pH SENSITIVE CARRIER AND PREPARATION METHOD THEREOF, AND pH SENSITIVE DRUG AND pH SENSITIVE DRUG COMPOSITION EACH CONTAINING THE CARRIER, AND METHOD FOR TREATING OR PREVENTING DISEASES USING THE SAME

Abstract

A pH sensitive carrier which includes at least one pH sensitive compound selected from the group consisting of deoxycholic acid, cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, C27 bile acid, glycodeoxycholic acid, glycyrrhizic acid, glycyrrhetinic acid and salts thereof, and at least one amphipathic substance selected from the group consisting of a phosphatidylcholine having 10 to 12 carbon atoms, a polyoxyethylene sorbitan monofatty acid ester having 12 to 18 carbon atoms, a sorbitan fatty acid ester having 16 to 18 carbon atoms, glycerol monooleate, glycerol dilaurate, glycerol distearate, glycerol dioleate, polyoxyethylene castor oil and α-tocopherol, and which is capable of developing a membrane disruptive function promoting effect.

1 .- 10 . (canceled) 
     
     
         11 . A method for treating tumor or inflammation in a patient in need thereof which comprises:
 administering a pH sensitive drug which comprises a pH sensitive carrier and a physiologically active substance supported in the pH sensitive carrier to induce the pH sensitive carrier to develop a membrane disruptive function and to deliver the physiologically active substance to the site.   
     
     
         12 . The method as defined in  claim 11 , wherein said pH sensitive carrier includes at least one pH sensitive compound selected from the group consisting of deoxycholic acid, cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, C27 bile acid, glycodeoxycholic acid, glycyrrhizic acid, glycyrrhetinic acid and salts thereof, and at least one amphipathic substance selected from the group consisting of a phosphatidylcholine having 10 to 12 carbon atoms, a polyoxyethylene sorbitan monofatty acid ester having 12 to 18 carbon atoms, a sorbitan fatty acid ester having 16 to 18 carbon atoms, glycerol monooleate, glycerol dilaurate, glycerol distearate, glycerol dioleate, polyoxyethylene castor oil and α-tocopherol, and is capable of developing a membrane disruptive function promoting effect. 
     
     
         13 . The method as defined in  claim 11 , wherein the pH sensitive compound is present in an amount of not less than 10 moles per 100 moles of the amphipathic substance. 
     
     
         14 . The method as defined in  claim 11 , wherein the pH sensitive compound and the amphipathic substance form micellar particles. 
     
     
         15 . The method as defined in  claim 14 , wherein the particle size is 10 to 200 nm. 
     
     
         16 . The method as defined in  claim 11 , wherein when a leakage of the pH sensitive compound alone in a leaching test is taken as La, a leakage of the amphipathic substance alone taken as Lb, a leakage of the pH sensitive carrier taken as Lc, leakages at a pH of 7.4, respectively, taken as Lc7.4, La7.4 and Lb7.4, and leakages at a pH of 5.0 or 4.5, respectively, taken as Lcx, Lax and Lbx, Δ represented by the following formula (1) is not smaller than 5 and Δ′ represented by the following formula (2) is not smaller than 5.
   Δ=( Lcx−Lc 7.4)−( Lax−La 7.4)  Equation (1)
 
   Δ′= Lcx −( Lax+Lbx )  Equation (2).
 
 
     
     
         17 . The method as defined in  claim 11 , wherein the physiologically active substance is made of a protein or peptide. 
     
     
         18 . A method for treating tumor or inflammation in a patient in need thereof which comprises:
 administering a pH sensitive drug composition which comprises a pH sensitive carrier and a physiologically active substance to induce the pH sensitive carrier to develop a membrane disruptive function and to deliver the physiologically active substance to the site.   
     
     
         19 . The method as defined in  claim 18 , wherein said pH sensitive carrier includes at least one pH sensitive compound selected from the group consisting of deoxycholic acid, cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, C27 bile acid, glycodeoxycholic acid, glycyrrhizic acid, glycyrrhetinic acid and salts thereof, and at least one amphipathic substance selected from the group consisting of a phosphatidylcholine having 10 to 12 carbon atoms, a polyoxyethylene sorbitan monofatty acid ester having 12 to 18 carbon atoms, a sorbitan fatty acid ester having 16 to 18 carbon atoms, glycerol monooleate, glycerol dilaurate, glycerol distearate, glycerol dioleate, polyoxyethylene castor oil and α-tocopherol, and is capable of developing a membrane disruptive function promoting effect. 
     
     
         20 . The method as defined in  claim 18 , wherein the pH sensitive compound is present in an amount of not less than 10 moles per 100 moles of the amphipathic substance. 
     
     
         21 . The method as defined in  claim 18 , wherein the pH sensitive compound and the amphipathic substance form micellar particles. 
     
     
         22 . The method as defined in  claim 21 , wherein the particle size is 10 to 200 nm. 
     
     
         23 . The method as defined in  claim 18 , wherein when a leakage of the pH sensitive compound alone in a leaching test is taken as La, a leakage of the amphipathic substance alone taken as Lb, a leakage of the pH sensitive carrier taken as Lc, leakages at a pH of 7.4, respectively, taken as Lc7.4, La7.4 and Lb7.4, and leakages at a pH of 5.0 or 4.5, respectively, taken as Lcx, Lax and Lbx, Δ represented by the following formula (1) is not smaller than 5 and Δ′ represented by the following formula (2) is not smaller than 5.
   Δ=( Lcx−Lc 7.4)−( Lax−La 7.4)  Equation (1)
 
   Δ′= Lcx −( Lax+Lbx )  Equation (2)
 
 
     
     
         24 . The method as defined in  claim 18 , wherein the physiologically active substance is made of a protein or peptide. 
     
     
         25 . A method for delivering a physiologically active substance to a cellular cytosol which comprises:
 taking up a pH sensitive drug which comprises a pH sensitive carrier and the physiologically active substance supported in the pH sensitive carrier in a cell via endocytosis thereby forming an endosome containing the pH sensitive drug to induce the pH sensitive carrier to develop a membrane disruptive function and to directly deliver the physiologically active substance to the cellular cytosol.   
     
     
         26 . The method as defined in  claim 25 , wherein said pH sensitive carrier includes at least one pH sensitive compound selected from the group consisting of deoxycholic acid, cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, C27 bile acid, glycodeoxycholic acid, glycyrrhizic acid, glycyrrhetinic acid and salts thereof, and at least one amphipathic substance selected from the group consisting of a phosphatidylcholine having 10 to 12 carbon atoms, a polyoxyethylene sorbitan monofatty acid ester having 12 to 18 carbon atoms, a sorbitan fatty acid ester having 16 to 18 carbon atoms, glycerol monooleate, glycerol dilaurate, glycerol distearate, glycerol dioleate, polyoxyethylene castor oil and α-tocopherol, and is capable of developing a membrane disruptive function promoting effect. 
     
     
         27 . The method as defined in  claim 25 , wherein the pH sensitive compound is present in an amount of not less than 10 moles per 100 moles of the amphipathic substance. 
     
     
         28 . The method as defined in  claim 25 , wherein the pH sensitive compound and the amphipathic substance form micellar particles. 
     
     
         29 . The method as defined in  claim 28 , wherein the particle size is 10 to 200 nm. 
     
     
         30 . The method as defined in  claim 25 , wherein when a leakage of the pH sensitive compound alone in a leaching test is taken as La, a leakage of the amphipathic substance alone taken as Lb, a leakage of the pH sensitive carrier taken as Lc, leakages at a pH of 7.4, respectively, taken as Lc7.4, La7.4 and Lb7.4, and leakages at a pH of 5.0 or 4.5, respectively, taken as Lcx, Lax and Lbx, Δ represented by the following formula (1) is not smaller than 5 and Δ′ represented by the following formula (2) is not smaller than 5.
   Δ=( Lcx−Lc 7.4)−( Lax−La 7.4)  Equation (1)
 
   Δ′= Lcx −( Lax+Lbx )  Equation (2)
 
 
     
     
         31 . The method as defined in  claim 25 , wherein the physiologically active substance is made of a protein or peptide. 
     
     
         32 . A method for delivering a physiologically active substance to a cellular cytosol which comprises:
 taking up the pH sensitive drug composition which comprises a pH sensitive carrier and a physiologically active substance in a cell by endocytosis of the pH sensitive carrier by the cell thereby forming endosomes independently containing the pH sensitive carrier and the physiologically active substance to induce the pH sensitive carrier to develop a membrane disruptive function and to directly deliver the physiologically active substance to the cellular cytosol.   
     
     
         33 . The method as defined in  claim 32 , wherein said pH sensitive carrier includes at least one pH sensitive compound selected from the group consisting of deoxycholic acid, cholic acid, ursodeoxycholic acid, chenodeoxycholic acid, hyodeoxycholic acid, C27 bile acid, glycodeoxycholic acid, glycyrrhizic acid, glycyrrhetinic acid and salts thereof, and at least one amphipathic substance selected from the group consisting of a phosphatidylcholine having 10 to 12 carbon atoms, a polyoxyethylene sorbitan monofatty acid ester having 12 to 18 carbon atoms, a sorbitan fatty acid ester having 16 to 18 carbon atoms, glycerol monooleate, glycerol dilaurate, glycerol distearate, glycerol dioleate, polyoxyethylene castor oil and α-tocopherol, and is capable of developing a membrane disruptive function promoting effect. 
     
     
         34 . The method as defined in  claim 32 , wherein the pH sensitive compound is present in an amount of not less than 10 moles per 100 moles of the amphipathic substance. 
     
     
         35 . The method as defined in  claim 32 , wherein the pH sensitive compound and the amphipathic substance form micellar particles. 
     
     
         36 . The method as defined in  claim 35 , wherein the particle size is 10 to 200 nm. 
     
     
         37 . The method as defined in  claim 32 , wherein when a leakage of the pH sensitive compound alone in a leaching test is taken as La, a leakage of the amphipathic substance alone taken as Lb, a leakage of the pH sensitive carrier taken as Lc, leakages at a pH of 7.4, respectively, taken as Lc7.4, La7.4 and Lb7.4, and leakages at a pH of 5.0 or 4.5, respectively, taken as Lcx, Lax and Lbx, Δ represented by the following formula (1) is not smaller than 5 and Δ′ represented by the following formula (2) is not smaller than 5.
   Δ=( Lcx−Lc 7.4)−( Lax−La 7.4)  Equation (1)
 
   Δ′= Lcx− ( Lax+Lbx )  Equation (2)
 
 
     
     
         38 . The method as defined in  claim 32 , wherein the physiologically active substance is made of a protein or peptide.