Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Patent
1986-08-18
1989-03-07
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
26039745, A61L 904, C07J 500
Patent
active
048104884
DESCRIPTION:
BRIEF SUMMARY
This invention relates to beclomethasone dipropionate and in particular to the physical modification thereof to provide crystals suitable for incorporation into stable suspension aerosol formulations.
Anti-inflammatory steroids, e.g. beclomethasone dipropionate, have been micronised into particles of a size suitable for endopulmonary or nasal inhalation, i.e. particles in the size range 2 to 5 microns, which display crystal growth when incorporated into aerosol formulations containing halogenated hydrocarbons, e.g. trichloromonofluoromethane (Propellant 11), dichlorotetrafluoroethane (Propellent 114) and dichlorodifluoromethane (Propellent 12). Crystals of a size larger than 20 microns are formed and such crystals are unsuitable for inhalation since their particle size is too great adequately to penetrate the trachea or nasal cavities. Investigations have revealed that the large crystals are not pure steroid but a solvate with one of the propellents, particularly Propellent 11.
There are several methods of inhibiting or reducing crystal growth of steroids in chlorofluorocarbon propellents.
British Patent Specification No. 1 429 184 discloses the preparation of a stable aerosol formulation in which the steroid is contacted with a halogenated hydrocarbon to form a crystalline solvate therewith, the crystalline solvate so formed being reduced to a particle size suitable for inhalation and thereafter being dispersed in an aerosol propellent.
United Kingdom Patent Application No. GB 2076422A discloses a process in which the increase of particle size is prevented at the suspending stage when the solubility of the steroid is reduced by using a low temperature (5.degree. to -40.degree. C.) and by initially mixing only a small quantity of the propellent with the steroid.
German Offenlegungsschrift No. 3 018 550 discloses the formation of a solvate of beclomethasone dipropionate with ethyl acetate, reducing the crystals of a solvate to a particle size suitable for inhalation and thereafter contacting the micronised particles with chlorofluorocarbon propellents to form an aerosol formulation.
Canadian Patent Specification No. 1 147 652 discloses a method in which beclomethasone dipropionate is contacted with an alkane having from 5 to 8 carbon atoms to form a solvate and the crystalline material is reduced to a particle size suitable for inhalation and thereafter contacted with chlorofluorocarbon propellents to form an aerosol formulation.
British Patent Specification No. 2 052 506A discloses a process for making a hemihydrate crystalline form of flunisolide by crystallizing flunisolide from an aqueous solution of an alkanol. The patent also discloses that when solvents such as ethyl acetate and methanol are used for crystallization of flunisolide clathrate, solvate or related solvent inclusion complexes are formed.
Journal of Pharmaceutical Sciences, Vol. 52, No. 8, August 1963, pages 781-791 discloses the formation of a pentanol solvent of fluorocortisone acetate. All the dissolution investigations were conducted in aqueous media and there is no reference to aerosol formulations.
We have now found that chlorofluorocarbon propellent stable forms of beclomethasone dipropionate can be achieved by forming crystalline solvates with lower alkanols.
Therefore according to the present invention there is provided a method for preparing a stable aerosol formulation of a beclomethasone dipropionate in which the steroid is contacted with an alcohol containing 1 to 5 carbon atoms to form a crystalline solvate therewith, the crystalline material so formed being reduced to a particle size below 10 microns and thereafter dispersed in a composition comprising chloro-fluorocarbon propellents.
The process of the invention provides stable suspension aerosol formulations of beclomethasone dipropionate, in a simple and effective manner. The process has significant procedural advantages over the more complex methods disclosed in British Patent Specification No. 1 429 184, United Kingdom Patent Application No. GB 2076422 and Canadian Pate
Dentz Bernard I.
Kirn Walter N.
Lee Mary C.
Riker Laboratories Inc.
Sell Donald M.
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