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WO2024133620A1 - Test de dissolution in vitro - Google Patents

Test de dissolution in vitro Download PDF

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Publication number
WO2024133620A1
WO2024133620A1 PCT/EP2023/087180 EP2023087180W WO2024133620A1 WO 2024133620 A1 WO2024133620 A1 WO 2024133620A1 EP 2023087180 W EP2023087180 W EP 2023087180W WO 2024133620 A1 WO2024133620 A1 WO 2024133620A1
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WO
WIPO (PCT)
Prior art keywords
calcium
acetate
diphenylpyrazin
aqueous medium
propan
Prior art date
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PCT/EP2023/087180
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English (en)
Inventor
Michelle MALLANTS
Johannes Moes
Daisy PEETERS
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Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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Publication of WO2024133620A1 publication Critical patent/WO2024133620A1/fr
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N13/00—Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N13/00—Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects
    • G01N2013/006—Dissolution of tablets or the like

Definitions

  • the present invention relates to testing samples comprising calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof:
  • Formula (I) in the form of microparticles and/or nanoparticles, such as suspensions, and measuring the dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in an aqueous medium.
  • the present invention also relates to quality control testing of said samples and to releasing batches comprising said samples for pharmaceutical use.
  • the present invention also relates to a medium for use in dissolution testing.
  • Selexipag is 2- ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ -N- (methanesulfonyl)acetamide (ACT-293987, NS-304, CAS: 475086-01-2; 2- ⁇ 4-[N-(5,6- diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide), also known as UptraviTM.
  • the metabolite of selexipag is 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid (MRE-269, ACT-333679, JNJ-68006861 , 2- ⁇ 4-[(5,6- diphenylpyrazin-2-yl)-propan-2-ylamino]butoxy ⁇ acetic acid; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(isopropyl)amino]butoxy ⁇ acetic acid; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)-(propan-2- yl)amino]butoxy ⁇ acetic acid; CAS: 475085-57-5 (MW 419.52)).
  • Salts of selexipag metabolite are described in JP 2019-149945.
  • Calcium; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate is the calcium salt of the metabolite of selexipag (calcium salt of ACT-333679), and has the formula Ca(C 2 5H28N 3 O3)2, i.e. CsoHseNeOeCa (MW: 877.109).
  • Intravenous formulations of selexipag are disclosed in WO2018/162527. Salts of selexipag metabolites are described in JP2019- 149945.
  • LIS20190022004 describes liposome compositions comprising weak acid drugs and uses thereof.
  • EP3718537 describes stealth liposomes having a prostaglandin I2 receptor agonist encapsulated therein.
  • Selexipag is thought to function as a prodrug (while retaining some agonistic activity on the IP receptor on its own) which can exert long-lasting selective IP receptor agonist activity of the active metabolite 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid in mammals, especially humans.
  • the in vivo metabolism of selexipag effectively may act as a kind of ‘slow-release mechanism’ that potentially both prolongs activity and reduces typical adverse effects associated with high concentrations of PGI2 agonists (Kuwano et al., J Pharmacol Exp Ther (2007), 322(3), 1181-1188).
  • Selexipag was shown to be beneficial in the treatment of pulmonary arterial hypertension.
  • the risk of the primary composite end point of death or a complication related to pulmonary arterial hypertension was significantly lower among patients who received selexipag than among those who received placebo.
  • Selexipag received market approval e.g. in the US and is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH.
  • PAH pulmonary arterial hypertension
  • LAI Long-acting injectable
  • WO 2022/162158 discloses an aqueous suspension of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate or a pharmaceutically acceptable hydrate or solvate thereof suitable for intramuscular or subcutaneous injection, which can be used as a LAI formulation.
  • Dissolution testing is a standardized method for measuring drug release from a given dosage form. Dissolution testing should be both robust and reproducible, with the ability to detect any key changes in product performance, e.g.
  • dissolution test method is also used to guide formulation development and select formulations and batches for clinical trials.
  • a reliable dissolution test is thus a key tool during several stages of pharmaceutical development.
  • dissolution testing is a valuable tool.
  • the results obtained by dissolution testing can be employed to detect potential variances that may occur during manufacturing as well as ensure batch-to-batch reproducibility, or to release batches for further manufacture into an approved product.
  • the conditions used for dissolution testing which is an in vitro technique, are typically chosen to mimic as closely as possible the conditions in vivo in which the drug is released from its dosage form. This is one way for the results of the in vitro test to be considered biorelevant.
  • the conditions include the temperature of the medium used in the dissolution test.
  • Another variable of a dissolution test is the nature of the medium in which the drug substance is dissolved, e.g. its composition and pH.
  • Several methods for dissolution testing of dosage forms are described in compendia such as the US and European pharmacopeia. Also the US FDA publishes methods for dissolution testing of drugs approved by the FDA, specifying conditions and the medium (e.g.
  • the invention provides a method of testing a sample of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof:
  • the invention provides a method of quality control testing a sample of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, wherein the sample comprises calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles, the method comprising: performing the method of the first aspect on the sample; and determining based on the measured dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium whether the sample has passed the quality control test.
  • the invention provides a method of releasing a batch of calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, for pharmaceutical use, the method comprising: providing a batch of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles, optionally in suspension; performing the method of quality control of the second aspect on a sample taken from the batch; and if the sample passes the quality control test, releasing the batch for pharmaceutical use.
  • the invention provides an aqueous medium for use in dissolution testing, the aqueous medium: comprising 0.01-8 %w/v, or 0.05-1 %w/v, or 0.1-0.5 %w/v, or 0.14-0.16 %w/v of a surfactant, in particular a non-ionic surfactant such as polysorbate 20; comprising a buffer, such as 0.05 M sodium phosphate buffer; and having a pH of at least 5.5, 6-12, 6-9, 6.5-7.5, or 6.9-7.1.
  • a surfactant in particular a non-ionic surfactant such as polysorbate 20
  • a buffer such as 0.05 M sodium phosphate buffer
  • Figure 1 Dissolution studies with calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate suspensions of varying particle size
  • Figure 2 Dissolution studies of calcium ; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate suspensions using dissolution mediums with 0.15 % w/v polysorbate 20 at pH 7, and 0.3 % w/v polysorbate 20 at pH 9
  • Figure 3(a) Dissolution studies with calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate suspensions using dissolution mediums with 0.05 % w/v polysorbate 20 at 5, 25, and 37 °C
  • Figure 3(b) Dissolution studies with calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate suspensions using dissolution mediums with 0.075 % w/v polysorbate 20 at 5 and 25 °C
  • Figure 3(c) Dissolution studies of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate suspensions using dissolution mediums with 0.1 % w/v polysorbate 20 at 5, 25, and 37 °C
  • Figure 4 Dissolution studies of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate suspensions using dissolution mediums with 0.05 and 0.1 % w/v polysorbate 20 at 5 and 25 °C
  • Figure 5 Dissolution studies of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate suspensions at using dissolution mediums with 0.05, 0.075, and 0.1 % w/v polysorbate 20 at 25 °C
  • Figure 7 Dissolution studies of calcium ; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate suspensions using dissolution mediums with 0.15 and 7 % w/v polysorbate 20 with the addition of 20 and 40 g/L CaCh
  • Figure 8(a) Dissolution studies with calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate suspensions using dissolution mediums with 0.15 % w/v polysorbate 20 and 10 % w/v NaCI in demineralised water at 37, 5 and -5 °C
  • Figure 8(b) Dissolution studies with calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate suspensions using dissolution mediums with 0.15 % w/v polysorbate 20 and 20 % w/v NaCI in demineralised water at 37, 5 and -5 °C
  • the method of the first aspect of the invention is unusual in that it measures the dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof:
  • Formula (I) at temperatures significantly below physiological temperatures.
  • Physiological temperatures are typically chosen for dissolution testing as they may render the in vitro test representative of the behaviour of the drug substance in vivo.
  • the typical temperature for measuring the dissolution of an oral formulation form is thus 37 °C.
  • the inventors have surprisingly found that the dissolution of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles can be measured at the low temperatures of ⁇ 15 °C, for example, 2-15 °C, which was found to improve the discriminating abilities of the method, in particular enabling samples of different particle size to be discriminated. Lowering the temperature was also found to slow down the dissolution, thus allowing the method to evaluate the potential for burst release of the drug substance from the dosage form. Given the discriminative properties of the test, it can be considered to provide biorelevant results.
  • the method was found to enable, over a practical timescale suitable for laboratory testing purposes, the in vitro studies of the dissolution of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles intended for prolonged release.
  • the invention also provides in a second aspect an improved method of quality control testing a sample of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles.
  • the invention provides an improved method of releasing a batch of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, for pharmaceutical use.
  • the aqueous medium is maintained at a temperature of below 0°C, or below 5 °C, or -5-10 °C, or 4-6 °C, preferably 4.5-5.5 °C, in particular 5 °C. In further embodiments the aqueous medium is maintained at a temperature of at least -80°C, at least -40°C, at least -30°C, at least -21°C, at least -20°C, at least -10°C, or at least -5°C. In further embodiments the aqueous medium is maintained at a temperature of below 0°C, below -1°C, or below -2°C.
  • the lower and upper end points for the temperature at which the aqueous medium is maintained are intended to be read in combination.
  • the aqueous medium may be maintained at a temperature of -21°C to below 0°C or -20 to -1°C.
  • a temperature within a narrow range e.g. a set temperature ⁇ 0.5 °C, for each iteration of the dissolution method may improve the robustness of the method.
  • the sample or the formulation to be tested is a suspension of microparticles and/or nanoparticles of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in a pharmaceutically acceptable carrier, such as a pharmaceutically acceptable aqueous carrier.
  • a pharmaceutically acceptable carrier such as a pharmaceutically acceptable aqueous carrier.
  • Suspensions are described further below.
  • the homogenization may comprise mechanical homogenization, for example using a vortex mixer; may comprise manual homogenization, for example shaking by hand; and may comprise both mechanical homogenization and manual homogenization.
  • a homogenization protocol may be established to be used for each iteration of the dissolution test to eliminate any potential dependence of the results on the homogenization conditions. For example, a homogenization protocol may require homogenizing a vial containing the sample using a vortex mixer for at least 15 seconds followed by manually shaking the vial horizontally 30 times over approximately 25 cm within approximately 10 seconds.
  • Sink conditions are defined as conditions wherein the equilibrium solubility of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium is at least 5 times higher, preferably at least 3 times higher than the concentration that would be obtained if all the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample dissolves in the aqueous medium.
  • equilibrium solubility refers to the concentration of a substance in a solvent when that substance is in dynamic equilibrium between the solid state and the dissolved state in the solvent.
  • Sink conditions are usually deemed to be essential in dissolution testing methods to allow the dissolution rate to be consistently measured: otherwise, when the concentration of the dissolved drug substance in the aqueous medium approaches the equilibrium solubility, the dissolution rate is believed to reduce in such a way as to affect the reproducibility of the test results.
  • the method of the invention may be performed not at sink conditions while still providing excellent reproducibility and discriminating abilities; the discriminating abilities may be better when the method is performed not at sink conditions than when it is performed at sink conditions.
  • the concentration that would be obtained if all the calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample dissolves in the aqueous medium is equal to or lower than the equilibrium solubility of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium.
  • the dissolution of all of the calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample can be measured, for example using an infinity point as discussed further below.
  • the concentration that would be obtained if all the calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample dissolves in the aqueous medium is equal to or higher than the equilibrium solubility of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium.
  • Whether a system, e.g. a specific sample in combination with a specific aqueous medium, is at sink conditions can be controlled by varying parameters which affect the equilibrium concentration, e.g. the temperature, pH, and/or surfactant concentration of the aqueous medium.
  • Whether a system, e.g. a specific sample in combination with a specific aqueous medium, is at sink conditions can be controlled by varying the concentration that would be obtained if all the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample dissolves in the medium, e.g.
  • the sample may contain 10-450 mg, 10-125 mg, 15-60 mg, or 20-30 mg, or about 25 mg calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof,.
  • the volume of the aqueous medium may be 500-1500 mL, or 700-1,100 mL, or about 900 mL.
  • the concentration of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous media may be (i) about 25-30 pg/mL, or about 27.5-28.1 pg/mL, or about 27.8 pg/mL; or (ii) about 50-61 pg/mL, or about 55-56 pg/mL, or about 55.6 pg/mL; or (iii)
  • the aqueous medium comprises a surfactant.
  • the surfactant aids the dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium.
  • the surfactant should be selected such that it does not crystallise at the low temperature used for the method.
  • the surfactant may be a non-ionic surfactant such as a polysorbate (available as TweenTM surfactants); a poly(alkylene-oxide) block copolymer such as poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (available as PluronicTM surfactants), polypropylene oxide)-poly(ethylene oxide)-poly(propylene oxide) (available as Pluronic RTM surfactants), poly(ethylene oxide)-poly(butylene oxide)-poly(ethylene oxide), poly(butylene oxide)-poly(ethylene oxide), and tetrafunctional poly(alkylene-oxide) block copolymers (available as TetronicTM surfactants); an oligomeric alkyl-ethylene oxide (available as BrijTM or TergitolTM surfactants); an alkyl-phenol-polyethylene (available as TritonTM surfactants); and mixtures thereof.
  • a non-ionic surfactant such as a polysorbate
  • the surfactant may be a non-ionic surfactant such as a polysorbate (available as TweenTM surfactants); an oligomeric alkyl-ethylene oxide (available as BrijTM or TergitolTM surfactants).
  • a non-ionic surfactant such as a polysorbate (available as TweenTM surfactants); an oligomeric alkyl-ethylene oxide (available as BrijTM or TergitolTM surfactants).
  • the surfactant is polysorbate 20.
  • the surfactant is a sorbitan ester, e.g. sorbitan oleate (available as SpanTM surfactants).
  • the concentration of the surfactant may be controlled to further improve the discriminating properties of the dissolution method.
  • the surfactant concentration may be controlled to affect the dissolution profile, and hence the performance of the method.
  • a suitable performing method is able to detect a potential burst release (initial release of the reference (first time point to measure the dissolution is preferably measured between 1 or 5 minutes after start of the experiment, e.g. at 1, 2, 3, 4 or 5 minutes; preferably about 2 minutes) is preferably below 50% dissolved, or below 40% dissolved, or below 30% dissolved, below 20% dissolved or below 10% dissolved), characterize the release profile (sufficient time points between 20% and 65% dissolved), and detect final release above 50%, or 60%, or 70%, or 80%, or 90% dissolved, preferably 100% dissolved.
  • the performance of each method can be defined by calculating the difference between the lowest and highest %dissolved in the dissolution profile, i.e. the delta % dissolved.
  • the delta % dissolved in the method of Example 1 is at least 50% for all particle sizes.
  • the delta % dissolved is at least 40%, at least 50%, at least 60%, at least 70%, at least 80%.
  • the surfactant e.g.
  • polysorbate 20 may be present in the aqueous medium at a concentration of or 0.01-8 %w/v, or 0.05-1 %w/v, or 0.1-0.5 %w/v, or 0.14-0.16 % w/v, or 0.15% w/v.
  • concentration within a narrow range e.g. a set concentration ⁇ 1%, for each iteration of the dissolution method may improve the robustness of the method.
  • the aqueous medium may contain a buffer. It has been found that a variety of buffers may be used while maintaining the discriminating properties of the method. Suitable buffers include phosphate buffer, citrate buffer, citrate-phosphate buffer (e.g. Mcllvaine buffer), tris(hydroxymethyl)aminomethane buffer, borate buffer, phthalate buffer, acetate buffer, and mixtures thereof. A preferred buffer is 0.05 M sodium phosphate buffer.
  • the aqueous medium when the temperature of the aqueous medium is maintained below 0 °C the aqueous medium does not contain a phosphate buffer. In some embodiments, when the temperature of the aqueous medium is maintained below 0 °C the aqueous medium does not contain a buffer. In some embodiments, when a buffer is present in the aqueous medium, the molarity of the buffer can be increased to allow the temperature of the aqueous medium to be reduced, for example, to temperatures below 0 °C, in order to prevent the aqueous medium from freezing. In some embodiments, the molarity of the buffer is 1M, or 2M or 3M.
  • the aqueous medium may comprise a calcium salt. Since calcium is the counter-ion of the ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, the inventors have found that the inclusion of a calcium salt may decrease the rate of dissolution by the common ion effect, providing for a further optimised dissolution profile.
  • the calcium salt may be selected from calcium dichloride, calcium citrate and calcium carbonate, and it will preferably be calcium dichloride.
  • the concentration of the calcium salt may be 10-50 g/L, or 15-45 g/L, or 20-40 g/L.
  • the aqueous medium contains a pH adjusting agent, e.g. sodium hydroxide.
  • the aqueous medium may have a pH of at least 5.5, 6-12, 6-9, 6.5-7.5, or 6.9-7.1.
  • a pH within a narrow range e.g. a set pH ⁇ 0.1 , for each iteration of the dissolution method may improve the robustness of the method.
  • the method comprises a first iteration of the dissolution test on a first sample and a second iteration of the dissolution test on a second sample, wherein the concentration of the surfactant in the aqueous medium in the second iteration is maintained within ⁇ 1% of the concentration of surfactant in the aqueous medium in the first iteration, the temperature of the aqueous medium in the second iteration is maintained within ⁇ 0.5 °C of the temperature of the aqueous medium in the first iteration, and the pH of the aqueous medium in the second iteration is maintained within ⁇ 0.1 of the pH of the aqueous medium in the first iteration. In this way the results of the first iteration and the second iteration can be directly compared.
  • the aqueous medium comprises 0.14-0.16 %w/v polysorbate 20; comprises 0.05 M sodium phosphate buffer; has a pH of 6.9-7.1 ; and is maintained at a temperature of 4.5-5.5 °C.
  • the aqueous medium may comprise a substance that depresses the freezing point of the aqueous medium, i.e. a freezing point depression substance. It is widely known that when a solute dissolves in a solvent the freezing point of the solvent is lowered because the Gibbs free energy is lowered for the dissolved system versus the undissolved system. For example, this is typically observed in the freezing point of seawater being below 0°C due to the presence of dissolved sodium chloride. Including a freezing point depression substance in the aqueous medium is particularly advantageous as the freezing point depression substance facilitates the aqueous medium being cooled to temperatures of below 0 °C without the aqueous medium freezing.
  • the freezing point depression substance is preferably dissolved in the aqueous medium such that the concentration of the freezing point depression substance is below the equilibrium solubility of the freezing point depression substance in the aqueous medium.
  • the aqueous medium is not saturated with the freezing point depression substance. In this way the presence of solid freezing point depression substance in the aqueous medium may be avoided.
  • the concentration of the freezing point depression substance dissolved in the aqueous medium may be less than 95%, less than 90%, or less than 80% of the equilibrium solubility of the freezing point depression substance in the aqueous medium.
  • the freezing point depression substance may be present in the aqueous medium in an amount of up to about 60 % w/v, or up to about 45 % w/v, or about 1-28 % w/v, or about 1- 15 % w/v, or about 5-23 % w/v, or about 8-22 % w/v, or about 10-20 % w/v.
  • the freezing point depression substance when the freezing point depression substance is a solid at room temperature and pressure, the freezing point depression substance may be present in the aqueous medium in an amount of up to about 45 % w/v.
  • the freezing point depression substance is a liquid at room temperature and pressure, the freezing point depression substance may be present in the aqueous medium in an amount of up to about 60 % w/v.
  • the freezing point depression substance is present in the aqueous medium at concentrations above the eutectic point such that the aqueous medium is in the liquid phase.
  • the aqueous medium may be kept in the liquid state for some temperatures below 0°C (e.g. at about -2°C) without the presence of a freezing point depression substance by stirring the medium.
  • the freezing point depression substance may be an inorganic salt, for example, a chloride salt. Suitable inorganic salts include sodium chloride, calcium chloride, magnesium chloride and mixtures thereof.
  • the freezing point depression substance may be an organic salt. Suitable organic salts include sodium formate, potassium formate, sodium acetate, potassium acetate, calcium magnesium acetate and mixtures thereof.
  • the freezing point depression substance may be an alcohol, for example, methanol, ethanol, propanol, and mixtures thereof.
  • the freezing point depression substance may be selected from acetic acid, lithium chloride, 2-propanol, acetone, magnesium chloride, silver nitrate, ammonia, magnesium sulfate, sodium acetate, ammonium chloride, maltose, sodium bicarbonate, ammonium sulfate, manganese(ll) sulfate, sodium bromide, barium chloride, D-mannitol, sodium carbonate, calcium chloride, methanol, sodium chloride, cesium chloride, nitric acid, sodium citrate, citric acid, oxalic acid, sodium hydroxide, copper sulfate, phosphoric acid, sodium nitrate, disodium ethylenediamine, potassium bicarbonate, sodium phosphate, tetraacetate (EDTA sodium), potassium bromide, sodium hydrogen phosphate, ethanol, potassium carbonate, sodium dihydrogen phosphate, ethylene glycol, potassium chloride, sodium sulfate, ferric chloride, potassium hydroxide
  • the freezing point depression substance is selected from calcium chloride, sodium chloride, magnesium nitrate, glycerol, ethanol, propanol, ethylene glycol, acetic acid, ammonia, iron(lll) chloride, formic acid, hydrochloric acid, lithium chloride, methanol, nitric acid, phosphoric acid, potassium bromide, potassium carbonate, sodium hydroxide, strontium chloride, sulfuric acid, urea and mixtures thereof.
  • the freezing point depression substance is selected from calcium chloride, sodium chloride, glycerol, ethanol, propanol, ethylene glycol, methanol, hydrochloric acid, sodium hydroxide and mixtures thereof.
  • the freezing point depression substance is sodium chloride.
  • a particular example of the freezing point depression substance is sodium chloride.
  • Sodium chloride allows the depression of the freezing point of water to -21°C.
  • calcium chloride allows depression of the freezing point of water to -50°C.
  • the freezing point depression substance may be used in the aqueous medium in addition to a buffer.
  • the aqueous medium may not contain a phosphate buffer, or may not contain a buffer.
  • the dissolution method may be performed in any suitable apparatus, such as standard dissolution instrumentation described in the pharmacopeia, for example USP 42 - NF 37 2019.
  • Dispersing the sample of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles into the aqueous medium typically comprises agitation.
  • a paddle apparatus may be used, in particular a USP type 2 apparatus.
  • the rotation speed of the apparatus is typically 10-100 rpm, or 25-75 rpm, or about 50 rpm.
  • the aqueous medium can be maintained at the desired temperature by placing the aqueous medium into a vessel which has a cooling jacket comprising a cooling fluid.
  • the cooling fluid may be water, for example deionised water or water comprising a dissolved freezing point depression substance as defined above.
  • the cooling fluid may be selected based on the desired maintenance temperature for the aqueous medium. For example, for temperatures above 0°C deionised water may be an acceptable cooling fluid. At temperatures below 0°C alternative cooling fluids may be used such as a water-glycol based fluid, e.g. water-ethylene glycol.
  • a water-glycol based fluid is a 1:1 wt:wt mixture of water and ethylene glycol.
  • Water-glycol based cooling fluids may be used at temperatures of -30°C and above.
  • Other cooling fluids include silicone-based fluids, for example fluids comprising dodecamethylcyclohexasiloxane. Silicone-based fluids may be used at temperatures of -80°C and above.
  • the cooling fluid is a glycol-based fluid, for example, a waterethylene glycol based fluid, and the freezing point depression substance in the aqueous medium is sodium chloride.
  • the dissolution of a drug is generally monitored for a time period which is similar to the time needed for in vivo drug release. Accordingly, this would mean monitoring the dissolution over several weeks or several months for a sample of calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles intended for administration by intramuscular or subcutaneous injection for the long-term treatment of the diseases and/or disorders disclosed herein, in particular PAH and CTEPH, e.g.
  • a sample of a prolonged release injectable calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate suspension Long-term treatment of the diseases and/or disorders disclosed herein, in particular PAH and CTEPH, in a subject can be understood as the treatment of the diseases and/or disorders disclosed herein in a subject wherein the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles, optionally in suspension, is administered subcutaneously or intramuscularly intermittently at a time interval of one week to three months, notably at a time interval of two weeks to one month, preferably one week or one month or three months.
  • the measurement of the dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium may be performed over 24 hours or less, e.g. over a period of 1-24 hours, 1-12 hours, 1-8 hours, 2-6 hours, or 3-5 hours, or about 4 hours.
  • the inventors have found that the in vitro method provides a result that is biorelevant due to its discriminative properties despite the significant difference between the in vitro monitoring period (in the order of hours) and the in vivo drug release period (in the order of weeks or months).
  • the dissolution test may be operated such that at least 80% or at least 85% of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample has dissolved in the aqueous medium after about 4 hours. In this way, the dissolution of a sufficient amount of the sample to provide robust results is determined over a practical timescale.
  • the dissolution test may comprise measuring the dissolution of the calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium at an infinity point wherein at least about 80%, at least about 85%, at least about 90%, at least about 95%, or preferably about 100% (i.e., about all) of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample dissolves in the aqueous medium.
  • the infinity point may be achieved by increasing the temperature of the aqueous medium from the initial temperature (e.g. ⁇ 15, 2-15, 3-10, 4-6, or 4.5-5.5 °C) to room temperature (e.g. about 22 °C) or above such as about 37 °C, and optionally maintaining the aqueous medium at the increased temperature for about 1 hour.
  • Achieving the infinity point may also include increasing the rotation speed if using a paddle apparatus.
  • the rotation speed may be increased by at least 50, 100, or 150 rpm, such as increasing the rotation speed from about 50 rpm to about 250 rpm.
  • the dissolution test may comprise measuring the dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium at ⁇ 15 °C, for example 2-15 °C, as a function of time, optionally over a period of 2-7 hours, or 2-6 hours, or 3-5 hours, or about 4 hours, and comprising a subsequent step of increasing the temperature of the aqueous medium to room temperature (e.g.
  • the dissolution test may comprise measuring the dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium at ⁇ 15 °C, for example 2-15 °C, until at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, or at least about 90%, or at least about 95% of the calcium; ⁇ 4-[(5,6-diphenylpyrazin- 2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample dissolves, and comprising a subsequent step of increasing the temperature of the aqueous medium to room temperature (e.g.
  • the dissolution test may comprise measuring the dissolution of the calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium at ⁇ 15 °C, for example 2-15 °C, until about 40%, about 50%, about 60%, about 70%, about 80%, about 85%, or about 90%, or about 95% of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample dissolves, and comprising a subsequent step of increasing the temperature of the aqueous medium to room temperature (e.g.
  • the dissolution test may comprise measuring the dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium at ⁇ 15 °C, for example 2-15 °C, as a function of time, over a period of 2-7 hours, or 2-6 hours, or 3-5 hours, or about 4 hours, and until at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, or at least about 90%, or at least about 95% of the calcium ; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample dissolves, and comprising a subsequent step of increasing the temperature of the aqueous medium
  • the dissolution test may comprise measuring the dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium at ⁇ 15 °C, for example 2-15 °C, as a function of time, over a period of 2-7 hours, or 2-6 hours, or 3-5 hours, or about 4 hours, and until about 40%, about 50%, about 60%, about 70%, about 80%, about 85%, or about 90%, or about 95% of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample dissolves, and comprising a subsequent step of increasing the temperature of the aqueous medium to room temperature (e.g.
  • the dissolution test may comprise measuring the dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium at ⁇ 15 °C, for example 2-15 °C, as a function of time, over a period of 2-7 hours, or 2-6 hours, or 3-5 hours, or about 4 hours, and until at least about 80%, at least about 85%, or at least about 90%, or at least about 95% of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample dissolves, and comprising a subsequent step of increasing the temperature of the aqueous medium to room temperature (e.g.
  • the dissolution test may comprise measuring the dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium at ⁇ 15 °C, for example 2-15 °C, as a function of time, over a period of 2-7 hours, or 2-6 hours, or 3-5 hours, or about 4 hours, and until about 80%, about 85%, or about 90%, or about 95% of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, from the sample dissolves, and comprising a subsequent step of increasing the temperature of the aqueous medium to room temperature (e.g.
  • Measuring the dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium can be readily achieved by removing an aliquot from the medium, optionally filtering the aliquot, and measuring the amount of calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, dissolved in the aliquot.
  • the filtering removes undissolved calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate particles. It has been found that a filter, e.g. a syringe filter, with a pore size of 0.1 pm, e.g. a regenerated cellulose or polyvinylidene difluoride (PVDF) membrane, is suitable. If the aliquot is filtered, typically a new filter is used for each aliquot to avoid possible contamination.
  • PVDF polyvinylidene difluoride
  • the aliquot could be centrifuged, cooled, and/or diluted before measuring the amount of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, dissolved in the aliquot.
  • the %dissolved should be corrected to reflect the removal of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, and volume of dissolution medium.
  • the quantity of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, present in the aliquots may be determined by standard techniques such as high performance liquid chromatography (HPLC), in particular gradient ultra-high performance liquid chromatography (LIHPLC) with UV detection.
  • HPLC high performance liquid chromatography
  • LIHPLC gradient ultra-high performance liquid chromatography
  • Measuring the dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium can also be achieved without removal of an aliquot using in-line spectroscopy techniques such as in-line UV spectroscopy.
  • the invention provides an aqueous medium for use in dissolution testing, the medium comprising 0.01-8 %w/v, or 0.05-1 %w/v, or 0.1-0.5 %w/v, or 0.14- 0.16 %w/v of a surfactant, e.g. a non-ionic surfactant such as polysorbate 20; comprising a buffer, such as 0.05 M sodium phosphate buffer; and having a pH of at least 5.5, 6-12, 6-9, 6.5-7.5, or 6.9-7.1.
  • a surfactant e.g. a non-ionic surfactant such as polysorbate 20
  • a buffer such as 0.05 M sodium phosphate buffer
  • the aqueous medium comprises 0.14-0.16 %w/v of polysorbate 20; comprises a buffer, such as 0.05 M sodium phosphate buffer; and has a pH of 6.9-7.1.
  • the aqueous medium may be maintained at a temperature of ⁇ 15, 2-15, 3-10, 4-6, or preferably 4.5-5.5 °C.
  • the aqueous medium may be maintained at a temperature of at least -80°C, at least -40°C, at least -30°C, at least -21°C, at least -20°C, at least -10°C, or at least -5°C and/or below 0°C, below -1°C, or below -2°C.
  • the aqueous medium may be maintained at a temperature of -21°C to below 0°C or -20 to -1°C.
  • the aqueous medium may comprise dissolved calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, e.g. present from the dissolution testing.
  • the results of the dissolution test are used for quality control testing of the sample of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof.
  • the test of the first aspect discriminates between different particle size distributions.
  • the measured dissolution of the calcium; ⁇ 4- [(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium is preferably used to determine whether the sample comprising calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles meets a specified particle size distribution, e.g.
  • a specified Dv50, or a specified Dv90, or a specified Dv10, or a specified Dv10, Dv50 and Dv90 Determining whether a specified particle size distribution has been achieved is an important step in the manufacture of certain formulations of calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, for pharmaceutical use.
  • some agglomeration may occur on storing calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles, altering the particle size distribution.
  • the measured dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate in the medium may be used to determine whether calcium; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles which has been stored for a period of time retained its particle size distribution.
  • Determining whether the sample has passed the quality control test may be achieved by comparing the measured dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan- 2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium with one or more reference values of the dissolution of a reference sample of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles and determining, based on the comparison, whether the sample has passed the quality control test.
  • the determining may comprise comparing the measured dissolution with one or more reference values at a single time point, or at least two time points, or preferably at least three time points.
  • the properties, e.g. the particle size distribution, of the reference sample may have been independently verified by another technique, such as laser diffraction.
  • the reference values are for the dissolution of the reference sample in an identical medium to the medium into which the sample was dispersed, most preferably wherein the dissolution of the reference sample and the sample were tested using an identical method, since this allows for a direct comparison.
  • the concentration of the surfactant in the aqueous medium when testing the sample is maintained within ⁇ 1% of the concentration of surfactant in the aqueous medium when testing the reference sample
  • the temperature of the aqueous medium when testing the sample is maintained within ⁇ 0.5 °C of the temperature of the aqueous medium when testing the reference sample
  • the pH of the aqueous medium when testing the sample is maintained within ⁇ 0.1 of the pH of the aqueous medium when testing the reference sample.
  • the reference values may be obtained from dissolution in a different medium, provided that the relationship between dissolution in the different mediums is established so that dissolution in the different medium can be correlated to the dissolution of the sample in the chosen medium.
  • the method of quality control is used to determine whether a batch of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles can be released for pharmaceutical use.
  • the batch can be released for sale, for supply or for export.
  • Releasing the batch may include providing the batch with documents certifying that the batch is suitable for pharmaceutical use.
  • the batch may be of an approved pharmaceutical product, such as a product approved by the FDA (US Food and Drug Administration), EMA (European Medicines Agency), and/or MHRA (UK Medicines & Healthcare products Regulatory Agency).
  • the batch may be of an NDA drug product, an ANDA drug product, a supplemental New Drug Application drug product, or a 505(b)(2) drug product.
  • the pharmaceutical use may comprise the treatment and/or prevention of a disease and/or disorder selected from the group consisting of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pressure ulcer (bedsore), hypertension, pulmonary hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud's disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion/restenosis after percutaneous transluminal coronary
  • cardiovascular diseases e.g, myocardial fibrosis
  • bone and articular diseases e.g, bone marrow fibrosis and rheumatoid arthritis
  • skin diseases e.g, cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix
  • obstetric diseases e.g., hysteromyoma
  • urinary diseases e.g., prostatic hypertrophy
  • other diseases e.g., Alzheimer’s disease, sclerosing peritonitis, type I diabetes and organ adhesion after operation
  • erectile dysfunction e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic operation for removing prostate, and vascular
  • Preferred disease and I or disorders are selected from the group consisting of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pulmonary hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension (CTEPH), Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance, connective tissue disease, chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, diseases in which fibrosis of organs or tissues is involved, and respiratory diseases.
  • the pharmaceutical use preferably comprises the treatment and/or prevention of pulmonary hypertension, in particular, pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, pulmonary hypertension associated with Fontan disease, or pulmonary hypertension associated with sarcoidosis.
  • pulmonary hypertension in particular, pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension, pulmonary hypertension associated with Fontan disease, or pulmonary hypertension associated with sarcoidosis.
  • the pharmaceutical use more preferably comprises the treatment of PAH or CTEPH in a subject, most preferably the long-term treatment of PAH or CTEPH in a subject, in particular the treatment of PAH or CTEPH in a subject wherein the calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles, optionally in suspension, is administered subcutaneously or intramuscularly intermittently at a time interval of one week to three months, notably at a time interval of two weeks to one month, preferably one week or one month or three months.
  • the method may be performed as part of a process of manufacturing calcium ; ⁇ 4-[(5, 6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles for pharmaceutical use. Therefore, providing the batch may comprise manufacturing the batch.
  • the method may be performed as a means for checking the quality of calcium; ⁇ 4- [(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles obtained from a supplier.
  • providing the batch may comprise obtaining the batch from a supplier.
  • the method may be performed as a means for checking whether a batch of pharmaceutical product that has been stored is in suitable condition for use. Therefore, the batch may have been stored for a period of time before the sample is taken; for example for at least 1 month, 3 months, or 6 months.
  • the batch refers to a larger amount of calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles, and that the sample taken from the batch is a smaller amount considered as representative of the batch.
  • the batch may comprise at least 100g, at least 1 kg, or at least 10 kg of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles, optionally in suspension.
  • the batch encompasses continuous manufacturing processes of calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles.
  • the method of quality control may be performed on a sample taken from the product of a continuous manufacturing process, and if the sample passes the quality control test, releasing for pharmaceutical use the batch of the manufacturing process which is contemporaneous with the sample. Samples may be taken from the product of a continuous manufacturing process at set periods of time to confirm whether the process is operating as intended, e.g. that the intended particle size distribution is obtained.
  • Calcium ; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate is the calcium salt of the metabolite of selexipag (calcium salt of ACT-333679), and has the formula Ca(C25H28N3C>3)2, i.e. CsoHseNeOeCa (MW: 877.109).
  • the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, is in the form of microparticles and/or nanoparticles, e.g.
  • microparticles and/or nanoparticles of the calcium are microparticles and/or nanoparticles of the calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in a suspension, in particular microparticles and/or nanoparticles of the calcium ; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, suspended in a pharmaceutically acceptable carrier, such as for example a pharmaceutically acceptable aqueous carrier.
  • a pharmaceutically acceptable carrier such as for example a pharmaceutically acceptable aqueous carrier.
  • Calcium ; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate may be in anhydrous form, or in a hydrate form or a pharmaceutically acceptable solvate form.
  • pharmaceutically acceptable solvate refers to solvates that retain the desired biological activity of the compound and exhibit minimal undesired toxicological effects. Preferred is an anhydrous form or a hydrate form.
  • Calcium ; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate may be in a hydrate form.
  • the hydrate form may be from about 0.1 to about 1 water molecules per calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate molecules.
  • the molar ratio of water to calcium; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate ranges from about 0.1 to about 1, such as about 0.1 to about 0.15, about 0.15 to about 0.2, about 0.2 to about 0.25, about 0.25, to about 0.3, about 0.3 to about 0.35, about 0.35 to about 0.4, about 0.4 to about 0.45, about 0.45 to about 0.5, about 0.5 to about 0.55, about 0.55 to about 0.6, about 0.6 to about 0.65, about 0.65 to about 0.7, about 0.7 to about 0.75, about 0.75 to about 0.8, about 0.8 to about 0.85, about 0.85 to about 0.9, about 0.9 to about 0.95, about 0.95 to about 1.
  • the molar ratio of water in the hydrate form may change based on storage conditions of the compound, the method of formation of the compound, and the crystal structure of the compound.
  • the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, used in the invention is calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate.
  • the size of the microparticles and/or nanoparticles should be below a maximum size above which administration by subcutaneous or intramuscular injection becomes impaired or even is no longer possible.
  • the maximum size depends for example on the limitations imposed by the needle diameter or by adverse reactions of the body to large particles, or both.
  • the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, is in the form of nanoparticles.
  • the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof is in the form of microparticles, e.g. having a particle size distribution Dv50 of 1 to 50 pm.
  • the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate or hydrate or solvate thereof microparticles have a particle size distribution (PSD) Dv50 of 1 to 50 pm, or 1 to 40 pm, or 1 to 30 pm, or 1 to 20 pm, or 1 to 18 pm, or 1 to 15 pm, or 2 to 50 pm, or 2 to 40 pm, or 2 to 30 pm, or 2 to 20 pm, or 2 to 18 pm, or 2 to 15 pm, or 3 to 50 pm, or 3 to 40 pm, or 3 to 30 pm, or 3 to 20 pm, or 3 to 18 pm, or 3 to 15 pm, or 4 to 50 pm, or 4 to 40 pm, or 4 to 30 pm, or 4 to 20 pm, or 4 to 18 pm, or 2 to 15 pm, or 5 to 50 pm, or 5 to 40 pm, or 5 to 30 pm, or 5 to 20 pm, or 5 to 18 pm, or 5 to 15 pm.
  • PSD particle size distribution
  • the particle size distribution (PSD) Dv50 is 5 pm ⁇ 10%, or 5 pm ⁇ 5%; in some embodiments, the particle size distribution (PSD) Dv50 is 6 pm ⁇ 10%, or 6 pm ⁇ 5%; in some embodiments, the particle size distribution (PSD) Dv50 is 7 pm ⁇ 10%, or 7 pm ⁇ 5%; in some embodiments, the particle size distribution (PSD) Dv50 is 8 pm ⁇ 10%, or 8 pm ⁇ 5%; in some embodiments, the particle size distribution (PSD) Dv50 is 9 pm ⁇ 10%, or 9 pm ⁇ 5%; in some embodiments, the particle size distribution (PSD) Dv50 is 10 pm ⁇ 10%, or 10 pm ⁇ 5%; in some embodiments, the particle size distribution (PSD) Dv50 is 11 pm ⁇ 10%, or 11 pm ⁇ 5%; in some embodiments, the particle size distribution (PSD) Dv50 is 12 pm ⁇ 10%, or 12 pm ⁇ 5%; in some embodiments, the particle size distribution (PS
  • Dv50 also known as the median diameter. Median values are defined as the value where half of the population resides above this point, and half resides below this point. For particle size distributions the median is called the D50 (or x50 when following certain ISO guidelines). The D50 is the size in microns (micrometer, pm) that splits the distribution with half above and half below this diameter. The Dv50 (or Dv0.5) is the median for a volume distribution. The volume distribution is the primary result from laser diffraction. Herein, PSD is given in volume distribution.
  • Particle size distributions can be measured by well-known methods in the art, for example, laser diffraction, sedimentation field flow fractionation, photon correlation spectroscopy or disk centrifugation.
  • laser diffraction measures particle size distribution by measuring the angular variation in intensity of light scattered as a laser beam passes through a dispersed particulate sample.
  • the Dv50 as used herein is determined by routine laser diffraction techniques, e.g. in accordance with ISO 13320:2009.
  • particle size distribution may be measured by the conventional Malvern MastersizerTM 3000 particle size analyser from Malvern Instruments.
  • the Malvern MastersizerTM 3000 particle size analyser operates by projecting a helium-neon gas laser beam through a transparent cell containing the particles of interest suspended in an aqueous solution.
  • Light rays which strike the particles are scattered through angles which are inversely proportional to the particle size and a photodetector array measures the intensity of light at several predetermined angles and the measured intensities at different angles are processed by a computer using standard theoretical principles to determine the particle size distribution.
  • Laser diffraction values may be obtained using a wet dispersion of the particles in distilled water. A measurement method is disclosed in the example part.
  • Samples with a larger particle size were found to have a slower rate of dissolution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the aqueous medium than samples with a lower particle size (see Figure 1).
  • Increasing the temperature of the aqueous medium increases the rate of dissolution (see Figures 3(a)-(c)).
  • the temperature at which the aqueous medium is maintained may be further optimised based on the expected particle size distribution of the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles.
  • the aqueous medium may be maintained at a higher temperature when testing samples of higher particle sizes in order to provide results within a reasonable timescale (e.g. wherein over 85% of the drug substance is dissolved after 4 hours).
  • the aqueous medium may be maintained at a lower temperature when testing samples of lower particle sizes since this will still provide results within a reasonable timescale while the low temperature improves the discriminative properties of the test.
  • the aqueous medium may be maintained at a temperature of 3- 10°C, or 4-6 °C, or 4.5-5.5 °C.
  • calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate having the structure as indicated above, is used in crystalline form.
  • the sample or batch of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles is preferably in the form of a pharmaceutical composition which is a suspension comprising a pharmaceutically acceptable aqueous carrier in which the microparticles and/or nanoparticles are suspended.
  • the pharmaceutical composition comprises a surfactant and/or wetting agent, or a mixture of surfactants and/or wetting agents.
  • a “surfactant and/or wetting agent” (surfactant/wetting agent) as used herein is pharmaceutically acceptable and able to stabilise the aqueous suspension in order to avoid particle size growth during shelf-life.
  • the surfactant and/or wetting agent may be non-ionic or ionic. Surfactants and/or wetting agents are well known in the art.
  • surfactants and/or wetting agents include gelatin, casein, lecithin, salts of negatively charged phospholipids or the acid form thereof (such as phosphatidyl glycerol, phosphatidyl inosite, phosphatidyl serine, phosphatic acid, and their salts such as alkali metal salts, e.g.
  • egg phosphatidyl glycerol sodium such as the product available under the tradename LipoidTM EPG
  • gum acacia stearic acid
  • benzalkonium chloride polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives such as polyoxyl 35 castor oil (CremophorTM EL) or polyoxyl 40 hydrogenated castor oil (CremophorTM RH40); polyoxyethylene stearates, colloidal silicon dioxide, sodium dodecylsulfate, carboxymethylcellulose sodium, bile salts such as sodium taurocholate, sodium desoxytaurocholate, sodium desoxycholate; methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminate silicate, polyvinyl alcohol (PVA), poloxamers (which are block copolymers of
  • the surfactants/wetting agents may be selected from one or more of a polysorbate, a poloxamer, an a-tocopheryl polyethylene glycol succinate, a salt of a negatively charged phospholipid (e.g. egg phosphatidylglycerols), lecithin, polyvinylpyrrolidone (PVP), docusate sodium, sodium deoxycholate, sodium dodecyl sulphate (SDS), polyoxyethylene castor oil derivatives, macrogol 15 hydroxystearate, or mixtures thereof.
  • a polysorbate e.g. egg phosphatidylglycerols
  • PVP polyvinylpyrrolidone
  • SDS sodium dodecyl sulphate
  • Preferred surfactants/wetting agents are polysorbates, poloxamers and a-tocopheryl polyethylene glycol succinates, for example polysorbate 20, polysorbate 80, poloxamer 188, poloxamer 338, poloxamer 407, vitamin E TPGS, egg phosphatidylglycerol (Egg PG), and mixtures thereof.
  • Particularly preferred surfactants/wetting agents are polysorbate 20, poloxamer 338, and vitamin E TPGS, for instance polysorbate 20 and/or poloxamer 338.
  • Polysorbates are polyoxyethylene sorbitan fatty acid esters. Polyoxyethylene sorbitan fatty acid esters/polysorbates is the nonprorietary name, and several grades thereof are available, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80. Polysorbates are derived from ethoxylated sorbitan (a derivative of sorbitol) esterified with fatty acids.
  • polysorbates examples include Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), and Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate).
  • the different types of polysorbate differ in the fatty acid, the average number of polyoxyethylene units in the molecule and the degree of esterification.
  • the second digit indicates the type of esterification: 0 for a monoester with 20 polyoxyethylene units, 1 for a monoester with 4 or 5 polyoxyethylene units and the number 5 stands for a triester with 20 polyoxyethylene units.
  • the preferred polysorbate 20 (CAS No 9005-64-5, E 432) is for instance sold under the brand name TweenTM 20.
  • Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)), i.e. they are polyoxypropylene-polyoxyethylene copolymers.
  • Preferred poloxamers are poloxamer 188, poloxamer 338, and poloxamer 407, in particular poloxamer 338.
  • a-Tocopheryl polyethylene glycol succinate as used herein refers to vitamin E TPGS, i.e. d- a -tocopheryl polyethylene glycol 1000 succinate, also referred to as tocophersolan (INCI), CAS No. 9002-96-4.
  • Lecithins are phosphatidylcholines.
  • lecithin refers to any of a group of phospholipids, occurring in animal and plant tissues and egg yolk, composed of elements of choline, phosphoric acid, fatty acids, and glycerol.
  • Salts of a negatively charged phospholipid or the acid form thereof are for example phosphatidyl glycerol, phosphatidyl inosite, phosphatidyl serine, phosphatic acid, and their salts such as alkali metal salts, e.g. their sodium salts, for example egg phosphatidyl glycerol sodium, such as the product available under the tradename LipoidTM EPG).
  • Polyvinylpyrrolidone has the molecular formula of (CeHgNO) ⁇ United States Pharmacopeia (USP) 32 describes povidone as a synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidinone groups, the differing degree of polymerization of which results in polymers of various molecular weights. It is characterized by its viscosity in aqueous solution, relative to that of water, expressed as a K-value, in the range 10-120. The K-value is calculated using Fikentscher’s equation.
  • PVP K12, PVP K15, PVP K17, PVP K25, PVP K30, PVP K60, PVP K90 or PVP K120 is PVP K17.
  • the optimal relative amount of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate, in relation to the surfactant/wetting agent depends on the surfactant/wetting agent selected, the specific surface area of the drug suspension which is determined by the average effective particle size and the drug concentration, the critical micelle concentration of the surfactant/wetting agent if it forms micelles, etc.
  • the relative amount (w/w) of drug to the surfactant/wetting agent preferably is in the range 20:1 to 2:1, in particular in the range of 18: 1 to 4: 1.
  • the pharmaceutical composition optionally comprises a resuspending agent.
  • a resuspending agent as used herein is pharmaceutically acceptable and able to stabilise the aqueous suspension in order to avoid caking during shelf-life, or needly clogging, or to facilitate resuspending the formulation after storage.
  • the resuspending agent is selected from the group consisting of polyethylene glycol (PEG) of various polymerization grades, carmellose sodium, and poloxamers, or a mixture thereof; preferably polyethylene glycol (PEG) of various polymerization grades, and carmellose sodium, or a mixture thereof.
  • PEG polyethylene glycol
  • Preferred resuspending agents are selected from the group consisting of PEG 4000, PEG 3350, PEG 6000, PEG 8000, PEG 20000, and carmellose sodium, or a mixture thereof; in particular PEG 4000.
  • poloxamers can function as surfactants/wetting agents, but also as resuspending agents, because they contribute some viscosity in the suspension.
  • the resuspending agent is selected from the group consisting of PEG 4000, PEG 3350, PEG 6000, PEG 8000, PEG 20000, carmellose sodium, Poloxamer 338, and Poloxamer 407, or a mixture thereof.
  • Preferred resuspending agents are selected from the group consisting of PEG 4000, PEG 3350, PEG 6000, PEG 8000, PEG 20000, and carmellose sodium, or a mixture thereof, in particular polyethylene glycol 4000.
  • Polyethylene glycol exists in various polymerization grades.
  • the structure of PEG is commonly expressed as H-(O-CH 2 -CH2)n-OH.
  • Polyethylene glycols (PEGs) are available in various grades, which is indicated as a number, for instance PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000, PEG 8000 or PEG 20000. The number is indicative for the average molecular weight of the polymer.
  • a preferred carmellose sodium (carboxymethylcellulose sodium) has a viscosity of 27-50 mPa.s (Viscosity 2%), 0.65 to 0.90 degree of substitution and 7.0-8.8 % Na content (calculated vs DS). The product conforms to the monograph for carmellose sodium in the current European Pharmacopeia.
  • the optimal relative amount (w/w) of the drug i.e. calcium; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate, in relation to the resuspending agent depends on the resuspending agent selected, and is preferably in the range of 2:1 to 1:3, in particular 2:1 to 1:1.
  • each indicated surfactant/wetting agent described above may be combined with each resuspending agent mentioned herein.
  • Particularly preferred combinations are polysorbate 20 with PEG 4000, poloxamer 338 with PEG 4000, vitamin E TPGS with PEG 4000, poloxamer 338 and carmellose sodium, polysorbate 80 and carmellose sodium, and poloxamer 338 and vitamin E TPGS.
  • the pharmaceutical composition comprises a pharmaceutically acceptable aqueous carrier.
  • Said aqueous carrier comprises sterile water, i.e. water suitable for injection, optionally in admixture with other pharmaceutically acceptable ingredients. These ingredients may be selected from one or more of a buffering agent, a pH adjusting agent, a preservative or an isotonizing agent.
  • the aqueous carrier has a pH in the range of 6 to 8.5. Further pH ranges are from 7 to 8.5, or pH 8, i.e. pH 8 ⁇ 1/2, or pH 7.5, i.e. 7.5 ⁇ 1/2.
  • the pharmaceutical composition is formulated for administration by subcutaneous or intramuscular injection. In an embodiment, the pharmaceutical composition is formulated for administration by subcutaneous injection. In an embodiment, the pharmaceutical composition is formulated for administration by intramuscular injection.
  • the pharmaceutical composition comprises one or more buffering and/or pH adjusting agent(s), rendering the pH of the aqueous carrier in the range of 6 to 8.5; 7 to 8.5, or pH 8, i.e. pH 8 ⁇ 1/2, or pH 7.5, i.e. 7.5 ⁇ 1/2.
  • the buffering and/or pH adjusting agent(s) is/are selected from the group consisting of disodium hydrogen phosphate, citric acid, tris(hydroxymethyl)aminomethane (TRIS), histidine, HCI and NaOH, or a mixture thereof.
  • the buffering agents are disodium hydrogen phosphate, citric acid, tris(hydroxymethyl)aminomethane (TRIS) and histidine; and the pH-adjusting agents are HCI or NaOH, preferably in aqueous solution.
  • the buffering and/or pH adjusting agent(s) is/are selected from the group consisting of disodium hydrogen phosphate, citric acid, tris(hydroxymethyl)aminomethane (TRIS), HCI and NaOH, or a mixture thereof.
  • the buffering agents are disodium hydrogen phosphate, citric acid, and tris(hydroxymethyl)aminomethane (TRIS); and the pH-adjusting agents are HCI or NaOH, preferably in aqueous solution.
  • the pharmaceutically acceptable aqueous carrier comprises citric acid.
  • Citric acid thereby serves as buffering agent, but also as chelating agent and antioxidant.
  • a preferred pH of the pharmaceutical composition is pH 8 ⁇ 1/2.
  • Micro-suspensions may be formulated with TRIS buffer, however, Mcllvaine buffer (citric acid and disodium hydrogen phosphate) is preferred.
  • Mcllvaine buffer at pH 8 ⁇ 1/2 consists of disodium hydrogen phosphate anhydrous and citric acid, the buffer strength ranging from 5 to 100 mM. 10 to 50 mM is preferred. However, it is also possible to add more citric acid and adjust the pH with NaOH to pH 8 ⁇ 1/2.
  • the buffering agent or buffer is able to provide stability to the formulation, i.e. to prevent dissociation into the free from of the metabolite of selexipag, i.e. the free acetic acid derivative.
  • the buffer strength ranges from 5 to 100 millimolar (mM), or from 10 to 50 mM.
  • Suitable optional preservatives for the pharmaceutical compositions comprise antimicrobials and anti-oxidants which can be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), chlorbutol, a gallate, a hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-y-piccolinium chloride, phenylmercuric acetate and thimerosal.
  • Radical scavengers include BHA, BHT, Vitamin E and ascorbyl palmitate, and mixtures thereof.
  • Oxygen scavengers include sodium ascorbate, sodium sulfite, L- cysteine, acetylcysteine, methionine, thioglycerol, acetone sodium bisulfite, isoacorbic acid, hydroxypropyl cyclodextrin.
  • Chelating agents include sodium citrate, sodium EDTA and malic acid. In one embodiment, the pharmaceutical composition does not contain a perseverative.
  • An isotonizing agent or isotonifier may be present to ensure isotonicity of the pharmaceutical composition, and includes sugars such as mannitol, glucose, dextrose, sucrose, fructose, trehalose, lactose; polyhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol.
  • sugars such as mannitol, glucose, dextrose, sucrose, fructose, trehalose, lactose
  • polyhydric sugar alcohols preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol.
  • sodium chloride, sodium sulfate, or other appropriate inorganic salts may be used to render the solutions isotonic.
  • the pharmaceutical compositions conveniently comprise from 0 to 10% (w/v), in particular 0 to 6% of isotonizing agent.
  • isotonizing agent e.g. glucose
  • electrolytes may affect colloidal stability.
  • the pharmaceutical composition contains an isotonizing agent or isotonifier, which, in a further embodiment is a nonionic isotonifier, such as a suitable sugar such as mannitol.
  • the batch contains multiple doses of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, formulated to be suitable for administration by intramuscular or subcutaneous injection, optionally for the long-term treatment of the diseases and/or disorders disclosed herein, in particular PAH and CTEPH, in a subject.
  • a desirable feature for a pharmaceutical composition relates to the ease of administration.
  • the viscosity of the pharmaceutical composition should be sufficiently low to allow administration by injection, and sufficiently high to maintain slow sedimentation and good resuspendability.
  • the viscosity of the pharmaceutical composition is from 1 mPa ⁇ s to 75 mPa ⁇ s at 200 s -1 , or from 5 mPa ⁇ s to 40 mPa ⁇ s at 200 s’ 1 .
  • the pharmaceutical composition will comprise as much calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, as can be tolerated so as to keep the injection volume to a minimum, in particular 2% to 50% (w/v), or from 2% to 45% (w/v), or from 2% to 40% (w/v), or from 2% to 35% (w/v), or from 2% to 30% (w/v), or from 2% to 25% (w/v), or from 2% to 20% (w/v), or from 2% to 15% (w/v), in particular from 2.5% to 10% (w/v).
  • the amount of surfactant/wetting agent is selected as low as possible but effective and robust, in particular from 0.5% to 20% (w/v), or from 0.5% to 15% (w/v), or from 0.5% to 12% (w/v) or from 0.5% to 10% (w/v), or from 0.5% to 8% (w/v), or from 0.5% to 7% (w/v), or from 0.5% to 6% (w/v), or from 0.5% to 5% (w/v), or from 0.5% to 4% (w/v), or from 0.5% to 3% (w/v), or from 0.5% to 2% (w/v), of a surfactant/wetting agent, or a mixture of surfactants/wetting agents.
  • the amount of resuspending agent is selected as low as possible but effective, in particular from 0% to 30% (w/v), or from 1% to 30% (w/v), or from 1% to 25%, or from 1% to 20% (w/v), or from 1 to 15% (w/v), or from 3 to 10% (w/v) of a resuspending agent or a mixture of resuspending agents.
  • the amount of buffering agent is selected as low as possible but effective, in particular from 0 to 100 mM, or from 5 to 100 mM, or from 5 to 50 mM, or from 10 to 50 mM of a buffering agent, or a mixture of buffering agents.
  • the batch contains multiple doses formulated for administration, preferably by subcutaneous or intramuscular injection, intermittently at a time interval of one week to three months, notably at a time interval of two weeks to one month, preferably one week or one month or three months.
  • the pharmaceutical composition comprises by weight based on the total volume of composition
  • the pharmaceutical composition comprises by weight based on the total volume of composition
  • the pharmaceutical composition of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, as described herein is suitable for administration by a manual injection process.
  • the pharmaceutical compositions described herein, in particular for the treatment of the above-indicated diseases and/or disorders are preferably in the form of an intramuscular or subcutaneous injectable.
  • the injectable is a long-acting injectable (LAI).
  • LAI long-acting injectable
  • the term "long acting injectable" is used herein for an administration interval of one week to three months, or 1 week to two months, or 1 week to one month, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks.
  • compositions described herein provide release of the active ingredient over a prolonged period of time and therefore it can also be referred to as sustained or delayed release composition.
  • the composition stays in the body and steadily releases 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid or its calcium salt, keeping such levels of this active ingredient in the patient's system for a prolonged period of time, thereby providing, during said period, the appropriate treatment or prevention of the above-given diseases and/or disorders, in particular PAH and CTEPH.
  • pharmaceutical composition suitable as long-acting (or depot) formulations Because of the fact that the pharmaceutical compositions described herein facilitate that the active ingredient stay in the body and steadily releases the active ingredient.
  • compositions described herein may be applied in the long-term treatment or the long-term prevention of the diseases and/or disorders disclosed herein, in particular PAH and CTEPH.
  • compositions as described herein includes the active ingredient, i.e. calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate (or a pharmaceutically acceptable hydrate or solvate thereof) in a therapeutically effective amount.
  • active ingredient i.e. calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate (or a pharmaceutically acceptable hydrate or solvate thereof) in a therapeutically effective amount.
  • a therapeutically effective amount refers to amounts, or concentrations, of the composition (or amounts/ concentrations of active ingredient within such composition) that result in efficacious plasma levels for treating the indicated diseases, in particular PAH and CTEPH.
  • a therapeutically effective amount may be 1 to 200 mg, for example 2 to 150 mg or 5 to 100 mg, and notably 25 mg to 100 mg of calcium; ⁇ 4-[(5,6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate per month.
  • efficacious plasma levels those plasma levels of ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetic acid, that provide effective treatment or effective prevention of the indicated diseases and/or disorders, in particular PAH and CTEPH.
  • the dose (or amount) of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate (or a pharmaceutically acceptable hydrate or solvate thereof) administered also depends on the frequency of the administrations (i.e. the time interval between each administration). Usually, the dose will be higher where administrations are less frequent.
  • subject in particular relates to a human being.
  • Disclosed herein is a method of treating a subject suffering from the above-indicated diseases and/or disorders, in particular PAH and CTEPH, said method comprising the administration of a therapeutically effective amount of a pharmaceutical composition as described herein to a human subject in need thereof.
  • the administration of the present pharmaceutical composition will be via intramuscular or subcutaneous injection.
  • Also disclosed herein is the use of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for the manufacture of a medicament for the treatment of the aboveindicated diseases and/or disorders, in particular PAH and CTEPH, said medicament comprising a therapeutically effective amount of calcium ; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, in the form of an aqueous suspension.
  • Also disclosed herein is the use of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for the manufacture of a medicament for the treatment of the aboveindicated diseases and/or disorders, in particular PAH and CTEPH, said medicament comprising a therapeutically effective amount of calcium ; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, in the form of a lyophilized cake.
  • Also disclosed herein is the use of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for the manufacture of a medicament for the treatment of the aboveindicated diseases and/or disorders, in particular PAH and CTEPH, said medicament comprising a therapeutically effective amount of calcium ; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof having a particle size distribution Dv50 of 1 to 50 pm, preferably 2 to 30 pm or 2 to 20 pm or 5 to 15 pm; a surfactant and/or wetting agent; and a pharmaceutically acceptable aqueous carrier at a pH in the range of 6 to 8.5, in the form of an aqueous suspension.
  • Also disclosed herein is the use of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for the manufacture of a medicament for the treatment of the aboveindicated diseases and/or disorders, in particular PAH and CTEPH, said medicament comprising a therapeutically effective amount of calcium ; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, in the form of an intramuscular or subcutaneous injectable.
  • Also disclosed herein is the use of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, for the manufacture of a medicament for the treatment of the aboveindicated diseases and/or disorders, in particular PAH and CTEPH, said medicament comprising a therapeutically effective amount of calcium ; ⁇ 4-[(5,6-diphenylpyrazin-2- yl)(propan-2-yl)amino]butoxy ⁇ acetate of formula (I), or of a pharmaceutically acceptable hydrate or solvate thereof, wherein said medicament is administered at a time interval of one week to three months, preferably one week or one month or three months.
  • compositions for use as a long acting injectable in the treatment of and/or prevention of pulmonary hypertension wherein the pharmaceutical composition is in the form of an aqueous suspension comprising calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof:
  • said pharmaceutical composition for use as a long acting injectable will be for the treatment of and/or prevention of pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, pulmonary hypertension associated with Fontan disease, or pulmonary hypertension associated with sarcoidosis.
  • Said pharmaceutical composition for use as a long acting injectable may notably be for use in the treatment and/or prevention of pulmonary arterial hypertension (PAH).
  • Said pharmaceutical composition for use as a long acting injectable may also be for use in the treatment and/or prevention of chronic thromboembolic pulmonary hypertension (CTEPH).
  • Said pharmaceutical composition for the previously mentioned uses may be in the form of an intramuscular or subcutaneous injectable.
  • said intramuscular or subcutaneous injectable may be administered at a time interval of one week to three months, notably at a time interval of two weeks to one month.
  • the suspended particles of said intramuscular or subcutaneous injectable may have a particle size distribution Dv50 of 1 to 50 pm, preferably 2 to 30 pm or 2 to 20 pm or 5 to 15 pm.
  • Formula (I) having a particle size distribution Dv50 of 1 to 50 pm, preferably 2 to 30 pm or 2 to 20 pm or 5 to 15 pm.
  • Formula (I) having a particle size distribution Dv50 of 1 to 50 pm, preferably 2 to 30 pm or 2 to 20 pm or 5 to 15 pm, wherein said particles are suspended in an aqueous medium.
  • Said aqueous medium in addition to water, may comprise (i) a surfactant and/or wetting agent; and optionally (ii) a resuspending agent.
  • the pH of said aqueous medium may be in the range of 6 to 9, and in particular in the range of 6 to 8.5.
  • Formula (I) having a particle size distribution Dv50 of 1 to 50 pm, preferably 2 to 30 pm or 2 to 20 pm or 5 to 15 pm, wherein said particles are suspended in an aqueous medium, for use in the treatment of a disease and/or disorder selected from the group consisting of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pressure ulcer (bedsore), hypertension, pulmonary hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, Fontan disease and pulmonary hypertension associated with Fontan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud's disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion/restenosis after percutaneous translumina
  • cardiovascular diseases e.g, myocardial fibrosis
  • bone and articular diseases e.g, bone marrow fibrosis and rheumatoid arthritis
  • skin diseases e.g, cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix
  • obstetric diseases e.g., hysteromyoma
  • urinary diseases e.g., prostatic hypertrophy
  • other diseases e.g., Alzheimer’s disease, sclerosing peritonitis, type I diabetes and organ adhesion after operation
  • erectile dysfunction e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic operation for removing prostate, and vascular
  • Said aqueous medium in addition to water, may comprise (i) a surfactant and/or wetting agent; and optionally (ii) a resuspending agent.
  • the pH of said aqueous medium may be in the range of 6 to 9, and in particular in the range of 6 to 8.5.
  • Formula (I). having a particle size distribution Dv50 of 1 to 50 pm, preferably 2 to 30 pm or 2 to 20 pm or 5 to 15 pm, wherein said particles are suspended in an aqueous medium, for use in the treatment of pulmonary hypertension, especially PAH or CTEPH, wherein said particles suspended in said aqueous medium are for administration by intramuscular or subcutaneous injection.
  • Said aqueous medium in addition to water, may comprise (i) a surfactant and/or wetting agent; and optionally (ii) a resuspending agent.
  • the pH of said aqueous medium may be in the range of 6 to 9, and in particular in the range of 6 to 8.5.
  • said intramuscular or subcutaneous injection is for administration at a time interval of one week to three months, notably at a time interval of two weeks to one month.
  • an investigational drug in the form of an aqueous suspension comprising calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2- yl)amino]butoxy ⁇ acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof:
  • Investigational New Drug or “investigational drug” is meant herein a new drug or biological drug that is used in a clinical investigation.
  • the investigational drug will be used in a clinical investigation regarding the treatment of pulmonary hypertension, in particular PAH or CTEPH.
  • said ID will be safe and efficacious for the treatment of and/or prevention of pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, pulmonary hypertension associated with Fontan disease, or pulmonary hypertension associated with sarcoidosis, notably for the treatment of pulmonary hypertension and in particular the treatment of PAH or CTEPH.
  • Said ID for the previously mentioned uses may be in the form of an intramuscular or subcutaneous injectable.
  • said intramuscular or subcutaneous injectable may be administered at a time interval of one week to three months, notably at a time interval of two weeks to one month.
  • the suspended particles of said intramuscular or subcutaneous injectable may have a particle size distribution Dv50 of 1 to 50 pm, preferably 2 to 30 pm or 2 to 20 pm or 5 to 15 pm.
  • an ID in the form of an aqueous suspension comprising calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof
  • Formula (I) having a particle size distribution Dv50 of 1 to 50 pm, preferably 2 to 30 pm or 2 to 20 pm or 5 to 15 pm.
  • an ID in the form of an aqueous suspension comprising calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof
  • Formula (I) having a particle size distribution Dv50 of 1 to 50 pm, preferably 2 to 30 pm or 2 to 20 pm or 5 to 15 pm, wherein said particles are suspended in an aqueous medium.
  • Said aqueous medium in addition to water, may comprise (i) a surfactant and/or wetting agent; and optionally (ii) a resuspending agent.
  • the pH of said aqueous medium may be in the range of 6 to 9, and in particular in the range of 6 to 8.5.
  • an ID in the form of an aqueous suspension comprising calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof
  • Formula (I). having a particle size distribution Dv50 of 1 to 50 pm, preferably 2 to 30 pm or 2 to 20 pm or 5 to 15 pm, wherein said particles are suspended in an aqueous medium, for use in the treatment of pulmonary hypertension, especially PAH or CTEPH, wherein said particles suspended in said aqueous medium are for administration by intramuscular or subcutaneous injection.
  • Said aqueous medium in addition to water, may comprise (i) a surfactant and/or wetting agent; and optionally (ii) a resuspending agent.
  • the pH of said aqueous medium may be in the range of 6 to 9, and in particular in the range of 6 to 8.5.
  • said intramuscular or subcutaneous injection is for administration at a time interval of one week to three months, notably at a time interval of two weeks to one month.
  • a pharmaceutical composition as described herein can be prepared by a process comprising the steps of:
  • the particle size of the microparticles and/or nanoparticles can be prepared by mechanical means known in the art.
  • a method comprising the steps of dispersing calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof (drug) in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the drug to an average effective particle size of 50 pm or less, in particular to the desired particle size distribution Dv50 as indicated above.
  • the grinding media for the particle size reduction step can be selected from rigid media preferably spherical or particulate in form having an average size less than 3 mm and, more preferably, less than 2 mm, such as 1 mm ⁇ 10%, or 1 mm ⁇ 5%.
  • Examples of grinding media are ZrC>2 such as 95% ZrC>2 stabilized with magnesia or stabilized with yttrium, zirconium silicate, glass grinding media, polymeric beads, stainless steel, titania, alumina and the like.
  • Preferred grinding media have a density greater than 2.5 g/cm 3 and include 95% ZrC>2 stabilized with magnesia and polymeric beads.
  • the particles should be reduced in size at a temperature that does not significantly degrade the drug. Processing temperatures of less than 30 to 40°C are ordinarily preferred. If desired, the processing equipment may be cooled with conventional cooling equipment. The method is conveniently carried out under conditions of ambient temperature and at processing pressures, which are safe and effective for the milling process.
  • the liquid medium for milling comprises a surfactant/wetting agent, optionally a resuspending agent; and a pharmaceutically acceptable aqueous carrier at a pH in the range of 6 to 8.5, to form a premix/predispersion.
  • the surfactant/wetting agent, the optional resuspending agent, and the pharmaceutically acceptable aqueous carrier, including buffering and pH adjusting agents are preferably those described above.
  • the premix/predispersion is over-concentrated, and subsequently diluted to final volume directly before filling.
  • the final formulation is separated from the grinding media by adequate separation methods known in the field.
  • the calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate can be sterilized using gamma irradiation, and used for aseptically manufacturing final drug product.
  • the final drug product can be sterilized using gamma irradiation or heat sterilization, e.g. autoclaving (steam sterilising) at elevated temperatures.
  • Suitable conditions for autoclavation are 15 min at 121-124 °C ( ⁇ 2 °C). A pressure is built up to allow for the desired temperature. Conditions relating to validation as prescribed in the Pharmacopeia, e.g. “US Pharmacopeia”, or “The International Pharmacopoeia, Ninth Edition 2019”, etc. should be taken into account.
  • Suitable conditions for gamma irradiation are achieved by exposure to ionizing radiation in the form of gamma radiation from a suitable radioisotopic source such as 60 Co (cobalt 60) or of electrons energized by a suitable electron accelerator.
  • Suitable conditions are radiation levels of 5 to 40 kGy, for instance 5 kGy, 25 kGy or 40 kGy.
  • Conditions relating to validation as prescribed in the Pharmacopeia e.g. “US Pharmacopeia”, or “The International Pharmacopoeia, Ninth Edition 2019”, etc. should be taken into account.
  • a process for preparing a sterile pharmaceutical composition as described above, wherein the pharmaceutical composition is sterilized with autoclavation (steam sterilisation), or with gamma-irradiation; or wherein calcium ; ⁇ 4-[(5, 6- diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate is sterilised with gamma-irradiation and which is then used for preparing the pharmaceutical composition.
  • a sterile pharmaceutical composition is obtainable by said process.
  • the bioindicator strain proposed for validation of autoclavation (steam sterilisation) process is: spores of Bacillus stearothermophilus (e.g. ATCC 7953 or CIP 52.81) for which the D-value (i.e. 90% reduction of the microbial population) is 1.5-2 minutes at 121 °C, using about 106 spores per indicator.
  • bioindicator strains proposed for validation of gamma-irradiation sterilisation process in general are: spores of Bacillus pumilus (e.g. ATCC 27142 or CIP 77.25) with 25 kGy (2.5 Mrad) for which the D-value is about 3 kGy (0.3 Mrad) using 107-108 spores per indicator; for higher doses, spores of Bacillus cereus (e.g. SSI C 1/1) or Bacillus sphaericus (e.g. SSI C1A) are used.
  • compositions as described herein can further be lyophilized, i.e. freeze-dried, and a lyophilized injectable composition will be obtained.
  • the pharmaceutical composition will, prior to freeze drying, preferably be filled into containers (unit dose or multi-dose containers such as vials) suitable for storage of the lyophilized cake, and suitable for the later reconstitution of the pharmaceutical composition.
  • containers may be filled under an inert gas atmosphere (such as notably a nitrogen atmosphere).
  • inert gas atmosphere may reduce oxidative degradation of the active ingredient.
  • a further embodiment thus relates to a container such as for example a vial, an ampoule, a syringe, a coupled chamber device, a pen device, or an autoinjector device, especially a vial, filled with a pharmaceutical composition as described above.
  • the steps for lyophilisation/freeze-drying of the pharmaceutical composition in the form of an aqueous suspension as described herein comprise a step of freezing the pharmaceutical composition in a container, and drying it by applying a vacuum.
  • the freezing temperature is in the range from -55°C to -35°C, preferably from -50°C to -35°C, preferably from -45°C to -35°C; for instance -40°C ⁇ 3°C.
  • the drying temperature is in the range from -55°C to +30°C, preferably from -50°C to 28°C, preferably from -45°C to 28°C.
  • the freezing and the drying temperature may be applied as a fixed temperature, or as a temperature ramp.
  • the end temperatures of each procedural step are reached via a temperature ramp.
  • a vacuum is applied to the pharmaceutical composition.
  • a vacuum of 0.05 to 1.5 mbar is applied, for instance 0.1 mbar. The vacuum is applied after the freezing step, and during drying.
  • the drying procedure may be divided into several steps, for instance a primary drying step, and a secondary drying step, whereby each step may be followed by a holding step, i.e. holding the pharmaceutical composition at the temperature and pressure reached at the end of the preceding drying step.
  • the container can be stoppered after the freeze-drying procedure. Stoppering the container may further include a step of capping the container.
  • the method of freeze-drying preferably comprises the following steps: a) preparing an aqueous pharmaceutical composition as described above; and b) freeze-drying said aqueous pharmaceutical composition to form a cake using a method comprising the steps of:
  • step (ii) optionally holding the frozen composition at the temperature of step (i);
  • step (iii) applying a primary drying step by subjecting the frozen composition at the temperature of step (i) or (ii) to a vacuum (preferably a vacuum of 0.05 to 1.5 mbar), and applying a temperature ramp in the range from -55°C to -25°C; preferably from -50°C to -25°C, preferably from -45°C to -25°C, for instance from -40°C ⁇ 3°C to -20°C ⁇ 3°C;
  • step (iv) optionally holding the frozen composition at the end temperature of step (iii) under vacuum (preferably a vacuum of 0.05 to 1.5 mbar);
  • step (v) applying a secondary drying step by subjecting the composition of step (iii) or (iv) to a vacuum (preferably a vacuum of 0.05 to 1.5 mbar), and applying a temperature ramp, starting with the end-temperature of step (iii) or step (iv) and proceeding to a temperature in a range from 15°C to 30°C, preferably from 20°C to 28°C, for instance 25°C ⁇ 3°C;
  • step (vi) optionally holding the end-temperature of step (v) and the vacuum;
  • This method may be applied to a pharmaceutical composition as described above, contained in a container, whereby the container is stoppered, and optionally capped, after releasing of the vacuum.
  • cake refers to a dry solid material that results when a liquid formulation has been lyophilized or freeze dried.
  • the pharmaceutical compositions as described herein can be in the form of a lyophilised pharmaceutical composition.
  • it can be a lyophilised pharmaceutical composition obtainable by the lyophilisation process described above, e.g. by freezing the pharmaceutical composition in a container, and drying it by applying a vacuum.
  • the lyophilised pharmaceutical composition as described herein may be reconstituted by adding at least one diluent to said lyophilised pharmaceutical composition to provide a reconstituted pharmaceutical composition.
  • Suitable diluents to reconstitute said pharmaceutical composition include any diluent that is a safe, stable and pharmaceutically acceptable carrier.
  • Preferred is water for injection (WFI) such as especially sterile water for injection (SWFI) or bacteriostatic water for injection (BWFI), optionally containing a tonicity modifier, or mixtures of several tonicity modifiers, such as aqueous (preferably physiological) saline.
  • composition “comprising” encompasses “including” as well as “consisting”, e.g. a composition “comprising” X may consist exclusively of X or may include something additional, e.g. X + Y.
  • composition “comprising” used herein also encompasses “consisting essentially of”, e.g. a composition “comprising” X may consist of X and any other components that do not materially affect the essential characteristics of the composition.
  • Y is optional and means, for example, Y ⁇ 10%.
  • a time interval When a time interval is expressed as a specified number of months, it runs from a given numbered day of a given month to the same numbered day of the month that falls the specified number of months later. Where the same numbered day does not exist in the month that falls the specified number of months later, the time interval runs into the following month for the same number of days it would have run if the same numbered day would exist in the month that falls the specified number of months later.
  • a time interval is expressed as a number of years, it runs from a given date of a given year to the same date in the year that falls the specified number of years later.
  • the time interval runs for the same number of days it would have run if the same numbered day would exist in the month that falls the specified number of years later. In other words, if the time interval starts on 29th February of a given year but ends in a year where there is no 29th February, the time period ends instead on 1st March in that year.
  • the term “about” in relation to such a definition means that the time interval may end on a date that is ⁇ 10% of the time interval.
  • the time interval may start up to 7 days before or after the start of the time interval and end up to 7 days before or after the end of the time interval.
  • TweenTM 20 has been used.
  • PSD PSD was measured with a Malvern Mastersizer 3000 apparatus from Malvern Panalytical using the laser diffraction measurement method and the Mie theory. The results of the laser diffraction analysis are reported based on the particle size volume distribution as the cumulative undersize values Dv50. The following settings were used:
  • Example 1 Discriminating between different particle sizes
  • the dissolution of the suspensions was tested using a paddle apparatus (USP type 2, Ph. Eur, JP) with a rotation speed of 50 rpm in 900 mL 0.15% w/v polysorbate 20 in 0.05 M sodium phosphate buffer pH 7 at 5 °C.
  • the sample amount corresponds to 25 mg calcium salt of ACT-333679.
  • the quantity of dissolved drug substance was determined by a gradient ultra-high performance liquid chromatographic (LIHPLC) method with UV detection at 300 nm.
  • LIHPLC ultra-high performance liquid chromatographic
  • the dissolution method provides a convenient method of quality control of batches of calcium; ⁇ 4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy ⁇ acetate, or a pharmaceutically acceptable hydrate or solvate thereof, in the form of microparticles and/or nanoparticles.
  • the use of a 2-minute sampling time point was found to provide a dissolution profile with a low onset.
  • the method is able to detect a potential burst release.
  • the dissolution of suspensions comprising calcium salt of ACT-333679 having a Dv50 of 0.1 pm was measured using a paddle apparatus (USP type 2, Ph. Eur, JP) with a rotation speed of 50 rpm in 900 mL.
  • Two dissolution mediums were tested, one at pH 7 and comprising 0.05 M sodium phosphate buffer and 0.15 % w/v polysorbate 20, and the other at pH 9 and comprising 0.05 M borate buffer and 0.3 % w/v polysorbate 20.
  • the dissolution profiles are shown in Figure 2.
  • the dissolution of suspensions comprising calcium salt of ACT-333679 having a Dv50 of 7 pm was measured using a paddle apparatus (USP type 2, Ph. Eur, JP) with a rotation speed of 50 rpm in 900 mL.
  • the dissolution mediums were at pH 7 and comprised 0.05 M sodium phosphate buffer. Mediums comprising different concentrations of polysorbate 20 surfactant were used at different temperatures.
  • the dissolution profiles are shown in Figures 3(a)-(c):
  • dissolution medium temperatures below the physiological temperature of 37 °C was found to be crucial to the ability of the dissolution test to discriminate between different particle sizes of calcium salt of ACT-333679.
  • the calcium salt of ACT-333679 is rapidly dissolved to completion in around 60 minutes.
  • the use of lower temperatures slowed the release of calcium salt of ACT-333679 to such an extent that the discriminative power of the method was significantly increased.
  • the drug substance is less than or around equal to 40% dissolved at 5 minutes, thereby allowing the detection of potential initial increased (burst) release.
  • the delta % dissolved is more significant at lower temperatures.
  • the delta % dissolved is approximately 50 % at 5 °C compared to approximately 27 % at 37 °C.
  • the dissolution of suspensions comprising calcium salt of ACT-333679 having a Dv50 of 11.5 pm was measured using a paddle apparatus (USP type 2, Ph. Eur, JP) with a rotation speed of 50 rpm in 900 mL.
  • the dissolution mediums were at pH 7 and comprised 0.05 M sodium phosphate buffer.
  • Mediums comprising polysorbate 20 at 0.05 % w/v and 0.1 % w/v were used at temperatures of 5 °C and 25 °C; the resulting dissolution profiles are shown in Figure 4.
  • the use of the low temperature of 5 °C was found to enable the concentration of polysorbate 20 to be varied to result in dissolution profiles that are further optimised.
  • the performance of each method can also be defined by calculating the difference between the lowest and highest %dissolved in the dissolution profile, i.e. the delta % dissolved.
  • the delta % dissolved of the 0.1% polysorbate 20 method is higher than the 0.05% polysorbate 20 method at 5 °C.
  • the higher the % dissolved the higher the ability of the method to discriminate between different particle sizes of calcium salt of ACT- 333679.
  • the dissolution was too rapid even with a low polysorbate 20 concentrations of 0.05%, 0.075%, and 0.1% to allow for further optimisation by varying the concentration.
  • the addition of the calcium salt was found to improve the ability of the dissolution test to discriminate between different particle sizes of calcium salt of ACT-333679 for suspensions with a range of surfactant concentrations. For instance, as shown in Figure 6, for suspensions with 7 % w/v polysorbate 20, the calcium salt of ACT-333679 is rapidly dissolved to completion in around 60 minutes. However, the addition of 20 g/L CaCh slowed the release of calcium salt of ACT-333679 and lowered the onset of the dissolution profile. With the addition of 20 g/L CaCh for suspensions with all surfactant concentrations tested, the drug substance is less than or around equal to 40% dissolved at 2 minutes, thereby allowing the detection of potential initial increased (burst) release.
  • dissolution medium temperatures below the physiological temperature of 37 °C were found to be crucial to the ability of the dissolution test to discriminate between different particle sizes of calcium salt of ACT-333679.
  • test example A (37 °C) had a dissolution of about 70 % after 60 minutes, whereas test examples B and C (5 °C and -5 °C, respectively) had dissolutions of about 45% and 35%, respectively after 60 minutes.
  • the use of lower temperatures slowed the release of calcium salt of ACT-333679 to provide a method with suitable discriminative power.
  • the dissolution onset (the first datapoint at 2 minutes) was significantly lower for test examples B and C than A, showing the improved ability of the method to detect burst release compared to typical physiological temperatures.
  • the dissolution onset was lowest at the lowest temperature of -5°C, showing how the ability to detect burst release can be further optimised within the scope of the invention.
  • test example D (37 °C) had a dissolution of about 70 % after 60 minutes
  • test examples E and F (5 °C and -5 °C, respectively) had dissolutions of about 30% and 20%, respectively after 60 minutes.
  • the use of lower temperatures slowed the release of calcium salt of ACT-333679 to provide a method with suitable discriminative power and the ability to detect burst release.
  • the dissolution onset is lower for test example G (-2 °C) than for test example H (5 °C), showing the ability to further optimise the detection of burst release by reducing the temperature of a medium comprising phosphate buffer without NaCI.
  • a medium comprising phosphate buffer without NaCI When the phosphate buffer is replaced with 10 % and 20 % NaCI in demineralised water and the temperature is reduced to -5 °C (test examples C and F, respectively), a further decrease in the dissolution onset is observed.

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Abstract

La présente invention concerne le test d'échantillons comprenant du calcium ; {4- [(5,6-diphénylpyrazin-2-yl) (propan-2-yl) amino] butoxy} acétate, ou un hydrate ou solvate pharmaceutiquement acceptable de celui-ci, sous la forme de microparticules et/ou de nanoparticules, telles que des suspensions, et la mesure de la dissolution du calcium ; {4- [(5,6-diphénylpyrazin-2-yl) (propan-2-yl) amino] butoxy} acétate, ou un hydrate ou solvate pharmaceutiquement acceptable de celui-ci, dans un milieu aqueux. La présente invention concerne également le test de contrôle de qualité desdits échantillons et la libération de lots comprenant lesdits échantillons pour un usage pharmaceutique. La présente invention concerne également un milieu destiné à être utilisé dans un test de dissolution.
PCT/EP2023/087180 2022-12-22 2023-12-21 Test de dissolution in vitro Ceased WO2024133620A1 (fr)

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