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1. WO2012092528 - TREATMENT OF ERECTILE DYSFUNCTION AND OTHER INDICATIONS

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[ EN ]

CLAIMS

A composition for topical delivery to the skin of a subject, the composition comprising: a hostile biophysical environment;

a stabilization polymer;

propylene glycol;

a polysorbate surfactant;

a phosphodiesterase type 5 inhibitor and/or a salt thereof; and, optionally, a nitric oxide donor.

The composition of claim 1, wherein each of the nitric oxide donor, the hostile biophysical environment, the xanthan gum, the propylene glycol, the polysorbate surfactant, and the phosphodiesterase type 5 inhibitor and/or salt thereof are contained within a delivery vehicle.

The composition of any one of claims 1 or 2, wherein the composition is stable when exposed to a temperature of 40 °C for at least about a day.

The composition of any one of claims 1-3, wherein the composition is stable when exposed to a temperature of 40 °C for at least about a week.

The composition of any one of claims 1-4, wherein the composition is stable when exposed to a temperature of 40 °C for at least about 4 weeks.

The composition of any one of claims 1-5, wherein the composition is a cream.

The composition of any one of claims 1-5, wherein the composition is a gel.

8. The composition of any one of claims 1-5, wherein the composition is a lotion.

The composition of any one of claims 1-5, wherein the composition is contained within a transdermal patch.

The composition of any one of claims 1-9, wherein the nitric oxide donor comprises L-arginine.

The composition of any one of claims 1-10, wherein the nitric oxide donor comprises an L-arginine salt.

The composition of any one of claims 1-11, wherein the nitric oxide donor comprises L-arginine HC1.

The composition of any one of claims 1-12, wherein the nitric oxide donor is present at a concentration of at least about 0.5% by weight of the composition.

The composition of any one of claims 1-13, wherein the nitric oxide donor is present at a concentration of at least about 5% by weight of the composition.

The composition of any one of claims 1-14, wherein the nitric oxide donor is present at a concentration of at least about 7% by weight of the composition.

The composition of any one of claims 1-15, wherein the hostile biophysical environment is capable of driving the phosphodiesterase type 5 inhibitor and/or salt thereof through stratum corneum.

The composition of any one of claims 1-16, wherein the hostile biophysical environment comprises an ionic salt.

The composition of claim 17, wherein the ionic salt is present at a concentration of at least about 5% by weight of the composition.

19. The composition of any one of claims 17 or 18, wherein the ionic salt is present at a concentration of at least about 7% by weight of the composition.

20. The composition of any one of claims 17-19, wherein the ionic salt is present at a

concentration of at least about 10% by weight of the composition.

21. The composition of any one of claims 1-20, wherein the hostile biophysical environment comprises choline chloride.

22. The composition of any one of claims 1-21, wherein the hostile biophysical environment comprises magnesium chloride.

23. The composition of claim 22, wherein the magnesium chloride is present at a

concentration of between about 0.1% and about 5% by weight of the composition.

The composition of any one of claims 1-23, wherein the hostile biophysical environment comprises calcium chloride.

The composition of any one of claims 1-24, wherein the hostile biophysical environment has an ionic strength of at least about 0.25 M.

26. The composition of any one of claims 1-25, wherein the hostile biophysical environment has an ionic strength of at least about 1 M.

27. The composition of any one of claims 1-26, wherein the composition has a pH of

between about 5 and about 9.

28. The composition of any one of claims 1-27, wherein the composition has a pH of

between about 5 and about 8.5.

29. The composition of any one of claims 1-28, wherein the hostile biophysical environment comprises a component having an octanol- water partition coefficient of at least about 1000.

30. The composition of any one of claims 1-29, wherein the hostile biophysical environment is able to cause the nitric oxide donor to migrate from the composition into the skin of a subject when the composition is applied to the subject.

31. The composition of any one of claims 1-30, wherein the subject is human.

32. The composition of any one of claims 1-31, wherein the composition further comprises a package containing the nitric oxide donor, the package being selected from the group consisting of liposomes, emulsions of collagen, collagen peptides and combinations thereof.

33. The composition of any one of claims 1-32, wherein the stabilization polymer comprises xanthan gum.

34. The composition of any one of claims 1-33, wherein the stabilization polymer comprises KELTROL® BT.

35. The composition of any one of claims 1-32, wherein the stabilization polymer consists essentially of KELTROL® BT and/or KELTROL® RD.

36. The composition of claim 35, wherein the ratio of KELTROL® BT to KELTROL® RD within the composition is 3:5.

37. The composition of any one of claims 35 or 36, wherein the KELTROL® BT is present at a concentration of about 0.3% by weight of the composition and the KELTROL® RD is present at a concentration of 0.5% by weight of the composition.

38. The composition of any one of claims 1-37, wherein the stabilization polymer is present at a concentration of at least about 0.5% by weight of the composition.

39. The composition of any one of claims 1-38, wherein the stabilization polymer is present at a concentration of at least about 0.8% by weight of the composition.

40. The composition of any one of claims 1-39, wherein the propylene glycol is present at a concentration of at least about 3% by weight of the composition.

41. The composition of any one of claims 1-40, wherein the propylene glycol is present at a concentration of at least about 5% by weight of the composition.

42. The composition of any one of claims 1-41, wherein the polysorbate surfactant comprises Polysorbate 20.

43. The composition of any one of claims 1-42, wherein the polysorbate surfactant comprises a polysorbate comprising a sorbitan monolaurate moiety.

44. The composition of any one of claims 1-43, wherein the polysorbate surfactant is present at a concentration of at least about 1% by weight of the composition.

45. The composition of any one of claims 1-44, wherein the polysorbate surfactant is present at a concentration of at least about 2% by weight of the composition.

The composition of any one of claims 1-45, wherein the polysorbate surfactant comprises a compound having a formula:


47. The composition of claim 46, wherein w+x+y+z is 20.

48. The composition of any one of claims 1-47, wherein the composition has a ratio of the stabilization polymer to propylene glycol to the polysorbate surfactant of about

1:6.25:2.5.

49. The composition of any one of claims 1-48, wherein the composition comprises a

phosphodiesterase type 5 inhibitor.

50. The composition of any one of claims 1-49, wherein the composition comprises a salt of a phosphodiesterase type 5 inhibitor.

51. The composition of claim 50, wherein the composition comprises a sodium salt of a phosphodiesterase type 5 inhibitor.

52. The composition of any one of claims 50 or 51, wherein the composition comprises a citrate salt of a phosphodiesterase type 5 inhibitor.

53. The composition of any one of claims 1-52, wherein the phosphodiesterase type 5

inhibitor is avanafil.

54. The composition of any one of claims 1-52, wherein the phosphodiesterase type 5 inhibitor is lodenafil.

55. The composition of any one of claims 1-52, wherein the phosphodiesterase type 5

inhibitor is mirodenafil.

56. The composition of any one of claims 1-52, wherein the phosphodiesterase type 5

inhibitor is sildenafil.

57. The composition of any one of claims 1-52, wherein the phosphodiesterase type 5

inhibitor is tadalafil.

58. The composition of any one of claims 1-52, wherein the phosphodiesterase type 5

inhibitor is vardenafil.

59. The composition of any one of claims 1-52, wherein the phosphodiesterase type 5

inhibitor is udenafil.

60. The composition of any one of claims 1-52, wherein the phosphodiesterase type 5

inhibitor is acetildenafil.

61. The composition of any one of claims 1-52, wherein the phosphodiesterase type 5

inhibitor is thiomethisosildenafil.

62. The composition of any one of claims 1-61, wherein the a phosphodiesterase type 5

inhibitor and/or salt thereof is present at a concentration of at least about 1 % by weight of the composition.

63. The composition of any one of claims 1-62, wherein the a phosphodiesterase type 5

inhibitor and/or salt thereof is present at a concentration of at least about 5% by weight of the composition.

The composition of any one of claims 1-63, wherein the a phosphodiesterase type 5 inhibitor and/or salt thereof is present at a concentration of at least about 7% by weight of the composition.

The composition of any one of claims 1-64, wherein the a phosphodiesterase type 5 inhibitor and/or salt thereof is present at a concentration of between about 1% and about 10% by weight of the composition.

A method, comprising applying the composition of any one of claims 1-65 to a subject.

A composition for topical delivery to the skin of a subject, wherein at least about 80% by weight of the composition comprises:

water;

at least one chloride salt;

a stabilization polymer;

propylene glycol;

a polysorbate surfactant;

a phosphodiesterase type 5 inhibitor and/or a salt thereof; and optionally, a nitric oxide donor.

The composition of claim 67, wherein the composition further comprises glyceryl stearate.

The composition of any one of claims 67 or 68, wherein the composition further comprises cetyl alcohol.

The composition of any one of claims 67-69, wherein the composition further comprises squalane.

71. The composition of any one of claims 67-70, wherein the composition further comprises isopropyl myristate.

72. The composition of any one of claims 67-71, wherein the composition further comprises oleic acid.

73. The composition of any one of claims 67-72, wherein the water is present at a

concentration of at least about 35% by weight of the composition.

74. The composition of any one of claims 67-73, wherein the water is present at a

concentration of at least about 40% by weight of the composition.

75. The composition of any one of claims 67-74, wherein the composition has a pH of

between about 5 and about 8.5.

76. The composition of any one of claims 67-75, wherein the at least one chloride salt

includes magnesium chloride.

77. The composition of claim 76, wherein the magnesium chloride is present at a

concentration of between about 0.1% and about 5% by weight of the composition.

78. The composition of any one of claims 67-77, wherein the at least one chloride salt creates a hostile biophysical environment.

79. The composition of any one of claims 67-78, wherein the at least one chloride salt

includes sodium chloride.

80. The composition of any one of claims 67-79, wherein the at least one chloride salt is present at a concentration of at least about 5% by weight of the composition.

81. The composition of any one of claims 67-80, wherein the at least one chloride salt is present at a concentration of at least about 10% by weight of the composition.

82. The composition of any one of claims 67-81, wherein the at least one chloride salt is present at a concentration of at least about 15% by weight of the composition.

83. The composition of any one of claims 67-82, wherein the nitric oxide donor comprises L- arginine.

84. The composition of any one of claims 67-83, wherein the nitric oxide donor comprises an L-arginine salt.

85. The composition of any one of claims 67-84, wherein the nitric oxide donor is present at a concentration of at least about 3% by weight of the composition.

86. The composition of any one of claims 67-85, wherein the nitric oxide donor is present at a concentration of at least about 7% by weight of the composition.

87. The composition of any one of claims 67-86, wherein the phosphodiesterase type 5

inhibitor and/or salt thereof is present at a concentration of at least about 1 % by weight of the composition.

88. The composition of any one of claims 67-87, wherein the a phosphodiesterase type 5 inhibitor and/or salt thereof is present at a concentration of between about 1% and about 10% by weight of the composition.

89. The composition of any one of claims 67-88, wherein the composition comprises a

phosphodiesterase type 5 inhibitor.

90. The composition of any one of claims 67-89, wherein the composition comprises a salt of a phosphodiesterase type 5 inhibitor.

91. The composition of claim 90, wherein the composition comprises a sodium salt of a phosphodiesterase type 5 inhibitor.

92. The composition of any one of claims 90 or 91, wherein the composition comprises a citrate salt of a phosphodiesterase type 5 inhibitor.

93. The composition of any one of claims 67-92, wherein the stabilization polymer consists essentially of KELTROL® BT and/or KELTROL® RD.

94. The composition of any one of claims 67-93, wherein the stabilization polymer is present at a concentration of at least about 0.5%

95. The composition of any one of claims 67-94, wherein the stabilization polymer is present at a concentration of at least about 0.8%

96. The composition of any one of claims 67-95, wherein the propylene glycol is present at a concentration of at least about 3%.

97. The composition of any one of claims 67-96, wherein the propylene glycol is present at a concentration of at least about 5%.

98. The composition of any one of claims 67-97, wherein the polysorbate surfactant is

present at a concentration of at least about 1% by weight of the composition.

99. The composition of any one of claims 67-98, wherein the polysorbate surfactant is

present at a concentration of at least about 2% by weight of the composition.

100. The composition of any one of claims 67-99, wherein the polysorbate surfactant

comprises Polysorbate 20.

101. A method, comprising applying the composition of any one of claims 67-100 to a subject.

102. A composition for topical delivery to the skin of a subject, the composition comprising:

a hostile biophysical environment;

a phosphodiesterase type 5 inhibitor and/or a salt thereof; and, optionally, a nitric oxide donor.

103. The composition of claim 102, wherein the hostile biophysical environment has an ionic strength of at least about 0.25 M.

104. The composition of any one of claims 102 or 103, wherein the hostile biophysical

environment has an ionic strength of at least about 1 M.

105. The composition of any one of claims 102-104, wherein the hostile biophysical

environment has an ionic strength of between about 0.25 M and about 15 M.

106. The composition of any one of claims 102-105, wherein the hostile biophysical

environment is capable of driving the phosphodiesterase type 5 inhibitor and/or salt thereof through stratum corneum.

107. The composition of any one of claims 102-106, wherein the hostile biophysical

environment comprises an ionic salt.

108. The composition of any one of claims 102-107, wherein the hostile biophysical

environment comprises one or more of sodium chloride, choline chloride, magnesium chloride, calcium chloride.

109. The composition of any one of claims 102-108, wherein the hostile biophysical

environment comprises magnesium chloride.

110. The composition of claim 109, wherein the magnesium chloride is present at a concentration of between about 0.1% and about 5% by weight of the composition.

The composition of any one of claims 102-110, wherein the composition has a pH of between about 5 and about 8.5.

112. The composition of any one of claims 102-111, wherein the nitric oxide donor comprises L-arginine.

113. The composition of any one of claims 102-112, wherein the nitric oxide donor is present in an amount effective to increase blood flow within the skin.

114. The composition of any one of claims 102-113, wherein the composition is a cream.

115. The composition of any one of claims 102-113, wherein the composition is a gel.

116. The composition of any one of claims 102-113, wherein the composition is a lotion.

117. The composition of any one of claims 102-116, wherein the phosphodiesterase type 5 inhibitor and/or salt thereof is present at a concentration of between about 1% and about

10% by weight of the composition.

118. A method, comprising applying the composition of any one of claims 102-117 to a

subject.

119. A method, comprising an act of:

applying, to a portion of the skin of a subject, a delivery vehicle comprising a phosphodiesterase type 5 inhibitor and/or a salt thereof in a hostile biophysical environment.

120. The method of claim 119, wherein the hostile biophysical environment has an ionic strength of at least about 1 M.

121. The method of any one of claims 119 or 120, wherein the hostile biophysical

environment has an ionic strength of between about 0.25 M and about 15 M.

122. The method of any one of claims 119-121, wherein the hostile biophysical environment is capable of driving the phosphodiesterase type 5 inhibitor and/or salt thereof through stratum corneum.

123. The method of any one of claims 119-122, wherein the hostile biophysical environment comprises an ionic salt.

124. The method of any one of claims 119-123, wherein the hostile biophysical environment comprises one or more of sodium chloride, choline chloride, magnesium chloride, calcium chloride.

125. The method of any one of claims 119-124, wherein the hostile biophysical environment comprises magnesium chloride.

126. The method of claim 125, wherein the magnesium chloride is present at a concentration of between about 0.1% and about 5% by weight of the delivery vehicle.

127. The method of any one of claims 119-126, wherein the delivery vehicle has a pH of

between about 5 and about 8.5.

128. The method of any one of claims 119-127, wherein the delivery vehicle further comprises a nitric oxide donor.

129. The method of claim 128, wherein the nitric oxide donor comprises L-arginine.

130. The method of any one of claims 128 or 129, wherein the nitric oxide donor is present in an amount effective to increase blood flow within the skin.

131. The method of any one of claims 119-130, wherein the delivery vehicle is a cream.

132. The method of any one of claims 119-130, wherein the delivery vehicle is a gel.

133. The method of any one of claims 119-130, wherein the delivery vehicle is a lotion.

134. The method of any one of claims 119-133, wherein the phosphodiesterase type 5 inhibitor and/or salt thereof is present at a concentration of between about 1% and about 10% by weight of the delivery vehicle.

135. A composition for topical delivery to the skin of a subject, the composition consisting essentially of:

water;

sodium chloride;

a nitric oxide donor;

glyceryl stearate;

cetyl alcohol;

magnesium chloride;

squalane;

a stabilization polymer;

isopropyl myristate;

oleic acid;

propylene glycol;

a polysorbate surfactant; and

a phosphodiesterase type 5 inhibitor and/or a salt thereof.

136. The composition of claim 135, wherein the water is present at a concentration of about 40.9% by weight of the composition.

137. The composition of any one of claims 135 or 136, wherein the sodium chloride is present at a concentration of about 10% by weight of the composition.

138. The composition of any one of claims 135-137, wherein the nitric oxide donor comprises L-arginine HC1.

139. The composition of any one of claims 135-138, wherein the nitric oxide donor is present at a concentration of about 7.5% by weight of the composition.

140. The composition of any one of claims 135-139, wherein the composition comprises a phosphodiesterase type 5 inhibitor.

141. The composition of any one of claims 135-140, wherein the composition comprises a sodium salt of a phosphodiesterase type 5 inhibitor.

142. The composition of any one of claims 135-141, wherein the composition comprises a citrate salt of a phosphodiesterase type 5 inhibitor.

143. The composition of any one of claims 135-142, wherein the phosphodiesterase type 5 inhibitor and/or salt thereof is present at a concentration of between about 1% and about 10% by weight of the composition.

144. The composition of any one of claims 135-143, wherein the glyceryl stearate is present at a concentration of about 7% by weight of the composition.

145. The composition of any one of claims 135-144, wherein the cetyl alcohol is present at a concentration of about 7% by weight of the composition.

146. The composition of any one of claims 135-145, wherein the magnesium chloride is present at a concentration of between about 0.1% and about 5% by weight of the composition.

147. The composition of any one of claims 135-146, wherein the squalene is present at a

concentration of about 4% by weight of the composition.

148. The composition of any one of claims 135-147, wherein the stabilization polymer

comprises xanthan gum.

149. The composition of any one of claims 135-148, wherein the stabilization polymer

consists essentially of KELTROL® BT and/or KELTROL® RD.

150. The composition of any one of claims 135-149, wherein the stabilization polymer is

present at a concentration of about 0.8% by weight of the composition.

151. The composition of any one of claims 135-150, wherein the isopropyl myristate is present at a concentration of about 1% by weight of the composition.

152. The composition of any one of claims 135-151, wherein the oleic acid is present at a concentration of about 1% by weight of the composition.

153. The composition of any one of claims 135-152, wherein the propylene glycol is present at a concentration of 5%.

154. The composition of any one of claims 135-153, wherein the polysorbate surfactant

comprises Polysorbate 20.

155. The composition of any one of claims 135-154, wherein the composition has a pH of between about 5 and about 8.5.

156. A method, comprising applying the composition of any one of claims 135-155 to a subject.

157. A composition for topical delivery to the skin of a subject, the composition comprising each of the following compounds at concentrations of no more than +20% of the stated concentrations:

water at a concentration of about 35% to about 55% by weight;

sodium chloride at a concentration of about 2.5% to about 15% by weight;

a nitric oxide donor at a concentration of about 2.5% to about 15% by weight; glyceryl stearate at a concentration of about 4% to about 10% by weight;

cetyl alcohol at a concentration of about 4% to about 10% by weight; magnesium chloride at a concentration of about 0.1% to about 5% by weight; squalane at a concentration of about 1% to about 8% by weight;

a polysorbate surfactant at a concentration of about 0.2% to about 2% by weight; isopropyl myristate at a concentration of about 0.1% to about 5% by weight;

oleic acid at a concentration of about 0.1% to about 5% by weight; propylene glycol at a concentration of about 1% to about 10% by weight;

a stabilization polymer at a concentration of about 1% to about 10% by weight; and

a phosphodiesterase type 5 inhibitor and/or a salt thereof at a concentration of about 1% to about 10% by weight.

158. The composition of claim 157, wherein the stabilization polymer comprises xanthan gum.

159. The composition of any one of claims 157 or 158, wherein the stabilization polymer

consists essentially of KELTROL® BT and/or KELTROL® RD.

160. The composition of any one of claims 157-159, wherein the polysorbate surfactant

comprises polysorbate glucose.

161. The composition of any one of claims 157-160, wherein the composition comprises the compounds recited in the claim at concentrations of no more than +10% of the stated concentrations.

162. The composition of any one of claims 157-161, wherein the composition has a pH of between about 5 and about 8.5.

163. The composition of any one of claims 157-162, wherein the phosphodiesterase type 5 inhibitor and/or salt thereof comprises sildenafil.

164. The composition of any one of claims 157-162, wherein the phosphodiesterase type 5 inhibitor and/or salt thereof comprises tadalafil.

165. The composition of any one of claims 157-162, wherein the phosphodiesterase type 5 inhibitor and/or salt thereof comprises vardenafil.

166. A method, comprising applying the composition of any one of claims 157-165 to a subject.

167. A method, comprising applying, to at least a portion of the skin of a subject, a

composition comprising:

a hostile biophysical environment;

a stabilization polymer;

propylene glycol;

a polysorbate surfactant;

a phosphodiesterase type 5 inhibitor and/or a salt thereof; and, optionally, a nitric oxide donor.

168. A composition for topical delivery to the skin of a subject, the composition comprising:

a stabilization polymer;

propylene glycol;

a polysorbate surfactant; and

a phosphodiesterase type 5 inhibitor and/or a salt thereof.

169. A composition for topical delivery to the skin of a subject, wherein at least about 80% by weight of the composition comprises:

water;

at least one chloride salt;

a stabilization polymer;

propylene glycol;

a polysorbate surfactant; and

a phosphodiesterase type 5 inhibitor and/or a salt thereof.