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 treating a disease or disorder comprising, administering to a subject in need of treatment a crystalline diketopiperazine composition comprising a plurality of microcrystalline primary particles of about 0.4 pm in diameter having a substantially hollow spherical structure and comprising a shell comprising interlocking crystallites of the diketopiperazine that do not irreversibly self-assemble, the diketopiperazine crystallites having a specific trans isomer content of about 45% to 65%, and wherein the primary particles are disrupted then dispersed by atomization and formed into larger microcrystalline particles of about 2.4 pm in diameter by spray-drying surfactant-free solutions comprising the primary particles, wherein about 92% of the microcrystalline larger particles have a volumetric median geometric diameter less than 5.8 pm and further comprise one or more active ingredients comprising a prostaglandin, prostaglandin analog, or derivative thereof,
wherein said crystalline diketopiperazine composition comprises a diketopiperazine of the formula:
2 . The method of treating a disease or disorder of claim 1 , wherein the prostaglandin, prostaglandin analog, or derivative thereof is a PG-I2.
3 . The method of treating a disease or disorder of claim 1 , wherein the one or more active ingredients comprises a prostaglandin.
4 . The method of treating a disease or disorder of claim 1 , wherein the one or more active ingredients comprises a prostaglandin analog.
5 . The method of treating a disease or disorder of claim 4 , wherein the one or more active ingredients comprises a neuroactive agent.
6 . The method of treating a disease or disorder of claim 4 , wherein the one or more active ingredients comprises 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, an LTB receptor blocker, including LY29311, 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.
7 . The method of treating a disease or disorder of claim 1 , wherein said treatment comprises administering to the subject the crystalline diketopiperazine composition by inhalation using a dry powder inhaler.
8 . The method of treating a disease or disorder of claim 7 , wherein said dry powder inhaler comprises a cartridge.
9 . The method of treating a disease or disorder of claim 8 , wherein said cartridge is a unit dose dry powder medicament container.
10 . The method of treating a disease or disorder of claim 9 , wherein one or more active ingredients comprises a prostaglandin.
11 . The method of treating a disease or disorder of claim 10 , wherein the prostaglandin is a PG-I2.
12 . The method of treating a disease or disorder of claim 1 , wherein the crystalline diketopiperazine composition is provided in a cartridge having a powder content or fill mass of between 1 mg to 50 mg of powder.
13 . The method of treating a disease or disorder of claim 12 , wherein the powder content comprises a drug content of from about 0.01% (w/w) to about 75% (w/w) of the crystalline diketopiperazine composition.
14 . A method of treating a disease or disorder comprising, administering to a subject in need of treatment a crystalline diketopiperazine composition comprising a plurality of microcrystalline primary particles of about 0.4 μm diameter having a substantially hollow spherical structure and comprising a shell comprising interlocking crystallites of a diketopiperazine that do not irreversibly self-assemble, the diketopiperazine crystallites having a specific trans isomer content of about 45% to 65% and wherein the primary particles are disrupted then dispersed by atomization and formed into larger microcrystalline particles by spray-drying surfactant-free solutions comprising the primary particles, and the diketopiperazine has the formula:
wherein the plurality of microcrystalline particles comprise a prostaglandin or an analog thereof, and about 74% of the larger microcrystalline particles have a diameter of about 2.4 μm.
15 . The method of treating a disease or disorder of claim 14 , wherein the prostaglandin is PG I2, or an analog thereof.
16 . The method of treating a disease or disorder of claim 15 , wherein the PG-I2 or analog thereof is in an amount of 1% (w/w) to 50% (w/w) of the crystalline diketopiperazine composition.
17 . The method of treating a disease or disorder of claim 1 , wherein the crystalline diketopiperazine composition is provided in a cartridge having a powder content or fill mass of between 1 mg to 50 mg of powder.
18 . The method of treating a disease or disorder of claim 14 , wherein the crystalline diketopiperazine composition comprises a salt.
19 . The method of treating a disease or disorder of claim 1 , wherein the prostaglandin, prostaglandin analog, or derivative thereof is a prostaglandin analog.
20 . The method of treating a disease or disorder of claim 1 , wherein the prostaglandin, prostaglandin analog, or derivative thereof is a prostaglandin derivative.