Oral insulin and a method of making the same

• US 4,963,526 A
• Filed: 11/02/1988
• Issued: 10/16/1990
• Est. Priority Date: 05/09/1984
• Status: Expired due to Fees

• Current Assignee: Quixote Corporation (Trinity Industries Incorporated)
• Original Assignee: Synthetic Blood Corporation
• Inventors: Ecanow, Bernard
• Primary Examiner(s): Waddell, Frederick E.
• Application Number:
  US07/267,749
• Time in Patent Office: 713 Days
• Field of Search: 514/3, 514/456, 514/468, 514/963
• US Class Current: 424/456
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/5089 Processes

Abstract

The present invention provides for a composition of matter useful as an oral dosage form of insulin based upon a two phase liquid aqueous system in which insulin component or components are incorporated. The invention also provides for a method of preparing the oral dosage form of insulin, as well as a further process whereby sustained release dosage forms of oral insulin are produced. The oral form of insulin eliminates or reduces the need to use injection as a mode of administering insulin.

Claims

1. A composition of matter useful as an oral dosage form of insulin;

said composition derived from a non-toxic two phase liquid coacervate composition, both phases being aqueous;

(a) one of said phases being a relatively non-polar coacervate phase;

(b) the other of said phases being a relatively polar equilibrium water phase;

(c) said relatively non-polar coacervate phase being insoluble in and in equilibrium with said relatively polar liquid aqueous phase;

(d) said two phase coacervate composition including an effective amount of insulin in the coacervate phase of the coacervate composition, to form a delivery system for the oral administration of insulin.

2. A composition according to claim 1, wherein the relatively non-polar coacervate phase comprises from 0.5% to 99.5% by volume, and the relatively polar aquilibrium water phase comprises from 0.5 to 99.5% by volume, of the two phase liquid system.

3. A composition according to claim 1 wherein the two liquid phases include any non-toxic surface active agent or mixtures thereof selected from the group consisting of albumin;

gelatin;

a phospholipid;

acacia gel;

two gelatins of the same or different isoelectric points;

or two modified fluid gelatins of the same or different isoelectric points.

4. A composition according to claim 1 wherein the phospholipid is selected from the group consisting of lecithin, cephalin, isoecithin, sphingomyelin, phosphatidyl serine, phosphatidyl inositol, phosphatidic acid, phosphatidyl choline and mixtures thereof.

5. A composition according to claim 3 wherein the two phase liquid coacervate composition comprises albumin and lecithin emulsified in water, and wherein the concentration of albumin in said two phase system is equal to or less than the concentration of lecithin.

6. The composition according to claim 3 wherein the two phase liquid coacervate composition comprise albumin and lecithin emulsified in water, and wherein the concentration of albumin is greater than the concentration of lecithin.

7. A composition according to claim 1 wherein the insulin is selected from the group consisting of regular insulin, globin zinc insulin, isophane insulin suspension, insulin zinc suspension, protamine zinc insulin, prompt insulin zinc suspension, extended insulin, zinc suspension insulin, insulin directly recrystallized from animal, genetic recombinant insulin, synthetic insulin and mixtures thereof.

8. A composition according to claim 1 wherein the insulin is a prompt or sustained release form of insulin, or mixtures thereof.

9. A composition according to claim 8 wherein a dose of said insulin is included in the coacervate phase in any pharmaceutically beneficial amount as is medically indicated.

10. A composition according to claim 1 wherein the relatively non-polar coacervate phase is separated from the relatively polar equilibrium water phase and the insulin is added to said coacervate phase, said coacervate phase comprising a useful oral, liquid dosage form of insulin.

11. A composition according to claim 1 including combining with said coacervate phase an equilibrium water phase derived from said two phase coacervate composition and emulsifying the two phases together and thereafter heating the two phases from 1 minute to 15 minutes at a temperature of 20°

C. to 70°

C. in order to harden a surface film encapsulating the insulin and form particles.

12. The composition according to claim 11 wherein the particles are filtered and the filtered particles are removed and resuspended in an appropriate non-toxic liquid vehicle or placed in the appropriate dose in gelatin capsules or any appropriate oral dosage forms.

13. A composition as defined in claim 11 wherein the particles of the composition are in prompt release in time release form or any combination thereof.

14. A composition as defined according to claim 1 wherein the composition is stored under refrigeration, until needed.

15. A method of preparing a composition of matter which is useful as an oral dosage form of insulin, said method based upon a non-toxic two phase liquid coacervate composition, both phases being aqueous, comprising emulsifying water and at least one surface active agent under conditions to form a two phase coacervate composition one of said phases being a relatively non-polar coacervate phase;

the other of said phases being a relatively polar equilibrium water phase;

said relatively non-polar coacervate phase being insoluble in and in equilibrium with said relatively polar equilibrium water phase; and

adding insulin to the coacervate phase of the two phase coacervate composition.

16. The method of claim 15 wherein the relatively non-polar coacervate phase comprises from 0.5% to 99.5% by volume and the relatively polar liquid aqueous phase comprises from 0.5% to 99.5% by volume, of the two phase liquid composition.

17. The method of claim 15 wherein the two phase coacervate composition comprises a non-toxic surface active agent or mixtures thereof selected from the group consisting of albumin;

gelatin;

a phospholipid;

acacia gel;

two gelatins of the same or differing isoelectric points; and

two modified fluid gelatins of the same or differing isoelectric points.

18. The method of claim 17 wherein the phospholipid is selected from the group consisting of cephalin, lecithin, isolecithin, sphingomyelin, phosphatidyl series, phosphatidyl choline, phosphatidyl inositol, phosphatidic acid and mixtures thereof.

19. The method of claim 15 including albumin and lecithin as surface active agents and the concentration of albumin in said two phase liquid composition is equal to or less than the concentration of lecithin.

20. The method of claim 15 including albumin and lecithin as surface active agents and wherein the concentration of albumin is greater than the concentration of lecithin.

21. The method of claim 15 including (a) combining albumin and lecithin in sterile water to form an aqueous albumin, lecithin solution, (b) thoroughly mixing the aqueous albumin, lecithin solution to form an aqueous mixture (c) storing the aqueous mixture essentially undisturbed until the aqueous mixture separates into two layers one above the other, a lower layer being a substantially non-polar coacervate phase, and an upper phase being an equilibrium water phase;

(d) continuing the separation process until essentially no increase in the volume of the coacervate phase can be observed;

(e) centrifuging the composition until inspection reveals a clear demarcation of the two phases; and

(f) separating the two phases.

22. The method of claim 21 wherein the insulin component is mixed into the coacervate phase.

23. The method of claim 22 wherein the insulin component is selected from the group consisting of regular insulin, globin insulin with zinc, isophane insulin suspension, insulin zinc suspension, protamine zinc insulin, prompt insulin zinc suspension, extended insulin zinc suspension and mixtures thereof.

24. The method of claim 23 wherein the insulin is derived from animal, recombinant genetics or other sources or mixtures thereof.

25. The method of claim 21 including recombining the relatively polar equilibrium water phase with the relatively non-polar coacervate phase, said coacervate phase containing the insulin component and the emulsifying the two phases together to produce either an emulsion or a suspension of encapsulated particles in the composition.

26. The method of claim 25 wherein the encapsulated particles of the emulsion range from 10^-8 microns to 10 microns in size.

27. The method of claim 25 wherein the emulsified composition is subjected to a process to harden the surface films of the particles of the composition.

28. The method of claim 27 wherein the hardening process is based upon either a physical or chemical procedure.

29. The method of claim 27 wherein the hardening process comprises a heating step.

30. The method of claim 27 wherein the hardening process is a chemical process comprising the addition of a non-toxic aldehyde cross-linking agent.

31. The method of claim 29 wherein the emulsion is heated at a temperature between 20°

and 70°

C. for 15 seconds to 15 minutes.

32. The method of claim 31 which yields time release particles containing the insulin component ranging from relatively prompt release to sustained release particles.

33. The method of claim 25 further including filtering the composition;

removing the encapsulated particles containing the insulin component; and

drying the particles.

34. The method of claim 21 wherein the composition is comprised of prompt release particles or sustained release particles or combinations thereof.

35. The method of claim 34 wherein the prompt release particles, or sustained release particles or combinations thereof in medically appropriate doses are placed in any suitable oral dosage form selected from the group consisting of gelatin capsules, solid tablets, and a liquid vehicle, for oral administration.

36. A composition useful as an oral dosage form of insulin for introduction into a bloodstream comprising an aqueous coacervate phase derived from a two-phase coacervate composition, said coacervate phase including water, a surface active agent and an effective amount of insulin, said aqueous coacervate phase including an aqueous coacervate-based film encapsulating the insulin.

37. A method of preparing a composition containing insulin for oral administration comprising mixing an aqueous solution of water, a surface active agent and an effective amount of insulin to form a coacervate composition comprising a coacervate phase and an equilibrium water phase, and adding the insulin to one or both of the two phases to envelope the insulin, bound in liquid particles, within a coacervate=based aqueous film.

38. The method of claim 37 wherein the insulin is added to the coacervate phase.

39. A method of preparing a composition containing insulin for oral administration comprising:

mixing an aqueous solution of water, and a non-toxic surface active agent to from a two-phase aqueous system;

one of said phases being a relatively non-polar coacervate phase containing the insulin and the other of said phases being a relatively polar equilibrium water phase, said relatively non-polar coacervate phase being insoluble in and in equilibrium with said relatively polar equilibrium water phase; and

admixing insulin with said coacervate phase either before or after formation of the two phases.