Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-06-04
2002-02-12
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S411000, C424S452000, C424S405000, C424S502000
Reexamination Certificate
active
06346537
ABSTRACT:
TECHNICAL FIELD
This invention relates to a pharmaceutical composition comprising a water-insoluble medicinally active substance, surfactant(s) and solid carrier(s), which has very satisfactory dissolution property, oral absorbability and so on. The pharmaceutical composition of the present invention can be used in the field of medical care.
BACKGROUND ART
To provide a pharmaceutical preparation of a water-insoluble medicinally active substance, particularly a pharmaceutical composition for oral administration, it is common practice to cause a polymer such as hydroxypropylmethylcellulose and the medicinally active substance to form a solid dispersion, and typically such a solid dispersion has been proposed for the under-mentioned FK506 (or FR-900506) which is well known to have a potent immunosuppressive activity but be insoluble in water (Japanese Tokkyo Kokai Koho S62-277321).
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
However, it is generally acknowledged that the absorption of such a solid dispersion after oral administration has a tendency toward some variation. The inventors of this invention did intensive research and have succeeded in developing a pharmaceutical composition which, even in cases where the active ingredient is a substance which is insoluble in water (i.e. a water-insoluble medicinally active substance), assures very satisfactory characteristics such as favorable dissolution property, high absorption, and/or less variation in said absorption.
DISCLOSURE OF THE INVENTION
This invention is essentially directed to a pharmaceutical composition comprising a water-insoluble medicinally active substance, surfactant (s) and solid carrier(s) and to a process for producing said composition. This invention is now described in detail.
The “water-insoluble medicinally active substance” which can be used in the pharmaceutical composition of the instant application includes any and all medicinally active substances that are insoluble in water, such as, for example, tricyclic compounds of the formula (I), represented by FK506 mentioned above, and their pharmaceutically acceptable salts.
(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
3
;
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 R23, 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 compound (I) and its pharmaceutically acceptable salt are known as immunosuppressants (Japanese Tokkyo Kokai Koho S61-148181, EP0323042), and FK506, inparticular, has already been put to use in the therapy and prophylaxis of rejection reactions by transplantation of organs such as the heart, liver, kidney, bone marrow, skin, cornea, lung, pancreas, small intestine, muscle, nerve, limb, etc. and of various autoimmune diseases.
The above-mentioned compound (I) and its pharmaceutically acceptable salt can be provided by the same methods as disclosed in the two patent gazettes mentioned above. Particularly the tricyclic compounds produced by cultivation of
Streptomyces tsukubaensis
No. 9993 (FERM-BP 927) or
Streptomyces hygroscopicus
subsp.
yakushimaensis
No. 7238 (FERM-BP 928) have been given the identification numbers FR-900506, FR-900520, FR-900523, and FR-900525 (Japanese Tokkyo Kokai Koho S61-148181).
First, 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” 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 methylthiomethyl group;
trisubstituted silyl group such as a tri(lower)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl, tri-tert-butylsilyl, etc.) or lower alkyldiarylsilyl (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 one or more suitable substituents such as carboxy, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, arboxyhexanoyl, etc.; a cyclo(lower)alkoxy(lower)alkanoyl group optionally having one or more suitable substituents such as lower alkyl, e.g., cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl, menthyloxyhexanoyl, etc.; a camphorsulfonyl group; or a lower alkylcarbamoyl group having one or more suitable substituents such as carboxy or protected carboxy, for example, carboxy(lower)alkylcarbamoyl group (e.g., carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentyl
Hata Takehisa
Hirose Takeo
Kimura Sumihisa
Shimojo Fumio
Tokunaga Yuji
Fujisawa Pharmaceutical Co. Ltd.
Reamer James H.
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