Diketopiperazine microparticles with defined specific surface areas

• US 9,630,930 B2
• Filed: 04/11/2014
• Issued: 04/25/2017
• Est. Priority Date: 06/12/2009
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Grant, Marshall L., Stowell, Grayson W., Menkin, Paul
• Primary Examiner(s): Parad, Dennis J
• Application Number:
  US14/251,513
• Publication Number:
  US 20140271888A1
• Time in Patent Office: 1,110 Days
• Field of Search: 424489, 544389
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 9/145 with organic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61M 15/0028 using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
• CPC Class Codes: A61M 15/0091 mechanically breath-triggered
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

Disclosed herein are diketopiperazine microparticles having a specific surface area of less than about 67 m²/g. The diketopiperazine microparticle can be fumaryl diketopiperazine and can comprise a drug such as insulin.

Claims

1. A method for forming diketopiperazine microparticles comprising:

a) dissolving a diketopiperazine in a water-based solution;

b) adding an acid solution to the water-based solution to precipitate the diketopiperazine microparticles out of the solution to form a microparticle suspension;

c) adjusting manufacturing conditions to target production microparticles with a specific surface area (SSA) of 52 m²/g;

d) and collecting the precipitate after washing with deionized water;

wherein the precipitate comprises diketopiperazine microparticles having a SSA of 35 m²/g to 67 m²/g.

2. The method of claim 1 wherein the water-based diketopiperazine solution comprise ammonia.

3. The method of claim 1 wherein the acid solution comprises acetic acid.

4. The method of claim 1, wherein the water-based diketopiperazine solution and the acid solution are at a temperature of 14°

C. to 18°

C.

5. The method of claim 1, further comprising adding a solution comprising an active agent.

6. The method of claim 5 wherein the active agent comprises at least one of proteins, polypeptides, peptides, nucleic acids, organic macromolecules, synthetic organic compounds, polysaccharides and other sugars, fatty acids, lipids, or antibodies and fragments thereof.

7. The method of claim 5 wherein the active agent comprises at least one of vasoactive agents, neuroactive agents, hormones, anticoagulants, immunomodulating agents, cytotoxic agents, antibiotics, antiviral agents, antigens, infectious agents, inflammatory mediators, hormones, and cell surface antigens.

8. The method of claim 7 wherein the active agent comprises at least one of a cytokine, a lipokine, an enkephalin, an alkyne, a cyclosporin, an anti-IL-8 antibody, an IL-8 antagonist including ABX-IL-8;

a prostaglandin including PG-12, an LTB receptor blocker including LY29311, BIIL 284, CP105696;

insulin or analogs thereof, growth hormone or analogs thereof, parathyroid hormone (PTH) or analogs thereof, parathyroid hormone related peptide (PTHrP), ghrelin, an obestatin, an enterostatin, a granulocyte macrophage colony stimulating factor (GM-CSF), amylin, an amylin analog, glucagon-like peptide 1 (GLP-1), clopidogrel, PPACK (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone), oxyntomodulin (OXM), peptide YY(3-36) (PYY), adiponectin, cholecystokinin (CCK), secretin, gastrin, glucagon, motilin, somatostatin, brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), IGF-1, growth hormone releasing factor (GHRF), integrin beta-4 precursor (ITB4) receptor antagonist, nociceptin, nocistatin, orphanin FQ2, calcitonin, CGRP, angiotensin, substance P, neurokinin A, pancreatic polypeptide, neuropeptide Y, delta-sleep-inducing peptide and vasoactive intestinal peptide.

9. The method of claim 5 wherein the active agent comprises a peptide.

10. The method of claim 9 wherein the active agent comprises insulin or an analog thereof.

11. The method of claim 9 wherein the active agent comprises GLP-1 or an analog thereof.

12. The method of claim 5 wherein the active agent is adsorbed to the microparticle.

13. The method of claim 12 wherein the SSA of the microparticle is reduced following adsorption of the active agent.

14. The method of claim 1 wherein the diketopiperazine is fumaryl diketopiperazine.

15. The method of claim 8 wherein the insulin is human insulin.

16. The method of claim 1 wherein collecting the precipitate comprises tangential flow filtration.

17. A method of forming diketopiperazine microparticles with an SSA of 35 m²/g to 67 m²/g within a 95% confidence limit comprising, feeding equal masses of 10.5 wt % acetic acid and 2.5 wt % diketopiperazine solutions at 14°

C. to 18°

C. through a high shear mixer.

18. The method of claim 17 further comprising adding a solution comprising an active agent to a suspension of the microparticles.

19. The method of claim 18, further comprising increasing the pH of the suspension of diketopiperazine microparticles to pH 4.5 with an aqueous ammonia solution.

20. The method of claim 18, further comprising increasing the concentration of ammonia in the suspension of diketopiperazine microparticles to yield a pH of from pH 3.5 to pH 4.5.

21. The method of claim 18 wherein the active agent comprises at least one of proteins, polypeptides, peptides, nucleic acids, organic macromolecules, synthetic organic compounds, polysaccharides and other sugars, fatty acids, lipids, or antibodies and fragments thereof.