High capacity diketopiperazine microparticles and methods
View Patent ↗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 composition comprising a plurality of diketopiperazine microparticles and a drug or an active agent; wherein each of the diketopiperazine microparticles comprises a plurality of structural domains, each structural domain comprising a nucleus surrounded by layers of a porous crystalline material, and said diketopiperazine microparticles have a mass-weighted average particle size of about 33,000 to about 216,000 voxels measured by X-ray tomography for particle size measuring about 0.5 μm to about 4 μm in geometric diameter.
2. The composition of claim 1 , wherein the diketopiperazine microparticles comprise structural domains ranging in number-weighted size from about 250 voxels to about 1,400 voxels.
3. The composition of claim 1 , wherein the diketopiperazine microparticles comprise structural domains ranging in voxel-weighted size from about 500 voxels to about 2,000 voxels.
4. The composition of claim 1 , wherein each of the diketopiperazine microparticles have a specific surface area greater than 35 m 2 /g.
5. The composition of claim 1 , wherein each of the diketopiperazine microparticles have a specific surface area greater than 70 m 2 /g.
6. The composition of claim 1 , wherein the plurality of structural domains have an average size from about 300 nm to about 450 nm as measured by radius of gyration.
7. The composition of claim 1 , wherein said drug or active agent is a small organic molecule, peptide or protein, or a nucleic acid molecule or combinations thereof.
8. The composition of claim 7 , wherein said peptide is an endocrine hormone.
9. The composition of claim 7 , 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-Asp) peptide, growth hormone releasing peptide, DDAVP (desamino-Cys-1, D-arg8) vasopressin peptide, cyclosporine, detirelex, somatostatin, interferon-a, granulocyte colony stimulating factor, IgG, or an analog or active fragment thereof.
10. The composition of claim 7 , 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, a cell receptor antagonist molecule, an immunosuppressant, a statin, or an anti-infective agent.
11. The composition of claim 1 , wherein said diketopiperazine is fumaryl diketopiperazine (3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine; or salt thereof.
12. The composition of claim 1 in the form of a dry powder.
13. The composition of claim 12 , further comprising insulin in an amount greater than 4 units per milligram of the dry powder.
14. The composition of claim 13 , wherein the amount of insulin is 6 units per milligram of dry powder.
15. The composition of claim 14 , wherein the dry powder comprises an insulin dose comprising 60 units or more of insulin for delivering to a patient in a single inhalation using a dry powder inhaler.
16. 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.
17. The method according to claim 16 , wherein said surfactant is polysorbate 80.
18. The method according to claim 17 , further comprising the step of washing the suspension with deionized water to remove excess acid.
19. The method according to claim 17 , 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.
20. A method of delivering insulin to a patient in need thereof comprising administering to a subject the composition dry powder composition of claim 1 to the deep lung by inhalation of said dry powder formulation by said patient.
21. A diketopiperazine microparticle comprising a plurality of structural domains, each structural domain comprising a nucleus surrounded by layers of a porous crystalline material, and having a mass-weighted average particle size of about 33,000 to about 216,000 voxels measured by X-ray tomography for a particle size measuring about 0.5 μm to about 4 μm in geometric size.