Inhalable rapamycin formulation for the treatment of pulmonary hypertension
The present invention relates to methods and compositions for the treatment and prophylaxis of pulmonary arterial hypertension (PAH) in a human subject in need of such treatment, the methods comprising the pulmonary administration to the subject, preferably via inhalation of a composition comprising rapamycin or a prodrug or derivative thereof.
1 . A pharmaceutical aerosol composition formulated as a dry powder for pulmonary delivery comprising microparticles of a crystalline rapamycin, wherein the crystalline rapamycin in the composition is from about 0.25% to 2% (w/w), based upon total weight of the composition; particles of a carrier; and optionally one or more excipients, for use in treatment or prophylaxis of pulmonary arterial hypertension (PAH) in a human subject in need thereof.
2 . The composition of claim 1 , wherein the composition persists for at least 12 or 24 hours after delivery.
3 . The composition of claim 2 , wherein the lung to blood concentration ratio of the crystalline rapamycin at 12 or 24 hours after delivery is from about 5 to 50 or from about 10 to 30.
4 . The composition of claim 1 , wherein the crystalline rapamycin-in the composition is from 5 to 500 micrograms, from 10 to 250 micrograms, from 15 to 150 micrograms, or from 20 to 100 micrograms.
5 . The composition of claim 1 , wherein the amount of the crystalline rapamycin in the lungs is from about 1 ng/g to about 1 microgram (ug)/g at 12 or 24 hours after administration.
6 . The composition of claim 5 , wherein the amount of the crystalline rapamycin in the lungs is from about 1 to 10 ng/g or about 1 to 5 ng/g.
7 . The composition of claim 1 , wherein the amount of the crystalline rapamycin in the composition is an amount that produces a blood trough level in the subject of less than 5 ng/ml, less than 2 ng/ml, less than 1 ng/ml, less than 0.5 ng/ml, or less than 0.25 ng/ml.
8 . The composition of claim 1 , wherein the microparticles of the crystalline rapamycin have diameters from 0.1 to 10 microns and a mean diameter of from about 1 to 5 microns.
9 . The composition of claim 1 , wherein the microparticles of the crystalline rapamycin have a mean diameter from 1.5 to 4 microns, from 1.5 to 3.5 microns, or from 2 to 3 microns.
10 . The composition of claim 1 , wherein the carrier is selected from the group consisting of arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran, mannitol, lysine, leucine, isoleucine, dipalmitylphosphatidylcholine, lecithin, polylactic acid, poly (lactic-co-glutamic) acid, and xylitol, and mixtures thereof.
11 . The composition of claim 1 , wherein the particles of carrier have diameters ranging from 1 to 200 microns, from 30 to 100 microns, or less than 10 microns.
12 . The composition of claim 1 , wherein the carrier comprises a blend of two different carriers, a first carrier and a second carrier.
13 . The composition of claim 12 , wherein the carrier comprises a blend of two different lactose carriers.
14 . The composition of claim 12 , wherein the first carrier has particles having diameters ranging from about 30-100 microns and the second carrier has particles having diameters of less than 10 microns.
15 . The composition of claim 14 , wherein the ratio of the first to second carrier is in the range of from 95-98 to 2-5.
16 . The composition of claim 1 , wherein the crystalline rapamycin to carrier ratio in the powder is from 0.5% to 2% (w/w).
17 . The composition of claim 16 , wherein the crystalline rapamycin to carrier ratio in the powder is 1% (w/w).
18 . The composition of claim 1 , wherein the one or more optional excipients is present and is selected from a phospholipid and a metal salt of a fatty acid.
19 . The composition of claim 18 , wherein the phospholipid is selected from dipalmitylphosphatidylcholine and lecithin.
20 . The composition of claim 19 , wherein the metal salt of a fatty acid is magnesium stearate.
21 . The composition of claim 18 , wherein the optional excipient or excipients is coated on the carrier particles in a weight ratio of excipient to the carrier particle ranging from 0.01 to 0.5% (w/w).
22 . The composition of claim 1 , wherein the amount of the crystalline rapamycin is an amount effective to inhibit the biological activity of mTORC1 in lung tissue.
23 . The composition of claim 1 , wherein the amount of the crystalline rapamycin is an amount effective to inhibit the phosphorylation of the S6 protein in lung tissue.
24 . The composition of claim 1 , wherein the amount of the crystalline rapamycin is an amount effective to treat pulmonary arterial hypertension (PAH) in a subject.
25 . The composition of claim 1 , wherein the amount of the crystalline rapamycin is an amount effective to achieve a respirable dose of from 5 to 500 micrograms delivered to the lung.
26 . The composition of claim 25 , wherein the respirable dose is about 20, about 50, about 100 or about 250 micrograms.
27 . The composition of claim 1 , wherein the composition has a fine particle fraction (FPF) greater than 20% with a corresponding fine particle dose (FPD) ranging from 5 micrograms to 2 milligrams, following 1 to 12 months or 1 to 36 months of storage.
28 . The composition of claim 1 , wherein the composition is administered in combination with one or more additional therapeutic agents.
29 . The composition of claim 28 , wherein the one or more additional therapeutic agents is selected from a prostanoid, a phosphodiesterase inhibitor, or an endothelin antagonist.
30 . The composition of claim 29 , wherein the prostanoid is selected from the group consisting of a prostaglandin, a thromboxane, and a prostacyclin.
31 . The composition of claim 1 , where the composition delivers an amount of the crystalline rapamycin effective to improve the subject's pulmonary function as measured by forced vital capacity (PVC) and forced expiratory volume (FEV1).
32 . The composition of claim 1 , where the composition delivers an amount of the crystalline rapamycin effective to inhibit abnormal proliferation of smooth muscle cells and/or endothelial cells.
33 . The composition of claim 1 , where the composition is adapted for once daily administration.
34 . The composition of claim 1 , wherein the composition is produced by a wet polishing process comprising the steps of preparing an aqueous suspension of the crystalline rapamycin, subjecting the aqueous suspension of the crystalline rapamycin to microfluidization, and spray-drying the resulting particles to form a dry powder.
35 . A pharmaceutical package containing one or more vials, each vial containing a sterile unit dose of the composition of claim 1 .
36 . The composition of claim 27 , wherein the fine particle dose (FPD) is 5 micrograms to 0.5 milligrams.