Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-05
2001-03-13
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S724000, C514S784000, C514S767000, C514S212050, C514S212060, C540S545000
Reexamination Certificate
active
06200968
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to non-aqueous, particle-forming pharmaceutical compositions containing fused pyrrolocarbazoles or derivatives thereof. The invention is also directed to stable solutions which result upon contacting the particle-forming compositions of the present invention with an aqueous medium. The invention is further directed to methods of medical treatment which include treatment of a subject with the compositions or solutions of the present invention.
BACKGROUND OF THE INVENTION
Fused pyrrolocarbazoles display various pharmacological activities. For example, fused pyrrolocarbazoles are useful for treatment of neurological diseases or disorders, and some display antifungal, antimicrobial, or antitumor activity. In some cases this is accomplished by modulation of neurotrophic responses through effects on protein kinase activity (Berg et al.,
J. Biol. Chem.
267:13-16 (1992)). Fused carbazoles and their derivatives have been isolated from a various microorganisms, including
S. staurosporeus, N. aerocoligenes,
Actinomadura and Nocardiopsis sp, (Kase et al.,
Biochem. Biophys. Res. Commun.
142: 436-440, (1987)).
Specific fused pyrrolocarbazoles, such as indolocarbazoles, which have been characterized include the following: staurosporine and rebeccamycin (Moody et al., supra); K-252a, K-252b (Kase et al., supra); K-252c (also called staurosporine aglycon) (Moody et al., supra), K-252d and derivatives thereof (published Japanese patent applications 60-257652, 60-295172, 62-327858, 62-327859, and 60-295173). K-252a, K-252b, K-252c, and K-252d are insoluble in water (Nakanishi et al.,
J. Antibodies,
34:1066, (1986)).
In general, fused pyrrolocarbazoles display very low water solubility. Dry pharmaceutical preparations (dragees, tablets and capsules) of staurosporine derivatives that may contain polyethylene glycol and polyvinylpyrrolidone have been described in U.S. Pat. No. 5,093,330. Conventional pharmaceutical formulations that include indolocarbazoles are described in U.S. Pat. No. 5,043,335 and PCT publication No. WO 93/00909. Aqueous indolocarbazole compositions are described in U.S. Pat. No. 5,599,808.
Self-emulsifying drug delivery systems (“SEDDS”) have been developed for drugs that display very low water solubility but good oil solubility. See, e.g., Shah et al.,
International Journal of Pharmaceutics
(
Netherlands
) 106:15-23, (1994). Despite their low water solubility, fused carbazoles are generally unsuited for SEDDS because of their low oil solubility.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide particle-forming compositions containing fused pyrrolocarbazoles or derivatives thereof. Particularly, the compositions of the present invention are non-aqueous and contain an amount of surfactant sufficient to make an fused pyrrolocarbazole or a derivative thereof particle-forming.
It is another object of the invention to provide a stable suspension that comprises suspended fused pyrrolocarbazole-containing particles that greatly improves bioavailability upon oral administration.
It is another object of the invention to provide a method of forming a stable suspension of fused pyrrolocarbazole-containing particles which comprises contacting the particle-forming compositions of the present invention with an aqueous medium.
It is another object of the invention to provide a method of treating a disease or disorder in a mammal which comprises administering a therapeutically effective amount of the particle-forming compositions of the present invention.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventor's discovery that fused pyrrolocarbazoles and derivatives thereof can be formulated with suitable concentrations of one or more surfactants to make a non-aqueous, particle-forming composition, wherein the composition spontaneously disperses into suspended particles upon contact with an aqueous medium.
DETAILED DESCRIPTION OF THE INVENTION
Thus, in a first embodiment, the present invention provides a non-aqueous, particle-forming composition comprising a fused pyrrolocarbazole and a surfactant. In a preferred embodiment, the fused pyrrolocarbazole has Formula I:
or a stereoisomer or pharmaceutically acceptable salt form hereof, wherein:
ring B and ring F, are independently selected from:
a) an unsaturated 6-membered carbocyclic aromatic ring in which from 1 to 3 carbon atoms may be replaced by nitrogen atoms;
b) an unsaturated 5-membered carbocyclic aromatic ring; and
c) an unsaturated 5-membered carbocyclic aromatic ring in which either:
1) one carbon atom is replaced with an oxygen, nitrogen, or sulfur;
2) two carbon atoms are replaced with a sulfur and a nitrogen, an oxygen and a nitrogen, or two nitrogens; or
3) three carbon atoms are replaced with three nitrogens;
G—X—W is selected from:
a) —(Z
1
Z
2
)C—N(R
1
)—C(Z
1
Z
2
)—;
b) —CH(R
1
)—C(═O)—N(R
1
)—; and
c) —N (R
1
)—C(═O)—CH(R)—;
Z
1
and Z
2
at each occurrence, are independently selected from H, H; H, OR; H, SR; H, N(R)
2
; and a group wherein Z
1
and Z
2
together form a moiety selected from ═O, ═S, and ═NR; with the proviso that at least one of the pairs Z
1
and Z
2
form ═O;
R is selected from H, substituted or unsubstituted alkyl having from 1 to 6 carbons, OH, alkoxy having from 1 to 4 carbons, OC(═O)R
1a
, OC(═O)NR
1c
R
1d
, O(CH
2
)
p
NR
1c
R
1d
, O(CH
2
)
p
OR
1b
, substituted or unsubstituted arylalkyl having from 6 to 10 carbons, and substituted or unsubstituted heteroarylalkyl;
R
1
is selected independently from:
a) H, substituted or unsubstituted alkyl having from 1 to 6 carbons, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;
b) C(═O)R
1a
;
c) OR
1b
;
d) C(═O)NHR
1b
, NR
1c
R
1d
, (CH
2
)
p
NR
1c
R
1
, (CH
2
)
p
OR
1b
, (CH
2
)
p
OR
1b
and O(CH
2
)
p
NR
1c
R
1d
;
R
1a
is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl and heteroaryl;
R
1b
is selected from H and substituted or unsubstituted alkyl having from 1 to 6 carbons;
R
1c
and R
1d
are each independently selected from H, substituted or unsubstituted alkyl having from 1 to 4 carbons, and a linking group of the formula —(CH
2
)
2
—X
1
—(CH
2
)
2
—;
X
1
is selected from —O—, —S—, and —CH
2
—;
R
2
selected from H, SO
2
R
2a
, CO
2
R
2a
, C(═O)R
2a
, C(═O)NR
2c
R
2d
, and alkyl of 1-8 carbons, alkenyl of 2-8 carbons, alkynyl of 2-8 carbons, wherein:
1) each alkyl, alkenyl, and alkynyl is unsubstituted; or
2) each alkyl, alkenyl, and alkynyl is substituted with 1-3 R
5
;
R
2a
selected from alkyl of 1 to 6 carbons, aryl, OR
2b
, CONH
2
, NR
2c
R
2d
, (CH
2
)
p
NR
2c
R
2d
, and O(CH
2
)
p
NR
2c
R
2d
;
R
2b
is selected from H and substituted or unsubstituted alkyl having from 1 to 6 carbons;
R
2c
and R
2d
are each independently selected from H, substituted or unsubstituted alkyl having from 1 to 6 carbons, and a linking group of the formula —(CH
2
)
2
—X
1
—(CH
2
)
2
—;
R
3
and R
4
, at each occurrence, are independently selected from:
a) H, aryl, heteroaryl, F, Cl, Br, I, CN, CF
3
, NO
2
, OH, OR
9
, O(CH
2
)
p
NR
11
R
12
, OC(═O)R
9
, OC(═O)NR
11
R
12
, O(CH
2
)
p
OR
10
, CH
2
OR
10
, NR
11
R
12
, NR
10
S(═O)
2
R
9
, and NR
10
C(═O)R
9
;
b) CH
2
OR
14
;
c) NR
10
C(═O)NR
11
R
12
, CO
2
R
10
, C(═O)R
9
, C(═O)NR
11
R
12
, CH═NOR
10
, CH═NR
10
, (CH
2
)
p
NR
11
R
12
, (CH
2
)
p
NHR
14
, and CH═NNR
11
R
12
;
d) S(O)
y
R
9
, (CH
2
)
p
S(O)
y
R
9
, CH
2
S(O)
y
R
14
;
e) alkyl having from 1 to 8 carbons, alkenyl having from 2 to 8 carbons, and alkynyl having 2 to 8 carbons, wherein
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl, or alkynyl group is substituted with 1 to 3 R
5
;
R
5
is selected from aryl having from 6 to 10 carbons, heteroaryl, arylalkoxy, heterocycloalkoxy, hydroxyalkoxy, a
Corvari Vincent
Dickason David A.
Herman Joseph L.
Patel Piyush R.
Shek Efraim
Cephalon Inc.
Shah Mukund J.
Sripada Pavanaram K
Woodcock Washburn Kurtz Mackiewicz & Norris LLP
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