Stable oral solutions for combined API

1. A pharmaceutical composition comprising, in the form of a solution:

baclofen or a pharmaceutically acceptable salt thereof, sorbitol or a pharmaceutically acceptable salt thereof, and naltrexone or a pharmaceutically acceptable salt thereof as active ingredients, and

an acetate or citrate buffer, or a combination thereof;

wherein the solution has a pH of between about 4 and about 7.

2. The composition of claim 1 , comprising naltrexone or a pharmaceutically acceptable salt thereof in an amount between about 1 and about 200 μg/mL.

3. The composition of claim 2 , comprising naltrexone or a pharmaceutically acceptable salt thereof in an amount between about 10 and about 100 μg/mL.

4. The composition of claim 2 , wherein naltrexone or a pharmaceutically acceptable salt thereof is in an amount of about 70 μg/mL.

5. The composition of claim 2 , comprising naltrexone or a pharmaceutically acceptable salt thereof in an amount of about 140 μg/mL.

6. The composition of claim 1 , wherein baclofen or a pharmaceutically acceptable salt thereof, sorbitol or a pharmaceutically acceptable salt thereof, and naltrexone or a pharmaceutically acceptable salt thereof are present in a relative weight ratio of about 8.6/300/1.

7. The composition of claim 1 , comprising:

sorbitol, or a pharmaceutically acceptable salt thereof, in an amount of about 4.2 mg/mL,

naltrexone, or a pharmaceutically acceptable salt thereof, in an amount of about 0.014 mg/mL, and

baclofen, or a pharmaceutically acceptable salt thereof, in an amount of about 0.12 mg/mL.

8. The composition of claim 1 , comprising:

sorbitol, or a pharmaceutically acceptable salt thereof, in an amount of about 21 mg/mL,

naltrexone, or a pharmaceutically acceptable salt thereof, in an amount of about 0.07 mg/mL, and

baclofen, or a pharmaceutically acceptable salt thereof, in an amount of about 0.6 mg/mL.

9. The composition of claim 1 , comprising:

sorbitol, or a pharmaceutically acceptable salt thereof, in an amount of about 42 mg/mL,

naltrexone, or a pharmaceutically acceptable salt thereof, in an amount of about 0.14 mg/mL, and

baclofen, or a pharmaceutically acceptable salt thereof, in an amount of about 1.2 mg/mL.

10. The composition of claim 1 , further comprising at least one flavoring agent.

11. The composition of claim 10 , wherein the at least one flavoring agent is isoamyl acetate.

12. The composition of claim 11 , comprising isoamyl acetate in an amount between about 0.1 and about 2.0 mg/mL.

13. The composition of claim 12 , comprising isoamyl acetate in an amount of about 0.4 mg/mL.

14. The composition of claim 1 , further comprising at least one preservative.

15. The composition of claim 14 , wherein the at least one preservative is a paraben.

16. The composition of claim 15 , wherein the at least one preservative is methyl paraben, propyl paraben, or a combination thereof.

17. The composition of claim 16 , comprising methyl paraben in a concentration of about 0.18 g per 100 mL or propyl paraben in a concentration of about 0.02 g per 100 mL of the composition, respectively; or a combination thereof.

18. A pharmaceutical composition comprising, in the form of a solution:

sorbitol, or a pharmaceutically acceptable salt thereof, in an amount of about 4.2 mg/mL,

naltrexone, or a pharmaceutically acceptable salt thereof, in an amount of about 0.014 mg/mL,

baclofen, or a pharmaceutically acceptable salt thereof, in an amount of about 0.12 mg/mL,

isoamyl acetate in an amount of about 0.4 mg/mL,

sodium methyl paraben in an amount of about 0.18 mg/mL,

sodium propyl paraben in an amount of about 0.02 mg/mL, and

an acetate buffer;

wherein the solution has a pH of between 4 and 7.

19. The composition of claim 18 , wherein the pH of the solution is about 5.5.

20. The composition of claim 18 , wherein the acetate buffer comprises:

sodium acetate in an amount of about 2.221 g per 100 g of the final composition;

acetic acid in an amount of about 0.241 g per 100 g of the final composition; and

water in an amount of about 93.070 g per 100 g of the final composition.

21. The composition of claim 1 , wherein the composition is free of paraben.

22. The composition of claim 1 , comprising at least one further compound selected from the group consisting of antioxidants, emulsifiers, viscosity modifiers, sweeteners, flavor enhancers, coloring agents, co-solvents, solubilizers, and combinations thereof.

23. The composition of claim 1 , wherein the sorbitol or a pharmaceutically acceptable salt thereof is D-sorbitol, the baclofen or a pharmaceutically acceptable salt thereof is RS baclofen, and the naltrexone or a pharmaceutically acceptable salt thereof is naltrexone HCl.

24. The composition of claim 7 , wherein the sorbitol or a pharmaceutically acceptable salt thereof is D-sorbitol, the baclofen or a pharmaceutically acceptable salt thereof is RS baclofen, and the naltrexone or a pharmaceutically acceptable salt thereof is naltrexone HCl.

25. The composition of claim 8 , wherein the sorbitol or a pharmaceutically acceptable salt thereof is D-sorbitol, the baclofen or a pharmaceutically acceptable salt thereof is RS baclofen, and the naltrexone or a pharmaceutically acceptable salt thereof is naltrexone HCl.

26. The composition of claim 9 , wherein the sorbitol or a pharmaceutically acceptable salt thereof is D-sorbitol, the baclofen or a pharmaceutically acceptable salt thereof is RS baclofen, and the naltrexone or a pharmaceutically acceptable salt thereof is naltrexone HCl.

27. A method for preparing the composition of claim 1 , comprising the steps of providing baclofen or a pharmaceutically acceptable salt thereof, sorbitol or a pharmaceutically acceptable salt thereof, and naltrexone or a pharmaceutically acceptable salt thereof; and admixing said baclofen or a pharmaceutically acceptable salt thereof, sorbitol or a pharmaceutically acceptable salt thereof, and naltrexone or a pharmaceutically acceptable salt thereof in a citrate or acetate buffer, wherein the resulting solution has a pH between 4 and 7.

28. The method of claim 27 , comprising the steps of:

i) preparing a first solution by:

dispensing about 20% of a desired final volume of an acetate buffer;

then dissolving sodium methyl paraben and sodium propyl paraben;

then heating to 45-55° C., optionally with stirring, until dissolved;

then cooling to about 25-35° C.;

ii) preparing a second solution by:

dispensing about 70% of the desired final volume of acetate buffer;

then adding sorbitol, naltrexone, and baclofen;

then mixing until dissolved;

iii) mixing the first and second solutions obtained in step i) and ii);

iv) optionally, adding a flavoring agent to the solution obtained in step iii) and mixing until dissolved;

v) if needed, adjusting pH to 5.4-5.6 with 50% w/w NaOH solution or acetic acid; and

vi) if needed, adding sufficient acetate buffer to reach the desired final volume.

29. The method of claim 27 , comprising the steps of:

i) dispensing about 90% of an amount of water required for a total batch size;

ii) optionally adding sodium methyl paraben and sodium propyl paraben, then mixing until dissolved;

iii) adding sodium acetate and acetic acid, then mixing until dissolved;

iv) adding sorbitol, naltrexone and baclofen;

v) adding isoamyl acetate, then mixing until dissolved;

vi) if needed, adjusting pH to 5.4-5.6 with a 50% w/w NaOH solution or acetic acid; and

vii) if needed, adding sufficient water to provide a total weight consistent with the total batch size.

30. A method of treating Charcot-Marie-Tooth disease of type 1A (CMT1A), comprising administering the composition of claim 1 to a human subject in need thereof.

31. A container comprising the composition of claim 1 .

32. A container comprising the composition of claim 1 in a volume of 100 mL.

33. A patient pack comprising a set of single-dose sachets or ampoules containing the composition of claim 1 in a suitable amount for treating CMT1A in a human subject in need thereof.

34. A pharmaceutical kit of parts comprising a bottle comprising the composition of claim 1 ; a cap or a pipette or a pipette-cap system; and optionally instructions for administration of the composition.

35. A pharmaceutical kit of parts that allows preparation of the composition of claim 1 , and optionally instructions for preparing the composition.