Pharmaceutical compositions

• US 4,849,227 A
• Filed: 03/03/1987
• Issued: 07/18/1989
• Est. Priority Date: 03/21/1986
• Status: Expired due to Fees

• Current Assignee: Eurasiam Laboratories Incorporated
• Original Assignee: Eurasiam Laboratories Incorporated
• Inventors: Cho, Young W.
• Primary Examiner(s): WADDELL, FREDERICK
• Application Number:
  US07/021,625
• Time in Patent Office: 868 Days
• Field of Search: 424/476, 424/456, 424/490, 424/498, 424/499, 424/460, 424/461, 424/463, 514/3
• US Class Current: 424/498
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• 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 9/5015 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5078 with drug-free core

Abstract

A composition adapted to administer a pharmocologically effective amount of a pharmaceutical agent when ingested orally comprising (a) a pharmaceutical agent; (b) a lipid coating materials; and (c) an enteric coating materials optionally comprising water soluble coating materials; emulsifying and solubilizing agents; binding agents; stabilizing and enzyme inhibiting agents surfactants and antimicrobial agents. The composition can also include a low density lipoprotein composition and lipolytic enzymes.

Claims

1. A composition adapted for the oral administration of a selected proteinaceous material in biologically active form, said composition comprising:

(a) particles having an average diameter of approximately 1 to about 100 microns and consisting essentially of a solid emulsifying agent and a surfactant;

(b) a selected biologically active proteinaceous material bound to the surface of said particles with a binder agent; and

(c) a lipid coating having a thickness of approximately 0.05 to about 1.0 microns surrounding said particles having said proteinaceous material bound to their surfaces.

2. A composition according to claim 1 further including:

(d) an enteric coating layer surrounding said lipid coating on said surfaces.

3. A composition of claim 2 wherein the proteinaceous material is insulin.

4. A composition according to claim 1 wherein the solid emulsifying agent is selected from the group consisting of cholesterol, glyceryl monostearate, oleic acid, polyethylene 50 stearate, polyoxy 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol diacetate, propylene glycol monostearate, arginine HCl, gum acacia, cholesterol ester, phospholipids, and fatty acids.

5. A composition according to claim 1 wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, sodium stearate, stearic acid, sorbitan monolaurate, sorbitan monostearate and emulsifying wax.

6. The composition of claim 1 wherein the biologically active proteinaceous composition is selected from the group consisting of insulin, urokinase, Factor VIII, leuprolid, gangliocides, vincristine, belomyein, lidocaine, gentamicin, bretylium tosylate, cetiedile, cyclandelate, erythromycin, chloramphenicol, adriamycin, streptokinase, and cephalosporidines.

7. A composition according to claim 1 wherein the composition includes a binder agent that comprises materials selected from the group consisting of sodium carboxymethylcellulose, microcrystalline cellulose, ethylcellulose, gelatin, hydroxypropylmethylcellulose, methylcellulose, povidone, and hydroxypropylcellulose.

8. A composition according to claim 1 wherein the lipid coating comprises materials selected from the group consisting of polyethylene glycol fatty acid esters, glycerophosphatides, phosphatidylophosphates, egg yolk lecithin, oleic acid, mono, di, and tri-glycerides, stearic acid, palmitate, cholesterol, cholesterol ester, and thromethan.

9. A composition according to claim 2 wherein the enteric coating layer comprises materials selected from the group consisting of hydroxypropyl methylcellulose phthalate, polyethylene glycol-6000 shellac, cellulose phthalate, and polyvinyl acetate phthalate.

10. A composition according to claim 1 wherein said particles further include anti-microbial agents.

11. A composition according to claim 10 wherein the anti-microbial agents are selected from the group consisting of dehydroacetic acid, methylparaben, ethylparaben, phenol, phenylethyl alcohol, propylparaben, sodium benzoate, sorbic acid, thymol, thimerosal, sodium dehydroacetate, benzyl alcohol and butylparaben.

12. The composition of claim 1 including a lipolytic enzyme.

13. The composition of claim 12 wherein the lipolytic enzyme is selected from the group consisting of lipase, pancreatic lipase, amylase, protease, and bile salts.

14. A composition according to claim 1 wherein the composition further includes enzyme inhibitors.

15. A composition according to claim 14 wherein the enzyme inhibitors are selected from the group consisting of stearylamine, stearyl alcohol, triethylamine HCl, citric acid, lactic acid, pyrophosphate, triethanolamine, ethylamine tetraacetate, iodoacetamide, phenylhydrazine, hydroxylamine 3 and 8-hydroquinoline.

16. A composition according to claim 1 wherein the composition further includes antifoaming agents.

17. A composition according to claim 16 wherein the antifoaming agents are selected from the group consisting of stearyl alcohol and silicones.

18. A composition adapted for the oral administration of insulin in biologically active form, said composition comprising:

(a) particles having an average diameter of from about 1 to about 100 microns and consisting essentially of cholesterol, sodium lauryl sulfate and, methyl and propylparabens;

(b) insulin bound to the surface of said particles with a solution consisting essentially of hydroxypropylcellulose, sodium lauryl sulfate, triethylamine HCl and citric acid;

(c) a lipid coating having a thickness of from about 0.1 to 0.3 microns; and

(d) an enteric coating layer comprising hydroxypropylmethylcellulose phthalate, shellac and PEG-6000 with the thickness of 0.1 microns surrounding said polyethylene glycol monostearate coating on said particles.

19. A method for the preparation of compositions adapted for oral administration of selected proteinaceous material in biologically active form comprising the steps:

(a) forming particles having an average diameter of from about 1 micron to 1/2 millimeter and consisting essentially of a solid emulsifying agent and a surfactant;

(b) binding a selected biologically active proteinaceous material to the surfaces of said particles with a binder agent; and

(c) coating said particles having said proteinaceous material bound to their surfaces with a lipid coating layer having a thickness of 0.05 to 1.0 microns.

20. The method according to claim 19 further including the step of

(d) coating said particles with an enteric coating layer surrounding said lipid coating layer.

21. The method according to claim 19 further including the step of

(d) coating the particles with a water soluble coating before the lipid coating is applied.

22. The product of the process of claim 19.

23. The product of the process of claim 20.

24. The product of the process of claim 21.

25. A composition adapted for the oral administration of insulin in biologically active form comprising:

particles having an average diameter of approximately 1 to 100 microns consisting essentially of an emulsifying agent and a surfactant;

insulin bound to the surface of the particles;

a lipid coating surrounding the particles having the proteinaceous material bond to their surfaces; and

an enteric coating layer surrounding the lipid coating.

26. A method of orally administering insulin comprising:

providing a composition for oral ingestion comprising insulin bound to a surface of a solid emulsifier/solubilizing particle, the insulin and particles being coated with a lipid coating, the particles having an average diameter of approximately 1 micron to about 100 microns, and the lipid coating being coated by an enteric coating.

27. A method orally administering insuling composition:

providing a composition for oral ingestion comprising insulin bound to a surface of lipoprotein particles, the insulin and particles being coated by a lipid coating, and the lipid coating being coated by an enteric coating.

28. The method of claim 27 including the step of administering a lipolytic enzyme.

29. The method of claim 27 including orally administering at least one second capsule containing at least one lipolytic enzyme.

30. A composition adapted for the oral administration of a selected proteinaceous material in biologically active form, said composition comprising:

(a) a lipoprotein composition;

(b) a selected biologically active proteinaceous material bound to the surface of the lipoprotein composition; and

(c) a lipid coating surrounding said lipoprotein composition and proteinaceous material.

31. The composition of claim 30 including a water soluble coating surrounding the lipoprotein and proteinaceous material, the lipid coating coating the water soluble coating.

32. The composition of claim 30 wherein the liproprotein is low density lipoprotein.

33. The composition of claim 30 wherein the lipoprotein comprises at least one amino acid.

34. The composition of claim 30 including a gel capsule, the lipid coating material being packed into the gel capsule.

35. The composition of claim 34 wherein the gel capsule is coated with an enteric coating.

36. The composition of claim 30 wherein the biologically active proteinaceous composition is selected from the group consisting of insulin, urokinase, Factor VIII, leuprolid, gangliocides, vincristine, belomyein, lidocaine, gentamicyin, bretylium, tosylate, cetiedile, cyclandelate, erythromycin, chloroamphenicol, adriamycin, streptokinase, and cephalosporidines.

37. The composition of claim 30 including a lipolytic enzyme.

38. The composition of claim 37 wherein the lipolytic enzyme is selected from the group consisting of lipase, pancreatic lipase, amylase, protease, and bile salts.

39. The composition of claim 38 wherein the lipolytic enzyme comprises lipase and bile salts.

40. A composition according to claim 30 wherein the lipid coating comprises materials selected from the group consisting of polyethylene glycol fatty acid esters, glycerophosphatides, phosphatidylophosphates, egg yolk lecithin, oleic acid, mono, di, and tri-glycerides, stearic acid, palmitate, cholesterol, cholesterol ester, and thromethan.

41. A composition according to claim 35 wherein the enteric coating layer comprises materials selected from the group consisting of hydroxypropyl methylcellulose phthalate, polyethylene glycol-6000 shellac, cellulose phthalate, and polyvinyl acetate phthalate.

42. A composition according to claim 30 wherein said particles further include anti-microbial agents.

43. A composition according to claim 42 wherein the anti-microbial agents are selected from the group consisting of dehydroacetic acid, methylparaben, ethylparaben, phenol, phenylethyl alcohol, propylparaben, sodium benzoate, sorbic acid, thymol, thimersal, sodium dehydroacetate, benzyl alcohol and butylparaben.

44. A composition according to claim 30 wherein the composition further includes enzyme inhibitors.

45. A composition according to claim 44 wherein the enzyme inhibitors are selected from the group consisting of stearylamine, stearyl alcohol, triethylamine HCl, citric acid, lactic acid, pyrophosphate, triethanolamine, ethylamine tetraacetate, iodoacetamide, phenylhydrazine, hydroxylamine 3 and 8-hydroquinoline.

46. A composition according to claim 30 wherein the composition further includes antifoaming agents.

47. The composition according to claim 30 wherein the lipoprotein includes a lipid and an amino acid.

48. The composition of claim 47 where in the lipid is selected from the group consisting of cholesterol, oleic acid, stearic acid, sodium lauryl sulfate, lecithin, phosphatides, sodium lauryl sulfate and lecithin, palmitic and phosphatide phosphate choline.

49. The composition of claim 47 wherein the amino acid is selected from the group consisting of arginine, lysine, histidine, and aspartic acid.

50. A composition according to claim 46 wherein the antifoaming agents are selected from the group consisting of stearyl alcohol and silicones.

51. A composition adapted for the oral administration of insulin in biologically active form, said composition comprising:

(a) particles having an average diameter of from about 1 micron to about 1/2 millimeter and including a low density of lipoprotein composition;

(b) insulin bound to the surface of said particles with a binder;

(c) a water soluble coating layer, for coating the particles and insulin; and

(d) a lipid coating for coating the water soluble layer, particles and insulin.

52. The composition of claim 51 including a lipolytic enzyme.

53. The composition of claim 51 including an enteric coating layer for coating the lipid layer.

54. A method for the preparation of compositions adapted for the oral administration of selected proteinaceous material in biologically active form comprising the steps of:

(a) forming low density lipoprotein particles having an average diameter of from about 1 micron to 1/2 millimeter;

(b) binding a selected biologically active proteinaceous material to the surfaces of said particles with a binder agent;

(c) coating the particles and proteinaceous material with a water soluble coating; and

(d) coating the water soluble coated particles having said proteinaceous material bound to their surfaces with a lipid coating layer having a thickness of 0.05 to 1.0 microns.

55. A method according to claim 54 further including the step

(e) coating said particles with an enteric coating layer surrounding said lipid coating layer.

56. The product of the process of claim 54.

57. The product of the process of claim 55.

58. A composition adapted for the oral administration of insulin in biologically active form comprising:

low density lipoprotein particles;

insulin bound to the surface of the particles;

a water soluble coating surrounding the particles and insulin;

a lipid coating surrounding the water soluble coating and particles having insulin bound to their surfaces;

a gel capsule for surrounding the lipid coating; and

an enteric coating layer surrounding the gel capsule.

59. A method of treating diabetes comprising the steps of:

administering orally at least one capsule having a composition including a low density lipoprotein, insulin bound to the lipoprotein, a water soluble coating over the insulin and lipoprotein, and a lipid coating over the water soluble coating; and

administering orally at least one capsule having a composition icluding lipolytic enzymes and bile salts.

60. The method of treating diabetes comprising the steps of:

administering orally at least one capsule having a composition including emulsifier/solubilizer particles, insulin bound to the particles, and a lipid coating over the particles; and

administering orally at least one capsule having a composition including lipolytic enzymes.

61. A composition useful for the oral administration of a proteinaceous compound comprising lipolytic enzymes selected from the group including, pancreatic lipase, amylase, protease, and bile salts.

62. The composition of claim 61 wherein the lipolytic enzymes selected are pancreatic lipase and bile salts.

63. A composition adapted for the oral administration of insulin comprising the following components:

(a) particles of pancreatic lipase;

(b) particles of bile salt;

(c) lipid coated insulin bound lipid particles;

(d) sodium bicarbonate; and

(e) citric acid.

64. The composition of claim 63 wherein the components are placed in hard gel capsules.

65. The composition of claim 63 wherein the components are pressed into tablets.

66. The composition of claim 63 wherein the weight percent ratio of sodium bicarbonate to citric acid is between 3:

1 to 1;

1.

67. The composition of claim 63 wherein the insulin bound particle has a spherical size of less than 1.5 millimeters.

68. The composition of claim 63 wherein the pancreatic lipase and bile salt particles are enteric coated.

69. A composition adapted for the oral administration of insulin comprising a sodium bicarbonate and citric acid mixture in a ratio of approximately 3:

1 to about 1;

1, the mixture forming a seed that is coated with a layer of an insulin lipid mixture, and a resultant particle is then coated with an enteric coating.