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

• US 10,328,044 B2
• Filed: 12/14/2018
• Issued: 06/25/2019
• 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:
  US16/220,766
• Publication Number:
  US 20190117605A1
• Time in Patent Office: 193 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 method of administering a pharmaceutical composition to a subject, the method comprising:

(a) inserting a drug delivery device having a reservoir containing the pharmaceutical composition into the mouth of the subject;

(b) continuously or semicontinuously administering the pharmaceutical composition from the delivery device into the mouth of a patient at a rate between 0.001 mL/hour and 1.25 mL/hour, wherein said pharmaceutical composition comprises 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; and

(c) removing said drug delivery device from the subject'"'"'s mouth.

6. The method of claim 1, wherein said suspension has a dynamic viscosity of at least 1,000 cP at 37°

C.

10. The method of claim 1, wherein said pharmaceutical composition comprises an emulsion.

13. The method of claim 1, wherein said pharmaceutical composition comprises a paste.

16. The method of claim 1, wherein the drug particles have a D₅₀ that is less than or equal to 100 μ

m.

19. The method of claim 1, wherein the pharmaceutical composition is administered into the mouth of the subject for a period of at least 4 hours at a frequency of at least once every 120 minutes.

22. The method of claim 19, wherein during the period the administration produces a drug level in plasma having a fluctuation index that is less than or equal to 2.0.

25. The method of claim 1, wherein the subject suffers from gastroparesis.

28. The method of claim 1, wherein said drug particles comprise levodopa or a levodopa prodrug, and wherein the levodopa or levodopa prodrug is administered into the mouth of the subject at a rate of from 10 mg/hour to 200 mg/hour.

2. A method of administering a pharmaceutical composition to a subject, the method comprising:

(a) inserting a drug delivery device having a reservoir containing the pharmaceutical composition into the mouth of the subject;

(b) continuously or semicontinuously administering the pharmaceutical composition from the delivery device into the mouth of a patient at a rate between 0.001 mL/hour and 1.25 mL/hour, wherein said pharmaceutical composition comprises 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; and

(c) removing said drug delivery device from the subject'"'"'s mouth.

7. The method of claim 2, wherein said suspension has a dynamic viscosity of at least 1,000 cP at 37°

C.

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

14. The method of claim 2, wherein said pharmaceutical composition comprises a paste.

17. The method of claim 2, wherein the drug particles have a D₅₀ that is less than or equal to 100 μ

m.

20. The method of claim 2, wherein the pharmaceutical composition is administered into the mouth of the subject for a period of at least 4 hours at a frequency of at least once every 120 minutes.

23. The method of claim 20, wherein during the period the administration produces a drug level in plasma having a fluctuation index that is less than or equal to 2.0.

3. A method of administering a pharmaceutical composition to a subject suffering from Parkinson'"'"'s disease, the method comprising:

(a) inserting a drug delivery device having a reservoir containing the pharmaceutical composition into the mouth of the subject;

(b) continuously or semicontinuously administering the pharmaceutical composition from the delivery device into the mouth of a patient at a rate between 0.001 mL/hour and 1.25 mL/hour, wherein said pharmaceutical composition comprises 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.; and

(c) removing said drug delivery device from the subject'"'"'s mouth.

4. The method of claim 3, wherein said suspension comprises about 19% (w/w) to about 30% (w/w) of said oil.

5. The method of claim 4, wherein said suspension comprises water and a surfactant.

8. The method of claim 3, wherein said suspension has a dynamic viscosity of at least 1,000 cP at 37°

C.

9. The method of claim 3, wherein said suspension has a dynamic viscosity of at least 100,000 cP at 37°

C.

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

15. The method of claim 3, wherein said pharmaceutical composition comprises a paste.

18. The method of claim 3, wherein the drug particles have a D₅₀ that is less than or equal to 100 μ

m.

21. The method of claim 3, wherein the pharmaceutical composition is administered into the mouth of the subject for a period of at least 4 hours at a frequency of at least once every 120 minutes.

24. The method of claim 21, wherein during the period the administration produces a drug level in plasma having a fluctuation index that is less than or equal to 2.0.

26. The method of claim 3, wherein the subject suffers from gastroparesis.

27. The method of claim 26, wherein the subject has a score of 4 or 5 on the Hoehn and Yahr scale.

29. The method of claim 3, wherein the levodopa or levodopa prodrug is administered into the mouth of the subject at a rate of from 10 mg/hour to 200 mg/hour.

30. A method of treating a disease comprising administering a pharmaceutical composition comprising one or more drugs into the mouth of a patient via continuous or frequent intermittent administration for a period of at least 4 hours, said method comprising:

(i) inserting a drug delivery device into the mouth of a patient;

(ii) administering said pharmaceutical composition into the mouth of said patient via continuous or frequent intermittent administration at a rate between 0.001 mL/hour and 1.25 mL/hour for a period of at least 4 hours; and

(iii) removing said drug delivery device from the mouth of said patient;

wherein said pharmaceutical composition has a dynamic viscosity greater than 100 poise at 37°

C. and comprises greater than about 35% (w/w) of said one or more drugs, and wherein the fluctuation index of one of said one or more drugs is less than or equal to 2.0 during said period.