CA1116082A - Pharmaceutical compositions and method of use - Google Patents
Pharmaceutical compositions and method of useInfo
- Publication number
- CA1116082A CA1116082A CA311,816A CA311816A CA1116082A CA 1116082 A CA1116082 A CA 1116082A CA 311816 A CA311816 A CA 311816A CA 1116082 A CA1116082 A CA 1116082A
- Authority
- CA
- Canada
- Prior art keywords
- oxide
- pyridyl
- bis
- disulfide
- c5h4nos
- 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
Links
- 238000000034 method Methods 0.000 title description 4
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- ZHDBTKPXEJDTTQ-UHFFFAOYSA-N dipyrithione Chemical compound [O-][N+]1=CC=CC=C1SSC1=CC=CC=[N+]1[O-] ZHDBTKPXEJDTTQ-UHFFFAOYSA-N 0.000 claims abstract description 67
- 239000000203 mixture Substances 0.000 claims abstract description 42
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims abstract description 27
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 18
- 239000011777 magnesium Substances 0.000 claims abstract description 18
- 206010061218 Inflammation Diseases 0.000 claims abstract description 12
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 12
- 230000004054 inflammatory process Effects 0.000 claims abstract description 12
- 239000003246 corticosteroid Substances 0.000 claims abstract description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 8
- 150000001450 anions Chemical class 0.000 claims abstract description 6
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims abstract description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 5
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 229910052793 cadmium Inorganic materials 0.000 claims abstract description 5
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052742 iron Inorganic materials 0.000 claims abstract description 5
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims abstract description 5
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims abstract description 5
- 150000007524 organic acids Chemical class 0.000 claims abstract description 5
- 229910052718 tin Inorganic materials 0.000 claims abstract description 5
- 239000011135 tin Substances 0.000 claims abstract description 5
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 5
- 239000011701 zinc Substances 0.000 claims abstract description 5
- 229910052726 zirconium Inorganic materials 0.000 claims abstract description 5
- 150000001342 alkaline earth metals Chemical class 0.000 claims abstract description 4
- 239000003937 drug carrier Substances 0.000 claims abstract description 4
- 241001465754 Metazoa Species 0.000 claims abstract 4
- 150000007522 mineralic acids Chemical class 0.000 claims abstract 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 80
- 229960000890 hydrocortisone Drugs 0.000 claims description 40
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 230000000699 topical effect Effects 0.000 claims description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 claims description 3
- 229960001067 hydrocortisone acetate Drugs 0.000 claims description 3
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 3
- MEZCUMCMVYZPAH-UHFFFAOYSA-N 6-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound O=C1CCC2(C)C3C(O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CC(F)C2=C1 MEZCUMCMVYZPAH-UHFFFAOYSA-N 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- 150000001805 chlorine compounds Chemical group 0.000 claims description 2
- BMCQMVFGOVHVNG-TUFAYURCSA-N cortisol 17-butyrate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O BMCQMVFGOVHVNG-TUFAYURCSA-N 0.000 claims description 2
- FZCHYNWYXKICIO-FZNHGJLXSA-N cortisol 17-valerate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O FZCHYNWYXKICIO-FZNHGJLXSA-N 0.000 claims description 2
- HUPFGZXOMWLGNK-UHFFFAOYSA-N diflunisal Chemical compound C1=C(O)C(C(=O)O)=CC(C=2C(=CC(F)=CC=2)F)=C1 HUPFGZXOMWLGNK-UHFFFAOYSA-N 0.000 claims description 2
- 229960001347 fluocinolone acetonide Drugs 0.000 claims description 2
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 229960001524 hydrocortisone butyrate Drugs 0.000 claims description 2
- 229960000631 hydrocortisone valerate Drugs 0.000 claims description 2
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 150000002823 nitrates Chemical class 0.000 claims description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 2
- 229960002117 triamcinolone acetonide Drugs 0.000 claims description 2
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 claims description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims 1
- 229910052788 barium Chemical group 0.000 claims 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical group [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 150000002739 metals Chemical class 0.000 claims 1
- 229960001334 corticosteroids Drugs 0.000 abstract description 8
- 230000002195 synergetic effect Effects 0.000 abstract description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- GICMNOWCGVPPPO-UHFFFAOYSA-L magnesium;1-oxido-2-[(1-oxidopyridin-1-ium-2-yl)disulfanyl]pyridin-1-ium;sulfate Chemical compound [Mg+2].[O-]S([O-])(=O)=O.[O-][N+]1=CC=CC=C1SSC1=CC=CC=[N+]1[O-] GICMNOWCGVPPPO-UHFFFAOYSA-L 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 235000001055 magnesium Nutrition 0.000 description 12
- 229940091250 magnesium supplement Drugs 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- -1 bis-(2-pyridyl-n-oxide) disulfide com-pound Chemical class 0.000 description 10
- 229960003390 magnesium sulfate Drugs 0.000 description 10
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 10
- 229940117173 croton oil Drugs 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000002674 ointment Substances 0.000 description 8
- 230000004044 response Effects 0.000 description 8
- 206010030113 Oedema Diseases 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000006071 cream Substances 0.000 description 6
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical class [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- 239000002085 irritant Substances 0.000 description 5
- 231100000021 irritant Toxicity 0.000 description 5
- 235000013336 milk Nutrition 0.000 description 5
- 239000008267 milk Substances 0.000 description 5
- 210000004080 milk Anatomy 0.000 description 5
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 229940012831 stearyl alcohol Drugs 0.000 description 5
- 230000003637 steroidlike Effects 0.000 description 5
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000006210 lotion Substances 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000004166 Lanolin Substances 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241001456035 Stachys crenata Species 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 229940000425 combination drug Drugs 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 229940039717 lanolin Drugs 0.000 description 3
- 235000019388 lanolin Nutrition 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000002304 perfume Substances 0.000 description 3
- 235000019271 petrolatum Nutrition 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 239000003871 white petrolatum Substances 0.000 description 3
- 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 description 2
- 244000060011 Cocos nucifera Species 0.000 description 2
- 235000013162 Cocos nucifera Nutrition 0.000 description 2
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- 239000005662 Paraffin oil Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- IWOUKMZUPDVPGQ-UHFFFAOYSA-N barium nitrate Chemical compound [Ba+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O IWOUKMZUPDVPGQ-UHFFFAOYSA-N 0.000 description 2
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 2
- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical compound [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 229960002089 ferrous chloride Drugs 0.000 description 2
- 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 description 2
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 description 2
- IIPYXGDZVMZOAP-UHFFFAOYSA-N lithium nitrate Chemical compound [Li+].[O-][N+]([O-])=O IIPYXGDZVMZOAP-UHFFFAOYSA-N 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- DHEQXMRUPNDRPG-UHFFFAOYSA-N strontium nitrate Chemical compound [Sr+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O DHEQXMRUPNDRPG-UHFFFAOYSA-N 0.000 description 2
- UBXAKNTVXQMEAG-UHFFFAOYSA-L strontium sulfate Chemical compound [Sr+2].[O-]S([O-])(=O)=O UBXAKNTVXQMEAG-UHFFFAOYSA-L 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 description 2
- OERNJTNJEZOPIA-UHFFFAOYSA-N zirconium nitrate Chemical compound [Zr+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O OERNJTNJEZOPIA-UHFFFAOYSA-N 0.000 description 2
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- FABAOYOFJNAVHB-KVVVOXFISA-N (z)-octadec-9-enoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O FABAOYOFJNAVHB-KVVVOXFISA-N 0.000 description 1
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- DUFCMRCMPHIFTR-UHFFFAOYSA-N 5-(dimethylsulfamoyl)-2-methylfuran-3-carboxylic acid Chemical compound CN(C)S(=O)(=O)C1=CC(C(O)=O)=C(C)O1 DUFCMRCMPHIFTR-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- HJEINPVZRDJRBY-UHFFFAOYSA-N Disul Chemical compound OS(=O)(=O)OCCOC1=CC=C(Cl)C=C1Cl HJEINPVZRDJRBY-UHFFFAOYSA-N 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 241000124008 Mammalia Species 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
- 244000037795 Pachira macrocarpa Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- MCDLETWIOVSGJT-UHFFFAOYSA-N acetic acid;iron Chemical compound [Fe].CC(O)=O.CC(O)=O MCDLETWIOVSGJT-UHFFFAOYSA-N 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- ITHZDDVSAWDQPZ-UHFFFAOYSA-L barium acetate Chemical compound [Ba+2].CC([O-])=O.CC([O-])=O ITHZDDVSAWDQPZ-UHFFFAOYSA-L 0.000 description 1
- ISFLYIRWQDJPDR-UHFFFAOYSA-L barium chlorate Chemical compound [Ba+2].[O-]Cl(=O)=O.[O-]Cl(=O)=O ISFLYIRWQDJPDR-UHFFFAOYSA-L 0.000 description 1
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 1
- 229910001626 barium chloride Inorganic materials 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940067573 brown iron oxide Drugs 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- YALMXYPQBUJUME-UHFFFAOYSA-L calcium chlorate Chemical compound [Ca+2].[O-]Cl(=O)=O.[O-]Cl(=O)=O YALMXYPQBUJUME-UHFFFAOYSA-L 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000007799 cork Substances 0.000 description 1
- 150000001886 cortisols Chemical class 0.000 description 1
- PNOXNTGLSKTMQO-UHFFFAOYSA-L diacetyloxytin Chemical compound CC(=O)O[Sn]OC(C)=O PNOXNTGLSKTMQO-UHFFFAOYSA-L 0.000 description 1
- SPCNPOWOBZQWJK-UHFFFAOYSA-N dimethoxy-(2-propan-2-ylsulfanylethylsulfanyl)-sulfanylidene-$l^{5}-phosphane Chemical compound COP(=S)(OC)SCCSC(C)C SPCNPOWOBZQWJK-UHFFFAOYSA-N 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 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 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000011874 heated mixture Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- XQHAGELNRSUUGU-UHFFFAOYSA-M lithium chlorate Chemical compound [Li+].[O-]Cl(=O)=O XQHAGELNRSUUGU-UHFFFAOYSA-M 0.000 description 1
- INHCSSUBVCNVSK-UHFFFAOYSA-L lithium sulfate Inorganic materials [Li+].[Li+].[O-]S([O-])(=O)=O INHCSSUBVCNVSK-UHFFFAOYSA-L 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- VKJKEPKFPUWCAS-UHFFFAOYSA-M potassium chlorate Chemical compound [K+].[O-]Cl(=O)=O VKJKEPKFPUWCAS-UHFFFAOYSA-M 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- RCIVOBGSMSSVTR-UHFFFAOYSA-L stannous sulfate Chemical compound [SnH2+2].[O-]S([O-])(=O)=O RCIVOBGSMSSVTR-UHFFFAOYSA-L 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- FRTABACCYANHFP-UHFFFAOYSA-L strontium chlorate Chemical compound [Sr+2].[O-]Cl(=O)=O.[O-]Cl(=O)=O FRTABACCYANHFP-UHFFFAOYSA-L 0.000 description 1
- 229910001631 strontium chloride Inorganic materials 0.000 description 1
- AHBGXTDRMVNFER-UHFFFAOYSA-L strontium dichloride Chemical compound [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 description 1
- RXSHXLOMRZJCLB-UHFFFAOYSA-L strontium;diacetate Chemical compound [Sr+2].CC([O-])=O.CC([O-])=O RXSHXLOMRZJCLB-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 201000004415 tendinitis Diseases 0.000 description 1
- RBTVSNLYYIMMKS-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CC(N)C1 RBTVSNLYYIMMKS-UHFFFAOYSA-N 0.000 description 1
- 230000003096 thymolvtic effect Effects 0.000 description 1
- 229910000375 tin(II) sulfate Inorganic materials 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000004260 weight control Methods 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- GTQFPPIXGLYKCZ-UHFFFAOYSA-L zinc chlorate Chemical compound [Zn+2].[O-]Cl(=O)=O.[O-]Cl(=O)=O GTQFPPIXGLYKCZ-UHFFFAOYSA-L 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- ZXAUZSQITFJWPS-UHFFFAOYSA-J zirconium(4+);disulfate Chemical compound [Zr+4].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O ZXAUZSQITFJWPS-UHFFFAOYSA-J 0.000 description 1
- MKPKCNXKRRNKMM-UHFFFAOYSA-J zirconium(4+);tetrachlorate Chemical compound [Zr+4].[O-]Cl(=O)=O.[O-]Cl(=O)=O.[O-]Cl(=O)=O.[O-]Cl(=O)=O MKPKCNXKRRNKMM-UHFFFAOYSA-J 0.000 description 1
Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4933—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having sulfur as an exocyclic substituent, e.g. pyridinethione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/63—Steroids; Derivatives thereof
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/59—Mixtures
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Birds (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
A B S T R A C T
The present invention relates to a novel synergistic composition for the treatment of inflammation in warm blooded animals which comprises an effective amount of bis-(2-pyridyl-1-oxide) disulfide and/or at least one adduct of bis-12-pyridyl-1-oxide) disulfide having the empirical formula:
(C5H4NOS)2MYt (I) wherein M represents a member selected from the group con-sisting of zinc, iron, magnesium, tin, cadmium, zirconium, alkali and alkaline earth metals; Y is the anion of an inor-ganic or organic acid and t is either 1 or 2 in admixture with a pharmaceutical carrier. Bis-(2-pyridyl-1-oxide) disulfide or its adducts have been further found to enhance the anti-inflammatory activity of corticosteroids and non-steroidal anti-inflammatory agents.
The present invention relates to a novel synergistic composition for the treatment of inflammation in warm blooded animals which comprises an effective amount of bis-(2-pyridyl-1-oxide) disulfide and/or at least one adduct of bis-12-pyridyl-1-oxide) disulfide having the empirical formula:
(C5H4NOS)2MYt (I) wherein M represents a member selected from the group con-sisting of zinc, iron, magnesium, tin, cadmium, zirconium, alkali and alkaline earth metals; Y is the anion of an inor-ganic or organic acid and t is either 1 or 2 in admixture with a pharmaceutical carrier. Bis-(2-pyridyl-1-oxide) disulfide or its adducts have been further found to enhance the anti-inflammatory activity of corticosteroids and non-steroidal anti-inflammatory agents.
Description
.2 The present invent~on relates to the novel compo-sition for the treatment of inflammation in mammals which comprises bis-(2-pyridyl-1-oxide) disulfide alone or in combi-nation with non-steroidal anti-inflammatory agents or cortico-steroids in admixture with a pharmaceutical carrier.
Bis-(2-pyridyl-n-oxide) disulfide and its adducts have been found to be effective for the relieF and inhibition of inflammatory conditions through their topical adminis-tration.
It has been further found that even more pronounced pharmacological properties for the relief and inhibition of inflammation conditions can be provided by providing a topical combination of a non-steroidal anti-inflammatory agent or a corticosteroid and a bis-(2-pyridyl-n-oxide) disulfide com-pound, that is, bis-(2-pyridyl-1-oxide) disulfide and/or the adducts of bis-(2-pyridyl-1-oxide) disulfide according to this invention. More specifically, these adducts have the formula:
(C5H4NOs)2MYt (I) wherein M represents a member selected from the group consist-ing of zinc, iron, magnesium, tin, cadmium, zirconium, alkali and alkaline earth metals; Y is the anion of an inorganic. or organic acid and t is either 1 or 2. More particularly, the anion Y is selected from the group consisting of halides, sul-fates, nitrates, chlorates and acetates~ with the chlorides and sulfates being most preferable. More particularly preferred are the water-soluble adducts, especially calcium chloride (CaC12) or magnesium sulfate (MgS04). Also included in the adducts of this invention are the hydrates of the afore-mentioned compounds, i.e., adducts including nH20 groups where n is an integer of 0 to 10. Additionally, the adducts (I) may contain one or more substituents on either or both pyridine ~:
8.~
ring structures such as alkyls, halogens and alkoxy groups.
It is further noted that (C5H4NOS)2 as used in (I) above and throughout the specification and claims represents bis-(2-pyridyl-l-oxide) disulFide and the structural formula (I).
Among the adducts which may be utilized in combi-nation with the non-steroidal anti-inflammatory ayents or corticosteroids in this invention may be mentioned:
Bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate, bis-(2-pyridyl-1-oxide) disulfide magnesium acetate, bis-(2-pyridyl-l-oxide) disulfide magnesium chloride, bis-(2-pyridyl-l-oxide) disulfide magnesium bromide, bis-(2-pyridyl-1-oxide) disulfide calcium chloride, bis-(2-pyridyl-1-oxide) disulfide calcium sulfate, bis-(2-pyridyl-1-oxide) disulfide calcium nitrate, bis-(2-pyridyl-1-oxide) disulfide calcium acetate, bis-(2-pyridyl-1-oxide) disulfide calcium chlorate, bis-(2-pyridyl-1-oxide) disulfide barium chloride, bis-(2-pyridyl-1-oxide) disulfide barium sulfate, bis-(2-pyridyl-1-oxide) disulfide barium nitrate, bis-(2-pyridyl-1-oxide) disulfide barium acetate, bis-(2-pyridyl-1-oxide) disulfide barium chlorate, bis-(2-pyridyl-1-oxide) disulfide strontiu~ chloride, bis-(2-pyridyl-1-oxide) disulFide strontium sulfate, bis-(2-pyridyl-l-oxide) disulfide strontium nitrate, bis-(2-pyridyl-1-oxide) disulfide strontium acetate, bis-(2-pyridyl-1-oxide) disulfide strontium chlorate, bis-(2-pyridyl-1-oxide) disulfide potassium chloricle, bis-(2-pyridyl-1-oxide) disulfide potassium sulfate, bis-(2-pyridyl-1-oxide) disulfide potassium nitrate, bis-(2-pyridyl-1-oxide) disulfide potassium acetate, bis-(2-pyridyl-l-oxide) disulfide potassium chlorate, bis-(2-pyridyl-l-oxide) disulfide sodium chloride, bis-(2-pyridyl-1-oxide) disulfide sodium sulfate, bis-(2-pyridyl-1-oxide) disulfide sodium nitrate, bis-(2-pyridyl-1-oxide) disulfide sodium ,;
: , , acetate, bis-(2-pyridyl-l-oxide) disulfide sodium chlorate, bis-(2-pyridyl-1-oxide) disulfide zinc chloride, bis-(2-pyridyl-l-oxide) disulfide zinc sulfate, bis-(2-pyridyl-1-oxide) disulfide zinc nitrate, bis-(2-pyridyl-1-oxide) disulfide zinc acetate, bis-(2-pyridyl-1-oxide) disulfide zinc chlorate, bis-(2-pyridyl-1-oxide) disulfide stannous chloride, bis-(2 pyridyl-l-oxide) disulfide stannous sulfate, bis-(2-pyridyl-l-oxide) disulfide stannous nitrate, bis-(2-pyridyl-1-oxide) disulfide stannous acetate, bis-(2-pyridyl-l~oxide) disulfide stannous chlorate, bis-(2-pyridyl-1-oxide) disulfide zirconium chloride, bis-(2-pyridyl-1-oxide) disulfide zirconium sulfate, bis-(2-pyridyl-1-oxide) disulfide zirconium nitrate, bis-(2-pyridyl-1-oxide) disulfide zirconium acetate, bis-(2-pyridyl-l-oxide) disulfide zirconium chlorate, bis-(2-pyridyl-1-oxide) disulfide ferrous chloride, bis-(2-pyridyl-1-oxide) disulfide ferrous sulfate, bis-(2-pyridy1-1-oxide) disulfide ferrous nitrate, bis-(2-pyridyl-1-oxide) disulfide ferrous acetate, bis-(2-pyridyl-1-oxide) disulfide ferrous chlorate, bis-(2-pyridyl-1-oxide) disulfide lithium sulfate, bis-(2-pyridyl-l-oxide) disulfide lithium nitrate, bis-(2-pyridyl-1-oxide) disulfide lithium acetate, and bis-(2-pyridyl-1-oxide) disulfide lithium chlorate.
Any one of the known effective anti-inFlammatory corticosteroids may be utilized in this invention. Among the suitable corticosteroids include hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, triamcinolone acetonide, fluocinolone acetonide, 16~-hydroxy-prednisolone-16~,17~-acetonide, fluorohydrocortisone, 1-dehydrocortisone, and the like. Preferably, the hydrocortisone compounds are used in connection with the active adducts I.
A number of known effective anti-inflammatory non-: . .' , .
steroidal agents may be utilized in this invention. Among thesuitable non-steroidal agents may be mentioned l-(p-chloro-ben~oyl)-5-methoxy-2-methylindole-3-acetic acid d-2-(6-methoxy-
Bis-(2-pyridyl-n-oxide) disulfide and its adducts have been found to be effective for the relieF and inhibition of inflammatory conditions through their topical adminis-tration.
It has been further found that even more pronounced pharmacological properties for the relief and inhibition of inflammation conditions can be provided by providing a topical combination of a non-steroidal anti-inflammatory agent or a corticosteroid and a bis-(2-pyridyl-n-oxide) disulfide com-pound, that is, bis-(2-pyridyl-1-oxide) disulfide and/or the adducts of bis-(2-pyridyl-1-oxide) disulfide according to this invention. More specifically, these adducts have the formula:
(C5H4NOs)2MYt (I) wherein M represents a member selected from the group consist-ing of zinc, iron, magnesium, tin, cadmium, zirconium, alkali and alkaline earth metals; Y is the anion of an inorganic. or organic acid and t is either 1 or 2. More particularly, the anion Y is selected from the group consisting of halides, sul-fates, nitrates, chlorates and acetates~ with the chlorides and sulfates being most preferable. More particularly preferred are the water-soluble adducts, especially calcium chloride (CaC12) or magnesium sulfate (MgS04). Also included in the adducts of this invention are the hydrates of the afore-mentioned compounds, i.e., adducts including nH20 groups where n is an integer of 0 to 10. Additionally, the adducts (I) may contain one or more substituents on either or both pyridine ~:
8.~
ring structures such as alkyls, halogens and alkoxy groups.
It is further noted that (C5H4NOS)2 as used in (I) above and throughout the specification and claims represents bis-(2-pyridyl-l-oxide) disulFide and the structural formula (I).
Among the adducts which may be utilized in combi-nation with the non-steroidal anti-inflammatory ayents or corticosteroids in this invention may be mentioned:
Bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate, bis-(2-pyridyl-1-oxide) disulfide magnesium acetate, bis-(2-pyridyl-l-oxide) disulfide magnesium chloride, bis-(2-pyridyl-l-oxide) disulfide magnesium bromide, bis-(2-pyridyl-1-oxide) disulfide calcium chloride, bis-(2-pyridyl-1-oxide) disulfide calcium sulfate, bis-(2-pyridyl-1-oxide) disulfide calcium nitrate, bis-(2-pyridyl-1-oxide) disulfide calcium acetate, bis-(2-pyridyl-1-oxide) disulfide calcium chlorate, bis-(2-pyridyl-1-oxide) disulfide barium chloride, bis-(2-pyridyl-1-oxide) disulfide barium sulfate, bis-(2-pyridyl-1-oxide) disulfide barium nitrate, bis-(2-pyridyl-1-oxide) disulfide barium acetate, bis-(2-pyridyl-1-oxide) disulfide barium chlorate, bis-(2-pyridyl-1-oxide) disulfide strontiu~ chloride, bis-(2-pyridyl-1-oxide) disulFide strontium sulfate, bis-(2-pyridyl-l-oxide) disulfide strontium nitrate, bis-(2-pyridyl-1-oxide) disulfide strontium acetate, bis-(2-pyridyl-1-oxide) disulfide strontium chlorate, bis-(2-pyridyl-1-oxide) disulfide potassium chloricle, bis-(2-pyridyl-1-oxide) disulfide potassium sulfate, bis-(2-pyridyl-1-oxide) disulfide potassium nitrate, bis-(2-pyridyl-1-oxide) disulfide potassium acetate, bis-(2-pyridyl-l-oxide) disulfide potassium chlorate, bis-(2-pyridyl-l-oxide) disulfide sodium chloride, bis-(2-pyridyl-1-oxide) disulfide sodium sulfate, bis-(2-pyridyl-1-oxide) disulfide sodium nitrate, bis-(2-pyridyl-1-oxide) disulfide sodium ,;
: , , acetate, bis-(2-pyridyl-l-oxide) disulfide sodium chlorate, bis-(2-pyridyl-1-oxide) disulfide zinc chloride, bis-(2-pyridyl-l-oxide) disulfide zinc sulfate, bis-(2-pyridyl-1-oxide) disulfide zinc nitrate, bis-(2-pyridyl-1-oxide) disulfide zinc acetate, bis-(2-pyridyl-1-oxide) disulfide zinc chlorate, bis-(2-pyridyl-1-oxide) disulfide stannous chloride, bis-(2 pyridyl-l-oxide) disulfide stannous sulfate, bis-(2-pyridyl-l-oxide) disulfide stannous nitrate, bis-(2-pyridyl-1-oxide) disulfide stannous acetate, bis-(2-pyridyl-l~oxide) disulfide stannous chlorate, bis-(2-pyridyl-1-oxide) disulfide zirconium chloride, bis-(2-pyridyl-1-oxide) disulfide zirconium sulfate, bis-(2-pyridyl-1-oxide) disulfide zirconium nitrate, bis-(2-pyridyl-1-oxide) disulfide zirconium acetate, bis-(2-pyridyl-l-oxide) disulfide zirconium chlorate, bis-(2-pyridyl-1-oxide) disulfide ferrous chloride, bis-(2-pyridyl-1-oxide) disulfide ferrous sulfate, bis-(2-pyridy1-1-oxide) disulfide ferrous nitrate, bis-(2-pyridyl-1-oxide) disulfide ferrous acetate, bis-(2-pyridyl-1-oxide) disulfide ferrous chlorate, bis-(2-pyridyl-1-oxide) disulfide lithium sulfate, bis-(2-pyridyl-l-oxide) disulfide lithium nitrate, bis-(2-pyridyl-1-oxide) disulfide lithium acetate, and bis-(2-pyridyl-1-oxide) disulfide lithium chlorate.
Any one of the known effective anti-inFlammatory corticosteroids may be utilized in this invention. Among the suitable corticosteroids include hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone valerate, triamcinolone acetonide, fluocinolone acetonide, 16~-hydroxy-prednisolone-16~,17~-acetonide, fluorohydrocortisone, 1-dehydrocortisone, and the like. Preferably, the hydrocortisone compounds are used in connection with the active adducts I.
A number of known effective anti-inflammatory non-: . .' , .
steroidal agents may be utilized in this invention. Among thesuitable non-steroidal agents may be mentioned l-(p-chloro-ben~oyl)-5-methoxy-2-methylindole-3-acetic acid d-2-(6-methoxy-
2-naphthyl) propionic acid, 1-methyl-5-(4-methylbenzoyl)-1 H-pyrrole-2-acetic acid, ~-methyl-4-(2-methylpropyl) benzene-acetic acid, 4-(2-methylpropyl) benzeneacetic acid, ~-methyl-3-phenoxybenzeneacetic acid, ~,3-dichloro-4-cyclohexylphenyl-acetic acid, 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid, and the like.
It has been surprisingly found that the anti-inflammatory activity of corticosteroids or non-steroidal anti-inflammatory agents are enhanced when combined with bis-(2-pyridyl-l-oxide) disulfide and/or its adducts.
Additionally, the effective compositions utilized in the present invention have been shown to have the property of remaining on the skin and retaining anti-inflammatory activity over a period of time after washing and rinsing uf the skin.
More specifically the compositions of the present invention for the anti-inflammatory treatment including skin conditions such as contact dermatitis, seborrheic dermatitis, atopic dermatitis, neurodermatitis and the like, as well as other mammalian conditions where the symptoms of inflammation and associated pain and fever manifest, such as rheumatic diseases including arthritis, tendinitis, erythema, sciatic pain and similar associated veterinary conditions, comprise from 0.1 to 5% by weight of at least one active compound, preferably from 0.2 to 1.5% by weight. These compositions can be in the Form of a solution, a cream, powder, gel, ointment, ~
salve, lotion, or milk. For the treatment of skin conditions `
the active compounds can also constitute make-up products or dermatological cakes containing the ingredients standard to this type of composition.
When associated with corticosteroids are utilized the compositions comprise an amount of 0.01-2.5% by weight of bis-(2-pyridyl-1-oxide) disulfide compound, preferably 0.1-1% by weight of bis-(2-pyridyl-1-oxide) disulfide compound present.
These compositions can be in the form of a solution, a cream, powder, gel, ointment, salve, lotion, or milk. For the treatment of skin conditions they can also constitute make-up products or dermatological cakes containing the ingredients standard to this type of composition.
When associated with non-steroidal anti-in~lammatory agents the compositions comprise bis-(2-pyridyl-1-oxide) disulfide or one of its adducts I in an amount of from about 0.05-10% by weight of the composition, preferably from about 0.25-5.0% by weight. The non-steroidal agents are utilized in the composition in an amount of 1-40% by weight of bis-(2-pyridyl-l oxide) disulfide compound in the composition, prefer-ably 5-25% by weight of the compound present. These compo-sitions can be in the form of a solution, a cream, powder, gel, ointment, salve, lotion, or milk. For the treatment of skin conditions, they can also constitute make-up products or dermatological cakes containing the ingredients standard to this type of composition.
The following examples will further illustrate the formulations containing the bis-(2-pyridyl-1-oxide) disulfide compound and/or its adducts of Formula I but are not to be considered as limiting the scope of this invention. -A cream was prepared as follows:
Bis-(2-pyridyl-1-oxide) disulfide calcium chloride2 9.
Hydrocortisone 0.05 g.
Titanium oxide 10 g Red iron oxide 0.3 g.
Yellow iron oxide 0.2 g.
Brown iron oxide 0.4 g.
Chestnut iron oxide 0.2 g.
Several stearyl alcohols oxyethylenated with 33 mols of ethylene oxide 7 9.
Polyglycol stearate 6 g.
Propyl parahydroxybenzoate0.2 g.
Water, 4.S.P. 100 g.
Testing of the synergistic effect of the combination of hydrocortisone and the adducts of Formula I, using as a representative compound bis-(2-pyridyl-1-oxide) disulfide ~ ;
magnesium sulfate was performed utilizing a modiFication of the experimental technique described by Tonelli, G., Thibault, L.
and Ringler, L., A Bioassay for the Concomitant Assessment of the Anti-phlogistic and Thymolytic Activities of Topically Applied Corticoids. Endocrinology 77, 625 (1965) and Roszkowski, A.P., Rooks, W.H. II, Tomolonis, A.J. and Miller, L.M., Anti-inflammatory and Analgetic Properties of d-2-(6'-Methoxy-2'-Naphthyl~ Propionic Acid (Naproxen). J. Pharm. Exp.
Ther. 179, 11~ (l971). Mathematical determination of the synergistic effects of combinations of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate and hydrocortisone was done using a modification of the method described by Van Arman, C.G., Nuss, .. . . .
:. ' . ; : "
.. . ~, ~ 6 ~
G.W. and Risley. E.A., Interactions of Aspirin, Indomethacin and Other Drugs In Adjuvant-induced Arthritis in the Rat (appendix). J. Pharmacol, Exp. Therap. 187, 400, (1973).
Hydrocortisone and bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate were suspended or dissolved in ethanol U.S.P.
(200 proof) at concentrations of 20, 40 and 80 mg/ml oF b1s-(2-pyridyl-1-oxide) disulfide magnesium sulfate and 0.01, 1 and 10 mg of hydrocortisone. In experiments where the interaction of hydrocortisone and bis-(2-pyridyl-1-oxide) disulfide mag-nesium sulfate were to be determined, equipotent doses of eachagent were simultaneously co-applied after admixture in the alcohol vehicle. Bis-(2-pyridyl-1-oxide)disulfide magnesium sulfate formed a fine suspension, while hydrocortisone was completely soluble in the alcohol.
Therapeutic effects of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate at topical doses of 2, 4 and 8 mg/ear (0.01 ml) of hydrocortisone at doses of 0.01, 0.1 and 1 mg/ear (0.1 ml) were measured after application to the left ear of mice, 1 hour after inflammation was induced by the topical application of an irritant solution containing 2%
croton oil (Amend Drug and Chemical Co., Irvington, N.J. Lot 710034), 73% diethyl ether, U.S.P. (Corco Chemical Corp., Fairless Hills, PA), 20% pyridine (J.T. Baker Chemical Co., Phillipsburg, PA, Lot 3348) and 5% distilled water. Groups of mice treated with only the croton-oil irritant solution served as controls. The right ear of mice in any group was not treated.
Four hours after application of the irritant vehicle (three hours after drug application) both ears were amputated and one circular section was excised from each ear using a No. 4 cork borer (7 mm i.d.). The ear sections were then weighed. The increase in weight due to edema formation caused by the croton-oil in the treated ear and reduction of the edema caused by treatment with bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate hydrocortisone or combinations thereof was determined by subtracting the weight of the untreated right ear section from that of the treated left ear section.
The anti-inflammatory eflects of either bis-(2-pyridyl-l-oxide) disulfide magnesium sulfate or hydrocortisone or of co-applied equipotent dose pair combinations of the two agents expressed as percent inhibition were calculated by:
Edema weight (controls) - Edema wei ~ (treated) X 100 Edema weight controls The immediate anti-inflammatory effects of bis-(2-pyridyl-l-oxide) disulfide magnesium sulfate were measured by direct application to the ear of the drug suspended in a 2%
solution of croton-oil in 95% ethanol. Ethanol was used as the vehicle; pyridine contained in the usual irritant vehicle as described previously produces an alkaline reaction. Controls were treated with only the croton-oil vehicle.
TABLE I
THE INTERACTION OF BTS-(2-PYRIDYL-l-OXIDE) DISULFIDE MAGNESIUM SULFATE WITH HYDROCORTISONE
AFTER IMMEDIATE CO-ADMINISTRATION TO CROTON-OIL
INDUCED INFLAMMATION TO THE MOUSE'S EAR
-Ear Percent Treatmenta Topica1 Dose Edema Weight Inhibition mg/ear mg ~ S.D.b oF Ear Control - 16.9 -~ 3.0 -Bis-(2-pyridyl-1-oxide) disulfide magnesium 4 12.7 ~ 3.0 24.9 sulfate Hydrocortisone 0.01 13.0 + 3.8 23.1 0.1 7.9 + 2.3 53.3 1.0 5.5 + 2.6 67.5 Bis-(2-pyridyl-1-oxide) disulfide magnesium 4 14.3 + 2.2 15.4 sulfate 20 Hydrocortisone 0.01 Bis-(2-pyridyl-1-oxide) disulfide magnesium 4 10.2 + 2.6 39.6 sulfate Hydrocortisone 0.1 Bis-(2-pyridyl-1-oxide) disulfide magnesium 4 8.4 + 2.1 50.3 sulfate Hydrocortisone 1.0 a 2% Croton-oil in 95% ethanol as irritant, bis-(2-pyridyl-1-oxide) disulfide magnesium sul-Fate alone or bis-(2-pyridyl-l-oxide) disulfide magnesium sulfate and hydrocortisone suspended in the same vehicle.
b Standard Deviation.
- .
,. .
.. . ,, :. . . ~ ~ :
&~
The potential synergistic effects induced by topical co-application of doses of hydrocortisone and bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate were investigated by both immediate application (Table I) and by delayed application to an existing inflammation (Table II).
A. _ynergism after Immediate Application A fixed dose of 4 mg/ear of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate was co-applied with 0.01, 0.1 and 1 mg/ear of hydrocortisone. Such co-application at the time of induction of the inf`lammatory process (Table I) resulted in effects that were less than those which would be expected from simple addition, i.e., there was evidence that some antagonism of therapeutic effects occurred under these conditions. At the dose of 0.01 mg/ear, hydrocortisone produced 53.3% inhibition.
When that same dose of hydrocortisone was co-applied with 4 mg/
ear of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate (24.9% inhibition by itself), a response of only 39.6% was obtained; a response of 58.5% inhibition was expected. This reduction in response obtained after co-application of combi-nations of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate and hydrocortisone was evident at all dose levels.
B. Synergism after Delayed Application When equipotent dose-pair combinations of bis-(2-pyridyl-l-oxide) disulfide magnesium sulfate and hydrocortisone were co-applied to an existing inflammation in the mouse's ear, the results in Table II were obtained. The observed responses at each dose level of the combinations were compared with the expected responses calculated on the basis of simple addition.
The type of interaction between bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate and hydrocortisone was dose-dependent and varied from potentiation to simple addition.
.~. .
Doses of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate (0.87 mg/ear) and hydrocortisone (0.00125 mg/ear) each by themselves would be expected, by extrapolation of their respective dose-response lines, to produce little, if any, significant anti-inflammatory response. When the expected response that would result in simple addition was calculated from that dose-pair combination, a value of 10.6% inhibition was obtained; the observed response was 46.3%. In order to achieve a similar response from either hydrocortisone or bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate by themselves, it would have been necessary to apply 0.25 mg/ear or 17.7 mg/
ear, respectively.
Similar potentiation was observed with combinations of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate 1/5 mg/
ear and hydrocortisone 0.004 mg/ear, or bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate 1.9 mg/ear and hydrocortisone 0.005 mg/ear. Higher doses of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate in combination with equipotent doses of hydrocortisone resulted in simple addition.
..
,;
TABLE II
T~IE INTERACTION OE BIS-(2-PYRIDYL-l-OXIDE) DISULFIDE ~AGNESIUM SULFATE WITH HYDROCORTISONE
AFTER DELAYED CO-APPLICATION TO CROTON-OIL
INDUCED INFLAMMATION TO THE MOUSE'S EAR
Ear Percent Treatmenta Topical Dose Edema Weight Inhibition mg/earmg -~ S.D.b oF Ear Control - 14.9 L 3.8 Bis-(2-pyridyl-1-oxide) disulFide magnesium 2 12.7 -~ 2.4 14.8 sulfate 4 11.4 ~ 2.8 23.5 8 9.6 ~ 2.2 35.6 Hydrocortisone 0.01 12.3 -~ 3.3 17.5 (free alcohol) 0.1 8.9 -~ 2.3 40.3 1.0 6.2 ~ 2.4 58.4 Bis-(2-pyridyl-1-oxide) disulfide magnesium 0.87 7.9 ~ 2.5 47.3 sulfate Hydrocortisone 0.00125 Bis-(2-pyridyl-1-oxide) disulfide magnesium 1.5 9.2 ~ 2.7 38.1 sulfate Hydrocortisone 0.004 Bis-(2-pyridyl-1-oxide) disulfide magnesium 1.9 9.5 ~ 2.4 36.4 sulfate Hydrocortisone 0.005 Bis-(2-pyridyl-1-oxide) disulfide magnesium 3.7 9.87 ~2.7 34.0 sulfate Hydrocortisone 0.02 Bis-(2-pyridyl-1-oxide) disulfide magnesium 7.0 8.7 ~ 2.4 41.6 sulfate Hydrocortisone 0.08 a Drug suspended or dissolved in 95% ethanol and applied 1 hour after 2% croton-oil.
b Standard Deviation.
~x~
A dermatological cleansing cake is prepared by mixingtogether the following components:
Esters o-f sodium isothionate and coprafatty acids (sold under the name "IG~PON A"(Trademark)having the :Eormula R-COO-CH2~ H2-SO Na, wherein R equals fatty acid derivatives having 12-15 carbon atoms) 75 g Lanolin derivatives 22.75 g (CsH~Nos)2 MgC12 2 g Hydrocortisone acetate 0.02 g Other dermatologicalclean3ing cakes, identical to the above, are prepared by replacing the magnesium chloride salt of bis-(2-pyridyl-1-oxide) disulfide with any one of the aforementioned active compounds. Also, any one of the cortico-steroids mentioned may be utilized.
EX~PLE ~
A powder comprising the following mixtures:
Talc 86.85 g Glycerine oleate 3 g Isopropyl myristate 7 g Bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate 1 g l-methyl-5-(4-methyl-benzoyl)-l H-pyrrole-2-acetic acid 1 g Perfume 2 cc ('_,approx. 1.9 g) ~ ther equally~effective powder compositio~ns identical to the above are prepared except that the active ingredient component bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate is replaced by any of the other aforementioned active compounds.
A tincture is prepared as Follows:
Bis-(2-pyrjdyl-1-oxide) disul~ide barlum acetate1%
Ethanol 20%
Propylene glycol 10%
Water ~ 69%
Bis-(Z-pyridyl-l-oxide) disulfide magnesium chloride 1%
Vitamin E 2%
Propylene glycol 20%
Ethanol 20%
Water 57%
The following ointment base was utilized as a vehicle for the active ingredients of this invention:
Ingredient Amount in grams Polyoxyethylene stearyl ether 5.0 White petrolatum 5.0 Stearyl alcohol 15.0 Distilled water 63.5 The ointment containing the above active ingredients were manufactured in the following manner. 3.0 grams bis-(2-pyridyl-l-oxide) disulfide magnesium sulfate were dissolved in a heated mixture of 59 ml of distilled water and 11.50 9 of propylene glycol. This solution was heated to a temperature of ~ ~
75C and added to a mixture having a like temperature consist- ~:
ing of 15.0 g of stearyl alcohol, 5.0 9 of white petrolatum, 1.0 ml of concentrated ammonia solution and 5.0 9 of polyoxy-ethylene stearyl ether, molecular weight about 700. While the - ... , .~ : .
~. . , ~. .. .
..6~82 resulting mixture was still hot, lactic acid was added to adjust the pH thereof to about 5.5 to approximate the pH oF
skin. The resulting mixture was thereafter cooled to form a cream which was further worked utilizing a three-roller frame and filled into tubes.
In an analogous manner, o;ntments were prepared ukilizing the following ingredients to form the initial solutions:
a. 2.27 grams bis-(2-pyridyl-1-oxide) disulFide ferrous chloride in 53.23 ml of distilled water and 11.5 g of propylene glycol;
b. 2.51 grams of bis-(2-pyridyl-1-oxide) disulfide lithium acetate in 56.19 ml of distilled water and 11.5 g of propylene glycol;
c. 2.62 grams of bis-(2-pyridyl-1-oxide) disulfide zirconium chloride in 56.35 ml of distilled water and 11.5 g of propylene glycol, d. 1.0 gram of bis-(2-pyridyl-1-oxide) disulfide strontium chloride in 60.7 ml of distilled water and 11.5 g propylene glycol and 0.80 sodium hydroxide. In this example the solution was heated to 75C and added to a mixture having a like temperature and containing 1.0 gram of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate, 13.0 grams of stearyl alcohol, 5.0 grams of polyoxyethylene stearyl ether, molecular weight about 700 and 5.0 grams of white petrolatum, the pH
adjusted with lactic acid and the mixture cooled to form a cream which was worked up as above.
2.5 g of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate and 0.05 9 hydrocortisone are predispersed in 30.0 g of propylene glycol. The mixture is then homogenized into 97.
.
grams of finished crearn, ointment or lotion following a modifi-cation of any one of the procedures of Examples 2, 6 and 7 or as described in F.W. Martin et al, "Remlngton's Pharmaceutical Sciences", 14th Ed., Mack Publishing Co., Easton, Pa., 1965.
Other agents which have medic~nal or therapeutic value may be incorporated in the compositions of this invention.
An anti-inflammatory composition in milk form having the following composition:
ngredient Weight in grams l~ydrogenated, ethoxylated (10 mol) lanolin 1.8 Triglyceride of fatty acid of coconut 7.0 Cetylalcohol 0.6 Stearylalcohol 0.6 Paraffin oil (lightweight) 5.0 Hydrocortisone 0.05 Stearic acid 3.0 Bis-(2-pyridyl-1-oxide) disulfide magnesium 2.0 sulfate Demineralized water72.2 Triethanolamine 0.8 Perfume 0.5 Carboxyvinylpolymer 2.0 Conservation agent 2.0 was manufactured as follows:
A mixture of 1.8 9 hydrogenated, ethoxylated (10 mol) lanolin, 7.0 9 triglyceride of fatty acid of coconut, 0.6 g cetylalcohol, 0.6 9 stearyl alcohol, 5.0 g paraffin oil, 0.05 9 hydrocortisone and 3.0 9 of stearic was blended at 70C. After " ~
addition of 2.0 g bis-(2-pyridyl-l-oxide) disulfide magnesium sulfate, 2.0 g carboxyvinylpolymer in 72.2 9 demineralized water were added at 70C with stirring to the resulting suspension. The mixture was stirred for 15 minutes and then cooled. 0.8 g of triethanolamine and 0.5 g of perfume were added at 60C and 45C respectively. The resulting mixture was stirred until cold and a white milk, which was stable at 3,000 Rpm for l hour was obtained. Viscosity: 6,000 Cp (Brockfield, Spindel, 5, 10 Rpm).
It has been surprisingly found that the anti-inflammatory activity of corticosteroids or non-steroidal anti-inflammatory agents are enhanced when combined with bis-(2-pyridyl-l-oxide) disulfide and/or its adducts.
Additionally, the effective compositions utilized in the present invention have been shown to have the property of remaining on the skin and retaining anti-inflammatory activity over a period of time after washing and rinsing uf the skin.
More specifically the compositions of the present invention for the anti-inflammatory treatment including skin conditions such as contact dermatitis, seborrheic dermatitis, atopic dermatitis, neurodermatitis and the like, as well as other mammalian conditions where the symptoms of inflammation and associated pain and fever manifest, such as rheumatic diseases including arthritis, tendinitis, erythema, sciatic pain and similar associated veterinary conditions, comprise from 0.1 to 5% by weight of at least one active compound, preferably from 0.2 to 1.5% by weight. These compositions can be in the Form of a solution, a cream, powder, gel, ointment, ~
salve, lotion, or milk. For the treatment of skin conditions `
the active compounds can also constitute make-up products or dermatological cakes containing the ingredients standard to this type of composition.
When associated with corticosteroids are utilized the compositions comprise an amount of 0.01-2.5% by weight of bis-(2-pyridyl-1-oxide) disulfide compound, preferably 0.1-1% by weight of bis-(2-pyridyl-1-oxide) disulfide compound present.
These compositions can be in the form of a solution, a cream, powder, gel, ointment, salve, lotion, or milk. For the treatment of skin conditions they can also constitute make-up products or dermatological cakes containing the ingredients standard to this type of composition.
When associated with non-steroidal anti-in~lammatory agents the compositions comprise bis-(2-pyridyl-1-oxide) disulfide or one of its adducts I in an amount of from about 0.05-10% by weight of the composition, preferably from about 0.25-5.0% by weight. The non-steroidal agents are utilized in the composition in an amount of 1-40% by weight of bis-(2-pyridyl-l oxide) disulfide compound in the composition, prefer-ably 5-25% by weight of the compound present. These compo-sitions can be in the form of a solution, a cream, powder, gel, ointment, salve, lotion, or milk. For the treatment of skin conditions, they can also constitute make-up products or dermatological cakes containing the ingredients standard to this type of composition.
The following examples will further illustrate the formulations containing the bis-(2-pyridyl-1-oxide) disulfide compound and/or its adducts of Formula I but are not to be considered as limiting the scope of this invention. -A cream was prepared as follows:
Bis-(2-pyridyl-1-oxide) disulfide calcium chloride2 9.
Hydrocortisone 0.05 g.
Titanium oxide 10 g Red iron oxide 0.3 g.
Yellow iron oxide 0.2 g.
Brown iron oxide 0.4 g.
Chestnut iron oxide 0.2 g.
Several stearyl alcohols oxyethylenated with 33 mols of ethylene oxide 7 9.
Polyglycol stearate 6 g.
Propyl parahydroxybenzoate0.2 g.
Water, 4.S.P. 100 g.
Testing of the synergistic effect of the combination of hydrocortisone and the adducts of Formula I, using as a representative compound bis-(2-pyridyl-1-oxide) disulfide ~ ;
magnesium sulfate was performed utilizing a modiFication of the experimental technique described by Tonelli, G., Thibault, L.
and Ringler, L., A Bioassay for the Concomitant Assessment of the Anti-phlogistic and Thymolytic Activities of Topically Applied Corticoids. Endocrinology 77, 625 (1965) and Roszkowski, A.P., Rooks, W.H. II, Tomolonis, A.J. and Miller, L.M., Anti-inflammatory and Analgetic Properties of d-2-(6'-Methoxy-2'-Naphthyl~ Propionic Acid (Naproxen). J. Pharm. Exp.
Ther. 179, 11~ (l971). Mathematical determination of the synergistic effects of combinations of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate and hydrocortisone was done using a modification of the method described by Van Arman, C.G., Nuss, .. . . .
:. ' . ; : "
.. . ~, ~ 6 ~
G.W. and Risley. E.A., Interactions of Aspirin, Indomethacin and Other Drugs In Adjuvant-induced Arthritis in the Rat (appendix). J. Pharmacol, Exp. Therap. 187, 400, (1973).
Hydrocortisone and bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate were suspended or dissolved in ethanol U.S.P.
(200 proof) at concentrations of 20, 40 and 80 mg/ml oF b1s-(2-pyridyl-1-oxide) disulfide magnesium sulfate and 0.01, 1 and 10 mg of hydrocortisone. In experiments where the interaction of hydrocortisone and bis-(2-pyridyl-1-oxide) disulfide mag-nesium sulfate were to be determined, equipotent doses of eachagent were simultaneously co-applied after admixture in the alcohol vehicle. Bis-(2-pyridyl-1-oxide)disulfide magnesium sulfate formed a fine suspension, while hydrocortisone was completely soluble in the alcohol.
Therapeutic effects of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate at topical doses of 2, 4 and 8 mg/ear (0.01 ml) of hydrocortisone at doses of 0.01, 0.1 and 1 mg/ear (0.1 ml) were measured after application to the left ear of mice, 1 hour after inflammation was induced by the topical application of an irritant solution containing 2%
croton oil (Amend Drug and Chemical Co., Irvington, N.J. Lot 710034), 73% diethyl ether, U.S.P. (Corco Chemical Corp., Fairless Hills, PA), 20% pyridine (J.T. Baker Chemical Co., Phillipsburg, PA, Lot 3348) and 5% distilled water. Groups of mice treated with only the croton-oil irritant solution served as controls. The right ear of mice in any group was not treated.
Four hours after application of the irritant vehicle (three hours after drug application) both ears were amputated and one circular section was excised from each ear using a No. 4 cork borer (7 mm i.d.). The ear sections were then weighed. The increase in weight due to edema formation caused by the croton-oil in the treated ear and reduction of the edema caused by treatment with bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate hydrocortisone or combinations thereof was determined by subtracting the weight of the untreated right ear section from that of the treated left ear section.
The anti-inflammatory eflects of either bis-(2-pyridyl-l-oxide) disulfide magnesium sulfate or hydrocortisone or of co-applied equipotent dose pair combinations of the two agents expressed as percent inhibition were calculated by:
Edema weight (controls) - Edema wei ~ (treated) X 100 Edema weight controls The immediate anti-inflammatory effects of bis-(2-pyridyl-l-oxide) disulfide magnesium sulfate were measured by direct application to the ear of the drug suspended in a 2%
solution of croton-oil in 95% ethanol. Ethanol was used as the vehicle; pyridine contained in the usual irritant vehicle as described previously produces an alkaline reaction. Controls were treated with only the croton-oil vehicle.
TABLE I
THE INTERACTION OF BTS-(2-PYRIDYL-l-OXIDE) DISULFIDE MAGNESIUM SULFATE WITH HYDROCORTISONE
AFTER IMMEDIATE CO-ADMINISTRATION TO CROTON-OIL
INDUCED INFLAMMATION TO THE MOUSE'S EAR
-Ear Percent Treatmenta Topica1 Dose Edema Weight Inhibition mg/ear mg ~ S.D.b oF Ear Control - 16.9 -~ 3.0 -Bis-(2-pyridyl-1-oxide) disulfide magnesium 4 12.7 ~ 3.0 24.9 sulfate Hydrocortisone 0.01 13.0 + 3.8 23.1 0.1 7.9 + 2.3 53.3 1.0 5.5 + 2.6 67.5 Bis-(2-pyridyl-1-oxide) disulfide magnesium 4 14.3 + 2.2 15.4 sulfate 20 Hydrocortisone 0.01 Bis-(2-pyridyl-1-oxide) disulfide magnesium 4 10.2 + 2.6 39.6 sulfate Hydrocortisone 0.1 Bis-(2-pyridyl-1-oxide) disulfide magnesium 4 8.4 + 2.1 50.3 sulfate Hydrocortisone 1.0 a 2% Croton-oil in 95% ethanol as irritant, bis-(2-pyridyl-1-oxide) disulfide magnesium sul-Fate alone or bis-(2-pyridyl-l-oxide) disulfide magnesium sulfate and hydrocortisone suspended in the same vehicle.
b Standard Deviation.
- .
,. .
.. . ,, :. . . ~ ~ :
&~
The potential synergistic effects induced by topical co-application of doses of hydrocortisone and bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate were investigated by both immediate application (Table I) and by delayed application to an existing inflammation (Table II).
A. _ynergism after Immediate Application A fixed dose of 4 mg/ear of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate was co-applied with 0.01, 0.1 and 1 mg/ear of hydrocortisone. Such co-application at the time of induction of the inf`lammatory process (Table I) resulted in effects that were less than those which would be expected from simple addition, i.e., there was evidence that some antagonism of therapeutic effects occurred under these conditions. At the dose of 0.01 mg/ear, hydrocortisone produced 53.3% inhibition.
When that same dose of hydrocortisone was co-applied with 4 mg/
ear of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate (24.9% inhibition by itself), a response of only 39.6% was obtained; a response of 58.5% inhibition was expected. This reduction in response obtained after co-application of combi-nations of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate and hydrocortisone was evident at all dose levels.
B. Synergism after Delayed Application When equipotent dose-pair combinations of bis-(2-pyridyl-l-oxide) disulfide magnesium sulfate and hydrocortisone were co-applied to an existing inflammation in the mouse's ear, the results in Table II were obtained. The observed responses at each dose level of the combinations were compared with the expected responses calculated on the basis of simple addition.
The type of interaction between bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate and hydrocortisone was dose-dependent and varied from potentiation to simple addition.
.~. .
Doses of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate (0.87 mg/ear) and hydrocortisone (0.00125 mg/ear) each by themselves would be expected, by extrapolation of their respective dose-response lines, to produce little, if any, significant anti-inflammatory response. When the expected response that would result in simple addition was calculated from that dose-pair combination, a value of 10.6% inhibition was obtained; the observed response was 46.3%. In order to achieve a similar response from either hydrocortisone or bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate by themselves, it would have been necessary to apply 0.25 mg/ear or 17.7 mg/
ear, respectively.
Similar potentiation was observed with combinations of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate 1/5 mg/
ear and hydrocortisone 0.004 mg/ear, or bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate 1.9 mg/ear and hydrocortisone 0.005 mg/ear. Higher doses of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate in combination with equipotent doses of hydrocortisone resulted in simple addition.
..
,;
TABLE II
T~IE INTERACTION OE BIS-(2-PYRIDYL-l-OXIDE) DISULFIDE ~AGNESIUM SULFATE WITH HYDROCORTISONE
AFTER DELAYED CO-APPLICATION TO CROTON-OIL
INDUCED INFLAMMATION TO THE MOUSE'S EAR
Ear Percent Treatmenta Topical Dose Edema Weight Inhibition mg/earmg -~ S.D.b oF Ear Control - 14.9 L 3.8 Bis-(2-pyridyl-1-oxide) disulFide magnesium 2 12.7 -~ 2.4 14.8 sulfate 4 11.4 ~ 2.8 23.5 8 9.6 ~ 2.2 35.6 Hydrocortisone 0.01 12.3 -~ 3.3 17.5 (free alcohol) 0.1 8.9 -~ 2.3 40.3 1.0 6.2 ~ 2.4 58.4 Bis-(2-pyridyl-1-oxide) disulfide magnesium 0.87 7.9 ~ 2.5 47.3 sulfate Hydrocortisone 0.00125 Bis-(2-pyridyl-1-oxide) disulfide magnesium 1.5 9.2 ~ 2.7 38.1 sulfate Hydrocortisone 0.004 Bis-(2-pyridyl-1-oxide) disulfide magnesium 1.9 9.5 ~ 2.4 36.4 sulfate Hydrocortisone 0.005 Bis-(2-pyridyl-1-oxide) disulfide magnesium 3.7 9.87 ~2.7 34.0 sulfate Hydrocortisone 0.02 Bis-(2-pyridyl-1-oxide) disulfide magnesium 7.0 8.7 ~ 2.4 41.6 sulfate Hydrocortisone 0.08 a Drug suspended or dissolved in 95% ethanol and applied 1 hour after 2% croton-oil.
b Standard Deviation.
~x~
A dermatological cleansing cake is prepared by mixingtogether the following components:
Esters o-f sodium isothionate and coprafatty acids (sold under the name "IG~PON A"(Trademark)having the :Eormula R-COO-CH2~ H2-SO Na, wherein R equals fatty acid derivatives having 12-15 carbon atoms) 75 g Lanolin derivatives 22.75 g (CsH~Nos)2 MgC12 2 g Hydrocortisone acetate 0.02 g Other dermatologicalclean3ing cakes, identical to the above, are prepared by replacing the magnesium chloride salt of bis-(2-pyridyl-1-oxide) disulfide with any one of the aforementioned active compounds. Also, any one of the cortico-steroids mentioned may be utilized.
EX~PLE ~
A powder comprising the following mixtures:
Talc 86.85 g Glycerine oleate 3 g Isopropyl myristate 7 g Bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate 1 g l-methyl-5-(4-methyl-benzoyl)-l H-pyrrole-2-acetic acid 1 g Perfume 2 cc ('_,approx. 1.9 g) ~ ther equally~effective powder compositio~ns identical to the above are prepared except that the active ingredient component bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate is replaced by any of the other aforementioned active compounds.
A tincture is prepared as Follows:
Bis-(2-pyrjdyl-1-oxide) disul~ide barlum acetate1%
Ethanol 20%
Propylene glycol 10%
Water ~ 69%
Bis-(Z-pyridyl-l-oxide) disulfide magnesium chloride 1%
Vitamin E 2%
Propylene glycol 20%
Ethanol 20%
Water 57%
The following ointment base was utilized as a vehicle for the active ingredients of this invention:
Ingredient Amount in grams Polyoxyethylene stearyl ether 5.0 White petrolatum 5.0 Stearyl alcohol 15.0 Distilled water 63.5 The ointment containing the above active ingredients were manufactured in the following manner. 3.0 grams bis-(2-pyridyl-l-oxide) disulfide magnesium sulfate were dissolved in a heated mixture of 59 ml of distilled water and 11.50 9 of propylene glycol. This solution was heated to a temperature of ~ ~
75C and added to a mixture having a like temperature consist- ~:
ing of 15.0 g of stearyl alcohol, 5.0 9 of white petrolatum, 1.0 ml of concentrated ammonia solution and 5.0 9 of polyoxy-ethylene stearyl ether, molecular weight about 700. While the - ... , .~ : .
~. . , ~. .. .
..6~82 resulting mixture was still hot, lactic acid was added to adjust the pH thereof to about 5.5 to approximate the pH oF
skin. The resulting mixture was thereafter cooled to form a cream which was further worked utilizing a three-roller frame and filled into tubes.
In an analogous manner, o;ntments were prepared ukilizing the following ingredients to form the initial solutions:
a. 2.27 grams bis-(2-pyridyl-1-oxide) disulFide ferrous chloride in 53.23 ml of distilled water and 11.5 g of propylene glycol;
b. 2.51 grams of bis-(2-pyridyl-1-oxide) disulfide lithium acetate in 56.19 ml of distilled water and 11.5 g of propylene glycol;
c. 2.62 grams of bis-(2-pyridyl-1-oxide) disulfide zirconium chloride in 56.35 ml of distilled water and 11.5 g of propylene glycol, d. 1.0 gram of bis-(2-pyridyl-1-oxide) disulfide strontium chloride in 60.7 ml of distilled water and 11.5 g propylene glycol and 0.80 sodium hydroxide. In this example the solution was heated to 75C and added to a mixture having a like temperature and containing 1.0 gram of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate, 13.0 grams of stearyl alcohol, 5.0 grams of polyoxyethylene stearyl ether, molecular weight about 700 and 5.0 grams of white petrolatum, the pH
adjusted with lactic acid and the mixture cooled to form a cream which was worked up as above.
2.5 g of bis-(2-pyridyl-1-oxide) disulfide magnesium sulfate and 0.05 9 hydrocortisone are predispersed in 30.0 g of propylene glycol. The mixture is then homogenized into 97.
.
grams of finished crearn, ointment or lotion following a modifi-cation of any one of the procedures of Examples 2, 6 and 7 or as described in F.W. Martin et al, "Remlngton's Pharmaceutical Sciences", 14th Ed., Mack Publishing Co., Easton, Pa., 1965.
Other agents which have medic~nal or therapeutic value may be incorporated in the compositions of this invention.
An anti-inflammatory composition in milk form having the following composition:
ngredient Weight in grams l~ydrogenated, ethoxylated (10 mol) lanolin 1.8 Triglyceride of fatty acid of coconut 7.0 Cetylalcohol 0.6 Stearylalcohol 0.6 Paraffin oil (lightweight) 5.0 Hydrocortisone 0.05 Stearic acid 3.0 Bis-(2-pyridyl-1-oxide) disulfide magnesium 2.0 sulfate Demineralized water72.2 Triethanolamine 0.8 Perfume 0.5 Carboxyvinylpolymer 2.0 Conservation agent 2.0 was manufactured as follows:
A mixture of 1.8 9 hydrogenated, ethoxylated (10 mol) lanolin, 7.0 9 triglyceride of fatty acid of coconut, 0.6 g cetylalcohol, 0.6 9 stearyl alcohol, 5.0 g paraffin oil, 0.05 9 hydrocortisone and 3.0 9 of stearic was blended at 70C. After " ~
addition of 2.0 g bis-(2-pyridyl-l-oxide) disulfide magnesium sulfate, 2.0 g carboxyvinylpolymer in 72.2 9 demineralized water were added at 70C with stirring to the resulting suspension. The mixture was stirred for 15 minutes and then cooled. 0.8 g of triethanolamine and 0.5 g of perfume were added at 60C and 45C respectively. The resulting mixture was stirred until cold and a white milk, which was stable at 3,000 Rpm for l hour was obtained. Viscosity: 6,000 Cp (Brockfield, Spindel, 5, 10 Rpm).
Claims (13)
1. A topical composition for treating inflammation in warm blooded animals characterized by an effective amount of bis-(2-pyridyl-1-oxide) disulfide or the adducts of bis-(2-pyridyl-1 oxide) disulfide having the empirical formula:
(C5H4NOS)2MYt (I) wherein M represents zinc, iron, magnesium, tin, cadmium, zirconium, alkali or alkaline earth metals; Y is the anion of an inorganic or organic acid and t is either 1 or 2, together with a suitable pharmaceutical carrier.
(C5H4NOS)2MYt (I) wherein M represents zinc, iron, magnesium, tin, cadmium, zirconium, alkali or alkaline earth metals; Y is the anion of an inorganic or organic acid and t is either 1 or 2, together with a suitable pharmaceutical carrier.
2. The composition of Claim 1, characterized by the fact that M is magnesium, Y is sulfate and t is 1.
3. The composition of Claim 1, characterized by the fact that M is calcium, Y is chloride and t is 2.
4. The composition of Claim 1, characterized by the fact that M is calcium, magnesium or barium.
5. The composition of Claim 1, characterized by the fact that the formula is (C5H4NOS)2CaC12, (C5H4NOS)2MgSO
(C5H4NOS)2 SrC12, (C5H4NOS)2SrBr2, (C5H4NOS)2Ca (NO3)2 or (C5H4NOS)2 Ba(C103)2.
(C5H4NOS)2 SrC12, (C5H4NOS)2SrBr2, (C5H4NOS)2Ca (NO3)2 or (C5H4NOS)2 Ba(C103)2.
6. The composition of Claim 1, characterized by the fact that said adducts are water-soluble.
7. The composition of Claim 1, characterized by the fact that Y is selected from the group consisting of halides, sulfates, nitrates and acetates.
8. A topical composition for treating inflammation in warm blooded animals characterized by an effective amount of bis-(2-pyridyl-1-oxide) disulfide or the adducts of bis-(2-pyridyl-1-oxide) disulfide having the empirical formula:
(C5H4NOS)2MYt (I) wherein M represents zinc, iron, magnesium, tin, cadmium, zirconium, alkali or alkaline earth metals; Y is the anion of an inorganic or organic acid and t is either 1 or 2, together with a non-steroidal anti-inflammatory agent.
(C5H4NOS)2MYt (I) wherein M represents zinc, iron, magnesium, tin, cadmium, zirconium, alkali or alkaline earth metals; Y is the anion of an inorganic or organic acid and t is either 1 or 2, together with a non-steroidal anti-inflammatory agent.
9. The composition of Claim 8, characterized by the fact that the formula is (C5H4NOS)2CaC12, (C5H4NOS)2MgSO4, (C5H4NOS)2SrCl2, (C5H4NOS)2SrBr2, (C5H4NOS)2Ca (NO3) or (C5H4NOS)2Ba(Cl03)2
10. The composition of Claims 8 or 9, characterized by the fact that said non-steroida] agent is l-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid, d-2-(6-methoxy-2-naphthyl) propionic acid, l-methyl-5-(4-methylbenzoyl)-1 H-pyrrole-2-acetic acid, .alpha.-methyl-4-(2-methylpropyl) benzene-acetic acid, 4-(2-methylpropyl) benzeneacetic acid, .alpha.-methyl-3-phenoxybenzeneacetic acid, .alpha., 3-dichloro-4-cyclohexylphenyl-acetic acid and 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid.
11. A topical composition for treating inflammation in warm blooded animals characterized by an effective amount of bis-(2-pyridyl-1-oxide) disulfide or the adducts of bis-(2-pyridyl-l oxide)disulfide having the empirical formula:
(C5H4NOS)2MYt (I) wherein M represents zinc, iron, magnesium, tin, cadmium, zirconium, alkali or alkaline earch metals; Y is the anion of an inorganic or organic acid and t is either 1 or 2, together with a corticosteroid having anti-inflammatory activity and a suitable pharmaceutical carrier.
(C5H4NOS)2MYt (I) wherein M represents zinc, iron, magnesium, tin, cadmium, zirconium, alkali or alkaline earch metals; Y is the anion of an inorganic or organic acid and t is either 1 or 2, together with a corticosteroid having anti-inflammatory activity and a suitable pharmaceutical carrier.
12. The composition of Claim 11, characterized by the fact that the formula is (C5H4NOS)2CaC12, (C5H4NOS)2MgSO4, (C5H4NOS)2SrCl2, (C5H4NOS)2SrBr2, (C5H4NOS)2Ca(NO3) or (C5H4NOS)2Ba(C103)2.
13. The composition of Claims 11 or 12, characterized by the fact that said corticosteroid is hydrocortisone, hydrocor-tisone acetate, hydrocortisone butyrate, hydrocortisone valerate, triamcinolone acetonide, fluocinolone acetonide, 16.alpha.-hydroxy-prednisolone-16.alpha.,17.alpha.-acetonide, fluorohydrocortisone or 1-dehydrocortisone.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US83559477A | 1977-09-22 | 1977-09-22 | |
| US835,595 | 1977-09-22 | ||
| US05/835,595 US4152430A (en) | 1977-09-22 | 1977-09-22 | Synergistic compositions and method of use |
| US835,596 | 1977-09-22 | ||
| US05/835,596 US4137311A (en) | 1977-09-22 | 1977-09-22 | Synergistic compositions and method of use |
| US835,594 | 1986-03-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1116082A true CA1116082A (en) | 1982-01-12 |
Family
ID=27420252
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA311,816A Expired CA1116082A (en) | 1977-09-22 | 1978-09-21 | Pharmaceutical compositions and method of use |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS5455732A (en) |
| CA (1) | CA1116082A (en) |
| DE (1) | DE2840684A1 (en) |
| FR (1) | FR2403798A1 (en) |
| GB (1) | GB2004742B (en) |
| NL (1) | NL7809562A (en) |
| SE (1) | SE7809906L (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5636411A (en) * | 1979-08-31 | 1981-04-09 | Sumitomo Chem Co Ltd | Liquid agent for external use |
| JPS59137408A (en) * | 1983-01-27 | 1984-08-07 | Taisho Pharmaceut Co Ltd | ointment |
| JPS59139315A (en) * | 1983-01-31 | 1984-08-10 | Taisho Pharmaceut Co Ltd | Cream agent |
| DE3508666A1 (en) * | 1985-03-12 | 1986-09-18 | Hoechst Ag, 6230 Frankfurt | HETEROCYCLIC DISULFIDES AND THEIR USE AS IMMUNO MODULATORS |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE790244A (en) * | 1971-10-18 | 1973-04-18 | Olin Corp | BIS- (2-PYRIDYL-1-OXIDE) DISULPHIDE ADDITION PRODUCTS, THEIR PREPARATION AND USES |
| JPS5212207A (en) * | 1975-07-21 | 1977-01-29 | Kao Corp | Shampoo composition having ecxcellent effect for preventing dandruff |
-
1978
- 1978-09-18 FR FR7826729A patent/FR2403798A1/en active Granted
- 1978-09-19 DE DE19782840684 patent/DE2840684A1/en not_active Withdrawn
- 1978-09-20 SE SE7809906A patent/SE7809906L/en unknown
- 1978-09-20 NL NL7809562A patent/NL7809562A/en not_active Application Discontinuation
- 1978-09-21 CA CA311,816A patent/CA1116082A/en not_active Expired
- 1978-09-22 JP JP11606878A patent/JPS5455732A/en active Pending
- 1978-09-22 GB GB7837779A patent/GB2004742B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5455732A (en) | 1979-05-04 |
| GB2004742B (en) | 1982-07-07 |
| FR2403798B1 (en) | 1981-12-11 |
| NL7809562A (en) | 1979-03-26 |
| DE2840684A1 (en) | 1979-04-05 |
| FR2403798A1 (en) | 1979-04-20 |
| GB2004742A (en) | 1979-04-11 |
| SE7809906L (en) | 1979-03-23 |
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