MXPA97002699A - Pharmaceutical compositions that comprise a unsaturated fatty alcohol and use of a fatty alcohol unsaturated in the mis - Google Patents
Pharmaceutical compositions that comprise a unsaturated fatty alcohol and use of a fatty alcohol unsaturated in the misInfo
- Publication number
- MXPA97002699A MXPA97002699A MXPA/A/1997/002699A MX9702699A MXPA97002699A MX PA97002699 A MXPA97002699 A MX PA97002699A MX 9702699 A MX9702699 A MX 9702699A MX PA97002699 A MXPA97002699 A MX PA97002699A
- Authority
- MX
- Mexico
- Prior art keywords
- fatty alcohol
- compound
- macrolide
- alcohol
- emulsion
- Prior art date
Links
- 150000002191 fatty alcohols Chemical class 0.000 title claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 239000003120 macrolide antibiotic agent Substances 0.000 claims abstract description 25
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical class C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims abstract description 24
- 230000000699 topical Effects 0.000 claims abstract description 19
- 239000000725 suspension Substances 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims description 9
- 210000003491 Skin Anatomy 0.000 claims description 8
- ZDQSOHOQTUFQEM-XZQJPUKSSA-N ascomycin Chemical compound C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)CC(C)=C[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 ZDQSOHOQTUFQEM-XZQJPUKSSA-N 0.000 claims description 5
- 230000002757 inflammatory Effects 0.000 claims description 5
- 230000001404 mediated Effects 0.000 claims description 5
- QFJCIRLUMZQUOT-HPLJOQBZSA-N Sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 4
- 208000006641 Skin Disease Diseases 0.000 claims description 4
- 230000003463 hyperproliferative Effects 0.000 claims description 4
- 229960002930 sirolimus Drugs 0.000 claims description 4
- 230000000087 stabilizing Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- ZDQSOHOQTUFQEM-NURRSENYSA-N ASCOMYCIN Chemical group C/C([C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@@H](OC)C[C@@H](C)C/C(C)=C/[C@H](C(C[C@H](O)[C@H]1C)=O)CC)=C\[C@@H]1CC[C@@H](O)[C@H](OC)C1 ZDQSOHOQTUFQEM-NURRSENYSA-N 0.000 claims 1
- 150000002500 ions Chemical class 0.000 claims 1
- 239000000839 emulsion Substances 0.000 abstract description 28
- -1 ether diol Chemical class 0.000 abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 8
- 239000002904 solvent Substances 0.000 abstract description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 7
- 125000004432 carbon atoms Chemical group C* 0.000 abstract description 6
- 239000012049 topical pharmaceutical composition Substances 0.000 abstract description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 14
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
- ALSTYHKOOCGGFT-KTKRTIGZSA-N Oleyl alcohol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 10
- 229940055577 oleyl alcohol Drugs 0.000 description 10
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 9
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- 239000003995 emulsifying agent Substances 0.000 description 9
- 201000004681 psoriasis Diseases 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229960004063 Propylene glycol Drugs 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 239000007764 o/w emulsion Substances 0.000 description 8
- 235000013772 propylene glycol Nutrition 0.000 description 8
- 239000001993 wax Substances 0.000 description 8
- 229960000541 cetyl alcohol Drugs 0.000 description 7
- FCSHDIVRCWTZOX-DVTGEIKXSA-N clobetasol Chemical group C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O FCSHDIVRCWTZOX-DVTGEIKXSA-N 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 229920001888 polyacrylic acid Polymers 0.000 description 7
- 239000002562 thickening agent Substances 0.000 description 7
- 239000004166 Lanolin Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- BXWNKGSJHAJOGX-UHFFFAOYSA-N Cetyl alcohol Chemical class CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 5
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
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- 230000001684 chronic Effects 0.000 description 5
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- 239000000194 fatty acid Substances 0.000 description 5
- 235000019388 lanolin Nutrition 0.000 description 5
- 239000012188 paraffin wax Substances 0.000 description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 5
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-Methyl-2,4-pentanediol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical compound OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N Stearyl alcohol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 229940051250 hexylene glycol Drugs 0.000 description 4
- 230000003902 lesions Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000001587 sorbitan monostearate Substances 0.000 description 4
- 235000011076 sorbitan monostearate Nutrition 0.000 description 4
- 229940035048 sorbitan monostearate Drugs 0.000 description 4
- 206010015150 Erythema Diseases 0.000 description 3
- RFVNOJDQRGSOEL-UHFFFAOYSA-N Glycol stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 3
- 241000357291 Monodactylus argenteus Species 0.000 description 3
- 229920001214 Polysorbate 60 Polymers 0.000 description 3
- NWGKJDSIEKMTRX-AAZCQSIUSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229960004217 benzyl alcohol Drugs 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960002842 clobetasol Drugs 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 231100000321 erythema Toxicity 0.000 description 3
- 239000003349 gelling agent Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 3
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000002335 preservative Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- 239000007762 w/o emulsion Substances 0.000 description 3
- YQEMORVAKMFKLG-UHFFFAOYSA-N 2-stearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 2
- HMFKFHLTUCJZJO-UHFFFAOYSA-N 2-{2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy}ethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCOCC(OCCO)C1OCC(OCCO)C1OCCO HMFKFHLTUCJZJO-UHFFFAOYSA-N 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N Diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 2
- 229940041033 Macrolides Drugs 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical class CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229940066842 Petrolatum Drugs 0.000 description 2
- 239000004264 Petrolatum Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N Propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O Pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 2
- 229940075582 Sorbic Acid Drugs 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 210000001138 Tears Anatomy 0.000 description 2
- 229940099259 Vaseline Drugs 0.000 description 2
- NWGKJDSIEKMTRX-BFWOXRRGSA-N [(2R)-2-[(3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)C1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-BFWOXRRGSA-N 0.000 description 2
- HVUMOYIDDBPOLL-IIZJTUPISA-N [2-[(2R,3S,4R)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@@H](O)[C@@H]1O HVUMOYIDDBPOLL-IIZJTUPISA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 230000000111 anti-oxidant Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
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- 125000003118 aryl group Chemical group 0.000 description 2
- 230000001580 bacterial Effects 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 229960002216 methylparaben Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 2
- 229960004889 salicylic acid Drugs 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- WJNMPINWDAQWSW-UNTBIKODSA-N (12R)-12-hydroxyoctadec-9-enoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCC[C@@H](O)CC=CCCCCCCCC(O)=O WJNMPINWDAQWSW-UNTBIKODSA-N 0.000 description 1
- HFBYLYCMISIEMM-FFHNEAJVSA-N (4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,4,4a,5,6,7,7a,13-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid Chemical compound OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC HFBYLYCMISIEMM-FFHNEAJVSA-N 0.000 description 1
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-Methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 1
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 1
- WITKSCOBOCOGSC-UHFFFAOYSA-N 2-dodecanoyloxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCCCCC WITKSCOBOCOGSC-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-hydroxypropyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N AC1LDCW0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
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- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- OJTDGPLHRSZIAV-UHFFFAOYSA-N CC(O)CO.CC(O)CO Chemical compound CC(O)CO.CC(O)CO OJTDGPLHRSZIAV-UHFFFAOYSA-N 0.000 description 1
- BXJFNJQMRLFHGI-UHFFFAOYSA-N COC1(C(N(CCC1)OC)(OC)OC)OC Chemical class COC1(C(N(CCC1)OC)(OC)OC)OC BXJFNJQMRLFHGI-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
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- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M Dioctyl sodium sulfosuccinate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
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- 125000003545 alkoxy group Chemical group 0.000 description 1
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
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- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- PWEOPMBMTXREGV-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O.CCCCCCCCCC(O)=O PWEOPMBMTXREGV-UHFFFAOYSA-N 0.000 description 1
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- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- LLRANSBEYQZKFY-UHFFFAOYSA-N dodecanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCCCCCC(O)=O LLRANSBEYQZKFY-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002118 epoxides Chemical group 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000001861 immunosuppresant Effects 0.000 description 1
- 230000001506 immunosuppresive Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N oxane Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atoms Chemical group O* 0.000 description 1
- PXDJXZJSCPSGGI-UHFFFAOYSA-N palmityl palmitate Chemical compound CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 235000013533 rum Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 239000008117 stearic acid Chemical class 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229930003799 tocopherols Natural products 0.000 description 1
- 231100000730 tolerability Toxicity 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Abstract
This invention provides a topical composition, in the form of an emulsion, comprising a compound of the FK506 class, an alkanediol, ether diol or diether alcohol containing up to 8 carbon atoms, physiologically acceptable, as a solvent for the compound of the invention. class of FK506, a fatty alcohol unsaturated in water. In another aspect, this invention provides a topical pharmaceutical composition comprising a macrolide in suspension. In a traditional aspect, this invention provides the use of an unsaturated fatty alcohol to stabilize a macrolide in a pharmaceutical composition.
Description
PHARMACEUTICAL COMPOSITIONS
FIELD OF THE INVENTION
The present invention relates to topical pharmaceutical compositions comprising a macrolide, and in particular to formulations comprising a macrolide such as an ascomycin, a rapamycin or a compound of the class of FK506.
BACKGROUND OF THE INVENTION
FK506 is a known macrolide antibiotic, which is produced by S trept myces tsukubaensis No. 9993. It is also a potent immunosuppressant. The structure of FK506 is listed in the appendix found in Merck ndex, lia. Edition as subsection A5. The method of preparation of FK506 is described in EP 184,162. A large number of derivatives, antagonists, agonists and analogues of FK506 are known, which contain the basic structure and at least one of the biological properties (for example,
REF: 24360
base oil and do not contain water. Lag compositions containing water have been reported in the literature and the compounds of FK506 have also been formulated as fine suspensions (EP 484,936).
DESCRIPTION OF THE INVENTION
It has now been found, surprisingly, that the compounds of FK506 can be formulated in stable emulsions. The emulsions, since they contain an aqueous phase, are much less occlusive than the oil-based compositions and hence are better tolerated in many situations. Accordingly, in one aspect, this invention provides a topical composition, in the form of an emulsion, comprising a composition of the class of FK506; an alkanediol; physiologically acceptable diethyl ether or jiol alcohol, containing up to 8 carbon atoms, as a solvent for the compound of the class FK506; an unsaturated fatty alcohol and water Est; topical composition is effective, well
R? Erj independently (a) is a pair of H atoms but R2 can also be alkyl or (b) forms a second bond between the carbonp atoms to which they are attached; R7 is H, OH, a protected OH group, a formyl group xi or an alkoxy group, or R7, together with Ri, forms an oxo group; Re and R9 are, independently, H or OH; R? Is H, an alkyl group, an alkyl group substituted by one or more OH groups, 1 group or alken, an alkenyl group substituted by one OH groups, or an alkyl group substituted by oxo group; is H or OH; it's H; or and X2, together, are an oxo group or
and Y2 together are an oxo group, N-NRnRi2 O N-OR13; Rii and 12 independently, are H, an alkyl group, an aryl group or a tosyl group;
R 13 i4 / Ri5 Rie i7 ißf R19, R22 and R23 are independently H, or an alkyl group;
R20 and] 2if together, form an oxygen atom in an epoxide ring, or (c) a 5- or 6-membered cycloalkyl group, which may be optionally substituted. For example R24 may be a cyclopentyl group substituted by methoxymethyl ilo, optionally protected hydroxymethyl, acyloxymethyl, (wherein the acyl moiety contains either a dimethylamino group which may be in the quaternary form, or a carboxy group which may be is teri fied), or one or more amino and / or hydroxy groups that may be protected, or aminooxalyloxymethyl. A preferred example is a 2-formyl-cyclopentyl group. Suitable alkyl groups, alkenyl groups, aryl groups, protecting groups and acyl groups are defined in EP 484,936. The macrolide used in the compositions of the present invention preferably has immunosuppressive properties. The macrolide can be rapamycin or an O-subs tu derivative in which the hydroxy which is at position 40 of formula A, illustrated on page 1 of WO 95/16691, incorporated herein by reference, is find replaced by -OR? wherein Ri is hydroxyalkyl, hydroalkoxyalkyl, acylaminalkyl and aminoalkyl; for example 40-0- (2-hydroxy) ethyl-rapamycin, 40-0- (3-hydroxy) propi 1-rapamycin, 40-0- [2- (2-hydroxy) ethoxy] eti 1-rapamicinia and 40-0- (2- (ace toaminoe ti 1) -rapamycin These 0-substi-uidos derivatives can be produced by reacting Rapamycin (or dihydro or deoxorapamycin) with an organic radical attached to a leaving group (for example RX wherein R is the organic radical that is desired as the 0 -subthi ": uder, such as an alkyl, allyl, or benzyl moiety, and X is a leaving group such as CC13C (NH) 0 or CF3SO3) under suitable reaction conditions Conditions may be acidic or neutral conditions, for example in the presence of an acid such as trifluoromethanesulfonic acid, camphor sulfonic acid, p-acid phonyl toluensul or their respective pyridinium or substituted pyridinium salts when X is CCl3C (NH) 0, or in the presence of a base such as pyridine, a substituted pyridine, diisopropylethylamine, or pentamethoxypiperidine when X is CF3SO3. is 40-0- (2-hydroxy) et ilrapamycin (from here hereinafter the component A) as described in WO 94/09010. A preferred component of class FK 506 is describede in EP 427,680, for example, in the E] empl > 66a (also called 33-epi-chloro-33-deoxy iscomycin), hereinafter com- pound B. Other preferred compounds of the class FK 506 are described in EP 465,426, EP 569, 337 and in EP 626,385, for example the compound of Example 6d in EP 569,337, hereinafter compound C, or the compound of Example 8 of EP 626,385, hereinafter the compound D. Exemplary impurity of solvents of alkanediol, which are able to dissolve compounds of the class of FK506, are propylene glycol (1,2-propanediol), butylene glycol, 2-yl-l, 3-hexanediol, hexylene glycol (2-met il-2) , -pentanediol) and the like. Examples of ether diol solvents are propylene glycol, diethylene glycol and the like. Examples of diether alcohol solvents are diethylene glycol monomethyl ether. Preferably the solvent is hexylene glycol. Solvent is present, preferably, in an amount from about 5 hast to about 50% w / w, more preferably from 5 to 20% w / w and even more preferably from 5 to 20%. 10% w / w of the emulsion. The oil phase of the emulsion may comprise from about 20 to about 80% w / w, more preferably from 25 to 75 and even more preferably from 35 to 75%.
65 by weight of the composition. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. The oil-in-water emulsion can be in the form of an emulsion gel (in which case the aqueous phase can still be thickened using a polymeric thickener) or in the form of a cream. The unsaturated fatty alcohol forms part of the oil phase, of the emulsion, and is preferably a lanolin alcohol a fatty alcohol of 16 to 18 carbon atoms; more preferably oleyl alcohol, or alcohol elaidype, although the alcohol is particularly preferred. oleic The composition preferably contains sufficient amounts of the unsaturated fatty alcohol to promote the absorption of the compound of the FK506 class, in the skin, more preferably from about 2 to about 10% w / w, and even more preferably from 5 to about Approximately 10% p / p. The oil phase may also contain other liquid oils, thickening agents and fatty bases that are usually used in topical compositions. Suitable liquid oils include medium chain triglycerides, obtained from fractionated vegetable oils, such as the triglycerides of capric / caprinic acid. An example of one of these triglycerides is one that is commercially available under the trade name Miglyol 812 (which has an ileal weight of about 520, a value of nD20 from about 1,448 to 1,450 and a viscosity from 0.28 to 0.32 Pa.s). The liquid oil may comprise from about 5 to about 60% w / w of the emulsion and preferably from 5 to 15% w / w.
Suitable thickening agents include thickened, conventional teas such as alcohol cetyl, cetostearyl alcohol, tear alcohol, hydrogenated castor oil (Cutina HR), Yellow wax, White wax, cetyl ester wax, wax emulsifier, microcrystalline talin wax, and the like. Preferably the thickening agent forms from about 2 to about 30% w / w of the emulsion and more preferably from 2 to 10% w / w. Suitable fatty bases include bases such as natural wax, Vaseline (petroleum in the form of a gel, also commercially available as an ether), coarse paraffin, wool wax alcohols (such as those sold under the trademarks Eucerinum or Eucerin). , wool wax derivatives, triglyceride waxes (such as those commercially available under the trade names Softisan 378) and the like. The composition may also include suitable emulsifiers as is usual in emulsion compositions. These emulsifiers are described in standard texts such as Fiedler, H. P .; 1989; Lexikon der Hilfsstoffe für Pharma ie, Kosmetic und angrenzende Gebiete,
Edit io Cantor, D-7960 Aulendorf, Germany and in the
Handboq > k of Pharmaceutical Excipients a
Joint publication of the Association
American Pharmaceutical, Washington DC, United States of America and the Pharmaceutical Society of Great Britain, London, United Kingdom; 1986. Examples of suitable emulsifiers include: (a) esters of mono-fatty acids and propylene glycol digesters, such as propylene glycol di capitol (which is commercially available under the trademark of Miglyol 840) , propylene glycol dilaurate, hydroxypropyl glycol, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, and propylene glycol stearate; (b) fatty acid esters of polyoxylenesorbitan, such as the monolauryl and trilauryl, palmityl, tear, and oleyl esters. Examples of commercially available esters are those that are available under the trade name of T een (see Fiedler, pages from 1,300 to 1,30) and particularly the Tween 60
(polyexyethylene (20) sorbitan monoether);
(c) esters of polyoxyethylene fatty acids, for example esters of polyoxyethylene stearic acid of the type known and commercially available under the trade name of Myrj (see Fiedler, pages 834 and 835) and in particular Myrj 52 (which has an O¿ of about 1.1, a melting point of about 40 to 44 ° C, and a Hydro-lipo-Lipo fí 1 ico (HLB) value of about 16.9) ); (b) copolymers and block copolymers, of polyoxyethylene-polyoxypropylene, such as those known and commercially available under the 1> names of Pluronic, Emkalyx and Polaxamex
(see Fiedler, page 959) and in particular the
Pluron c F68 (which has a melting point of approximately 52 ° C and a molecular weight of approximately 6,800 to 8,975) and the Poloxamer
188; the dioctyl sulfosuccinate or the di- [2-ethylhe il] succinate; (f phospholipids and in particular lecithins
(see F edler, pages 943 and 944); (g) salts of fatty alcohol sulphates such as sodium lauryl sulfate and cetyl are sodium tearl sulfate (esters of sorbitan fatty acids such as sorbitan monostearate and sorbitan monolose which are commercially available). are available under the trademarks Arlacel 60 (which has an HLB of approximately 4.7 and a melting point of approximately 53 ° C) and Span 80 (which has a
D25 is approximately 1, an HLB of approximately 4.3 and a viscosity of approximately 950 to 1100 cP); (i) monos: glycerin earate which is commercially available under the trade name of Imwitor (see Fiedler, page 645) and par ticularly the Imwitor 960; (j) glycerol esters of polyethylene glycol, having at least one free hydroxyl group, and aliphatic carboxylic acids of 6 to 22 carbon atoms. examples include glycerin monostearate of PEG-20; (k) reaction products of a castor oil, natural or hydrogenated, and of ethylene oxide and of which examples are available under the trade name of
Cremophor as the Cremophor RH 40 (which has a
Do not . of saponification of about 50 to 60, and an acid number < 1, a nD of approximately 1,453 to 1,457 and a value of HLB 224 and 284); (p) glycerin sorbitan fatty acid esters such as those which are available under the tradename Arlacel 481 (which has a molecular weight of about 630 and an HLB value of about 4.5) and (q) mixtures of the same. Preferably the emulsifier is selected from polyethylene glycol monostearate. (20) glycerin, sorbitan monostearate (Arlacel 60), sorbitan monooleate (Span 60), Tween 60, Tween 80, glycerin monostearate (Inwitor 960), stearic acid, cetyl alcohol, wool wax derivatives and alcohols and the Labrafil M2130 CS and mixtures thereof. If the emulsion is a water-in-oil emulsion, the selected emulsifier preferably has a HLB value of 10 to 15. If the emulsion is an oil-in-water emulsion, the selected emulsifier preferably has an HLB value of 4. to 8. Preferably the emulsifiers are present in an amount of about 1 to about 30% w / w and preferably 10 to 25% w / w.
It is also possible to add gelling agents to provide a gelled emulsion. Suitable gelling agents are carbomers (polyacrylic acid derivatives); such as those commercially available under the trade name of Carbopol (see Fiedler, pages 254 to 256). Carbopol 974 and Carbopol 1342 are preferred. The gelling agents are preferably present in an amount of 0. 2 w / w; more preferably less than about 1% w / w. The emulsion may also include preservatives and antioxidants such as benzyl alcohol, butyl hydroxy toluene, ascorbyl palote, sodium pyrosulfite, butyl idroxianisole, propyl p-hydroxybenzoate.
(commercially available, for example, under the name of Paraben), methyl p-hydroxybenzoate (commercially available, for example as
Paraben), sorbic acid and tocopherol. The preservatives and antioxidants serve to prevent bacterial growth, and are preferably present in a c ant i d d from about 0.01 to about 2.5% w / w. The pH modifying agents may be included to bring the pH of the emulsion to values that are between 4 and 6 or by the addition of a pharmaceutically acceptable buffer system. To avoid skin irritation a pH between 4 and 6 is desirable. The aqueous phase of the emulsion may comprise from about 20 to about 80% w / w, more preferably from 25 to 75% and in the form even more preferred from 35 to 65% of the emulsion. The aqueous phase is preferably in the form of sterilized water. The compound of the FK506 class is preferably present in the emulsion in an amount from about 0.01 to about 10% w / w and most preferably in an amount from 0.1 to 1% w / w. Preferably, the compound of the FK506 class and the unsaturated fatty alcohol are present in a weight ratio of from 1: 1,000 to 5: 1; preferably from 1: 100 to 1: 5. It has now been found in a surprising manner, that the macrolides can be formulated into stable pharmaceutical compositions, when the compounds are in suspensions. Accordingly, in another aspect, this invention provides a topical pharmaceutical composition comprising a macrolide in suspension. The term macrolide has the meaning described above. The pharmaceutical composition may be in the solid form, but is preferably in the semisolid form suitable for topical administration. These compositions in suspension, of this? invention, are effective, well tolerated on the skin, and stable from a reasonable degree to a large or extreme. The suspension contains macrolide particles from about 5, for example from 10, to about 90 microns in diameter. The particles of the macrolide can be produced in a conventional manner, as for example by empl < by crushing or grinding. The suspension can be prepared as a cream, a water-free ointment, a water-in-oil emulsion, an oil-in-water emulsion, an emulsion gel or a gel. In another aspect, this invention provides a topical taxation which is in the form of an oil in water emulsion gel, which comprises a) a macrolide in an amount of up to 5% in weight b) a thickener found in a quantity of up to 20% by weight, c) a hydrophilic component which is present in an amount of up to 40% by weight, d) one or more organic acids which are present in a total amount of up to 5% by weight , e) one or more stabilizers, which are in a total amount of up to 5% by weight, f) water that is in an amount of up to 90% by weight. Thickening agents are as defined above and may include paraffin, waxes and petrol ato. Suitable hydrophilic components include in propylene glycol, alcohols such as the cetyl hollic ale, the stearyl alcohol and the oleyl alcohol. Examples of suitable organic acids, containing sides for use in this invention, include sorbic acid. The acid functions as a preservative and serves to substantially prevent bacterial growth. In another aspect the invention provides a topical composition, in the form of an emulsion or suspension, as defined above., For e. use in the treatment of diseases of the foot L, inflammatory and hyperproliferative diseases, and of cutaneous manifestations of immune-mediated diseases. In another aspect, the invention provides a method for the treatment of skin diseases, inflammatory or hyperproliferative, or cutaneous manifestations of immunologically mediated diseases, which comprises administering a topical composition, as defined above. previously, to the skin of a patient who ne esite of the same. In still another aspect, the invention provides the use of a compound of the class of FK506; anodiol, ether diol, or diethyl alcohol, p-gically acceptable, which contains up to 8 carbon atoms, as the solvent for the compound of the class of FK506; an unsaturated fatty alcohol and water in the preparation of a medicament, in the form of an emulsion, for the treatment of skin diseases, inflammatory and hyperproliferative diseases, and skin infections of immune-mediated diseases. Emulsion compositions can be obtained by dissolving the compound of the FK class! 06, in the solvent and the unsaturated fatty alcohol, to provide the oil phase. If desired, in the oil phase, liquid oils, fatty bases * and thickening agents can be mixed. The oil phase is then emulsified with the aqueous phase and, if necessary, suitable emulsifiers. Other excipients may be added, at the appropriate time, to the proper phase, as is conventional. Applicants have found that the macrolides may be unsightly in topical compositions. It is believed that this instability is caused by gradation or rearrangement routes which are not fully understood. After extensive experimental work the applicants have found that unsaturated fatty alcohol can be used to stabilize macrolide compositions. In a further aspect, this invention provides the use of an unsaturated fatty alcohol to stabilize a macrolide in a pharmaceutical composition. In another aspect, this invention provides a method for stabilizing a macrolide in a pharmaceutical composition, a method comprising mixing: an unsaturated fatty alcohol with the macrolide. The unsaturated fatty alcohol can be an alcohol having 8 to 22 carbon atoms, or it can comprise a mixture of alcohols. Unsaturated fatty alcohol may have one, two or three weak bonds. Preferably the unsaturated fatty alcohol has a double bond, and a cis-configuration. Oleyl alcohol is preferred. An effect can be observed when the weight ratio of the unsaturated fatty alcohol to the active agent is at least about 1: 5, for example from 1: 2 to 1: 1 f higher, for example about 5: 1. . It has been found herein that the unsaturated fatty alcohol, for example the oleyl alcohol, is suitable for stabilizing a macrolide in a topical pharmaceutical composition. Examples of topical compositions are as described herein. The unsaturated fatty alcohol can be used, for example oleyl alcohol, to stabilize a macfolide having at least a portion as the following
In the present application it has been found that oleyl alcohol is useful for slizing ascomynes and compounds of the FK506 class, for example FK506, ascomycin and 33-epi-chloro-3-deoxyscomycin. The topically defined topical compositions are useful in the treatment of skin diseases, inflammatory and hyperp. oli eratives, and cutaneous manifestations of immunologically mediated diseases, s. Examples of these diseases are psoriasis, atopic dermatitis, contagious dermatitis and other eczematous dermatitis, seborrhoeic dermatitis, Lichen planus, Pénfigi, Bullous pemphigoid, Epidermolisis bulosa, urtica, angioedemas, vasculi tidos, erythema, eosinolias Cutaneous, Lupus erythematosus and Alopec a areata. The usefulness of the topical compositions can be observed in standard clinical tests such as 1 to the test described in Example 12 using a concentration of 0.01 to 10% w / w (preferably 0.1 to 1% w / w). of the compound of the FK506 class. Utility can also be observed using models of animal models as described in EP 315,978. The exact amount of the compound of the FK506 class and the composition to be administered depends on several factors, eg, the desired duration of treatment and the release rate of the compound of the FK506 class. . Smaller mammalian results are obtained by (2-pro enyl) -15, 19-epoxy-3H-pyrido [2, 1-c] [1,4] oxaazacycloticosin-1, 7, 20, 21 (4H, 23H) -tet rum (i) [3S- [3R * [E (1S *, 3S *, 4S *)], 4S *, - 5R, -8S *, 9E, 12R *, 14R *, 15S *, 16R *, 18S *, - 19S *, 26aR *]] - 5,6,8, 1,12, 13, 14, 15, 16, 17, 18, 19, 24, 25, 26, 26a-hexade ahydro-5,19-dihydroxy-3- [2- (4-hydroxy-3-methoxy-cyclohexyl) -1-methylethenyl) 1-14,16-dimethoX i-4,10,12,18 -tetramethyl-8 -ethyl-15, 19-epoxy-H-pyridy [2, 1-c 1 [1,] oxaazacyclics in-1, 1, 2 0 21 (4H, 23H) -tetrone, and (ii) [3S - [3R * [E (1S *, 3S *, 4S *) 1.4S *, 5R *, 8S *, 9E, -12R *, - 4R *, 15S *, 16R *, 18S *, 19S *, 26aR *]] - 5, 6, 8, 1.12, 13, 14, 15, 16, -17, 18, 19, 24, 25, 26, 26a-hexade ahydro-5,19-dihydroxy-3- (3 -hydrox methylcyclopentyl) -1-methylethenyl)] -14, 16-dimethoX i-4,10,12,18, -tetramethyl-8-ethyl-15, 19-epoxy- $ H -pyrido [2, 1-c ] [1, 4] oxaazacycloticosin-1, 7, 20 21 (H, 23H) -tetrone, the topical application of with: 0.01 to 1% w / w, a once a day, in the treatment of psoriasis, chronic plaque, in humans. In these applications, the compositions are as effective as the ultra-potent composition of Clobetasol (0.05%). It > Examples below describe compounds 14,15, [L6,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3- [2- (4-hydroxy-3-methoxy-cyclohexyl)] -1-methylethhenyl)] -14, 16-dimethoxy-4, 10, lp, 18, -tetramethyl-8-ethyl-15, 19-epoxy-3H-pyrido [2, 1-c] [1,4] oxaazacyclotrichosin -1, 7, 20L 21 (4H, 23H) -tetron. This compound is known as Ascomycin. "Compound A, Compound B, Compound Compound D have the respective meanings as described above. The se term, as used in the following Examples, means that no separation of the components is observed. of the respective composition when stored at ambient temperature for a period of four months or longer Chemical analysis of the active agent is carried out using reverse phase HPLC with UV detection; λ = 210 nm The limit of quantification is 0.1 % by weight The tolerability of the compositions is carried out, in vivo, in pig skin and in human skin, and a visual evaluation is carried out at 0.5, 1, 2 and 4 hours after the application.
Benzyl alcohol 1.00 Arlacel 481 7.00 White oil 15.00 Coarse paraffin 5.00 Water 58.4 MgS04.7H20 0.5
The emulsion is se
Example 4
An oil-in-water emulsion is prepared in one m; similar to that of Example 1, and which contains the following ingredients (in parts by weight):
Compound 2 0.10 Oleyl alcohol 7.50 PEG glycerin monostearate 7.00 Propylene glycol 10.00 Cetyl alcohol 6.00 Glycerin monostearate 4.00 Paraffin 10.00 (coarse) Example 8 to 11
The following emulsions are prepared in a manner analogous to that of Example 1.
Example 10 11 Compound 3 0.10 0.10 0.10 0.10 Hexylene glycol 5 00 10.00 10.00 5.00 Cetyl Palmitate 2 00. Oleyl Alcohol 10.00 10.00 Lanolin Alcohols 1.50 T :: MC glycerides * 10.00 10.00 5.00 Isopropyl Myristate 8.00 - Cetyl Alcohol 4.00 5.00 5.00 2.00 Stearyl alcohol 4.00 5.00 2.00 Benzyl alcohol 1.00 1.00 1.00 1.00 Sorbitan monostearate 1.90 2.00 3.00 Sorbitan monooleate - 4.00 Glycerin monostearate - 3.00 10.00 - Tween 80 6.10 - Petrolatum, white 23.50
Water 67.90 49.90 53.90 56.40
Magnesium sulfate, heptahydrate 0.50
MO medium chain, for example Miglyol 812 The compositions of Examples 4 to 11 are straight.
Example 12
A double-blind, single-center, double-blind, controlled trial or test is carried out to determine the efficacy of the compositions of Examples 4 to 7 in rheological plaque psoriasis. Ten patients over 18 years of age who have plaque psoriasis are chosen; and who have not received systemic or topical therapy for chronic plaque psoriasis, in 1 month and: week, respectively. On day -1, the scales were removed with a topical composition containing 10% salicylic acid in Vasel iha. On day 0, the compositions of Examples 4 to 7, a composition of Clobetasol at 0.05%, available under 1, are applied. Trademark Dermovate and a placebo, to the desquamated plates under semi-active conditions and left for 24 hours. The patient is allowed to bathe and the lesions are gently dried. The lesions were evaluated visually (erythema) and by no adverse events were observed with the compositions of Examples 4 and 7, but skin atrophy was observed in the 2 patients who received Dermovate. However, the compositions of Examples 4 through 7 are at least as effective as Dermovate. The active agent used in the compositions described in Examples 1 to 11 can be replaced by Compound A, B, C or D.
Examples from 13 to 16
Oil-in-water emulsions are prepared in a manner analogous to that of Example 1 and having the following compositions.
Example 13 14 15 16 Oleyl alcohol 10 10 10 10 Mi fcrlyol 812 15 15 15 15 Cetyl alcohol Stearyl alcohol Glycerol moho stearate Sorbitan sorbitan Polysorbate 20 The degradation product increases up to 0.5%. No separation of the compounds is observed when stored at room temperature for four months.
Examples from 17 to 19
Oil-in-water compositions containing 1% by weight of the active ingredient are prepared.
Example 17 18 19 Oleyl alcohol 2.5 10 Miglyol 812 22.5 20 15 Cetyl alcohol Stearyl monomer Glycerol monostearate Sorbitan monostearate Polysorbate 60 Methylparaben 0.07 0.07 0.07 Propi lparaben 0.03 0.03 0.03 Citric acid 0.05 0.05 0.05 NaOH 1M p.abs./lOO g 0.02 0.02 0.02 Propylene glycol Compound B Up to up to Water des in 100 100 100
Lab emulsions of Examples 17, 18 and 19 are stable and no separation of the components is observed. It is found that the compositions are well tolerated in human skin. The compositions are stored at 40 ° C for eight weeks and the chemical analysis is carried out using HPLC. The analysis of the main degreasing product for compositions 17, 18 and 19 is .1%, 0.8% and 0.4%, respectively. In the compositions of Examples 13 to 19, the active agent of compound B may be Plied by compound A, by compound C, by compound D, by compound 1, by compound 2 or by compound 3.
Example 20
An oil-in-water emulsion composition, such as a cream, is prepared using Compound C as the active agent:
Component Quantity weight-% Compound C 0.3 Hexylene glycol 10 Alcohol oleic 1 ico 10 Miglyol 812 10 Methylparaben 0.07 Propylparaben 0.03 Cetyl alcohol 5 Glycerol monostearate Water up to 100 to reduce the efficacy of the compositions of Example 21 in the psoriasis of chronic plaque. It is igen 10 patients who are over 18 years of age, who have chronic plaque psoriasis and who have not received systemic or topical therapy for chronic plaque psoriasis, in 1 month and 1 week respectively. On day 1, n scales are removed with a topical composition containing 10% salicylic acid in Vaseline. On day 0, the compositions of Example 21, a Clobetasol composition at 0.05%, available under the trademark Dermovate, and a glass, are applied to the desquamated plates, under semi-occlusive conditions, and left for 24 hours. . The patient is allowed to bathe and the lesions dry gently. The lesions are evaluated visually (erythema) and by palpation (inflmation) with scores ranging from 0 (aus €; ntes) up to 3 (severe). The procedure is repeated daily until 10/11; the separation of psoriasis is observed.
Example 24 Quantity (g / 100 g)
Compound B 0.1 Paraf i .na, coarse 48 Glycerol monoestrate 8 Petro > lato, white 43.9
Example 25 Amount (g / 100 g)
Compound B 0.1 Parafiha, thin 20 Petrolatum, white 71.9 Wax, crystalline beginning 8
E j p e 26 Amount (g / 100 g)
Paraf iha, thick 30 Cetyl alcohol 5 Stearyl alcohol 5 Monoes sorbitan epoxide 2 Pol iso bato 80 (polyhydroxyethylenesorbitan monooleate) 4 Monoes glycerol monostea 3 Ascorbyl acetate 0.05 Compound B 0.1 Orbital acid 0.1 Propi 1: ngl icol 5 Water 45.75 Example 27 Quantity (g / 100 g)
Propylene glycol 10 Paraffin. thick 15 Compound B 0.1 Carbopol 1342 (polyacrylic acid, partially long chain alkyl alkyl ester) 1 Methylparabens 0.07 Propylparabens 0.03 Aqueous solution of NaOH 2.5 to 5 < Water 71.30
Example 28 Amount (g / 100 g)
Compue to B 0.1 Carbop 1 947 1 Aqueous solution IN of NaOH 2.5 Water 96.4
Example 29 Quantity (g / 100 g)
Compue to B 0.1 Cetilestearyl alcohol 0.5 Alcoho is of wool wax 6 Petrol to, white 93.4 Ej empl 30 Amount (g / 100 g
Compue s to B 0.1 To the coho 1 cetiles tearí 1 ico 0.25 Alcohols of wool wax 3 Petrol ato, white 46.65 Water 50
Good to very good stability is observed for the suspension compositions of Examples 24 through 30. The suspensions are applied to healthy volunteers and are found to be well tolerated. Compound B can be replaced by compound 1, 2, 3, A, C or D in any of the compositions described in Examples 23 to 30. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as antecedent property is claimed as contained in the following:
Claims (1)
- A pharmaceutical composition, topical, characterized in that it comprises a macrolide in ion suspensions. A composition according to claim 5, characterized in that the macrolide is an ascomycin, a rapamycin or a compound of the class of FK506. A composition according to claim 6, characterized in that the macrolide is ascomycin, 33-epi-chloro-33-deoxy ascomycin or FK506. 8. A method for the treatment of skin diseases, inflammatory or hyperproliferative, skin manifestations or immunologically mediated diseases, characterized in that it comprises administering a topical composition according to any of claims 1 to 7, to the skin of a patient who needs it. The use of an unsaturated fatty alcohol to ablate a macrolide, in a pharmaceutical composition A method for stabilizing a macrolide in a pharmaceutical composition, characterized in that it comprises mixing unsaturated fatty alcohol with macrolide.
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
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GB9421612.4 | 1994-10-26 | ||
GB9421612A GB9421612D0 (en) | 1994-10-26 | 1994-10-26 | Organic compounds |
GB9422306A GB9422306D0 (en) | 1994-11-04 | 1994-11-04 | Organic compounds |
GB9422306.2 | 1994-11-04 | ||
GB9503553.1 | 1995-02-22 | ||
GBGB9503553.1A GB9503553D0 (en) | 1995-02-22 | 1995-02-22 | Organic compounds |
PCT/EP1995/004208 WO1996013249A1 (en) | 1994-10-26 | 1995-10-26 | Pharmaceutical compositions |
Publications (2)
Publication Number | Publication Date |
---|---|
MXPA97002699A true MXPA97002699A (en) | 1997-06-01 |
MX9702699A MX9702699A (en) | 1997-06-28 |
Family
ID=27267447
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
MX9702699A MX9702699A (en) | 1994-10-26 | 1995-10-26 | Pharmaceutical compositions. |
Country Status (26)
Country | Link |
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US (1) | US6352998B2 (en) |
EP (2) | EP1147766B1 (en) |
JP (3) | JP4155593B2 (en) |
KR (1) | KR100434682B1 (en) |
CN (2) | CN100335063C (en) |
AT (2) | ATE299017T1 (en) |
AU (1) | AU714254B2 (en) |
BR (1) | BR9509530A (en) |
CA (1) | CA2200966C (en) |
CY (1) | CY2211B1 (en) |
CZ (1) | CZ289773B6 (en) |
DE (3) | DE19581804T1 (en) |
DK (2) | DK1147766T3 (en) |
ES (2) | ES2173978T3 (en) |
FI (2) | FI119754B (en) |
GB (1) | GB2308546B (en) |
HK (1) | HK1053611A1 (en) |
HU (1) | HU223840B1 (en) |
MX (1) | MX9702699A (en) |
NO (2) | NO316963B1 (en) |
NZ (2) | NZ331824A (en) |
PL (1) | PL184750B1 (en) |
PT (2) | PT786986E (en) |
SI (1) | SI0786986T1 (en) |
SK (1) | SK284591B6 (en) |
WO (1) | WO1996013249A1 (en) |
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-
1995
- 1995-10-26 AU AU38451/95A patent/AU714254B2/en not_active Expired
- 1995-10-26 DE DE19581804T patent/DE19581804T1/en not_active Ceased
- 1995-10-26 AT AT01117396T patent/ATE299017T1/en active
- 1995-10-26 SI SI9530589T patent/SI0786986T1/en unknown
- 1995-10-26 SK SK520-97A patent/SK284591B6/en not_active IP Right Cessation
- 1995-10-26 AT AT95936554T patent/ATE214593T1/en active
- 1995-10-26 DK DK01117396T patent/DK1147766T3/en active
- 1995-10-26 PT PT95936554T patent/PT786986E/en unknown
- 1995-10-26 ES ES95936554T patent/ES2173978T3/en not_active Expired - Lifetime
- 1995-10-26 BR BR9509530A patent/BR9509530A/en not_active Application Discontinuation
- 1995-10-26 GB GB9707484A patent/GB2308546B/en not_active Expired - Lifetime
- 1995-10-26 KR KR1019970702752A patent/KR100434682B1/en not_active IP Right Cessation
- 1995-10-26 NZ NZ331824A patent/NZ331824A/en not_active IP Right Cessation
- 1995-10-26 DE DE69534306T patent/DE69534306T2/en not_active Expired - Lifetime
- 1995-10-26 EP EP01117396A patent/EP1147766B1/en not_active Expired - Lifetime
- 1995-10-26 JP JP51431096A patent/JP4155593B2/en not_active Expired - Lifetime
- 1995-10-26 CN CNB021243700A patent/CN100335063C/en not_active Expired - Lifetime
- 1995-10-26 ES ES01117396T patent/ES2243369T3/en not_active Expired - Lifetime
- 1995-10-26 PT PT01117396T patent/PT1147766E/en unknown
- 1995-10-26 MX MX9702699A patent/MX9702699A/en active IP Right Grant
- 1995-10-26 CA CA002200966A patent/CA2200966C/en not_active Expired - Lifetime
- 1995-10-26 CN CN95195900A patent/CN1089233C/en not_active Expired - Lifetime
- 1995-10-26 CZ CZ19971232A patent/CZ289773B6/en not_active IP Right Cessation
- 1995-10-26 PL PL95319599A patent/PL184750B1/en unknown
- 1995-10-26 WO PCT/EP1995/004208 patent/WO1996013249A1/en active IP Right Grant
- 1995-10-26 DE DE69525957T patent/DE69525957T2/en not_active Expired - Lifetime
- 1995-10-26 EP EP95936554A patent/EP0786986B1/en not_active Expired - Lifetime
- 1995-10-26 NZ NZ295170A patent/NZ295170A/en not_active IP Right Cessation
- 1995-10-26 HU HU9701928A patent/HU223840B1/en active IP Right Revival
- 1995-10-26 DK DK95936554T patent/DK0786986T3/en active
-
1997
- 1997-03-11 FI FI971018A patent/FI119754B/en not_active IP Right Cessation
- 1997-04-25 NO NO19971951A patent/NO316963B1/en not_active IP Right Cessation
-
2000
- 2000-12-01 CY CY0000067A patent/CY2211B1/en unknown
-
2001
- 2001-01-23 US US09/767,656 patent/US6352998B2/en not_active Expired - Lifetime
-
2003
- 2003-08-20 HK HK03105954A patent/HK1053611A1/en not_active IP Right Cessation
-
2004
- 2004-09-08 NO NO2004005C patent/NO2004005I2/en unknown
-
2007
- 2007-02-27 JP JP2007047216A patent/JP2007145860A/en not_active Withdrawn
- 2007-12-28 FI FI20071025A patent/FI119755B/en not_active IP Right Cessation
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2012
- 2012-03-29 JP JP2012077545A patent/JP5599422B2/en not_active Expired - Lifetime
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