Claims for Patent: 10,421,729

Summary for Patent: 10,421,729

Title:	Microcrystalline diketopiperazine compositions and methods
Abstract:	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.
Inventor(s):	Wilson; Bryan R. (Brewster, NY), Guarneri; Joseph J. (Stamford, CT), Grant; Marshall L. (Newtown, CT)
Assignee:	MannKind Corporation (Westlake Village, CA)
Application Number:	14/774,311
Patent Claims:	1. A crystalline diketopiperazine composition comprising a plurality of microcrystalline particles comprising an active agent, said microcrystalline particles being substantially uniform in size and having a volumetric median geometric diameter less than 5 .mu.m, and further having hollow spherical structures; each of said hollow spherical structures comprising a core and a shell, wherein said shell is porous and comprises crystallites of the diketopiperazine, said diketopiperazine having the formula: ##STR00005## and a trans isomer content ranging from 45% to 65%, wherein said microcrystalline particles dissolve into crystallites when dispersed in water; wherein said microcrystalline particles are prepared in a surfactant-free solution, and said microcrystalline particles do not self-assemble in said solution, wherein the microcrystalline particles are formed by a method comprising the steps of; combining 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine dissolved in a solution of aqueous ammonia with a solution of acetic acid and concurrently homogenizing the solutions in a high shear mixer at high pressure of up to 2000 psi to form a precipitate; washing the precipitate in suspension with deionized water; concentrating the suspension; and drying the suspension in a spray drying apparatus. 2. The crystalline diketopiperazine composition of claim 1, wherein up to 92% of the microcrystalline particles have a volumetric median geometric diameter of <5.8 .mu.m. 3. The crystalline diketopiperazine composition of claim 1, wherein the one or more active ingredients is a peptide, a protein, a nucleic acid molecule, or a small organic molecule. 4. The crystalline diketopiperazine composition of claim 3, wherein the peptide is an endocrine hormone. 5. The crystalline diketopiperazine composition of claim 4, wherein the endocrine hormone is insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide 1, oxyntomodulin, peptide YY, leptin, or an analog of said endocrine hormone. 6. A method of making microcrystalline diketopiperazine particles of claim 1 suitable for pulmonary administration as a dry powder comprising: a) forming diketopiperazine particles in a suspension having a bimodal distribution in the particle sizes which range from about 0.05 pm to about 10 pm; b) atomizing the suspension using a spray dryer under an air or gas stream, and c) reforming particles by spray-drying into a dry powder comprising the microcrystalline diketopiperazine particles having hollow spheres. 7. The method of claim 6 wherein a first peak of particles of the bimodal distribution in particle sizes has an average of about 0.2 pm to about 2.4 pm and a second peak of particles has an average size of about 2.1 pm to about 2.4 pm. 8. The method of claim 6, wherein the diketopiperazine is of the formula 3,6-bis(N-X-4-aminobutyl)-2,5-diketopiperazine, wherein X is selected from the group consisting of fumaryl, succinyl, maleyl, malonyl, and glutaryl. 9. The method of claim 8, wherein the diketopiperazine is 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine. 10. The method of claim 6, further comprising the step of adding a solution comprising one or more active agents to the suspension in step a). 11. The method of claim 6, further comprising the step of adding a surfactant to the solution or suspension. 12. The method of claim 11, wherein the surfactant is polysorbate 80. 13. The method of claim 10, wherein the one or more active agent is a peptide, a protein, a nucleic acid molecule, or a small organic molecule. 14. The method of claim 13, wherein the peptide is an endocrine hormone. 15. The method of claim 14, wherein the endocrine hormone is insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide 1, oxyntomodulin, peptide YY, leptin, or an analog of said endocrine hormone. 16. The crystalline diketopiperazine composition of claim 1, wherein said active agent comprises at least one of small molecule pharmaceuticals, biologicals, and bioactive agents. 17. The crystalline diketopiperazine composition of claim 1, wherein said active agent comprises at least one of proteins, polypeptides, peptides, nucleic acids, organic macromolecules, synthetic organic compounds, polysaccharides and other sugars, fatty acids, and lipids, and antibodies and fragments thereof. 18. The crystalline diketopiperazine composition of claim 1, wherein said agent comprises at least one of humanized or chimeric antibodies, F(ab), F(ab).sub.2, a single- chain antibody alone or fused to other polypeptides or therapeutic or diagnostic monoclonal antibodies to cancer antigens, vasoactive agents, neuroactive agents, hormones, anticoagulants, immunomodulating agents, cytotoxic agents, antibiotics, antiviral agents, antigens, infectious agents, inflammatory mediators, hormones, cell surface receptor agonists and antagonists, and cell surface antigens. 19. The crystalline diketopiperazine composition of claim 1, wherein said agent comprises at least one of cytokines, lipokines, enkephalins, alkynes, cyclosporins, anti-IL-8 antibodies, IL-8 antagonists including ABX-IL-8; PG-i2, LTB receptor blockers; triptans, insulin and analogs thereof, growth hormone and analogs thereof, parathyroid hormone (PTH) and analogs thereof, parathyroid hormone related peptide (PTHrP), ghrelin, obestatin, enterostatin, granulocyte macrophage colony stimulating factor (GM-CSF), amylin, amylin analogs, glucagon-like peptide 1 (GLP-1), clopidogrel, PPACK (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone), oxyntomodulin (OXM), peptide YY(3-36) (PYY), adiponectin, cholecystokinin (CCK), secretin, gastrin, glucagon, 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, calcitonin, CGRP, angiotensin, substance P, neurokinin A, pancreatic polypeptide, neuropeptide Y, delta-sleep-inducing peptide, vasoactive intestinal peptide; and analogs of the active agents. 20. The crystalline diketopiperazine composition of claim 1, wherein said agent comprises a prostaglandin. 21. The crystalline diketopiperazine composition of claim 20, wherein said prostaglandin comprises PG-I2.