CN100534530C - 用于抗炎化合物局部释放的载体 - Google Patents
用于抗炎化合物局部释放的载体 Download PDFInfo
- Publication number
- CN100534530C CN100534530C CNB031650058A CN03165005A CN100534530C CN 100534530 C CN100534530 C CN 100534530C CN B031650058 A CNB031650058 A CN B031650058A CN 03165005 A CN03165005 A CN 03165005A CN 100534530 C CN100534530 C CN 100534530C
- Authority
- CN
- China
- Prior art keywords
- camphora
- compositions
- menthol
- isomer
- inflammatory
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 230000000699 topical effect Effects 0.000 title claims abstract description 6
- 230000003110 anti-inflammatory effect Effects 0.000 title claims description 24
- 150000001875 compounds Chemical class 0.000 title abstract description 13
- 239000000374 eutectic mixture Substances 0.000 claims abstract description 27
- 239000007788 liquid Substances 0.000 claims abstract description 18
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims description 74
- 239000010238 camphora Substances 0.000 claims description 46
- 229940025250 camphora Drugs 0.000 claims description 46
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 claims description 45
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims description 41
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 38
- 229940041616 menthol Drugs 0.000 claims description 38
- 229960000905 indomethacin Drugs 0.000 claims description 27
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 27
- 229960001193 diclofenac sodium Drugs 0.000 claims description 17
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical group [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 14
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 claims description 14
- 229960002702 piroxicam Drugs 0.000 claims description 11
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 claims description 11
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 claims description 10
- 229940042585 tocopherol acetate Drugs 0.000 claims description 10
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 claims description 6
- 239000005844 Thymol Substances 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 229960000790 thymol Drugs 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 4
- 239000002076 α-tocopherol Substances 0.000 claims description 4
- 235000004835 α-tocopherol Nutrition 0.000 claims description 4
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims 6
- 229930003427 Vitamin E Natural products 0.000 claims 3
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims 3
- 229940046009 vitamin E Drugs 0.000 claims 3
- 239000011709 vitamin E Substances 0.000 claims 3
- 235000019165 vitamin E Nutrition 0.000 claims 3
- 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 claims 3
- 239000003814 drug Substances 0.000 description 42
- 229940079593 drug Drugs 0.000 description 27
- 239000000839 emulsion Substances 0.000 description 24
- 239000003921 oil Substances 0.000 description 23
- 235000019198 oils Nutrition 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 22
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 18
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 17
- 239000012071 phase Substances 0.000 description 14
- 238000011068 loading method Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 239000012049 topical pharmaceutical composition Substances 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 8
- 239000002674 ointment Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 6
- 229960001680 ibuprofen Drugs 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- 208000006820 Arthralgia Diseases 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- -1 dimethyl sulfoxine Chemical compound 0.000 description 4
- 230000002500 effect on skin Effects 0.000 description 4
- 230000005496 eutectics Effects 0.000 description 4
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 4
- 229960000991 ketoprofen Drugs 0.000 description 4
- 210000003205 muscle Anatomy 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 229920000136 polysorbate Polymers 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 229960003604 testosterone Drugs 0.000 description 3
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 2
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 description 2
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000004816 latex Substances 0.000 description 2
- 229920000126 latex Polymers 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 235000019615 sensations Nutrition 0.000 description 2
- 230000035943 smell Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- OIQXFRANQVWXJF-QBFSEMIESA-N (2z)-2-benzylidene-4,7,7-trimethylbicyclo[2.2.1]heptan-3-one Chemical compound CC1(C)C2CCC1(C)C(=O)\C2=C/C1=CC=CC=C1 OIQXFRANQVWXJF-QBFSEMIESA-N 0.000 description 1
- FCGXLCNBWYIEAA-UHFFFAOYSA-N 1,3-benzothiazol-6-ylmethanamine Chemical compound NCC1=CC=C2N=CSC2=C1 FCGXLCNBWYIEAA-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- ARIWANIATODDMH-AWEZNQCLSA-N 1-lauroyl-sn-glycerol Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)CO ARIWANIATODDMH-AWEZNQCLSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 description 1
- ZBCATMYQYDCTIZ-UHFFFAOYSA-N 4-methylcatechol Chemical compound CC1=CC=C(O)C(O)=C1 ZBCATMYQYDCTIZ-UHFFFAOYSA-N 0.000 description 1
- VTDOEFXTVHCAAM-UHFFFAOYSA-N 4-methylpent-3-ene-1,2,3-triol Chemical compound CC(C)=C(O)C(O)CO VTDOEFXTVHCAAM-UHFFFAOYSA-N 0.000 description 1
- IOAISUCAQCEHTA-UHFFFAOYSA-N 5-methyl-2-propan-2-ylphenol Chemical compound CC(C)C1=CC=C(C)C=C1O.CC(C)C1=CC=C(C)C=C1O IOAISUCAQCEHTA-UHFFFAOYSA-N 0.000 description 1
- 235000007173 Abies balsamea Nutrition 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 239000004857 Balsam Substances 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 229940019097 EMLA Drugs 0.000 description 1
- 206010053155 Epigastric discomfort Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 244000018716 Impatiens biflora Species 0.000 description 1
- ARIWANIATODDMH-UHFFFAOYSA-N Lauric acid monoglyceride Natural products CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 240000000203 Salix gracilistyla Species 0.000 description 1
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000003555 analeptic effect Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 210000003423 ankle Anatomy 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- KVYGGMBOZFWZBQ-UHFFFAOYSA-N benzyl nicotinate Chemical class C=1C=CN=CC=1C(=O)OCC1=CC=CC=C1 KVYGGMBOZFWZBQ-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 210000000078 claw Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 230000015961 delipidation Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000008344 egg yolk phospholipid Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 210000005081 epithelial layer Anatomy 0.000 description 1
- BEGBSFPALGFMJI-UHFFFAOYSA-N ethene;sodium Chemical group [Na].C=C BEGBSFPALGFMJI-UHFFFAOYSA-N 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000003811 finger Anatomy 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 210000004247 hand Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- CATSNJVOTSVZJV-UHFFFAOYSA-N heptan-2-one Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000012051 hydrophobic carrier Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000005067 joint tissue Anatomy 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940060184 oil ingredients Drugs 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000008321 opodeldoc Substances 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000011297 pine tar Substances 0.000 description 1
- 229940068124 pine tar Drugs 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960001807 prilocaine Drugs 0.000 description 1
- MVFGUOIZUNYYSO-UHFFFAOYSA-N prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000003507 refrigerant Substances 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 210000002832 shoulder Anatomy 0.000 description 1
- RNVYQYLELCKWAN-UHFFFAOYSA-N solketal Chemical compound CC1(C)OCC(CO)O1 RNVYQYLELCKWAN-UHFFFAOYSA-N 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000003813 thumb Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 229940063674 voltaren Drugs 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
- A61K31/125—Camphor; Nuclear substituted derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
一种用于局部释放的载体，其包括疏水性化合物的液相低共熔混合物。
Description
发明领域
本发明涉及用于控制疼痛和治疗炎症而设计的药物活性成分局部释放的半固体制剂的制备。
背景技术
不同类型的局部药物制剂已经用于治疗风湿病和关节炎疼痛长达数十年。半固体组合物包含植物衍生物，如辣椒素(红热胡椒粉刺激物质)或松节油(松焦油成分)软膏，顺势疗法的提取物和搽剂(Opodeldoc Rus)，芥末膏药，薄荷醇擦，精油香膏和许多其他药物主要被用作局部刺激物已经有相当长的时间。这些刺激物增进了局部血液流动，加速了受伤组织的康复，并转移了由炎症的慢性疼痛引起的注意力。
通过在所需部位施用含非甾族抗炎药(NSAID)的软膏或乳膏可以有效控制肌肉和关节疼痛程度。而且，当NSAID被局部使用时，肌肉和关节组织中的局部药物浓度显著高于没有治疗过的部位。另外，由于这些药在起效前不需要通过肝脏所以避免了肝内的强化代谢(也称为“首过效应”)。
这些中所需的NSAID量低于口服剂型所需量就可以达到相似的抗炎和止痛效果。NSAID最常见的副作用是对胃和胃肠道黏膜的严重刺激。这种副作用在局部使用时几乎没有。
NSAID的局部制剂在欧洲，亚洲和远东地区是非常普遍的。这类组合物的例子有Voltaren
(英国的VoltarolTM)、含有异丙醇的1.16％双氯酚酸钠二乙基铵乳膏、凝胶(0.5％吡罗昔康-水-乙醇凝胶)、不同浓度(5-10％)的布洛芬凝胶和酮洛芬凝胶和1-10％消炎痛的乙醇溶液。含DMSO的乳膏和其他许多制剂作为缓解肌肉疼痛、运动小损伤、风湿和背部疼痛治疗等的OTC药在许多国家已广泛应用。
通常，局部用NSAID制剂不产生副作用如胃刺激和内出血。有益的是，这些化合物在治疗局部肌肉和关节疼痛时提供了相对较快的起效和缓和作用。这些产品的主要问题是由于在乳膏成分中溶解度低而使得载药量低。高载药量可以通过使用浓的醇实现，如乙醇，含聚乙二醇的异丙醇和丙二醇都适合用作NSAID的溶剂。载药量能够增高并可以轻易的达到5-10％或更高，如用异丙醇的5％布洛芬凝胶，基于乙醇的1％消炎痛凝胶，或含有二甲亚砜的10％消炎痛软膏。
这些溶剂广泛用于凝胶制剂中，但是由于对皮肤的刺激的倾向而经常限制了它们的普遍使用。进一步的限制是由于身体组织的吸水后药物从溶液中沉淀从而导致凝胶制剂作用的快速终止。此外，高浓度的溶剂由于干燥和去脂作用(delipidisation)经常刺激皮肤，可能引起接触性皮炎和过敏。不溶于水溶剂和体液的药物在上皮层中沉淀并不能渗透到内部，严重地限制了抗炎作用。聚乙二醇(PEG-4000和PEG-400的混合物)亲水性局部基质也被发现有相似的现象。
传统疏水性载体如固定油、矿物油、凡士林、羊毛脂和蜡基质软膏以及乳膏(O/W型或W/O型)都很少刺激人类皮肤，但是这些也存在着另外的难题-溶解度。药物在脂相中的溶解度限制了药物在这类载体中的载药量。例如，消炎痛在橄榄油和玉米油中的溶解度低于0.2％，而酮洛芬大约是1.5％，吡罗昔康低于0.05％。根据Benita等“亚微乳剂作为静脉给药的胶体药物载体：综合的理化性质”，J.Pharm Sci，1993，11.82(11)，第1069-79页中所述，甚至对于低载药量，分散系的稳定性还存在问题。0.1％的消炎痛亚微粒乳液在储存一个月后就失去了稳定性。
更极性疏水性化合物的使用可以帮助提高NSAID的溶解度。维生素E醋酸酯、柠檬酸三乙酯、甘油月桂酸酯、甘油单油酸酯(MyverolTM 18-9)能多溶解消炎痛或双氯酚酸钠(以酸形式)1.5到2倍。尽管如此，该载药量仍不足以获得有效的NSAID乳液。透皮贴剂如带有消炎痛或双氯酚酸钠的皮肤贴片或药膏由于同样的原因而表现出低效。
进一步提高药物在油相中溶解度的方法是通过使用与指定相易混合的高极性化合物。溶剂如乙氧基乙二醇(TranscutolTM)、二甲基异山梨醇(DMIS)、异亚丙基丙三醇(SolketalTM)，和乙氧基化呋喃醇(GlucofurolTM)能够明显提高了药物在疏水分散相中的溶解(implementing)。然而，在与水混合时，大多数的溶剂被水所萃取，溶解的药物迅速并几乎全部地从油相中沉淀出来。
近来将先进的亚微粒乳液(SME)用作NSAIDs的基质，提供了非常有效的释放并使药物作用显著提高，参见Friedman等，美国专利US6,113,921。然而NSAIDs在这些乳液脂相中的低溶解度造成了有效期缩短及在存储过程中药物从油相中沉淀。NSAID的局部用制剂在SME中最佳活性所需的高载药量，只有通过高亲脂性化合物如具有显著较低抗炎活性的萘普生，酮洛芬或布洛芬实现。
局部使用的低共熔混合物受到一定程度的限制。一个例子就是由Astra-Zeneca开发的EMLA乳膏。该乳膏的液相通过混合两种局部麻醉剂利多卡因和丙胺卡因的结晶基质形成，低共熔混合物用作局部使用的乳膏剂中的油相。含5％的这种油相的乳膏提供了优良的稳定性和麻醉效果。
考虑到抗炎药物领域的局限性，需要一种能解决现在遇到的问题的改进的组合物。
发明概述
已经发现樟脑、薄荷醇、麝香草酚和相似化合物所组成的低共熔混合物对于非甾族类抗炎药及其他物质是一种特效溶剂。消炎痛，双氯酚酸钠，或酮洛芬在这些混合物中的溶解度增加了3到20倍。特别有益的是，发现该低共熔混合物是安全、无毒的并由于樟脑的抗炎性质和薄荷醇的透皮加强性质而在NSAID的抗炎作用中存在协同作用。
该低共溶混合物可与药学上可接受的油相和脂混合并加入局部制剂中。发现该药物组合物可以含有高于现有的软膏基质和乳膏中的载药量，并对皮肤没有刺激作用及提供了混合药物提高的释放性能。
在进一步讨论该制剂之前，确定薄荷醇和樟脑的一些普通性质。
所用的薄荷醇是分子量为156.27，熔点为42的(1R，2S，5R)-5-甲基-2-(1-甲基乙基)-环己醇。薄荷醇通常具有薄荷味。它在Tsuk的美国专利US4,933,184)里作为皮肤刺激物和渗透促进剂是众所周知的。它被广泛用于很多局部制剂中减轻关节和风湿疼痛。天然L-薄荷醇由于直接与皮肤中冷敏感受体作用产生清凉或提神感觉。这些在《药物赋形剂手册》第三版，由A.H.Kibbe编辑，药学出版社，伦敦，英国，2000，第334-335页上已经确立。薄荷醇已经用作轻度局部麻醉剂和在阻塞和感冒治疗中用作缓解呼吸的挥发性芳香物质，见Hughes等美国专利US5,322,689。
对于分子量为152.24的樟脑1，7，7-三甲基双环〔2，2，1〕庚酮-2也已知相似的性质。樟脑是一种具有高熔点(180)和带有强烈的松油气味甚至在室温和常压下就能升华的挥发性物质。最初，樟脑被用作***，但是现在樟脑主要被用作局部制剂中的成分。它经常用于鼻解除充血剂和芳香组合物中。
单独的薄荷醇或樟脑或两者的组合物都在局部制剂中广泛使用，这主要是由于它们的刺激作用，与受体的相互作用和特殊的传统气味，从而使它们经常与一些历史悠久的药物相联系。Ben GayTM软膏，TigerTM止痛药膏，薄荷醇胸擦(Menthol Chest Rub)及相似的组合物都众所周知和普遍。
含10％-60％水杨酸甲基酯、大于3％-11％的樟脑和1.25％-16％的薄荷醇的某些外用止痛产品，单独或结合使用，都能通过刺激降低的皮肤感觉受体引起皮肤的刺激或轻度发炎从而缓解使用部位的肌肉，关节疼痛或内脏末梢传递，见lvy等的美国专利US5,013,726)。
用于缓解关节疼痛的局部制剂包括Lang等在美国专利US4,731,200中公开的包含亚苄基樟脑衍生物的水溶性醇组合物，lvy等在美国专利US5,013,726中公开的包含水杨酸甲基酯、樟脑和薄荷醇的洗液，lvy等在美国专利US5,124,320中公开的包含薄荷醇和樟脑的止痛洗液，Heywang等在美国专利US5,144,081)中公开的包含樟脑的一种药用组合物和Singh在美国专利US5,175,152中公开的含水杨酸甲基酯、薄荷醇和樟脑的组合物。
这些物质已经被广泛用于缓解如肘部、膝盖、拇指区域、脚踝、脖子、手腕、手和手指、肩膀等处的关节疼痛。
为了提高非甾类抗炎药物的溶解度，一种表面活性剂聚乙二醇和甘油酯的复杂混合物已经和聚合物的化合物和氢氧化钠或氢氧化钾溶液一起使用，见Morton等的美国专利US5,376,688。
在Kaplun-Fischoff等“用薄荷醇与药物形成低共熔混合物促进睾酮的皮肤渗透并与皮肤脂质反应”，药物科学杂志，1997，12月，86(12)第.1394-9页中，研究者发现薄荷醇与结晶睾酮形成低共熔混合物。形成的混合物不是液态的，但是证实了睾酮透皮渗透的显著提高。根据Kaplun-Fischoff等所述，薄荷醇通过双重机制影响皮肤渗透：一是通过与渗透化合物形成低共熔混合物从而提高其在皮肤神经酰胺中的溶解度，二是通过改变角质层的屏障性质。
一份有关现有的包含不同比例薄荷醇和樟脑组合物的详细调查显示出没有一个为了提高组合物中药物的溶解度而在其中使用薄荷醇和樟脑的具体例子。在这些制剂中所有的抗炎成分都是液态的(水杨酸甲基酯，烟酸苯甲基酯)并容易和乳膏或软膏中的油性成分易混合。没有溶解度的限制，并且这些局部制剂中可以包含高达60％的活性成分，如水杨酸甲基酯，Altadonna(美国专利US5,853,768)。
在文献里没有关于在低共熔区域里薄荷醇与樟脑比例的认识。在各种情况下，使用现有的制剂只是由于它们的轻度刺激或抗炎活性(樟脑、烟酸衍生物)或薄荷醇本身加强皮肤渗透的性质。
现在认识到在极性疏水化合物的低共熔混合物中药物溶解度的根本增加使用于外部的这些药成为有效和***部制剂。
对本发明进行了上述描述后，现在参考图说明优选的实施方案。
附图简要说明
图1：是在MCT和薄荷醇/樟脑混合物的混合物中抗炎物质溶解度的图表；
图2：是在油质载体和薄荷醇/樟脑载体中消炎痛溶解度的图表；
图3：是在油质载体和低共熔混合物载体中吡罗昔康溶解度的图表；和
图4：是存储过程中药物含量变化的图表；
图表中相同的数字表示相同的要素。
优选实施方案的详细说明
结晶樟脑和薄荷醇等摩尔量的混合物在室温下迅速使结晶液化。这些混和物在制剂中用作对一些NSAID化合物有效的溶剂。
图1用图表说明了在含有不同浓度的薄荷醇-樟脑低共熔混合物的中等碳链甘油三酯(MCT，标准油载体，
TGCC)混合物中双氯酚酸钠(以游离酸形式)的溶解度。用HPLC测定双氯酚酸钠在25时的饱和浓度。发现在纯等摩尔量的薄荷醇-樟脑低共熔混合物中的溶解度比在纯MCT中的溶解度高11.8倍。
观察到消炎痛也有相似的现象，如图2中图表所述，在等摩尔量的低共熔薄荷醇-樟脑混合物中消炎痛的最大溶解度是160mg/ml，相比之下在大豆油中为2mg/ml，在MCT油中为4.8mg/ml。为了比较，Ho等“在混合溶剂***中具有增溶作用的薄荷醇促进渗透”，控制释放杂志，1998，2月，12；51(2-3)，第301-11页公开了在不同药学载体如水、乙醇、丙二醇及它们的化合物中加入薄荷醇(以重量计高达12％)增溶剂对消炎痛的影响。但无论如何最高溶解度几乎达不到2％(大约20mg/ml)。
在图3中，显示了吡罗昔康的图表数据。
吡罗昔康溶解度显著低于芳香族的NSAID，但是在室温下用低共熔薄荷醇-樟脑混合物能够增加药物溶解度8-11倍，在MCT中的溶解度为0.35mg/ml到在纯低共熔混合物中的2.9-3.2mg/ml，及在含有60％薄荷醇-樟脑(1∶1)含量的MCT中溶解度为1.8mg/ml。
如果α-维生素E或维生素E醋酸酯用作为油相，对于维生素E-薄荷醇-樟脑组合物5∶3∶3(以重量份计)溶解度可以达到30-35mg/ml。
使用另外比例的薄荷醇-樟脑低共熔混合物(如2∶1或1∶2；3∶4或4∶3)也可以提高大多数研究物质的溶解度但是范围略小。用另外的低共熔形成物取代薄荷醇，如麝香草酚(2-异丙基-5-甲基苯酚，麝香草酚油成分)也可以实现溶解度的显著提高。
在含薄荷醇-樟脑或其他低共溶混合物载体的脂相中所得到的NSAID溶液在较宽温度范围内是稳定的并对人类和动物皮肤没有刺激性(Dreize试验)。基于这些发现在下面的例子中制备和讨论含NSAID的不同局部制剂。
实施例1：1％消炎痛乳膏
载体(低共熔混合物)的制备：
在40-50℃加热将(±)樟脑和L-薄荷醇混合得到透明液体。
油相的制备：
在45℃将大豆卵磷脂，MCT油和TPGS混合直到得到均匀的溶液。然后加入吐温TM-80，接着加入低共熔混合物载体。搅拌混合物直到完全溶解。向保温混合物中加入消炎痛(USP)并在45℃搅拌十分钟直到完全溶解。
水相的制备：
将乙二胺四乙酸(EDTA)二钠盐、甘油和吐温TM-80加入水(占计算量90％)中并搅拌直至完全溶解。
乳化作用：
将溶液与油相混合，用适当的搅拌器充分混合，并使用高压均化器(
C-5)在8000-12000psi(600-800bar)的压力下使其均匀。将混合物通过均化器1-2次。
乳膏的制备：
在另外的容器中
971P与占计算量10％的水混合并保温2-6小时。将
糊和均匀的乳液用高剪切转子一定子型搅拌器(Omni GLH搅拌器)在18,000-24,000rpm下混合。混合中缓缓加入三乙醇胺直到达到要求的PH值和粘度。
实施例2：2％消炎痛乳膏
按照实施例1的方法制备该组合物。
实施例3：1％双氯酚酸钠乳膏
表3列出了1％双氯酚酸钠乳剂的组成。该乳膏包含大约14％的MCT∶樟脑∶薄荷醇的比例为：6∶3∶4的油相。
通过在45℃溶解MCT油、维生素E琥珀酸酯、卵磷脂、樟脑以及薄荷醇制备油相。
通过在85℃纯水中溶解双氯酚酸钠和吐温TM-80中制备水相。
将温油相和热水相混合后，将盐酸加入粗的乳液中同时剧烈搅拌。调节PH值到3.5-4.2之间。如同实施例2进行均匀化操作。得到精制的乳液后，通过0.45微米的PTFE膜过滤器进行过滤。该乳液用于乳膏的制备：加入971P胶凝剂得到最后1.5％的浓度并调节PH值为4.5到5.0。
通过相似方法制备1.5％的双氯酚酸钠乳膏(高载药量)。组合物成分同表3。用水和盐酸来调节平衡。
实施例4：5％布洛芬乳膏
如同实施例2所述制备5％布洛芬乳膏。表4列出了5％布洛芬乳膏乳液的组成。乳膏中包含大约26％的MCT∶樟脑∶薄荷醇比例约为4.25∶1∶1的油相。
实施例5：0.5％吡罗昔康乳膏
按照实施例4所述的方法制备该组合物，但是用麝香草酚(2-异丙基5-甲基苯酚)替代L-(-)-薄荷醇。该乳膏中包含大约28％的MCT∶樟脑∶麝香草酚∶维生素E醋酸酯比例约：2∶5∶5∶2的油相。
实施例6：对照
按美国专利US6,113,921所述制备消炎痛乳液。
将消炎痛(对于低载药量乳液为0.5g和对于高载药量乳液为1.0g)溶于蛋卵磷脂、维生素E琥珀酸酯和MCT油的预加热(60℃)的混合物中。该混合物用水相(含乳化剂EL-620、乙二胺四乙酸钠、甘油的水溶液)，并用高速剪切混合器以20,000rpm的速度乳化5分钟制成乳液。
在高压均化器中在800bar(12000psi)下进行乳液的进一步的处理6个循环。然后将其冷却到室温，调节PH值到5.6-6.5之间。部分乳液用
940凝胶化形成乳膏；其余部分乳液放入密闭的琥珀玻璃容器中常温储藏6个月观察其物理稳定性。
用类似于实施例6的方法制备双氯酚酸钠乳液(1.0％和1.5％载药量)。
为了估计药物的沉淀，用PTFE膜过滤器过滤实施例6中已储存的乳液样品或本发明所涉及的(实施例1和2)低载药量和高载药量乳液样品。通过高效液相色谱(HPLC)法来测定滤液中消炎痛的含量。图4列出了结果。
如美国专利US6,113,921所述制备的低载药量乳液在储藏期间显示了一定的稳定性，但是随着最初消炎痛的载药量的增长，非沉淀药物的最终浓度会急剧下降。相反，按照本发明制备的低共熔混合物载体的乳液却可以保持药物的含量。
从双氯酚酸钠乳液也获得了相似的结果。在含有1％药的组合物中，观察两种剂型的稳定性。在薄荷醇-樟脑低共熔混合物中双氯酚酸钠乳液含量为1.5％的组合物，室温下观察其稳定性至少3个月，相同载药量的对照乳液则会在同样时间内出现明显的药物沉淀。
“体内”抗炎活性：
动物实验研究(用角叉菜胶引起爪子浮肿的大鼠模型)证明局部涂敷含有低共熔混合物载体的组合物会产生明显的抗炎作用。
对于浮肿体积的AUC率(通过梯形规则计算其中t＝0-6小时)
| 对照(非处理) | 消炎痛乳膏(实施例2)2mg消炎痛/鼠 | 消炎痛凝胶(sumitomo Pharm.)2mg消炎痛/鼠 |
| 100％ | 32％(±12％) | 114％(±39％) |
尽管上面已经描述了本发明的实施方案，但它不是限制本发明的，本领域技术熟练人员在不背离本发明所述的和所要求保护的本发明精神、特点和范围内显然可以对本发明部分作许多改进。
Claims (21)
1.用于局部施用的药物组合物，包括：非甾族抗炎药，和用于溶解非甾族抗炎药的溶剂载体，所述非甾族抗炎药选自双氯酚酸钠、消炎痛和吡罗昔康，所述溶剂载体基本上由下列物质组成：樟脑和薄荷醇的液体低共熔混合物以及任选的液态疏水性成分；其中所述的樟脑和薄荷醇的比例为4∶1到1∶4。
2.如权利要求1所述的组合物，其中所述的樟脑和薄荷醇在所述低共熔混合物中的存在比例为2∶1到1∶2。
3.如权利要求1所述的组合物，其中所述的非甾族抗炎药是双氯酚酸钠或消炎痛。
4.如权利要求1所述的组合物，其中所述的非甾族抗炎药是吡罗昔康。
5.如权利要求1所述的组合物，其中所述的樟脑选自D-异构体、L-异构体、外消旋樟脑或樟脑异构体混合物。
6.如权利要求1所述的组合物，其中所述的薄荷醇选自D-异构体，L-异构体，外消旋薄荷醇或薄荷醇异构体混合物。
7.如权利要求1所述的组合物，其中所述液态疏水性成分是维生素E。
8.如权利要求1所述的组合物，其中所述液态疏水性成分是α-维生素E或维生素E乙酸酯。
9.用于局部施用的组合物，包括：非甾族抗炎药，和用于溶解非甾族抗炎药的溶剂载体，所述非甾族抗炎药选自双氯酚酸钠、吡罗昔康和消炎痛，所述溶剂载体基本上由下列物质组成：中等碳链的甘油三酯和樟脑和薄荷醇的液体低共熔混合物；所述组合物还任选包含液态疏水性成分，其中低共熔混合物中樟脑和薄荷醇的比例为4∶1至1∶4。
10.如权利要求9所述的组合物，其中低共熔混合物中所述的樟脑和薄荷醇的比例为2∶1到1∶2。
11.如权利要求9所述的组合物，其中所述的非甾族抗炎药是双氯酚酸钠。
12.如权利要求9所述的组合物，其中所述的非甾族抗炎药是吡罗昔康。
13.如权利要求9所述的组合物，其中所述的非甾族抗炎药是消炎痛。
14.如权利要求9所述的组合物，其中所述的樟脑选自D-异构体、L-异构体、外消旋樟脑或樟脑异构体混合物。
15.如权利要求9所述的组合物，其中所述的薄荷醇选自D-异构体，L-异构体，外消旋薄荷醇或薄荷醇异构体混合物。
16.如权利要求9所述的组合物，其中所述液体疏水性成分是维生素E。
17.如权利要求9所述的组合物，其中所述液体疏水性成分是α-维生素E或维生素E乙酸酯。
18.用于局部施用的组合物，包括：非甾族抗炎药吡罗昔康，和用于溶解吡罗昔康的溶剂载体，所述溶剂载体基本上由下列物质组成：中等碳链的甘油三酯以及樟脑和麝香草酚的液体低共熔混合物；所述组合物还任选包含液态疏水性成分，其中中等链长的甘油三酯、樟脑和麝香草酚的比例为2∶5∶5。
19.如权利要求18所述的组合物，其中所述的樟脑选自D-异构体、L-异构体、外消旋樟脑或樟脑异构体混合物。
20.如权利要求18所述的组合物，其中所述液态疏水性成分是维生素E。
21.如权利要求18所述的组合物，其中所述液态疏水性成分是α-维生素E或维生素E乙酸酯。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/255,951 | 2002-09-27 | ||
| US10/255,951 US7138394B2 (en) | 2002-09-27 | 2002-09-27 | Vehicle for topical delivery of anti-inflammatory compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1500524A CN1500524A (zh) | 2004-06-02 |
| CN100534530C true CN100534530C (zh) | 2009-09-02 |
Family
ID=32029201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB031650058A Expired - Fee Related CN100534530C (zh) | 2002-09-27 | 2003-09-27 | 用于抗炎化合物局部释放的载体 |
Country Status (4)
| Country | Link |
|---|---|
| US (3) | US7138394B2 (zh) |
| JP (1) | JP2004115525A (zh) |
| CN (1) | CN100534530C (zh) |
| MX (1) | MXPA03008947A (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105324130A (zh) * | 2013-02-01 | 2016-02-10 | D滴公司 | 液体薄荷醇组合物 |
Families Citing this family (41)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7138394B2 (en) * | 2002-09-27 | 2006-11-21 | Alpharx Inc. | Vehicle for topical delivery of anti-inflammatory compounds |
| US20060241175A1 (en) * | 2002-09-27 | 2006-10-26 | Joseph Schwarz | Vehicle for topical delivery of anti-inflammatory compounds |
| EP1858556A1 (en) * | 2005-03-16 | 2007-11-28 | Alpharx Inc. | Vehicle for topical delivery of anti-inflammatory compounds |
| US20060240051A1 (en) * | 2005-04-26 | 2006-10-26 | Singleton Andy H | Eutectic blends containing a water soluble vitamin derivative |
| DE602006008132D1 (de) * | 2005-05-05 | 2009-09-10 | Reckitt Benckiser Inc | Topische zusammensetzungen |
| US20070042007A1 (en) * | 2005-08-19 | 2007-02-22 | Joseph Schwarz | Topical composition for delivery of salicylate esters |
| US20070048360A1 (en) * | 2005-08-23 | 2007-03-01 | R Carrara Dario N | Pharmaceutical compositions with melting point depressant agents and method of making same |
| GT200600405A (es) * | 2005-09-07 | 2007-04-16 | Formula de microemulsión | |
| US9301919B2 (en) * | 2005-12-22 | 2016-04-05 | Oakwood Laboratories, Llc | Sublimable sustained release delivery system and method of making same |
| JP5028885B2 (ja) * | 2006-07-04 | 2012-09-19 | 大正製薬株式会社 | ユビデカレノン含有自己乳化組成物 |
| DE102006042742A1 (de) * | 2006-09-12 | 2008-03-27 | Barnikol-Keuten, Doris, Dr. | Nano-Vehikel für den transkutanen Transport, diese enthaltende Zubereitungen und deren Anwendung |
| MX2009004038A (es) | 2006-10-17 | 2009-08-24 | Nuvo Res | Gel de diclofenaco. |
| HU227970B1 (en) * | 2007-07-10 | 2012-07-30 | Egis Gyogyszergyar Nyrt | Pharmaceutical compositions containing silicones of high volatility |
| US8618164B2 (en) | 2009-03-31 | 2013-12-31 | Nuvo Research Inc. | Treatment of pain with topical diclofenac compounds |
| CN101524325B (zh) * | 2009-04-03 | 2010-12-29 | 龚志成 | 复方薄荷脑微乳及其鼻用制剂 |
| MX2011010547A (es) * | 2009-04-08 | 2011-12-16 | Cadila Healthcare Ltd | Composiciones farmaceuticas estables de diclofenaco. |
| CN102770123A (zh) | 2009-12-23 | 2012-11-07 | 纽沃研究股份有限公司 | 用于治疗甲癣的高渗透性特比萘芬制剂 |
| DE102010013064A1 (de) | 2010-03-26 | 2011-12-15 | Gabriele Blume | Neuartiges Trägersystem für den Transport von Wirkstoffen in die Haut |
| EP2457554A1 (de) * | 2010-11-24 | 2012-05-30 | Symrise AG | Menthol enthaltende Mischung |
| US9545429B1 (en) | 2011-09-03 | 2017-01-17 | Biolyte Laboratories, Llc | Homeopathic formulations |
| US11154535B2 (en) | 2012-07-31 | 2021-10-26 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
| US10045935B2 (en) | 2012-07-31 | 2018-08-14 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
| US10045965B2 (en) | 2012-07-31 | 2018-08-14 | Egis Pharmaceuticals Plc | Transdermal formulation containing COX inhibitors |
| FR2994386B1 (fr) * | 2012-08-07 | 2016-06-24 | Thorel Jean-Noel | Inhibition de l'adhesion de micro-organismes pathogenes par un ester de saccharose et/ou de sorbitan dans le traitement cosmetique de l'atopie cutanee |
| MX352771B (es) | 2012-12-20 | 2017-12-07 | Unilever Nv | Mezclas eutecticas en composiciones de cuidado personal. |
| CN104884034B (zh) * | 2012-12-20 | 2017-06-06 | 荷兰联合利华有限公司 | 个人护理组合物中的低共熔混合物 |
| WO2014127458A1 (en) * | 2013-02-22 | 2014-08-28 | Eastgate Pharmaceuticals Inc. | Pharmaceutical composition for transmucosal administration of benzodiazepines |
| US10568936B2 (en) | 2014-03-04 | 2020-02-25 | Eastgate Pharmaceuticals Inc. | Pharmaceutical composition for transmucosal delivery and methods for treating diabetes in a subject in need thereof |
| JP6580305B2 (ja) * | 2014-03-30 | 2019-09-25 | 小林製薬株式会社 | 外用医薬組成物 |
| JP6599083B2 (ja) * | 2014-03-30 | 2019-10-30 | 小林製薬株式会社 | 外用医薬組成物 |
| US9012402B1 (en) | 2014-06-11 | 2015-04-21 | James Blanchard | Gel for topical delivery of NSAIDs to provide relief of musculoskeletal pain and methods for its preparation |
| US9623062B2 (en) * | 2014-06-27 | 2017-04-18 | Jeju National University Industryacademic Cooperation Foundation | Anti-ageing activity of camphor in fibroblast cell line |
| US10828251B1 (en) | 2017-01-14 | 2020-11-10 | Biolyte Laboratories, Llc | Homeopathic formulations |
| US10617634B1 (en) | 2017-03-10 | 2020-04-14 | Biolyte Laboratories, Llc | Topical homeopathic formulations for menstrual cramps |
| US10821075B1 (en) | 2017-07-12 | 2020-11-03 | James Blanchard | Compositions for topical application of a medicaments onto a mammalian body surface |
| AR115781A1 (es) * | 2018-07-13 | 2021-02-24 | Upl Ltd | Composición que comprende mezcla eutéctica de boscalid y un fungicida de estrobilurina |
| FR3085849B1 (fr) * | 2018-09-17 | 2021-01-01 | Soc Dexploitation De Produits Pour Les Industries Chimiques Seppic | Composition pharmaceutique a usage topique comprenant au moins une substance anti-inflammatoire |
| AU2019363244A1 (en) | 2018-10-15 | 2021-05-20 | Cipla Limited | Pharmaceutical formulation |
| WO2020188547A1 (en) * | 2019-03-21 | 2020-09-24 | Universidade Nova De Lisboa | Terpene based therapeutic deep eutectic system, method of obtaining and uses thereof |
| US20220079873A1 (en) * | 2020-09-11 | 2022-03-17 | Ps Therapy Ltd. | Topical compositions and methods of use |
| CN118084849A (zh) * | 2024-01-22 | 2024-05-28 | 南京默可思泰医药科技有限公司 | 一种含有麝香草酚及其衍生物的胶束制剂的制备方法和应用 |
Family Cites Families (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5446818A (en) * | 1977-09-21 | 1979-04-13 | Lion Dentifrice Co Ltd | Surgical antiiinflammatory and anodyne agent |
| JPS5446816A (en) | 1977-09-21 | 1979-04-13 | Kirie Kawasaki | Extracting of vitamin c and extracting container |
| JPS5467022A (en) * | 1977-11-07 | 1979-05-30 | Toko Yakuhin Kogyo Kk | Topical agent and production thereof |
| JPS5562013A (en) * | 1978-11-02 | 1980-05-10 | Rakuule Yakuhin Hanbai Kk | Aqueous poultice comprising transcutaneous absorbable anti-inflammatory agent |
| DE3048369C2 (de) * | 1980-12-22 | 1983-01-05 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V., 8000 München | Abrasiv wirkende Mittel und deren Verwendung |
| JPS58189115A (ja) * | 1982-04-30 | 1983-11-04 | Kowa Co | 外用剤 |
| LU84607A1 (fr) * | 1983-01-26 | 1984-10-24 | Oreal | Compositions alcooliques ou hydroalcooliques contenant des essences naturelles et du benzylidene camphre ou ses derives |
| US4933184A (en) * | 1983-12-22 | 1990-06-12 | American Home Products Corp. (Del) | Menthol enhancement of transdermal drug delivery |
| JPS6112614A (ja) * | 1984-06-27 | 1986-01-21 | Lion Corp | 水性パップ剤 |
| JPS63179820A (ja) * | 1987-01-22 | 1988-07-23 | Kao Corp | 坐剤組成物 |
| JPS63201119A (ja) * | 1987-02-17 | 1988-08-19 | Kao Corp | 貼付剤組成物 |
| JPS6388125A (ja) * | 1987-08-29 | 1988-04-19 | Rakuule Yakuhin Hanbai Kk | インドメタシン配合のパップ剤 |
| US5013726A (en) * | 1989-09-12 | 1991-05-07 | Ivy Jeffery W | External analgesic lotion containing active ingredients of methyl salicylate and camphor and menthol and method of making such lotion |
| US5124320A (en) * | 1989-09-12 | 1992-06-23 | Ivy Jeffery W | An external analgesic lotion containing active ingredients of camphor and menthol and method of making such lotion |
| CA2028496A1 (en) * | 1989-10-31 | 1991-05-01 | Tohru Nakao | Thiophene compounds and their pharmaceutical uses |
| US5013728A (en) * | 1990-05-04 | 1991-05-07 | Colgate - Palmolive Company | Composition for treating osteoporosis and hormonal imbalance |
| DE4027980A1 (de) * | 1990-09-04 | 1992-03-05 | Merck Patent Gmbh | Dialkoxybenzylidenkampfer-derivate |
| US5175152A (en) * | 1990-09-28 | 1992-12-29 | Singh Nikhilesh N | Composition containing ephedrine base and alkyl salicylate for the delivery of ephedrine base in vapor form |
| US5322689A (en) * | 1992-03-10 | 1994-06-21 | The Procter & Gamble Company | Topical aromatic releasing compositions |
| US5376688A (en) * | 1992-12-18 | 1994-12-27 | R. P. Scherer Corporation | Enhanced solubility pharmaceutical solutions |
| US6113921A (en) * | 1993-03-23 | 2000-09-05 | Pharmos Corp. | Topical and transdermal delivery system utilizing submicron oil spheres |
| US5853768A (en) * | 1995-03-01 | 1998-12-29 | Altadonna; James | Topical preparation and method for pain relief |
| US5961997A (en) * | 1997-03-25 | 1999-10-05 | Swinehart; James M. | Antipruritic composition |
| WO1998051283A1 (en) * | 1997-05-14 | 1998-11-19 | Galen (Chemicals) Limited | Topical compositions |
| US6447817B1 (en) * | 1998-08-10 | 2002-09-10 | Nippon Hypox Laboratories Inc. | Anti-inflammatory analgesic |
| JP2002154952A (ja) * | 2000-11-15 | 2002-05-28 | Ikeda Mohandou:Kk | ｌ−メントール高含有含水膏剤及びパッチ剤 |
| US20060241175A1 (en) * | 2002-09-27 | 2006-10-26 | Joseph Schwarz | Vehicle for topical delivery of anti-inflammatory compounds |
| US7138394B2 (en) * | 2002-09-27 | 2006-11-21 | Alpharx Inc. | Vehicle for topical delivery of anti-inflammatory compounds |
-
2002
- 2002-09-27 US US10/255,951 patent/US7138394B2/en not_active Expired - Fee Related
-
2003
- 2003-09-27 CN CNB031650058A patent/CN100534530C/zh not_active Expired - Fee Related
- 2003-09-29 MX MXPA03008947A patent/MXPA03008947A/es active IP Right Grant
- 2003-09-29 JP JP2003338818A patent/JP2004115525A/ja active Pending
-
2005
- 2005-03-16 US US11/080,812 patent/US20050158348A1/en not_active Abandoned
-
2006
- 2006-05-18 US US11/435,939 patent/US7781429B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105324130A (zh) * | 2013-02-01 | 2016-02-10 | D滴公司 | 液体薄荷醇组合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| US20060211688A1 (en) | 2006-09-21 |
| CN1500524A (zh) | 2004-06-02 |
| MXPA03008947A (es) | 2005-04-19 |
| US7138394B2 (en) | 2006-11-21 |
| US20050158348A1 (en) | 2005-07-21 |
| US7781429B2 (en) | 2010-08-24 |
| US20040063794A1 (en) | 2004-04-01 |
| JP2004115525A (ja) | 2004-04-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100534530C (zh) | 用于抗炎化合物局部释放的载体 | |
| EP0672422B1 (en) | Antiinflammatory and analgesic transdermal gel containing Ketoprofen | |
| JP5734479B2 (ja) | ジクロフェナクの新規な非水性外用溶液およびそれを調製するためのプロセス | |
| US20060241175A1 (en) | Vehicle for topical delivery of anti-inflammatory compounds | |
| CN106572970B (zh) | 用于局部给药非甾体抗炎药以缓解肌肉骨骼疼痛的新型凝胶及其制备方法 | |
| EP1858556A1 (en) | Vehicle for topical delivery of anti-inflammatory compounds | |
| JP2002519366A (ja) | 医薬的に活性な作用物質を迅速かつ非刺激的に経皮送達するための組成物、およびそのような組成物の調剤法およびそれらの送達 | |
| CN109414405A (zh) | 递送*** | |
| JP4549006B2 (ja) | ゲル軟膏 | |
| JP5052558B2 (ja) | ゲル軟膏 | |
| Dua et al. | Aceclofenac topical dosage forms: and characterization | |
| US20200301526A1 (en) | Novel non-aqueous topical solution of diclofenac and process for preparing the same | |
| TW200403077A (en) | Trans-dermal absorption preparation | |
| US20070042007A1 (en) | Topical composition for delivery of salicylate esters | |
| JP2022543703A (ja) | Ｃｂｄ製剤およびその使用 | |
| JP3091285B2 (ja) | 外用消炎鎮痛剤 | |
| CA2500907A1 (en) | Vehicle for topical delivery of anti-inflammatory compounds | |
| CN103505414B (zh) | 丁苯酞滴鼻剂及其制备方法 | |
| RU2582278C2 (ru) | Трансдермальное средство для лечения и профилактики болезней суставов и мягких тканей, способ его получения и комбинированный трансдермальный препарат для лечения и профилактики болезней суставов и мягких тканей | |
| EP3795146B1 (en) | Pain-relieving and anti-inflammatory composition for local use | |
| NO313616B1 (no) | Terapeutiske og kosmetiske sammensetninger og deres anvendelse | |
| AU2016200684B2 (en) | Use of heptyl glucoside as skin penetration enhancer in transdermal pharmaceutical compositions | |
| KR102213669B1 (ko) | 카페인 가용화 조성물 | |
| WO2012047007A2 (ko) | 손톱 또는 발톱 성장 촉진용 조성물 | |
| JP7253328B2 (ja) | 外用医薬組成物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: UME WORLD LIMITED Free format text: FORMER NAME: ALFARIX INC. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: Ontario Patentee after: UMEWORLD Address before: Ontario Patentee before: Alfarix Inc. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090902 Termination date: 20150927 |
|
| EXPY | Termination of patent right or utility model |