Claims
- 1. A method for preparing a polysaccharide for non-invasive delivery, comprising:
neutralizing a polysaccharide, to thereby prepare the polysaccharide for non-invasive delivery.
- 2. The method of claim 1, further comprising reducing the mass of the polysaccharide.
- 3. The method of claim 1, further comprising determining a chemical signature for the polysaccharide, and neutralizing the polysaccharide based upon its chemical signature.
- 4. The method of claim 3, further comprising reducing the mass of the polysaccharide based upon its chemical signature.
- 5. The method of claim 1, wherein the net negative or net positive charge of the polysaccharide is reduced by at least 30% or more.
- 6. The method of claim 1, wherein the polysaccharide is neutralized such that there is a net negative and net positive charge of 0.
- 7. The method of claim 3, wherein the polysaccharide is neutralized by digesting the polypeptide with at least one agent which cleaves the polysaccharide at known locations in the polysaccharide based upon it chemical signature.
- 8. The method of claim 7, wherein the agent is an enzyme.
- 9. The method of claim 8, wherein the enzyme is a heparin lyase.
- 10. The method of claim 9, wherein the heparin lyase is selected from the group consisting of heparinase I, heparinase II, heparinase III, heparinase IV, heparanase, and functionally active fragments and variants thereof.
- 11. The method of claim 7, wherein the agent is a chemical.
- 12. The method of claim 11, wherein the chemical is selected from group consisting of oxidative depolymerization with H2O2 or Cu+ and H2O2, deaminative cleavage with isoamyl nitrite, or nitrous acid, and 1-eliminative cleavage with benzyl ester of heparin by alkaline treatment.
- 13. The method of claim 1, wherein the polysaccharide is neutralized by contacting the polysaccharide with a charge neutralizing agent.
- 14. The method of claim 13, wherein the charge neutralizing agent is a counter ion.
- 15. The method of claim 14, wherein the counterion is selected from the group consisting of barium, calcium, sodium, potassium, lithium, ammonium, magnesium, and zinc.
- 16. The method of claim 13, wherein the charge neutralizing agent is a transition metal.
- 17. The method of claim 16, wherein the transition metal is selected from the group consisting of iron, nickel and copper.
- 18. The method of claim 13, wherein the charge neutralizing agent is selected from the group consisting of a small organic compound, spermine, spermidine, low molecular weight protamine, and a basic peptide.
- 19. The method of claim 1, wherein the polysaccharide is a HLGAG.
- 20. The method of claim 1, further comprising creating particles of the polysaccharide.
- 21. The method of claim 20, wherein the particles have a mean geometric diameter of about 1-500 microns.
- 22. The method of claim 1, further comprising formulating the polysaccharide with a delivery enhancer.
- 23. The method of claim 22, wherein the delivery enhancer is selected from the group consisting of a surfactant, an absorption enhancer, and a polymer.
- 24. A method for preparing a heparin, for non-invasive in vivo delivery, comprising:
neutralizing a heparin, to thereby prepare the heparin for non-invasive in vivo delivery.
- 25. The method of claim 24, further comprising reducing mass of the heparin.
- 26. The method of claim 24, wherein the heparin to be neutralized is unfractionated heparin, fractioned heparin or a synthetic pentasaccharide.
- 27. The method of claim 26, wherein the fractionated heparin is LMWH.
- 28. The method of claim 27 wherein the LMWH is selected from the group consisting of enoxaparin, dalteparin, reviparin, tinzaparin, nadroparin, certoparin, ardeparin, and parnaparin.
- 29. The method of claim 26, further comprising determining a chemical signature for heparin and neutralizing the heparin based upon its chemical signature.
- 30. The method of claim 29, further comprising reducing the mass of the heparin based upon its chemical signature.
- 31. The method of claim 29, wherein the net negative charge of the heparin is reduced by at least 30% or more.
- 32. The method of claim 29, wherein the heparin is neutralized such that there is a total net charge of 0.
- 33. The method of claim 29, wherein the heparin is neutralized by digesting the heparin with at least one agent selected based upon the chemical signature of the heparin.
- 34. The method of claim 33, wherein the heparin is neutralized such that at least one biological activity of the heparin is maintained or enhanced.
- 35. The method of claim 34, wherein the activity is anti-Xa activity, anti-IIa activity, protamine neutralization, FGF-2 binding activity, platelet factor 4 binding activity or other measures of HIT propensity, or combinations thereof.
- 36. The method of claim 33 or 34, wherein the agent is an enzyme.
- 37. The methods of claim 36, wherein the enzyme is a heparin lyase.
- 38. The method of claim 37, wherein the heparin lyase is selected from the group consisting of heparinase I, heparinase II, heparinase III, heparinase IV, heparanase, and functionally active fragments and variants thereof.
- 39. The method of claim 33 or 34, wherein the agent is a chemical.
- 40. The method of claim 39, wherein the chemical is selected from the group consisting of oxidative depolymerization with H2O2 or Cu+ and H2O2, deaminative cleavage with isoamyl nitrite, or nitrous acid, and β-eliminative cleavage with benzyl ester of heparin by alkaline treatment.
- 41. The method of claim 29, wherein the heparin is neutralized by contacting the heparin with a charge neutralizing agent.
- 42. The method of claim 41, wherein the charge neutralizing agent is a counter ion such as mono- or divalent ion.
- 43. The method of claim 42, wherein the counterion is selected from the group consisting of barium, calcium, sodium, potassium, lithium, ammonium, and magnesium.
- 44. The method of claim 41, wherein the charge neutralizing agent is a transition metal.
- 45. The method of claim 44, wherein the transition metal is selected from the group consisting of iron, nickel, zinc and copper.
- 46. The method of claim 41, wherein the charge neutralizing agent is a small organic compound, spermine, spermidine, low molecular weight protamine, or a basic peptide.
- 47. The method of claim 30, wherein the heparin is derived from enoxaparin and the enoxaparin is neutralized and the mass reduced such that the heparin has a charge to mass ratio that is less than 19.32/4200.
- 48. The method of claim 30, wherein the heparin is derived from nadroparin and the nadroparin is neutralized and the mass reduced such that the heparin has a charge to mass ratio that is less than 27.6/6000.
- 49. The method of claim 30, wherein the heparin is derived from dalteparin and the dalteparin is neutralized and the mass reduced such that the heparin has a charge to mass ratio that is less than 23/6000.
- 50. The method of claim 30, wherein the heparin is derived from reviparin and the reviparin is neutralized and the mass reduced such that the heparin has a charge to mass ratio that is less than 25.3/5500.
- 51. The method of claim 30, wherein the heparin is derived from parnaparin and the parnaparin is neutralized and the mass reduced such that the heparin has a charge to mass ratio that is less than 30.4/6610.
- 52. The method of claim 30, wherein the heparin is derived from tinzaparin and the tinzaparin is neutralized and the mass reduced such that the heparin has a charge to mass ratio that is less than 28.06/6100.
- 53. The method of claim 30, wherein the heparin is derived from enoxaparin and the net charge of the heparin is less than about 18.
- 54. The method of claim 30, wherein the heparin is derived from dalteparin and the net charge of the heparin is less than about 21.
- 55. The method of claim 30, wherein the heparin is derived from nadroparin and the net charge of the heparin is less than about 26.
- 56. The method of claim 30, wherein the heparin is derived from reviparin and the net charge of the heparin is less than about 24.
- 57. The method of claim 30, wherein the heparin is derived from parnaparin and the net charge of the heparin is less than about 29.
- 58. The method of claim 30, wherein the heparin is derived from tinzaparin and the net charge of the heparin is less than about 27.
- 59. The method of claim 24, wherein the heparin is prepared for a non-invasive delivery selected from the group consisting of: pulmonary delivery, transdermal delivery and mucosal delivery.
- 60. A method for preparing a polysaccharide for non-invasive in vivo delivery, comprising:
providing a polysaccharide; determining a chemical signature for the polysaccharide; and reducing the mass of the polysaccharide based upon its chemical signature, to thereby prepare the polysaccharide for non-invasive in vivo delivery.
- 61. The method of claim 60, wherein the mass of the polysaccharide is reduced such that at least one or more activity of the polysaccharide is at least partially maintained.
- 62. The method of claim 60, wherein the mass of the polysaccharide is reduced such that at least one activity of the polysaccharide is at least partially maintained and at least one other activity of the polysaccharide is reduced.
- 63. The method of claim 60, further comprising neutralizing the polysaccharide.
- 64. The method of claim 60, wherein the mass of the polysaccharide is reduced at least 20% from the mass of the provided polysaccharide.
- 65. The method of claim 60, wherein the mass of the polysaccharide is reduced by at least 100 Da or more from the mass of the provided polysaccharide.
- 66. The method of claim 63, wherein the net negative or net positive charge of the polysaccharide is reduced by at least 30% or more.
- 67. The method of claim 63, wherein the polysaccharide is neutralized such that there is a net negative and net positive charge of 0.
- 68. The method of claim 60, wherein the mass of the provided polysaccharide is reduced by digesting the polypeptide with at least one agent selected based upon the chemical signature of the polysaccharide.
- 69. The method of claim 68, wherein the agent is an enzyme.
- 70. The method of claim 69, wherein the heparin is a heparin lyase.
- 71. The method of claim 70, wherein the heparin lyase is selected from the group consisting of heparinase I, heparinase II, heparinase III, heparinase IV, heparanase, and functionally active fragments and variants thereof.
- 72. The method of claim 68, wherein the agent is a chemical.
- 73. The method of claim 72, wherein the chemical is selected from group consisting of oxidative depolymerization with H2O2 or Cu+ and H2O2, deaminative cleavage with isoamyl nitrite, or nitrous acid, and β-eliminative cleavage with benzyl ester of heparin by alkaline treatment.
- 74. The method of claim 60, wherein the polysaccharide is a HLGAG.
- 75. A method for preparing a heparin for non-invasive in vivo delivery, comprising:
providing a heparin; determining a chemical signature for the heparin; and reducing the mass of the heparin based upon its chemical signature, to thereby prepare the heparin for in vivo mucosal delivery.
- 76. The method of claim 75, wherein the mass of the heparin, is reduced such that at least one or more activity of the heparin is at least partially maintained or enhanced.
- 77. The method of claim 76, wherein the activity is one or more of anti-Xa activity, anti-IIa activity, PF4 activity or other measure of HIT propensity, FGF-2 activity, protamine neutralization.
- 78. The method of claim 76, wherein the mass of the heparin is reduced such that at least one other activity of the heparin is reduced.
- 79. The method of claim 78, wherein PF4 binding or other measure of HIT propensity is reduced
- 80. The method of claim 75, further comprising neutralizing the heparin.
- 81. The method of claim 75, wherein the mass of the heparin, is reduced at least 10% from the mass of the provided heparin.
- 82. The method of claim 75, wherein the mass of the heparin is reduced by at least 100 Da or more from the mass of the provided heparin.
- 83. The method of claim 75 or 80, wherein the heparin is LMWH.
- 84. The method of claim 83, wherein the LMWH is derived enoxaparin and wherein the mass of enoxaparin is reduced such that the mass is about 4100 Da or less.
- 85. The method of claim 83, wherein the LMWH is derived from nadroparin and wherein the mass of nadroparin is reduced such that the mass is about 5900 Da or less.
- 86. The method of claim 83, wherein the LMWH is derived from dalteparin and wherein the mass of dalteparin is reduced such that the mass is about 4700 Da or less.
- 87. The method of claim 83, wherein the LMWH is derived from reviparin and wherein the mass of reviparin is reduced such that the mass is about 5400 Da or less.
- 88. The method of claim 83, wherein the LMWH is derived from parnaparin and wherein the mass of parnaparin is reduced such that the mass is about 6,500 Da or less.
- 89. The method of claim 83, wherein the LMWH is derived from tinzaparin and wherein the mass of tinzaparin is reduced such that the mass is about 6,000 Da or less.
- 90. The method of claim 80, wherein the net negative or net positive charge of the heparin is reduced by at least 10% or more.
- 91. The method of claim 80, wherein the heparin, is neutralized such that there is a net negative and net positive charge of 0.
- 92. The method of claim 75, wherein the mass of the provided heparin is reduced by digesting the heparin with at least one agent selected based upon the chemical signature of the heparin.
- 93. The method of claim 92, wherein the agent is an enzyme.
- 94. The method of claim 93, wherein the enzyme is a heparin lyase.
- 95. The method of claim 94, wherein the heparin lyase is selected from the group consisting of heparinase I, heparinase II, heparinase III, heparinase IV, heparanase, and functionally active fragments and variants thereof.
- 96. The method of claim 92, wherein the agent is a chemical.
- 97. The method of claim 96, wherein the chemical is selected from group consisting of oxidative depolymerization with H2O2 or Cu+ and H2O2, deaminative cleavage with isoamyl nitrite, or nitrous acid, and β-eliminative cleavage with benzyl ester of heparin by alkaline treatment.
- 98. The method of claim 83, wherein the LMWH is derived from enoxaparin or unfractionated heparin and the enoxaparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 19.32/4200.
- 99. The method of claim 83, wherein the LMWH is derived from nadroparin or unfractionated heparin and the nadroparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 27.6/6000.
- 100. The method of claim 83, wherein the LMWH is derived from dalteparin or unfractionated heparin and the dalteparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 23/5000.
- 101. The method of claim 83, wherein the LMWH is derived from reviparin or unfractionated heparin and the reviparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 25.3/5500.
- 102. The method of claim 83, wherein the LMWH is derived from parnaparin or unfractionated heparin and the parnaparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 30.4/6610.
- 103. The method of claim 83, wherein the LMWH is derived from tinzaparin or unfractionated heparin and the tinzaparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 28.06/6100.
- 104. The method of claim 75, wherein the heparin is prepared for non-invasive delivery selected from the group consisting of pulmonary delivery, transdermal delivery and mucosal delivery.
- 105. A polysaccharide composition for non-invasive in vivo delivery made by the method of claim 1 or 24.
- 106. A composition for oral delivery of a heparin wherein the heparin has a net negative charge which is less than a reference net charge for the heparin.
- 107. The composition of claim 106, wherein the heparin has a mass which is less than a reference mass for heparin.
- 108. The composition of claim 106 or 107, wherein the heparin is a LMWH.
- 109. The composition of claim 108, wherein the reference net charge is the net charge of enoxaparin.
- 110. The composition of claim 109, wherein the net charge of the LMWH is at least 30% less than the net charge of enoxaparin.
- 111. The composition of claim 110, wherein the net charge of the LMWH is less than 18.
- 112. The composition of claim 107, wherein the reference mass is the mass of enoxaparin and the mass of the LMWH is at least 30 Da less than the mass of enoxaparin.
- 113. The composition of claim 112, wherein the mass of the LMWH is about 4100 Da or less.
- 114. The composition of claim 106, wherein the heparin is in a dry particle formulation.
- 115. The method of claim 114, wherein the dry particle has a mean geometric diameter of at least 5 microns or more.
- 116. The composition of claim 106, wherein the heparin is in an aqueous formulation.
- 117. The composition of claim 106, further comprising a charge neutralization agent.
- 118. A composition for pulmonary delivery of a heparin, comprising a heparin and a charge neutralizing agent, wherein the heparin has a net negative charge which is less than a reference net charge for the heparin.
- 119. The composition of claim 118, wherein the heparin has a mass which is less than a reference mass for heparin.
- 120. The composition of claim 118 or 119, wherein the heparin is a LMWH.
- 121. The composition of claim 120, wherein the reference net charge is the net charge of enoxaparin.
- 122. The composition of claim 121, wherein the net charge of the LMWH is at least 30% less than the net charge of enoxaparin.
- 123. The composition of claim 121, wherein the net charge of the LMWH is less than 18.
- 124. The composition of claim 119, wherein the reference mass is the mass of enoxaparin and the mass of the LMWH is at least 30 Da less than the mass of enoxaparin.
- 125. The composition of claim 118, wherein the heparin is in a dry particle formulation.
- 126. The composition of claim 118, wherein the heparin is in an aqueous formulation.
- 127. The composition of claim 117 or claim 118, wherein the charge neutralization agent is a counter ion.
- 128. The composition of claim 127, wherein the counter ion is selected from the group consisting of barium, calcium, sodium, potassium, lithium, ammonium, magnesium, zinc).
- 129. The composition of claim 117 or claim 118, wherein the charge neutralizing agent is a transition metal.
- 130. The composition of claim 129, wherein the transition metal is selected from the group consisting of iron, nickel, and copper.
- 131. The composition of claim 117 or claim 118, wherein the charge neutralizing agent is selected from the group consisting of spermine, spermidine, low molecular weight protamine, and a basic peptide.
- 132. The composition of claim 106 or claim 118, wherein the composition further comprises an active agent.
- 133. The composition of claim 132, wherein the active agent and the heparin are distinct.
- 134. The composition of claim 106 or claim 118, wherein the heparin is a carrier and an active agent.
- 135. The composition of claim 106 or claim 118, further comprising a delivery enhancer.
- 136. A composition for mucosal delivery comprising M405.
- 137. A composition for mucosal delivery comprising M108.
- 138. A method for delivering a sulfonated polysaccharide to a subject, comprising:
orally administering to a subject a sulfonated polysaccharide in a therapeutically effective amount, to thereby deliver to polysaccharide to the subject.
- 139. The method of claim 138, wherein the sulfonated polysaccharide is heparin.
- 140. The method of claim 139, wherein the heparin is a unfractionated heparin or a fractioned heparin.
- 141. The method of claim 140, wherein the heparin is a fractioned heparin, and the fractioned heparin is a LMWH.
- 142. The method of claim 141, wherein the LMWH is selected from the group consisting of enoxaparin, dalteparin, reviparin, tinzaparin, nadroparin, certoparin, ardeparin, parnaparin, M118, M312, M405, M108, M115, and M411.
- 143. A method for in vivo delivery of a polysaccharide to a subject, comprising:
administering to a subject a therapeutically effective amount of a composition made by the method of claim 1 or 24, to thereby deliver the polysaccharide to the subject.
- 144. A method for oral delivery of heparin to a subject, comprising:
orally administering therapeutically effective amount of a heparin, to a subject, wherein the heparin has a net negative charge which is less than a reference net charge for the heparin, to thereby delivery the heparin to the subject.
- 145. The method of claim 144, wherein the heparin is a LMWH.
- 146. The method of claim 145, wherein the reference net charge is the net charge of enoxaparin.
- 147. The method of claim 145, wherein the net charge of the LMWH is at least 30% less than the net charge of enoxaparin.
- 148. The method of claim 145, wherein the net charge of the LMWH is less than 18.
- 149. The method of claim 144, wherein the heparin further has a mass which less than a reference mass for the heparin.
- 150. The method of claim 149, wherein the heparin is a LMWH.
- 151. The method of claim 150, wherein the reference mass for the LMWH is selected from the group consisting of the mass of enoxaparin, the mass of nadroparin, the mass of dalteparin, the mass of reviparin, the mass of parnaparin, and the mass of tinzaparin.
- 152. The method of claim 151, wherein the mass of the LMWH is less than at least 30 Da than the mass of enoxaparin.
- 153. The method of claim 151, wherein the mass of the LMWH is less than at least 30 Da than the mass of nadroparin.
- 154. The method of claim 151, wherein the mass of the LMWH is less than at least 30 Da than the mass of dalteparin.
- 155. The method of claim 151, wherein the mass of the LMWH is less than at least 30 Da than the mass of reviparin.
- 156. The method of claim 151, wherein the mass of the LMWH is less than at least-30 Da than the mass of parnaparin.
- 157. The method of claim 151, wherein the mass of the LMWH is less than at least 30 Da than the mass of tinzaparin.
- 158. The method of claim 151, wherein the mass of the LMWH is about 4100 Da or less.
- 159. The method of claim 150, wherein the LMWH is derived from enoxaparin or unfractionated heparin and the enoxaparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 19.32/4200.
- 160. The method of claim 150, wherein the LMWH is derived from nadroparin or unfractionated heparin and the nadroparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 27.6/6000.
- 161. The method of claim 150, wherein the LMWH is derived from dalteparin or unfractionated heparin and the dalteparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 23/5000.
- 162. The method of claim 150, wherein the LMWH is derived from reviparin or unfractionated heparin and the reviparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 25.3/5500.
- 163. The method of claim 150, wherein the LMWH is derived from parnaparin or unfractionated heparin and the parnaparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 30.4/6610.
- 164. The method of claim 150, wherein the LMWH is derived from tinzaparin or unfractionated heparin and the tinzaparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 28.06/6100.
- 165. The method of claim 158, wherein the therapeutically effective amount of the LMWH is about 2 mg/kg or more.
- 166. The method of claim 158, wherein the LMWH has an absorption rate in the gastrointestinal tract of about 0.25 IU/ml or more over a period of about 1-5 hours.
- 167. The method of claim 158, wherein the at least 5% or more of the LMWH is delivered to the intestinal mucosa.
- 168. The method of claim 158, wherein the LMWH is delivered to the intestinal mucosa in an amount effective to produce a peak plasma concentration of the LWMH within 2 to 7 hours after delivery.
- 169. The method of claim 158, wherein 10% or more of the LMWH is detectable in the blood within about 2 to 7 hours after delivery.
- 170. The method of claim 158, wherein the bioavailability of the LMWH is at least about 10% or more.
- 171. A method for delivering M405 to a subject, comprising:
orally administering to a subject a composition comprising M405 in an effective amount to deliver a therapeutic dose of M405 to the subject, thereby delivering M405 to the subject.
- 172. A method for delivering M108 to a subject, comprising:
orally administering to a subject a composition comprising M108 in an effective amount to deliver a therapeutic dose of M108 to the subject, thereby delivering M108 to the subject.
- 173. A method for pulmonary delivery of heparin to a subject, comprising:
administering a therapeutically effective amount of a heparin to pulmonary tissue of a subject, wherein the heparin has a net negative charge which is less than a reference net charge for the heparin, to thereby delivery the heparin to the subject.
- 174. The method of claim 173, wherein the heparin is a LMWH.
- 175. The method of claim 174, wherein the reference net charge is the net charge of enoxaparin.
- 176. The method of claim 175, wherein the net charge of the LMWH is at least 30% less than the net charge of enoxaparin.
- 177. The method of claim 176, wherein the net charge of the LMWH is less than 18.
- 178. The method of claim 173, wherein the heparin further has a mass which less than a reference mass for the heparin.
- 179. The method of claim 178, wherein the heparin is a LMWH.
- 180. The method of 179, wherein the reference mass for the LMWH is the mass of enoxaparin.
- 181. The method of claim 180, wherein the mass of the LMWH is less than at least 30 Da than the mass of enoxaparin.
- 182. The method of claim 179, wherein the reference mass is selected from the group consisting of the mass of nadroparin, the mass of dalteparin, the mass of reviparin, the mass of parnaparin, and the mass of tinzaparin.
- 183. The method of claim 182, wherein the reference mass is the mass of nadroparin and the mass of the LMWH is less than at least 30 Da than the mass of nadroparin.
- 184. The method of claim 182, wherein the reference mass is the mass of dalteparin and the mass of the LMWH is less than at least 30 Da than the mass of dalteparin.
- 185. The method of claim 182, wherein the reference mass is the mass of reviparin and the mass of the LMWH is less than at least 30 Da than the mass of reviparin.
- 186. The method of claim 182, wherein the reference mass is the mass of parnaparin and the mass of the LMWH is less than at least 30 Da than the mass of parnaparin.
- 187. The method of claim 182, wherein the reference mass is the mass of tinzaparin and the mass of the LMWH is less than at least 30 Da than the mass of tinzaparin.
- 188. The method of claim 180, wherein the mass of the LMWH is about 4100 Da or less.
- 189. The method of claim 180, wherein the LMWH is derived from enoxaparin or unfractionated heparin and the enoxaparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 19.32/4200.
- 190. The method of claim 180, wherein the LMWH is derived from nadroparin or unfractionated heparin and the nadroparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 27.6/6000.
- 191. The method of claim 180, wherein the LMWH is derived from dalteparin or unfractionated heparin and the dalteparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 23/5000.
- 192. The method of claim 180, wherein the LMWH is derived from reviparin or unfractionated heparin and the reviparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 25.3/5500.
- 193. The method of claim 180, wherein the LMWH is derived from parnaparin or unfractionated heparin and the parnaparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 30.4/6610.
- 194. The method of claim 180, wherein the LMWH is derived from tinzaparin or unfractionated heparin and the tinzaparin or unfractionated heparin is neutralized and the mass reduced such that the LMWH has a charge to mass ratio of less than 28.06/6100.
- 195. The method of claim 174, wherein the LMWH has an absorption rate in the pulmonary tissue of about 0.25 IU/ml or more over a period of about 10 minutes to 5 hours.
- 196. The method of claim 174, wherein the at least 5% or more of the LMWH is delivered to the pulmonary tissue.
- 197. The method of claim 196, wherein at least 2% or more of the LMWH is delivered to the deep lung.
- 198. The method of claim 174, wherein the LMWH is delivered to the pulmonary tissue in an amount effective to produce a peak plasma concentration of the LWMH within 10 minutes to 3 hours after delivery.
- 199. The method of claim 174, wherein 2% or more of the LMWH is detectable in the blood within about 5 minutes to 5 hours after delivery.
- 200. The method of claim 174, wherein the therapeutically effective amount is at least 20 mg/puff.
- 201. The method of any of claims 138-200, wherein the subject has or is at risk of a disorder selected from the group consisting of disease associated with coagulation, such as thrombosis, cardiovascular disease, vascular conditions or atrial fibrillation; migraine, atherosclerosis; an inflammatory disorder, such as autoimmune disease or atopic disorders; an allergy; a respiratory disorder, such as asthma, emphysema, adult respiratory distress syndrome (ARDS), cystic fibrosis, or lung reperfusion injury; a cancer or metastatic disorder; an angiogenic disorder, such as neovascular disorders of the eye, osteoporosis, psoriasis, arthritis, Alzheimer's, or is undergoing or having undergone surgical procedure, organ transplant, orthopedic surgery, hip replacement, knee replacement, treatment for a fracture, e.g., a hip fracture, percutaneous coronary intervention (PCI), stent placement, angioplasty, coronary artery bypass graft surgery (CABG).
- 202. A method for delivery of an HLGAG to the pulmonary system of a subject, comprising:
administering a therapeutically effective amount of an HLGAG to pulmonary tissue of a subject to provide a preselected effect in the subject wherein the dose of the HLGAG is at least 2 times greater than a subcutaneous or intravenous dose of the HLGAG which is effective to give the preselected therapeutic effect.
- 203. The method of claim 202, wherein the HLGAG is a synthetic HLGAG.
- 204. The method of claim 203, wherein the synthetic HLGAG is a synthetic pentasaccharide.
- 205. The method of claim 204, wherein the synthetic pentasaccharide is Arixtra.
- 206. The method of claim 202, wherein the preselected therapeutic effect is one or more of: anti-Xa activity and anti-IIa activity.
- 207. The method of claim 202, wherein the HLGAG is in a device which provides a therapeutically effective unit dose of the HLGAG.
- 208. The method of claim 207, wherein the HLGAG is a synthetic HLGAG and the therapeutically effective unit dose is about 0.06 mg/kg or more.
- 209. The method of claim 207, wherein the HLGAG is a synthetic HLGAG and the therapeutically effective unit dose is about 8 mg or more.
- 210. The method of claim 208 or 209, wherein the synthetic HLGAG is Arixtra or a derivative thereof.
- 211. The method of claim 208 or 209, wherein the synthetic HLGAG is one or more of the compounds provided in FIG. 9 and derivatives thereof.
- 212. The method of claim 207, wherein the HLGAG is a synthetic HLGAG and the therapeutically effective unit dose is amount effective to produce a peak plasma concentration of the HLGAG within about 5 minutes to about 5 hours after delivery.
- 213. The method of claim 212, wherein the synthetic HLGAG is Arixtra or a derivative thereof.
- 214. The methods of claim 202, wherein the HLGAG is in the form of a solid.
- 215. The method of claim 202, wherein the HLGAG has an absorption rate in the pulmonary tissue of at least about 0.25 IU/ml or more over a period of about 10 minutes to 5 hours.
- 216. The method of claim 215, wherein the HLGAG is a synthetic HLGAG.
- 217. The method of claim 216, wherein the synthetic HLGAG is Arixtra or derivatives thereof.
- 218. The method of claim 202, wherein at least 5% or more of the HLGAG is delivered to the upper and/or lower respiratory tract of the lung.
- 219. The method of claim 218, wherein the HLGAG is a synthetic HLGAG.
- 220. The method of claim 219, wherein the synthetic HLGAG is Arixtra or a derivative thereof.
- 221. The method of claim 202, wherein the HLGAG is in a composition and the composition further comprises a pharmaceutically acceptable carrier.
- 222. The method of claim 221, wherein the composition further comprises a delivery enhancer.
- 223. The method of claim 202, wherein the subject has or is at risk of a disorder selected from the group consisting of disease associated with coagulation, such as thrombosis, cardiovascular disease, vascular conditions or atrial fibrillation; migraine, atherosclerosis; an inflammatory disorder, such as autoimmune disease or atopic disorders;
an allergy; a respiratory disorder, such as asthma, emphysema, adult respiratory distress syndrome (ARDS), cystic fibrosis, or lung reperfusion injury; a cancer or metastatic disorder; an angiogenic disorder, a cardiovascular disorder, diabetes, obesity, osteoporosis, psoriasis, arthritis, Alzheimer's, a subject to undergo, undergoing or having undergone surgical procedure, organ transplant, orthopedic surgery, treatment for a fracture, e.g., a hip fracture, hip replacement, knee replacement, percutaneous coronary intervention (PCI), stent placement, angioplasty, and coronary artery bypass graft surgery (CABG).
- 224. A composition for pulmonary delivery, wherein the composition comprises a therapeutically effective amount of a synthetic HLGAG to provide a preselected effect, wherein the composition is in a device which delivers the HLGAG at a unit dose which is at least 2 times greater than the unit dose used for subcutaneous or intravenous delivery of the HLGAG to provide the preselected effect.
- 225. The composition of 224, wherein the preselected therapeutic effect is one or more of anti-Xa activity and anti-IIa activity.
- 226. The composition of claim 224, wherein the unit dose of the HLGAG to provide the preselected therapeutic effect is at least about 0.05 mg/kg.
- 227. The composition of claim 224, wherein unit dose of the HLGAG to provide the preselected therapeutic effect is at least about 16 mg.
- 228. The composition of claim 226 or 227, wherein the synthetic HLGAG is Arixtra or a derivative thereof.
- 229. The composition of claim 226 or 227, wherein the synthetic HLGAG is one or more of the synthetic HLGAGs of FIG. 9 and derivatives thereof.
- 230. The composition of claim 228, wherein the preselected therapeutic effect is one or more of anti-Xa activity and anti-IIa activity.
- 231. The composition of claim 229, wherein the preselected therapeutic effect is one or more of anti-Xa activity and anti-IIa activity.
- 232. The composition of claim 224, further comprising a surfactant.
- 233. A pressurized container or dispenser comprising the composition of claim 224, 230 or 231.
- 234. The pressurized container or dispenser of claim 233, wherein the pressurized container or dispenser comprises one or more of a suitable propellant and a nebulizer.
Parent Case Info
[0001] This application claims priority to U.S. Provisional Patent Application Serial Nos. 60/375,927, filed Apr. 25, 2002; 60/375,970, filed Apr. 25, 2002; 60/383,926, filed May 28, 2002; 60/393,959, filed Jul. 23, 2002; and 60/446,432, filed Feb. 10, 2003, the entire contents of which are hereby incorporated by reference.
Provisional Applications (5)
|
Number |
Date |
Country |
|
60375927 |
Apr 2002 |
US |
|
60375970 |
Apr 2002 |
US |
|
60383926 |
May 2002 |
US |
|
60393959 |
Jul 2002 |
US |
|
60446432 |
Feb 2003 |
US |