Stabilized pharmaceutical composition in lyophilized form

Details Stabilized pharmaceutical composition in lyophilized form Stabilized pharmaceutical composition in lyophilized form

2001-03-01

2004-08-10

Brumback, Brenda (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C514S009100, C514S011400, C514S015800, C530S317000, C530S323000

Reexamination Certificate

active

06774104

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a stabilized pharmaceutical composition in lyophilized form containing a cyclic polypeptide compound. More particularly, the present invention relates to a stabilized pharmaceutical composition in lyophilized form containing a cyclic polypeptide compound or its pharmaceutically acceptable salt and a stabilizer.
The cyclic polypeptide compound of the present invention is represented by the general formula (I):
wherein R
1
is a hydrogen atom or an acyl group and R
2
and R
3
are, the same or different, a hydrogen atom or a hydroxyl group. The compound has an antimicrobial activity, particularly an antifungal activity and a &bgr;-1,3-glucan synthase inhibiting action, and is useful for preventing and treating various kinds of infectious diseases including Pneumocystis carinii infection, e.g., carinii pneumonia.
BACKGROUND ART
Among the cyclic polypeptide compounds represented by the above formula (I), a compound wherein R
1
is a hydrogen atom and R
2
and R
3
are hydroxyl groups and a compound wherein R
1
, R
2
and R
3
are hydrogen atoms are obtained by a fermentation process disclosed by European Patent No. 0462531 and processes disclosed by WO97/32975 and by WO97/47738. A compound wherein R
1
is an acyl group and its production process are disclosed by U.S. Pat. Nos. 5,376,634 and 5,569,646 and WO96/11210 and WO99/40108.
The cyclic polypeptide compounds (I) and their salts are generally unstable to light, humidity, acids, heat and the like. Therefore, desired is development of pharmaceutical preparations in which the cyclic polypeptide compounds and their salts are stabilized.
DISCLOSURE OF INVENTION
The present invention provides a stabilized pharmaceutical composition in lyophilized form containing a cyclic polypeptide compound (I) or its pharmaceutically acceptable salt and a stabilizer.
The “acyl group” for R
1
in the formula (I) representing the cyclic polypeptide compound of the present invention is now explained. In the context of the present specification, “lower” means having one to six carbon atoms unless otherwise indicated.
As examples of the acyl group, may be mentioned aliphatic acyl groups, aromatic acyl groups, aromatic-aliphatic acyl groups and heterocyclic acyl groups derived from aliphatic, aromatic, aromatic-aliphatic and heterocyclic carboxylic acids.
Examples of the aliphatic acyl groups include lower or higher alkanoyl groups such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.; cycloalkanoyl groups such as cyclopentanoyl and cyclohexanoyl; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.; lower alkanesulfonyl groups such as methanesulfonyl, ethanesulfonyl, etc.; lower alkoxysulfonyl groups such as methoxysulfonyl, ethoxysulfonyl, etc.; and the like.
Examples of the aromatic acyl groups include aroyl groups such as benzoyl, toluoyl, naphthoyl and the like.
Examples of the aromatic-aliphatic acyl groups include
ar(lower)alkanoyl groups such as phenyl(C
1
-C
6
)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(C
1
-C
6
)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.) and the like;
ar(lower)alkenoyl groups such as phenyl(C
3
-C
6
)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentanoyl, phenylhexenoyl, etc.), naphthyl (C
3
-C
6
)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.) and the like;
ar(lower)alkoxycarbonyl groups such as phenyl(C
1
-C
6
)alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), fluorenyl (C
1
-C
6
) alkoxycarbonyl (e.g., fluorenylmethoxycarbonyl, etc.) and the like;
aryloxycarbonyl groups such as phenoxycarbonyl, naphthoxycarbonyl, etc.;
aryloxy(lower)alkanoyl groups such as phenoxyacetyl, phenoxypropionyl, etc.;
arylcarbamoyl groups such as phenylcarbamoyl, etc.;
arylthiocarbamoyl groups such as phenylthiocarbamoyl, etc.;
arylglyoxyloyl groups such as phenylglyoxyloyl, naphthylglyoxyloyl, etc.;
arylsulfonyl groups which may be optionally substituted by a lower alkyl group such as phenylsulfonyl, p-tolylsulfonyl, etc.; and the like.
Examples of the heterocyclic acyl groups include heterocyclic
carbonyl groups such as thenoyl, furoyl, nicotinoyl, etc.;
heterocyclic(lower)alkanoyl groups such as heterocyclic acetyl, heterocyclic propanoyl, heterocyclic butanoyl, heterocyclic pentanoyl, heterocyclic hexanoyl, etc.;
heterocyclic(lower)alkenoyl groups such as heterocyclic propenoyl, heterocyclic butenoyl, heterocyclic pentenoyl, heterocyclic hexenoyl, etc.;
heterocyclic glyoxyloyl and the like.
The acyl group for R
1
may have one, or more suitable substituent(s). Among the above-mentioned examples for the acyl groups, an aroyl group which may have one or more suitable substituent(s) is particularly preferable.
Examples of suitable substituents in the acyl group include a heterocyclic group substituted by an aryl group having a lower alkoxy group, a heterocyclic group substituted by an aryl group having a lower alkoxy(lower)alkoxy group, a heterocyclic group substituted by an aryl group having a lower alkoxy(higher)alkoxy group, a heterocyclic group substituted by an aryl group having a cyclo(lower)alkyloxy group, a heterocyclic group substituted by an aryl group having a heterocyclic group, a heterocyclic group substituted by a cyclo(lower)alkyl group having a cyclo(lower)alkyl group, a heterocyclic group substituted by an aryl group having an aryl group substituted by a lower alkoxy(lower)alkoxy and a heterocyclic group substituted by an aryl group having a heterocyclic group substituted by a cyclo(lower)alkyl group.
Among these examples, preferred are an unsaturated 3- to 8-membered heteromonocyclic group containing one to two oxygen atom(s) and one to three nitrogen atom(s) and substituted by phenyl having (C
4
-C
6
)alkoxy, an unsaturated condensed heterocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s) and substituted by phenyl having (C
4
-C
6
)alkoxy, an unsaturated 3- to 8-membered heteromonocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s) and substituted by phenyl having (C
1
-C
4
)alkoxy(C
4
-C
6
)alkoxy, an unsaturated 3- to 8-membered heteromonocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s) and substituted by phenyl having (C
1
-C
4
)alkoxy(C
7
-C
14
)alkoxy, a saturated 3- to 8-membered heteromonocyclic group containing one to four nitrogen atom(s) and substituted by phenyl having (C
1
-C
4
)alkoxy(C
7
-C
14
)alkoxy, an unsaturated condensed heterocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s) and substituted by phenyl having cyclo(C
4
-C
6
)alkyloxy, an unsaturated condensed heterocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s) and substituted by phenyl, a saturated 3- to 8-membered heteromonocyclic group containing one to two oxygen atom(s) and one to three nitrogen atom(s), a saturated 3- to 8-membered heteromonocyclic group having one to four nitrogen atom(s) and substituted by cyclo(C
4
-C
6
)alkyl having cyclo(C
4
-C
6
)alkyl, an unsaturated 3- to 8-membered heteromonocyclic group having one to two sulfur atom(s) and one to three nitrogen atom(s) and substituted by phenyl having phenyl substituted by (C
1
-C
4
)alkoxy(C
1
-C
4
)alkoxy, an unsaturated 3- to 8-membered heteromonocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s) and substituted by phenyl having a saturated 3- to 8-membered heteromonocyclic group which contains one to four nitrogen atom(s) and is substituted by cyclo(C
4
-C
6
)alkyl and an unsaturated condensed heterocyclic group containing one to two sulfur atom(s) and one to three nitrogen

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