Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Patent
1994-07-12
1997-12-09
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
514180, A61L 904
Patent
active
056957440
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 PCT/E993/00223 filed on Feb. 2, 1993, published as WO93/15741 Aug. 19, 1993.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to improvements in or relating to pharmaceutical compositions comprising a beclomethasone ester. In particular the invention relates to novel aerosol formulations of use in the administration of beclomethasone dipropionate by inhalation.
2. Description of the Prior Art
Beclomethasone dipropionate is 9.alpha.-chloro-16.beta.-methyl-1,4-pregnadiene-11.beta., 17.alpha.-21-triol-3,20-dione 17.alpha.,21-dipropionate and may be represented by the formula (I) ##STR1##
The corticosteroid of formula (I) is known to exhibit topical antiinflammatory activity and is described and claimed in GB 1047519. In the treatment of asthmatic conditions it has been found to be effective to administer the compound in the form of dry powders or aerosols containing small particles of the medicament, conventionally prepared by micronization. However, the particle size of conventional formulations containing anhydrous beclomethasone dipropionate is known to increase on storage, due to solvate formation, to the extent that the medicament particles become too large to penetrate the bronchial system.
A number of potential solutions to this problem have been proposed. In dry powder compositions containing beclomethasone dipropionate it has been suggested that the problem may be overcome by using beclomethasone dipropionate in the form of its monohydrate (GB 2107715). In aerosol formulations, the use of micronized solvates of beclomethasone dipropionate, for example chlorofluorocarbon solvates (GB 1429184). ethyl acetate solvate (DE-3018550), C.sub.5-8 alkane solvates (EP-0039369), diisopropyl ether solvate (EP-0172672) and C.sub.1-5 alcohol solvates (WO86/03750) has been proposed. GB 2076422 discloses a process for the preparation of chlorofluorocarbon aerosols which incorporates a low temperature (5 to -40.degree. C.) step which is also claimed to inhibit crystal growth.
The presence of water in conventional aerosol formulations is known to be associated with a number of potential problems and it is generally accepted that these preparations should be maintained substantially free of water. The rigourous exclusion of atmospheric moisture during both the manufacture and storage of such formulations increases the difficulties of preparing satisfactory aerosols containing the drug and raises the overall cost of the final product.
SUMMARY OF THE INVENTION
We have now found that certain novel aerosol formulations containing beclomethasone dipropionate and water are surprisingly stable.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
According to one aspect of the invention we provide an aerosol formulation comprising :-- substantially all the monohydrate being less than 20 microns; the water of crystallization associated with said monohydrate; and
Beclomethasone dipropionate monohydrate may be prepared by methods known in the art, for example as disclosed in GB 2107715. The particle size of the crystalline monohydrate may be reduced by conventional methods, for example by micronization and should be such as to permit inhalation of substantially all of the medicament into the lungs upon administration of the aerosol formulation. The particle size is thus desirably in the range of 1 to 10 microns e.g. 1 to 5 microns.
The final aerosol formulation desirably contains 0.005-10% w/w, preferably 0.005-5% w/w, especially 0.01-1.0% w/w, of beclomethasone dipropionate monohydrate relative to the total weight of the formulation.
The aerosol formulations according to the invention contain at least 0.015% (e.g. 0.015 to 0.1%) by weight of the formulation of water (excluding the water of crystallization associated with the beclomethasone dipropionate monohydrate), preferably at least 0.02%, for example 0.025% by weight or more of added water. Surprisingly, aerosol formulations of micronised beclomethasone dipropionate monohydrate and fluorocarbon or hydrogen-containing chlorof
REFERENCES:
patent: 4347236 (1982-08-01), Tanskanen
patent: 4810488 (1989-03-01), Jinks
patent: 4866051 (1989-09-01), Hunt et al.
Neale Philip John
Taylor Anthony James
Cintins Marianne M.
Glaxo Group Limited
Jones Dwayne C.
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