Dry powder drug delivery system and methods
View Patent ↗A pulmonary drug delivery system is disclosed, including a breath-powered, dry powder inhaler, and a cartridge for delivering a dry powder formulation. The inhaler and cartridge can be provided with a drug delivery formulation comprising, for example, a diketopiperazine and an active ingredient, including, small organic molecules, peptides and proteins, including, insulin and glucagon-like peptide 1 for the treatment of disease and disorders, for example, endocrine disease such as diabetes and/or obesity.
1. A dry powder inhaler comprising:
a) a mouthpiece;
b) a housing comprising a cartridge-mounting area and a cartridge, the cartridge comprising a movable container having a dry powder, the container configured to move with respect to the cartridge and the cartridge configured to form a flow path between one or more inlet ports and one or more dispensing ports within the housing; and
c) at least one rigid air conduit;
wherein the rigid air conduit is configured so that the dry powder inhaler emits greater than about 75% of the dry powder from the container oriented in the container housing as powder particles in a single inhalation, and the powder particles emitted have a volumetric median geometric diameter of less than about 5 microns when the single inhalation through the mouthpiece generates a peak inspiratory pressure of about 2 kPa within two seconds.
2. The dry powder inhaler of claim 1 having a resistance value to airflow ranging from about 0.065 (√kPa)/liter per minute to about 0.200 (√kPa)/liter per minute.
3. The dry powder inhaler of claim 1 , wherein the dry powder is a formulation for pulmonary delivery and comprises an amount from about 1 mg to about 30 mg of the dry powder.
4. The dry powder inhaler of claim 1 , wherein the dry powder comprises a diketopiperazine or a pharmaceutically acceptable salt thereof.
5. The dry powder inhaler of claim 4 , wherein the diketopiperazine is of the formula 2,5-diketo-3,6-bis(N—X-4-aminobutyl)piperazine,
wherein X is selected from the group consisting of fumaryl, succinyl, maleyl, and glutaryl.
6. The dry powder inhaler of claim 5 , wherein the diketopiperazine is
7. The dry powder inhaler of claim 1 , wherein the dry powder comprises a drug or an active agent.
8. The dry powder inhaler of claim 7 , wherein the active agent is an endocrine hormone.
9. The dry powder inhaler of claim 1 , wherein the dry powder comprises a peptide, a polypeptide, or fragments thereof, a small organic molecule or a nucleic acid molecule.
10. The dry powder inhaler of claim 9 , wherein said peptide is insulin, glucagon, glucagon-like peptide-1, parathyroid hormone, oxytocin, oxyntomodulin, peptide YY, an exendin, analogs thereof or fragments thereof.
11. The dry powder inhaler of claim 9 , wherein the small organic molecule is a vasodialator, a vasoconstrictor, a neurotransmitter agonist or a neurotransmitter antagonist.
12. The dry powder inhaler of claim 1 , wherein the single inhalation generates an area under the curve (AUC) from a pressure versus time curve within one second of at least about 1.0, 1.1 or 1.2 kPa*sec.
13. The dry powder inhaler of claim 1 , wherein the container is integrated into the container housing and filled with a dry powder.
14. A method of delivering of a dry powder using a high resistance dry powder inhaler comprising:
providing a dry powder inhaler with an airflow resistance value ranging from about 0.065 (√kPa)/liter per minute to about 0.200 (√kPa)/liter per minute, and containing the dose of the dry powder within cartridge comprising a container configured to move with respect to the cartridge to form a flow path for the delivery of the dry powder;
applying sufficient force to reach a peak inspiratory pressure of at least 2 kPa within 2 seconds; and
generating an area under the curve in the first second (AUC0-1 sec) of a inspiratory pressure versus time curve of at least about 1.0, 1.1 or 1.2 kPa*sec;
wherein greater than 75% of the dose of the dry powder is discharged or emitted from the inhaler as powder particles.
15. The method of claim 14 , wherein the dry powder is a formulation for pulmonary delivery and comprises an amount from about 1 mg to about 30 mg of the dry powder.
16. The method of claim 15 , wherein the dry powder comprises a diketopiperazine or a pharmaceutically acceptable salt thereof.
17. The method of claim 16 , 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, and glutaryl.
18. The method of claim 17 , wherein the diketopiperazine is
19. The method of claim 18 , wherein the dry powder formulation comprises fumaryl diketopiperazine microparticles which upon discharge from the dry powder inhaler are measured to have a volumetric median geometric diameter (VMGD) ranging from about 2 μm to 8 μm and a geometric standard deviation of less than 4 μm.
20. The method of claim 14 , wherein the dry powder formulation comprises a drug or an active agent selected from the group consisting of a small organic molecule, peptide, polypeptide, a protein, or a nucleic acid molecule.
21. The method of claim 20 , wherein the small organic molecule is a vasoactive agent, a neurotransmitter agonist, a neurotransmitter antagonist, or a steroid molecule.