Process for producing an injectable medicament preparation

Abstract

The invention relates to a method for producing injectable medicament preparations containing a therapeutically and/or diagnostically effective substance which is comprised of an active agent, of a spacer molecule and of at least one protein-binding molecule. After being brought into contact with the body, said therapeutically and/or diagnostically effective substance covalently bonds to the body fluid constituents or tissue constituents via the protein-binding molecule, thus providing a form of transport of the active agent that an be hydrolytically or enzymatically cleaved, according to pH, in the body while releasing the active agent.

1 - 19 . (canceled) 
     
     
         20 . A process for producing an injectable medicament preparation comprising dissolving at least one therapeutically effective substance in an injectable carrier liquid, wherein the therapeutically effective substance comprises an active compound that is a cytostatic agent, at least one covalently protein-binding molecular residue that is maleimide, and a spacer comprising an organic molecular residue, which contains at least one aliphatic carbon chain or at least one aliphatic carbon ring having 1-12 carbon atoms, some of which can be replaced with oxygen, wherein the protein-binding molecular residue is linked to the active compound through the spacer, wherein the spacer, or the bond or the chemical group between the active compound and the spacer, can be cleaved hydrolytically enzymatically in the body of a subject in a pH-dependent manner. 
     
     
         21 . The process according to  claim 20 , wherein the substance has the chemical formula: 
       
         
           
           
               
               
           
         
         wherein A is the active compound; 
         SM is the spacer; and 
         PM is the protein-binding molecular residue. 
       
     
     
         22 . The process according to  claim 21 , wherein the substance has the chemical formula: 
       
         
           
           
               
               
           
         
         wherein, 
         X is a chemical group shared between the active compound and the spacer, and is selected from 
       
       
         
           
           
               
               
           
         
         wherein, 
         R is H, alkyl, phenyl, or substituted phenyl, and 
         Z is a chemical group belonging to the active compound. 
       
     
     
         23 . The process according to  claim 22 , wherein the substance has the chemical formula: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The process according to  claim 20 , wherein the cytostatic agent is an anthracycline. 
     
     
         25 . The process according to  claim 24 , wherein the anthracycline comprises doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, or ametantrone, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of the foregoing. 
     
     
         26 . The process according to  claim 25 , wherein the anthracycline comprises doxorubicin, or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The process according to  claim 20 , wherein the spacer comprises at least one aliphatic carbon chain having 1-12 carbon atoms which is optionally substituted. 
     
     
         28 . The process according to  claim 27 , wherein the at least one aliphatic carbon chain comprises 5 carbon atoms. 
     
     
         29 . The process according to  claim 22 , wherein the cytostatic agent is an anthracycline, the spacer is an aliphatic carbon chain comprising 5 carbon atoms, and the chemical group between the active compound and the spacer is 
       
         
           
           
               
               
           
         
       
     
     
         30 . The process according to  claim 20 , wherein the cytostatic agent is doxorubicin, the spacer is an aliphatic carbon chain comprising 5 carbon atoms, and the chemical group between the active compound and the spacer is 
       
         
           
           
               
               
           
         
       
     
     
         31 . The process according to  claim 20 , wherein the therapeutically effective substance has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         32 . An injectable medicament preparation produced by a process comprising dissolving at least one therapeutically effective substance in an injectable carrier liquid, wherein the therapeutically effective substance comprises at least one active compound that is a cytostatic agent, at least one covalently protein-binding molecular residue that is maleimide, and a spacer comprising an organic molecular residue, which contains at least one aliphatic carbon chain or at least one aliphatic carbon ring having 1-12 carbon atoms, some of which can be replaced with oxygen, wherein the protein-binding molecular residue is linked to the active compound through the spacer, wherein the spacer, or the bond or the chemical group between the active compound and the spacer, can be cleaved hydrolytically or enzymatically in the body of a subject in a pH-dependent manner, and
 wherein the protein-binding molecular residue is not bound to a carrier protein prior to administration.   
     
     
         33 . The preparation according to  claim 32 , wherein the substance has the chemical formula: 
       
         
           
           
               
               
           
         
         wherein A is the active compound; 
         SM is the spacer; and 
         PM is maleimide, the protein-binding molecular residue. 
       
     
     
         34 . The preparation according to  claim 33 , wherein the substance has the chemical formula: 
       
         
           
           
               
               
           
         
         wherein, 
         X is a chemical group shared between the active compound and the spacer, and is selected from 
       
       
         
           
           
               
               
           
         
         wherein, 
         R is H, alkyl, phenyl, or substituted phenyl, and 
         Z is a chemical group belonging to the active compound. 
       
     
     
         35 . The preparation according to  claim 34 , wherein the substance has the chemical formula: 
       
         
           
           
               
               
           
         
       
     
     
         36 . The preparation according to  claim 32 , wherein the cytostatic agent is an anthracycline. 
     
     
         37 . The preparation according to  claim 36 , wherein the anthracycline comprises doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, or ametantrone, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of the foregoing. 
     
     
         38 . The preparation according to  claim 37 , wherein the anthracycline comprises doxorubicin, or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The preparation according to  claim 32 , wherein the spacer comprises at least one aliphatic carbon chain having 1-12 carbon atoms which is optionally substituted. 
     
     
         40 . The preparation according to  claim 39 , wherein the at least one aliphatic carbon chain comprises 5 carbon atoms. 
     
     
         41 . The preparation according to  claim 34 , wherein the cytostatic agent is an anthracycline, the spacer is an aliphatic carbon chain comprising 5 carbon atoms, and the chemical group between the active compound and the spacer is 
       
         
           
           
               
               
           
         
       
     
     
         42 . The preparation according to  claim 32 , wherein the cytostatic agent is doxorubicin, the spacer is an aliphatic carbon chain comprising 5 carbon atoms, and the chemical group between the active compound and the spacer is 
       
         
           
           
               
               
           
         
       
     
     
         43 . A method for treating a disease selected from a cancer, a virus disease, autoimmune disease, acute or chronic inflammatory disease, and a disease caused by bacteria, fungi, or other micro-organisms, comprising administering to a patient in need thereof a therapeutically effective amount of a substance comprising:
 at least one active compound selected from a cytostatic agent, a cytokine, an immunosuppressive agent, a virostatic agent, an antirheumatic agent, an analgesic, an anti-inflammatory agent, an antibiotic, an antimycotic agent, a signal transduction inhibitor, an angiogenesis inhibitor, and a protease inhibitor;   at least one covalently protein-binding molecular residue selected from a maleimide, a haloacetamide, a haloacetate, a pyridylthio, a N-hydroxysuccinimide ester, an isothiocyanate, a disulfide, a vinylcarbonyl, an aziridine, and an acetylene; and   a spacer comprising an organic molecular residue, which contains at least one aromatic moiety or at least one aliphatic carbon chain or an aliphatic carbon ring having 1-12 carbon atoms, some of which can be replaced with oxygen;   wherein the protein-binding molecular residue is linked to the active compound through the spacer, and   wherein the protein-binding molecular residue is not bound to a carrier protein prior to administration.   
     
     
         44 . The method according to  claim 43 , wherein the spacer, or the bond or the chemical group between the active compound and the spacer, can be cleaved hydrolytically or enzymatically in the body of a subject in a pH-dependent manner. 
     
     
         45 . The method according to  claim 43 , wherein:
 the disease is a cancer;   the at least one active compound is a cytostatic agent;   the at least one covalently protein-binding molecular residue is maleimide;   the spacer comprises an organic molecular residue, which contains at least one aromatic moiety or at least one aliphatic carbon chain or an aliphatic carbon ring having 1-12 carbon atoms, some of which can be replaced with oxygen; and   wherein the spacer, or the bond or the chemical group between the active compound and the spacer, can be cleaved hydrolytically or enzymatically in the body of a subject in a pH-dependent manner.   
     
     
         46 . The method according to  claim 45 , wherein the substance has the chemical formula: 
       
         
           
           
               
               
           
         
         wherein A is the active compound; 
         SM is the spacer; and 
         PM is maleimide, the protein-binding molecular residue. 
       
     
     
         47 . The method according to  claim 46 , wherein the substance has the chemical formula: 
       
         
           
           
               
               
           
         
         wherein, 
         X is a chemical group shared between the active compound and the spacer, and is selected from 
       
       
         
           
           
               
               
           
         
         wherein, 
         R is H, alkyl, phenyl, or substituted phenyl, and 
         Z is a chemical group belonging to the active compound. 
       
     
     
         48 . The method according to  claim 47 , wherein the substance has the chemical formula: 
       
         
           
           
               
               
           
         
       
     
     
         49 . The method according to  claim 45 , wherein the cytostatic agent is an anthracycline. 
     
     
         50 . The method according to  claim 49 , wherein the anthracycline comprises doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, or ametantrone, or a derivative of any of the foregoing, or a pharmaceutically acceptable salt of the foregoing. 
     
     
         51 . The method according to  claim 50 , wherein the anthracycline comprises doxorubicin, or pharmaceutically acceptable salt thereof. 
     
     
         52 . The method according to  claim 43 , wherein the spacer comprises at least one aliphatic carbon chain having 1-12 carbon atoms which is optionally substituted. 
     
     
         53 . The method according to  claim 52 , wherein the at least one aliphatic carbon chain comprises 5 carbon atoms. 
     
     
         54 . The method according to  claim 47 , wherein the cytostatic agent is an anthracycline, the spacer is an aliphatic carbon chain comprising 5 carbon atoms, and the chemical group between the active compound and the spacer is 
       
         
           
           
               
               
           
         
       
     
     
         55 . The method according to  claim 45 , wherein the cytostatic agent is doxorubicin, the spacer is an aliphatic carbon chain comprising 5 carbon atoms, and the chemical group between the active compound and the spacer is 
       
         
           
           
               
               
           
         
       
     
     
         56 . The method according to  claim 43 , wherein the cancer is renal cell carcinoma or soft tissue sarcoma.