Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-20
2002-05-14
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S214020
Reexamination Certificate
active
06387918
ABSTRACT:
TECHNICAL FIELD
This invention relates to a pharmaceutical composition comprising a tricyclic compound of general formula (I) or a pharmaceutically acceptable salt thereof which features stability, excellent absorbability, and/or a reduced irritation potential. This pharmaceutical composition is of value for the treatment or prevention of inflammatory or hyperproliferative skin diseases or cutaneous manifestations of immunologically-mediated diseases.
BACKGROUND ART
The tricyclic compound (I) and its pharmaceutically acceptable salt 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 [Japanese Kokai Tokkyo Koho S61-1481B1, EP-A-0323042, etc.].
Particularly, those species of tricyclic compound (I) which are designated as FR900506 (=FK506 Substance), FR900520, FR900523, and FR900525 are products produced by microorganisms of the genus Streptomyces, such as
Streptomyces tsukubaensis
No. 9993 [deposited with National Institute of Bioscience and Human Technology Agency of Industrial Science and Technology (formerly Fermentation Research Institute Agency of Industrial Science and Technology ), at 1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan, date of deposit Oct. 5, 1984, accession number FERM BP-927] or
Streptomyces hygroscopicus
subsp.
vakushimaensis
No. 7238 [deposited with National Institute off Bioscience and Human Technology Agency of Industrial Science and Technology (formerly Fermentation Research Institute Agency of Industrial Science and Technology ), at 1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan, date of deposit Jan. 12, 1985, accession number FERM BP-928]. The FK506 Substance of the following chemical formula, in particular, is a representative compound.
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
It has been demonstrated that the above-mentioned FK506 Substance has quite excellent immunosuppressive activity and is useful for the treatment or prevention of rejection by organ transplantation and the treatment or prevention of diseases in the field of ophthalmology.
Japanese Kokai Tokkyo Koho H1-157913 discloses that a solution of FK506 Substance in ethanol is effective in the suppression of inflammation and that FK506 Substance can be formulated into a lotion, gel, or cream. However no specific dosage forms of the kinds are described.
Japanese Kokai Tokkyo Koho H5-17481 discloses an ointment comprising a tricyclic compound (I) or its pharmaceutically acceptable salt, at least a sufficient amount of a dissolution/absorption promoter to dissolve the same, and an ointment base.
W094/28894 discloses a lotion comprising a tricyclic compound (I) or its pharmaceutically acceptable salt, a dissolution/absorption promoter, a liquid medium, and optionally an emulsifier and/or a thickening (rheology modifier).
Heretofore, ointments have mainly been used in the treatment of skin diseases. However, different dosage forms suited to different clinical manifestations and different application sites are being demanded.
The inventors of this invention have studied possible pharmaceutical compositions for compounds of general formula (I) inclusive of FK506 Substance and found a dosage form having many desirable characteristics such as high stability, high transdermal absorbability, and/or reduced dermal irritancy. Thus, specifically this invention is directed to an hydrophilic semi-solid composition for external use containing said tricyclic compound.
DISCLOSURE OF INVENTION
In accordance with this invention there is provided a pharmaceutical composition comprising a tricyclic compound (I) or its pharmaceutically acceptable salt, an oil substance, a surfactant, a hydrophilic substance, and water, and further optionally a pH control agent.
The tricyclic compound for use in this invention can be expressed by the following general formula (I).
(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 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 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
)).
The above compound (I) or its pharmaceutically acceptable salt can be provided by the same technology as that described in the two patent gazettes referred to above. Particularly, the tricyclic compounds produced by fermenting
Streptomyces tsukubaensis
No. 9993 (FERM BP-927) or
Streptomyces hygroscopicus
subsp.
yakushimaensis
No. 7238 (FERM BP-928) are known by the identification nos. of FR-900506, FR-900520, FR-900523, and FR-900525 (Japanese Kokai Tokkyo Koho S61-148181).
The various definitions given in the above general formula (I), generic and subgeneric examples thereof, and preferred species are now explained and shown in detail.
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 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” 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 methylthiome
Ibuki Rinta
Ohnishi Norio
Shimojo Fumio
Toyoda Toshihiko
Ueda Satoshi
Criares Theodore J.
Fujisawa Pharmaceutical Co. Ltd.
Kim Jennifer
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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