Agent for Applying to Mucosa and Method for the Production Thereof

Abstract

An agent for applying to mucosa capable of persistently exerting a therapeutic effect on disorders such as inflammation and lesions in the mucosa even by a lower frequency of administration because the agent can stay at a diseased site for a long period of time by exhibiting a high staying property in a mucosal epithelial layer is provided, said agent for application to mucosa containing glycosaminoglycan (GAG) into which a hydrophobic group is introduced via a binding chain, as an active ingredient.

1 . An agent for applying to mucosa containing glycosaminoglycan into which a hydrophobic group is introduced via a binding chain, as an active ingredient. 
   
   
       2 . The agent for applying to mucosa according to  claim 1  wherein the glycosaminoglycan is selected from hyaluronic acid, chondroitin, chondroitin sulfate, heparin, heparan sulfate, dermatan sulfate and keratan sulfate, and salts thereof. 
   
   
       3 . The agent for applying to mucosa according to  claim 1  wherein the glycosaminoglycan is sodium hyaluronate. 
   
   
       4 . The agent for applying to mucosa according to  claim 1  wherein the hydrophobic group is selected from alkyl groups having 2 to 18 carbon atoms, alkenyl groups having 2 to 18 carbon atoms, alkynyl groups having 2 to 18 carbon atoms, aryl groups, heteroaryl groups, arylalkyl groups, arylalkenyl groups, arylalkynyl groups and amino acid groups. 
   
   
       5 . The agent for applying to mucosa according to  claim 1  wherein the hydrophobic group is arylalkenyl group. 
   
   
       6 . The agent for applying to mucosa according to  claim 5  wherein the hydrophobic group is phenylethenyl group. 
   
   
       7 . The agent for applying to mucosa according to  claim 1  wherein the binding chain is selected from —CONH—, —COO—, -0-, —S0 3 - and —S0 2 NH—. 
   
   
       8 . The agent for applying to mucosa according to  claim 1  wherein “the glycosaminoglycan into which a hydrophobic group is introduced via a binding chain” further includes a spacer chain between the binding chain and the hydrophobic group (the spacer chain further includes a binding chain at a hydrophobic group side). 
   
   
       9 . The agent for applying to mucosa according to  claim 8  wherein the spacer chain further having the binding chain at the hydrophobic group side is selected from —COO—(CH 2 ) m —, —COO—(CH 2 )—(OCH 2 ) n —, —CONH—(CH 2 ) m — and —CONH—(CH 2 )—(OCH 2 ) n — (wherein m and n represent integers of 1 to 18, respectively). 
   
   
       10 . An agent for applying to mucosa containing glycosaminoglycan into which Ph-CH═CH—COO—(CH 2 ) m —NH; Ph-CH═CH—COO—CH 2 —(OCH 2 ) n —NH; Ph-CH═CH—CONH—(CH 2 ) m —NH; Ph-CH═CH—CONH—CH 2 —(OCH 2 ) n —NH; Ph-CH═CH—COO—(CH 2 ) m —O; Ph-CH═CH—COO—CH 2 —(OCH 2 ) n —O; Ph-CH═CH—CONH—(CH 2 ) m —O; Ph-CH═CH—CONH—CH 2 —(OCH 2 ) n —O; CH 3 —(CH 2 ) 1 —COO-Ph-COHN—(CH 2 ) m —NH or CH 3 —(CH 2 ) 1 —COO-Ph-CONH—CH 2 —(OCH 2 ) n —NH (wherein Ph represents phenyl group, m and n represent integers of 1 to 18, respectively, and 1 represents 0 or an integer of 1 to 18) is introduced, as the active ingredient. 
   
   
       11 . An agent for applying to mucosa containing glycosaminoglycan having a repeat structure of a structural unit represented by the following formula, as a basic skeleton: 
     
       
         
         
             
             
         
       
       wherein R represents R 1  or R 2 ; 
       Ac represents an acetyl group; 
       R 1  represents ONa or OH; 
       R 2  represents Ph-CH═CH—COO—(CH 2 ) m —NH—; Ph-CH═CH—COO—CH 2 —(OCH 2 ) n —NH—; Ph-CH═CH—CONH—(CH 2 ) m —NH—; Ph-CH═CH—CONH—CH 2 —(OCH 2 ) n —NH—; Ph-CH═CH—COO—(CH 2 ) m —O—; Ph-CH═CH—COO—CH 2 —(OCH 2 ) n —O—; Ph-CH═CH—CONH—(CH 2 ) m —O—; Ph-CH═CH—CONH—CH 2 —(OCH 2 ) n —O—; CH 3 (CH 2 ) 1 —COO-Ph-CONH—(CH 2 ) m —NH—; or CH 3 (CH 2 ) 1 —COO-Ph-CONH—CH 2 —(OCH 2 ) n —NH—; (wherein Ph represents phenyl, m and n represent integers of 1 to 18, respectively, and 1 represents 0 or an integer of 1 to 18) as a basic skeleton, wherein the ratio of the above structural unit wherein R represents R 2  is 5 to 30% in molar equivalent relative to the disaccharide repeat unit in molar equivalent of the glycosaminoglycan. 
     
   
   
       12 . The agent for applying to mucosa according to  claim 1  wherein the agent is a liquid. 
   
   
       13 . The agent for applying to mucosa according to  claim 12  wherein the concentration of glycosaminoglycan into which the hydrophobic group is introduced via the binding chain is 0.02 to 5% by weight. 
   
   
       14 . The agent for applying to mucosa according to  claim 1  wherein the mucosa is cornea, conjunctiva, oral cavity mucosa or urinary bladder mucosa. 
   
   
       15 . The agent for applying to mucosa according to  claim 1  which is used for the treatment of a mucosal disorder. 
   
   
       16 . The agent for applying to mucosa according to  claim 15  wherein the mucosal disorder is a mucosal epithelial layer disorder. 
   
   
       17 . The agent for applying to mucosa according to  claim 1  which is eye drops. 
   
   
       18 . The agent for applying to mucosa according to  claim 17  which is used for the prevention of a corneal disorder due to ultraviolet rays. 
   
   
       19 . A method for applying to mucosa an agent containing glycosaminoglycan into which a hydrophobic group is introduced via a binding chain, as an active ingredient. 
   
   
       20 . The method according to  claim 19  wherein the glycosaminoglycan is selected from hyaluronic acid, chondroitin, chondroitin sulfate, heparin, heparan sulfate, dermatan sulfate and keratan sulfate, and salts thereof. 
   
   
       21 . The method according to  claim 19  wherein the glycosaminoglycan is sodium hyaluronate. 
   
   
       22 . The method according to  claim 19  wherein the hydrophobic group is selected from alkyl groups having 2 to 18 carbon atoms, alkenyl groups having 2 to 18 carbon atoms, alkynyl groups having 2 to 18 carbon atoms, aryl groups, heteroaryl groups, arylalkyl groups, arylalkenyl groups, arylalkynyl groups and amino acid groups. 
   
   
       23 . The method according to  claim 19  wherein the hydrophobic group is arylalkenyl group. 
   
   
       24 . The method according to  claim 19  wherein the hydrophobic group is phenylethenyl group. 
   
   
       25 . The method according to  claim 19  wherein the binding chain is selected from —CONH—, —COO—, -0-, —S0 3  and —S0 2 NH—. 
   
   
       26 . The method according to  claim 19  wherein “the glycosaminoglycan into which a hydrophobic group is introduced via a binding chain” further includes a spacer chairs between the binding chain and the hydrophobic group (the spacer chain further includes a binding chain at a hydrophobic group side). 
   
   
       27 . The method according to  claim 26  wherein the spacer chain further having the binding chain at the hydrophobic group side is selected from —COO—(CH 2 ) m —, —COO—(CH 2 )—(OCH 2 ) n —, —CONH—(CH 2 ) m — and —CONH—(CH 2 )—(OCH 2 ) n  (wherein m and n represent integers of 1 to 18, respectively). 
   
   
       28 . A method for applying to mucosa an agent containing glycosaminoglycan into which Ph-CH═CH—COO—(CH 2 ) m —NH; Ph-CH═CH—COO—CH 2 —(OCH 2 ) n —NH; Ph-CH═CH—CONH—(CH 2 ) m —NH; Ph-CH═CH—CONH—CH 2 —(OCH 2 ) n —NH; Ph-CH═CH—COO—(CH 2 ) m —O; Ph-CH═CH—COO—CH 2 —(OCH 2 ) n —O; Ph-CH═CH—CONH—(CH 2 ) m —O; Ph-CH═CH—CONH—CH 2 —(OCH 2 ) n —O; CH 3 —(CH 2 ) 1 —COO-Ph-COHN—(CH 2 ) m —NH or CH 3 —(CH 2 ) 1 —COO-Ph-CONH—CH 2 —(OCH 2 ) n —NH (wherein Ph represents phenyl group, m and n represent integers of 1 to 18, respectively, and 1 represents 0 or an integer of 1 to 18) is introduced, as an active ingredient. 
   
   
       29 . A method for applying to mucosa an agent containing glycosaminoglycan having a repeat structure of a structural unit represented by the following formula, as a basic skeleton: 
     
       
         
         
             
             
         
       
       wherein R represents R 1  or R 2 ; 
       Ac represents an acetyl group; 
       R 1  represents ONa or OH; 
       R 2  represents Ph-CH═CH—COO—(CH 2 ) m —NH—; Ph-CH═CH—COO—CH 2 —(OCH 2 ) n —NH—; Ph-CH═CH—CONH—(CH 2 ) m —NH—; Ph-CH═CH—CONH—CH 2 —(OCH 2 ) n —NH—; Ph-CH═CH—COO—(CH 2 ) m —O—; Ph-CH═CH—COO—CH 2 —(OCH 2 ) n —O—; Ph-CH═CH—CONH—(CH 2 ) m —O—; Ph-CH═CH—CONH—CH 2 —(OCH 2 ) n —O—; CH 3 —(CH 2 ) 1 —COO-Ph-CONH— (CH 2 ) m —NH—; or CH 3 —(CH 2 ) 1 COO-Ph-CONH—CH 2 —(OCH 2 ) n —NH—; (wherein Ph represents phenyl, m and n represent integers of 1 to 18, respectively, and 1 represents 0 or an integer of 1 to 18) as a basic skeleton, wherein the ratio of the above structural unit wherein R represents R 2  is 5 to 30% in molar equivalent relative to the disaccharide repeat unit in molar equivalent of the glycosaminoglycan. 
     
   
   
       30 . The method according to  claim 19  wherein the agent is a liquid. 
   
   
       31 . The method according to  claim 30  wherein the concentration of glycosaminoglycan into which the hydrophobic group is introduced via the binding chain is 0.02 to 5% by weight. 
   
   
       32 . The method according to  claim 19  wherein the mucosa is cornea, conjunctiva, oral cavity mucosa or urinary bladder mucosa. 
   
   
       33 . A method for the treatment of a mucosal disorder comprising applying to mucosa an agent containing glycosaminoglycan into which a hydrophobic group is introduced via a binding chain, as an active ingredient. 
   
   
       34 . The method according to  claim 33  wherein the mucosal disorder is a mucosal epithelial layer disorder. 
   
   
       35 . The method according to  claim 19  wherein the agent is eye drops. 
   
   
       36 . A method for the prevention of a corneal disorder due to ultraviolet rays comprising applying to mucosa eye drops containing glycosaminoglycan into which a hydrophobic group is introduced via a binding chain, as an active ingredient.