Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-12
2001-11-13
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...
C514S423000, C514S428000, C514S422000
Reexamination Certificate
active
06316473
ABSTRACT:
TECHNICAL FIELD
This invention relates to a medicinal composition comprising a sparingly water-soluble medicinal substance and two or more surfactants and expressing very satisfactory release and oral absorption characteristics. The medicinal composition of this instant invention finds application in the field of medical care.
BACKGROUND ART
To provide a medicinal preparation of a medicinal substance which is only sparingly soluble in water (hereinafter referred to briefly as an insoluble drug), particularly such a preparation for oral administration, it is common practice to prepare a solid dispersion by mix-crystallizing a polymer such as hydroxypropylmethyl cellulose and the drug. By way of illustration, such a solid dispersion has been provided for the following FK506 (or FR-900506) Substance which, as is well known, has excellent immunosuppressant activity but is only sparingly soluble in water [Kokai Tokkyo 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 oral absorbability of solid dispersions such as the above tends to vary rather appreciably.
After intensive investigations, the inventors of this invention have created a medicinal composition which, even when its active ingredient is an only sparingly water-soluble medicinal substance (insoluble drug), shows a very satisfactory drug release profile plus high oral absorption efficiency and absorbability with little variation.
DISCLOSURE OF INVENTION
This invention is essentially directed to a medicinal composition comprising an insoluble drug and two or more surfactants, at least one of said two or more surfactants having as dissolved therein the insoluble drug and the other surfactant or surfactants and to a process for producing said composition. This invention is now described in detail.
The “insoluble drug” to which the medicinal composition of this invention can be applied with advantage may be any pharmaceutical substance (drug) that is only sparingly soluble in water and includes, among others, the following tricyclic compound (I), which is represented by said FK506 Substance, and its pharmaceutically acceptable salt.
(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 compound (I) and its pharmaceutically acceptable salt are known as immunosuppressants (Japanese Tokkyo Kokai Koho S61-148181, EP 0323042), and FK506, in particular, 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) [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] or
Streptomyces hygroscopicus
subsp.
yakushimaensis
No. 7238 (FERM BP-928) [deposited with National Institute of Bioscience and Human Technology Agency of Industrial Science and Technology (date of deposit Jan. 12, 1985)] 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-(lowerlkylthio) (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 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 su
Hirose Takeo
Ibuki Rinta
Kimura Sumihisa
Ohnishi Norio
Shimojo Fumio
Fujisawa Pharmaceutical Co. Ltd.
Jarvis William R. A.
Kim Vickie
Oblon, Spivak, McLelland, Maier & Neustadt, P.C.
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