Diketopiperazine salts for drug delivery and related methods

• US 9,675,674 B2
• Filed: 01/08/2016
• Issued: 06/13/2017
• Est. Priority Date: 08/23/2004
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Leone-Bay, Andrea, Wilson, Bryan R., Moye-Sherman, Destardi
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US14/991,777
• Publication Number:
  US 20160250297A1
• Time in Patent Office: 522 Days
• Field of Search: None
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1682 Processes
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 241/02 not condensed with other rings
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: Y02P 20/582 Recycling of unreacted starting or intermediate materials

Abstract

Drug delivery systems have been developed based on the formation of diketopiperazine carboxylate salts and microparticles containing the same. The systems may further comprise a bioactive agent. Related methods for making and using the biologically active agent delivery compositions are also provided. In certain embodiments, the pharmaceutically acceptable salts described can be formed by removal of solvent by methods including distillation, evaporation, spray drying or lyophilization.

Claims

1. A method of preparing a solid composition for drug delivery comprising:

preparing a solution containing a biologically active agent and a pharmaceutically-acceptable salt of a heterocyclic compound in a solvent;

and a step for removing said solvent;

wherein said pharmaceutically acceptable salt of a heterocyclic compound has the structure according to Formula 1;

2. The method of claim 1, wherein said step for removing said solvent comprises distillation.

3. The method of claim 1, wherein said step for removing said solvent comprises evaporation.

4. The method of claim 1, wherein said step for removing said solvent comprises spray drying.

5. The method of claim 1, wherein said step for removing said solvent comprises lyophilization.

6. The method of claim 1, wherein said at least one cation is selected from the group consisting of sodium, potassium, calcium, magnesium, lithium, triethylamine, butylamine, diethanolamine, and triethanolamine.

7. The method of claim 1, wherein said at least one cation is sodium.

8. The method of claim 1, wherein said biologically active agent is selected from the group consisting of hormones, anticoagulants, immunomodulating agents, cytotoxic agents, antibiotics, antivirals, antisense, anti-inflammatories, vasoactive agents, neuroactive agents, cannabinoids, antigens, antibodies and active fragments and analogues thereof.

9. The method of claim 1 further comprising the step of micronizing said solid to form a dry powder.

10. The method of claim 9, wherein the particles of said dry powder are suitable for pulmonary delivery.

11. The method of claim 9, wherein the particles of said dry powder have a rugosity of less than 2.

12. The method of claim 1, wherein said solid composition comprises microparticles.

13. The method of claim 12, wherein at least 50% of said particles have a diameter less than 5 μ

m.

14. The method of claim 12, wherein at least 70% of said particles have a diameter less than 5 μ

m.

15. diameter The method of claim 12, wherein said microparticles have a rugosity of less than 2.

16. The method of claim 12, wherein said microparticles comprise a dry powder.

17. The method of claim 12, wherein said microparticles are suitable for pulmonary delivery.

18. The method of claim 1, wherein said solid composition is a precipitate.

19. The method of claim 1, wherein said solid composition is formulated into a solid dosage form.

20. The method of claim 19, wherein said solid dosage form is selected from the group consisting of tablets and capsules.