Hepatoselective pharmaceutical actives

Abstract

The invention provides an analogue of a pharmaceutical active whose molecular weight is less than 25,000 Daltons, the analogue comprising a pharmaceutical active whose molecular weight is less than 25,000 Daltons covalently linked to a pendant molecular group wherein as a result of the administration of the composition to the human or animal body an active complex having a molecular weight of 25,000 Daltons or greater is present in the human or animal circulatory system. The analogue is hepatoselective when administered to the circulatory system. Preferably the analogue is an insulin analogue comprising an insulin or functional equivalent thereof covalently linked to the pendant molecular group wherein the active complex is an insulin complex. Such an insulin analogue may be used in a method of insulin replacement therapy.

1. A method of treating diabetes in a human or an animal, comprising the step of:
 administering a conjugate compound having a molecular weight of less than 25 kD comprised of a pharmaceutically active compound and a pendant molecular moiety which is a naturally occurring hormone or an analogue thereof, wherein the pendant molecular moiety has an affinity for one or more binding proteins naturally present in the circulatory system of a human or an animal whereby the conjugate reaches the systemic circulation of the human or the animal and in the circulation forms a complex having a molecular weight of more than 25 kD with the one or more binding proteins.  
 
     
     
       2. A treatment method according to  claim 1 , wherein the pharmaceutically active compound is insulin or a functional equivalent of insulin. 
     
     
       3. A treatment method according to  claim 1 , wherein the pendant molecular moiety is a thyroid hormone. 
     
     
       4. A treatment method according to  claim 3 , wherein the thyroid hormone is thyroxine. 
     
     
       5. A treatment method according to  claim 1 , wherein the pendant molecular moiety if IGF1. 
     
     
       6. A treatment method according to  claim 2 , wherein the pendant molecular moiety is a thyroid hormone. 
     
     
       7. A treatment method according to  claim 6 , wherein the thyroid hormone is thyroxine. 
     
     
       8. A treatment method according to  claim 1 , wherein the pendant molecular moiety is linked to the pharmaceutically active compound by a spacer. 
     
     
       9. A treatment method according to  claim 8 , wherein the spacer is a linear chain of from 3 to 10 carbon atoms in length. 
     
     
       10. A treatment method according to  claim 1 , wherein the binding protein is selected from the group consisting of albumin, thyroxine-binding pre-albumin, thyroxine-binding globulin, and combinations of those proteins. 
     
     
       11. A treatment method according to  claim 2 , wherein the binding protein is selected from the group consisting of albumin, thyroxine-binding pre-albumin, thyroxine-binding globulin, and combinations of those proteins. 
     
     
       12. A method according to  claim 7 , wherein the binding protein is selected from the group consisting of albumin, thyroxine-binding pre-albumin, thyroxine-binding globulin, and combinations of those proteins. 
     
     
       13. A method of delivering a pharmaceutically active compound to a human or an animal comprising:
 a) covalently bonding to the pharmaceutically active compound a pendant molecular moiety which is a naturally occurring hormone or an analogue thereof to form a conjugate compound which has a molecular weight of less than 25 kD; and  
 b) administering the said conjugate compound to a human or an animal whereby the conjugate compound is delivered to the circulatory system of the said human or animal and forms a complex therein with one or more binding proteins naturally present in the said circulatory system, said complex having a molecular weight of more than 25 kD.  
 
     
     
       14. A method of directing a pharmaceutically active compound selectively to the liver of a human or animal comprising the steps:
 a) covalently bonding to the pharmaceutically active compound a pendant molecular moiety which is a naturally occurring hormone or an analogue thereof to form a conjugate compound which has a molecular weight of less than 25 kD; and  
 b) administering the said conjugate compound to a human or an animal whereby the conjugate compound is delivered to the circulatory system of the said human or animal and forms a complex therein with one or more binding proteins naturally present in the said circulatory system, said complex having a molecular weight of more than 25 kD.  
 
     
     
       15. A method of forming a complex in the systemic circulation of a human or animal comprising the Steps of:
 a) covalently bonding to the pharmaceutically active compound a pendant molecular moiety which is a naturally occurring hormone or an analogue thereof to form a conjugate compound which has a molecular weight of less than 25 kD; and  
 b) administering the said conjugate compound to a human or an animal whereby the conjugate compound is delivered to the circulatory system of the said human or animal and forms a complex therein with one or more binding proteins naturally present in the said circulatory system, said complex having a molecular weight of more than 25 kD.  
 
     
     
       16. A method according to  claim 2  in which the pendant molecular moiety is conjugated at the alpha amino group of the B1 residue of the insulin molecule. 
     
     
       17. A method according to  claim 6  wherein the pendant molecular moiety is conjugated at the alpha amino group of the B1 residue of the insulin molecule. 
     
     
       18. A method of treating diabetes in a human or animal with insulin, or a functional equivalent thereof, comprising the step of administering a conjugate compound having a molecular weight of less than  25  kD comprised of insulin, or a functional equivalent of insulin, covalently bound to a molecule having an affinity for one or more binding proteins naturally present in blood plasma of a human or animal, whereby the conjugate reaches the systemic circulation of the human or the animal and in the circulation forms a complex having a molecular weight of more than  25  kD with the one or more binding proteins. 
     
     
       19. A method of selectively delivering a pharmaceutically active compound to hepatocytes in a human or animal comprising
 ( a )  covalently bonding to the pharmaceutically active compound a pendant molecular moiety to form a conjugate compound which has a molecular weight of less than  25  kD and      ( b )  administering said conjugate compound to a human or an animal whereby said conjugate compound is delivered to the circulatory system of the said human or animal and forms a complex therein with one or more binding proteins naturally present in said circulatory system, said complex having a molecular weight of more than  25  kD.     
     
     
       20. A method as claimed in  claim 19  wherein the pharmaceutically active compound is insulin or a functional equivalent thereof.