CS269849B1 - Process for the preparation of an oral dosage form containing 7- (D-4'-amino-α-phenylacetamido) -3-methyl-3-cephem-4-carboxylic acid monohydrate - Google Patents

Abstract

The solution relates to a method for producing an oral dosage form, in which 7-[D-<i’-amino-<ú’-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate with a filler and a binder in a dry state is converted by a humectant into a spherical agglomerate and then into tablets, coated tablets or capsules. The dosage form produced in this way ensures rapid release of the active ingredient into solution upon contact with the gastric environment and increases bioavailability and usability.

Description

CS 269 849 Bl

The invention relates to a method for producing a solid oral dosage form containing 7-[D-α6-amino-[4-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate.

Common diseases include infectious diseases caused by bacterial invasion of the body. 7-/D-<^-amino-e^-phenylacetamido/-3-methyl-3-cephem-4-carboxylic acid is a highly effective broad-spectrum antibiotic, active against gram-positive and gram-negative bacteria with a direct inhibitory effect on the formation of bacterial cell walls. In addition to its use in the treatment of skin, bone, joint and intestinal infections caused by strains of staphylococci and streptococci, it is mainly used in the treatment of infectious diseases of the respiratory and urogenital tracts.

Oral dosage forms - tablets, capsules, suspensions, syrups - are almost exclusively used as application forms containing 7-[(R)-[( ^R) -amino-[alpha]-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid. These orally administered forms are very well tolerated, side effects have been described only in isolated cases, and therefore they can be considered in therapeutic practice as very advantageous for the patients being treated. Oral forms are less usable in terms of bioavailability than parenteral dosage forms, especially in the case of active ingredients with a larger molecule or reduced resistance to the environment of the gastrointestinal tract. The general requirements for antibiotics, i.e. rapid achievement of therapeutic levels with maximum utilization of the active ingredient, result in the fact that in the case of the preparation of an oral application form containing 7-[(R)-[alpha]-amino-[alpha]-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid, it is necessary to choose a preparation procedure that ensures sufficient utilization of the active ingredient.

With regard to the higher solubility of 7-[D-ci-amino-<&-phenylacetamido/-3-methyl-3-cephem-4-carboxylic acid monohydrate in dilute hydrochloric acid (1 part in 30 parts) compared to a neutral medium (1 part in 100 parts of water) and stability in an acidic medium, it is necessary to convert the oral dosage form into the starting components in the shortest possible time. The best bioavailability of 7-[D-ci*-amino-<j«-phenylacetamido/-3-methyl-3-cephem-4-carboxylic acid monohydrate is therefore achieved in the case of converting the oral dosage form into the starting components already in the stomach. High doses of 7-[D-ci-amino-<j«-phenylacetamido/-3-methyl-3-cephem-4-carboxylic acid monohydrate in the dosage form and the very low specific gravity do not allow direct processing into the dosage form. In the preparation of capsules or tablets, the procedure of agglomeration of 7-/D-α-amino-<6-phenylacetamido/-3-methyl-3-cephem-4-carboxylic acid monohydrate using binder solutions is exclusively used, as stated, for example, in Japanese patent No. 054925, where a powder mixture of 7-/D-α-amino-α-phenylacetamido/'3-methyl-3-cephem-4-carboxylic acid monohydrate with fillers is first prepared and after homogenization it is granulated with a binder solution - starch hydrogel, the granulate is dried, sieved and after the addition of tableting additives tablets are prepared, or the granulate can be filled into hard gelatin capsules. A double-arm granulator is used to process the granulate. The above procedure ensures the compaction of 7-[D-C1-amino-d'-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate and its conversion into a form suitable for application. With considerable variability in particle size of 7-[D-d-amino-a^-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate and thus a significantly different surface and relatively high percentage representation in a tablet or capsule, after the addition of a binder solution of the prescribed concentration, insufficient wetting and compaction of the granulate occurs with subsequent difficulties in processing into an application form. In the opposite case, i.e. with particles with a larger average size and a small surface, over-wetted granulate is formed and, as a result, agglomerates with a high specific gravity are formed. Such an agglomerate can be easily processed compared to a granulate with a low specific gravity, but after the disintegration of the dosage form into a granulate, the subsequent conversion to the starting elemental components in the dissolution medium is considerably slow, which has an adverse effect on the speed of onset of action and the bioavailability of the solid oral form. According to the above procedure, a standard dosage form cannot be produced, which is due to the difficulty of producing 7-/D-oí-.amino-éí’-phenylacetamido/-3-methyl-3-cephem-4-carboxylic acid monohydrate with a standard particle size.

The above-mentioned shortcomings are eliminated by the method of producing a solid oral dosage form containing 7(D-o6-amino-c6*-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid monohydrate according to the invention, the principle of which is to control the degree and intensity of agglomeration during the conversion of a dry mixture of mono2

CS 269 849 Bl hydrate of 7-/D-o-amino-o6-phenylacetamido/-3-methyl-3-cephem-4-carboxylic acid with fillers and a binder readily soluble in water and organic solvents using a wetting agent to a constantly compacted agglomerate regardless of the particle size of the monohydrate of 7-/D-o^amino-o6-phenylacetamido/-3-methyl-3-cephem-4-carboxylic acid. The desired effect is achieved by gradually adding the wetting agent itself until the optimum granulosity is formed.

The basic condition for the usability of this invention is the use of a binder that is well soluble in water and the used humectant. Polymer-type binders are preferred, for example, the following - cellulose derivatives soluble in water and organic solvents, polyethylene glycol, polyvinylpyrrolidone, soluble starch derivatives, dextrin, carbohydrates, e.g. glucose, fructose, alcoholic sugars, e.g. sorbitol, etc. As a humectant, it is possible to use water or organic solvents of the type of low molecular weight alcohols, e.g. ethanol, isopropanol or halogenated hydrocarbons, e.g. methylene chloride or mixtures thereof.

A solid oral dosage form containing 7-[D

The process according to the invention provides for the processing of 7-[D-[alpha]-amino-[alpha]-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate into a solid oral dosage form at a constant degree of granulate compaction. In addition, a polymer binder film is formed on the periphery of the granulate so that the powder mixture remains in its original state without wetting inside the agglomerates. This results in a granulate with advantageous rheological properties and a suitable specific gravity for processing into capsules or tablets, and after disintegration of the dosage form it is immediately converted into the starting components, as documented by the liberation of 7-[D-[alpha]-amino-[alpha]-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate into the gastric juice: Tablet interval according to the invention tablets produced using a solution binder ' ' active substance released (%) active substance released (%)

6331

8765

9284

The results of the release rate of 7-[D- ^α- amino-<J>-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate from tablets indicate better bioavailability and enhanced therapeutic effect in tablets produced by the method according to the invention.

The method of producing a solid oral dosage form containing 7-[D-α-amino-[4-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate is explained in the following examples, which illustrate the method of production but are not intended to limit it in any way.

Example 1 7-[D-[6-amino-[6-phenylacetamido]-3-methyl-3-cephem- acid monohydrate

-4-carboxylic 72.5 parts hydroxypropylmethylcellulose 1.0 part cornstarch 2.0 parts lactose 22.8 parts calcium stearate 2.0 parts

The above-mentioned amount of 7-/D-o-amino-c-phenylacetamido/-3-methyl-3-cephem-4-carboxylic acid monohydrate, hydroxypropylmethylcellulose and lactose are homogenized in a rotary granulator. A mixture of ethanol and methylene chloride ⁽ 1:1) is gradually added to the perfectly homogenized mixture until a granule is formed, which is dried at a temperature of up to 50 °C. The specified amount of corn starch and calcium stearate is added to the dried granulate. After homogenization, it is filled into hard gelatin capsules with a filling weight of 730 mg or tablets weighing 730 mg are prepared, which are covered with a suitable coating layer.

Example 2 7-[D-α-amino-α-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate 35.0 parts lactose 9.6 parts polyvinylpyrrolidone 2.0 parts sodium carboxymethyl starch 1.0 parts calcium stearate 1.0 parts

The procedure is identical to example 1, with the difference that distilled water is used to moisten the homogeneous powder mixture and the produced tablets are coated with 3.84% hydroxypropylmethylcellulose in the form of a lacquer dispersion.

Example 3 7-[D-α6-amino-α-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate 35.0 parts lactose 9.6 parts polyvinylpyrrolidone 2.0 parts sodium carboxymethyl starch 1.0 part calcium stearate 1.0 part

The preparation procedure is identical to Example 2, with the difference that ethanol is used as the wetting agent.

Example 4 7-[D-[1-amino-[1-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate 35.0 parts lactose 6.7 parts sucrose 4.8 parts sodium carboxymethyl starch 1.0 part calcium stearate 1.0 part

The preparation procedure is identical to Example 3, with the difference that distilled water is used as the wetting agent.

Claims (2)

.OBJECT OF THE INVENTION 1. A method for producing an oral dosage form containing 7-(D-[D-[alpha]-amino-[alpha]-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate, characterized in that a homogeneous mixture of 7-(D-[alpha]-amino-[alpha]-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate is prepared by mixing it with constitutional physiologically inert substances of the type of fillers based on carbohydrates and dry polymeric binders soluble in water and at the same time in organic solvents, which are of the type of cellulose derivatives and/or starch and/or polyvinylpyrrolidone with an average molecular weight of 20 to 90,000, preferably 25,000, in a concentration of 0.1 to 20% by weight based on the active ingredient, preferably 4%, this mixture is treated with water and/or halogenated paraffins and/or organic solvents of the type of low molecular alcohols and/or their mixture in an amount of 0.1 to 44% by weight based on the active ingredient and after evaporation of the solvents with drying air, the said mixture is converted into spherical agglomerate particles, which are processed into an oral dosage form of tablets and/or coated tablets and/or hard gelatin capsules. CS 269 849 Bl 2. The method according to item 1, characterized in that 7-[D-eph-alumino-[1,2,3-phenylacetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate with different sized particles and different total particle surface area is processed to form a granulate with a constant apparent specific gravity.