MXPA00000996A - Self-emulsifying formulation for lipophilic compounds - Google Patents
Self-emulsifying formulation for lipophilic compoundsInfo
- Publication number
- MXPA00000996A MXPA00000996A MXPA/A/2000/000996A MXPA00000996A MXPA00000996A MX PA00000996 A MXPA00000996 A MX PA00000996A MX PA00000996 A MXPA00000996 A MX PA00000996A MX PA00000996 A MXPA00000996 A MX PA00000996A
- Authority
- MX
- Mexico
- Prior art keywords
- pharmaceutical composition
- weight
- composition according
- amount
- diglyceride
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 121
- 238000009472 formulation Methods 0.000 title claims abstract description 14
- 150000002634 lipophilic molecules Chemical class 0.000 title 1
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 49
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical compound OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 claims abstract description 37
- -1 pyranone compound Chemical class 0.000 claims abstract description 37
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 239000008180 pharmaceutical surfactant Substances 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 23
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical group CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 15
- 229940074096 monoolein Drugs 0.000 claims description 15
- 239000004094 surface-active agent Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 12
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 10
- 239000008389 polyethoxylated castor oil Substances 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- XLMXUUQMSMKFMH-UZRURVBFSA-N 2-hydroxyethyl (Z,12R)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(=O)OCCO XLMXUUQMSMKFMH-UZRURVBFSA-N 0.000 claims description 8
- 229920002690 Polyoxyl 40 HydrogenatedCastorOil Polymers 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 239000004530 micro-emulsion Substances 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 6
- 239000004359 castor oil Substances 0.000 claims description 6
- 235000019438 castor oil Nutrition 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 5
- 229960002887 Deanol Drugs 0.000 claims description 5
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 claims description 5
- 229920002675 Polyoxyl Polymers 0.000 claims description 5
- 239000000839 emulsion Substances 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 150000003973 alkyl amines Chemical class 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000005456 glyceride group Chemical group 0.000 claims description 4
- 125000005842 heteroatoms Chemical group 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Chemical group 0.000 claims description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 229910052717 sulfur Chemical group 0.000 claims description 4
- 239000011593 sulfur Chemical group 0.000 claims description 4
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 3
- 229940068965 Polysorbates Drugs 0.000 claims description 3
- 150000001413 amino acids Chemical class 0.000 claims description 3
- 230000001804 emulsifying Effects 0.000 claims description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical group NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 3
- 229920001983 poloxamer Polymers 0.000 claims description 3
- 229920000136 polysorbate Polymers 0.000 claims description 3
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3S,3aR,6R,6aR)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- CTPDSKVQLSDPLC-UHFFFAOYSA-N 2-(oxolan-2-ylmethoxy)ethanol Chemical compound OCCOCC1CCCO1 CTPDSKVQLSDPLC-UHFFFAOYSA-N 0.000 claims description 2
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 claims description 2
- 239000004475 Arginine Substances 0.000 claims description 2
- 229940075419 Choline Hydroxide Drugs 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- UJTMLNARSPORHR-UHFFFAOYSA-N OC2H5 Chemical compound C=C=[O+] UJTMLNARSPORHR-UHFFFAOYSA-N 0.000 claims description 2
- 229960000502 Poloxamer Drugs 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229920001451 Polypropylene glycol Polymers 0.000 claims description 2
- RUOJZAUFBMNUDX-UHFFFAOYSA-N Propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 claims description 2
- 229920001304 Solutol HS 15 Polymers 0.000 claims description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N Triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 2
- 229960002622 Triacetin Drugs 0.000 claims description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229940113088 dimethylacetamide Drugs 0.000 claims description 2
- 239000001087 glyceryl triacetate Substances 0.000 claims description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 229920002696 Polyoxyl 40 castor oil Polymers 0.000 claims 1
- 230000035536 Oral bioavailability Effects 0.000 abstract description 12
- 230000036220 oral bioavailability Effects 0.000 abstract description 12
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2-Pyrone Chemical class O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 abstract description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 9
- 230000035533 AUC Effects 0.000 description 7
- 230000001177 retroviral Effects 0.000 description 7
- 210000004369 Blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 6
- 230000036912 Bioavailability Effects 0.000 description 5
- 230000035514 bioavailability Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drugs Drugs 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 4
- 150000003626 triacylglycerols Chemical class 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- PMATZTZNYRCHOR-CGLBZJNRSA-N (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17 Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 description 3
- 108010036949 Cyclosporine Proteins 0.000 description 3
- 102000033147 ERVK-25 Human genes 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- 108091005771 Peptidases Proteins 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 230000035493 absolute bioavailability Effects 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- 229940042399 direct acting antivirals Protease inhibitors Drugs 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000035489 relative bioavailability Effects 0.000 description 3
- 230000036868 Blood Concentration Effects 0.000 description 2
- 206010038997 Retroviral infection Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000011068 load Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000005721 HIV Infections Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020460 Human T-cell lymphotropic virus type I infection Diseases 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- 241000714259 Human T-lymphotropic virus 2 Species 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 210000000936 Intestines Anatomy 0.000 description 1
- 210000004731 Jugular Veins Anatomy 0.000 description 1
- 229940093448 POLOXAMER 124 Drugs 0.000 description 1
- 210000002381 Plasma Anatomy 0.000 description 1
- 229920002507 Poloxamer 124 Polymers 0.000 description 1
- 229940044519 Poloxamer 188 Drugs 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229940068977 Polysorbate 20 Drugs 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 229940068968 Polysorbate 80 Drugs 0.000 description 1
- 210000002966 Serum Anatomy 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- 208000000389 T-Cell Leukemia Diseases 0.000 description 1
- 210000002620 Vena Cava, Superior Anatomy 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 229940027983 antiseptics and disinfectants Quaternary ammonium compounds Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
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- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
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Abstract
The present invention provides a novel pharmaceutical composition based on the use of a particular oil phase which comprises a pyranone compound as a pharmaceutically active agent, a mixture of diglyceride and monoglyceride in a ratio of from about 9:1 to about 6:4 (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, one or more pharmaceutically acceptable solvents, and one or more pharmaceutically acceptable surfactants. The composition is in a form of a self-emulsifying formulation which provides high concentration and high oral bioavailability for lipophilic pyranone compounds.
Description
PHARMACEUTICAL COMPOSITION IN THE FORM OF SELF EMULSING FORMULATION FOR LIPOFILIC COMPOUNDS
FIELD OF THE INVENTION The present invention relates to new pharmaceutical compositions in the form of a self-emulsifying formulation that provides high concentration and high oral bioavailability of pyranone compounds that are retroviral protease inhibitors.
BACKGROUND OF THE INVENTION It has recently been discovered that certain pyranone compounds inhibit retroviral protease and thus are useful for treating patients infected with the human immunodeficiency virus (HIV) which results in the acquired immunodeficiency syndrome (AIDS). In particular, it has been found that the pyranone compound of formula I is especially effective as a retroviral protease inhibitor.
However, like many other protease inhibitors, these compounds are characteristically lipophilic and thus poorly soluble in water. For example, the compound of formula I has a solubility in water of about 1 μg / ml in the buffer of pH 6.5 (close to the pH of the intestine), which is considered as an extremely low solubility in water and would be expected to provide bioavailability very low oral in the form of free acid. It is well known that an active drug substance or a therapeutic portion administered by any route should have some solubility in water for systemic absorption and therapeutic response. The poorly soluble compounds in water often exhibit either incomplete or erratic absorption and thus produce a minimal response at the desired dose. Attempts were made to identify salts of the pyranone compounds in solid forms that could improve water solubility. However, an essential defect that has remained is that the formulations in salt form are prone to precipitation of the free acid precursor in the gastrointestinal tract and therefore do not have the ability to provide a dose in the desired high concentration that allows the use convenient and still meets the criteria required in terms of bioavailability. Recognizing the problems, the present invention is directed towards pharmaceutical compositions in the form of self-emulsifying formulations that 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-like inhibitor of retroviral protease at an extremely high concentration up to about 400 mg / g which allows convenient oral administration while at At the same time, improved bioavailability is achieved, which is at least twice as high as that of the aqueous suspension of the free acid.
INFORMATION REVEIATION International Publication No. WO 95/30670 discloses useful pyranone compounds for treating retroviral infections. International Publication No. WO 96/39142 discloses compositions that increase the bioavailability of protease inhibitors. The United Kingdom Patent Application, GB
2,222,770A discloses pharmaceutical compositions comprising a cyclosporin in the form of a microemulsion and
P961 pre-concentrated microemulsion. UK Patent Application GB 2,228,198A discloses pharmaceutical compositions comprising a cyclosporin as active ingredient, a triglyceride of fatty acid, a partial ester of glycerol and fatty acid or partial or complete ester of propylene glycol or sorbitol and a surfactant which it has a BHL of at least 10. The United Kingdom Patent, GB 2, 257, 359B discloses pharmaceutical compositions suitable for oral administration comprising a cyclosporin, 1,2-propylene glycol, a mixture of mono-, di- and tri glyceride and a hydrophilic surfactant. U.S. Patent No. 4,230,702 discloses enterally readily absorbable pharmaceutical compositions of pharmacologically active agents, which by themselves are poorly absorbable enterally.
SUMMARY OF THE INVENTION An object of the present invention is to provide a pharmaceutical composition comprising a pyranone-like compound of formulas I, II, III or IV having high oral bioavailability. Another object of the present invention is to provide a pharmaceutical composition containing a
P961 high drug loading of a pyranone compound of formulas I, II, III or IV for convenient administration. Another object of the present invention is to provide pharmaceutical compositions that exhibit adequate physical and chemical stability in self-emulsifying formulations. 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 achieved in that the present invention provides pharmaceutical compositions in the form of self-emulsifying formulations which allow a high load of pyranone compounds (up to about 400 mg / g) while at the same time achieving good oral bioavailability. The present invention specifically provides a pharmaceutical composition that is based on the use of a particular oil phase comprising: (a) a pyranone compound of formula I, II, III or IV, (b) a mixture of diglyceride and monoglyceride in a proportion from about 9: 1 to 6: 4 by weight (diglyceride: monoglyceride) wherein the diglyceride and the monoglyceride are mono- or diesters of glycerol unsaturated fatty acids having a chain length of between sixteen and twenty-two carbon atoms, (c) one or more pharmaceutically acceptable solvents, and (d) one or more pharmaceutically acceptable surfactants.
DETAILED DESCRIPTION OF THE INVENTION According to the present invention, there are pharmaceutical compositions comprising a pyranone compound as a pharmaceutically active agent in a vehicle of self-emulsifying formulation. For the purpose of the present invention, the term "pyranone compounds" refers to compounds of formula II
p where Rx is H-; , is C3-C5 alkyl, f-enyl- (CH2) 2-, het-S02NH- (CH2) 2-, cyclopropyl- (CH2) _-, Ff enyl- (CH2) 2-, het-S02NH-phenyl- F3C- (CH2) 2-; or R ± and R2 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-S02NH- (CH2) 2 -, (HOCH2) 3C-NH-C (0) -NH- (CH2) 3-, (H02C) (H2N) CH- (CH2) 2-C (0) -NH (CH2) 3-, piperazin-1 -il-C (O) -NH- (CH2) ,, H03S (CH2) 2-N (CH3) -C (O) - (CH2) 6-C (O) -NH- (CH2) 3-, cyclopropyl - (CH2) 2-, F-phenyl- (CH2) 2, het-S02NH-phenyl or F3C- (CH2) 2-; n is 0, 1 or 2; R4 is phenyl, het, cyclopropyl, H3C- [0 (CH2) 2] 2-, het-S02NH-, Br-, N3-, or H03S (CH2) 2-N (CH3) -C (O) - (CH2 ) 6-C (0) NH-; R5 is -CH2-CH3 or -CH2-cyclopropyl; R6 is cyclopropyl, CH3-CH2- or t-butyl; R7 is -NR8S02-het, -NR8S02-phenyl, optionally substituted with R9 or -CH2-S02-phenyl, optionally substituted with R ^ or -CH2-S02-het; R8 is -H or -CH3; R9 is -CN, -F, -OH or N02; wherein het is a saturated or unsaturated 5-, 6- or 7-membered ring containing between one and three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and including any bicyclic group in which any of the heterocyclic rings above is fused to a benzene ring or other heterocycle, optionally substituted with -CH3, -CN, -OH, -C (0) OC2H6, -CF3, -NH2 or -C (0) -NH2 or a pharmaceutically acceptable salt of the same. 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
ni IV
wherein R10 is H-, CH30- or CH30- [(CH2) 20] 3-; Ru is cyclopropyl or -CH 2 -CH (CH 3) 2; R12 is -NR14S02-phenyl, optionally substituted with R15, -NR14S02-het, -CH2-S02-phenyl, optionally substituted with R15 or -CH2-S02-het; R 13 is -H, - (CH 2) 2 -CH 3, -CH 2 -cyclopropyl or -CH 2 -phenyl; R 14 is -H or -CH 3; R15 is -CN, -F, -CH3, -COOH or -OH; het is a saturated or unsaturated 5-, 6- or 7-membered ring containing between one and 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 with a benzene ring or another heterocycle; optionally substituted with one or two -CH3, -CN, -C (0) OC2H5 or -OH; or a pharmaceutically acceptable salt thereof. These compounds inhibit the retroviral protease and thus inhibit the replication of the virus. They are useful for treating patients infected with human retroviruses, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia virus (HTLV-I or HTLV-II) which result in the syndrome of acquired immunodeficiency (AIDS) and / or related diseases. The compounds of formulas I, II, III and IV are disclosed and claimed in International Application No. PCT / US95 / 05219, which is considered part of this, as a reference and may be prepared according to the procedures described in International Publication No. WO 95/30670. In particular, it has been found that the pyranone compound of formula I is especially effective as a retroviral protease inhibitor. In the sense in which the term "self emulsifying formulation" is used herein, it refers to a concentrated composition that has the ability to generate emulsions or microemulsions when mixed with sufficient aqueous medium. The emulsions or microemulsions generated from the present invention are conventional solutions comprising a hydrophilic phase and a lipophilic phase. Microemulsions are also characterized by thermodynamic stability, optical transparency and small average particle size, usually less than about 0.15 microns. In the sense in which the term "self-emulsifying formulation vehicle" is used herein refers to a composition comprising a mixture of diglyceride and monoglyceride in a ratio of approximately 9: 1 to 6: 4 by weight (diglyceride : monoglyceride) wherein the diglyceride and the monoglyceride are esters of mono- or di-unsaturated glycerol fatty acids having a chain length of between sixteen and twenty-two carbon atoms, one or more pharmaceutically acceptable solvents and one or more surfactants pharmaceutically acceptable Optionally, the self-emulsifying formulation vehicle may further comprise a basic amine. The diglyceride of the present invention refers to a glycerol fatty acid ester having structural formula H0CH2-CH (02CR) -CH2 (02CR) or (RC02) CH2-CH (OH) -CH (02CR), wherein R is a monounsaturated or diunsaturated alkyl group having between fifteen and twenty-one carbon atoms. The preferred diglyceride is diolein (R is monounsaturated alkyl group with seventeen carbon atoms), dilinoleate (R is diunsaturated alkyl group with seventeen carbon atoms) or a mixture of diolein and dilinoleate. The most preferred diglyceride is diolein. The monoglyceride of the present invention refers to a glycerol fatty acid ester having the structural formula H0CH2-CH (OH) -CH2 (02CR) or H0CH2-CH (02CR) -CH20H, wherein R is a mono-unsaturated alkyl group or diunsaturated that has between fifteen and twenty one carbon atoms. The preferred monoglyceride is monoolein (R is a monounsaturated alkyl group with seventeen carbon atoms), monolinoleate (R is a diunsaturated alkyl group with seventeen carbon atoms) or a mixture of monoolein and monolinoleate. The most preferred monoglyceride is monoolein. The mixture of diglyceride and monoglyceride can be prepared by mixing individual diglyceride and monoglyceride in suitable relative proportion or by partial hydrolysis of triglyceride or by transesterification reaction of triglycerides diglycerides with glycerol. All glycerides of the present invention are known and can be prepared by conventional methods. The amount of active ingredient in the composition may vary or adjust depending on the planned route of administration, the potency of the particular active ingredient to be used, the severity of the retroviral infection and the concentration required. However, if desired, a pyranone compound such as a retroviral protease inhibitor may be present in the self emulsifying formulation vehicle of the present invention in an amount of up to about 400 mg / g with excellent ease of
P961 dispersion and high oral bioavailability in vivo, usually achieving 70 to 84% in rats. The compositions of the present invention with high oral bioavailability (84% in rats) show an almost transparent or translucent solution when diluted with water, which indicates that a microemulsion is formed. The compositions of the present invention with moderately high bioavailability (from 60 to 70% in rats) usually show a visible fine white emulsion without precipitation of the drug when diluted with water, indicating that an emulsion is formed. In one aspect, the present invention specifically provides a pharmaceutical composition based on the use of a particular oil phase comprising: (a) a pyranone compound of formulas I, II, III or IV as a pharmaceutically active agent, (b) a mixture of diglyceride and monoglyceride in a ratio of approximately between 9: 1 and 6: 4 by weight (diglyceride: monoglyceride) wherein the diglyceride and the monoglyceride are esters of mono- or di-unsaturated glycerol fatty acids having a chain length of between sixteen and twenty-two carbon atoms, (c) one or more pharmaceutically acceptable solvents and
P961 (d) one or more pharmaceutically acceptable surfactants. In addition, the composition may also comprise a pharmaceutically acceptable basic amine. In the sense in which the term "pharmaceutically acceptable" is used herein refers to those properties that are biologically compatible with the treated subjects from a pharmacological and toxicological point of view. The solvents of the present invention relate to propylene glycol, polypropylene glycol, polyethylene glycol (such as PEG300, 400, 600, etc.), glycerol, ethanol, triacetin, dimethyl isosorbide, glycofurol, propylene carbonate, water, dimethyl acetamide or a mix of them. The preferred solvent is propylene glycol or a mixture comprising propylene glycol and ethanol 95% Jv / v) (hereinafter ethanol). In the mixture of propylene glycol and ethanol, the propylene glycol is in an amount of approximately between 50% and 95%. The surfactants of the present invention relate to nonionic surfactants including hydrogenated castor oil Polyoxyl 40 marketed under the tradename Cremophor RH40; Polyoxyl 35 castor oil marketed under the name
P961 commercial, among others, Cremophor EL or Cremophor EL-P;
Polysorbates; Solutol HS-15; Tagat TO; Peglycol-6-oleate;
Polyoxyethylene stearates; Polyglycolized glycerides
Saturated or the so-called Poloxamer; of which all are commercially available. The preferred surfactant is Cremophor RH40 or Cremophor EL. Saturated Polyglycolized Glycerides used in the present include Gelucire 44/14 or Gelucire
50/13. The polyoxyethylene stearates used herein include Poloxyl 6 stearate, Poloxyl 8 stearate,
Poloxyl 12 stearate and Poloxyl 20 stearate. The Poloxamers used herein include
Poloxamer 124 and Poloxamer 188. The Polysorbates used herein include Polysorbate 20, Polysorbate 40, Polysorbate 60 and
Polysorbate 80. As used herein, the term "basic amine" refers to lower alkylamines such as, for example, ethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, tris (hydroxymethyl) aminomethane or ethylenediamine; quaternary ammonium compounds such as, for example, choline hydroxide; basic amino acids such as, for example, arginine, lysine or guanidine. The lower alkylamine that is preferred
P961 is dimethylaminoethanol or tris (hydroxymethyl) aminomethane. A typical composition of the invention comprises:
(a) a pyranone compound of formulas I, II, III or IV in an amount of approximately between 1% and 40% by weight of the total composition, (b) a mixture of diglyceride and monoglyceride in a ratio of approximately between 9: 1 and 6: 4 by weight (diglyceride: monoglyceride) wherein the diglyceride and monoglyceride are esters of mono- or di-unsaturated fatty acids of glycerol having a chain length of between sixteen and twenty-two carbon atoms in an amount of approximately between 5% and 35% by weight of the total composition, (c) one or more pharmaceutically acceptable solvents in an amount of approximately between 10% and 30% by weight of the total composition and (d) a pharmaceutically acceptable surfactant in an amount of approximately between 10% and 50% by weight of the total composition. Optionally, the composition above also comprises a basic amine in an amount of between about 0.1% and 10% by weight of the total composition. A preferred composition of the invention comprises:
P961 (a) a pyranone compound of formulas I, II, III or IV in an amount of approximately between 20% and 30% by weight of the total composition, (b) a mixture of diolein and monoolein in a ratio of approximately 9: 1 in weight
(diolein: monoolein) in an amount of about 5% to 20% by weight of the total composition, (c) a solvent comprising propylene glycol or a mixture of propylene glycol and ethanol in an amount of about 15% to 25%. % by weight of the total composition and (d) a surfactant comprising Cremophor RH40 or Cremophor EL in an amount of approximately between 30% and 45% by weight of the total composition. Another preferred composition of the invention comprises: (a) a pyranone compound of formulas I, II, III or IV in an amount of about 20% to 30% by weight of the total composition, (b) a mixture of diolein and monoolein in a ratio of approximately 8: 2 by weight
(diolein: monoolein) in an amount of approximately between 5% and 20% by weight of the total composition,
P961 (c) a solvent comprising propylene glycol or a mixture of propylene glycol and ethanol in an amount of approximately between 15% and 25% by weight of the total composition and (d) a surfactant comprising Cremophor RH40 or Cremophor EL in a amount of about 30% to 45% by weight of the total composition. Optionally, the preferred compositions may further comprise a basic amine in an amount of between about 0.1% and 7% by weight of the total composition. In the preferred compositions of the present invention, an even more preferred composition comprises a pyranone compound of formula I in an amount of about 20% to 30% by weight of the total composition. In the preferred compositions of the present invention, the mixture of propylene glycol and ethanol is in a ratio of about 1: 1. In the preferred compositions of the present invention, an even more preferred composition comprises tris (hydroxymethyl) aminomethane or dimethylaminoethanol in an amount of between about 0.1% and 7% by weight of the total composition. In the preferred compositions of the present
P961 invention, an even more preferred composition comprises a mixture of diolein and monoolein in a proportion of about 8: 2 by weight. In particular, the most preferred composition of the present invention comprises the pyranone compound of formula I. The composition of the present invention may be in the form of a liquid for soft elastic capsules or hard gelatin capsules for oral application. The composition may also be in the form of a liquid solution for oral, parenteral, rectal or topical application. The preferred dosage form is in the form of a liquid for soft elastic capsules. If desired, the compositions of the present invention may further comprise conventional pharmaceutical additives such as co-surfactants (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, fragrances, preservatives, stabilizers, antioxidants and / or thickening agents. The compositions of the present invention may be prepared in a conventional manner, for example, by dissolving an active agent in the solvent, then adding the oil phase, the surfactant and optionally the basic amine. The resulting solution is then formulated in the desired dosage form as for example,
P961 soft elastic capsules or hard gelatin capsules using the known manufacturing technology. The pharmaceutical compositions of the present invention will be better understood by considering the following examples, which are projected as an illustration of the scope of the invention and not as a limitation thereof. Without further explanation, it is considered that one skilled in the art, using the foregoing description and the information provided in the examples below, puts the present invention into practice to its fullest expression.
A. General Procedure for Preparing the Compositions of the Present Invention. The drug is placed in a container. A solvent comprising propylene glycol or a mixture of solvents selected from ethanol is added
(95%) and propylene glycol (1: 1 by weight) and the lid closes.
The container is placed in a water bath at about 60 ° C and stirred gently until all the pharmaceutical material dissolves. After the vessel is cooled to room temperature, appropriate amounts of a mixture of diglyceride (such as diolein) and monoglyceride (such as monoolein), a surfactant (such as Cremophor RH40 or Cremophor EL) and optionally an amine are added thereto.
Basic P961 (such as ethanolamine or diethanolamine). The container is sealed and placed in a water bath at about 60 ° C and stirred gently until a clear solution is formed. The container is normally left at ambient conditions for future use.
EXAMPLE 1
EXAMPLE 2
P961 EXAMPLE 3 EXAMPLE 4 EXAMPLE 5 P961 EXAMPLE 6 EXAMPLE 7 EXAMPLE 8 P961 EXAMPLE 9 EXAMPLE 10 EXAMPLE 11 P961 EXAMPLE 12 EXAMPLE 13 EXAMPLE 14
P961 EXAMPLE 15 EXAMPLE 16
EXAMPLE 17 P961 EXAMPLE 18 EXAMPLE 19 EXAMPLE 20
P961 B. Oral Bioavailability Test (i) Sprague-Dawley rats were selected for oral bioavailability study in vivo. Each rat was prepared by surgically implanting a cannula to stay in the superior vena cava. Each rat, in the weight range between 300 and 400 g, was fasted overnight before dosing. Each formulation was administered orally to a group of rats (n = 3) at a dose of 20 mg / kg. Formulations with high concentration of the compound of formula I (usually 200-300 mg / g) were diluted 100 times with water and injected directly into the rat's stomach using oral gavage. Blood samples of 0.25 ml were obtained serially from the permanent cannula at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after dosing. These blood samples were analyzed using a HPLC test specific for the compound of formula I. The concentrations of the drug in the blood of the test rats were plotted against the time after the drug was administered intravenously (iv) or orally. and the AUCs (Under the Plasma Concentration-Time Cjurve Area) were integrated using the trapezoidal rule to calculate absolute bioavailability as shown in Table 1.
P961 (AUC) oral / Oral DOSE Absolute bioavailability (F) = (AUC), »/ Dosage v
(ii) Male Beagle dogs were also selected for the oral bioavailability study in vivo. Each dog, in the weight range between 13.5 and 17.5 kg was fasted during the night before dosing. Each formulation was administered orally to a group of dogs (n = 4) at a dose of 20 mg / kg. The high concentration formulation of the compound of formula I (300 mg / g) was encapsulated in gelatin capsules and administered. Blood samples of 2 ml were obtained in series from the jugular vein at 20, 40 minutes and 1, 2, 4, 6, 8, 12 and 24 hours after dosing. These blood samples were analyzed using a HPLC test specific for the compound of formula I. The blood concentrations of the compound of formula I are plotted against time and the AUCs are obtained to calculate the absolute bioavailability. The results are shown in Table 2. (üi) Ten healthy volunteers were orally administered eight doses of 150 mg (single dose of 1200 mg) of disodium salt of compound of formula I encapsulated in hard gelatine capsules as a reference . Weeks later, the same group was administered by
P961 orally four doses of 300 mg (single dose of 1200 mg) of compound of formula I in a formulation as presented in Example 15. Serum blood samples were obtained from the volunteers ~ a. 30 minutes and 1, 2, 4, 6, 8, 12 and 24 hours after dosing. These blood samples were analyzed using a HPLC test specific for the compound of formula I. The blood concentrations of the compound of formula I are plotted against time and the AUCs are obtained to calculate the relative bioavailability. The results are shown in table 3.
Relative bioavailability = AUC / AUC ref x 100%
The present invention achieves the desired results as evidenced by the increase in absolute or relative oral bioavailabilities in Tables 1, 2 and 3.
P961
TABLE 2 Absolute Mean Oral Bioavailability in Dogs
P961 TABLE 3 Relative Bioavailability in Humans (1200 Single Dose)
P961
Claims (35)
- CLAIMS. A pharmaceutical composition comprising: (a) a pyranone compound of formula II as a pharmaceutically active agent, n (b) a mixture of diglyceride and monoglyceride in a ratio of approximately 9: 1 to 6: 4 by weight (diglyceride: monoglyceride), wherein the diglyceride and monoglyceride are esters of mono- or di-unsaturated fatty acids of glycerol having a chain length of between sixteen and twenty-two carbon atoms, (c) one or more pharmaceutically acceptable solvents and (d) one or more pharmaceutically acceptable surfactants; where R ^ is H-; Rj is C3-C5 alkyl, phenyl- (CH2) 2-, het-S02NH- (CH2) -, cyclopropyl- (CH2) -, F-phenyl- (CH2) het-SO, NH-phenyl- or FC- ( CH2) 2-; or Rj and E, together they are a double bond; R, is R4- (CH2) n-CH (R5) -, H3C- [O (CH2) 2] 2-CH2-, C3-C5 alkyl, P961 phenyl- (CH2) 2-, het-S02NH- (CH2) 2-, (HOCH2) 3C-NH-C (O) -NH- (CH2) 3-, (H02C) (H2N) CH- (CH2) 2-C (O) -NH (CH2) 3-, piperazin-1-yl-C (O) -NH- (CH2) 3, H03S (CH2) 2-N (CH3) -C (0) - (CH2) ) 6-C (0) -NH- (CH2) 3-, cyclopropyl- (CH2) 2-, Ff enyl- (CH2) 2-, het- S02NH-phenyl or F3C- (CH2) 2-; n is 0, 1 or 2; R4 is phenyl, het, cyclopropyl, H3C- [O (CH2) 2] 2-, het-S02NH-, Br-, N3-, or H03S (CH2) 2-N (CH3) -C (0) - (CH2) 6-C (0) NH-; R5 is -CH-CH3 or -CH2-cyclopropyl; R6 is cyclopropyl, CH3-CH2- or t-butyl; R ^ is -NR8S02-het, -NR8S02-phenyl, optionally substituted with Rg or -CH2-S02-phenyl, optionally substituted with R9 or -CH2-S02-het; R8 is -H or -CH3; R9 is -CN, -F, -OH or N02; wherein het is a saturated or unsaturated 5-, 6- or 7-membered ring containing between one and three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and including any bicyclic group in which any of the heterocyclic rings above is fused to a benzene ring or other heterocycle, optionally substituted with -CH3, -CN, -OH, -C (0) OC2H5, CF3, -NH2 or -C (0) -NH2 or a pharmaceutically acceptable salt thereof .
- 2. The pharmaceutical composition according to P961 claim 1, wherein the pyranone compound of formula II is a compound of formula I I 3. A pharmaceutical composition comprising: (a) a pyranone compound of formula III or IV as a pharmaceutically active agent, ni IV (b) a mixture of diglyceride and monoglyceride in a ratio of approximately 9: 1 to 6: 4 by weight (diglyceride: monoglyceride) wherein the diglyceride and the monoglyceride are esters of mono- or di-unsaturated fatty acids of glycerol which they have a chain length of between sixteen and twenty-two carbon atoms, (c) one or more pharmaceutically acceptable solvents P961 (d) one or more pharmaceutically acceptable surfactants; wherein R10 is H-, CH30- or CH30- [(CH2) 2-0] 3-; RX1 is cyclopropyl or -CH2-CH (CH3) 2; R ^ is -NR14S02-phenyl, optionally substituted with R15, NR14S02-het, -CH2-S02-phenyl, optionally substituted with R15 or -CH2-S02-het; R 13 is -H, - (CH 2) 2 -CH 3 / -CH 2 -cyclopropyl or -CH 2 -phenyl; R 14 is -H or -CH 3; R15 is -CN, -F, -CH3, -COOH or -OH; het is a saturated or unsaturated 5-, 6- or 7-membered ring containing between one and 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 with a benzene ring or another heterocycle; optionally substituted with one or two -CH3, -CN, -C (0) 0C2H5 or -OH; or a pharmaceutically acceptable salt thereof. 4. The pharmaceutical composition according to claim 1 or 3, wherein the compound of formula II, III or IV is in an amount of about 1% to 40% by weight of the total composition. 5. The pharmaceutical composition according to claim 2, wherein the compound of formula I is P961 in an amount of approximately between 20% and 30% by weight of the total composition. 6. The pharmaceutical composition according to claim 1 or 3, wherein the diglyceride is diolein, dilinoleate or a mixture thereof. 7. The pharmaceutical composition according to claim 1 or 3, wherein the diglyceride is diolein. The pharmaceutical composition according to claims 1 or 3, wherein the monoglyceride is monoolein, monolinoleate or a mixture thereof. 9. The pharmaceutical composition according to claim 1 or 3, wherein the monoglyceride is monoolein. The pharmaceutical composition according to claims 1 or 3, wherein the mixture of diglyceride and monoglyceride is in an amount of about between 5% and 35% by weight of the total composition. The pharmaceutical composition according to claims 1 or 3, wherein the mixture of diglyceride and monoglyceride is in an amount of about between 5% and 20% by weight of the total composition. 12. The pharmaceutical composition according to claim 1 or 3, wherein the mixture of diglyceride and monoglyceride is in a ratio of about 8: 2. P961 by weight (diglyceride: monoglyceride) and in an amount of approximately between 5% and 35% by weight of the total composition. The pharmaceutical composition according to claims 1 or 3, wherein the mixture of diglyceride and monoglyceride is in a proportion of about 8: 2 by weight (diglyceride: monoglyceride) and in an amount of about 5% and 20% by weight of the total composition. The pharmaceutical composition according to claims 1 or 3, wherein the mixture of diglyceride and monoglyceride is in a proportion of about 9: 1 by weight (diglyceride: monoglyceride) and in an amount of about between 5% and 20% by weight of the total composition. The pharmaceutical composition according to claims 1 or 3, wherein the pharmaceutically acceptable solvent is propylene glycol, polypropylene glycol, polyethylene glycol, glycerol, ethanol, triacetin, dimethyl isosorbide, glycofurol, propylene carbonate, water, dimethyl acetamide or a mixture thereof . 16. The pharmaceutical composition according to claims 1 or 3, wherein the pharmaceutically acceptable solvent is propylene glycol. 17. The pharmaceutical composition according to P961 claims 1 or 3, wherein the pharmaceutically acceptable solvent is a mixture comprising propylene glycol and 95% (v / v) ethanol in a ratio of about 1: 1. 18. The pharmaceutical composition according to claim 1 or 3, wherein the pharmaceutically acceptable solvent is in an amount of about 10% to 30% by weight of the total composition. 19. The pharmaceutical composition according to claims 1 or 3, wherein the pharmaceutically acceptable solvent is in an amount of about 15% to 25% by weight of the total composition. The pharmaceutical composition according to claims 1 or 3, wherein the pharmaceutically acceptable surfactant is hydrogenated castor oil Polyoxyl 40, castor oil Polyoxyl 35, Solutol HS-15, Tagat TO, Peglycol 6-oleate, Polyoxyethylene stearates, Poloxamer , Polyglycolized Polysorbates or Glycerides. The pharmaceutical composition according to claims 1 or 3 wherein the pharmaceutically acceptable surfactant is hydrogenated castor oil Polyoxyl 40 or polyoxyl 35 castor oil. 22. Hydrogenated castor oil Polyoxyl 40 P961 according to claim 21 which is Cremophor RH40. 23. Polyoxyl 35 hydrogenated castor oil according to claim 21 which is Cremophor EL or Cremophor EL-P. 24. The pharmaceutical composition according to claims 1 or 3, wherein the surfactant is in an amount of approximately between 10% and 50% by weight of the total composition. 25. The pharmaceutical composition according to claims 1 or 3, wherein the surfactant is in an amount of approximately between 30% and 45% by weight of the total composition. 26. The pharmaceutical composition according to claims 1 or 3, wherein the composition further comprises a basic amine. 27. The pharmaceutical composition according to claim 26, wherein the basic amine is lower alkylamine, basic amino acid or choline hydroxide. 28. The pharmaceutical composition according to claim 27, wherein the lower alkylamine is ethanolamine, diethanolamine, triethanolamine, ethylenediamine, dimethylaminoethanol or tris (hydroxymethyl) aminomethane. 29. The pharmaceutical composition according to claim 27, wherein the basic amino acid is arginine, lysine or guanidine. P961 30. The pharmaceutical composition according to claim 26, wherein the basic amine is in an amount of between about 0.1% and 10% by weight of the total composition. 31. A pharmaceutical composition comprising: (a) a pyranone compound of formula I in an amount of about 20% to 30% by weight of the total composition, (b) a mixture of diolein and monoolein in a proportion of about 9: 1 by weight . { diolein: monoolein) and in an amount of approximately between 5% and 20% by weight of the total composition(c) a solvent comprising propylene glycol or a mixture of propylene glycol and 95% (v / v) ethanol in a ratio of about 1: 1 and in an amount of about 15% to 25% by weight of the composition total and (d) a surfactant comprising Cremophor RH40 or Cremophor EL in an amount of approximately between 30% and 45% by weight of the total composition. 32. A pharmaceutical composition comprising: (a) a pyranone compound of formula I in an amount of about 20% to 30% by weight of the total composition, P961 (b) a mixture of diolein and monoolein in a ratio of approximately 8: 2 (diolein: monoolein) and in an amount of approximately between 5% and 20% by weight of the total composition, (c) a solvent comprising propylene glycol or a mixture of propylene glycol and 95% ethanol solution (v / v) in a ratio of approximately 1: 1 in an amount of approximately 15% and 25% by weight of the total composition and (d) a surfactant comprising Cremophor RH40 or Cremophor EL in an amount of approximately between 30% and 45% by weight of the total composition. 33. The pharmaceutical composition according to claim 31 or 32 further comprising dimethylaminoethanol or tris (hydroxymethyl) aminomethane in an amount of between about 0.1% and 7% by weight of the total composition. 34. The pharmaceutical composition according to claims 1, 3, 31 or 32 which is a self emulsifying formulation having the ability to generate emulsions or microemulsions when mixed with sufficient aqueous medium. 35. The pharmaceutical composition according to claims 1, 3, 32 or 33 which is in the form of a liquid for soft elastic capsules. P961
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/054,078 | 1997-07-29 |
Publications (1)
Publication Number | Publication Date |
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MXPA00000996A true MXPA00000996A (en) | 2001-05-07 |
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