(12) United States Patent (10) Patent No.: US 9,265,749 B2 Gerhart Et Al

US009265749B2

(12) United States Patent (10) Patent No.: US 9,265,749 B2 Gerhart et al. (45) Date of Patent: *Feb. 23, 2016

(54) METHODS FOR THE TREATMENT OF 3,790,580 A 2, 1974 Johnson et al. SYSTEMC DSORDERS TREATABLE WITH 3. A 8. 3. Siles et al. MAST CELL STABILIZERS, INCLUDING 3972.995 A 8, 1976 f MAST CELL RELATED DISORDERS 3.993.072 A 1/1976 Zafaroni 3,993,073. A 11/1976 Zaffaroni (71) Applicant: Patara Pharma, LLC, San Diego, CA 3.996,934. A 12/1976 Zaffaroni (US) 4,031,894 A 6/1977 Urquhartet al. 4,060,084 A 11/1977 Chandrasekaran et al. (72) Inventors: WilliamO O Gerhart, Del Mar, CA (US); 4,069,3074,067,992 A 1/1978 HiguchiKingsley et et al. al. Manfred Keller, Munich (DE); Ahmet 4,077.407 A 3/1978 Theeuwes et al. Tutuncu, Del Mar, CA (US); Pravin 4,151.273 A 4, 1979 Chiou et al. Soni, Sunnyvale, CA (US) 4,152,448 A 5, 1979 Wardell 4,189,571 A 2f1980 Bodor et al. (73) Assignee: PATARA PHARMA, LLC, San Diego, 4,229.4474,201,211 A 10/19805/1980 PorterChandrasekaran et al. CA (US) 4,230,105. A 10/1980 Harwood 4,268,519 A 5/1981 Turner (*) Notice: Subject to any disclaimer, the term of this 4,292,299 A 9/1981 Suzuki et al. patent is extended or adjusted under 35 2. A . E. th al 1 U.S.C. 154(b) by 0 days. 4,362,742- I - A 12/1982 SullivanaWa ca. This patent is Subject to a terminal dis- 4476,116 A 10/1984 Anik claimer 4496,086 A 1/1985 Duchadeau 4,596,795 A 6, 1986 Pitha 4,634,699 A 1/1987 McDermed et al. (21) Appl. No.: 14/686,535 4,683,135 A 7/1987 Pecht et al. 4,755,386 A 7, 1988 Hsiao et al. (22) Filed: Apr. 14, 2015 4,847.286 A 7/1989 Tamaki et al. 4,871,865 A 10/1989 Lever, Jr. et al. (65) Prior Publication Data 1932. A 39 Stal US 2015/0297557 A1 Oct. 22, 2015 (Continued) Related U.S. Application Data FOREIGN PATENT DOCUMENTS (63) Continuation of application No. 14/617,130, filed on EP O163683 A1 12, 1985 Feb. 9, 2015. EP O3O4802 A2 3, 1989 (60) Provisional application No. 62/105,423, filed on Jan. (Continued) 20, 2015, provisional application No. 61/978,71 1. OTHER PUBLICATIONS filed on Apr. 11, 2014, provisional application No. 61/971,709, filed on Mar. 28, 2014, provisional Edwards, A.M. et al., Journal of Medical Case Reports vol. 4, pp. application No. 61/937,928, filed on Feb. 10, 2014. 193-200. Published 2010. Taylor, K. M. G. et al., Pharmaceutical Research vol. 6 pp. 633-637. (51) Int. Cl. PublishedAllistone etal. 1989. The effect of intravenous sodium cromoglycate on the A6 IK3I/35 (2006.01) bronchoconstriction induced by Sulphur dioxide inhalation in man. A6 IK3I/335 (2006.01) Clinical Science, 68:227-232 (1985). A6 IK3I/352 (2006.01) Salmon et al. How much aerosol reaches the lungs of wheezy infants A6 IK9/00 (2006.01) and toddlers? Archives of Disease in Childhood, 65:401-403 (1990). 52) U.S. C. Ariyanayagam et al., Topical Sodium cromoglycate in the manage (52) CPC A61 K3I/352 (2013.01); A61 K9/0075 ment of atopic eczema-a controlled trial. British Journal of Derma ------• us tology, 112:343-348 (1985). (2013.01); A61 K9/0078 (2013.01) Ashton et al., The absorption, metabolism and excretion of disodium (58) Field of Classification Search cromoglycate in nine animal studies. Toxicology and Applied Phar USPC ...... 514/451, 456 macology, 26:319-328 (1973). See application file for complete search history. (Continued) (56) References Cited Primary Examiner — Paul Zarek U.S. PATENT DOCUMENTS Assistant Examiner — George W. Kosturko (74) Attorney, Agent, or Firm — Wilson Sonsini Goodrich & 3.419,578 A 12, 1968 Fitzmaurice et al. Rosati 3,598,122 A 8, 1971 Zaffaroni 3,683,320 A 8, 1972 Woods et al. 3,686,320 A 8, 1972 Fitzmaurice et al. (57) ABSTRACT 3,686.412 A 8, 1972 Fitzmaurice et al. 3,710,795 A 1/1973 Higuchi et al. Methods for the treatment of systemic disorders treatable 3,720,690 A 3/1973 King et al. with mast cell stabilizers, including mast cell related disor 3,731,683 A 5, 1973 Zaffaroni ders, are provided. 3,742,951 A 7, 1973 Zaffaroni 3,777,033. A 12/1973 Fitzmaurice et al. 27 Claims, No Drawings US 9,265,749 B2 Page 2

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In certain embodiments, the MAST CELL RELATED DSORDERS systemic mast cell related disorder is selected from the group consisting of a mast cell activation syndrome; mastocytosis: CROSS-REFERENCE TO RELATED idiopathic urticaria; chronic urticaria; atopic dermatitis; idio APPLICATIONS pathic anaphylaxis; Ig-E and non Ig-E mediated anaphylaxis; angioedema; allergic disorders; irritable bowel syndrome; This application is a continuation of U.S. patent applica mastocytic gastroenteritis; mastocytic colitis; fibromyalgia; tion Ser. No. 14/617,130, filed Feb. 9, 2015, which claims the benefit of U.S. Provisional Application No. 62/105,423, filed 10 kidney fibrosis; atherosclerosis; myocardial ischemia; hyper Jan. 20, 2015, U.S. Provisional Application No. 61/978,711, tension; congestive heart failure; pruritus; chronic pruritus; filed Apr. 11, 2014, U.S. Provisional Application No. 61/971, pruritus secondary to chronic kidney failure; heart, vascular, 709, filed Mar. 28, 2014, and U.S. Provisional Application intestinal, brain, kidney, liver, pancreas, muscle, bone and No. 61/937,928, filed Feb. 10, 2014, all of which are incor skin conditions associated with mast cells; CNS diseases such porated herein by reference in their entireties. 15 as Parkinson's disease and Alzheimer's disease; metabolic diseases such as diabetes; sickle cell disease; autism; chronic BACKGROUND OF THE INVENTION fatigue syndrome; lupus; chronic lyme disease; interstitial cystitis; multiple Sclerosis; cancer, migraine headaches; pso Mast cells play a key role in the inflammatory process. riasis; eosinophilic esophagitis; eosinophilic gastroenteritis; They are found in the perivascular spaces of most tissues and Churg-Strauss syndrome; hypereosinophilic syndrome; eosi contain pro-inflammatory and vasoactive mediators, such as nophilic fasciitis; eosinophilic gastrointestinal disorders; serine proteases, tryptase, histamine, serotonin, proteogly chronic idiopathic urticaria; myocarditis; Hirschsprungs-as cans, thromboxane, prostaglandin D2, leukotriene C4, plate Sociated enterocolitis; postoperative ileus; wound healing; let-activating factor, and eosinophil chemotactic factor. When stroke; transient ischemic attack; pain; neuralgia; peripheral activated, mast cells rapidly release granules and various 25 neuropathy; acute coronary syndromes; pancreatitis; cutane hormone mediators into the interstitium, a process referred to ous mastocytosis; systemic mastocytosis; systemic indolent as degranulation. Degranulation of mast cells can be caused by physical or chemical injury, crosslinking of immunoglo mastocytosis; dermatomyositis; fibrotic skin diseases; pain bulin G receptors, or by activated complement proteins. associated with cancer, ulcerative colitis; inflammatory Systemic mast cell related disorders may result from bowel disease; radiation colitis; celiac disease; gluten enter excessive proliferation of mast cells or abnormal release of 30 opathy; radiation cystitis; painful bladder syndrome; hepati pro-inflammatory and vasoactive mediators. Symptoms of tis; hepatic fibrosis; cirrhosis; rheumatoid arthritis; lupus systemic mast cell related disorders include pruritus, flush erythematosus; and vasculitis. In some embodiments, admin ing, nausea, vomiting, diarrhea, headaches, abdominal pain, istration of a composition disclosed herein in a method dis vascular instability, urticaria, itching, and anaphylaxis. Accu closed herein is well-tolerated by the patient. In some mulation of mast cells in the skin, gastrointestinal tract, bone 35 embodiments, the mast cell stabilizer is selected from cro marrow, liver, spleen, and lymph nodes may result in a par molyn Sodium, cromolyn lysinate, ammonium cromoglycate, ticular systemic mast cell related disorder, systemic masto magnesium cromoglycate, dihydropyridines such as nicar cytosis, or mastocytosis. dipine and nifedipine, lodoxamide, nedocromil, barnidipine, The utility of mast cell stabilizers in the treatment of sys YC-114. elgodipine, niguldipine, ketotifen, methylxanthines, temic mast cell related disorders, such as mastocytosis, has 40 and quercetin. In some embodiments, administration of a been limited. For example, cromolyn Sodium (also known as composition disclosed herein in a method disclosed herein disodium cromoglycate or DSCG) was first approved in 1973 does not cause one or more adverse events selected from the and is widely considered safe, but it has found limited utility group consisting of oropharyngeal pain, dysgeusia, because the amount of the compound that can be delivered nasopharygitis, and abdominal discomfort. systemically is inadequate. An oral solution of cromolyn 45 In some embodiments, the methods disclosed herein com sodium is available for the treatment of systemic mast cell prise administering a composition comprising a mast cell related disorders. Such as mastocytosis (GastrocromR). How ever, the oral solution is only modestly effective for treating stabilizer to a patient having a systemic mast cell related localized gastrointestinal symptoms, and it is not effective for disorder, wherein the bioavailability of the mast cell stabilizer the treatment of systemic symptoms because of the low oral is greater than about 5%, and wherein administration of the bioavailability of cromolyn sodium (less than 1%). 50 composition produces in a human Subject group an average Efforts have been made to increase the oral bioavailability AUCo. of the mast cell stabilizer greater than about 120 of cromolyn sodium in order to provide systemically effective nghr/mL and/or an average C of the mast cell Stabilizer amounts for the treatment of systemic mast cell related dis greater than about 55 ng/mL. In some embodiments of the orders, but these efforts have not yielded products that methods disclosed herein, the composition is administered by achieve significantly higher oral bioavailability of cromolyn 55 a route selected from inhalation administration, oral admin Sodium in a practical, safe, and well-tolerated manner. istration, parenteral administration, Subcutaneous adminis Accordingly, a need exists for methods of delivering mast cell tration, topical administration, buccal administration, nasal stabilizers. Such as cromolyn Sodium, that achieve higher administration, rectal administration, vaginal administration, systemic levels than previously considered or thought pos and Sublingual administration. In some embodiments, the sible, in a practical, safe, and well-tolerated manner, in order 60 composition is administered with a dry powder inhaler, to significantly improve clinical outcomes for patients suffer metered dose inhaler, nebulizer, soft mist inhaler, or high ing from systemic mast cell related disorders. efficiency nebulizer. In some embodiments wherein the com position is administered with a dry powder inhaler, the com SUMMARY OF THE INVENTION position comprises lactose. In some embodiments wherein 65 the composition is administered with a dry powder inhaler, The foregoing and further needs are satisfied by embodi the composition does not comprise lactose. In some embodi ments of the methods disclosed herein. Specifically, disclosed ments, a composition comprising a mast cell stabilizer is US 9,265,749 B2 3 4 administered once a day. In some embodiments, a composi ited lung dose of cromolyn sodium at least about 25%. In tion comprising a mast cell Stabilizer is administered twice a Some embodiments, the composition comprises greater than day. In some embodiments, a composition comprising a mast about 2% cromolyn Sodium. In some embodiments, the com cell stabilizer is administered three times a day. In some position comprises about 4% cromolyn Sodium. In some embodiments, a composition comprising a mast cell stabi- 5 embodiments, the median particle size of the cromolyn lizer is administered four times a day. In some embodiments, Sodium aerosol is between about 3 um and about 4 Lum. the composition comprises about 1 mg to about 120 mg of In certain embodiments of the methods disclosed herein, a cromolyn Sodium. In some embodiments, the composition composition comprising a mast cell stabilizer is administered comprises about 5 mg to about 80 mg of cromolyn Sodium. In with an inhalation device, wherein administration of the com Some embodiments, the composition comprises about 20 mg 10 position with the inhalation device produces in a human Sub to about 60 mg of cromolyn Sodium. In some embodiments, ject group an average AUCo. of the mast cell stabilizer the composition comprises about 30 mg to about 50 mg of greater than about 120 nghr/mL and/or an average C of cromolyn Sodium. In some embodiments, the composition the mast cell stabilizer greater than about 55 ng/mL. In some comprises about 40 mg of cromolyn Sodium. embodiments the mast cell stablizer is cromolyn Sodium, and In some embodiments, disclosed herein is a method of 15 administration of the composition with an inhalation device treating a patient having a systemic mast cell related disorder produces in a human subject group an average AUCo., of the comprising administering to the patient a composition com cromolyn Sodium greater than about 120 nghr/mL and an prising a nominal dose of a mast cell stabilizer with a high average C of the cromolyn Sodium greater than about 55 efficiency nebulizer, wherein administration of the composi ng/mL. In some embodiments the mast cell stabilizer is cro tion to the patient with a high efficiency nebulizer provides a molyn Sodium, and administration of the composition with an systemically effective amount of the mast cell stabilizer to inhalation device produces in a human Subject group an aver treat the systemic mast cell related disorder. In certain age AUCo. of the cromolyn Sodium greater than about 200 embodiments, the bioavailability of the mast cell stabilizer is nghr/mL and an average C of the cromolyn sodium greater than about 5% of the nominal dose administered with greater than about 80 ng/mL. In some embodiments the mast the high efficiency nebulizer. In certain embodiments, admin 25 cell stabilizer is cromolyn Sodium, and administration of the istration of the composition comprising a mast cell stabilizer composition with an inhalation device produces in a human with a high efficiency nebulizer produces in a human Subject subject group an average AUCo. of the cromolyn Sodium group an average AUCo. of the mast cell stabilizer greater greater than about 330 nghr/mL and an average C of the than about 120 nghr/mL and/or an average C of the mast cromolyn Sodium greater than about 150 ng/mL. In some cell stabilizergreater than about 55 ng/mL. In certain embodi 30 embodiments the mast cell stabilizer is cromolyn Sodium, and ments, administration of the composition comprising a mast administration of the composition with an inhalation device cell stabilizer with a high efficiency nebulizer produces in a produces in a human Subject group an average AUCo. of the human subject group an average AUCo. of the mast cell cromolyn Sodium greater than about 525 nghr/mL and an stabilizer greater than about 120 nghr/mL and an average average C of the cromolyn Sodium greater than about 230 C of the mast cell stabilizer greater than about 55 ng/mL. 35 ng/mL. In some embodiments wherein the mast cell Stabilizer In certain embodiments, the composition comprising a mast is cromolyn Sodium and a nominal dose of 40 mg of cromolyn cell stabilizer comprises a high concentration, hypotonic, Sodium is administered with the inhalation device, adminis room temperature stable solution formulation of the mast cell tration of the composition with the inhalation device produces stabilizer. In certain embodiments, the composition is stable in a human subject group an average AUCo. of the cro at room temperature for more than about two years. In some 40 molyn sodium greater than about 200 nghr/mL and an aver embodiments, the composition comprises one or more of age C of the cromolyn Sodium greater than about 80 purified water, Sodium chloride, mannitol, and sodium ng/mL. In some embodiments wherein the mast cell Stabilizer EDTA. In some embodiments, the composition has an osmo is cromolyn Sodium and a nominal dose of 40 mg of cromolyn lality greater than about 70 mOsm/kg. In some embodiments, Sodium is administered with the inhalation device, adminis the composition has a fill volume of about 0.1 mL to about 5 45 tration of the composition with the inhalation device produces mL. In some embodiments, the composition has a fill Volume in a human subject group an average AUCo. of the cro of about 2 mL or less. In some embodiments, the composition molyn sodium greater than about 330 nghr/mL and an aver is administered in less than about five minutes. In some age C of the cromolyn Sodium greater than about 150 embodiments, the composition is administered in less than ng/mL. In some embodiments wherein the mast cell Stabilizer about three minutes. In some embodiments, the high effi- 50 is cromolyn Sodium and a nominal dose of 80 mg of cromolyn ciency nebulizer emits droplets having an MMAD of about Sodium is administered with the inhalation device, adminis 4.1 um or less and a GSD of about 1.7. In some embodiments, tration of the composition with the inhalation device produces the high efficiency nebulizer emits droplets having an in a human subject group an average AUCo. of the cro MMAD of about 3.5 um or less and a GSD of about 1.7. In molyn Sodium greater than about 525 nghr/mL and an aver some embodiments, the RF (s3.3 um) is at least about 30%. 55 age C of the cromolyn Sodium greater than about 230 and/or the RF (s.5um) is at least about 65%. In some embodi ng/mL. In some embodiments wherein the mast cell Stabilizer ments, the RF (s3.3 um) is at least about 45% and/or the RF is cromolyn Sodium, administration of a composition with an (s.5um) is at least about 75%. inhalation device provides a bioavailability of the mast cell In some embodiments, the mast cell stabilizer is cromolyn stabilizer greater than about 5% and produces in a human Sodium. In some embodiments, the deposited lung dose of 60 subject group an average AUCo. of cromolyn Sodium cromolyn sodium is at least about 25% after administration of greater than about 120 nghr/mL. In some embodiments the composition to the patient with a high efficiency nebu wherein the mast cell Stabilizer is cromolyn Sodium, admin lizer. In some embodiments, administration of the composi istration of a composition with an inhalation device provides tion with a high efficiency nebulizer produces in a human a bioavailability of cromolyn sodium greater than about 5% subject group an average AUCo. of the cromolyn sodium 65 and produces in a human subject group an average AUCo. greater than about 120 nghr/mL, an average C of the of cromolyn sodium greater than about 200 nghr/mL. In cromolyn Sodium greater than about 55 ng/mL, and a depos some embodiments wherein the mast cell stabilizer is cro US 9,265,749 B2 5 6 molyn Sodium, administration of a composition with an inha device prior to administration to the patient. The volume of lation device provides a bioavailability of the mast cell stabi solution containing the nominal dose is referred to as the “fill lizer greater than about 5% and produces in a human Subject Volume.” group an average AUCo. of cromolyn Sodium greater than “AUC” as used herein refers to the area under the curve about 330 nghr?mL. In some embodiments wherein the mast 5 from time Zero to time of last measurable concentration of cell stabilizer is cromolyn Sodium, administration of a com active pharmaceutical ingredient (API). position with an inhalation device provides a bioavailability “AUC.' as used herein refers to the area under a of the mast cell stabilizer greater than about 5% and produces blood plasma concentration curve up to the last time point for in a human subject group an average AUCo. of cromolyn the nominal dose of active pharmaceutical ingredient (API) 10 administered with a high efficiency nebulizer. sodium greater than about 525 nghr/mL. In some embodi “AUC” as used herein refers to the area under a ments wherein the mast cell Stabilizer is cromolyn Sodium, blood plasma concentration curve up to the last time point for administration of a composition with an inhalation device a nominal dose of active pharmaceutical ingredient (API) produces in a human subject group an average AUCo. of administered with a conventional inhalation device. cromolyn sodium greater than about 120 nghr/mL, and the 15 “AUCo...” as used herein refers to the total area under a composition has an RF (s3.3 m) of at least about 30%. In blood plasma concentration curve for an active pharmaceuti some embodiments wherein the mast cell stabilizer is cro cal ingredient (API). molyn Sodium, administration of a composition with an inha “AUCfENas used herein refers to the total area under lation device produces in a human Subject group an average a blood plasma concentration curve for a nominal dose of AUCo. of cromolyn sodium greater than about 200 ng*hr/ active pharmaceutical ingredient (API) administered with a mL, and the composition has an RF (s3.3 um) of at least about high efficiency nebulizer. 30%. In some embodiments wherein the mast cell stabilizer is “AUC, or as used herein refers to the total area under cromolyn Sodium, administration of a composition with an a blood plasma concentration curve for a nominal dose of inhalation device produces in a human Subject group an aver active pharmaceutical ingredient (API) administered with a age AUCo. of cromolyn sodium greater than about 330 25 conventional inhalation device. nghr/mL, and the composition has an RF (s3.3 um) of at AUCo. can be determined by methods known to those of least about 40%. In some embodiments wherein the mast cell skill in the art. For example, the AUCo. of an API can be stabilizer is cromolyn Sodium, administration of a composi determined by collecting blood samples from a Subject at tion with an inhalation device produces in a human Subject various time points after administration of an API to the 30 Subject, separating plasma from the blood samples, extracting group an average AUCo. of cromolyn Sodium greater than the API from the separated plasma samples, e.g., by Solid about 525 nghr/mL, and the composition has an RF (s3.3 phase extraction, quantifying the amount of the API extracted um) of at least about 40%. In some embodiments the compo from each sample of separated plasma, e.g., by liquid chro sition administered with an inhalation device is not co-admin matography-tandem mass spectrometry (LC-MS/MS), plot istered with an oral formulation of cromolyn sodium. 35 ting the concentration of API in each sample versus the time of collection after administration, and calculating the area DETAILED DESCRIPTION OF THE INVENTION under the curve. “Substantially the same nominal dose” as used herein Unless defined otherwise, all technical and scientific terms means that a first nominal dose of an active pharmaceutical used herein have the same meaning as commonly understood 40 ingredient (API) contains approximately the same number of by one of skill in the art to which the inventions described millimoles of the mast cell stabilizer as a second nominal dose herein belong. All publications, patents, and patent applica of the mast cell stabilizer. tions mentioned in this specification are hereby incorporated “Bioavailability” as used herein refers to the amount of by reference to the same extent as if each individual publica unchanged API that reaches the systemic circulation, tion, patent, or patent application was specifically and indi 45 expressed as a percentage of the dosage of the API that is vidually indicated to be incorporated by reference. administered to a subject. By definition, the bioavailability of an intravenous Solution containing the active pharmaceutical DEFINITION OF TERMS ingredient (API) is 100%. The bioavailability of an API can be determined by methods known to those of skill in the art. As used herein, the term “about is used synonymously 50 For example, the bioavailability of an API can be determined with the term “approximately.” Illustratively, the use of the by collecting urine samples from a subject at various time term “about with regard to a certain therapeutically effective points following administration of the API to the subject, pharmaceutical dose indicates that values slightly outside the extracting the API from the urine samples, e.g., by Solid cited values, e.g., plus or minus 0.1% to 10%, are also effec phase extraction, quantifying the amount of the API in each tive and safe. 55 urine sample, adjusting the amount of API collected from the As used herein, the terms “comprising.” “including.” “such urine by a factor based on the amount of API reaching sys as and “for example' (or “e.g.) are used in their open, temic circulation that is excreted in the urine, and calculating non-limiting sense. the percentage of the API administered to the subject that As used herein, the phrase “consisting essentially of is a reaches the systemic circulation of the Subject. In a specific transitional phrase used in a claim to indicate that the follow 60 embodiment, the bioavailability of cromolyn sodium can be ing list of ingredients, parts or process steps must be present determined as described in Walker et al., 24.J. Pharm. Phar in the claimed composition, machine or process, but that the macol. 525-31 (1972). In the case of cromolyn sodium, the claim is open to unlisted ingredients, parts or process steps amount of the compound isolated from the urine is multiplied that do not materially affect the basic and novel properties of by two to calculate the total amount reaching systemic circu the invention. 65 lation after administration because the compound is known to “Nominal dose” as used herein, refers to the loaded dose, be excreted unmetabolized in equal parts in the urine and which is the amount of mast cell stabilizer in an inhalation feces, i.e., approximately 50% of the amount of cromolyn US 9,265,749 B2 7 8 Sodium that reaches systemic circulation is excreted in the “Drug absorption' or simply “absorption' typically refers urine and approximately 50% of the amount of cromolyn to the process of movement of drug from site of delivery of a Sodium that reaches systemic circulation is excreted in the drug across a barrier into a blood vessel or the site of action, feces. e.g., a drug being absorbed via the pulmonary capillary beds “Enhanced lung deposition' as used herein refers to an of the alveoli into the systemic circulation. increase in drug deposition (deposited lung dose) arising out “T” as used herein refers to the amount of time neces of for example, improved efficiency of drug delivery. sary for an active pharmaceutical ingredient (API) to attain “Deposited dose” or “deposited lung dose” is the amount maximum blood plasma concentration. of mast cell stabilizer deposited in the lung. The deposited “T'” as used herein refers to the amount of time dose or deposited lung dose may be expressed in absolute 10 necessary for a nominal dose of an active pharmaceutical terms, for example in mg or ug of API deposited in the lungs. ingredient (API) to attain maximum blood plasma concentra The deposited lung dose may also be expressed in relative tion after administration with a high efficiency nebulizer. terms, for example calculating the amount of API deposited “T” as used herein refers to the amount of time as a percentage of the nominal dose. 15 necessary for a nominal dose of an active pharmaceutical “C” as used herein refers to the maximum plasma con ingredient (API) to attain maximum blood plasma concentra centration for an active pharmaceutical ingredient (API). tion after administration with a conventional inhalation “C.'” as used herein refers to the maximum blood device. plasma concentration for a nominal dose of the active phar The term “treat' and its grammatical variants (e.g., “to maceutical ingredient (API) administered with a high effi treat,” “treating,” and “treatment') refer to administration of ciency nebulizer. an active pharmaceutical ingredient to a patient with the pur “C” as used herein refers to the maximum blood pose of ameliorating or reducing the incidence of one or more plasma concentration for a nominal dose of the active phar symptoms of a condition or disease state in the patient. Such maceutical ingredient (API) administered with a conven symptoms may be chronic or acute; and Such amelioration tional inhalation device. 25 may be partial or complete. In the present context, treatment C. can be determined by methods known to those of skill entails administering a mast cell Stabilizer to a patient via any in the art. For example, the C of an API can be determined route of administration disclosed herein. by collecting blood samples from a subject at various time As used herein, the term “high concentration” refers to a points after administration of an API to the Subject, separating concentration greater than 1% by weight. For example, in a plasma from the blood samples, extracting the API from the 30 separated plasma samples, e.g., by solid-phase extraction, specific embodiment, a “high concentration’ formulation of quantifying the amount of the API extracted from each cromolyn sodium comprises cromolyn sodium at a concen sample of separated plasma, e.g., by LC-MS/MS, plotting the tration of greater than 1% by weight. concentration of API in each sample versus the time of col As used herein, the term “hypotonic' refers to a formula lection after administration, and identifying the peak concen 35 tion that has a tonicity less than 295 mCsm/kg. tration of the API on the curve. The term “prophylaxis' refers to administration of an "Enhanced pharmacokinetic profile' means an improve active pharmaceutical ingredient to a patient with the purpose ment in some pharmacokinetic parameter. Pharmacokinetic of reducing the occurrence or recurrence of one or more acute parameters that may be improved include AUC (0-4 or 0-6 or symptoms associated with a disease state or a condition in the 0-8 h), AUC, AUCo., T, T12, and C. In some 40 patient. In the present context, prophylaxis entails adminis embodiments, the enhanced pharmacokinetic profile may be tering a mast cell stabilizer to a patient via any route of measured quantitatively by comparing a pharmacokinetic administration disclosed herein. Thus, prophylaxis includes parameter obtained for a nominal dose of an active pharma reduction in the occurrence or recurrence rate of a systemic ceutical ingredient (API) administered by one route of admin mast cell related disorder. However, prophylaxis is not istration, such as an inhalation device (e.g., a high efficiency 45 intended to include complete prevention of onset of a disease nebulizer) with the same pharmacokinetic parameter state or a condition in a patient who has not previously been obtained with the same nominal dose of active pharmaceuti identified as suffering from the disease or the condition. cal ingredient (API) administered by a different route of As used herein, a “systemically effective amount' is an administration, Such as a different type of inhalation device or amount of mast cell stabilizer in the body of a patient as a an oral formulation (e.g., oral tablet, oral capsule, or oral 50 whole that is effective for the treatment or prophylaxis of a Solution). systemic mast cell related disorder. A “systemically effective “Blood plasma concentration” refers to the concentration amount may be expressed, for example, as the mass of a mast of an active pharmaceutical ingredient (API) in the plasma cell stabilizer, or concentration of a mast cell stabilizer, in a component of blood of a subject or patient population. patient’s plasma. A “systemically effective amount may dif “Patient' or “subject” refers to the animal (especially 55 fer depending on the specific mast cell stabilizer and the mammal) or human being treated. specific systemic mast cell related disorder. A “subject group' or “patient group” has a Sufficient num As used herein, a difference is “significant' if a person ber of Subjects or patients to provide a statistically significant skilled in the art would recognize that the difference is prob average measurement of the relevant pharmacokinetic ably real. In some embodiments, significance may be deter parameter. All members of the “subject group' or “patient 60 mined statistically, in which case two measured parameters group” have pharmacokinetic parameters for the mast cell may be referred to as statistically significant. In some stabilizers that fall within statistically normal ranges (i.e., embodiments, statistical significance may be quantified in there are no outliers), and no member is included on the basis terms of a stated confidence interval (CI), e.g., greater than of non-standard or unusual measurements. 90%, greater than 95%, greater than 98%, etc. In some “Nebulizer, as used herein, refers to a device that turns 65 embodiments, statistical significance may be quantified in medications, compositions, formulations, Suspensions, and terms of a p value, e.g., less than 0.5, less than 0.1, less than mixtures, etc. into a fine aerosol mist for delivery to the lungs. 0.05, etc. The person skilled in the art will recognize these US 9,265,749 B2 9 10 expressions of significance and will know how to apply them not limited to autoimmune disorders, inflammatory condi appropriately to the specific parameters that are being com tions, allergic diseases and conditions, and viral and bacterial pared. infections. Methods of Treating Systemic Mast Cell Related Disorders In some embodiments of the methods disclosed herein, the with Mast Cell Stabilizers number of mast cells in a patient is stabilized after adminis Disclosed herein are methods for the treatment or prophy tration of a composition comprising a mast cell Stabilizer to laxis of systemic mast cell related disorders comprising the patient. In some embodiments of the methods disclosed administering compositions comprising one or more mast herein, the activity of mast cells is stabilized in a patient after cell stabilizers. As used herein, a “systemic mast cell related administration of a composition comprising a mast cell sta 10 bilizer to the patient. In some embodiments of the methods disorder is a disease or condition that is caused by or asso disclosed herein, one or more of total tryptase and histamine ciated with excessive proliferation or activation of mast cells in a patient’s blood, and prostaglandin D2, 11beta-prostag or abnormal release of vasoactive or pro-inflammatory landin F2-alpha, and N-methylhistamine in the patients mediators in the body as a whole, and is thus treatable by urine, is reduced after administration of a composition com administration of a systemically effective amount of a mast 15 prising a mast cell stabilizer to a patient. cell stabilizer, e.g., cromolyn Sodium. A systemic mast cell As used herein, a “mast cell stabilizer” refers to an agent related disorder is distinct from a local mast cell related that inhibits degranulation and/or the release of pro-inflam disorder, in which symptoms of the disease or condition matory and vasoactive mediators from mast cells. Mast cell manifestina particular region of the body. Systemic mast cell stabilizers include, but are not limited to, cromolyn, dihydro related disorders include, but are not limited to, a mast cell pyridines Such as nicardipine and nifedipine, lodoxamide, activation syndrome; mastocytosis; idiopathic urticaria; nedocromil, barnidipine, YC-114. elgodipine, niguldipine, chronic urticaria; atopic dermatitis; idiopathic anaphylaxis; ketotifen, methylxanthines, quercetin, and pharmaceutically Ig-E and non Ig-E mediated anaphylaxis; angioedema; aller salts thereof. In some embodiments, the mast cell stabilizer is gic disorders; irritable bowel syndrome; mastocytic gastro a pharmaceutically acceptable salt of cromolyn, Such as cro enteritis; mastocytic colitis; fibromyalgia; kidney fibrosis: 25 molyn Sodium, cromolyn lysinate, ammonium cromongly atherosclerosis; myocardial ischemia; hypertension; conges cate, and magnesium cromoglycate. In some embodiments, tive heart failure; pruritus; chronic pruritus; pruritus second mast cell stabilizers include but are not limited to compounds ary to chronic kidney failure; heart, vascular, intestinal, brain, disclosed in U.S. Pat. Nos. 6,207,684; 4,634,699; 6,207,684; kidney, liver, pancreas, muscle, bone and skin conditions 4,871,865; 4,923,892; 6.225,327; 7,060,827; 8,470,805; associated with mast cells; CNS diseases such as Parkinson's 30 5,618,842; 5,552,436; 5,576,346; 8,252,807; 8,088,935; 8,617,517; 4,268,519; 4,189,571; 3,790,580: 3,720,690; disease and Alzheimer's disease; metabolic diseases such as 3,777,033; 4,067,992: 4,152,448; 3.419,578; 4,847,286; diabetes; sickle cell disease; autism; chronic fatigue Syn 3.683,320; and 4.362,742; U.S. Patent Application Publica drome; lupus; chronic lyme disease; interstitial cystitis; mul tion Nos. 2011/112183 and 2014/140927: European Patent tiple Sclerosis; cancer, migraine headaches; psoriasis; eosi 35 Nos. 2391618; 0163683; 0413583; and 0304802: Interna nophilic esophagitis; eosinophilic gastroenteritis; Churg tional Patent Application Nos. WO2010/042504; WO85/ Strauss syndrome; hypereosinophilic syndrome; eosinophilic 02541; WO2014/115098: WO2005/063732; WO2009/ fasciitis; eosinophilic gastrointestinal disorders; chronic idio 131695; and WO2010/08.8455; all of which are incorporated pathic urticaria; myocarditis; Hirschsprungs-associated by reference. Mast cell stabilizers, including cromolyn and enterocolitis; postoperative ileus; wound healing; stroke; 40 pharmaceutically acceptable salts, prodrugs, and adducts transient ischemic attack; pain; neuralgia; peripheral neur thereof, may be prepared by methods known in the art. opathy; acute coronary syndromes; pancreatitis; cutaneous In some embodiments, mast cell stabilizers described mastocytosis; systemic mastocytosis; systemic indolent mas herein may be prepared as prodrugs. A "prodrug” refers to an tocytosis; dermatomyositis; fibrotic skin diseases; pain asso agent that is converted into the parent drug in vivo. The ciated with cancer; ulcerative colitis; inflammatory bowel 45 prodrug can be designed to alter the metabolic stability or the disease; radiation colitis; celiac disease; gluten enteropathy; transport characteristics of a drug, to mask side effects or radiation cystitis; painful bladder syndrome; hepatitis; toxicity, to improve the flavor of a drug, or to alter other hepatic fibrosis; cirrhosis; rheumatoid arthritis; lupus erythe characteristics or properties of a drug. In some embodiments, matosus; and vasculitis. the prodrug has improved bioavailability relative to the parent In some embodiments of the methods disclosed herein 50 drug. In some embodiments, the prodrug has improved solu wherein the systemic mast cell related disorder is a CNS bility in pharmaceutical compositions over the parent drug. In disease Such as Parkinson's disease and Alzheimer's disease, Some embodiments, prodrugs may be designed as reversible a mast cell stabilizer is neuroprotective. In some embodi drug derivatives, for use as modifiers to enhance drug trans ments of the methods disclosed herein wherein the systemic port to site-specific tissues. In some embodiments, a prodrug mast cell related disorder is a CNS disease such as Parkin 55 of a mast cell stabilizer is an ester of the mast cell stabilizer, son's disease and Alzheimer's disease, a mast cell stabilizer which is hydrolyzed to the carboxylic acid, the parent mast crosses the blood brain barrier. In some embodiments of the cell stabilizer. In some embodiments, a prodrug comprises a methods disclosed herein wherein the systemic mast cell short peptide (polyaminoacid) bonded to an acid group, related disorder is Alzheimer's disease, a mast cell stabilizer wherein the peptide is metabolized in vivo to reveal the parent prevents amyloid-beta protein polymerization and/or plaque 60 drug. In certain embodiments, upon in vivo administration, a formation. In some embodiments of the methods disclosed prodrug is chemically converted to the biologically, pharma herein wherein the systemic mast cell related disorder is a ceutically or therapeutically active form of the mast cell sta heart condition, a mast cell stabilizer is cardioprotective. bilizer. In certain embodiments, a prodrug is enzymatically In some embodiments of the methods disclosed herein, a metabolized by one or more steps or processes to the parent composition comprising a mast cell stabilizer is administered 65 mast cell stabilizer. In certain embodiments, the mast cell for the treatment or prophylaxis of a condition that is associ stabilizer is a prodrug of cromolyn. In a specific embodiment, ated with a systemic mast cell related disorder, including but the prodrug of cromolyn is cromoglicate lisetil. US 9,265,749 B2 11 12 To produce a prodrug, a pharmaceutically active mast cell about 700 mg, about 750 mg, about 800 mg, about 850 mg. stabilizer compound is modified Such that the active com about 900 mg, about 950 mg. or about 1000 mg doses. pound will be regenerated upon in vivo administration. In In some embodiments of the methods disclosed herein, Some embodiments, prodrugs of mast cell Stabilizers are cromolyn Sodium is administered at a dosage or nominal designed by virtue of knowledge of pharmacodynamic pro dosage of less than about 1 mg/dose, about 1 mg/dose to about cesses and drug metabolism in vivo. See, e.g., Nogrady 100 mg/dose, about 1 mg/dose to about 120 mg/dose, about 5 (1985) Medicinal Chemistry A Biochemical Approach, mg/dose to about 80 mg/dose, about 20 mg/dose to about 60 Oxford University Press, New York, pages 388-392: Silver mg/dose, or about 30 mg/dose to about 50 mg/dose, or greater man (1992), The Organic Chemistry of Drug Design and than about 100 mg/dose. In other embodiments, cromolyn Drug Action, Academic Press, Inc., San Diego, pages 352 10 Sodium is administered in less than about 1 mg, about 1 mg, 401, Saulnier et al., (1994), Bioorganic and Medicinal Chem about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 istry Letters, Vol. 4, p. 1985: Rooseboom et al., Pharmaco mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg. logical Reviews, 56:53-102, 2004; Milleretal.J.Med. Chem. about 50 mg, about 55 mg, about 60 mg, about 65 mg, about Vol. 46, no. 24, 5097-5116, 2003: Aesop Cho, “Recent 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg. Advances in Oral Prodrug Discovery'. Annual Reports in 15 about 95 mg, about 100 mg, about 105 mg, about 110 mg. Medicinal Chemistry, Vol. 41,395-407, 2006. about 115 mg, about 120 mg, about 125 mg, about 130 mg In some embodiments, mast cell stabilizers described doses, about 135 mg, about 140 mg, about 145 mg, about 150 herein include isotopically-labeled compounds, which are mg, about 200 mg, about 250 mg, about 300 mg, about 350 identical to those recited herein, but for the fact that one or mg, about 400 mg, about 450 mg, about 500 mg, about 550 more atoms are replaced by anatom having an atomic mass or mg, about 600 mg, about 650 mg, about 700 mg, about 750 mass number different from the atomic mass or mass number mg, about 800 mg, about 850 mg, about 900 mg, about 950 usually found in nature. Examples of isotopes that can be mg, or about 1000 mg doses. incorporated into the present compounds include isotopes of In some embodiments of the methods disclosed herein, hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, further active agents other than a mast cell stabilizer that are such as, forexample, H, H, C, C, N, O, 7O, S, F, 25 effective for the treatment or prophylaxis of a systemic mast Cl, respectively. Certain isotopically labeled compounds cell related disorder are administered or co-administered with described herein, for example those with isotopes such as the mast cell stabilizer. Such further active agents may be deuterium, i.e., H. can afford certain therapeutic advantages administered separately, or may be incorporated into a com resulting from greater metabolic stability, such as, for position comprising a mast cell stabilizer. Such further active example, increased in vivo half-life or reduced dosage 30 agents include, but are not limited to, leukotriene antagonists, requirements. In certain embodiments, the mast cell Stabilizer steroidal and non-steroidal anti-inflammatory drugs, anti-al is isotopically labeled cromolyn, or a pharmaceutically lergics, B-agonists, anticolinergics, corticosteroids, testoster acceptable salt thereof. Such as cromolyn Sodium. In some one derivatives, phosphodiesterase inhibitors, endothelin embodiments, the mast cell stabilizer is deuterium-labeled antagonists, mucolytics, antibiotics, antifungals, antivirals, cromolyn Sodium. 35 antioxidants, vitamins, heparinoids, C.-antitrypsin, lung Sur In some embodiments, mast cell stabilizers described factants, anti-inflammatory compounds, glucocorticoids, herein may be PEGylated, wherein one or more polyethylene anti-infective agents, antibiotics, antifungals, antivirals, anti glycol (PEG) polymers are covalently attached to the mast septics, vasoconstrictors, vasodilators, woundhealing agents, cell stabilizers. In some embodiments, pegylated mast cell local anesthetics, peptides, and proteins. stabilizers increase the half-life of the mast cell stabilizers in 40 Anti-inflammatory compounds which may be adminis the body. In some embodiments, pegylation of the mast cell tered or co-administered with a mast cell stabilizer in the stabilizers increases the hydrodynamic size of the mast cell methods disclosed herein include but are not limited to stabilizers and reduces their renal clearance. In some embodi betamethasone, beclomethasone, budesonide, ciclesonide, ments, pegylation of the mast cell stabilizers increases the dexamethasone, desoxymethasone, fluoconolone acetonide, solubility of the mast cell stabilizers. In some embodiments, 45 flucinonide, flunisolide, fluticaSone, icomethasone, rofile pegylation of the mast cell stabilizers protects the mast cell ponide, triamcinolone acetonide, fluocortin butyl, hydrocor stabilizers from proteolytic degradation. tisone, hydroxycortisone-17-butyrate, prednicarbate, 6-me Mast cell stabilizers may be administered in the methods thylprednisolone aceponate, mometasone furoate, elastane-, disclosed herein in a suitable dose or nominal dose as deter prostaglandin-, leukotriene, bradykinin-antagonists, non-ste mined by one of ordinary skill in the art. In some embodi 50 roidal anti-inflammatory drugs (NSAIDs), such as ibuprofen ments, the mast cell stabilizer is administered at a dosage or and indometacin. nominal dosage of less than about 1 mg/dose, about 1 Anti-allergic agents which may be administered or co mg/dose to about 100 mg/dose, about 1 mg/dose to about 120 administered with a mast cell stabilizer in the methods dis mg/dose, about 5 mg/dose to about 80 mg/dose, about 20 closed herein include but are not limited to glucocorticoids, mg/dose to about 60 mg/dose, about 30 mg/dose to about 50 55 nedocromil, cetirizine, loratidine, montelukast, roflumilast, mg/dose, or greater than about 100 mg/dose. In some embodi Ziluton, omalizumab, heparins and heparinoids and other ments, the mast cell stabilizer is administered in less than antihistamines, azelastine, cetirizine, desloratadine, ebastine, about 1 mg, about 1 mg, about 5 mg, about 10 mg, about 15 fexofenadine, levocetirizine, loratadine. mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg. Anti-infective agents which may be administered or co about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 administered with a mast cell stabilizer in the methods dis 60 mg, about 65mg, about 70 mg, about 75 mg, about 80 mg. closed herein include but are not limited to benzylpenicillins about 85 mg, about 90 mg, about 95 mg, about 100 mg, about (penicillin-G-Sodium, clemizone penicillin, benzathine peni 105 mg, about 110 mg, about 115 mg, about 120 mg, about cillin G), phenoxypenicillins (penicillin V, propicillin), ami 125 mg, about 130 mg doses, about 135 mg, about 140 mg. nobenzylpenicillins (ampicillin, amoxycillin, bacampicillin), about 145 mg, about 150 mg, about 200 mg, about 250 mg. 65 acylaminopenicillins (azlocillin, mezlocillin, piperacillin, about 300 mg, about 350 mg, about 400 mg, about 450 mg. apalcillin), carboxypenicillins (carbenicillin, ticarcillin, about 500 mg, about 550 mg, about 600 mg, about 650 mg. temocillin), isoxazolyl penicillins (oxacillin, cloxacillin, US 9,265,749 B2 13 14 dicloxacillin, flucloxacillin), and amidine penicillins (mecil Mucolytics which may be administered or co-administered linam); cephalosporins, including cefazolins (cefazolin, with a mast cell stabilizer in the methods disclosed herein cefazedone), cefuroximes (cefuroxime, cefamandole, cefo include but are not limited to DNase, P2Y2-agonists (denu tiam), cefoxitins (cefoxitin, cefotetan, latamoxef flomoxef), foSol), heparinoids, guaifenesin, acetylcysteine, carbocys cefotaximes (cefotaxime, ceftriaxone, ceftizoxime, teine, ambroXol, bromhexine, lecithins, myrtol, and recom cefinenoXime), ceftazidimes (ceftazidime, ce?pirome, binant Surfactant proteins. cefepime), cefalexins (cefalexin, cefaclor, cefadroxil, cefra Local anesthetic agents which may be administered or dine, loracarbef, cefprozil), and cefiximes (cefixime, cefpo co-administered with a mast cell stabilizer in the methods doxim proxetile, cefuroxime axetil, cefetamet pivoxil, cefo disclosed herein include but are not limited to benzocaine, 10 tetracaine, procaine, lidocaine and bupivacaine. tiam hexetil), loracarbef, cefepim, clavulanic acid/ Peptides and proteins which may be administered or co amoxicillin, ceftobiprole; synergists, including beta administered with a mast cell stabilizer in the methods dis lactamase inhibitors, such as clavulanic acid, Sulbactam, and taZobactam; carbapenems, including imipenem, cilastin, closed herein include but are not limited to antibodies against meropenem, doripenem, tebipenem, ertapenem, ritipenam, toxins produced by microorganisms, antimicrobial peptides 15 Such as cecropins, defensins, thionins, and cathelicidins. and biapenem; monobactams, including aztreonam, ami Immunomodulators which may be administered or co-ad noglycosides. Such as apramycin, gentamicin, amikacin, ministered with a mast cell stabilizer in the methods disclosed isepamicin, arbekacin, tobramycin, netilmicin, spectinomy herein include but are not limited to methotrexate, azathio cin, Streptomycin, capreomycin, neomycin, paromoycin, and prine, cyclosporine A, tacrolimus, Sirolimus, rapamycin, kanamycin; macrollides, including erythromycin, clarythro mycophenolate, mofetil, cytostatics and metastasis inhibi mycin, roXithromycin, azithromycin, dithromycin, josamy tors, alkylants, such as nimustine, melphanlane, carmustine, cin, spiramycin and tellithromycin; gyrase inhibitors or fluo lomustine, cyclophosphosphamide, ifosfamide, trofosfa roquinolones, including ciprofloxacin, gatifloxacin, mide, chlorambucil, buSulfane, treosulfane, prednimustine, norfloxacin, ofloxacin, levofloxacin, perfloxacin, lomefloxa thiotepa; antimetabolites, e.g. cytarabine, fluorouracil, meth cin, fleroxacin, garenoxacin, clinafloxacin, sitafloxacin, pru 25 otrexate, mercaptopurine, tioguanine; alkaloids. Such as Vin lifloxacin, olamufloxacin, caderofloxacin, gemifloxacin, blastine, Vincristine, Vindesine; antibiotics, such as alcarubi balofloxacin, trovafloxacin, and moxifloxacin, tetracycline, cine, bleomycine, dactinomycine, daunorubicine, including tetracyclin, oxytetracyclin, rollitetracyclin, minocy doxorubicine, epirubicine, idarubicine, mitomycine, plica clin, doxycycline, tigecycline and aminocycline; glycopep mycine; complexes of secondary group elements (e.g. Ti, Zr, tides, including Vancomycin, teicoplanin, ristocetin, avopar 30 V. Nb, Ta, Mo, W. Pt) such as carboplatinum, cis-platinum cin, oritavancin, ramoplanin, and peptide 4. polypeptides, and metallocene compounds such as titanocendichloride; including plectasin, dalbavancin, daptomycin, oritavancin, amsacrine, dacarbazine, estramustine, etoposide, beraprost, ramoplanin, dalbavancin, telavancin, bacitracin, tyrothricin, hydroxycarbamide, mitoxanthrone, procarbazine, temipo neomycin, kanamycin, mupirocin, paromomycin, polymyxin side, paclitaxel, iressa, Zactima, poly-ADP-ribose-poly B and colistin; Sulfonamides, including Sulfadiazine, Sul 35 merase (PRAP) enzyme inhibitors, banoxantrone, gemcitab famethoxazole, Sulfalene, co-trimoxazole, co-trimetrol, co ine, pemetrexed, bevacizumab, ranibizumab. trimoxazine, and co-tetraxazine; azoles, including clotrima Proteinase inhibitors which may be administered or co Zole, oxiconazole, miconazole, ketoconazole, itraconazole, administered with a mast cell stabilizer in the methods dis fluconazole, metronidazole, tinidazole, bifonazole, ravu closed herein include but are not limited to alpha-anti-trypsin; conazole, posaconazole, Voriconazole, and ornidazole and 40 antioxidants, such as tocopherols, glutathion; pituitary hor other antifungals including flucytosin, griseofluvin, tonofital, mones, hypothalamic hormones, regulatory peptides and naftifine, terbinafine, amorolfine, ciclopiroXolamin, echi their inhibiting agents, corticotropine, tetracosactide, chori nocandins, such as micafungin, caspofungin, anidulafungin; ogonandotropine, urofolitropine, urogonadotropine, Soma nitrofurans, including nitrofurantoin and nitrofuranZone; totropine, metergoline, desmopressine, oxytocine, argipress polyenes, including amphotericin B, natamycin, nystatin, flu 45 ine, ornipressine, leuproreline, triptoreline, gonadoreline, cocytosine; other antibiotics, including tithromycin, linco busereline, nafareline, goselerine. Somatostatine; parathyroid mycin, clindamycin, oxazolidinones (lineZolids), ranbeZolid, gland hormones, calcium metabolism regulators, dihydro streptogramine A+B, pristinamycin A+B, Virginiamycin tachysterole, calcitonine, clodronic acid, etidronic acid; thy A+B, dalfopristin/quinupristin (Synercid), chloramphenicol, roid gland therapeutics; sex hormones and their inhibiting ethambutol, pyrazinamide, terizidon, dapson, prothionamide, 50 agents, anabolics, androgens, estrogens, gestagenes, anties fosfomycin, flucidinic acid, rifampicine, isoniazid, cyclos trogenes; anti-migraine drugs, such as proxibarbal, lisuride, erine, terizidone, ansamycin, lysostaphin, iclaprim, mirocin methysergide, dihydroergotamine, ergotamine, clonidine, B17, clerocidin, filgrastim, and pentamidine; antivirals, pizotifene; hypnotics, sedatives, benzodiazepines, barbitu including aciclovir, ganciclovir, birivudine, Valaciclovir, rates, cyclopyrrolones, imidazopyridines, antiepileptics, Zidovudine, didanosine, thiacytidin, stavudine, lamivudine, 55 Zolpidem, barbiturates, phenyloin, primidone, mesuXimide, Zalcitabine, ribavirin, nevirapirine, delaviridine, trifluridine, ethoSuximide, Sultiam, carbamazepin, valproic acid, ritonavir, saquinavir, indinavir, foscarnet, amantadine, podo vigabatrine; antiparkinson drugs, such as levodopa, carbi phyllotoxin, Vidarabine, tromantadine, and proteinase inhibi dopa, benserazide, selegiline, bromocriptine, amantadine, tors; plant extracts or ingredients, such as plant extracts from tiapride; antiemetics, such as thiethylperazine, bromopride, chamomile, hamamelis, echinacea, calendula, papain, pellar 60 domperidone, granisetrone, ondasetrone, tropisetrone, pyri gonium, essential oils, myrtol, pinen, limonen, cineole, thy doxine; analgesics, such as buprenorphine, fentanyl, mor mol, mentol, tee tree oil, alpha-hederin, bisabolol, lycopodin, phine, codeine, hydromorphone, methadone; fenpipramide, Vitapherole; wound healing compounds including dexpan fentanyl, piritramide, pentazocine, buprenorphine, nalbu tenol, allantoin, vitamins, hyaluronic acid, alpha-antitrypsin, phine, tilidine; drugs for narcosis, such as N-methylated bar inorganic and organic Zinc salts/compounds, interferones (al 65 biturates, thiobarbiturates, ketamine, etomidate, propofol. pha, beta, gamma), tumor necrosis factors, cytokines, inter benzodiazepines, droperidol, haloperidol, alfentanyl, Sulfen leukins. tanyl; antirheumatism drugs including tumor necrosis factor US 9,265,749 B2 15 16 alfa, nonsteroidal antiinflammatory drugs; antidiabetic drugs, greater than about 190 nghr/mL, greater than about 200 Such as insulin, Sulfonylurea derivatives, biguanids, glitizols, nghr/mL, greater than about 225 nghr/mL, greater than glucagon, diaZoxid; cytokines, such as interleukines, interfer about 250 nghr/mL, greater than about 275 nghr/mL, ones, tumor necrosis factor (TNF), colony stimulating factors greater than about 300 nghr/mL, greater than about 325 (GM-CSF, G-CSF, M-CSF); proteins, e.g. epoetine, and pep nghr/mL, greater than about 350 nghr/mL, greater than tides, e.g. parathyrin, Somatomedin C; heparine, heparinoids, about 375 nghr/mL, greater than about 400 nghr/mL, urokinases, streptokinases, ATP-ase, prostacycline, sexual greater than about 425 nghr/mL, greater than about 450 stimulants, and genetic material. nghr/mL, greater than about 475 nghr/mL, greater than Formulations for the Administration of Mast Cell Stabiliz about 500 nghr/mL, greater than about 525 nghr/mL, CS 10 greater than about 550 nghr/mL, greater than about 575 In some embodiments, formulations administered in the nghr/mL, greater than about 600 nghr/mL, greater than methods disclosed herein produce in a human Subject group about 625 nghr/mL, greater than about 650 nghr/mL, an average AUCo. of a mast cell stabilizer greater than greater than about 675 nghr/mL, greater than about 700 about 100 nghr/mL, greater than about 110 nghr/mL, nghr/mL, greater than about 725 nghr/mL, greater than greater than about 120 nghr/mL, greater than about 130 15 about 750 nghr/mL, greater than about 775 nghr/mL, nghr/mL, greater than about 140 nghr/mL, greater than greater than about 800 nghr/mL, greater than about 825 about 150 nghr/mL, greater than about 160 nghr/mL, nghr/mL, greater than about 850 nghr/mL, greater than greater than about 170 nghr/mL, greater than about 180 about 875 nghr/mL, greater than about 900 nghr/mL, nghr/mL, greater than about 190 nghr/mL, greater than greater than about 925 nghr/mL, greater than about 950 about 200 nghr/mL, greater than about 225 nghr/mL, nghr/mL, greater than about 975 nghr/mL, or greater than greater than about 250 nghr/mL, greater than about 275 about 1000 nghr/mL after administration of the formulation nghr/mL, greater than about 300 nghr/mL, greater than to the patient. In some embodiments, formulations adminis about 325 nghr/mL, greater than about 350 nghr/mL, tered in the methods disclosed herein produce in a human greater than about 375 nghr/mL, greater than about 400 subject group an average AUCo. of cromolyn sodium of nghr/mL, greater than about 425 nghr/mL, greater than 25 about 100 nghr/mL, about 110 nghr?mL, about 120 nghr? about 450 nghr/mL, greater than about 475 nghr/mL, mL, about 130 nghr/mL, about 140 nghr?mL, about 150 greater than about 500 nghr/mL, greater than about 525 nghr/mL, about 160 nghr/mL, about 170 nghr?mL, about nghr/mL, greater than about 550 nghr/mL, greater than 180 nghr/mL, about 190 nghr/mL, about 200 nghr/mL, about 575 nghr/mL, greater than about 600 nghr/mL, about 225 nghr/mL, about 250 nghr/mL, about 275 nghr? greater than about 625 nghr/mL, greater than about 650 30 mL, about 300 nghr/mL, about 325 nghr/mL, about 350 nghr/mL, greater than about 675 nghr/mL, greater than nghr/mL, about 375 nghr/mL, about 400 nghr?mL, about about 700 nghr/mL, greater than about 725 nghr/mL, 425 nghr/mL, about 450 nghr/mL, about 475 nghr/mL, greater than about 750 nghr/mL, greater than about 775 about 500 nghr/mL, about 525 nghr/mL, about 550 nghr? nghr/mL, greater than about 800 nghr/mL, greater than mL, about 575 nghr/mL, about 600 nghr/mL, about 625 about 825 nghr/mL, greater than about 850 nghr/mL, 35 nghr/mL, about 650 nghr/mL, about 675 nghr?mL, about greater than about 875 nghr/mL, greater than about 900 700 nghr/mL, about 725 nghr/mL, about 750 nghr/mL, nghr/mL, greater than about 925 nghr/mL, greater than about 775ng*hr/mL, about 800 nghr/mL, about 825 nghr? about 950 nghr/mL, greater than about 975 nghr/mL, or mL, about 850 nghr/mL, about 875 nghr/mL, about 900 greater than about 1000 nghr/mL after administration of the nghr/mL, about 925 nghr/mL, about 950 nghr?mL, about formulation to the patient. In some embodiments, formula 40 975 nghr/mL, or about 1000 nghr/mL after administration tions administered in the methods disclosed herein produce in of the formulation to the patient. a human subject group an average AUCo. of a mast cell In some embodiments, formulations administered in the stabilizer of about 100 nghr/mL, about 110 nghr?mL, about methods disclosed herein produce in a human Subject group 120 nghr/mL, about 130 nghr/mL, about 140 nghr/mL, an average Cofa mast cell stabilizer greater than about 40 about 150 nghr/mL, about 160 nghr/mL, about 170 nghr? 45 ng/mL, greater than about 50 ng/mL, greater than about 60 mL, about 180 nghr/mL, about 190 nghr?mL, about 200 ng/mL, greater than about 70 ng/mL, greater than about 80 nghr/mL, about 225 nghr/mL, about 250 nghr?mL, about ng/mL, greater than about 90 ng/mL, greater than about 100 275 nghr/mL, about 300 nghr/mL, about 325 nghr/mL, ng/mL, greater than about 110 ng/mL, greater than about 120 about 350 nghr/mL, about 375 nghr/mL, about 400 nghr? ng/mL, greater than about 130 ng/mL, greater than about 140 mL, about 425 nghr/mL, about 450 nghr?mL, about 475 50 ng/mL, greater than about 150 ng/mL, greater than about 160 nghr/mL, about 500 nghr/mL, about 525 nghr?mL, about ng/mL, greater than about 170 ng/mL, greater than about 180 550 nghr/mL, about 575 nghr/mL, about 600 nghr/mL, ng/mL, greater than about 190 ng/mL, greater than about 200 about 625 nghr/mL, about 650 nghr/mL, about 675 nghr? ng/mL, greater than about 210 ng/mL, greater than about 220 mL, about 700 nghr/mL, about 725 nghr/mL, about 750 ng/mL, greater than about 230 ng/mL, greater than about 240 nghr/mL, about 775 nghr/mL, about 800 nghr?mL, about 55 ng/mL, greater than about 250 ng/mL, greater than about 260 825 nghr/mL, about 850 nghr/mL, about 875 nghr/mL, ng/mL, greater than about 270 ng/mL, greater than about 280 about 900 nghr/mL, about 925 nghr/mL, about 950 nghr? ng/mL, greater than about 290 ng/mL, greater than about 300 mL, about 975 nghr/mL, or about 1000 nghr/mL after ng/mL, greater than about 310 ng/mL, greater than about 320 administration of the formulation to the patient. ng/mL, greater than about 330 ng/mL, greater than about 340 In some embodiments, formulations administered in the 60 ng/mL, greater than about 350 ng/mL, greater than about 360 methods disclosed herein produce in a human Subject group ng/mL, greater than about 370 ng/mL, greater than about 380 an average AUCo. of cromolyn Sodium greater than about ng/mL, greater than about 390 ng/mL, or greater than about 100 nghr/mL, greater than about 110 nghr/mL, greater than 400 ng/mL after administration of the formulation to the about 120 nghr/mL, greater than about 130 nghr/mL, patient. In some embodiments, formulations administered in greater than about 140 nghr/mL, greater than about 150 65 the methods disclosed herein produce in a human Subject nghr/mL, greater than about 160 nghr/mL, greater than group an average C of a mast cell Stabilizer of about 50 about 170 nghr/mL, greater than about 180 nghr/mL, mg/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, US 9,265,749 B2 17 18 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 liposomes, liquids, gels, implants, depots, syrups, elixirs, ng/mL, about 130 ng/mL, about 140 ng/mL, about 150 slurries, Suspensions, lotions, gels, pastes, medicated Sticks, ng/mL, about 160 ng/mL, about 170 ng/mL, about 180 balms, creams, ointments, aerosols, controlled release formu ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 lations, fast melt formulations, effervescent formulations, ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 lyophilized formulations, tablets, powders, pills, dragees, ng/mL, about 250 ng/mL, 260 ng/mL, about 270 ng/mL, capsules, delayed release formulations, extended release for about 280 ng/mL, about 290 ng/mL, about 300 ng/mL, about mulations, pulsatile release formulations, multiparticulate 310 ng/mL, about 320 ng/mL, about 330 ng/mL, about 340 formulations, mixed immediate release formulations, con ng/mL, about 350 ng/mL, about 360 ng/mL, about 370 trolled release formulations, enemas, rectal gels, rectal ng/mL, about 380 ng/mL, about 390 ng/mL, or about 400 10 foams, rectal aerosols, vaginal gels, vaginal foams, vaginal ng/mL after administration of the formulation to the patient. aerosols, Suppositories, jelly suppositories, or retention In some embodiments, formulations administered in the enemas. Such formulations may be manufactured in a con methods disclosed herein produce in a human Subject group ventional manner. Such as, by way of example only, conven an average C of cromolyn sodium greater than about 40 tional mixing, dissolving, granulating, dragee-making, levi ng/mL, greater than about 50 ng/mL, greater than about 60 15 gating, emulsifying, encapsulating, entrapping or ng/mL, greater than about 70 ng/mL, greater than about 80 compression processes. ng/mL, greater than about 90 ng/mL, greater than about 100 In some embodiments, the formulations disclosed herein ng/mL, greater than about 110 ng/mL, greater than about 120 may include one or more inactive ingredients or pharmaceu ng/mL, greater than about 130 ng/mL, greater than about 140 tical excipients that provide suitable properties of the formu ng/mL, greater than about 150 ng/mL, greater than about 160 lation. Such inactive ingredients may include one or more of ng/mL, greater than about 170 ng/mL, greater than about 180 the following classes. ng/mL, greater than about 190 ng/mL, greater than about 200 Albumin’ refers to a family of globular proteins, the most ng/mL, greater than about 210 ng/mL, greater than about 220 common of which is serumalbumin. Albumins are commonly ng/mL, greater than about 230 ng/mL, greater than about 240 found in blood plasma and function to regulate colloidal ng/mL, greater than about 250 ng/mL, greater than about 260 25 osmotic pressure of the blood. Albumin proteins found in the ng/mL, greater than about 270 ng/mL, greater than about 280 plasma bind some pharmaceutical compounds to form com ng/mL, greater than about 290 ng/mL, greater than about 300 plexes. Complexation of albumin with pharmaceutical com ng/mL, greater than about 310 ng/mL, greater than about 320 pounds, e.g., mast cell stabilizers, can influence the pharma ng/mL, greater than about 330 ng/mL, greater than about 340 ceutical compounds plasma half-life and/or biological half ng/mL, greater than about 350 ng/mL, greater than about 360 30 life in the body by preventing metabolism and/or excretion of ng/mL, greater than about 370 ng/mL, greater than about 380 the complexed compounds. In some embodiments, composi ng/mL, greater than about 390 ng/mL, or greater than about tions disclosed herein include albumin and a mast cell stabi 400 ng/mL after administration of the formulation to the lizer, e.g., cromolyn Sodium. patient. In some embodiments, formulations administered in "Antifoaming agents’ reduce foaming during processing the methods disclosed herein produce in a human Subject 35 which can result in coagulation of aqueous dispersions, group an average C of cromolyn Sodium of about 50 bubbles in the finished film, or generally impair processing. mg/mL, about 60 ng/mL, about 70 ng/mL, about 80 ng/mL, Exemplary anti-foaming agents include silicon emulsions or 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 Sorbitan Sesquoleate. ng/mL, about 130 ng/mL, about 140 ng/mL, about 150 Antioxidants' include, for example, butylated hydroxy ng/mL, about 160 ng/mL, about 170 ng/mL, about 180 40 toluene (BHT), sodium ascorbate, ascorbic acid, sodium met ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 abisulfite and tocopherol. In certain embodiments, antioxi ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 dants enhance chemical stability where required. ng/mL, about 250 ng/mL, 260 ng/mL, about 270 ng/mL, “Binders' impart cohesive qualities and include, e.g., alg about 280 ng/mL, about 290 ng/mL, about 300 ng/mL, about inic acid and salts thereof; cellulose derivatives Such as car 310 ng/mL, about 320 ng/mL, about 330 ng/mL, about 340 45 boxymethylcellulose, methylcellulose (e.g., Methocel(R), ng/mL, about 350 ng/mL, about 360 ng/mL, about 370 hydroxypropylmethylcellulose, hydroxyethylcellulose, ng/mL, about 380 ng/mL, about 390 ng/mL, or about 400 hydroxypropylcellulose (e.g., Klucel(R), ethylcellulose (e.g., ng/mL after administration of the formulation to the patient. Ethocel(R), and microcrystalline cellulose (e.g., Avicel(R): Mast cell stabilizers may be administered to a subject in the microcrystalline dextrose; amylose; magnesium aluminum methods disclosed herein by multiple administration routes, 50 silicate; polysaccharide acids; bentonites; gelatin; polyvi either alone or concurrently, including but not limited to oral, nylpyrrolidone/vinyl acetate copolymer; crosspoVidone; oral inhalation, parenteral (e.g., intravenous, Subcutaneous, poVidone; starch; pregelatinized Starch; tragacanth, dextrin, a intramuscular), implants such as osmotic pumps and depot Sugar, such as Sucrose (e.g., Dipac.R.), glucose, dextrose, implants, intranasal, buccal, topical, rectal, transdermal, molasses, mannitol, Sorbitol. Xylitol (e.g., XylitabR), and vaginal, or Sublingual administration routes. In some embodi 55 lactose; a natural or synthetic gum Such as acacia, tragacanth, ments of the methods disclosed herein, mast cell stabilizers ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone may be administered by a single route of administration. For (e.g., Polyvidone(R) CL, Kollidon R CL, Polyplasdone(R) example, in certain specific embodiments, the methods dis XL-10), larcharabogalactan, Veegum(R), polyethylene glycol, closed herein comprise administration of a mast cell stabi waxes, sodium alginate, and the like. lizer, such as cromolyn Sodium, with an inhalation device, 60 “Carriers' or “carrier materials” include any commonly e.g., a high efficiency nebulizer, without coadministration of used excipients in pharmaceutics and should be selected on a mast cell stabilizer, e.g., cromolyn Sodium, by another route the basis of compatibility with the specific mast cell stablizier of administration, e.g., an oral solution. and the release profile properties of the desired dosage form. Mast cell stabilizers may be formulated into any suitable Exemplary carrier materials include, e.g., binders, Suspend dosage form, including but not limited to aerosols, aqueous 65 ing agents, disintegration agents, filling agents, Surfactants, oral dispersions, Solid oral dosage forms, self-emulsifying solubilizers, stabilizers, lubricants, wetting agents, diluents, dispersions, Solid solutions, liposomal dispersions, pegylated and the like. “Pharmaceutically compatible carrier materials” US 9,265,749 B2 19 20 may include, but are not limited to, acacia, gelatin, colloidal a more stable environment. Salts dissolved in buffered solu silicon dioxide, calcium glycerophosphate, calcium lactate, tions, including, but not limited to, a phosphate buffered maltodextrin, glycerine, magnesium silicate, polyvinylpyr saline Solution, are utilized as diluents in the art, and can also rollidone (PVP), cholesterol, cholesterol esters, sodium provide pH control or maintenance. In certain embodiments, caseinate, Soy lecithin, taurocholic acid, phosphotidylcho diluents increase bulk of the composition to facilitate com line, sodium chloride, tricalcium phosphate, dipotassium pression or create sufficient bulk for homogenous blend for phosphate, cellulose and cellulose conjugates, Sugars sodium capsule filling. Such compounds include e.g., lactose, starch, Stearoyl lactylate, carrageenan, monoglyceride, diglyceride, mannitol, Sorbitol, dextrose, microcrystalline cellulose Such pregelatinized starch, and the like. See, e.g., Remington. The as Avice R.; dibasic calcium phosphate, dicalcium phosphate Science and Practice of Pharmacy, Nineteenth Ed (Easton, 10 dihydrate; tricalcium phosphate, calcium phosphate; anhy Pa. Mack Publishing Company, 1995); Hoover, John E. drous lactose, spray-dried lactose; pregelatinized starch, Remington's Pharmaceutical Sciences, Mack Publishing compressible Sugar, Such as Di-Pac(R) (Amstar); mannitol, Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., hydroxypropylmethylcellulose, hydroxypropylmethylcellu Eds. Pharmaceutical Dosage Forms, Marcel Decker, New lose acetate Stearate, Sucrose-based diluents, confectioner's York, N.Y., 1980; and Pharmaceutical Dosage Forms and 15 Sugar; monobasic calcium Sulfate monohydrate, calcium Sul Drug Delivery Systems, Seventh Ed. (Lippincott Williams & fate dihydrate; calcium lactate trihydrate, dextrates; hydro Wilkins 1999). lyzed cereal Solids, amylose; powdered cellulose, calcium "Dispersing agents' and/or "viscosity modulating agents' carbonate; glycine, kaolin; mannitol, Sodium chloride; inosi include materials that control the diffusion and homogeneity tol, bentonite, and the like. of a drug through liquid media or a granulation method or The term "disintegrate' includes both the dissolution and blend method. In some embodiments, these agents also facili dispersion of the dosage form when contacted with gas tate the effectiveness of a coating or eroding matrix. Exem trointestinal fluid. “Disintegration agents’ or “disintegrants’ plary diffusion facilitators/dispersing agents include, e.g., facilitate the breakup or disintegration of a Substance. hydrophilic polymers, electrolytes, Tween R. 60 or 80, PEG, Examples of disintegration agents include a starch, e.g., a Tyloxapol, polyvinylpyrrolidone (PVP; commercially known 25 natural starch Such as corn starch or potato starch, a pregela as Plasdone(R), and the carbohydrate-based dispersing agents tinized starch such as National 1551 or Amijel R., or sodium Such as, for example, hydroxypropyl celluloses (e.g., HPC. starch glycolate such as Promogel(R) or Explotab(R), a cellu HPC-SL, and HPC-L), hydroxypropyl methylcelluloses lose such as a wood product, methylcrystalline cellulose, e.g., (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC Avice(R), Avice1(R) PH101, Avicel(R) PH102, Avicel(R) PH105, K10OM), carboxymethylcellulose sodium, methylcellulose, 30 Elcema(R) P100, Emcocel(R), Vivacel(R, Ming TiaR), and hydroxyethylcellulose, hydroxypropylcellulose, hydrox Solka-FlocR), methylcellulose, croscarmellose, or a cross ypropylmethylcellulose phthalate, hydroxypropylmethylcel linked cellulose, such as cross-linked sodium carboxymeth lulose acetate stearate (HPMCAS), noncrystalline cellulose, ylcellulose (Ac-Di-SolR), cross-linked carboxymethylcellu magnesium aluminum silicate, triethanolamine, polyvinyl lose, or cross-linked croScarmellose, a cross-linked starch alcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer 35 Such as Sodium starch glycolate, a cross-linked polymer Such (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with as crosspoVidone, a cross-linked polyvinylpyrrolidone, algi ethylene oxide and formaldehyde (also known as tyloxapol), nate such as alginic acid or a salt of alginic acid Such as poloxamers (e.g., Pluronics F68(R), F88(R), and F108(R), which Sodium alginate, a clay Such as Veegum R. HV (magnesium are block copolymers of ethylene oxide and propylene aluminum silicate), a gum Such as agar, guar, locust bean, oxide); and poloxamines (e.g., Tetronic 908R, also known as 40 Karaya, pectin, or tragacanth, sodium starch glycolate, ben Poloxamine 908R, which is a tetrafunctional block copoly tonite, a natural Sponge, a Surfactant, a resin Such as a cation mer derived from sequential addition of propylene oxide and exchange resin, citrus pulp, sodium lauryl Sulfate, sodium ethylene oxide to ethylenediamine (BASF Corporation, Par lauryl Sulfate in combination starch, and the like. Sippany, N.J.)), polyvinylpyrrolidone K12, polyvinylpyrroli An "enteric coating is a Substance that remains substan done K17, polyvinylpyrrolidone K25, or polyvinylpyrroli 45 tially intact in the stomach but dissolves and releases the drug done K30, polyvinylpyrrolidone/vinyl acetate copolymer in the Small intestine or colon. Generally, the enteric coating (S-630), polyethylene glycol, e.g., the polyethylene glycol comprises a polymeric material that prevents release in the can have a molecular weight of about 300 to about 6000, or low pH environment of the stomach but that ionizes at a about 3350 to about 4000, or about 7000 to about 5400, higher pH, typically a pH of 6 to 7, and thus dissolves suffi Sodium carboxymethylcellulose, methylcellulose, polysor 50 ciently in the small intestine or colon to release the active bate-80, Sodium alginate, gums, such as, e.g., gum tragacanth agent therein. and gum acacia, guar gum, Xanthans, including Xanthan gum, "Erosion facilitators' include materials that control the Sugars, cellulosics, such as, e.g., sodium carboxymethylcel erosion of a particular material in gastrointestinal fluid. Ero lulose, methylcellulose, sodium carboxymethylcellulose, sion facilitators are generally known to those of ordinary skill polysorbate-80, Sodium alginate, polyethoxylated Sorbitan 55 in the art. Exemplary erosion facilitators include, e.g., hydro monolaurate, polyethoxylated Sorbitan monolaurate, povi philic polymers, electrolytes, proteins, peptides, and amino done, carbomers, polyvinyl alcohol (PVA), alginates, chito acids. Combinations of one or more erosion facilitator with sans and combinations thereof. Plasticizcers such as cellulose one or more diffusion facilitator can also be used in the or triethyl cellulose can also be used as dispersing agents. present compositions. Dispersing agents particularly useful in liposomal disper 60 "Filling agents' include compounds Such as lactose, cal sions and self-emulsifying dispersions are dimyristoyl phos cium carbonate, calcium phosphate, dibasic calcium phos phatidyl choline, natural phosphatidyl choline from eggs, phate, calcium Sulfate, microcrystalline cellulose, cellulose natural phosphatidylglycerol from eggs, cholesterol and iso powder, dextrose, dextrates, dextran, starches, pregelatinized propyl myristate. starch, Sucrose, Xylitol, lactitol, mannitol, Sorbitol, Sodium “Diluent” refers to chemical compounds that are used to 65 chloride, polyethylene glycol, and the like. dilute the compound of interest prior to delivery. Diluents can “Flavoring agents' and/or “sweeteners' useful in the for also be used to stabilize compounds because they can provide mulations described herein, include, e.g., acacia syrup, US 9,265,749 B2 21 22 acesulfame K, alitame, anise, apple, aspartame, banana, nylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvi Bavarian cream, berry, black currant, butterscotch, calcium nylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate citrate, camphor, caramel, cherry, cherry cream, chocolate, copolymer (S630), polyethylene glycol, e.g., the polyethyl cinnamon, bubble gum, citrus, citrus punch, citrus cream, ene glycol can have a molecular weight of about 300 to about cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, 6000, or about 3350 to about 4000, or about 7000 to about cylamate, dentomint, dextrose, eucalyptus, eugenol, fructose, 5400, sodium carboxymethylcellulose, methylcellulose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) hydroxypropylmethylcellulose, hydroxymethylcellulose syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon acetate stearate, polysorbate-80, hydroxyethylcellulose, cream, monoammonium glyrrhizinate (MagnaSweet(R), mal Sodium alginate, gums, such as, e.g., gum tragacanthandgum tol, mannitol, maple, marshmallow, menthol, mint cream, 10 acacia, guar gum, Xanthans, including Xanthan gum, Sugars, mixed berry, neohesperidine DC, neotame, orange, pear, cellulosics, such as, e.g., sodium carboxymethylcellulose, peach, peppermint, peppermint cream, ProSweet R Powder, methylcellulose, sodium carboxymethylcellulose, hydrox raspberry, root beer, rum, saccharin, Safrole, Sorbitol, spear ypropylmethylcellulose, hydroxyethylcellulose, polysor mint, spearmint cream, Strawberry, strawberry cream, Stevia, bate-80, Sodium alginate, polyethoxylated Sorbitan monolau Sucralose. Sucrose, Sodium saccharin, Saccharin, aspartame, 15 rate, polyethoxylated Sorbitan monolaurate, povidone and the acesulfame potassium, mannitol, talin, Sylitol. Sucralose, Sor like. bitol, Swiss cream, tagatose, tangerine, thaumatin, tutti "Surfactants' include compounds such as sodium lauryl fruitti, Vanilla, walnut, watermelon, wild cherry, wintergreen, sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E Xylitol, or any combination of these flavoring ingredients, TPGS, sorbitan monooleate, polyoxyethylene sorbitan e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry monooleate, polysorbates, polaxomers, bile salts, glyceryl cinnamon, chocolate-mint, honey-lemon, lemon-lime, monostearate, copolymers of ethylene oxide and propylene lemon-mint, menthol-eucalyptus, orange-cream, Vanilla oxide, e.g., Pluronic R (BASF), and the like. Some other mint, and mixtures thereof. Surfactants include polyoxyethylene fatty acid glycerides and “Lubricants' and "glidants' are compounds that prevent, Vegetable oils, e.g., polyoxyethylene (60) hydrogenated cas reduce or inhibit adhesion or friction of materials. Exemplary 25 tor oil; and polyoxyethylene alkylethers and alkylphenyl lubricants include, e.g., Stearic acid, calcium hydroxide, talc, ethers, e.g., octoxynol 10, Octoxynol 40. In some embodi Sodium Stearyl fumerate, a hydrocarbon Such as mineral oil, ments, Surfactants may be included to enhance physical sta or hydrogenated vegetable oil Such as hydrogenated soybean bility or for other purposes. oil (SteroteXCR), higher fatty acids and their alkali-metal and 'Viscosity enhancing agents' include, e.g., methyl cellu alkaline earth metal salts, such as aluminum, calcium, mag 30 lose, Xanthan gum, carboxymethyl cellulose, hydroxypropyl nesium, Zinc, Stearic acid, sodium Stearates, glycerol, talc, cellulose, hydroxypropylmethyl cellulose, hydroxypropylm waxes, Stearowet(R), boric acid, sodium benzoate, sodium ethyl cellulose acetate stearate, hydroxypropylmethyl cellu acetate, Sodium chloride, leucine, a polyethylene glycol (e.g., losephthalate, carbomer, polyvinyl alcohol, alginates, acacia, PEG-4000) or a methoxypolyethylene glycol such as Carbo chitosans, and combinations thereof. waxTM, sodium oleate, sodium benzoate, glyceryl behenate, 35 “Wetting agents' include compounds such as oleic acid, polyethylene glycol, magnesium or sodium lauryl Sulfate, glyceryl monostearate, Sorbitan monooleate, Sorbitan mono colloidal silica such as SyloidTM, Cab-O-Sil.R., a starch such laurate, triethanolamine oleate, polyoxyethylene Sorbitan as corn starch, silicone oil, a Surfactant, and the like. monooleate, polyoxyethylene Sorbitan monolaurate, Sodium “Plasticizers' are compounds used to soften the microen docusate, Sodium oleate, sodium lauryl Sulfate, sodium doc capsulation material or film coatings to make them less 40 cusate, triacetin, Tween 80, vitamin E TPGS, ammonium brittle. Suitable plasticizers include, e.g., polyethylene gly salts and the like. cols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG It should be appreciated that there is considerable overlap 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, between classes of inactive ingredients. Thus, the above triethyl cellulose and triacetin. In some embodiments, plasti listed ingredients should be taken as merely exemplary, and cizers can also function as dispersing agents or wetting 45 not limiting, of the types of inactive ingredients that can be agents. included in formulations described herein. The amounts of In certain embodiments, compositions provided herein Such inactive ingredients can be readily determined by one may also include one or more preservatives to inhibit micro skilled in the art, according to the particular properties bial activity. Suitable preservatives include mercury-contain desired. ing Substances such as merfen and thiomersal; stabilized 50 In certain specific embodiments, formulations for admin chlorine dioxide; Octinidine; and quaternary ammonium istration of mast cell stabilizers in the methods disclosed compounds such as benzalkonium chloride, cetyltrimethy herein include, but are not limited to, Aararre, Acecromol. lammonium bromide and cetylpyridinium chloride. Acromax, Acticrom, Aeropaxyn, Alercom, Alercrom, Aler “Solubilizers’ include compounds such as triacetin, trieth crom Nasal, Alerg, Alerg AT, Alerg Nasenspray, Alergocrom, ylcitrate, ethyl oleate, ethyl caprylate, Sodium lauryl Sulfate, 55 Alerion, Allercrom, Allerg-Abak, Allergo-COMOD, Aller sodium doccusate, vitamin E TPGS, polysorbates (Tweens) gocomod, Allergocrom, Allergocrom Kombi, Allergocrom dimethylacetamide, N-methylpyrrolidone, N-hydroxyeth Kombinations.packung, Allergojovis, Allergostop, Aller ylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl gotin, Allergoval, Allersol, Alloptrex, Apo-Cromolyn, Botas cellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, tin, Brol-Eze, Chromosol Ophta, Clariteyes, Clarityn Allergy isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 60 Eyedrops, Clarityn Eye Drops, Claroftal, Clo-5, Coldacrom, 200-600, glycofurol, transcutol, propylene glycol, and dim Colimune, Croglina, Crolidin, Crolom, Crom-Ophtal, Crom ethyl isosorbide and the like. Ophtal Kombipackung, Crom-Ophtal Sine, Cromabak, Cro "Stabilizers' include compounds such as any antioxidation madoses, Cromal, Cromantal, Cromedil, Cromedil Unidose, agents, e.g., citric acid, EDTA and pharmaceutically accept Cromese, Cromex, Cromo, Cromo Asma, Cromo EDP, able salts thereof, buffers, acids, preservatives and the like. 65 Cromo Einzeldosis, Cromo Kombipackung, Cromo UD, "Suspending agents include compounds such as polyvi Cromo-Comod, Cromo-Pos, Cromo-Spray, Cromobene, nylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvi Cromocato, Cromodyn, Cromofital, Cromogen, Cromoglicin, US 9,265,749 B2 23 24 Cromohexal, Cromohexal Kombipackung, Cromohexal UD, ceutical excipients to form a bulk blend composition. When Cromol, Cromolerg, Cromolergin UD, Cromolind, Cro referring to these bulk blend compositions as homogeneous, mollux, Cromophtal, Cromopp, Cromoptic, Cromoptic Uni it is meant that the particles of the mast cell stabilizer are dose, Cromorhinol, Cromosan, Cromosoft, Cromosol, Cro dispersed evenly throughout the composition so that the com mosol UD, Cromovet, Cromunal, Cronacol, Cronase, position may be readily subdivided into equally effective unit CropoZ, CropoZ, G, CropoZ N. Crorin, Cusicrom, Cusilyn, dosage forms, such as tablets, pills, and capsules. The indi Diffusyl, Dilospir, Dispacromil, Dispacromil Sine, DNCG, vidual unit dosages may also include film coatings, which DNCG PPS, Duobetic. Duracroman, Erystamine-K, Esirhi disintegrate upon oral ingestion or upon contact with diluent. nol. Exaler, Farmacrom, Fenistil Eye Drops, Fenolip, Fintal, These formulations can be manufactured by conventional Fivent, Flenid, Flui-DNCG, Fluvet, Frenal, Gaster, Gastro 10 pharmacological techniques, e.g., one or a combination of (1) crom, Gastrofrenal, Gelodrin, Gen-Cromoglycate, Gen-Cro dry mixing, (2) direct compression, (3) milling, (4) dry or moglycate Sterinebs, Gen-Cromolyn, Glicacil, Glicinal, Gli non-aqueous granulation, (5) wet granulation, and (6) fusion. nor. Hay-Crom, Hayfever Eye Drops, Hexacroman, Humex See, e.g., Lachman et al., The Theory and Practice of Indus Conjonctivite Allergique, Ifiral, Indoprex, Inostral, Intal, trial Pharmacy (1986). Other methods include, e.g., spray Intal 5, Intal Forte, Intal N, Intal Nasal, Intal Nebulizador, 15 drying, pan coating, melt granulation, granulation, fluidized Intal Nebulizer, Intal Spincaps, Intal Syncroner, Intercron, bedspray drying or coating (e.g., wurster coating), tangential Introl, Iopanchol, Kaosyl, Kiddicrom, Klonalcrom, Lecro coating, top spraying, tableting, extruding and the like. lyn, Logomed Heuschnupfen-Spray, Lomudal, Lomudal Pharmaceutical preparations for oral use can be obtained Nebuliser, Lomudal sans FCKW, Lomudas, Lomupren, by mixing one or more solid excipient with one or more mast Lomusol, Lomuspray, Maxicrom, Multicrom, Multicrom cell Stabilizers, optionally grinding the resulting mixture, and Unidose, Nalcrom, Nalcron, Nasalcrom, Nasivin gegen processing the mixture of granules, after adding Suitableaux Heuschnupfen, Nasmil, Natriumcromoglicaat, Nebulasma, iliaries, if desired, to obtain tablets or dragee cores. In some Nebulcrom, Novacro Novo-Cromolyn, Novo-Cromolyn embodiments, dragee cores are provided with Suitable coat Nebulizer, Nu-Cromolyn Plast Ophtacalm, Ophtacalm Uni ings. For this purpose, concentrated Sugar Solutions may be dose, Opticrom, Opticrom Allergy, Opticrom Aqueous, Opti 25 used, which may optionally contain gum arabic, talc, polyvi crom UD, Opticron, Opticron Unidose, Optrex Hayfever nylpyrrolidone, carbopol gel, polyethylene glycol, and/or Allergy, Oralcrom, Otriven H. Otrivin Hooikoorts, Padiac titanium dioxide, lacquer Solutions, and Suitable organic Sol rom, Pentacrom, Pentatop, PMS-Sodium Cromoglycate, vents or solvent mixtures. Dyestuffs or pigments may be Poledin, Pollenase Allergy, Pollyferm, Prevalin, Primover, added to the tablets or dragee coatings for identification or to Prothanon Cromo, Pulbil, Pulmosin, Renocil, Resiston Two, 30 characterize different combinations of active compound Rhinaris-CS Anti-Allergic Nasal Mist, Rilan, Rinil, Rinilyn, doses. Rinofrenal, Rynacrom, Rynacrom M. Sificrom, Sofro, Solu In other embodiments, a powder including a mast cell Crom, Spaziron, Spralyn, Stadaglicin, Steri-Neb Cromogen, stabilizer may be formulated to include one or more pharma Stop-Allerg, Taleum, Ufocollyre, Vekfanol, Vicrom, Vistac ceutical excipients and flavors. Such a powder may be pre rom, Vivicrom, Vividrin, Vividrin iso EDO, Viz-On, Zineli, or 35 pared, for example, by mixing the formulation and optional Zulboral. pharmaceutical excipients to form a bulk blend composition. Solid Oral Formulations Additional embodiments also include a suspending agent In some embodiments, the solid dosage forms disclosed and/or a wetting agent. This bulk blend is uniformly subdi herein may be in the form of a tablet, (including a suspension Vided into unit dosage packaging or multi-dosage packaging tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid 40 units. disintegration tablet, an effervescent tablet, an osmotic pump Compressed tablets are solid dosage forms prepared by tablet, or a caplet), a pill, a powder (including a sterile pack compacting the bulk blend of the formulations described aged powder, a dispensable powder, or an effervescent pow above. In some embodiments, the compressed tablets will der), a capsule (including both soft or hard capsules, e.g., include a film Surrounding the final compressed tablet. In capsules made from animal-derived gelatin or plant-derived 45 Some embodiments, the film coating can provide a delayed HPMC, or “sprinkle capsules'), solid dispersion, solid solu release of the mast cell stabilizer from the formulation. In tion, bioerodible dosage form, controlled release formula other embodiments, the film coating aids in patient compli tions, pulsatile release dosage forms, multiparticulate dosage ance. Film coatings such as Opadry(R) typically range from forms, pellets, or granules. In some embodiments, systemi about 1% to about 3% of the tablet weight. In other embodi cally effective amounts of mast cell stabilizers are achieved 50 ments, the compressed tablets include one or more pharma with solid oral formulations by including one or more of ceutical excipients. permeation enhancers and enteric coatings in the Solid oral A capsule may be prepared, for example, by placing the formulations. In some embodiments, enteric coatings regu bulk blend of the formulation of the mast cell stabilizer inside late the delivery a mast cell stabilizer during its passage of a capsule. In some embodiments, the formulations (non through the stomach and intestine. 55 aqueous Suspensions and solutions) are placed in a soft gela The pharmaceutical Solid dosage forms described herein tin capsule. In other embodiments, the formulations are can include a mast cell stabilizer and one or more pharma placed in standard gelatin capsules or non-gelatin capsules ceutically inactive ingredients such as a compatible carrier, such as capsules comprising HPMC. In other embodiments, binder, filling agent, Suspending agent, flavoring agent, the formulation is placed in a sprinkle capsule, wherein the Sweetening agent, disintegrating agent, dispersing agent, Sur 60 capsule may be Swallowed whole or the capsule may be factant, lubricant, colorant, diluent, Solubilizer, moistening opened and the contents sprinkled on food prior to eating. In agent, plasticizer, stabilizer, penetration enhancer, wetting Some embodiments, the therapeutic dose is split into multiple agent, anti-foaming agent, antioxidant, preservative, or one or (e.g., two, three, or four) capsules. In some embodiments, the more combination thereof. entire dose of the formulation is delivered in a capsule form. In some embodiments, Solid dosage forms, e.g., tablets, 65 In some embodiments, dosage forms may include effervescent tablets, and capsules, are prepared by mixing microencapsulated formulations. Materials useful for the particles of a mast cell stabilizer with one or more pharma microencapsulation include materials compatible with mast US 9,265,749 B2 25 26 cell stabilizers, which sufficiently isolate mast cell stabilizers form described herein, at least one mast cell stabilizer and from other non-compatible excipients. Materials compatible optional pharmaceutically acceptable excipient(s) are dis with mast cell stabilizers are those that delay the release of the persed within a polymeric matrix, which typically comprises mast cell stabilizers in vivo. Exemplary microencapsulation one or more water-soluble polymers and/or one or more materials useful for delaying the release of the formulations 5 water-insoluble polymers. The drug can be released from the include, but are not limited to, hydroxypropyl cellulose ethers dosage form by diffusion and/or erosion. Suitable water (HPC) such as Klucel(R) or Nisso HPC, low-substituted soluble polymers include, but are not limited to, polyvinyl hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypro methyl cellulose ethers (HPMC) such as Seppi film-LC, Phar pylcellulose, hydroxypropylmethylcellulose, or polyethyl macoat(R), Metolose SR, Methocel(R)-E, Opadry YS, Prima 10 ene glycol, and/or mixtures thereof. Suitable water-insoluble Flo, Benecel MP824, and Benecel MP843, methylcellulose polymers also include, but are not limited to, ethylcellulose, polymers such as Methocel(R-A, hydroxypropylmethylcellu cellulose acetate, cellulose propionate, cellulose acetate pro lose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) and pionate, cellulose acetate butyrate, cellulose acetate phtha Metolose(R), Ethylcelluloses (EC) and mixtures thereof such late, cellulose triacetate, poly (methyl methacrylate), poly as E461, Ethocel(R), Aqualon(R)-EC, Surelease.R., Polyvinyl 15 (ethyl methacrylate), poly (butyl methacrylate), poly (isobu alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses tyl methacrylate), and poly (hexyl methacrylate), poly (iso such as Natrosol(R), carboxymethylcelluloses and salts of car decyl methacrylate), poly (lauryl methacrylate), poly (phenyl boxymethylcelluloses (CMC) such as Aqualon(R)-CMC, methacrylate), poly (methyl acrylate), poly (isopropyl acry polyvinyl alcohol and polyethylene glycol co-polymers such late), poly (isobutyl acrylate), poly (octadecyl acrylate), poly as Kollicoat monoglycerides (Myverol), triglycerides (KLX), (ethylene), poly (ethylene) low density, poly (ethylene) high polyethylene glycols, modified food starch, acrylic polymers density, poly (ethylene oxide), poly (ethylene terephthalate), and mixtures of acrylic polymers with cellulose ethers such as poly (vinyl isobutyl ether), poly (vinyl acetate), poly (vinyl EudragitR) EPO, Eudragit R. L30D-55, Eudragit R FS 30D chloride) or polyurethane, and/or mixtures thereof. Suitable Eudragit R L100-55, EudragitR) L100, EudragitR) S100, pharmaceutically acceptable excipients include, but are not Eudragit R. RD 100, EudragitR) E100, EudragitR) L12.5, 25 limited to, carriers, such as sodium citrate and dicalcium Eudragit R S12.5, Eudragit R NE30D, and Eudragit R NE phosphate; fillers or extenders, such as Stearates, silicas, gyp 40D, cellulose acetate phthalate, sepifilms such as mixtures Sum, starches, lactose. Sucrose, glucose, mannitol, talc, and of HPMC and stearic acid, cyclodextrins, and mixtures of silicic acid; binders, such as hydroxypropyl methylcellulose, these materials. In some embodiments, plasticizers such as hydroxymethyl-cellulose, alginates, gelatin, polyvinyl pyr polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, 30 rolidone, Sucrose, and acacia: humectants, such as glycerol; PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene disintegrating agents, such as agar, calcium carbonate, potato glycol, oleic acid, and triacetin are incorporated into the and tapioca starch, alginic acid, certain silicates, microencapsulation material. EXPLOTAB, crospovidone, and sodium carbonate; solution Microencapsulated mast cell stabilizers may beformulated retarding agents, such as paraffin; absorption accelerators, by methods known by one of ordinary skill in the art. Such 35 Such as quaternary ammonium compounds; wetting agents, known methods include, e.g., spray drying processes, spin Such as cetyl alcohol and glycerol monostearate; absorbents, ning disk-solvent processes, hot melt processes, spray chill Such as kaolin and bentonite clay; lubricants, such as talc, ing methods, fluidized bed, electrostatic deposition, centrifu calcium Stearate, magnesium Stearate, Solid polyethylene gly gal extrusion, rotational Suspension separation, cols, and sodium lauryl Sulfate; stabilizers, such as fumaric polymerization at liquid-gas or solid-gas interface, pressure 40 acid; coloring agents; buffering agents; dispersing agents: extrusion, or spraying solvent extraction bath. In addition to preservatives; organic acids; and organic bases. The afore these, several chemical techniques, e.g., complex coacerva mentioned excipients are given as examples only and are not tion, solvent evaporation, polymer-polymer incompatibility, meant to include all possible choices. Additionally, many interfacial polymerization in liquid media, in situ polymer excipients can have more than one role or function, or can be ization, in-liquid drying, and desolvation in liquid media 45 classified in more than one group; the classifications are could also be used. Furthermore, other methods such as roller descriptive only, and are not intended to limit any use of a compaction, extrusion/spheronization, coacervation, or particular excipient. nanoparticle coating may also be used. Matrix formulations of the present invention can be pre In other embodiments, the formulations described herein pared by using, for example, direct compression or wet granu are solid dispersions. Methods of producing Such solid dis 50 lation. A functional coating can then be applied. Additionally, persions are known in the art and include, but are not limited a barrier or sealant coat can be applied over a matrix tablet to, for example, U.S. Pat. Nos. 4.343,789, 5,340,591, 5,456, core prior to application of a functional coating. The barrier or 923, 5,700,485, 5,723,269, and U.S. Pub. Appl 2004/ sealant coat can serve the purpose of separating an active 0013734, each of which is specifically incorporated by refer ingredient from a functional coating, which can interact with ence. In still other embodiments, the formulations described 55 the active ingredient, or it can prevent moisture from contact herein are solid solutions. Solid solutions incorporate a Sub ing the active ingredient. stance together with the mast cell stabilizer and other excipi In some embodiments, the modified-release formulations ents such that heating the mixture results in dissolution of the described herein are provided as osmotic pump dosage forms. drug and the resulting composition is then cooled to provide In an osmotic pump dosage form, a core containing at least a solid blend which can be further formulated or directly 60 one mast cell stabilizer and optionally at least one osmotic added to a capsule or compressed into a tablet. Methods of excipient is typically encased by a selectively permeable producing such solid solutions are known in the art and membrane having at least one orifice. The selectively perme include, but are not limited to, for example, U.S. Pat. Nos. able membrane is generally permeable to water, but imper 4,151,273, 5,281,420, and 6,083.518, each of which is spe meable to the drug. When the system is exposed to body cifically incorporated by reference. 65 fluids, water penetrates through the selectively permeable In other embodiments, formulations described herein membrane into the core containing the drug and optional include a matrix based dosage form. In a matrix-based dosage osmotic excipients. The osmotic pressure increases within the US 9,265,749 B2 27 28 dosage form. Consequently, the drug is released through the uncoated) containing granules, powder, pellets, beads or par orifice(s) in an attempt to equalize the osmotic pressure ticles of the active ingredient and/or other composition com across the selectively permeable membrane. ponents, which are themselves coated or uncoated. The In more complex pumps, the dosage form can contain two enteric coated oral dosage form may also be a capsule (coated internal compartments in the core. The first compartment or uncoated) containing pellets, beads or granules of the Solid contains the drug and the second compartment can contain a carrier or the composition, which are themselves coated or polymer, which Swells on contact with aqueous fluid. After uncoated. ingestion, this polymer Swells into the drug-containing com The term “delayed release' as used herein refers to the partment, diminishing the Volume occupied by the drug, delivery so that the release can be accomplished at Some thereby forcing the drug from the device at a controlled rate 10 over an extended period of time. Such dosage forms are often generally predictable location in the intestinal tract more used when a Zero order release profile is desired. Suitable distal to that which would have been accomplished if there Swellable polymers typically interact with water and/or aque had been no delayed release alterations. In some embodi ous biological fluids, which causes them to Swell or expand to ments the method for delay of release is coating. Any coatings an equilibrium state. Acceptable polymers exhibit the ability 15 should be applied to a sufficient thickness such that the entire to Swell in water and/or aqueous biological fluids, retaining a coating does not dissolve in the gastrointestinal fluids at pH significant portion of such imbibed fluids within their poly below about 5, but does dissolve at pH about 5 and above. It meric structure, so as to increase the hydrostatic pressure is expected that any anionic polymer exhibiting a pH-depen within the dosage form. The polymers can Swell or expand to dent solubility profile can be used as an enteric coating in the a very high degree, usually exhibiting a 2- to 50-fold volume methods and compositions described herein to achieve deliv increase. The polymers can be non-cross-linked or cross ery to the lower gastrointestinal tract. In some embodiments linked. In some embodiments, the Swellable polymers are the polymers described herein are anionic carboxylic poly hydrophilic polymers. mers. In other embodiments, the polymers and compatible In some embodiments, mast cell stabilizers can be pro mixtures thereof, and some of their properties, include, but vided in a multiparticulate membrane-modified formulation. 25 are not limited to shellac acrylic polymers, cellulose deriva Membrane-modified formulations can be made by preparing tives, and poly vinyl acetate phthalate (PVAP). a rapid release core, which can be a monolithic (e.g., tablet) or Conventional coating techniques such as spray or pan coat multi-unit (e.g., pellet) type, and coating the core with a ing are employed to apply coatings. The coating thickness membrane. The membrane-modified core can then be further must be sufficient to ensure that the oral dosage form remains coated with a functional coating. In between the membrane 30 intact until the desired site of topical delivery in the intestinal modified core and functional coating, a barrier or sealant can tract is reached. be applied. The mast cell stabilizer can be formed into an Liduid Oral Formulations active core by applying the compound to a nonpareil seed. Liquid formulation dosage forms for oral administration The at least one mast cell stabilizer can be applied with or can be acqueous Suspensions selected from the group includ without additional excipients onto the inert cores, and can be 35 ing, but not limited to, pharmaceutically acceptable aqueous sprayed from Solution or Suspension using a fluidized bed oral dispersions, emulsions, solutions, elixirs, gels, and Syr coater (e.g., Wurster coating) or pan coating system. Alterna ups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical tively, a mast cell stabilizer can be applied as a powder onto Technology 2" Ed., pp. 754-757 (2002). In addition to the the inert cores using a binder to bind the mast cell stabilizer particles of a mast cell stabilizer, the liquid dosage forms may onto the cores. Active cores can also be formed by extrusion 40 include additives, such as: (a) disintegrating agents; (b) dis of the core with Suitable plasticizers and any other processing persing agents; (c) wetting agents; (d) at least one preserva aids as necessary. tive, (e) viscosity enhancing agents, (f) at least one Sweeten The pharmaceutical Solid oral dosage forms described ing agent, and (g) at least one flavoring agent. In some herein can be further formulated to provide a controlled embodiments, the aqueous dispersions can further include a release of the mast cell stabilizer. Controlled release refers to 45 crystalline inhibitor. In some embodiments, systemically the release of the mast cell stabilizer from a dosage form in effective amounts of mast cell stabilizers are achieved with which it is incorporated according to a desired profile over an liquid oral formulations by including permeation enhancers extended period of time. Controlled release profiles include, in the liquid oral formulations. for example, Sustained release, prolonged release, pulsatile Examples of disintegrating agents for use in the aqueous release, and delayed release profiles. In contrast to immediate 50 Suspensions and dispersions include, but are not limited to, a release compositions, controlled release compositions allow starch, e.g., a natural starch Such as corn starch or potato delivery of an agent to a Subject over an extended period of starch, a pregelatinized starch such as National 1551 or time according to a predetermined profile. Such release rates Amijel R., or sodium starch glycolate Such as Promogel(R) or can provide therapeutically effective levels of agent for an Explotab(R); a cellulose such as a wood product, methylcrys extended period of time and thereby provide a longer period 55 talline cellulose, e.g., Avicel(R), Avicel(R) PH101, Avicel(R) of pharmacologic response while minimizing side effects as PH102, Avice1(R) PH105, Elcema(R) P100, Emcocel(R), compared to conventional rapid release dosage forms. Such Vivacel(R), Ming TiaR), and Solka-FlocR, methylcellulose, longer periods of response provide for many benefits that are croScarmellose, or a cross-linked cellulose, Such as cross not achieved with the corresponding short acting, immediate linked sodium carboxymethylcellulose (Ac-Di-SolR), cross release preparations. 60 linked carboxymethylcellulose, or cross-linked croScarmel In some embodiments, the Solid dosage forms described lose; a cross-linked starch Such as sodium starch glycolate; a herein can be formulated as enteric coated delayed release cross-linked polymer Such as crospovidone; a cross-linked oral dosage forms, i.e., as an oral dosage form of a pharma polyvinylpyrrolidone; alginate Such as alginic acid or a salt of ceutical composition as described herein which utilizes an alginic acid Such as Sodium alginate; a clay Such as Veegum R enteric coating to affect release in the Small intestine of the 65 HV (magnesium aluminum silicate); a gum Such as agar, gastrointestinal tract. The enteric coated dosage form may be guar, locust bean, Karaya, pectin, or tragacanth; sodium a compressed or molded or extruded tablet/mold (coated or starch glycolate; bentonite; a natural sponge; a surfactant; a US 9,265,749 B2 29 30 resin Such as a cation-exchange resin; citrus pulp; sodium Such as pH adjusters, emulsifiers or dispersing agents, vis lauryl Sulfate; sodium lauryl Sulfate in combination starch; cosity enhancing agents, preservatives, Surfactants, gelling and the like. agents, or buffering and other stabilizing and solubilizing In some embodiments, the dispersing agents suitable for agents may also be present. In some embodiments, the nasal the aqueous Suspensions and dispersions described herein 5 dosage form is isotonic with nasal Secretions. In some include, for example, hydrophilic polymers, electrolytes, embodiments a nasal dosage form is formulated to achieve Tween R. 60 or 80, PEG, polyvinylpyrrolidone (PVP; com Sustained delivery. Examples of Sustained delivery nasal mercially known as Plasdone(R), and the carbohydrate-based doSeage forms include, but are not limited to, dosage forms dispersing agents such as, for example, hydroxypropylcellu that include mucoadhesive agents such as microcrystalline lose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, 10 cellulose. In some embodiments, systemically effective and HPC-L), hydroxypropyl methylcellulose and hydrox amounts of mast cell stabilizers are achieved with intranasal ypropyl methylcellulose ethers (e.g. HPMC K100, HPMC formulations by one or more of optimizing the droplet or K4M, HPMC K15M, and HPMC K100M), carboxymethyl particle size and including permeation enhancers in the intra cellulose sodium, methylcellulose, hydroxyethylcellulose, nasal formulation. hydroxypropylmethyl-cellulose phthalate, hydroxypropylm 15 Buccal Formulations ethyl-cellulose acetate Stearate, noncrystalline cellulose, Buccal formulations that include mast cell stabilizers may magnesium aluminum silicate, triethanolamine, polyvinyl be administered using a variety of formulations known in the alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copoly art. For example, such formulations include, but are not lim mer (Plasdone(R), e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)- ited to, those described in U.S. Pat. Nos. 4,229,447, 4,596, phenol polymer with ethylene oxide and formaldehyde (also 795, 4,755,386, and 5,739,136, each of which is specifically known as tyloxapol), poloxamers (e.g., Pluronics F68(R), incorporated by reference. In addition, the buccal dosage F88(R), and F108(R), which are block copolymers of ethylene forms can further include a bioerodible (hydrolysable) poly oxide and propylene oxide); and poloxamines (e.g., Tetronic meric carrier that also serves to adhere the dosage form to the 908(R), also known as Poloxamine 908R, which is a tetrafunc buccal mucosa. The buccal dosage form is fabricated so as to tional block copolymer derived from sequential addition of 25 erode gradually over a predetermined time period, wherein propylene oxide and ethylene oxide to ethylenediamine the delivery of the mast cell stabilizer is provided essentially (BASF Corporation, Parsippany, N.J.)). In other embodi throughout. Buccal drug delivery, as will be appreciated by ments, the dispersing agent is selected from a group not those skilled in the art, avoids the disadvantages encountered comprising one of the following agents: hydrophilic poly with oral drug administration, e.g., slow absorption, degrada mers; electrolytes; Tween R. 60 or 80; PEG, polyvinylpyrroli 30 tion of the active agent by fluids present in the gastrointestinal done (PVP); hydroxypropylcellulose and hydroxypropyl cel tract and/or first-pass inactivation in the liver. With regard to lulose ethers (e.g., HPC, HPC-SL, and HPC-L): the bioerodible (hydrolysable) polymeric carrier, it will be hydroxypropyl methylcellulose and hydroxypropyl methyl appreciated that virtually any such carrier can be used, so long cellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC as the desired drug release profile is not compromised, and the K15M, HPMC K100M, and Pharmacoat(R) USP2910 (Shin 35 carrier is compatible with the mast cell stabilizer and any Etsu)); carboxymethylcellulose sodium; methylcellulose; other components that may be present in the buccal dosage hydroxyethylcellulose; hydroxypropylmethyl-cellulose unit. Generally, the polymeric carrier comprises hydrophilic phthalate; hydroxypropylmethyl-cellulose acetate Stearate; (water-soluble and water-swellable) polymers that adhere to non-crystalline cellulose; magnesium aluminum silicate; tri the wet surface of the buccal mucosa. Examples of polymeric ethanolamine; polyvinyl alcohol (PVA): 4-(1,1,3,3-tetram 40 carriers useful herein include acrylic acid polymers, e.g., ethylbutyl)-phenolpolymer with ethylene oxide and formal those known as “carbomers’ (Carbopol R, which may be dehyde; poloxamers (e.g., Pluronics F68(R), F88(R), and obtained from B.F. Goodrich, is one such polymer). Other F108(R), which are block copolymers of ethylene oxide and components may also be incorporated into the buccal dosage propylene oxide); or poloxamines (e.g., Tetronic 908R, also forms described herein include, but are not limited to, disin known as Poloxamine 908R). 45 tegrants, diluents, binders, lubricants, flavoring, colorants, Wetting agents suitable for the aqueous Suspensions and preservatives, and the like. In some embodiments, systemi dispersions described herein include, but are not limited to, cally effective amounts of mast cell stabilizers are achieved cetyl alcohol, glycerol monostearate, polyoxyethylene Sorbi with buccal formulations by one or more of optimizing the tan fatty acid esters (e.g., the commercially available erosion time of the formulation and by including permeation Tweens(R such as e.g., Tween 20R) and Tween 80R (ICI 50 enhancers in the buccal formulations. Specialty Chemicals)), and polyethylene glycols (e.g., Car Transdermal Formulations bowaxs 3350R) and 1450R, and Carbopol 934.R. (Union Car Transdermal formulations described herein may be admin bide)), oleic acid, glyceryl monostearate, Sorbitan istered using a variety of devices which have been described monooleate, Sorbitan monolaurate, triethanolamine oleate, in the art. For example, such devices include, but are not polyoxyethylene Sorbitan monooleate, polyoxyethylene Sor 55 limited to, those described in U.S. Pat. Nos. 3,598,122,3,598, bitan monolaurate, Sodium oleate, Sodium lauryl Sulfate, 123,3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, sodium docusate, triacetin, vitamin E TPGS, sodium tauro 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, cholate, simethicone, phosphotidylcholine and the like. 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, Intranasal Formulations 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, Intranasal formulations are known in the art and are 60 5,869,090, 6,923,983, 6,929,801 and 6,946,144, each of described in, for example, U.S. Pat. Nos. 4.476,116, 5,116, which is specifically incorporated by reference in its entirety. 817 and 6.391,452, each of which is specifically incorporated Transdermal dosage forms for use in the methods disclosed by reference. The choice of suitable carriers is highly depen herein may incorporate certain pharmaceutically acceptable dent upon the exact nature of the nasal dosage form desired, excipients which are conventional in the art. In one embodi e.g., Solutions, Suspensions, ointments, or gels. Nasal dosage 65 ment, the transdermal formulations include at least three forms generally contain large amounts of water in addition to components: (1) a formulation of a mast cell stabilizer; (2) a the active ingredient. Minor amounts of other ingredients penetration enhancer; and (3) an aqueous adjuvant. In addi US 9,265,749 B2 31 32 tion, transdermal formulations can include additional com permeated are used in the formulation. Such penetrants are ponents such as, but not limited to, gelling agents, creams and generally known in the art. For other parenteral injections, ointment bases, and the like. In some embodiments, the trans appropriate formulations may include aqueous or nonaque dermal formulation can further include a woven or non-wo ous Solutions, preferably with physiologically compatible ven backing material to enhance absorption and prevent the buffers or excipients. Such excipients are generally known in removal of the transdermal formulation from the skin. In the art. other embodiments, the transdermal formulations described Parenteral injections may involve bolus injection or con herein can maintain a Saturated or Supersaturated State to tinuous infusion. Pharmaceutical formulations for parenteral promote diffusion into the skin. In some embodiments, sys administration include aqueous solutions of the mast cell temically effective amounts of mast cell stabilizers are 10 stabilizers in water-soluble form. Additionally, suspensions achieved with transdermal dosage forms by including skin of the mast cell stabilizers may be prepared as appropriate permeation enhancers in the transdermal dosage forms. oily injection Suspensions. Suitable lipophilic solvents or Transdermal formulations used in the methods described vehicles include fatty oils such as Sesame oil, or synthetic herein may employ transdermal delivery devices and trans fatty acid esters, such as ethyl oleate or triglycerides, or dermal delivery patches and can be lipophilic emulsions or 15 liposomes. Aqueous injection Suspensions may contain Sub buffered, aqueous solutions, dissolved and/or dispersed in a stances which increase the viscosity of the Suspension, Such polymer oran adhesive. Such patches may be constructed for as sodium carboxymethyl cellulose, Sorbitol, or dextran. continuous, pulsatile, or on demand delivery of pharmaceu Optionally, the Suspension may also contain Suitable stabiliz tical agents. Still further, transdermal delivery of mast cell ers or agents which increase the Solubility of the compounds stabilizers can be accomplished by means of iontophoretic to allow for the preparation of highly concentrated Solutions. patches, microneedle systems, and the like. Additionally, Alternatively, the active ingredient may be in powderform for transdermal patches can provide controlled delivery of the constitution with a suitable vehicle, e.g., sterile pyrogen-free mast cell stabilizer. The rate of absorption can be slowed by water, before use. In some embodiments, parenteral formu using rate-controlling membranes or by trapping the com lations are prepared to provide Sustained release of a mast cell pound within a polymer matrix or gel. Conversely, absorption 25 stabilizer. In some embodiments, Sustained release is pro enhancers can be used to increase absorption. An absorption vided by incorporating liposomes, stealth liposomes, bio enhancer or carrier can include absorbable pharmaceutically erodible polymers, and the like into parenteral formulations acceptable solvents to assist passage through the skin. For to maximize the residence time in circulation and/or to example, transdermal devices are in the form of a bandage increase absorption of the mast cell stabilizer. comprising a backing member, a reservoir containing the 30 Implantable Formulations compound optionally with carriers, optionally a rate control Formulations that include a mast cell stabilizer suitable for ling barrier to deliver the compound to the skin of the host at implantation may contain physiologically acceptable sterile a controlled and predetermined rate over a prolonged period aqueous or non-aqueous solutions, dispersions, Suspensions, of time, and means to secure the device to the skin. In some or emulsions. In some embodiments, the formulations are embodiments, transdermal delivery of a mast cell stabilizer, 35 contained in and delivered from an osmotic pump implant to e.g., cromolyn Sodium, is provided using topical formulations achieve sustained delivery of the mast cell stabilizer over long of the mast cell stabilizer, e.g., cromolyn Sodium. durations. In some embodiments, a mast cell stabilizer is Injectable Formulations formulated with a bioerodible polymer, which, upon admin Formulations that include a mast cell stabilizer suitable for istration facilitatse the formation of a depot containing the intramuscular, Subcutaneous, or intravenous injection may 40 mast cell stabilizer. The depot would then erode and release contain physiologically acceptable sterile aqueous or non the mast cell stabilizer over a duration determined by the aqueous solutions, dispersions, Suspensions or emulsions, composition of the bioerodible polymer. In some embodi and sterile powders for reconstitution into sterile injectable ments, viscosity modifying agents, stabilizers, and other Solutions or dispersions. Examples of Suitable aqueous and excipients may be used in the formulation to achieve opti non-aqueous carriers, diluents, solvents, or vehicles includ 45 mum delivery over an extended duration. ing water, ethanol, polyols (propyleneglycol, polyethylene Inhalation Therapy glycol, glycerol, cremophor and the like), Suitable mixtures An “inhalation device.” as used herein, refers to any device thereof, vegetable oils (such as olive oil) and injectable that is capable of administering a drug formulation to the organic esters such as ethyl oleate. Proper fluidity can be respiratory airways of a patient. Inhalation devices include maintained, for example, by the use of a coating such as 50 conventional inhalation devices such as metered dose inhal lecithin, by the maintenance of the required particle size in the ers (MDIs), dry powder inhalers (DPIs), jet nebulizers, ultra case of dispersions, and by the use of Surfactants. Formula Sonic wave nebulizers, heat vaporizers, and soft mistinhalers. tions Suitable for Subcutaneous injection may also contain Inhalation devices also include high efficiency nebulizers. additives such as preserving, wetting, emulsifying, and dis Nebulizers, metered dose inhalers, and soft mist inhalers pensing agents. Prevention of the growth of microorganisms 55 deliver pharmaceuticals by forming an aerosol which can be ensured by various antibacterial and antifungal agents, includes droplet sizes that can easily be inhaled. The aerosol Such as parabens, chlorobutanol, phenol, Sorbic acid, and the can be used by a patient within the bounds of an inhalation like. It may also be desirable to include isotonic agents. Such therapy, whereby the mast cell stabilizer reaches the patients as Sugars, sodium chloride, and the like. Prolonged absorp respiratory tract upon inhalation. In some embodiments, the tion of the injectable pharmaceutical form can be brought 60 methods disclosed herein comprise administering to a patient about by the use of agents delaying absorption, such as alu a nominal dose of a mast cell stabilizer by an inhalation minum monostearate and gelatin. device. In some embodiments of the methods disclosed For intravenous injections, compounds described herein herein, an inhalation device is not a bronchoscope. may be formulated in aqueous solutions, preferably in physi In some embodiments of the methods disclosed herein, ologically compatible buffers such as Hank’s solution, Ring 65 administration of a composition comprising a mast cell sta er's Solution, or physiological saline buffer. For transmucosal bilizer, e.g., cromolyn Sodium, to a patient with an inhalation administration, penetrants appropriate to the barrier to be device, e.g., a high efficiency nebulizer, a dry powder inhaler, US 9,265,749 B2 33 34 a metered dose inhaler, a thermal aerosol inhaler, or an elec metabolism and excretion of a drug Substance. One way of trohydrodynamic-based solution misting inhaler, is effective visualizing a pharmacokinetic profile is by means of a blood for the treatment or prophylaxis of a systemic mast cell plasma concentration curve, which is a graph depicting mean related disorder because both a systemically effective amount active ingredient blood plasma concentration on the Y-axis of the mast cell stabilizer and a high deposited lung dose of 5 and time (usually in hours) on the X-axis. Some pharmaco the mast cell stabilizer is achieved in the patient. Thus, in kinetic parameters that may be visualized by means of a blood Some embodiments of the methods disclosed herein, admin plasma concentration curve include AUCAUCo., C. istration of a composition comprising a mast cell stabilizer, T, and T. An enhanced pharmacokinetic profile in a e.g., cromolyn Sodium, to a patient with an inhalation device, patient can be indicated by increased AUC, AUCo. e.g., a high efficiency nebulizer, a dry powder inhaler, a 10 C, or T1/2, a decreased T. or an increased T. metered dose inhaler, a thermal aerosol inhaler, or an electro Enhanced levels of a mast cell stabilizer in the blood plasma hydrodynamic-based solution misting inhaler, is effective for of a patient may result in better control of or improved symp the treatment or prophylaxis of a systemic mast cell related toms of a systemic mast cell related disorder. disorder that is not believed to be susceptible to treatment or The deposited lung dose may be expressed as a percentage prophylaxis with a mast cell stabilizer because both a sys 15 of the nominal dose that is deposited in the lung. For example, temically effective amount of the mast cell stabilizer and a a lung deposition of 30% means 30% of the nominal dose is high deposited lung dose of the mast cell stabilizer are deposited in the lung. Likewise, a lung deposition of 60% achieved in the patient. Furthermore, in some embodiments means 60% of the nominal dose is deposited in the lung, and where a mast cell stabilizer is administered with an inhalation So forth. Lung deposition (deposited lung dose) can be deter device, e.g., a high efficiency nebulizer, a dry powder inhaler, mined using methods of Scintigraphy or deconvolution. a metered dose inhaler, a thermal aerosol inhaler, or an elec RF, DD, RD, and RDDR are calculated parameters based trohydrodynamic-based solution misting inhaler, the meth on in vitro data that provide technical dimensions for the ods disclosed herein provide improved efficacy for the treat efficiency of an inhalation device. RF represents the percent ment or prophylaxis of a systemic mast cell related disorder age of the delivered aerosol, or inhaled mass, that penetrates relative to administration of a systemically effective amount 25 into the gas-exchange region of the lungs. RF may be mea of the mast cell stabilizer by a different route of administra Sured with a cascade impactor or laser diffraction apparatus. tion, e.g., parenterally or orally, because administration of the RF is expressed herein as the percentage of an aerosol deliv mast cell Stabilizer with an inhalation device, e.g., a high ered with an inhalation device that has a particular particle efficiency nebulizer, a dry powder inhaler, a metered dose diameter or range of particle diameters. For example, the term inhaler, a thermal aerosol inhaler, or an electrohydrody 30 "RF (s3.3 m) as used herein refers to the percentage of an namic-based solution misting inhaler, provides both a sys aerosol delivered with an inhalation device that has a particle temically effective amount of the mast cell stabilizer and a diameter less than or equal to 3.3 um. Similarly, the terms “RF high deposited lung dose of the mast cell stabilizer in the (1-5 um) and "RF (s5 um) as used herein refer to the patient. In some embodiments, a systemically effective percentage of an aerosol delivered with an inhalation device amount of a mast cell stabilizer is achieved by delivering the 35 that has aparticle diameter in the range of 1 um to 5um, or less mast cell stabilizer in an aerosol generated by a vibrating than 5um, respectively. DD is the portion or percentage of the mesh nebulizer that produces droplets with a MMD of 3.0-4.0 nominal dose that is actually emitted from the mouthpiece of um and a GSD of 1.5-1.8. In some embodiments of the meth the device. The difference between the nominal dose and the ods disclosed herein, an aerosol is administered through a DD is the amount of drug lost primarily as residues, i.e., the mouthpiece of a nebulizer using normal tidal breathing. 40 amount of drug remaining in the inhalation device after Characterization of Inhalation Devices administration or lost in aerosol form. RD is an expression of The efficiency of a particular inhalation device can be the delivered mass of drug contained within droplets or par characterized in many different ways, including by pharma ticles having a certain diameter emitted from an inhalation cokinetic properties, lung deposition (deposited lung dose), device, such as a DPI, MDI, or nebulizer, that are small respirable dose (RD), delivered dose (DD), respirable frac 45 enough to penetrate into the lung of a patient. The RD is tion (RF), respirable drug delivery rate (RDDR), volumetric determined by multiplying the DD by the RF. RDDR is the or mass median diameter (VMD or MMD), mass median speed at which a respirable dose of the drug is delivered to a aerodynamic diameter (MMAD) in combination with the patient’s lungs. RDDR, measured as a function of jug or geometric standard deviation (GSD), and total output rate mg/min, is determined by dividing the RD by the amount of (TOR), among others. The MMAD and GSD can be mea 50 time necessary for inhalation. The amount of time necessary Sured using a cascade impactor as described in United States for inhalation is measured as the amount of time from the first Phamacopeia (USP<1601 >). The DD can be measured by moment of administration of the emitted droplet or powder using breath simulation apparatus as described in from the nebulizer, DPI, or MDI until the emitted ordelivered USP<1601 >. The RF is derived from measuring the amount droplet or powder of a respirable diameter is delivered to the of drug deposited on the cascade impactor plates with a par 55 lung. ticular cut-off particle size, and expressing that as a fraction of Aerosol particle/droplet size is one factor determining the the total amount deposited on the cascade impactor plates, the deposition of aerosol drugs in the airways. The distribution of induction port and the filter. The RD is calculated by multi aerosol particle/droplet size can be expressed in terms of one plying the DD by the RF. The TOR is measured by the or more of VMD/MMAD and GSD. GSD is a dimensionless difference in weight of the nebulizer before and after comple 60 measure of a droplet size distribution curve relevant for char tion of nebulization divided by the duration of nebulization. acterizing terms such as VMD, MMD, and MMAD. In gen VMD or MMD can be measured with a standard laser light eral, the smaller the GSD for a particular particle size distri scattering apparatus Such as the Malvern Spraytec. bution, the narrower the distribution curve. Pharmacokinetics is concerned with the uptake, distribu Conventional Inhalation Devices tion, metabolism and excretion of a drug Substance. A phar 65 Conventional inhalation devices may be mechanical or macokinetic profile comprises one or more biological mea electrical, and include, for example, jet nebulizers and ultra Surements designed to measure the absorption, distribution, Sonic nebulizers. Jet nebulizers generally utilize compressors US 9,265,749 B2 35 36 to generate compressed air, which breaks the liquid medica by pelletizing a mast cell Stabilizer, e.g., cromolyn Sodium, to tion into small breathable droplets, which forman aerosolized form free-flowing spherical agglomerates. (atomized) mist. In some embodiments, when the patient In some embodiments of the methods disclosed herein, breathes in, a valve at the top opens, which then allows air into compositions comprising mast cell stabilizers are adminis the apparatus, thereby speeding up the mist generation; when 5 tered with a metered dose inhaler. In some embodiments, a the patient breathes out, the top valve closes, thereby slowing composition administered with a metered dose inhaler in the down the mist generation while simultaneously permitting methods disclosed herein comprises one or more of nanopar the patient to breathe out through the opening of a mouthpiece ticles, spray dried materials, engineered porous particles with flap. Some nebulizers may provide the aerosol in a continuous low mass median diameter but a high geometric diameter, mode (e.g., the eFlow from PARI Pharma Starnberg), by a 10 liposomes, and stealth (or PEGylated) liposomes. breath enhanced mode (e.g., the PARILC Plus or Sprint from PARI Starnberg), by breath actuated mode dependent on the In some embodiments of the methods disclosed herein, breathing pattern of the patient (e.g., the AeroEclipse from compositions comprising mast cell stabilizers are adminis Trudell, Canada or the I-Neb from Philips Respironics), or tered with a thermal aerosol inhaler. In some embodiments, according to given inhalation profile (e.g., the Akita from 15 the aerosol in a thermal aerosol inhaler is generated by Activaero. Gmuenden, Germany). directly heating and vaporizing a thin Solid film of the mast Some conventional inhalation devices are disclosed in U.S. cell stabilizer, e.g., cromolyn Sodium, or by heating and Pat. Nos. 6,513,727, 6,513,519, 6,176,237, 6,085,741, 6,000, vaporizing a solution of a mast cell stabilizer, e.g., cromolyn 394, 5,957,389, 5,740,966, 5,549,102, 5,461,695, 5,458,136, Sodium in solvents such as propylene glycol and/or glycerol 5,312,046, 5,309,900, 5,280,784, and 4,496,086, each of and water. which is hereby incorporated by reference in its entirety. In some embodiments of the methods disclosed herein, Commercial conventional inhalation devices are available compositions comprising mast cell stabilizers are adminis from: PARI (Germany) under the trade names PARI LC tered with an electrohydrodynamic-based solution misting Plus.(R), LC Star R, and PARI-JetR); A & H Products, Inc. inhaler. In some embodiments, the aerosol in the electrohy (Tulsa, Okla.) under the trade name AquaTower(R); Hudson 25 drodynamic-based solution-misting inhaler is generated by RCI (Temecula, Calif.) under the trade name AVA-NEB(R): Subjecting a solution of a mast cell stabilizer, e.g., cromolyn Intersurgical, Inc. (Liverpool, N.Y.) under the trade name Sodium, or a liposome or pegylated liposome comprising a Cirrus(R); Salter Labs (Arvin, Calif.) under the trade name mast cell stabilizer, e.g., cromolyn Sodium, to electrohydro Salter 8900R); Respironics (Murrysville, Pa.) under the trade dynamic forces through electrostatic energy. name Sidestream(R); Bunnell (Salt Lake City, Utah) under the 30 High Efficiency Nebulizers trade name WhisperJetR); Smiths-Medical (Hyth Kent, UK) High efficiency nebulizers are inhalation devices that com under the trade name Downdraft(R), and DeVilbiss (Somerset, prise a micro-perforated membrane through which a liquid Pa.) under the trade name DeVilbiss(R); or Trudell, Canada Solution is converted through electrical or mechanical means under the trade name AeroEclipse R. into aerosol droplets suitable for inhalation. High efficiency In some embodiments of the methods disclosed herein, 35 nebulizers can deliver a large fraction of a loaded dose to a compositions comprising mast cell stabilizers are adminis patient. In some embodiments, the high efficiency nebulizer tered with a dry powder inhaler. In some embodiments of the also utilizes one or more actively or passively vibrating methods disclosed herein, compositions administered with microperforated membranes. In some embodiments, the high dry powder inhalers comprise one or more of nanoparticles, efficiency nebulizer contains one or more oscillating mem spray dried materials, engineered porous particles with low 40 branes. In some embodiments, the high efficiency nebulizer mass median diameter but a high geometric diameter, lipo contains a vibrating mesh or plate with multiple apertures and somes, and stealth (or PEGylated) liposomes. In some optionally a vibration generator with an aerosol mixing embodiments, compositions administered by dry powder chamber. In some Such embodiments, the mixing chamber inhalers administered in the methods disclosed herein com functions to collect (or stage) the aerosol from the aerosol prise nanoparticle clusters that aggregate into micrometer 45 generator. In some embodiments, an inhalation valve is also sized particles at neutral or basic pH but dissociate into nano used to allow an inflow of ambient air into the mixing cham particles at the pH encountered in the lung. In some embodi ber during an inhalation phase and is closed to prevent escape ments the nanoparticle clusters comprise fumaryl diketopip of the aerosol from the mixing chamber during an exhalation erazine. In some embodiments, compositions administered phase. In some such embodiments, the exhalation valve is with dry powder inhalers comprise lactose. In some embodi 50 arranged at a mouthpiece which is removably mounted at the ments, compositions administered with dry powder inhalers mixing chamber and through which the patient inhales the do not comprise lactose. In some embodiments, compositions aerosol from the mixing chamber. Still yet, in some embodi administered with a dry powder inhaler have a MMAD ments, the high efficiency nebulizer contains a pulsating between 2 and 4 um, a GSD between 1.5 and 2.5 um, and an membrane. In some embodiments, the high efficiency nebu RF (s.5um) between 30% and 80%. In some embodiments, a 55 lizer is continuously operating. dry powder inhaler used to administer an inhalation formula In some embodiments, the high efficiency nebulizer con tion in the methods disclosed herein comprises a pre-metered tains a vibrating micro-perforated membrane of tapered dose. Such as Plastiape Monodose inhaler, which comprises a nozzles that generates a plume of droplets without the need capsule pre-filled with a powder. In some embodiments, a dry for compressed gas. In these embodiments, a solution in the powder inhaler used to administer an inhalation formulation 60 micro-perforated membrane nebulizer is in contact with a in the methods disclosed herein has a device-metered system membrane, the opposite side of which is open to the air. The such as Twisthaler, sold by Schering Plough, which com membrane is perforated by a large number of nozzle orifices prises a reservoir to store a powder and a twisting top to of an atomizing head. An aerosol is created when alternating dispense each dose. Inhalation formulations for administra acoustic pressure in the solution is built up in the vicinity of tion with a dry powder inhaler may be prepared by blending 65 the membrane causing the fluid on the liquid side of the a mast cell stabilizer, e.g., cromolyn Sodium, with lactose, or membrane to be emitted through the nozzles as uniformly spray drying a mast cell stabilizer, e.g., cromolyn Sodium, or sized droplets. US 9,265,749 B2 37 38 Some embodiments of high efficiency nebulizers use pas Such as gastrointestinal irritation, or associated with conven sive nozzle membranes and a separate piezoelectric trans tional inhalation devices, such as cough; and (6) a longer ducer that stimulates the membrane. In contrast, Some high duration of therapeutic effect as compared to administration efficiency nebulizers employ an active nozzle membrane, of an oral Solution or an inhaled formulation with a conven which use the acoustic pressure in the nebulizer to generate tional inhalation device. very fine droplets of solution via the high frequency vibration In some embodiments, the DD expressed as the percentage of the nozzle membrane. of the nominal dose of a mast cell stabilizer administered with Some high efficiency nebulizers contain a resonant system. a high efficiency nebulizer in the methods disclosed herein is In some such high efficiency nebulizers, the membrane is at least about 30%, at least about 35%, at least about 40%, at driven by a frequency for which the amplitude of the vibra 10 least about 45%, at least about 50%, at least about 55%, at tional movement at the center of the membrane is particularly least about 60%, at least about 65%, about 65%, about 70%, large, resulting in a focused acoustic pressure in the vicinity about 30% to about 90%, about 40% to about 80%, about 45% of the nozzle; the resonant frequency may be about 100 kHz. to about 75%, about 50% to about 70%, about 30% to about A flexible mounting is used to keep unwanted loss of vibra 75%, about 40% to about 70%, about 45% to about 60%, or tional energy to the mechanical Surroundings of the atomiz 15 about 60% to about 70%. ing head to a minimum. In some embodiments, the vibrating TOR is the speed at which the liquid containing a mast cell membrane of the high efficiency nebulizer may be made stabilizer is administered from the inhalation device. In some stainless steel, or of a nickel-palladium alloy by electroform embodiments, administration of the mast cell stabilizer with ing. the high efficiency nebulizer provides a TOR of at least about In some embodiments, a high efficiency nebulizer may be 2 times, 3 times or 4 times the TOR achievable with a con adapted or adaptable to operate in conjunction with a unit ventional inhalation device. Such as a nebulizer. For example, dosage form, Such as an ampule or vial, which contains a in some embodiments the TOR is at least about at least about single dose of a mast cell stabilizer composition for the treat 150 mg/min, at least about 200 mg/min, at least about 250 ment of a systemic mast cell related disorder. The unit dosage mg/min, at least 300 mg/min, at least 350 mg/min, at least 400 form comprises a container that contains an inhalation for 25 mg/min, at least 500 mg/min, or from 200 to about 700 mulation comprising the mast cell stabilizer, Such as cro mg/min. molyn Sodium. The container is adapted to cooperate with the In some embodiments, use of a high efficiency nebulizer in high efficiency nebulizer device in Such a way as to permit the methods disclosed herein provides a RF (s3.3 um) of mast administration of the nominal dose of the inhalation formu cell stabilizer of at least about 20%, at least about 25%, at lation to a patient. In some embodiments, the high efficiency 30 least about 30%, at least about 35%, at least about 40%, at nebulizer and the unit dosage form are configured so that they least about 45%, at least about 50%, at least about 55%, at are useable together, but not with other devices or dosage least about 60%, at least about 65%, at least about 70%, at forms. In some particular embodiments, the unit dosage form least about 75%, at least about 80%, at least about 85%, at is configured such that it fits into a keyhole-like structure in least about 90%, at least about 95%, about 20% to about 95%, the high efficiency nebulizer, but will not operate with other 35 about 35% to about 90%, or about 40% to about 80%, about nebulizer devices. In such embodiments, the high efficiency 40% to about 90%, about 40% to about 95%, about 45% to nebulizer is configured such that it will accept and properly about 90%, about 45% to about 95%, about 50% to about operate with the unit dosage form containing the mast cell 90%, about 65% to about 90%, about 60% to about 95%, stabilizer, but not with other dosage forms. about 65% to about 95%, about 70% to about 90%, or about Commercial high efficiency nebulizers are available from: 40 55% to about 90%. In some embodiments, use of a high PARI (Germany) under the trade name eFlow(R); Aerogen, efficiency nebulizer in the methods disclosed herein provides Ltd. (Ireland) under the trade names AeroNeb(R) Go and a RF (s3.3 um) of cromolyn sodium of at least about 20%, at AeroNebR Pro, AeroNeb(R) Solo, and other nebulizers utiliz least about 25%, at least about 30%, at least about 35%, at ing the OnOR nebulizer technology: Respironics (Murrys least about 40%, at least about 45%, at least about 50%, at ville, Calif.) under the trade names I-NebR); Omron (Ban 45 least about 55%, at least about 60%, at least about 65%, at nockburn, Ill.) under the trade name Micro-AirR); Activaero least about 70%, at least about 75%, at least about 80%, at (Germany) under the trade name Akita R, and AerovectRX least about 85%, at least about 90%, at least about 95%, about (Atlanta, Ga.) under the trade name AerovectRX(R). 20% to about 95%, about 35% to about 90%, or about 40% to In some embodiments, the methods disclosed herein com about 80%, about 40% to about 90%, about 40% to about prise administration to a patient a nominal dose of a mast cell 50 95%, about 45% to about 90%, about 45% to about 95%, stabilizer with a high efficiency nebulizer, wherein adminis about 50% to about 90%, about 65% to about 90%, about 60% tration of the nominal dose of the mast cell stabilizer to the to about 95%, about 65% to about 95%, about 70% to about patient provides one or more of the following advantages: (1) 90%, about 55% to about 90%, about 40% to about 50%, an enhanced pharmacokinetic profile as compared to admin about 35% to about 45%, about 35% to about 50%, about 30% istration of an oral Solution oran inhalation formulation with 55 to about 50%, about 44%, or about 36%. a conventional inhalation device; (2) an enhanced therapeutic In some embodiments, use of a high efficiency nebulizer in effect as compared to administration of an oral Solution oran the methods disclosed herein provides a RF (1-5 um) of mast inhalation formulation with a conventional inhalation device; cell stabilizer of at least about 20%, at least about 25%, at (3) an enhanced lung deposition (deposited lung dose) as least about 30%, at least about 35%, at least about 40%, at compared with a conventional inhalation device evidenced by 60 least about 45%, at least about 50%, at least about 55%, at Scintigraphy or deconvolution, or derived from Suitable in least about 60%, at least about 65%, at least about 70%, at vitro indicators such as enhanced RD, RDDR, RF, and lower least about 75%, at least about 80%, at least about 85%, at GSDs, as compared to administration with a conventional least about 90%, at least about 95%, about 20% to about 95%, inhalation device; (4) reduced administration times, periods, about 35% to about 90%, or about 40% to about 80%, about and/or Volumes as compared to administration with a conven 65 40% to about 90%, about 40% to about 95%, about 45% to tional inhalation device; (5) a reduction inadverse side effects about 90%, about 45% to about 95%, about 50% to about associated with oral formulations of a mast cell stabilizer, 90%, about 65% to about 90%, about 60% to about 95%, US 9,265,749 B2 39 40 about 65% to about 95%, about 70% to about 90%, or about particular embodiments, administration of a mast cell Stabi 55% to about 90%. In some embodiments, use of a high lizer in the methods disclosed herein provides droplets having efficiency nebulizer in the methods disclosed herein provides a particular combination of MMAD and GSD, for example: a RF (1-5 um) of cromolyn sodium of at least about 20%, at an MMAD of less than about 5um and a GSD of about 1.1 to least about 25%, at least about 30%, at least about 35%, at about 2.1; an MMAD of less than about 4.5um and a GSD of least about 40%, at least about 45%, at least about 50%, at about 1.1 to about 2.1; an MMAD of about 1 um to about 5um least about 55%, at least about 60%, at least about 65%, at and a GSD of about 1.1 to about 2.1; an MMAD of about 1.5 least about 70%, at least about 75%, at least about 80%, at to about 4.5 um and a GSD of about 1.1 to about 2.1; an least about 85%, at least about 90%, at least about 95%, about MMAD of less than about 5um and a GSD of about 1.1 to 20% to about 95%, about 35% to about 90%, or about 40% to 10 about 2.0; an MMAD of less than about 4.5um and a GSD of about 80%, about 40% to about 90%, about 40% to about about 1.1 to about 2.0; an MMAD of about 1 um to about 5um 95%, about 45% to about 90%, about 45% to about 95%, and a GSD of about 1.1 to about 2.0; an MMAD of about 1.5 about 50% to about 90%, about 65% to about 90%, about 60% to about 4.5 um and a GSD of about 1.1 to about 2.0; an to about 95%, about 65% to about 95%, about 70% to about MMAD of less than about 5um and a GSD of about 1.1 to 90%, or about 55% to about 90%. 15 about 1.9; an MMAD of less than about 4.5um and a GSD of In Some embodiments, use of a high efficiency nebulizer in about 1.1 to about 1.9; an MMAD of about 1 um to about 5um the methods disclosed herein provides a RF (s.5um) of mast and a GSD of about 1.1 to about 1.9; an MMAD of about 1.5 cell stabilizer of at least about 20%, at least about 25%, at to about 4.5 um and a GSD of about 1.1 to about 1.9; an least about 30%, at least about 35%, at least about 40%, at MMAD of less than about 5um and a GSD of about 1.1 to least about 45%, at least about 50%, at least about 55%, at about 1.8; an MMAD of less than about 4.5um and a GSD of least about 60%, at least about 65%, at least about 70%, at about 1.1 to about 1.8; an MMAD of about 1 um to about 5um least about 75%, at least about 80%, at least about 85%, at and a GSD of about 1.1 to about 1.8; an MMAD of about 1.5 least about 90%, at least about 95%, about 20% to about 95%, to about 4.5 um and a GSD of about 1.1 to about 1.8; an about 35% to about 90%, or about 40% to about 80%, about MMAD of about 3.5 um or less and a GSD of about 1.7; an 40% to about 90%, about 40% to about 95%, about 45% to 25 MMAD of about 4.1 um or less and a GSD of about 1.7; an about 90%, about 45% to about 95%, about 50% to about MMAD of about 3.5 um and a GSD of about 1.7; or an 90%, about 65% to about 90%, about 60% to about 95%, MMAD of about 4.1 um and a GSD of about 1.7. about 65% to about 95%, about 70% to about 90%, about 55% In some embodiments, the median particle size of a mast to about 90%, about 70% to about 80%, or about 75%. In cell stabilizer aerosol administered with a high efficiency Some embodiments, use of a high efficiency nebulizer in the 30 nebulizer is between about 1 um and about 6 um, between methods disclosed herein provides a RF (s.5um) of cromolyn about 2 um and about 5um, between about 3 um and about 5 sodium of at least about 20%, at least about 25%, at least um, between about 3 Lum and about 4 Lum, about 1 lum, about about 30%, at least about 35%, at least about 40%, at least 2 um, about 3 Lim, about 4 um, about 5um, or about 6 um. In about 45%, at least about 50%, at least about 55%, at least Some embodiments, the median particle size of cromolyn about 60%, at least about 65%, at least about 70%, at least 35 sodium aerosol administered with a high efficiency nebulizer about 75%, at least about 80%, at least about 85%, at least is between about 1 Lum and about 6 um, between about 2 um about 90%, at least about 95%, about 20% to about 95%, and about 5um, between about 3 um and about 5um, between about 35% to about 90%, or about 40% to about 80%, about about 3 um and about 4 um, about 1 um, about 2 um, about 3 40% to about 90%, about 40% to about 95%, about 45% to um, about 4 Lim, about 5um, or about 6 Lum. about 90%, about 45% to about 95%, about 50% to about 40 Inhalation Formulations 90%, about 65% to about 90%, about 60% to about 95%, In some embodiments of the methods disclosed herein, about 65% to about 95%, about 70% to about 90%, about 55% inhalation formulations are administered by an inhalation to about 90%, about 70% to about 80%, about 65% to about device, e.g., a high efficiency nebulizer, to provide a systemi 75%, about 65% to about 80%, about 60% to about 80%, cally effective amount of a mast cell stabilizer for the treat about 66%, or about 75%. 45 ment of a systemic mast cell related disorder. In some In Some embodiments, use of a high efficiency nebulizer in embodiments, the methods disclosed herein comprise admin the methods disclosed herein provides a RDDR of at least istering a nominal dose of one or more mast cell Stabilizers in about 2 times, at least about 3 times or at least about 4 times an aqueous inhalation Solution to the patient with an inhala the RDDR achievable with a conventional inhalation device. tion device, e.g., a high efficiency nebulizer. For example, where the mast cell stabilizer is cromolyn 50 In some embodiments of the methods disclosed herein, an sodium, in some embodiments the RDDR is at least about 5 inhalation formulation administered with an inhalation mg/min, at least about 10 mg/min, at least about 15 mg/min, device, e.g., a high efficiency nebulizer, produces in a human at least about 20 mg/min, at least about 25 mg/min, at least subject group an average AUCo. of a mast cell stabilizer about 30 mg/min, at least about 35 mg/min, at least about 40 greater than about 100 nghr/mL, greater than about 110 mg/min, at least about 45 mg/min, at least about 50 mg/min, 55 nghr/mL, greater than about 120 nghr/mL, greater than at least about 55 mg/min, or at least about 60 mg/min. about 130 nghr/mL, greater than about 140 nghr/mL, In some embodiments, administration of a mast cell Stabi greater than about 150 nghr/mL, greater than about 160 lizer with a high efficiency nebulizer in the methods disclosed nghr/mL, greater than about 170 nghr/mL, greater than herein provides a GSD of emitted droplet size distribution of about 180 nghr/mL, greater than about 190 nghr/mL, about 1.1 to about 2.1, about 1.2 to about 2.0, about 1.3 to 60 greater than about 200 nghr/mL, greater than about 225 about 1.9, less than about 2, at least about 1.4 to about 1.8, at nghr/mL, greater than about 250 nghr/mL, greater than least about 1.5 to about 1.7, about 1.4, about 1.5, about 1.6, or about 275 nghr/mL, greater than about 300 nghr/mL, about 1.7. In some embodiments, administration of a mast greater than about 325 nghr/mL, greater than about 350 cell stabilizer with a high efficiency nebulizer in the methods nghr/mL, greater than about 375 nghr/mL, greater than disclosed herein provides a MMAD of droplet size of about 1 65 about 400 nghr/mL, greater than about 425 nghr/mL, um to about 5um, about 2 to about 4 Lim, about 3 to about 4 greater than about 450 nghr/mL, greater than about 475 um, about 3.5 to about 4.5 um, or about 3.5 um. In some nghr/mL, greater than about 500 nghr/mL, greater than US 9,265,749 B2 41 42 about 525 nghr/mL, greater than about 550 nghr/mL, efficiency nebulizer, produces in a human Subject group an greater than about 575 nghr/mL, greater than about 600 average AUCo., of cromolyn sodium of about 100 nghr? nghr/mL, greater than about 625 nghr/mL, greater than mL, about 110 nghr/mL, about 120 nghr?mL, about 130 about 650 nghr/mL, greater than about 675 nghr/mL, nghr/mL, about 140 nghr/mL, about 150 nghr?mL, about greater than about 700 nghr/mL, greater than about 725 160 nghr/mL, about 170 nghr/mL, about 180 nghr/mL, nghr/mL, greater than about 750 nghr/mL, greater than about 190 nghr/mL, about 200 nghr/mL, about 225 nghr? about 775 nghr/mL, greater than about 800 nghr/mL, mL, about 250 nghr/mL, about 275 nghr/mL, about 300 greater than about 825 nghr/mL, greater than about 850 nghr/mL, about 325 nghr/mL, about 350 nghr?mL, about nghr/mL, greater than about 875 nghr/mL, greater than 375 nghr/mL, about 400 nghr/mL, about 425 nghr/mL, about 900 nghr/mL, greater than about 925 nghr/mL, 10 about 450 nghr/mL, about 475 nghr/mL, about 500 nghr? greater than about 950 nghr/mL, greater than about 975 mL, about 525 nghr/mL, about 550 nghr/mL, about 575 nghr/mL, or greater than about 1000 nghr/mL after admin nghr/mL, about 600 nghr/mL, about 625 nghr?mL, about istration of the formulation to the patient. In some embodi 650 nghr/mL, about 675 nghr/mL, about 700 nghr/mL, ments of the methods disclosed herein, an inhalation formu about 725 nghr/mL, about 750 nghr/mL, about 775 nghr? lation administered with an inhalation device, e.g., a high 15 mL, about 800 nghr/mL, about 825 nghr/mL, about 850 efficiency nebulizer, produces in a human Subject group an nghr/mL, about 875 nghr/mL, about 900 nghr?mL, about average AUCo. ofa mast cell stabilizer of about 100 nghr? 925 nghr/mL, about 950 nghr/mL, about 975 nghr/mL, or mL, about 110 nghr/mL, about 120 nghr?mL, about 130 about 1000 nghr/mL after administration of the formulation nghr/mL, about 140 nghr/mL, about 150 nghr?mL, about to the patient. 160 nghr/mL, about 170 nghr/mL, about 180 nghr/mL, In some embodiments of the methods disclosed herein, an about 190 nghr/mL, about 200 nghr/mL, about 225 nghr? inhalation formulation administered with an inhalation mL, about 250 nghr/mL, about 275 nghr/mL, about 300 device, e.g., a high efficiency nebulizer, produces in a human nghr/mL, about 325 nghr/mL, about 350 nghr?mL, about Subject group an average C of a mast cell stabilizergreater 375 nghr/mL, about 400 nghr/mL, about 425 nghr/mL, than about 40 ng/mL, greater than about 50 ng/mL, greater about 450 nghr/mL, about 475 nghr/mL, about 500 nghr? 25 than about 60 ng/mL, greater than about 70 ng/mL, greater mL, about 525 nghr/mL, about 550 nghr/mL, about 575 than about 80 ng/mL, greater than about 90 ng/mL, greater nghr/mL, about 600 nghr/mL, about 625 nghr?mL, about than about 100 ng/mL, greater than about 110 ng/mL, greater 650 nghr/mL, about 675 nghr/mL, about 700 nghr/mL, than about 120 ng/mL, greater than about 130 ng/mL, greater about 725 nghr/mL, about 750 nghr/mL, about 775 nghr? than about 140 ng/mL, greater than about 150 ng/mL, greater mL, about 800 nghr/mL, about 825 nghr/mL, about 850 30 than about 160 ng/mL, greater than about 170 ng/mL, greater nghr/mL, about 875 nghr/mL, about 900 nghr?mL, about than about 180 ng/mL, greater than about 190 ng/mL, greater 925 nghr/mL, about 950 nghr/mL, about 975 nghr/mL, or than about 200 ng/mL, greater than about 210 ng/mL, greater about 1000 nghr/mL after administration of the formulation than about 220 ng/mL, greater than about 230 ng/mL, greater to the patient. than about 240 ng/mL, greater than about 250 ng/mL, greater In some embodiments of the methods disclosed herein, an 35 than about 260 ng/mL, greater than about 270 ng/mL, greater inhalation formulation administered with an inhalation than about 280 ng/mL, greater than about 290 ng/mL, greater device, e.g., a high efficiency nebulizer, produces in a human than about 300 ng/mL, greater than about 310 ng/mL, greater subject group an average AUCo. of cromolyn sodium than about 320 ng/mL, greater than about 330 ng/mL, greater greater than about 100 nghr/mL, greater than about 110 than about 340 ng/mL, greater than about 350 ng/mL, greater nghr/mL, greater than about 120 nghr/mL, greater than 40 than about 360 ng/mL, greater than about 370 ng/mL, greater about 130 nghr/mL, greater than about 140 nghr/mL, than about 380 ng/mL, greater than about 390 ng/mL, or greater than about 150 nghr/mL, greater than about 160 greater than about 400 ng/mL after administration of the nghr/mL, greater than about 170 nghr/mL, greater than formulation to the patient. In some embodiments of the meth about 180 nghr/mL, greater than about 190 nghr/mL, ods disclosed herein, an inhalation formulation administered greater than about 200 nghr/mL, greater than about 225 45 with an inhalation device, e.g., a high efficiency nebulizer, nghr/mL, greater than about 250 nghr/mL, greater than produces in a human Subject group an average C. ofa mast about 275 nghr/mL, greater than about 300 nghr/mL, cell stabilizer of about 50 mg/mL, about 60 ng/mL, about 70 greater than about 325 nghr/mL, greater than about 350 ng/mL, about 80 ng/mL, 90 ng/mL, about 100 ng/mL, about nghr/mL, greater than about 375 nghr/mL, greater than 110 ng/mL, about 120 ng/mL, about 130 ng/mL, about 140 about 400 nghr/mL, greater than about 425 nghr/mL, 50 ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 greater than about 450 nghr/mL, greater than about 475 ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 nghr/mL, greater than about 500 nghr/mL, greater than ng/mL, about 210 ng/mL, about 220 ng/mL, about 230 about 525 nghr/mL, greater than about 550 nghr/mL, ng/mL, about 240 ng/mL, about 250 ng/mL, 260 ng/mL, greater than about 575 nghr/mL, greater than about 600 about 270 ng/mL, about 280 ng/mL, about 290 ng/mL, about nghr/mL, greater than about 625 nghr/mL, greater than 55 300 ng/mL, about 310 ng/mL, about 320 ng/mL, about 330 about 650 nghr/mL, greater than about 675 nghr/mL, ng/mL, about 340 ng/mL, about 350 ng/mL, about 360 greater than about 700 nghr/mL, greater than about 725 ng/mL, about 370 ng/mL, about 380 ng/mL, about 390 nghr/mL, greater than about 750 nghr/mL, greater than ng/mL, or about 400 ng/mL after administration of the for about 775 nghr/mL, greater than about 800 nghr/mL, mulation to the patient. greater than about 825 nghr/mL, greater than about 850 60 In some embodiments of the methods disclosed herein, an nghr/mL, greater than about 875 nghr/mL, greater than inhalation formulation administered with an inhalation about 900 nghr/mL, greater than about 925 nghr/mL, device, e.g., a high efficiency nebulizer, produces in a human greater than about 950 nghr/mL, greater than about 975 Subject group an average C of cromolyn sodium greater nghr/mL, or greater than about 1000 nghr/mL after admin than about 40 ng/mL, greater than about 50 ng/mL, greater istration of the formulation to the patient. In some embodi 65 than about 60 ng/mL, greater than about 70 ng/mL, greater ments of the methods disclosed herein, an inhalation formu than about 80 ng/mL, greater than about 90 ng/mL, greater lation administered with an inhalation device, e.g., a high than about 100 ng/mL, greater than about 110 ng/mL, greater US 9,265,749 B2 43 44 than about 120 ng/mL, greater than about 130 ng/mL, greater embodiments of the methods disclosed herein, an inhalation than about 140 ng/mL, greater than about 150 ng/mL, greater formulation administered with an inhalation device, e.g., a than about 160 ng/mL, greater than about 170 ng/mL, greater high efficiency nebulizer, produces in a human Subject group than about 180 ng/mL, greater than about 190 ng/mL, greater an average AUCo. of cromolyn sodium greater than about than about 200 ng/mL, greater than about 210 ng/mL, greater 120 nghr/mL and an average C of cromolyn Sodium than about 220 ng/mL, greater than about 230 ng/mL, greater greater than about 55 ng/mL. In some embodiments of the than about 240 ng/mL, greater than about 250 ng/mL, greater methods disclosed herein, an inhalation formulation admin than about 260 ng/mL, greater than about 270 ng/mL, greater istered with an inhalation device, e.g., a high efficiency nebu than about 280 ng/mL, greater than about 290 ng/mL, greater lizer, produces in a human subject group an average AUCo. than about 300 ng/mL, greater than about 310 ng/mL, greater 10 than about 320 ng/mL, greater than about 330 ng/mL, greater of cromolyn sodium greater than about 200 nghr/mL and an than about 340 ng/mL, greater than about 350 ng/mL, greater average C of cromolyn sodium greater than about 80 than about 360 ng/mL, greater than about 370 ng/mL, greater ng/mL. In some embodiments of the methods disclosed than about 380 ng/mL, greater than about 390 ng/mL, or herein, an inhalation formulation administered with an inha greater than about 400 ng/mL after administration of the 15 lation device, e.g., a high efficiency nebulizer, produces in a formulation to the patient. In some embodiments of the meth human subject group an average AUCo. of cromolyn ods disclosed herein, an inhalation formulation administered Sodium greater than about 330nghr/mL and an average C. with an inhalation device, e.g., a high efficiency nebulizer, of cromolyn Sodium greater than about 150 ng/mL. In some produces in a human Subject group an average C of cro embodiments, of the methods disclosed herein, an inhalation molyn sodium of about 50 mg/mL, about 60 ng/mL, about 70 formulation administered with an inhalation device, e.g., a ng/mL, about 80 ng/mL, 90 ng/mL, about 100 ng/mL, about high efficiency nebulizer, produces in a human Subject group 110 ng/mL, about 120 ng/mL, about 130 ng/mL, about 140 an average AUCo. of cromolyn sodium greater than about ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 525 nghr/mL and an average C of cromolyn Sodium ng/mL, about 180 ng/mL, about 190 ng/mL, about 200 greater than about 230 ng/mL. ng/mL, about 210 ng/mL, about 220 ng/mL, about 230 25 In some embodiments of the methods disclosed herein, an ng/mL, about 240 ng/mL, about 250 ng/mL, 260 ng/mL, inhalation formulation administered with an inhalation about 270 ng/mL, about 280 ng/mL, about 290 ng/mL, about device, e.g., a high efficiency nebulizer, produces in a human 300 ng/mL, about 310 ng/mL, about 320 ng/mL, about 330 subject group an average AUCo. of cromolyn sodium of ng/mL, about 340 ng/mL, about 350 ng/mL, about 360 about 200 nghr/mL and an average C of cromolyn ng/mL, about 370 ng/mL, about 380 ng/mL, about 390 30 ng/mL, or about 400 ng/mL after administration of the for sodium of about 80 ng/mL when a nominal dose of 40 mg of mulation to the patient. cromolyn sodium is administered with the inhalation device. In some embodiments of the methods disclosed herein, an In some embodiments of the methods disclosed herein, an inhalation formulation administered with an inhalation inhalation formulation administered with an inhalation device, e.g., a high efficiency nebulizer, produces in a human 35 device, e.g., a high efficiency nebulizer, produces in a human subject group an average AUCo. of a mast cell stabilizer subject group an average AUCo., of cromolyn sodium of greater than about 120 nghr/mL and/or an average C of about 330 nghr/mL and an average C of cromolyn the mast cell stabilizer greater than about 55 ng/mL. In some sodium of about 150 ng/mL when a nominal dose of 40 mg of embodiments of the methods disclosed herein, an inhalation cromolyn Sodium is administered with the inhalation device. formulation administered with an inhalation device, e.g., a 40 In some embodiments of the methods disclosed herein, an high efficiency nebulizer, produces in a human Subject group inhalation formulation administered with an inhalation an average AUCo. of a mast cell stabilizer greater than device, e.g., a high efficiency nebulizer, produces in a human about 120 nghr/mL and an average C of the mast cell subject group an average AUCo. of cromolyn sodium of stabilizergreater than about 55 ng/mL. In some embodiments about 525 nghr/mL and an average C of cromolyn of the methods disclosed herein, an inhalation formulation 45 sodium of about 230 ng/mL when a nominal dose of 80 mg of administered with an inhalation device, e.g., a high efficiency cromolyn Sodium is administered with the inhalation device. nebulizer, produces in a human Subject group an average In some embodiments of the methods disclosed herein, an AUCo. of a mast cell stabilizer greater than about 200 inhalation formulation administered with an inhalation nghr/mL and an average C of the mast cell stabilizer device, e.g., a high efficiency nebulizer, produces in a human greater than about 80 ng/mL. In some embodiments of the 50 subject group an average AUCo. of cromolyn sodium of methods disclosed herein, an inhalation formulation admin about 180 nghr/mL to about 220 nghr/mL and an average istered with an inhalation device, e.g., a high efficiency nebu C of cromolyn sodium of about 70 ng/mL to about 90 lizer, produces in a human subject group an average AUCo. ng/mL when a nominal dose of 40 mg of cromolyn Sodium is of a mast cell stabilizer greater than about 330 nghr/mL and administered with the inhalation device. In some embodi an average C of the mast cell stabilizer greater than about 55 ments of the methods disclosed herein, an inhalation formu 150 ng/mL. In some embodiments, of the methods disclosed lation administered with an inhalation device, e.g., a high herein, an inhalation formulation administered with an inha efficiency nebulizer, produces in a human Subject group an lation device, e.g., a high efficiency nebulizer, produces in a average AUCo. of cromolyn sodium of about 300 nghr? human subject group an average AUCo. of a mast cell mL to about 360 nghr/mL and an average C of cromolyn stabilizer greater than about 525 nghr/mL and an average 60 sodium of about 135 ng/mL to about 165 ng/mL when a C of the mast cell stabilizergreater than about 230 ng/mL. nominal dose of 40 mg of cromolyn Sodium is administered In some embodiments of the methods disclosed herein, an with the inhalation device. In some embodiments, of the inhalation formulation administered with an inhalation methods disclosed herein, an inhalation formulation admin device, e.g., a high efficiency nebulizer, produces in a human istered with an inhalation device, e.g., a high efficiency nebu subject group an average AUCo. of cromolyn sodium 65 lizer, produces in a human subject group an average AUCo. greater than about 120 nghr/mL and/or an average C of of cromolyn sodium of about 475 nghr/mL to about 575 cromolyn Sodium greater than about 55 ng/mL. In some nghr/mL and an average C of cromolyn Sodium of about US 9,265,749 B2 45 46 200 ng/mL to about 260 ng/mL when a nominal dose of 80 mg In some embodiments of the methods disclosed herein, an of cromolyn sodium is administered with the inhalation inhalation formulation administered with an inhalation device. device, e.g., a high efficiency nebulizer, provides cromolyn In some embodiments of the methods disclosed herein, an Sodium lung deposition (deposited lung dose) of greater than inhalation formulation administered with an inhalation 5 about 0.5 mg, greater than about 1 mg, greater than about 1.5 device, e.g., a high efficiency nebulizer, provides mast cell mg, greater than about 2 mg, greater than about 2.5 mg. stabilizer lung deposition (deposited lung dose) of at least greater than about 3 mg, greater than about 3.5 mg, greater about 15%, at least about 20%, at least about 25%, at least than about 4 mg., greater than about 5 mg, greater than about about 30%, at least about 35%, at least about 40%, at least 6 mg, greater than about 7 mg, greater than about 8 mg, about 45%, at least about 50%, at least about 55%, at least 10 greater than about 9 mg, greater than about 10 mg, greater about 60%, about 20% to about 40%, about 25% to about than about 11 mg, greater than about 12 mg, greater than 35%, about 25 to about 30%, about 25% to about 75%, about about 13 mg, greater than about 14 mg. or greater than about 30% to about 50%, about 35% to about 90%, about 40% to 15 mg. In some embodiments of the methods disclosed about 80%, about 40% to about 60%, about 50% to about herein, an inhalation formulation administered with an inha 60%, about 50% to about 70%, or about 60% to about 75% 15 lation device, e.g., a high efficiency nebulizer, provides cro based on the nominal dose of the mast cell stabilizer. In some molyn Sodium lung deposition (deposited lung dose) of about embodiments of the methods disclosed herein, an inhalation 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 formulation administered with an inhalation device, e.g., a mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg. high efficiency nebulizer, provides cromolyn Sodium deposi about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg. tion (deposited lung dose) of at least about 15%, at least about about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 20%, at least about 25%, at least about 30%, at least about 14 mg. or about 15 mg. 35%, at least about 40%, at least about 45%, at least about In some embodiments of the methods disclosed herein, an 50%, at least about 55%, at least about 60%, about 20% to inhalation formulation containing a mast cell stabilizer is about 40%, about 25% to about 35%, about 25 to about 30%, administered with an inhalation device, e.g., a high efficiency about 25% to about 75%, about 30% to about 50%, about 35% 25 nebulizer, at an administration of less than about 1 mg/dose, to about 90%, about 40% to about 80%, about 40% to about about 1 mg/dose to about 100 mg/dose, about 5 mg/dose to 60%, about 50% to about 60%, about 50% to about 70%, or about 80 mg/dose, about 20 mg/dose to about 60 mg/dose, about 60% to about 75% based on the nominal dose of the about 30 mg/dose to about 50 mg/dose, or greater than 100 cromolyn Sodium. mg/dose. In some embodiments of the methods disclosed In some embodiments of the methods disclosed herein, an 30 herein, an inhalation formulation containing cromolyn inhalation formulation administered with an inhalation Sodium is administered with an inhalation device, e.g., a high device, e.g., a high efficiency nebulizer, provides mast cell efficiency nebulizer, at an administration of less than about 1 stabilizer lung deposition (deposited lung dose) of about mg/dose, about 1 mg/dose to about 100 mg/dose, about 5 15%, about 20%, about 25%, about 30%, about 35%, about mg/dose to about 80 mg/dose, about 20 mg/dose to about 60 40%, about 45%, about 50%, about 55%, about 60%, about 35 mg/dose, about 30 mg/dose to about 50 mg/dose, or greater 65%, about 70%, about 75% about 80%, about 85%, about than 100 mg/dose. In some embodiments of the methods 90%, about 95%, or about 100% based on the nominal dose of disclosed herein, a mast cell stabilizer is administered in an the mast cell stabilizer. In some embodiments of the methods inhalation formulation with an inhalation device, e.g., a high disclosed herein, an inhalation formulation administered with efficiency nebulizer, in about 1 mg, about 5 mg, about 10 mg. an inhalation device, e.g., a high efficiency nebulizer, pro 40 about 15 mg, about 20 mg, about 25 mg, about 30 mg, about vides cromolyn Sodium lung deposition (deposited lung dose) 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg. of about 15%, about 20%, about 25%, about 30%, about 35%, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about about 40%, about 45%, about 50%, about 55%, about 60%, 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg. about 65%, about 70%, about 75% about 80%, about 85%, about 105 mg, about 110 mg, about 115 mg, about 120 mg. about 90%, about 95%, or about 100% based on the nominal 45 about 125 mg, about 130 mg doses, about 135 mg, about 140 dose of the cromolyn Sodium. mg, about 145 mg, about 150 mg, about 200 mg, about 250 In some embodiments of the methods disclosed herein, an mg, about 300 mg, about 350 mg, about 400 mg, about 450 inhalation formulation administered with an inhalation mg, about 500 mg, about 550 mg, about 600 mg, about 650 device, e.g., a high efficiency nebulizer, provides mast cell mg, about 700 mg, about 750 mg, about 800 mg, about 850 stabilizer lung deposition (deposited lung dose) of greater 50 mg, about 900 mg, about 950 mg. or about 1000 mg doses. In than about 0.5 mg, greater than about 1 mg, greater than about some embodiments of the methods disclosed herein, cro 1.5 mg, greater than about 2 mg, greater than about 2.5 mg. molyn Sodium is administered in an inhalation formulation greater than about 3 mg, greater than about 3.5 mg, greater with an inhalation device, e.g., a high efficiency nebulizer, in than about 4 mg., greater than about 5 mg, greater than about about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 6 mg, greater than about 7 mg, greater than about 8 mg, 55 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg. greater than about 9 mg, greater than about 10 mg, greater about 45 mg, about 50 mg, about 55 mg, about 60 mg, about than about 11 mg, greater than about 12 mg, greater than 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg. about 13 mg, greater than about 14 mg. or greater than about about 90 mg, about 95 mg, about 100 mg, about 105 mg. 15 mg. In some embodiments of the methods disclosed about 110 mg, about 115 mg, about 120 mg, about 125 mg. herein, an inhalation formulation administered with an inha 60 about 130 mg doses, about 135 mg, about 140 mg, about 145 lation device, e.g., a high efficiency nebulizer, provides mast mg, about 150 mg, about 200 mg, about 250 mg, about 300 cell Stabilizer lung deposition (deposited lung dose) of about mg, about 350 mg, about 400 mg, about 450 mg, about 500 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 3.0 mg, about 3.5 mg, about 4.0 mg, about 5.0 mg. mg, about 750 mg, about 800 mg, about 850 mg, about 900 about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg. 65 mg, about 950 mg. or about 1000 mg doses. about 10 mg, about 11 mg, about 12 mg, about 13 mg, about In some embodiments of the methods disclosed herein, an 14 mg. or about 15 mg. inhalation formulation administered with an inhalation US 9,265,749 B2 47 48 device, e.g., a high efficiency nebulizer provides a bioavail and produces in a human subject group an average AUCo. ability of a mast cell stabilizer of greater than about 5%, of the mast cell stabilizer greater than about 330 nghr/mL greater than about 6%, greater than about 7%, greater than and an average C of the mast cell stabilizer greater than about 8%, greater than about 9%, greater than about 10%, about 150 ng/mL. In some embodiments, of the methods greater than about 11%, greater than about 12%, greater than disclosed herein, an inhalation formulation administered with about 13%, greater than about 14%, greater than about 15%, an inhalation device, e.g., a high efficiency nebulizer, pro greater than about 16%, greater than about 17%, greater than vides a bioavailability of a mast cell stabilizer greater than about 18%, greater than about 19%, greater than about 20%, about 5% and produces in a human Subject group an average greater than about 25%, greater than about 30%, greater than AUCo., of the mast cell stabilizer greater than about 525 about 35%, greater than about 40%, greater than about 45%, 10 nghr/mL and an average C of the mast cell Stabilizer greater than about 50%, greater than about 55%, or greater greater than about 230 ng/mL. than about 60% of the nominal dose. In some embodiments, In some embodiments of the methods disclosed herein, an an inhalation formulation administered with an inhalation inhalation formulation administered with an inhalation device, e.g., a high efficiency nebulizer, in the methods dis device, e.g., a high efficiency nebulizer, provides a bioavail closed herein provides a bioavailability of a mast cell stabi 15 ability of cromolyn sodium greater than about 5% and pro lizer of about 5%, about 6%, about 7%, about 8%, about 9%, duces in a human subject group an average AUCo. of cro about 10%, about 11%, about 12%, about 13%, about 14%, molyn Sodium greater than about 120 nghr/mL and/or an about 15%, about 16%, about 17%, about 18%, about 19%, average C of cromolyn Sodium greater than about 55 about 20%, about 25%, about 30%, about 35%, about 40%, ng/mL. In some embodiments of the methods disclosed about 45%, about 50%, about 55%, or about 60% of the herein, an inhalation formulation administered with an inha nominal dose. lation device, e.g., a high efficiency nebulizer, provides a In some embodiments of the methods disclosed herein, an bioavailability of cromolyn sodium greater than about 5% inhalation formulation administered with an inhalation and produces in a human subject group an average AUCo., device, e.g., a high efficiency nebulizer provides a bioavail of cromolyn Sodium greater than about 120 nghr/mL and an ability of cromolyn sodium of greater than about 5%, greater 25 average C of cromolyn Sodium greater than about 55 than about 6%, greater than about 7%, greater than about 8%, ng/mL. In some embodiments of the methods disclosed greater than about 9%, greater than about 10%, greater than herein, an inhalation formulation administered with an inha about 11%, greater than about 12%, greater than about 13%, lation device, e.g., a high efficiency nebulizer, provides a greater than about 14%, greater than about 15%, greater than bioavailability of cromolyn sodium greater than about 5% about 16%, greater than about 17%, greater than about 18%, 30 and produces in a human subject group an average AUCo., greater than about 19%, greater than about 20%, greater than of cromolyn sodium greater than about 200 nghr/mL and an about 25%, greater than about 30%, greater than about 35%, average C of cromolyn sodium greater than about 80 greater than about 40%, greater than about 45%, or greater ng/mL. In some embodiments of the methods disclosed than about 50% of the nominal dose. In some embodiments, herein, an inhalation formulation administered with an inha an aqueous inhalation formulation administered with an inha 35 lation device, e.g., a high efficiency nebulizer, provides a lation device, e.g., a high efficiency nebulizer, in the methods bioavailability of cromolyn sodium greater than about 5% disclosed herein provides a bioavailability of cromolyn and produces in a human subject group an average AUCo. sodium of about 5%, about 6%, about 7%, about 8%, about of cromolyn sodium greater than about 330 nghr/mL and an 9%, about 10%, about 11%, about 12%, about 13%, about average C of cromolyn Sodium greater than about 150 14%, about 15%, about 16%, about 17%, about 18%, about 40 ng/mL. In some embodiments, of the methods disclosed 19%, about 20%, about 25%, about 30%, about 35%, about herein, an inhalation formulation administered with an inha 40%, about 45%, or about 50% of the nominal dose. lation device, e.g., a high efficiency nebulizer, provides a In some embodiments of the methods disclosed herein, an bioavailability of cromolyn sodium greater than about 5% inhalation formulation administered with an inhalation and produces in a human subject group an average AUCo. device, e.g., a high efficiency nebulizer, provides a bioavail 45 of cromolyn sodium greater than about 525 nghr/mL and an ability of a mast cell stabilizer greater than about 5% and average C of cromolyn Sodium greater than about 230 produces in a human subject group an average AUCo., of the ng/mL. mast cell stabilizer greater than about 120 nghr/mL and/or In some embodiments of the methods disclosed herein, an an average C of the mast cell stabilizer greater than about inhalation formulation administered with an inhalation 55 ng/mL. In some embodiments of the methods disclosed 50 device, e.g., a high efficiency nebulizer, provides a bioavail herein, an inhalation formulation administered with an inha ability of a mast cell stabilizer greater than about 5% and lation device, e.g., a high efficiency nebulizer, provides a produces in a human subject group an average AUCo. of a bioavailability of a mast cell stabilizer greater than about 5% mast cell stabilizer greater than about 120 nghr/mL. In some and produces in a human subject group an average AUCo. embodiments of the methods disclosed herein, an inhalation of the mast cell stabilizer greater than about 120 nghr/mL 55 formulation administered with an inhalation device, e.g., a and an average C of the mast cell stabilizer greater than high efficiency nebulizer, provides a bioavailability of a mast about 55 ng/mL. In some embodiments of the methods dis cell stabilizer greater than about 5% and produces in a human closed herein, an inhalation formulation administered with an subject group an average AUCo. of a mast cell stabilizer inhalation device, e.g., a high efficiency nebulizer, provides a greater than about 200 nghr/mL. In some embodiments of bioavailability of a mast cell stabilizer greater than about 5% 60 the methods disclosed herein, an inhalation formulation and produces in a human subject group an average AUCo. administered with an inhalation device, e.g., a high efficiency of the mast cell stabilizer greater than about 200 nghr/mL nebulizer, provides a bioavailability of a mast cell stabilizer and an average C of the mast cell stabilizer greater than greater than about 5% and produces in a human Subject group about 80 ng/mL. In some embodiments of the methods dis an average AUCo. of a mast cell stabilizer greater than closed herein, an inhalation formulation administered with an 65 about 330 nghr/mL. In some embodiments of the methods inhalation device, e.g., a high efficiency nebulizer, provides a disclosed herein, an inhalation formulation administered with bioavailability of a mast cell stabilizer greater than about 5% an inhalation device, e.g., a high efficiency nebulizer, pro US 9,265,749 B2 49 50 vides a bioavailability of a mast cell stabilizer greater than about 40% and produces in a human Subject group an average about 5% and produces in a human Subject group an average AUCo., of a mast cell stabilizer greater than about 525 AUCo. of a mast cell stabilizer greater than about 525 nghr/mL. nghr/mL. In some embodiments of the methods disclosed herein, an In some embodiments of the methods disclosed herein, an 5 inhalation formulation administered with an inhalation inhalation formulation administered with an inhalation device, e.g., a high efficiency nebulizer, has an RF (s3.3 um) device, e.g., a high efficiency nebulizer, provides a bioavail of at least about 30% and produces in a human Subject group ability of cromolyn sodium greater than about 5% and pro an average AUCo. of cromolyn sodium greater than about duces in a human subject group an average AUCo. of cro 120 nghr/mL. In some embodiments of the methods dis molyn Sodium greater than about 120 nghr/mL. In some 10 closed herein, an inhalation formulation administered with an embodiments of the methods disclosed herein, an inhalation inhalation device, e.g., a high efficiency nebulizer, has an RF formulation administered with an inhalation device, e.g., a (s3.3 um) of at least about 30% and produces in a human high efficiency nebulizer, provides a bioavailability of cro subject group an average AUCo. of cromolyn Sodium molyn Sodium greater than about 5% and produces in a greater than about 200 nghr/mL. In some embodiments of human subject group an average AUCo. of cromolyn 15 the methods disclosed herein, an inhalation formulation sodium greater than about 200 nghr/mL. In some embodi administered with an inhalation device, e.g., a high efficiency ments of the methods disclosed herein, an inhalation formu nebulizer, has an RF (s3.3 um) of at least about 40% and lation administered with an inhalation device, e.g., a high produces in a human subject group an average AUCo. of efficiency nebulizer, provides a bioavailability of cromolyn cromolyn sodium greater than about 330 nghr/mL. In some Sodium greater than about 5% and produces in a human embodiments, of the methods disclosed herein, an inhalation subject group an average AUCo. of cromolyn sodium formulation administered with an inhalation device, e.g., a greater than about 330 nghr?mL. In some embodiments, of high efficiency nebulizer, has an RF (s3.3 um) of at least the methods disclosed herein, an inhalation formulation about 40% and produces in a human Subject group an average administered with an inhalation device, e.g., a high efficiency AUCo. of cromolyn Sodium greater than about 525 ng*hr/ nebulizer, provides a bioavailability of cromolyn sodium 25 mL. greater than about 5% and produces in a human Subject group In some embodiments of the methods disclosed herein, an an average AUCo. of cromolyn Sodium greater than about inhalation formulation comprising 40 mg cromolyn Sodium 525 nghr/mL. administered with an inhalation device, e.g., a high efficiency In some embodiments of the methods disclosed herein, an nebulizer, has an RF (s3.3 um) of at least about 30% and inhalation formulation comprising 40 mg cromolyn Sodium 30 produces in a human subject group an average AUCo. of administered with an inhalation device, e.g., a high efficiency cromolyn sodium greater than about 200 nghr/mL. In some nebulizer, provides a bioavailability of cromolyn sodium embodiments of the methods disclosed herein, an inhalation greater than about 5% and produces in a human Subject group formulation comprising 40 mg cromolyn Sodium adminis an average AUCo. of cromolyn Sodium greater than about tered with an inhalation device, e.g., a high efficiency nebu 200 nghr/mL. In some embodiments of the methods dis 35 lizer, has an RF (s3.3 m) of at least about 40% and produces closed herein, an inhalation formulation comprising 40 mg in a human subject group an average AUCo. of cromolyn cromolyn Sodium administered with an inhalation device, sodium greater than about 330 nghr/mL. In some embodi e.g., a high efficiency nebulizer, provides a bioavailability of ments of the methods disclosed herein, an inhalation formu cromolyn Sodium greater than about 5% and produces in a lation comprising 80 mg cromolyn Sodium administered with human subject group an average AUCo. of cromolyn 40 an inhalation device, e.g., a high efficiency nebulizer, has an sodium greater than about 330 nghr/mL. In some embodi RF (s3.3 m) of at least about 40% and produces in a human ments, of the methods disclosed herein, an inhalation formu subject group an average AUCo. of cromolyn sodium lation comprising 80 mg cromolyn Sodium administered with greater than about 525 nghr/mL. an inhalation device, e.g., a high efficiency nebulizer, pro In some embodiments of the methods disclosed herein, an vides a bioavailability of cromolyn sodium greater than about 45 inhalation formulation administered with an inhalation 5% and produces in a human Subject group an average device, e.g., a high efficiency nebulizer, produces in a human AUCo. of cromolyn sodium greater than about 525 ng*hr/ subject group an average AUCo., of cromolyn sodium of mL. about 8.5 nghr/mL and an average C of cromolyn Sodium In some embodiments of the methods disclosed herein, an of about 3.9 ng/mL per mg of cromolyn Sodium administered inhalation formulation administered with an inhalation 50 with the inhalation device. In some embodiments of the meth device, e.g., a high efficiency nebulizer, has an RF (s3.3 um) ods disclosed herein, an inhalation formulation administered of at least about 30% and produces in a human Subject group with an inhalation device, e.g., a high efficiency nebulizer, an average AUCo. of a mast cell stabilizer greater than produces in a human subject group an average AUCo. of about 120 nghr/mL. In some embodiments of the methods cromolyn Sodium of about 6.6 nghr/mL and an average C. disclosed herein, an inhalation formulation administered with 55 of cromolyn Sodium of about about 3.0 ng/mL per mg of an inhalation device, e.g., a high efficiency nebulizer, has an cromolyn sodium administered with the inhalation device. In RF (s3.3 um) of at least about 30% and produces in a human Some embodiments of the methods disclosed herein, an inha subject group an average AUCo. of a mast cell stabilizer lation formulation administered with an inhalation device, greater than about 200 nghr/mL. In some embodiments of e.g., a high efficiency nebulizer, produces in a human Subject the methods disclosed herein, an inhalation formulation 60 group an average AUCo. of cromolyn Sodium of about 5.3 administered with an inhalation device, e.g., a high efficiency nghr/mL and an average C of cromolyn sodium of about nebulizer, has an RF (s3.3 um) of at least about 40% and 2.2 ng/mL per mg of cromolyn Sodium administered with the produces in a human subject group an average AUCo. of a inhalation device. In some embodiments of the methods dis mast cell stabilizer greater than about 330 nghr/mL. In some closed herein, an inhalation formulation administered with an embodiments, of the methods disclosed herein, an inhalation 65 inhalation device, e.g., a high efficiency nebulizer, produces formulation administered with an inhalation device, e.g., a in a human subject group an average AUCo. of cromolyn high efficiency nebulizer, has an RF (s3.3 um) of at least sodium of from about 5.3 nghr?mL to about 8.5 nghr/mL US 9,265,749 B2 51 52 and an average C of cromolyn Sodium of about 2.2 ng/mL the methods disclosed herein, an inhalation formulation con to about 3.9 ng/mL per mg of cromolyn Sodium administered taining cromolyn Sodium is administered with an inhalation with the inhalation device when the nominal dose of cro device, e.g., a high efficiency nebulizer, wherein the concen molyn Sodium administered is in the range of about 40 mg to tration of the cromolyn sodium is from about 1% by weight to about 80 mg. about 10% by weight, from about 2% by weight to about 8% In some embodiments of the methods disclosed herein, an by weight, from about 2% by weight to about 6% by weight, inhalation formulation containing a mast cell Stabilizer Such or from about 3% by weight to about 5% by weight. In some as cromolyn Sodium is administered with an inhalation embodiments of the methods disclosed herein, an inhalation device, e.g., a high efficiency nebulizer, at a fill Volume of less formulation containing cromolyn Sodium is administered than about 0.25 mL, less than about 0.5 mL, at least about 0.5 10 mL to about 1.5 mL, at least about 0.5 mL to about 1.8 mL, at with an inhalation device, e.g., a high efficiency nebulizer, least about 1.5 mL, or at least about 2.0 mL. In some embodi wherein the concentration of the cromolyn Sodium is about ments, an inhalation formulation is administered with an 1% by weight, about 2% by weight, about 3% by weight, inhalation device, e.g., a high efficiency nebulizer, at a fill about 4% by weight, about 5% by weight, about 6% by Volume about 0.1 mL to about 5.0 mL, about 0.25 mL to about 15 weight, about 7% by weight, about 8% by weight, about 9% 2.0 mL, about 0.5 mL to about 1.8 mL, about 0.5 mL to about by weight, or about 10% by weight. 2 mL, about 0.5 mL to about 1.5 mL, about 0.5 mL to about In some embodiments, an inhalation formulation contain 1.0 mL, about 0.5 mL or less, about 1 mL or less, about 1.5 mL ing a mast cell stabilizer is administered with an inhalation or less, about 2.0 mL or less, about 2.5 mL or less, about 3.0 device, e.g., a high efficiency nebulizer, in about 0.25 to about mL or less, about 3.5 mL or less, about 4.0 mL or less, about 10 minutes, about 0.50 to about 8 minutes, less than about 8 4.5 mL or less, or about 5.0 mL or less. In some embodiments, minutes, less than about 7 minutes, less than about 6 minutes, an inhalation formulation is administered with an inhalation less than about 5 minutes, less than about 4 minutes, less than device, e.g., a high efficiency nebulizer, at a fill Volume of about 3 minutes, less than about 2 minutes, less than about 1.8 about 0.5 mL, about 1.0 mL, about 1.5 mL, about 1.8 mL, minutes, less than about 1.5 minutes, or less than 1 minute. In about 2.0 mL, about 2.5 mL, about 3.0 mL, about 3.5 mL, 25 Some embodiments, the inhalation formulation is adminis about 4.0 mL, about 4.5 mL, or about 5.0 mL. In some tered in about 3 minutes or less. In some embodiments, the embodiments, an inhalation formulation is administered with inhalation formulation is administered in about 1 minute, an inhalation device, e.g., a high efficiency nebulizer, which about 2 minutes, about 3 minutes, about 4 minutes, about 5 provides for a residual volume of mast cell stabilizer after minutes, about 6 minutes, about 7 minutes, about 8 minutes, administration of the mast cell stabilizer of less than about 30 about 9 minutes, or about 10 minutes. 10%, less than about 5%, or less than about 3% of the nominal In some embodiments of the methods disclosed herein, dose. administration of a mast cell stabilizer with a high efficiency In some embodiments of the methods disclosed herein, an nebulizer provides at least about a 1.5-fold, at least about a inhalation formulation containing a mast cell stabilizer is 1.8-fold, at least about a two-fold, at least about a three-fold, administered with an inhalation device, e.g., a high efficiency 35 at least about a four-fold, or at least about a five-fold increase nebulizer, wherein the concentration of the mast cell stabi in one or more of AUCAUCo., or C, as compared to lizer is greater than about 1% by weight, greater than about the same or lower nominal dose of the mast cell stabilizer 2% by weight, greater than about 3% by weight, greater than administered with a conventional inhalation device oran oral about 4% by weight, greater than about 5% by weight, greater formulation, e.g., a liquid oral formulation, tablet, or capsule. than about 6% by weight, greater than about 7% by weight, 40 In some embodiments of the methods disclosed herein, greater than about 8% by weight, greater than about 9% by inhalation formulations administered with a high efficiency weight, or greater than about 10% by weight. In some nebulizer are substantially free of a preservative, such as embodiments of the methods disclosed herein, an inhalation benzyl alcohol. In some embodiments of the methods dis formulation containing a mast cell stabilizer is administered closed herein, inhalation formulations administered with a with an inhalation device, e.g., a high efficiency nebulizer, 45 high efficiency nebulizer further comprise at least one excipi wherein the concentration of the mast cell stabilizer is from ent. In some embodiments, the excipient is selected from the about 1% by weight to about 10% by weight, from about 2% group consisting of stabilizers and antioxidants (such as citric by weight to about 8% by weight, from about 2% by weight to acid, ascorbic acid, ethylenediamine tetra acetic acid about 6% by weight, or from about 3% by weight to about 5% (EDTA), sodium metabisulfite, or a salt of any thereof), an by weight. In some embodiments of the methods disclosed 50 osmolarity adjusting agent (such as sodium chloride, manni herein, an inhalation formulation containing a mast cell sta tol, or sorbitol), a surfactant (such as polysorbate 80, vitamin bilizer is administered with an inhalation device, e.g., a high E, tocopherol polyethylene glycol, and Tyloxapol), or a pH efficiency nebulizer, wherein the concentration of the mast buffer. cell stabilizer is about 1% by weight, about 2% by weight, In some embodiments of the methods disclosed herein, about 3% by weight, about 4% by weight, about 5% by 55 inhalation formulations administered with an inhalation weight, about 6% by weight, about 7% by weight, about 8% device, e.g., a high efficiency nebulizer, are hypotonic. In by weight, about 9% by weight, or about 10% by weight. some embodiments of the methods disclosed herein, inhala In some embodiments of the methods disclosed herein, an tion formulations administered with an inhalation device, inhalation formulation containing cromolyn Sodium is e.g., a high efficiency nebulizer, are Sub-isotonic. In some administered with an inhalation device, e.g., a high efficiency 60 embodiments of the methods disclosed herein, inhalation for nebulizer, wherein the concentration of the cromolyn sodium mulations administered with an inhalation device, e.g., a high is greater than about 1% by weight, greater than about 2% by efficiency nebulizer, have an osmolality greater than about 70 weight, greater than about 3% by weight, greater than about mOsm/kg. In some embodiments of the methods disclosed 4% by weight, greater than about 5% by weight, greater than herein, inhalation formulations administered with an inhala about 6% by weight, greater than about 7% by weight, greater 65 tion device, e.g., high efficiency nebulizer, have an osmolality than about 8% by weight, greater than about 9% by weight, or of at least about 100 mOsm/kg. In some embodiments of the greater than about 10% by weight. In some embodiments of methods disclosed herein, inhalation formulations adminis US 9,265,749 B2 53 54 tered with an inhalation device, e.g., high efficiency nebu prising a mast cell stabilizer, e.g., cromolyn Sodium, is lizer, have an osmolality of at least about 150 mOsm/kg. co-administered in a liquid oral formulation to treat a sys Combination Therapies temic mast cell related disorder. In some embodiments, a In some embodiments of the methods disclosed herein, one composition comprising a mast cell stabilizer, e.g., cromolyn or more different formulations of mast cell stabilizers are 5 sodium, is administered with a jet nebulizer and a different co-administered by different routes of administration to pro composition comprising a mast cell stabilizer, e.g., cromolyn vide systemically effective amounts of the mast cell stabiliz Sodium, is co-administered in a solid oral formulation, e.g., a ers. For example, in some embodiments, a composition com tablet or capsule, to treat a systemic mast cell related disorder. prising a mast cell stabilizer, e.g., cromolyn Sodium, is administered with a dry powder inhaler and a different com 10 EXAMPLES position comprising a mast cell stabilizer, e.g., cromolyn Sodium, is co-administered in a liquid oral formulation to The examples below describe some embodiments of the treat a systemic mast cell related disorder. In some embodi methods described herein. Methods and materials that are not ments, a composition comprising a mast cell Stabilizer, e.g., specifically described in the following examples are within cromolyn Sodium, is administered with a dry powder inhaler 15 the scope of the invention and will be apparent to those skilled and a different composition comprising a mast cell stabilizer, in the art with reference to the disclosure herein. e.g., cromolyn Sodium, is co-administered in a solid oral formulation, e.g., a capsule or tablet, to treat a systemic mast Example 1 cell related disorder. In some embodiments, a composition comprising a mast cell stabilizer, e.g., cromolyn Sodium, is 2O Formulations administered with a metered dose inhaler and a different composition comprising a mast cell stabilizer, e.g., cromolyn The formulations described in Table 1 are prepared as Sodium, is co-administered in a liquid oral formulation to follows: The composition ingredients are added sequentially treat a systemic mast cell related disorder. In some embodi to a glass beaker with a magnet stirrer and about 90 g of ments, a composition comprising a mast cell Stabilizer, e.g., 25 purified water in the order listed in Table 1, ensuring that each cromolyn Sodium, is administered with a metered dose ingredient is dissolved before the next is added. The weight is inhaler and a different composition comprising a mast cell then adjusted to 100.0 g by adding additional purified water. stabilizer, e.g., cromolyn Sodium, is co-administered in a The resulting solutions are then sterilized by filtration Solid oral formulation, e.g., a tablet or capsule, to treat a through 0.2-0.22 um sterile filters, and 0.5 to 5 mL aliquots systemic mast cell related disorder. In some embodiments, a 30 are added to pre-sterilized glass or sterile polyethylene or composition comprising a mast cell stabilizer, e.g., cromolyn polypropylene blow fill and seal vials by a standard blow fill sodium, is administered with a dry powder inhaler and a and seal procedure. Alternative sterilization methods may be different composition comprising a mast cell stabilizer, e.g., applied using heat sterilization in an autoclave. TABLE 1.

Formulation No. 1 2 3 4 5 6 7 8 9 10 11 12 13 Cromolyn Sodium 2.0 3.0 4.0 4.0 4.O 4.0 4.0 SO 6.0 3.0 3.0 3.0 3.0 (DSCG) (wt %) NaCl (wt %) 0.7 0.5 O3 0.25 O2 O2 O2 (0.15 0.1 O2 (0.3 0.4 OS Mannitol (wt %) 0.4 O.8 1.O. 11 12 1.25 1.25 14 15 EDTA-Na (wt %) O.O1 O.O2 O.O3 O.O1 O.O2 O.O3 O.O2 O.O3 0.04 OO1 O.O2 O.O3 0.04 Hyaluronic acid (wt %) O2S O.S 1.0 O.25 O.S 1.0 Propylene glycol (wt %) 1.O 2.0 3.0 4.0 Purified Water (wt %) 96.9 95.7 944 94.1 93.6 94.5 94.5 93.4 92.4 95.8 94.4 93.1 91.5 cromolyn Sodium, is co-administered with a metered dose Example 2 inhaler to treat a systemic mast cell related disorder. In some embodiments, a composition comprising a mast cell stabi lizer, e.g., cromolyn Sodium, is administered with a dry pow 50 Characterization of Aerosols Produced with a High der inhaler and a different composition comprising a mast cell Efficiency Nebulizer stabilizer, e.g., cromolyn Sodium, is co-administered with a metered dose inhaler to treat a systemic mast cell related disorder. In some embodiments, a composition comprising a The MMAD, GSD, DD, and RF of a representative inhaled mast cell stabilizer, e.g., cromolyn Sodium, is administered 55 cromolyn sodium formulation (PA-101) delivered via a high with a high efficiency nebulizer and a different composition efficiency nebulizer (eFlow(R), PARI, 30L) were determined comprising a mast cell stabilizer, e.g., cromolyn Sodium, is as described in USP<1601->. The values determined were: co-administered in a liquid oral formulation to treat a sys MMAD=3.5 um; GSD=1.7; DD=68%; RF (<5 um)=75%: temic mast cell related disorder. In some embodiments, a and RF (s3.3 um)=44%. composition comprising a mast cell stabilizer, e.g., cromolyn 60 Sodium, is administered with a high efficiency nebulizer and The MMAD, GSD, and RF of a representative inhaled a different composition comprising a mast cell stabilizer, e.g., cromolyn Sodium, is co-administered in a solid oral formula cromolyn sodium formulation (PA-101) delivered via a high tion, e.g., a tablet or capsule, to treat a systemic mast cell efficiency nebulizer (eFlow(R), PARI, 40L) were determined as described in USP<1601->. The values determined were: related disorder. In some embodiments, a composition com 65 prising a mast cell stabilizer, e.g., cromolyn Sodium, is admin MMAD=4.1 um; GSD=1.7: RF (s.5um)=66%; and RF (s3.3 istered with a jet nebulizer and a different composition com um)-36%. US 9,265,749 B2 55 56 Example 3 the clinic in the morning for baseline (pre-dose) assessments. Subjects were required to remain in the clinic for 12 h after Single-Dose, Dose Escalation Study study drug administration on each dosing day. Treatment Visits were separated by a washout period of 2 to 5 days. Objectives: In Part 2, all study subjects received each study treatment The objectives of the study are as follows: three times daily (TID) (at 08:00am, 14:00 Lum and 20:00 um, Primary: +/-30 minutes) as a single day treatment. Prior to each dosing Part 1: To determine the systemic availability and pharma day, Subjects were admitted to the clinic in the morning for cokinetic (PK) profile of single doses of a representative baseline (pre-dose) assessments. Subjects were required to inhaled cromolyn sodium formulation (PA-101) delivered via 10 remain in the clinic for 24h after study drug administration on a high efficiency nebulizer (eFlow(R), PARI) using two differ each dosing day. ent aerosol membranes (30L and 40L) in comparison with The main delivery device for administering PA-101 was marketed formulations of cromolyn Sodium (oral Solution the open system eFlow nebulizer using the 30L aerosol head, and an inhalation aerosol) in healthy Subjects. which generates aerosol particles with a median size of about Part 2: To assess the pharmacokinetic profile of PA-101 15 3.0 The 40L aerosol head (generating aerosol particles with a administered as single day three times daily dosing via a high median size of about 4.0 um) was tested as a comparator arm efficiency nebulizer (eFlow(R), PARI) in comparison with in Part 1 only. marketed formulations of cromolyn Sodium (oral Solution Duration of Study: and inhalation aerosol) administered as single day TID dos The duration of both Parts 1 and 2 of the study was one day. ing in patients with systemic mastocytosis. Criteria for Evaluation: Secondary: Pharmacokinetic measurements: The PK parameters To assess the safety and tolerability of PA-101 in compari evaluated for plasma cromolyn sodium (DSCG) were maxi son with marketed formulations of cromolyn Sodium (oral mum concentration (C), time to maximum concentration Solution and an inhalation aerosol). (T), terminal elimination half-life (T2), area under the Methodology: 25 plasma concentration-time curve from time–0 to time of last This was a Phase 1, randomized, open-label, single-centre, measurable drug concentration (AUC), and area under the dose-ranging, cross-over study conducted in two parts in total plasma concentration-time curve from time-0 to infinity of 18 subjects. Part 1 was conducted in total of 12 healthy (AUC). Urine DSCG levels were measured for total DSCG adult subjects of 18-45 years of age. Part 2 was conducted in excretion in the urine, and the bioavailability of the DSCG a total of 5 adult patients of 18–45 years of age with systemic 30 was calculated from the measured levels. mastocytosis. Parts 1 and 2 were conducted in parallel. Safety measurements: Adverse events including gas Study Treatments, Dose and Mode of Administration: trointestinal disturbance (e.g., abdominal pain, nausea, vom Part 1: iting), changes in vital signs, 12-lead ECG and clinical labo 1.40 mg. PA-101 (4% DSCG, 40 mg/1 mL), oral inhalation ratory tests (hematology, chemistry and urinalysis). via eFlow 3OL. 35 Statistical Measurements: 2.80 mg. PA-101 (4% DSCG, 80 mg/2 mL), oral inhalation Pharmacokinetic parameters and plasma concentrations via eFlow 3OL. are listed and Summarized. The Summary statistics are pre 3.40 mg. PA-101 (4% DSCG, 40 mg/1 mL), oral inhalation sented as the geometric mean, arithmetic mean, arithmetic via eFlow 40L. standard deviation (SD), min, median, max and n. The geo 4. 20 mg cromolyn sodium inhalation aerosol (1% DSCG, 40 metric statistics are not presented for T. Analysis of vari 20 mg/2 mL) (commercially available product), oral ance (ANOVA) including terms for subject and treatment are inhalation via LC Plus. used to calculate point estimates, and confidence intervals 5. 200 mg oral Sodium cromoglycate solution (commer (CI) for treatment differences with respect to PK parameters cially available product), oral administration. (90% CI) are calculated. Part 2: 45 The incidence of AES was compared between treatment 1. 40 mg. PA-101 (4% DSCG 40 mg/1 mL), oral inhalation groups. Summary tables and individual Subject listings are via eFlow 3OL provided for all safety measurements and the results are pre 2. 200 mg oral Sodium cromoglycate solution (commer sented by treatment group. Descriptive statistics are used to cially available product), oral administration. Summarise data where appropriate. In Part 1, all study subjects received each study treatment in 50 Results: the morning (at 8:00 am, +/-30 minutes) as a single dose The pharmacokinetic parameters measured in the single treatment. Prior to each dosing day, Subjects were admitted to dose study (Part 1) are shown in the following table: TABLE 2

Ratio Ratio (PA-101 (PA-101 Oral Inhalation PA-101 PA-101 PA-101 (3OL: 40 mg)). (30L.; 40 mg). Solution, aerosol, (40L), (3OL), (30L), (oral solution (inhalation aerosol PK parameter 200 mg 20 mg 40 mg 40 mg 80 mg (200 mg)) (20 mg)) C. (ng/mL) 5.2 (+3.1) 17.8 (+10.4) 88.6 (45.5) 156 (+104) 236 (+124) x30 x8.8 Tmax (h) 3.2 (+2.1) 0.6 (+0.1) 0.6 (+0.1) O.7 (+0.1) O.7 (+0.1) AUCo. 29.4 (+10.4) 39.1 (+15.1) 206 (94.3) 329 (+144) 514 (+186) X11 x8.4 (hing/mL) AUCo.) 33.3 (+11.7) 40.6 (+15.6) 212 (+96.0) 338 (+146) 526 (+198) (hing/mL) US 9,265,749 B2 58 TABLE 2-continued

Ratio Ratio (PA-101 (PA-101 Oral Inhalation PA-101 PA-101 PA-101 (30L.; 40 mg)), (30L.; 40 mg) Solution, aerosol, (40L), (30L), (30L), (oral Solution (inhalation aerosol PK parameter 200 mg 20 mg 40 mg 40 mg 80 mg (200 mg)) (20 mg)) T12 (h) 4.3 (+1.3) 2.5 (+0.8) 2.5 (+0.7) 2.2 (+0.6) 2.1 (+0.5) Bioavailability (%) O6 6.5 16.3 2SO 22.7 X42 X3.8 Values shown in parentheses are (+SD).

Modeling of lung deposition with an aerosol from the 30L using a high efficiency nebulizer, to compare the pharmaco and 40L devices using the Finally model (Finlay, W H, and A kinetic profile of cromolyn Sodium inhalation formulation R Martin, “Recent advances in predictive understanding res when administered using a high efficiency nebulizer in com piratory tract deposition”, Journal of Aerosol Medicine, Vol 15 parison with oral formulation of cromolyn Sodium in patients 21:189-205 (2008)) indicated that the lung deposition with with indolent systemic mastocytosis. the two devices should be very similar. However, the AUC Methodology value obtained with 40 mg dose using the 30L device (338 This is a Phase 2, randomized, double-blind, active-con nghr/mL) was Surprisingly high compared to the value (212 trolled, parallel arm, efficacy study in patients with indolent nghr/mL) from the 40L device. Cromlyn sodium is not systemic mastocytosis. metabolized in the body and is excreted intact via bile and At least about thirty six (36) adult human systemic masto urine. Cromolyn Sodium deposited in the lung during inhala cytosis patients are randomized to one of three treatment tion will appear in the plasma, and the AUC would therefore groups: (1) cromolyn Sodium inhalation formulation admin be a Surrogate for cromolyn Sodium deposited in the lung. 25 istered thrice daily with a high efficiency nebulizer; (2) pla Any cromolyn Sodium Swallowed during inhalation will con cebo formulation administered three times daily with a high tribute negligibly to the AUC since the oral bioavailability of efficiency nebulizer; and, (3) oral formulation of cromolyn cromolyn is only about 1% (Richards et al., J Pharmacol Exp Sodium administered four times daily. Ther, Vol. 241, No. 3: 1028-1032 (1987)). The AUC data Following the Screening Visit (SV), eligible subjects enter therefore indicate that at the same dose (40 mg), the lung 30 a 4-week Washout/Baseline Period for daily assessment of deposition with the 30L device was surprisingly higher than baseline symptoms using a diary and to washout cromolyn that with the 40L device. sodium in oral cromolyn sodium users. At the end of the The numbers of adverse events observed in the single dose Washout Period, eligible subjects are randomized to receive study (Part 1) are shown in the following table: cromolyn Sodium inhalation formulation using a high effi 35 ciency nebulizer or oral cromolyn Sodium formulation or TABLE 3 placebo for 6 weeks. The main criteria for inclusion are: a) Indolent systemic PA-101 PA-101 PA-101 Inhalation Oral mastocytosis patients uncontrolled with antihistaminic Adverse Pla (40L), (30L), (30L), aerosol, Solution, Event cebo 40 mg 40 mg 80 mg 20 mg 200 mg therapy; b) 18-65 years of age; c) mastocytosis diagnosis 40 confirmed by positive bone marrow biopsy; d) no recent Cough 1 1 1 1 systemic corticosteroid or immunosuppressive therapy; e) no Oropharyn 1 geal pain history of cancer except basal cell carcinoma; and, f) no Rhinorrhoea 1 concurrent uncontrolled disease. Dizziness Criteria for Evaluation: Headache 45 Dysgeusia The primary efficacy variable is significant improvement in Somnolence clinical symptoms at the end of treatment period following Catheter-site treatment with cromolyn Sodium inhalation formulation Reaction when administered using a high efficiency nebulizer in com Naso parison with oral formulation of cromolyn Sodium. pharygiitis 50 Sinusitis The PK parameters evaluated for plasma cromolyn sodium Abdominal 1. are maximum concentration (C), time to maximum con Discomfort centration (T,), terminal elimination half-life (T), area Increased under the plasma concentration-time curve from time–0 to Appetite time of last measurable drug concentration (AUC), and area 55 under the plasma concentration-time curve from time–0 to infinity (AUCo.). Example 4 The safety parameters include adverse events (AEs) including assessment of gastrointestinal disturbance (e.g., Efficacy Study abdominal pain, nausea, vomiting), and changes invital signs 60 and clinical laboratory tests. Objective The objectives of the study are: to determine the efficacy RESULTS profile of cromolyn sodium inhalation formulation when administered using a high efficiency nebulizer in comparison At the end of the treatment period, patients exhibit a sig with oral formulation of cromolyn sodium in patients with 65 nificant improvement inclinical symptoms with minimal AES systemic mastocytosis; to assess the safety and tolerability of as compared to placebo and the oral formulation of cromolyn cromolyn Sodium inhalation formulation when administered Sodium. US 9,265,749 B2 59 60 What is claimed is: 15. The method of claim 1, wherein the median particle 1. A method of treating a patient having mastocytosis, size of the cromolyn Sodium aerosol produced by the high comprising using a high efficiency nebulizer to administer to efficiency nebulizer is between about 3 um and about 4 um. the patient a composition comprising a mast cell stabilizer, 16. The method of claim 1, wherein administration of the 5 composition produces in a human Subject group an average purified water, and Sodium chloride as an excipient, wherein AUCo. of the cromolyn sodium greater than about 200 the mast cell stabilizer is cromolyn Sodium, and wherein nghr/mL. administration of the composition using the high efficiency 17. The method of claim 1, wherein administration of the nebulizer produces in a human Subject group an average composition produces in a human Subject group an average AUCo. of the cromolyn sodium greater than about 120 AUCo. of the cromolyn sodium greater than about 330 nghr/mL. 10 nghr/mL. 2. The method of claim 1, wherein the high efficiency 18. The method of claim 1, wherein administration of the nebulizer provides an RF (s3.3 m) of at least about 30% composition produces in a human Subject group an average and/or an RF (s.5um) of at least about 65%. AUCo. of the cromolyn sodium greater than about 525 3. The method of claim 1, wherein the high efficiency nghr/mL. 15 19. The method of claim 16, wherein 40 mg of cromolyn nebulizer provides an RF (s3.3 m) of at least about 45% Sodium is administered. and/or an RF (s.5um) of at least about 75%. 20. The method of claim 17, wherein 60 mg of cromolyn 4. The method of claim 1, wherein the composition com Sodium is administered. prises greater than about 2% cromolyn Sodium. 21. The method of claim 18, wherein 80 mg of cromolyn 5. The method of claim 1, wherein the composition com Sodium is administered. prises about 4% to about 6% cromolyn sodium. 22. The method of claim 1, wherein administration of the 6. The method of claim 1, wherein the composition com composition does not cause one or more adverse events prises sodium EDTA. selected from the group consisting of dysgeusia and abdomi 7. The method of claim 1, wherein the composition further nal discomfort. comprises mannitol. 25 23. The method of claim 1, wherein administration of the 8. The method of claim 1, wherein the composition has a composition produces in the human Subject group an average fill volume of about 0.1 mL to about 5 mL. Cmax of the cromolyn Sodium greater than about 55 ng/mL. 9. The method of claim 1, wherein the composition has a 24. The method of claim 23, wherein administration of the fill volume of about 2 mL or less. composition produces in the human Subject group an average 10. The method of claim 1, wherein the composition com 30 Cmax of the cromolyn Sodium greater than about 80 ng/mL. prises about 1 mg to about 120 mg of cromolyn Sodium. 25. The method of claim 24, wherein administration of the 11. The method of claim 1, wherein the composition com composition produces in the human Subject group an average prises about 5 mg to about 80 mg of cromolyn Sodium. Cmax of the cromolyn Sodium greater than about 150 ng/mL. 12. The method of claim 1, wherein the composition com 26. The method of claim 25, wherein administration of the prises about 20 mg to about 60 mg of cromolyn Sodium. 35 composition produces in the human Subject group an average 13. The method of claim 1, wherein the composition com Cmax of the cromolyn Sodium greater than about 230 ng/mL. prises about 30 mg to about 50 mg of cromolyn sodium. 27. The method of claim 1, wherein an oral formulation of 14. The method of claim 1, wherein the composition com cromolyn Sodium is not administered in the method. prises about 40 mg of cromolyn Sodium. k k k k k