Concentrated stable iv epoprostenol and epoprostenol sodium formulations

Abstract

Pharmaceutical compositions comprising epoprostenol or epoprostenol sodium, and a pharmaceutically acceptable carrier are described. One example use of such pharmaceutical compositions is the treatment of pulmonary arterial hypertension. In certain embodiments, the pharmaceutical composition is a solution and has enhanced stability over time (i.e., product will be supplied as a solution in a vial). The presently commercially available pharmaceutical products containing epoprostenol or epoprostenol sodium are in lyophilized forms to provide required product stability, and therefore require reconstitution before use.

Description

CONCENTRATED STABLE IV EPOPROSTENOL AND EPOPROSTENOL SODIUM FORMULATIONSCROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 672,628, filed July 17, 2024, which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] This disclosure relates to pharmaceuticals and treatments for pulmonary arterial hypertension, and specifically to pharmaceutical formulations of epoprostenol.BACKGROUND

[0003] Epoprostenol, while a powerful drug that is administered as an intravenous (i.v.) infusion for the treatment of pulmonary arterial hypertension, is not stable longterm in aqueous solutions. Due to the instability when in aqueous solution, epoprostenol undergoes lyophilization or freeze-drying process in which water is removed from the product after it is frozen and placed under a vacuum. Epoprostenol is supplied as a freeze-dried powder in a vial which allows for long term storage. The major disadvantages of a freeze-dried powder include the need for sterile diluent upon reconstitution, cost and complexity of equipment and increased handling and processing time of drug preparation. One problem with freeze dried powders is poor solubility. An increased time for reconstitution by the user may result in partial loss of potency if the drug is not completely dissolved.SUMMARY

[0004] In some aspects, disclosed herein are embodiments of a pharmaceutical composition comprising epoprostenol or epoprostenol sodium, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition has unexpected long-term stability. In certain embodiments, the pharmaceutical composition has self-preservation. In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable base. In certain embodiments, the pharmaceutical composition is a stable suspension. In certainembodiments, the pharmaceutical composition is a stable solution. In certain embodiments, the pharmaceutical composition is non-aqueous. In certain embodiments, the pharmaceutical composition is a non-aqueous solution. In certain embodiments, the pharmaceutical composition further comprises one or more antioxidants.

[0005] In other aspects, disclosed herein are embodiments of a pharmaceutical product comprising the pharmaceutical composition disclosed and a container containing the pharmaceutical composition. In certain embodiments, the container is for single use or multiple use for days, weeks, or months (e.g., use of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or more times as needed). In certain embodiments, the container is a vial, e.g., without limitation, multi-use vial and single-use vial. In certain embodiments, the container is a prefilled syringe. In certain embodiments, the container is a container closure system. In certain embodiments, the container closure system allows transfer of the pharmaceutical composition therein to a drug reservoir wherein the pharmaceutical composition is further diluted to form a solution for administration. In certain embodiments, the pharmaceutical composition can be transferred directly without reconstitution. In certain embodiments, the pharmaceutical composition is used for treating a subject suffering from pulmonary arterial hypertension. In certain embodiments, the pharmaceutical product has a unit dose of about 0.5 mg to about 12.5 mg of epoprostenol. In certain embodiments, the pharmaceutical product has an amount of about 0.5 mg to about 500 mg of epoprostenol per container for single or multiple use for days, weeks, or months (e.g., use of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or more times as needed). In certain embodiments, the container is a polymer vial for single dose and multiple dose or prefilled syringe for single and multiple doses. In certain embodiments, the polymer is cyclic olefin polymer.

[0006] In other aspects, disclosed herein are embodiments of a pharmaceutical acceptable diluent that can be mixed with the pharmaceutical compositions disclosed herein to provide a ready to use composition of epoprostenol or epoprostenol sodium. In certain embodiments, the ready to use epoprostenol compositions have good stabilities at room temperature for at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 36 hours, at least about 48 hours, at least about 60hours, at least about 72 hours, at least about 4 days, at least about 5 days, at least about 6 days, and at least about 7 days. In certain embodiments, the pharmaceutical composition is diluted to 50 ml_ or 100 mL ready to use composition. In certain embodiments, the pharmaceutical composition is diluted about 10 times to about 2,000 times, about 20 times to about 2000 times, or about 25 times to about 2000 times as needed. In certain embodiments, the pharmaceutical acceptable diluent has a pH of about 10 or above, about 11 or above, about 11.5 or above, about 11.7 to about 12.5, about 10, about 10.5, about 11 , about 11 .5, about 11 .6, about 11 .7, about 1 1 .8, about 11.9, about 12.0, about 12.1 , about 12.2, about 12.3, about 12.3, about 12.4, about12.5, or any range therebetween. In certain embodiments, the pharmaceutical acceptable diluent comprises mannitol, arginine, glycine, lysine, one or more other pharmaceutically acceptable bases, one or more pharmaceutically acceptable salts, or any combination thereof. In certain embodiments, the pharmaceutical acceptable diluent comprises arginine and the pharmaceutically acceptable diluent has a pH of about 10 or above, about 11 or above, about 11 .5 or above, about 10, about 11 , about11.5, about 11.6, about 11.7, about 11.8, about 11.9, about 12.0, about 12.1 , about12.2, about 12.3, about 12.4, about 12.5, or any range therebetween. In certain embodiments, the arginine has a concentration of about 10 mM to 100 mM, about 20 mM to about 90 mM, about 30 mM to about 80 mM, about 40 mM to about 70 mM, or about 50 mM to about 60 mM. In certain embodiments, the pharmaceutical acceptable diluent comprises glycine and has a pH of about 10 or above, about 11 or above, about 11.5 or above, about 10, about 11 , about 11.5, about 11.6, about 11.7, about 1 1.8, about 11.9, about 12.0, about 12.1 , about 12.2, about 12.3, about 12.4, about 12.5, or any ranges therebetween. In certain embodiments, the glycine has a concentration of about 10 mM to 100 mM, about 15 mM to about 90 mM, about 20 mM to about 80 mM, about 25 mM to about 70 mM, or about 25 mM to about 60 mM. In certain embodiments, the pharmaceutical acceptable diluent comprises lysine and has a pH of about 10 or above, about 11 or above, about 11 .5 or above, about 10, about 11 , about 11 .5, about11.6, about 11.7, about 11.8, about 11.9, about 12.0, about 12.1 , about 12.2, about12.3, about 12.4, about 12.5, or any range therebetween. In certain embodiments, the lysine has a concentration of about 10 mM to 100 mM, about 15 mM to about 90 mM, about 20 mM to about 80 mM, about 25 mM to about 70 mM, or about 25 mM to about 60 mM. In certain embodiments, the pharmaceutical acceptable diluent furthercomprises one or more pharmaceutical acceptable salts. In certain embodiments, the pharmaceutical acceptable diluent comprises a buffer with a pH of about 10 or above, about 11 or above, about 11 .5 or above, about 10, about 1 1 , about 1 1 .5, about 11 .6, about 11.7, about 11.8, about 11.9, about 12.0, about 12.1 , about 12.2, about 12.3, about 12.4, about 12.5, orany ranges therebetween. In certain embodiments, the buffer is a phosphate buffer. In certain embodiments, the phosphate buffer has a concentration of about 10 mM to 100 mM, about 15 mM to about 90 mM, about 20 mM to about 80 mM, about 25 mM to about 70 mM, or about 25 mM to about 60 mM. In certain embodiments, the phosphate buffer is a sodium phosphate buffer. In certain embodiments, the pharmaceutical acceptable diluent is 1 % NaOH in sterile water. In certain embodiments, the pharmaceutical acceptable diluent is commercially available Veletri diluent. In certain embodiments, the pharmaceutical acceptable diluent comprises 8.4% sodium bicarbonate.

[0007] In other aspects, disclosed herein are methods for treating pulmonary arterial hypertension in a subject comprising administering to the subject a therapeutically effective amount of epoprostenol via i.v. injection of a diluted ready to use composition of the pharmaceutical composition disclosed herein. In certain embodiments, the diluted ready to use composition of the pharmaceutical composition is prepared by mixing the pharmaceutical composition with a pharmaceutically acceptable diluent disclosed herein. In certain embodiments, the pharmaceutical composition is diluted to 50 mL or 100 mL ready to use composition.

[0008] In some embodiments, the pharmaceutically acceptable carrier is selected from the group consisting of alcohols, polyols, esters of polyols, DMSO, 1-methyl-2- pyrrolidone, and mixtures thereof. In some embodiments, the pharmaceutically acceptable carrier comprises at least about 90% propylene glycol.

[0009] In some embodiments, the pharmaceutical composition has a concentration of epoprostenol ranging from about 0.1 mg / mL to about 30 mg / mL, from about 0.1 mg / mL, about 0.3 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, or about 12 mg / mL to about 12.5 mg / mL. In someembodiments, the pharmaceutical composition has a concentration of epoprostenol of about 1 mg / mL to about 10 mg / mL.

[0010] In some embodiments, the pharmaceutical composition has a concentration of water of less than about 5%, less than about 4.5%, less than about 4%, less than about 3.5%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1.5%, less than about 1 %, less than about 0.5%, or any ranges therebetween.

[0011] In some embodiments, the pharmaceutically acceptable base comprises one or more bases selected from the group consisting of hydroxides (e.g., metal hydroxides and NH4OH), arginine, glycine, and lysine. In some embodiments, the concentration of the pharmaceutically acceptable base is about 0.125 mol / L to about 0.600 mol / L.

[0012] In some embodiments, the loss of epoprostenol in the pharmaceutical composition or the pharmaceutical product disclosed herein is less than about 10% or not detectable after about 1 day to about 36 months of storage at a temperature of about 0 °C to about 30 °C.

[0013] In some embodiments, the pharmaceutical composition or the pharmaceutical product disclosed herein has a shelf life of about 36 months at a temperature of about 0 °C to about 30 °C.

[0014] Those and other aspects and associated implementations and benefits of the disclosed technology are described in greater detail in the drawings, the description and the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fees.

[0016] FIG. 1A shows a graph displaying the average peak area versus the concentration of epoprostenol in solution.

[0017] FIG. 1 B shows representative HPLC chromatograms for a diluent, a 50% standard epoprostenol solution (0.05 mg / mL STD), a 100% standard epoprostenolsolution (0.10 mg / mL STD), and a 150% standard epoprostenol solution (0.15 mg / mL STD) to show linearity.

[0018] FIG. 1C shows representative HPLC chromatograms for a diluent, a 100% standard epoprostenol solution at time zero, and a 100% standard epoprostenol solution at 24 hours to show stability.

[0019] FIG. 2A shows a graph displaying the percent assay loss rate versus pH for solutions S1 through S5 at 30 °C, 40 °C, and 50 °C.

[0020] FIG. 2B shows a graph displaying the percent assay loss rate versus pH for solutions S6 through S10 at 30 °C, 40 °C, and 50 °C.

[0021] FIG. 2C shows a graph displaying the percent impurity increase rate versus pH for solutions S1 through S5 at 30 °C, 40 °C, and 50 °C.

[0022] FIG. 2D shows a graph displaying the percent impurity increase rate versus pH for solutions S6 through S10 at 30 °C, 40 °C, and 50 °C.

[0023] FIG 2E shows representative HPLC chromatograms for a 0.1 mg / mL epoprostenol standard and solutions S1 through S5 after being stored at 50 °C for four days.

[0024] FIG. 2F shows representative HPLC chromatograms for a 0.1 mg / mL epoprostenol standard and solutions S6 through S10 after being stored at 50 “C forfour days.

[0025] FIG. 3 shows a plot displaying the percent assay loss versus pH at 50 °C over a day for solutions in WFI and in propylene glycol.

[0026] FIG. 4A shows a graph displaying the percent assay loss versus time for solution S26.

[0027] FIG. 4B shows a graph displaying the percent assay loss versus sodium hydroxide concentration for solution S26 over 4 days and 7 days.

[0028] FIG. 5A shows a graph displaying the percent assay loss versus sodium hydroxide concentration for solutions in propylene glycol over 4 days and 7 days.

[0029] FIG. 5B shows a graph displaying the percent assay loss versus sodium hydroxide concentration for solutions in glycerol over 4 days and 7 days.

[0030] FIG. 6 shows HPLC chromatograms for solution S29.

[0031] FIG. 7 shows representative HPLC chromatograms for a diluent, a 0.1 mg / mL epoprostenol standard solution, an S47 vehicle, and solution S47.

[0032] FIG. 8A shows representative HPLC chromatograms for a diluent, a 0.1 mg / mL epoprostenol standard solution, an S47 vehicle, and solution S47.

[0033] FIG. 8B shows zoomed in representative HPLC chromatograms for a diluent, a 0.1 mg / mL epoprostenol standard solution, an S47 vehicle, and solution S47.

[0034] FIG. 9A shows representative HPLC chromatograms for a diluent, a 0.1 mg / mL epoprostenol standard solution, and solution S47.

[0035] FIG. 9B shows representative HPLC chromatograms for a diluent, a 0.1 mg / mL epoprostenol standard solution, as well as solutions S47, S46, S48, and S51.

[0036] FIG. 10A shows %recovery of epoprostenol of Compositions F1 , F2, F3, F4, and F5 when stored at -20°C at ti -month, t2-month, and ts -month relative to to.

[0037] FIG. 10B shows %recovery of epoprostenol of Compositions F1 , F2, F3, F4, and F5 when stored at 2-8°C at ti -month, t2-month, and ts -month relative to to.

[0038] FIG. 10C shows %recovery of epoprostenol of Compositions F1 , F2, F3, F4, and F5 when stored at 25°C / 60%RH at ti-month, t2-month, and ts-month relative to t0.

[0039] FIG. 10D shows %recovery of epoprostenol of Compositions F1 , F2, F3, F4, and F5 when stored at 40°C / 75%RH at ti-month,t2-month, and ts-month relative to t0DETAILED DESCRIPTION

[0040] As used in the specification and claims, the singularform “a,” “an,” and “the” includes plural references unless the context clearly dictates otherwise. It should be understood that the terms “a” and “an” as used herein refer to “one or more” of the enumerated components.

[0041] The use of the alternative (e.g., “or”) should be understood to mean either one, both, or any combination thereof of the alternatives.

[0042] The term “about” as used herein in the context of a number refers to a range centered on that number and spanning 10% less than that number and 10% more than that number. The term “about” used in the context of a range refers to an extendedrange spanning 10% less than that the lowest number listed in the range and 10% more than the greatest number listed in the range.

[0043] Throughout this disclosure, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range of this disclosure relating to any physical feature, such as polymer subunits, size, or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. Throughout this disclosure, numerical ranges are inclusive of their recited endpoints, unless specifically stated otherwise.

[0044] Unless the context requires otherwise, throughout the present specification and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is, as "including, but not limited to." As used herein, the terms “include” and “comprise” are used synonymously.

[0045] Unless specified otherwise, the terms “composition” and “composite” may be used interchangeably.

[0046] Unless specified otherwise, the term “non-aqueous” means a water concentration of less than 5% by weight. For example, a non-aqueous solution has a water concentration of less than 5% by weight.

[0047] Epoprostenol has been utilized as a medication to treat high blood pressure in the lungs, or pulmonary arterial hypertension. The existing product is supplied in lyophilized vials which requires reconstitution immediately before use. As the available unit doses are low (e.g., 0.5 mg and 1.5 mg epoprostenol sodium), patients may need to prepare and mix multiple vials for daily treatment, which can be time-consuming and create risks for medication errors, partial loss of potency if the drug is not completely dissolved during reconstitution, contamination and infection. Provided herein are embodiments of a pharmaceutical composition with higher concentration of epoprostenol or epoprostenol sodium with unexpected long-term stability. Such pharmaceutical composition can be provided at higher unit doses and significantly improve patients’ quality of life and product safety.

[0048] As shown in the Examples provided herein, the use of predominately nonaqueous solutions, such as propylene glycol, along with bases, such as sodium hydroxide, provided enhanced stability for epoprostenol and epoprostenol sodium over extended time periods.

[0049] As shown in the Examples provided herein, pharmaceutical compositions comprising epoprostenol or epoprostenol sodium and a pharmaceutically acceptable carrier showed unexpected long-term stability. In certain examples, pharmaceutical compositions comprising epoprostenol or epoprostenol sodium and propylene glycol showed <5% epoprostenol loss after storage at -20°C, or 2 to 8°C for at least one year.

[0050] Epoprostenol was not stable in various aqueous solutions for an extended period at 30 °C, 40 °C, and 50 °C (e.g., see Example 2). Epoprostenol showed better stability at higher pH (e.g., pH 13.5 v. pH 12.5) in tested aqueous solutions, e.g., as evidenced by lower loss rate of epoprostenol (e.g., see Example 2, Table 15) and impurity increase rate (e.g., see Example 2, Table 16). Higher temperature increased the loss rate of epoprostenol (e.g., see Example 2, Table 15) and impurity increase rate (e.g., see Example 2, Table 16) in aqueous epoprostenol compositions.

[0051] Epoprostenol showed better long-term stability in propylene glycol than glycerol in tested NaOH concentrations (ranging from 0.5% to 3.0%, see, e.g., Example 5, Table 25). Epoprostenol in anhydrous ethanol showed delayed precipitation in all samples tested (0.5% to 3.0% NaOH), while epoprostenol (10 mg / mL) in propylene glycol did not show delayed precipitation in samples with NaOH concentration of 0.5% and 1.0% (see, e.g., Example 5, Table 24).

[0052] Epoprostenol in propylene glycol showed better long-term stability in the presence of NaOH than arginine or KOH (e.g., see Example 3, Table 20). An optimal NaOH concentration range for epoprostenol in propylene glycol appeared to be from 0.75% to 1.25% (e.g., see Example 4, Table 22). Additional examples showed epoprostenol pharmaceutical compositions in propylene glycol had better stabilities with NaOH concentrations at 0.75% to 0.9% over NaOH concentrations of 0.6% and 1 .25%. See, e.g., Example 7, Table 29 and Example 8, Table 31. Epoprostenol in propylene glycol with the same NaOH concentrations (0.75%) showed higher stability at a water content of 0.75% than about 2% (Example 8, Table 33).

[0053] Epoprostenol pharmaceutical compositions in propylene glycol with various NaOH concentrations (Example 10, Table 33) showed self preservation (e.g., Example 11 , Table 51 ) and stability after placed at -20°C, 2-8°C, 25°C / 60%RH, or 40°C / 75%RH for weeks or months (e.g., Example 10(C)-(F)). Water content of the tested pharmaceutical compositions remained lower than 1.5% after 3 months at the tested condition (Example 10, Table 43). Tested compositions with a NaOH concentration 0.75% w / v showed better stability than compositions with a lower NaOH concentration (0.15% or 0.05%, Tables 44-50). The loss of epoprostenol was less than 5% after the tested epoprostenol pharmaceutical compositions were placed at 2-8°C for 6 months and at 25°C for 3 months (Example 10, T ables 37 and 40).

[0054] Epoprostenol pharmaceutical compositions in propylene glycol with 0.75% NaOH showed stability after placed at 2-8°C, 25°C, or 40°C for weeks or months (e.g., Example 10). None of the tested epoprostenol pharmaceutical compositions showed visible particles (Example 10, Tables 35 and 39). The loss of epoprostenol was less than 5% after the tested epoprostenol pharmaceutical compositions were placed at 2- 8°C for 6 months and at 25°C for 3 months (Example 10, T ables 37 and 40).

[0055] Embodiments of epoprostenol pharmaceutical compositions in propylene glycol with 0.75% NaOH were diluted with various aqueous diluents comprising glycine, arginine, or lysine with pH of about 11.7 to about 12.3, about 12, about 12.2, about 12.3, or about 12.5 (Example 12). The pharmaceutically acceptable diluents comprising arginine and NaCI (pH 12.2, pH 12.3, Example 12C, Table 59) provided ready to use compositions with good stability (e.g., less than about 5% loss of epoprostenol compared with the initial epoprostenol) after the ready to use compositions were placed at 25°C for 48 h or at 2-8°C for 8 days and then at 25°C for 48 h (Example 12C, Table 60). 8.4% sodium bicarbonate diluent (Table 57), diluents comprising lysine and NaCI (pH 12.2 Lysine / NaCI, Table 61 ), and diluents comprising glycine and NaCI (pH 12.5 glycine / NaCI, Table 60) provided good ready to use stability for the epoprostenol pharmaceutical compositions.

[0056] In some aspects, disclosed herein are embodiments of a pharmaceutical composition comprising epoprostenol or epoprostenol sodium and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition has longterm stability at a temperature of about -20°C to about 50°C, about -20°C or lower, about2°C or lower, about 2°C to about 8°C, about 8°C or lower, about 25°C or lower, about 40°C or lower, and / or about 50°C or lower. The term “stable” or “stability” of a pharmaceutical composition disclosed herein means when compared with the initial epoprostenol content, the loss of epoprostenol is about 5% or less. The term “long-term stability” of a pharmaceutical composition means the pharmaceutical composition is stable for at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 1 month, at least about 40 days, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 25 months, at least about 26 months, at least about 27 months, at least about 28 months, at least about 29 months, at least about 30 months, at least about 31 months, at least about 32 months, at least about 33 months, at least about 34 months, at least about 35 months, or at least about 36 months. In certain embodiments, the pharmaceutical composition has a loss of epoprostenol over the initial epoprostenol content that is about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4.5% or less, about 4% or less, about 3.5% or less, about 3% or less, about 2.5% or less, about 2% or less, about 1 .5% or less, about 1 % or less, or about 0.5% or less when stored at a temperature of about -20°C to about 50°C, about -20°C or lower, about 2°C or lower, about 2°C to about 8°C, about 8°C or lower, about 25°C or lower, about 40°C or lower, and / or about 50°C or lower for at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 1 month, at least about 40 days, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months,at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 25 months, at least about 26 months, at least about 27 months, at least about 28 months, at least about 29 months, at least about 30 months, at least about 31 months, at least about 32 months, at least about 33 months, at least about 34 months, at least about 35 months, or at least about 36 months. In certain embodiments, the pharmaceutical composition has a shelf-life of at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 1 month, at least about 40 days, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 25 months, at least about 26 months, at least about 27 months, at least about 28 months, at least about 29 months, at least about 30 months, at least about 31 months, at least about 32 months, at least about 33 months, at least about 34 months, at least about 35 months, or at least about 36 months when stored at a temperature of about -20°C to about 50°C, about -20°C or lower, about 2°C or lower, about 2°C to about 8°C, about 8°C or lower, about 25°C or lower, about 40°C or lower, and / or about 50°C or lower. In certain embodiments, the relative humidity (RH) of the storage condition is about 60% or lower, or about 75% or lower.

[0057] In certain embodiments, the pharmaceutical composition has selfpreservation, i.e., the ability to pass USP preservative effectiveness test, which is also known as antimicrobial effectiveness test (AET), without the presence of preservatives. In certain embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable base. In certain embodiments, the pharmaceutical composition further comprises one or more preservatives. In certain embodiments, the pharmaceutical composition further comprises one or more antioxidants. In certain embodiments, the pharmaceutical composition is a stable suspension. In certain embodiments, the pharmaceutical composition is a stable solution. In certainembodiments, the pharmaceutical composition is a non-aqueous solution. In certain embodiments, the pharmaceutical composition has a water content of about 5% or lower, about 4.5% or lower, about 4% or lower, about 3.5% or lower, about 3% or lower, about 2.5% or lower, about 2% or lower, about 1.5% or lower, about 1.4% or lower, about 1.3% or lower, about 1.2% or lower, about 1.1 % or lower, about 1 % or lower, about 0.9% or lower, about 0.8% or lower, about 0.7% or lower, about 0.6% or lower, about 0.5% or lower, about 0.4% or lower, about 0.3% or lower, about 0.2% or lower, or about 0.1 % or lower.

[0058] In other aspects, disclosed herein are embodiments of a pharmaceutical product comprising the pharmaceutical composition disclosed and a container containing the pharmaceutical composition. In certain embodiments, the container is for single use or multiple use for days, weeks, or months (e.g., use of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or more times as needed). In certain embodiments, the container is a vial, e.g., without limitation, multi-use vial and single-use vial. In certain embodiments, the container is a prefilled syringe. In certain embodiments, the container is a container closure system. In certain embodiments, the container closure system allows transfer of the pharmaceutical composition therein to a drug reservoir wherein the pharmaceutical composition is further diluted to form a solution for administration. In certain embodiments, the pharmaceutical composition can be transferred directly without reconstitution. In certain embodiments, the pharmaceutical composition is used for treating a subject suffering from pulmonary arterial hypertension. In certain embodiments, the pharmaceutical product has multiple doses of about 1 mg to about 500 mg of epoprostenol in cyclic olefin polymer vial. In certain embodiments, the pharmaceutical product further comprises one or more pharmaceutically acceptable diluent disclosed herein.

[0059] In certain embodiments, the pharmaceutical product has a unit dose of about 0.5 mg to about 500 mg, or about 0.5 mg to about 12.5 mg of epoprostenol. In certain embodiments, the unit dose is about 0.5 mg to about 10 mg of epoprostenol. In certain embodiments, the unit dose is about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about11.5 mg, about 12 mg, or about 12.5 mg epoprostenol. In certain embodiments, the pharmaceutical product has an epoprostenol concentration of about 0.1 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, about 10.5 mg / mL, about 11 mg / mL, about 11 .5 mg / mL, about 12 mg / mL, or about 20.0 mg / mL. In certain embodiments, the pharmaceutical product has an amount of about 0.5 mg to about 500 mg of epoprostenol for single or multiple use for days, weeks, or months (e.g., use of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or more times as needed). In certain embodiments, the amount of epoprostenol in a container is about 0.5 mg to about 500 mg, about 1 mg to about 500 mg, about 3 mg to about 500 mg, about 5 mg to about 500 mg, about 10 mg to about 500 mg, about 3 mg to about 100 mg, about 3 mg to about 200 mg, about 3 mg to about 300 mg, about 3 mg to about 400 mg, about 1 mg, about 1 .5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, or any ranges therebetween. In certain embodiments, the unit dose is about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 30 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, or about 300 mg epoprostenol. In certain embodiments, the pharmaceutical product has an epoprostenol concentration of about 0.1 mg / mL, 0.5 mg / mL, about 1 mg / mL, about1 .5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, about 10.5 mg / mL, about 11 mg / mL, about 1 1.5 mg / mL, about 12 mg / mL, about 18 mg / mL, or about 24 mg / mL, about 30 mg / mL, or any ranges therebetween. In certain embodiments, the pharmaceutical product has an epoprostenol concentration of about 0.1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 10 mg / mL, or about 3 mg / mL to about 10 mg / mL. In certainembodiments, the container is a polymer vial or prefilled syringe. In certain embodiments, the polymer is cyclic olefin polymer.

[0060] In other aspects, disclosed herein are embodiments of a pharmaceutical acceptable diluent that can be mixed with the pharmaceutical compositions disclosed herein to provide a ready to use composition of epoprostenol or epoprostenol sodium. In certain embodiments, the ready to use epoprostenol compositions have good stabilities at room temperature for at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 36 hours, at least about 48 hours, at least about 60 hours, at least about 72 hours, at least about 4 days, at least about 5 days, at least about 6 days, and at least about 7 days. In certain embodiments, the pharmaceutical composition is diluted to 50 ml_ or 100 mL ready to use composition. In certain embodiments, the pharmaceutical composition is diluted about 10 times to about 2,000 times, about 20 times to about 2000 times, or about 25 times to about 2000 times as needed. In certain embodiments, the pharmaceutical acceptable diluent has a pH of about 10 or above, about 11 or above, about 11 .5 or above, about 11.7 to about 12.5, about 10, about 10.5, about 11 , about 11 .5, about 11 .6, about 11 .7, about 1 1 .8, about 11.9, about 12.0, about 12.1 , about 12.2, about 12.3, about 12.3, about 12.4, about 12.5, or any range therebetween. In certain embodiments, the pharmaceutical acceptable diluent comprises mannitol, arginine, glycine, lysine, one or more other pharmaceutical acceptable base, one or more pharmaceutically acceptable salts, or any combination thereof. In certain embodiments, the pharmaceutical acceptable diluent comprises arginine and the pharmaceutically acceptable diluent has a pH of about 10 or above, about 11 or above, about 11.5 or above, about 10, about 11 , about 1 1.5, about 11.6, about 11.7, about 11.8, about 11.9, about 12.0, about 12.1 , about 12.2, about 12.3, about 12.4, about 12.5, or any range therebetween. In certain embodiments the pharmaceutical acceptable diluent further comprises a pharmaceutically acceptable salt, e.g., without limitation, NaCI, KOI, etc. In certain embodiments, the arginine has a concentration of about 10 mM to 100 mM, about 20 mM to about 90 mM, about 30 mM to about 80 mM, about 40 mM to about 70 mM, or about 50 mM to about 60 mM. In certain embodiments, the pharmaceutical acceptable diluent comprises glycine and has a pH of about 10 or above, about 11 or above, about 11.5 or above, about 10, about 11 , about 11.5, about 11.6, about 11.7, about 11.8, about 11.9, about 12.0, about 12.1 , about 12.2, about 12.3, about 12.4, about 12.5, or any ranges therebetween. In certainembodiments, the glycine has a concentration of about 10 mM to 100 mM, about 15 mM to about 90 mM, about 20 mM to about 80 mM, about 25 mM to about 70 mM, or about 25 mM to about 60 mM. In certain embodiments, the pharmaceutical acceptable diluent comprises lysine and has a pH of about 10 or above, about 1 1 or above, about 11.5 or above, about 10, about 11 , about 11.5, about 11.6, about 11.7, about 1 1.8, about 11.9, about 12.0, about 12.1 , about 12.2, about 12.3, about 12.4, about 12.5, or any range therebetween. In certain embodiments, the lysine has a concentration of about 10 mM to 100 mM, about 15 mM to about 90 mM, about 20 mM to about 80 mM, about 25 mM to about 70 mM, or about 25 mM to about 60 mM.

[0061] In certain embodiments, the pharmaceutical acceptable diluent comprises a buffer with a pH of about 10 or above, about 11 or above, about 11 .5 or above, about 10, about 11 , about 1 1.5, about 11 .6, about 11.7, about 1 1 .8, about 1 1 .9, about 12.0, about 12.1 , about 12.2, about 12.3, about 12.4, about 12.5, or any ranges therebetween. In certain embodiments, the buffer is a phosphate buffer. In certain embodiments, the phosphate buffer has a concentration of about 10 mM to 100 mM, about 15 mM to about 90 mM, about 20 mM to about 80 mM, about 25 mM to about 70 mM, or about 25 mM to about 60 mM. In certain embodiments, the phosphate buffer is a sodium phosphate buffer. In certain embodiments, the pharmaceutical acceptable diluent is 1 % NaOH in sterile water. In certain embodiments, the pharmaceutical acceptable diluent is commercially available Veletri diluent. In certain embodiments, the pharmaceutical acceptable diluent comprises 8.4% sodium bicarbonate.

[0062] In certain embodiments the pharmaceutically acceptable salt is a chloride (e.g., without limitation, NaCI, KCI), iodide (e.g., without limitation, KI, Nal), carbonate (e.g., without limitation, sodium carbonate, potassium carbonate), bicarbonate (e.g., without limitation, sodium bicarbonate, potassium bicarbonate), phosphate (e.g., without limitation, sodium phosphate, potassium phosphate), hydrogenphosphate (e.g., without limitation, sodium hydrogenphosphate, potassium hydrogenphosphate), or dihydrogen phosphate (e.g., without limitation, sodium dihydrogenphosphate, potassium dihydrogenphosphate). Examples of the pharmaceutically acceptable salts may further include, without limitation, sodium salts of acetic acid, phosphoric acid, HCI, and methyl sulfonic acid; potassium salts of acetic acid, phosphoric acid, HCI, and methyl sulfonic acid; calcium salts of acetic acid, phosphoric acid, HCI, and methylsulfonic acid; and zinc salts of acetic acid, phosphoric acid, HCI, and methyl sulfonic acid.

[0063] In other aspects, disclosed herein are methods for treating pulmonary arterial hypertension in a subject comprising administering to the subject a therapeutically effective amount of epoprostenol via i.v. injection of a diluted ready to use composition of the pharmaceutical composition disclosed herein. In certain embodiments, the diluted ready to use composition of the pharmaceutical composition is prepared by mixing the pharmaceutical composition with a pharmaceutically acceptable diluent disclosed herein. In certain embodiments, the pharmaceutical composition is diluted to about 50 ml_ or about 100 mL ready to use composition.

[0064] In some embodiments, the pharmaceutically acceptable carrier is selected from the group consisting of alcohols, polyols, esters of polyols, DMSO, 1-methyl-2- pyrrolidone, and mixtures thereof.

[0065] Examples of alcohols include, without limitation, ethanol, isopropanol, and benzyl alcohol. Examples of polyols include, without limitation, propylene glycol, glycerol, polyethylene glycol (e.g., without limitation, PEG-300, PEG-400, PEG-600, PEG-3350, and PEG-4000), poloxamer 188, polysorbate 20, polysorbate 40, and polysorbate 80. Examples of esters of polyols include, without limitation, triglycerides (e.g., medium chain triglycerides, long chain triglycerides, Castor oil polyoxyethylene ether), mono-glycerides, and di-glycerides.

[0066] In some embodiments, the pharmaceutically acceptable carrier comprises at least about 90% propylene glycol.

[0067] In some embodiments, the pharmaceutical composition has a concentration of epoprostenol of about 0.1 mg / mL to about 30 mg / mL, about O.1 mg / mL, about 0.3 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, about 10.5 mg / mL, about 11 mg / mL, about 11 .5 mg / mL, about 12 mg / mL, about 12.5 mg / mL, about 13 mg / mL, about 13.5 mg / mL, about 14 mg / mL, about 14.5 mg / mL, about 15 mg / mL, about 20 mg / mL, about 24 mg / mL, about 25 mg / mL, about 30 mg / mL, or any ranges therebetween. In someembodiments, the pharmaceutical composition has a concentration of epoprostenol of about 1 mg / mL to about 10 mg / mL. In some embodiments, the pharmaceutical composition has a concentration of epoprostenol of about 0.1 mg / mL to about 30 mg / mL, from about 0.1 mg / mL, about 0.3 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 12.5 mg / mL, or any ranges therebetween.

[0068] In some embodiments, the pharmaceutical composition has a concentration of water of less than about 5%, less than about 4.5%, less than about 4%, less than about 3.5%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1.5%, less than about 1 %, less than about 0.5%, or any ranges therebetween.

[0069] In some embodiments, the pharmaceutically acceptable base comprises one or more bases selected from the group consisting of hydroxides (e.g., metal hydroxides, and NH4OH)), arginine, glycine, and lysine. Examples of hydroxides include, without limitation, NaOH, KOH, Ca(OH)2, and NH4OH.

[0070] In some embodiments, the concentration of the pharmaceutically acceptable base ranges from about 0.100 mol / L, about 0.125 mol / L, about 0.150 mol / L, about 0.1875 mol / L, about 0.200 mol / L, about 0.225 mol / L, about 0.250 mol / L, about 0.275 mol / L, about 0.300 mol / L, about 0.3125 mol / L, about 0.350 mol / L, about 0.400 mol / L, about 0.450 mol / L, about 0.500 mol / L, about 0.550 mol / L, to about 0.600 mol / L. In some embodiments, the concentration of the pharmaceutically acceptable base is about 0.125 mol / L, about 0.1875 mol / L, about 0.250 mol / L, about 0.3125 mol / L, or about 0.500 mol / L.

[0071] In some embodiments, the pharmaceutically acceptable base is NaOH, and the concentration of NaOH (w / v or w / w) ranges from about 0.01 % to about 5%, about 0.01 % to about 4%, about 0.01 % to about 3%, about 0.01 % to about 2%, about 0.01 % to about 1.5%, about 0.15% to about 1.25%, about 0.5% to about 1.2%, about 0.70% to about 1 .2%, about 0.75% to about 1 .25%, about 0.7% to about 1.1 %, about 0.7% to about 1.0%, about 0.7% to about 0.9%, about 0.7% to about 0.8%, about 0.01 % to about 0.05%, about 0.01 % to about 0.10%, about 0.01 % to about 0.15%, about 0.01 %to about 0.20%, about 0.01 % to about 0.25%, about 0.01 % to about 0.30%, about 0.01 % to about 0.35%, about 0.01 % to about 0.40%, about 0.01 % to about 0.45%, about 0.01 % to about 0. 50%, about 0.01 % to about 0.55%, about 0.01 % to about 0.60%, about 0.01 % to about 0.65%, about 0.01 % to about 0.70%, about 0.01 % to about 0.75%, about 0.01 % to about 0.80%, about 0.01 % to about 0.85%, about 0.01 % to about 0.90%, or about 0.01 % to about 0.95%.

[0072] In some embodiments, the loss of epoprostenol in the pharmaceutical composition or the pharmaceutical product disclosed herein is less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1 %, or not detectable after about 1 month, after about 2 months, after about 3 months, after about 4 months, after about 5 months, after about 6 months, after about7 months, after about 8months, after about 9 months, after about 10 months, after about 11 months, after about 12 months, after about 13 months, after about 14 months, after about 15 months, after about 16 months, after about 17 months, after about 18months, after about 19 months, after about 20 months, after about 21 months, after about 22 months, after about 23 months, after about 24 months, after about 25 months, after about 26 months, after about 27 months, after about 28months, after about 29 months, after about 30 months, after about 31 months, after about 32 months, after about 33 months, after about 34 months, after about 35 months, after about 36 months of storage at a temperature of about -20°C to about 50°C, about -20°C or lower, about 2°C or lower, about 2°C to about 8°C, about 8°C or lower, about 25°C or lower, about 40°C or lower, and / or about 50°C or lower, about 0 °C to about 30 °C, about 0 °C to about 8 °C, about 1 °C to about 8 °C, about 2 °C to about 8 °C, about 3 °C to about 8 °C, about 4 °C to about 8 °C, about 5 °C to about 8 °C, about 6 °C to about 8 °C, about 7 °C to about8 °C, about 0 °C to about 10 °C, about 1 °C to about 10 °C, about 2 °C to about 10 °C, about 3 °C to about 10 °C, about 4 °C to about 10 °C, about 5 °C to about 10 °C, about 6 °C to about 10 °C, about 7 °C to about 10 °C, about 8 °C to about 10 °C, about 9 °C to about 10 °C, about 0 °C to about 15°C, about 1 °C to about 15°C, about 2 °C to about 15 °C, about 3 °C to about 15 °C, about 4 °C to about 15 °C, about 5 °C to about 15°C, about 6 °C to about 15 °C, about 7 °C to about 15 °C, about 8 °C to about 15°C, about9 °C to about 15°C, about 10 °C to about 15°C, about 11 °C to about 15°C, about 12 °C to about 15°C, about 13 °C to about 15°C, about 14 °C to about 15°C, about 15 °C toabout 30 °C, about 15 °C to about 29 °C, about 16 °C to about 30 °C, about 16 °C to about 29 °C, about 15 °C to about 28 °C, about 16 °C to about 28 °C, about 17 °C to about 28 °C, about 18 °C to about 27 °C, about 19 °C to about 26 °C, about 20 °C to about 25 °C, about 20 °C to about 24 °C, about 20 °C to about 23 °C, about 20 °C to about 22 °C, about 20 °C to about 21 °C, about 0 °C, about 1 °C, about 2 °C, about 3 °C, about 4 °C, about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, about 10 °C, about 11 °C, about 12 °C, about 13 °C, about 14 °C, about 15 °C, about 16 °C, about 17 °C, about 18 °C, about 19 °C, about 20 °C, about 21 °C, about 22 °C, about 23 °C, about 24 °C, about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C, or about 30 °C. .

[0073] In some embodiments, after the pharmaceutical composition or the pharmaceutical product is diluted by the pharmaceutically acceptable diluent disclosed herein, (e.g., without limitation, with pH of about 10 or above), the loss of epoprostenol in the diluted composition is less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1 %, or not detectable after about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days of storage at a temperature of about -20°C to about 50°C, about -20°C or lower, about 2°C or lower, about 2°C to about 8°C, about 8°C or lower, about 25°C or lower, about 40°C or lower, about 50°C or lower, about 0 °C to about 30 °C, about 0 °C to about 8 °C, about 1 °C to about 8 °C, about 2 °C to about 8 °C, about 3 °C to about 8 °C, about 4 °C to about 8 °C, about 5 °C to about 8 °C, about 6 °C to about 8 °C, about 7 °C to about8 °C, about 0 °C to about 10 °C, about 1 °C to about 10 °C, about 2 °C to about 10 °C, about 3 °C to about 10 °C, about 4 °C to about 10 °C, about 5 °C to about 10 °C, about 6 °C to about 10 °C, about 7 °C to about 10 °C, about 8 °C to about 10 °C, about 9 °C to about 10 °C, about 0 °C to about 15°C, about 1 °C to about 15°C, about 2 °C to about 15 °C, about 3 °C to about 15 °C, about 4 °C to about 15 °C, about 5 °C to about 15°C, about 6 °C to about 15 °C, about 7 °C to about 15 °C, about 8 °C to about 15°C, about9 °C to about 15°C, about 10 °C to about 15°C, about 11 °C to about 15°C, about 12 °Cto about 15°C, about 13 °C to about 15°C, about 14 °C to about 15°C, about 15 °C to about 30 °C, about 15 °C to about 29 °C, about 16 °C to about 30 °C, about 16 °C to about 29 °C, about 15 °C to about 28 °C, about 16 °C to about 28 °C, about 17 °C to about 28 °C, about 18 °C to about 27 °C, about 19 °C to about 26 °C, about 20 °C to about 25 °C, about 20 °C to about 24 °C, about 20 °C to about 23 °C, about 20 °C to about 22 °C, about 20 °C to about 21 °C, about 0 °C, about 1 °C, about 2 °C, about 3 °C, about 4 °C, about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, about 10 °C, about 11 °C, about 12 °C, about 13 °C, about 14 °C, about 15 °C, about 16 °C, about 17 °C, about 18 °C, about 19 °C, about 20 °C, about 21 °C, about 22 °C, about 23 °C, about 24 °C, about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C, or about 30 °C.

[0074] In some embodiments, the pharmaceutical composition or the pharmaceutical product disclosed herein has a shelf life of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, after about7 months, about 8months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 25 months, about 26 months, about 27 months, about 28months, about 29 months, about 30 months, about 31 months, about 32 months, about 33 months, about 34 months, about 35 months, about 36 months at a temperature of about -20°C to about 50°C, about -20°C or lower, about 2°C or lower, about 2°C to about 8°C, about 8°C or lower, about 25°C or lower, about 40°C or lower, about 50°C or lower, about 0 °C to about 30 °C, about 0 °C to about 8 °C, about 1 °C to about 8 °C, about 2 °C to about 8 °C, about 3 °C to about8 °C, about 4 °C to about 8 °C, about 5 °C to about 8 °C, about 6 °C to about 8 °C, about 7 °C to about 8 °C, about 0 °C to about 10 °C, about 1 °C to about 10 °C, about 2 °C to about 10 °C, about 3 °C to about 10 °C, about 4 °C to about 10 °C, about 5 °C to about 10 °C, about 6 °C to about 10 °C, about 7 °C to about 10 °C, about 8 °C to about 10 °C, about 9 °C to about 10 °C, about 0 °C to about 15°C, about 1 °C to about 15°C, about 2 °C to about 15 °C, about 3 °C to about 15 °C, about 4 °C to about 15 °C, about 5 °C to about 15°C, about 6 °C to about 15 °C, about 7 °C to about 15 °C, about 8 °C to about 15°C, about 9 °C to about 15°C, about 10 °C to about 15°C, about 11 °C to about 15°C, about 12 °C to about 15°C, about 13 °C to about 15°C, about 14 °C to about 15°C, about15 °C to about 30 °C, about 15 °C to about 29 °C, about 16 °C to about 30 °C, about 16 °C to about 29 °C, about 15 °C to about 28 °C, about 16 °C to about 28 °C, about 17 °C to about 28 °C, about 18 °C to about 27 °C, about 19 °C to about 26 °C, about 20 °C to about 25 °C, about 20 °C to about 24 °C, about 20 °C to about 23 °C, about 20 °C to about 22 °C, about 20 °C to about 21 °C, about 0 °C, about 1 °C, about 2 °C, about 3 °C, about 4 °C, about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, about 10 °C, about 11 °C, about 12 °C, about 13 °C, about 14 °C, about 15 °C, about 16 °C, about 17 °C, about 18 °C, about 19 °C, about 20 °C, about 21 °C, about 22 °C, about 23 °C, about 24 °C, about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C, or about 30 °C.

[0075] In some embodiments, the pharmaceutical composition further comprises one or more antioxidants. Examples of antioxidants include, without limitation, benzyl benzoate, cysteine, ascorbic acid, vitamin E, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), thioglycerol, methionine, EDTA, glutathione, lecithin, cholesterol, phospholipid, oleic acid, and stearic acid.

[0076] In some embodiments, the pharmaceutical product further comprises an inert gas to prevent oxidation. Examples of inert gas include, without limitation, nitrogen gas, Ar, and mixtures thereof.

[0077] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable acids. Examples of acids include, without limitation, acetic acid, phosphoric acid, HCI, and methyl sulfonic acid.

[0078] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include, without limitation, sodium salts of acetic acid, phosphoric acid, HCI, and methyl sulfonic acid; potassium salts of acetic acid, phosphoric acid, HCI, and methyl sulfonic acid; calcium salts of acetic acid, phosphoric acid, HCI, and methyl sulfonic acid; and zinc salts of acetic acid, phosphoric acid, HCI, and methyl sulfonic acid.EXAMPLES

[0079] The following examples are intended to illustrate various embodiments of the invention. As such, the specific embodiments discussed are not to be constructedas limitations on the scope of the invention. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of invention, and it is understood that such equivalent embodiments are to be included herein. Further, all references cited in the disclosure are hereby incorporated by reference in their entirety, as if fully set forth herein, to the extent that they do not contradict or are not inconsistent with the instant disclosure.Example 1 : Transfer in the HPLC Method of Epoprostenol

[0080] The objective of this example was to transfer in the HPLC method of epoprostenol while establishing linearity, stability, and repeatability of the method.

[0081] In this example, an HPLC with a VWD detector (Agilent 1100 / 1200) was used with a Phenomenex Gemini C18 analytical column (5 pm, 110A, 4.6 x 250 mm). The experiments were run in three separate mobile phases, Mobile Phase A (80.0% 25mM Borate Buffer: 20.0% Acetonitrile (v / v)) , Mobile Phase B (50.0% Dl-Water: 50.0% Acetonitrile (v / v)), and Mobile Phase C (100% methanol). The experiments were run over a 36 minute gradient program where at 15-16 min, % Mobile Phase B was 100% and at 16-27 min Mobile Phase C was 100% (1.0 mL / min flow rate, 205 nm detection wavelength, 25 °C column temperature, 5 °C sample thermostat, 20 pL injection volume, 0.1 mg / mL nominated concentration, 50 mM arginine buffer pH 12 diluent).

[0082] To prepare a 25 mM borate buffer solution, 3092.5 mg of boric acid, 21992.5 mg sodium chloride, and 2515.5 mg of sodium tetraborate were first added to 2L of distilled water. Next, the pH of the mixture was adjusted to 9 using NaOH or HCI, generating the borate buffer solution.

[0083] Mobile Phase A, a 4:1 v / v 25 mM Borate Buffer solution: acetonitrile solution, was prepared by first adding 800 mL Borate Buffer to 200 mL acetonitrile. Next, the solution was mixed and sonicated to generate Mobile Phase A. Mobile Phase B, a 1 :1 deionized water: acetonitrile solution, was prepared by first adding 500 mL deionized water to 500 mL acetonitrile. Next, the solution was mixed and sonicated to generate Mobile Phase B. Mobile Phase C was 100% methanol.

[0084] A diluent was prepared by first adding 872.0 mg arginine to 100 mL water for injection (WFI). The solution was mixed, and then the pH was adjusted to 12.0 with NaOH to generate the diluent.

[0085] A 150% standard epoprostenol sodium solution was prepared by first dissolving 30 mg of epoprostenol sodium in water in a 200 mL volumetric flask. The mixture was then blended with enough diluent to create a concentration of about 0.15 mg / mL to generate the 150% standard epoprostenol sodium solution. A 50% standard epoprostenol sodium solution was prepared by diluting about 1 mL of the 150% standard epoprostenol sodium solution with about 2 mL the diluent to create a concentration of 0.05 mg / mL.

[0086] The standard solutions and the diluent were then injected into the HPLC in the amounts and order as described below in Table 1 .Table 1 : HPLC Injection Procedure

[0087] The epoprostenol method produced a linear assay response in the concentration range of 0.05-0.15 mg / mL, with R2 equivalent to 1.0, as shown below in Table 2 and in FIG. 1 A. The average peak area found in FIG. 1A and Table 2 is shown in HPLC chromatograms FIGS. 1 B and 1 C.Table 2: Linear Assay Response for St1-St3

[0088] The repeatability of the experiment was confirmed to be high with consistent peak areas and response factors at the same retention time, as shown below in Table 3.Table 3: Repetition Experiment for St2

[0089] The stability of the epoprostenol sodium standard solutions on the autosamplerat 5°C was checked after 24 hours. The assay recovery, shown below in Table 4, confirmed a high stability after 24 hours.Table 4: Percent Assay Recovery

[0090] The HPLC method passed the qualification specifications for precision, linearity, and solution stability and is suitable for assays of epoprostenol in an IV formulation.Example 2: A pH Study for Epoprostenol in Aqueous Solution

[0091] The objective of this example was to determine and compare the stability of epoprostenol in various 50 mM arginine buffers between pH 12.5-13.5 at high temperatures. The comparison would show optimal pH for epoprostenol stability, and utilized an Arrhenius equation to predict the shelf life between 5 °C to 25 °C.

[0092] In this example, the HPLC and HPLC conditions were identical to those used in Example 1 .

[0093] An epoprostenol standard was prepared by adding 10 mg of epoprostenol (about 10.8 mg of epoprostenol sodium) into a 100 mL volumetric flask. The flask was filled with diluent to reach a concentration of 0.1 mg / mL and mixed well to generate the epoprostenol standard.

[0094] To prepare a 50 mM arginine buffer solution, adding 872.0 mg arginine to 100 mL water for injection (WFI). The solution was mixed, and then split into five parts.The pH of the five parts were separately adjusted to 12.5, 12.8, 13.0, 13.2, and 13.5 with NaOH.

[0095] For each pH solution, 10 mg (S1-S5) or 20 mg (S6-S10) of epoprostenol (about 10.8 mg and 21 .5 mg of epoprostenol sodium) was added into a separate 15 mL falcon tube, which was then filled to 10 mL with each buffer. The solutions were then mixed well until no particles remained. The pH was adjusted to the target pH with HCI or NaOH as needed. Each solution was then filtered through a 0.2-micron filter and transferred into 20 HPLC 0.5 mL vials. The vials were then added into stability chambers, six vials in a 30 °C chamber, six vials in a 40 °C chamber, and six vials in a 50 °C chamber for each of S1 through S10.

[0096] Each of the vials were removed from the chamber, assay and impurity tested by HPLC, checked for appearance (color, particulate matter), and then returned to the chambers at 0 days, 1 day, 4 days, and 7 days.

[0097] Sample solutions for the HPLC for each of S1 -S10 were prepared by removing the HPLC vials from the sample chamber and mixing well. For each of S1-S5, the HPLC volume was changed to 2 microliters, and for each of S6-S10, the injection volume was changed to 1 microliter.

[0098] The stability results for each of samples S1-S10 are summarized below in Tables 5-14. In the Tables below, ND means not detected.Table 5: Stability results of S1 (pH 12.5)Table 6: Stability results of S2 (pH 12.8)Table 7: Stability results of S3 (pH 13.0)Table 8: Stability results of S4 (pH 13.2)Table 9: Stability results of S5 (pH 13.5)Table 10: Stability results of S6 (pH 12.5)Table 11 : Stability results of S7 (pH 12.8)Table 12: Stability results of S8 (pH 13.0)Table 13: Stability results of S9 (pH 13.2)Table 14: Stability results of S10 (pH 13.5)

[0099] The assay loss rate is shown below in Table 15 and in FIGS. 2A and 2B.Table 15: Assay Loss Rate of Epoprostenol for S1-S10

[0100] The impurity increase rate is shown below in Table 16 and in FIGS. 2C and2D. The relative impurity percentages found in FIG. 2C and 2D are shown in HPLC chromatograms FIGS. 2E and 2F.Table 16: Impurity Increase Rate for S1-S10

[0101] The pHmax determination based on the Arrhenius equation is found below in Table 17.Table 17: Determination of pHmax Using the Arrhenius Equation

[0102] The Arrhenius equation is Kapp= Ae-EaRTwhere K3PPis the apparent rate constant for the reaction, T is the absolute temperature in Kelvin, A is the frequency factor, R is the gas constant (1.987 cal / deg.mole), and Eais the activation energy for the reaction.

[0103] The example determined that epoprostenol is not stable in aqueous solution for extended periods, and that a 13.5 pH was the ideal pH for stability in the pH range of 12.5-13.5.Example 3: Stability Study for Epoprostenol in a Non-aqueous Solution

[0104] The objective of this Example was to determine and compare stability of epoprostenol in propylene glycol with arginine, sodium hydroxide, and potassium hydroxide and compare which of the alkaline base solutions provides the greatest epoprostenol stability.

[0105] In this example, the HPLC and HPLC conditions were identical to those used in Example 1 .

[0106] The non-aqueous buffer solutions were prepared. The 50 mM arginine in propylene glycol solution (S11V) was prepared by adding 87.2 mg arginine into 10 mL propylene glycol and mixing the solution. The saturated arginine in propylene glycol solution (S12V) was prepared by adding enough arginine (approximately 8%) into 10 mL PG and mixing the solution. The saturated arginine in water for injection solution (S13V) was prepared adding enough arginine (approximately 25%) into 10 mL water for injection and mixing the solution. The saturated NaOH in propylene glycol solution (S14V) was prepared by adding enough NaOH (approximately 8%) into 10 mL propylene glycol and mixing the solution. The saturated KOH in propylene glycol solution (S15V) was prepared by adding enough KOH (approximately 18%) into 10mL propylene glycol and mixing the solution. The 50mM arginine in water for injection solution (S16V) was prepared by adding 87.2 mg arginine into 10 mL water for injection and mixing the solution.

[0107] Each of solutions S11V, S13V, and S16V were then filtered through a 0.2- micron filter, and each of solutions S12V, S14V, and S 15V were filtered through a 0.45- micron filter.

[0108] Each of S12V-S15V were then diluted to 60% and 30% with propylene glycol or water for injection respectively. Each pH of the solution was then checked, but not altered.

[0109] The stability samples were then prepared by weighing out, for each solution, 2 mg of epoprostenol (about 2.15 mg epoprostenol sodium) into separate 15mL falcon tubes. The falcon tubes were then filled to 2 mL with each buffer solution respectively as shown in Tables 18 and 19 below.Table 18: Stability Sample Preparation for Samples S11-S16Table 19: Stability Sample Preparation

[0110] Each of the above solutions was then transferred into 3 separate HPLC vials (about 0.5 mL per vial). Each of the vials for S11-S16 were then placed into 50 °C stability chambers. Each of the vials, at zero days, 1 day, and four days, were pulled out of the stability chambers, assay and impurity tested by HPLC, checked for appearance, particulate matter, and color, and returned to the stability chamber.

[0111] The HPLC epoprostenol sample was then prepared by adding 10 mg epoprostenol (about 10.8 mg epoprostenol sodium) into a 100 mL volumetric flask and adding diluent until the concentration reached 0.1 mg / mL. The solution was then mixed well.

[0112] Each of the above vials was then removed from stability chambers and mixed well. HPLC analysis was performed on the samples directly with a 2-microliter injection volume.

[0113] The alkaline buffer solution comparison data for each sample is found below in Table 20 as well as FIG. 3. Solution S5 was utilized from Example 2 as a comparative sample.Table 20: Alkaline Buffer Solution Comparison

[0114] When paired with the same alkaline material, propylene glycol provided greater stability than water. When the solutions were at the same relative pH level, propylene glycol provided greater stability than water. In propylene glycol, the bestmeasured alkaline was determined to be NaOH when about 2.5% was added, leading to a pH of about 13.5. Propylene glycol provided a pHmax from a bell curve, which was a positive for patients receiving the solution in their treatment. It may be possible to develop a ready-to-use liquid formulation in propylene glycol.Example 4: Stability Study for Epoprostenol (1 mg / mL) in propylene glycol

[0115] In this example, the objective was to compare epoprostenol stability (1 mg / mL) in propylene glycol with different concentrations of NaOH.

[0116] In this example, the HPLC and HPLC conditions were identical to those used in Example 1 .

[0117] To prepare solutions S17-S27, 1.0 mg epoprostenol was added to NaOH as detailed in Table 21 below.Table 21 : Epoprostenol Sample Preparation

[0118] Propylene glycol was then added to each sample QS. Each solution was then separately filtered through a 0.2-micron filter. Finally, each solution was transferred into 10 HPLC vials each (about 0.5 mL / vial) and the solutions were placed in 50 °C stability chambers.

[0119] Each of the vials were removed from the chamber, assay and impurity tested by HPLC, checked for appearance (color, particulate matter), and then returned to the chambers at 0 days, 1 day, 4 days, and 7 days.

[0120] An epoprostenol standard was prepared by adding 10 mg of epoprostenol (about 10.8 mg of epoprostenol sodium) into a 100 mL volumetric flask. The flask was filled with diluent to reach a concentration of 0.1 mg / mL and mixed well to generate the epoprostenol standard.

[0121] Sample solutions for the HPLC for each of S17-S27 were prepared by removing the HPLC vials from the sample chamber and mixing well. For each of S17- S27, the HPLC volume was changed to 2 microliters.

[0122] The data for the comparative study between sodium hydroxide concentrations for epoprostenol solutions is found below in Table 22 and in FIGS. 4A and 4B.Table 22: Sodium Hydroxide Concentration Comparison Data

[0123] Based on the results from this example, 1 mg / mL of epoprostenol in propylene glycol, the presence of NaOH at 0.75% to 1 .25%, 0.75% and 1 .25% provided the best epoprostenol stability in tested samples. At 50°C, S26 (0.75% NaOH) had an estimated T90 of 17.9 days, a great improvement. The T90 for S26 was estimated to be greater than 3 years at 5 °C using an activation of 21.13 Kcal / mol, and for less than a year at 25°C using an activation of 19.71 Kcal / mol. These numbers were obtained from the Arrenhenius Equation: In Kapp = 17.265 -5876.8x 1 / T for F5 in Example 2.Example 5: Stability Study for Epoprostenol (10 mg / mL) in Propylene Glycol (PG), Anhydrous Ethanol, and Glycerol

[0124] The objective of this example was to compare epoprostenol stability (10 mg / mL) in propylene glycol, glycerol, and anhydrous ethanol in varying NaOH concentrations to determine the best alkaline solution to maintain epoprostenol stability.

[0125] In this example, the HPLC and HPLC conditions were identical to those used in Example 1 .

[0126] Solutions S28-S45 were prepared by adding sodium hydroxide to 10.0 mg / mL epoprostenol as detailed below in Table 23, and then adding the corresponding organic carriers, respectively.Table 23: Epoprostenol Sample Preparation

[0127] Solutions S28-S39 were then filtered through a 0.2-micron filter and solutions S40-S45 were filtered through a 0.45-micron filter. Each solution was then transferred into 10 HPLC plastic vials each (about 0.5 mL / vial), and each vial was then transferred into 50 °C stability chambers. Each of the vials, at zero days, 1 day, 4 days, and 8 days, were pulled out of the stability chambers, assay and impurity tested by HPLC, checked for appearance, particulate matter, and color, and returned to the stability chamber.

[0128] The HPLC epoprostenol sample was then prepared by adding 10 mg epoprostenol (about 10.8 mg epoprostenol sodium) into a 100 mL volumetric flask and adding diluent until the concentration reached 0.1 mg / mL. The solution was then mixed well.

[0129] Sample solutions were prepared by removing the solutions from the stability chamber, adding 50 mg of each sample into separate falcon tubes, QS with diluent to about 5g, and mix well.

[0130] The pH and appearance data for the samples is found below in Tables 24 and 25 as well as FIGS. 5A and 5B.Table 24: pH and Appearance of Solutions S28-S39Table 25: HPLC assay of solutions S28-S45

[0131] This example determined that in the tested samples, ethanol alone was not a good solvent for epoprostenol pharmaceutical compositions due to the delayed precipitation; glycerol alone was also not a good solvent because of the higher rate of loss of epoprostenol. Propylene glycerol with 1% NaOH was still found to be the best solvent for epoprostenol (S29). The stability profile of the 10 mg / mL solution inpropylene glycol with 1 %NaOH (S29) is similar to the 1 mg / mL solution in the same solvent vehicle (S26).Example 6: Stability Testing and Impurity Detection

[0132] The objective of this example was to observe the appearance, assay, and impurity of residual vials (1 mg / mL and 10 mg / mL) at 50°C.

[0133] In this example, the HPLC and HPLC conditions were identical to those used in Example 1 .

[0134] An epoprostenol standard was prepared by adding 10 mg of epoprostenol (about 10.8 mg of epoprostenol sodium) into a 100 mL volumetric flask. The flask was filled with diluent to reach a concentration of 0.1 mg / mL and mixed well to generate the epoprostenol standard.

[0135] Sample solutions were prepared by removing the vials from stability chamber, adding 50 mg of each sample into separate falcon tubes, and QS with diluent (1 % NaOH in propylene glycol) to 5 g.

[0136] The appearance and the assay results for sample solutions S26-S31 are shown below in Tables 26 and 27 as well as FIG. 6.Table 26: Appearance Data for Solutions S26-S31Table 27: HPLC Assay Data for Solutions S26-S31

[0137] After 28 days in a 50°C stability chamber, the total assay loss for the S29 solution (1 % NaOH) was only 17.41 %, the lowest among all the tested formulations. The chromatograms of S29 did not show significant increase of impurity peaks, which indicated that epoprostenol sodium had chemical stability. It is not clear what caused the loss of epoprostenol sodium.Example 7: Stability Study for Refined Sodium Hydroxide Concentrations of Epoprostenol (10 mg / mL) in Propylene Glycol

[0138] The objective of this example was to further optimize the sodium hydroxide concentrations (0.6-1.25%) in epoprostenol propylene glycol formulations and perform the epoprostenol (10 mg / mL) stability study for those formulations.

[0139] In this example, the HPLC and HPLC conditions were identical to those used in Example 1 .

[0140] To prepare sample solutions S46-S50, 1 .0% epoprostenol was mixed with 0.6, 0.75, 0.8, 0.9, and 1.25 % NaOH respectively, and then QS with propylene glycol. Each solution was then filtered through a 0.2-micron filter, and then each solution was transferred into 10 separate HPLC vials (about 0.5 mL / vial). The vials were then placed in 50 °C stability chambers. Each of the vials, at zero days, 1 day, 4 days, and 8 days, were pulled out of the stability chambers, assay and impurity tested by HPLC, checked for appearance, particulate matter, and color, and returned to the stability chamber.

[0141] The HPLC epoprostenol sample was then prepared by adding 10 mg epoprostenol (about 10.8 mg epoprostenol sodium) into a 100 mL volumetric flask and adding diluent until the concentration reached 0.1 mg / mL. The solution was then mixed well.

[0142] Sample solutions were prepared by removing the solutions from the stability chamber, adding 50 mg of each sample into separate falcon tubes, QS with diluent to about 5g, and mix well.

[0143] The appearance and the assay results for sample solutions S46-S50 are shown below in Tables 28 and 29 as well as FIG. 7.Table 28: Appearance Data for Solutions S46-S50Table 29: HPLC Assay Data for Solutions S46-S50

[0144] Based on the HPLC assay results through eight days, there was no significant difference between formulations S47-S50. The assay results in this example were out of trend, and no impurity peak growth was observed. Future investigations may be needed to review whether the formulation process introduced water or other factors that impacted the assay results, e.g., without being bound to any theory, NaOH was hygroscopic and the grinding and addition process may have introduced moisture in the formulations. Additionally, future investigations may also optimize the compatibility of formulation with packaging. Based on current data, an alkali resistant serum vial / stopper was recommended.Example 8: Repeat Stability Study for S46-S50

[0145] The objective of the example was to further optimize sodium hydroxide concentrations (0.6%-1.25%) with pellets in propylene glycol formulation as well as perform an epoprostenol (10 mg / mL) stability study, including appearance, assay / im purity, and pH at 50°C.

[0146] In this example, the HPLC and HPLC conditions were identical to those used in Example 1 .

[0147] To prepare sample solutions S46B-S50B, 1.0% epoprostenol was mixed with 0.6, 0.75, 0.8, 0.9, and 1.25 % NaOH respectively, and then QS with propyleneglycol. Each solution was then filtered through a 0.2-micron filter, and then each solution was transferred into 10 separate HPLC vials (about 0.5 mL / vial). The vials were then placed in 50 °C stability chambers. Each of the vials, at zero days, 4 days, and 8 days, were pulled out of the stability chambers, assay and impurity tested by HPLC, checked for appearance, particulate matter, and color, and returned to the stability chamber.

[0148] The HPLC epoprostenol sample was then prepared by adding 10 mg epoprostenol (about 10.8 mg epoprostenol sodium) into a 100 mL volumetric flask and adding diluent until the concentration reached 0.1 mg / mL. The solution was then mixed well.

[0149] Sample solutions were prepared by removing the solutions from the stability chamber, adding 50 mg of each sample into separate falcon tubes, QS with diluent to about 5g, and mix well.

[0150] The appearance and the assay results for sample solutions S26-S31 are shown below in Tables 30-32 as well as FIGS. 8A and 8B.Table 30: Appearance Data for Solutions S46B-S50BTable 31 : HPLC Assay Data for Solutions S46-S50Table 32: Water Content by KF and its Effect on Assay Recovery

[0151] Propylene glycol with 0.75% NaOH (S47B) was confirmed as the lead formulation. Water was determined to impact assay recovery, with greater water levels impeding assay recovery. Dry NaOH pellets and water level control for solutions such as S47B can impact the overall water content of the solutions. Based on the observations in this example, S47B is ready for in-use studies and process development.Example 9: Variant Pharmaceutical Compositions of F47 Compositions

[0152] In this example, F47 composition was prepared and several prophetic variant formulations of F47 compositions are provided.

[0153] F47 composition was a propylene glycol solution of epoprostenol (10 mg / mL) and NaOH (7.5 mg / mL). F47 composition was prepared by mixing propylene glycol and NaOH until clear, adding epoprostenol or epoprostenol sodium, mixing until clear. The solution obtained were passed through 0.2-micron filter, and the filtration was collected as the F47 composition.

[0154] Composition F47A can be prepared by mixing F47 composition with about 0.1 % to 100% w / w or w / v ethanol.

[0155] Composition F47B can be prepared by mixing F47 composition with about 0.1 % to 100% w / w or w / v of PEG-300, PEG-400, PEG-600, PEG-3350, PEG-4000, or a mixture thereof.

[0156] Composition F47C can be prepared by mixing F47 composition with about 0.1 % to 100% w / w or w / v benzyl alcohol.

[0157] Composition F47D can be prepared by mixing F47 composition with about 0.1 % to 100% w / w or w / v benzyl benzoate.

[0158] Composition F47E can be prepared by mixing F47 composition with about 0.1 % to 100% w / w or w / v medium chain triglycerides.

[0159] Composition F47F can be prepared by mixing F47 composition with about 0.1 % to 100% w / w or w / v long chain triglycerides.

[0160] Composition F47G can be prepared by mixing F47 composition with about 0.1 % to 100% w / w or w / v polysorbate 20 or polysorbate 80.

[0161] Composition F47H can be prepared by mixing F47 composition with about 0.1 % to 100% w / w or w / v DMSO.

[0162] Composition F47I can be prepared by mixing F47 composition with about 0.1 % to 100% w / w or w / v 1-methyl-2-pyrrolidone.

[0163] Composition F47J can be prepared by mixing F47 composition with about 0.1 % to 100% w / w or w / v castor oil polyoxyethylene ether.

[0164] Composition F47K can be prepared by mixing F47 composition with about 0.1 % to 99% w / w or w / v water.

[0165] Composition F47L can be prepared similarly to F47 composition, with the final concentration of NaOH adjusted to 0-7.4 mg / mL and addition of about 0.1 % to 5% w / w or w / v KOH, CaOH2, NH4OH, lysine, or arginine.

[0166] Composition F47M can be prepared by mixing F47 composition with about 0.1 % to 5.0% w / w or w / v ascorbic acid, vitamin E, BHT, BHA, thioglycerol, cysteine, methionine, EDTA, glutathione, nitrogen gas or a mixture thereof.

[0167] Composition F47N can be prepared by mixing F47 composition with about 0.1 % to 5.0% w / w or w / v acetic acid, phosphoric acid, HCI, methyl sulfonic acid, or a mixture thereof.

[0168] Composition F47O can be prepared by mixing F47 composition with about 0.1 % to 5.0% w / w or w / v NaCI, CaCl2, KCI, sodium phosphate, ZnCb, or a mixture thereof.

[0169] Composition F47p can be prepared by mixing F47 composition with about 0.1 % to 5.0% w / w or w / v lecithin, cholesterol, phospholipid, oleic acid, stearic acid, mono-glycerides, di-glycerides or a mixture thereof.Example 10: Stability of various embodiments of the pharmaceutical compositions disclosed herein

[0170] Seven embodiments of the pharmaceutical compositions disclosed herein were prepared (Compositions F1 , F2, F3, F4, F5, F47, and F48, Table 33) and their long-term stabilities at various storage conditions were evaluated.Table 33: Compositions F1, F2, F3, F4, F5, F47

[0171] Two batches of F47 were prepared (Table 34) and placed in a glass vial (EVERIC SCHOTT Type I Borosilicate vial from SCHOTT EVERIC pure) or a plastic vial (DS CZ Daikyo vial from West pharmaceutical) and stored at 2-8°C, 25°C, or 40°C for months and checked for appearance (e.g., color, particulate matter), pH (Table 35), %recovery of epoprostenol relative to to (Table 36) and impurity content (Table 37).

[0172] Two batches of F48 were prepared (Table 38) and placed in a plastic vial (DS CZ Daikyo vial from West pharmaceutical) with N2 headspace or without N2 and stored at -20°C, 2-8°C, 25°C, or 40°C for months and checked for appearance (e.g., color, particulate matter), pH (Table 39), %recovery of epoprostenol relative to to (Table 40) and impurity content (Table 41 ).

[0173] Each of the test Compositions F1 to F5 was placed in a vial (CZ) and stored under a test storage condition (-20°C, 2-8°C, 25°C / 60%RH, and 40°C / 75%RH). Compositions F1 to F3 placed in prefilled syringe (PFS) were also evaluated under test storage conditions of -20°C, and 2-8°C. At the initial time point (to), a time point of 1- month (ti-month), 2-month (t2-month), and / or 3-month (te-month), the vials or PFS were removed from their corresponding storage conditions, checked for appearance (e.g., color, particulate matter), pH (Table 42), water content (Table 43), %recovery of epoprostenol relative to to (Table 45), and impurity content (Tables 46-50),A) Stability evaluation of F47 (10 mq / mL, 0.75% NaOH, PG) after storage at 2-8°C, 25°C, or 40°C for months

[0174] Two batches of F47 were prepared for stability assays (Table 34). One had an initial pH of 12.7 (F47 pH 12.7), the second one had an initial pH of 12.8 (F47 pH 12.8).Table 34: Two batches of F47 prepared for stability assays*: Eq to 10mg / mL of Epoprostenol. **: The specific gravity of F47 is 1.016 g / mL. F47 compounding was performed by weight and the final product was labeled as mg / mL using the specific gravity for conversion from mg / g to mg / mL.

[0175] F47 pH 12.7 sample placed in vials showed good stabilities after storage at2-8°C for 90 days, with a small impurity (0.21 %) detected at RRT=0.80. F47 pH 12.7 lost about 4.5% epoprostenol and generated about 0.86% impurities at 25°C after 90 days.

[0176] F47 pH 12.8 sample placed in glass vials or plastic vials were stored at 2-8°C, 25°C, or 40°C for months and the sample stabilities were evaluated. No detectable difference between glass vials and plastic vials were observed after all storage conditions for 6 months. Samples in glass vials were placed upright or inverted after storage for 6 months, although no detectable difference was observed from the samples placed at different orientations.

[0177] F47 pH 12.8 samples showed good stability at 2-8°C, with about 100% recovery after 9 months, and total impurity is at 0.4% for both upright and inverted glass via.

[0178] F47 pH 12.8 samples lost about 10% epoprostenol and generated less than 2% total impurities at 25°C for both upright and inverted glass vial after 9 months.

[0179] F47 pH 12.8 samples lost about 50% epoprostenol and generated about15% total impurities at 40°C for both upright and inverted glass vial after 9 months.Table 35: pH and appearance of F47 before and after storage in CZ vialsTable 36: Epoprostenol recovery of F47 before and after storage*: “ND” means not detectedTable 37: Impurity of F47 before and after storageB) Stability evaluation of F48 (3 mq / mL, 0.75% NaOH, PG) after storage at 2-8°C, 25°C, or 40°C for months

[0180] Two batches of F48 were prepared for stability assays (Table 38). One had an initial pH of 13.35 (F48 pH 13.35), the second one had an initial pH of 12.98 (F48 pH 12.98).Table 38: Two batches of F48 prepared for stability assays*: Eq to 3 mg / mL of Epoprostenol. **: The specific gravity of F48 is 1.019 g / nnL. F48 compounding was performed by weight and the final product was labeled as mg / mL using the specific gravity for conversion from mg / g to mg / mL.

[0181] F48 pH 13.35 was placed in plastic vials with N2 headspace (+N2) or withoutN2. No detectable difference between samples +N2 and without N2 up to 3-month time point. Some F48 pH 13.35 samples stored at 25°C and 40°C were inverted after 3 months, and samples in inverted vials showed lower stability than the samples placed in upright vials at 6-month time point.

[0182] F48 pH 12.98 was placed in plastic vials without N2 and tested for stability.

[0183] F48 pH 13.35 showed good stabilities after storage at 2-8°C for 6 months, with epoprostenol recovery of 98 to 100% and total impurity of 0.6%.

[0184] F48 pH 13.35 and F48 pH 12.98 showed consistent stability results after 6- month storage.Table 39: pH and appearance of F48 before and after storageTable 40: Epoprostenol and impurity content of F48 before and after storageTable 41 : Impurity of F48 before and after storageC) Appearance of Compositions F1 , F2, F3, F4, and F5 after storage

[0185] None of Compositions F1 to F5 showed visible particles after three months under the test storage conditions. Both compositions having 0.75%w / v NaOH (Compositions F1 and F4) appeared pale yellow after three months at 40°C / 75%RH. Composition F4 stored at 25°C / 60%RH also appeared pale yellow after 3 months. Similar observations were also made with ti-month samples. Both Compositions F1 andF4 showed yellow after one month storage at 40°C / 75%RH, and F4 showed yellow after one month storage at 25°C / 60%RH.D) pH of Compositions F1 , F2, F3, F4, and F5 after storage

[0186] Each sample was diluted 2xwith deionized (DI) water for pH measurement.The pH values were rounded to 1 decimal point and shown in Table 42.Table 42: pH of Compositions F1, F2, F3, F4, and F5 at ti -month and ts-monthE) Water content of Compositions F1 , F2, F3, F4, and F5 after storage

[0187] The water content of Compositions F1 , F2, F3, F4, and F5 after storage were measured by Karl Fischer (KF) titration. Results are shown in Table 43. Water contents of all test compositions remained <1.5% w / v at to, ti-month, and ts-month.Table 43: Water content of Compositions F1, F2, F3, F4, and F5 at ti-month and ts- monthF) Epoprostenol and impurity content of Compositions F1 , F2, F3, F4, and F5 after storage.

[0188] Epoprostenol and impurity content of Compositions F1 , F2, F3, F4, and F5 after storage were measured by liquid chromatography (LC). The epoprostenol stock solution of HPLC standard solutions of epoprostenol were prepared by dissolvingepoprostenol sodium reference standard in a LC diluent (50 mM Arginine in deionized water, pH 12.1 , filtered by 0.22 pm PES syringe filter). The epoprostenol stock solution was further diluted with the LC diluent to prepare the HPLC standard solutions of epoprostenol with desired concentration. Samples of compositions F1 to F5 were diluted with the LC diluent to reach an epoprostenol concentration of 0.1 mg / mL for HPLC measurement of epoprostenol content, and to an epoprostenol concentration of 0.2 mg / mL for HPLC measurement of impurity content.

[0189] Epoprostenol concentration of Compositions F1 , F2, F3, F4, and F5 was measured by HPLC at to, ti-month, te-month, and ts-month under the test storage conditions, and compared to the corresponding epoprostenol concentration at to. In this example, HPLC analysis was run on Agilent 1260 Infinity II, using a Gemini 3 pm, NX-C18 110 A, LC Column, 150 mm x 3mm. 10% IPA was used as the seal wash and needle wash. The UV detection was at 205 nm, column temperature was 25°C, and the autosampler temperature was 5°C. The injection volume was 10 pL. Mobile phase A was 25 mM borate buffer: acetonitrile (80:20 v / v), and mobile phase B was acetonitrile:water (50:50 v / v). The flow rate was 0.5 mL / min, the gradient was 6.67% B / min, and a max. pressure limit was 600.00 bar. An example of a gradient profile used in the HPLC analysis is shown in Table 44.Table 44: An example of HPLC gradient profile

[0190] Table 45 and FIGs. 10A to 10D show the % recovery of epoprostenol at ti- month, t2-month, and ts-month at the test storage condition of -20°C (FIG. 10A), 2-8°C (FIG. 10B), 25°C / 60%RH (FIG. 10C), and 40°C / 75%RH (FIG. 10D). Negligible difference was observed between the same compositions stored in vials and pre-filled syringes (PFS). %Recovery of epoprostenol increased with increase in storage temperature. At 40°C / 75%RH (and to some extent at 25°C / 60%RH), the %recovery of epoprostenol decreased with decrease in NaOH concentration in compositions having the same epoprostenol composition. For %Recovery at 40<C / 75%RH, Composition F1 Composition F2>Composition F3, and Composition F4>Composition F5.Table 45: Recovery of epoprostenol of Compositions F1, F2, F3, F4, and F5 at ti- month, t2 -month, and ts -month relative to to

[0191] Impurity peaks that were > 0.05% and > S / N 10 were integrated and reported (Table 45). Manual integration / adjustment was done for peaks where the baseline was improper and led to overestimation of %peak area. Processing method parameters were modified as needed due to baseline differences and peak separation differences between sample traces. Minor differences in RRT labels across tables and traces might be observed since they slightly differed from chromatogram to chromatogram. Traces of 6-keto PGI appeared to be present in 25°C / 60%RH & 40°C / 75%RH samples of F1 , 25°C / 60%RH & 2-8°C (PFS only) of F3 and 40°C / 75%RH of F4 (S / N ratio <10 with a broad bump, not integrated and reported).Table 46: Impurity peaks that were > 0.05% and > S / N 10 in Composition F1 at ti- month and ts -monthTable 47: Impurity peaks that were > 0.05% and > S / N 10 in Composition F2 at ti- month and ts -month‘appeared as a broad peak, not very well separated, so the %peak area might be an overestimation, refer appendix for chromatogramTable 48: Impurity peaks that were > 0.05% and > S / N 10 in Composition F3 at ti- month and ts -monthTable 49: Impurity peaks that were > 0.05% and > S / N 10 in Composition F4 at ti- month and ts -monthTable 50: Impurity peaks that were > 0.05% and > S / N 10 in Composition F5 at ti- month and ts -month

[0192] New impurity peaks (> 0.05% and S / N >10) at RRT 0.273 and RRT 0.678 were observed in some samples.Example 11 : Self-preservation of various embodiments of the pharmaceutical composition disclosed herein

[0193] Five embodiments (Table 51) of the pharmaceutical composition disclosed herein were prepared and tested fortheir self-preservation, i.e. , the ability to pass USP preservative effectiveness test (PET), also known as Antimicrobial Effectiveness Testing (AET) without the presence of preservatives.Table 51 : Five compositions of epoprostenol (3 mg / mL) in propylene glycol prepared for AET

[0194] All compositions tested passed the AET. See Tables 44-48.Table 52: AET results for Composition F1, a 3 mg / mL epoprostenol composition without preservative.Table 53: AET results for Composition F1 A, a 3 mg / mL epoprostenol composition with 0.005% w / w BAKTable 54: AET results for Composition F1, a 3 mg / mL epoprostenol composition with 0.01 % w / w BAK.Table 55: AET results for Composition F2, a 3 mg / mL epoprostenol composition without preservative.Table 56: AET results for Composition F3, a 3 mg / mL epoprostenol composition without preservative.Example 12: Various embodiments of diluents disclosed herein and uses of same in preparation of embodiments of ready to use preparation compositionsA) pH 12 glycine / NaCI diluent and uses of pH 12 glycine / NaCI diluent in dilution ofF47 pH 12 glycine / NaCI diluent (1.88 mg / mL glycine, 1.47 mg / mL NaCI, pH 11 .7-12.3) was prepared by first mixing glycine and NaCI with water for injection (WFI), and then adjusting pH to 11.7-12.3 with 10 N or 1 N NaOH. pH 12 glycine / NaCI diluent and sodium bicarbonate (8.4%) diluent (Exela Parma Sciences) were used to dilute F47 to prepare various samples of ready to use compositions for stability evaluation (Table57). The ready to use compositions prepared from F47 using sodium bicarbonate (8.4%) diluent showed almost 100% loss of epoprostenol after placed at 25°C for 48h.

[0195] F47 was prepared as described in Example 9, and diluted with pH 12 glycine / NaCI diluent or sodium bicarbonate (8.4%) diluent to a desired epoprostenol concentration as shown in Table 57. The epoprostenol content and impurity content of the diluted ready to use compositions were measured by HPLC 48 hours after the samples were held at 25°C and compared to the initial epoprostenol content and impurity content at to.Table 57: Ready to use stability results for F47 diluted with pH 12 glycine / NaCI diluent or sodium bicarbonate (8.4%) diluentB) pH 12.5 glycine / NaCI diluent and uses of pH 12.4 phosphate diluent in dilution of F47

[0196] pH 12.5 glycine / NaCI diluent was prepared by mixing glycine (1.88 mg / mL) and NaCI (1.47 mg / mL) with WFI and adjusting the pH to pH 12.5 using NaOH (10 N or 1 N).

[0197] pH 12.4 phosphate diluent was prepared by mixing trisodium phosphate (4.1 mg / mL) with WFI, and adjusting pH to 12.4 with NaOH (10 N or 1 N).

[0198] F47 was prepared as described in Example 9, and diluted with pH 12.5 glycine / NaCI diluent or pH 12.4 phosphate diluent to a desired epoprostenol concentration as shown in Table 58. The epoprostenol content and impurity content of the diluted ready to use compositions were measured by HPLC after the samples were held 1 ) at 25°C for 48 hours, or 2) 8 days at 2-8°C and then 24 or 48 hours at 25°C, and compared to the initial epoprostenol content and impurity content at to.

[0199] F47 showed good stability after storage at 2-8°C after 28 days, as evidenced by the low epoprostenol loss and no detection of impurity by HPLC. F47 was stable at 25°C with a small impurity (0.5%) detected at RRT=0.80 at 25°C after 28 daysTable 58: Ready to use stability results for F47 diluted with pH 12.5 glycine / NaCI aqueous diluent or pH 12.4 phosphate aqueous diluentand pH 12.2 lysine / NaCI diluent, and uses thereof in dilution of F47 and F48

[0200] pH 12.2 and pH 12.3 arginine / NaCI diluents, pH 12.2 arginine-mannitol diluent and pH 12.2 lysine / NaCI diluent were prepared by mixing components other than NaOH listed in Table 59 with WFI, and adjusting pH to the desired pH of 12.2 and 12.3 with NaOH (10 N or 1 N)..Table 59: pH 12.2 and pH 12.3 arginine / NaCI diluents, pH 12.2 arginine-mannitol diluent and pH 12.2 lysine / NaCI diluent

[0201] F47 was F47 pH 12.8 and F48 was F48 pH 13.35 as described in Example10. F48 was diluted with pH 12.2 arginine / NaCI diluent, and F47 was diluted with pH 12.2 arginine / NaCI diluent, pH 12.3 arginine / NaCI diluent, pH 12.2 arginine-mannitol diluent or pH 12.2 lysine / NaCI diluent to a desired epoprostenol concentration as shownin Table 60. The epoprostenol content and impurity content of the diluted ready to use compositions were measured by HPLC after the samples were held 1) at 25°C for 48 hours, or 2) 8 days at 2-8°C and then 24 or 48 hours at 25°C, and compared to the initial epoprostenol content and impurity content at to.Table 60: Ready to use stability results for F48 diluted with pH 12.2 arginine / NaCI diluent, and F47 diluted with pH 12.2 arginine / NaCI diluent, pH 12.3 arginine / NaCI diluent, pH 12.2 arginine-mannitol diluent or pH12.2 lysine / NaCI diluent*Passed In-use stability specifications; **Did not pass In-use stability specificationsTable 61 : Ready to use stability comparation of F47 and F48

[0202] While this specification contains many specifics, these should not be construed as limitations on the scope of an invention or of what may be claimed, but rather as descriptions of features specific to particular embodiments of the invention. Certain features that are described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable subcombination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or a variation of a sub-combination.

[0203] Only a few implementations are disclosed. However, variations and enhancements of the disclosed implementations and other implementations can be made based on what is described and illustrated in this specification.

Claims

CLAIMSI / We claim:

1. A pharmaceutical composition comprising epoprostenol or epoprostenol sodium, and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1 , further comprising a pharmaceutically acceptable base.

3. The pharmaceutical composition of claim 1 or claim 2, further comprising a pharmaceutically acceptable salt.

4. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutically acceptable carrier is selected from the group consisting of propylene glycol, ethanol, glycerol, polyethylene glycol, Poloxamer 188, polysorbate 20, polysorbate 40, and polysorbate 80.

5. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutically acceptable base comprises one or more bases selected from the group consisting of hydroxides, arginine, and glycine.

6. The pharmaceutical composition of Claim 5, wherein the one or more hydroxides are selected from the group consisting of NaOH, KOH, Ca(OH)2, and NH4OH.

7. The pharmaceutical composition of any one of the preceding claims, having a concentration of epoprostenol of about 0.1 mg / mL to about 30 mg / mL, or about 1 mg / mL to about 10 mg / mL.

8. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutically acceptable carrier comprises at least about 90% propylene glycol.

9. The pharmaceutical composition of any one of the preceding claims, wherein the concentration of the pharmaceutically acceptable base is about 0.125 mol / L, about 0.1875 mol / L, about 0.250 mol / L, about 0.312.5 mol / L, about 0.500 mol / L, or about 0.100 mol / L to about 0.6 mol / L.

10. The pharmaceutical composition of any one of the preceding claims, having a concentration of water of less than about 5%, less than about 4.5%, less than about 4%, less than about 3.5%, less than about 3%, less than about 2.5%, less than about 2%, less than about 1 .5%, less than about 1 %, less than about 0.5%, or any ranges therebetween.11 . The pharmaceutical composition of any one of the preceding claims, wherein the loss of epoprostenol is less than about 10% after about 36 months at about 0 °C to about 30 °C.

12. The pharmaceutical composition of any one of the preceding claims, having a shelf life of about 36 months at about -20°C to about 50°C, or about 0 °C to about 30 °C.

13. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is non-aqueous.

14. The pharmaceutical composition of the preceding claims, the pharmaceutically acceptable salt is NaOH.

15. The pharmaceutical composition of Claim 14, the concentration of NaOH is about 0.01 % w / v to about 1 .5% w / v.

16. A pharmaceutical product comprising the pharmaceutical composition of any one of the preceding claims.

17. The pharmaceutical product or pharmaceutical composition of any one of the preceding claims, having a unit dose of about 0.5 mg to about 500 mg, or about 0.5 mg to about 12.5 mg of epoprostenol.

18. The pharmaceutical product or pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical product or pharmaceutical composition remains stable after multiple-use.

19. The pharmaceutical product of any one of claims 16-18, further comprising one or more pharmaceutically acceptable diluents.

20. The pharmaceutically acceptable diluent of claim 19, comprising mannitol, arginine, glycine, lysine, one or more other pharmaceutical acceptable base, one or more pharmaceutically acceptable salts, or any combination thereof.21 . The pharmaceutically acceptable diluent of claim 20, having a pH of about 10 or above, about 11 or above, about 11 .5 or above, about 11 .7 to about 12.5, about 10, about 10.5, about 11 , about 11.5, about 11 .6, about 11 .7, about 1 1 .8, about 11.9, about 12.0, about 12.1 , about 12.2, about 12.3, about 12.3, about 12.4, about 12.5, or any range therebetween.

22. A method for treating pulmonary arterial hypertension in a subject comprising administering to the subject a therapeutically effective amount of epoprostenol via i.v. injection of a diluted ready to use composition of the pharmaceutical composition or pharmaceutical product of any one of the preceding claims.

23. The method of claim 22, wherein the pharmaceutical composition is diluted with the pharmaceutically acceptable diluent of any one of claims 20 and 21 .

24. The method of claim 23, the pharmaceutical composition is diluted to prepare a 50 mL or 100 mL fully diluted ready to use composition.

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