An inhalable rapamycin formulation for the treatment of pulmonary hypertension

Abstract

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.

What is claimed is: 
     
         1 . A pharmaceutical aerosol composition in the form of a dry powder for pulmonary delivery comprising an amount of microparticles of a rapamycin composition, particles of a carrier, and one or more optional excipients, for use in the treatment and prophylaxis of pulmonary arterial hypertension (PAH) in a human subject in need of such therapy or treatment, wherein the formulation is effective to deliver a therapeutic amount of the rapamycin composition to the lungs. 
     
     
         2 . The composition of  claim 1 , wherein the therapeutic amount 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 rapamycin composition at 12 or 24 hours after delivery is from about 5 to 50 or from about 10 to 30. 
     
     
         4 . The composition of any of  claims 1  to  3 , wherein the amount of the rapamycin composition in the formulation 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 any of  claims 1  to  4 , wherein the amount of the rapamycin composition in the aerosol formulation is from about 0.1% to 20% (w/w) or from about 0.25% to 2% (w/w), based upon total weight of the composition. 
     
     
         6 . The composition of any of  claims 1  to  5 , wherein the therapeutic amount of the rapamycin composition in the lungs is from about 1 ng/g to about 1 microgram (ug)/g at 12 or 24 hours after administration. 
     
     
         7 . The composition of  claim 6 , wherein the therapeutic amount of the rapamycin composition in the lungs is from about 1 to 10 ng/g or about 1 to 5 ng/g in a human. 
     
     
         8 . The composition of any of  claims 1  to  7 , wherein the therapeutic amount of the rapamycin composition in the aerosol formulation 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. 
     
     
         9 . The composition of any of  claims 1  to  8 , wherein the microparticles consist of particles having diameters from 0.1 to 10 microns and a mean diameter of from 1 to 5 microns 
     
     
         10 . The composition of any of  claims 1  to  9 , wherein the particles have a mean diameter from 1.5 to 4 microns, from 1.5 to 3.5 microns, or from 2 to 3 microns. 
     
     
         11 . The composition of any of  claims 1  to  10 , 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, or mixtures of any of the foregoing. 
     
     
         12 . The composition of any of  claims 1  to  11 , wherein the particles of carrier have diameters ranging from 1 to 200 microns, from 30 to 100 microns, or less than 10 microns. 
     
     
         13 . The composition of any of  claims 1  to  12 , wherein the carrier comprises or consists of a blend of two different carriers, a first carrier and a second carrier. 
     
     
         14 . The composition of  claim 13 , wherein the carrier consists of a blend of two different lactose carriers. 
     
     
         15 . The composition of  claim 13  or  14 , wherein the first carrier consists of particles having diameters ranging from about 30-100 microns and the second carrier consists of particles having diameters of less than 10 microns. 
     
     
         16 . The composition of  claim 15 , wherein the ratio of the two different carriers is in the range of from 95-98 to 2-5. 
     
     
         17 . The composition of any of  claims 1  to  16 , wherein the drug to carrier ratio in the powder is from 0.5% to 2% (w/w). 
     
     
         18 . The composition of  claim 17 , wherein the drug to carrier ratio in the powder is 1% (w/w). 
     
     
         19 . The composition of any of  claims 1  to  18 , wherein the one or more optional excipients is present and is selected from a phospholipid and a metal salt of a fatty acid. 
     
     
         20 . The composition of  claim 19 , wherein the phospholipid is selected from dipalmitylphosphatidylcholine and lecithin. 
     
     
         21 . The composition of  claim 20 , wherein the metal salt of a fatty acid is magnesium stearate. 
     
     
         22 . The composition of any of  claims 19  to  21 , wherein the optional excipient or excipients is coated on the carrier particles in a weight ratio of excipient to large carrier particle ranging from 0.01 to 0.5%. 
     
     
         23 . The composition of any of  claims 1  to  22 , wherein the therapeutic amount of the rapamycin composition is an amount effective to inhibit the biological activity of mTORC1 in lung tissue. 
     
     
         24 . The composition of any of  claims 1  to  22 , wherein the therapeutic amount of the rapamycin composition is an amount effective to inhibit the phosphorylation of the S6 protein in lung tissue. 
     
     
         25 . The composition of any of  claims 1  to  22 , wherein the therapeutic amount of the rapamycin composition is an amount effective to treat pulmonary arterial hypertension (PAH) in a subject, preferably a human subject. 
     
     
         26 . The composition of any of  claims 1  to  25 , wherein the therapeutic amount of the rapamycin composition is an amount effective to achieve a respirable dose of from 5 to 500 micrograms delivered to the lung. 
     
     
         27 . The composition of  claim 26 , wherein the respirable dose is about 5, about 20, about 50, about 100 or about 250 micrograms. 
     
     
         28 . The composition of any of  claims 1  to  27 , 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, preferably less than 0.5 milligrams, following 1 to 12 months or 1 to 36 months of storage. 
     
     
         29 . The composition of any of  claims 1  to  28 , wherein the rapamycin composition is sirolimus. 
     
     
         30 . The composition of any of  claims 1  to  28 , wherein the method further comprising administering one or more additional therapeutic agents to the subject. 
     
     
         31 . The composition of  claim 30 , wherein the one or more additional therapeutic agents is selected from a prostanoid, a phosphodiesterase inhibitor, or an endothelin antagonist. 
     
     
         32 . The composition of  claim 31 , wherein the prostanoid is selected from the group consisting of a prostaglandin, a thromboxane, and a prostacyclin. 
     
     
         33 . The composition of any of  claims 1  to  32 , where the composition delivers an amount of drug effective to improve the subject's pulmonary function as measured by forced vital capacity (FVC) and forced expiratory volume (FEV1). 
     
     
         34 . The composition of any of  claims 1  to  33 , where the composition delivers an amount of drug effective to inhibit abnormal proliferation of smooth muscle cells and/or endothelial cells. 
     
     
         35 . The composition of any of  claims 1  to  34 , where the composition is adapted for once daily administration. 
     
     
         36 . The composition of any of  claims 1  to  35 , wherein the pharmaceutical aerosol formulation is produced by a wet polishing process comprising the steps of preparing an aqueous suspension of the rapamycin composition, subjecting the rapamycin composition suspension to microfluidization, and spray-drying the resulting particles to form a dry powder. 
     
     
         37 . A pharmaceutical package containing one or more vials, each vial containing a sterile unit dose of the composition of any of  claims 1  to  36 . 
     
     
         38 . A unit dose form comprising the composition of any of  claims 1  to  36 , wherein the amount of the rapamycin composition is from about 5 to 2500 micrograms, from 20-500 micrograms, or from 50-150 micrograms. 
     
     
         39 . The unit dosage form of  claim 38 , wherein the amount of the rapamycin composition is from about 20-100 micrograms. 
     
     
         40 . The unit dosage form of  claim 38 , wherein the dosage form is a capsule suitable for use in a dry powder inhaler device. 
     
     
         41 . The unit dosage form of any of  claims 38  to  40 , wherein the capsule contains from 1 mg to 100 mg of the powder. 
     
     
         42 . The unit dosage form of  claim 41 , wherein the capsule contains from 10 mg or 40 mg of the powder. 
     
     
         43 . The unit dosage form of claim any of  claims 38  to  42 , wherein the capsule is a gelatin, plastic, polymeric, or cellulosic capsule, or is in the form of a foil/foil or foil/plastic blister. 
     
     
         44 . A pharmaceutical package or kit comprising the composition of any of  claims 1  to  36  or the unit dosage form of any of  claims 38  to  43 , and instructions for use. 
     
     
         45 . A dry powder delivery device comprising a reservoir containing the unit dosage form of any of  claims 38  to  43 . 
     
     
         46 . The dry powder delivery device of  claim 45 , wherein the reservoir is an integral chamber within the device, a capsule, or a blister. 
     
     
         47 . The dry powder delivery device of  claim 45  or  46 , wherein the device is selected from Plastiape® RS01 Model 7, Plastiape® RS00 Model 8, XCaps®, Handihaler®, Flowcaps® TwinCaps®, and Aerolizer®. 
     
     
         48 . A method for the treatment and prophylaxis of PAH in a human subject in need of such treatment, the method comprising administering to the subject the composition of any one of  claims 1  to  36 , wherein the composition is effective to deliver a therapeutic amount of the rapamycin composition to the lungs. 
     
     
         49 . The method of  claim 48 , wherein the administering is once daily or twice daily. 
     
     
         50 . The method of  claim 48 , wherein the administering is performed using the dry powder delivery device of any of  claims 45  to  47 . 
     
     
         51 . The method of any of  claims 48  to  50 , further comprising administering at least one additional agent in a therapeutic regimen or combination therapy with the composition of any one of  claims 1  to  36 .