Methods of hormonal treatment utilizing ascending-dose extended cycle regimens

• US 20080125402A1
• Filed: 08/17/2007
• Published: 05/29/2008
• Est. Priority Date: 10/07/2004
• Status: Active Grant

• Current Assignee: Teva Women's Health Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Duramed Pharmaceuticals Incorporated
• Inventors: Diliberti, Charles E., Bronnenkant, Lance J., Reape, Kathleen Z.
• Granted Patent: US 8,415,332 B2
• Time in Patent Office: Days
• US Class Current: 514/170
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/567 substituted in position 17 alpha, e.g. mestranol, norethandrolone
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides ascending-dose extended cycle regimens in which a female is administered an estrogen and a progestin for a period of greater than 30 or 31 consecutive days, optionally followed by a hormone-free period or by a period of administration of estrogen. The disclosed regimens can be administered to a female to provide contraceptive and non-contraceptive benefits.

Claims

1-135. -135. (canceled)

136. A method of contraception, the method comprising:

administering to a female in need thereof a dosage comprising estrogen and progestin for a period of 83 to 89 consecutive days,

wherein the dosage comprising estrogen and progestin is administered in at least three phases,

wherein the daily dosage of estrogen in the first phase is equivalent to 15 μ

g to 25 μ

g of ethinyl estradiol, the daily dosage of estrogen in the second phase is equivalent to 20 μ

g to 30 μ

g of ethinyl estradiol, and the daily dosage of estrogen in the third phase is equivalent to 25 μ

g to 35 μ

g of ethinyl estradiol,

wherein the total daily dosage of estrogen and progestin in the second phase is higher than the total daily dosage of estrogen and progestin in the first phase, and

wherein the total daily dosage of estrogen and progestin in the third phase is higher than the total daily dosage of estrogen and progestin in the second phase.

137. The method of claim 136, wherein the daily dosage of progestin in each of the three phases is equivalent to 100 μ

g to 150 μ

g of levonorgestrel.

138. The method of claim 136, wherein the progestin is selected from the group consisting of levonorgestrel, norethindrone, norethindrone acetate, desogestrel, gestodene, dienogest, norgestimate, cyproterone acetate, norelgestromin, etonogestrel, progesterone, ethynodiol diacetate, norgestrel, trimegestone, medroxyprogesterone acetate, chlormadinone acetate, drospirenone, and esters, conjugates, and prodrugs thereof.

139. The method of claim 136, wherein the estrogen is selected from the group consisting of ethinyl estradiol, estradiol, estradiol acetate, estradiol valerate, mestranol, and esters, conjugates, and prodrugs thereof.

140. The method of claim 136, further comprising administering to the female a daily dosage consisting essentially of estrogen for a period of 2 to 8 consecutive days following the administration of the dosage comprising estrogen and progestin for 83 to 89 consecutive days.

141. The method of claim 140, wherein the daily dosage of estrogen that is administered for a period of 2 to 8 consecutive days is 5 μ

g to 30 μ

g of ethinyl estradiol.

142. The method of claim 140, further comprising administering an additional active agent that is administered (i) in combination with the dosage consisting essentially of estrogen for a period of 2 to 8 consecutive days following the administration of the dosage comprising estrogen and progestin for 83 to 89 consecutive days, (ii) continuously, (iii) intermittently, (iv) one time, or (v) once weekly.

143. The method of claim 136, wherein the female is also treated for acne, headache or pelvic pain.

144. The method of claim 136, wherein the first phase is 35 to 49 days, the second phase is 14 to 28 days, and the third phase is 14 to 32 days.

145. The method of claim 144, wherein the first phase is 42 days, the second phase is 21 days, and the third phase is 21 days.

146. The method of claim 145,

wherein the daily dosage of estrogen in the first phase is 20 μ

g of ethinyl estradiol, the daily dosage of estrogen in the second phase is 25 μ

g of ethinyl estradiol, and the daily dosage of estrogen in the third phase is 30 μ

g of ethinyl estradiol, and

wherein the daily dosage of progestin in each of the three phases is 150 μ

g of levonorgestrel.

147. The method of claim 146, further comprising administering to the female a daily dosage consisting essentially of 10 μ

g of ethinyl estradiol for 7 consecutive days following the administration of the dosage comprising estrogen and progestin.

148. The method of claim 136, wherein the first phase is 14 to 28 days, the second phase is 35 to 49 days, and the third phase is 14 to 32 days,

149. The method of claim 148, wherein the first phase is 21 days, the second phase is 42 days, and the third phase is 21 days.

150. The method of claim 149,

wherein the daily dosage of estrogen in the first phase is 20 μ

g of ethinyl estradiol, the daily dosage of estrogen in the second phase is 25 μ

g of ethinyl estradiol, and the daily dosage of estrogen in the third phase is 30 μ

g of ethinyl estradiol, and

wherein the daily dosage of progestin in each of the three phases is 150 μ

g of levonorgestrel.

151. The method of claim 150, further comprising administering to the female a daily dosage consisting essentially of 10 μ

g of ethinyl estradiol for 7 consecutive days following the administration of the dosage comprising estrogen and progestin.

152. The method of claim 136, wherein the first phase is 14 to 28 days, the second phase is 14 to 28 days, and the third phase is 35 to 53 days.

153. The method of claim 152, wherein the first phase is 21 days, the second phase is 21 days, and the third phase is 42 days.

154. The method of claim 153,

wherein the daily dosage of estrogen in the first phase is 20 μ

g of ethinyl estradiol, the daily dosage of estrogen in the second phase is 25 μ

g of ethinyl estradiol, and the daily dosage of estrogen in the third phase is 30 μ

g of ethinyl estradiol, and

wherein the daily dosage of progestin in each of the three phases is 150 μ

g of levonorgestrel.

155. The method of claim 154, further comprising administering to the female a daily dosage consisting essentially of 10 μ

g of ethinyl estradiol for 7 consecutive days following the administration of the dosage comprising estrogen and progestin.

156. A pharmaceutical kit comprising 83 to 89 daily dosages in sequential order for administration in at least three phases, each daily dosage comprising estrogen and progestin,

wherein the daily dosage of estrogen in the first phase is equivalent to 15 μ

g to 25 μ

g of ethinyl estradiol,

the daily dosage of estrogen in the second phase is equivalent to 20 μ

g to 30 μ

g of ethinyl estradiol,

and the daily dosage of estrogen in the third phase is equivalent to 25 μ

g to 35 μ

g of ethinyl estradiol,

wherein the total daily dosage of estrogen and progestin in the second phase is higher than the total daily dosage of estrogen and progestin in the first phase, and

wherein the total daily dosage of estrogen and progestin in the third phase is higher than the total daily dosage of estrogen and progestin in the second phase.

157. The pharmaceutical kit of claim 156, wherein the daily dosage of progestin in each of the three phases is equivalent to 100 μ

g to 150 μ

g of levonorgestrel.

158. The pharmaceutical kit of claim 156, wherein the progestin is selected from the group consisting of levonorgestrel, norethindrone, norethindrone acetate, desogestrel, gestodene, dienogest, norgestimate, cyproterone acetate, norelgestromin, etonogestrel, progesterone, ethynodiol diacetate, norgestrel, trimegestone, medroxyprogesterone acetate, chlormadinone acetate, drospirenone, and esters, conjugates, and prodrugs thereof.

159. The pharmaceutical kit of claim 156, wherein the estrogen is selected from the group consisting of ethinyl estradiol, estradiol, estradiol acetate, estradiol valerate, mestranol, and esters, conjugates, and prodrugs thereof.

160. The pharmaceutical kit of claim 156, further comprising 2 to 8 daily dosages, each of the 2 to 8 daily dosages consisting essentially of estrogen for administration following the administration of the dosages comprising estrogen and progestin.

161. The pharmaceutical kit of claim 160, wherein each of the 2 to 8 daily dosages of estrogen is equivalent to 5 μ

g to 30 μ

g of ethinyl estradiol.

162. The pharmaceutical kit of claim 156, wherein the kit contains 35 to 49 daily dosages in the first phase, 14 to 28 daily dosages in the second phase, and 14 to 32 daily dosages in the third phase.

163. The pharmaceutical kit of claim 162, wherein the kit contains 42 daily dosages in the first phase, 21 daily dosages in the second phase, and 21 daily dosages in the third phase.

164. The pharmaceutical kit of claim 163, wherein the daily dosage of estrogen in the first phase is 20 μ

g of ethinyl estradiol, the daily dosage of estrogen in the second phase is 25 μ

g of ethinyl estradiol, and daily dosage of estrogen in the third phase is 30 μ

g of ethinyl estradiol, and

wherein the daily dosage of progestin in each of the three phases is 150 μ

g of levonorgestrel.

165. The pharmaceutical kit of claim 164, further comprising 7 daily dosages, each of the 7 daily dosages consisting essentially of 10 μ

g of ethinyl estradiol for administration following the dosages comprising estrogen and progestin.

166. The pharmaceutical kit of claim 156, wherein the kit contains 14 to 28 daily dosages in the first phase, 35 to 49 daily dosages in the second phase, and 14 to 32 dosages in the third phase.

167. The pharmaceutical kit of claim 166, wherein the kit contains 21 daily dosages in the first phase, 42 daily dosages in the second phase, and 21 daily dosages in the third phase.

168. The pharmaceutical kit of claim 167, wherein the daily dosage of estrogen in the first phase is 20 μ

g of ethinyl estradiol, the daily dosage of estrogen in the second phase is 25 μ

g of ethinyl estradiol, and daily dosage of estrogen in the third phase is 30 μ

g of ethinyl estradiol, and

wherein the daily dosage of progestin in each of the three phases is 150 μ

g of levonorgestrel.

169. The pharmaceutical kit of claim 168, further comprising 7 daily dosages, each of the 7 daily dosages consisting essentially of 10 μ

g of ethinyl estradiol for administration following the administration of the dosages comprising estrogen and progestin.

170. The pharmaceutical kit of claim 156, wherein the kit contains 14 to 28 daily dosages in the first phase, 14 to 28 daily dosages in the second phase, and 35 to 53 daily dosages in the third phase.

171. The pharmaceutical kit of claim 170, wherein the kit contains 21 daily dosages in the first phase, 21 daily dosages in the second phase, and 42 daily dosages in the third phase.

172. The pharmaceutical kit of claim 171, wherein the daily dosage of estrogen in the first phase is 20 μ

g of ethinyl estradiol, the daily dosage of estrogen in the second phase is 25 μ

g of ethinyl estradiol, and daily dosage of estrogen in the third phase is 30 μ

g of ethinyl estradiol, and

wherein the daily dosage of progestin in each of the three phases is 150 μ

g of levonorgestrel.

173. The pharmaceutical kit of claim 172, further comprising 7 daily dosages, each of the 7 daily dosages consisting essentially of 10 μ

g of ethinyl estradiol for administration following the administration of the dosages comprising estrogen and progestin.

174. A method of contraception, the method comprising:

administering to a female in need thereof a dosage comprising estrogen and progestin for a period of greater than 30 consecutive days,

wherein the dosage comprising estrogen and progestin is administered in at least two phases,

wherein the daily dosage of estrogen in the first phase is equivalent to 15 μ

g to 25 μ

g of ethinyl estradiol,

the daily dosage of estrogen in the second phase is equivalent to 20 μ

g to 30 μ

g of ethinyl estradiol,

wherein the total daily dosage of estrogen and progestin in a second phase is higher than the total daily dosage of estrogen and progestin in the first phase, and

wherein the daily dosage of progestin in the second phase is less than twice the daily dosage of progestin in the first phase.

175. The method of claim 174, wherein the daily dosage of estrogen in the second phase is higher than a daily dosage of estrogen in the first phase.

176. The method of claim 174, wherein the progestin is selected from the group consisting of levonorgestrel, norethindrone, norethindrone acetate, desogestrel, gestodene, dienogest, norgestimate, cyproterone acetate, norelgestromin, etonogestrel, progesterone, ethynodiol diacetate, norgestrel, trimegestone, medroxyprogesterone acetate, chlormadinone acetate, drospirenone, and esters, conjugates, and prodrugs thereof.

177. The method of claim 174, wherein the estrogen is selected from the group consisting of ethinyl estradiol, estradiol, estradiol acetate, estradiol valerate, mestranol, and esters, conjugates, and prodrugs thereof.

178. The method of claim 174, wherein the dosage comprising estrogen and progestin is administered for a period of 31 to 190 consecutive days.

179. The method of claim 178, wherein each phase is 7 to 84 days.

180. The method of claim 174, further comprising administering a daily dosage consisting essentially of estrogen for a period of 2 to 8 consecutive days.

181. The method of claim 180, wherein the dosage of estrogen that is administered for the period of 2 to 8 consecutive days is 5 μ

g to 30 μ

g of ethinyl estradiol.

182. The method of claim 180, wherein the dosage of estrogen that is administered for the period of 2 to 8 consecutive days is 10 μ

g of ethinyl estradiol.

183. The method of claim 182, further comprising administering an additional active agent that is administered (i) in combination with a dosage consisting essentially of an estrogen for a period of 2 to 8 consecutive days following the administration of the dosage comprising estrogen and progestin for a period of greater than 30 consecutive days, (ii) continuously, (iii) intermittently, (iv) one time, or (v) once weekly.

184. A pharmaceutical kit comprising greater than 30 daily dosages in sequential order for administration in at least two phases, each daily dosage comprising estrogen and progestin,

wherein the daily dosage of estrogen in the first phase is equivalent to 15 μ

g to 25 g of ethinyl estradiol,

the daily dosage of estrogen in the second phase is equivalent to 20 μ

g to 30 μ

g of ethinyl estradiol,

wherein the total daily dosage of estrogen and progestin in the second phase is higher than the total daily dosage of estrogen and progestin in the first phase, and

wherein the total daily dosage of estrogen and progestin in the second phase is less than twice the daily dosage of progestin in the first phase.

185. The pharmaceutical kit of claim 184, wherein the daily dosage of progestin in each of the two phases is equivalent to 100 μ

g to 150 μ

g of levonorgestrel.

186. The pharmaceutical kit of claim 184, wherein the progestin is selected from the group consisting of levonorgestrel, norethindrone, norethindrone acetate, desogestrel, gestodene, dienogest, norgestimate, cyproterone acetate, norelgestromin, etonogestrel, progesterone, ethynodiol diacetate, norgestrel, trimegestone, medroxyprogesterone acetate, chlormadinone acetate, drospirenone, and esters, conjugates, and prodrugs thereof.

187. The pharmaceutical kit of claim 184, wherein the estrogen is selected from the group consisting of ethinyl estradiol, estradiol, estradiol acetate, estradiol valerate, mestranol, and esters, conjugates, and prodrugs thereof.

188. The pharmaceutical kit of claim 184, further comprising 2 to 8 daily dosages, each of the 2 to 8 daily dosages consisting essentially of estrogen for administration following the administration of the dosages comprising estrogen and progestin.

189. The pharmaceutical kit of claim 188, wherein each of the 2 to 8 daily dosages of estrogen is equivalent to 5 μ

g to 30 μ

g of ethinyl estradiol.

190. The pharmaceutical kit of claim 184, wherein the daily dosage of estrogen in the first phase is 20 μ

g of ethinyl estradiol, the daily dosage of estrogen in the second phase is 25 μ

g of ethinyl estradiol, and wherein the daily dosage of progestin in each of the two phases is 150 μ

g of levonorgestrel.

191. The pharmaceutical kit of claim 190, further comprising 7 daily dosages, each of the 7 daily dosages consisting essentially of 10 μ

g of ethinyl estradiol for administration following the administration of the dosages comprising estrogen and progestin.