Aerosol compositions

Details Aerosol compositions Aerosol compositions

1998-04-22

2002-03-26

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Effervescent or pressurized fluid containing

Organic pressurized fluid

C424S067000, C546S089000, C514S277000

Reexamination Certificate

active

06361760

ABSTRACT:

TECHNICAL FIELD
This invention relates to a medicinal aerosol composition and a process for the preparation of the same and, as such, finds application in the field of medicine.
BACKGROUND ART
A tricyclic compound (I) and a pharmaceutically acceptable salt thereof used in the present invention have been known to possess excellent pharmacological activities such as an immunosuppressive activity and an antimicrobial activity, thereby being useful for treating and/or preventing rejection by organ-transplantation or tissue-transplantation, graft-versus-host diseases, various autoimmune diseases and infectious diseases (for example, see EP-A-0184162 and WO 89/05304).
Particularly, compounds referred to as FR900506(=FK506), FR900520, FR900523 and FR900525 which belong to the tricyclic compound (I) are produced from genus Streptomyces, in particular,
Streptomyces tsukubaensis
No. 9993 (Depositary Authority: 1-3, Higashi 1 chome, Yatabe-machi, Tsukuba-gun, Ibaraki-ken, Japan, Fermentation Research Institute Agency of Industrial Science and Technology, Ministry of International Trade and Industry; Date of the Deposit: Oct. 5, 1984; Accession Number: FERM BP-927) or
Streptomyces hygroscopicus Subsp. yakushimaensis
No. 7238 (Depositary Authority: 1-3, Higashi 1 chome, Yatabe-machi, Tsukuba-gun, Ibaraki-ken, Japan, Fermentation Research Institute Agency of Industrial Science and Technology, Ministry of International Trade and Industry; Date of the Deposit: Jan. 12, 1985; Accession Number: FERM BP-928). Such situations are shown in EP-A-0184162.
Among those tricyclic compound (I), FK506 represented by the following structural formula is a typical compound.
Generic name: Tacrolimus
Chemical name: 17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo -[22.3.1.0
4,9
]octacos-18-ene-2,3,10,16-tetraone.
On the other hand, a medicinal aerosol is a drug delivery system adapted to deliver a medicinally active substance in a finely divided form along with inspired air into the recipient's airway for the treatment of attacks of bronchial asthma, for instance, and is in broad use in the field of medicine.
The conventional medicinal aerosol utilizes one or more kinds of liquefied chlorofluorocarbons (hereinafter referred to collectively as CFC) as the propellant and is available in a system such that a finely divided medicinally active substance has been dispersed in CFC with the aid of a suitable dispersant.
For example, aerosol of the tricyclic compound (I) comprising such CFC were already suggested in WO 90/14826.
However, CFC is associated with the on-going destruction of the ozone layer of the atmosphere and a worldwide total ban on its use is foreseen within this century. Under the circumstances, the use of liquefied hydrofluoroalkanes (hereinafter sometimes referred to collectively as HFA) is being contemplated as substitute propellants for aerosols. However, despite their advantage of being lenient to the ozonosphere in comparison with CFC, HFA has the disadvantage that because of the total insolubility of the conventional dispersants (e.g. soybean lecithin) therein, medicinally active substances cannot be successfully dispersed in HFA.
To overcome the above disadvantage, an aerosol system providing for a uniform dispersion of a medicinally active substance has been proposed which comprises HFA and, as a dispersant, a polymer containing an HFA-soluble amide or carboxylic ester as a recurrent unit (such as polyvinylpyrrolidone, polyvinyl acetate, acrylic acid-methacrylic ester copolymer) (WO 93/05765).
The polymer used in the above aerosol system is a solid substance, with the result that when a premix of the polymer with the active substance is to be dispersed in the propellant, there occurs a segregation of the active ingredient. Therefore, it is common practice to feed the active substance and the polymer respectively to a cooling agitation tank or a pressure tank, then adding HFA under cooling or elevated pressure with stirring to disperse the active substance in the HFA, and distributing the dispersion into dispensing containers. However, this procedure is not only complicated but also has the disadvantage that because the proportion of the active ingredient is quite small, a uniformity of its content for each dispenser can hardly be insured in the stage of portion-wise distribution of the propellant dispersing the active ingredient.
SUMMARY OF THE INVENTION
This inventors of this invention did much research for overcoming the above-mentioned disadvantages and discovered that when a medium-chain fatty acid triglyceride is used as the dispersant in the manufacture of a medicinal aerosol, the tricyclic compound (I) can be uniformly dispersed in HFA by kneading the tricyclic compound (I) with the medium-chain fatty acid triglyceride in the first place, distributing the kneaded mass into aerosol dispensers, and filling the respective dispensers with HFA under cooling or elevated pressure and that, as a result, not only the aerosol preparation process is simplified but also the final aerosol has a minimal dispenser-to-dispenser variation in content of the active ingredient. They accordingly have perfected this invention.
DETAILED DESCRIPTION OF THE INVENTION
The aerosol composition of this invention comprises a tricyclic compound (I) or a pharmaceutically acceptable salt thereof mentioned below, a liquefied hydrofluoroalkane, and a medium-chain fatty acid triglyceride.
The tricyclic compound (I) used in the present invention is represented by the following formula:
wherein
each of adjacent pairs of R
1
and R
2
, R
3
and R
4
or R
5
and R
6
independently
(a) is two adjacent hydrogen atoms, or
(b) may form another bond formed between the carbon atoms to which they are attached,
 and further, R
2
may be an alkyl group;
R
7
is a hydrogen atom, a hydroxy group, a protected hydroxy group or an alkoxy group, or an oxo group together with R
1
;
each of R
8
and R
9
is independently a hydrogen atom or a hydroxy group;
R
10
is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups or an alkyl group substituted by an oxo group;
X is an oxo group, (a hydrogen atom and a hydroxy group), (a hydrogen atom and a hydrogen atom), or a group represented by the formula —CH
2
O—;
Y is an oxo group, (a hydrogen atom and a hydroxy group), (a hydrogen atom and a hydrogen atom), or a group represented by the formula N—NR
11
R
12
or N—OR
13
;
each of R
11
and R
12
is independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group;
each of R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
22
and R
23
is independently a hydrogen atom or an alkyl group;
each of R
20
and R
21
is independently an oxo group or (R
20
a and a hydrogen atom) or (R
21
a and a hydrogen atom) in which each of R
20
a and R
21
a is independently a hydroxy group, an alkoxy group or a group represented by the formula —OCH
2
OCH
2
CH
2
OCH
3
, or R
21
a is a protected hydroxy group, or R
20
a and R
21
a may together represent an oxygen atom in an epoxide ring;
n is an integer of 1, 2 or 3; and
in addition to the above definitions, Y, R
10
and R
23
, together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkyl substituted by one or more hydroxy groups, an alkoxy, a benzyl and a group of the formula —CH
2
Se(C
6
H
5
).
Hereinafter, various terms which are included in the scope of the present invention will be defined;
Each definition in the formula (I) will be detailed as follows.
The term “lower” means, unless otherwise indicated, a group having 1 to 6 carbon atoms. Preferable examples of the “alkyl groups” include a straight or branched chain aliphatic hydro

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