High capacity diketopiperazine microparticles and methods

• US 10,130,709 B2
• Filed: 05/11/2016
• Issued: 11/20/2018
• Est. Priority Date: 06/17/2011
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Grant, Marshall, Menkin, Paul, Stowell, Grayson W.
• Primary Examiner(s): Gudibande, Satyanarayana R
• Application Number:
  US15/152,355
• Publication Number:
  US 20160346394A1
• Time in Patent Office: 923 Days
• 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 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• 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: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

Disclosed herein are diketopiperazine microparticles having high capacity for adsorbing a drug or active agent. In particular, the diketopiperazine microparticle are formed using fumaryl diketopiperazine and can comprise a drug in large doses for the treatment of disease or disorders by pulmonary delivery via oral inhalation.

Claims

1. A method of synthesizing fumaryl diketopiperazine microparticles, the method comprising:

feeding equal masses of a first solution comprising about 11 wt % to about 12 wt % acetic acid and a second solution comprising about 2.75 wt % fumaryl diketopiperazine solutions and containing a surfactant at a concentration of 0.05 wt % at a temperature of about 22°

C. through a high shear mixer, and

collecting the fumaryl diketopiperazine microparticles.

2. A method of synthesizing diketopiperazine microparticles comprising:

collecting a suspension of diketopiperazine microparticles that are a product of feeding a precursor solution through a high shear mixer;

wherein the precursor solution comprises a first solution comprising about 11 wt % to about 12 wt % acetic acid, and a second solution comprising about 2.75 wt % diketopiperazine, and the precursor solution comprises a surfactant at a concentration of about 0.05 wt %, and further wherein an active agent comprising a small organic molecule, peptide or protein, or a nucleic acid molecule or combinations thereof is added to said suspension and the pH of said suspension is adjusted to 4.5 with an aqueous ammonia solution.

3. The method according to claim 2, wherein said surfactant is polysorbate 80.

4. The method according to claim 3, further comprising the step of washing the suspension with deionized water to remove excess acid.

5. The method of claim 2, wherein said peptide or protein is insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide 1, oxyntomodulin, oxytocin, CCK-8, PYY3-36, ghrelin, vasoactive intestinal peptide, leuprolide, growth hormone, RGD (Arg-Gly-Assp) peptide, growth hormone releasing peptide, DDAVP (desamino-Cys-1,D-arg8)vasopressin peptide, cyclosporine, detirelex, somatostatin, interferon-α

, granulocyte colony stimulating factor, IgG, an analog or active fragment thereof.

6. The method of claim 2, wherein the small organic molecule is a neurotransmitter agonist, a neurotransmitter antagonist, a pain inhibitory agent, a vaccine, an anti-inflammatory agent, an anti-cancer agent, a cell receptor agonist molecule, cell receptor antagonist molecule, an immunosuppressant, a statin or an anti-infective agent.

7. The method of claim 6, wherein said diketopiperazine is fumaryl diketopiperazine 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine;

or a salt thereof.

8. The method of claim 7, wherein the active agent is insulin.

9. A method of delivering insulin to a patient in need thereof comprising administering to a subject the composition dry powder composition of claim 8 to the deep lung by inhalation of said dry powder formulation by said patient.