SUBLINGUAL SPRAY FORMULATION COMPRISING DIHYDROARTEMESININ

Abstract

The invention provides pharmaceutical compositions for the treatment of neoplastic diseases, fluke infestations and Lyme disease, comprising compounds capable of providing dihydroartemesinin and a medium chain triglyceride formulated for transmucosal sublingual, buccal or nasal delivery, especially by a spray. Also provided are delivery devices containing the compositions.

Claims

1. A method of treating a neoplastic disease, said method comprising the administration to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition by the transmucosal sublingual, buccal, or nasal route, said composition comprising: a compound capable of providing dihydroartemesinin; and a pharmaceutically-acceptable excipient selected from the group consisting of: a medium chain length triglyceride; a short chain triglyceride; an omega-3-marine triglyceride; and a fish oil, rich in omega-3-acids; said composition formulated for transmucosal sublingual, buccal, or nasal dosage.

2. The method according to claim 1, wherein said disease comprises a malignant neoplasm.

3. The method according to claim 2, wherein said disease is selected from the group consisting of: pituitary adenoma; squamous cell carcinoma; breast cancer; non-Hodgkin's Lymphoma; skin cancer; lung cancer; and non-small cell lung carcinoma.

4. The method according to claim 1, wherein said composition consists essentially of: a compound capable of providing dihydroartemesinin; and a pharmaceutically-acceptable excipient selected from the group consisting of: a medium chain length triglyceride; a short chain triglyceride; an omega-3-marine triglyceride; and a fish oil, rich in omega-3-acids; said composition formulated for transmucosal sublingual, buccal, or nasal dosage.

5. The method according to claim 1, wherein said composition consists essentially of: a compound capable of providing dihydroartemesinin; and a pharmaceutically acceptable excipient consisting essentially of: a triglyceride, which is liquid at 37° C.; and a medium chain length triglyceride; said composition formulated for transmucosal sublingual, buccal, or nasal dosage.

6. The method according to claim 1, wherein said composition is substantially free of water.

7. The method according to claim 1, wherein said composition is substantially free of ethanol.

8. The method according to claim 1, wherein said composition further comprises an essential oil selected from the group consisting of menthol, vanillin oil, orange oil, lemon oil, clove oil, peppermint oil, and spearmint oil.

9. The method according to claim 1, wherein said composition is formulated for sublingual delivery.

10. The method according to claim 1, wherein the compound capable of providing dihydroartemesinin is artemether or arteether.

11. The method according to claim 1, wherein the excipient is a medium chain length triglyceride.

12. The method according to claim 8, wherein the essential oil is menthol.

13. The method according to claim 1, wherein the compound capable of providing dihydroartemesinin is artemether, the excipient is a medium chain length triglyceride, the composition further comprises menthol, and the composition is formulated as a transmucosal sublingual dosage.

14. A method of treating a fluke infestation, said method comprising the administration to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition by the transmucosal sublingual, buccal, or nasal route, said composition comprising: a compound capable of providing dihydroartemesinin; and a pharmaceutically-acceptable excipient selected from the group consisting of: a medium chain length triglyceride; a short chain triglyceride; an omega-3-marine triglyceride; and a fish oil, rich in omega-3-acids; said composition formulated for transmucosal sublingual, buccal, or nasal dosage.

15. The method according to claim 14, wherein said composition consists essentially of: a compound capable of providing dihydroartemesinin; and a pharmaceutically-acceptable excipient selected from the group consisting of: a medium chain length triglyceride; a short chain triglyceride; an omega-3-marine triglyceride; and a fish oil, rich in omega-3-acids; said composition formulated for transmucosal sublingual, buccal, or nasal dosage.

16. The method according to claim 14, wherein said composition consists essentially of: a compound capable of providing dihydroartemesinin; and a pharmaceutically acceptable excipient consisting essentially of: a triglyceride, which is liquid at 37° C.; and a medium chain length triglyceride; said composition formulated for transmucosal sublingual, buccal, or nasal dosage.

17. The method according to claim 14, wherein said composition is formulated for sublingual delivery.

18. A method of treating Lyme disease (borreliosis), said method comprising the administration to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition by the transmucosal sublingual, buccal, or nasal route, said composition comprising: a compound capable of providing dihydroartemesinin; and a pharmaceutically-acceptable excipient selected from the group consisting of: a medium chain length triglyceride; a short chain triglyceride; an omega-3-marine triglyceride; and a fish oil, rich in omega-3-acids; said composition formulated for transmucosal sublingual, buccal, or nasal dosage.

19. The method according to claim 18, wherein said composition consists essentially of: a compound capable of providing dihydroartemesinin; and a pharmaceutically-acceptable excipient selected from the group consisting of: a medium chain length triglyceride; a short chain triglyceride; an omega-3-marine triglyceride; and a fish oil, rich in omega-3-acids; said composition formulated for transmucosal sublingual, buccal, or nasal dosage.

20. The method according to claim 18, wherein said composition consists essentially of: a compound capable of providing dihydroartemesinin; and a pharmaceutically acceptable excipient consisting essentially of: a triglyceride, which is liquid at 37° C.; and a medium chain length triglyceride; said composition formulated for transmucosal sublingual, buccal, or nasal dosage.

Description

FIGURE CAPTIONS

[0086] FIG. 1: Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of 15 mg Artemether Sublingual Spray 3 mg/actuation (T1) and single oral administration of 30 mg Artemether Tablets 10 mg/tablet (T4). Mean±SD (•=reference, T4, □=test, T1)

[0087] FIG. 2: Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of 30 mg Artemether Sublingual Spray 3 mg/actuation (T2) and single oral administration of 30 mg Artemether Tablets 10 mg/tablet (T4). Mean±SD (•=reference, T4, □=test, T2)

[0088] FIG. 3: Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of 30 mg Artemether Sublingual Spray 6 mg/actuation (T3) versus single oral administration of 30 mg Artemether Tablets 10 mg/tablet (T4). Mean±SD (•=reference, T4, □=test, T3)

[0089] FIG. 4: Plot of mean plasma artemether concentration vs time with standard deviation following a single sublingual administration of 15mg Artemether Sublingual Spray 3 mg/actuation (T1) versus single sublingual administration of 30 mg Artemether Sublingual Spray 3 mg/actuation (T2). Mean±SD (•=reference, T2, □=test, T1)

[0090] FIG. 5: Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of 30 mg Artemether Sublingual Spray 3 mg/actuation (T2) versus single sublingual administration of 30 mg Artemether Sublingual Spray 6 mg/actuation (T3). Mean±SD (•=reference, T3, □=test, T2)

[0091] FIG. 6: Plot of mean plasma Artemether concentration vs time with standard deviation following a single sublingual administration of 15 mg Artemether Sublingual Spray 3 mg/actuation (T1) versus single sublingual administration of 30 mg Artemether Sublingual Spray 6 mg/actuation (T3). Mean±SD (•=reference, T3, □=test, T1)

[0092] FIG. 7: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single sublingual administration of 15 mg Artemether Sublingual Spray 3mg/actuation (T1) and single oral administration of 30 mg Artemether Tablets 10 mg/tablet (T4). Mean±SD (•=reference, T4, □=test, T1)

[0093] FIG. 8: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single sublingual administration of 30 mg Artemether Sublingual Spray 3 mg/actuation (T2) and single oral administration of 30 mg Artemether Tablets 10 mg/tablet (T4). Mean±SD (•=reference, T4, □=test, T2)

[0094] FIG. 9: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single sublingual administration of 30 mg Artemether Sublingual Spray 6 mg/actuation (T3) versus single oral administration of 30 mg Artemether Tablets 10 mg/tablet (T4). Mean±SD (•=reference, T4, □=test, T3)

[0095] FIG. 10: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single sublingual administration of 15 mg Artemether Sublingual Spray 3 mg/actuation (T1) versus single sublingual administration of 30 mg Artemether Sublingual Spray 3 mg/actuation (T2). Mean±SD (•=reference, T2, □=test, T1)

[0096] FIG. 11: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single sublingual administration of 30 mg Artemether Sublingual Spray 3 mg/actuation (T2) versus single sublingual administration of 30 mg Artemether Sublingual Spray 6 mg/actuation (T3). Mean±SD (•=reference, T3, □=test, T2)

[0097] FIG. 12: Plot of mean plasma Dihydroartemisinin concentration vs time with standard deviation following a single sublingual administration of 15 mg Artemether Sublingual Spray 3 mg/actuation (T1) versus single sublingual administration of 30 mg Artemether Sublingual Spray 6 mg/actuation (T3). Mean±SD (•=reference, T3, □=test, T1)

[0098] FIG. 13A: Representative chromatogram of Artemether formulation in a 20% v/v ethanol +80% v/v propellant solvent system.

[0099] FIG. 13B: Representative chromatogram of Artemether formulation in a 50% v/v ethanol +50% v/v propellant solvent system.

[0100] FIG. 13C: Representative chromatogram of Artemether formulation in an ethanol solvent system.

[0101] FIG. 13D: Representative chromatogram of Artemether formulation in a Miglyol® solvent system.

[0102] FIG. 14: Day 1 vs Day 5 Dihydroartemisinin Mean Concentration (ng/mL) vs Time for 3 mg/actuation (•=Day 1, □=Day 5).