Acetaminophen pregabalin combinations and methods of treating pain

1. A pharmaceutical composition comprising, in a liquid unit dosage form:

a) a gabapentinoid, wherein the gabapentinoid is pregabalin, or a pharmaceutically acceptable salt thereof;

b) acetaminophen;

c) a pH-adjusting agent; and

d) water;

wherein the liquid unit dosage form has a pH of between 5 and 7;

wherein the gabapentinoid is present in the liquid unit dosage form in an amount from about 0.1 mg/mL to about 50 mg/mL; and

wherein the acetaminophen is present in the liquid unit dosage form in an amount from about 2 mg/mL to about 20 mg/mL.

2. The pharmaceutical composition of claim 1 , wherein the gabapentinoid is the pharmaceutically acceptable salt of pregabalin.

3. The pharmaceutical composition of claim 1 , wherein the liquid unit dosage form further comprises an acid, a conjugate base of the acid, or both the acid and the conjugate base of the acid.

4. The pharmaceutical composition of claim 3 , wherein the acid is citric acid.

5. The pharmaceutical composition of claim 3 , wherein the acid is acetic acid.

6. The pharmaceutical composition of claim 3 , wherein the acid is phosphoric acid.

7. The pharmaceutical composition of claim 1 , wherein the liquid unit dosage form further comprises an isotonicity inducing agent.

8. The pharmaceutical composition of claim 7 , wherein the isotonicity inducing agent is sodium chloride.

9. The pharmaceutical composition of claim 7 , wherein the isotonicity inducing agent is mannitol.

10. The pharmaceutical composition of claim 1 , wherein the pH-adjusting agent is sodium hydroxide.

11. The pharmaceutical composition of claim 1 , wherein the pH-adjusting agent is hydrochloric acid.

12. The pharmaceutical composition of claim 1 , wherein the liquid unit dosage form further comprises a decomposition product of the gabapentinoid at a level of no more than about 5%.

13. The pharmaceutical composition of claim 12 , wherein the decomposition product of the gabapentinoid is 4-(2-methylpropyl)pyrrolidin-2-one.

14. The pharmaceutical composition of claim 1 , wherein the liquid unit dosage form further comprises a decomposition product of the acetaminophen at a level of no more than about 0.5%.

15. The pharmaceutical composition of claim 14 , wherein the decomposition product of the acetaminophen is 4-aminophenol.

16. The pharmaceutical composition of claim 1 , wherein the pH of the liquid unit dosage form is 5.

17. The pharmaceutical composition of claim 1 , wherein the pH of the liquid unit dosage form is about 5.5.

18. The pharmaceutical composition of claim 1 , wherein the pH of the liquid unit dosage form is about 6.

19. The pharmaceutical composition of claim 1 , wherein the liquid unit dosage form further comprises:

e) an acid, a conjugate base of the acid, or both the acid and the conjugate base of the acid;

f) sodium chloride;

g) a decomposition product of the gabapentinoid; and

h) a decomposition product of the acetaminophen.

20. The pharmaceutical composition of claim 1 , wherein the liquid unit dosage form comprises:

a) the gabapentinoid, wherein the gabapentinoid is pregabalin, or a pharmaceutically acceptable salt thereof, wherein the pregabalin is present in the liquid unit dosage form in an amount of about 0.1 to about 20 mg/mL;

b) the acetaminophen, wherein the acetaminophen is present in the liquid unit dosage form in an amount of about 10 mg/mL;

c) the pH-adjusting agent, wherein the pH-adjusting agent is sodium hydroxide;

d) about 1.87 mg/mL sodium dihydrogen phosphate;

e) about 5.5 mg/mL sodium chloride; and

f) water.

21. The pharmaceutical composition of claim 20 , wherein the pH of the liquid unit dosage form is about 6.

22. The pharmaceutical composition of claim 1 , wherein the liquid unit dosage form comprises:

a) the gabapentinoid, wherein the gabapentinoid is pregabalin, or a pharmaceutically acceptable salt thereof, wherein the pregabalin is present in the liquid unit dosage form in an amount of about 0.1 to about 20 mg/mL;

b) the acetaminophen, wherein the acetaminophen is present in the liquid unit dosage form in an amount of about 10 mg/mL;

c) the pH-adjusting agent, wherein the pH-adjusting agent is sodium hydroxide;

d) equal or less than 0.5 mg/mL citric acid monohydrate;

e) equal or less than 6.0 mg/mL sodium chloride; and

f) water.

23. The pharmaceutical composition of claim 22 , wherein the pH of the liquid unit dosage is about 6.

24. The pharmaceutical composition of claim 1 , wherein the liquid unit dosage form comprises:

a) the gabapentinoid, wherein the gabapentinoid is pregabalin, or a pharmaceutically acceptable salt thereof, wherein the pregabalin is present in the liquid unit dosage form in an amount of about 0.1 to about 20 mg/mL;

b) the acetaminophen, wherein the acetaminophen is present in the liquid unit dosage form in an amount of about 10 mg/mL;

c) the pH-adjusting agent, wherein the pH-adjusting agent is sodium hydroxide;

d) about 1.55 mg/mL L-Histidine;

e) about 2.25 mg/mL sodium chloride; and

f) water.

25. The pharmaceutical composition of claim 24 , wherein the pH of the liquid unit dosage form is about 6.

26. The pharmaceutical composition of claim 1 , wherein the liquid unit dosage form comprises:

a) the gabapentinoid, wherein the gabapentinoid is pregabalin, or a pharmaceutically acceptable salt thereof, wherein the pregabalin is present in the liquid unit dosage form in an amount of about 0.1 to about 20 mg/mL;

b) the acetaminophen, wherein the acetaminophen is present in the liquid unit dosage form in an amount of about 10 mg/mL;

c) the pH-adjusting agent, wherein the pH-adjusting agent is sodium hydroxide;

d) between 0.2 mg/mL and 0.6 mg/mL citric acid monohydrate;

e) between 1.5 mg/mL and about 6 mg/mL sodium chloride; and

f) water.

27. The pharmaceutical composition of claim 26 , wherein the pH of the liquid unit dosage form is about 5.5.

28. The pharmaceutical composition of claim 1 , wherein the liquid unit dosage form comprises:

a) the gabapentinoid, wherein the gabapentinoid is pregabalin, or a pharmaceutically acceptable salt thereof, wherein the pregabalin is present in the liquid unit dosage form in an amount of about 0.1 to about 20 mg/mL;

b) the acetaminophen, wherein the acetaminophen is present in the liquid unit dosage form in an amount of about 10 mg/mL;

c) the pH-adjusting agent, wherein the pH-adjusting agent is sodium hydroxide;

d) about 0.6 mg/mL acetic acid;

e) about 5 mg/mL sodium chloride; and

f) water.

29. The pharmaceutical composition of claim 28 , wherein the pH of the liquid unit dosage form is about 5.5.

30. The pharmaceutical composition of claim 1 , wherein the liquid unit dosage form comprises:

a) the gabapentinoid, wherein the gabapentinoid is pregabalin, or a pharmaceutically acceptable salt thereof, wherein the pregabalin is present in the liquid unit dosage form in an amount of about 0.1 to about 20 mg/mL;

b) the acetaminophen, wherein the acetaminophen is present in the liquid unit dosage form in an amount of about 10 mg/mL;

c) the pH-adjusting agent, wherein the pH-adjusting agent is sodium hydroxide;

d) about 1.2 mg/mL sodium dihydrogen phosphate;

e) about 5.5 mg/mL sodium chloride; and

f) water.

31. The pharmaceutical composition of claim 30 , wherein the pH of the liquid unit dosage form is about 6.

32. The pharmaceutical composition of claim 1 , wherein the liquid unit dosage form further comprises an impurity, wherein the impurity is determined based on:

(a) injecting the liquid unit dosage form into a high performance liquid chromatography apparatus, wherein the apparatus comprises:

(i) a chromatography column containing adsorbent particles as a stationary phase;

(ii) a first mobile phase passing through the chromatography column, wherein the first mobile phase is aqueous potassium dihydrogen phosphate at pH 7 with 2% acetonitrile; and

(iii) a second mobile phase passing through the chromatography column, wherein the second mobile phase is aqueous potassium dihydrogen phosphate at pH 7 with 60% acetonitrile;

(b) running the liquid unit dosage form through the chromatography column for 34 minutes;

(c) eluting the impurity from the chromatography column using a gradient of the first mobile phase, and a gradient of the second mobile phase, wherein each of the first mobile phase and second mobile phase are run at a flow rate of 1.5 mL/min through the chromatography column;

(d) passing the impurity through a UV detector to generate a UV spectrum of the eluted unit dosage form and the impurity;

(e) identifying the impurity based on a retention time of the impurity relative to a standard; and

(f) calculating an amount of the impurity based on an integration of a peak obtained for the impurity from the UV spectrum.

33. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for packaging in a bag, a glass vial, or a prefilled syringe.

34. The pharmaceutical composition of claim 33 , wherein the pharmaceutical composition is formulated for packaging in a bag, wherein the bag is a polymer bag.

35. The pharmaceutical composition of claim 34 , wherein the polymer bag is a polypropylene bag, and the polypropylene bag is further packaged in an aluminum over-pouch.

36. The pharmaceutical composition of claim 35 , wherein the aluminum over-pouch contains an oxygen scavenger.