1) with a humidifier solution 1: AFC 5%, potato starch 10% and an aqueous solution of SSMA 0.1% in a ratio (1: 1: 1) on sugar grains (kernels) to a diameter 3 mm dragees in a coating pan. 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 coat of mebeverine hydrochloride (100 mg per 1 tablet), and, moistening 2-3 times with humidifier 1, diameter 4 mm, the tablet is dried.

3 stage. Knurling of a layer of starch of potato and milk sugar (1: 1) with humidifier 1, after which the dragee is dried, diameter 4.5 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 5 mm.

5 stage. Then apply a layer of a solution of collidone 90F povidone - 3% and CCMA 0.1% (1: 1) - 2-3 layers (humidifier 2).

6th stage. Application of the 2nd layer of mebeverin hydrochloride (100 mg per 1 tablet) with a moisturizer 1–2 times, after which the tablets are dried, 5.5 mm in diameter.

7th stage. Cover with a layer of moisturizer 2 and then apply the 2nd layer of oxymethyluracil (100 mg per 1 tablet) with moisturizer 1, diameter 6 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 and milk sugar starch (1: 1) up to a dragee diameter of 8 mm; dragees are 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. Evaluation of the quality of dragees with oxymethyluracil and mebeverin hydrochloride is carried out according to the following indicators: appearance, authenticity and quantitative content of oxymethyluracil and mebeverin hydrochloride in dragees, average weight, diameter, integrity and strength, the time of their disintegration in artificial digestive juices, and the rate of release of oxymethylucil and mebeverin hydrochloride 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 mebeverin hydrochloride 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.

Received dragees of the correct 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 (Figure 1, Figure 2).

Example 1. Composition on 1 dragee weighing 0.56-0.60 g: oxymethyluracil - 0.25; mebeverin hydrochloride - 0.2; milk sugar and potato starch (1: 1); humectant 1: 10% potato starch solution; 0.1% aqueous solution of SSMA; alcohol-acetone solution of acetylphthalyl cellulose 5% (1: 1: 1) - 10-15 layers; humidifier 2: 3% aqueous solution of Collidone 90F povidone and aqueous solution of SSMA 0.1% (1: 1) - 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 mebeverin hydrochloride is prolonged - retard - within 1 hour (Figure 3).

The effect on the processes of free radical oxidation (SRO) of oxymethyluracil (WMD) and mebeverine hydrochloride was studied. The studied drugs in dosages comparable to the therapeutic one - oxymethyluracil 250 mg and mebeverine hydrochloride 200 mg, were added to model systems in which the formation of ROS and LP was initiated. The initial model systems without the addition of drugs were used as a control. Antioxidant activity (AOA) was determined by the degree of suppression of chemiluminescence (CL) (Farkhutdinov PP, Erokhina A.I., Baimbetov F.L. Use of the method of registration of chemiluminescence for assessing the antioxidant activity of spatially hindered phenols // Pharmacology and Toxicology of Antioxidants. Sat. Scientific. tr. - Ufa, 1983. - S.9-13), in the presence of the investigated substances, and was recounted as a percentage of the control. In the model system, where ROS, OMU, and mebeverine hydrochloride were generated at a final concentration of 1 mg / ml, the CL indices were significantly inhibited. The greatest AO effect in this system was shown by oxymethyluracil, reducing the luminosity of light by 92%. Mebeverine hydrochloride reduced CL by 34%. With the simultaneous addition of WMD and mebeverine hydrochloride to the model system, the chemiluminescence indices decreased by 94%. The control was taken as 100% (Table 1).

To evaluate the effects of WMD and mebeverine hydrochloride on lipid peroxidation, they were added to chicken yolk lipids, similar in composition to blood lipids. In the model liposome system, preparations at a concentration of 1 mg / ml showed themselves differently: WMD reduced the CL indices by 70%, mebeverin hydrochloride decreased the luminosity indices by 40%. With the simultaneous addition of OMU OMU and mebeverine hydrochloride to the model system, the chemiluminescence indices decreased by 45%. The control was taken as 100% (Table 2).

The antioxidant activity of oxymethyluracil and mebeverin was evaluated by the method of detecting CL of model systems in which the CPO reactions — ROS and LPO generation — occur. For the first time, it was revealed that the drugs we studied have antioxidant properties and can be recommended, in addition to the main therapeutic effect, for the prevention and correction of free radical oxidation processes.

Example 2. Composition on 1 dragee weighing 0.56-0.60 g: oxymethyluracil - 0.25; mebeverin hydrochloride - 0.2; milk sugar and potato starch (1: 1); humectant 1: 10% potato starch solution; 0.1% aqueous solution of SSMA; (1: 1) - 10-15 layers; humidifier 2: 3% aqueous solution of Collidone 90F povidone and aqueous solution of SSMA 0.1% (1: 1) - 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). The antioxidant effect of dragees is similar.

Example 3. Composition on 1 dragee weighing 0.56-0.60 g: oxymethyluracil - 0.25; mebeverin hydrochloride - 0.2; milk sugar and potato starch (1: 1); humectant 1: 10% potato starch solution; 0.1% aqueous solution of SSMA; alcohol-acetone solution of acetylphthalyl cellulose 5% (1: 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. Dragees are made in a similar manner, but there is no 3% aqueous solution of collidone 90F povidone. Dragee dissolves after 1 hour, the release of oxymethyluracil and mebeverin hydrochloride begins 1 hour after ingestion and lasts for 15 minutes, dissolving the dragee after 1.5 hours also allows the local therapeutic effect of oxymethyluracil and mebeverin hydrochloride in the treatment of functional diseases of the gastrointestinal tract intestinal tract.

Example 4. Composition on 1 dragee weighing 0.56-0.60 g: oxymethyluracil - 0.25; mebeverin hydrochloride - 0.2; milk sugar and potato starch (1: 1); humectant 1: 10% potato starch solution; 0.1% aqueous solution of SSMA; alcohol-acetone solution of acetylphthalyl cellulose 5% (1: 1: 1) - 10-15 layers; humidifier 2: 3% aqueous solution of Collidone 90F povidone and aqueous solution of SSMA 0.1% (1: 1) - 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 mebeverin hydrochloride 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 mebeverine hydrochloride was prolonged for 1 hour.

Example 5. Composition on 1 dragee weighing 0.56-0.60 g: oxymethyluracil - 0.25; mebeverin hydrochloride - 0.2; milk sugar and potato starch (1: 1); humidifier 1: 0.3% aqueous solution of SSMA; alcohol-acetone solution of acetylphthalyl cellulose 5% (1: 1) - 10-15 layers; humidifier 2: 5% aqueous solution of Collidone 90F povidone and aqueous solution of SSMA 0.3% (1: 1) - 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. Dragees when dried were brittle and cracked. Dragee dissolves unsatisfactorily, has an unsatisfactory appearance.

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 the drug used for this ratio of components and the prolonged release of oxymethyluracil and mebeverine hydrochloride 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 recommend individually necessary amount of tablets with controlled dissolution time for independent treatment of functional diseases of the gastrointestinal tract and correction of free radical oxidation processes, which makes the claimed tablets 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.

Table 1 OXYMETHYLURACYL AND MEBEVERIN HYDROCHLORIDE FOR THE TREATMENT OF FUNCTIONAL DISEASES OF THE GASTROINTESTINAL TRACT Try Light sum,% Maximum luminosity,% The control one hundred% one hundred% Oxymethyluracil 8 ± 2 7 ± 2 Mebeverina hydrochloride 66 ± 3 74 ± 8 Oxymethyluracil and mebeverine hydrochloride 6 ± 2 6 ± 2

table 2 OXYMETHYLURACYL AND MEBEVERIN HYDROCHLORIDE FOR THE TREATMENT OF FUNCTIONAL DISEASES OF THE GASTROINTESTINAL TRACT Try Light sum,% Maximum luminosity,% The control one hundred% one hundred% Oxymethyluracil 30 ± 2 29 ± 2 Mebeverina hydrochloride 60 ± 3 63 ± 3 Oxymethyluracil and mebeverine hydrochloride 55 ± 3 57 ± 3

Claims (1)

A therapeutic agent in the form of a dragee with solubility in the intestine after 2 hours, with a retard action for 1 hour, characterized in that it consists of a kernel consisting of sugar grains, on which successively layers of starch of potato and milk sugar are applied in a ratio of 1: 1 with a humidifier solution of a 1: 5% alcohol-acetone solution of acetylphthalyl cellulose (AFC), a 10% aqueous solution of potato starch and a 0.1% aqueous solution of styrene-maleic anhydride copolymer (CCMA) in a ratio of 1: 1: 1 to a diameter dragee 3 m a layer of mebeverin hydrochloride and 2-3 layers of a humidifier 1 to a diameter of 4 mm, a starch layer of potato and milk sugar in a 1: 1 ratio with a humidifier 1 to a diameter of 4.5 mm, a layer of oxymethyluracil with a humidifier 1 to a diameter of 5 mm, 2-3 a layer of a 3% aqueous solution of Collidone 90F povidone and a 0.1% aqueous solution of SSMA in a 1: 1 ratio as a humidifier 2, 2 layers of mebeverine hydrochloride with a humidifier 1 to a diameter of 5.5 mm, a layer of humidifier 2, a layer of oxymethyluracil with a humidifier 1 up to a diameter of 6 mm, a starch layer of potato and milk sugar, respectively 1: 1 to a diameter of 8 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 a 1% aqueous solution of collidone 25 in a ratio of 5: 1 in as a humidifier 4 to a dragee diameter of 8.5-9 mm in the following ratio of components in 1 dragee, g:
Oxymethyluracil 0.250 Mebeverina hydrochloride 0,200
A mixture of potato and milk starch
sugar in a ratio of 1: 1 to a mass of 0.56-0.60

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