Sublingual fentanyl spray

• US 20090176834A1
• Filed: 08/01/2008
• Published: 07/09/2009
• Est. Priority Date: 08/02/2007
• Status: Active Grant

• Current Assignee: BTcP Pharma, LLC
• Original Assignee: INSYS Therapeutics, Inc.
• Inventors: Zhu, Zhongyuan, Parikh, Neha, Kattookaran, Linet, Kottayil, S. George, Goskonda, Venkat R.
• Granted Patent: US 8,486,973 B2
• Time in Patent Office: Days
• US Class Current: 514/329
• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61M 11/00 Sprayers or atomisers specially adapted for therapeutic purposes in general B05B; aerosol containers B65D83/14
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids

Abstract

The present invention is directed to sublingual formulations containing fentanyl, a pharmaceutically acceptable salt thereof, or derivative thereof, suitable for administration to a patient, and methods for treatment with the formulations.

Claims

1-139. -139. (canceled)

140. A sublingual spray formulation comprising an effective amount of fentanyl and at least one pharmaceutically acceptable excipient, the formulation providing a mean T_max of about 1.28+/−

0.60 hours when a dose is administered sublingually to humans.

141. The sublingual formulation of claim 140, wherein the concentration of fentanyl is from about 1 mg/mL to about 8 mg/mL.

142. The sublingual formulation of claim 140, wherein the concentration of fentanyl is selected from the group consisting of about 1 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL and about 8 mg/mL.

143. The sublingual formulation of claim 140, exhibiting a mean C_max of about 0.813 ng/ml+/−

0.252 based on a sublingual dose of about 400 mcg fentanyl when administered to humans.

144. The sublingual formulation of claim 140, which provides a dosage amount of fentanyl selected from the group consisting of about 100 mcg, about 200 mcg, about 600 mcg and about 800 mcg, and provides a mean C_max which is substantially dose proportional to the sublingual formulation containing 400 mcg fentanyl dosage amount, when administered to humans.

145. The sublingual formulation of claim 140, which provides a substantially dose proportional mean C_max based on a mean C_max of about 0.813 ng/ml+/−

0.252 for a 400 mcg fentanyl dose when administered to humans.

146. The sublingual formulation of claim 140, which provides a mean T_max when administered to humans selected from the group consisting of:

about 1.12 hours when the formulation provides a 100 mcg dose, about 1.04 hours when the formulation provides a 200 mcg dose, about 0.97 hours when the formulation provides a 400 mcg dose, about 0.987 hours when the formulation provides a 600 mcg dose, and about 1.06 hours when the formulation provides a 800 mcg dose.

147. The sublingual formulation of claim 140, which provides a plasma concentration after administration to humans selected from the group consisting of:

about 60% of the mean C_max in about 10 minutes, about 86% of the mean C_maxby about 20 minutes and a combination thereof.

148. The sublingual formulation of claim 140, that when administered to humans provides a plasma concentration that is greater than about 80% of the mean C_max for about 2 hours.

149. The sublingual formulation of claim 140, comprising 400 mcg of fentanyl, providing one or more mean pharmacokinetic values selected from the group consisting of:

AUC_last 4.863+/−

1.70821 hr*ng/mL, AUC_inf 5.761+/−

1.916 hr*ng/mL, and AUC_extrap 10.26+/−

5.66%, when administered to humans.

150. The sublingual formulation of claim 140, which provides a dosage amount of fentanyl when administered to humans which is substantially dose proportional to the dosage which contains about 400 mcg fentanyl selected from the group consisting of about 100 mcg, about 200 mcg, about 600 mcg, about 800 mcg, and provides one or more pharmacokinetic values selected from the group consisting of:

mean AUC_last, mean AUC_inf, and mean AUC_extrap.

151. The sublingual formulation of claim 140, which provides a substantially dose proportional mean AUC_last based on a mean AUC₁at of about 4.863+/−

1.70821 hr*ng/mL for a 400 mcg fentanyl dose when administered to humans.

152. The sublingual formulation of claim 140, comprising a 400 mcg dose of fentanyl, providing a geometric mean ln(C_max) of about 0.7865 ng/ml when a dose is administered to humans.

153. The sublingual formulation of claim 140, comprising a 400 mcg dose of fentanyl, providing a mean F(AUC₁ at) of about 0.721+/−

0.199 ng/mL when a dose is administered to humans.

154. The sublingual formulation of claim 140, comprising a 400 mcg dose of fentanyl when a dose is administered to humans, providing a mean F (bioavailability) selected from the group consisting of:

about 71%+/−

16%, 0.721+/−

0.199 based on AUC_last and about 0.756+/−

0.212 based on AUC_inf, or combinations thereof.

155. The sublingual spray formulation of claim 140 further comprising water.

156. The sublingual formulation of claim 155, further comprising dehydrated alcohol.

157. A method of treating pain comprising administering to a patient in need thereof a sublingual spray formulation comprising an effective amount of fentanyl and at least one pharmaceutically acceptable excipient, the formulation providing a mean T_max of about 1.28+/−

0.60 hours when a dose is administered sublingually to humans.

158. The method of claim 157 wherein the sublingual formulation provides a substantially dose proportional mean C_max based on a mean C_max of about 0.813 ng/ml+/−

0.252 for a 400 mcg fentanyl dose when administered to humans.

159. The method of claim 157 wherein the sublingual formulation provides a substantially dose proportional mean AUC_last based on a mean AUC_last of about 4.863+/−

1.70821 hr*ng/mL for a 400 mcg fentanyl dose when administered to humans.

160. The method of manufacturing a sublingual spray formulation comprising an effective amount of fentanyl and at least one pharmaceutically acceptable excipient comprising:

admixing fentanyl, purified water and dehydrated alcohol and

placing the mixture into a sublingual delivery device;

the formulation providing a mean T_max of about 1.28+/−

0.60 hours when a dose is administered sublingually to humans and upon delivery, providing a mean aerodynamic particle size of at least about 10 microns.