CN1207687A - Pharmaceutical compositions with vitamin D analogues - Google Patents
Pharmaceutical compositions with vitamin D analogues Download PDFInfo
- Publication number
- CN1207687A CN1207687A CN96199734A CN96199734A CN1207687A CN 1207687 A CN1207687 A CN 1207687A CN 96199734 A CN96199734 A CN 96199734A CN 96199734 A CN96199734 A CN 96199734A CN 1207687 A CN1207687 A CN 1207687A
- Authority
- CN
- China
- Prior art keywords
- vitamin
- analogues
- cyclodextrin
- hydrogen atom
- preparation
- 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.)
- Pending
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- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 title claims abstract description 24
- 229930003316 Vitamin D Natural products 0.000 title claims abstract description 22
- 235000019166 vitamin D Nutrition 0.000 title claims abstract description 22
- 239000011710 vitamin D Substances 0.000 title claims abstract description 22
- 150000003710 vitamin D derivatives Chemical class 0.000 title claims abstract description 22
- 229940046008 vitamin d Drugs 0.000 title claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract 4
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 18
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000000699 topical effect Effects 0.000 claims abstract description 9
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 14
- -1 -isopropyl ester Chemical class 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 125000003435 aroyl group Chemical group 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 description 18
- 239000013543 active substance Substances 0.000 description 14
- 239000003814 drug Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 7
- 239000000839 emulsion Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000003995 emulsifying agent Substances 0.000 description 5
- 239000002674 ointment Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000011149 active material Substances 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 229940099259 vaseline Drugs 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 3
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 235000021318 Calcifediol Nutrition 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 2
- 239000010775 animal oil Substances 0.000 description 2
- 238000003287 bathing Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229960002882 calcipotriol Drugs 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 2
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 235000013599 spices Nutrition 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 2
- 235000005282 vitamin D3 Nutrition 0.000 description 2
- 239000011647 vitamin D3 Substances 0.000 description 2
- 229940021056 vitamin d3 Drugs 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- JWUBBDSIWDLEOM-XHQRYOPUSA-N (3e)-3-[(2e)-2-[1-(6-hydroxy-6-methylheptan-2-yl)-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexan-1-ol Chemical compound C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2\C1=C\C=C1/CC(O)CCC1=C JWUBBDSIWDLEOM-XHQRYOPUSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- JWUBBDSIWDLEOM-UHFFFAOYSA-N 25-Hydroxycholecalciferol Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CCC1=C JWUBBDSIWDLEOM-UHFFFAOYSA-N 0.000 description 1
- JWUBBDSIWDLEOM-NQZHSCJISA-N 25-hydroxy-3 epi cholecalciferol Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@H](O)CCC1=C JWUBBDSIWDLEOM-NQZHSCJISA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 102000055207 HMGB1 Human genes 0.000 description 1
- 101710168537 High mobility group protein B1 Proteins 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000221095 Simmondsia Species 0.000 description 1
- 235000004433 Simmondsia californica Nutrition 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- JWUBBDSIWDLEOM-DTOXIADCSA-N calcidiol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C JWUBBDSIWDLEOM-DTOXIADCSA-N 0.000 description 1
- 229960004361 calcifediol Drugs 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000007766 cera flava Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- GPTXWRGISTZRIO-UHFFFAOYSA-N chlorquinaldol Chemical compound ClC1=CC(Cl)=C(O)C2=NC(C)=CC=C21 GPTXWRGISTZRIO-UHFFFAOYSA-N 0.000 description 1
- 229960002172 chlorquinaldol Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- FBHSPRKOSMHSIF-GRMWVWQJSA-N deflazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O FBHSPRKOSMHSIF-GRMWVWQJSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- RNTRDTWDTOZSEV-UHFFFAOYSA-N norphytene Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)=C RNTRDTWDTOZSEV-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 238000006864 oxidative decomposition reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- BJYLYJCXYAMOFT-RSFVBTMBSA-N tacalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CC[C@@H](O)C(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C BJYLYJCXYAMOFT-RSFVBTMBSA-N 0.000 description 1
- 229960004907 tacalcitol Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
Pharmaceutical compositions preferably for topical application are characterised by their content of cyclodextrine clathrates and vitamin D analogues. They are useful for treating psoriasis.
Description
The present invention relates to contain the pharmaceutical preparation of cyclodextrin clathrate and non-natural vitamin D analogues.
But the invention particularly relates to this class pharmaceutical preparation of local application.This class preparation preferably is suitable for treating psoriasis.
Containing vitamin D analogues treats known to psoriatic topical preparation has been, Psorcutan (the rood catalogue 1994 that for example contains Calcipotriol, BDI Pharm-Index (Rote Liste 1994Arzneimittelverzeichnis des BDI), Editio Cantor, DE Aulendorf, No. 31271).These preparations not only have the shortcoming that causes skin irritation symptom such as rubescent, pruritus or burn feeling, hypercalcemia occurs when also having serious systemic side effects such as large tracts of land medication and essential therapy discontinued.Other shortcoming is, vitamin D analogues is the same with the vitamin D series chemical compound, itself is easy to because of oxygen and/or decomposed by light, and the pharmaceutical preparation that therefore contains these chemical compounds has only very low stability.
Once the someone attempted by preparing the clathrate compound of these chemical compounds with cyclodextrin, to improve vitamin D series chemical compound itself and some its metabolites (ostelin=vitamin D for example
2, cholecalciferol=vitamin D
3And 25-hydroxy-vitamin D
3Calcifediol) stability and dissolubility (35 phases of pharmaceutics (Pharmazie),, 779-787 page or leaf in 1993; North Acta Pharmaceutica Sinica (Acta Pharm.Nord), 2 phases, nineteen ninety, 303-312 page or leaf, pharmaceutical progress and industrial pharmaceutics (Drug Dev.and Ind.Pharm.), 19 phases,, 875-885 page or leaf and GB-A2,037,773 in 1993).Known to us, still do not have research up to now and contain the topical preparation of cyclodextrin clathrate and non-natural synthetic vitamin D analogues and detect its effect with preparation.
As if having now found that some topical drugs have splendid effect to other symptom of treatment psoriasis vulgaris and this class disease like this, they are compared with the medicine of above-mentioned tool same function, can not cause serious undesirable systemic side effects.
The vitamin D analogues that is suitable for preparing medicine of the present invention for example has calitriol (Calcitriol) (1 α, 25-dihydrovitamin D
3), calcifediol (25-hydroxy-vitamin D
3), Calcipotriol (CAS-1128-00-9), cholecalciferol (vitamin D
3) and Tacalcitol (CAS-57333-96-7).For example also have the vitamin D analogues of mentioning in the US-patent specification 5,098,899 also to be suitable for preparing medicine of the present invention in addition.
Suitable vitamins D-analog especially also has the chemical compound of explanation among the WO 94/07853, and the 25-carboxylic acid-derivant in the vitamin D-series of general formula I is wherein arranged
R wherein
1, R
2And R
3Be respectively a hydrogen atom, a saturated chain alkanoyl or an aroyl that has the straight or branched of 1 or 3 to 9 carbon atoms independently of each other, and-OH-means a α-or the hydroxyl of β-position, R
4And R
4aSimultaneously respectively be a hydrogen atom, chlorine atom or fluorine atom, trifluoromethyl, one have the saturated or undersaturated alkyl of the straight or branched of 4 carbon atoms, perhaps R at the most
4And R
4aWith carbon atom 25 be that the cycloalkyl and the Y of 3-to a 7-unit is one of following residue jointly
-C (O) NR
5R
5a,-C (O) OR
6Perhaps-CN R wherein
5, R
5a, and R
6Be respectively a hydrogen atom or an alkyl that has the straight or branched of 1 or 3 to 8 carbon atoms, and R
6It can also be group
Wherein m=0 or 1 He
N=2,3,4,5 or 6
If m=1 then n=1.
For example (5Z, 7E, 22E)-(1S, 3R, 24R)-1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetraene-25-carboxylic acid-isopropyl ester.
The clathrate compound of this vitamin D analogues was not compared with the clathrate compound of previously known vitamin D-series known to not being in the past, it is characterized by to have superior characteristic, and it also belongs to theme of the present invention.By comprise the bioavailability that has improved active substance with cyclodextrin, especially when shallow table skin layer local application, and therefore can reduce the dosage (slow release) of active substance.
These cyclodextrin derivative not only are suitable for preparing topical drug, can also advantageously be applied to prepare the dosage form of systemic administration, and similarly have the advantage of the present invention of slow release active substance.The serious systemic side effects that can reduce active substance like this makes simultaneously this material stable again.
Such low dose of the oral and systemic administration of preparation contain calitriol-analog pharmaceutical dosage form the time, the obvious fluctuation (content uniformity deficiency) of active material concentration in the dosage unit almost invariably appears, and active substance dosage is more little, and then this wave phenomenon is obvious more.
Being also shown in the concentration that makes active substance because of the oxidative decomposition of active substance in the storage of this preparation reduces.
In addition, the bioavailability of Xiao Jiliang these calitriol-analog has tangible first pass effect like this, and has between the very big individuality and intraindividual fluctuation variation.
Have now found that for oral medication:, then can avoid especially observed advantage when the pharmaceutical dosage form that contains low dose of calitriol-analog is stored at least basically if the pharmaceutical dosage form of preparation contains the Powdered cyclodextrin-inclusion compound of these active substances.
The cyclodextrin that is applicable to this clathrate compound of preparation is for example shown in general formula I I
Wherein R ' is a hydrogen atom, methyl, 2-ethoxy or 2-hydroxypropyl R " be a hydrogen atom or, work as R
1When being a methyl, also be that a methyl and r are numeral 4 to 7.
This cyclodextrin is preferably alpha-cyclodextrin, gamma-cyclodextrin, DM-, 2-hydroxyethyl-beta-schardinger dextrin-, 2-hydroxypropyl-beta-schardinger dextrin-and especially beta-schardinger dextrin-(pharmaceutical progress and industrial pharmaceutics (Drug Dev.and Ind.Pharm.)
17 phases, 1991, the 1503-1549 page or leaf, seal phenomenon magazine (J.Incl.Phenom.), 1 phase, nineteen eighty-three, 135-150 page or leaf and WO93/13138).In preparation during clathrate compound, vitamin D analogues and cyclodextrin can be chosen wantonly under the situation of the pharmacopedics adjuvant that adds other and mixes fully (for example by stirring, knead), perhaps that each component is soluble in water and/or suitable solvent (C for example
1-C
4-alcohols such as methanol, ethanol or isopropyl alcohol, perhaps C
2-C
4-ketone such as acetone, methyl ethyl ketone) in, for example remove solvent then by vacuum distilling, lyophilizing or spray drying.The vitamin D analogues that is dissolved in the suitable solvent (one of for example above-mentioned alcohols or ketone) can also be added in a kind of cyclodextrin aqueous solution in addition, sedimentary clathrate compound is filtered and drying.
It is evident that for the professional, need test in advance usually to understand which cyclodextrin energy best-fit in comprising desirable vitamin D analogues.Is the best for very micromolecular vitamin D analogues to use alpha-cyclodextrin, when comprising quite macromolecular vitamin D analogues, even may need to use gamma-cyclodextrin δ-cyclodextrin as host's molecule.Select generally speaking cyclodextrin to the ratio of vitamin D analogues to form 1: 1 mole: the mole complex, but be not precluded within the individual cases comparatively suitable be select mol ratio with for example form 2: 1,3: 1,3: 2 or 1: 2 complex.
The method itself for preparing topical drug is known.But the preparation that also can prepare new suitable skin special requirement on the other hand.
The preparation of this local application preparation is carried out according to common mode, wherein active substance and suitable additive is made desirable pharmaceutical dosage form, for example solvent, Emulsion, lotion, cream, ointment, oily ointment or unguentum.In the preparation of preparation like this, the concentration of active substance is relevant with pharmaceutical dosage form.Preferred active material concentration is 5-30 weight %.
Emulsion, lotion or cream (oil/water-emulsion) and ointment (water/oil-emulsion) can common mode be used conventional emulsifying agent preparation (Kirk Othmer: encyclopedia of chemical technology (Enzyclopedia ofChemical Technology), the 3rd edition, 1979, John Wiley ﹠amp; Sons, New York, the 8th volume, 900-930 page or leaf and Otto-Albrecht doctor Neumueller: Lv Mupusi chemistry dictionary (Roempps Chemie Lexikon), the 7th edition,, Frankh ' sche publishing house, Stuttgart, 1009-1013 page or leaf in 1973).Applied identical (Otto-Albrecht doctor Neumueller: Lv Mupusi chemistry dictionary in the wax, emulsifying agent that is applied to these Emulsions and additive commonly used and the conventional method, the 7th edition, 1973, Frankh ' sche publishing house, the Stuttgart, the 1427-1428 page or leaf).
Topical preparation of the present invention can be made up of a kind of or two kinds of active substance, hydrophilic and/or lipotropy additive, fat phase, oil/water emulsifier, water and preservative agents.
Can use Moisture factor (water complex), for example propylene glycol, glycerol, Polyethylene Glycol, carbamide, live body complex (for example intacellin), enzyme, herb extracts (for example collagen) as hydrophilic and/or lipotropy additive.As the oil phase in oil/water-Emulsion or as fat mutually suitable carbohydrate, for example fish zamene, vaseline, paraffin, triglyceride or stearin arranged, perhaps wax, for example Cera Flava or animal or plant oil are as olive oil, Oleum Arachidis hypogaeae semen, thin animal oil, almond oil, Oil of jojoba, lanoline or Oleum Helianthi.Suitable oil/water-emulsifying agent for example has octadecanol, Myrj 45 (MYRJ for example
), compound emulsifying agent (Amphoterin for example
) and fatty acid esters of sorbitan (tween80 for example
), CVP Carbopol ETD2050 (Carbopol for example
), aliphatic alcohol spermol, myristyl alcohol or mixed ester (Dehymuls for example for example
).Water can add and contain buffer agent, ethylenediamine-N for example, N, N ', the disodium salt of N '-tetraacethyl and preservative agent such as benzoic acid, Chlorquinaldol, Parabee or Benzalkoniumchlorid.
In addition with emulsion and a kind of or two kinds of active substances and also optional and spice, for example Crematest
The spice of series mixes mutually, and stirs until uniform distribution.
The concentration of active substance is relevant with drug formulation in the medicament of preparation like this.Active material concentration is preferably 0.0001% to 3% in lotion and ointment.
Following examples further specify the present invention.Embodiment 1
200mg DM-(0.15mmol) is dissolved in the 1.00ml water, under vigorous stirring, drip 50mg (5Z, 7E, 22E)-(1S, 3R, 24R)-1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), in the solution of 22-tetraene-carboxylic acid-isopropyl ester (0.10mmol) in the 0.5ml diox.After continuing stirring 15 minutes and adding the 1.2ml diox, limpid solution is freezing in dry ice-methanol-bathing pool, and follow lyophilizing 36 hours.
In order to prepare solution, it is 50 μ g/g that the weighing complex makes the concentration of active substance, and water is supplemented to 100g.Embodiment 2
With ultrasonic irradiation at least 5 minutes, make 3.93g DM-and 0.209g (5Z, 7E, 22E)-(1S, 3R, 24R)-1,3-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetraene-25-carboxylic acid-isopropyl ester is suspended in the 100ml water.Suspension was stirred 48 hours and then filtered.With filtrate freezing and lyophilizing 24 hours in acetone-dry ice-bathing pool.
In order to prepare hydrogel, the complex that produces 80 μ g/g active material concentrations is dissolved in the 99.0g water, and with gel former (Carbopol for example
-B.F.Goodrich Chem.) is processed into the dosage form that to smear.Embodiment 3
Under 38 ℃ temperature, the natural beta-schardinger dextrin-of 680mg (0.6mmol) is dissolved in 40ml 60% aquiferous ethanol by means of ultrasonic.Then under stable the stirring and under the inflated with nitrogen situation in 3 minutes with 100mg (5Z, 7E, 22E)-(1S, 3R, 24R)-1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), the drips of solution of 22-tetraene-25-carboxylic acid-isopropyl ester in 10ml 60% ethanol water adds.Under 38 ℃ of temperature, stirred 15 minutes and at 1 hour internal cooling to 13 ℃.
With formed precipitate filter, with mother solution washing and dry in a vacuum.
In order to prepare the fat gel, it is that 40 μ g/g and grinding are advanced in the 20g vaseline that the weighing complex makes active ingredient concentration.Then add vaseline until 100g in batches.
Claims (7)
1. pharmaceutical preparation is characterized by and contains cyclodextrin clathrate and vitamin D analogues.
2. according to the topical pharmaceutical formulations of claim 1.
3. according to the topical pharmaceutical formulations of claim 2, in order to the treatment psoriasis.
4. according to the pharmaceutical preparation of claim 1 to 3, contain calitriol as vitamin D analogues.
5. the clathrate compound that contains the cyclodextrin of general formula I vitamin D analogues
R wherein
1, R
2And R
3Be respectively a hydrogen atom, a saturated chain alkanoyl or an aroyl that has the straight or branched of 1 or 3 to 9 carbon atoms independently of each other, OH means a α-or the hydroxyl of β-position, R
4And R
4aBe respectively simultaneously a hydrogen atom, chlorine atom or fluorine atom, trifluoromethyl, one have the saturated or undersaturated alkyl of the straight or branched of 4 carbon atoms, perhaps R at the most
4And R
4aWith carbon atom 25 be that the cycloalkyl and the Y of 3-to a 7-unit is one of following group jointly
-C (O) NR
5R
5a,-C (O) OR
6Perhaps-CN R wherein
5, R
5a, and R
6Respectively be a hydrogen atom or an alkyl that has the straight or branched of 1 or 3 to 8 carbon atoms, and R
6It can also be group
Wherein m=0 or 1 He
N=2,3,4,5 or 6 and
If m=1 then other n=1.
6. according to the cyclodextrin clathrate of claim 5, it contain (5Z, 7E, 22E)-(1S, 3R, 24R)-1,3,24-trihydroxy-9,10-secocholesta-5,7,10 (19), 22-tetraene-25-carboxylic acid-isopropyl ester.
7. according to the pharmaceutical preparation of claim 1 to 6, it contains the cyclodextrin of general formula I I
Wherein R ' is a hydrogen atom, methyl, 2-ethoxy or 2-hydroxypropyl R " be a hydrogen atom or, work as R
1When being a methyl, also be that a methyl and r are numeral 4 to 7.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19549243A DE19549243A1 (en) | 1995-12-21 | 1995-12-21 | Pharmaceutical preparations containing clathrates of cyclodextrins and unnatural vitamin D analogues |
| DE19549243.9 | 1995-12-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1207687A true CN1207687A (en) | 1999-02-10 |
Family
ID=7781710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96199734A Pending CN1207687A (en) | 1995-12-21 | 1996-12-20 | Pharmaceutical compositions with vitamin D analogues |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0869819A1 (en) |
| JP (1) | JP2000502733A (en) |
| KR (1) | KR19990076637A (en) |
| CN (1) | CN1207687A (en) |
| AU (1) | AU1306997A (en) |
| CA (1) | CA2241205A1 (en) |
| DE (1) | DE19549243A1 (en) |
| HU (1) | HUP9903935A3 (en) |
| IL (1) | IL125020A0 (en) |
| IS (1) | IS4774A (en) |
| NO (1) | NO982874L (en) |
| WO (1) | WO1997023242A1 (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6538037B2 (en) | 1991-01-08 | 2003-03-25 | Bone Care International, Inc. | Methods for preparation and use of 1α,24(S)-dihydroxyvitamin D2 |
| US6566353B2 (en) | 1996-12-30 | 2003-05-20 | Bone Care International, Inc. | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
| US6503893B2 (en) | 1996-12-30 | 2003-01-07 | Bone Care International, Inc. | Method of treating hyperproliferative diseases using active vitamin D analogues |
| US6573256B2 (en) | 1996-12-30 | 2003-06-03 | Bone Care International, Inc. | Method of inhibiting angiogenesis using active vitamin D analogues |
| GB9826656D0 (en) | 1998-12-03 | 1999-01-27 | Novartis Ag | Organic compounds |
| DE102005017775A1 (en) * | 2005-04-13 | 2006-10-19 | Schering Ag | New complex of vitamin-D-compounds with 5Z,7E,10(19)-triene system and methylene derivatives of beta-cyclodextrin, useful for the preparation of medicament and to treat psoriasis |
| HUE029572T2 (en) | 2006-02-03 | 2017-03-28 | Opko Renal Llc | Treating vitamin d insufficiency and deficiency with 25-hydroxyvitamin d2 and 25-hydroxyvitamin d3 |
| US8329677B2 (en) | 2006-06-21 | 2012-12-11 | Cytochroma, Inc. | Method of treating and preventing secondary hyperparathyroidism |
| KR100822133B1 (en) * | 2006-11-06 | 2008-04-15 | 한미약품 주식회사 | Complex formulation for preventing or treating osteoporosis which comprises solid dispersion of vitamin d or its derivative and bisphosphonate |
| WO2008134518A2 (en) | 2007-04-25 | 2008-11-06 | Cytochroma Inc. | Methods and compounds for vitamin d therapy |
| KR101495578B1 (en) | 2007-04-25 | 2015-02-25 | 사이토크로마 인코포레이티드 | Method of treating vitamin d insufficiency and deficiency |
| EP3542792B1 (en) | 2007-04-25 | 2023-06-28 | EirGen Pharma Ltd. | Controlled release 25-hydroxyvitamin d |
| WO2008134523A1 (en) | 2007-04-25 | 2008-11-06 | Proventiv Therapeutics, Llc | Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease |
| KR101852042B1 (en) | 2008-04-02 | 2018-04-25 | 사이토크로마 인코포레이티드 | Methods, compositions, uses, and kits useful for vitamin d deficiency and related disorders |
| LT2552484T (en) | 2010-03-29 | 2020-04-27 | Opko Ireland Global Holdings, Ltd. | Methods and compositions for reducing parathyroid levels |
| KR101847947B1 (en) | 2013-03-15 | 2018-05-28 | 옵코 아이피 홀딩스 Ⅱ 인코포레이티드 | Stabilized modified release vitamin d formulation |
| CN114681468A (en) | 2014-08-07 | 2022-07-01 | 欧普科爱尔兰环球控股有限公司 | Adjunctive therapy with 25-hydroxyvitamin D |
| TW202214257A (en) | 2016-03-28 | 2022-04-16 | 愛爾蘭商歐科愛爾蘭全球控股股份有限公司 | Methods of vitamin d treatment |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU177586B (en) * | 1978-12-19 | 1981-11-28 | Chinoin Gyogyszer Es Vegyeszet | New process for preparing stable inclusion complexes of vitamine d with cyclodextrin |
| JPS5910562A (en) * | 1982-07-07 | 1984-01-20 | Teijin Ltd | Preparation of pre-1alpha-hydroxycholecalciferol compound |
| JPS5936656A (en) * | 1982-08-23 | 1984-02-28 | Teijin Ltd | Novel clathrate compound and drug containing said compound as active component |
| JPS60120812A (en) * | 1983-12-02 | 1985-06-28 | Teijin Ltd | Remedy for diabetic osteopenia |
| DE59101404D1 (en) * | 1990-01-10 | 1994-05-26 | Hoffmann La Roche | Topical preparations. |
| IL107185A (en) * | 1992-10-06 | 1998-02-22 | Schering Ag | Vitamin d, 25-carboxylic acid derivatives and pharmaceutical compositions containing the same |
-
1995
- 1995-12-21 DE DE19549243A patent/DE19549243A1/en not_active Withdrawn
-
1996
- 1996-12-20 JP JP9523335A patent/JP2000502733A/en active Pending
- 1996-12-20 AU AU13069/97A patent/AU1306997A/en not_active Abandoned
- 1996-12-20 WO PCT/EP1996/005856 patent/WO1997023242A1/en not_active Application Discontinuation
- 1996-12-20 KR KR1019980704745A patent/KR19990076637A/en not_active Application Discontinuation
- 1996-12-20 IL IL12502096A patent/IL125020A0/en unknown
- 1996-12-20 HU HU9903935A patent/HUP9903935A3/en unknown
- 1996-12-20 EP EP96944669A patent/EP0869819A1/en not_active Withdrawn
- 1996-12-20 CN CN96199734A patent/CN1207687A/en active Pending
- 1996-12-20 CA CA002241205A patent/CA2241205A1/en not_active Abandoned
-
1998
- 1998-06-15 IS IS4774A patent/IS4774A/en unknown
- 1998-06-19 NO NO982874A patent/NO982874L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO982874D0 (en) | 1998-06-19 |
| WO1997023242A1 (en) | 1997-07-03 |
| CA2241205A1 (en) | 1997-07-03 |
| NO982874L (en) | 1998-08-20 |
| IL125020A0 (en) | 1999-01-26 |
| DE19549243A1 (en) | 1997-06-26 |
| IS4774A (en) | 1998-06-15 |
| JP2000502733A (en) | 2000-03-07 |
| KR19990076637A (en) | 1999-10-15 |
| HUP9903935A2 (en) | 2000-03-28 |
| HUP9903935A3 (en) | 2000-05-29 |
| AU1306997A (en) | 1997-07-17 |
| EP0869819A1 (en) | 1998-10-14 |
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