Self-emulsifying formulation for lipophilic compounds

Details Self-emulsifying formulation for lipophilic compounds Self-emulsifying formulation for lipophilic compounds

1998-07-27

2003-03-11

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

C424S451000, C424S455000, C424S456000, C514S002600, C514S009100, C514S169000, C514S315000, C514S336000, C514S456000, C514S459000, C514S460000, C514S557000, C514S558000, C514S560000, C514S573000, C514S937000, C514S011400

Reexamination Certificate

active

06531139

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel pharmaceutical compositions in a form of a self-emulsifying formulation which provide high concentration and high oral bioavailability for lipophilic, pharmaceutically active agents.
BACKGROUND OF THE INVENTION
It has recently been discovered that certain pyranone compounds inhibit retroviral protease and thus they are useful for treating patients infected with human immunodeficiency virus (HIV) which results in acquired immunodeficiency syndrome (AIDS). In particular, the pyranone compound of formula I has been found to be especially effective as an inhibitor of retroviral protease.
However, like many other HIV protease inhibitors, these compounds are characteristically lipophilic and thus poorly water soluble. For example, the compound of formula I has an aqueous solubility about 1 &mgr;g/ml in the buffer of pH 6.5 (close to the pH of the intestine), which is considered as extremely poor aqueous solubility and would be expected to provide very low oral bioavailability in the free acid form. It is well known that an active drug substance or therapeutic moiety administered by any route must possess some aqueous solubility for systemic absorption and therapeutic response. Poorly water soluble compounds often exhibit either incomplete or erratic absorption and thus produce a minimal response at desired dosage.
Attempts were made to identify salts of the pyranone compounds in solid forms which could improve aqueous solubility. An overriding defect which has however remained is that the formulations in the form of salt are prone to precipitation of the parent free acid in the gastrointestinal tract and hence are not capable to provide a dosage in the desired high concentration to permit convenient use and yet meet the required criteria in terms of bioavailability.
Recognizing the problems, the present invention is directed toward pharmaceutical compositions in a form of self-emulsifying formulations which provide high concentration and high oral bioavailability for pyranone compounds. In particular it has been discovered that the compositions of the present invention allow the preparation of self-emulsifying formulations containing a pyranone inhibitor of retroviral protease in an exceedingly high concentration up to about 400 mg/g to permit convenient oral administration while at the same time achieving improved bioavailability, which is at least two fold higher than the aqueous suspension of the free acid.
It has also been discovered that the compositions of the present invention are applicable to the lipophilic compounds as defined in this invention.
INFORMATION DISCLOSURE
The International Publication No. WO 95/30670 discloses pyranone compounds useful to treat retroviral infections.
The International Publication No. WO 96/39142 discloses compositions which increase the bioavailability of protease inhibitors.
UK Patent Application, GB 2,222,770A discloses pharmaceutical compositions comprising a cyclosporin in microemulsion pre-concentrate and microemulsion form.
UK Patent Application, GB 2,228,198A discloses pharmaceutical compositions comprising a cyclosporin as active ingredient, a fatty acid triglyceride, a glycerol fatty acid partial ester or propylene glycol or sorbitol complete or partial ester and a tenside having an HLB of at least 10.
UK Patent, GB 2,257,359B discloses pharmaceutical compositions suitable for oral administration comprising a cyclosporin, 1,2-propylene glycol, a mixed mono-, di-, and tri-glyceride and a hydrophilic surfactant.
U.S. Pat. No. 4,230,702 discloses a readily enterally absorbable pharmaceutical composition of pharmacologically active agents, which per se are poorly enterally absorbable.
SUMMARY OF THE INVENTION
One object of the present invention is to provide a pharmaceutical composition comprising a lipophilic, pharmaceutically active agent which possesses high oral bioavailability.
A further object of the present invention is to provide a pharmaceutical composition containing a high drug load of a lipophilic, pharmaceutically active agent for convenient administration.
Another object of the present invention is to provide pharmaceutical compositions which exhibit adequate physical and chemical stability in a self-emulsifying formulation.
Still another object of the present invention is to provide a liquid composition for soft elastic capsules.
The objects of the present invention have been accomplished in that the present invention provides pharmaceutical compositions in a self-emulsifying formulation which allow a high loading of lipophilic compounds (up to about 400 mg/g) while at the same time achieving good oral bioavailability.
The present invention specifically provides a pharmaceutical composition based on the use of a particular oil phase which comprises:
(a) a lipophilic, pharmaceutically active agent,
(b) a mixture of diglyceride and monoglyceride in a ratio of from about 9:1 to about 6:4 by weight (diglyceride:monoglyceride) wherein the diglyceride and monoglyceride are mono- or di- unsaturated fatty acid esters of glycerol having sixteen to twenty-two carbon chain length,
(c) one or more pharmaceutically acceptable solvents, and
(d) one or more pharmaceutically acceptable surfactants.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there are pharmaceutical compositions comprising a pyranone compound as a pharmaceutically active agent in a self-emulsifying formulation vehicle.
For the purpose of the present invention, the term “pyranone compounds” refers to compounds of formula II
wherein R
1
is H—; R
2
is C
3
-C
5
alkyl, phenyl-(CH
2
)
2
—, het-SO
2
NH—(CH
2
)
2
—, cyclopropyl-(CH
2
)
2
—, F-phenyl-(CH
2
)
2
—, het-SO
2
NH-phenyl-, or F
3
C—(CH
2
)
2
—; or R
1
and R
2
taken together are a double bond; R
3
is R
4
—(CH
2
)
n
—CH(R
5
)—, H
3
C—[O(CH
2
)
2
]
2
—CH
2
—, C
3
-C
5
alkyl, phenyl-(CH
2
)
2
—, het-SO
2
NH—(CH
2
)
2
—, (HOCH
2
)
3
C—NH—C(O)—NH—(CH
2
)
3
—, (HO
2
C)(H
2
N)CH—(CH
2
)
2
—C(O)—NH—(CH
2
)
3
—, piperazin-1-yl-C(O)—NH—(CH
2
)
3
, HO
3
S(CH
2
)
2
—N(CH
3
)—C(O)—(CH
2
)
6
—C(O)—NH—(CH
2
)
3
—, cyclopropyl-(CH
2
)
2
—, F-phenyl-(CH
2
)
2
—, het-SO
2
NH-phenyl, or F
3
C—(CH
2
)
2
—; n is 0, 1 or 2; R
4
is phenyl, het, cyclopropyl, H
3
C—[O(CH
2
)
2
]
2
—, het-SO
2
NH—, Br—, N
3
—, or HO
3
S(CH
2
)
2
—N(CH
3
)—C(O)—(CH
2
)
6
—(O)—NH—; R
5
is —CH
2
—CH
3
, or —CH
2
-cyclopropyl; R
6
is cyclopropyl, CH
3
-CH
2
—, or t-butyl; R
7
is —NR
8
SO
2
-het, —NR
8
SO
2
-phenyl, optionally substituted with R
9
, —CH
2
—SO
2
-phenyl, optionally substituted with R
9
, or —CH
2
—SO
2
-het; R
8
is —H, or —CH
3
; R
9
is —CN, —F, —OH, or —NO
2
; wherein het is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle, optionally substituted with —CH
3
, —CN, —OH, —C(O)OC
2
H
5
, —CF
3
, —NH
2
, or —C(O)—NH
2
; or a pharmaceutically acceptable salt thereof. The preferred compound of formula II is a compound of formula I.
The term “pyranone compounds” also refers to compounds of formula III and formula IV
wherein R
10
is H—, CH
3
O—, or CH
3
O—[(CH
2
)
2
O]
3
—; R
11
is cyclopropyl, or —CH
2
—CH(CH
3
)
2
; R
12
is —NR
14
SO
2
-phenyl, optionally substituted with R
15
, —NR
14
SO
2
-het, —CH
2
—SO
2
-phenyl, optionally substituted with R
15
, or —CH
2
—SO
2
-het; R
13
is —H, —(CH
2
)
2
—CH
3
, —CH
2
-cyclopropyl, or —CH
2
-phenyl; R
14
is —H, or —CH
3
; R
15
is —CN, —F, —CH
3
, —COOH, or —OH; het is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle; optionally substituted with one or two —CH
3
, —CN, —C(O)OC
2
H
5
, or —OH; or a ph

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