LIQUID BUPRENORPHINE FORMULATIONS
The invention provides liquid formulations containing buprenorphine, a pharmaceutically acceptable salt thereof, or a derivative thereof. The invention further provides liquid formulations containing buprenorphine and naloxone, pharmaceutically acceptable salts thereof or derivatives thereof. The invention further provides a method of treating pain or opioid dependence by administering liquid formulations containing buprenorphine or a combination of buprenorphine and naloxone, a pharmaceutically acceptable salt thereof, or a derivative thereof to a patient in need thereof.
1 . A liquid formulation comprising from about 0.05% to about 10% w/w buprenorphine, a pharmaceutically acceptable salt thereof, or a derivative thereof, water as a solvent, and a mixture of an alcohol and a glycol as a cosolvent.
2 . The liquid formulation of claim 1 further comprising naloxone, a pharmaceutically acceptable salt thereof, or a derivative thereof.
3 . The liquid formulation of claim 1 , wherein the formulation is a liquid spray formulation.
4 . The liquid formulation of claim 1 , further comprising an antioxidant.
5 . The liquid formulation of claim 4 , wherein the antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), methionine, sodium ascorbate, sodium thiosulfate, thioglycerol, cysteine hydrochloride monohydrate and a mixture thereof.
6 . A sublingual spray formulation comprising:
buprenorphine, a pharmaceutically acceptable salt thereof or a derivative thereof in an amount from about 0.07% to about 1.3% w/w;
water as a solvent in an amount from about 38% to about 40% w/w;
a cosolvent consisting of a mixture of ethanol in an amount of about 55% w/w and propylene glycol in an amount of about 5% w/w; and
an antioxidant in an amount from about 0.0001% to about 0.5% w/w, wherein the % w/w is of the total formulation.
7 . The formulation of claim 6 further comprising from about 0.005% to about 0.5% w/w menthol.
8 . The formulation of claim 7 , wherein:
the antioxidant consists of a mixture of butylated hydroxyanisole (BHA) in an amount of about 0.01% w/w and butylated hydroxytoluene (BHT) in an amount of about 0.005% w/w; and
menthol is at an amount of about 0.05% w/w.
9 . The liquid formulation of claim 1 wherein the formulation is a sublingual spray formulation and is capable of producing a droplet size distribution wherein greater than 98% of the composition particles are greater than 10 microns in diameter during administration.
10 . The liquid formulation of claim 1 wherein the formulation is a sublingual spray formulation and is capable of producing a droplet size distribution wherein:
the mean Dv(10) is from about 10 to about 40 microns during administration;
the mean Dv(50) is from about 30 to about 80 microns during administration; and
the mean Dv(90) is from about 80 to about 200 microns during administration.
11 . The liquid formulation of claim 1 wherein the formulation is a sublingual spray formulation and is capable of producing a spray plume that has an ovality ratio of from about 1.1 to 2.4.
12 . The liquid formulation of claim 1 wherein the formulation is capable of producing a spray plume width that is from about 25 to about 45 millimeters during administration and a spray plume angle that is from about 30 to about 55 degrees during administration.
13 . The liquid formulation of claim 1 that is capable of producing a D(4,3) of 50 to 95 microns.
14 . The liquid formulation of claim 1 wherein the formulation is a sublingual spray formulation that is capable of producing a droplet size distribution wherein the C max (ng/mL) of buprenorphine is from 0.125±0.0203 to 1.57±0.453.
15 . The liquid formulation of claim 1 wherein the formulation is a sublingual spray formulation that is capable of producing a droplet size distribution wherein the T max of buprenorphine is from about 0.5 to about 2.0 hours following administration.
16 . The liquid formulation of claim 1 wherein the formulation is a sublingual spray formulation that is capable of producing a droplet size distribution wherein the AUCinf of buprenorphine (h*ng/mL) is from 0.6387±0.1844 to 11.36±3.153.
17 . The liquid formulation of claim 2 wherein the formulation is a sublingual spray formulation that is capable of producing a droplet size distribution wherein the Cmax (ng/mL) of buprenorphine is from 2470±850 to 5670±1590 and the Cmax (ng/mL) of naloxone is from 4.26±2.52 to 12.0±5.38.
18 . The liquid formulation of claim 2 wherein the formulation is a sublingual spray formulation that is capable of producing a droplet size distribution wherein the Tmax of buprenorphine is from 1.63±0.5 to 1.68±0.73 hours and the Tmax of naloxone is from about 1.17 to about 1.40 hours following administration.
19 . The liquid formulation of claim 2 wherein the formulation is a sublingual spray formulation that is capable of producing a droplet size distribution wherein the AUCinf (h*ng/mL) of buprenorphine is from 19320±6190 to 48970±13810 and the AUCinf (h*ng/mL) of naloxone is from 11.87±3.903 to 36.22±10.45.
20 . A method of treating pain comprising administering the liquid formulation of claim 1 to a patient in need thereof.
21 . A method of treating opioid dependence comprising administering the liquid formulation of claim 2 to a patient in need thereof.