WO2017223400A1 - Composés prostacycline et compositions pour le traitement de la sarcoidose - Google Patents

Composés prostacycline et compositions pour le traitement de la sarcoidose Download PDF

Info

Publication number
WO2017223400A1
WO2017223400A1 PCT/US2017/038932 US2017038932W WO2017223400A1 WO 2017223400 A1 WO2017223400 A1 WO 2017223400A1 US 2017038932 W US2017038932 W US 2017038932W WO 2017223400 A1 WO2017223400 A1 WO 2017223400A1
Authority
WO
WIPO (PCT)
Prior art keywords
linear
alkyl
branched
patient
alkenyl
Prior art date
Application number
PCT/US2017/038932
Other languages
English (en)
Inventor
Walter Perkins
Vladimir Malinin
Keith DIPETRILLO
Kuan-Ju CHEN
Original Assignee
Insmed Incorporated
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Insmed Incorporated filed Critical Insmed Incorporated
Publication of WO2017223400A1 publication Critical patent/WO2017223400A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/708—Ethers
    • C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/14—Benz[f]indenes; Hydrogenated benz[f]indenes

Definitions

  • 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.
  • Symptoms and signs of the disease are due to the granulomas altering organs and tissues.
  • 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.
  • NSAIDs Nonsteroidal anti- inflammatory drugs
  • corticosteroid therapy has been the standard treatment. Fatigue and persistent cough are usually improved with steroid treatment.
  • a method for treating a sarcoidosis patient in need thereof comprises administering to the patient a composition comprising an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt:
  • 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
  • n is an integer from 0 to 5, with the proviso that the prostacyclin compound is not treprostinil.
  • composition is administered via inhalation.
  • a method for treating a sarcoidosis patient in need thereof comprises administering to the patient a composition comprising an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt:
  • 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
  • n is an integer from 0 to 5.
  • the composition is administered via inhalation, e.g., via a nebulizer, dry powder inhaler or metered dose inhaler.
  • 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.
  • R2 is a linear Cs-Cis alkyi or a branched Cs-Cis alkyl.
  • R2 is a linear Ce-Ci 2 alkyl or a branched Ce-Cn alkyl.
  • 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.
  • 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.
  • 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 N and n is 0.
  • 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.
  • n is 0 or 1.
  • Ri is N or O.
  • 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?.
  • R> is a linear C , Cs Cio, Cj 2, CM alkyl or Cie alkyl.
  • R?. is a linear Ci6 alkyl.
  • 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.
  • n is 0 or 1.
  • Ri is N or O.
  • the branched alkyl is hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl or octadecyl.
  • a method for treating sarcoidosis in a patient in need thereof via inhalation administration 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
  • n is 0 or 1.
  • Ri is N or O.
  • the branched alkyl is hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl or octadecyl.
  • 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
  • the composition administered via the methods provided herein comprises a prostacyclin compound of Formula (I), (II) or (III) and a hydrophobic additive.
  • the hydrophobic additive is a hydrocarbon, a terpene or a hydrophobic lipid.
  • 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.
  • the hydrophobic additive is squalane.
  • the composition in another embodiment comprises a compound of Formula (I), (II) or (III), and an amphiphilic agent.
  • the amphiphilic agent is a PEGylated lipid, a surfactant or a block copolymer.
  • 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.
  • 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).
  • 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.
  • the amphiphilic agent is a PEGylated lipid, a surfactant or a block copolymer.
  • the hydrophobic additive is squalane.
  • a PEGylated lipid is present in the composition and comprises PEG400, PEG500, PEGIOOO, PEG2000, PEG3000, PEG4000 or PEG5000.
  • alkyl 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.
  • 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).
  • alkenyl refers to a carbon chain containing one or more carbon-carbon double bonds.
  • aryl refers to a cyclic hydrocarbon, where the ring is characterized by delocalized ⁇ electrons (aromaticity) shared among the ring members, and wherein the number of ring atoms is indicated by a range of numbers.
  • 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.
  • alkoxy refers to -O-(alkyl), wherein “alkyl” is as defined above.
  • 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 .
  • 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
  • amino acid for example, the amino acid moieties H 5 H
  • non-natural ammo acids amenable for use with the present invention include ⁇ -alanine ( ⁇ -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
  • 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); ⁇ -aminohexanoic acid (Aha); ⁇ -aminovaleric acid (Ava); N-methylglycine (MeGly).
  • 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).
  • 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.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • 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
  • 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.
  • 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.
  • a prostacyclin compound for example, a treprostinil alkyl ester
  • the prostacyclin compound provided herein in one embodiment, can be administered less frequently than treprostinil, with equal or greater efficacy.
  • the side effect profile of the compounds provided herein is less deleterious than the side effect profile resulting from treprostinil administration.
  • composition administered to the sarcoidosis patient in need of treatment is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
  • 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;
  • 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.
  • the composition comprises the compound of Formula (I), wherein J3 ⁇ 4 is OH and n is 0 or 1.
  • R 4 is an optionally substituted linear or branched C1-C15 alkyl.
  • Ri is NH or O.
  • 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.
  • Ri is NH or O and R2 is a linear Cs-C is alkyl or a branched Cs-Cis alkyl.
  • 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.
  • R 4 is an optionally substituted linear or branched Ci-Cis alkyl.
  • 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:
  • R 4 is , with the proviso that the compound is not treprostinil, i.e., R2 and Rs cannot both be H.
  • R2 is a
  • 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.
  • R 2 is r m2 and ml and ml are both 4.
  • R2 is m ⁇ ' m2 and ml is 3 and m2 is 4, or ml is 2 and m2 is 3.
  • R3 is OH and R 4 is , where R5 is Fl, optionally substituted linear or branched Ci-
  • 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.
  • 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,
  • 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'):
  • Rs is Fl
  • optionally substituted linear or branched C1-C15 alkyl optionally substituted linear or branched C2-C15 alkenyl
  • 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.
  • 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:
  • 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
  • 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.
  • R is decyl, undecvl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
  • R2 is a linear aikyl.
  • 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").
  • R2 is a linear Cs-Cis aikyl or a branched Cs-Cis aikyl.
  • R2 is a linear Ce-Cis aikyl or a branched Ce-Cis aikyl
  • R2 is a linear C6-C1 aikyl, e.g., a linear C 6 aikyl, Cs aikyl, C10 aikyl, C12 aikyl or CM aikyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • composition is administered to the patient via a nebulizer, dry powder inhaler or a metered dose inhaler,
  • a method for treating a sarcoidosis patient comprises administering to the patient a composition comprising a compound ofFormula
  • ml and ml are each independently an integer selected from 1 to 9.
  • compositions comprising compounds
  • ml and m2 are each independently an integer selected from 1 to 9.
  • 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.
  • 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.
  • 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?
  • composition comprising a compound of Formula (I), (la), (Ib), (Ic), (Id), (la'), (lb'), (Ic'), (Id'), (la"), (lb"), (Ic") or (Id") is administered to the
  • ft? is ml A .
  • 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.
  • R' is independently H, a linear or branched Ci-Cg aikyl, or a linear or branched Ci-Cs alkenyi.
  • 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.
  • 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.
  • a sarcoidosis patient is administered a composition comprising the following compound:
  • Ri is NH, O or S.
  • Ri is O or N
  • one of the following compounds (5-nonanyl treprostinil (aikyl ester, SCs-TR) or 5-nonanyl treprostinil (amide linked; 5C9-TR-A), is provided:
  • a prostacyclin compound of Formula (I), (la), (lb), (Ic) or (Id) is
  • 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.
  • the sarcoidosis patient is administed a composition comprising a compound of Formula (I), (la), (lb), (Ic), (Id), (la'), (lb'), (Ic' '), (la"), (lb"),
  • the compounds administered via the methods provided herein can include a symmetrical branched alkyl or an asymmetrical branched alkyl as the 2 moiety.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • R2 is a linear Cs-Cis alkenyl selected from pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenvl, tridecenvl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl or octadecenyl.
  • R3 is OH.
  • R2 is a branched Cs-Cis alkenyl selected from pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenvl, tridecenvl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl or octadecenyl.
  • R3 is OH.
  • composition comprising a, a ed thereof, and
  • a composition comprising a compound of Formula (I), (la), (lb), (Ic) or (Id) is administered to a patient in need of sarcoidosis tre .
  • R 2 a linear C5-C18 alkyl
  • R3 is OH and .
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • the compound is a compound of Formula (Ic").
  • 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.
  • the compound is a compound of Formula (la”).
  • the composition is a lipid nanoparticle formulation as described in more detail below.
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • a method for treating sarcoidosis 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),
  • 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;
  • n is an integer from 0 to 5.
  • a method for treating sarcoidosis 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.
  • 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 (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.
  • 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.
  • a compound of Formula (II), (Ila), (lib), (lie) or (lid) wherein one or more hydrogen atoms is substituted with a deuterium.
  • 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.
  • the composition administered to the patient comparises an effective amount of a compound of Formula (lie).
  • R2 is a linear Cs-Cis alkyl or a branched Cs-Cis alkyl.
  • R2 is a linear Ce-Cis alkyl.
  • R2 is a linear Ce-Cio alkyl.
  • R2 is a hexyl, heptyl or octyl.
  • 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
  • R.2 linear Cio-Cis alkyl
  • R2 branched Cio-Cis alkyl
  • R ⁇ branched C , , alkyl
  • R.2 linear C12-C18 alkyl
  • R.2 branched C12-C18 alkyl
  • R2 linear C15 alkyl
  • R2 branched Co 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 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 C12 alkyl
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the prostacyclin compound and amphiphilic agent form micro- or nanoparticles.
  • the amphiphilic agent is a PEGylated lipid, a surfactant or a block copolymer.
  • 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).
  • an amphiphilic agent e.g., PEGylated lipid, a lipid, a surfactant or a block copolymer.
  • the prostacyclin composition comprising the prostacyclin compound component and amphiphilic agent, when formulated together, comprise a plurality of nanoparticles.
  • 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.
  • 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.
  • 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.
  • the PEGylated lipid comprises PEG400-PEG5000.
  • the PEGylated lipid comprises PEG400, PEG500, PEG! 000, PEG2000, PEG3000, PEG4000, or PEG5000.
  • 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).
  • the PEGylated lipid is cholesterol-PEG2000 or DSPE-PEG2000.
  • 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.
  • 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.
  • the PEG has a MW of 1000 g/mol or 2000 g/mol.
  • 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.
  • the lipid is a sterol.
  • the sterol is cholesterol.
  • 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).
  • the phospholipid is an egg phospholipid, a soya phospholipid or a hydrogenated egg and soya phospholipid.
  • the PEGyiated lipid comprises a phospholipid.
  • 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.
  • 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).
  • DSPE distearoylphosphoethanolamme
  • DPPC dipalmitoylphosphatidyl choline
  • DOPC dioleoylphosphatidyl choline
  • DMPE dipalmitoylphosphoethanolamine
  • DSPE dimyristoylglycerol
  • DMG dimyristoylglycerol
  • DPG diphosphat
  • 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).
  • DMPC dimyristoylphosphati
  • 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).
  • DLEP dilauroyl ethylphosphocholine
  • DMEP dimyristoyl ethylphosphocholine
  • DPEP dipalmitoyl ethylphosphocholine
  • DSEP distearoyl ethylphosphocho
  • 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,
  • the PEGylated lipid is cholesterol-PEG2000, DSPE-PEG1 000 or DSG-PEG2000.
  • 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.
  • the composition comprises an amphophilic agent, e.g. , a PEGylated lipid, as described above.
  • 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.
  • an amphiphilic agent e.g., PEGylated lipid, a lipid, a surfactant or a block copolymer
  • 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.
  • 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.
  • 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.
  • the amphiphilic agent is a surfactant, a PEGylated lipid or a block copolymer.
  • the amphiphilic agent is a PEGylated lipid.
  • 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%.
  • the amphiphilic agent e.g., a PEGylated lipid
  • 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%.
  • the PEGylated lipid is present in the composition at about 10 mol% or 20 mol%.
  • 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%.
  • the prostacyclin composition in one embodiment, comprises a compound of
  • the hydrophobic additive ⁇ e.g., an additive that is at least partially hydrophobic
  • 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.
  • the hydrocarbon is an aikane (i.e., a saturated hydrocarbon).
  • the hydrocarbon is a C15-C50 hydrocarbon.
  • the hydrocarbon is a C15, C20, C25, C30, C35, C40, C45 or C50 hydrocarbon.
  • 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.
  • 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.
  • 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).
  • 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.
  • the hydrophobic additive is squalane.
  • compositions of the present invention are compositions of the present invention.
  • the composition provided herein in one embodiment, comprises a prostacyclin compound and one or more PEGylated lipids.
  • the composition comprises a hydrophobic additive, as described above.
  • 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.
  • the hydrophobic additive comprises a hydrocarbon e.g, a terpene compound.
  • the treprostiml derivative composition provided herein includes the components provided in Tables 4 and 5, below.
  • R 2 is Smear C6-Ci6
  • R2 is linear Ce-Cie
  • R2 is linear Ce-Cu
  • R2 is linear C10-C16
  • R2 is linear Cio-Cie
  • R is linear Cio-Cie
  • R2 is linear Cio-Cj6
  • R2 is linear C12-C16
  • R2 is linear C12-C16
  • R> is linear C12-C16
  • R2 is Smear CU-CM
  • R2 is branched C6 ⁇ Ci6
  • R2 is branched C6-C16
  • R2 is branched Ce-Cie
  • R 2 is branched Ce-Cie
  • R2 is linear Ce-Cie Table 4. Representative Treprostinil Compositions.
  • R 2 is linear d-d 6
  • R2 is linear Ce-Cio
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • NSG sarcoid granulomatosis
  • 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.
  • pulmonary opacification 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.
  • 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).
  • a composition of the present invention is administered to a patient via inhalation, wherein the patient has pulmonary sarcoidosis resistant to steroid treatment.
  • the patient was non-responsive to previous sarcoidosis treatment, or experienced adverse effects from a previous sarcoidosis treatment.
  • the patient has cutaneous sarcoidosis in addition to pulmonary sarcoidosis.
  • the patient is a human.
  • the human patient can be a child (i.e., ⁇ eighteen years old) or adult (i.e., > eighteen years old).
  • the methods provided herein are amenable for use with teen-aged patients, e.g., from about 13 years old to about 18 years old.
  • 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.
  • the subject treated with the methods, compositions and kits provided herein is from about 25 years old to about 40 years old.
  • 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.
  • the pulmonary sarcoidosis patient treated with the methods provided herein has a pre-existing, simultaneous or subsequent malignancy.
  • 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.
  • 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).
  • 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.
  • a compound described herein is suspended in a propellant and delivered to a patient via an MDI.
  • 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.
  • administration of the composition occurs every other day or once per week.
  • 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.
  • 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.
  • MDI metered dose inhaler
  • 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.
  • inhalation delivery devices include a jet nebulizer, electronic nebulizer, a soft mist inhaler, and a capsule-based dry powder inhaler.
  • the compound is provided to the patient as a composition comprising a lipid component.
  • a metered dose inhalator is employed as the inhalation delivery device for the compositions of the present invention.
  • one of the compounds described herein is suspended in a propellant (e.g., hydrofluorocarbon) prior to loading into the MDI.
  • a propellant e.g., hydrofluorocarbon
  • 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.
  • 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.
  • a compound of the present invention is administered via a metered dose inhaler (IVIDI) to a patient in need of sarcoidosis treatment.
  • IVIDI metered dose inhaler
  • the patient in one embodiment, is administered the composition once daily or twice daily.
  • the administration is with food.
  • 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.
  • 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.
  • 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.
  • the administration is with food.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a nebulizer type inhalation deliver ⁇ ' device can contain the compositions of the present invention as a solution, usually aqueous, or a suspension.
  • the composition can be suspended in saline and loaded into the inhalation deliver ⁇ ' device.
  • 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.
  • 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
  • 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.
  • blister packs containing single doses of the composition may be employed.
  • 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.
  • the nebulizer may be employed to ensure the sizing of particles is optimal for positioning of the particle within, for example, the pulmonary membrane.
  • a metered dose inhalator 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.
  • 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.
  • 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.
  • HFC 134a 1, 1,1,2,3,3,3- heptafluoropropane
  • HFA-22-7 1, 1,1,2,3,3,3- heptafluoropropane
  • HFA-22 difluorochloromethane
  • HFA-152 difluoroethane and isobutene
  • 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.
  • 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 ⁇ . 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).
  • an effective amount of a prostacyclin compound, or a pharmaceutically acceptable salt thereof is reduced in particle size.
  • the particle size is reduced by milling, spray drying, using supercritical fluids, and/or by an emulsion template process.
  • the compound is passed through a sieve. In yet another embodiment, the sieve size is about 5 ⁇ .
  • the aerosolized composition 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.
  • GSD Global Standard deviation
  • 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 ⁇ or about 1 ⁇ to about 5 ⁇ , 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.
  • FPF Frine particle fraction
  • the nebulizer may be employed to ensure the sizing of particles is optimal for positioning of the particle within, for example, the pulmonary membrane.
  • the mass median aerodynamic diameter (MMAD) of the aerosol particles is about 1 ⁇ to about 5 ⁇ , or about 1 ⁇ to about 4 ⁇ , or about 1 ⁇ to about 3 ⁇ , or about 2 ⁇ to about 3 ⁇ , or about 1 ⁇ to about 2 ⁇ , as measured by cascade impaction, for example, by the ACI or NGI.
  • the MMAD of the aerosol particles is about 5 ⁇ or less, about 4 ⁇ or less, about 3 ⁇ or less, about 2 ⁇ or less, or about 1 ⁇ or less, as measured by cascade impaction, for example, by the ACI or NGI.
  • GSD Global Standard deviation
  • 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 ⁇ or about 1 ⁇ to about 5 ⁇ , 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.
  • Respirable mass or "RM”, as used herein, is usually expressed as ⁇ and is the total amount of emitted drug product that exits the metered dose inhaler upon actuation.
  • the respirable mass of the aerosol particles is about 1 ⁇ g/shot to about 100 or about 1 ⁇ / ⁇ to about 50 £/8 ⁇ , or about 1 ⁇ / ⁇ to about 40 ⁇ , or about 1 ⁇ /8 ⁇ to about 30 ⁇ /8 ⁇ 1, or about 3 ⁇ to about 80 ⁇ /8 ⁇ , or about 3 £/8 ⁇ to about 70 to about 50 ⁇ , about 3 £/8 ⁇ to about 40 ⁇ , about 3 £/8 ⁇ to about 30 ⁇ , as measured by the ACT or NGI.
  • FPF fine particle fraction
  • 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.
  • 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.
  • Percent throat deposition or "PTD” is the amount of drug deposited on the throat of the cascade impactor and is expressed as a percentage.
  • 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.
  • a dry powder inhaler is employed as the inhalation delivery device for the compositions of the present invention.
  • the DPI generates particles having an MMAD of from about 1 ⁇ to about 10 ⁇ , or about 1 ⁇ to about 9 ⁇ , or about 1 ⁇ to about 8 ⁇ , or about 1 ⁇ to about 7 ⁇ , or about 1 ⁇ to about 6 ⁇ , or about 1 ⁇ to about 5 ⁇ , or about 1 ⁇ to about 4 ⁇ , or about 1 ⁇ to about 3 ⁇ , or about 1 ⁇ to about 2 ⁇ in diameter, as measured by the NGI or ACI.
  • the DPI generates a particles having an MMAD of from about 1 ⁇ to about 10 ⁇ , or about 2 ⁇ to about 10 ⁇ , or about 3 ⁇ to about 10 ⁇ , or about 4 ⁇ to about 10 ⁇ , or about 5 ⁇ to about 10 ⁇ , or about 6 ⁇ to about 10 ⁇ , or about 7 ⁇ to about 10 ⁇ , or about 8 ⁇ to about 10 ⁇ , or about 9 ⁇ to about 10 ⁇ , as measured by the NGI or ACI.
  • the MMAD of the particles generated by the DPI is about 10 ⁇ or less, about 9 ⁇ or less, about 8 ⁇ or less, about 7 ⁇ or less, about 6 ⁇ or less, about 5 ⁇ or less, about 4 ⁇ or less, about 3 ⁇ or less, about 2 ⁇ or less, or about 1 ⁇ or less, as measured by the NGI or ACL
  • the MMAD of the particles generated by the DPI is less than about 9.9 ⁇ , less than about 9.5 ⁇ , less than about 9.3 ⁇ , less than about 9.2 ⁇ , less than about 9.1 ⁇ , less than about 9.0 ⁇ , less than about 8.5 ⁇ , less than about 8.3 ⁇ , less than about 8.2 ⁇ , less than about 8.1 ⁇ , less than about 8.0 ⁇ , less than about 7.5 ⁇ , less than about 7.3 ⁇ , less than about 7.2 ⁇ , less than about 7.1 ⁇ , less than about 7.0 ⁇ , less than about 6.5 ⁇ , less than about 6.3 ⁇ , less than about 6.2 ⁇ , less than about 6.1 ⁇ , less than about 6.0 ⁇ , less than about 5.5 ⁇ , less than about 5.3 ⁇ , less than about 5.2 ⁇ , less than about 5.1 ⁇ , less than about 5.0 ⁇ , less than about 4.5 ⁇ , less than about 4.3 ⁇ , less than about 4.2 ⁇ , less than
  • the MMAD of the particles generated by the DPI is from about 1.0 ⁇ to about 10.0 ⁇ , from about 2.0 ⁇ to about 9.5 ⁇ , from about 2.5 ⁇ to about 9.0 ⁇ , from about 3.0 ⁇ to about 9.0 ⁇ , from about 3.5 ⁇ to about 8.5 ⁇ or from about 4.0 ⁇ to about 8.0 ⁇ .
  • 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.
  • 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.
  • 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).
  • 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.
  • 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 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.
  • 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.
  • the non-inhalation route of administration is subcutaneous, intravenous or oral.
  • 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.
  • the corticosteroid compound is prednisone, prednisolone, fiunisolide, fluticasone furoate, fluticasone propionate, triamcinolone acetonide, beclomethasone dipropionate and/or budesonide.
  • 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).
  • Fatigue is very often manifested in sarcoidosis patients.
  • a 10- item Fatigue is very often manifested in sarcoidosis patients.
  • FAS Assessment Scale
  • administering one of the compositions provided herein results in decreased severity of fatigue.
  • the decreased severity of fatigue is measured by the Fatigue Assessment Scale (FAS).
  • FAS Fatigue Assessment Scale
  • 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
  • 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.
  • 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.
  • administering 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.
  • the corticosteroid compound is prednisone, prednisolone, flunisoiide, fluticasone furoate, fluticasone propionate, triamcinolone acetonide, beclomethasone dipropionate and/or budesonide.
  • 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.
  • 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.
  • FEVi Form expiratory volume in one second
  • FVC and FEVi are measured with a pneumotachograph and are usually expressed as a percentage predicted (FVC%, FEVi%).
  • the diffusing capacity of the lung for carbon monoxide 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.
  • 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.
  • FVC% percentage predicted forced vital capacity
  • FEVi% percentage predicted forced expiratory volume in one second
  • 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.
  • 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.
  • 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.
  • 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.
  • SASI Sarcoidosis Activity and Severity Index
  • 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.
  • 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.
  • 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.
  • 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.
  • lesion types that connote specific significance when present, including lupus pernio and erythema nodosum.
  • 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.
  • SASI Sarcoidosis Activity and Severity Index
  • LiPASl Lupus Pernio Activity and Severity Index
  • CSAMI Cutaneous Sarcoidosis Activity and Morphology Instrument
  • 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.
  • compositions provided herein may also be used in combination with an enhancer agent and/or with a second active ingredient.
  • 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.
  • Patents, patent applications, patent application publications, journal articles and protocols referenced herein are incorporated by reference in their entireties, for ail purposes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Méthodes pour le traitement d'un patient souffrant d'une sarcoïdose pulmonaire. Les compositions sont formulées pour l'administration à un patient ayant besoin d'un traitement par inhalation. Dans un mode de réalisation, la méthode de traitement de la sarcoïdose pulmonaire chez un patient qui en a besoin consiste à administrer aux poumons du patient par inhalation une composition comprenant une quantité efficace d'un promédicament de tréprostinil, par exemple, un promédicament d'ester d'alkyle de tréprostinil (par exemple, un alkyle linéaire C13-C18, un alkyle ramifié C13-C18) ou une composition comprenant celui-ci. Dans un mode de réalisation, la composition comprend un lipide pégylé et du squalane.
PCT/US2017/038932 2016-06-24 2017-06-23 Composés prostacycline et compositions pour le traitement de la sarcoidose WO2017223400A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662354234P 2016-06-24 2016-06-24
US62/354,234 2016-06-24

Publications (1)

Publication Number Publication Date
WO2017223400A1 true WO2017223400A1 (fr) 2017-12-28

Family

ID=60784878

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/038932 WO2017223400A1 (fr) 2016-06-24 2017-06-23 Composés prostacycline et compositions pour le traitement de la sarcoidose

Country Status (1)

Country Link
WO (1) WO2017223400A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10343979B2 (en) 2014-11-18 2019-07-09 Insmed Incorporated Methods of manufacturing treprostinil and treprostinil derivative prodrugs
US10526274B2 (en) 2013-10-25 2020-01-07 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
US11458098B2 (en) 2019-04-29 2022-10-04 Insmed Incorporated Dry powder compositions of treprostinil prodrugs and methods of use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010039531A1 (fr) * 2008-09-23 2010-04-08 Resolvyx Pharmaceuticals, Inc. Composés thérapeutiques
WO2014110491A1 (fr) * 2013-01-11 2014-07-17 Theratrophix Llc Promédicaments de tréprostinil
US20150148414A1 (en) * 2013-10-25 2015-05-28 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
WO2016081658A1 (fr) * 2014-11-18 2016-05-26 Insmed Incorporated Procédés de fabrication de tréprostinil et promédicaments dérivés de tréprostinil

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010039531A1 (fr) * 2008-09-23 2010-04-08 Resolvyx Pharmaceuticals, Inc. Composés thérapeutiques
WO2014110491A1 (fr) * 2013-01-11 2014-07-17 Theratrophix Llc Promédicaments de tréprostinil
US20150148414A1 (en) * 2013-10-25 2015-05-28 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
WO2016081658A1 (fr) * 2014-11-18 2016-05-26 Insmed Incorporated Procédés de fabrication de tréprostinil et promédicaments dérivés de tréprostinil

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10526274B2 (en) 2013-10-25 2020-01-07 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
US10995055B2 (en) 2013-10-25 2021-05-04 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
US11795135B2 (en) 2013-10-25 2023-10-24 Insmed Incorporated Prostacyclin compounds, compositions and methods of use thereof
US10343979B2 (en) 2014-11-18 2019-07-09 Insmed Incorporated Methods of manufacturing treprostinil and treprostinil derivative prodrugs
US11148997B2 (en) 2014-11-18 2021-10-19 Insmed Incorporated Methods of manufacturing treprostinil and treprostinil derivative prodrugs
US11458098B2 (en) 2019-04-29 2022-10-04 Insmed Incorporated Dry powder compositions of treprostinil prodrugs and methods of use thereof
US11759425B2 (en) 2019-04-29 2023-09-19 Insmed Incorporated Dry powder compositions of treprostinil prodrugs and methods of use thereof

Similar Documents

Publication Publication Date Title
JP7430766B2 (ja) プロスタサイクリン化合物、組成物およびその使用方法
KR100234864B1 (ko) 기도 및 폐질환을 치료하기 위한 모메타손푸로에이트 약제
AU2014339866A1 (en) Prostacyclin compounds, compositions and methods of use thereof
US20160318844A1 (en) Prostacyclin compounds, compositions and methods of use thereof
WO2017223400A1 (fr) Composés prostacycline et compositions pour le traitement de la sarcoidose

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17816263

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17816263

Country of ref document: EP

Kind code of ref document: A1