High capacity diketopiperazine microparticles and methods

Abstract

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.

What is claimed: 
     
         1 . A pulmonary drug delivery system comprising:
 an inhaler;   a unit dose dry powder medicament container adaptable to said inhaler; and   a dry powder within the unit dose dry powder medicament container comprising synthesized diketopiperazine microparticles and a drug or an active agent, the diketopiperazine microparticles 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.   
     
     
         2 . The pulmonary drug delivery system of  claim 1  wherein the unit dose dry powder medicament container is a cartridge. 
     
     
         3 . The pulmonary drug delivery system of  claim 1 , wherein the inhaler is a high resistance inhaler further comprising air conduits configured to impart a high resistance to airflow through the air conduits for deagglomerating and dispensing the dry powder. 
     
     
         4 . The pulmonary drug delivery system of  claim 3  having a resistance value of between 0.065 to about 0.200 (√kPa) per liter per minute. 
     
     
         5 . The pulmonary drug delivery system of  claim 1 , further configured to deliver the dry powder by inhalation wherein the peak inhalation pressure differential can range from about 2 to about 20 kPa, which can produce flow rates having peaks between about 7 to about 70 liters per minute. 
     
     
         6 . The pulmonary drug delivery system of  claim 1 , further configured to provide a single dose by discharging powder from the inhaler as a continuous flow, or as one or more pulses of powder delivered to a patient. 
     
     
         7 . The pulmonary drug delivery system of  claim 1 , further comprising a predetermined mass flow balance within the inhaler. 
     
     
         8 . The pulmonary drug delivery system of  claim 7 , further comprising a dispensing flow having a mass flow balance between about 10% to about 70% of the total air flow exiting the inhaler by one or more dispensing ports, which airflow passes through the area containing the powder formulation. 
     
     
         9 . The pulmonary drug delivery system of  claim 8 , further comprising other conduits configured to flow between about 30% to about 90% of the total air flow. 
     
     
         10 . The pulmonary drug delivery system of  claim 9 , wherein one or more of the other conduits comprise bypass flow not entering and exiting a dry powder medicament container area, or optionally a dry powder medicament cartridge area. 
     
     
         11 . The pulmonary drug delivery system of  claim 10 , wherein the bypass flow recombines with the dispensing flow exiting the dispensing port to dilute, accelerate, deagglomerate, or a combination thereof; forming a fluidized powder prior to exiting the inhaler. 
     
     
         12 . The pulmonary drug delivery system of  claim 1 , wherein a flow rate of the inhaler is between about 7 to about 70 liters per minute resulting in greater than about 75% of the container, or optionally the cartridge, contents dispensed in fill masses between 1 and 30 mg. 
     
     
         13 . The pulmonary drug delivery system of  claim 1 , wherein a respirable fraction/fill of a powder dose emission is greater than 40% in a single inhalation. 
     
     
         14 . The pulmonary drug delivery system of  claim 1 , wherein a respirable fraction/fill of a powder dose emission is greater than 60% in a single inhalation. 
     
     
         15 . The pulmonary drug delivery system of  claim 1 , wherein a respirable fraction/fill of a powder dose emission is about 90% to about 100% in a single inhalation. 
     
     
         16 . The pulmonary drug delivery system of  claim 1 , wherein the drug or active agent is an endocrine hormone. 
     
     
         17 . The pulmonary drug delivery system of  claim 16 , wherein the endocrine hormone is insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide 1, oxyntomodulin, oxytocin, CCK-8, PYY3-36, ghrelin, vasoactive intestinal peptide or analogs thereof. 
     
     
         18 . The pulmonary drug delivery system of  claim 1 , wherein the active agent is small organic molecule. 
     
     
         19 . The pulmonary drug delivery system of  claim 18 , wherein the small organic molecule is neurotransmitter agonist, a neurotransmitter antagonist, a pain inhibitory agent, respectively selected from the group consisting of morphine, morphine derivatives, triptans, a vaccine, an anti-inflammatory agent, an anti-cancer agent, a cell receptor agonist molecule, or cell receptor antagonist molecule. 
     
     
         20 . The pulmonary drug delivery system of  claim 1 , wherein the active agent is prostaglandin. 
     
     
         21 . An inhalation system comprising:
 a dry powder inhaler; and   a dry powder formulation comprising microparticles of fumaryl diketopiperazine, wherein the FDKP microparticles have a plurality of structural domains, each structural domain comprising a nucleus surrounded by layers of a porous crystalline material, wherein the domain comprises more than 500 voxels as measured using X-ray tomography.   
     
     
         22 . The inhalation system of  claim 21 , wherein the dry powder formulation is provided in a unit dose cartridge for using with a reusable inhaler. 
     
     
         23 . The inhalation system of  claim 21 , wherein the dry powder formulation can be preloaded in a single use disposable inhaler, the disposable inhaler comprising a deagglomeration mechanism configured to produce respirable fractions greater than 50%, thereby emitting particles of less than 5.8 μm. 
     
     
         24 . The inhalation system of  claim 21 , further comprising a container within said dry powder inhaler wherein a dosing discharge of the dry powder formulation from the container exceeds 85%. 
     
     
         25 . The inhalation system of  claim 21 , wherein the dry powder inhaler discharges greater than 85% of the dry powder formulation within in a single inhalation. 
     
     
         26 . The inhalation system of  claim 21 , further comprising a container, or optionally a cartridge, within said dry powder inhaler and containing the dry powder formulation, wherein the dry powder inhaler is configured to discharge from about 90% to about 100% of the dry powder formulation in less than 3 seconds at pressure differentials between 2 and 5 kPa with fill masses ranging to about 30 mg or greater.