Method for drug delivery to the pulmonary system
View Patent ↗Drug delivery to the pulmonary system has been achieved by encapsulation of the drug to be delivered in microparticles having a size range between 0.5 and ten microns, preferably in the range of two to five microns, formed of a material releasing drug at a pH of greater than 6.4. In a preferred embodiment, the drug delivery system is based on the formation of diketopiperazine microparticles which are stable at a pH of 6.4 or less and unstable at pH of greater than 6.4, or which are stable at both acidic and basic pH, but which are unstable at pH between about 6.4 and 8. Other types of materials can also be used, including biodegradable natural and synthetic polymers, such as proteins, polymers of mixed amino acids (proteinoids), alginate, and poly(hydroxy acids). In another embodiment, the microparticles have been modified to effect targeting to specific cell types and to effect release only after reaching the targeted cells.
1. A method for delivery of an active agent to the pulmonary system comprising:
administering the active agent by inhalation of a diketopiperazine composition to a patient in need of treatment,
wherein an effective amount of a dry powder comprising microparticles which comprise the diketopiperazine composition is administered to the patient using air as a carrier,
wherein the diketopiperazine composition comprises a diketopiperazine and the active agent, and
wherein the microparticles have a diameter between 0.5 microns and ten microns,
wherein the microparticles are administered from a dry powder inhaler or from a container for a dry powder inhaler; and
wherein the active agent is released from the microparticle at a pH of 6.0 or greater.
2. The method of claim 1 , wherein the diketopiperazine has the formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is selected from the group consisting of succinyl, glutaryl, maleyl, and fumaryl.
3. The method of claim 2 , wherein X is fumaryl.
4. The method of claim 1 , wherein the active agent is a therapeutic agent selected from the group consisting of insulin, calcitonin, felbamate, heparin, parathyroid hormone and fragments thereof, growth hormone, erythropoietin, zidovudine (AZT), didanosine (DDI), granulocyte colony stimulating factor (G-CSF), lamotrigine, chorionic gonadotropin releasing factor, luteinizing releasing hormone, β-galactosidase, and Argatrohan.
5. A microparticulate system for drug delivery to the pulmonary system comprising:
an inhaler component containing a diketopiperazine composition;
wherein the inhaler component is a dry powder inhaler or a container for a dry powder inhaler;
wherein the diketopiperazine composition is a dry powder comprising microparticles having a size range of between 0.5 and ten microns,
wherein the microparticles comprise an effective amount of a drug to be delivered and a diketopiperazine, and
wherein the microparticles release the drug at a pH of 6.0 or greater,
in a pharmaceutically acceptable carrier for administration to the lungs, wherein the carrier is air.
6. The system of claim 5 , wherein the microparticles consist essentially of the drug and the diketopiperazine.
7. The system of claim 5 , wherein the diketopiperazine has the formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine wherein X is selected from the group consisting of succinyl, glutaryl, maleyl, and fumaryl.
8. The system of claim 7 , wherein X is fumaryl.
9. The system of claim 5 , wherein the drug is selected from the group consisting of insulin, calcitonin, felbamate, heparin, parathyroid hormone and fragments thereof, growth hormone, erythropoietin, zidovudine (AZT), didanosine (DDI), granulocyte colony stimulating factor (C-CSF), lamotrigine, chorionic gonadotropin releasing factor, luteinizing releasing hormone, β-galactosidase, and Argatroban.
10. The system of claim 9 , wherein the drug is insulin.
11. The method of claim 4 , wherein the active agent is insulin.