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1. (WO2018222874) MÉTHODES ET DISPOSITIFS POUR LE TRAITEMENT D'ALLERGIES ALIMENTAIRES
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

CLAIMS

1. A method for treating a food allergy in a subject in need thereof, comprising,

delivering an effective amount of an allergen associated with the food allergy into the subject's cutis skin layer, wherein the delivering step is carried out one or more times during an administration period, and comprises,

(i) inserting one or more solid microneedles each comprising a base, shaft and tip into the subject's skin, wherein at least one microneedle of the one or more solid microneedles does not extend beyond the cutis once inserted, and is coated with an amount of the allergen; and

(ii) allowing the allergen to dissociate from the at least one microneedle while inserted in the subject's cutis; and

(iii) removing the one or more solid microneedles from the subject's skin.

2. The method of claim 1, wherein the one or more solid microneedles extends from an adhesive substrate.

3. The method of claim 1 or claim 2, wherein the one or more solid microneedles is stainless steel.

4. The method of any one of claims 1 -3, wherein the one or more solid microneedles is present in a microneedle array comprising a plurality of microneedles extending from a common substrate.

5. The method of claim 4, wherein the microneedles of the plurality are stainless steel.

6. The method of claim 4 or claim 5, wherein the microneedles of the plurality are substantially the same length.

7. The method of claim 4 or claim 5, wherein two or more of the microneedles have different lengths.

8. The method of any one of claims 1-7, wherein the average length of the one or more microneedles is from about 100 μηι to about 1000 μιτι, as measured from the base of the tip.

9. The method of claim 8, wherein the average length of the one or more microneedles is from about 100 μηι to about 900 μιτι, or from about 100 μηι to about 800 μηι, or from about 100 μηι to about 700 μηι, or from about 100 μηι to about 600 μιτι, or from about 100 μηι to about 500 μηι.

10. The method of any one of claims 1-9, wherein the average width of the one or more microneedles, as measured at the widest cross section of each respective microneedle of the one or more microneedles, is from about 20 μηι to about 500 μιτι, or from about 50 μηι to about 350 μηι, or from about 100 μηι to about 250 μηι.

11. The method of any one of claims 1-10, wherein the one or more microneedles comprises a plurality of microneedles, and substantially all the microneedles of the plurality are coated with the allergen.

12. The method of any one of claims 1-10, wherein the one or more microneedles comprises a plurality of microneedles, and at least one microneedle of the plurality is not coated with the allergen.

13. The method of any one of claims 1-12, wherein the one or more microneedles comprises from about 10 to about 200 microneedles.

14. The method of claim 13, wherein the one or more microneedles comprises from about 20 to about 150 microneedles.

15. The method of claim 13, wherein the one or more microneedles comprises from about 20 to about 150 microneedles.

16. The method of claim 13, wherein the one or more microneedles comprises from about 30 to about 100 microneedles.

17. The method of claim 13, wherein the one or more microneedles comprises from about 40 to about 100 microneedles.

18. The method of any one of claims 1-17, wherein the food allergy is a groundnut, peanut, milk, egg, tree nut, seed, fish, shellfish, crustacean, cereal, legume allergy, or a combination thereof.

19. The method of any one of claim 1-17, wherein the food allergy is a peanut allergy.

20. The method of claim 18, wherein the food allergy is a seed allergy.

21. The method of claim 20, wherein the seed allergy is a hazelnut, cashew, walnut, pecan, brazil nut, macadamia, chestnut, pistachio, coconut, almond, sesame, or a mustard seed allergy, or a combination thereof.

22. The method of claim 20, wherein the food allergy is a legume allergy.

23. The method of claim 22, wherein the legume allergy is a soy, kidney bean, black bean, common bean, chickpea, pea, cow pea, lentil or lupine allergy, or a combination thereof.

24. The method of claim 19, wherein the peanut allergen comprises Ara hi, Ara h2, Ara h3, Ara h4, Ara h5, Ara h6, Ara hi, Ara h8, Ara h9, Ara hl O, Ara hi 1, Ara hl2, Ara hl3, a peptide fragment thereof, or a combination thereof.

25. The method of claim 19 or claim 24, wherein the peanut allergen comprises Ara hi, Ara h2, Ara h6, a peptide fragment thereof, or a combination thereof.

26. The method of any one of claims 19 and 24-25, wherein the peanut allergen is provided as peanut protein extract.

27. The method of any one of claims 1 -26, wherein the one or more solid microneedles is coated with an adjuvant.

28. The method of claim 27, wherein the adjuvant is alum.

29. The method of claim 27, wherein the adjuvant is L-Tyrosine.

30. The method of claim 27, wherein the adjuvant is monophoshoryl lipid A (MPL).

31. The method of claim 27, wherein the adjuvant is L-Tyrosine and monophoshoryl lipid A (MPL).

32. The method of claim 27, wherein the adjuvant is an aluminium salt, inulin, L-Tyrosine, algammulin, combination of inulin and aluminium hydroxide, monophosphoryl lipid A (MPL), L-Tyrosine in combination with MPL, resiquimoid, muramyl dipeptide (MDP), N-glycolyl dipeptide (GMDP), poly IC, CpG oligonucleotide, resiquimod, aluminium hydroxide with MPL or a water in oil emulsion.

33. The method of claim 32, wherein the adjuvant is a water in oil emulsion.

34. The method of claim 27, wherein the adjuvant is IFN-gamma (IFN-γ).

35. The method of claim 33, wherein the water in oil emulsion contains one or more of squalene or its analogues or any pharmaceutically acceptable oil, tween-80, sorbitan trioleate, alpha-tocopherol, cholecalciferol, calcium phosphate or a combination two or more of the foregoing.

36. The method of claim 33, wherein the adjuvant is complete Freund's adjuvant.

37. The method of claim 33, wherein the adjuvant is incomplete Freund's adjuvant.

38. The method of claim 27, wherein the adjuvant is Corynebacterium parvum, Bacillus Calmette Guerin, aluminum hydroxide, glucan, dextran sulfate, iron oxide, sodium alginate, Bacto- Adjuvant, a synthetic polymer such as a poly amino acid or a co-polymer of amino acids, saponin, Avridine (N, N-dioctadecyl-N',N'-bis(2-hydroxyethyl)-propanediamine), paraffin oil, muramyl dipeptide or a combination thereof.

39. The method of claim 27, wherein the adjuvant is a CpG oligonucleotide (ODN).

40. The method of claim 27, wherein the adjuvant is alum; a CpG oligonucleotide (ODN); polyA-polyU; dimethyldioctadecylammonium bromide (DDA), N,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)propanediamine, carbomer or chitosan.

41. The method of claim 40, wherein the adjuvant is N ,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)propanediamine.

42. The method of claim 27, wherein the adjuvant is a stimulator of interferon genes (STING) ligand adjuvant.

43. The method of claim 42, wherein the STING adjuvant is a cyclic dinucleotide or a xanthenone derivative.

44. The method of claim 43, wherein the STING ligand is a xanthenone derivative.

45. The method of claim 43, wherein the STING ligand is a cyclic dinucleotide.

46. The method of claim 45, wherein the STING ligand is cyclic di-GMP (c-diGMP).

47. The method of claim 45, wherein the STING ligand is cyclic-di-AMP (c-di-AMP).

48. The method of claim 45, wherein the STING ligand is cyclic-GMP-AMP (cGAMP).

49. The method of claim 48, wherein the STING ligand 2'2'-cGAMP, 2'3'-cGAMP or 3'3'-cGAMP.

50. The method of claim 42, wherein the STING ligand is cyclic guanosine monophosphate (cGMP).

51. The method of claim 42, wherein the STING ligand is cyclic adenosine monophosphate (cAMP).

52. The method of any one of claims 27-51, wherein the adjuvant and allergen are coated on separate microneedles.

53. The method of claim 52, wherein the adjuvant and allergen are coated on separate rows of microneedles.

54. The method of any one of claims 1-53, wherein each microneedle of the one or more microneedles does not extend beyond the epidermis skin layer.

55. The method of any one of claims 1-53, wherein each microneedle of the one or more microneedles does not extend beyond the dermis skin layer.

56. The method of any one of claims 1-55, wherein at least about 40% of the allergen disassociates from the at least one microneedle while inserted in the subject's cutis.

57. The method of any one of claims 1-55, wherein at least about 50% of the allergen disassociates from the at least one microneedle while inserted in the subject's cutis.

58. The method of any one of claims 1-55, wherein at least about 60% of the allergen disassociates from the at least one microneedle while inserted in the subject's cutis.

59. The method of any one of claims 1-55, wherein at least about 70% of the allergen disassociates from the at least one microneedle while inserted in the subject's cutis.

60. The method of any one of claims 1-55, wherein at least about 80% of the allergen disassociates from the at least one microneedle while inserted in the subject's cutis.

61. The method of any one of claims 1-55, wherein at least about 90% of the allergen disassociates from the at least one microneedle while inserted in the subject's cutis.

62. The method of any one of claims 1-61, wherein the allowing step is carried out for about 1 minute to about 10 minutes.

63. The method of claim 62, wherein the allowing step is carried out for about 1 minute to about 8 minutes.

64. The method of claim 62, wherein the allowing step is carried out for about 1 minute to about 6 minutes.

65. The method of claim 62, wherein the allowing step is carried out for about 1 minute to about 4 minutes.

66. The method of claim 62, wherein the allowing step is carried out for about 5 minutes.

67. The method of any one of claims 1-66, wherein the delivering is carried out once daily during the administration period.

68. The method of any one of claims 1-66, wherein the delivering is carried out twice daily during the administration period.

69. The method of any one of claims 1-66, wherein the delivering is carried out three times daily during the administration period.

70. The method of any one of claims 1-66, wherein the delivering is carried out every other day during the administration period.

71. The method of any one of claims 1-66, wherein the delivering is carried out twice a week during the administration period.

72. The method of any one of claims 1-66, wherein the method is carried out once weekly during the administration period.

73. The method of any one of claims 1-72, wherein the delivering an effective amount of an allergen results in delivering substantially the same amount of allergen each time during the administration period.

74. The method of any one of claims 1-72, wherein the delivering an effective amount of an allergen results in delivering an escalating dosage of the allergen at least once during the administration period.

75. The method of any one of claims 1-72, wherein the delivering an effective amount of an allergen results in delivering an escalating dosage of the allergen at least twice during the administration period.

76. The method of any one of claims 1-72, wherein the delivering an effective amount of an allergen results in delivering an escalating dosage of the allergen at least three times during the administration period.

77. The method of any one of claims 1-76, wherein the treating results in desensitization to the allergen.

78. The method of claim 77, wherein the desensitization to the allergen is by at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, about 70%, about 75%, at least about 80%, at least about 85%, or at least about 90% as compared to the subject prior to commencing the treatment, a subject receiving a placebo or a subject not receiving the treatment.

79. The method of any one of claims 1-78, wherein the treating results in a decrease in the number of allergen specific IgE antibodies in the subject, as compared to the number secreted prior to the treating.

80. The method of any one of claims 1-79, wherein the treating results in an increase in the number of allergen specific IgG antibodies in the subject, as compared to the number secreted prior to the treating.

81. The method of claim 80, wherein the subject is human and the allergen specific IgG antibodies are allergen specific IgG4 antibodies.

82. The method of any one of claims 1-81, wherein the treating results in a decreased number of mast cells in the subject, as compared to the number secreted prior to the treating.

83. The method of any one of claims 1-82, wherein the treating results in a decreased number of basophils in the subject, as compared to the number secreted prior to the treating.

84. The method of any one of claims 1 -83, wherein the treating results in an increased cytokine production in the subject, as compared to the number secreted prior to the treating.

85. The method of claim 84, wherein the cytokine is IL-10.

86. The method of claim 84, wherein the cytokine is TGF-β.

87. The method of any one of claims 1 -86, wherein the treating results in an increased number of T-regulatory cells in the subject, as compared to the number of T-regulatory cells prior to the treating.

88. The method of claim 87, wherein the T-regulatory cells are Trl cells, Th3, CD4+CD25+forkhead box P3 :Foxp3+ T-regulatory cells, or a combination thereof.

89. The method of any one of claims 1-88, wherein the treating results in an increase in the eliciting dose of the allergen, as compared to the eliciting dose prior to initiation of treatment.

90. The method of claim 89, wherein the increase in the eliciting dose of the allergen is an increase by 10%, by 20%, by 30%, by 40%, by 50%, by 60%, by 70%, by 80%, by 90%, by 100%, by 500% or by 1000%.

91. The method of claim 89, wherein the increase in the eliciting dose of the allergen is an increase by at least about 10%, by at least about 20%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, by at least about 80%, by at least about 90%, by at least about 100%, by at least about 500% or by at least about 1000%.

92. The method of any one of claims 1-91, wherein the treating results in a sustained unresponsiveness to the allergen.

93. The method of claim 92, wherein the sustained unresponsiveness lasts for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 1 1 months or about 12 months after the final delivering step of the administration period.

94. The method of claim 89, wherein the sustained unresponsiveness lasts for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months or at least about 12 months after the final delivering step of the administration period.

95. The method of any one of claims 1-94, wherein the subject is a human subject.

96. The method of any one of claims 1-95, wherein the subject is from about 2 years old to about 12 years old.

97. The method of any one of claims 1-95, wherein the subject is from about 3 years old to about 12 years old.

98. The method of any one of claims 1-95, wherein the subject is from about 4 years old to about 12 years old.

99. The method of any one of claims 1-95, wherein the subject is from about 4 years old to about 11 years old.

100. The method of any one of claims 1-95, wherein the subject is from about 4 years old to about 10 years old.

101. The method of any one of claims 1-95, wherein the subject is from about 2 years old to about 9 years old.

102. The method of any one of claims 1-101, wherein the administration period is about 1 month, about 3 months, about 6 months, about 9 months, aboutl2 months, about 15 months, about 18 months, about 24 months, about 27 months, about 30 months, about 33 months or about 36 months.

103. The method of any one of claims 1-101, wherein the administration period is at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months, at least aboutl2 months, at least about 15 months, at least about 18 months, at least about 24 months, at least about 27 months, at least about 30 months, at least about 33 months or at least 36 months.

104. The method of any one of claims 1-101, wherein the administration period is from about 1 month to about 24 months.

105. The method of any one of claims 1-101, wherein the administration period is from about 1 month to about 18 months.

106. The method of any one of claims 1-101, wherein the administration period is from about 1 month to about 12 months.

107. The method of any one of claims 1-101, wherein the administration period is from about 3 months to about 12 months.

108. The method of any one of claims 1-101, wherein the administration period is from about 3 months to about 18 months.

109. The method of any one of claims 1-101, wherein the administration period is from about 6 months to about 18 months.

110. The method of any one of claims 1-109, wherein the administration period is the amount of time sufficient to achieve desensitization to the allergen being administered.

111. The method of any one of claims 1-110, wherein the administration period is the amount of time sufficient to achieve long term unresponsiveness to the allergen being administered.

112. A microneedle array comprising a plurality of solid microneedles extending from a common substrate, wherein each microneedle of the plurality has a base, shaft and tip, wherein at least one microneedle of the plurality is coated with an effective amount of a food allergen.

113. The microneedle array of claim 112, wherein the substrate is adhesive.

114. The microneedle array of claim 112 or 113, wherein the substrate is rigid.

115. The microneedle array of claim 112 or 113, wherein the substrate is flexible.

116. The microneedle array of any one of claims 112-115, wherein the average length of the plurality of microneedles in the array is from about 100 μιτι to about 1000 μιτι, as measured from the base of the tip.

117. The microneedle array of claim 116, wherein the average length of the plurality of microneedles in the array is from about 100 μιτι to about 900 μιη.

118. The microneedle array of claim 116, wherein the average length of the plurality of microneedles in the array is from about 100 μιτι to about 800 μιη.

119. The microneedle array of claim 116, wherein the average length of the plurality of microneedles in the array is from about 100 μηι to about 700 μηι.

120. The microneedle array of claim 116, wherein the average length of the plurality of microneedles in the array is from about 100 μηι to about 600 μηι.

121. The microneedle array of claim 116, wherein the average length of the plurality of microneedles in the array is from about 100 μηι to about 500 μηι.

122. The microneedle array of any one of claims 112-121, wherein the average width of the plurality of microneedles in the array, as measured at the widest cross section of each respective microneedle in the array, is from about 20 μηι to about 500 μηι.

123. The microneedle array of claim 122, wherein the average width of the plurality of microneedles, as measured at the widest cross section of each respective microneedle in the array, is from about 50 μηι to about 350 μιτι, or from about 100 μηι to about 250 μηι.

124. The microneedle array of any one of claims 112-123, wherein the average aspect ratio (width: length) of the plurality of microneedles in the array is from about 1 : 1 and 1 : 10.

125. The microneedle array of any one of claims 112-124, wherein the microneedle array comprises from about 10 to about 200 microneedles.

126. The microneedle array of claim 125, wherein the microneedle array comprises from about 20 to about 150 microneedles.

127. The microneedle array of claim 125, wherein the microneedle array comprises from about 20 to about 150 microneedles.

128. The microneedle array of claim 125, wherein the microneedle array comprises from about 30 to about 100 microneedles.

129. The microneedle array of claim 125, wherein the microneedle array comprises from about 40 to about 100 microneedles.

130. The microneedle array of any one of claims 112-129, wherein the food allergen is a groundnut, peanut, milk, egg, tree nut, seed, fish, shellfish, crustacean, cereal, legume allergen, or a combination thereof.

131. The microneedle array of any one of claims 112-129, wherein the food allergen is a peanut allergen.

132. The microneedle array of claim 130, wherein the food allergen is a seed allergen.

133. The microneedle array of claim 132, wherein the seed allergen is a hazelnut, cashew, walnut, pecan, brazil nut, macadamia, chestnut, pistachio, coconut, almond, sesame, or a mustard seed allergen, or a combination thereof.

134. The microneedle array of claim 130, wherein the food allergen is a legume allergen.

135. The microneedle array of claim 134, wherein the legume allergen is a soy, kidney bean, black bean, common bean, chickpea, pea, cow pea, lentil or lupine allergen, or a combination thereof.

136. The microneedle array of claim 131, wherein the peanut allergen comprises Ara hi, Ara h2, Ara h3, Ara h4, Ara h5, Ara h6, Ara h7, Ara h8, Ara h9, Ara hlO, Ara hl l , Ara hl2, Ara hl3, a peptide fragment thereof, or a combination thereof.

137. The microneedle array of claim 131, wherein the peanut allergen comprises Ara hi, Ara h2, Ara h6, a peptide fragment thereof, or a combination thereof.

138. The microneedle array of any one of claims 131 and 136-137, wherein the peanut allergen is provided as peanut protein extract.

139. The microneedle array of any one of claims 112-138, wherein at least one microneedle of the plurality comprises an adjuvant.

140. The microneedle array of claim 139, wherein the adjuvant is alum.

141. The microneedle array of claim 139, wherein the adjuvant is L-Tyrosine.

142. The microneedle array of claim 139, wherein the adjuvant is monophoshoryl lipid A (MPL).

143. The microneedle array of claim 139, wherein the adjuvant is L-Tyrosine and monophoshoryl lipid A (MPL).

144. The microneedle array of claim 139, wherein the adjuvant is an aluminium salt, inulin, L-Tyrosine, algammulin, combination of inulin and aluminium hydroxide, monophosphoryl lipid A (MPL), L-Tyrosine in combination with MPL, resiquimoid, muramyl dipeptide (MDP), N-glycolyl dipeptide (GMDP), poly IC, CpG oligonucleotide, resiquimod, aluminium hydroxide with MPL or a water in oil emulsion

145. The microneedle array of claim 144, wherein the adjuvant is a water in oil emulsion.

146. The microneedle array of claim 145, wherein the water in oil emulsion contains one or more of squalene or its analogues or any pharmaceutically acceptable oil, tween-80, sorbitan trioleate, alpha-tocopherol, cholecalciferol, calcium phosphate or a combination two or more of the foregoing.

147. The microneedle array of claim 145, wherein the adjuvant is complete Freund's adjuvant.

148. The microneedle array of claim 145, wherein the adjuvant is incomplete Freund's adjuvant.

149. The microneedle array of claim 139, wherein the adjuvant is Corynebacterium parvum, Bacillus Calmette Guerin, aluminum hydroxide, glucan, dextran sulfate, iron oxide, sodium alginate, Bacto- Adjuvant, a synthetic polymer such as a poly amino acid or a co-polymer of amino acids, saponin, Avridine (N, N-dioctadecyl-N',N'-bis(2-hydroxyethyl)-propanediamine), paraffin oil, muramyl dipeptide or a combination thereof.

150. The microneedle array of claim 139, wherein the adjuvant is a CpG oligonucleotide (ODN).

151. The microneedle array of claim 139, wherein the adjuvant is alum; a CpG oligonucleotide (ODN); polyA-polyU; dimethyldioctadecylammonium bromide (DDA), N,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)propanediamine, carbomer or chitosan.

152. The microneedle array of claim 151, wherein the adjuvant is N ,N-dioctadecyl-N',N'-bis(2-hydroxyethyl)propanediamine.

153. The microneedle array of claim 139, wherein the adjuvant is a stimulator of interferon genes (STING) ligand adjuvant.

154. The microneedle array of claim 153, wherein the STING adjuvant is a cyclic dinucleotide or a xanthenone derivative.

155. The microneedle array of claim 154, wherein the STING ligand is a xanthenone derivative.

156. The microneedle array of claim 154, wherein the STING ligand is a cyclic dinucleotide.

157. The microneedle array of claim 156, wherein the STING ligand is cyclic di-GMP (c-diGMP).

158. The microneedle array of claim 156, wherein the STING ligand is cyclic-di-AMP (c-di-AMP).

159. The microneedle array of claim 156, wherein the STING ligand is cyclic-GMP-AMP (cGAMP).

160. The microneedle array of claim 159, wherein the STING ligand 2'2'-cGAMP, 2'3'-cGAMP or 3'3'-cGAMP.

161. The microneedle array of claim 153, wherein the STING ligand is cyclic guanosine monophosphate (cGMP).

162. The microneedle array of claim 153, wherein the STING ligand is cyclic adenosine monophosphate (cAMP).

163. The microneedle array of claim 139, wherein the adjuvant is IFN-γ.

164. The microneedle array of any one of claims 139-163, wherein the allergen and adjuvant are coated on different microneedles.

165. The microneedle array of claim 164, wherein the allergen coated microneedles and adjuvant coated microneedles are present in separate microneedle rows.

166. The microneedle array of any one of claims 139-163, wherein at least a portion of the microneedles of the plurality comprise both an allergen coating and an adjuvant coating.