[0001] This application claims priority from U.S. Provisional Application No. 62/354,234 filed June 24, 2016, which is incorporated by reference herein in its entirety for all purposes.

BACKGROUND OF THE I VENTION

[0002] Sarcoidosis is an inflammatory disease characterized by abnormal masses or nodules called granulomas that may occur in many organs, such as the lung, lymph nodes, skin, eyes, liver, heart, bone and brain. The noncaseatmg, or non-necrotic, granulomas are small collections of modified macrophages called epithelioid cells. These collections of cells are usually encircled by lymphocytes and often contain giant ceils.

[0003] Symptoms and signs of the disease are due to the granulomas altering organs and tissues. In chronic sarcoidosis cases, inflammation can eventually lead to fibrosis and permanent organ dysfunction. Sarcoidosis leads to organ damage in about one-third of the people diagnosed with the disease and may occur over many years and involve multiple organs. Sarcoidosis may also cause lupus pernio, a serious skin condition. Sarcoidosis can also be fatal. Death usually is the result of complications associated with the lungs, heart, or brain.

[0004] Sarcoidosis most often occurs in patients between 20 and 40 years of age, with women being diagnosed more frequently than men. The disease is 10 to 17 times more common in African-Americans than in Caucasians. People of Scandinavian, German, Irish, or Puerto Rican origin are also more susceptible to the disease than those of Caucasian descent. It is estimated that up to four in 10,000 people in the United States (U.S.) have sarcoidosis.

[0005] The exact cause of sarcoidosis is not known. It is a type of autoimmune disease associated with an abnormal immune response, but what triggers this response is uncertain. How sarcoidosis spreads from one part of the body to another is still being studied.

[0006] Sarcoidosis drug treatments are used to relieve symptoms and reduce the inflammation of the affected tissues. Nonsteroidal anti- inflammatory drugs (NSAIDs) are used for the treatment of arthralgias and other rheumatic complaints. For sarcoidosis involving such critical organs as the lungs, heart, liver, eyes, kidneys, or central nervous system, corticosteroid therapy has been the standard treatment. Fatigue and persistent cough are usually improved with steroid treatment.

[0007] Although the indications for medical therapy in sarcoidosis are controversial, standard therapy for serious, progressive, or life-threatening sarcoidosis includes the administration of systemic corticosteroids (Balzen et al. (1999). American Journal of Respiratory and Critical Care Medicine 160, pp. 192-197). Even though corticosteroids are the standard of care, systemic corticosteroids given for periods of 6 months or longer have limited effectiveness in advanced or chronic pulmonary sarcoidosis and do not appear to alter the natural history of the disease (Balzen et al. (1999). American Journal of Respiratory and Critical Care Medicine 160, pp. 192- 197). Moreover, side effects with high-dose and long-term steroids are numerous and disabling in pulmonary sarcoidosis patients. Although other agents have been used to treat pulmonary sarcoidosis, the results have varied, with mainly small uncontrolled trials and anecdotal evidence being reported.

[0008] Accordingly, new methods and compositions for the treatment of pulmonary sarcoidosis are needed. The present invention addresses this and other needs.

SUMMARY OF THE INVENTION

[0009] In one aspect of the invention, a method is provided for treating a sarcoidosis patient in need thereof. The method comprises administering to the patient a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt:

Formula (I) wherein Ri is NH, O or S; ft? is H, a linear Cs-Cis alkyi, branched Cs-Cis alkyl, linear C ₂ - Cis alkenyl, branched C3-C18 alkenyl, aryl; aryl-Ci-Cis alkyi; an amino acid or a peptide; R3 is H, OH, O-alkyl or O-alkenyl; R ₄ is an optionally substituted linear or branched C1-C15 alkyl, or an optionally substituted linear or branched C2-C15 alkenyl; and n is an integer from 0 to 5, with the proviso that the prostacyclin compound is not treprostinil.

[0010] In a further embodiment, the composition is administered via inhalation.

[0011] In another aspect of the invention, a method is provided for treating a sarcoidosis patient in need thereof. The method comprises administering to the patient a composition comprising an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt:

Formula (II)

[0012] wherein Ri is NH, 0 or S; R2 is a Smear or branched Cs-Cis alkyl, a linear O2-C18 alkenyl or a branched C3-C18 alkenyl, aryl, aryl-Ci-Qs alkyl, an amino acid or a peptide; and n is an integer from 0 to 5. In a further embodiment, the composition is administered via inhalation, e.g., via a nebulizer, dry powder inhaler or metered dose inhaler.

[0013] In one embodiment of the methods described herein, the composition administered to the patient comprises a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, wherein Ri is N and n is 1. In a further embodiment, R2 is a linear Cs-Cis alkyi or a branched Cs-Cis alkyl. In a further embodiment, R2 is a linear Ce-Ci ₂ alkyl or a branched Ce-Cn alkyl.

[0014] Another embodiment of the invention provides a method for treating sarcoidosis in a patient in need thereof, comprising administering to the patient a composition comprising an effective amount of a compound of Formula (I) or (II), wherein Ri is O and n is 1. In another embodiment, the method comprises administering a composition comprising an effective amount of a compound of Formula (I) or (II), wherein Rj is S and n is 1. In yet another embodiment of the invention a method for treating sarcoidosis in a patient in need thereof is provided comprising administering to the patient a composition comprising an effective amount of a compound of Formula (I) or (II), wherein Ri is N and n is 0. j0015J Another embodiment of the invention provides a method for treating pulmonary sarcoidosis in a patient in need thereof comprising administering to the patient a composition comprising an effective amount of a compound of Formula (I) or (II), wherein R ₂ is a linear Ci4- Cis alkyl. In a further embodiment, n is 0 or 1. In even a further embodiment, Ri is N or O. In yet a further embodiment, Rz is Ci6. Yet another embodiment provides a method for treating pulmonary sarcoidosis in a patient in need thereof comprising administering to the patient a composition comprising an effective amount of a compound of Formula (I) or (II), wherein Ri is N, R?. is a linear Ce-Cis alkyl, and n is 1. In even a further embodiment, R> is a linear C , Cs Cio, Cj 2, CM alkyl or Cie alkyl. In even a further embodiment, R?. is a linear Ci6 alkyl.

[0016] Another embodiment of the invention provides a method for treating sarcoidosis in a patient in need thereof via inhalation administration of a composition comprising an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, wherein R ₂ is a branched Cs-Ci s alkyl. In a further embodiment, n is 0 or 1. In yet a further embodiment, Ri is N or O. In even a further embodiment, the branched alkyl is hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl or octadecyl.

[0017] In yet another embodiment, a method for treating sarcoidosis in a patient in need thereof via inhalation administration is provided. The method comprises administering to the patient a composition comprising an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, wherein R? is a linear Cs-Ci s alkenyl In a further embodiment, n is 0 or 1. In yet a further embodiment, Ri is N or O. In even a further embodiment, the branched alkyl is hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl or octadecyl.

[0018] Yet another embodiment of the invention relates to a method for treating sarcoidosis in a patient in need thereof comprising administering to the patient a composition comprising an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt,: wherein Ri and R2 are defined above, and

R5 and Re are independently selected from H, optionally substituted linear or branched C1-C15 alkyl, optionally substituted linear or branched C2-C15 alkenyl, (C=0)-optionally substituted linear or branched C1-C15 alkyl, or (C=0)-op†ionally substituted linear or branched C ₂ -C ₁₅ alkenyl, with the proviso that the prostacyclin compound of Formula (III) is not treprostinil.

[0019] In one embodiment, the composition administered via the methods provided herein comprises a prostacyclin compound of Formula (I), (II) or (III) and a hydrophobic additive. In a further embodiment, the hydrophobic additive is a hydrocarbon, a terpene or a hydrophobic lipid. In another embodiment, the hydrophobic additive is cholesteryl acetate, ethyl stearate, palmitate, myristate, palmityl palmitate, tocopheryl acetate, a monoglyceride, a diglyceride, a triglyceride like palmitate, myristate, dodecanoate, decanoate, octanoate or squalane. In even a further embodiment, the hydrophobic additive is squalane.

[0020] The composition in another embodiment comprises a compound of Formula (I), (II) or (III), and an amphiphilic agent. In one embodiment, the amphiphilic agent is a PEGylated lipid, a surfactant or a block copolymer. In a further embodiment, the composition comprises a compound of Formula (I), (II) or (III), and a PEGylated lipid, in a further embodiment, the PEGylated lipid comprises PEG400, PEG500, PEG1000, PEG2000, PEG3000, PEG4000, or PEG5000. In a further embodiment the lipid component of the PEGylated lipid comprises PEG covalently linked to dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphoethanolamme (DPPE), distearoylphosphatidylethanolamine (DSPE), dimyristoyf glycerol glycerol (DMG), diphosphatidylglycerol (DPG), disteraroylgl cerol (DSG). |Ό021] In another embodiment of the invention, a composition comprising a prostacyclin compound of Formula (I), (II) or (III), a hydrophobic additive and an amphiphihc agent is administered to the patient in need of sarcoidosis treatment. In one embodiment, the amphiphilic agent is a PEGylated lipid, a surfactant or a block copolymer. In a further embodiment, the hydrophobic additive is squalane. In a further embodiment, a PEGylated lipid is present in the composition and comprises PEG400, PEG500, PEGIOOO, PEG2000, PEG3000, PEG4000 or PEG5000.

DETAILED DESCRIPTION OF THE INVENTION

[0022] The term "alkyl" as used herein refers to both a straight chain alkyl, wherein alkyl chain length is indicated by a range of numbers, and a branched alkyl, wherein a branching point in the chain exists, and the total number of carbons in the chain is indicated by a range of numbers. In exemplary embodiments, "alkyl" refers to an alkyl chain as defined above containing 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 carbons {i.e., Ce-Cie alkyl).

[0023] The term "alkenyl" as used herein refers to a carbon chain containing one or more carbon-carbon double bonds.

[0024] The term "aryl" as used herein refers to a cyclic hydrocarbon, where the ring is characterized by delocalized π electrons (aromaticity) shared among the ring members, and wherein the number of ring atoms is indicated by a range of numbers. In exemplar}' embodiments, "aryl" refers to a cyclic hydrocarbon as described above containing 6, 7, 8, 9, or 10 ring atoms {i.e., Ce-Cio aryl). Examples of an aryl group include, but are not limited to, benzene, naphthalene, tetralin, indene, and indane.

[0025] The term "alkoxy" as used herein refers to -O-(alkyl), wherein "alkyl" is as defined above.

[0026] The term "substituted" in connection with a moiety as used herein refers to a further substituent which is attached to the moiety at any acceptable location on the moiety. Unless otherwise indicated, moieties can bond through a carbon, nitrogen, oxygen, sulfur, or any other acceptable atom .

[0027] The term "amino acid" refers to both natural (genetically encoded) and non-natural (non- genetically encoded) amino acids, and moieties thereof. Of the twenty natural ammo acids, 19 R

H ₂ N-C-C0 ₂ H

have the general structure: H _; where R is the amino acid sidechain. The 20 ^th amino acid, proline, is also within the scope of the present invention, and has the following structure: . Of the twenty natural amino acids, all but glycine is chiral, and both the D- and L- amino acid isomers, as well as mixtures thereof, are amenable for use with the prostacyclin compounds described herein. It is also noted that an amino acid moiety is encompassed by the

R , , R

, i , H !

-C-C0 ₂ H }— N-C-C0 ₂ H term "amino acid." For example, the amino acid moieties H ₅ H

are encompassed by the term "amino acid."

[0028] Examples of non-natural ammo acids amenable for use with the present invention include β-alanine (β-Ala); 2,3-diaminopropionic acid (Dpr); nipecotic acid (Nip); pipecolic acid (Pip); ornithine (Om); citrulline (Cit); t-butylalanine (t-BuA); 2-tbutylglycine (t-BuG); N- methylisoleucine (Melle); phenylglycine (PhG); cyclohexylalanine (ChA); norleucine (Nle); naphthylalanine (Nal); 4-chlorophenylalanine (Phe(4-Cl)); 2-fluorophenylalanine (Phe(2-F)); 3- fluorophen ylalanine (Phe(3-F)); 4-fluorophenylalanine (Phe( 4~F)); penicillamine (Pen); 1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic acid (Tic); β-2-thienylalanine (Thi); methionine sulfoxide (MSO); homoarginine (hArg); N-acetyllysine (AcLys); 2,4-diaminobutyric acid (Dbu); 2,3- diaminobutyric acid (Dab); p-aminophenylalanine (Phe (pNFfc)); N-methyl valine (MeVal); homocysteine (hCys), homophenylalanine (hPhe); homoserine (hSer); hydroxyproline (Hyp); homoproline (hPro); and the corresponding D-enantiomer of each of the foregoing. Other non- genetically encoded ammo acid residues include 3-aminopropionic acid; 4-aminobutyric acid; isompecotic acid (Inp); aza-pipecolic acid (azPip); aza-proline (azPro); a-aminoisobutyric acid (Aib); ε-aminohexanoic acid (Aha); δ-aminovaleric acid (Ava); N-methylglycine (MeGly).

[0029] A "peptide" is a polymer of amino acids (or moieties thereof) linked by a peptide bond. Peptides for use with the present invention, comprise from about two to about fifteen amino acids, for example, two, three, four, five, six, seven, eight, nine or ten ammo acids (or moieties thereof).

[0030] The term "salt" or "salts" as used herein encompasses pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Exemplary pharmaceutical salts are disclosed in Stahl, P.H., Wermuth, C.G., Eds. Handbook of Pharmaceutical Salts: Properties, Selection and Use; Verlag Helvetica Chimica Acta/Wiley-VCH: Zurich, 2002, the contents of which are hereby incorporated by reference in their entirety. Specific non-limiting examples of inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids include, without limitation, aliphatic, cycioaiiphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, for example formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p~ hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxy ethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric or galacturonic acid. Suitable pharmaceutically acceptable salts of free acid-containing compounds disclosed herein include, without limitation, metallic salts and organic salts. Exemplary metallic salts include, but are not limited to, appropriate alkali metal (group ia) salts, alkaline earth metal (group Ila) salts, and other physiological acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Exemplary organic salts can be made from primary amines, secondary amines, tertiary amines and quaternary ammonium salts, for example, tromethamine, diethylamine, tetra-N-methylammonium, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyiglucamine) and procaine.

[0031] In one aspect, the present invention provides a composition comprising a prostacyclin compound, for example, a treprostinil alkyl ester, that is effective when employed in a once- daily, twice-daily or three-times daily dosing regimen, for the treatment of sarcoidosis in a patient in need thereof.

|0032J In one embodiment, the prostacyclin compound provided herein, in one embodiment, can be administered less frequently than treprostinil, with equal or greater efficacy. Moreover, in one embodiment, the side effect profile of the compounds provided herein is less deleterious than the side effect profile resulting from treprostinil administration. These advantages, in one embodiment, allow for greater patient compliance. Treatment, in one embodiment, occurs through pulmonary administration of one of the compounds provided herein, for example via a nebulizer, dry powder inhaler, or a metered dose inhaler. In some embodiments, a composition comprising one of the compounds provided herein is administered via a nebulizer to a patient in need of PH treatment. In some embodiments a compound described herein is suspended in a propellant and delivered to a patient via a metered dose inhaler.

[0033] In one embodiment, the composition administered to the sarcoidosis patient in need of treatment is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

Formula (I),

wherein Ri is NH, O or S;

R.2 is H, a linear C5-C18 alkyl, branched C5-C18 alkyi, linear C2-C18 alkenyl, branched C3- Ci8 alkenyl, aryl, aryl-d-Cis alkyl; an amino acid or a peptide;

R3 is H, OH, optionally substituted linear or branched C1-C15 alkyoxy, O-optionally substituted linear or branched C2-C15 alkenyl, 0-(C=0)-optionally substituted linear or branched C1-C15 alkyl, or 0-(C=0)-optionally substituted linear or branched C ₂ -C ₁₅ alkenyl;

R ₄ is an optionally substituted linear or branched C1-C15 alkyl, or an optionally substituted linear or branched C2-C 15 alkenyl; and n is an integer from 0 to 5, with the proviso that the prostacyclin compound of Formula (I) is not treprostinil.

0034J In a further embodiment, the composition comprises the compound of Formula (I), wherein J¾ is OH and n is 0 or 1. In even a further embodiment, R ₄ is an optionally substituted linear or branched C1-C15 alkyl. In even a further embodiment, Ri is NH or O.

[0035] In one embodiment, the composition comprises the compound of Formula (I) is provided, wherein Ri is NH, 0 or S; R2 is a linear Cs-C is alkyl, branched Cs-Cis alkyl, linear C2-C18 alkenyl, branched C3-C18 alkenyl; R3 is H, OH or O-alkyl; R ₄ is an optionally substituted linear or branched 0,-0, 5 alkyl, or an optionally substituted linear or branched C2-O5 alkenyl; and n is an integer from 0 to 5. In even a further embodiment, Ri is NH or O and R2 is a linear Cs-C is alkyl or a branched Cs-Cis alkyl.

[0036] In one embodiment, the composition administered to the patient in need thereof comprises the compound of Formula (I) where R2 is aryl or aryl-O-Os alkyl; R3 is OH and n is 0 or 1. In even a further embodiment, R ₄ is an optionally substituted linear or branched Ci-Cis alkyl.

[0037] In one embodiment, a composition comprising a compound of Formula (I) is administered to the patient, wherein the compound is a compound of one of Formulae (la), (lb), (Ic) or (Id), or a pharmaceutically acceptable salt thereof:

Formula (la) Formula (lb) Formula (Ic) Formula (Id) wherein, R2 is H, a linear or branched Cs-Cis alkyl, linear C2-C18 alkenyl, or a branched C3-C18 alkenyl; R.3 is H, OH, optionally substituted linear or branched C1-C15 alkyoxy, O-optionally bstituted Smear or branched C2-Q5 alkenyl, -0(C=0)-optionally substituted linear or branched -Ci5 alkyl, or -0(C=0)-optionally substituted linear or branched C ₂ -Cis alkenyl; and

R ₄ is ₅ an optionally substituted linear or branched CI -CJ S alkyl, or an optionally substituted linear or branched C ₂ -Cj 5 alkenyl, where Rs is H, optionally substituted linear or branched C1-C15 alkyl, optionally substituted linear or branched C2-C15 alkenyl, (C=0)- optionaliy substituted linear or branched C1-C15 alkyl, or (C=0)-optionally substituted linear or

branched C ₂ -Cis alkenyl. In a further embodiment, R ₄ is , with the proviso that the compound is not treprostinil, i.e., R2 and Rs cannot both be H.

[0038] In one embodiment of Formula (la), Formula (lb). Formula (Ic) and Formula (Id), R2 is a

linear or branched C5-C18 alkyl. In even a further embodiment, R ₂

where ml and ml are each independently an integer selected from 1 to 9 and each occurrence of R' is independently H, a linear or branched O-Cs alkyl, or a linear or branched Ci-Cs alkenyl.

In even a further embodiment, R ₂ is ^{r m2} and ml and ml are both 4. In another embodiment, R2 is ^m ^ ' ^m2 and ml is 3 and m2 is 4, or ml is 2 and m2 is 3.

|0039] When ml and/or m2 is an integer from 2-9, the ml/m2 at the end of the carbon chain is Clij, while the remaining ml/m2 groups are CH2. Ό040 In one embodiment of Formula la Formula lb and Formula Id R is

In a further embodiment R3 is OH and R ₄ is , where R5 is Fl, optionally substituted linear or branched Ci-

Ci5 alkyl, optionally substituted linear or branched C2-C15 alkenyl, substituted linear or branched C1-C15 alkyl, or (C=0)-optionally substituted linear or branched C2-C15 alkenyl.

In one embodiment of the methods described herein, the composition administered to the patient comprise a compound of Formulae (la), (lb), (Ic) wherein R2 is H, R3 is OH and

R4 is and Rs is or , where ml and m2 are each independently an integer selected from I to 9 and each occurrence of R' is independently H, a linear or branched Ci-Cs alkyl, or a linear or branched Ci-Cs alkenyl. When ml and/or m2 is an integer from 2-9, the ml/m2 at the end of the carbon chain is CH3, while the remaining ml/m2 groups are CH2,

[0042] In another embodiment of the methods described herein, the composition administered to the patient comprise a compound of one of Formula (la), (lb), (Ic) or (Id), wherein R3 is OH, as provided in one of Formulae (la'), (lb'), (Ic') or (Id'):

Formula (la') Formula (lb') Formula (Ic') Formula (Id') where branched C5-C18 alkyl, or a linear or branched C5-C18 alkenyl; and

R ₄ is , an optionally substituted linear or branched C1-C15 alkyl, or an optionally substituted linear or branched C2-C15 alkenyl, wherein Rs is Fl, optionally substituted linear or branched C1-C15 alkyl, optionally substituted linear or branched C2-C15 alkenyl, (C=0)- optionally substituted linear or branched Ci-ds alkyl, or (C=0)-optionally substituted linear or branched C2-C15 alkenyl, with the proviso that R?. and R5 are not both H. In one embodiment of

Formula (la'), Formul and

R2 i _s mV ^{V ;} m2 _or

, where mi and m2 are each independently an integer selected from 1 to 9 and each occurrence of R' is independently H, a linear or branched O-Cs alkyl, or a linear or branched Ci-Cg alkenvl. In even a further

[0043] Yet another embodiment of the invention relates to a method of treating a sarcoidosis patient in need of treatment. The method comprises administering to the patient, e.g., via inhalation, a composition comprising an effective amound of a compound of one of Formula (la"), (lb"), (Ic") or (Id"), or a pharmaceutically acceptable salt thereof:

Formula (la' Formula (lb'

Formula (Ic") Formula (Id") wherein,

R2 is H, a linear or branched Cs-Cis aikyl, linear C2-C18 alkenyl, branched C3-C18 alkenyl, aryl, aryl-Cj -Cis aikyl; an amino acid or a peptide; and

R.3 is H, OH, optionally substituted linear or branched C1-C15 alkyoxy, O-optionally substituted linear or branched C2-C15 alkenyl, 0-(C=0)-optionally substituted linear or branched C1-C15 aikyl, or 0-(C=0)-optionally substituted linear or branched C2-C 15 alkenyl; and

Rs is H, optionally substituted linear or branched Cj -Cis aikyl, optionally substituted linear or branched C2-C15 alkenyl, (C=0)-optionally substituted linear or branched C1-C15 aikyl, or (C=0)-optionally substituted linear or branched C2-C15 alkenyl, with the proviso that R2 and R5 are not both H. In a further embodiment, R3 is OH and R2 is 5-nonanyl, 4-heptyl, 4-octyl, 3- octyl, 2-dimethyl- 1 -propyl, 3, 3 -dimethyl- 1 -butyl, 2-ethyl-l -butyl, 3-pentyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecvl, dodecyl, tridecvl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl. In even a further embodiment, R is decyl, undecvl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl. In even a further embodiment, R2 is a linear aikyl.

[0044] One embodiment of the present invention is directed to a method for treating a sarcoidosis patient via administration of a composition comprising a compound of Formula (Ic), (ic') and/or (ic"). In a further embodiment, R2 is a linear Cs-Cis aikyl or a branched Cs-Cis aikyl. In even a further embodiment, R2 is a linear Ce-Cis aikyl or a branched Ce-Cis aikyl In yet a further embodiment, R2 is a linear C6-C1 aikyl, e.g., a linear C ₆ aikyl, Cs aikyl, C10 aikyl, C12 aikyl or CM aikyl. |Ό045] In one embodiment of the methods described herein, a composition comprising aompound of Formula (Ic") is administered to the patient, wherein ft? is a linear Cw-Cis alkyl; R3 is OH and Rs is H. In another embodiment of the methods described herein, a compound of Formula (Ic") is administered to the patient wherein R ₂ is a linear Ce-Cis alkyl; R3 is OH and Rs is H. In yet embodiment of the methods described herein, a compound of Formula (Ic") is administered to the patient, wherein R2 is a linear Ce-Cie alkyl; R3 is OH and R5 is H. In even another embodiment of a method for treating a sarcoidosis patient, a composition comprising a compound of Formula (Ic") is administered to the patient, wherein R2 is a linear Cs-Ci4 alkyl: R3 is OH and Rs is OH.

[0046] In one embodiment of the methods described herein, a composition comprising a compound of Formula (Ic") is administered to the patient, wherein R2 is a linear Cj4-Ci8 alkyl; R3 is OH and Rs is H. In another embodiment of the methods described herein, a composition comprising a compound of Formula (Ic' ') is administered to the patient, wherein R2 is a branched Ce-Cis alkyl; R3 is OH and Rs is H. In yet embodiment, a composition comprising a compound of Formula (Ic") is administered to the sarcoidosis patient, wherein R2 is a branched Ce-Cie alkyl; R3 is OH and Rs is H, In even another embodiment, a composition comprising a compound of Formula (Ic") is administered to the patient, wherein R2 is a branched Cs-Ci4 alkyl; R3 is OH and 5 is H.

[0047] In even a further embodiment, the composition is administered to the patient via a nebulizer, dry powder inhaler or a metered dose inhaler,

[0048] In yet another embodiment, a method for treating a sarcoidosis patient is provided. The method comprises administering to the patient a composition comprising a compound ofFormula

(la"), (lb"), (Ic") or (Id" ), wherein R3 is OH, Rs is H and ft is

where ml and ml are each independently an integer selected from 1 to 9. In even a further

0049] In yet another embodiment of the administration of compositions comprising compounds

of Formula (la"), (Ib"), (Ic") or (Id"), ft? is H, ft is OH, and Rs is

where ml and m2 are each independently an integer selected from 1 to 9. In even a further

[005Θ] In one embodiment of a method for treating a sarcoidosis patient, a composition comprising a compound of Formula (I), (la), (Ib), (Ic) or (Id) is administered to the patient, e.g., via inhalation, where ft? is a linear or branched Cs-Cis alkyl. In a further embodiment, R2 is 5- nonanyl, 4-heptanyl, 4-octanyi, 3-octanyl, 2-dimethyl-l-propanyl, 3,3 -dimethyl- 1 -butanyl, 2- ethyl-I -butanyl, 3-pentanyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.

[0051] In one embodiment of a method for treating a sarcoidosis patient, a composition comprising a compound of Formula (I), (la), (Ib), (Ic), (Id), (la ^" ). (Ib'), (Ic'), (Id'), (la"), (Ib"), (Ic") or (Id") is administered to the patient, e.g., via inhalation, where ft? is a linear or branched C5-C18 alkyl. In even a further embodiment, ft? is a linear C5-C18 alkyl In another embodiment of a method for treating a sarcoidosis patient, a composition comprising a compound of Formula (I), (la), (Ib), (Ic), (Id), (la'), (lb'), (Ic'), (Id'), (la"), (lb"), (Ic") or (Id") is administered to the

patient, e.g., via inhalation, wherein ft? is ml A . and ml and m2 are each independently an integer selected from 1 to 9 and each occurrence of R' is independently H, a linear or branched Ci-Cg aikyl, or a linear or branched Ci-Cs alkenyi. In even a further

[0052] In another embodiment, a composition comprising a compound of Formula (I), (la), (lb), (Ic) or (Id) is administered to the patient, wherein 2 is a branched Cs-Cis aikyl. In a further embodiment, R_ is 5-nonaiiyl, 4-heptyl, 4-octyl, 3-octyl, 2-dimethyl-l -propyl, 3, 3 -dimethyl- 1- butyl, 2-ethyl-l -butyl, 3-pentyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.

[0053] In one embodiment of the invention, a sarcoidosis patient is administered a composition comprising the following compound:

wherein Ri is NH, O or S.

[0054] For example, Ri is O or N, and one of the following compounds (5-nonanyl treprostinil (aikyl ester, SCs-TR) or 5-nonanyl treprostinil (amide linked; 5C9-TR-A), is provided:

0055] In one embodiment, a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id) is

provided wherein R ₂ is , where ml and m2 are each independently each an integer selected from 1 to 9 and each occurrence of R' is independently H, a linear or branched Ci-Cs alk l, or a linear or branched Ci-Cs alkenyl.

[0056] When ml and/or m2 is an integer from 2-9, the ml/m2 at the end of the carbon chain is CH3, while the remaining ml/m2 groups are CH ₂ ,

[0057] In even another embodiment, the sarcoidosis patient is administed a composition comprising a compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic' '), (la"), (lb"),

[0058] The compounds administered via the methods provided herein can include a symmetrical branched alkyl or an asymmetrical branched alkyl as the 2 moiety. For example, where R2 is 'mi ^ _m \ _anc f _m 2 _can b _e the same integer and R2 is therefore a symmetrical branched alkyl. R2 is an assymetrical branched alkyl when ml and m2 are different.

[0059] In another embodiment, a sarcoidosis patient is administed a composition comprising a compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic'), (Id'), (la"), (lb"), (Ic") or (Id" ), e.g., via inhalation, and R2 is ^{m1% m2} , ml is 2 and m2 is 3, ml and m2 are each independently 4, or ml and m2 are each independently 3.

[0060] In another embodiment, the composition administered via one of the methods described herein comprises a compound comprising an asymmetrical branched alkyl at the R2 position, such as, for example, 3-hexanyl (3C ₆ ), 2-heptanyl (2C?), 3-heptanyl (3C?), 2-octanyl (2Cg), 3- octanyl (3Cs), or 4-octanyl (4Cg).

|Ό061] In another embodiment of a sarcoidosis treatment method, a composition comprising a compound of Formula (I), (la), (lb), (Ic) or (Id) is administered to a patient in need thereof, wherein R ₂ is a branched alkyl selected from 2,2-diethyl-l-pent l, 3-pentyi, 4-octyl, 5-nonanyl, 2-ethyl-l -butyl, 2-propyl-l-pentyl, 12-butyl-l-octyl, 2-dimethyl- 1 -propyl, and 3,3-dimethyl-l- butyl.

[0062] In another embodiment of a sarcoidosis treatment method, a composition comprising a compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic') or (Id') is administered to a patient in need thereof, e.g., via inhalation, , wherein, R2 is a linear or branched C5-C18 alkenyl. For example, in one embodiment, R2 is a linear Cs-Cis alkenyl selected from pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenvl, tridecenvl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl or octadecenyl. In a further embodiment, R3 is OH. In another embodiment, R2 is a branched Cs-Cis alkenyl selected from pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenvl, tridecenvl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl or octadecenyl. In a further embodiment, R3 is OH.

[0063] In one embodiment of a sarcoidosis treatment method, a composition comprising a, a ed thereof, and

[0064] In one embodiment, a composition comprising a compound of Formula (I), (la), (lb), (Ic) or (Id) is administered to a patient in need of sarcoidosis tre . In a further embodiment, R ₂ a linear C5-C18 alkyl, R3 is OH and . In a further embodiment, R2 is 5-nonanyl, 4-heptyi, 4-octanyl, 3-octanyi, 2-dimethyl- 1 -propyl, 3,3- dimethyi-1 -butyl, 2-ethyl-l -butyl, 3-pentyl, pentyi, hexyl, heptyl, octyi, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyi.

[0065] In one embodiment, a composition comprising a compound of Formula (I), (la), (lb), (Ic) or (Id) is administered to a patient in need of sarcoidosis therapy and R2 hexyl, dodecyl, tetradecyl, hexadecyl, 5-nonanyl, 4-heptanyl, 4-octanyl, 3-octanyl, 2-dimethyl-l-propyl, 3,3- dimethyl-1 -butyl, 2-ethyl-l -butyl, 3-pentyl, R3 is OH and RA is

[0066] In one embodiment, a composition comprising a compound of Formula (I), (la), (lb), (Ic) or (Id), wherein R2 is hexyl, R3 is OH and R ₄ is administered to a patient in need of sarcoidosis therapy.

[0067] In one embodiment, a composition comprising a compound of Formula (I), (la), (lb), (Ic) or (Id) is wherein R2 hexyl, R3 is OH _JS administered to a patient in need of sarcoidosis therapy.

[0068] In another embodiment, a composition comprising a compound of Formula (la"), (lb"), (Ic") or (id") wherein R2 hexyl, R3 is OH Ri is H is administered to a patient in need of sarcoidosis therapy. In a further embodiment, the compound is a compound of Formula (Ic"). In yet another embodiment, a composition comprising a compound of Formula (la"), (lb"), (Ic") or (Id") is administered to a patient in need of sarcoidosis treatment, and R?. dodecyl, tetradecyl, pentadecyl or hexadecyl, R3 is OH R ₄ is H. In a further embodiment, the compound is a compound of Formula (la"). In even a further embodiment, the composition is a lipid nanoparticle formulation as described in more detail below.

[0069] In one embodiment, a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt, is provided in a composition for the treatment of a sarcoidosis patient, and R2 heptyl, R3 is OH and R ₄ is

[0070] In one embodiment, a compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt, is provided in a composition for the treatment of a sarcoidosis patient, and R2 octyl, R3 is OH an In one embodiment, a compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt, is provided in a composition for the treatment of a sarcoidosis patient, and R?. nonyl, R3 is OH and R ₄

10072] In another embodiment, a prostacyclm compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt, is provided in a composition for the treatment of a sarcoidosis patient, and R2 decyl, R3 is OH and R ₄ is

73] In yet another embodiment, a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt, is provided in a composition for the treatment of a sarcoidosis patient, and R2 undecyl, R3 is OH and R is

[0074] In even another embodiment, a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt, is provided in a composition for the treatment of a sarcoidosis patient, and R2 dodecyl, 3 is OH and R is

[0075] In one embodiment, a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (id), or pharmaceutically acceptable salt, is provided in a composition for the treatment of a sarcoidosis patient, and R2 tridecyl, R3 is OH and R ₄ is

[0076] In another embodiment, an effective amount of a compound of Formula (I), (la) (Ic), or (Id), or pharmaceutically acceptable salt, is provi the treatment of a sarcoidosis patient, and R2 tetradecyl, R3 is OH and R ₄

[0077] In even another embodiment, an effective amount of a compound of Formula (I), (la), (lb), (Ic) or (Id), or pharmaceutically acceptable salt, is provided in a composition for the treatment of a sarcoidosis patient, and R2 pentadecyl, R3 is OH and R ₄ |Ό078] Another embodiment of the invention concerns a method for treating a patient in need of sarcoidosis treatment, comprising administering to the patient a composition comprising an effective amount of a compound of Formula (I), (la), pharmaceutically acceptable salt, wherein R2 hexadecyl, R3 is OH and R ₄ is

[0079] Yet another embodiment of the invention concerns a method for treating a patient in need of sarcoidosis treatment, comprising administering to the patient a composition comprising an effective amount of a compound of Formula (I), (la), (l pharmaceutically acceptable salt, wherein R2 heptadecyl, R3 is OH and R is j OOSOJ Yet another embodiment of the invention concerns a method for treating a patient in need of sarcoidosis treatment, comprising administering to the patient a composition comprising an effective amount of a compound of Formula (I), (la), (lb), (Ic) or (Id), or a pharmaceutically acceptable salt, wherein R2 octadecyi, R3 is OH and R ₄ is

[0081] In one embodiment, a compound of Formula (I), (la), (lb), (Ic) or (Id), or a pharmaceutically acceptable salt, is administered to the patient via inhalation, wherein one or more hydrogen atoms is substituted with a deuterium. Accordingly, in one embodiment, the present invention relates to the administration of an isotopologue of Formula (I), (la), (lb), (Ic) or (Id), substituted with one or more deuterium atoms. The isotopologue of Formula (I), (la), (lb), (Ic) or (Id) may be used to accurately determine the concentration of compounds of Formula (I), (la), (lb), (Ic) or (Id) in biological fluids and to determine metabolic patterns of compounds of Formula (I), (la), (lb), (Ic) or (Id) and its isotopologues.

[0082] In another aspect of the invention, a method for treating sarcoidosis is provided. The method comprises administering to a patient in need of sarcoidosis treatment, a composition comprising an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, is provided: Formula (IT),

wherein Ri is NH, O or S;

R2 is a linear or branched C5-C18 alkyi, a linear C2-C18 alkenyl or a branched C3-C18 alkenyl, aryl, aryl-O-ds alkyl, an amino acid or a peptide; and

n is an integer from 0 to 5.

[0083] In one embodiment, a method for treating sarcoidosis is provided. The method comprises administering to a patient in need of sarcoidosis treatment, a composition comprising an effective amount of a compound of Formula (IT), or a pharmaceutically acceptable salt thereof, wherein Ri is NH, O or S; R2 is a linear or branched C5-C18 alkyl, a linear C2-C18 alkenyl or a branched C3- Ci8 alkenyl; and n is an integer from 0 to 5. In a further embodiment, n is 1 and Ri is NIT or O.

[0084] In one embodiment, the present invention relates to the aforeme tioned method, wherein the compound is a compound of formula (Ila), (lib), (lie) or (lid), or a pharmaceutically acceptable salt thereof:

Formula (Ila) Formula (lib)

Formula (lie) Formula (lid) wherein ft? is a linear or branched Cs-Cis alkyl, a linear C2-C18 alkenyl or a branched C3- Cis alkenyl, aryl, aryl-Cj -Cis alkyl, an ammo acid or a peptide. In a further embodiment, a compound of formula (Ila), (lib), (lie) or (lid) is provided wherein R2 is a linear or branched Cs- Ci8 alkyl, a linear C2-C18 alkenyl or a branched Cs-Cj g alkenyl. In one embodiment, a compound of Formula (II), (Ila), (lib), (lie) or (lid) is provided, wherein one or more hydrogen atoms is substituted with a deuterium. Accordingly, in one embodiment, the present invention relates to an isotopologue of Formula (II), (Ila), (lib), (He) or (lid), substituted with one or more deuterium atoms. The isotopologue of Formula (II), (Ila), (lib), (lie) or (lid) may be used to accurately determine the concentration of compounds of Formula (II), (Ila), (lib), (lie) or (lid) in biological fluids and to determine metabolic patterns of compounds of Formula (II), (Ila), (lib), (lie) or (lid) and its isotopologues. The invention further provides compositions comprising these deuterated isotopologues and methods of treating diseases and conditions, as set forth herein.

[0085] In one embodiment, the composition administered to the patient comparises an effective amount of a compound of Formula (lie). In a further embodiment, R2 is a linear Cs-Cis alkyl or a branched Cs-Cis alkyl. For example, in one embodiment, R2 is a linear Ce-Cis alkyl. In another embodiment of Formula (lie), R2 is a linear Ce-Cio alkyl. In even a further embodiment of Formula (lie), R2 is a hexyl, heptyl or octyl.

[0086] Compounds of Formula (Ila) and Formula (He) amenable for use in the methods provided herein, are provided in Tables 1 and 2 below.

Table 1. Compemids of Formula (Ila)

- linear C5-C18 alkyl R ₂ = branched ( ^' --·( ^' _:x alkyl R2 = linear C» alkyl R-2 = branched C& alkyl

R2 - linear Ce-Cis alkyl R2 - branched Ce-C - B alkyl R2 - lineai" C9 alkyl R2 - branched C7 alkyl Table 1. Compounds of Formula ilia)

R.2 = linear C7-C18 alkyl R2 - branched C7-C18 alkyl R2 - lineai" Cio alkyl R2 - branched Cg alkyl

R.2 = linear Cs-Cis alkyl R.2 = branched Cs-Cis alkyl. . · linear Cn alkyl. R - = branched C9 alkyl

R2 - linear C9-C18 alkyl R2 - branched C9-C18 alkyl R2 - linear C12 alkyl R2 - branched Cso alkyl

R.2 = linear Cio-Cis alkyl R2 = branched Cio-Cis alkyl R - linear ( ^' · : alkyl R · = branched C , , alkyl

R2 - linear Cn-Cis alkyl R2 - branched Cn-Cis alkyl R.2 --- lineai" Ci4 alkyl R2 - branched Ci2 alkyl

R.2 = linear C12-C18 alkyl R.2 = branched C12-C18 alkyl R2 = linear C15 alkyl. R2 = branched Co alkyl

Table 2. Compounds of Formula (He)

R2 - linear Cj-Ci8 alkyl R2 - branched Cs-Cis alkyl R2 - linear Ce alkyl R2 - branched Ce alkyl 2 = linear Ce-Ci8 alkyl R2 = branched Ce-Ci8 alkyl. R2 = linear C? alkyl R.2 = branched C7 alkyl

R.2 = linear C7-C18 alkyl R2 - branched C7-C18 alkyl R2 -- lineai" Cs alkyl R2 - branched Cg alkyl

R.2 = linear Cs-Cis alkyl R2 = branched Cs-Cis alkyl R2 = linear C9 alkyl R;2 = branched C9 alkyl

R2 = linear C9-C18 alkyl R2 = branched C9-C18 alkyl R2 = linear Cio alkyl R2 = branched Cio alkyl

R2 = linear Cio-Cis alkyl R;2 = branched Cio-Cis alkyl R2 = linear Cu alky! R2 = branched C] 1 a!kyl

R2 = linear C5-C12 alkyl R2 = branched C5-C12 alkyl 2 = linear C12 alkyl R2 = branched C12 alkyl

R.2 - linear Ce-Cso alkyl R2 - branched Ce-Cso alkyl R2 - linear Csj alkyl R2 - branched C13 alkyl

[0087] Yet another embodiment of the invention relates to a method for treating sarcoidosis comprising administering to a patient in need of treatment, a composition comprising an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt thereof:

(Formula III), wherein Ri and R2 are defined as provided for Formula (I) and (II), and

R-3 and Re are independently selected from H, optionally substituted linear or branched Ci-Cis alkyl, optionally substituted linear or branched C ₂ -Cis alkenyl, (C=0)-optionally substituted linear or branched Ci-Cis alkyl, or (C=0)-optionally substituted Smear or branched C2-C15 alkenyl, with the proviso that the prostacyclin compound of Formula (III) is not treprostinil.

[0088] In one embodiment, the branched chain prostacyclin compounds provided herein exhibit both higher solubility and slower enzymatic conversion to treprostinil relative to a linear chain derivatized prostacyclin compound. In one embodiment, an asymmetrical branched chain prostacyclin compound is provided, wherein the asymmetrical branched chain prostacyclin compound is more stable than a corresponding symmetrical branched chain prostacyclin compound.

[0089] In one embodiment, the composition administered to the patient comprises a compound that contains a chiral moiety at one or more of the R2, Rs and/or Re positions. For example, the moiety at position R2, in one embodiment, is a chiral moiety and comprises either the R isomer, the S isomer, or a mixture thereof. An optical isomer at position R2, Rs and/or Re can also be classified with the D. L nomenclature. For example, where R2 is an ammo acid or an ammo acid moiety, the amino acid or amino acid moiety can be the D-isomer, L-isomer, or a mixture thereof.

[009Θ] In one embodiment, one or more of the R2, Rs and/or Re moieties is the R isomer or S isomer. In another embodiment, one or more of the R2, Rs and/or Re moieties provided herein comprise a mixture of R and S moieties. The "R isomer" or "S isomer" as used herein refers to an enantiomerically pure isomer. An "enantiomerically pure isomer" has at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure R- or S- isomer or when using the D/L nomenclature, D- or L-isomer. A racemic compound is a compound having a mixture in equal amounts of both enantiomers.

[0091] In one embodiment, the composition administered to the patient in need thereof includes a a cationic compound and a surfactant, e.g., as previously described in PCX publication no. WO 2014/085813, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.

|0092] In one embodiment, the composition comprises one of the prostacyclin compounds described herein, i.e., a compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic'), (Id'), (la"), (lb"), (Ic"), (Id"), (II), (Ila), (lib), (lie) (lid), or (III), and an amphiphilic agent. When formulated together, in one embodiment, the prostacyclin compound and amphiphilic agent form micro- or nanoparticles. In one embodiment, the amphiphilic agent is a PEGylated lipid, a surfactant or a block copolymer. In another embodiment, the prostacyclin composition provided herein comprises two or more of the prostacyclin compounds described herein (e.g., a compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic'), (Id'), (la"), (lb"), (Ic"), (Id"), (II), (Ila), (lib), (lie) (lid), or (III), including deuterated compounds) and an amphiphilic agent (e.g., PEGylated lipid, a lipid, a surfactant or a block copolymer). In one embodiment, the prostacyclin composition comprising the prostacyclin compound component and amphiphilic agent, when formulated together, comprise a plurality of nanoparticles. In a further embodiment, the mean diameter of the plurality of nanoparticles is from about 20 nm to about 700 nm, for example about 50 nm to about 500 nm, about 100 nm to about 600 nm or about 100 nm to about 500 nm. When the amphiphilic agent comprises a lipid, e.g., a PEGylated lipid such as Cholesteroi-PEG or distearoylphosphatidylethanolamine-PEG (DSPE-PEG), the composition is described as comprising lipid nanoparticles.

[0093] In a further embodiment, the prostacyclin composition comprises a prostacyclin compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic'), (Id'), (la"), (lb"), (Ic"), (Id"), (II), (Ila), (lib), (lie) (lid), or (III), and a PEGylated lipid as the amphilphilic agent. In a further embodiment, the PEGylated lipid comprises PEG400-PEG5000. For example, in one embodiment, the PEGylated lipid comprises PEG400, PEG500, PEG! 000, PEG2000, PEG3000, PEG4000, or PEG5000. In a further embodiment the lipid component of the PEGylated lipid comprises cholesterol, dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphoethanolamine (DPPE), distearoylphosphatidylethanolamine (DSPE), dimyristoylglycerol glycerol (DMG), diphosphate dylglycerol (DPG) or disteraroylglycerol (DSG). In even a further embodiment, the PEGylated lipid is cholesterol-PEG2000 or DSPE-PEG2000. [0094] Depending on its molecular weight (MW), PEG is also referred to in the art as polyethylene oxide (PEO) or polyoxyethylene (PQE). The PEGyiated lipid can include a branched or unbranched PEG molecule, and is not limited by a particular PEG MW.

[0095] For example, the PEGyiated lipid, in one embodiment, comprises a PEG molecule having a molecular weight of 300 g/mol, 400 g/mol, 500 g/mol, 1000 g/mol, 1500 g/mol, 2000 g/mol, 2500 g/mol, 3000 g/mol, 3500 g/mol, 4000 g/mol, 4500 g/mol, 5000 g/mol or 10,000 g/mol. In one embodiment, the PEG has a MW of 1000 g/mol or 2000 g/mol.

[0096] The lipid component of the PEGyiated lipid, can have a net-charge (e.g., catiomc or anionic), or can be net-neutral. The lipids used in the PEGyiated lipid component of the present invention can be synthetic, semi-synthetic or naturally-occurring lipid, including a phospholipid, a sphmgolipid, a glycoiipid, a ceramide, a tocopherol, a sterol, a fatty acid, or a glycoprotein such as albumin. In one embodiment, the lipid is a sterol. In a further embodiment, the sterol is cholesterol. In another embodiment, the lipid is a phospholipid. Phospholipids include, but are not limited to phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidyiethanolamine (PE), and phosphatidic acid (PA). In one embodiment, the phospholipid is an egg phospholipid, a soya phospholipid or a hydrogenated egg and soya phospholipid. In one embodiment, the PEGyiated lipid comprises a phospholipid. In a further embodiment, the phospholipid comprises ester linkages of fatty acids in the 2 and 3 of glycerol positions containing chains of 12 to 26 carbon atoms and different head groups in the 1 position of glycerol that include choline, glycerol, inositol, serine, ethanolamine, as well as the corresponding phosphatidic acids. The chains on these fatty acids can be saturated or unsaturated, and the phospholipid can be made up of fatty acids of different chain lengths and different degrees of unsaturation. In particular, in one embodiment, the PEGyiated lipid of the prostacyclin composition provided herein comprises distearoylphosphoethanolamme (DSPE), dipalmitoylphosphatidyl choline (DPPC), dioleoylphosphatidyl choline (DOPC) dimyristoyl phosphatidyiethanolamine (DMPE), dipalmitoylphosphoethanolamine (DPPE), distearoylphosphatidylethanolamine (DSPE), dimyristoylglycerol (DMG), diphosphatidylglycerol (DPG) or disteraroylgiycerol (DSG).

[0097] Other examples of lipids for use in the compositions comprising PEGyiated lipids disclosed herein include dimyristoylphosphatidylcholine (DMPC), dimyristoyiphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG) dioleylphosphatidylethanolamine (DOPE), and mixed phospholipids such as palmitoylstearoylphosphatidylcholine (PSPC) and palmitoylstearoylphosphatidylglycerol (PSPG), triacylglycerol, diacylglycerol, ceramide, sphingosine, sphingomyelin and single acylated phospholipids such as mono-oleoyl-phosphatidylethanolamine (MOPE). In another embodiment lipid portion of the PEGylated lipid comprises an ammonium salt of a fatty acid, a phospholipid, a glyceride, a phospholipid and glyceride, a sterol (e.g., cholesterol), phosphatidylglycerol (PG), phosphatide acid (PA), a phosphotidylcholine (PC), a phosphatidylinositol (PI), a phosphatidylserine (PS), or a combination thereof. The fatty acid, in one embodiment, comprises fatty acids of carbon chain lengths of 12 to 26 carbon atoms that are either saturated or unsaturated. Some specific examples include: myristylamine, palmitylamine, laurylamine and stearylamine, dilauroyl ethylphosphocholine (DLEP), dimyristoyl ethylphosphocholine (DMEP), dipalmitoyl ethylphosphocholine (DPEP) and distearoyl ethylphosphocholine (DSEP), N-(2,3-di-(9(Z)-octadecenyloxy)-prop-l-yl-N,N,N- trimethylammonium chloride (DOTMA) and l ,2-bis(oleoyloxy)-3-(trimethylammonio)propane (DOTAP). Examples of sterols for use in the compositions provided herein include cholesterol and ergosterol. Examples of PGs, PAs, Pis, PCs and PSs for use in the compositions provided herein include DMPG, DPPG, DSPG, DMPA, DPPA, DSPA, DMPI, DPPI, DSPI, DMPS, DPPS and DSPS, DSPC, DPPG, DMPC, DOPC, egg PC and soya PC,

[0098] In one embodiment, the PEGylated lipid is cholesterol-PEG2000, DSPE-PEG1 000 or DSG-PEG2000.

[0099] In another embodiment, the prostacyclin composition provided herem comprises a prostacyclin compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb ¹ ), (Ic'), (Id'), (la"), (lb"), (Ic"), (Id"), (II), (Ha), (lib), (lie) (lid), or (III), and a hydrophobic additive. In a further embodiment, the composition comprises an amphophilic agent, e.g. , a PEGylated lipid, as described above.

[00100] In yet another embodiment, two or more of the prostacyclin compounds described herein (e.g., a compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic'), (Id'), (la"), (lb"), (Ic"), (Id"), (II), U fa). (lib), (lie) (lid), or (III)) an amphiphilic agent (e.g., PEGylated lipid, a lipid, a surfactant or a block copolymer) and a hydrophobic additive are provided in a composition.

jOOlOl] In one embodiment, the prostacyclin composition comprises a prostacyclin compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic'), (Id'), (la"), (lb"), (Ic"), (Id"), (II), (Ila), (lib), (lie) (lid), or (III) and a PEGylated lipid. In another embodiment, the prostacyclin composition comprises a prostacyclin compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic'), (Id'), (la"), (lb"), (Ic"), (Id"), (II), (Ila), (lib), (He) (Ild), or (III) and a surfactant. In yet another embodiment, the prostacyclin composition comprises a prostacyclin compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic'), (Id'), (la"), (lb"), (Ic"), (Id"), (II), (Ila), (lib), (lie) (Ild), or (III), a hydrophobic additive and an amphiphilic agent. In a further embodiment, the amphiphilic agent is a surfactant, a PEGylated lipid or a block copolymer. In even a further embodiment, the amphiphilic agent is a PEGylated lipid.

[00102] In one embodiment, the prostacyclin compound is present in the composition at 5 mol% - 99 mol%. In a further embodiment, the prostacyclin compound is present in the composition at 40 mol% - 95 mol%. In a further embodiment, the prostacyclin compound is present in the composition at 40 mol% - 60 mol%. In one embodiment, the prostacyclin compound is present in the composition at about 40 mol% or about 45 mol%.

[001Θ3] The amphiphilic agent, e.g., a PEGylated lipid, when present in the composition, in one embodiment, is present at 10 mol% - 30 mol%, for example, 10 mol% - 20 mol% or 15 mol% - 25 mol%. In even a further embodiment, the PEGylated lipid is present in the composition at about 10 mol% or 20 mol%.

[001Θ4] The hydrophobic additive, when present in the composition, in one embodiment, is present in the composition at 25 mol% - 50 mol%, for example, 30 mol% - 50 mol%, 35 mol% - 45 mol%. In even a further embodiment, the hydrophobic additive is present in the composition at about 40 mol% or about 45 mol%.

[001Θ5] The prostacyclin composition, in one embodiment, comprises a compound of

Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic'), (Id'), (la"), (lb"), (Ic"), (Id"), (II), (Ila), (lib), (lie) (Ild), or (III), or a pharmaceutically acceptable salt thereof, as described herein, an amphophilic agent and a hydrophobic additive. In one embodiment, the hydrophobic additive {e.g., an additive that is at least partially hydrophobic) is a hydrocarbon, a terpene compound or a hydrophobic lipid (e.g., tocopherol, tocopherol acetate, sterol, sterol ester, alkyl ester, vitamin A acetate, a triglyceride, a phospholipid). In one embodiment, the composition comprises a prostacyclin compound, for example, a compound of Formula (I) or (II), an amphiphilic agent, and a hydrocarbon. The hydrocarbon can be aromatic, an aikane, alkene, cycloaikane or an alkyne. In one embodiment, the hydrocarbon is an aikane (i.e., a saturated hydrocarbon). In another embodiment, the hydrocarbon is a C15-C50 hydrocarbon. In a further embodiment, the hydrocarbon is a C15, C20, C25, C30, C35, C40, C45 or C50 hydrocarbon. In yet another embodiment the hydrophobic additive is a Cis-C ₂ 5 hydrocarbon, CJ 5-C35 hydrocarbon, C]5-C45 hydrocarbon, C15-C20 hydrocarbon, C20-C25 hydrocarbon, C25-C30 hydrocarbon, C30-C35 hydrocarbon, C35-C40 hydrocarbon, C40-C45 hydrocarbon or a C45-C50 hydrocarbon.

[00106] In one embodiment, a composition comprising a prostacyclin compound, an amphiphilic agent and a terpene compound (e.g., the hydrophobic additive) is provided. The composition, in a further embodiment, comprises a PEGylated lipid as the amphiphilic agent. However, as noted above, block copolymers as well as surfactants can be used as the amphiphilic component of the composition. The terpene compound (hydrophobic additive), in one embodiment, is a hydrocarbon (e.g., isoprene, squalaneor squalene). In another embodiment, the terpene compound is a hemiterpene (CsHg), monoterpene (CioHie), sesquiterpene (C15H24), diterpene (C20H32) (e.g., cafestol, kahweol, cembrene, taxadiene), sesterterpene (C25H40), triterpene (C30H48), sesquaterpene (C35H56), tetraterpene (C40H64), polyterpene (e.g., a polyisoprene with trans double bonds) or a norisoprenoid (e.g., 3-oxo-a-ionol, 7,8- dihydroionone derivatives). The terpene compound, in another embodiment, is selected from one of the compounds provided in Table 3, below. In one embodiment, the hydrophobic additive is squalane.

Table S. T erpene hydroph obk add itives an lenable for use in the

compositio m of the presen ; inventi on.

Name Formula

Isoprene ^^^ _^ J-l^ Table 3. Terpene hydrophobic additives amenable for use in the

compositions of the present invention.

Name Formula

Limonene

humulene

farnasene squalene

squalane

[001Θ7] As provided above, the composition provided herein, in one embodiment, comprises a prostacyclin compound and one or more PEGylated lipids. In a further embodiment, the composition comprises a hydrophobic additive, as described above. In one embodiment, the composition provided herein comprises a prostacyclin compound of one of Formula (I), (la), (lb), (Ic), (Id), (Fa'), (lb ¹ ), (Ic'), (Id'), (la"), (lb"), (Ic"), (Id"), (II), (Ila), (lib), (lie) (lid), or (III), a hydrophobic additive and a PEGylated lipid. In a further embodiment, the hydrophobic additive comprises a hydrocarbon e.g, a terpene compound.

[00108] In one embodiment, the treprostiml derivative composition provided herein includes the components provided in Tables 4 and 5, below.

Table 4, Representative Treprostinil Compositions. Hvdronhob

Composition TreorostinU coniDOund AmDhiDhilic Additiona

k additive

# ageirct 1 lipid

Formula (II) where Ri is 0,

1 Terpene PEGylated lipid n/a

R ₂ is Smear C6-Ci6

Formula (II) where Ri is O,

2 Terpene PEGylated lipid DOPC

R2 is linear Ce-Cie

Formula (II) where Ri is 0,

3 Squalane Chol-PEG2k n/a

R2 is linear Ce-Cu

Formula (II) where Ri is 0,

4 Squalane DSPE-PEG2k n/a

R ··. is linear (Vi ^' V

Formula (II) where Ri is 0,

5 Terpene PEGylated lipid n/a

R2 is linear C10-C16

Formula (II) where Ri is 0,

6 Terpene PEGylated lipid DOPC

R2 is linear Cio-Cie

Formula (11) where Ri is 0,

7 Squalane Chol-PEG2k n/a

R is linear Cio-Cie

Formula (II) where Ri is 0,

8 Squalane DSPE-PEG2k n/a

R2 is linear Cio-Cj6

Formula (II) where Ri is 0, Terpene

9 PEGylated lipid n/a

R2 is linear C12-C16

Formula (II) where Ri is 0, Terpene

10 PEGylated lipid DOPC

R2 is linear C12-C16

Formula (II) where Ri is 0, Squalane

1 1 Chol-PEG2k n/a

R> is linear C12-C16

Formula (II) where Ri is 0,

12 Squalane DSPE-PEG2k n/a

R2 is Smear CU-CM,

Formula (II) where Ri is 0,

13 Terpene PEGylated lipid n/a

R2 is branched C6~Ci6

Formula (II) where Ri is 0,

14 Terpene PEGylated lipid DOPC

R2 is branched C6-C16

Formula (II) where Ri is 0,

15 Squalane Chol-PEG2k n/a

R2 is branched Ce-Cie

Formula (II) where Ri is 0,

16 Squalane DSPE-PEG2k n/a

R ₂ is branched Ce-Cie

Formula (II) where Ri is N,

17 Terpene PEGylated lipid n/a

R2 is linear Ce-Cie Table 4. Representative Treprostinil Compositions.

Hydrophob

Composition Treprostinil compound Amphophilic Additiona ic additive

# agent 1 lipid

Formula (II) where Ri is N,

18 Terpene PEGylated lipid DOPC ft is linear CVCie

Formula (Π) where Ri is N,

19 Squalane Chol-PEG2k n/a

ft? is linear Ce-de

Formula (II) where Ri is N,

20 Squalane DSPE-PEG2k n/a

R ₂ is linear d-d 6

Formula (II) where Ri is N,

21 Terpene PEGylated lipid n/a

R2 is linear Ce-Cio

Formula (II) where Ri is N,

22 Terpene PEGylated lipid DOPC ft is linear CVCio

Formula (Π) where Ri is N,

23 Squalan Chol-PEG2k n/a

ft is linear Ce-do

Formula (II) where Ri is N,

24 Squalane DSPE-PEG2k iv ^' a

ft is linear CVCio

Tabk S. Cos nponents of prostacyclin alky! ester compositions

Hydrophobic

Coaipositi Hydrophobic PEGylated Cx-TR PEG-lipid DOPC

Cx-TR Additive

m Additive lipid mol% mol% mol% mol%

Chol-

T493 C2-TR Squalane PEG2k 40 40 20 0

Choi-

T500 C ₄ -TR Squalane PEG2k 40 40 20 0

Chol-

T507 C ₆ -TR Squalane PEG2k 40 40 20 0

Chol-

T508 Cg-TR Squalane PEG2k 40 40 20 0

Chol-

T509 Cio-TR Squalane PEG2k 40 40 20 0

Chol-

T554 C ₂ -TR Squalane PEG2k 40 40 10 10

Chol-

T555 Cs-TR Squalane PEG2k 40 40 10 10

Chol-

T556 Cio-TR Squalane PEG2k 40 40 10 10

T568 Ci ₂ -TR Squalane Chol- 40 40 10 10 Table 5. Components of prostacyclin alkyl ester compositions

Hydrophobic

Compositi Hydrophobic PEGylated Cx-TR PEG-!ipid BOPC

Cx-TR Additive

on Additive lipid mol% mol% mol% mol%

PEG2k

Chol-

T623 C16-TR Squaiane PEG2k 40 40 10 10

Chol-

T637 C18-TR Squalane PEG2k 40 40 10 10

[00109] The present invention also provides methods for treating a patient in need of sarcoidosis treatement, with a composition comprising one of the compounds described herein. It is understood that reference to a compound in a treatment method includes the use of a pharmaceutically acceptable salt of the compound.

[00110] Pulmonary sarcoidosis has been classified in different stages according to chest radiography, and the methods provided herein can be used to treat a patient at any stage of the disease. Stage (0): no intrathoracic involvement; stage (I): bilateral hilar lymphadenopathy; stage (II): bilateral hilar lymphadenopathy and reticulonodular infiltrates: stage (III): pulmonary infiltrates with fibrosis; and stage (IV): end-stage lung disease with pulmonary fibrosis and honeycombing. The present invention is amenable for use for the treatment of a subject with stage (0), stage (I), stage (II), stage (III) and/or stage (IV) pulmonary sarcoidosis.

[00111] Without wishing to be bound by theory, it is thought that the present invention provides more direct and effective pulmonary sarcoidosis treatment methods by delivering one of the compounds described herein directly to the sites of sarcoid granulomas in the lung and to the sites of granuloma formation. Additionally, delivery of the compound directly to the site of the sarcoidosis infection without wishing to be bound by theory allows for pulmonary fibrosis to be attenuated and/or prevented in treated patients.

[00112] In one embodiment, the pulmonary sarcoidosis treatable by the methods, compositions and kits provided herein is necrotising sarcoid granulomatosis (NSG), which is characterized by sarcoid like granuloma formation, vasculitis and variable degrees of necrosis. 00113] In another embodiment, the patient in need of treatment has been diagnosed with alveolar sarcoidosis. Alveolar sarcoidosis without wishing to be bound by theory, is thought to result from aggregation of large numbers of interstitial granulomas rather than representing a true alveolar process. In patients with alveolar sarcoidosis, there can be large areas of pulmonary opacification ranging in diameter from 1 to 4 cm. These can be rounded or elongated in shape, have irregular edges and blurred margins with or without air bronchograms. They are typically found either along the bronchovascular bundles or in the lung periphery adjacent to the pleural surface. Small nodules can be often visible around these large opacities, which is often termed the galaxy sign. Another pattern of alveolar sarcoidosis is an appearance termed "fairy ring" which refers to circumferentially organized opacities.

[00114] In yet another embodiment, the subject has been diagnosed with cavitatory pulmonary sarcoidosis. Cavitatory pulmonary sarcoidosis is usually reported in those with severe and active disease and its reported prevalence is around 2% of all pulmonary sarcoidosis (Hours et al. Medicine (Baltimore) 87, pp. 142-151, incorporated by reference herein in its entirety for all purposes).

[00115] In one embodiment, a composition of the present invention is administered to a patient via inhalation, wherein the patient has pulmonary sarcoidosis resistant to steroid treatment. In another embodiment, the patient was non-responsive to previous sarcoidosis treatment, or experienced adverse effects from a previous sarcoidosis treatment.

[00116] In one embodiment, the patient has cutaneous sarcoidosis in addition to pulmonary sarcoidosis.

[00117] As provided above, in one embodiment, the patient is a human. The human patient can be a child (i.e., < eighteen years old) or adult (i.e., > eighteen years old).

[00118] The majority of reported childhood sarcoidosis cases have occurred in patients aged 13-15 years old (Shetty and Gedalia (2008). Pediatric Rheumatology 6: 16 doi: l 0.1186/1546-0096-6-16, incorporated by reference herein in its entirety for all purposes). However, in one study of childhood sarcoidosis associated with joint involvement, the mean age at onset was 10.6 years (range, 0.1-16 years) (Lindsley and Petty (2000). Curr. Reheumatol. Rep. 2, pp. 343-348, incorporated by reference herein in its entirety for all purposes). Importantly, the methods provided herein are not limited to a particular age of a subject. For example, in one embodiment, the methods provided herein are amenable for use with teen-aged patients, e.g., from about 13 years old to about 18 years old. In another embodiment the subject is from about 5 years old to about 13 years old, for example from about 5 years old to about 12 years old, or about 10 years old. 00119] In one embodiment, the subject treated with the methods, compositions and kits provided herein is from about 25 years old to about 40 years old.

[00120] In another embodiment, the subject is from about 1 month to about 6 months old, from about 6 months to about 12 months old, from about 1 year old to about 5 years old from about, from about 5 to about 10 years old, from about 10 to about 15 years old, from about 15 to 20 years old, from about 20 to 25 years old, 25 to about 30 years old at the onset of treatment, from about 30 to about 35 years old, from about 35 to about 40 years old at the onset of treatment, from about 40 to about 45 years old, from about 45 to about 50 years old at the onset of treatment, from about 50 to about 55 years old, from about 55 to about 60 years old at the onset of treatment, from about 60 to about 65 years old, from about 65 to about 70 years old at the onset of treatment, from about 70 to about 75 years old at the onset of treatment, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to 95 years old, or from about 95 to 100 years old.

[00121] In one embodiment, the pulmonary sarcoidosis patient treated with the methods provided herein has a pre-existing, simultaneous or subsequent malignancy. In a further embodiment, the malignancy comprises a lymphoma, a leukemia, lung cancer, uterine cancer, thyroid cancer, laryngeal cancer, pharyngeal cancer, skin cancer, liver cancer, breast cancer, prostate cancer and colon cancer.

[00122] Administration of a composition comprising an effective amount of one or more of the compounds provided herein occurs through pulmonary deliver}' to the lungs of a patient, for example via a nebulizer, soft mist inhaler, dry powder inhaler (DPI), or a metered dose inhaler (MDI). In some embodiments, a composition comprising an effective amount of one of the compounds provided herein is administered via a nebulizer to a patient in need of pulmonary sarcoidosis treatment. In some embodiments a compound described herein is suspended in a propellant and delivered to a patient via an MDI.

[00123] In one embodiment, a patient is administered one of the compositions described herein via inhalation for the treatment of pulmonary sarcoidosis once daily, twice daily or three times daily. In another embodiment, administration of the composition occurs every other day or once per week.

[00124] The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the renal and hepatic function of the patient: and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[00125] As provided throughout, in some embodiments, the methods provided herein comprise administration of a composition via a pulmonary route and an inhalation deliver}' device, to a patient in need of treatment. The inhalation delivery device can be a nebulizer, dry powder inhaler, or a metered dose inhaler (MDI), or any other suitable inhalation delivery device known to one of ordinary skill in the art. The device can contain and be used to deliver a single dose or the device can contain and be used to deliver multi-doses of the composition. The device, in one embodiment, is constructed to ascertain optimum metering accuracy and compatibility of its constructive elements, such as container, valve and actuator with the formulation and could be based on a mechanical pump system. For example, inhalation delivery devices include a jet nebulizer, electronic nebulizer, a soft mist inhaler, and a capsule-based dry powder inhaler. In one embodiment, where compound delivery is via a nebulizer, the compound is provided to the patient as a composition comprising a lipid component.

[00126] In one embodiment, a metered dose inhalator (MDI) is employed as the inhalation delivery device for the compositions of the present invention. In a further embodiment, one of the compounds described herein is suspended in a propellant (e.g., hydrofluorocarbon) prior to loading into the MDI. The basic structure of the MDI comprises a metering valve, an actuator and a container. A propellant is used to discharge the formulation from the device. The composition may consist of particles of a defined size suspended in the pressurized propellant(s) liquid, or the composition can be in a solution or suspension of pressurized liquid propellant(s). The propellants used are primarily atmospheric friendly hydrofluoroalkanes (HFAs) such as 134a and 227. The device of the inhalation system may deliver a single dose via, e.g., a blister pack, or it may be multi dose in design. The pressurized metered dose inhalator of the inhalation system can be breath actuated to deliver an accurate dose of the lipid-containing formulation. To insure accuracy of dosing, the delivery of the formulation may be programmed via a microprocessor to occur at a certain point in the inhalation cycle. The MDI may be portable and hand held.

[00127] In one embodiment a compound of the present invention, or a composition comprising the same, is administered via a metered dose inhaler (IVIDI) to a patient in need of sarcoidosis treatment. The patient, in one embodiment, is administered the composition once daily or twice daily. In one embodiment, the administration is with food. In one embodiment, each administration comprises 1 to 5 doses (puffs) from an MDI, for example 1 dose (1 puff), 2 dose (2 puffs), 3 doses (3 puffs), 4 doses (4 puffs) or 5 doses (5 puffs). The MDI, in one embodiment, is small and transportable by the patient.

[00128] In another embodiment, the composition is administered via a nebulizer to a patient in need of sarcoidosis treatment. The administration occurs, in one embodiment, once daily or twice daily, or once weekly.

[00129] In one embodiment, a composition or compound of the present invention is administered to a patient in need thereof via a dry powder inhaler (DPI) to a patient in need of pulmonary sarcoidosis treatment. The patient, in one embodiment, is administered the composition once daily or twice daily. In one embodiment, the administration is with food. In one embodiment, each administration comprises 1 to 5 doses (puffs) from a DPI, for example 1 dose (1 puff), 2 dose (2 puffs), 3 doses (3 puffs), 4 doses (4 puffs) or 5 doses (5 puffs). The DPI, in one embodiment, is small and transportable by the patient.

[00130] The compositions of the present invention may be used in any dosage dispensing device adapted for pulmonary administration. Accordingly, in one aspect, the present invention provides systems comprising one or more of the compositions described herein and an inhalation delivery device. The device, in one embodiment, is constructed to ascertain optimum metering accuracy and compatibility of its constructive elements, such as container, valve and actuator with the composition and could be based on a mechanical pump system, e.g., that of a metered- dose nebulizer, dry powder inhaler, metered dose inhaler (MDI), soft mist inhaler, or a nebulizer. For example, pulmonary deliver}' devices include a jet nebulizer, electronic nebulizer, a soft mist inhaler, and a capsule-based dry powder inhaler, all of which are amenable for use with the compositions of the present invention.

[00131] The composition, in one embodiment, is administered via a nebulizer, which provides an aerosol mist of the composition for deliver}' to the lungs of a subject in need of treatment. A nebulizer type inhalation delivery device can contain the compositions of the present invention as an aqueous solution or a suspension. In generating the nebulized spray of the compositions for inhalation, the nebulizer type delivery device may be driven ultrasonically, by compressed air, by other gases, electronically or mechanically. The ultrasonic nebulizer device usually works by imposing a rapidly oscillating waveform onto the liquid film of the composition via an electrochemical vibrating surface. At a given amplitude the waveform becomes unstable, whereby it disintegrates the liquids film, and it produces small droplets of the composition. The nebulizer device driven by air or other gases operates on the basis that a high pressure gas stream produces a local pressure drop that draws the liquid composition into the stream of gases via capillary action. This fine liquid stream is then disintegrated by shear forces.

[00132] A nebulizer type inhalation deliver}' device can contain the compositions of the present invention as a solution, usually aqueous, or a suspension. For example, the composition can be suspended in saline and loaded into the inhalation deliver}' device. In generating the nebulized spray of the compositions for inhalation, the nebulizer delivery device may be driven ultrasonically, by compressed air, by other gases, electronically or mechanically (e.g., vibrating mesh or aperture plate). Vibrating mesh nebulizers generate fine particle, low velocity aerosol, and nebulize therapeutic solutions and suspensions at a faster rate than conventional jet or ultrasonic nebulizers. Accordingly, the duration of treatment can be shortened with a vibrating mesh nebulizer, as compared to a jet or ultrasonic nebulizer. Vibrating mesh nebulizers amenable for use with the methods described herein include the Philips Respironics I-Neb®, the

Omron MicroAir, the Nektar Aeroneb®, and the PARI eFlow®. Other devices that can be used with the compositions described herein include jet nebulizers (e.g., PARI LC Star, AKITA), soft mist inhalers, and capsule-based dry powder inhalers (e.g., PH&T Turbospm).

[00133] The nebulizer may be portable and hand held in design, and may be equipped with a self-contained electrical unit. The nebulizer device may comprise a nozzle that has two coincident outlet channels of defined aperture size through which the liquid composition can be accelerated. This results in impaction of the two streams and atomization of the composition. The nebulizer may use a mechanical actuator to force the liquid composition through a multionfice nozzle of defined aperture size(s) to produce an aerosol of the composition for inhalation. In the design of single dose nebulizers, blister packs containing single doses of the composition may be employed.

[00134] The device can contain, and be used to deliver, a single dose of the compositions of the invention, or the device can contain, and be used to deliver, multi-doses of the compositions of the invention.

[00135] In the present invention the nebulizer may be employed to ensure the sizing of particles is optimal for positioning of the particle within, for example, the pulmonary membrane.

[00136] A metered dose inhalator (MDI) may be employed as the inhalation delivery device for the compositions of the present invention. This device is pressurized (pMDI) and its basic structure comprises a metering valve, an actuator and a container. A propellant is used to discharge the composition from the device. Suitable propellants, e.g., for MDI delivery, may be selected among such gases as fluorocarbons, chlorofluorocarbons (CFCs), hydrocarbons, hydrofluorocarboiis, hydrofluoroalkane propellants (e.g., HFA-134a and HFA-227), nitrogen and dinitrogen oxide or mixtures thereof.

[00137] In one embodiment, a propellant is present in a composition intended for MDI delivery, and is selected from a fluorocarbon, chlorofluorocarbon (CFC), hydrocarbons, hydrofluoroalkane propellants (e.g., UFA- 134a and HFA-227), nitrogen and dinitrogen oxide or mixtures thereof. In embodiments of the present invention, the propellant is CFC- 12 or an ozone-friendly, non-CFC propellant, such as 1 , 1 , 1 ,2-tetrafiuoroethane (HFC 134a), 1, 1,1,2,3,3,3- heptafluoropropane (HFA-227), HCFC-22 (difluorochloromethane), HFA-152 (difluoroethane and isobutene), trans-l ,3,3,3,-tetrafluoropro-l -ene (HFO 1234ze) and 2,3,3,3,-tetrafluoroprop-l- ene (HFO 1234yf), or combinations thereof.

|00138J The composition may consist of particles of a defined size suspended in the pressurized propeliant(s) liquid, or the composition can be in a solution or suspension of pressurized liquid propeilant(s). The propellants used are primarily atmospheric friendly hydroflourocarbons (HFCs) such as 134a and 227. The inhalation delivery device, in one embodiment, delivers a single dose via, e.g., a blister pack, or it may be multi dose in design. The pressurized metered dose inhalator of the inhalation system can be breath actuated to deliver an accurate dose of the composition. To insure accuracy of dosing, the delivery of the composition may be programmed via a microprocessor to occur at a certain point in the inhalation cycle. The MDX may be portable and hand held.

[00139] For MDI delivery, in one embodiment, the prostacyclin compound is reduced in particle size prior to formulating in a composition. Particle size reduction can be achieved by milling, spray drying or using supercritical fluids. Milling can include cryo milling, ball milling, fluid-energy milling and cryogenic continuous bead milling. Bail mills and fluid-energy mills (such as jet mills) are the primaiy modes of milling powders to achieve particles with diameters of 1 to 5 μηι. Ball mills use balls that grind the drug as the balls tumble inside the mill. Jet milling reduces particle size of coarse powders by high velocity particle-particle collisions. Alternatively, spray drying may be used to reduce particle size. Spray drying converts a solution or liquid dispersion (also known as "feed") to dried particulates by the process of atomizing a spray of the liquid containing the drug followed by quickly drying the droplets, which yields solid particles. Compared to milling, spray drying often produces relatively spherical, amorphous particles. Finally, supercritical fluids may also be utilized to manufacture particles for inhalation. A supercritical fluid is any substance at a temperature and pressure above its critical point, the point where both the liquid and gas phases have the same density. The prostacyclin compound is dissolved in the supercritical fluid, at high pressure and temperature, followed by decrease in pressure and/or temperature which yields a reduction in the density of the solution, thereby decreasing the solvation power of the supercritical fluid, leading to precipitation of the drug. Supercritical fluids can be used in multiple ways to micronize drug particles. They may be used to micronize drug material through rapid expansion of supercritical solutions, using supercritical fluid as an antisolvent and precipitation of particles from gas saturated solutions. Particle size reduction can also be done by an emulsion template process (Dugas et al, 2013, International Journal of Pharmaceutics 441 : 19-29, incorporated by reference herein in its entirety for all purposes).

[00140] In one embodiment, an effective amount of a prostacyclin compound, or a pharmaceutically acceptable salt thereof, is reduced in particle size. In another embodiment, the particle size is reduced by milling, spray drying, using supercritical fluids, and/or by an emulsion template process. In a further embodiment, the compound is passed through a sieve. In yet another embodiment, the sieve size is about 5 μιη.

[00141] Yet another aspect of the invention relates to the compositions described above in aerosolized form. Upon nebulization or aerosolization, the aerosolized composition is in the form of aerosolized particles. The aerosolized composition can be characterized by the particle size of the aerosol, for example, by measuring the "mass median aerodynamic diameter" or "fine particle fraction" associated with the aerosolized composition. "Mass median aerodynamic diameter" or "MMAD" is normalized regarding the aerodynamic separation of aqua aerosol droplets and is determined by impactor measurements, e.g., the Andersen Cascade Impactor (ACI) or the Next Generation Impactor (NGI). The gas flow rate, in one embodiment, is 28 Liter per minute for the ACI and 15 liter per minute for the NGI.

[00142] "Geometric standard deviation" or "GSD" is a measure of the spread of an aerodynamic particle size distribution. Low GSDs characterize a narrow droplet size distribution (homogeneously sized droplets), which is advantageous for targeting aerosol to the respiratory system. The average droplet size of the nebulized composition provided herein, in one embodiment is less than 5 μηι or about 1 μηι to about 5 μπι, and has a GSD in a range of 1.0 to 2.2, or about 1.0 to about 2.2, or 1.5 to 2.2, or about 1.5 to about 2.2.

[00143] "Fine particle fraction" or "FPF," as used herein, refers to the fraction of the aerosol having a particle size less than 5 um in diameter, as measured by cascade impaction. FPF is usually expressed as a percentage [00144] In the present invention the nebulizer may be employed to ensure the sizing of particles is optimal for positioning of the particle within, for example, the pulmonary membrane.

[00145] In one embodiment, the mass median aerodynamic diameter (MMAD) of the aerosol particles is about 1 μηι to about 5 μηι, or about 1 μιη to about 4 μιη, or about 1 μηι to about 3 μιη, or about 2 μιη to about 3 μηι, or about 1 μηι to about 2 μηι, as measured by cascade impaction, for example, by the ACI or NGI.

[00146] In another embodiment, the MMAD of the aerosol particles is about 5 μιη or less, about 4 μιη or less, about 3 μηι or less, about 2 μιη or less, or about 1 μιη or less, as measured by cascade impaction, for example, by the ACI or NGI.

[00147] "Geometric standard deviation" or "GSD" is a measure of the spread of an aerodynamic particle size distribution. Low GSDs characterize a narrow droplet size distribution (homogeneously sized droplets), which is advantageous for targeting aerosol to the respiratory system. The average droplet size of the aerosolized composition provided herein, in one embodiment is less than 5 μιη or about 1 μηι to about 5 μηι, and has a GSD in a range of from about 1.0 to about 2.2, or from about 1.5 to about 2.2, as measured by the ACI or NGI.

[00148] "Respirable mass" or "RM", as used herein, is usually expressed as μ^ηοί and is the total amount of emitted drug product that exits the metered dose inhaler upon actuation.

[00149] In one embodiment, the respirable mass of the aerosol particles is about 1 μg/shot to about 100 or about 1 §/δηοΐ to about 50 £/8ηοΐ, or about 1 μ§/δηοΙ to about 40 ^ηοΐ, or about 1 μ§/8ηοί to about 30 §/8ηο1, or about 3 ^ηοί to about 80 μ§/8ηοΐ, or about 3 £/8ηοί to about 70 to about 50 ^δΐιοΐ, about 3 £/8ηοί to about 40 ^δΐιοΐ, about 3 £/8ηοί to about 30 ^δΐιοΐ, as measured by the ACT or NGI.

[00150] "Fine particle fraction" or "FPF", as used herein, refers to the fraction of the aerosol having a particle size less than 5 μηι in diameter, as measured by cascade impaction. FPF is usually expressed as a percentage. [00151] In one embodiment, the fine particle fraction (FPF) of the aerosol particles is greater is greater than or equal to about 40%, is greater than or equal to about 50%, is greater than or equal to about 60%, is greater than or equal to about 70%, is greater than or equal to about 80%, greater than or equal to about 85%, greater than or equal to about 90%, or greater than or equal to about 95%, as measured by the ACI or NGI.

[00152] In another embodiment, the FPF of the aerosol particles is about 40% to about 99%, is about 50% to about 99%, is about 60% to about 99%, is about 70% to about 99%, is about 75% to about 99%>, is about 80% to about 99%, is about 80% to about 95%, is about 80% to about 90%, or is about 85% to about 90%, or is about 85% to about 95%, as measured by the ACI or NGI.

[00153] "Percent throat deposition" or "PTD" is the amount of drug deposited on the throat of the cascade impactor and is expressed as a percentage.

[00154] In one embodiment, the percent throat deposition is less than or equal to about 60%, less than or equal to about 50%, less than or equal to about 40%, less than or equal to about 30%, less than or equal to about 25%, as measured by the ACI or NGI.

[00155] In one embodiment, a dry powder inhaler (DPI) is employed as the inhalation delivery device for the compositions of the present invention. In one embodiment, the DPI generates particles having an MMAD of from about 1 μιη to about 10 μτη, or about 1 μηι to about 9 μιη, or about 1 μηι to about 8 μηι, or about 1 μτη to about 7 μιη, or about 1 μηι to about 6 μιη, or about 1 μιη to about 5 μηι, or about 1 μηι to about 4 μηι, or about 1 μηι to about 3 μπι, or about 1 μηι to about 2 μιη in diameter, as measured by the NGI or ACI. In another embodiment, the DPI generates a particles having an MMAD of from about 1 μηι to about 10 μιη, or about 2 μηι to about 10 μηι, or about 3 μηι to about 10 μηι, or about 4 μηι to about 10 μηι, or about 5 μηι to about 10 μιη, or about 6 μηι to about 10 μηι, or about 7 μιη to about 10 μιη, or about 8 μηι to about 10 μιη, or about 9 μιη to about 10 μιη, as measured by the NGI or ACI.

[00156] In one embodiment, the MMAD of the particles generated by the DPI is about 10 μηι or less, about 9 μιη or less, about 8 μηι or less, about 7 μηι or less, about 6 μιη or less, about 5 μηι or less, about 4 μτη or less, about 3 μτη or less, about 2 μιη or less, or about 1 μηι or less, as measured by the NGI or ACL

[00157] In one embodiment, the MMAD of the particles generated by the DPI is less than about 9.9 μηι, less than about 9.5 μτη, less than about 9.3 μηι, less than about 9.2 μηι, less than about 9.1 μηι, less than about 9.0 μηι, less than about 8.5 μηι, less than about 8.3 μτη, less than about 8.2 μηι, less than about 8.1 μιη, less than about 8.0 μηι, less than about 7.5 μηι, less than about 7.3 μηι, less than about 7.2 μηι, less than about 7.1 μιη, less than about 7.0 μτη, less than about 6.5 μηι, less than about 6.3 μτη, less than about 6.2 μηι, less than about 6.1 μηι, less than about 6.0 μηι, less than about 5.5 μηι, less than about 5.3 μηι, less than about 5.2 μηι, less than about 5.1 μίη, less than about 5.0 μηι, less than about 4.5 μηι, less than about 4.3 μιη, less than about 4.2 μηι, less than about 4.1 μηι, less than about 4.0 μιη or less than about 3.5 μηι, as measured by the NGI or ACI.

[00158] In one embodiment, the MMAD of the particles generated by the DPI is from about 1.0 μιη to about 10.0 μηι, from about 2.0 μηι to about 9.5 μηι, from about 2.5 μηι to about 9.0 μηι, from about 3.0 μηι to about 9.0 μηι, from about 3.5 μηι to about 8.5 μιη or from about 4.0 μηι to about 8.0 μηι.

[00159] In one embodiment, the FPF of the aerosol particulate composition generated by the DPI is greater than or equal to about 40%, greater than or equal to about 50%, greater than or equal to about 60%, or greater than or equal to about 70%, as measured by the ACI or NGI. In another embodiment, the FPF of the aerosolized composition is about 80% to about 99%, about 80% to about 95%, about 80% to about 90%>, or about 85%> to about 90%, or about 85% to about 95%, as measured by the NGI or ACI.

[00160] Symptoms of pulmonary sarcoidosis include dry cough, fatigue, shortness of breath, weight loss, tender reddish bumps or patches on the skin, inflammation of the eyes, swollen and painful joints, enlarged and tender lymph glands in the neck, armpits, and groin, enlarged lymph glands in the chest and around the lungs, hoarse voice, pain in the hands, feet, or other bony areas due to the formation of cysts (an abnormal sac-like growth) in bones, kidney stone formation, enlarged liver, development of abnormal or missed heart beats (arrhythmias), inflammation of the covering of the heart (pericarditis), or heart failure, nervous system effects, including hearing loss, meningitis, seizures, or psychiatric disorders (for example, dementia, depression, psychosis).

[00161] In one aspect of the invention, inhalation administration of one of the compositions provided herein to a patient in need of pulmonary sarcoidosis treatment results in a decreased number of pulmonary sarcoidosis symptoms experienced by the patient, or a decreased seventy of one or more symptoms experienced by the patient, as compared to the number of symptoms or severity of the one or more symptoms experienced by the patient prior to administration of the composition.

[00162] Lofgren's syndrome is a classic set of signs and symptoms that is typical in some people who have sarcoidosis. Lofgren's syndrome may cause fever, enlarged lymph nodes, arthritis (usually in the ankles), and/or erythema nodosum, a rash of red or reddish-purple bumps on ankles and shins. The present invention, in one embodiment, serves to decrease one or more symptoms of Lofgren's syndrome in a patient via inhalation of one of the or compositions provided herein, as compared to the number or severity of the one or more symptoms prior to administration of the composition.

[00163] In another embodiment, the inhalation administration of one of the compositions provided herein results in a decreased number of sarcoidosis symptoms experienced by the patient, or a decreased severity of one or more symptoms experienced by the patient, as compared to the number of symptoms or severity of the one or more symptoms experienced by the patient when administered the same antisarcoid compound present in the composition (or a derivative or pharmaceutically acceptable salt thereof) via a non-inhalation route of administration. In a further embodiment, the non-inhalation route of administration is subcutaneous, intravenous or oral.

[00164] In another embodiment, the administration of the effective amount of one of the compositions provided herein results in a decreased number of sarcoidosis symptoms experienced by the patient, or a decreased severity of the one or more symptoms experienced by the patient, as compared to the number of symptoms or severity of the one or more symptoms experienced by the patient when administered a corticosteroid compound, a derivative thereof, or pharmaceutically acceptable salt thereof, via oral or inhaled administration. In one embodiment, the corticosteroid compound is prednisone, prednisolone, fiunisolide, fluticasone furoate, fluticasone propionate, triamcinolone acetonide, beclomethasone dipropionate and/or budesonide.

[00165] In one embodiment, the one or more symptoms is dry cough, fatigue, shortness of breath, weight loss, tender reddish bumps or patches on the skin, inflammation of the eyes, swollen and painful joints, enlarged and tender lymph glands in the neck, armpits, and groin, enlarged lymph glands in the chest and around the lungs, hoarse voice, pain in the hands, feet, or other bony areas due to the formation of cysts (an abnormal sac-like growth) in bones, kidney stone formation, enlarged liver, development of abnormal or missed heart beats (arrhythmias), inflammation of the covering of the heart (pericarditis), or heart failure, nervous system effects, including hearing loss, meningitis, seizures, or psychiatric disorders (for example, dementia, depression, psychosis).

[00166] Fatigue is very often manifested in sarcoidosis patients. A 10- item Fatigue

Assessment Scale (FAS) has been developed to measure fatigue in sarcoidosis patients and to assess progress in combating fatigue during treatment (Michielson et ai. 2004, Eur. J. Psychological Assessment 20(1): 39-48, incorporated by reference in its entirety herein for all purposes). The scale indicates both physical and psychological fatigue. Each item has a five- point rating scale and FAS scores range from 10 to 50. FAS scores <22 indicate nonfatigued persons, scores of 22-34 indicate fatigued persons and scores of >35 indicate extremely fatigued persons. The psychometric properties of the FAS are also good in sarcoidosis.

[00167] In one embodiment, administration of one of the compositions provided herein results in decreased severity of fatigue. In another embodiment, the decreased severity of fatigue is measured by the Fatigue Assessment Scale (FAS). In one embodiment the severity of fatigue decreases at least about I point, by at least about 2 points, by at least about 3 points, by at least about 4 points, by at least about 5 points, by at least about 6 points, by at least about 7 points, by at least about 8 points, by at least about 9 points, by at least about 10 points, by at least about 11 points, by at least about 12 points, by at least about 3 points, by at least about 14 points, by at least about 15 points, by at least about 16 points, by at least about 17 points, by at least about 18 points, by at least about 19 points, by at least about 20 points, by at least about 21 points, by at least about 22 points, by at least about 23 points, by at least about 24 points, by at least about 25 points, by at least about 26 points, by at least about 27 points, by at least about 28 points, by at least about 29 points, by at least about 30 points, by at least about 31 points, by at least about 32 points, by at least about 33 points, by at least about 34 points, by at least about 35 points, by at least about 36 points, by at least about 37 points, by at least about 38 points, by at least about 39 points or by at least about 40 points, as measured by the FAS.

| 00168] In one embodiment, administration of a composition of the present invention for the treatment of pulmonary sarcoidosis via inhalation results in reduced inflammation in the patient, as compared to the inflammation experienced by the patient prior to administration of the composition.

| 00169] In one embodiment, administration of one of the compounds provided herein to a patient in need of pulmonary sarcoidosis treatment via inhalation results in reduced inflammation experienced by the patient, as compared to the inflammation experienced by the patient when administered the same compound, or pharmaceutically acceptable salt thereof, via a different route of administration, e.g., an oral, subcutaneous or intravenous route of administration.

[00170] In one embodiment, administration of one of the compositions provided herein to a patient in need of pulmonary sarcoidosis treatment via inhalation results in reduced inflammation experienced by the patient, as compared to the inflammation experienced by the patient when administered a corticosteroid compound, a derivative thereof, or pharmaceutically acceptable salt thereof, via oral or inhaled administration. In a further embodiment, the corticosteroid compound is prednisone, prednisolone, flunisoiide, fluticasone furoate, fluticasone propionate, triamcinolone acetonide, beclomethasone dipropionate and/or budesonide.

[00171] Patients can be evaluated by chest radiographs (X-rays), CT scan of chest, positron emission tomography scan, CT-guided biopsy, mediastinoscopy, open lung biopsy, bronchoscopy with biopsy, endobronchial ultrasound, and endoscopic ultrasound with fine needle aspiration of mediastinal lymph nodes to determine whether they are in need of treatment and whether treatment is effective. [00172] Pulmonary function tests are used routinely in evaluation and follow-up of pulmonary sarcoidosis patients. "Forced vital capacity" (FVC) denotes the volume of gas which is exhaled during a forced expiration starting from a position of full inspiration and ending at complete expiration and is one measure of treatment efficacy. "Forced expiratory volume in one second" (FEVi) is another measure of treatment efficacy and is the volume of gas exhaled in a specified time (typically 1 second) from the start of the forced vital capacity maneuver (Quanjer et al. (1993). Eur. Respir. J. 6, Suppl. 16, pp. 5-40, incorporated by reference herein in its entirety for all purposes). FVC and FEVi are measured with a pneumotachograph and are usually expressed as a percentage predicted (FVC%, FEVi%).

[00173] The diffusing capacity of the lung for carbon monoxide (DLCO) is the extent to which oxygen passes from the air sacs of the lungs into the blood. The DLCO test involves measuring the partial pressure difference between inspired and expired carbon monoxide. It relies on the strong affinity and large absorption capacity of erythrocytes for carbon monoxide and thus demonstrates gas uptake by the capillaries that are less dependent on cardiac output. FVC%, FEVi% and DLCO are decreased in sarcoidosis patients. In one embodiment, an increase in one or more of these measurements denotes an effective treatment.

[00174] In one embodiment, administration of one of the compositions provided herein via inhalation results in improved percentage predicted forced vital capacity (FVC%), percentage predicted forced expiratory volume in one second (FEVi%), and/or chest radiograph of the patient, as compared to a FVC%, FEVi% and/or a chest radiograph of the patient prior to treatment, or as compared to a FVC%, FEVi% and/or a chest radiograph improvement experienced by a pulmonary sarcoidosis patient undergoing corticosteroid treatment.

[00175] In one embodiment, the FVC% of a patient administered a composition of the present invention via inhalation is greater by about 1%, greater by about 2%, greater by about 3%, greater by about 4%, greater by about 5%, greater by about 6%, greater by about 7%, greater by about 8%, greater by about 9%, greater by about 10%, greater by about %, greater by about 12%, greater by about 13%, greater by about 14%, greater by about 15%, greater by about 16%, greater by about 17%, greater by about 18%, greater by about 19%, greater by about 20%, greater by about 25%, greater by about 30%, greater by about 35%, greater by about 40%, greater by about 45%, greater by about 50%, greater by about 55%, greater by about 60%, greater by about 65%, greater by about 70%, greater by about 75%, greater by about 80%, greater by about 85%, greater by about 90%, and all values in between compared to a FVC% of the patient prior to treatment. 00176] In another embodiment, the FEVi% of a patient administered a composition of the present invention via inhalation is greater by about 1%, greater by about 2%, greater by about 3%, greater by about 4%, greater by about 5%, greater by about 6%, greater by about 7%, greater by about 8%, greater by about 9%, greater by about 10%, greater by about 11%, greater by about 12%, greater by about 13%, greater by about 14%, greater by about 15%, greater by about 16%, greater by about 17%, greater by about 18%, greater by about 19%, greater by about 20%, greater by about 25%, greater by about 30%, greater by about 35%, greater by about 40%, greater by about 45%, greater by about 50%, greater by about 55%, greater by about 60%, greater by about 65%, greater by about 70%, greater by about 75%, greater by about 80%, greater by about 85%, greater by about 90%, and all values in between compared to a FEVi% of the patient prior to treatment.

[00177] In one embodiment, the stage of the chest radiograph of a patient administered a composition of the present invention via inhalation improves from stage 4 to stage 3, from stage 4 to stage 2, from stage 4 to stage 1, from stage 3 to stage 2, from stage 3 to stage 1, from stage 2 to stage I, compared to the stage of a chest radiograph of the patient prior to treatment.

[00178] The skin is the second most affected organ in sarcoidosis, occurring in about 25% to 30% of cases. The most common lesions include erythema nodosum, plaques, maculopapular eruptions, subcutaneous nodules and lupus pernio. Some lesions spontaneously resolve within a few weeks. Skin lesions can be evaluated by a number of scoring systems for chronic facial lesions such as: the Sarcoidosis Activity and Severity Index (SASI) (Baughman et al. (2008) Am. J. of Clinical Dermatology 9, pp. 155-161, incorporated by reference herein in its entirety for all purposes), the Lupus Pernio Activity and Severity Index (LuPASI), a scoring system specific for this skin condition (Baughman et al. (2004) Chest Journal 126 (4_Meeting Abstracts): 891 S, incorporated by reference herein in its entirety for all purposes) and the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) (Rosenbach et al. 2013, JAMA Dermatology

149(5): 550-556, incorporated by reference herein in its entirety for all purposes).

[00179] SASI evaluates the following four features for each of the four facial quadrants and the nose: erythema, induration, and desquamation, each ranging from 0 (none) to 4 (very severe), and an area score ranging from 0 (0%) to 6 (90%- 100%). Thus, SASI produces 5 separate sets of scores per patient. The Facial SASI score weighs these SASI components to provide a composite index for the face. SASI can be modified and incorporated into clinical trials. For example, the sums of the erythema, induration, and desquamation scores for each quadrant of the face and the nose can be multiplied by their respective area scores and then averaged with equal weight on ail 5 regions. The maximal range of the modified Facial SASI scores is 0 to 72.

[00180] The LuPASI is specific for scoring lupus pernio and is based on the psoriasis activity and severity index. The face is divided into specific areas and each area is separately scored on a five point scale for erythema (E), induration (I), and desquamation (D). The total amount of the area (A) involved is also assessed on a 7 point scale. The divisions are the four quadrants of the face, with the division of upper and lower being through the mid eye, and the nose is scored separately.

[00181] The CSAMI consists of 2 scores measuring disease activity and damage done by the disease. The Activity and Damage scales are considered separately to aid the instrument in detecting changes in disease activity, rather than remaining stable as a single conglomerate outcome as inflammatory activity subsides and chronic damage develops. Activity is scored based on inflammation, induration and/or depression, surface changes, such as scaling and ulceration, and area of involvement. Damage is scored based on dyspigmentation and scarring. Clinical signs are documented according to the worst affected lesion within each anatomical area and summed, with maximal score ranges of 0 to 165 for the Activity scale and 0 to 22 for the Damage scale. In addition, CSAMI assesses morphologic types of cutaneous sarcoidosis lesions, documenting a predominant type and all other types present. The instrument also examines the presence of lesion types that connote specific significance when present, including lupus pernio and erythema nodosum. [00182] In one embodiment, the patient has cutaneous sarcoidosis in addition to pulmonary sarcoidosis. In another embodiment administration of the composition results in improved Sarcoidosis Activity and Severity Index (SASI), Lupus Pernio Activity and Severity Index (LuPASl) or Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) of the patient, as compared to the patient's SASI, LuPASl or CSAMI prior to treatment.

[00183] In one embodiment, the patient's SASI, LuPASl or CSAMI score improves by less than 1 point, by about 1 point, by about 2 points, by about 3 points, by about 4 points, by about 5 points, by about 6 points, by about 7 points, by about 8 points, by about 9 points, by about 10 points, or more, as compared to the patient's SASI, LuPASl or CSAMI score prior to treatment.

[00184] The compositions provided herein may also be used in combination with an enhancer agent and/or with a second active ingredient. In certain embodiments, the compounds are administered in combination in the same composition, or administered serially. Such other therapeutic agents include those known for treatment, prevention, or amelioration of one or more symptoms associated with sarcoidosis.

[00185] While the described invention has been described with reference to the specific embodiments thereof it should be understood by those skilled in the art that various changes may ^¬ be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adopt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the described invention. All such modifications are intended to be within the scope of the claims appended hereto.

[00186] Patents, patent applications, patent application publications, journal articles and protocols referenced herein are incorporated by reference in their entireties, for ail purposes.