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

• US 9,901,561 B2
• Filed: 03/02/2017
• Issued: 02/27/2018
• Est. Priority Date: 05/06/2015
• Status: Active Grant

• Current Assignee: Synagile Corporation
• Original Assignee: Synagile Corporation
• Inventors: Heller, Adam, Heller, Ephraim, Westerberg, Karl Gran, Spiridigliozzi, John
• Primary Examiner(s): Henley, III, Raymond J
• Application Number:
  US15/448,208
• Publication Number:
  US 20170172961A1
• Time in Patent Office: 362 Days
• Field of Search: 514561, 514565
• 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) an oil, and (ii) from about 35% to 70% (w/w) solid drug particles comprising levodopa and/or carbidopa, wherein the pharmaceutical composition is physically stable and wherein said pharmaceutical composition is a non-pourable, plastically deformable paste.

2. The pharmaceutical composition of claim 1, wherein after 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 4%.

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

C.

4. The pharmaceutical composition of claim 1, 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 3, wherein said suspension comprises water and a surfactant.

7. The pharmaceutical composition of claim 1, wherein said solid drug particles comprise carbidopa, and wherein said pharmaceutical composition comprises less than 4 μ

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

3°

C., or less than 1 μ

g of hydrazine per mg of carbidopa after 3 month storage at 5±

3°

C.

8. The pharmaceutical composition of claim 1, said pharmaceutical composition comprising a suspension comprising (i) from about 35% to 70% (w/w) solid drug particles comprising levodopa and/or carbidopa, (ii) from 19% to 30% (w/w) of one or more water-immiscible compounds comprising an oil, (iii) from 2% to 16% (w/w) water, and (iv) from 1% to 8% (w/w) surfactant, wherein the pharmaceutical composition is suitable for continuous or frequent intermittent intra-oral delivery.

9. The pharmaceutical composition of claim 8, wherein said suspension has a dynamic viscosity of at least 10,000 cP at 37°

C.

10. The pharmaceutical composition of claim 9, wherein said suspension has a dynamic viscosity of at least 100,000 cP at 37°

C.

11. The pharmaceutical composition of claim 9, wherein after 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 4%.

12. The pharmaceutical composition of claim 9, 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.

13. The pharmaceutical composition of claim 9, wherein said suspension is a non-pourable, plastically deformable paste, and retains its shape at ambient temperature following extrusion through an orifice.

14. The pharmaceutical composition of claim 9, wherein said pharmaceutical composition comprises an emulsion.

15. The pharmaceutical composition of claim 9, wherein the suspension comprises greater than 50% (w/w) solid drug particles.

16. The pharmaceutical composition of claim 9, wherein the D₅₀ of the solid drug particles is less than or equal to 25 μ

m when measured by light scattering with the particles dispersed in a non-solvent.

17. The pharmaceutical composition of claim 16, wherein the D₅₀ of the solid drug particles is greater than or equal to 1 μ

m when measured by light scattering with the particles dispersed in a non-solvent.

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

19. The pharmaceutical composition of claim 18, wherein said suspension comprises 8±

2% (w/w) water.

20. The pharmaceutical composition of claim 9, 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.

21. The pharmaceutical composition of claim 20, wherein said oil comprises a medium-chain fatty acid triglyceride.

22. The pharmaceutical composition of claim 9, wherein said pharmaceutical composition comprises a non-ionic surfactant.

23. The pharmaceutical composition of claim 22, wherein said non-ionic surfactant comprises a polyglycolized glyceride, an alkyl saccharide, an ester saccharide, or a polysorbate surfactant.

24. The pharmaceutical composition of claim 22, wherein said non-ionic surfactant comprises a poloxamer.

25. The pharmaceutical composition of claim 22, wherein said suspension comprises about 5±

2% (w/w) of said surfactant.

26. The pharmaceutical composition of claim 9, wherein the pH of the composition measured by inserting a glass walled pH electrode into the formulation is less than pH 5 and remains less than pH 5 after 3 months storage at 25°

C.

29. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises:

(i) from about 50% to about 75% (w/w) of said solid drug particles;

(ii) 8±

2% (w/w) water, (iii) 24±

2% (w/w) of said oil, wherein said oil is a medium-chain fatty acid triglyceride; and

(iv) 5±

2% (w/w) of a surfactant that is a poloxamer.

27. A pharmaceutical composition comprising a suspension comprising (i) from about 35% to 70% (w/w) solid drug particles comprising levodopa and/or carbidopa, (ii) from 19% to 30% (w/w) of one or more water-immiscible compounds comprising an oil, (iii) from 2% to 16% (w/w) water, (iv) from 1% to 8% (w/w) surfactant, and (v) benzoic acid or a benzoate salt wherein the pharmaceutical composition is physically stable, wherein the pharmaceutical composition is suitable for continuous or frequent intermittent intra-oral delivery, and wherein said suspension has a dynamic viscosity of at least 10,000 cP at 37°

C.

28. A pharmaceutical composition comprising a suspension comprising (i) from about 35% to 70% (w/w) solid drug particles comprising levodopa and/or carbidopa, (ii) from 19% to 30% (w/w) of one or more water-immiscible compounds comprising an oil, (iii) from 2% to 16% (w/w) water, (iv) from 1% to 8% (w/w) surfactant, and (v) EDTA or its salt or salts, wherein the combined concentrations of EDTA and its salt or salts is between 0.05 weight % and 0.25 weight %, wherein the pharmaceutical composition is physically stable, wherein the pharmaceutical composition is suitable for continuous or frequent intermittent intra-oral delivery, and wherein said suspension has a dynamic viscosity of at least 10,000 cP at 37°

C.