ADJUVANT FORMULATION COMPRISING A SUBMICRON OIL DROPLET EMULSION

• US 20090191226A2
• Filed: 09/17/2002
• Published: 07/30/2009
• Est. Priority Date: 05/25/1989
• Status: Abandoned Application

• Current Assignee: Novartis Vaccines And Diagnostics Incorporated (Novartis Ag)
• Original Assignee: Novartis Vaccines And Diagnostics Incorporated (Novartis Ag)
• Inventors: Van Nest, Gary, Ott, Gary, Barchfeld, Gail
• Application Number:
  US10/246,195
• Publication Number:
  US 20030147898A1
• Time in Patent Office: Days
• US Class Current: 424/184.1
• CPC Class Codes: A61K 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• CPC Class Codes: A61K 2039/55566 Emulsions, e.g. Freund's adjuvant, MF59
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• 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 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y10S 977/802 Virus-based particle
• CPC Class Codes: Y10S 977/918 Immunological

Abstract

An adjuvant composition, comprising a metabolizable oil and an emulsifying agent, wherein the oil and the detergent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are less than 1 micron in diameter. In preferred embodiments, the emulsifying agent is also an immunostimulating agent, such as a lipophilic muramyl peptide. Alternatively, an immunostimulating agent separate from the emulsifying agent can be used.

Claims

1-35. -35. (canceled)

36. A composition comprising:

(1) an adjuvant composition comprising;

(a) 4-5% by volume of squalene; and

(b) an emulsifying agent consisting essentially of polyoxyethylenesorbitan monooleate and sorbitan trioleate, wherein the total amount of polyoxyethylenesorbitan monooleate and sorbitan trioleate present is about 1% by weight (w/w);

wherein said squalene and said emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are less than 1 micron in diameter and wherein said composition exists in the absence of any polyoxypropylene-polyoxyethylene block copolymer; and

(2) an antigenic substance, wherein said antigenic substance is one or more antigenic substances selected from the group consisting of an antigenic substance from a virus, an antigenic substance from a bacterium and an antigenic substance from a parasite, wherein said adjuvant composition is capable of increasing the immune response to the antigenic substance, and further wherein said antigenic substance is not present in the internal phase of the adjuvant composition.

37. The composition of claim 36 wherein the antigenic substance comprises a viral subunit.

38. The composition of claim 36 wherein the antigenic substance is from a virus selected from the group consisting of hepatitis C virus (HCV), herpes simplex virus (HSV), human immunodeficiency virus (HIV), cytomegalovirus (CMV), influenza virus (flu), poliovirus, and rabies virus.

39. The composition of claim 38 wherein the antigenic substance is from herpes simplex virus (HSV).

40. The composition of claim 39 wherein the antigenic substance comprises HSV glycoprotein gD.

41. The composition of claim 38 wherein the antigenic substance is from human immunodeficiency virus (HIV).

42. The composition of claim 41 wherein the antigenic substance comprises HIV glycoprotein gp120.

43. The composition of claim 36 wherein the antigenic substance is from a bacterium.

44. The composition of claim 43 wherein the bacterium is selected from the group consisting of cholera, diphtheria, tetanus, and pertussis.

45. The composition of claim 36 wherein the antigenic substance is from a parasite.

46. The composition of claim 45 wherein the parasite comprises a malaria parasite.

47. The composition of claim 36 wherein the antigenic substance is used to immunize against meningitis.

48. The composition of claim 36 wherein the antigenic substance is selected from the group consisting of a protein, protein-polysaccharide, protein-lipopolysaccharide, polysaccharide, and lipopolysaccharide.

49. The composition of claim 36 wherein the antigenic substance comprises a hapten.

50. The composition of claim 36 further comprising an additional immunostimulatory agent.

51. The composition of claim 50 wherein the additional stimulatory agent is a muramyl peptide.

52. The composition of claim 36, wherein said oil-in-water emulsion has oil droplets substantially all of which are less than 0.6 micron in diameter.

53. The composition of claim 36, wherein said oil-in-water emulsion has oil droplets substantially all of which are less than 0.5 micron in diameter.

54. The composition of claim 52, wherein said oil-in-water emulsion has oil droplets substantially all of which are 0.1 to 0.75 micron in diameter.

55. The composition of claim 38 wherein the antigenic substance is from influenza virus.

56. The composition of claim 55 wherein the antigenic substance comprises at least one influenza HA antigen.

57. The composition of claim 50 wherein the additional immunostimulatory agent is a component of a bacterial cell wall.

58. An immunogenic composition comprising:

(1) an adjuvant composition comprising;

(a) 1% to 12% by volume of oil comprising squalene; and

(b) 0.02% to 2.5% by weight of an emulsifying agent comprising polyoxyethylenesorbitan monooleate;

wherein said oil and said emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are less than 1 micron in diameter and wherein said composition exists in the absence of any polyoxypropylene-polyoxyethylene block copolymer; and

(2) an antigenic substance, wherein said antigenic substance is one or more antigenic substances selected from the group consisting of an antigenic substance from a virus, an antigenic substance from a bacterium and an antigenic substance from a parasite, wherein said adjuvant composition is capable of increasing the immune response to the antigenic substance, and further wherein said antigenic substance is present in the external phase of the adjuvant composition.

59. The composition of claim 58 wherein the antigenic substance comprises a viral subunit.

60. The composition of claim 59 wherein the antigenic substance is from a virus selected from the group consisting of hepatitis C virus (HCV), herpes simplex virus (HSV), human immunodeficiency virus (HIV), cytomegalovirus (CMV), influenza virus (flu), poliovirus, and rabies virus.

61. The composition of claim 60 wherein the antigenic substance is from herpes simplex virus (HSV).

62. The composition of claim 61 wherein the antigenic substance comprises HSV glycoprotein gD.

63. The composition of claim 59 wherein the antigenic substance is from human immunodeficiency virus (HIV).

64. The composition of claim 63 wherein the antigenic substance comprises HIV glycoprotein gp120.

65. The composition of claim 59 wherein the antigenic substance is from influenza virus.

66. The composition of claim 65 wherein the antigenic substance comprises an influenza HA antigen.

67. The composition of claim 58 wherein the antigenic substance is from a bacterium.

68. The composition of claim 67 wherein the bacterium is selected from the group consisting of cholera, diphtheria, tetanus, and pertussis.

69. The composition of claim 58 wherein the antigenic substance is from a parasite.

70. The composition of claim 69 wherein the parasite comprises a malaria parasite.

71. The composition of claim 58 wherein the antigenic substance is used to immunize against meningitis.

72. The composition of claim 58 wherein the antigenic substance is selected from the group consisting of a protein, protein-polysaccharide, protein-lipopolysaccharide, polysaccharide, and lipopolysaccharide.

73. The composition of claim 58 wherein the antigenic substance comprises a hapten.

74. The composition of claim 58 further comprising an additional immunostimulatory agent.

75. The composition of claim 74 wherein the additional immunostimulatory agent is a muramyl peptide.

76. The composition of claim 58, wherein said oil-in-water emulsion has oil droplets substantially all of which are less than 0.8 micron in diameter.

77. The composition of claim 58, wherein said oil-in-water emulsion has oil droplets substantially all of which are less than 0.6 micron in diameter.

78. The composition of claim 58, wherein said oil-in-water emulsion has oil droplets substantially all of which are 100 nm to 750 nm in diameter.

79. The composition of claim 78, wherein said oil-in-water emulsion has oil droplets substantially all of which are 100 nm to 750 nm in diameter.

80. The composition of claim 58, wherein squalene is present in the immunogenic composition in an amount of 1% to 4% by volume and the polyoxyethylenesorbitan monooleate is present in the immunogenic composition in an amount of about 1% by weight.

81. The composition of claim 79, wherein the squalene is present in an amount of about 2.5% by volume.

82. An immunogenic composition comprising:

(1) an adjuvant composition comprising;

(a) 1% to 12% by volume of oil comprising squalene; and

(b) 0.02% to 2.5% by weight of an emulsifying agent comprising polyoxyethylenesorbitan monooleate;

wherein said oil and said emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are less than 0.6 micron in diameter and wherein said composition exists in the absence of any polyoxypropylene-polyoxyethylene block copolymer; and

(2) an influenza HA antigen, wherein said adjuvant composition is capable of increasing the immune response to the influenza HA antigen, and further wherein said antigenic substance is present in the external phase of the adjuvant composition.

85. The composition of claim 82, wherein the influenza antigen comprises HA from two A strains and one B strain.

87. The composition of claim 82, wherein the adjuvant composition includes a phosphate buffer.

89. The composition of claim 87, wherein the phosphate buffer has a pH between 6.0-8.0.

83. A composition comprising:

(1) an immunostimulating amount of an adjuvant composition comprising;

(a) 1-12% by volume of squalene; and

(b) an emulsifying agent consisting essentially of polyoxyethylenesorbitan monooleate and sorbitan trioleate, wherein the total amount of polyoxyethylenesorbitan monooleate and sorbitan trioleate present is 0.02-2.5% by weight (w/w);

wherein said squalene and said emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are less than 1 micron in diameter and wherein said composition exists in the absence of any polyoxypropylene-polyoxyethylene block copolymer; and

(2) an antigenic substance, wherein said antigenic substance is one or more antigenic substances selected from the group consisting of an antigenic substance from a virus, an antigenic substance from a bacterium and an antigenic substance from a parasite, wherein said adjuvant composition is capable of increasing the immune response to the antigenic substance, and further wherein said antigenic substance is present in the external phase of the adjuvant composition.

84. A composition produced by the method comprising:

mixing (1) an immunostimulating amount of an oil-in-water emulsion adjuvant composition comprising;

(a) 4-5% by volume of squalene; and

(b) 0.02-2.5% by weight of an emulsifying agent consisting essentially of polyoxyethylenesorbitan monooleate, wherein the oil-in-water emulsion has droplets substantially all of which are less than 0.5 micron in diameter, and wherein said composition exists in the absence of any polyoxypropylene-polyoxyethylene block copolymer; and

(2) an influenza antigen.

86. The composition of claim 84, wherein the influenza antigen comprises HA from two A strains and one B strain.

88. The composition of claim 84, wherein the adjuvant composition includes a phosphate buffer.

90. The composition of claim 88, wherein the phosphate buffer has a pH between 6.0-8.0.

91. A composition comprising:

(1) an adjuvant composition comprising;

(a) 1-12% by volume of squalene; and

(b) an emulsifying agent comprising a sorbitan fatty acid ether, wherein the total amount of sorbitan fatty acid ether present is 0.02-2.5% by weight (w/w);

wherein said squalene and said emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets substantially all of which are less than 0.5 microns in diameter and wherein said composition exists in the absence of any polyoxypropylene-polyoxyethylene block copolymer; and

(2) an antigenic substance, wherein said antigenic substance is one or more antigenic substances selected from the group consisting of an antigenic substance from a virus, an antigenic substance from a bacterium and an antigenic substance from a parasite, wherein said adjuvant composition is capable of increasing the immune response to the antigenic substance, and further wherein said antigenic substance is present in the external phase of the adjuvant composition.

92. The composition of claim 91, wherein the sorbitan fatty acid ether is selected from the group consisting of:

sorbitan monolaurate, sorbitan monopalmitate, sorbitan monoestearate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate.

93. The composition of claim 92, wherein the antigenic substance is an influenza antigen.

96. The composition of claim 92, further comprising mannitol.

94. A composition produced by the method comprising:

mixing (1) an oil-in-water emulsion adjuvant composition comprising;

(a) 4-5% by volume of squalene; and

(b) 0.02-2.5% by weight of an emulsifying agent comprising a sorbitan fatty acid ether, wherein the oil-in-water emulsion has droplets substantially all of which are less than 0.5 microns in diameter, and wherein said emulsion exists in the absence of any polyoxypropylene-polyoxyethylene block copolymer; and

(2) an influenza antigen.

95. The composition of claim 94, wherein the sorbitan fatty acid ether is selected from the group consisting of:

sorbitan monolaurate, sorbitan monopalmitate, sorbitan monoestearate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate.