RAPAMYCIN FOR THE TREATMENT OF LYMPHANGIOLEIOMYOMATOSIS

1 . A pharmaceutical aerosol formulation 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, wherein the formulation is effective to deliver a therapeutic amount of the rapamycin composition to the lungs.

2 . The aerosol formulation of claim 1 , wherein the therapeutic amount persists for at least 12 or 24 hours after pulmonary delivery.

3 . The aerosol formulation of claim 2 , wherein the rapamycin composition persists in the lungs at therapeutic levels of from 5 to 100 ng/g and the amount of rapamycin in the blood is less than 1 ng/ml for a period of time that is from 12 to 24 hours after pulmonary delivery.

4 . The aerosol formulation of claim 1 , wherein the amount of the rapamycin composition in the formulation is from 5 to 500 micrograms.

5 . The aerosol formulation of claim 1 , wherein the amount of the rapamycin composition in the aerosol formulation is from about 0.1% to 20% (w/w) based upon total weight of the composition.

6 . The aerosol formulation of claim 1 , wherein the amount of the rapamycin composition in the aerosol formulation is an amount effective to produce a concentration of drug in the lung tissue of from 5 to 100 ng/g for a period of time that is from 12 to 24 hours after pulmonary delivery.

7 . The aerosol formulation of claim 6 , wherein the concentration of drug in the lung tissue is from 5 ng/g to 30 ng/g.

8 . The aerosol formulation of claim 1 , wherein the amount of the rapamycin composition in the aerosol formulation is an amount that produces a blood trough level in the subject of less than 1 ng/ml.

9 . The aerosol formulation of claim 1 , 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 aerosol formulation of claim 9 , wherein the particles have a mean diameter from 1.5 to 4 microns.

11 . The aerosol formulation 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, or mixtures of any of the foregoing.

12 . The aerosol formulation claim 1 , wherein the particles of carrier have diameters ranging from 1 to 200 microns.

13 . The aerosol formulation of claim 1 , wherein the carrier comprises or consists of a blend of two different carriers, a first carrier and a second carrier.

14 . The aerosol formulation of claim 13 , wherein the carrier consists of a blend of two different lactose carriers.

15 . The aerosol formulation of claim 13 , 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 aerosol formulation of claim 15 , wherein the ratio of the two different carriers is in the range of from 3:97 to 97:3.

17 . The aerosol formulation of claim 1 , wherein the drug to carrier ratio in the powder is from 0.5% to 20% (w/w).

18 . The aerosol formulation of claim 17 , wherein the drug to carrier ratio in the powder is from 0.5% to 2% (w/w).

19 . The aerosol formulation 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.

20 . The aerosol formulation of claim 19 , wherein the phospholipid is selected from dipalmitylphosphatidylcholine and lecithin.

21 . The aerosol formulation of claim 20 , wherein the metal salt of a fatty acid is magnesium stearate.

22 . The aerosol formulation of any of claim 19 , 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 aerosol formulation of claim 1 , wherein the amount of drug is an amount effective to inhibit the biological activity of mTORC1 in the lung.

24 . The aerosol formulation of claim 1 , wherein the amount of drug is an amount effective to inhibit the phosphorylation of the S6 protein in the lung.

25 . The aerosol formulation of claim 1 , wherein the amount of drug is an amount effective to treat Lymphangioleiomyomatosis (LAM) in a subject.

26 . The aerosol formulation of claim 1 , wherein the amount of drug is an amount effective to achieve a respirable dose of from 5 to 500 micrograms delivered to the lung.

27 . The aerosol formulation of claim 26 , wherein the respirable dose is from 20 to 100 micrograms.

28 . The aerosol formulation 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 of storage.

29 . The aerosol formulation of claim 1 , wherein the rapamycin composition is sirolimus.

30 . The aerosol formulation of claim 1 , further comprising one or more additional therapeutic agents.

31 . The aerosol formulation of claim 30 , wherein the one or more additional therapeutic agents is selected from an estrogen antagonist, a statin, a src inhibitor, and a VEGF-R inhibitor.

32 . The aerosol formulation of claim 31 , wherein the one or more additional therapeutic agents is selected from the group consisting of letrozole, tamoxifen, simvastatin, saracatinib, pazopanib, imatinib, and combinations thereof.

33 . The aerosol formulation of claim 1 , where the composition delivers an amount of drug effective to improve a subject's pulmonary function as measured by forced vital capacity (FVC) and forced expiratory volume (FEV1).

34 . The aerosol formulation of claim 1 , where the composition delivers an amount of drug effective to reduce the size or amount of pleural effusion detectable by radiologic examination.

35 . The aerosol formulation of claim 1 , where the composition is adapted for once daily administration.

36 . The aerosol formulation of claim 1 , produced by a wet polishing process comprising the steps of preparing an aqueous suspension of drug, subjecting the drug suspension to microfluidization, and spray-drying the resulting particles to form a dry powder.

37 . A unit dosage form for treating Lymphangioleiomyomatosis comprising the aerosol formulation of claim 1 , wherein the amount of the rapamycin composition is from about 5 to 2500 micrograms.

38 . The unit dosage form of claim 37 , wherein the amount of the rapamycin composition is from about 20 to 100 micrograms.

39 . The unit dosage form of claim 37 , wherein the dosage form is a capsule suitable for use in a dry powder inhaler device.

40 . The unit dosage form of claim 37 , wherein the capsule contains from 1 mg to 100 mg of the powder.

41 . The unit dosage form of claim 40 , wherein the capsule contains from 10 mg to 40 mg of the powder.

42 . The unit dosage form of claim 37 , wherein the capsule is a gelatin, plastic, polymeric, or cellulosic capsule, or is in the form of a foil/foil or foil/plastic blister.

43 . A pharmaceutical package or kit comprising the aerosol formulation of claim 1 , and instructions for use.

44 . A dry powder delivery device comprising a reservoir containing the aerosol formulation of claim 1 .

45 . The dry powder delivery device of claim 44 , wherein the reservoir is an integral chamber within the device, a capsule, or a blister.

46 . The dry powder delivery device of claim 44 , wherein the device is selected from Plastiape® RS01 Model 7, Plastiape® RS00 Model 8, XCaps®, Handihaler®, Flowcaps® TwinCaps®, and Aerolizer®.

47 . A method for treating Lymphangioleiomyomatosis in a human subject in need of such treatment, the method comprising administering to the subject via inhalation the aerosol formulation of any of claim 1 .

48 . The method of claim 47 , further comprising administering at least one additional agent in a therapeutic regimen or combination therapy with the aerosol formulation of unit dosage form.