CS248246B1 - Medicinal product containing nitrlylycerin and its preparation - Google Patents

Abstract

The solution described concerns a medicinal preparation containing nitroglycerin with a retarding effect in the therapy of ischemic heart disease, from which the medicinal substance is gradually released. This is made possible by the use of a neutral polymer of poly-(meth)acrylic acid esters in the preparation of the granulate, by the use of a combination of cellulose derivatives and anionic polymer of poly-(meth)acrylic acid and acrylic acid esters for film coatings. In the case of granules, an aqueous dispersion of a neutral polymer of poly-(meth)acrylic acid esters is used as the granulation fluid, which helps the aggregation of dusty substances, since the mixture also contains polyvinylpyrrolidone as a binder.

Description

248246

The present invention relates to an oral preparation comprising nitroglycerin (glyceryl nitrate), from which said drug substance is released over several hours, as well as to its preparation.

Nitroiglycerin is a classic drug substance that was first used in 1860 by American physician Brunton and is an important drug substance in the treatment of ischemic disease because it quickly and reliably suppresses stenocardia foundations. The main pharmacological effect is vasodilation of vascular smooth muscle. In the region, the dilatation of the larger arteries causes the blood flow to flow in the favor of theischemid region.

The disadvantage of nitroglyceirine is the short-term effect. The half-life of the effect is about 6 minutes. However, in prolonged therapy, preparations with a longer, several-hour half-life may be employed. By incorporating nitroglycerin into the retarded form, the bioavailability of the drug has been improved, the resorption time has subsided, thereby giving a 6 to 8 hour preclinical effect. At present, in the world of oral preparations Sustac-retard (Rho-dia Pharma Hamburg), Nitro-Mack retard (Mack-niertissen), Nitrozell-retard 'Byk - Gulden Konstans, Klavikordal-retard (Dr.Bayer KG Munchen ), Nitroglyn tablets (Fo-rest Lab. New York), Nitrong (US EthicalsNew York), Nitrostat (Parke Davis Comp) dose of nitroglycerin ranges from 2 to 6.5 mg, with drug release for 6 to 12 hours. U.S. Patent No. 3,665,297 discloses a retard tab-nitroglycerin-containing tablet prepared by microcapsule compression (Su-stac). The microcapsule shell consists of cellulose derivatives (methylcellulose, ethylcellulose, acetylcellulose).

The use of higher fatty acids (lauric, myristic, stearic, benign, lignoceric) is described in British Patent No. 1,443,923.

The use of resorbable synthetic polymers, such as polyvinyl alcohol, poly (vinyl alcohol) polymer and exemplified U.S. Patent No. 4,012,498. Rialdialization of nitroglycerin release from tablets is ensured by the coating of said polymers.

A disadvantage of the above processes for the manufacture of nitroglycerin-containing compositions is the complicated technology, the use of high concentrations of release-controlling excipients, as well as the use of large amounts of organic solvents in the various stages of manufacture.

The substance of the invention is based on the fact that it contains, in addition to nitroglycerins and auxiliary substances, such as milk sugar, polyvinylpyrrolidone, talc, calcium stearate, other auxiliaries, namely the neutral polymer of the poly (meth) -acrylic acid esters.

The principle of the production process is that the mixture of nitroglycerin-lactic sugar, preferably in a ratio of 1:10, is mixed with milk sugar, talc and vinyl pyrrolidine. -) acrylic. The granules are compressed with cores which are packaged with at least the film layers.

The main advantage of the present invention is that the process for preparing a medicament consists of three technologically conventional and uncomplicated processes (granulation, tabletting and film wrapping). The reproducibility of the results is very good. In addition to wrapping cores with cellulose film coatings, the use of organic solvents is not necessary in other technological operations, which is important in terms of safety of work and environmental protection a. long-term release of the drug substance.

The sustained release of the drug substance provides a neutral ester ester of poly (meth) acrylic acid (EudragitRE 30 D). EudragitR is a trademark of Rohm Pharma G. m. H. Darmstadt, SNR. This polymer forms a spherical latex particle in the aqueous phase with a coated emulsifier. After the water has been separated off, the individual latex particles are joined together to form a film layer (Lehmann, K., Dreher, D., Pharm. Ind. 34, 894-899, 1972. At the same time, it assists in aggregation of dormant substances since Such a coated granulate is tabletable and the film layer is so elastic that about 80% of the granulation grains are not broken.

Other excipients for controlling the release of the drug substance from the drug form of cellulose derivatives; ethylcellulose and hydroxypropylmethylcellulose in combination and pre-achieving the desired release for 1 hour (10-20%) of anionic polymer of poly (meth) acrylic acid and acrylic ester (Eudragit.RTM. L30D). In the following, three examples of the invention will be explained without limiting it exclusively. Example 1

Core composition

Nitroglycerin - Milk Cuc. Mixture (1: 10 j 0.025000 g Milk Sugar 0.213050 g Polyvinylpyrrolidone 0.013500 g Talc 0.013050 g Eúdragit E 30 D (dry varnish substance) 0.002700 g Calcium stearate 0.002700 g 248246 5

Film cover composition

Ethylcellulose 0.001350 g Hydroxypropylmethylcellulose 0.001890 g Polyethylene glycol 0.000400 g Magnesium stearate 0.000405 g Eudragit L 30 D (dry lacquer substance) 0.000810 g Talc 0.001202 g Silicone antifoam emulsion 0.000015 g Example 1 - preparation method

Nitroglycerin Milk Sugar 1: 10, Milk Sugar, Talc and Polyvinyl Pyrrolidone are treated through suitable sewing and homogenising. Eudragit E 30 D is applied to the powder mixture. The wet granules are dried to a final moisture content of 0.5 to 1% and dry, the granulate is sieved with a mesh size of 1 mm. The granulate thus prepared is homogenized with glidants (talc, calcium stearate) and 9 mm diameter cores are pressed to a weight of 0.270 g.

The finished skeletal cores are lined with a 40-50 ° C feed rate of ethylcellulose and hydroxypropylmethylcellulose with the addition of a magnesium stearate and a polyethylene glycol wetting agent and an aqueous dispersion of Eudragit L 30 D with the addition of an antiadhesive talc. polyethylene glycol softeners. Example 2

The core composition of Example 1

Film Cover Composition 6

Hydroxyprofyl methylcellulose 0.001890 g Polyethylene glycol 0.000446 g Magnesium stearate 0.000405 g Eudragit L 30 D (dry lacquer substance) 0.001215 g Talc 0.000304 g Silicone antifoam emulsion 0.000015 g Example 2 - Preparation method

The process for preparing cores and coated tablets is the same as in Example 1. Example 3

Core composition

Nitroglycerin Milk Sugar Mix (1:10) 0.050000 g Milk Sugar 0.187375 g Polyvinylpyrrolidone 0.013500 g Talc 0.013050 g Eudragit E 30 D (dry varnish substance) 0.003375 g Calcium stearate 0.002700 g Composition Example 3 - Preparation Method

The cores and coated tablets are prepared as described in Example 1.

The sequential release of nitroglycerin invitro was monitored according to USP XVIII method, cart. The nitro-glycerin content was determined by liquid chromatography. Recovery results from tablets prepared. Examples of the various embodiments are shown in the table.

Ethyl cellulose 0.001350 g Example no.

Amount of 'released nitroglycerin in% time (hour) 1 4 8 1 17.69 50.72 76.59 2 11.65 61.53 82.32 3 11.18 32.45 81.83

The strength of the tablets prepared according to individual exemplary embodiments of bare in the range of 6 to 7 kg / cm 2, the abrasion was less than 0.05%, which satisfies the requirements of ČSN66 4031 and D. 3.

Claims (7)

248246 PREDMET 1. Healing. a composition comprising nitroglycerine in the form of a mixture, with a milk sugar, preferably in a 1:10 ratio by weight of 9 to 27 parts by weight of nitro-glycerin, 80 to 90 parts by weight of milk sugar, excipients such as calcium stearate and / or stearate in amounts From 5.5 to 6.5 weight percent further comprising auxiliaries, such as polyvinyl pyrrolidone having a molecular weight of 2,500 to 700,000 in an amount of 3 to 10 parts by weight, a neutral ester based on acid esters poly (methacrylic in an amount of 0.75 to 2 parts by weight, ethyl cellulose in an amount of 0.25 to 0.75 parts by weight, hydroxypropylmethylcellulose in an amount of 0.5 to 1.5 parts by weight of the aanionic polymeric acid polymer) - (meth) -acrylic acid and acrylic esters in an amount of 0.25 to 0.75 weight percent. 2. A medicament as claimed in claim 1 comprising ipolyethylene glycol having a molecular weight of 1,500 to 20,000 in an amount of 0.15 to 0.3% by weight. 3. A process for preparing a medicament preparation according to claim 1, wherein the mixture of nitroglycerin and milk sugar, preferably in a ratio of 1: 10 in an amount of 9 to 27 parts by weight, is mixed with lactic sucrose in an amount of 70 to 80 parts by weight, polyvinylpyrrolidone having a molecular weight of 2,500 to 700,000 in an amount of 3 to 10 parts by weight and talc in an amount of 4 to 5 parts by weight, the additive being applied to the powder mixture in water (dispersion of neutral polymer to polysaccharide esters (methacrylic in a quantity of 0.75 to 2) and the granules in the presence of glidants are coated with cores which are coated with at least two film layers. 4. A method for preparing a healing preparation of claim 3, wherein the sardines are coated with a film layer of a solution of ethylcellulose and hydroxypropylmethylcellulose in a ratio of 1: 1 to 1: 3 in an amount of 1 to 3 parts by weight and further coated with a film layer of an aqueous dispersion and polyionic poly (methacrylic acid and acrylic ester esters in an amount of 0.25 to 0.75 weight percent). 5. Process according to claim 4, characterized in that the first film layer comprises further auxiliaries, namely polyethoxyglycol having a molecular weight of 1 500 to 20 000 in an amount of 0.1 to 0.3 weight percent and a magnesium stearate in 0.1 to 0.3 parts by weight. 6. Preparation according to claim 4, characterized in that the second film layer comprises further auxiliaries, namely polyethylene glycol having a molecular weight of from 1500 to 20,000 in an amount of 0.025 to 0.075 weight percent and a talc of 0, 1 to 1 part by weight. Severografla, n. P., Race 7, Most Price 2,40 Kčs