Oral insulin-oligomer conjugates

Abstract

A therapeutic formulation comprising a microemulsion of a therapeutic agent in free and/or conjugatively coupled form, wherein the microemulsion comprises a water-in-oil (w/o) microemulsion including a lipophilic phase and a hydrophilic phase, and has a hydrophilic and lipophilic balance (HLB) value between 3 and 7, wherein the therapeutic agent may for example be selected from the group consisting of insulin, calcitonin, ACTH, glucagon, somatostatin, somatotropin, somatomedin, parathyroid hormone, erythropoietin, hypothalamic releasing factors, prolactin, thyroid stimulating hormones, endorphins, enkephalins, vasopressin, non-naturally occurring opioids, superoxide dismutase, interferon, asparaginase, arginase, arginine deaminease, adenosine deaminase, ribonuclease, trypsin, chymotrypsin, papain, Ara-A (Arabinofuranosyladenine), Acylguanosine, Nordeoxyguanosine, Azidothymidine, Didesoxyadenosine, Dideoxycytidine, Dideoxyinosine Floxuridine, 6-Mercaptopurine, Doxorubicin, Daunorubicin, or I-darubicin, Erythromycin, Vancomycin, oleandomycin, Ampicillin; Quinidine and Heparin. In a particular aspect, the invention comprises an insulin composition suitable for parenteral as well as non-parenteral administration, preferably oral or parenteral administration, comprising insulin covalently coupled with a polymer including (i) a linear polyalkylene glycol moiety and (ii) a lipophilic moiety, wherein the insulin, the linear polyalkylene glycol moiety and the lipophilic moiety are conformationally arranged in relation to one another such that the insulin in the composition has an enhanced in vivo resistance to enzymatic degradation, relative to insulin alone. The microemulsion compositions of the invention are usefully employed in therapeutic as well as non-therapeutic, e.g., diagnostic, applications.

What is claimed is:  
     
         1 . An insulin compound comprising insulin covalently coupled to an oligomer having a formula:  
       —A—(CH 2 ) in —(OC 2 H 4 ) n —XR 
       wherein 
 A is —NHC(O)—O—, —C(O)O—, or —NH—C(O)—;  
 m is 2 to 15;  
 n is 5 to 120;  
 X is —O—, —S—, —C(O)O—, or —C(O)NH—; and  
 R is an alkyl.  
 
     
     
         2 . The compound according to  claim 1 , wherein A is —NHC(O)—O—.  
     
     
         3 . The compound according to  claim 1 , wherein A is —C(O)O—.  
     
     
         4 . The compound according to  claim 1 , wherein A is —NH—C(O)—.  
     
     
         5 . The compound according to  claim 1 , wherein X is O.  
     
     
         6 . The compound according to  claim 1 , wherein R is methyl.  
     
     
         7 . The compound according to  claim 1 , wherein the insulin is human insulin and A is attached to the human insulin at one or more amine functions selected from the group consisting of Glycine A1 amine function, Lysine B29 amine function, and Phenylalanine B1 amine function.  
     
     
         8 . The compound according to  claim 1 , wherein the compound is a monoconjugate.  
     
     
         9 . The compound according to  claim 1 , wherein the compound is a diconjugate.  
     
     
         10 . The compound according to  claim 1 , wherein the compound is a triconjugate.  
     
     
         11 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         12 . A method of treating insulin deficiency in a subject exhibiting such deficiency, comprising orally administering to the subject an effective amount of the compound of  claim 1 .  
     
     
         13 . A conjugate comprising insulin coupled to a methyl(ethyleneglycol) 7 -O-hexanoic acid polymer.  
     
     
         14 . A pharmaceutical composition comprising the conjugate of  claim 13  and a pharmaceutically acceptable carrier.  
     
     
         15 . The conjugate of  claim 13 , wherein the conjugate is a monoconjugate.  
     
     
         16 . The conjugate of  claim 13 , wherein the conjugate is a diconjugate.  
     
     
         17 . The conjugate of  claim 13 , wherein the conjugate is a triconjugate.  
     
     
         18 . The conjugate of  claim 13 , wherein the insulin is human insulin and the methyl(ethyleneglycol) 7 -O-hexanoic acid is attached to the human insulin at one or more amine functions selected from the group consisting of Glycine A1 amine function, Lysine B29 amine function, and Phenylalanine B1 amine function.  
     
     
         19 . A method of treating insulin deficiency in a subject exhibiting such deficiency, comprising orally administering to the subject an effective amount of the conjugate of  claim 13.