Microcapsules and methods for making

• US 5,827,531 A
• Filed: 12/02/1994
• Issued: 10/27/1998
• Est. Priority Date: 12/02/1994
• Status: Expired due to Term

• Current Assignee: The United States of America As Represented By The Secretary of Agriculture
• Original Assignee: United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration
• Inventors: Mosier, Benjamin, Morrison, Dennis R.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Spear, James M.
• Application Number:
  US08/349,169
• Time in Patent Office: 1,425 Days
• Field of Search: 424/450, 424/1, 424/489, 424/490, 427/213.3, 428/402.21, 428/402.24, 264/4.32, 264/4.33
• US Class Current: 424/450
• CPC Class Codes: A61K 41/0028 Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: B01F 33/30 Micromixers
• CPC Class Codes: B01J 13/06 by phase separation
• CPC Class Codes: Y10T 428/2985 Solid-walled microcapsule from synthetic polymer
• CPC Class Codes: Y10T 428/2989 Microcapsule with solid core [includes liposome]

Abstract

Methods of forming multi-lamellar microcapsules having alternating layers of hydrophilic and hydrophobic immiscible liquid phases have been developed using different polymer/solvent systems. The methods use liquid-liquid diffusion and simultaneous lateral phase separation, controlled by proper timed-sequence exposures of immiscible phases and low shear mixing, to form narrow size distributions of spherical, multilamellar microcapsules. The use of special formulations of solubilized drugs, surfactants, and polymeric co-surfactants in aqueous vehicles which are dispersed in hydrocarbon solvents containing small quantities of oil, low molecular weight co-surfactants and glycerides that are aqueous insoluble enables the formation of unique microcapsules which can carry large amounts of pharmaceuticals in both aqueous and non-aqueous solvent compartments. The liquid microcapsules are quickly formed in a single step and can include a polymeric outer "skin" which protects the microcapsules during physical manipulation or exposure to high shear forces. Water-in-oil and oil-in-water microcapsules have been formed both in 1×g and in microgravity, which contain several types of drugs co-encapsulated within different fluid compartments inside the same microcapsule. Large, spherical multi-lamellar microcapsules have been formed including a cytotoxic drug co-encapsulated with a radiocontrast medium which has advantages for chemoembolization of vascular tumors. In certain cases, crystals of the drug form inside the microcapsules providing zero-order and first order, sustained drug release kinetics.

Claims

1. A method of making a multi-layered microcapsule, comprising:

formulating a first phase comprising a first solvent, a first microcapsule layer-forming compound soluble in said first phase and immiscible in a second phase, a co-solvent, oil, and water;

formulating said second phase immiscible with said first phase, said second phase comprising a second solvent, a second microcapsule layer-forming compound soluble in said second phase and immiscible in said first phase, a surface active agent, and a salt;

said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first microcapsule layer-forming compound;

said second microcapsule layer-forming compound having a hydrophilic/lipophilic balance value lower than that of said surface active agent;

creating an interface between said first and second phases in a manner that limits fluid shear equal to or less than about 12 dynes/cm² , and

maintains adsorptive surface characteristics at said interface.

2. The method of claim 1 wherein said first solvent is organic.

3. The method of claim 2 wherein said organic solvent is selected from the group of organic solvents consisting of methyl alcohol, ethyl alcohol, and isopropyl alcohol.

4. The method of claim 1 wherein said first microcapsule layer-forming compound is selected from the group consisting of glycerol monosterate, glycerol monooleate, glycerol monolaurate, glycerol dioleate, glycerol distearate, cholesterol, stigmasterol, phytosterol, campesterol, polyvinyl pyrrolidone, polyvinyl alcohols, hydrocolloids, and lecithins.

5. The method of claim 1 wherein said first solvent is aqueous.

6. The method of claim 4 wherein said hydrocolloid is selected from the group of hydrocolloids consisting of gelatin, gum tragacanth, carrageenan, Karaya gum, Guar gum, gum arabic, alginates, carboxymethyl cellulose, hydroxypropyl cellulose, and carboxypropyl cellulose.

7. The method of claim 1, said first phase further comprising a co-solvent, wherein said co-solvent is selected from the group of co-solvents consisting of C₃ -C₈ alcohols, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide.

8. The method of claim 1 wherein said oil is selected from the group of oils consisting of poppy seed oil, olive oil, peanut oil, sesame oil, cotton seed oil, soybean oil, safflower oil, corn oil, sunflower seed oil, canola oil, mineral oil, C₂₀ -C₃₈ paraffinic oil, and liquid petrolatum.

9. The method of claim 1 wherein said oil is an unsaturated oil which has been halogenated.

10. The method of claim 1 wherein said second microcapsule layer-forming compound is selected from the group consisting of polyethyleneglycol, polyvinylpyrrolidone, polyvinyl alcohols, and hydrocolloids.

11. The method of claim 1 wherein said surface active agent has a hydrophilic/lipophilic balance value of about 10.0 or greater.

12. The method of claim 11 wherein said surface active agent is selected from the group of surface active agents consisting of sorbitan monooleate treated with ethylene oxide, dextran, polyethylene glycol, C₁₂ -C₂₀ fatty acids, 2-amino-2-methyl-1-propyl aminomethyl propanol amphoteric salts, and quaternary ammonium salts.

13. The method of claim 1 wherein said salt is selected from the group of salts consisting of NaCl, KCl, CaCl₂, MgCl₂, quaternary ammonium salts, cetyl trimethylammonium bromide, and 4-methoxy-4(3-phosphatidyl choline)spiro(1,2-dioxetane-3-g,l-adamantane) disodium salt.

14. The method of claim 1 wherein said first phase further comprises a pharmaceutical composition.

15. The method of claim 14 wherein said pharmaceutical composition is selected from the group of pharmaceutical compositions consisting of cytotoxins, proteases, cytokines, anti-nauseants, steroids, anti-fungal agents, fibrinolytic enzymes, and antibiotics.

16. The method of claim 14 wherein said pharmaceutical composition is in suspension.

17. The method of claim 1 wherein said second phase further comprises a pharmaceutical composition.

18. The method of claim 17 wherein said pharmaceutical composition is selected from the group of pharmaceutical compositions consisting of cytotoxins, proteases, cytokines, anti-nauseants, steroids, anti-fungal agents, fibrinolytic enzymes, and antibiotics.

19. The method of claim 17 wherein said pharmaceutical composition is in suspension.

20. The method of claim 14 wherein said pharmaceutical is at a concentration sufficient to allow nascent crystal formation within said microcapsule.

21. The method of claim 1, wherein after said microcapsule forms, taking additional steps comprising:

formulating a third phase comprising an oil or C₂₀ -C₃₈ paraffin; and

,

contacting said microcapsule with said third phase.

22. The method of claim 21, wherein said third phase further comprises a polymer.

23. The method of claim 21, wherein said third phase further comprises a pharmaceutical composition.

24. The method of claim 1, wherein after said microcapsule forms, taking additional steps comprising:

formulating a third phase comprising an aqueous solution; and

,

contacting said microcapsule with said third phase.

25. The method of claim 24, wherein said third phase further comprises a pharmaceutical composition.

26. The method of claim 24, wherein said third phase further comprises an adjuvant.

27. The method of claim 24, wherein said third phase further comprises an activator agent.

28. The method of claim 26, wherein said adjuvant further comprises an immunoglobulin, peptide, protein, hydrocolloid or polysaccharide.

29. The method of claim 28, wherein said hydrocolloid is selected from the group of such hydrocolloids consisting of collagen, isoelectric gelatin, agar, gum arabic, gum tragacanth, carboxymethylcellulose (CMS), carboxymethyl/ethyl cellulose (CMEC), hydroxyethylcellulose (HEC), hydroxymethyl/ethyl cellulose (HMEC), hydroxypropyl cellulose (HPC), alginates and carrageenans.

30. The method of claim 24, wherein said third phase further comprises a surface active agent compatible with the hydrophilic/lipophilic balance value of an outer coating of said microcapsule.

31. The method of claim 1 wherein one or more of said phases further comprise fluorescent molecules selected from the group of fluorescent molecules consisting of fluoresceins, cyanins, naturally fluorescent molecules, and rhodamines.

32. The method of claim 1 wherein said adsorptive surface characteristics comprise a Helmholtz charge distribution at said interface.

33. The method of claim 1 wherein said maintenance of adsorptive surface characteristics is promoted by carrying out the method under microgravity of less than or about equal to 1×

10^-2 g and with fluid shear of no more than between about 2-12 dynes/cm².

34. The method of claim 33 wherein said microgravity is at least 1.0 minute in duration.

35. The method of claim 1 wherein said maintenance of adsorptive surface characteristics is promoted by carrying out the method below ambient temperature.

36. The method of claim 1 wherein said maintenance of adsorptive surface characteristics is promoted by substantially balancing the specific gravity between said phases.

38. Microcapsules produced by any of the methods of the preceding claims.

39. The microcapsules of claim 38 wherein said microcapsules are of a uniform distribution of diameters.

40. The microcapsules of claim 39 wherein said diameter distribution is in a range of about 1.0 to 350.0 microns.

41. The microcapsule of claim 38 further comprising at least one nascent crystal of a pharmaceutical composition.

42. The microcapsules of claim 41 wherein said crystal occupies at least about 10 percent of the volume of said microcapsule.

37. A method of making a multi-layered microcapsule, comprising:

formulating a first phase comprising an organic solvent selected from the group of organic solvents consisting of methyl alcohol, ethyl alcohol and isopropyl alcohol, a first microcapsule layer-forming compound soluble in said first phase selected from the group of polymers consisting of glycerol monosterate, glycerol monooleate, glycerol monolaurate, glycerol dioleate, glycerol distearate, cholesterol, stigmasterol, phytosterol, campesterol, and lecithins, a co-solvent selected from the group of co-solvents consisting of C₃ -C₈ alcohols, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, an oil selected from the group of oils consisting of poppy seed oil, olive oil, peanut oil, sesame oil, cotton seed oil, soybean oil, safflower oil, corn oil, sunflower seed oil, canola oil, mineral oil, C₂₀ -C₂₈ paraffinic oil, liquid petrolatum, and water;

formulating a second phase immiscible with said first phase, said second phase comprising water, a second microcapsule layer-forming compound soluble in said second phase selected from the group consisting of polyethyleneglycol, dextran, polyvinylpyrrolidone, polyvinyl alcohols, hydrocolloids, and lecithins, a surface active agent selected from the group consisting of sorbitan monooleate treated with ethylene oxide, dextran, polyethylene glycol, C₁₂ -C₂₀ fatty acids, 2-amino-2-methyl-1-propyl aminomethyl propanol, quaternary ammonium salts, and a salt selected from the group of salts consisting of NaCl, KCl, CaCl₂, MgCl₂, quaternary ammonium salts, cetyl trimethylammonium bromide, and 4-methoxy-4(3-phosphatidyl choline)spiro(1,2-dioxetane-3-g,l-adamantane) disodium salt;

said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first microcapsule layer-forming compound;

said second microcapsule layer-forming compound having a hydrophilic/lipophilic balance value lower than that of said surface active agent;

creating an interface between said first and second phases in a manner that limits fluid shear to less than about 12 dynes/cm² , and

maintains adsorptive surface characteristics at said interface.

43. A microcapsule produced by the method of claim 37.

44. A multi-layered microcapsule, comprising:

a first layer comprising a first solvent, a first microcapsule layer-forming compound soluble in said first layer and immiscible with a second layer, a co-solvent, oil, and water;

said second layer immiscible with said first layer, said second layer comprising a second solvent, a second microcapsule layer-forming compound soluble in said second layer and immiscible with said first layer, a surface active agent, and a salt;

said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first microcapsule layer-forming compound; and

,

said second microcapsule layer-forming compound having a hydrophilic/lipophilic balance value lower than that of said surface active agent.

45. The microcapsule of claim 44 wherein said first solvent is organic.

46. The microcapsule of claim 45 wherein said organic solvent is selected from the group of organic solvents consisting of methyl alcohol, ethyl alcohol and isopropyl alcohol.

47. The microcapsule of claim 45 wherein said first microcapsule layer-forming compound is selected from the group consisting of glycerol monosterate, glycerol monooleate, glycerol monolaurate, glycerol dioleate, glycerol distearate, cholesterol, stigmasterol, phytosterol, campesterol, and lecithins.

48. The microcapsule of claim 44 wherein said first solvent is aqueous.

49. The microcapsule of claim 48 wherein said first microcapsule layer-forming compound is selected from the group of microcapsule layerforming compounds consisting of polyvinyl pyrrolidone, polyvinyl alcohols, hydrocolloids, and lecithins.

50. The microcapsule of claim 49 wherein said hydrocolloid is selected from the group of hydrocolloids consisting of gelatin, gum tragacanth, carrageenan, Karaya gum, Guar gum, gum arabic, alginates, carboxymethyl cellulose, hydroxypropyl cellulose, and carboxypropyl cellulose.

51. The microcapsule of claim 44, said first layer further comprising a co-solvent, wherein said co-solvent is selected from the group of co-solvents consisting of C₃ -C₈ alcohols, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide.

52. The microcapsule of claim 44 wherein said oil is selected from the group of oils consisting of poppy seed oil, olive oil, peanut oil, sesame oil, cotton seed oil, soybean oil, safflower oil, corn oil, sunflower seed oil, canola oil, mineral oil, C₂₀ -C₃₈ paraffinic oil, and liquid petrolatum.

53. The microcapsule of claim 44 wherein said oil is an unsaturated oil which has been halogenated.

54. The microcapsule of claim 44 wherein said second microcapsule layer-forming compound is selected from the group consisting of polyethyleneglycol, dextran, polyvinylpyrrolidone, polyvinyl alcohols, gelatin, gum tragacanth, carrageenan, Karaya gum, Guar gum, gum arabic, alginates, carboxymethyl cellulose, hydroxypropyl cellulose, carboxypropyl cellulose, and lecithins.

55. The microcapsule of claim 44 wherein said surface active agent has a hydrophilic/lipophilic balance value of about 10.0 or greater.

56. The microcapsule of claim 55 wherein said surface active agent is selected from the group of nonionic surface active agents consisting of sorbitan monooleate treated with ethylene oxide, dextran, polyethylene glycol, C₁₂ -C₂₀ fatty acids, 2-amino-2-methyl-1-propyl aminomethyl propanol, amphoteric salts, and quaternary ammonium salts.

57. The microcapsule of claim 44 wherein said salt is selected from the group of salts consisting of NaCl, KCl, CaCl₂, MgCl₂, quaternary ammonium salts, cetyl trimethylammonium bromide, and 4-methoxy-4(3-phosphatidyl choline)spiro(1,2-dioxetane-3-g,l-adamantane) disodium salt.

58. The microcapsule of claim 44 wherein said first layer further comprises a pharmaceutical composition.

59. The microcapsule of claim 58 wherein said pharmaceutical composition is selected from the group of pharmaceutical compositions consisting of cytotoxins, proteases, cytokines, anti-nauseants, steroids, anti-fungal agents, fibrinolytic enzymes, and antibiotics.

60. The microcapsule of claim 58 wherein said pharmaceutical composition is in suspension.

61. The microcapsule of claim 44 wherein said second layer further comprises a pharmaceutical composition.

62. The microcapsule of claim 61 wherein said pharmaceutical composition is selected from the group of pharmaceutical compositions consisting of cytotoxins, proteases, cytokines, anti-nauseants, steroids, anti-fungal agents, fibrinolytic enzymes, and antibiotics.

63. The microcapsule of claim 61 wherein said pharmaceutical composition is in suspension.

64. The microcapsule of claim 58 or 61 wherein said pharmaceutical is at a concentration sufficient to allow nascent crystal formation within said microcapsule.

65. The microcapsule of claim 44 comprising a third layer, said third layer comprising an oil or paraffin.

66. The microcapsule of claim 65, wherein said third layer further comprises a pharmaceutical composition.

67. The microcapsule of claim 65, wherein said third layer further comprises a surface active agent.

68. The microcapsule of claim 44 comprising a third layer, said third layer comprising an aqueous solution.

69. The microcapsule of claim 68, wherein said third layer further comprises a pharmaceutical composition.

70. The microcapsule of claim 68, wherein said third layer further comprises an adjuvant.

71. The microcapsule of claim 70, wherein said adjuvant further comprises an immunoglobulin, peptide, protein, hydrocolloid or polysaccharide.

72. The microcapsule of claim 71, wherein said peptide or said protein selectively adheres to a target cell, tissue or tumor.

73. The microcapsule of claim 71, wherein said hydrocolloid is selected from the group of such hydrocolloids consisting of collagen, isoelectric gelatin, agar, gum arabic, gum tragacanth, carboxymethylcellulose (CMS), carboxymethyl/ethyl cellulose (CMEC), hydroxyethylcellulose (HEC), hydroxymethyl/ethyl cellulose (HMEC), hydroxypropyl cellulose (HPC), and carrageenans.

74. The microcapsule of claim 68, wherein said third layer further comprises a surface active agent.

75. The microcapsule of claim 44 wherein one or more of said layers further comprise fluorescent molecules selected from the group of fluorescent molecules consisting of fluoresceins, cyanins, naturally fluorescent molecules, and rhodamines.

76. The microcapsule of claim 44 formed under microgravity.

77. The microcapsule of claim 76 wherein said microgravity is at least 1.0 minutes in duration.

78. The microcapsule of claim 44 formed below ambient temperature.

79. The microcapsule of claim 44 comprising layers at least initially substantially balanced as to specific gravity between said layers.

81. The microcapsule of claim 58 further comprising at least two different pharmaceuticals, a first pharmaceutical in said first phase and a second pharmaceutical in said second phase.

82. The microcapsule of claim 44 further comprising a radiopaque contrast agent.

83. The microcapsule of claim 44 further comprising a magnetic resonance contrast agent.

84. The microcapsule of claim 83 wherein said contrast agent is selected from the group of metallo-organic compounds consisting of ferrous gluconate, Gadolinium diethylenetriamine pentaacetic acid, and iron pentacarbonyl.

80. A multi-layered microcapsule, comprising:

a first layer comprising an organic solvent selected from the group of organic solvents consisting of methyl alcohol, ethyl alcohol and isopropyl alcohol, a first microcapsule layer-forming compound soluble in said first phase selected from the group consisting of glycerol monosterate, glycerol monooleate, glycerol monolaurate, glycerol dioleate, glycerol distearate, cholesterol, stigmasterol, phytosterol, campesterol, and lecithins, a co-solvent selected from the group of co-solvents consisting of C₃ -C₈ alcohols, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, oil selected from the group of oils consisting of poppy seed oil, olive oil, peanut oil, sesame oil, cotton seed oil, soybean oil, safflower oil, corn oil, sunflower seed oil, canola oil, mineral oil, a C₂₀ -C₃₈ paraffinic oil, liquid petrolatum, and water;

a second layer immiscible with said first layer, said second layer comprising water, a second microcapsule layer-forming compound soluble in said second phase selected from the group consisting of polyethyleneglycol, dextran polyvinylpyrrolidone, polyvinyl alcohols, gelatin, gum tragacanth, carrageenan, Karaya gum, Guar gum, gum arabic, alginates, carboxymethyl cellulose, hydroxypropyl cellulose, carboxypropyl cellulose, and lecithins, a surface active agent sorbitan monooleate treated with ethylene oxide, dextran, polyethylene glycol, C₁₂ -C₂₀ fatty acids, 2-amino-2-methyl-1-propyl aminomethyl propanol, amphoteric salts, and quaternary ammonium salts, and a salt selected from the group of salts consisting of NaCl, KCl, CaCl₂, MgCl₂, quaternary ammonium salts, cetyl trimethylammonium bromide, and 4-methoxy-4(3-phosphatidyl choline)spiro(1,2-dioxetane-3-g,l-adamantane) disodium salt;

said surface active agent having a hydrophilic/lipophilic balance value greater than that of said first microcapsule layer-forming compound; and

,

said second microcapsule layer-forming compound having a hydrophilic/lipophilic balance value lower than that of said surface active agent.