Topical formulations containing as a therapeutic active agent fatty acids or fatty alcohols or monoglyceride derivatives thereof for treating of mucosa infections
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/21
A61K-031/20
A61K-031/045
출원번호
US-0297921
(1700-01-01)
우선권정보
IS-4386 (1996-11-14)
국제출원번호
PCT/DK97/00524
(1997-11-14)
발명자
/ 주소
Thormar, Halldor
Kristmundsdottir, Thordis
출원인 / 주소
Lipomedica ehf.
대리인 / 주소
Wenderoth, Lind & Ponack, L.L.P.
인용정보
피인용 횟수 :
23인용 특허 :
3
초록▼
The present invention relates to a method for counteracting infections caused by bacteria, fungi or virus such as Herpes Simplex Virus in skin or mucosal membranes, in particular genital membranes, of a mammal. The method comprises topically administering to the skin or mucosal membrane an effective
The present invention relates to a method for counteracting infections caused by bacteria, fungi or virus such as Herpes Simplex Virus in skin or mucosal membranes, in particular genital membranes, of a mammal. The method comprises topically administering to the skin or mucosal membrane an effective amount of a formulation comprising a) at least one microbicidal lipid, b) at least one solubilizing agent which keeps the lipid dissolved in the formulation, and optionally 3) a gel-forming agent. The formulation used in the method may suitable be in the form of a hydrogel. The microbicidal lipid is preferably a C6-18fatty acid, such as, e.g., lauric acid, or a derivative thereof, e.g., a monoglyceride such as capric acid 1-monoglyceride. The solubilizing agent may suitably be a glycofurol such as the commercially-available glycofurol 75. The invention also relates to novel pharmaceutical formulations for use in the method.
대표청구항▼
The present invention relates to a method for counteracting infections caused by bacteria, fungi or virus such as Herpes Simplex Virus in skin or mucosal membranes, in particular genital membranes, of a mammal. The method comprises topically administering to the skin or mucosal membrane an effective
The present invention relates to a method for counteracting infections caused by bacteria, fungi or virus such as Herpes Simplex Virus in skin or mucosal membranes, in particular genital membranes, of a mammal. The method comprises topically administering to the skin or mucosal membrane an effective amount of a formulation comprising a) at least one microbicidal lipid, b) at least one solubilizing agent which keeps the lipid dissolved in the formulation, and optionally 3) a gel-forming agent. The formulation used in the method may suitable be in the form of a hydrogel. The microbicidal lipid is preferably a C6-18fatty acid, such as, e.g., lauric acid, or a derivative thereof, e.g., a monoglyceride such as capric acid 1-monoglyceride. The solubilizing agent may suitably be a glycofurol such as the commercially-available glycofurol 75. The invention also relates to novel pharmaceutical formulations for use in the method. >SZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13r14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CO-morpholino-X(OCH2CH2)nSZ, --CO-piperazino-X(OCH2CH2)nSZ, --CO-piperidino-X(OCH2CH2)nSZ, and --CO-N-methylpiperazino-X(OCH2CH2)nSZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms or heterocyclic, and R12can in addition be H, R13and R14are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, 1 is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000. 6. A compound of formula (I): wherein: R1is H, an electron withdrawing group, or an electron donating group; R1' and R1" are the same or different and are H, an electron withdrawing group, or an electron donating group; R2is --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nO(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nO(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nO(CR13R14)l(CH2)m(CR13R14)lSZ, --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)lSZ, --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)lSZ, --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l)CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CO-morpholino-X(OCH2CH2)nSZ, --CO-piperazino-X(OCH2CH2)nSZ, --CO-piperidino-X(OCH2CH2)nSZ, and --CO-N-methylpiperazino-X(OCH2CH2)nSZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms or heterocyclic, and R12can in addition be H, R13and R14are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, 1 is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000; R3is aryl, or is linear, branched or cyclic alkyl having 1 to 10 carbon atoms; R4is --OC(CH3)3or --C6H5; and R5is H, a heterocyclic, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of formula --CNR10R11,wherein R10and R11are the same or different and are H, linear, branched, or cyclic alkyl having 1 to 10 atoms or simple or substituted aryl having 1 to 10 carbon atoms. 7. A compound of formula (I): wherein: R1is H, an electron withdrawing group, or an electron donating group; R1' and R1" are the same or different and are H, an electron withdrawing group, or an electron donating group; R2is H, a heterocyclic, a linear, branched, or cyclic ester or ether having from 1 to 10 carbon atoms or a carbamate of the formula --CNR10R11,wherein R10and R11are the same or different and are H, linear, branched, or cyclic alkyl having 1 to 10 atoms or simple or substituted aryl having 1 to 10 carbon atoms; R3is aryl, or is linear, branched or cyclic alkyl having 1 to 10 carbon atoms; R4is --OC(CH 3)3or --C6H5; and R5is --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nO(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nO(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nO(CR13R14)l(CH2)m(CR13R14)lSZ, --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)lSZ, --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)lSZ, --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CO-morpholino-X(OCH2CH2)nSZ, --CO-piperazino-X(OCH2CH2)nSZ, --CO-piperidino-X(OCH2CH2)nSZ, and --CO-N-methylpiperazino-X(OCH2CH2)nSZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12are the same or different and represent line ar alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms or heterocyclic, and R12can in addition be H, R13and R14are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, 1 is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000. 8. The compound of claim 6 or 7, wherein R1is H, F, NO2,CN, Cl, CHF2,CF3,--OCH3,--OCH2CH3,--NR7,or --OR8. 9. The compound of claim 6 or 7, wherein R1is OMe, OEt, Cl, F, NO2,or CF3. 10. The compound of claim 6 or 7, wherein R1is in the meta position, R1' is OMe, and R1" is H. 11. The compound of claim 6 or 7, wherein R1' and R1" are the same or different and are H, F, NO2,CN, Cl, CHF2,CF3,--OCH3,OCH2CH3,--NR6R7,or --O8,wherein: R6and R7are the same or different and are each H, linear, branched, or cyclic alkyl groups having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms, and R8is linear, branched or cyclic alkyl having 1 to 10 carbon atoms. 12. The compound of claim 11, wherein R6and R7are same or different and are each H, or are alkyl or aryl having 1 to 4 carbon atoms. 13. The compound of claim 11, wherein --NR6R7is dimethyl amino, diethyl amino, dipropyl amino, or dibutyl amino, where the butyl moiety is any of primary, secondary, tertiary or isobutyl. 14. The compound of claim 6 or 7, wherein R3is --CH2CH(CH3)2or --CH=C(CH3)2. 15. The compound of claim 6 or 7, wherein R4is --OC(CH3)3or --C6H5. 16. The compound of claim 6, wherein R5is H, --COCH3,--COCH2CH3and --COCH2CH2CH3. 17. The compound of claim 7, wherein R2is H, --COCH3,--COCH2CH3and --COCH2CH2CH3. 18. The compound of claim 6, wherein R5is H, or --CONHCH2CH3,--CONHCH2CH2CH3,--CO-morpholino, --CO-piperazino, --CO-piperidino, or --CO-N-methylpiperazino. 19. The compound of claim 7, wherein R2is H, or --CONHCH2CH3,--CONHCH2CH2CH3,--CO-morpholino, --CO-piperazino, --CO-piperidino, or --CO-N-methylpiperazino. 20. A cytotoxic agent comprising one or more taxanes linked to a cell binding agent through a polyethylene glycol-containing linking group at C-7 or C-10 of at least one of the taxanes. 21. The cytotoxic agent of claim 20, wherein the polyethylene glycol-containing linking group comprises a thiol or disulfide as the linking moiety. 22. The cytotoxic agent of claim 21, wherein the polyethylene glycol-containing linking group is carried on a side chain that is a linear or branched, aromatic or heterocyclic group. 23. The cytotoxic agent of claim 20, wherein at least one of the taxanes is linked to the cell binding agent through a cleavable linking group. 24. The cytotoxic agent of claim 23, wherein the cleavable linking group is acid labile, photolabile, peptidase labile or esterase labile. 25. The cytotoxic agent of claim 20, wherein at least one of the taxanes is linked to the cell binding agent through a non-cleavable linking group. 26. The cytotoxic agent of claim 20, wherein the substituent comprising the polyethylene glycol-containing linking group is selected from the group consisting of: --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nO(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nO(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nO(CR13R14)l(CH2)m(CR13R14)lSZ, --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)lSZ, --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)lSZ, --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13r14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CO-morpholino-X(OCH2CH2)nSZ, --CO-piperazino-X(OCH2CH2)nSZ, --CO-piperidino-X(OCH2CH2)nSZ, and --CO-N-methylpiperazino-X(OCH2CH2)nSZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbo n atoms or heterocyclic, and R12can in addition be H, R13and R14are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, 1 is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000. 27. The cytotoxic agent of claim 20, wherein the cell binding agent is an antibody or an antibody fragment. 28. The cytotoxic agent of claim 20, wherein the cell binding agent is an antibody, a single chain antibody or a binding fragment of an antibody or single chain antibody. 29. The cytotoxic agent of claim 20, wherein the cell binding agent is a monoclonal antibody, a single chain monoclonal antibody or a binding fragment of a single chain monoclonal antibody a monoclonal antibody which is or is not humanized or resurfaced or chimeric. 30. The cytotoxic agent of claim 29, wherein the cell binding agent binds specifically to the CD33 antigen. 31. The cytotoxic agent of claim 29, wherein the cell binding agent binds specially to the CD56 antigen. 32. The cytotoxic agent of claim 20, wherein the cell binding agent is an interferon, a lymphokines, a hormone, a vitamin, a growth factor, a colony-stimulating factor, or transferrin. 33. The cytotoxic agent of claim 20, wherein the cell binding agent is epidermal growth factor, transforming growth factor, vascular endothelial growth factor, fibroblast growth factor, insulin like growth factor 1 and 2, platelet derived growth factor, melanocyte stimulating hormone, thyroid stimulating hormone, somatostatin, estrogen, estrogen analogue, androgen, androgen analogue, or folate. 34. A therapeutic composition comprising: (A) An effective amount of a cytotoxic agent comprising one or more taxanes linked to a cell binding agent through a polyethylene glycol-containing linking group at C-7 or C-10 of at least one of the taxanes; and (B) A pharmaceutically acceptable carrier, diluent, or excipient. 35. The therapeutic composition of claim 34, wherein the polyethylene glycol-containing linking group comprises a thiol or disulfide as the linking moiety. 36. The therapeutic composition of claim 35, wherein the polyethylene glycol-containing linking group is carried on a side chain that is a linear or branched, aromatic or heterocyclic group. 37. The therapeutic composition of claim 34, wherein at least one of the taxanes is linked to the cell binding agent through a cleavable linking group. 38. The therapeutic composition of claim 37, wherein the cleavable linking group is acid labile, photolabile, peptidase labile or esterase labile. 39. The therapeutic composition of claim 34, wherein at least one of the taxanes is linked to the cell binding agent through a non-cleavable linking group. 40. The therapeutic composition of claim 34, wherein the substituent comprising the polyethylene glycol-containing linking group is selected from the group consisting of: --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nO(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nO(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nO(CR13R14)l(CH2)m(CR13R14)lSZ, --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14 )l(CH2)m(CR13R14)lSZ, --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)lSZ, --(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R4)l(CH2)m(CR13R14)lSZ, --CO(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nOCO(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14)l(OCH2CH2)nNR12CO(CR13R14)l(CH2)m(CR13R14)lSZ, --CONR12(CR13R14)l(CH2)m(CR13R14))l(OCH2H2)nOCONR12(CR13R14)l(CH2)m(CR13R14)lSZ, --CO-morpholino-X(OCH2CH2)nSZ, --CO-piperazino-X(OCH2CH2)nSZ, --CO-piperidino-X(OCH2CH2)nSZ, and --CO-N-methylpiperazino-X(OCH2CH2)nSZ, wherein Z is H or SR, X is a linear alkyl or branched alkyl having 1-10 carbon atoms, R and R12are the same or different and represent linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or simple or substituted aryl having 1 to 10 carbon atoms or heterocyclic, and R12can in addition be H, R13and R14are same or different and represent H or linear alkyl, branched alkyl or cyclic alkyl having 1 to 10 carbon atoms, or aryl, 1 is 0 or an integer from 1 to 10, m is an integer of 1 to 10, and n is 2 to 1000. 41. The therapeutic composition of claim 34 or 35, wherein the cell binding agent is an antibody or an antibody fragment. 42. The therapeutic composition of any one of claims 34, 35, 36 or 40, wherein the cell binding agent is an antibody, a single chain antibody or a binding fragment of an antibody or single chain antibody. 43. The therapeutic composition of any one of claims 34, 35, 36 or 40, wherein the cell binding agent is a monoclonal antibody, a single chain monoclonal antibody or a binding fragment of a single chain monoclonal antibody a monoclonal antibody which is or is not humanized or resurfaced or chimeric?. 44. The therapeutic composition of claim 43, wher
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Isaacs Charles E. (30 Devon Dr. North Manalapan NJ 07726) Kim Kwang S. (178 Dahlia St. Staten Island NY 10312) Thormar Halldor (Langagerdi 15 Reykjavik TX ISX) Heird William C. (2001 Holcombe Blvd. ;, Antibacterial fatty acid compositions.
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