Method of preparing a controlled-release pharmaceutical preparation, and resulting composition

Abstract

A method of preparing a controlled-release pharmaceutical compound for oral administration, which pharmaceutical compound is subject to enzymatic hydrolysis on oral administration, which method comprises encapsulating the pharmaceutical compound with a synthetic phosphatidyl compound having a modified polarhead moiety which increases the resistance of the phosphatidyl compound to phospholipase C hydrolysis.

What I claim is: 
     
       1. In a method for preparing a controlled-release pharmaceutical composition for oral administration, the method which comprises: forming an aqueous emulsion of phospholipid encapsulating agent with the pharmaceutical compound whose release is to be controlled; coagulating the emulsion to entrap the pharmaceutical compound within the phospholipid agent; and recovering the pharmaceutical composition as prepared, the improvement which comprises: employing as the phospholipid encapsulating agent a synthetic fatty-acid phosphatidyl .[.C 1  -C 10  alkyl-N-C 1  -C 4  trialkyl.]. quaternary-ammonium hydroxide compound.[., with the proviso that the alkyl of the alkyl-N group is not an ethyl group when the alkyl groups of the N-trialkyl radicals are methyl groups.]. .Iadd.represented by the structural formula: .Iaddend. ##STR2## .Iadd.wherein R 4  is a C 1  -C 10  methylene radical and R 1 , R 2  and R 3  are C 1  -C 4  alkyl radicals, with the proviso that R 1 , R 2  and R 3  at the same time are not all methyl radicals and wherein R is a fatty-acid radical.Iaddend., and which phosphatidyl quaternary-ammonium compound is resistant to enzymatic hydrolysis of phospholipase C.   
     
     
       2. The method of claim 1 wherein the .[.fatty acid.]. .Iadd.fatty-acid radical .Iaddend.is a C 14  to C 20  fatty-acid radical. 
     
     
       3. The method of claim 1 wherein .[.the alkyl-N of the quaternary-ammonium compound is butyl-N or propyl-N, and.]. the .[.trialkyl groups.]. .Iadd.R 1 , R 2  and R 3  alkyl radicals .Iaddend.are all the same alkyl .[.group.]. .Iadd.radical.Iaddend.. 
     
     
       4. The method of claim 3 wherein the .[.trialkyl groups.]. .Iadd.R 1 , R 2  and R 3  alkyl radicals .Iaddend.are methyl or ethyl .[.groups.]. .Iadd.radicals.Iaddend.. 
     
     
       5. The method of claim 1 wherein the quaternary-ammonium compound is selected from the group consisting of: dimyristoyl phosphatidyl ethyl-N-dimethyl, propyl ammonium hydroxide; .Iadd.and .Iaddend.dimyristoyl phosphatidyl ethyl-N-dimethyl, ethyl ammonium hydroxide.[.; dimyristoyl phosphatidyl propyl-N-trimethyl ammonium hydroxide; dimyristoyl phosphatidyl butyl-N-trimethyl ammonium hydroxide; and dimyristoyl phosphatidyl propyl-N-triethyl ammonium hydroxide.].. 
     
     
       6. The method of claim 1 wherein the pharmaceutical compound is insulin. 
     
     
       7. The controlled-release composition prepared by the method of claim 6. 
     
     
       8. The method of claim 1 wherein the encapsulated pharmaceutical compound is enzymatically hydrolyzed by phospholipase C in the stomach. 
     
     
       9. The controlled-release pharmaceutical composition prepared by the method of claim 1. 
     
     
       10. The method of claim 1 which comprises: sonification of the pharmaceutical compound and the synthetic phospholipid compound together to encapsulate the pharmaceutical compound.