Delivery systems for pharmacological agents encapsulated with proteinoids

Abstract

Methods are described for targeting the release of an active pharmacological agent in an animal by administering that agent encapsulated in proteinoid microspheres which are stable to the environment encountered from the point of introduction until they migrate to the targeted body organs, fluids or cells and are there unstable. Orally administered delivery systems for insulin, heparin and physostigmine utilize encapsulating microspheres which are predominantly of less than about 10 microns in diameter and pass readily through the gastrointestinal mucosa and which are made of an acidic proteinoid that is stable and unaffected by stomach enzymes and acid, but which releases the microencapsulated agent in pharmacologically active form in the near neutral blood stream. Basic proteinoid microspheres encapsulating a dopamine redox carrier system are administered in the weakly basic, where they are stable, and then enter the blood stream, where the encapsulated agent is similarly released.

We claim: 
     
       1. Composition comprising a pharmacologically active agent encapsulated within protenoid microspheres having diameters predominantly less than about 10 microns and formed from linear thermal condensation polymers of mixed amino acids. 
     
     
       2. Composition of claim 1 wherein said microspheres are stable in at least a segment of the gastrointestinal tract, are unstable in the blood stream and are predominatly less than about 10 microns in diameter so as to readily penetrate the gastrointestinal mucosa and release said active agent in the blood stream in physiologically active form. 
     
     
       3. Composition of claim 2 wherein said polymer is acidic and said microspheres are stable to acids and enzymes in the mouth. 
     
     
       4. Composition of claim 2 wherein said polymer is basic and said microspheres are stable in the weakly basic lower digestive tract. 
     
     
       5. Composition of claim 4 wherein said pharmacological agent is a dopamine redox carrier system. 
     
     
       6. Composition of claim 2 wherein said polymer is acidic and said microspheres are stable to acids and enzymes in the stomach. 
     
     
       7. Composition of claim 6 wherein said pharmacological agent is insulin. 
     
     
       8. Composition of claim 6 wherein said pharmacological agent is heparin. 
     
     
       9. Composition of claim 6 wherein said pharmacological agent is physostigmine. 
     
     
       10. Composition of claim 1 wherein said polymer is neutral and said microspheres are stable in the blood stream and are unstable at reduced pH. 
     
     
       11. Composition of claim 1 wherein said microspheres are predominantly from about 0.5 to about 5.0 microns in diameter. 
     
     
       12. Method for microencapsulating a pharmacologically active agent within microspheres for targeted release within a selected pH range comprising forming a mixture of said agent with a pharmaceutically acceptable liquid, said mixture having a pH outside said selected range, and contacting said mixture with proteinoids formed of linear thermal condensation polymers of mixed amino acids which are soluble within said selected pH range and insoluble in said mixture to form microspheres having diameters predominately less than about 10 microns containing the active agent. 
     
     
       13. Method of claim 12 wherein said pharmaceutically acceptable liquid is water. 
     
     
       14. Method of claim 12 including preliminary purification of said polymers by mixing the polymers with water having a pH within said selected range and separating the resulting aqueous solution of said polymers from any insoluble material. 
     
     
       15. Method for producing an orally administerable composition for delivering insulin to the blood stream in physiologically active form comprising mixing insulin with water and contacting said mixture with a thermal condensation polymer derived from about two parts glutamic acid, about two parts aspartic acid and about one part of neutral or basic alpha-aminoacid. 
     
     
       16. Method for targeting release of a pharmacologically active agent in an animal comprising administering to said animal an effective amount of said active agent encapsulated within proteinoid microspheres formed from linear thermal condensation polymers of mixed amino acids having diameters predominately less than about 10 microns, said microspheres being stable to the conditions encountered during migration from the point of introduction into said animal to a targeted release zone and being unstable at said zone. 
     
     
       17. Method of claim 16 wherein said microspheres are predominantly from about 0.5 to about 5.0 microns in diameter. 
     
     
       18. Method of claim 16 wherein said microspheres are enterically administered for targeted release in the blood stream and said microspheres are stable in that segment of the gastrointestinal tract into which they are introduced and are unstable in the blood stream. 
     
     
       19. Method of claim 18 wherein said encapsulated active agent is sublingually introduced into the bloodstream and said microspheres are sufficiently acidic to be stable at a pH of from about 4 to about 6.8 and unstable at a pH of from about 7.35 to about 7.45. 
     
     
       20. Method of claim 18 wherein said encapsulated active agent is introduced into the bloodstream from the weakly basic lower gastrointestinal tract and said microspheres are sufficiently basic to be stable at a pH of about 8 and unstable at a pH of from about 7.35 to about 7.45. 
     
     
       21. Method of claim 18 wherein said encapsulated active agent is gastrically introduced into the bloodstream and said microspheres are sufficiently acidic to be stable at a pH of from about 2 to about 6 and unstable at a pH of from about 7.35 to about 7.45. 
     
     
       22. Method of claim 16 wherein said microspheres are intravenously administered and are stable at a pH of from about 7.35 to about 7.45 and unstable at reduced pH. 
     
     
       23. Method of treating a diabetic conditions in an animal comprising orally administering to said animal an effective amount of insulin which is encapsulated within acidic protenoid microspheres formed from linear thermal condensation polymers of mixed amino acids, said microspheres being predominantly from about 0.5 to about 5.0 microns in diameter, stable at a pH of up to about 6 and unstable at a pH of from about 7.35 to about 7.45. .Iadd. 
     
     
       24.  Composition comprising a pharmacologically active agent encapsulated within proteinoid microspheres having diameters predominantly less than about 10 microns and formed from thermal condensation polymers of mixed amino acids..Iaddend..Iadd.25. Method for microencapsulating a pharmacologically active agent within microspheres for targeted release within a selected pH range comprising forming a mixture of said agent with a pharmaceutically acceptable liquid, said mixture having a pH outside said selected range, and contacting said mixture with proteinoids formed of thermal condensation polymers of mixed amino acids which are soluble within said selected pH range and insoluble in said mixture to form microspheres having diameters predominantly less than about 10 microns containing the active agent..Iaddend..Iadd.26. Method for targeting release of a pharmacologically active agent in an animal comprising administering to said animal an effective amount of said active agent encapsulated within proteinoid microspheres formed from thermal condensation polymers of mixed amno acids having diameters predominately less than about 10 microns, said microspheres being stable to the conditions encountered during migration from the point of introduction into said animal to a targeted release zone and being unstable at said 
     
     
        zone..Iaddend..Iadd.27.  Method of treating diabetic conditions in an animal comprising orally administering to said animal an effective amount of insulin which is encapsulated within acidic proteinoid microspheres formed from thermal condensation polymers of mixed amino acids, said microspheres being predominantly from about 0.5 to about 5.0 microns in diameter, stable at a pH of up to about 6 and unstable at a pH of from about 7.35 to about 7.45..Iaddend..Iadd.28. Composition comprising a pharmacologically active agent encapsulated within proteinoid microspheres having diameters predominantly less than about 10 microns and formed from condensation polymers of mixed amino acids..Iaddend..Iadd.29. Method for microencapsulating a pharmacologically active agent within microspheres for targeted release within a selected pH range comprising forming a mixture of said agent with a pharmaceutically acceptable liquid, said mixture having a pH outside said selected range, and contacting said mixture with proteinoids formed of condensation polymers of mixed amino acids which are soluble within said selected pH range and insoluble in said mixture to form microspheres having diameters predominantly less than about 10 microns containing the active agent..Iaddend..Iadd.30. Method for targeting release of a pharmacologically active agent in an animal comprising administering to said animal an effective amount of said active agent encapsulated within proteinoid microspheres formed from condensation polymers of mixed amino acids having diameters predominately less than about 10 microns, said microspheres being stable to the conditions encountered during migration from the point of introduction into said animal to a targeted release zone and being unstable at said zone..Iaddend..Iadd.31. Method of treating diabetic conditions in an animal comprising orally administering to said animal an effective amount of insulin which is encapsulated within acidic proteinoid microspheres formed from condensation polymers of mixed amino acids, said microspheres being predominantly from about 0.5 to about 5.0 microns in diameter, stable at a pH of up to about 6 and unstable at a pH of from about 7.35 to about 7.45..Iaddend..Iadd.32. Composition comprising a pharmacologically active agent encapsulated within proteinoid microspheres having diameters predominantly less than about 10 microns and formed from polymers of mixed amino acids..Iaddend..Iadd.33. Method for microencapsulating a pharmacologically active agent within microspheres for targeted release within a selected pH range comprising forming a mixture of said agent with a pharmaceutically acceptable liquid, said mixture having a pH outside said selected range, and contacting said mixture with proteinoids formed of polymers of mixed amino acids which are soluble within said selected pH range and insoluble in said mixture to form microspheres having diameters predominantly less than about 10 microns containing the active agent..Iaddend..Iadd.34. Method for targeting release of a pharmacologically active agent in an animal comprising administering to said animal an effective amount of said active agent encapsulated within proteinoid microspheres formed from polymers of mixed amino acids having diameters predominately less than about 10 microns, said microspheres being stable to the conditions encountered during migration from the point of introduction into said animal to a targeted release zone and being unstable at said zone..Iaddend..Iadd.35. Method of treating diabetic conditions in an animal comprising orally administering to said animal an effective amount of insulin which is encapsulated within acidic proteinoid microspheres formed from polymers of mixed amino acids, said microspheres being predominantly from about 0.5 to about 5.0 microns in diameter, stable at a pH of up to about 6 and unstable at a pH of from about 7.35 to about 7.45..Iaddend..Iadd.36. Composition comprising a pharmacologically active agent encapsulated within proteinoid microspheres having diameters predominantly less than about 10 microns and formed from mixed amino 
     
     
        acids..Iaddend..Iadd.37.  Method for microencapsulating a pharmacologically active agent within microspheres for targeted release within a selected pH range comprising forming a mixture of said agent with a pharmaceutically acceptable liquid, said mixture having a pH outside said selected range, and contacting said mixture with proteinoids formed of mixed amino acids which are soluble within said selected pH range and insoluble in said mixture to form microspheres having diameters predominantly less than about 10 microns containing the active agent..Iaddend..Iadd.38. Method for targeting release of a pharmaceutically active agent in an animal comprising administering to said animal an effective amount of said active agent encapsulated within proteinoid microspheres formed from mixed amino acids having diameters predominately less than about 10 microns, said microspheres being stable to the conditions encountered during migration from the point of introduction into said animal to a targeted release zone and being unstable at said zone..Iaddend..Iadd.39. Method of treating diabetic conditions in an animal comprising orally administering to said animal an effective amount of insulin which is encapsulated within acidic proteinoid microspheres formed from mixed amino acids, said microspheres being predominantly from about 0.5 t about 5.0 microns in diameter, stable at a pH of up to about 6 and unstable at a pH of from about 7.35 to about 
     
     
        7.45..Iaddend..Iadd.40.  Composition comprising a pharmacologically active agent encapsulated within proteinoid microspheres having diameters predominantly less than about 10 microns and formed from directed polymers of mixed amino acids..Iaddend..Iadd.41. Method for microencapsulating a pharmacologically active agent within microspheres for targeted release within a selected pH range comprising forming a mixture of said agent with a pharmaceutically acceptable liquid, said mixture having a pH outside said selected range, and contacting said mixture with proteinoids formed of directed polymers of mixed amino acids which are soluble within said selected pH range and insoluble in said mixture to form microspheres having diameters predominantly less than about 10 microns containing the active agent..Iaddend..Iadd.42. Method for targeting release of a pharmacologically active agent in an animal comprising administering to said animal an effective amount of said active agent encapsulated within proteinoid microspheres formed from directed polymers of mixed amino acids having diameters predominately less than about 10 microns, said microspheres being stable to the conditions encountered during migration from the point of introduction into said animal to a targeted release zone and being unstable at said zone..Iaddend..Iadd.43. Method of treating diabetic conditions in an animal comprising orally administering to said animal an effective amount of insulin which is encapsulated within acidic proteinoid microspheres formed from directed polymers of mixed amino acids, said microspheres being predominantly from about 0.5 to about 5.0 microns in diameter, stable at a pH of up to about 6 and unstable at a pH of from about 7.35 to about 7.45..Iaddend..Iadd.44. Composition comprising a pharmacologically active agent encapsulated within proteinoid microspheres having diameters predominantly less than about 10 microns and formed from directed condensation polymers of mixed amino acids..Iaddend..Iadd.45. Method for microencapsulating a pharmacologically active agent within microspheres for targeted release within a selected pH range comprising forming a mixture of said agent with a pharmaceutically acceptable liquid, said mixture having a pH outside said selected range, and contacting said mixture with proteinoids formed of directed condensation polymers of mixed amino acids which are soluble within said selected pH range and insoluble in said mixture to form microspheres having diameters predominantly less than about 10 microns containing the active agent..Iaddend..Iadd.46. Method for targeting release of a pharmacologically active agent in an animal comprising administering to said animal an effective amount of said active agent encapsulated within proteinoid microspheres formed from directed condensation polymers of mixed amino acids having diameters predominately less than about 10 microns, said microspheres being stable to the conditions encountered during migration from the point of introduction into said animal to a targeted release zone and being unstable at said zone..Iaddend..Iadd.47. Method of treating diabetic conditions in an animal comprising orally administering to said animal an effective amount of insulin which is encapsulated within acidic proteinoid microspheres formed from directed condensation polymers of mixed amino acids, said microspheres being predominantly from about 0.5 to about 5.0 microns in diameter, stable at a pH of up to about 6 and unstable at a pH of from about 7.35 to about 7.45..Iaddend..Iadd.48. Composition comprising a pharmacologically active agent encapsulated within proteinoid microspheres having diameters predominantly less than about 10 microns and formed from random polymers of mixed amino acids..Iaddend..Iadd.49. Method for microencapsulating a pharmacologically active agent within microspheres for targeted release within a selected pH range comprising forming a mixture of said agent with a pharmaceutically acceptable liquid, said mixture having a pH outside said selected range, and contacting said mixture with proteinoids formed of random polymers of mixed amino acids which are soluble within said selected pH range and insoluble in said mixture to form microspheres having diameters predominantly less than about 10 microns containing the active agent..Iaddend..Iadd.50. Method for targeting release of a pharmacologically active agent in an animal comprising administering to said animal an effective amount of said active agent encapsulated within proteinoid microspheres formed from random polymers of mixed amino acids having diameters predominately less than about 10 microns, said microspheres being stable to the conditions encountered during migration from the point of introduction into said animal to a targeted release zone and being unstable at said zone..Iaddend..Iadd.51. Method of treating diabetic conditions in an animal comprising orally administering to said animal an effective amount of insulin which is encapsulated within acidic proteinoid microspheres formed from random polymers of mixed amino acids, said microspheres being predominantly from about 0.5 to about 5.0 microns in diameter, stable at a pH of up to about 6 and unstable at a pH of from about 7.35 to about 7.45..Iaddend..Iadd.52. Composition comprising a pharmacologically active agent encapsulated within proteinoid microspheres having diameters predominantly less than about 10 microns and formed from 
     
     
        random condensation polymers of mixed amino acids..Iaddend..Iadd.53. Method for microencapsulating a pharmacologically active agent within microspheres for targeted release within a selected pH range comprising forming a mixture of said agent with a pharmaceutically acceptable liquid, said mixture having a pH outside said selected range, and contacting said mixture with proteinoids formed of random condensation polymers of mixed amino acids which are soluble within said selected pH range and insoluble in said mixture to form microspheres having diameters predominantly less than about 10 microns containing the active agent..Iaddend..Iadd.54. Method for targeting release of a pharmacologically active agent in an animal comprising administering to said animal an effective amount of said active agent encapsulated within proteinoid microspheres formed from random condensation polymers of mixed amino acids having diameters predominately less than about 10 microns, said microspheres being stable to the conditions encountered during migration from the point of introduction into said animal to a targeted release zone and being unstable at said zone..Iaddend..Iadd.55. Method of treating diabetic conditions in an animal comprising orally administering to said animal an effective amount of insulin which is encapsulated within acidic proteinoid microspheres formed from random condensation polymers of mixed amino acids, said microspheres being predominantly from about 0.5 to about 5.0 microns in diameter, stable at a pH of up to about 6 and unstable at a pH of from about 7.35 to about 7.45..Iaddend.