Glycosaminoglycan derivative and method for producing same

Abstract

The present invention provides a glycosaminoglycan derivative in which a group derived from glycosaminoglycan and a group derived from a physiologically active substance having at least one of a carboxy group and a hydroxy group are coupled by covalent bond with a spacer therebetween, in which the spacer is selected in accordance with the decomposition rate of the covalent bond to the group derived from the physiologically active substance.

1 .- 4 . (canceled) 
     
     
         5 . A method for suppressing pain, the method comprising administering a pharmaceutical composition to a living body,
 wherein the pharmaceutical composition comprises a chondroitin sulfate derivative,   wherein the chondroitin sulfate derivative comprises a group derived from a chondroitin sulfate, a group derived from a steroid, and a spacer which couples the group derived from the chondroitin sulfate to the group derived from the steroid by a covalent bond,   wherein the group derived from the steroid and the spacer are covalently bonded through an ester bond,   wherein the group derived from chondroitin sulfate and the spacer are covalently bonded through an amide bond,   wherein a molecule for forming the spacer has a coupling group which may have one or more substituent and couples the ester bond and the amide bond, and the length of the coupling group between the ester bond and the amide bond is 2 to 12 atoms, and   wherein a dissociation rate of the steroid from the chondroitin sulfate derivative is 0.1 to 10%/day in a phosphate buffered saline with pH of 7.5 at 36° C., and   wherein the pharmaceutical composition is administered locally.   
     
     
         6 . A method for obtaining anti-inflammatory effect, the method comprising administering a pharmaceutical composition to a living body,
 wherein the pharmaceutical composition comprises a chondroitin sulfate derivative,   wherein the chondroitin sulfate derivative comprises a group derived from a chondroitin sulfate, a group derived from a steroid, and a spacer which couples the group derived from the chondroitin sulfate to the group derived from the steroid by a covalent bond,   wherein the group derived from the steroid and the spacer are covalently bonded through an ester bond,   wherein the group derived from chondroitin sulfate and the spacer are covalently bonded through an amide bond,   wherein a molecule for forming the spacer has a coupling group which may have one or more substituent and couples the ester bond and the amide bond, and the length of the coupling group between the ester bond and the amide bond is 2 to 12 atoms, and   wherein a dissociation rate of the steroid from the chondroitin sulfate derivative is 0.1 to 10%/day in a phosphate buffered saline with pH of 7.5 at 36° C., and   wherein the pharmaceutical composition is administered locally.   
     
     
         7 . A pharmaceutical composition containing a hyaluronic acid derivative,
 wherein the hyaluronic acid derivative in which a group derived from a hyaluronic acid and a group derived from a diclofenac are coupled by a covalent bond with a spacer therebetween,   wherein the group derived from the diclofenac and the spacer are covalently bonded through an ester bond,   wherein the group derived from hyaluronic acid and the spacer are covalently bonded through an amide bond,   wherein a molecule for forming the spacer has a coupling group derived from a divalent aliphatic hydrocarbon with 2 carbon atoms which couples the ester bond and the amide bond, and may have one or more substituent selected from the group of a methyl group, an ethyl group, a propyl group, or a butyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a cyclohexyl group, and a phenyl group, and   wherein the pharmaceutical composition stored at 60° C. for seven days has a dissociation ratio of the diclofenac from the hyaluronic acid derivative of 8.1% or less.   
     
     
         8 . The pharmaceutical composition according to  claim 7 ,
 wherein the pharmaceutical composition stored at 60° C. for 7 days has a dissociation ratio of the diclofenac from the hyaluronic acid derivative of 1.9% or more.   
     
     
         9 . The pharmaceutical composition according to  claim 7 ,
 wherein the pharmaceutical composition is a controlled release preparation.   
     
     
         10 . The pharmaceutical composition according to  claim 7 ,
 wherein the pharmaceutical composition is a continuous type pain suppressing agent.   
     
     
         11 . The pharmaceutical composition according to  claim 7 ,
 wherein the pharmaceutical composition is a treatment agent for arthritis.   
     
     
         12 . A glycosaminoglycan derivative comprising:
 a group derived from glycosaminoglycan and a group derived from a physiologically active substance having at least one of a carboxy group and a hydroxy group that are coupled by a covalent bond with a spacer therebetween, in which the spacer is selected in accordance with a decomposition rate of the covalent bond to the group derived from a physiologically active substance;   wherein the glycosaminoglycan is at least one selected from the group consisting of a chondroitin sulfate, a hyaluronic acid, a heparin, a heparan sulfate, a keratan sulfate, a dermatan sulfate, and a derivative thereof;   wherein the group derived from the physiologically active substance and the spacer are covalently bonded through an ester bond;   wherein the group derived from glycosaminoglycan and the spacer are covalently bonded through an amide bond;   wherein the spacer is a divalent group derived from an amino acid represented by the following formula (I):
   —HN—(CH 2 ) m —CR 11 R 12 —CR 13 R 14 —CO—  (I)
 
   wherein in formula (I), m is an integer of 0 to 12 and R 11  to R 14  each independently represents a hydrogen atom, an electron withdrawing group, an electron donating group, or a sterically hindered group; and   wherein a dissociation rate of the physiologically active substance from the glycosaminoglycan derivative is 0.1 to 5%/day in a phosphate buffered saline with pH of 7.5 at 36° C.   
     
     
         13 . The glycosaminoglycan derivative according to  claim 12 , wherein the physiologically active substance is at least one selected from the group consisting of a nonsteroidal anti-inflammatory drug, a steroid, an anti-rheumatic drug, an anti-allergic drug, a therapeutic agent for hyperlipidemia, and a β stimulator. 
     
     
         14 . A pharmaceutical composition comprising the glycosaminoglycan derivative described in  claim 12 . 
     
     
         15 . A controlled release preparation comprising the glycosaminoglycan derivative described in  claim 12 . 
     
     
         16 . A continuous type pain suppressing agent comprising the glycosaminoglycan derivative described in  claim 12 . 
     
     
         17 . A method for producing a glycosaminoglycan derivative, the method comprising:
 preparing a physiologically active substance having at least one of a carboxy group or a hydroxy group, selecting a spacer for forming a covalent bond with a group derived from the physiologically active substance in accordance with a decomposition rate of the covalent bond, and   forming a covalent bond between the group derived from the physiologically active substance and a group derived from glycosaminoglycan with the spacer therebetween;   wherein the glycosaminoglycan is at least one selected from the group consisting of a chondroitin sulfate, a hyaluronic acid, a heparin, a heparan sulfate, a keratan sulfate, a dermatan sulfate, and a derivative thereof;   wherein the group derived from the physiologically active substance and the spacer are covalently bonded through an ester bond;   wherein the group derived from glycosaminoglycan and the spacer are covalently bonded through an amide bond;   wherein the spacer is a divalent group derived from an amino acid represented by the following formula (I):
   —HN—(CH 2 ) m —CR 11 R 12 —CR 13 R 14 —CO—  (I)
 
   wherein in formula (I), m is an integer of 0 to 12 and R 11  to R 14  each independently represents a hydrogen atom, an electron withdrawing group, an electron donating group, or a sterically hindered group; and   wherein a dissociation rate of the physiologically active substance from the glycosaminoglycan derivative is 0.1 to 5%/day in a phosphate buffered saline with pH of 7.5 at 36° C.   
     
     
         18 . A glycosaminoglycan derivative comprising:
 a group derived from glycosaminoglycan,   a group derived from a physiologically active substance, and   a spacer which couples the group derived from glycosaminoglycan to the group derived from the physiologically active substance by a covalent bond,   wherein the glycosaminoglycan is at least one selected from the group consisting of a chondroitin sulfate, a hyaluronic acid, a heparin, a heparan sulfate, a keratan sulfate, a dermatan sulfate, and a derivative thereof,   wherein the physiologically active substance has a hydroxy group, a molecule for forming the spacer has a carboxy group corresponding to the hydroxy group, and the group derived from the physiologically active substance and the spacer are covalently bonded through an ester bond,   wherein the glycosaminoglycan has a carboxy group, the molecule for forming the spacer has an amino group corresponding to the carboxy group of the glycosaminoglycan, and the group derived from glycosaminoglycan and the spacer are covalently bonded through an amide bond,   wherein the molecule for forming the spacer has a coupling group which couples the carboxy group and the amino group and the length of the coupling group between the carboxy group and the amino group is 2 to 12 atoms, and   wherein a dissociation rate of the physiologically active substance from the glycosaminoglycan derivative is 0.1 to 5%/day in a phosphate buffered saline with pH of 7.5 at 36° C.   
     
     
         19 . The glycosaminoglycan derivative according to  claim 12 , wherein the physiologically active substance has a hydroxy group. 
     
     
         20 . The glycosaminoglycan derivative according to  claim 12 , wherein the physiologically active substance is steroid. 
     
     
         21 . The glycosaminoglycan derivative according to  claim 12 , wherein the glycosaminoglycan is at least one selected from the group consisting of chondroitin sulfate and a derivative thereof.