Sublingual buprenorphine spray
View Patent ↗The invention provides sublingual formulations containing buprenorphine, a pharmaceutically acceptable salt thereof, or a derivative thereof. The invention further provides sublingual 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 sublingual formulations containing buprenorphine, a pharmaceutically acceptable salt thereof, or a derivative thereof to a patient in need thereof.
1. A sublingual spray formulation comprising from 0.1625% to 1.3% w/w of buprenorphine, a pharmaceutically acceptable salt thereof, or a derivative thereof, water as a solvent, mixture of an alcohol and a glycol as a cosolvent, and from 0.005% to 0.02% w/w of an antioxidant selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium ascorbate, sodium thiosulfate, and a mixture thereof, wherein the ratio of antioxidant to buprenorphine is from 0.004:1 to 0.1:1 and the % w/w is of the total formulation.
2. The sublingual spray formulation of claim 1 further comprising naloxone, a pharmaceutically acceptable salt thereof, or a derivative thereof.
3. A sublingual spray formulation comprising:
buprenorphine, a pharmaceutically acceptable salt thereof or a derivative thereof in an amount from 0.1625% to 1.3% w/w;
water as a solvent in an amount from about 10% to about 95% w/w;
a cosolvent consisting of a mixture of about 55% w/w of an alcohol and about 5% w/w of a glycol; and
an antioxidant selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium ascorbate, sodium thiosulfate, and a mixture thereof, in an amount from 0.005% to 0.02% w/w,
wherein the ratio of antioxidant to buprenorphine is from 0.004:1 to 0.1:1 and the % w/w is of the total formulation.
4. The formulation of claim 3 further comprising menthol.
5. The formulation of claim 4 , wherein:
water as a solvent is at an amount from about 38% to about 40% w/w;
the cosolvent consists of a mixture of ethanol in an amount of 55% w/w and propylene glycol in an amount of about 5% w/w;
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 0.005% w/w; and
menthol is at an amount of about 0.05% w/w,
wherein the ratio of antioxidant to buprenorphine is from 0.01:1 to 0.1:1.
6. A sublingual spray formulation comprising:
buprenorphine, a pharmaceutically acceptable salt thereof or a derivative thereof at an amount from 1.4% to 8.6% w/w;
naloxone, a pharmaceutically acceptable salt thereof or a derivative thereof at an amount from about 0.005% to about 3% w/w;
water as a solvent at an amount from about 10% w/w to 95% w/w;
a cosolvent consisting of a mixture of about 55% of an alcohol and about 5% of a glycol;
an antioxidant selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium ascorbate, sodium thiosulfate, and a mixture thereof, in an amount from 0.005% to 0.02% w/w; and
a chelating agent in an amount from about 0.001% to about 0.1% w/w,
wherein the ratio of antioxidant to buprenorphine is from 0.0006:1 to 0.014:1 and the % w/w is of the total formulation.
7. The formulation of claim 6 further comprising menthol.
8. The sublingual spray formulation of claim 7 , wherein:
naloxone, a pharmaceutically acceptable salt thereof or a derivative thereof is at an amount from about 0.4% to about 2.4% w/w;
water as a solvent is at an amount from about 28% to about 38% w/w;
the cosolvent consists of a mixture of ethanol in an amount of 55% w/w and propylene glycol in an amount of about 5% w/w;
the antioxidant is sodium ascorbate at an amount of about 0.02% w/w;
the chelating agent is disodium edetate at an amount of about 0.005% w/w; and
menthol is at an amount of about 0.05% w/w.
9. The sublingual spray formulation of claim 1 that 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 sublingual spray formulation of claim 1 that is capable of producing a droplet size distribution wherein:
the mean Dv(10) is from about 10 to about 30 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 sublingual spray formulation of claim 1 that is capable of producing a spray span ((Dv90-Dv10)/Dv50) of from about 1.2 to about 3.3.
12. The sublingual spray formulation of claim 1 that is capable of producing a spray plume that has an ovality ratio of from about 1.1 to 2.4.
13. The sublingual spray formulation of claim 1 that 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.
14. The sublingual spray formulation of claim 1 that is capable of producing a D(4,3) of 55 to 95 microns.
15. The sublingual spray formulation of claim 1 that is capable of producing a droplet size distribution wherein the C max (ng/mL) of buprenorphine is from about 0.6 to about 0.8 following administration.
16. The sublingual spray formulation of claim 1 that is capable of producing a droplet size distribution wherein the T max of buprenorphine is from about 1.5 to about 1.9 hours following administration.
17. A method of treating pain comprising administering the sublingual spray formulation of claim 1 to a patient in need thereof.
18. A method of treating opioid dependence comprising administering the sublingual spray formulation of claim 6 to a patient in need thereof.