FI81257C - FRAMEWORK FOR PHARMACEUTICAL EQUIPMENT PHARMACEUTICAL BLANDING. - Google Patents

Description

'81257

The present invention relates to a process for the preparation of an aqueous pharmaceutical composition comprising salbutamol and / or a physiologically acceptable salt thereof and having a salbutamol and / or a physiologically acceptable salt thereof. better stability.

Sa1butamol, (α1-tert-butylaminomethyl) -4-hydroxy-m-xylene-α1, α3-di-1i, and its physiologically acceptable salts are described in British Patent Publication No. 1200886. This publication refers to pharmaceutical compositions containing salbutamol and describes solid liquid preparations for oral and intravenous use.

Liquid preparations of sabutbutam and / or a physiologically acceptable salt thereof are suitably aqueous and for oral use the preparations contain sucrose and sorbitol which act as both a sweetener and a thickener.

Such pharmaceutical compositions have been successfully marketed. However, it is known that the presence of a substance such as sucrose, sorbitol or glycerol in aqueous mixtures of salbutamol or a physiologically acceptable salt thereof is associated with a faster deterioration of the stability of salbutamol in the mixture.

We have now surprisingly found that the stability of salbutamol in aqueous formulations can be significantly improved by the presence of a cellulose derivative forming a colloidal dispersion in water.

The process according to the invention is characterized in that the process mixes at least one hydroxyalkylcellulose and / or hydroxyalkylalkylcellulose derivative with salbutamol and / or a physiologically acceptable salt thereof in the presence of water and any optional components are added before, during or after mixing to prepare the mixture. containing at least 0.1% W / v of a cellulose derivative.

Preferred cellulose derivatives include nonionic derivatives such as hydroxyalkyl ethers of cellulose, especially hydroxy C 1-4 alkyl ethers of cellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, hydroxy

Particularly preferred cellulose derivatives are hydroxyethylcellulose and especially hydroxypropylmethylcellulose.

One preferred salt of salbutamol that can be used in the pharmaceutical composition of the invention is sulfate.

The total amount of dispersible cellulose derivatives in the pharmaceutical composition of the invention is such that the resulting colloidal dispersion has the desired better stability and viscosity appropriate to the proposed route of administration. The pharmaceutical composition preferably contains at least 0.1% w / v of cellulose derivatives.

For liquid preparations suitable for oral administration, the total amount of cellulose derivatives is determined mainly by the requirements of li 3 81257 that the viscosity of the solution be suitable for oral administration, preferably between 5 and 10,000 centipoise, especially between 10 and 100 centipoise.

The concentration of salbutamol or a salt thereof in the formulation can be adjusted to suit the desired use of the formulation and / or the requirements of the patient. For oral use, the concentrate is, for example, suitably 1 mg to 4 mg, preferably 2 mg of salbutamol, expressed as free salbutamol base, per ml of liquid.

The pH of the pharmaceutical mixture is preferably between 2.5 and 7, in particular 3.5. This is achieved as intended by using a buffer. Suitable buffers for oral mixtures include sodium citrate / citric acid buffer.

The pharmaceutical composition obtained according to the invention may also contain an antimicrobial preservative such as benzoic acid or a salt thereof which forms an acid in situ, or methyl, ethyl, propyl or butyl hydroxybenzoate.

For oral use, the composition also preferably contains a flavoring agent, a sweetening agent such as sodium saccharin or sodium cyclamate and / or a coloring agent.

According to the invention, the pharmaceutical composition can be prepared by dispersing one or more cellulose derivatives in water, then adding or mixing with salbutamol or its physiologically acceptable salts, suitably dissolved in water, together with any component of the optional mixture.

The following are illustrative examples of formulations of the invention for oral administration (expressed as a 5 ml dose).

4,81257

Example 1 salbutamol sulphate 2.40 mg hydroxyethylcellulose 22.5 mg (Natrosol 250H) distilled water ad 5 ml

To prepare the formulation, the hydroxyethylcellulose is dispersed in water and then mixed with an aqueous solution of salbutamol sulfate.

Example 2 salbutamol sulphate 2.40 mg sodium citrate dihydrate 9.60 mg citric acid monohydrate 15.15 mg Natrosol 250H 15.0 mg distilled water ad 5.0 ml

To prepare the formulation, the hydroxyethylcellulose is dispersed in water and then mixed with a solution of salbutamol and buffer salts in water.

Example 3 Salbutamol sulphate 2.40 mg sodium citrate dihydrate 9.60 mg citric acid monohydrate 15.25 mg hydroxypropylmethylcellulose (viscosity type 4000) 22.5 mg distilled water ad 5 ml

Example 4 Salbutamol Sulfate B.P. 2.40 mg sodium citrate B.P. 7.5 mg citric acid monohydrate B.P. 25.0 mg hydroxypropylmethylcellulose (viscosity type 4000) 22.5 mg sodium benzoate B.P. 10.0 mg of 5 81257

Example 4 (cont.) Sodium saccharin B.P. 2.5 mg

flavor qS

purified water ad 5 ml

To prepare the formulations of Examples 3 and 4, hydroxypropylmethylcellulose is dispersed in hot water, then cooled and mixed with an aqueous solution containing salbutamol sulfate and the other components of the formulation.

Claims (10)

A process for preparing an aqueous pharmaceutical composition comprising salbutamol and / or a physiologically acceptable salt thereof, wherein the salbutamol and / or a physiologically acceptable salt thereof has improved stability, characterized in that the process comprises mixing at least one hydroxyalkylcellulose and / or hydroxyalkyl-alkylcellulose with salbutamol and / or a physiologically acceptable salt thereof in the presence of water and any optional components of the mixture are added before, during or after mixing to prepare a mixture containing at least 0.1% w / v of a cellulose derivative. A process for increasing the stability of salbutamol and / or its physiologically acceptable salts in an aqueous pharmaceutical composition containing salbutamol and / or a physiologically acceptable salt thereof as an active ingredient, characterized in that the process comprises mixing at least one hydroxyalkylcellulose and / or hydroxyalkylalkylalkyl with a physiologically acceptable salt thereof in the presence of water and any optional components of the mixture are added before, during or after mixing to obtain a mixture containing at least 0.1% w / v of the cellulose derivative. Process according to Claim 1 or 2, characterized in that the cellulose derivative is dispersed in water and then mixed with salbutamol and / or a physiologically acceptable salt thereof. 7 81257 Process according to one of Claims 1 to 3, characterized in that the cellulose derivative is chosen from hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose or hydroxyethylethylcellulose. Process according to Claim 4, characterized in that the cellulose derivative is hydroxypropylmethylcellulose. Process according to one of Claims 1 to 5, characterized in that the pharmaceutical mixture obtained is formulated as a liquid preparation suitable for oral administration, containing one or more cellulose derivatives in a total amount such that the viscosity of the liquid preparation obtained is between 5 and 10,000 centipoise. 6 81257 Process according to Claim 6, characterized in that the viscosity is between 10 and 100 centipoise. Process according to Claim 6 or 7, characterized in that the amount of salbutamol or physiologically acceptable salts is selected such that the pharmaceutical mixture obtained contains salbutamol and / or its physiologically acceptable salt in a concentration of 1 mg to 4 mg, expressed as free salbutamol base per 5 ml of liquid. Process according to Claim 8, characterized in that the concentration is 2 mg, expressed as free salbutamol base, per 5 ml of liquid. Process according to one of Claims 1 to 9, characterized in that the pH is adjusted so that the pH of the pharmaceutical mixture obtained is 3.5. 8 81257