Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-07
2003-07-01
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S214020, C514S336000, C514S947000
Reexamination Certificate
active
06586444
ABSTRACT:
TECHNICAL FIELD
This invention relates to a pharmaceutical composition containing macrolide compound, said composition being stable and having very satisfactory absorption kinetics and/or a low irritation potential. This composition finds application in the therapy and prophylaxis of various diseases of the skin.
BACKGROUND ART
The tricyclic compound and its pharmaceutically acceptable salt, which is a representative of the macrolide compound for use in accordance with this invention, is known to have excellent immunosuppressive activity, antimicrobial activity and other pharmacological activities and, as such, be of value for the treatment or prevention of rejection reactions by transplantation of organs or tissues, graft-vs.-host diseases, autoimmune diseases, and infectious diseases [EP-A-0184162, EP-A-0323042, etc.].
Particularly, FK506 Substance among such tricyclic compound (I), which has been shown to be useful for the therapy and prevention of graft rejection in organ transplantation due to its quite excellent immunosuppressive activity.
It is mentioned in EP-A-0315978 that an ethanol solution of FK506 Substance is effective in arresting inflammatory reactions and that FK506 Substance can be provided in the form of a lotion, a gel or a cream. However, there is no specific disclosure of such dosage forms.
Meanwhile, EP-A-0474126 discloses an ointment comprising FK506 substance and its analogs, a dissolution/absorption promoter added in a sufficient amount to dissolve the active compound, and an ointment base.
Further, WO94/28894 discloses a lotion comprising FK506 substance and its analogs, a dissolution/absorption promoter, a liquid base, and, optionally, an emulsifier and/or a thickener.
In the treatment of diseases of the skin, an ointment transitionally constitutes the cardinal regimen. However, a variety of dosage forms are needed, as a matter of fact, in order to cope with different symptoms or lesions in different sites.
DISCLOSURE OF INVENTION
The inventors of this invention explored in earnest for a pharmaceutical composition suited for the administration of a macrolide compound, a representative of which is FK506 Substance, and discovered a dosage form having very satisfactory characteristics, namely stability, good percutaneous absorption and/or low skin irritation potential. Thus, the present invention specifically relates to a gel preparation comprising the macrolide compound for external application.
In accordance with this invention there is provided a pharmaceutical composition comprising said macrolide compound, a dissolution/absorption promoter and a pharmaceutical base, and optionally a compatibilizing agent and/or a thickener.
The term “macrolide compound” for use in accordance with the invention is the generic name of compounds with 12 members or more, which belong to macrocyclic lactones. Abundant macrolide compounds generated by microorganisms of the genus Streptomyces, such as rapamycin, tacrolimus (FK506), and ascomycin, and the analogs and derivatives thereof are included in the term macrolide compound.
As a particular example of the macrolide compound, the tricyclic compound of the following formula (I) can be exemplified.
(wherein each of adjacent pairs of R
1
and R
2
, R
3
and R
4
and R
5
and R
6
independently
(a) is two adjacent hydrogen atoms, but R
2
may also be an alkyl group or
(b) may form another bond formed between the carbon atoms to which they are attached;
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
;
R
8
and R
9
are 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
;
R
11
and R
12
are independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group;
R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, R
22
and R
23
are independently a hydrogen atom or an alkyl group;
R
24
is an optionally substituted ring system which may contain one or more heteroatoms;
n is an integer of 1 or 2; 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 alkoxy, a benzyl, a group of the formula —CH
2
Se(C
6
H
5
), and an alkyl substituted by one or more hydroxy groups.
Preferable R
24
may be cyclo (C
5-7
)alkyl group, and the following ones can be exemplified.
(a) a 3,4-di-oxo-cyclohexyl group;
(b) a 3-R
20
-4-R
21
-cyclohexyl group,
in which
R
20
is hydroxy, an alkoxy group, an oxo group, or a —OCH
2
OCH
2
CH
2
OCH
3
group, and
R
21
is hydroxy, —OCN, an alkoxy group, a heteroaryloxy which may be substituted by suitable substituents, a —OCH
2
OCH
2
CH
2
OCH
3
group, a protected hydroxy group, chloro, bromo, iodo, aminooxalyloxy, an azido group, p-tolyloxythiocarbonyloxy, or R
25
R
26
CHCOO—,
in which
R
25
is optionally protected hydroxy or protected amino, and
R
26
is hydrogen or methyl, or
R
20
and R
21
together form an oxygen atom in an epoxide ring; or
(c) cyclopentyl group substituted by methoxymethyl, optionally protected hydroxymethyl, acyloxymethyl (in which the acyl moiety optionally contains either a dimethylamino group which may be quaternized, or a carboxy group which may be esterified), one or more amino and/or hydroxy groups which may be protected, or aminooxalyloxymethyl. A preferred example is a 2-formyl-cyclopentyl group.
The definitions used in the above general formula (I) and the specific and preferred examples thereof are now explained and set forth in detail.
The term “lower” means, unless otherwise indicated, a group having 1 to 6 carbon atoms.
Preferable examples of the “alkyl groups” and an alkyl moiety of the “alkoxy group” include a straight or branched chain aliphatic hydrocarbon residue, for example, a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl and hexyl.
Preferable examples of the “alkenyl groups” include a straight or branched chain aliphatic hydrocarbon residue having one double-bond, for example, a lower alkenyl group such as vinyl, propenyl (e.g., allyl group), butenyl, methylpropenyl, pentenyl and hexenyl.
Preferable examples of the “aryl groups” include phenyl, tolyl, xylyl, cumenyl, mesityl and naphthyl.
Preferable protective groups in the “protected hydroxy groups” and the “protected amino” are 1-(lower alkylthio)-(lower)alkyl group such as a lower alkylthiomethyl group (e.g., methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), more preferably C
1
-C
4
alkylthiomethyl group, most preferably methylthiomethyl group;
trisubstituted silyl group such as a tri(lower)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl, tri-tert-butylsilyl, etc.) or lower alkyl-diarylsilyl (e.g., methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenyl-silyl, etc.), more preferably tri(C
1
-C
4
)alkylsilyl group and C
1
-C
4
alkyldiphenylsilyl group, most preferably tert-butyldimethylsilyl group and tert-butyldiphenylsilyl group; and an acyl group such as an aliphatic, aromatic acyl group or an aliphatic acyl group substituted by an aromatic group, which are derived from a carboxylic acid, sulfonic acid or carbamic acid.
Examples of the aliphatic acyl groups include a lower alkanoyl group optionally having on
Ibuki Rinta
Shimojo Fumio
Toyoda Toshihiko
Ueda Satoshi
Yamanaka Masayuki
Fujisawa Pharmaceutical Co. Ltd.
Jarvis William R. A.
Kim Vickie
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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