Treatment and prevention of pulmonary conditions

• US 20050070477A1
• Filed: 10/22/2004
• Published: 03/31/2005
• Est. Priority Date: 04/25/2002
• Status: Active Grant

• Current Assignee: The Scripps Research Institute
• Original Assignee: The Scripps Research Institute
• Inventors: Cochrane, Charles G.
• Granted Patent: US 7,863,241 B2
• Time in Patent Office: Days
• US Class Current: 514/1.500
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/57 from animals; from humans A61K38/553, A61K38/556 take precedence
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07K 14/785 Alveolar surfactant peptides; Pulmonary surfactant peptides
• CPC Class Codes: C07K 14/8107 Endopeptidase (E.C. 3.4.21-99) inhibitors

Abstract

The invention provides compositions and methods for treating pulmonary conditions and for reducing the negative effects of pulmonary inflammation. Such compositions and methods employ protease inhibitors and a lung surfactant mixture. The compositions and methods can also include lipase inhibitors (e.g. a phospholipase inhibitors) and anti-oxidants.

Claims

1. A liquid composition comprising a lung surfactant polypeptide, and at least one inhibitor of a mediator of tissue destruction.

2. The liquid composition of claim 1, wherein the inhibitor is at least one protease inhibitor.

3. The liquid composition of claim 2, wherein the protease inhibitor is an inhibitor of trypsin, chymotrypsin, elastase, kallikrein, plasmin, coagulation factor XIa, coagulation factor IXa, cathepsin G, human leukocyte elastase or human secretory leukocyte protease.

4. The liquid composition of claim 2, wherein the protease inhibitor is a human leukocyte elastase inhibitor, alpha 1-proteinase inhibitor, alpha1-antitrypsin, alpha-1-antichymotrypsin, bikunin, C-reactive protein or a combination thereof.

5. The liquid composition of claim 2, wherein the protease inhibitor is elafin.

6. The liquid composition of claim 2, wherein the protease inhibitor is a human secretory leukocyte protease inhibitor.

7. The liquid composition of claim 2, wherein the protease inhibitor comprises a polypeptide comprising SEQ ID NO:

14, SEQ ID NO;

15, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NO;

18, SEQ ID NO;

19, SEQ ID NO;

20, SEQ ID NO;

21, SEQ ID NO;

22 or SEQ ID NO;

23.

8. The liquid composition of claim 1, wherein the lung surfactant polypeptide comprises a polypeptide having between 10-60 amino acid residues and an amino acid sequence of alternating hydrophobic and hydrophilic amino acid residue regions represented by the formula (Z_aU_b)_cZ_d,

wherein Z is a hydrophilic amino acid residue, U is a hydrophobic amino acid residue, a is an integer with an average value of 1-5, b is an integer with an average value of 3-20, c is an integer of about 1 to about 10, and d is an integer of about 0 to about 3.

9. The liquid composition of claim 8, wherein Z is histidine, lysine, arginine, aspartic acid, glutamic acid, 5-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, or a combination thereof.

10. The liquid composition of claim 8, wherein U is selected from the group consisting of valine, isoleucine, leucine, cysteine, tyrosine, phenylalanine, α

-aminobutanoic acid, α

-aminopentanoic acid, α

-amino-2-methylpropanoic acid, α

-aminohexanoic acid, or a combination thereof.

11. The liquid composition of claim 8, wherein U is α

-aminobutanoic acid, α

-aminopentanoic acid, α

-amino-2-methylpropanoic acid, or α

-aminohexanoic acid.

12. The liquid composition of claim 1, wherein the lung surfactant polypeptide comprises amino acid sequence:

13. The liquid composition of claim 1, wherein the lung surfactant polypeptide is KLLLLKLLLLKLLLLKLLLLK (SEQ ID NO:

1).

14. The liquid composition of claim 1, wherein the lung surfactant polypeptide comprises amino acid sequence SEQ ID NO:

25, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

28 or SEQ ID NO;

29.

15. The liquid composition of claim 1, comprising about 0.1 to 10 percent of the lung-surfactant polypeptide.

16. The liquid composition of claim 1, further comprising at least one phospholipid.

17. The liquid composition of claim 16, wherein the phospholipid comprises dipalmitoyl phosphatidylcholine and palmitoyl, oleoyl phosphatidyl glycerol, in a mole ratio of about 4:

1 to about 2;

1.

18. The liquid composition of claim 16, wherein the phospholipid comprises about 50 to about 95 dry weight percent of the composition.

19. The liquid composition of claim 1, wherein the composition further comprises a spreading agent.

20. The liquid composition of claim 19, wherein the spreading agent is a fatty acid or fatty alcohol having a fatty acyl chain length of at least 10 carbon atoms.

21. The liquid composition of claim 19, wherein the spreading agent is about 2 to about 25 dry weight percent of the composition.

22. The liquid composition of claim 19, wherein the spreading agent further includes tyloxapol.

23. The liquid composition of claim 1, wherein the inhibitor is at least one lipase inhibitor.

24. The liquid composition of claim 23, wherein the lipase inhibitor is a phospholipase A₂ inhibitor.

25. The liquid composition of claim 23, wherein the lipase inhibitor is p-bromophenacyl bromide, thielocin A1 beta, lipocortin, annexin I, Crotalus phospholipase A2 inhibitor or a combination thereof.

26. The liquid composition of claim 23 wherein the lipase inhibitor is LY311727.

27. The liquid composition of claim 1, wherein the inhibitor is at least one anti-oxidant.

28. The liquid composition of claim 27 wherein the anti-oxidant is catalase, glutathione, N-acetylcysteine, procysteine, alpha-tocopherol, rosemary leaf extract, 2,4-diaminopyrrolo-[2,3-d]pyrimidine, ascorbic acid, leutein, zeaxanthin, cryptoxanthin, violaxanthin, carotene diol, hydroxycarotene, hydroxylycopene, alloxanthin, ebselen, dehydrocryptoxanthin or a combination thereof.

29. The liquid composition of claim 1, wherein the liquid composition is administered by bronchoalveolar lavage, oral, intravenous, parenteral or bolus administration.

30. The liquid composition of claim 1, wherein the liquid composition is administered for treating or preventing pulmonary inflammation.

31. The liquid composition of claim 30, wherein the pulmonary inflammation is associated with pulmonary hypertension, neonatal pulmonary hypertension, neonatal bronchopulmonary dysplasia, chronic obstructive pulmonary disease, acute bronchitis, chronic bronchitis, emphysema, bronchiolitis, bronchiectasis, radiation pneumonitis, hypersensitivity, pneumonitis, acute inflammatory asthma, acute smoke inhalation, thermal lung injury, allergic asthma, iatrogenic asthma, cystic fibrosis, alveolar proteinosis, alpha-1-protease deficiency, pulmonary inflammatory disorders, pneumonia, acute respiratory distress syndrome, acute lung injury, idiopathic respiratory distress syndrome, or idiopathic pulmonary fibrosis.

32. An aerosolized composition, comprising a lung surfactant polypeptide, and at least one inhibitor of a mediator of tissue destruction.

33. The aerosolized composition of claim 32, wherein the inhibitor is at least one protease inhibitor.

34. The aerosolized composition of claim 33, wherein the protease inhibitor is an inhibitor of trypsin, chymotrypsin, elastase, kallikrein, plasmin, coagulation factor XIa, coagulation factor IXa, cathepsin G, human leukocyte elastase or human secretory leukocyte protease.

35. The aerosolized composition of claim 33, wherein the protease inhibitor is a human leukocyte elastase inhibitor, an alpha 1-proteinase inhibitor, alpha1-antitrypsin, alpha-1-antichymotrypsin, bikunin, C-reactive protein or a combination thereof.

36. The aerosolized composition of claim 33, wherein the protease inhibitor is elafin.

37. The aerosolized composition of claim 33, wherein the protease inhibitor is a human secretory leukocyte protease inhibitor.

38. The aerosolized composition of claim 33, wherein the protease inhibitor comprises a polypeptide comprising SEQ ID NO:

14, SEQ ID NO;

15, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NO;

18, SEQ ID NO;

19, SEQ ID NO;

20, SEQ ID NO;

21, SEQ ID NO;

22 or SEQ ID NO;

23.

39. The aerosolized composition of claim 32, wherein the lung surfactant polypeptide comprises a polypeptide having between 10-60 amino acid residues and an amino acid sequence of alternating hydrophobic and hydrophilic amino acid residue regions represented by the formula (Z_aU_b)_cZ_d,

wherein Z is a hydrophilic amino acid residue, U is a hydrophobic amino acid residue, a is an integer with an average value of 1-5, b is an integer with an average value of 3-20, c is an integer of about 1 to about 10, and d is an integer of about 0 to about 3.

40. The aerosolized composition of claim 39, wherein Z is histidine, lysine, arginine, aspartic acid, glutamic acid, 5-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline or a combination thereof.

41. The aerosolized composition of claim 39, wherein U is valine, isoleucine, leucine, cysteine, tyrosine, phenylalanine, α

-aminobutanoic acid, α

-aminopentanoic acid, α

-amino-2-methylpropanoic acid, α

-aminohexanoic acid or a combination thereof.

42. The aerosolized composition of claim 39, wherein U is α

-aminobutanoic acid, α

-aminopentanoic acid, α

-amino-2-methylpropanoic acid, α

-aminohexanoic acid or a combination thereof.

43. The aerosolized composition of claim 32, comprising about 0.1 to 10 percent of the lung-surfactant polypeptide.

44. The aerosolized composition of claim 32, wherein the lung surfactant polypeptide comprises amino acid sequence:

45. The aerosolized composition of claim 32, wherein the lung surfactant polypeptide is KLLLLKLLLLKLLLLKLLLLK (SEQ ID NO:

1).

46. The aerosolized composition of claim 32, wherein the lung surfactant polypeptide comprises amino acid sequence SEQ ID NO:

25, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

28 or SEQ ID NO;

29.

47. The aerosolized composition of claim 32, further comprising at least one phospholipid.

48. The aerosolized composition of claim 47, wherein the composition comprises about 50 to about 95 dry weight percent phospholipids.

49. The aerosolized composition of claim 47 or 48, wherein the phospholipid comprises dipalmitoyl phosphatidylcholine and palmitoyl, oleoyl phosphatidyl glycerol, in a mole ratio of about 4:

1 to about 2;

1.

50. The aerosolized composition of claim 32, further comprising a spreading agent.

51. The aerosolized composition of claim 32, further comprising about 2 to about 25 dry weight percent of a spreading agent.

52. The aerosolized composition of claim 50 or 51, wherein the spreading agent is a fatty acid or fatty alcohol having a fatty acyl chain length of at least 10 carbon atoms.

53. The aerosolized composition of claim 50 or 51, wherein the spreading agent further includes tyloxapol.

54. The aerosolized composition of claim 32, wherein the inhibitor is at least one lipase inhibitor.

55. The aerosolized composition of claim 54, wherein the lipase inhibitor is a phospholipase A₂ inhibitor.

56. The aerosolized composition of claim 54, wherein the lipase inhibitor is p-bromophenacyl bromide, thielocin A1 beta, lipocortin, annexin I or Crotalus phospholipase A2 inhibitor.

57. The aerosolized composition of claim 54, wherein the lipase inhibitor is LY311727.

58. The aerosolized composition of claim 32, wherein the inhibitor is at least one anti-oxidant.

59. The aerosolized composition of claim 58, wherein the anti-oxidant is catalase, glutathione, N-acetylcysteine, procysteine, alpha-tocopherol, rosemary leaf extract, 2,4-diaminopyrrolo-[2,3-d]pyrimidine, ascorbic acid, leutein, zeaxanthin, cryptoxanthin, violaxanthin, carotene diol, hydroxycarotene, hydroxylycopene, alloxanthin, ebselen or dehydrocryptoxanthin.

60. The aerosolized composition of claim 32, wherein the composition is a liquid composition.

61. The aerosolized composition of claim 32, wherein the composition is a dry composition.

62. The aerosolized composition of claim 32, wherein the composition comprises aerosol particles having a mass median aerodynamic diameter of about 1 μ

m to about 51m.

63. The aerosolized composition of claim 32, wherein the composition is formulated for treatment of asthma.

64. A method for treating pulmonary inflammation in a mammal comprising administering to the mammal a therapeutically effective amount of a composition comprising a lung surfactant polypeptide, and at least one inhibitor of a mediator of tissue destruction.

65. The method of claim 64, wherein the pulmonary inflammation is associated with pulmonary hypertension, neonatal pulmonary hypertension, neonatal bronchopulmonary dysplasia, chronic obstructive pulmonary disease, acute bronchitis, chronic bronchitis, emphysema, bronchiolitis, bronchiectasis, radiation pneumonitis, hypersensitivity, pneumonitis, acute inflammatory asthma, acute smoke inhalation, thermal lung injury, allergic asthma, iatrogenic asthma, cystic fibrosis, alveolar proteinosis, alpha-1-protease deficiency, pulmonary inflammatory disorders, pneumonia, acute respiratory distress syndrome, acute lung injury, idiopathic respiratory distress syndrome, or idiopathic pulmonary fibrosis.

66. The method of claim 64, wherein the inhibitor is at least one protease inhibitor.

67. The method of claim 66, wherein the protease inhibitor is an inhibitor of trypsin, chymotrypsin, elastase, kallikrein, plasmin, coagulation factor XIa, coagulation factor IXa, cathepsin G, human leukocyte elastase or human secretory leukocyte protease.

68. The method of claim 66, wherein the protease inhibitor is a human leukocyte elastase inhibitor, an alpha 1-proteinase inhibitor, alpha 1-antitrypsin, alpha-1-antichymotrypsin, bikunin, C-reactive protein or a combination thereof.

69. The method of claim 66, wherein the protease inhibitor is elafin.

70. The method of claim 66, wherein the protease inhibitor is a human secretory leukocyte protease inhibitor.

71. The method of claim 66, wherein the protease inhibitor comprises a polypeptide comprising SEQ ID NO:

14, SEQ ID NO;

15, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NO;

18, SEQ ID NO;

19, SEQ ID NO;

20, SEQ ID NO;

21, SEQ ID NO;

22 or SEQ ID NO;

23.

72. The method of claim 64, wherein the inhibitor is at least one lipase inhibitor.

73. The method of claim 72, wherein the lipase inhibitor is a phospholipase A₂ inhibitor.

74. The method of claim 72, wherein the lipase inhibitor is p-bromophenacyl bromide, thielocin A1 beta, lipocortin, annexin I or Crotalus phospholipase A2 inhibitor.

75. The method of claim 72, wherein the lipase inhibitor is LY311727.

76. The method of claim 64, wherein the inhibitor is at least one anti-oxidant.

77. The method of claim 76, wherein the anti-oxidant is catalase, glutathione, N-acetylcysteine, procysteine, alpha-tocopherol, rosemary leaf extract, 2,4-diaminopyrrolo-[2,3-d]pyrimidine, ascorbic acid, leutein, zeaxanthin, cryptoxanthin, violaxanthin, carotene diol, hydroxycarotene, hydroxylycopene, alloxanthin, ebselen, or dehydrocryptoxanthin.

78. The method of claim 64, wherein the composition is administered parenterally, orally or intravenously.

79. The method of claim 64, wherein the composition is administered by bronchoalveolar lavage, inhalation or liquid bolus administration to the lungs.

80. The method of claim 64, wherein the lung surfactant polypeptide comprises between 10-60 amino acid residues and an amino acid sequence of alternating hydrophobic and hydrophilic amino acid residue regions represented by the formula (Z_aU_b)_cZ_d,

wherein Z is a hydrophilic amino acid residue, U is a hydrophobic amino acid residue, a is an integer with an average value of 1-5, b is an integer with an average value of 3-20, c is an integer of about 1 to about 10, and d is an integer of about 0 to about 3.

81. The method of claim 80, wherein the composition comprises about 0.1 to 10 dry weight percent of the lung-surfactant polypeptide.

82. The method of claim 80, wherein Z is histidine, lysine, arginine, aspartic acid, glutamic acid, 5-hydroxylysine, 4-hydroxyproline or 3-hydroxyproline.

83. The method of claim 80, wherein U is valine, isoleucine, leucine, cysteine, tyrosine, phenylalanine, α

-aminobutanoic acid, α

-aminopentanoic acid, α

-amino-2-methylpropanoic acid, or α

-aminohexanoic acid.

84. The method of claim 80, wherein U is α

-aminobutanoic acid, α

-aminopentanoic acid, α

-amino-2-methylpropanoic acid, or aminohexanoic acid.

85. The method of claim 64, wherein the lung surfactant polypeptide comprises amino acid sequence:

86. The method of claim 64, wherein the lung surfactant polypeptide is KLLLLKLLLLKLLLLKLLLLK (SEQ ID NO:

1).

87. The method of claim 64, wherein the lung surfactant polypeptide comprises amino acid sequence SEQ ID NO:

25, SEQ ID NO;

26, SEQ ID NO;

27, SEQ ID NO;

28 or SEQ ID NO;

29.

88. The method of claim 64, wherein the composition further comprises a phospholipid.

89. The method of claim 64, wherein the composition further comprises about 50 to about 95 dry weight percent phospholipids.

90. The method of claim 88 or 89, wherein the phospholipid comprises dipalmitoyl phosphatidylcholine and palmitoyl, oleoyl phosphatidyl glycerol, in a mole ratio of about 4:

1 to about 2;

1.

91. The method of claim 64, wherein the composition further comprises about 2 to about 25 dry weight percent of a spreading agent.

92. The method of claim 91, wherein the spreading agent is a fatty acid or fatty alcohol having a fatty acyl chain length of at least 10 carbon atoms.

93. The method of claim 91, wherein the spreading agent further includes tyloxapol.

94. A composition for pulmonary delivery of an active agent to a patient, comprising a lung surfactant mixture and an active agent, wherein:

the lung surfactant mixture comprises a polypeptide having between 10-60 amino acid residues and an amino acid sequence of alternating hydrophobic and hydrophilic amino acid residue regions represented by the formula (Z_aU_b)_cZ_d,

wherein Z is a hydrophilic amino acid residue, U is a hydrophobic amino acid residue, a is an integer with an average value of 1-5, b is an integer with an average value of 3-20, c is an integer of about 1 to about 10, and d is an integer of about 0 to about 3.

95. The composition of claim 94, wherein the lung surfactant mixture comprises 50-95 dry weight percent phospholipid, 2-25 dry weight percent spreading agent, and 0.1-10 dry weight percent of the lung surfactant polypeptide.

96. The composition claim 95, wherein the phospholipid includes a mixture of dipalmitoyl phosphatidylcholine (DPPC) and palmitoyl-oleyl phosphatidyl glycerol (POPG) in a mole ratio of between 4:

1 to 2;

1.

98. The composition of claim 94, wherein the polypeptide comprises amino acid sequence:

99. The composition of claim 94, wherein the active agent is a protease inhibitor.

100. The composition of claim 99, wherein the protease inhibitor is an inhibitor of trypsin, chymotrypsin, elastase, kallikrein, plasmin, coagulation factor XIa, coagulation factor IXa, cathepsin G, human leukocyte elastase or human secretory leukocyte protease.

101. The composition of claim 99, wherein the protease inhibitor is a human leukocyte elastase inhibitor, an alpha 1-proteinase inhibitor, alpha1-antitrypsin, alpha-1-antichymotrypsin, bikunin, C-reactive protein or a combination thereof.

102. The composition of claim 99, wherein the protease inhibitor is elafin.

103. The composition of claim 99, wherein the protease inhibitor is a human secretory leukocyte protease inhibitor.

104. The composition of claim 99, wherein the protease inhibitor comprises a polypeptide comprising SEQ ID NO:

14, SEQ ID NO;

15, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NO;

18, SEQ ID NO;

19, SEQ ID NO;

20, SEQ ID NO;

21, SEQ ID NO;

22 or SEQ ID NO;

23.

105. The composition of claim 94, wherein the active agent is a lipase inhibitor.

106. The composition of claim 105, wherein the lipase inhibitor is a phospholipase A₂ inhibitor.

107. The composition of claim 105, wherein the lipase inhibitor is p-bromophenacyl bromide, thielocin A1 beta, lipocortin, annexin I or Crotalus phospholipase A2 inhibitor.

108. The composition of claim 105, wherein the lipase inhibitor is LY311727.

109. The composition of claim 94, wherein the active agent is an anti-oxidant.

110. The composition of claim 109, wherein the anti-oxidant is catalase, glutathione, N-acetylcysteine, procysteine, alpha-tocopherol, rosemary leaf extract, 2,4-diaminopyrrolo-[2,3-d]pyrimidine, ascorbic acid, leutein, zeaxanthin, cryptoxanthin, violaxanthin, carotene diol, hydroxycarotene, hydroxylycopene, alloxanthin, ebselen or dehydrocryptoxanthin.

111. The composition of claim 94, wherein the composition is a liquid composition.

112. The composition of claim 111, wherein the liquid composition is formulated for bolus or bronchoalveolar lavage administration.

113. The composition of claim 94, wherein the composition is a dry composition.

114. The composition of claim 94, wherein the composition is an aerosol composition.

97. The composition of claini 95, wherein the spreading agent is a fatty acid or fatty alcohol having a fatty acyl chain length of at least 12 carbon atoms.

115. An aerosolized composition for use in delivering an active agent to a patient via inhalation, comprising:

aerosol particles of a surfactant formulation, said particles having a mass median aerodynamic diameter in the 1-5 μ

m size range, said formulation being composed of (a) surfactant mixture containing (i) 50-95 dry weight percent phospholipid, (ii) 2-25 dry weight percent of a spreading agent effective to promote incorporation of the phospholipid into the surface lining layer of the lung, and (iii) 0.1 to 10 dry weight percent of lung-surfactant polypeptide having between 10-60 amino acid residues and an amino acid sequence of alternating hydrophobic and hydrophilic amino acid residue regions represented by the formula (Z_aU_b)_cZ_d, where Z is a hydrophilic amino acid residue, U is a hydrophobic amino acid residue, a has an average value of 1-5, b has an average value of 3-20, c is 1-110, and d is 0 to 3, and (b) the active agent, in an amount between 1 and 80 weight percent of the dry weight of the surfactant formulation.

116. The composition of claim 115, wherein the lung surfactant mixture comprises 80-90 dry weight percent phospholipid, 10-15 dry weight percent spreading agent, and 0.1-10 dry weight percent of the lung surfactant polypeptide.

117. The composition claim 116, wherein the phospholipid includes a mixture of dipalmitoyl phosphatidylcholine (DPPC) and palmitoyl-oleyl phosphatidyl glycerol (POPG) in a mole ratio of between 4:

1 to 2;

1.

118. The composition of claim 116, wherein the spreading agent is a fatty acid or fatty alcohol having a fatty acyl chain length of at least 12 carbon atoms.

119. The composition of claim 115, wherein the lung-surfactant polypeptide comprises amino acid sequence:

120. The composition of claim 115, wherein the active agent is a protease inhibitor.

121. The composition of claim 120, wherein the protease inhibitor is an inhibitor of trypsin, chymotrypsin, elastase, kallikrein, plasmin, coagulation factor XIa, coagulation factor IXa, cathepsin G, human leukocyte elastase or human secretory leukocyte protease.

122. The composition of claim 120, wherein the protease inhibitor is a human leukocyte elastase inhibitor, an alpha 1-proteinase inhibitor, alpha1-antitrypsin, alpha-1-antichymotrypsin, bikunin, C-reactive protein or a combination thereof.

123. The composition of claim 120, wherein the protease inhibitor is elafin.

124. The composition of claim 120, wherein the protease inhibitor is a human secretory leukocyte protease inhibitor.

125. The composition of claim 120, wherein the protease inhibitor comprises a polypeptide comprising SEQ ID NO:

14, SEQ ID NO;

15, SEQ ID NO;

16, SEQ ID NO;

17, SEQ ID NO;

18, SEQ ID NO;

19, SEQ ID NO;

20, SEQ ID NO;

21, SEQ ID NO;

22 or SEQ ID NO;

23.

126. The composition of claim 115, wherein the active agent is a lipase inhibitor.

127. The composition of claim 126, wherein the lipase inhibitor is a phospholipase A₂ inhibitor.

128. The composition of claim 126, wherein the lipase inhibitor is p-bromophenacyl bromide, thielocin A1 beta, lipocortin, annexin I or Crotalus phospholipase A2 inhibitor.

129. The composition of claim 126, wherein the lipase inhibitor is LY311727.

130. The composition of claim 115, wherein the active agent is an anti-oxidant.

131. The composition of claim 130, wherein the anti-oxidant is catalase, glutathione, N-acetylcysteine, procysteine, alpha-tocopherol, rosemary leaf extract, 2,4-diaminopyrrolo-[2,3-d]pyrimidine, ascorbic acid, leutein, zeaxanthin, cryptoxanthin, violaxanthin, carotene diol, hydroxycarotene, hydroxylycopene, alloxanthin, ebselen or dehydrocryptoxanthin.