Details for Patent: 6,069,135
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| Title: | Use of hyaluronic acid or its derivatives to enhance delivery of therapeutic agents |
| Abstract: | A pharmaceutical composition is provided comprising: (1) an agent selected from a medicinal agent and a therapeutic agent and combinations thereof in a therapeutically effective amount to treat a disease or condition in humans who will benefit from the treatment with the agent; and (2) hyaluronic acid and/or pharmaceutically acceptable salts thereof and/or fragments, and subunits of hyaluronic acid, characterized in that said composition (a) is in a dosage form which is suitable for administration in humans; and (b) is in a form in which (i) component (1) is in an effective dosage amount to treat said disease or condition by penetration at the site to be treated; and (ii) component (2) is immediately available to transport component (1) at the site to be treated, and which component (2) is in an effective non-toxic amount to facilitate the transport of component (1) upon administration, through the tissue including scar tissue, at the site to be treated and through the cell membranes or the individual cells to be treated, wherein said amount of component (2) is sufficient to provide a dosage greater than 10 mg/70 kg person of component (2). |
| Inventor(s): | Falk; Rudolf Edgar (Toronto, CA), Asculai; Samuel S. (Toronto, CA) |
| Assignee: | Hyal Pharmaceutical Corporation (Mississauga, CA) |
| Filing Date: | Jul 03, 1991 |
| Application Number: | 07/675,908 |
| Claims: | 1. In a method of treating a condition or disease involving underperfused or pathological tissue by administering a therapeutically useful agent to a patient, the improvement which comprises additionally administering an amount of a form of hyaluronic acid selected from the group consisting of hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid and combinations thereof, wherein the amount is between 10 mg and 3000 mg and is sufficient to facilitate passage of the agent and the form of hyaluronic acid to the underperfused or pathological tissue, and wherein the molecular weight of the form of hyaluronic acid is less than 750,000 daltons but greater than 150,000 daltons. 2. The method of claim 1 wherein the amount of the form of hyaluronic acid is between 10 mg and 1000 mg. 3. The method of claim 1 or 2 wherein the agent is selected from the group consisting of free radical scavengers, ascorbic acid (Vitamin C), anti-cancer drugs, chemotherapeutic drugs, anti-viral drugs, non-steroidal anti-inflammatory drugs (NSAID), steroidal anti-inflammatory drugs, anti-fungal drugs, detoxifying drugs, analgesics, bronchodilators, anti-bacterial drugs, antibiotic drugs for treatment of vascular ischemia, monoclonal antibodies, diuretics, immunosuppressants, lymphokines, .alpha. or .beta. interferon, insulin, estrogen, progestogen, anti-metabolites, calcium channel blockers, drugs for treatment of psoriasis and combinations thereof. 4. The method of claim 1 or 2 wherein the agent is selected from the group consisting of ascorbic acid, an anti-cancer drug, a non-steroidal anti-inflammatory drug, an antibiotic drug, a diuretic drug and combinations thereof. 5. The method of claim 1 or 2 wherein the agent is an anti-cancer drug. 6. The method of claim 1 or 2 wherein the agent is an anti-viral drug. 7. The method of claim 1 or 2 wherein the agent is an anti-fungal drug. 8. The method of claim 1 or 2 wherein the agent is an analgesic drug. 9. The method of claim 1 or 2 wherein the agent is a bronchodilator drug. 10. The method of claim 1 or 2 wherein the agent is an anti-bacterial drug. 11. The method of claim 1 or 2 wherein the agent is an antibiotic drug. 12. The method of claim 1 or 2 wherein the agent is an anti-inflammatory drug. 13. The method of claim 1 or 2 wherein the agent is a monoclonal antibody. 14. The method of claim 1 or 2 wherein the agent is an immunosuppressant drug. 15. The method of claim 1 or 2 wherein the agent is a lymphokine. 16. The method of claim 15 wherein the lymphokine is interleukin-2. 17. The method of claim 1 or 2 wherein the agent is interferon. 18. The method of claim 1 or 2 wherein the agent is ascorbic acid (Vitamin C). 19. The method of claim 1 or 2 wherein the agent is a free radical scavenger. 20. The method of claim 1 or 2 wherein the agent is a chemothereapeutic drug. 21. The method of claim 1 or 2 wherein the agent is a non-ionic surfactant drug. 22. The method of claim 1 or 2 wherein the agent is a non-steroidal anti-inflammatory drug (NSAID). 23. The method of claim 1 or 2 wherein the agent is a steroidal anti-inflammatory drug. 24. The method of claim 1 or 2 wherein the agent is a detoxifying drug. 25. The method of claim 1 or 2 wherein the agent is a diuretic drug. 26. The method of claim 21 wherein the non-ionic surfactant is nonoxynol-9. 27. The method of claim 21 wherein the non-ionic surfactant further comprises an ether or an amide linkage between the hydrophilic and hydrophobic portions of the surfactant. 28. The method of claim 22 wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of indomethacin, naproxen and ketorolac tromethamine salt and combinations thereof. 29. The method of claim 25 wherein the diuretic is furosemide. 30. The method of claim 1 or 2 wherein the method of administration is carried out intravenously, subcutaneously, intramuscularly or intratumourly. 31. The method of claim 1 or 2 wherein the method of administration is carried out topically. 32. The method of claim 1 or 2 wherein the disease or condition is selected from the group consisting of a neoplastic condition, acne, AIDS, Berger's disease, a condition requiring bronchodilation, canker sore, chronic bacterial infection, fungal infection, diabetes, viral disease, epitheloid sarcoma, herpes, shingles, hypertension, infection, inflammation, malfunctioning kidney, renal failure, kyphosis, leomyosarcoma, leukemia, mesothelioma, metastatic disease, mononucleosis, pain, psoriasis, vascular ischemia and cardiac insufficiency, wherein the agent is a pharmaceutical composition comprising a medicinal or therapeutic drug suitable for treating pathological or underperfused tissue, together with a pharmaceutically acceptable excipient. 33. The method of claim 1 or 2 wherein the disease or condition is a neoplastic condition. 34. The method of claim 1 or 2 wherein the disease or condition is acne and wherein the agent is selected from the group consisting of antibiotics, antibacterials, antimicrobials and ascorbic acid. 35. The method of claim 1 or 2 wherein the disease or condition is AIDS and wherein the agent is selected from the group consisting of Vitamin C, an NSAID, interferon, doxcycline or tetracycline. 36. The method of claim 35 wherein the NSAID is selected from the group consisting of indomethacin, naproxen, ketorolac tromethamine salt and diclofenac. 37. The method of claim 1 or 2 wherein the disease or condition is Berger's disease. 38. The method of claim 1 or 2 wherein the disease or condition is a condition requiring bronchodilation and wherein the agent is a bronchodilator drug. 39. The method of claim 38 wherein the bronchodilator is beclomethasone dipropionate. 40. The method of claim 1 or 2 wherein the disease or condition is a canker sore and wherein the agent is a surfactant selected from the group consisting of non-ionic surfactants, ionic surfactants and cationic surfactants. 41. The method of claim 40 wherein the surfactant is selected from the group consisting of nonoxynol-9, cetyl pyridinium chloride and benzalkonium chloride. 42. The method of claim 1 or 2 wherein the disease or condition is chronic bacterial infection and wherein the agent is selected from the group consisting of antibiotics, antibacterials, antimicrobials and ascorbic acid. 43. The method of claim 1 or 2 wherein the disease or condition is a fungal infection and wherein the agent is selected from the group consisting of antibiotics, antibacterials, antimicrobials and ascorbic acid. 44. The method of claim 1 or 2 wherein the disease or condition is diabetes and wherein the agent is insulin. 45. The method of claim 1 or 2 wherein the disease or condition is viral disease. 46. The method of claim 1 or 2 wherein the disease or condition is epitheloid sarcoma. 47. The method of claim 1 or 2 wherein the disease or condition is herpes and wherein the agent is a surfactant selected from the group consisting of nonoxynol-9, cetyl pyridinium chloride and benzalkonium chloride. 48. The method of claim 1 or 2 wherein the disease or condition is shingles and wherein the agent is a surfactant selected from the group consisting of nonoxynol-9, cetyl pyridinium chloride and benzalkonium chloride. 49. The method of claim 1 or 2 wherein the disease or condition is hypertension and wherein the agent is furosemide. 50. The method of claim 1 or 2 wherein the disease or condition is an infection at the site of an implant. 51. The method of claim 1 or 2 wherein the disease or condition is an infection and wherein the agent is selected from the group consisting of antibiotics, antibacterials, antimicrobials and ascorbic acid. 52. The method of claim 1 or 2 wherein the disease or condition is inflammation and wherein the agent is selected from the group consisting of non-steroidal anti-inflammatory drugs. 53. The method of claim 1 or 2 wherein the disease or condition is malfunctioning kidney or renal failure and wherein the agent is furosemide. 54. The method of claim 1 or 2 wherein the disease or condition is kyphosis. 55. The method of claim 1 or 2 wherein the disease or condition is leomyosarcoma. 56. The method of claim 1 or 2 wherein the disease or condition is leukemia. 57. The method of claim 1 or 2 wherein the disease or condition is mesothelioma. 58. The method of claim 1 or 2 wherein the disease or condition is metastatic disease. 59. The method of claim 1 or 2 wherein the disease or condition is mononucleosis and wherein the agent is selected from the group consisting of antibiotics, antibacterials, antimicrobials and ascorbic acid. 60. The method of claim 1 or 2 wherein the disease or condition is pain and wherein the agent is a non-steroidal anti-inflammatory drug (NSAID). 61. The method of claim 1 or 2 wherein the agent is selected from estrogen replacement drugs. 62. The method of claim 1 or 2 wherein the disease or condition is psoriasis. 63. The method of claim 1 or 2 wherein the disease or condition is vascular ischemia. 64. The method of claim 1 or 2 wherein the disease or condition is cardiac insufficiency and wherein the agent is selected from the group consisting of a diuretic drug and a calcium channel blocker drug. 65. The method of claim 1 wherein the amount of the form of hyaluronic acid is between 50 mg and 350 mg. 66. A method of treating a disease or condition involving underperfused or pathological tissue, comprising administering to a patient a therapeutically effective amount of an agent for treating the underperfused or pathological tissue, together with an amount of a form of hyaluronic acid selected from the group consisting of hyaluronic acid, a pharmaceutically acceptable salt of hyaluronic acid and combinations thereof, wherein the amount is between 10 mg and 3000 mg and is sufficient to facilitate passage of the agent and the form of hyaluronic acid to the underperfused or pathological tissue, and wherein the molecular weight of the form of hyaluronic acid is less than 750,000 daltons but greater than 150,000 daltons. 67. The method of claim 66 wherein the amount of the form of hyaluronic acid is between 10 mg and 1000 mg. 68. The method of claim 66 or 67 wherein the agent is selected from the group consisting of free radical scavengers, ascorbic acid (Vitamin C), anti-cancer drugs, chemotherapeutic drugs, anti-viral drugs, non-steroidal anti-inflammatory drugs (NSAID), steroidal anti-inflammatory drugs, anti-fungal drugs, detoxifying drugs, analgesics, bronchodilators, anti-bacterial drugs, antibiotic drugs for treatment of vascular ischemia, monoclonal antibodies, diuretics, immunosuppressants, lymphokines, .alpha. or .beta. interferon, insulin, estrogen, progestogen, anti-metabolites, calcium channel blockers, drugs for treatment of psoriasis and combinations thereof. 69. The method of claim 66 or 67 wherein the agent is selected from the group consisting of ascorbic acid, an anti-cancer drug, a non-steroidal anti-inflammatory drug, an antibiotic drug, a diuretic drug and combinations thereof. 70. The method of claim 66 or 67 wherein the agent is an anti-cancer drug. 71. The method of claim 66 or 67 wherein the agent is an anti-viral drug. 72. The method of claim 66 or 67 wherein the agent is an anti-fungal drug. 73. The method of claim 66 or 67 wherein the agent is an analgesic drug. 74. The method of claim 66 or 67 wherein the agent is a bronchodilator drug. 75. The method of claim 66 or 67 wherein the agent is an anti-bacterial drug. 76. The method of claim 66 or 67 wherein the agent is an antibiotic drug. 77. The method of claim 66 or 67 wherein the agent is an anti-inflammatory drug. 78. The method of claim 66 or 67 wherein the agent is a monoclonal antibody. 79. The method of claim 66 or 67 wherein the agent is an immunosuppressant drug. 80. The method of claim 66 or 67 wherein the agent is a lymphokine. 81. The method of claim 80 wherein the lymphokine is interleukin-2. 82. The method of claim 66 or 67 wherein the agent is interferon. 83. The method of claim 66 or 67 wherein the agent is ascorbic acid (Vitamin C). 84. The method of claim 66 or 67 wherein the agent is a free radical scavenger. 85. The method of claim 66 or 67 wherein the agent is a chemotherapeutic drug. 86. The method of claim 66 or 67 wherein the agent is a non-ionic surfactant drug. 87. The method of claim 66 or 67 wherein the agent is a non-steroidal anti-inflammatory drug (NSAID). 88. The method of claim 66 or 67 wherein the agent is a steroidal anti-inflammatory drug. 89. The method of claim 66 or 67 wherein the agent is a detoxifying drug. 90. The method of claim 66 or 67 wherein the agent is a diuretic drug. 91. The method of claim 86 wherein the non-ionic surfactant is nonoxynol-9. 92. The method of claim 86 wherein the non-ionic surfactant further comprises an ether or an amide linkage between the hydrophilic and hydrophobic portions of the surfactant. 93. The method of claim 87 wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of indomethacin, naproxen and ketorolac tromethamine salt and combinations thereof. 94. The method of claim 90 wherein the diuretic is furosemide. 95. The method of claim 66 or 67 wherein the method of administration is carried out intravenously, subcutaneously, intramuscularly or intratumourly. 96. The method of claim 66 or 67 wherein the method of administration is carried out topically. 97. The method of claim 66 or 67 wherein the disease or condition is selected from the group consisting of a neoplastic condition, acne, AIDS, Berger's disease, a condition requiring bronchodilation, canker sore, chronic bacterial infection, fungal infection, diabetes, viral disease, epitheloid sarcoma, herpes, shingles, hypertension, infection, inflammation, malfunctioning kidney, renal failure, kyphosis, leomyosarcoma, leukemia, mesothelioma, metastatic disease, mononucleosis, pain, psoriasis, vascular ischemia and cardiac insufficiency, wherein the agent is a pharmaceutical composition comprising a medicinal or therapeutic drug suitable for treating pathological or underperfused tissue, together with a pharmaceutically acceptable excipient. 98. The method of claim 66 or 67 wherein the disease or condition is a neoplastic condition. 99. The method of claim 66 or 67 wherein the disease or condition is acne and wherein the agent is selected from the group consisting of antibiotics, antibacterials, antimicrobials and ascorbic acid. 100. The method of claim 66 or 67 wherein the disease or condition is AIDS and wherein the agent is selected from the group consisting of Vitamin C, an NSAID, interferon, doxcycline or tetracycline. 101. The method of claim 100 wherein the NSAID is selected from the group consisting of indomethacin, naproxen, ketorolac tromethamine salt and diclofenac. 102. The method of claim 66 or 67 wherein the disease or condition is Berger's disease. 103. The method of claim 66 or 67 wherein the disease or condition is a condition requiring bronchodilation and wherein the agent is a bronchodilator drug. 104. The method of claim 103 wherein the bronchodilator is beclomethasone dipropionate. 105. The method of claim 66 or 67 wherein the disease or condition is a canker sore and wherein the agent is a surfactant selected from the group consisting of non-ionic surfactants, ionic surfactants and cationic surfactants. 106. The method of claim 105 wherein the surfactant is selected from the group consisting of nonoxynol-9, cetyl pyridinium chloride and benzalkonium chloride. 107. The method of claim 66 or 67 wherein the disease or condition is chronic bacterial infection and wherein the agent is selected from the group consisting of antibiotics, antibacterials, antimicrobials and ascorbic acid. 108. The method of claim 66 or 67 wherein the disease or condition is a fungal infection and wherein the agent is selected from the group consisting of antibiotics, antibacterials, antimicrobials and ascorbic acid. 109. The method of claim 66 or 67 wherein the disease or condition is diabetes and wherein the agent is insulin. 110. The method of claim 66 or 67 wherein the disease or condition is viral disease. 111. The method of claim 66 or 67 wherein the disease or condition is epitheloid sarcoma. 112. The method of claim 66 or 67 wherein the disease or condition is herpes and wherein the agent is a surfactant selected from the group consisting of nonoxynol-9, cetyl pyridinium chloride and benzalkonium chloride. 113. The method of claim 66 or 67 wherein the disease or condition is shingles and wherein the agent is a surfactant selected from the group consisting of nonoxynol-9, cetyl pyridinium chloride and benzalkonium chloride. 114. The method of claim 66 or 67 wherein the disease or condition is hypertension and wherein the agent is furosemide. 115. The method of claim 66 or 67 wherein the disease or condition is an infection at the site of an implant. 116. The method of claim 66 or 67 wherein the disease or condition is infection and wherein the agent is selected from the group consisting of antibiotics, antibacterials, antimicrobials and ascorbic acid. 117. The method of claim 66 or 67 wherein the disease or condition is inflammation and wherein the agent is selected from the group consisting of non-steroidal anti-inflammatory drugs. 118. The method of claim 66 or 67 wherein the disease or condition is malfunctioning kidney or renal failure and wherein the agent is furosemide. 119. The method of claim 66 or 67 wherein the disease or condition is kyphosis. 120. The method of claim 66 or 67 wherein the disease or condition is leomyosarcoma. 121. The method of claim 66 or 67 wherein the disease or condition is leukemia. 122. The method of claim 66 or 67 wherein the disease or condition is mesothelioma. 123. The method of claim 66 or 67 wherein the disease or condition is metastatic disease. 124. The method of claim 66 or 67 wherein the disease or condition is mononucleosis and wherein the agent is selected from the group consisting of antibiotics, anti-bacterials, antimicrobials and ascorbic acid. 125. The method of claim 66 or 67 wherein the disease or condition is pain and wherein the agent is a non-steroidal anti-inflammatory drug (NSAID). 126. The method of claim 66 or 67 wherein the agent is selected from estrogen replacement drugs. 127. The method of claim 66 or 67 wherein the disease or condition is psoriasis. 128. The method of claim 66 or 67 wherein the disease or condition is vascular ischemia. 129. The method of claim 66 or 67 wherein the disease or condition is cardiac insufficiency and wherein the agent is selected from the group consisting of a diuretic drug and a calcium channel blocker drug. 130. The method of claim 66 wherein the amount of the form of hyaluronic acid is between 50 mg and 350 mg. 131. The method of claim 1 or 66 wherein the amount of the form of hyaluronic acid is between 200 mg and 3000 mg. 132. The method of claim 14 wherein the immunosuppressant drug is cyclosporin. 133. The method of claim 79 wherein the immunosuppressant drug is cyclosporin. 134. The method of claim 20 wherein the chemotherapeutic drug is selected from the group consisting of novantrone, methotrexate, 5-fluorouracil, carboplatinum, mitomycin C, adriamycin, bleomycin, and combination thereof. 135. The method of claim 85 wherein the chemotherapeutic drug is selected from the group consisting of novantrone, methotrexate, 5-fluorouracil, carboplatinum, mitomycin C, adriamycin, bleomycin, and combination thereof. 136. The method of claim 60 wherein the NSAID is selected from the group consisting of indomethacin, naproxen, ketorolac tromethamine salt and diclofenac. 137. The method of claim 125 wherein the NSAID is selected from the group consisting of indomethacin, naproxen, ketorolac tromethamine salt and diclofenac. 138. The method of claim 64 wherein the agent is selected from the group consisting of furosemide, nifedipine, atenolol, propranolol and acetylsalicylic acid. 139. The method of claim 129 wherein the agent is selected from the group consisting of furosemide, nifedipine, atenolol, propranolol and acetylsalicylic acid. |
