Diketopiperazine salts for drug delivery and related methods

• US 10,130,685 B2
• Filed: 06/09/2017
• Issued: 11/20/2018
• Est. Priority Date: 08/23/2004
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Leone-Bay, Andrea, Moye-Sherman, Destardi, Wilson, Bryan R.
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US15/619,087
• Publication Number:
  US 20170274050A1
• Time in Patent Office: 529 Days
• Field of Search: 51425502
• 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 dry powder therapeutic composition comprising:

a biologically active agent; and

a pharmaceutically acceptable anion of a heterocyclic compound according to Formula 1;

2. The dry powder of claim 1, wherein the at least one carboxylate functional group is a terminal carboxylate functional group.

3. The dry powder of claim 1, wherein the powder is formed by the removal of a solvent from a solution containing the biologically active agent, the pharmaceutically acceptable anion of the heterocyclic compound, and the at least one cation.

4. The dry powder of claim 3, wherein removal of the solvent is achieved by spray drying.

5. The dry powder of claim 3, wherein removal of the solvent is achieved by distillation.

6. The dry powder of claim 3, wherein removal of the solvent is achieved by evaporation.

7. The dry powder of claim 3, wherein removal of the solvent is achieved by lyophilization.

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

9. The dry powder of claim 1, wherein the at least one cation is sodium.

10. The dry powder of claim 1, wherein the 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.

11. The dry powder of claim 1, wherein the dry powder is prepared by a method that includes micronizing a solid to form the dry powder.

12. The dry powder of claim 11, wherein the particles of the dry powder are suitable for pulmonary delivery.

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

14. The dry powder of claim 1, wherein the dry powder comprises microparticles.

15. The dry powder of claim 14, wherein at least 50% of the microparticles have a diameter less than 5 μ

m.

16. The dry powder of claim 14, wherein at least 70% of the microparticles have a diameter less than 5 μ

m.

17. The dry powder of claim 14, wherein the microparticles have a rugosity of less than 2.

18. The dry powder of claim 14, wherein the microparticles are suitable for pulmonary delivery.

19. The dry powder of claim 1, wherein the dry powder is formulated into a solid dosage form.