High capacity diketopiperazine microparticles and methods

Patent metadata

Field	Value
Publication number	US-2016346394-A1
Application number	US-201615152355-A
Country	US
Kind code	A1
Filing date	May 11, 2016
Priority date	Jun 17, 2011
Publication date	Dec 1, 2016
Grant date	—

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.

First claim

What is claimed:

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 17° C. to about 22° C. through a high shear mixer, and collecting the fumaryl diketopiperazine microparticles.

2 . A method of synthesizing diketopiperazine microparticles comprising: collecting 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, a second solution comprising about 2.75 wt % diketopiperazine, and the precursor solution comprises a surfactant at a concentration of about 0.05 wt %.

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 according to claim 3 , further comprising the step of adding a solution comprising an active agent to said suspension and adjusting the pH of the solution to pH 4.5 with an aqueous ammonia solution.

6 . The method of claim 5 , wherein said drug or active agent is a small organic molecule, peptide or protein, or a nucleic acid molecule or combinations thereof.

7 . The method of claim 6 , 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.

8 . The method of claim 6 , 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.

9 . The method of claim 8 , wherein said diketopiperazine is fumaryl diketopiperazine 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; or salt thereof.

10 . The method of claim 9 , wherein the active agent is insulin.

11 . A method of delivering insulin to a patient in need thereof comprising administering to a subject the composition dry powder composition of claim 10 to the deep lung by inhalation of said dry powder formulation by said patient.

Assignees

• Mannkind Corp

Inventors

• Grant Marshall
• Menkin Paul
• Stowell Grayson W

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P5/18

  of the parathyroid hormones · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title