CS239844B1 - Pharmaceutical agent containing mexiletine and its processing method - Google Patents

Abstract

The present invention is concerned with the formulation content of mexiletine in solid dosage form with retardant effect on cardiac therapy arrhythmias in which the drug substance is sequential releases. This is made possible by the use of a copolymer esters of acrylic acid and methacrylic acid containing quaternary ammonium group and neutral polymer base of poly (meth) acrylic acid esters in preparing the granulate and using the combination cellulose derivatives or neutral of polyesters based on polyesters - (met-) acrylic film coating. Vzhíadom on the physico-chemical properties of the active the granules is used as granulation liquid solution of a portion of mexiletine with polyvinylpyrrolidone in pharmaceutically acceptable polar solvent containing the solids of mexiletine remaining part of the mexiletine is granulated.

Description

The present invention relates to an oral formulation comprising mexiletine (1- (2 ', 6'-dimethylphenoxy) -2-aminopropane hydrochloride) from which said drug is gradually released over several hours, as well as a process for its preparation.

Mexiletine is a modern drug developed by Boehringer Ingelheim in 1966. It is used for the treatment of ventricular extrasysto-1 arrhythmias after myocardial infarction, ischemic heart disease, cardiac glycoside intoxication and idiopathic and other arrhythmias. Its main advantage over other antiarrhythmic drugs is the possibility of long-term oral treatment. Since frequent application at a relatively high dose is needed to maintain the therapeutic level, various attempts have been made to prepare a dosage form that provides a sufficient therapeutic level of the drug substance in the blood.

For example, V. Haselbarth et al. (Clin. Pharmacol. Ther. 29, 729-736 (1961)) discloses a sustained-action solid dosage form of mexiletine, the so-called. Perlonget principle, containing 432 mg of the active substance. This dose is divided into six film tablets with the same drug substance content, which are filled into a hard gelatin capsule and the gradual release of the drug substance is ensured by a special film coating of the cores. The preparation of the dosage form in this manner is complicated and the pharmacokinetic data are favorable, there is no known data on its widespread use or the availability of literature. -Production.

The essence of the dosage form according to the invention is that it contains, in addition to mexiletine and excipients such as talc, magnesium and calcium stearate and polyvinylpyrrolidone, other excipients, namely acrylic and methacrylic acid esters copolymers containing quaternary ammonium groups and neutral polyesters based on polyesters. (met-) acrylic love j.

The essence of the process is that up to one third of mexiletine is mixed with ipolyvinnylpyrrolidone and the remainder of mexiletine is granulated with the resulting substrate. A solution of the copolymerizate of the respective acid esters is applied to the granulate. Tablets are compressed from the granulate and coated with a semipermeable film layer and ethylcellulose and hydroxypropylmethylcellulose in combination with each other.

The main advantage of the present invention is the uniform and long-term release of the drug substance, which makes it possible to reduce the frequency of administration of the presently used formulation of mexiletine (hard gelatin capsules containing 50, 100 and 200 mg of drug substance).

The gradual release of the drug substance is provided by an excipient in which the ratio of methacrylic acid ester copolymerizate to quaternary ammonium groups is 1:40 (Eudragit RS). Said fluid contacting agent has swelled and becomes water permeable to pH independent pH (Lehmann, K., Dreher, D. Permeable Acrylic Resins for the Preparation of Depot Pharmaceutical Forms, Ph-arm. Ind., 31, 319-31). 322, 1969).

Another excipient that provides a sustained release of the drug is an aqueous dispersion of neutral poly (meth) acrylic acid polymer (Eudragit E 30 D). Eudragit * is a trademark of Rohm G. m. b. H., Darmstadt, Germany. This polymer forms emulsifiable coated latex particles in the aqueous phase. After evaporation of the water, the individual latex particles are joined to form a film layer (Lehmann, K., Dreher, D., Pharm. Ind., 34, 894-899, 1972). If said spherical particles or granules are coated with said film, they are tabletable; the film layer is elastic so that 80% of the granulate zones will remain undamaged.

Other excipients for the controlled release of the drug from the dosage form are cellulose derivatives; ethylceilulose and methylhydroxypropylcellulose in combination.

In the following, the invention is illustrated by the four examples without being limited thereto.

Example 1

Core composition mexiletine talc polyvinylpyrrolidone Eudragit RS Eudragit E 30 D (dry lobed substance) calcium stearate

Ethylcellulose hydroxypropylmethylcellulose polyethylene glycol magnesium stearate

0,400000 g 0,025000 g 0,020000 g 0,020000 g

0.040000 g 0.005000 g

0.005378 g 0.001912 g 0.000765 g 0.002136 g

Example 1

Preparation method

Two thirds of the mexiletine feed and a portion of the talc are treated through a suitable suture and homogenized. A 19% solution of polyvinylpyrolldone in anhydrous ethanol is prepared and one-third of the mexiletine feed is admixed to this solution and the homogenized portion of mexiletine and talc is granulated. This granulate is dried to a final moisture of 1-2 o / _o . and dry granules are passed through a sieve with a mesh side size of 1.0 mm. The granulate is isolated in a fluidization apparatus by spraying a solution of Eudragit RS dissolved in methylene chloride and ethanol at a ratio of 1: 1 at an inlet air temperature of 40 to 50 ° C. After drying, it is coated with a dispersion of Eudragit E 30 D at a supply air temperature of 30 to 40 ° C. The granulate so treated is homogenized with glidants (m-astene-c, calcium stearate) and pressed to a core diameter of 12 mm to an average weight of 0.510 g.

The finished skeleton cores are coated in a fluidized bed apparatus at a supply air temperature of 40 to 50 ° C with a mixture of ethylcellulose and hydroxypropylmethylcellulose with the addition of an anti-adhesive magnesium stearate and a polyethylene glycol plasticizer.

Example 1 a d 2

Kernel composition of Example 1

Film-coating Ethylcellulose 0.004860 Hydroxypropylmethylcellulose 0.002430 Polyethylene glycol 0.000765 Magnesium stearate 0.002136

EXAMPLE 1 a d 3

M fcfl M 00

Preparation method

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

Example 4

Kernel composition

Fold the film cover

Eudragit E 30 D (dry lacquer substance) 0.004080 g talc 0.00i2040 g

Example; 2

Preparation method

The process of preparing the cores is the same as that of Example 1. The cores are coated with talc polyvinylpyrrolidone Eudragit RS Eudragit E 30 D (dry lacquer) calcium stearate in fluidizing mexiletine.

Composition of the film package

0.430000 g 0.004517 g 0.011052 g 0.016315 g

0.043116 g 0.005000 g equipment at 30 Eudragit E 30 D.

Example 3

Core composition mexiletine talc polyvlnylpyrrolidone Eudragit RS Eudr-agit E 30 D calcium stearate up to 40 ° C by dispersion

Eudragit E 30 D talc

Example 4

Preparation method

0.006120 g 0.003060 g

0,3-70000 g

0.003541 g 0.018421 g 0.018421. g 0.036883 g 0.002734 g

The cores and coated tablets were prepared as described in Example 2.

Progressive release of mexiletine from in vitro tablets of the USP XVIII screened assay determined by the spectrophotometric method.

The results of the release from the tablets prepared according to each embodiment are shown in the table.

Amount of mexiletine released (%) Example Time (hours)

number 0-1 1-3 3-5 5-8 1 23.8 46.5 60.5 74.6 2 32.6 57.1 72.5 89.9 3 25.0 50.0 63.5 78.1 4 18.5 44.0 61.9 83.3

Claims (7)

A medicament comprising mexiletine in an amount of 70.0 to 85.0 parts by weight, excipients such as talc, magnesium stearate, calcium stearate, poilyvinylpyrrolidone m. h. 25,000 to 700,000 in an amount of 9.0 to 17.0 parts by weight, characterized in that it additionally contains auxiliary substances for achieving a retarding effect, namely a copolymer of esters of acrylic and methacrylic acid containing quaternary ammonium groups in an amount of 3, 0 to 4.0 parts by weight, neutral polymer based on poly (meth) acrylic esters in an amount of 7.0 to 10.0 parts by weight. 2. The medicament of claim 1 comprising polyethylene glycol m. h. 1,500 to 20,000 in an amount of 0.09 to 0.15 parts by weight, and ethyl cellulose and hydroxypropylmethylcellulose in a ratio of 2 to 1 to 5 to 1 in an amount of 1.2 to 1.8 parts by weight. 3. A medicament preparation as claimed in claim 1, comprising mexiletine in an amount of 78.8 to 77.1 parts by weight, talc in an amount of 4.7 to 4.8 parts by weight, polyvinylpyrrolidone m. h. 25,000 in an amount of 3.8 to 3.9 parts by weight, calcium stearate in an amount of 0.96 to 1.0 parts by weight, magnesium stearate in an amount of 0.4 to 0.5 parts by weight, polyethylene glycol m. h. 6,000 in an amount of 0.1 to 0.15 parts by weight, acrylic and methacrylic acid copolymerizate containing quaternary ammonium groups in an amount of 3.8 to 3.9% by weight OF THE INVENTION, a neutral poly (meth) acrylic ester ester polymer in an amount of 7.6 to 7.8 parts by weight, ethylcellulose and hydroxypropylmethylcellulose in a ratio of 3: 1 in an amount of 1.4 to 1.5 parts by weight. 4. A process for preparing a medicament as claimed in claim 1 or 2, wherein up to one third of 70 to 80 parts by weight of mexiletine is mixed with polyvinylpyrrolidone in a pharmaceutically acceptable polar solvent, the remaining mexiletine is granulated with the substrate, a solution of acrylic and methacrylic acid ester copolymer containing quaternary ammonium groups in an amount of 3.0 to 4.0 parts by weight and subsequently a dispersion of a neutral polymer based on poly (meth) acrylic esters in an amount of 7.0 to 8.5 parts by weight is applied tablets are compressed from the granulate and coated with a semipermeable film layer. 5. A method according to claim 4, wherein the tablets are coated with a film layer of a dispersion of a neutral polymer of poly (meth) acrylic acid ester in an amount of 0.5 to 1.5 parts by weight. 6. A method according to claim 4, wherein the tablet is coated with a film layer of a solution of ethylcellulose and hydroxypropylmethylcellulose in a ratio of 2 to 1.5 to 1 in an amount of 1.2 to 1.8 parts by weight.