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US 6,555,558 B2Granted
Oral dosage self-emulsifying formulations of pyranone protease inhibitors
AssigneeBoehringer Ingelheim Pharmaceuticals, Inc.
InventorsShirlynn Chen, Jocelyn A. Gunn
Life of this patent
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Abstract
A microemulsion of pyranone protease inhibitor compounds that is substantially free of alcohol and propylene glycol comprising a pyranone protease inhibitor, one or more pharmaceutically acceptable surfactants, and a polyethylene glycol solvent having a mean molecular weight of greater than 300 but lower than 600, and a lipophilic component comprising medium chain mono- and di-glycerides, and optionally a basic amine.
Claims37
A pharmaceutical composition substantially free of alcohol and propylene glycol comprising:
- (a) a pyranone compound of Formula I as a pharmaceutically active agent,
- wherein R1 is H—;
- R2 is C3-C5 alkyl, phenyl-(CH2)2—, het-SO2NH—(CH2)2—, cyclopropyl-(CH2)2—, F-phenyl-(CH2)2—, het-SO2NH-phenyl-, or F3C—(CH2)2—;
- or R1 and R2 taken together are a double bond;
- R3 is R4—(CH2)n—CH(R5)—, H3C—[O(CH2)2]2—CH2—, C3-C5 alkyl, phenyl-(CH2)2—, het-SO2NH—(CH2)2—, (HOCH2)3C—NH—C(O)—NH—(CH2)3—, (HO2C)(H2N)CH—(CH2)2—C(O)—NH—(CH2)3—, piperazin-1-yl-C(O)—NH—(CH2)3, HO3S(CH2)2—N(CH3)—C(O)—(CH2)6—C(O)—NH—(CH2)3—, cyclopropyl-(CH2)2—, F-phenyl-(CH2)2—, het-SO2 NH-phenyl, or F3C—(CH2)2—;
- n is 0, 1 or 2;
- R4 is phenyl, het, cyclopropyl, H3C—[O(CH2)2]2—, het-SO2NH—, Br—, N3—, or HO3S(CH2)2—N(CH3)—C(O)—(CH2)6—C(O)—NH—;
- R5 is —CH2—CH3, or —CH2-cyclopropyl;
- R6 is cyclopropyl, CH3—CH2—, or t-butyl;
- R7 is —NR8SO2-het, —NR8SO2-phenyl, optionally substituted with R9,—CH2—SO2-phenyl, optionally substituted with R9, or —CH2—SO2-het;
- R8 is —H, or —CH3;
- R9 is —CN, —F, —OH, or —NO2;
- 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 —CH3, —CN, —OH, —C(O)OC2H5, —CF3, —NH2, or —C(O)—NH2;
- or a pharmaceutically acceptable salt thereof;
- (b) one or more pharmaceutically acceptable surfactants;
- and
- (c) a polyethylene glycol solvent having a mean molecular weight of greater than 300 but lower than 600.
15 more elements
A pharmaceutical composition substantially free of alcohol and propylene glycol comprising:
- (a) a pyranone compound of Formula II or III as a pharmaceutically active agent,
- wherein R10 is H—, CH3O—, or CH3O—[(CH2)2O]3—;
- R11 is cyclopropyl, or —CH2—CH(CH3)2;
- R12 is —NR14SO2-phenyl, optionally substituted with R15,—NR14SO2-het, —CH2—SO2-phenyl, optionally substituted with R15, or —CH2—SO2-het;
- R13 is —H, —(CH2)2—CH3, —CH2-cycloproryl, or —CH2-phenyl;
- R14 is —H, or —CH3;
- R15 is —CN, —F, —CH3, —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 —CH3, —CN, —C(O)OC2H5, or —OH;
- or a pharmaceutically acceptable salt thereof;
- (b) one or more pharmaceutically acceptable surfactants;
- and
- (c) a polyethylene glycol solvent having a mean molecular weight of greater than 300 but lower than 600.
11 more elements
A substantially alcohol and propylene glycol free pharmaceutical pharmaceutical composition comprising:
- (a) a pyranone compound of Formula IV
- in an amount from about 1% to about 40% by weight of the total composition;
- (b) a lipophilic phase comprising from about 5% to about 35% by weight of the total composition;
- (c) polyethylene glycol having a mean molecular weight of greater than about 300 but less than about 600 in an amount from about 10% to about 40% by weight of the total composition;
- (d) a surfactant selected from the group comprising:
- a polyoxyl castor oil, a polyoxyethylene glycerol triricinoleate, and a saturated polyglycolyzed caprylic-capric glyceride, in an amount from about 20 to about 60 percent by weight of the total composition;
- and
- (e) a basic amine selected from the group comprising:
- a lower alkylamine, basic amino acid, or choline hydroxide, said basic amine in an amount from about 0.1% to about 10% by weight of the total composition.
6 more elements
A substantially alcohol and propylene glycol free pharmaceutical composition comprising:
- (a) a pyranone compound of Formula IV
- in an amount from about 1% to about 40% by weight of the total composition;
- (b) a lipophilic phase selected from the group consisting of:
- Capmul MCM, Labrafil M-1944 CS and Myglol-812 and a combination thereof, said lipophilic phase in an amount from about 5% to about 35% by weight of the total composition;
- (c) polyethylene glycol having a mean molecular weight of greater than about 300 but less than about 600 in an amount from about 10% to about 40% by weight of the total composition;
- (d) a surfactant selected from the group comprising:
- a polyoxyl castor oil, a polyoxyethylene glycerol triricinoleate, and a saturated polyglycolyzed caprylic-capric glyceride, in an amount from about 20% to about 60% by weight of the total composition.
4 more elements
Dependencies are inferred from the claim text.