COMPOSITIONS AND METHODS FOR TRANSMUCOSAL ABSORPTION
The invention provides compositions and methods for administering compounds for transmucosal absorption. The compositions and methods have a number of surprising pharmacokinetic benefits over oral administration of a compound.
1 .- 149 . (canceled)
150 . A method for treating fibromyalgia or reducing one or more associated symptoms of fibromyalgia in a subject in need thereof comprising administering a pharmaceutical composition comprising cyclobenzaprine hydrochloride, a basifying agent, and a pharmaceutically acceptable carrier,
wherein, on administration of the pharmaceutical composition, a combination of the saliva in the oral cavity and the basifying agent converts at least a portion of the cyclobenzaprine hydrochloride to cyclobenzaprine, and
wherein the cyclobenzaprine is transmucosally absorbed in the oral cavity.
151 . The method of claim 150 , wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.
152 . The method of claim 151 , wherein the basifying agent is dipotassium hydrogen phosphate.
153 . The method of claim 150 , wherein the saliva in the oral cavity has a pH of about 7.1 to 7.4 after administration of the pharmaceutical composition.
154 . The method of claim 150 , wherein the transmucosal absorption is sublingual absorption.
155 . The method of claim 154 , wherein the pharmaceutical composition is in a form selected from the group consisting of a liquid, a sublingual tablet, a sublingual film, a sublingual powder, and a sublingual spray solution.
156 . The method of claim 151 , wherein the cyclobenzaprine hydrochloride is present in the pharmaceutical composition in an amount of less than about 10 mg.
157 . The method of claim 156 , wherein the cyclobenzaprine hydrochloride is present in the pharmaceutical composition in an amount of less than about 5 mg.
158 . The method of claim 157 , wherein the cyclobenzaprine hydrochloride is present in the pharmaceutical composition in an amount of 2.8 mg.
159 . The method of claim 150 , wherein the administration of the pharmaceutical composition is chronic dosing.
160 . The method of claim 150 , wherein the pharmaceutical composition is administered at bedtime.
161 . The method according to claim 150 , wherein the cyclobenzaprine on transmucosal absorption affords a cyclobenzaprine dnAUC 0-20 min of greater than or equal to 0.02±25%×10 −6 hr mL −1 , a dnAUC 0-30 min of greater than or equal to 0.05±25%×10 −6 hr mL −1 , a dnAUC 0-45 min of greater than or equal to 0.14±25%×10 −6 hr mL −1 , a dnAUC 0-1 h of greater than or equal to 0.26±25%×10 −6 hr mL −1 , a dnAUC 0-2 h of greater than or equal to 0.87±25%×10 −6 hr mL −1 , or a dnAUC 0-2.5 h of greater than or equal to 1.23±25%×10 −6 hr mL −1 .
162 . The method of claim 150 , wherein the cyclobenzaprine on transmucosal absorption affords a cyclobenzaprine dnAUC 0-∞h of greater than or equal to 20 hr mL −1 .
163 . The method of claim 150 , wherein the cyclobenzaprine on transmucosal absorption affords a cyclobenzaprine dnC max * of greater than or equal to 1.0±25%×10 −6 mL −1 .
164 . The method of claim 150 , wherein the cyclobenzaprine on transmucosal absorption affords a cyclobenzaprine plasma concentration selected from the group consisting of: 50% or less of the C max 4 hours after administration; 50% or less of the C max 6 hours after administration; 50% or less of the C max 8 hours after administration; or 50% or less of the C max 12 hours after administration.
165 . The method of claim 150 , wherein the cyclobenzaprine on transmucosal absorption affords a C max of cyclobenzaprine selected from the group consisting of: greater than or equal to 10 ng/mL; greater than or equal to 15 ng/mL; greater than or equal to 20 ng/mL; greater than or equal to 25 ng/mL; greater than or equal to 30 ng/mL; greater than or equal to 10 ng/mL above the baseline level of cyclobenzaprine in the individual immediately prior to administration; greater than or equal to 15 ng/mL above the baseline level of cyclobenzaprine in the individual immediately prior to administration; greater than or equal to 20 ng/mL above the baseline level of cyclobenzaprine in the individual immediately prior to administration; greater than or equal to 25 ng/mL above the baseline level of cyclobenzaprine in the individual immediately prior to administration; and greater than or equal to 30 ng/mL above the baseline level of cyclobenzaprine in the individual immediately prior to administration.
166 . The method of claim 150 , wherein the cyclobenzaprine on transmucosal absorption affords a t max of cyclobenzaprine selected from the group consisting of: less than 4.7 hours, less than 4 hours; less than 3 hours; less than 2 hours; less than 1 hour; less than 45 minutes; less than 30 minutes; or less than 15 minutes.
167 . The method of claim 150 , wherein the cyclobenzaprine on transmucosal absorption affords a C max of cyclobenzaprine greater than or equal to 2 ng/mL.