[go: up one dir, main page]

WO2015138423A9 - Compositions de prostacycline et leurs procédés d'utilisation - Google Patents

Compositions de prostacycline et leurs procédés d'utilisation Download PDF

Info

Publication number
WO2015138423A9
WO2015138423A9 PCT/US2015/019661 US2015019661W WO2015138423A9 WO 2015138423 A9 WO2015138423 A9 WO 2015138423A9 US 2015019661 W US2015019661 W US 2015019661W WO 2015138423 A9 WO2015138423 A9 WO 2015138423A9
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
deuterated
peg
treprostinil
prostacyclin
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2015/019661
Other languages
English (en)
Other versions
WO2015138423A1 (fr
Inventor
Vladimir Malinin
Walter Perkins
Franziska LEIFER
Donna OMIATEK
Jane Ong
Renu Gupta
Zhili Li
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Insmed Inc
Original Assignee
Insmed Inc
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 Inc filed Critical Insmed Inc
Publication of WO2015138423A1 publication Critical patent/WO2015138423A1/fr
Publication of WO2015138423A9 publication Critical patent/WO2015138423A9/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant

Definitions

  • Pulmonary hypertension is characterized by an abnormally high blood pressure in the lung vasculature. It is a progressive, lethal disease that leads to heart failure and can occur in the pulmonary artery, pulmonary vein, or pulmonary capillaries. Symptomatically patients experience shortness of breath, dizziness, fainting, and other symptoms, all of which are made worse by exertion. There are multiple causes, and can be of unknown origin, idiopathic, and can lead to hypertension in other systems, for example, portopulmonary hypertension in which patients have both portal and pulmonary hypertension.
  • Group I PH or pulmonary arterial hypertension (PAH) is a dyspnea-fatigue syndrome defined by an isolated increase in pulmonary vascular resistance (PVR), which leads to progressive right heart failure.
  • PAH occurs in association with a variety of conditions which include connective tissue diseases (CTD), congenital heart diseases (CHD), portal hypertension, human immunodeficiency viral (HIV) infection, and intake of appetite suppressant drugs, mainly fenfluramines.
  • PAH afflicts 30,000-40,000 people in U.S. with 20,000-25,000 under treatment. It is a progressive disease ultimately causing patients to die of heart failure. Despite available treatments, the one-year mortality rate is 15%.
  • the current treatment for PAH is progressive combination therapy usually starting with calcium channel blockers (CCB), followed by phosphodiesterase-5 (PDE-5) inhibitors.
  • CB calcium channel blockers
  • PDE-5 phosphodiesterase-5
  • ERA endothelin receptor antagonists
  • prostanoids e.g., prostacyclins
  • Prostanoids are perceived to be the most effective class of drugs for PAH, but their effectiveness is limited due to significant toxicity/tolerability issues and inconvenient dosing regimens (e.g., daily IV infusions or 4-9 inhalations per day).
  • the current inhaled prostanoid products are iloprost (Ventavis®, 6-9 inhalation treatments per day) and treprostinil (Tyvaso®, 4 inhalation treatments per day, spaced 4 hours apart). While longer than that for iloprost, the half-life of treprostinil is still relatively short necessitating dosing every 4 hours over the time patients are awake. For the Tyvaso® (treprostinil) patient, dosing compliance is a major issue.
  • Portopulmonary hypertension is defined by the coexistence of portal and pulmonary hypertension, and is a serious complication of liver disease.
  • the diagnosis of portopulmonary hypertension is based on hemodynamic criteria: (1) portal hypertension and/or liver disease (clinical diagnosis-ascites/varices/splenomegaly), (2) mean pulmonary artery pressure > 25 mmHg at rest, (3) pulmonary vascular resistance > 240 dynes s cm -5 , (4) pulmonary artery occlusion pressure ⁇ 15mmHg or transpulmonary gradient > 12 mmHg.
  • intravenous treprostinil has been reported to be at least double that of subcutaneous infusion to maintain the same efficacy.
  • intravenous treprostinil appears to expose PAH patients to series of complications including blood stream infections, thrombosis, and delivery systems malfunctions resulting in poorly tolerated rapid overdosing or under dosing.
  • the cationic compound is a cationic lipid, cationic polymer, or an inorganic ion.
  • the prostacyclin is deuterated treprostinil or a deuterated treprostinil analog.
  • the inorganic ion is an aluminum ion.
  • the hydrophobic additive is squalane.
  • the pharmaceutical composition comprises a plurality of particles comprising the deuterated prostacyclin or analog thereof (e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog), and the cationic compound.
  • the mean diameter of the plurality of particles in one embodiment, is about 500 nm or less, about 400 nm or less, about 300 nm or less, about 200 nm or less, about 150 nm or less, about 100 nm or less, or about 50 nm or less.
  • the surfactant is associated with one or more of the plurality of particles in the pharmaceutical composition.
  • the surfactant in a further embodiment, is a PEGylated lipid.
  • the cationic compound is dioctadecyldimethyl ammonium bromide (diC18dMA), dimethyldihexadecylammonium chloride, N-[1-(2,3- dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl sulfate (DOTAP), N-[1-(2,3- dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), 1,2-distearoyl-3- (trimethylammonio)propane chloride (DSTAP), dimyristoyltrimethylammonium propane (DMTAP).
  • DOTAP dioctadecyldimethyl ammonium bromide
  • DOTAP N-[1-(2,3- dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl sulfate
  • DOTMA N-[1-(2,3
  • the at least one cationic compound in other embodiments is N,N’-dihexadecyl-1,2- ethanediamine, tetraethylhexadecane-1,16-diamine, or hexadecane-1,16-bis(trimethylammonium bromide).
  • the cationic compound is a one metal ion, for example, aluminum, magnesium, beryllium, strontium, barium, or calcium.
  • the cationic compound is a cationic lipid (e.g., diC18dMA).
  • an effective amount of the prostacyclin composition described herein is administered to a patient in need thereof, for example for the treatment of pulmonary hypertension or portopulmonary hypertension.
  • the administration is intranasal, oral, nasal, parenteral, by injection (e.g., subcutaneous, intravenous, intramuscular), by inhalation, or by infusion.
  • the prostacyclin composition is delivered in the lungs of the patient via inhalation.
  • the pharmaceutical composition is administered in a once-a-day dosing or a twice-a-day dosing regimen for the treatment of pulmonary hypertension (e.g., pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension) or portopulmonary hypertension.
  • pulmonary hypertension e.g., pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension
  • portopulmonary hypertension e.g., pulmonary hypertension, chronic thromboembolic pulmonary hypertension
  • the pharmaceutical composition is administered to the lungs of a patient via an inhalation device, e.g., a nebulizer.
  • an inhalation device e.g., a nebulizer.
  • the aerosolized composition upon aerosolization of the composition (e.g., with a nebulizer or other aerosol generator), the aerosolized composition has an average aerosol droplet size, i.e., a mass median aerodynamic diameter (MMAD) of less than 10 ⁇ m, as measured by cascade impaction.
  • MMAD mass median aerodynamic diameter
  • the aerosol upon aerosolization, has a MMAD of less than about 8 ⁇ m, less than about 7 ⁇ m, less than about 6 ⁇ m, less than about 5 ⁇ m, less than about 4 ⁇ m, less than about 3 ⁇ m or less than about 2 ⁇ m, as measured by cascade impaction.
  • a system for treating or providing prophylaxis against pulmonary hypertension for example, pulmonary arterial hypertension.
  • the system comprises, in one embodiment, a pharmaceutical composition comprising a deuterated prostacyclin or analog thereof (e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog), a cationic compound, a surfactant; and an inhalation device (e.g., a dry powder inhaler, a metered dose inhaler or a nebulizer).
  • a deuterated prostacyclin or analog thereof e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated
  • the inhalation device in one embodiment is an electronic nebulizer that is portable and easy to use.
  • the nebulizer is disposable.
  • the pharmaceutical composition comprises a hydrophobic additive.
  • the pharmaceutical composition comprises a plurality of particles, e.g., solid lipid nanoparticles comprising the deuterated prostacyclin or analog thereof, the cationic compound and the surfactant.
  • the inhalation device is a nebulizer.
  • the prostacyclin is deuterated treprostinil.
  • the cationic compound is a metal ion, a polymer, or a lipid.
  • Another aspect of the present invention relates to a method for treating or providing prophylaxis against pulmonary hypertension in a patient in need thereof.
  • the patient is administered a prostacyclin composition described herein intravenously, orally, nasally, subcutaneously or via inhalation.
  • the method involves aerosolizing the pharmaceutical composition and delivering the aerosol to the lungs of the patient in need thereof.
  • the pulmonary hypertension is group I pulmonary hypertension (i.e., PAH).
  • the pulmonary hypertension is group II, group III, group IV or group V pulmonary hypertension.
  • the method in one embodiment, involves administering an effective amount of the pharmaceutical composition described herein to a patient in need of treatment for pulmonary hypertension.
  • Another aspect of the present invention relates to a method for treating or providing prophylaxis against portopulmonary hypertension in a patient in need thereof.
  • the method in one embodiment, comprises administering an effective amount of one of the prostacyclin compositions described herein to the patient in need of treatment for portopulmonary hypertension.
  • administration is via inhalation, subcutaneous, oral, nasal or intravenous administration.
  • the pharmaceutical composition is administered once-a-day or twice- a-day to the patient in need thereof.
  • the deuterated prostacyclin or analog thereof e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog
  • the deuterated prostacyclin or analog thereof e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog
  • the deuterated prostacyclin or analog thereof e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprosten
  • an aerosol comprising a plurality of solid particles of one or more of the pharmaceutical compositions described herein.
  • the plurality of solid particles has an average diameter of less than 200 nm as measured by light scattering.
  • the plurality of solid particles has an average diameter of about 1 nm to about 1000 nm, or about 10 nm to about 500 nm, or about 100 nm to about 250 nm, as measured by light scattering.
  • the prostacyclin is treprostinil or deuterated treprostinil.
  • the present invention in one embodiment, also provides pulmonary hypertension and portopulmonary hypertension patients with an improved prostacyclin composition that is efficacious while improving patient tolerability and compliance with treatment.
  • Certain prostacyclins are indicated for the treatment of pulmonary hypertension, and the compositions provided herein, in one embodiment, reduce dose frequency from 4-times a day for currently approved prostacyclin therapies to 1X, 2X or 3X daily, while significantly reducing the incidence of severe cough, throat irritability, and pain, thus improving tolerability.
  • the pharmaceutical composition described herein in one embodiment, reduces patient burden and discomfort caused by the currently available pulmonary hypertension medications, for example, pulmonary arterial hypertension medications.
  • the bottom image is of a liposome where the deuterated prostacyclin or deuterated prostacyclin analog is complexed with a cationic compound inside the liposome, and a polymer lipid (surfactant) is part of the surface structure.
  • Figure 2 illustrates the chemical structures of representative treprostinil acid and salts, for use with the present invention.
  • One or more hydrogen atoms in each of these structures can be replaced with one or more deuterium atoms to form a deuterated compound.
  • Figure 3 is a diagram of one embodiment for manufacturing a treprostinil composition of the present invention.
  • Figure 4A is a graph of nanoparticle diameter of compositions of the present invention having a fixed ratio of treprostinil:cationic lipid, as a function of squalane concentration.
  • Figure 4B is a graph of nanoparticle diameter of compositions of the present invention having a fixed ratio of treprostinil:cationic lipid:PEGylated lipid, as a function of squalane concentration.
  • Figure 6B is a graph of free treprostinil as a function of (i) cationic lipid present in the respective treprostinil composition and (ii) particle charge of each composition.
  • Figure 6C is a graph of free treprostinil as a function of (i) cationic lipid present in the respective treprostinil composition and (ii) particle charge of each composition.
  • Figures 8A-C are graphs of relative cAMP response of CHO-K1-P4 cells (2.5 x 10 4 cells/well) as a function of time, in response to 10 ⁇ M treprostinil, 7 ⁇ M T527 and 5 ⁇ M T550 ( Figure 8A), 1 ⁇ M treprostinil, T527 and T550 ( Figure 8B) or 0.1 ⁇ M treprostinil, T527 and T550 ( Figure 8C) T527-4, as measured by a modified GloSensor assay.
  • Figures 9A is a graph of relative cAMP response of CHO-K1-P4 cells (2.5 x 10 4 cells/well) as a function of time, in response to free treprostinil (2 ⁇ M), T420 (pre-nebulization), T420 (post-nebulization, 2 ⁇ M), T471 (pre-nebulization, 2 ⁇ M) and T471 (post-nebulization, 2 ⁇ M).
  • Figure 9B is a graph of relative cAMP response of CHO-K1-P4 cells (2.5 x 10 4 cells/well) as a function of time, in response to free treprostinil (2 ⁇ M), T441 (pre-nebulization), T441 (post-nebulization, 2 ⁇ M), T470 (pre-nebulization, 2 ⁇ M) and T470 (post-nebulization, 2 ⁇ M).
  • Figures 11A-11D are graphs showing NR8383 rat alveolar cell proliferation inhibition a 48 as function of treprostinil concentration. Cells were treated for a 72 hr. period with the respective compositions. T527 (Figure 11A), T550 ( Figure 11B), T441 (Figure 11C), T420 ( Figure 11D).
  • Figure 12 is a graph of pulmonary arterial pressure (expressed as a percent of hypoxic baseline value) as a function of time, in animals challenged with free treprostinil T527 or T550.
  • the terms“about” and/or“approximately” may be used in conjunction with numerical values and/or ranges.
  • the term“about” is understood to mean those values near to a recited value.
  • “about 40 [units]” may mean within ⁇ 25% of 40 (e.g., from 30 to 50), within ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1%, less than ⁇ 1%, or any other value or range of values therein or there below.
  • the phrases“less than about [a value]” or“greater than about [a value]” should be understood in view of the definition of the term“about” provided herein.
  • the terms “about” and“approximately” are used interchangeably.
  • ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range“from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55- 75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).
  • a prostacyclin compound having one or more deuterium atoms in place of one or more hydrogen atoms is referred to herein as a“deuterated prostacyclin.”
  • deuterated treprostinil, deuterated epoprostenol, deuterated iloprost, or a deuterated analog thereof are encompassed by the term“deuterated prostacyclin.”
  • the term“treating” includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in the subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (3) relieving the condition (e.g., causing regression of the state,
  • “Prophylaxis,” as used herein, can mean complete prevention of an infection or disease, or prevention of the development of symptoms of that infection or disease; a delay in the onset of an infection or disease or its symptoms; or a decrease in the severity of a subsequently developed infection or disease or its symptoms.
  • Effective amount means an amount of prostacyclin composition used in the present invention sufficient to result in the desired therapeutic response.
  • An“aerosol,” as used herein, is a gaseous suspension of liquid or dry particles.
  • the aerosol provided herein in one embodiment, comprises the pharmaceutical composition described herein.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a deuterated prostacyclin or analog thereof (e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog), a cationic compound, and a surfactant.
  • Figure 1 depicts embodiments of this aspect, where the composition is in the form of a particle, e.g., a colloidal particle or nanoparticle.
  • the surfactant in one embodiment, provides surface coating of the particle to reduce interaction with biological tissue where exchange of the deuterated prostacyclin or deuterated prostacyclin analog would be hastened by collision exchange and erosion by interaction with biological materials.
  • the deuterated prostacyclin or deuterated prostacyclin analog in the pharmaceutical composition is deuterated treprostinil or a deuterated treprostinil analog.
  • the pharmaceutical composition comprises deuterated treprostinil or a deuterated treprostinil analog, a cationic compound, and a surfactant.
  • the pharmaceutical composition comprises deuterated treprostinil or a deuterated treprostinil analog, a cationic compound, a surfactant and a hydrophobic additive.
  • the pharmaceutical composition is in particle form, for example a micelle particle or a solid nanoparticle.
  • the cationic compound is a cationic lipid or an inorganic cation (e.g., a metal cation) ( Figure 1, middle).
  • the cationic compound is multicationic.
  • the pharmaceutical composition provided herein comprises a deuterated prostacyclin or analog thereof selected from deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost and a deuterated iloprost analog.
  • the composition in one embodiment, comprises a plurality of particles, e.g., nanoparticles.
  • the plurality of particles can comprise solid particles, nanoparticles, solid lipid nanoparticles, micelles, liposomes or proliposomes, or a mixture thereof ( Figure 1).
  • the pharmaceutical composition is a dispersion comprising a micellar, proliposomal, or liposomal complexed prostacyclin or a prostacyclin encapsulated in a micelle, liposome, or proliposome.
  • the composition provided herein is a micellar dispersion or a nanoparticle composition comprising a deuterated prostacyclin or deuterated prostacyclin analog, a cationic compound and a surfactant.
  • the micellar dispersion or nanoparticle composition comprises a hydrophobic additive, e.g., squalane.
  • the composition comprises deuterated treprostinil, a cationic lipid, a PEGylated lipid and squalane.
  • the composition comprises a deuterated prostacyclin and the cationic compound, e.g., the cationic lipid in a micelle or a nanoparticle.
  • the micellar dispersion or nanoparticle composition in one embodiment, has at least about 1% by weight of the deuterated prostacyclin associated with the cationic compound, for example electrostatically associated.
  • the fine particle fraction (FPF) of the composition post nebulization i.e., the aerosolized pharmaceutical composition
  • the FPF of the aerosol is greater than or equal to about 64%, as measured by the ACI, greater than or equal to about 70%, as measured by the ACI, greater than or equal to about 51%, as measured by the NGI, or greater than or equal to about 60%, as measured by the NGI.
  • the cationic compound in the pharmaceutical composition provided herein may be monocationic or multicationic.
  • the cationic compound is net cationic, i.e., the compound has both positive and negative charges with a net positive charge.
  • the cationic compound include, but are not limited to, a cationic lipid, alkyl-ammonium, alkyl- polyammonium, linear polyamine, linear polyethylenimine, branched polyethylenimine, poly-L- lysine, trimethyl-poly-glucosamine, an inorganic ion, a metal ion, a multivalent inorganic ion, or multivalent metal ion.
  • the cationic compound may be dioctadecyldimethyl ammonium bromide (diC18dMA), dimethyldihexadecylammonium chloride, N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl sulfate (DOTAP), N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), 1,2-distearoyl-3- (trimethylammonio)propane chloride (DSTAP), dimyristoyltrimethylammonium propane (DMTAP), or dioctadecyldimethylammonium bromide (DODAB).
  • DOTAP dioctadecyldimethyl ammonium bromide
  • DSTAP 1,2-distearoyl-3- (trimethylammonio)propane chloride
  • the cationic compound may also be N,N’-dihexadecyl-1,2-ethanediamine, tetraethylhexadecane-1,16-diamine, or hexadecane-1,16-bis(trimethylammonium bromide).
  • the cationic compound is a metal cation such as aluminum, magnesium, beryllium, strontium, barium, or calcium. Other multivalent metals may also be used.
  • the cationic compound is dioctadecyldimethyl ammonium bromide (dc18dMA).
  • 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-1-yl-N,N,N-trimethylammonium chloride (DOTMA), and 1,2- bis(oleoyloxy)-3-(trimethylammonio)propane (DOTAP).
  • DLEP dilauroyl ethylphosphocholine
  • DMEP dimyristoyl ethylphosphocholine
  • DPEP dipalmitoyl ethylphosphocholine
  • DSEP distearoyl ethylphosphocholine
  • the at least one surfactant in the composition is neutral, nonionic, cationic, or anionic.
  • the surfactant in one embodiment, is amphiphilic, a PEGylated lipid or a block copolymer.
  • the at least one surfactant comprises at least one anionic surfactant.
  • the surfactant in one embodiment, is a PEGylated lipid.
  • 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 phosphoethanolamine (DPPE), distearoylphosphatidylethanolamine (DSPE), dimyristoylglycerol glycerol (DMG), diphosphatidylglycerol (DPG), disteraroylglycerol (DSG) or cholesterol.
  • DMPE dimyristoyl phosphatidylethanolamine
  • DPPE dipalmitoyl phosphoethanolamine
  • DSPE dimyristoylglycerol glycerol
  • DMG diphosphatidylglycerol
  • DPG disteraroyl
  • PEG Depending on its molecular weight (MW), PEG is also referred to in the art as polyethylene oxide (PEO) or polyoxyethylene (POE).
  • PEO polyethylene oxide
  • POE polyoxyethylene
  • the PEGylated lipid can include a branched or unbranched PEG molecule, and is not limited by a particular PEG MW.
  • the PEGylated 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.
  • Phospholipids include, but are not limited to phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidic acid (PA).
  • the phospholipid is an egg phospholipid, a soya phospholipid or a hydrogenated egg and soya phospholipid.
  • the PEGylated 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 PEGylated lipid of the prostacyclin composition provided herein comprises distearoylphosphoethanolamine (DSPE), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC) dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoylphosphoethanolamine (DPPE), distearoylphosphatidylethanolamine (DSPE), dimyristoylglycerol (DMG), diphosphatidylglycerol (DPG) or disteraroylglycerol (DSG).
  • DSPE distearoylphosphoethanolamine
  • DPPC dipalmitoylphosphatidylcholine
  • DOPC dioleoylphosphatidylcholine
  • DMPE dipalmitoylphosphoethanolamine
  • DSPE dimyristoylglycerol
  • DMG dimyristoylglycerol
  • DPG diphosphatidylglyce
  • lipids for use in the compositions comprising PEGylated 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
  • 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 1, 2-bis(oleoyloxy)-3-(trimethylammonio)propane (DOTAP).
  • DLEP dilauroyl ethylphosphocholine
  • DMEP dimyristoyl ethylphosphocholine
  • DPEP dipalmitoyl ethylphosphocholine
  • DSEP distearoyl ethylphosphocholine
  • 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-PEG1000 or DSG-PEG2000.
  • the pharmaceutical composition comprising a hydrophobic additive may also include a surfactant, as described herein.
  • the pharmaceutical composition comprises a polyoxyethyleneglycol-phospholipid.
  • a suitable polyoxyethyleneglycol-phospholipid used for this embodiment of the invention is polyoxyethyleneglycol-cholesterol.
  • the pharmaceutical composition comprising the hydrophobic additive may also include a polyoxyethyleneglycol-lipid.
  • the polyoxyethyleneglycol-lipid may be without limitation distearoylphosphatidylethanolamine- polyoxyethyleneglycol or disteraroylglycerol- polyoxyethyleneglycol.
  • the hydrophobic additive may be present in the composition at 30%-50 mol%, for example, 35-45 mol%. In even a further embodiment, the hydrophobic additive is present in the composition at about 40 mol%.
  • the hydrophobic additive when present in a composition comprising the deuterated prostacyclin or analog thereof (e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog), and the cationic compound, is a hydrocarbon, a terpene compound or a hydrophobic lipid (e.g., tocopherol, tocopherol acetate, sterol, sterol ester, alkyl ester, vitamin A acetate, a triglyceride, a phospholipid).
  • deuterated prostacyclin or analog thereof e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, de
  • the terpene compound in one embodiment, is a hydrocarbon (e.g., isoprene, squalane or squalene).
  • the terpene compound is a hemiterpene (C 5 H 8 ), monoterpene (C 10 H 16 ), sesquiterpene (C 15 H 24 ), diterpene (C 20 H 32 ) (e.g., cafestol, kahweol, cembrene, taxadiene), sesterterpene (C 25 H 40 ), triterpene (C 30 H 48 ), sesquaterpene (C 35 H 56 ), tetraterpene (C 40 H 64 ), polyterpene (e.g., a polyisoprene with trans double bonds) or a norisoprenoid (e.g., 3-oxo- ⁇ -ionol, 7,8-dihydroionone derivatives).
  • the terpene compound is a hydrocarbon (e.g.
  • the prostacyclin composition provided herein is in particle form.
  • the pharmaceutical composition provided herein comprises a plurality of particles comprising the deuterated prostacyclin or analog thereof (e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog), and the cationic compound.
  • the surfactant is associated with at least one of the plurality of particles in the composition.
  • the plurality of particles in the pharmaceutical composition comprises solid colloidal particles, polymer-lipid hybrid nanoparticles (Vieira and Carmona- Ribeiro (2008). Journal of Nanobiotechnology 6:1-13, incorporated by reference in its entirety), nanostructured lipid carriers, polymeric microspheres (Liu et al. (2000). J Pharm Pharmacol, 53:1-12, incorporated by reference in its entirety), nanoparticles, micelles, liposomes, solid lipid nanoparticles (Wong et al. (2004). J Pharm Sci, 93:1993-2004, incorporated by reference in its entirety), or a combination thereof.
  • the pharmaceutical composition provided herein comprises a plurality of solid particles comprising at least one cationic compound and a deuterated prostacyclin or analog thereof (e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog).
  • the cationic compound forms the core of a particle of the invention, and the at least one surfactant stabilizes the cationic compound (Figure 1).
  • the at least one surfactant is a PEGylated lipid.
  • the pharmaceutical composition provided herein comprises a plurality of solid lipid nanoparticles (SLNs) comprising a solid lipid core stabilized by a surfactant.
  • the core lipid is a cationic lipid, for example, one of the cationic lipids described above.
  • the deuterated prostacyclin or analog thereof associates at the core of the particle, at the outer layer of the particle, or a combination thereof.
  • the plurality of particles are formed by electrostatic interactions between the at least one cationic polymer and the at least one surfactant polymer (see, e.g., Vieira and Carmona-Ribeiro (2008). Journal of Nanobiotechnology 6:1-13, incorporated by reference in its entirety).
  • the deuterated prostacyclin or analog thereof e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog
  • the deuterated prostacyclin such as deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog, cationic compound and surfactant, in one embodiment, self assemble into a plurality of particles.
  • certain lipids such as dioctadecyldimethylammonium bromide (DODAB) and sodium dihxadecylphosphate (DHP) self-assemble in aqueous solution depending on the procedure for dispersing the lipid.
  • DODAB dioctadecyldimethylammonium bromide
  • DHP sodium dihxadecylphosphate
  • At least about 1% or at least 10%, or at least 25%, or at least 50% or at least 75% or at least 90% of the composition is in particle form, either as a single particle or a plurality of particles.
  • the average diameter of the plurality of particles in the composition, prior to administration, in one embodiment is about 500 nm or less, as measured by light scattering.
  • the average diameter of the particle(s) in the composition is about 400 nm or less, or about 300 nm or less, or about 200 nm or less, or about 100 nm or less, or about 50 nm or less, as measured by light scattering.
  • the average diameter of the particle(s) in the composition is about 100 nm to about 500 nm, or about 150 nm to about 500 nm, or about 200 nm to about 500 nm, or about 250 nm to about 500 nm, or about 300 nm to about 500 nm, or about 350 nm to about 500 nm, as measured by light scattering.
  • the particle or plurality of particles is a solid particle or a plurality of solid particles (e.g., solid lipid nanoparticles).
  • the mean diameter of the plurality of particles in the composition is about 10 to about 100 nm, about 50 nm to about 100 nm, about 100 nm to about 200 nm, about 200 nm to about 300 nm, about 210 nm to about 290 nm, about 220 nm to about 280 nm, about 230 nm to about 280 nm, about 240 nm to about 280 nm, about 250 nm to about 280 nm or about 260 nm to about 280 nm, as measured by light scattering.
  • the particle or particle(s) is a solid lipid nanoparticle or a plurality of solid lipid nanoparticles, or a micelle or a plurality of micelle(s).
  • the plurality of particles is a plurality of micelles or liposomes.
  • Liposomes are completely closed lipid bilayer membranes containing an entrapped aqueous volume. Liposomes may be unilamellar vesicles (possessing a single membrane bilayer) or multilamellar vesicles (onion-like structures characterized by multiple membrane bilayers, each separated from the next by an aqueous layer) or a combination thereof.
  • the bilayer is composed of two lipid monolayers having a hydrophobic“tail” region and a hydrophilic“head” region.
  • the structure of the membrane bilayer is such that the hydrophobic (nonpolar)“tails” of the lipid monolayers orient toward the center of the bilayer while the hydrophilic“heads” orient towards the aqueous phase.
  • Liposomes can be produced by a variety of methods (see, e.g., Cullis et al. (1987)). In one embodiment, one or more of the methods described in U.S. Patent Application Publication No. 2008/0089927 are used herein to produce the prostacyclin encapsulated lipid compositions (liposomal dispersion). The disclosure of U.S. Patent Application Publication No. 2008/0089927 is incorporated by reference in its entirety for all purposes. For example, in one embodiment, at least one lipid and a prostacyclin are mixed with a coacervate (i.e., a separate liquid phase) to form the liposome composition. The coacervate can be formed prior to mixing with the lipid, during mixing with the lipid or after mixing with the lipid. Additionally, the coacervate can be a coacervate of the active agent.
  • a coacervate i.e., a separate liquid phase
  • the liposomal dispersion is formed by dissolving one or more lipids in an organic solvent forming a lipid solution, and the prostacyclin coacervate forms from mixing an aqueous solution of the prostacyclin with the lipid solution.
  • the organic solvent is ethanol.
  • the one or more lipids comprise a phospholipid and a sterol.
  • Unilamellar vesicles can be produced from MLVs by a number of techniques, for example, the extrusion techniques of U.S. Patent No. 5,008,050 and U.S. Patent No. 5,059,421, each incorporated by reference herein for all purposes. Sonication and homogenization cab be so used to produce smaller unilamellar liposomes from larger liposomes (see, for example, Paphadjopoulos et al. (1968); Deamer and Uster (1983); and Chapman et al. (1968), each of which is incorporated by reference herein in their entireties).
  • the liposome preparation of Bangham et al. involves suspending phospholipids in an organic solvent which is then evaporated to dryness leaving a phospholipid film on the reaction vessel. Next, an appropriate amount of aqueous phase is added, the 60 mixture is allowed to“swell”, and the resulting liposomes which consist of multilamellar vesicles (MLVs) are dispersed by mechanical means.
  • MUVs multilamellar vesicles
  • LUVs large unilamellar vesicles
  • reverse phase evaporation infusion procedures, and detergent dilution
  • liposomes for use in the pharmaceutical compositions provided herein.
  • a review of these and other methods for producing liposomes may be found in the text Liposomes, Marc Ostro, ed., Marcel Dekker, Inc., New York, 1983, Chapter 1, which is incorporated herein by reference. See also Szoka, Jr. et al., (Ann. Rev. Biophys. Bioeng.9, 1980, p.467, incorporated by reference herein in its entirety).
  • liposomes include those that form reverse-phase evaporation vesicles (REV), U.S. Patent No. 4,235,871, incorporated by reference herein in its entirety.
  • REV reverse-phase evaporation vesicles
  • Another class of liposomes that may be used is characterized as having substantially equal lamellar solute distribution.
  • This class of liposomes is denominated as stable plurilamellar vesicles (SPLV) as defined in U.S. Patent No. 4,522,803, incorporated by reference herein in its entirety, and includes monophasic vesicles as described in U.S. Patent No. 4,588,578, incorporated by reference herein in its entirety, and frozen and thawed multilamellar vesicles (FATMLV) as described above.
  • SPLV stable plurilamellar vesicles
  • FATMLV frozen and thawed multilamellar vesicles
  • a variety of sterols and their water soluble derivatives such as cholesterol hemisuccinate have been used to form liposomes; see, e.g., U.S. Patent No.4,721,612, incorporated by reference herein in its entirety. Mayhew et al., PCT Publication No. WO 1985/00968, incorporated by reference herein in its entirety, describes a method for reducing the toxicity of drugs by encapsulating them in liposomes comprising alpha-tocopherol and certain derivatives thereof. Also, a variety of tocopherols and their water soluble derivatives have been used to form liposomes, see PCT Publication No.87/02219, incorporated by reference herein for all purposes.
  • the pharmaceutical compositions herein described may have a surfactant comprising individual components in a molecular ratio of 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, or 9:1.
  • a surfactant comprising individual components in a molecular ratio of 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, or 9:1.
  • cholesterol-PEG, DSG-PEG, DSPE-PEG in one embodiment, are in a mol ratio of about 1:1, about 1:9, and about 1:9, respectively.
  • surfactants such as polyoxyethyleneglycol-lipid or polyoxyethyleneglycol-phospholipid are in a mol ratio of about 1:1 or about 1:9.
  • the pharmaceutical composition provided herein comprises a deuterated prostacyclin or deuterated analog thereof, a cationic compound and a surfactant.
  • the cationic compound and surfactant to deuterated prostacyclin e.g., deuterated treprostinil or deuterated treprostinil analog
  • weight ratio in the pharmaceutical composition provided herein in one embodiment, is 10 to 1 or less, 9 to 1 or less, 8 to 1 or less, 7 to 1 or less, 5 to 1 or less, 3 to 1 or less, 2.5 to 1 or less, 2 to 1 or less, 1.5 to 1 or less, 1 to 1 or less, 0.5 to 1 or less, or 0.1 to 1 or less.
  • the cationic compound to deuterated prostacyclin or analog thereof e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog
  • weight ratio in the pharmaceutical compositions provided herein in one embodiment, is 10 to 1 or less, 9 to 1 or less, 8 to 1 or less, 7 to 1 or less, 5 to 1 or less, 3 to 1 or less, 2.5 to 1 or less, 2 to 1 or less, 1.5 to 1 or less, 1 to 1 or less, 0.5 to 1 or less, or 0.1 to 1 or less.
  • the cationic compound is a cationic lipid and the cationic lipid to deuterated prostacyclin or analog thereof (e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog), weight ratio in the pharmaceutical compositions provided herein is 10 to 1 or less, 9 to 1 or less, 8 to 1 or less, 7 to 1 or less, 5 to 1 or less, 3 to 1 or less, 2.5 to 1 or less, 2 to 1 or less, 1.5 to 1 or less, 1 to 1 or less, 0.5 to 1 or less, or 0.1 to 1 or less.
  • deuterated treprostinil e.g., treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epopros
  • the cationic compound is diC18dMA and the deuterated prostacyclin is treprostinil or a deuterated treprostinil analog.
  • the cationic lipid to deuterated treprostinil weight ratio in the pharmaceutical compositions provided herein is 10 to 1 or less, 9 to 1 or less, 8 to 1 or less, 7 to 1 or less, 5 to 1 or less, 3 to 1 or less, 2.5 to 1 or less, 2 to 1 or less, 1.5 to 1 or less, 1 to 1 or less, 0.5 to 1 or less, or 0.1 to 1 or less.
  • compositions provided herein further comprise one or more pharmaceutical excipients, or other additives.
  • excipients or additives may include one or more stabilizing polyols, e.g., higher polysaccharides/polymers (for promoting controlled release), magnesium stearate, leucine and/or trileucine (as lubricants), and phospholipids and/or surfactants.
  • Blowing agents e.g., volatile salts such as ammonium carbonate, formic acid, etc. may also be included in the feedstock to produce reduced density particles in the present spray dried powders.
  • Spray aids may also be employed with the present compositions or systems. Such spray aids may reduce the viscosity and/or improve the fluid mechanical characteristics of the present compositions during the spray drying process.
  • Spray aids may include maltodextrin, lactose, gelatin, talc, triethylcitrate, and mixtures thereof.
  • Such spray aids may be present in the compositions in amounts ranging from about 1 wt% to about 15 wt% (e.g., about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, or any other value or range of values therein).
  • wt% e.g., about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, or any other value or range of values therein).
  • the spray aid is maltodextrin
  • the amount of maltodextrin in the composition is about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%.
  • the spray aid is lactose
  • the amount of lactose in the composition is about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%.
  • the spray aid is gelatin
  • the amount of gelatin in the composition is about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%.
  • a method for treating pulmonary hypertension is provided.
  • the World Health Organization (WHO) has classified PH into five groups.
  • Group I PH includes pulmonary arterial hypertension (PAH), idiopathic pulmonary arterial hypertension (IPAH), familial pulmonary arterial hypertension (FPAH), and pulmonary arterial hypertension associated with other diseases (APAH).
  • PAH pulmonary arterial hypertension
  • IPAH idiopathic pulmonary arterial hypertension
  • FPAH familial pulmonary arterial hypertension
  • APAH pulmonary arterial hypertension associated with other diseases
  • pulmonary arterial hypertension associated with collagen vascular disease e.g., scleroderma
  • congenital shunts between the systemic and pulmonary circulation portal hypertension and/or HIV infection are included in group I PH.
  • Group II PH includes pulmonary hypertension associated with left heart disease, e.g., atrial or ventricular disease, or valvular disease (e.g., mitral stenosis).
  • WHO group III pulmonary hypertension is characterized as pulmonary hypertension associated with lung diseases, e.g., chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and/or hypoxemia.
  • COPD chronic obstructive pulmonary disease
  • ILD interstitial lung disease
  • Group IV pulmonary hypertension is pulmonary hypertension due to chronic thrombotic and/or embolic disease.
  • Group IV PH is also referred to as chronic thromboembolic pulmonary hypertension.
  • Group IV PH patients experience blocked or narrowed blood vessels due to blood clots.
  • Group V PH is the“miscellaneous” category, and includes PH caused by blood disorders (e.g., polycythemia vera, essential thrombocythemia), systemic disorders (e.g., sarcoidosis, vasculitis) and/or metabolic disorders (e.g., thyroid disease, glycogen storage disease).
  • blood disorders e.g., polycythemia vera, essential thrombocythemia
  • systemic disorders e.g., sarcoidosis, vasculitis
  • metabolic disorders e.g., thyroid disease, glycogen storage disease.
  • the methods provided herein can be used to treat group I (i.e., pulmonary arterial hypertension or PAH), group II, group III, group IV or group V PH patients.
  • group I i.e., pulmonary arterial hypertension or PAH
  • PAH pulmonary arterial hypertension
  • a method for treating chronic thromboembolic pulmonary hypertension patient is provided.
  • the method comprises administering to a patient in need thereof an effective amount of one of the prostacyclin compositions described herein.
  • administration is to the patient via a pulmonary (inhalation), subcutaneous, oral, nasal or intravenous route.
  • the compositions of the present invention may be administered alone, or can be co-administered or sequentially administered with other immunological, antigenic, vaccine, or therapeutic compositions.
  • the patient in need of treatment is a Class I PAH patient, class II PAH patient, class III PAH patient or class IV PAH patient.
  • Class I PAH patients do not have a limitation of physical activity, as ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope.
  • Class II PAH patients have a slight limitation on physical activity. These patients are comfortable at rest, but ordinary physical activity causes undue dyspnoea or fatigue, chest pain or near syncope.
  • Class III PAH patients have a marked limitation of physical activity. Although comfortable at rest, class III PAH patients experience undue dyspnoea or fatigue, chest pain or near syncope as a result of less than ordinary physical activity.
  • Class IV PAH patients are unable to carry out any physical activity without symptoms. Class IV PAH patients might experience dyspnoea and/or fatigue at rest, and discomfort is increased by any physical activity. Signs of right heart failure are often manifested by class IV PAH patients.
  • a method for treating portopulmonary hypertension comprises administering to a patient in need thereof an effective amount of one of the prostacyclin compositions described herein.
  • administration is to the patient via a pulmonary (inhalation), oral, nasal, subcutaneous or intravenous route.
  • compositions of the present invention can be delivered to a patient in need thereof via inhalation, i.e., with an inhalation device.
  • An“inhalation device” is a device that is used to deliver a pharmaceutical composition to the lungs of a patient.
  • Inhalation devices include nebulizers and inhalers, e.g., a metered dose inhaler or a dry powder inhaler.
  • a dry powder or a liquid can be delivered to the lungs of a patient by an inhalation device.
  • a “nebulizer” is one type of inhalation device, and is a device that converts a liquid into an aerosol of a size that can be inhaled into the respiratory tract.
  • Pneumonic, ultrasonic, electronic nebulizers e.g., passive electronic mesh nebulizers, active electronic mesh nebulizers and vibrating mesh nebulizers are amenable for use with the invention if the particular nebulizer emits an aerosol with the required properties, and at the required output rate.
  • atomization The process of pneumatically converting a bulk liquid into small droplets is called atomization.
  • the operation of a pneumatic nebulizer requires a pressurized gas supply as the driving force for liquid atomization.
  • Ultrasonic nebulizers use electricity introduced by a piezoelectric element in the liquid reservoir to convert a liquid into respirable droplets.
  • Various types of nebulizers amenable for use with the present invention are described in Respiratory Care, Vol. 45, No. 6, pp.609-622 (2000), the disclosure of which is incorporated herein by reference in its entirety for all purposes.
  • administering results in a decreased number of side effects, or a reduced severity of one or more side effects (also referred to herein as“adverse events”), compared to the administration of an effective amount of treprostinil, when an effective amount of treprostinil is administered by inhalation, subcutaneous, oral, nasal or intravenous administration.
  • a PH, PAH or PPH patient experiences a reduced severity and/or frequency in cough or a reduced cough response when administered a prostacyclin composition of the invention via inhalation (e.g., via nebulization, a dry powder inhaler, or via a metered dose inhaler), compared to the severity and/or frequency of cough or cough response elicited by inhalation administration of treprostinil to the patient.
  • inhalation e.g., via nebulization, a dry powder inhaler, or via a metered dose inhaler
  • oral, nasal, intravenous, subcutaneous or inhalation administration of an effective amount of the prostacyclin composition of the invention results in a reduced severity of one or more of the following adverse events, or a decreased occurrence of one or more of the following adverse events: headache, throat irritation/pharyngolaryngeal pain, nausea, flushing and/or syncope.
  • the improved adverse event profile of the prostacyclin compositions of the invention exhibited patients, as compared to treprostinil, results in improved compliance of the patients.
  • the prostacyclin compositions of the present invention are administered on a less frequent basis, as compared to currently approved therapies for PH, PAH (e.g., Tyvaso®, Remodulin®) or PPH, while still achieving a substantially equivalent or better therapeutic response.
  • the therapeutic response of the patient in one embodiment, is a reduction in the pulmonary vascular resistance index (PVRI) from pretreatment value, a reduction in mean pulmonary artery pressure from pretreatment value, an increase in the hypoxemia score from pretreatment value, a decrease in the oxygenation index from pretreatment values, improved right heart function, as compared to pretreatment or improved exercise capacity (e.g., as measured by the six-minute walk test) compared to pretreatment.
  • the therapeutic response in one embodiment, is an improvement of at least 10%, at least 20%, at least 30%, at least 40% or at least 50%, as compared to pretreatment values.
  • the therapeutic response is an improvement of about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 30%, about 10% to about 20%, about 20% to about 70%, about 20% to about 60% or about 10% to about 50%, as compared to pretreatment levels.
  • compositions of the invention allow for improved patient compliance, as compared to the compliance of patients being administered a different PH, PAH or PPH treatment (e.g., treprostinil– Tyvaso®, Remodulin®).
  • the prostacyclin composition is administered via a nebulizer to a patient in need of PH, PAH or PPH treatment.
  • the administration occurs in one embodiment, once daily, twice daily, three times daily or once every other day.
  • the prostacyclin composition administered to a patient in need thereof via a pulmonary route by the PH, PAH or PAH treatment methods described herein provides a greater pulmonary elimination half-life (t 1/2 ) of the deuterated prostacyclin compound, compared to the t 1/2 of the free prostacyclin, when the free prostacyclin (e.g., free treprostinil or free deuterated treprostinil) is administered via a pulmonary route (e.g., by nebulization, dry powder inhaler, or a metered dose inhaler) to the patient in need of PH, PAH or PPH treatment.
  • a pulmonary route e.g., by nebulization, dry powder inhaler, or a metered dose inhaler
  • administration of the prostacyclin composition comprises oral, nasal, subcutaneous or intravenous administration.
  • the prostacyclin compound administered to a patient in need of PH, PAH or PPH treatment provides a greater mean pulmonary C max and/or lower plasma C max of the prostacyclin compound for the patient, compared to the respective pulmonary or plasma C max of the free prostacyclin, when the free prostacyclin (e.g., free treprostinil or free deuterated treprostinil) is administered to the patient.
  • administration of the prostacyclin composition and the free prostacyclin comprises oral, nasal, subcutaneous or intravenous administration.
  • the prostacyclin composition administered to a patient in need thereof provides a greater pulmonary or plasma time to peak concentration (t max ) of the prostacyclin compound, compared to the pulmonary or plasma time to peak concentration (t max ) of the prostacyclin compound, when the free prostacyclin (e.g., free deuterated treprostinil) is administered to the patient.
  • the free prostacyclin e.g., free deuterated treprostinil
  • the prostacyclin compositions of the present invention can be delivered to a patient in need thereof via pulmonary, oral, nasal, intravenous or subcutaneous route.
  • the prostacyclin compositions of the present invention may be used in any dosage dispensing device adapted for such administration.
  • 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, e.g., that of a metered-dose nebulizer, dry powder inhaler, soft mist inhaler, or a nebulizer.
  • pulmonary delivery devices include a jet nebulizer, electronic nebulizer, a soft mist inhaler, and a capsule-based dry powder inhaler.
  • the deuterated prostacyclin or analog thereof (e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog), in one embodiment, is sustainly delivered to the lungs, and the prostacyclin or analog thereof (e.g., deuterated analog) is released following administration over a period of time up to about 8 hours, or up to about 12 hours, or up to about 16 hours, or up to about 20 hours, or up to about 24 hours, or up to about 36 hours or up to about 48 hours.
  • the prostacyclin or analog thereof is sustainly delivered to the lungs, and the prostacyclin or analog thereof is released following administration over a period of time ranging from about 20 hours to about 48 hours, or about 24 hours to about 36 hours or about 30 hours to about 48 hours.
  • the pharmaceutical composition is administered in a once-a-day dosing or a twice-a-day dosing regimen to a patient in need thereof.
  • the composition is administered via nebulization.
  • the prostacyclin is deuterated treprostinil or a deuterated treprostinil analog.
  • compositions suitable for nasal administration include a coarse powder having a particle size, for example, in the range of about 3 to about 500 microns which is administered in the manner in which snuff is taken, e.g., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • suitable compositions wherein the carrier is a liquid for administration as, for example, nasal spray, nasal drops, or by aerosol administration by nebulizer include aqueous or oily solutions of the active ingredient.
  • a method of treating a disease, disorder or condition other than PH, PAH or PPH comprises administering a therapeutically effective amount of one of the prostacyclin compositions provided herein, for example, a nanoparticle composition comprising a deuterated prostacyclin or analog thereof (e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog), a cationic compound, a surfactant (e.g., PEGylated lipid) and a hydrophobic additive (e.g., squalane) to a patient in need thereof.
  • a deuterated prostacyclin or analog thereof e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol,
  • the diseases, disorders, and conditions include, but are not limited to, chronic thromboembolic pulmonary hypertension, congestive heart failure, peripheral vascular disease, asthma, severe intermittent claudication, immunosuppression, proliferative diseases, cancer such as lung, liver, brain, pancreatic, kidney, prostate, breast, colon, and head-neck cancer, ischemic lesions, neuropathic foot ulcers, and pulmonary fibrosis, kidney function, and interstitial lung disease.
  • the pharmaceutical formulation comprises one or more additional active ingredients in addition to treprostinil.
  • U.S. Patent No. 5,153,222 incorporated by reference herein in its entirety, describes use of treprostinil for treatment of pulmonary hypertension.
  • Treprostinil is approved for the intravenous as well as subcutaneous route, the latter avoiding potential septic events associated with continuous intravenous catheters.
  • Administration in one embodiment, is via inhalation (e.g., with a nebulizer or metered dose inhaler), subcutaneous or intravenous.
  • a nebulizer or metered dose inhaler e.g., a nebulizer or metered dose inhaler
  • other pharmacologically active substances may be present in the formulations of the present invention which are known to be useful for treating and/or preventing foot ulcers in patients with diabetic neuropathy.
  • the compositions of the invention may be present in combination with analgesics to treat pain, dressing changes, vasodilator medications, and topical or oral antibiotics.
  • the mass median aerodynamic diameter (MMAD) of the nebulized composition is about 1 ⁇ m to about 5 ⁇ m, or about 1 ⁇ m to about 4 ⁇ m, or about 1 ⁇ m to about 3 ⁇ m or about 1 ⁇ m to about 2 ⁇ m, as measured by the Anderson Cascade Impactor (ACI) or Next Generation Impactor (NGI).
  • the MMAD of the nebulized composition is about 5 ⁇ m or less, about 4 ⁇ m or less, about 3 ⁇ m or less, about 2 ⁇ m or less, or about 1 ⁇ m or less, as measured by cascade impaction, for example, by the ACI or NGI.
  • the FPF of the aerosolized composition is greater than or equal to about 50%, as measured by the ACI or NGI, greater than or equal to about 60%, as measured by the ACI or NGI or greater than or equal to about 70%, as measured by the ACI or NGI. In another embodiment, the FPF of the aerosolized composition is about 50% to about 80%, or about 50% to about 70% or about 50% to about 60%, as measured by the NGI or ACI.
  • a nebulizer type inhalation delivery device can contain the compositions of the present invention as a solution, usually aqueous, or a suspension.
  • the prostacyclin composition can be suspended in saline and loaded into the inhalation delivery 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 Omron MicroAir, the Nektar Aeroneb®, and the Pari eFlow®.
  • the nebulizer in one embodiment, is a single-use (e.g., disposable) or a multi-use nebulizer.
  • the system provided herein comprises a nebulizer selected from an electronic mesh nebulizer, pneumonic (jet) nebulizer, ultrasonic nebulizer, breath-enhanced nebulizer and breath-actuated nebulizer.
  • a nebulizer selected from an electronic mesh nebulizer, pneumonic (jet) nebulizer, ultrasonic nebulizer, breath-enhanced nebulizer and breath-actuated nebulizer.
  • the nebulizer is portable.
  • the inhalation delivery device can be a nebulizer, dry powder inhaler, or a metered dose inhaler (MDI), or any other suitable inhalation delivery device known to one of ordinary skill in the art.
  • the device can contain and be used to deliver a single dose of the prostacyclin composition or the device can contain and be used to deliver multi-doses of the composition of the present invention.
  • a nebulizer type inhalation delivery device can contain the compositions of the present invention as a solution, usually aqueous, or a suspension.
  • the prostacyclin composition can be suspended in saline and loaded into the inhalation delivery 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 Omron MicroAir, the Nektar Aeroneb®, and the Pari eFlow®.
  • a pressurized gas supply is used as the driving force for liquid atomization in a pneumatic nebulizer.
  • Compressed gas is delivered, which causes a region of negative pressure.
  • the solution to be aerosolized is then delivered into the gas stream and is sheared into a liquid film. This film is unstable and breaks into droplets because of surface tension forces.
  • droplet size and output rate can be tailored in a pneumonic nebulizer.
  • the gas velocity and/or pharmaceutical composition velocity is modified to achieve the output rate and droplet sizes of the present invention.
  • the flow rate of the gas and/or solution can be tailored to achieve the droplet size and output rate of the invention.
  • an increase in gas velocity in one embodiment, decreased droplet size.
  • the ratio of pharmaceutical composition flow to gas flow is tailored to achieve the droplet size and output rate of the invention.
  • an increase in the ratio of liquid to gas flow increases particle size.
  • a reservoir bag or chamber is used to capture aerosol during the nebulization process, and the aerosol is subsequently provided to the subject via inhalation.
  • the nebulizer provided herein includes a valved open-vent design. In this embodiment, when the patient inhales through the nebulizer, nebulizer output is increased. During the expiratory phase, a one-way valve diverts patient flow away from the nebulizer chamber.
  • the nebulizer provided herein is a continuous nebulizer. In other words, refilling the nebulizer with the pharmaceutical composition while administering a dose is not needed.
  • a vibrating mesh nebulizer is used to deliver the prostacyclin composition of the invention to a patient in need thereof.
  • the nebulizer membrane vibrates at an ultrasonic frequency of about 50 kHz to about 500 kHz, about 100 kHz to about 450 kHz, about 150 kHz to about 400 kHz, or about 200 kHz to about 350 kHz.
  • the nebulizer provided herein does not use an air compressor and therefore does not generate an air flow.
  • aerosol is produced by the aerosol head which enters the mixing chamber of the device. When the patient inhales, air enters the mixing chamber via one-way inhalation valves in the back of the mixing chamber and carries the aerosol through the mouthpiece to the patient. On exhalation, the patient’s breath flows through the one-way exhalation valve on the mouthpiece of the device. In one embodiment, the nebulizer continues to generate aerosol into the mixing chamber which is then drawn in by the subject on the next breath– and this cycle continues until the nebulizer medication reservoir is empty.
  • the nebulizer generates an aerosol of the pharmaceutical composition at a rate of about 0.1 to 1.0 mL/min.
  • the mass median aerodynamic diameter (MMAD) of the nebulized composition is about 1 ⁇ m to about 5 ⁇ m, or about 1 ⁇ m to about 4 ⁇ m, or about 1 ⁇ m to about 3 ⁇ m or about 1 ⁇ m to about 2 ⁇ m, as measured by the Anderson Cascade Impactor (ACI) or Next Generation Impactor (NGI).
  • the MMAD of the nebulized composition is about 5 ⁇ m or less, about 4 ⁇ m or less, about 3 ⁇ m or less, about 2 ⁇ m or less, or about 1 ⁇ m or less, as measured by cascade impaction.
  • the system provided herein comprises a prostacyclin composition, for example, a deuterated treprostinil composition, e.g., a deuterated treprostinil solid nanoparticle formulation.
  • a prostacyclin aerosol comprising a particulate composition, which comprises a deuterated prostacyclin or analog thereof (e.g., deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog), a cationic compound and a surfactant.
  • the particulate composition is a solid lipid nanoparticulate composition.
  • the aerosol is generated at a rate of about 0.1 to about 1.0 mL/min.
  • the prostacyclin prior to aerosolization of the prostacyclin composition, about 60% to about 100% of the prostacyclin present in the composition is in particle form.
  • the prostacyclin is deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog.
  • prior to nebulization about 65% to about 99%, about 75% to about 99%, about 85% to about 99%, about 95% to about 99%, or about 97% to about 99% is in particle form.
  • the prostacyclin prior to aerosolization of the prostacyclin composition, about 85% to about 99%, or about 90% to about 99% or about 95% to about 99% or about 96% to about 99% of the prostacyclin present in the composition is in particle form.
  • the prostacyclin is deuterated treprostinil, a deuterated treprostinil analog, deuterated epoprostenol, a deuterated epoprostenol analog, deuterated iloprost or a deuterated iloprost analog.
  • about 98% of the prostacyclin present in the composition prior to nebulization, about 98% of the prostacyclin present in the composition is in particle form.
  • the FPF of the aerosolized composition is greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, greater than or equal to 90%, greater than or equal to 95%, greater than or equal to 97.5%, or greater than or equal to 99%, as measured by cascade impaction.
  • the composition comprises treprostinil.
  • the composition comprises a cationic lipid.
  • the composition is a micellar composition.
  • the inhalation device described herein generates an aerosol (i.e., achieves a total output rate) of the prostacyclin pharmaceutical composition at a rate of about 0.1 to 1.0 mL/min.
  • An aerosol of the prostacyclin composition in one embodiment, is generated at a rate greater than about 0.25 g per minute, greater than about 0.35 g per minute, greater than about 0.45 g per minute, greater than about 0.55 g per minute, greater than about 0.60 g per minute, greater than about 0.65 g per minute or greater than about 0.70 g per minute.
  • the percent associated prostacyclin post-nebulization is measured by reclaiming the aerosol from the air by condensation in a cold-trap, and the liquid is subsequently assayed for free and encapsulated prostacyclin (associated prostacyclin).
  • Treprostinil compositions used in these experiments may include treprostinil either in the form of a free acid or a salt ( Figure 1).
  • Treprostinil can be synthesized, for example, by the methods disclosed in U.S. Patent Nos. 6,765,117 and 8,497,393. Syntheses of prostaglandin derivatives are described in U.S. Patent No. 4,668,814. The disclosures of U.S. Patent Nos. 6,765,117; 8,497,393; and 4,668,814 are each incorporated by reference in their entireties for all purposes.
  • Treprostinil concentration was measured by HPLC analysis using the Waters Alliance 2695 system with a Corona detector and PDA detector. UV absorbance was measured at 270 nm. Column ACE 3 C8 4.6x50 (Mac-Mod Analytical) was used.
  • Mobile phase A contained 25% acetonitrile 25% methanol, 50% water, 0.1% formic acid, and 0.01%, triethylamine.
  • Mobile phase B contained 50% acetonitrile, 50% methanol, 0.1% formic acid, and 0.01%, triethylamine. Mobile phase gradient was used with phase B increasing from 40 to 95% over 5 min.
  • Treprostinil compositions of the present invention were prepared as follows. A mixture of treprostinil, cationic lipid, hydrophobic filler, and a PEGylated lipid at a desired molar ratio were dissolved in ethanol. Table 2 shows a representative number of treprostinil compositions made by the method. Additionally, the average particle size (nm) for each composition is provided at the last column.
  • Total concentration of components in ethanol solution was usually 40 mM or 80 mM. Certain volumes of the solution (usually 1 mL) were mixed in-line with 9 part of an aqueous buffer by combining two streams in a mixing cross with a total flow rate of 100 mL/min. The flow rate ratio of buffer (aqueous input) to lipid was approximately 20:1. See Figure 3 for a schematic of the mixing process. Table 2. Representative treprostinil compositions made by the methods of Example 1. [00192] A Gilson 402 syringe pump was used to deliver the ethanol solution. A peristaltic pump was used to deliver the aqueous buffer solution. After mixing, the treprostinil nanoparticles spontaneously formed. Ethanol solvent remaining in the final mixture was then removed by blowing a stream of nitrogen gas, or sparging nitrogen gas.
  • compositions comprising different types of cationic lipids were made.
  • trioctyl-amine triC8-amine
  • diC12dMA didodecyldimethyl ammonium, as bromide salt
  • Figure 5 shows the role of PEGylated-lipid concentration in particle size of compositions comprising treprostinil, dC16 (cationic lipid) and either DSG-PEG2000 or DSPE- PEG2K.
  • PEGylated lipid concentration is inversely correlated to particle size, i.e., the size of the particles decreases with increasing mol% of PEGyated lipid for both compositions.
  • the particle size of the compositions comprising DSPE-PEG2K plateaus around 20% PEG (mol%).
  • Example 3 Treprostinil nanoparticle association as a function of composition components
  • Figure 6B also shows the measured amount of free treprostinil (%), which is inverse to the associated treprostinil, as a function of cationic lipid content.
  • Table 6 provides the cationic lipid/treprostinil molar ratio for each composition tested. PEGylated lipid: treprostinil molar ratio in these compositions was kept at a constant ratio of 0.5. Consistent with Figure 6A, the amount of associated treprostinil correlates with increasing cationic lipid content (Figure 6B). Figure 6B also shows the total charge of the particles for each composition tested.
  • the particle charge was calculated as sum of the concentrations of the charged components (taken with the corresponding sign of (–) for TRP and PEGylated lipid, and (+) for cationic lipid) in the particle. It was assumed that both PEGylated lipid and cationic lipid are 100% associated with particles, while TRP content in nanoparticles was calculated as TRPtotal (1-TRPfree% / 100%).
  • TRPtotal (1-TRPfree% / 100%.
  • the data in Figure 6B shows that the more positively charged particles retain treprostinil to a greater extent. Specifically, almost 100% retention (1-2% free TRP) is achieved when the particle charge becomes net positive.
  • Table 8 provides the compositions used in the dialysis study. The results of this study can be used as an indication of which compositions might provide a sustained release profile in vivo.
  • cAMP is a second messenger involved in signal transduction of G-protein coupled receptors (GPCRs) acting through G ⁇ -s and G ⁇ -i proteins. Because the treprostinil receptor is a GPCR, the assay provides an indication of whether the respective prostacyclin composition binds its receptor and activates the GPCR cell signaling cascade.
  • GPCRs G-protein coupled receptors
  • the GloSensorTM assay harnesses a genetically modified form of firefly luciferase into which a cAMP-binding protein moiety has been inserted. Upon binding of cAMP, a conformational change is induced leading to increased light output.
  • the EP2 prostanoid receptor was co-transfected with the GloSensorTM plasmid (Promega) into CHO-K1 cells as follows. CHO-K1 cells were harvested when the monoloayer was at 50-90% confluence. First, cells were washed with 5 mL PBS. Two mL of pre-warmed (37 °C) 0.05% trypsin-EDTA (Life Technologies, Cat #: 25300054) was added, and cells were dislodged by tapping the flask on the side.
  • the pGLoSensor-22F cAMP plasmid (Promega, Cat #: E2301) (2 ⁇ g): (EP2) (10 ng) (Origene, Cat #: SC126558) : pGEM- 3Zf(+) (10 ng) (Promega, Cat #: P2271) ratio was diluted to a final concentration of 12.6 ng/ ⁇ L (total plasmid) in Opti-MEM I reduced-serum medium (Life Technologies, Cat #: 1985062).
  • FuGENE HD transfection reagent Promega, Cat #: E2311
  • 160 ⁇ L of diluted plasmid was added to 160 ⁇ L of diluted plasmid and mixed carefully by gentle pipetting.
  • the complex was incubated at room temperature for 0 to 10 minutes, and then 8 ⁇ L of the complex was added per well of a 96 well white assay plate (Costar, Cat #: 3917) and gently mixed without disturbing the cell monolayer.
  • the plates were incubated for 20-24 hours at 37 °C and 5% CO 2 in a water-jacketed incubator. Following incubation, cells were treated and analyzed.
  • the cAMP assay was validated using free treprostinil.
  • Treprostinil (10 ⁇ M, 1 ⁇ M, 0.1 ⁇ M, 0.01 ⁇ M, 0.001 ⁇ M, 0.0001 ⁇ M, 0.00001 ⁇ M, and 0.000001 ⁇ M) was added to equilibrated CHO-K1 cells, and the cells were then incubated for 30 minutes. Luminescence was then measured at room temperature.
  • CHO-K1 cells co-transfected with the EP2 receptor and GloSensorTM plasmid were challenged with free treprostinil (10 ⁇ M,) and treprostinil compositions T527 and T550 (Table 9) at the indicated concentrations. cAMP levels were then measured every 5 minutes over a time course of 8 hours as shown in Figures 8A-C.
  • cAMP levels in response to the treprostinil compositions (2 ⁇ M) were equivalent to free treprostinil and the levels were sustained for at least 6 hours. The sustained cAMP level was not exhibited in response to free treprostinil.
  • Nebulizer Aeroneb Pro (Aerogen) was used to nebulize treprostinil compositions. Desired volume of the formulation (usually 3 mL) was loaded to the mesh head of the nebulizer. The head was connected directly to the glass impinger with air-tight seal. Nebulization was carried out using factory settings until the entire sample was nebulized. After nebulization was complete, the head was disconnected; impinger capped and centrifuged 5 min at 600 x g to settle the aerosol inside the impinger. The procedure provided nearly 100% yield in collecting the nebulized sample.
  • compositions tested in this experiment are provided in Table 10, below, results in Figure 9A-B.
  • cAMP levels were measured every 5 minutes over a time course of 240 minutes.
  • CHO-K1 cells were harvested when the cell monolayer was 50-90% confluent (use passage 4-11). Media was aspirated out of the flask, and cells were rinsed with 2 mL of F12 media. Next, 1 mL of pre-warmed (37 °C) 0.25% trypsin-EDTA (Life Technologies, Cat#: 25300054) was added, and cells were dislodged from the flask by tapping it on the side. Complete growth media (F12 (Life Technologies, Cat #: 31765092) +10%FBS (Hyclone, Cat #: SH30071.03) + 1X Pen-Strep (Life Technologies, cat # 15140-122) was then added at a volume of 10 mL.
  • Cells were centrifuged at 250 x g for 5 minutes at room temperature, and the media was aspirated. The cell pellet was resuspended in 10 mL complete growth media. Cell number was determined using a hemacytometer. Cells were then seeded at 2000 cells per well of a 96- well plate in 100 ⁇ L of complete growth media. The plate was incubated overnight at 37 °C and 5% CO 2 in a water-jacketed incubator.
  • Rat alveolar NR8383 cells were harvested when the monolayer was 50-90% confluent (use passage 5-11). Because the NR8383 cells include both adherent and non-adherent cells, media was transferred to a 50 mL Falcon tube. To obtain the cells remaining in the flask, 2 mL of plain media was added, and the remaining cells were scraped out of the 75 cm 2 flask with a cell scraper and added to the 50 mL tube. Cells were centrifuged at 200 x g for 5 minutes at room temperature, and the media was aspirated.
  • the cell pellet was resuspended in 10 mL complete growth media (F12 (Life Technologies, Cat #: 31765092) +15% FBS– heat inactivated (Hyclone, Cat #: SH30071.03) + 1XPen-Strep (Life Technologies, cat #: 15410– 122)).
  • Cell number was determined using a hemacytometer. Cells were then seeded at 4000 cells per well of a 96-well plate in 100 ⁇ L of complete growth media. The plate was incubated overnight at 37 °C and 5% CO 2 in a water-jacketed incubator.
  • Figure 11 summarizes the effect of the tested treprostinil compositions T527 (Figre 11A), T550 ( Figure 11B), T441 (Figure 11C) and T420 ( Figure 11D) on NR8383 cell proliferation. All tested treprostinil compositions showed some inhibition of cell proliferation from medium to the highest concentration. Specifically, of the four compositions, both T527 and T550 showed the significant inhibitory effect on NR8383 alveolar cell proliferation at 25 M concentration, 30% and 60% correspondingly ( Figures 11A and 11B).
  • a catheter was placed in the femoral artery for measurement of systolic (sys) and diastolic (dias) blood pressures.
  • sys systolic
  • diastolic diastolic
  • Oxygen saturation was measured with a pulse oximeter placed on the paw.
  • the actual achieved lung dose was about 5x lower than provided in Figure 12 (e.g., administration of 10 ⁇ g/kg yielded about 2 ⁇ g/kg in the lungs).
  • the hypoxic baseline PAP value was 100%, and the changes in pressure were measured in comparison to the hypoxic baseline.
  • the normalized variation of mean SAP is shown as a percentage from the hypoxic baseline value in Figure 13A-B.
  • Heart rate is shown in Figure 14A-B as a percentage of the hypoxic baseline value over time.
  • the various treatments were delivered (via inhalation of nebulized drug to the lungs of the rats.
  • the pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), and heart rate of the rats were measured continuously for 180 minutes.
  • the PAP signal was collected at 200 points per second.
  • Patents, patent applications, patent application publications, journal articles and protocols referenced herein are incorporated by reference in their entireties, for all purposes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques qui comportent une prostacycline, un composé cationique et un tensioactif. Des compositions particulaires, comprenant des compositions de prostacycline nanoparticulaires solides, liposomales, comprenant des formulations de tréprostinil et de tréprostinil deutéré comportant un composé cationique et le tensioactif, sont également décrites. La présente invention concerne également un système comportant la composition pharmaceutique et un dispositif d'inhalation. L'invention concerne également des méthodes de traitement de l'hypertension pulmonaire et de l'hypertension porto-pulmonaire par les compositions et les systèmes décrits.
PCT/US2015/019661 2014-03-11 2015-03-10 Compositions de prostacycline et leurs procédés d'utilisation Ceased WO2015138423A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201461951171P 2014-03-11 2014-03-11
US61/951,171 2014-03-11

Publications (2)

Publication Number Publication Date
WO2015138423A1 WO2015138423A1 (fr) 2015-09-17
WO2015138423A9 true WO2015138423A9 (fr) 2015-11-12

Family

ID=54072322

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2015/019661 Ceased WO2015138423A1 (fr) 2014-03-11 2015-03-10 Compositions de prostacycline et leurs procédés d'utilisation

Country Status (1)

Country Link
WO (1) WO2015138423A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9643911B2 (en) 2015-06-17 2017-05-09 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US9701616B2 (en) 2015-06-17 2017-07-11 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US9776982B2 (en) 2013-01-11 2017-10-03 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US9845305B2 (en) 2013-01-11 2017-12-19 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101875969B1 (ko) 2009-06-12 2018-07-06 맨카인드 코포레이션 한정된 비표면적을 갖는 디케토피페라진 마이크로입자
EP2970149B1 (fr) 2013-03-15 2019-08-21 MannKind Corporation Compositions de dicétopipérazine microcristallines et procédés
CN105451716A (zh) 2013-07-18 2016-03-30 曼金德公司 热稳定性干粉药物组合物和方法
EA031604B1 (ru) 2013-10-25 2019-01-31 Инсмед Инкорпорейтед Трепростинильные соединения, композиции и способы их использования
EP3221291B1 (fr) 2014-11-18 2021-03-31 Insmed Incorporated Procédés de fabrication de tréprostinil et promédicaments dérivés de tréprostinil
WO2017132601A1 (fr) * 2016-01-29 2017-08-03 Mannkind Corporation Inhalateur à poudre sèche
IL262720B2 (en) * 2016-05-05 2024-06-01 Liquidia Tech Inc Dry powder treprostinil for the treatment of pulmonary hypertension
PL3512495T3 (pl) 2016-09-15 2023-01-23 Camurus Ab Preparaty analogu prostacykliny
EP3784175A4 (fr) * 2018-04-27 2022-02-09 University of Pittsburgh - of the Commonwealth System of Higher Education Prothèse composite polymère métallique biodégradable pour remplacement de valve cardiaque
KR20220002600A (ko) 2019-04-29 2022-01-06 인스메드 인코포레이티드 트레프로스티닐 전구약물의 건조 분말 조성물 및 이의 사용 방법
KR20210149157A (ko) 2019-05-14 2021-12-08 파모사 바이오팜 인코포레이티드 약산성 약물의 약제학적 조성물 및 투여 방법
CN114401716A (zh) * 2019-07-22 2022-04-26 纳诺米有限公司 持续释放的曲前列环素-化合物微粒组合物
US20240238309A1 (en) * 2020-03-25 2024-07-18 Insmed Incorporated Pharmaceutical formulations of treprostinil prodrugs and methods of use thereof
CN115916212A (zh) * 2020-04-17 2023-04-04 联合治疗公司 曲前列尼尔用于治疗间质性肺病
JP2025506019A (ja) * 2022-02-08 2025-03-05 ユナイテッド セラピューティクス コーポレイション トレプロスチニルイロプロスト併用療法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6638621B2 (en) * 2000-08-16 2003-10-28 Lyotropic Therapeutics, Inc. Coated particles, methods of making and using
CA2451432A1 (fr) * 2001-06-23 2003-01-03 Lyotropic Therapeutics, Inc. Particules a capacite de solubilisation amelioree
WO2004012680A2 (fr) * 2002-08-06 2004-02-12 Lyotropic Therapeutics, Inc. Complexes medicamenteux lipidiques contenus dans des phases liquides inversees et des phases cristallines liquides
US20110294815A1 (en) * 2008-06-27 2011-12-01 Harbeson Scott L Prostacyclin analogs
JP6542128B2 (ja) * 2013-01-11 2019-07-10 コルセア ファーマ インコーポレイテッド トレプロスチニルのプロドラッグ

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10752605B2 (en) 2013-01-11 2020-08-25 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US12365663B2 (en) 2013-01-11 2025-07-22 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US9776982B2 (en) 2013-01-11 2017-10-03 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US9845305B2 (en) 2013-01-11 2017-12-19 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US11958822B2 (en) 2013-01-11 2024-04-16 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US11505535B2 (en) 2013-01-11 2022-11-22 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US11339139B2 (en) 2013-01-11 2022-05-24 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US10344012B2 (en) 2013-01-11 2019-07-09 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US10450290B2 (en) 2013-01-11 2019-10-22 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US11046666B2 (en) 2013-01-11 2021-06-29 Corsair Pharma, Inc. Treprostinil derivative compounds and methods of using same
US10246403B2 (en) 2015-06-17 2019-04-02 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US9643911B2 (en) 2015-06-17 2017-05-09 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US10464877B2 (en) 2015-06-17 2019-11-05 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US10759733B2 (en) 2015-06-17 2020-09-01 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US10988435B2 (en) 2015-06-17 2021-04-27 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US11034645B2 (en) 2015-06-17 2021-06-15 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US10464878B2 (en) 2015-06-17 2019-11-05 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US10703706B2 (en) 2015-06-17 2020-07-07 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US11407707B2 (en) 2015-06-17 2022-08-09 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US10053414B2 (en) 2015-06-17 2018-08-21 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US11802105B2 (en) 2015-06-17 2023-10-31 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US11866402B2 (en) 2015-06-17 2024-01-09 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US9957220B2 (en) 2015-06-17 2018-05-01 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof
US9701616B2 (en) 2015-06-17 2017-07-11 Corsair Pharma, Inc. Treprostinil derivatives and compositions and uses thereof

Also Published As

Publication number Publication date
WO2015138423A1 (fr) 2015-09-17

Similar Documents

Publication Publication Date Title
AU2013351934B2 (en) Prostacylin compositions and methods for using the same
WO2015138423A9 (fr) Compositions de prostacycline et leurs procédés d'utilisation
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
EP1962805B1 (fr) Compositions à base de lipide d'anti-infectieux pour traiter des infections pulmonaires
JP2025122086A (ja) 非結核性抗酸菌肺感染症を治療するための方法
RU2421209C2 (ru) Фармацевтические композиции, содержащие циклоспорин
AU2014339866A1 (en) Prostacyclin compounds, compositions and methods of use thereof
RU2660585C2 (ru) Фармацевтическая композиция для уменьшения осложнений применения стероидных препаратов при лечении офтальмологических заболеваний
WO2016176555A1 (fr) Composés de prostacycline, compositions et méthodes d'utilisation associées
CN115569115B (zh) 一种同时包载全氟化碳和二甲双胍的脂质纳米制剂及其制备方法与应用
HK40051638A (en) Prostacyclin compounds
HK1225229B (en) Prostacyclin compounds
HK1225229A1 (en) Prostacyclin compounds

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: 15762138

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: 15762138

Country of ref document: EP

Kind code of ref document: A1