Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1999-09-14
2001-09-04
Bawa, Raj (Department: 1619)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C514S826000, C514S018700
Reexamination Certificate
active
06284226
ABSTRACT:
TECHNICAL FIELD
This invention relates to an aerosol composition comprising the following compound of formula (A) and finds application in the field of health care.
BACKGROUND ART
The compound of the above formula (A) (hereinafter referred to briefly as compound (A)) is described in WO 93/21215. Being a neurokinin receptor antagonist, the compound is useful for the therapy of bronchial asthma and chronic bronchitis, among other diseases.
This compound (A) in the finely divided bulk state is apt to undergo agglomeration and caking so that when processed into a powder inhalant, the bulk substance cannot be sufficiently delivered to the target bronchi.
An apparently reasonable approach would be dispersing it in an aerosol propellant for administration. However, when dispersed in an aerosol propellant, compound (A) remains dispersed only for a short while following shaking of the package but soon begins to be segregated from the propellant, with the result that by the time of dispensing for administration the compound (A) will have separated out to a marked extent to frustrate sufficient medication owing to a variation in the administered dose.
The conventional aerosol product employs one or more kinds of liquefied chlorofluorocarbons (hereinafter referred to collectively as CFC) as a propellant and contains a finely divided powder of the active substance dispersed in CFC with the aid of a suitable dispersant.
However, CFC is involved in destruction of the ozonosphere and, in many countries, a total ban on its use is expected to be enforced within this century at earliest. Therefore, as substitute aerosol propellants, the use of liquefied hydrofluoroalkanes (hereinafter referred to sometimes collectively as HFA) is being evaluated. Being a better choice from the standpoint of preservation of the ozonosphere, HFA has the drawback that the dispersants (e.g. soybean lecithin) heretofore used in combination with CFC are not soluble in HFA at all, with the result that compound (A) cannot be dispersed in HFA and, hence, no satisfactory aerosol product of compound (A) can be provided.
DISCLOSURE OF THE INVENTION
The inventors of this invention did intensive investigations to solve the above problem and found that compound (A) can be uniformly dispersed in HFA by using a middle-chain fatty acid triglyceride as dispersant so that a satisfactory aerosol with little-variation in the dose dispensed can be obtained.
The aerosol composition according to this invention comprises said compound of formula (A), a middle-chain fatty acid triglyceride and a liquefied hydrofluoroalkane. Preferably, the aerosol composition of this invention contains polyvinylpyrrolidone in addition to said ingredients.
In the aerosol composition of this invention, the concentration of the active ingredient compound (A) is 0.05~10 w/v %, preferably 0.1~5 w/v %, and the compound (A) is used generally after size reduction to about 0.5~5 &mgr;m in particle diameter.
In the aerosol composition of this invention, the middle-chain fatty acid triglyceride used as the dispersant for compound (A) is chiefly the triglyceride of saturated fatty acids [CH
3
(CH
2
)
n
COOH, n=4~10], and many proprietary products, such as Miglyol 812 (trademark, Dynamit Nobel), Panacete 810 (trademark, NOF Corporation), Coconade (trademark, Kao Corporation), Myritol GM (trademark, Henckell Hakusui) and ODO (trademark, The Nisshin Oil Mills, Ltd.), are commercially available and can be utilized.
The formulating amount of the middle-chain fatty acid triglyceride is generally 0.01~1 w/v %, preferably 0.05~0.5 w/v %.
The liquefied hydrofluoroalkane for use as propellant in the aerosol composition of this invention includes but is not limited to HFA134a (1,1,1,2-tetrafluoroethane: CH
2
FCF
3
) and HFA227 (1,1,1,2,3,3,3-heptafluoropropane: CF
3
CHCF
3
) and those liquefied hydrofluoroalkanes can be used each alone or as a mixture.
For a further improved dispersibility of compound (A), the aerosol composition of this invention is preferably supplemented with 0.001~0.5 w/v %, more preferably 0.01~0.1 w/v %, of polyvinylpyrrolidone.
Furthermore, the aerosol composition of this invention may contain the conventional dispersant such as polyvinyl alcohol, sorbitan fatty acid ester, polyoxyethylene-sorbitan fatty acid ester (e.g. Tween 20, Span 85, etc.), fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, sucrose ester, lecithin, HCO-60 (polyoxyethylene-hydrogenated castor oil), oleic acid or isopropyl myristate in a proportion of 0.0001~0.01 w/v %.
The process for producing the aerosol composition of this invention is now described. Compound (A), comminuted in the routine manner in advance, and a middle-chain fatty acid triglyceride, optionally as well as polyvinylpyrrolidone, are added to a liquefied hydrofluoroalkane at −20° C. and the resulting composition is distributed into aerosol containers (usually aluminum cans) with sufficient stirring.
Then, each aerosol container is fitted with a valve for dispensing.
As an alternative, after addition of the above ingredients to the liquefied hydrofluoroalkane at atmospheric temperature and sufficient stirring, the resulting composition is distributed into aerosol containers fitted with valves under an elevated pressure of 20~30 atmospheres.
The dispensing amount of the aerosol product of this invention per actuation is 25~150 &mgr;l and the composition is dispensed by 1~4 actuations per dose once to 4 times daily.
INDUSTRIAL APPLICABILITY
When soybean lecithin was used as dispersant as in Comparative Example 1 which appears below, compound (A) could not be dispersed at all in the propellant HFA-227. However, when a middle-chain fatty acid triglyceride (Miglyol 812) was used as dispersant as in Example 1 of this invention, compound (A) could be well dispersed. Thus, in accordance with the aerosol composition of this invention, the active ingredient compound (A) can be provided as a uniform dispersion in the propellant. Accordingly there can be provided an aerosol product which shows no variation in the dose dispensed, thus being of use in the therapy of bronchial asthma and chronic bronchitis.
REFERENCES:
patent: 518600 (1992-12-01), None
patent: 93/21215 (1993-10-01), None
patent: 95/00536 (1995-01-01), None
patent: 95/04551 (1995-02-01), None
Ito Hideki
Shimojo Fumio
Tsuji Masahiro
Yoshida Hiromitu
Bawa Raj
Fujisawa Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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