IE80849B1 - Compounds - Google Patents

Abstract

Macrolide antibiotics which do not have an unpleasant taste are described. The compounds are salts of macrolide antibiotics with pamoic acid, especially roxithromycin emboate.

Description

The present invention relates to macrolide antibiotics.

Certain drugs especially compounds which are effective as macrolide-antibiotics have distinctly unpleasant tastes.

This invention is directed towards providing macrolide-antibiotics which will overcome this problem.

Statements of Invention The invention provides roxithromycin embonate.

It has been surprisingly found that the compound of the present invention has improved taste (or is even tasteless) and finds therapeutical use in cases in which erythromycin and roxithromycin and other macrolide-antibiotics are currently used.

The compound according to the invention is a light yellow microcrystalline powder.

The compound may be provided in any suitable pharmaceutical composition including capsules; solutions; syrups; ointments; injectable preparations; aerosols; creams; powders; and suspensions, for both human and veterinary use. The pharmaceutical compositions may contain suitable excipients and/or vehicles which are conventionally used in galenical pharmacy.

The compound is a true salt both from the chemical and physical point of view. -2The method for preparation of the compound according to the present invention comprises reacting a roxithromycin with pamoic acid in a stoichiometrical ratio or in the presence of a slight excess of the antibiotic nucleus. The reaction is carried out in an organic solvent and in the presence of water at a temperature of between 20eC-40°C.

Detailed Description The following example given by way of example only are for illustrative purposes and disclose the preparation of compounds of the invention.

Example 1 Salt of roxithromycin with pamoic add (embonic add).

Roxithromycin (20g) and Pamoic add (9.28g) were solved at room temperature in lOOmlsofDMF. To this solution 100 mis of water were added. The product was dried under vacuum at 40°C (39-55mbar).

Mdting point of product = 166°C. The Infra Red data for the product is plotted in Fig. 1.

The antimicrobial activity of the compound produced in Example 1 was tested as follows: Microbiological Assay of Roxithromycin Embonate (Pamoate) References: USP ΧΧΠ <81> Antibiotics - Microbial Assays. -3Code of Federal Regulations Tide 21:436.100 - 436.106 Test Organism: Inoculum Preparation: Culture Media: Solutions: Bacillus subtilis ATCC 6633 The test organism is maintained through periodic inoculations on agar slants containing Tryptone Soya Agar. The slants are incubated at 32 - 35 °C for 24 hours, and stored under refrigeration.

Using 5 ml of sterile USP saline T.S. the growth from an agar slant was washed and made up to 10 ml with sterile USP saline solution. This stock suspension was diluted with sterile saline so that the transmittance, at 580 nm, was 25% against saline as the blank. 1 ml of this solution that had 25% transmission was added to each 160 ml of culture media (Antibiotic Medium No. 3).

Tryptone Soya Agar (Oxoid) Antibiotic Medium No. 3, pH 7.0 after sterilisation (Oxoid).

Saline Solution 0.9% Sodium chloride 0.9g Purified Water 100ml Sterilised at 121°C for 20 minutes.

Buffer Solution (0.1 M potassium phosphate buffer pH 8.0) -416.73g 0.523g 1000 ml Standards: Standard: Sample: Dibasic potassium phosphate Monobasic potassium phosphate Purified Water Adjusted with 10 N potassium hydroxide to give pH 7.9 8.1. Sterilised at 121°C for 20 minutes.

About 100 mg of Roxithromyxin reference standard, accurately weighted, was added to a 100 ml volumetric flask. 10ml of methanol was added to dissolve the Roxithromycin and diluted with sterile buffer solution to obtain a 1000 pg/ml Roxithromycin solution.

From this stock solution the following dilutions were prepared: 1.56 pg/ml; 1.25 gg/ml; 1.0 gg/ml; 0.8 pg/ml; and, 0.64 pg/ml (using sterile buffer solution for dilutions).

Test Substance : About 100 mg of Roxithromycin embonate test substance, accurately weighed, was added to a 100 ml volumetric flask. 10 ml of methanol was added for dissolution and this in turn was diluted with sterile buffer solution to obtain a 1000 pg/ml Roxithromycin embonate solution.

From this stock solution the following dilution was prepared: -5Λ 1.0 gg/ral, using sterile buffer solution for dilution.

Method: Turbidimetric Method USPXXH ml of each standard dilution was added to 3 sterile test tubes positioned randomly in tube racks. 2 control tubes were added to each rack (containing 1 ml buffer solution without antibiotic). 1 ml test solution (nominal 1.0 gg/ml) was added to each of 4 sterile test tubes per tube rack. Upon completion of the racks of test solutions 9.0 ml of inoculum were added to each tube in turn. The completed racks were immediately incubated at 32 - 35 °C for 4 hours. After incubation 0.5 ml of dilute formaldehyde was added to each tube. The transmittance of each tube was read at 530 nm.

Estimation of Potency: The potency of the Roxithromycin embonate test substance was compared to the standard curve obtained for the Roxithromycin standard dilutions. This was calculated as a percentage of die potency of the 1.0 gg/ml Roxithromycin standard dilution.

Results: Roxithromycin embonate Mean potency (x) = 81.0% of the original Roxithromycin. -6Standard deviation (s.d.) = 1.628% Coefficient of variation (c.v.) = 0.020%

Claims (7)

1. Roxithromycin Embonate.

2. A pharmaceutical composition comprising Roxithromycin Embonate together with at least one pharmaceutically acceptable excipient and/or carrier. 10

3. A process for preparing Roxithromycin Embonate comprising the step of reacting roxithromycin with pamoic arid.

4. A process as claimed in claim 3 wherein the reaction is carried out in an organic solvent

5. A process as claimed in daim 3 or 4 wherein the reaction is carried out in an aqueous medium.

6. A process as claimed in any of claims 3 to 5 wherein the reaction is carried 20 out at a temperature offrom20°C to 40°C.

7. Roxithromycin Embonate whenever prepared by a process as claimed in any ofdaims3 to6.