Claims for Patent: 5,444,041

Summary for Patent: 5,444,041

Title:	Convertible microemulsion formulations
Abstract:	There is provided a water-in-oil (w/o) microemulsion which readily converts to an oil-in-water (o/w) emulsion by the addition of aqueous fluid to the w/o microemulsion, whereby any water-soluble biologically-active material in the aqueous phase is released for absorption by the body. The w/o microemulsion is particularly useful for storing proteins and the like for long periods of time at room temperature and above until they are ready for use, at which time the addition of aqueous fluid converts the microemulsion to an o/w emulsion and releases the protein.
Inventor(s):	Owen; Albert J. (West Chester, PA), Yiv; Seang H. (Wilmington, DE), Sarkahian; Ani B. (Bryn Mawr, PA)
Assignee:	Ibah, Inc. (Blue Bell, PA)
Application Number:	07/885,202
Patent Claims:	1. A liquid biologically compatible water-in-oil microemulsion composition which converts to an oil-in-water emulsion by the addition of water, comprising: (a) up to about 20 volume percent of an internal dispersed aqueous phase comprising an effective amount of a biologically-active material, said biologically-active material consisting of therapeutic water-soluble materials, (b) from about 30 to 99 volume percent of a continuous oil phase comprising diesters of propylene glycol having from about 15 to 40 carbon atoms, and (c) from about 1 to 70 volume percent of a surfactant or mixture of surfactants, wherein the surfactant or surfactant mixture has a hydrophilic-lipophilic balance value of from 7 to 14. 2. The composition of claim 1 wherein the biologically-active material is a protein or peptide. 3. The composition of claim 2 wherein the HLB of the surfactant, or mixture of surfactants, is from about 8 to 13. 4. The composition of claim 3 wherein the surfactant is a mixture of surfactants, said mixture comprising a surfactant having an HLB value of less than 5, and a surfactant having an HLB value of greater than 9. 5. The composition of claim 3 wherein the surfactant or mixture of surfactants is selected from the group consisting of cetyldimethylethylammonium bromide, cetylpyridinium chloride; C.sub.8-32 fatty acids and salts thereof; cholic acid; C.sub.8-56 diesters of tartaric acid; phospholipids; C.sub.5-29 monoesters of lactic acid; C.sub.8-20 sulfonates; tridecyl- and dodecylbenzene sulfonic acids; C.sub.5-33 sarcosine and betaine; phosphatidylethanolamine, sphingomyelins, ethoxylated castor oil; C.sub.5-29 mono-glycerides and ethoxylated derivatives thereof; C.sub.15-60 diglycerides and polyoxyethylene derivatives thereof having 1 to 90 POE groups; C.sub.10-40 esters of long chain fatty acids; C.sub.10-40 alcohols; C.sub.8-96 ethoxylated fatty esters; C.sub.14-130 sucrose fatty esters; and C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups. 6. The composition of claim 3 wherein the surfactant or mixture of surfactants is selected from the group consisting of C.sub.5-29 monoglycerides, C.sub.15-60 diglycerides, C.sub.8-96 ethoxylated fatty esters, C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups. 7. The composition of claim 3 wherein the surfactant comprises a mixture of mono- and diglycerides of capric and caprylic acid. 8. The composition of claim 3 which is stable when stored at temperatures of from about 20.degree. to 40.degree. C. and in which the stored biologically-active material has a higher activity compared to said biologically-active material that is stored in said aqueous phase alone but otherwise under the same storage conditions. 9. The composition of claim 7 wherein the biologically active material is calcitonin or insulin. 10. A biologically compatible water-in-oil microemulsion composition which converts to an oil-in-water emulsion by the addition of water, comprising: (a) up to about 20 volume percent of an internal dispersed aqueous phase comprising an effective amount of a biologically-active material, (b) about 30 to 99 volume percent of a continuous oil phase comprising at least one pharmaceutically-acceptable oil comprising diesters of propylene glycol having from 7 to 55 carbon atoms, and (c) about 1 to about 70 volume percent of a mixture of surfactants comprising mono- and di-glycerides of capric and caprylic acid, wherein the surfactant mixture has a hydrophilic-lipophilic balance value of from 7 to 14; and wherein the biologically-active material is selected from the group consisting of calcitonin and insulin, and wherein the microemulsion is a liquid. 11. The composition of claim 10 wherein the oil phase further comprises triesters of glycerol having from about 9 to 83 carbon atoms. 12. The composition of claim 11 wherein the mixture of surfactants additionally comprises a surfactant selected from the group consisting of cetyldimethylethylammonium bromide, cetylpyridinium chloride; C.sub.8-32 fatty acids and salts thereof; cholic acid; C.sub.8-56 diesters of tartaric acid; phospholipids; C.sub.5-29 monoesters of lactic acid; C.sub.8-20 sulfonates; tridecyl- and dodecylbenzene sulfonic acids; C.sub.5-33 sarcosine and betaine; phosphatidylethanolamine, sphingomyelins, ethoxylated castor oil; C.sub.5-29 mono-glycerides other than monoglycerides of capric and caprylic acid; ethoxylated derivatives of C.sub.5-29 mono-glycerides; C.sub.15-60 diglycerides other than diglycerides of capric and caprylic acid; polyoxyethylene derivatives of C.sub.15-60 diglycerides having 1 to 90 POE groups; C.sub.10-40 esters of long chain fatty acids; C.sub.10-40 alcohols; C.sub.8-96 ethoxylated fatty esters; C.sub.14-130 sucrose fatty esters; and C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups, and mixtures thereof. 13. The composition of claim 10 wherein the hydrophilic-lipophilic balance of the surfactant mixture is from about 8 to 13. 14. The composition of claim 13 wherein the biologically active agent is insulin. 15. A biologically compatible water-in-oil microemulsion composition which is a solid at room temperature and which converts to an oil-in-water emulsion by the addition of water, comprising: (a) up to about 20 volume percent of an internal dispersed aqueous phase comprising an effective amount of a biologically-active material, wherein the biologically-active material is water-soluble and is a therapeutic and is a protein, peptide, or other pharmaceutically-active material; (b) from about 30 to 99 volume percent of a continuous oil phase comprising at least one pharmaceutically-acceptable oil which is a solid at room temperature, and wherein the oil phase comprises a diester of propylene glycol; and (c) from about 1 to 70 volume percent a surfactant or mixture of surfactants, wherein the surfactant or surfactant mixture has a hydrophilic-lipophilic balance value of from 7 to 14. 16. The composition of claim 15 wherein the biologically-active material is a protein or peptide. 17. The composition of claim 16 wherein the oil phase comprises a diester of propylene glycol having from 15 to 40 carbon atoms. 18. The composition of claim 17 wherein the surfactant, or mixture of surfactants, comprises a mixture of mono- and di-glycerides of capric and caprylic acid. 19. The composition of claim 17 wherein the oil phase further comprises a triglyceride having from 20-60 carbon atoms. 20. The composition of claim 17 wherein the surfactant or mixture of surfactants is selected from the group consisting of cetyldimethylethylammonium bromide, cetylpyridinium chloride; C.sub.8-32 fatty acids and salts thereof; cholic acid; C.sub.8-56 diesters of tartaric acid; phospholipids; C.sub.5-29 monoesters of lactic acid; C.sub.8-20 sulfonates; tridecyl- and dodecylbenzene sulfonic acids; C.sub.5-33 sarcosine and betaine; phosphatidylethanolamine, sphingomyelins, ethoxylated castor oil; C.sub.5-29 mono-glycerides and ethoxylated derivatives thereof; C.sub.15-60 diglycerides and polyoxyethylene derivatives thereof having 1 to 90 POE groups; C.sub.10-40 esters of long chain fatty acids; C.sub.10-40 alcohols; C.sub.8-96 ethoxylated fatty esters; C.sub.14-130 sucrose fatty esters; C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups. 21. The composition of claim 17 wherein the surfactant or mixture of surfactants is selected from the group consisting of C.sub.5-29 monoglycerides, C.sub.15-60 diglycerides, C.sub.8-96 ethoxylated fatty esters, C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups. 22. The composition of claim 19 wherein the biologically-active material is calcitonin or insulin. 23. A liquid water-in-oil microemulsion composition that converts to an oil-in-water emulsion by the addition of water, comprising: (a) up to about 60 volume percent, based upon the total volume of the microemulsion, of an internally dispersed aqueous phase comprising an effective amount of a biologically-active material; (b) from about 5 to 99 volume percent of a continuous oil phase comprising propylene glycol diesters having from 7 to 55 carbon atoms; and (c) from about 1 to 70 volume percent of a surfactant or mixture of surfactants comprising C.sub.9-13 monoglycerides, wherein the surfactant or surfactant mixture has a hydrophilic-lipophilic balance value of from 7 to 14, wherein the biologically-active material is selected from the group consisting of calcitonins, insulins, fibrinogen antagonists, growth hormone releasing peptides, interleukins, erythropoietins, colony stimulating factors, hematoregulatory peptides, vasopressin, collagenase inhibitors, angiotensin inhibitors, mammalian growth hormones, heparins, clotting factors, tissue plasminogen activators, atrial natriuretic peptides, and tumor necrosis factor, and wherein the water:oil partition coefficient of the active material is greater than 10:1. 24. The composition of claim 23 wherein the oil phase comprises diesters of propylene glycol having from about 15 to 40 carbon atoms. 25. The composition of claim 23 wherein the composition comprises a surfactant mixture and wherein the additional surfactant is selected from the group consisting of cetyldimethylethylammonium bromide, cetylpyridinium chloride; C.sub.8-32 fatty acids and salts thereof; cholic acid; C.sub.8-56 diesters of tartaric acid; phospholipids; C.sub.5-29 monoesters of lactic acid; C.sub.8-20 sulfonates; tridecyl- and dodecylbenzene sulfonic acids; C.sub.5-33 sarcosine and betaine; phosphatidylethanolamine, sphingomyelins, ethoxylated castor oil; C.sub.5-29 mono-glycerides other than C.sub.9-13 monoglycerides; ethoxylated derivatives of C.sub.5-29 mono-glycerides; C.sub.15-60 diglycerides and polyoxyethylene derivatives thereof having 1 to 90 POE groups; C.sub.10-40 esters of long chain fatty acids; C.sub.10-40 alcohols; C.sub.8-96 ethoxylated fatty esters; C.sub.14-130 sucrose fatty esters; C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups and mixtures thereof. 26. The composition of claim 23 wherein the surfactant or surfactant mixture has a hydrophilic-lipophilic balance of 8 to 13. 27. The composition of claim 26 wherein the composition comprises a surfactant mixture wherein the additional surfactant is selected from the group consisting of C.sub.5-29 monoglycerides other than C.sub.9-13 monoglycerides, C.sub.15-60 diglycerides, C.sub.8-96 ethoxylated fatty esters, C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups, phospholipids, and C.sub.8-32 fatty acids and salts thereof. 28. The composition of claims 23, 25 or 26 wherein the biologically-active material is a fibrinogen antagonist. 29. The composition of claim 28 wherein the biologically-active material is a peptide having the sequence cyclo(S,S)-N.sup..alpha. -acetyl-Cys-(N.sup..alpha. -methyl)Arg-Gly-Asp-Pen-NH.sub.2 (SEQ ID NO:1). 30. The composition of claims 23, 25 or 26 wherein the biologically-active material is a growth hormone releasing peptide. 31. The composition of claim 30 wherein the biologically-active material is a peptide having the sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH.sub.2. 32. The composition of claims 23, 25 or 26 wherein the biologically-active material is selected from the group consisting of calcitonins, insulins, and mammalian growth hormones. 33. The composition of claim 26 wherein the aqueous phase is from about 30 to about 60 volume percent of the water-in-oil microemulsion. 34. A liquid water-in-oil microemulsion composition that converts to an oil-in-water emulsion by the addition of water, comprising: (a) up to about 60 volume percent, based upon the total volume of the microemulsion, of an internally dispersed aqueous phase comprising an effective amount of a biologically-active material wherein the biologically-active material consists of therapeutic materials which have a water:oil partition coefficient greater than 10:1; (b) from about 5 to 99 volume percent of a continuous oil phase comprising diesters of propylene glycol having from about 7 to 55 carbon atoms; (c) from about 1 to 70 volume percent of a surfactant or mixture of surfactants, wherein the surfactant or surfactant mixture has a hydrophilic-lipophilic balance value of from 7 to 14. 35. The composition of claim 34 wherein the biologically active material consists of proteins, peptides, or immunogens. 36. The composition of claim 35 wherein the surfactant or mixture of surfactants is selected from the group consisting of cetyldimethylethylammonium bromide, cetylpyridinium chloride; C.sub.8-32 fatty acids and salts thereof; cholic acid; C.sub.8-56 diesters of tartaric acid; phospholipids; C.sub.5-29 monoesters of lactic acid; C.sub.8-20 sulfonates; tridecyl- and dodecylbenzene sulfonic acids; C.sub.5-33 sarcosine and betaine; phosphatidylethanolamine, sphingomyelins, ethoxylated castor oil; C.sub.5-29 mono-glycerides and ethoxylated derivatives thereof; C.sub.15-60 diglycerides and polyoxyethylene derivatives thereof having 1 to 90 POE groups; C.sub.10-40 esters of long chain fatty acids; C.sub.10-40 alcohols; C.sub.8-96 ethoxylated fatty esters; C.sub.14-130 sucrose fatty esters; C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups. 37. The composition of claim 36 wherein the surfactant or surfactant mixture comprises C.sub.9-13 monoglycerides. 38. The composition of claim 36 wherein the aqueous phase is from about 30 to 60 volume percent. 39. The composition of claim 35 wherein the surfactant or mixture of surfactants is selected from the group consisting of C.sub.9-13 monoglycerides, C.sub.15-60 diglycerides, C.sub.8-96 ethoxylated fatty esters, C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups, phospholipids, and C.sub.8-32 fatty acids and salts thereof. 40. The composition of claims 35 or 36 wherein the biologically-active material is a fibrinogen antagonist. 41. The composition of claim 40 wherein the biologically-active material is a peptide having the sequence cyclo(S,S)-N.sup..alpha. -acetyl-Cys-(N.sup..alpha. -methyl)Arg-Gly-Asp-Pen-NH.sub.2 (SEQ ID NO:1). 42. The composition of claims 35 or 36 wherein the biologically-active material is a growth hormone releasing peptide. 43. The composition of claim 42 wherein the biologically-active material is a peptide having the sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH.sub.2. 44. The composition of claims 35 or 36 wherein the biologically-active material is selected from the group consisting of calcitonins, insulins, fibrinogen antagonists, growth hormone releasing peptides, interleukins, erythropoietins, colony stimulating factors, hematoregulatory peptides, vasopressin, collagenase inhibitors, angiotensin inhibitors, mammalian growth hormones, heparins, clotting factors, tissue plasminogen activators, atrial natriuretic peptides, and tumor necrosis factor. 45. The composition of claim 44 wherein the biologically-active material is selected from the group consisting of calcitonins, insulins, and human growth hormones. 46. The composition of claim 34 wherein the biologically-active material is a protein or a peptide. 47. A water-in-oil microemulsion composition which is a solid at room temperature and that converts to an oil-in-water emulsion by the addition of water, comprising: (a) up to about 60 volume percent, based upon the total volume of the microemulsion, of an internally dispersed aqueous phase comprising an effective amount of a biologically-active material, wherein the biologically-active material consists of water-soluble therapeutics which are either proteins, peptides, immunogens, or other pharmaceutically-active materials; (b) from about 5 to 99 volume percent of a continuous oil phase comprising at least one pharmaceutically-acceptable oil comprising a diester of propylene glycol; and (c) from about 1 to 70 volume percent of a surfactant or mixture of surfactants, wherein the surfactant or surfactant mixture has a hydrophilic-lipophilic balance value of from 7 to 14, wherein the water:oil partition coefficient of the biologically-active material is greater than 10:1, and wherein the oil phase, surfactant or surfactant mixture, or both, comprise a component that has a melting point above about 23.degree. C. 48. The composition of claim 47 wherein the biologically-active material is a protein or peptide. 49. The composition of claim 48 wherein the oil phase comprises diesters of propylene glycol having from about 15 to 40 carbon atoms. 50. The composition of claim 49 wherein the surfactant or mixture of surfactants is selected from the group consisting of cetyldimethylethylammonium bromide, cetylpyridinium chloride; C.sub.8-32 fatty acids and salts thereof; cholic acid; C.sub.8-56 diesters of tartaric acid; phospholipids; C.sub.5-29 monoesters of lactic acid; C.sub.8-20 sulfonates; tridecyl- and dodecylbenzene sulfonic acids; C.sub.5-33 sarcosine and betaine; phosphatidylethanolamine, sphingomyelins, ethoxylated castor oil; C.sub.5-29 mono-glycerides and ethoxylated derivatives thereof; C.sub.15-60 diglycerides and polyoxyethylene derivatives thereof having 1 to 90 POE groups; C.sub.10-40 esters of long chain fatty acids; C.sub.10-40 alcohols; C.sub.8-96 ethoxylated fatty esters; C.sub.14-130 sucrose fatty esters; C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups. 51. The composition of claim 50 wherein the oil phase comprises diesters of propylene glycol having from 19 to 23 carbon atoms. 52. The composition of claim 49 wherein the aqueous phase is from about 30-60 volume percent. 53. The composition of claims 48 or 50 wherein the biologically active material is selected from the group consisting of calcitonins, insulins, fibrinogen antagonists, growth hormone releasing peptides, interleukins, erythropoietins, colony stimulating factors, hematoregulatory peptides, vasopressin, collagenase inhibitors, angiotensin inhibitors, mammalian growth hormones, heparins, clotting factors, tissue plasminogen activators, atrial natriuretic peptides, and tumor necrosis factor. 54. The composition of claim 53 wherein the biologically-active material is selected from the group consisting of calcitonins, insulins, and human growth hormones. 55. The composition of claims 48 or 50 wherein the biologically-active material is a fibrinogen antagonist. 56. The composition of claim 55 wherein the biologically-active material is a peptide having the sequence cyclo(S,S)-N.sup..alpha. -acetyl-Cys-(N.sup..alpha. -methyl)Arg-Gly-Asp-Pen-NH.sub.2 (SEQ ID NO:1). 57. The composition of claims 49 or 50 wherein the biologically-active material is a growth hormone releasing peptide. 58. The composition of claim 57 wherein the biologically-active material is a peptide having the sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH.sub.2. 59. A water-in-oil microemulsion composition, comprising: (a) up to about 60 volume percent, based upon the total volume of the microemulsion, of an internally dispersed aqueous phase comprising an effective amount of a biologically-active material wherein the biologically-active material consists of therapeutic water-soluble materials having a water:oil partition coefficient greater than 10:1, and a modifier comprising sorbitol, polyethylene glycol, propylene glycol, mannitol, monosaccharides, or disaccharides, present in an amount of from 10-50% by weight of the aqueous phase and sufficient to cause the water-in-oil microemulsion to convert to an oil-in-water microemulsion upon the addition of aqueous medium; (b) a continuous oil phase comprising at least one pharmaceutically acceptable oil; and (c) a surfactant or mixture of surfactants, wherein the surfactant or mixture of surfactants comprises monoglycerides or diglycerides of capric or caprylic acid and has a hydrophilic-lipophilic balance value of greater than 7, wherein the amounts of the aqueous phase, oil phase, and surfactant or surfactant mixture are such that the water-in-oil microemulsion converts to an oil-in-water microemulsion upon the addition of water. 60. The composition of claim 59 wherein the biologically-active material is a protein, peptide, or immunogen, and wherein the aqueous phase contains 20-50% by weight of the modifier. 61. The composition of claim 60 wherein the biologically-active material is a protein or peptide. 62. The composition of claim 61 wherein the modifier consists of sorbitol, polyethylene glycol, propylene glycol, mannitol, monosaccharides, and disaccharides. 63. The composition of claim 61 wherein the aqueous phase is up to about 20 percent by weight of the water-in-oil microemulsion. 64. The composition of claim 61 comprising a surfactant mixture wherein the surfactant mixture further comprises a surfactant selected from the group consisting of cetyldimethylethylammonium bromide, cetylpyridinium chloride; C.sub.8-32 fatty acids and salts thereof; cholic acid; C.sub.8-56 diesters of tartaric acid; phospholipids; C.sub.5-29 monoesters of lactic acid; C.sub.8-20 sulfonates; tridecyl- and dodecylbenzene sulfonic acids; C.sub.5-33 sarcosine and betaine; phosphatidylethanolamine, sphingomyelins, ethoxylated castor oil; C.sub.5-29 mono-glycerides other than monoglycerides of capric and caprylic acid; ethoxylated derivatives of C.sub.5-29 mono-glycerides; C.sub.15-60 diglycerides other than diglycerides of capric and caprylic acid; polyoxyethylene derivatives of C.sub.15-60 diglycerides having 1 to 90 POE groups; C.sub.10-40 esters of long chain fatty acids; C.sub.10-40 alcohols; C.sub.8-96 ethoxylated fatty esters; C.sub.14-130 sucrose fatty esters; and C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups. 65. The composition of claim 61 wherein the oil phase comprises triesters of glycerol having from about 9 to 83 carbon atoms, diesters of propylene glycol having from about 7 to 55 carbon atoms, or mixtures thereof. 66. The composition of claim 61 comprising a surfactant mixture wherein the surfactant mixture further comprises a surfactant selected from the group consisting of C.sub.5-29 monoglycerides other than monoglycerides of capric and caprylic acid, C.sub.15-60 diglycerides other than diglycerides of capric and caprylic acid, C.sub.8-96 ethoxylated fatty esters, C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups. 67. The composition of claims 63 or 64 wherein the biologically-active material is a fibrinogen antagonist. 68. The composition of claim 67 wherein the biologically-active material is a peptide having the sequence cyclo(S,S)-N.sup..alpha. -acetyl-Cys-(N.sup..alpha. -methyl)Arg-Gly-Asp-Pen-NH.sub.2 (SEQ ID NO:1). 69. The composition of claims 63 or 64 wherein the biologically-active material is a growth hormone releasing peptide. 70. The composition of claim 69 wherein the biologically-active material is a peptide having the sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH.sub.2. 71. The composition of claims 63 or 64 wherein the biologically-active material is selected from the group consisting of calcitonins, insulins, fibrinogen antagonists, growth hormone releasing peptides, interleukins, erythropoietins, colony stimulating factors, hematoregulatory peptides, vasopressin, collagenase inhibitors, angiotensin inhibitors, mammalian growth hormones, heparins, clotting factors, tissue plasminogen activators, atrial natriuretic peptides, and tumor necrosis factor. 72. The composition of claim 71 wherein the biologically-active material is selected from the group consisting of calcitonins, insulins, and human growth hormones. 73. The composition of claims 59, 60, 61, 62 or 64 wherein the water-in-oil microemulsion is a solid at a temperature of about 23.degree. C. 74. A method of administering to animals by controlled release a biologically-active material which comprises: (a) providing a phase-reversible water-in-oil microemulsion composition that converts to an oil-in-water emulsion by the addition of water, comprising: (1) up to about 20 volume percent of an internal, dispersed aqueous phase comprising an effective amount of a biologically-active material wherein said biologically-active material is a therapeutic and is water-soluble, (2) from about 30 to 99 volume percent of a continuous oil phase comprising at least one pharmaceutically-acceptable oil, and (3) from about 1 to 70 volume percent of a surfactant mixture having a hydrophilic-lipophilic balance value of from 7 to 14 and comprising a mixture of mono-and di-glycerides of captic and caprylic acid, and (b) administering an effective amount of the microemulsion to the body of an animal, wherein the water-in-oil microemulsion is administered orally. 75. The method of claim 74 wherein the biologically-active material is a protein or peptide. 76. The method of claim 75 wherein the surfactant mixture further comprises an additional surfactant selected from the group consisting of cetyldimethylethylammonium bromide, cetylpyridinium chloride; C.sub.8-32 fatty acids and salts thereof; cholic acid; C.sub.8-56 diesters of tartaric acid; phospholipids; C.sub.5-29 monoesters of lactic acid; C.sub.8-20 sulfonates; tridecyl- and dodecylbenzene sulfonic acids; C.sub.5-33 sarcosine and betaine; phosphatidylethanolamine, sphingomyelins, ethoxylated castor oil; C.sub.5-29 mono-glycerides other than monoglycerides of capric and caprylic acid; ethoxylated derivatives of C.sub.5-29 mono-glycerides; C.sub.15-60 diglycerides other than diglycerides of capric and caprylic acid; polyoxyethylene derivatives of C.sub.15-60 diglycerides having 1 to 90 POE groups; C.sub.10-40 esters of long chain fatty acids; C.sub.10-40 alcohols; C.sub.8-96 ethoxylated fatty esters; C.sub.14-130 sucrose fatty esters; C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups and mixtures thereof. 77. The method of claim 75 wherein the surfactant mixture further comprises a surfactant selected from the group consisting of C.sub.5-29 monoglycerides other than monoglycerides of capric and caprylic acid, C.sub.15-60 diglycerides other than diglycerides of capric and caprylic acid, C.sub.8-96 ethoxylated fatty esters, C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups, phospholipids, and C.sub.8-32 fatty acids and salts thereof, and mixtures thereof. 78. The method of claim 75 wherein the oil phase comprises triglycerides having from 20-60 carbon atoms. 79. The method of claim 75 wherein the oil phase comprises a diester of propylene glycol having from 15 to 40 carbon atoms. 80. The method of claim 75 wherein the water-in-oil microemulsion is a liquid at room temperature. 81. The method of claim 75 further comprising converting the water-in-oil microemulsion to an oil-in-water emulsion after the administration step by the addition of aqueous body fluid. 82. The method of claim 81 wherein the water-in-oil microemulsion is converted in the intestine of the animal. 83. The method of claim 81 wherein the water-in-oil microemulsion is a liquid. 84. The method of claim 75 wherein said biologically-active material is a protein or peptide. 85. The method of claim 75 wherein said biologically-active material is calcitonin or insulin. 86. A method of administering to animals a biologically-active material which method comprises: (a) providing a water-in-oil microemulsion composition that converts to an oil-in-water emulsion by the addition of water, comprising: (1) up to about 60 volume percent, based upon the total volume of the microemulsion, of an internally dispersed aqueous phase comprising an effective amount of a biologically-active material that is water-soluble; (2) from about 5 to 99 volume percent of a continuous oil phase comprising diesters of propylene glycol having from about 7 to 55 carbon atoms; and (3) from about 1 to 70 volume percent of a surfactant or mixture of surfactants, wherein the surfactant or surfactant mixture has a hydrophilic-lipophilic balance value from 7 to 14, and (b) administering an effective amount of the microemulsion to the body of an animal, wherein the water-in-oil microemulsion is administered orally, rectally or via any other mucous membrane. 87. The method of claim 86 wherein the biologically-active material is a therapeutic and is a protein or peptide and wherein the administration is orally or rectally and wherein the biologically-active material is selected from the group consisting of materials having a water:oil partition coefficient greater than 10:1. 88. The method of claim 87 wherein the surfactant or surfactant mixture is selected from the group consisting of cetyldimethylethylammonium bromide, cetylpyridinium chloride; C.sub.8-32 fatty acids and salts thereof; cholic acid; C.sub.8-56 diesters of tartaric acid; phospholipids; C.sub.5-29 monoesters of lactic acid; C.sub.8-20 sulfonates; tridecyl- and dodecylbenzene sulfonic acids; C.sub.5-33 sarcosine and betaine; phosphatidylethanolamine, sphingomyelins, ethoxylated castor oil; C.sub.5-29 mono-glycerides and ethoxylated derivatives thereof; C.sub.15-60 diglycerides and polyoxyethylene derivatives thereof having 1 to 90 POE groups; C.sub.10-40 esters of long chain fatty acids; C.sub.10-40 alcohols; C.sub.8-96 ethoxylated fatty esters; C.sub.14-130 sucrose fatty esters; C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups. 89. The method of claim 87 wherein the surfactant or surfactant mixture is selected from the group consisting of C.sub.5-29 monoglycerides, C.sub.15-60 diglycerides, C.sub.8-96 ethoxylated fatty esters, C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups, phospholipids and C.sub.8-32 fatty acids and salts thereof. 90. The method of claim 87 wherein the oil phase comprises diesters of propylene glycol having from about 19 to 23 carbon atoms. 91. The method of claim 87 wherein the surfactant or surfactant mixture comprises a C.sub.9-13 monoglyceride, and wherein the hydrophilic-lipophilic balance of the surfactant or surfactant mixture is from 8-13. 92. The method of claim 87 wherein the aqueous phase is up to about 20 percent by weight of the water-in-oil microemulsion and wherein the administration is orally. 93. The method of claim 92 wherein said microemulsion is a liquid. 94. The method of claim 87 wherein the water-in-oil microemulsion is a solid at about 23.degree. C. 95. The method of claims 93 or 94 further comprising converting the water-in-oil microemulsion to an oil-in-water emulsion after the administration step by the addition of aqueous body fluid. 96. The method of claim 87 wherein the biologically-active material is selected from the group consisting of calcitonins, insulins, fibrinogen antagonists, growth hormone releasing peptides, interleukins, erythropoietins, colony stimulating factors, hematoregulatory peptides, vasopressin, collagenase inhibitors, angiotensin inhibitors, mammalian growth hormones, heparins, clotting factors, tissue plasminogen activators, atrial natriuretic peptides, and tumor necrosis factor. 97. A method of administering to animals a biologically-active material which method comprises: (a) providing a water-in-oil microemulsion composition that converts to an oil-in-water emulsion by the addition of water, comprising: (1) up to about 60 volume percent, based upon the total volume of the microemulsion, of an internally dispersed aqueous phase comprising an effective amount of a biologically-active material wherein the biologically-active material has a water:oil partition coefficient of greater than 10:1; (2) from about 5 to 99 volume percent of a continuous oil phase comprising at least one pharmaceutically-acceptable oil; and (3) from 1 to 70 volume percent of a surfactant or mixture of surfactants comprising monoglycerides or diglycerides of capric or caprylic acid and having a hydrophilic-lipophilic balance value of from 7 to 14, and (b) administering an effective amount of the microemulsion to the body of an animal, wherein the water-in-oil microemulsion is administered orally. 98. The method of claim 97 wherein the biologically-active material is a therapeutic and is a protein or peptide and wherein said microemulsion is a liquid. 99. The method of claim 98 wherein the water-in-oil microemulsion composition comprises a surfactant mixture further comprising a surfactant selected from the group consisting of cetyldimethylethylammonium bromide, cetylpyridinium chloride; C.sub.8-32 fatty acids and salts thereof; cholic acid; C.sub.8-56 diesters of tartaric acid; phospholipids; C.sub.5-29 monoesters of lactic acid; C.sub.8-20 sulfonates; tridecyl- and dodecylbenzene sulfonic acids; C.sub.5-33 sarcosine and betaine; phosphatidylethanolamine, sphingomyelins, ethoxylated castor oil; C.sub.5-29 mono-glycerides other than monoglycerides of capric and caprylic acid; ethoxylated derivatives of C.sub.5-29 mono-glycerides; C.sub.15-60 diglycerides other than diglycerides of capric and caprylic acid; polyoxyethylene derivatives of C.sub.15-60 diglycerides having 1 to 90 POE groups; C.sub.10-40 esters of long chain fatty acids; C.sub.10-40 alcohols; C.sub.8-96 ethoxylated fatty esters; C.sub.14-130 sucrose fatty esters; and C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups, and mixtures thereof. 100. The method of claim 98 wherein the water-in-oil microemulsion composition comprises a surfactant mixture further comprising a surfactant selected from the group consisting of C.sub.5-29 monoglycerides other than monoglycerides of capric and caprylic acid, C.sub.15-60 diglycerides other than diglycerides of captic and caprylic acid, C.sub.8-96 ethoxylated fatty esters, C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups, phospholipids, C.sub.8-32 fatty acids and salts thereof, and mixtures thereof. 101. The method of claim 98 wherein the oil phase comprises diesters of propylene glycol having from about 19 to 23 carbon atoms. 102. The method of claim 98 wherein the surfactant or mixture of surfactants has a hydrophilic-lipophilic balance of from 8-13. 103. The method of claim 98 wherein the aqueous phase is up to about 20 percent by weight of the water-in-oil microemulsion. 104. The method of claim 98 further comprising converting the water-in-oil microemulsion to an oil-in-water emulsion after the administration step by the addition of aqueous body fluid. 105. The method of claim 97 wherein the biologically-active material is a therapeutic and is a protein or peptide and wherein the water-in-oil microemulsion is a solid at about 23.degree. C. 106. The method of claim 98 wherein said biologically-active material is a peptide. 107. The method of claim 98 wherein said biologically-active material is selected from the group consisting of calcitonin, insulin, human growth hormone, and growth hormone releasing peptide. 108. The method of claim 98 wherein said water-in-oil microemulsion is a liquid at room temperature. 109. A method of administering to animals a biologically-active material which method comprises: (a) providing a water-in-oil microemulsion comprising: (1) up to about 60 volume percent, based upon the total volume of the microemulsion, of an internally dispersed aqueous phase comprising an effective amount of a biologically-active material which consists of therapeutic water-soluble materials having a water:oil partition coefficient of greater than 10:1, and a modifier, present in an amount of from 10-50% by weight of the aqueous phase and sufficient to cause the water-in-oil microemulsion to convert to an oil-in-water microemulsion upon the addition of aqueous medium; (2) from about 5 to 99 volume percent of a continuous oil phase comprising at least one pharmaceutically-acceptable oil; and (3) a surfactant or mixture of surfactants comprising monoglycerides or diglycerides of capric or caprylic acid, wherein the surfactant or surfactant mixture has a hydrophilic-lipophilic balance value of at least 7; (b) administering an effective amount of the water-in-oil microemulsion to the body of an animal, wherein the water-in-oil microemulsion is administered parenterally, enterally, or via any other mucous membrane; and (c) converting the water-in-oil microemulsion into an oil-in-water microemulsion. 110. The method of claim 109 wherein the biologically-active material is a protein or peptide. 111. The method of claim 110 wherein the modifier comprises sorbitol, polyethylene glycol, propylene glycol, mannitol, monosaccharides or disaccharides. 112. The method of claim 111 wherein the modifier is 20-50 percent by weight of the aqueous phase of the water-in-oil microemulsion. 113. The method of claim 110 wherein the aqueous phase is up to about 20 percent by weight of the water-in-oil microemulsion. 114. The method of claim 110 wherein the water-in-oil microemulsion comprises a surfactant mixture further comprising a surfactant selected from the group consisting of cetyldimethylethylammonium bromide, cetylpyridinium chloride; C.sub.8-32 fatty acids and salts thereof; cholic acid; C.sub.8-56 diesters of tartaric acid; phospholipids; C.sub.5-29 monoesters of lactic acid; C.sub.8-20 sulfonates; tridecyl- and dodecylbenzene sulfonic acids; C.sub.5-33 sarcosine and betaine; phosphatidylethanolamine, sphingomyelins, ethoxylated castor oil; C.sub.5-29 mono-glycerides other than monoglycerides of capric and caprylic acid; ethoxylated derivatives of C.sub.5-29 mono-glycerides; C.sub.15-60 diglycerides other than diglycerides of capric and caprylic acid; polyoxyethylene derivatives of C.sub.15-60 diglycerides having 1 to 90 POE groups; C.sub.10-40 esters of long chain fatty acids; C.sub.10-40 alcohols; C.sub.8-96 ethoxylated fatty esters; C.sub.14-130 sucrose fatty esters; C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups, and mixtures thereof. 115. The method of claim 110 wherein the oil phase comprises triesters of glycerol having from about 9 to 45 carbon atoms, diesters of propylene glycol having from about 19 to 23 carbon atoms, or mixtures thereof. 116. The method of claim 110 wherein the water-in-oil microemulsion comprises a surfactant mixture further comprising a surfactant selected from the group consisting of C.sub.8-96 ethoxylated fatty esters, C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups, phospholipids, C.sub.8-32 fatty acids and salts thereof, and mixtures thereof. 117. The method of claim 110 wherein the water-in-oil microemulsion is a solid at about 23.degree. C. 118. A water-in-oil microemulsion composition which is a solid at room temperature and that converts to an oil-in-water emulsion by the addition of water, comprising: (a) up to about 60 volume percent, based upon the total volume of the microemulsion, of an internally dispersed aqueous phase comprising an effective amount of a biologically-active material, wherein the biologically-active material is a therapeutic and is a protein, peptide, immunogen, or other pharmaceutically-active material; (b) from about 5 to 99 volume percent of a continuous oil phase comprising at least one pharmaceutically-acceptable oil comprising diesters of propylene glycol having from about 7 to 55 carbon atoms; and (c) from about 1 to 70 volume percent of a surfactant or mixture of surfactants comprising C.sub.9-13 monoglycerides, C.sub.15-23 diglycerides, or mixtures thereof, and wherein the surfactant or surfactant mixture has a hydrophilic-lipophilic balance value of from 7 to 14, wherein the water:oil partition coefficient of the active material is greater than 10:1, and wherein the oil phase, surfactant or surfactant mixture, or both, comprise a component that has a melting point above about 23.degree. C. 119. A method of administering to animals a biologically-active material which method comprises: (a) providing a water-in-oil microemulsion composition comprising: (1) up to about 60 volume percent, based upon the total volume of the microemulsion, of an internally dispersed aqueous phase comprising an effective amount of a biologically-active material that is water-soluble and is a therapeutic and is a protein or peptide; (2) from about 5 to 99 volume percent of a continuous oil phase comprising diesters of propylene glycol having from about 7 to 55 carbon atoms; (3) from about 1 to 70 volume percent of a surfactant or mixture of surfactants, wherein the surfactant or surfactant mixture has a hydrophilic-lipophilic balance value from 7 to 14; (b) administering an effective amount of the microemulsion to the body of an animal, wherein the water-in-oil microemulsion is administered parenterally, enterally, or via any other mucous membrane; and (c) converting the water-in-oil microemulsion to an oil-in-water emulsion after the administration step by the addition of aqueous body fluid. 120. The method of claim 119 wherein the water-in-oil microemulsion is a solid at about 23.degree. C. 121. A method of administering to animals a biologically-active material which method comprises: (a) providing a water-in-oil microemulsion composition that converts to an oil-in-water emulsion by the addition of water, comprising: (1) up to about 60 volume percent, based upon the total volume of the microemulsion, of an internally dispersed aqueous phase comprising an effective amount of a biologically-active, water-soluble material, said biologically-active material having a water:oil partition coefficient of greater than 10:1 and being selected from the group consisting of calcitonin, insulin, growth hormone releasing peptide and human growth hormone; (2) from about 5 to 99 volume percent of a continuous oil phase comprising at least one pharmaceutically-acceptable oil; and (3) from 1 to 70 volume percent of a surfactant or mixture of surfactants, said surfactant or surfactant mixture having a hydrophilic-lipophilic balance value of from 7 to 14, and (b) administering an effective amount of the microemulsion to the body of an animal, said administration being oral; and (c) achieving a therapeutically effective increase in the blood system of said animal of said biologically-active material. 122. The method of claim 121 wherein said biologically-active material is calcitonin. 123. The method of claim 121 wherein said biologically-active material is insulin. 124. The method of claim 121 wherein said biologically-active material is growth hormone releasing peptide. 125. The method of claim 121 wherein said biologically-active material is human growth hormone. 126. A method of administering to animals by controlled release a biologically-active material which comprises: (a) providing a solid phase-reversible water-in-oil microemulsion composition that converts to an oil-in-water emulsion by the addition of water, comprising: (1) up to about 20 volume percent of an internal, dispersed aqueous phase comprising an effective amount of a biologically-active material consisting of therapeutic water soluble materials, (2) from about 30 to 99 volume percent of a continuous oil phase comprising at least one pharmaceutically-acceptable oil, and (3) from about 1 to 70 volume percent of a surfactant or surfactant mixture having a hydrophilic-lipophilic balance value of from 7 to 14; and (b) administering an effective amount of the microemulsion to the body of an animal, wherein the water-in-oil microemulsion is administered rectally. 127. The method of claim 126 wherein the biologically-active material is a protein or peptide. 128. The method of claim 127 wherein the surfactant or surfactant mixture is selected from the group consisting of cetyldimethylethylammonium bromide, cetylpyridinium chloride; C.sub.8-32 fatty acids and salts thereof; cholic acid; C.sub.8-56 diesters of tartaric acid; phospholipids; C.sub.5-29 monoesters of lactic acid; C.sub.8-20 sulfonates; tridecyl- and dodecylbenzene sulfonic acids; C.sub.5-33 sarcosine and betaine; phosphatidylethanolamine, sphingomyelins, ethoxylated castor oil; C.sub.5-29 monoglycerides and ethoxylated derivatives thereof; C.sub.15-60 diglycerides and polyoxyethylene derivatives thereof having 1 to 90 POE groups; C.sub.10-40 esters of long chain fatty acids; C.sub.10-40 alcohols; C.sub.8-96 ethoxylated fatty esters; C.sub.14-130 sucrose fatty esters; and C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, and polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups. 129. The method of claim 127 wherein the surfactant or surfactant mixture is selected from the group consisting of C.sub.5-29 monoglycerides, C.sub.15-60 diglycerides, C.sub.8-96 ethoxylated fatty esters, C.sub.20-130 sorbitol and sorbitan monoesters, diesters, and triesters, polyoxyethylene (POE) derivatives thereof having 1 to 90 POE groups, phospholipids, and C.sub.8-32 fatty acids and salts thereof. 130. The method of claim 127 wherein the surfactant or surfactant mixture comprises a mixture of mono- and di-glycerides of capric and caprylic acid. 131. The method of claim 127 wherein the oil phase comprises a diester of propylene glycol having from 15 to 40 carbon atoms. 132. The method of claim 127 wherein the oil phase comprises a triglyceride having from 9 to 83 carbon atoms. 133. The method of claim 127 further comprising converting the water-in-oil microemulsion to an oil-in-water emulsion after the administration step by the addition of aqueous body fluid. 134. The compositions of claims 23, 34, 47, 59 or 118 wherein the composition is contained within an enterically coated capsule or tablet. 135. The methods of claims 74, 86, 93, 97 or 109 wherein the composition is administered within an enterically coated capsule or tablet. 136. The method of any of the claims 75, 80, 81, 83, 87, 94, 104, 105, 84, 85, 106, or 108 further comprising achieving a therapeutically effective increase in the blood system of said animal of said biologically-active material in response to said administration. 137. A water-in-oil microemulsion composition which is a solid at room temperature, comprising: (a) a liquid water-in-oil microemulsion composition that converts to an oil-in-water emulsion by the addition of water, comprising (1) up to about 60 volume percent, based upon the total volume of the microemulsion, of an internally dispersed aqueous phase comprising an effective amount of a biologically-active material, wherein the biologically-active material is a therapeutic and is a protein, peptide, or immunogen; (2) from about 5 to 99 volume percent of a continuous oil phase comprising at least one pharmaceutically-acceptable oil comprising diesters of propylene glycol having from about 7 to 55 carbon atoms; and (3) from about 1 to 70 volume percent of a surfactant or mixture of surfactants comprising C.sub.9-13 monoglycerides, C.sub.15-23 diglycerides, or mixtures thereof, and wherein the surfactant or surfactant mixture has a hydrophilic-lipophilic balance value of from 7 to 14, wherein the water:oil partition coefficient of the active material is greater than 10:1, and (b) a solid matrix for said liquid water-in-oil microemulsion, said matrix consisting of a high melting point oil which melts at a temperature of about 25.degree.-60.degree. C., wherein the volume ratio of the high melting point oil to the liquid water-in-oil microemulsion is from about 0.5:1 to about 2:1, wherein said liquid water-in-oil microemulsion is dispersed within said solid matrix to form a solid composition.

Details for Patent 5,444,041

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	10/28/1982		2012-08-22
Eli Lilly And Company	HUMULIN R U-500	insulin human	Injection	018780	12/29/2015		2012-08-22
Eli Lilly And Company	HUMULIN R U-100	insulin human	Injection	018780	08/06/1998		2012-08-22