Microcrystalline diketopiperazine compositions and methods
Disclosed herein are DKP microcrystals made by an improved method where they do not irreversibly self-assemble into microparticles. The microcrystals can be dispersed by atomization and re-formed by spray drying into particles having spherical shell morphology. Active agents and excipients can be incorporated into the particles by spray drying a solution containing the components to be incorporated into microcrystalline diketopiperazine particles. In particular, the microcrystalline particle compositions are suitable for pulmonary drug delivery of one or more peptides, proteins, nucleic acids and/or small organic molecules.
1. A method of making microcrystalline 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine particles suitable for pulmonary administration as a dry powder comprising:
adding 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine to a solution at an acidic pH to form a suspension of microcrystalline 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine particles having a bimodal distribution in particle sizes which range from about 0.05 μm to about 10 μm wherein a first peak of the microcrystalline diketopiperazine particles of the bimodal distribution in particle sizes has an average of about 0.2 μm to about 2.4 μm and a second peak of particles has an average size of about 2.1 μm to about 2.4 μm; adding a solution comprising one or more active ingredients to the suspension; washing said microcrystalline 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine particles formed in the suspension with deionized water; atomizing said suspension using a spray dryer under an air or gas stream; reforming said microcrystalline 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine particles by spray-drying into a dry powder comprising said 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine particles.
2. The method of claim 1 , wherein the one or more active ingredients is a vasoactive agent.
3. The method of claim 1 , further comprising the step of adding a surfactant to the solution or suspension.
4. The method of claim 3 , wherein the surfactant is polysorbate 80.
5. The method of claim 1 , wherein the one or more active ingredients is a peptide, a protein, a nucleic acid molecule, or a small organic molecule.
6. The method of claim 1 , wherein the one or more active ingredients is a vasoactive agent, a neuroactive agent including opioid agonists and antagonists, a hormone, an anticoagulant, an immunomodulating agent, a cytotoxic agent, an antibiotic, an antiviral agent, an antigen, an infectious agent, an inflammatory mediator, a cell surface receptor agonist or antagonist, or a cell surface antigen.
7. The method of claim 1 , wherein the one or more active ingredients is at least one of insulin or an analog thereof, a parathyroid hormone or an analog thereof, calcitonin, glucagon, glucagon-like peptide 1, oxyntomodulin, peptide YY, leptin, a cytokine, a lipokine, an enkephalin, a cyclosporin, an anti-IL-8 antibody, an IL-8 antagonist including ABX-IL-8; a prostaglandin including PG-I2, an LTB receptor blocker including LY2931 1, BIIL 284 and CP105696; a triptan such as sumatriptan or palmitoleate, a growth hormone or analogs thereof, a parathyroid hormone related peptide (PTHrP), ghrelin, obestatin, enterostatin, granulocyte macrophage colony stimulating factor (GM-CSF), amylin, amylin analogs, clopidogrel, PPACK (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone), adiponectin, cholecystokinin (CCK), secretin, gastrin, motilin, somatostatin, brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), IGF-1, growth hormone releasing factor (GHRF), integrin beta-4 precursor (ITB4) receptor antagonist, analgesics, nociceptin, nocistatin, orphanin FQ2, CGRP, angiotensin, substance P, neurokinin A, a pancreatic polypeptide, a neuropeptide Y, a delta-sleep-inducing peptide, or a vasoactive intestinal peptide.
8. The method of claim 1 , wherein one or more active ingredients comprise a prostaglandin, analog or derivative thereof.
9. The method of claim 8 , wherein the prostaglandin, analog or derivative thereof is a PG-I2.