High capacity diketopiperazine microparticles and methods
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.
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.