PHARMACEUTICAL COMPOSITION

Abstract

Compositions and devices comprising apomorphine or pharmaceutically acceptable salts are described. The compositions may comprise a solution of apomorphine, or a pharmaceutically acceptable salt thereof, and a propellant. The solution may be a non-aqueous solution or an aqueous solution comprising degassed water. Devices may be configured to deliver compositions in form of particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) greater than 10 pm; and/or a fine particle fraction (FRF) less than 30%.

Claims

1. A composition comprising a solution of apomorphine, or a pharmaceutically acceptable salt thereof, the composition comprising a propellant, wherein the solution: i) is a non-aqueous solution; or ii) comprises degassed water.

2. A composition according to claim 1, wherein the propellant comprises a hydrofluorocarbon (HFA).

3. A composition according to claim 2, wherein the propellant comprises HFA-134a.

4. A composition according to any preceding claim comprising a co-solvent.

5. A composition according to claim 4, wherein the co-solvent comprises an organic solvent.

6. A composition according to claim 5, wherein the organic solvent comprises an alcohol, preferably ethanol.

7. A composition according to any preceding claim, wherein the composition comprises an excipient.

8. A composition according to claim 7, wherein the excipient is a polymer.

9. A composition according to claim 8, wherein the excipient is polyethylene glycol.

10. A composition according to any of claims 7 to 9, wherein the excipient is present in an amount of 0.2% to 2% by weight.

11. A composition according to any preceding claim, in which the apomorphine is present in an amount of 1 to 50% by weight.

12. A composition according to claim 11, in which the apomorphine is present in an amount of at least 5%, 10%, 20% or 30% by weight.

13. A composition according to any preceding claim in which the solution of apomorphine comprises water, and the amount of water in the composition is 10 to 40% by weight.

14. A composition according to any preceding claim, in which the propellant is present in an amount of at least 30% by weight, optionally up to 99% by weight of the composition.

15. A kit comprising: a) a canister comprising a composition as defined in any preceding claim; and b) an actuator for dispensing the composition from the canister.

16. A kit according to claim 15 which is configured to deliver the composition in the form of particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) greater than 10 μm; and/or a fine particle fraction (FPF) less than 30%.

17. A kit comprising a) a canister; and b) an actuator for dispensing the composition from the canister, wherein the canister comprises a composition, the composition comprising apomorphine or a pharmaceutically acceptable salt thereof, wherein the kit is configured to deliver the composition in the form of particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) greater than 10 μm; and/or a fine particle fraction (FPF) less than 30%

18. A kit according to claim 17, wherein i) the apomorphine or pharmaceutically acceptable salt thereof is in solution, optionally i) a non-aqueous solution; or ii) a solution comprising degassed water; and/or b) the composition comprises a propellant.

19. A kit according to according any of claims 15 to 18, wherein the canister comprises a metering valve.

20. A kit according to any of claims according to any of claims 15 to 19, wherein the kit is configured to deliver a pre-determined, preferably wherein the dose is 0.05 mg to 100 mg of apomorphine or pharmaceutically acceptable salt thereof.

21. A dispensing device comprising a composition as defined in any of claims 1 to 14.

22. A device according to claim 21, which is configured to deliver the composition in the form of particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) greater than 10 μm; and/or a fine particle fraction (FPF) less than 30%.

23. A dispensing device comprising a composition, the composition comprising apomorphine or a pharmaceutically acceptable salt thereof, wherein the device is configured to deliver the composition in form of particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) greater than 10 μm; and/or a fine particle fraction (FPF) less than 30%.

24. A device according to claim 23, wherein i) the apomorphine or pharmaceutically acceptable salt thereof is in solution, optionally i) a non-aqueous solution or ii) a solution comprising degassed water; and/or b) the composition comprises a propellant,

25. A device according any of claims 21 to 24 which is a spray device, preferably a pressurised metered dose dispensing device for dispensing a predetermined dose of the composition.

26. A device according to claim 25, which comprises: a) a container comprising the composition, preferably wherein the container comprises a metering valve; and b) an actuator for dispensing the composition from the container.

27. A device according to any of claims 21 to 26, which is configured to deliver a predetermined dose, preferably wherein the predetermined dose is 0.05 mg to 100 mg of apomorphine or pharmaceutically acceptable salt thereof.

28. A composition according to any of claims 1 to 14, for use as a medicament.

29. A composition according to any of claims 1 to 14, for use in treating Parkinson's disease or Male Erectile Dysfunction.

30. The composition for the use according to claim 29, wherein the composition is administered to the subject topically, preferably by buccal administration.

31. The composition for the use according to claim 29 or claim 30 which is administered to the subject in the form of particles or droplets having i) a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) greater than 10 μm; and/or a fine particle fraction (FPF) less than 30%.

32. A composition for use in treating Parkinson's disease in a subject, the composition comprising apomorphine, or a pharmaceutically acceptable salt thereof, wherein the composition is administered in the form of particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) greater than 10 μm; and/or a fine particle fraction (FPF) less than 30%.

33. A composition for the use according to claim 32, wherein the composition is administered to the subject topically, preferably by buccal administration,

34. The composition for the use according to claim 32 or claim 33, wherein the apomorphine or pharmaceutically acceptable salt thereof is in solution, optionally i) a non-aqueous solution, or ii) a solution comprising degassed water; and/or wherein the composition comprises a propellant.

35. A method comprising atomising a composition, the composition comprising apomorphine, or a pharmaceutically acceptable salt thereof, to form particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) greater than 10 μm; and/or a fine particle fraction (FPF) less than 30%.

36. A method according to claim 35, wherein the apomorphine or pharmaceutically acceptable salt thereof is in solution, optionally i) a non-aqueous solution, or ii) a solution comprising degassed water; and/or wherein the composition comprises a propellant.

Description

EXAMPLES

[0102] Preparation of Formulations

Example 1

[0103] Formulations of apomorphine were prepared at a 1.0 and 10% concentration in HFA 134a propellant. The details of these preparations are shown in Table 1.

TABLE-US-00001 TABLE 1 Details of manufactured formulation systems. Apomorphine Ethanol Acid HFA 134a Formulation Concentration Concentration Concentration Concentration Batch (% w/w) (% w/w) (% w/w) (% w/w) NP-AP-94-C070 1.0 0.0 0.0 99.0 NP-AP-94-C075 10.0  0.0 0.0 90.0

[0104] In the case of manufacture of drug-only formulations with HFA134a, the required amount of drug was weighed into the MDI canister and a 50 μL with Butyl elastomer (Bespak, Kings Lynn, UK) was crimped on to the canister. The HFA was filled through the valve and formulation was sonicated for 20-mins. The canisters were then placed valve down for 14-days to laager.

[0105] The chemical stability of the different apomorphine formulations manufactured in HFA 134a at T-zero, 24 and 72-hours is shown in Table 2.

TABLE-US-00002 TABLE 2 Chemical stability of the different HFA-based formulations at T-zero, 24 and 72-hours. T-zero 24-hours 72-hours Total Total Total Assay Imps. Assay Imps. Assay Imps. Canister (%) (%) (%) (%) (%) (%) NP-AP-94-C070 99.89 ND 99.67 ND 99.22 ND NP-AP-94-C075 97.45 0.08 90.45 0.29 89.98 0.55

[0106] Formulations prepared at 1.0% w/w concentration in HFA134a were extremely stable. There was no indication of impurities being generated up to 72-hours. In the case of the 1.0% w/w formulations they had passed the acceptance criteria as no individual impurity has greater than 0.2% and the sum of all unknown impurities was below 2.0%.

[0107] For the 10% API and HFA134a formulation there was increase in the measured impurities overtime as at 72-hours had increased to 0.55% w/w. There was no individual impurity greater than 0.2% and since the total impurities was less than 2.0% the formulation was within specification.

[0108] Hence, these data suggest that all formulations were chemically stable in HFA 134a.

Example 2

[0109] Formulations of apomorphine were prepared at a 30% concentration in HFA 134a propellant with and without an excipient, polyethylene glycol 400 (PEG400). The details of these preparations are shown in Table 3. The aqueous solvent was degassed prior to its use, to eliminate dissolved oxygen and the formulations were made in the absence of oxygen.

TABLE-US-00003 TABLE 3 Details of manufactured formulation systems. Apomorphine Excipient Aqueous HFA 134a Formulation Concentration (PEG400; Component Concentration Batch (% w/w)* % w/w) (% w/w) (% w/w) NP-94-149-001 30 — 35   35   NP-94-149-004 30 0.7 20.65 48.65 *A 30% concentration equates to a delivered dose of 23.2 mg of apomorphine via a 75 μl valve.

[0110] The composition was added to an MDI canister.

[0111] The chemical stability of the different apomorphine formulations manufactured in HFA 134a at T-zero, 28-, 32-, 36-, 40-, and 48-days is shown in Table 4.

TABLE-US-00004 TABLE 4 Chemical stability of the different HFA- based formulations for up to 48 days. 0-days 28-days 32-days Total Total Total Assay Imps. Assay Imps. Assay Imps. (%) (%) (%) (%) (%) (%) NP-94-149-001 99.75 ND 99.45 ND 99.14 ND NP-94-149-004 100.12 ND 99.19 ND 99.83 ND 36-days 40-days 48-days Total Total Total Assay Imps. Assay Imps. Assay Imps. (%) (%) (%) (%) (%) (%) NP-94-149-001 99.14 ND 99.28 ND 98.99 ND NP-94-149-004 99.49 ND 98.97 ND 98.12 0.08

[0112] The formulations prepared at 30% concentration in HFA 134a propellant were extremely stable for up to 48 days despite not being acidified.