Pharmaceutical suspensions containing drug particles, devices for their administration, and methods of their use

• US 10,300,033 B2
• Filed: 02/02/2018
• Issued: 05/28/2019
• Est. Priority Date: 05/06/2015
• Status: Active Grant

• Current Assignee: Synagile Corporation
• Original Assignee: Synagile Corporation
• Inventors: Heller, Adam
• Primary Examiner(s): Henley, III, Raymond J
• Application Number:
  US15/887,243
• Publication Number:
  US 20180177752A1
• Time in Patent Office: 480 Days
• Field of Search: 514561
• CPC Class Codes: A61C 19/063 Medicament applicators for teeth or gums, e.g. treatment with fluorides
• CPC Class Codes: A61C 7/08 Mouthpiece-type retainers or positioners, e.g. for both the lower and upper arch arch-shaped medicament applicators for teeth or gums A61C19/063; mouthguards for protecting the teeth of sportsmen A63B71/085
• CPC Class Codes: A61J 7/0076 Medicament distribution means with pill counting devices A61J7/02; with time indication A61J7/04; containers or packages with special means for dispensing contents B65D83/00
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0097 Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips intradermal microneedle arrays A61K9/0021; MEMS in general B81B7/02
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61M 11/006 operated by applying mechanical pressure to the liquid to be sprayed or atomised
• CPC Class Codes: A61M 2205/07 having air pumping means
• CPC Class Codes: A61M 2205/3331 Pressure; Flow
• CPC Class Codes: A61M 2205/3368 Temperature
• CPC Class Codes: A61M 2205/8206 battery-operated
• CPC Class Codes: A61M 2210/0637 : Teeth
• CPC Class Codes: A61M 31/002 : Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: B81B 7/02 : containing distinct electrical or optical devices of particular relevance for their function, e.g. microelectro-mechanical systems [MEMS] B81B7/04 takes precedence

Abstract

The invention features a pharmaceutical suspension containing drug particles, a drug delivery device anchored in the mouth for continuously administering the pharmaceutical suspension, and methods of their use.

Claims

1. A pharmaceutical composition comprising a suspension comprising (i) from about 35% to 70% (w/w) drug particles, (ii) from 19% to 30% (w/w) of one or more water-immiscible compounds, (iii) from 2% to 16% (w/w) water, and (iv) from 1% to 8% (w/w) surfactant, wherein the pharmaceutical composition is physically stable.

7. The pharmaceutical composition of claim 1, wherein said suspension has a dynamic viscosity of at least 100 cP at 37°

C.

8. The pharmaceutical composition of claim 7, wherein the D₅₀ of the drug particles is greater than or equal to 1 μ

m and less than or equal to 500 μ

m.

9. The pharmaceutical composition of claim 8, wherein said suspension does not cream or sediment when centrifuged for 1 hour at an acceleration of about 5,000 G at 25±

3°

C.

10. The pharmaceutical composition of claim 9, wherein after said centrifugation for 1 hour at an acceleration of about 5,000 G at 25±

3°

C. the concentrations of drug in the layer containing the top 20 volume % and the layer containing the bottom 20 volume % of the composition differ by less than 6%.

11. The pharmaceutical composition of claim 8, wherein the shelf life of said pharmaceutical composition is 6 months or longer at 5±

3°

C. and said pharmaceutical composition does not substantially cream or sediment when stored for 6 months at 5±

3°

C.

12. The pharmaceutical composition of claim 9, wherein said suspension comprises less than or equal to about 12% (w/w) water.

13. The pharmaceutical composition of claim 12, wherein said suspension comprises 8±

2% (w/w) water.

14. The pharmaceutical composition of claim 7, comprising an edible oil.

15. The pharmaceutical composition of claim 14, wherein said oil comprises a saturated fatty acid triglyceride, an unsaturated fatty acid triglyceride, a mixed saturated and unsaturated fatty acid triglyceride, a medium-chain fatty acid triglyceride, canola oil, coconut oil, palm oil, olive oil, soybean oil, sesame oil, corn oil, or mineral oil.

16. The pharmaceutical composition of claim 15, wherein said oil comprises a medium-chain fatty acid triglyceride.

17. The pharmaceutical composition of claim 14, wherein said pharmaceutical composition comprises a non-ionic surfactant.

18. The pharmaceutical composition of claim 17, wherein said non-ionic surfactant comprises a polyglycolized glyceride, an alkyl saccharide, an ester saccharide, or a polysorbate surfactant.

19. The pharmaceutical composition of claim 17, wherein said pharmaceutical composition comprises about 5±

2% (w/w) of said surfactant.

20. The pharmaceutical composition of claim 7, wherein said pharmaceutical composition comprises an emulsion.

21. The pharmaceutical composition of claim 7, wherein said drug particles comprise baclofen.

22. The pharmaceutical composition of claim 7, wherein said drug particles comprise levodopa or a levodopa prodrug and/or carbidopa or a carbidopa prodrug.

23. The pharmaceutical composition of claim 22, wherein said drug particles comprise carbidopa, and further comprising less than 8 μ

g of hydrazine per mg of carbidopa after 12 months storage at 5±

3°

C.

24. The pharmaceutical composition of claim 23, wherein said composition comprises less than 1 μ

g of hydrazine per mg of carbidopa after said 12 month storage.

25. The pharmaceutical composition of claim 22, wherein said drug particles comprise carbidopa, and further comprising less than 8 μ

g of hydrazine per mg of carbidopa after 12 months storage at 25±

3°

C.

26. The pharmaceutical composition of claim 25, wherein said composition comprises less than 1 μ

g of hydrazine per mg of carbidopa after said 12 month storage.

27. The pharmaceutical composition of claim 7, wherein said suspension comprises a paste.

28. The pharmaceutical composition of claim 7, wherein said suspension comprises benzoic acid or a benzoate salt.

29. A method of treating Parkinson'"'"'s disease comprising administering the pharmaceutical composition of claim 22 to a patient.

30. A method for treating Parkinson'"'"'s disease in a patient, said method comprising:

(a) inserting a drug delivery device comprising the pharmaceutical composition of claim 22 into said patient'"'"'s mouth, said pharmaceutical composition comprising levodopa or levodopa prodrug;

(b) administering into said patient'"'"'s mouth said levodopa or levodopa prodrug for a period of at least 4 hours at an hourly rate in the range of 30 mg/hour to 150 mg/hour, such that a circulating plasma levodopa concentration greater than 1,200 ng/mL and less than 2,500 ng/mL is continuously maintained for a period of at least 4 hours during said administration; and

(c) removing said drug delivery device from the mouth.

32. The pharmaceutical composition of claim 1, wherein said suspension has a dynamic viscosity of at least 1,000 cP at 37°

C.

33. The pharmaceutical composition of claim 1, wherein said suspension has a dynamic viscosity of at least 10,000 cP at 37°

C.

36. The pharmaceutical composition of claim 1, wherein said suspension has a dynamic viscosity of at least 100,000 cP at 37°

C.

37. The pharmaceutical composition of claim 7, wherein the D₅₀ of the drug particles is less than or equal to 100 μ

m.

40. The pharmaceutical composition of claim 7, wherein the D₅₀ of the drug particles is less than or equal to 25 μ

m.

41. The pharmaceutical composition of claim 17, wherein said non-ionic surfactant comprises a poloxamer.

2. A pharmaceutical composition comprising a suspension comprising (i) from about 20% to about 80% (w/w) solid excipients;

(ii) from about 5% to 60% (w/w) drug particles, (iii) from 19% to 30% (w/w) of one or more water-immiscible compounds, (iv) from 2% to 25% (w/w) water, and (v) from 1% to 10% (w/w) surfactant, wherein the pharmaceutical composition is physically stable.

31. The pharmaceutical composition of claim 2, wherein said suspension has a dynamic viscosity of at least 100 cP at 37°

C.

34. The pharmaceutical composition of claim 2, wherein said suspension has a dynamic viscosity of at least 10,000 cP at 37°

C.

38. The pharmaceutical composition of claim 2, wherein the D₅₀ of the solid drug particles is less than or equal to 100 μ

m.

42. The pharmaceutical composition of claim 2, wherein said pharmaceutical composition comprises a non-ionic surfactant.

44. The pharmaceutical composition of claim 2, wherein the shelf life of said pharmaceutical composition is 6 months or longer at 5±

3°

C. and said pharmaceutical composition does not substantially cream or sediment when stored for 6 months at 5±

3°

C.

46. The pharmaceutical composition of claim 2, wherein said suspension comprises less than or equal to about 12% (w/w) water.

48. The pharmaceutical composition of claim 2, comprising an edible oil.

50. The pharmaceutical composition of claim 2, wherein said pharmaceutical composition comprises an emulsion.

52. The pharmaceutical composition of claim 2, wherein said suspension comprises a paste.

3. A pharmaceutical composition comprising a suspension comprising (i) an oil, and (ii) from about 35% to 70% (w/w) solid drug particles comprising levodopa or a levodopa prodrug and/or carbidopa or a carbidopa prodrug, wherein the pharmaceutical composition has a dynamic viscosity of at least 100 cP at 37°

C.

4. The pharmaceutical composition of claim 3, wherein said suspension comprises less than or equal to about 30% (w/w) of said oil.

5. The pharmaceutical composition of claim 4, wherein said suspension comprises greater than or equal to about 19% (w/w) of said oil.

6. The pharmaceutical composition of claim 4, wherein said suspension comprises water and a surfactant.

35. The pharmaceutical composition of claim 3, wherein said suspension has a dynamic viscosity of at least 10,000 cP at 37°

C.

39. The pharmaceutical composition of claim 3, wherein the D₅₀ of the solid drug particles is less than or equal to 100 μ

m.

43. The pharmaceutical composition of claim 3, wherein said pharmaceutical composition comprises a non-ionic surfactant.

45. The pharmaceutical composition of claim 3, wherein the shelf life of said pharmaceutical composition is 6 months or longer at 5±

3°

C. and said pharmaceutical composition does not substantially cream or sediment when stored for 6 months at 5±

3°

C.

47. The pharmaceutical composition of claim 3, wherein said suspension comprises less than or equal to about 12% (w/w) water.

49. The pharmaceutical composition of claim 3, comprising an edible oil.

51. The pharmaceutical composition of claim 3, wherein said pharmaceutical composition comprises an emulsion.

53. The pharmaceutical composition of claim 3, wherein said suspension comprises a paste.

54. The pharmaceutical composition of claim 3, wherein said drug particles comprise carbidopa, and further comprising less than 8 μ

g of hydrazine per mg of carbidopa after 12 months storage at 5±

3°

C.

55. The pharmaceutical composition of claim 54, wherein said composition comprises less than 1 μ

g of hydrazine per mg of carbidopa after said 12 month storage.

56. A method of treating Parkinson'"'"'s disease comprising administering the pharmaceutical composition of claim 3 to a patient.