Granted Patent B2

US 9,918,981 · App. 15/336,547 · Granted Mar 20, 2018

Abstract

Claims (55)

1. A liquid formulation comprising an effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a derivative thereof, water as a solvent, a mixture of an alcohol and a glycol as a cosolvent, and an antioxidant, wherein the ratio of antioxidant to buprenorphine is from 0.01:1 to 0.18:1.

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 , 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. The liquid formulation of claim 1 that is capable of producing a D(4,3) of 50 to 95 microns.

10. 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 about 0.6 to about 1.5.

11. 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 1.5 to about 1.9 hours following administration.

12. A sublingual spray formulation comprising:

buprenorphine, a pharmaceutically acceptable salt thereof or a derivative thereof;

water as a solvent in an amount from about 10% to about 95% w/w;

a cosolvent consisting of a mixture of an alcohol from about 10% w/w to about 80% w/w and a glycol in an amount from about 0.5% to about 50% w/w; and

an antioxidant,

wherein the ratio of antioxidant to buprenorphine is from 0.01:1 to 0.18:1 and the % w/w is weight by total weight of the formulation.

13. The formulation of claim 12 further comprising menthol from about 0.005% w/w to about 0.5% w/w.

14. The formulation of claim 13 , wherein:

water as a solvent is at an amount from about 20% to about 60% w/w;

the cosolvent consists of a mixture of an alcohol from about 30% w/w to about 60% w/w and a glycol in an amount from about 1% to about 10% w/w; and.

15. The formulation of claim 13 , 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) and butylated hydroxytoluene (BHT); and

menthol is at an amount of about 0.05% w/w.

16. A sublingual spray formulation comprising:

buprenorphine, a pharmaceutically acceptable salt thereof or a derivative thereof;

naloxone, a pharmaceutically acceptable salt thereof or a derivative thereof;

water;

a cosolvent consisting of a mixture of an alcohol and a glycol;

an antioxidant; and

a chelating agent,

wherein the ratio of antioxidant to buprenorphine is from 0.002:1 to 0.03:1.

17. The sublingual spray formulation of claim 16 , wherein:

naloxone, a pharmaceutically acceptable salt thereof or a derivative thereof at an amount from about 0.1% to about 3% w/w;

water as a solvent in an amount from about 20% to about 45% w/w;

the cosolvent consists of a mixture of ethanol in an amount of 50% w/w to about 60% w/w and propylene glycol in an amount of about 4% w/w to 6% w/w;

the antioxidant is sodium ascorbate;

the chelating agent is disodium edetate at an amount of about 0.001% to about 0.01% w/w; and

menthol is at an amount of about 0.005% to 0.5% w/w, wherein the % w/w is weight by total weight of the formulation.

18. The liquid formulation of claim 16 , wherein the formulation is a sublingual spray formulation comprising:

naloxone, a pharmaceutically acceptable salt thereof or a derivative thereof at an amount from about 0.1% to about 3% w/w;

menthol at an amount of about 0.05% w/w;

disodium edetate at an amount of about 0.005% w/w;

sodium ascorbate

ethanol in an amount of about 55%;

propylene glycol in an amount from about 5% w/w;

water in an amount from about 25% w/w to 40% w/w;

wherein the % w/w is weight by total weight of the formulation.

19. A method of treating pain comprising administering the liquid formulation of claim 16 to a patient in need thereof.

20. A method of treating opioid dependence comprising administering the liquid formulation of claim 2 to a patient in need thereof.

Assignments (9)