WO2017121806A1 - Composition pharmaceutique de selexipag - Google Patents

Composition pharmaceutique de selexipag Download PDF

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Publication number
WO2017121806A1
WO2017121806A1 PCT/EP2017/050572 EP2017050572W WO2017121806A1 WO 2017121806 A1 WO2017121806 A1 WO 2017121806A1 EP 2017050572 W EP2017050572 W EP 2017050572W WO 2017121806 A1 WO2017121806 A1 WO 2017121806A1
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Prior art keywords
selexipag
solid dispersion
pharmaceutically acceptable
acceptable excipient
solvent
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PCT/EP2017/050572
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English (en)
Inventor
Nolwenn Martin
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Sandoz Ag
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Priority claimed from EP16151562.2A external-priority patent/EP3192502A1/fr
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of WO2017121806A1 publication Critical patent/WO2017121806A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to a solid dispersion comprising amorphous selexipag and methods for preparing the same.
  • the invention also concerns a pharmaceutical composition comprising an effective amount of said solid dispersion and at least one further pharmaceutically acceptable excipient as well as methods for its preparation.
  • the pharmaceutical composition of the present invention may be used as a medicine in particular for the treatment of pulmonary arterial hypertension.
  • the diphenylpyrazin derivative selexipag known under the chemical name 2-[4-[A ⁇ -(5,6-diphenylpyrazin-2-yl)- - isopropylamino]butyloxy]-A ⁇ -(methylsulfonyl)acetamide can be represented by the following chemical structure according to Formula (A):
  • Selexipag previously also known as NS-304 or ACT-293987, is a potent orally available and highly selective long acting non-prostanoid prostaglandin 12 (PGI-2) receptor agonist, and has been filed for approval in the E.U. and in the U.S. by Actelion for the treatment of pulmonary arterial hypertension. As a prodrug it is in vivo transformed by the liver to its active metabolite.
  • PGI-2 non-prostanoid prostaglandin 12
  • Phase II clinical trials are also ongoing for the treatment of chronic thromboembolic pulmonary hypertension and arteriosclerosis obliterans.
  • Selexipag stimulates PGI-2 receptors in blood vessels and has been described to show, for example, vasodilating effects, bronchodilative effects and a lipid deposition inhibitory effect.
  • WO 2010/150865 Al discloses three crystalline forms of selexipag, designated form I, form II and form III. It is described that these forms were obtained either in pure form or as binary mixtures from a polymorph screening using 32 different solvents and 16 different solvent mixtures (see test example 4).
  • the crystalline forms of WO 2010/150865 are described as useful for the preparation of pharmaceutical formulations and oral dosage forms, such as tablets comprising crystalline selexipag, are described. It should be noted that amorphous selexipag was only described in one single experiment using 1,3,5-trimethylbenzene as solvent (table 4, experiment 30) in WO 2010/150865.
  • amorphous forms are thermodynamically metastable with respect to the crystalline state. Above their glass transition temperatures (Tg) amorphous materials show a high tendency towards crystallization. Crystallization is often accelerated by water adsorption because the plasticizing effect of water results in a decrease of the glass transition temperature. While amorphous solids have increased solubility and an accelerated dissolution rate in comparison to their crystalline counterparts, crystalline solid forms of an active pharmaceutical ingredient are often preferred for the preparation of pharmaceutical compositions, such as tablets, for various reasons such as stability with respect to the solid form or chemical stability or ease of handling during formulation of a pharmaceutical. As a consequence, slower dissolution and lower bioavailability of the drug are consciously accepted and pharmaceutical compositions, which are maybe not optimal with regard to these parameters, are produced and marketed.
  • the present inventors have realized that selexipag has a high tendency to crystallize.
  • the present inventors have then managed to prepare stable pharmaceutical compositions comprising amorphous selexipag despite selexipag's high tendency to crystallize.
  • the pharmaceutical compositions of the present invention are advantageous compared to pharmaceutical compositions comprising crystalline selexipag in that their faster dissolution can lead to a faster onset of action, which can be beneficial for the treatment of a disease like pulmonary arterial hypertension.
  • One objective of the present invention is thus to provide a pharmaceutical composition comprising an effective amount of amorphous selexipag which retains its amorphous character upon storage, for example throughout its shelf-life.
  • selexipag has a high tendency to crystallize. It was then surprisingly found that amorphous selexipag can be stabilized in the context of a solid dispersion further comprising at least one pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient is (i) a polymer, or (ii) a silicon-based inorganic adsorbent.
  • a solid dispersion with a particular polymer or using silica carriers and amorphous selexipag can be formed in that way. Therefore, the present invention relates to solid dispersions of amorphous selexipag with specific polymer and silica carriers respectively and to methods for their preparation.
  • the invention also relates to a pharmaceutical composition comprising an effective amount of amorphous selexipag, and to a method for the preparation thereof.
  • room temperature refers to temperatures in the range of from 20 to 30 °C.
  • amorphous is used for non-crystalline material, which lacks long-range inter-molecular order.
  • Amorphous solids are generally isotopic, i.e. exhibit similar properties in all directions. When analyzed by powder X-ray diffraction, no sharp characteristic peaks are observed, but instead one or several broad peaks (e.g. "halos") appear.
  • Figure 1 is an example of a powder X-ray diffraction pattern of an amorphous solid.
  • solid dispersion refers to a system in a solid state (as opposed to a liquid or gaseous state) wherein one component is dispersed more or less evenly throughout the other component or components, e.g. in the context of the present invention amorphous selexipag within the pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient is (i) a polymer, or (ii) a silicon-based inorganic adsorbent.
  • Preferred solid dispersions are "solid solutions", where the dispersion of the components is such that the system is chemically and physically uniform or homogeneous throughout or even consists of one phase as defined by measurement of thermodynamic properties of the system, e.g.
  • the amorphous selexipag and the pharmaceutically acceptable excipient wherein the at least one pharmaceutically acceptable excipient is (i) a polymer, or (ii) a silicon- based inorganic adsorbent, form a system that is chemically and physically uniform or homogeneous throughout or even consists of one phase as defined by measurement of thermodynamic properties of the system.
  • glass transition temperature corresponds to a change in physical state from a glassy (rigid, highly viscous, brittle) material to a more fluid or malleable rubbery state
  • reflection with regards to powder X-ray diffraction as used herein, means peaks in an X-ray diffractogram, which are caused at certain diffraction angles (Bragg angles) by constructive interference from X-rays scattered by parallel planes of atoms in solid material, which are distributed in an ordered and repetitive pattern in a long-range positional order.
  • a solid material is classified as crystalline material, whereas amorphous material is defined as solid material, which lacks long-range order and only displays short-range order (also see explanation above), thus resulting in broad scattering.
  • long-range order e.g.
  • the term "essentially the same" with reference to powder X-ray diffraction (PXRD) means that variabilities in peak positions and relative intensities of the peaks are to be taken into account.
  • a typical precision of the 2- Theta values is in the range of ⁇ 0.2° 2-Theta.
  • a diffraction peak that usually appears at 9.0° 2-Theta for example can appear between 8.8° and 9.2° 2-Theta on most X-ray diffractometers under standard conditions, that is when measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm.
  • relative peak intensities will show inter- apparatus variability as well as variability due to degree of crystallinity, preferred orientation, sample preparation and other factors known to those skilled in the art and should be taken as qualitative measure only.
  • a reference to X-ray powder diffraction patterns means that they were measured / are to be measured at a temperature in the range of from 15 to 25 °C with radiation having a wavelength of 0.15419 nm.
  • the terms "essentially pure” or “substantially pure” with reference to a physical form of selexipag means that the physical form includes less than about 10%, more preferably less than about 5%, even more preferably less than about 3%, and most preferably less than about 1% by weight of any other physical form of selexipag.
  • mother liquor refers to the solution remaining after crystallization of a solid.
  • Figure 1 Representative PXRD of amorphous selexipag prepared according to the procedure described in
  • the X-axis shows the 2-theta angle / °, with tick marks, from left to right, at 10, 20, 30 ° 2-theta.
  • the Y-axis shows the intensity / counts, with tick marks, from bottom to top, at 500, 1000.
  • Figure 2 Representative PXRD of amorphous selexipag prepared according to the procedure described in comparative example 1 herein, after 6 weeks at 40 °C and 75% RH.
  • the X-axis shows the 2-theta angle / °, with tick marks, from left to right, at 10, 20, 30 ° 2-theta.
  • the Y-axis shows the intensity / counts, with tick marks, from bottom to top, at 500, 1000.
  • Figure 3 Representative PXRD of amorphous solid dispersion of selexipag and HPMCAS prepared according to the procedure described in Example 1 herein.
  • the X-axis shows the 2-theta angle / °, with tick marks, from left to right, at 10, 20, 30 ° 2-theta.
  • the Y-axis shows the intensity / counts, with tick marks, from bottom to top, at 500, 1000.
  • Figure 4 Representative PXRD of amorphous solid dispersion of selexipag and HPMCAS after storage at 40
  • the X-axis shows the 2-theta angle / °, with tick marks, from left to right, at 10, 20, 30 ° 2-theta.
  • the Y-axis shows the intensity / counts, with tick marks, from bottom to top, at 500, 1000.
  • Figure 5 Representative PXRD of selexipag o-xylene solvate prepared according to Example 2 herein.
  • X-axis shows the 2-theta angle / °, with tick marks, from left to right, at 10, 20, 30 ° 2-theta.
  • the Y-axis shows the intensity / counts, with tick marks, from bottom to top, at 500, 1000, 1500.
  • Figure 6 Representative PXRD of selexipag chlorobenzene solvate prepared according to Example 3.1 herein.
  • the X-axis shows the 2-theta angle / °, with tick marks, from left to right, at 10, 20, 30 ° 2-theta.
  • the Y-axis shows the intensity / counts, with tick marks, from bottom to top, at 500, 1000.
  • Figure 7 Representative PXRD of selexipag chlorobenzene solvate prepared according to Example 3.2 herein.
  • the X-axis shows the 2-theta angle / °, with tick marks, from left to right, at 10, 20, 30 ° 2-theta.
  • the Y-axis shows the intensity / counts, with tick marks, from bottom to top, at 500, 1000.
  • Figure 8 Representative PXRD of selexipag toluene solvate prepared according to Example 4 herein.
  • the X- axis shows the 2-theta angle / °, with tick marks, from left to right, at 10, 20, 30 ° 2-theta.
  • the Y-axis shows the intensity / counts, with tick marks, from bottom to top, at 1000, 2000, 3000.
  • Figure 9 Dissolution profile of pharmaceutical compositions comprising solid dispersion of selexipag prepared according to Example 1B-2, Example lC-1, Example lC-2, Comparative Example 1-2 and Comparative Example 1-3. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention relates to a solid dispersion comprising amorphous selexipag and at least one pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient is (i) a polymer, or (ii) a silicon-based inorganic adsorbent.
  • the characteristic powder X-ray diffraction pattern of selexipag form I comprises peaks at 2-theta angles of 9.4 ⁇ 0.2°, 9.8 ⁇ 0.2°, 17.2 ⁇ 0.2° and 19.4 ⁇ 0.2°.
  • the characteristic X-ray powder diffraction pattern of selexipag form II comprises peaks at 2-theta angles of 9,0 ⁇ 0.2°, 12.9 ⁇ 0.2°, 20.7 ⁇ 0.2° and 22.6 ⁇ 0.2°.
  • the characteristic X-ray powder diffraction pattern of selexipag form III comprises peaks at 2-theta angles of 9.3 ⁇ 0.2°, 9.7 ⁇ 0.2°, 16.8 ⁇ 0.2°, 20.6 ⁇ 0.2°, and 23.5 ⁇ 0.2°.
  • the present invention circumvents the drawback of the known crystalline forms of selexipag, i.e. forms I, II and III, by providing a solid dispersion comprising amorphous selexipag and at least one pharmaceutically acceptable excipient as matrix material, wherein the at least one pharmaceutically acceptable excipient is (i) a polymer, or (ii) a silicon-based inorganic adsorbent.
  • the solid dispersion of the present invention is obtainable as a solid dispersion that is stable and pure with regard to the physical form of amorphous selexipag.
  • the selexipag in the context of the solid dispersion of the present invention is stable in the amorphous state upon storage, as judged by the absence of characteristic PXRD peaks after storage.
  • Amorphous selexipag itself readily converts to a mixture comprising selexipag form II and selexipag form III upon storage for as short as one week only.
  • Solid in the amorphous stage upon storage within the meaning of the present invention means that the solid dispersion of the present invention after storage at a relative humidity of 45% at 23°C for 14 days, preferably even after storage for 50 days, shows no signs of the presence of crystalline selexipag as judged by the absence of peaks at 2-theta angles of 9,0 ⁇ 0.2°, 12.9 ⁇ 0.2°, 20.7 ⁇ 0.2° and 22.6 ⁇ 0.2° or as judged by the absence of peaks at 2-theta angles of 9.3 ⁇ 0.2°, 9.7 ⁇ 0.2°, 16.8 ⁇ 0.2°, 20.6 ⁇ 0.2°, and 23.5 ⁇ 0.2°.
  • the solid dispersion of the present invention after storage at a relative humidity of 45% at 23°C for 14 days shows no signs of the presence of any one of the known forms I, II and III of crystalline selexipag, as judged by the absence of peaks at 2-theta angles of 9.4 ⁇ 0.2°, 9.8 ⁇ 0.2°, 17.2 ⁇ 0.2° and 19.4 ⁇ 0.2° (form I), 9.0 ⁇ 0.2°, 12.9 ⁇ 0.2°, 20.7 ⁇ 0.2° and 22.6 ⁇ 0.2° (form II), and 9.3 ⁇ 0.2°, 9.7 ⁇ 0.2°, 16.8 ⁇ 0.2°, 20.6 ⁇ 0.2°, and 23.5 ⁇ 0.2° (form III) in an powder X-ray diffractogram (PXRD).
  • PXRD powder X-ray diffractogram
  • Solid in the amorphous state upon storage under stress conditions in the context of the present invention means that the solid dispersion of the present invention when stored at a relative humidity of 70 % at 40 °C for 14 days, preferably after storage for 50 days, shows no signs of the presence of crystalline selexipag as judged by the absence of peaks at 2-theta angles of 9,0 ⁇ 0.2°, 12.9 ⁇ 0.2°, 20.7 ⁇ 0.2° and 22.6 ⁇ 0.2°, or as judged by the absence of peaks at 2-theta angles of 9.3 ⁇ 0.2°, 9.7 ⁇ 0.2°, 16.8 ⁇ 0.2°, 20.6 ⁇ 0.2°, and 23.5 ⁇ 0.2°, and in particular shows no signs of the presence of any one of the known forms I, II and III of crystalline selexipag, as judged by the absence of peaks at 2-theta angles of 9.4 ⁇ 0.2°, 9.8 ⁇ 0.2°, 17.2 ⁇ 0.2° and 19.
  • the solid dispersion of the present invention is a solid dispersion wherein the amorphous selexipag is stable in the amorphous physical form upon storage. More preferably, the solid dispersion of the present invention is a solid dispersion wherein the amorphous selexipag is stable in the amorphous physical form upon storage under stress conditions.
  • the solid dispersion of the invention itself is amorphous, i.e. that the solid dispersion of the present invention does not only show no sign of the presence of any crystalline selexipag, but that the solid dispersion comprising amorphous selexipag and at least one pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient is (i) a polymer, or (ii) a silicon-based inorganic adsorbent, shows no characteristic peak, preferably no peak, in an PXRD. It is more preferred that the amorphous solid dispersion is stable in the amorphous physical form upon storage, and in particular upon storage under stress conditions.
  • the pharmaceutically acceptable excipient is an organic polymer, preferably a hydrophilic organic polymer.
  • the at least one organic polymer is a homopolymer and/or copolymers. Polymers that contain only a single type of repeat unit are known as homopolymers, while polymers containing a mixture of repeat units are known as copolymers.
  • hydrophilic organic polymers include, but are not restricted to, polysaccharides, preferably cellulose derivatives, polyvinylpyrrolidones, polyethylene glycols, polyethylene glycol based copolymers, polyacrylic acids, salts of polyacrylic acids, polyvinyl alcohols, polyacrylamide copolymers, methacrylic acid copolymers, methacrylate copolymers, pectines, chitin derivatives, chitosan derivatives, polyphosphates, polyoxazolines, polyvinyl caprolactam-polyvinyl acetate -polyethylene glycol copolymers, and mixtures of two or more thereof.
  • hydrophilic polymers include, but are not restricted to, a cellulose derivative selected from the group consisting of alkylcellulose, preferably methylcellulose, ethylcellulose, or propylcellulose; hydroxyalkylcellulose, preferably hydroxymethylcellulose, hydroxyethylcellulose, or hydroxypropylcellulose; hydroxyalkylalkylcellulose, preferably hydroxyethylmethylcellulose (HEMC), or hydroxypropylmethylcellulose (HPMC); carboxyalkylcellulose, preferably carboxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxyethylcarboxymethylcellulose (HECMC); sodium carboxymethylcellulose, cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose acetate (HPMCA), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and a mixture of two or more thereof.
  • alkylcellulose preferably methylcellulose, ethylcellulose
  • the at least one hydrophilic, organic polymer comprises, preferably consists of a cellulose derivative selected from the group consisting of hydroxyalkylalkylcelluloses derivatives and a mixture of two or more thereof.
  • Hydroxypropylmethylcellulose acetate succinate (HPMCAS) and hydroxypropylcellulose are particularly preferred.
  • the polymer is a polyvinylcaprolactam-polyvinylacetate-polyethyleneglycol copolymer
  • the polymer is preferably a graft polymer.
  • graft polymer refers to a branched copolymer in which the side chains are structurally distinct from the main chain.
  • these graft polymers are based on polyethers and are obtained via free radical polymerization of the vinyl monomers in the presence of polyethers.
  • a vinylcapro lactam and vinylacetate are used as vinyl monomers. Graft polymers of this type are commercially available as Soluplus ® from BASF.
  • the pharmaceutically acceptable excipient is a silicon-based inorganic compound.
  • silicon-based inorganic compounds include, but are not restricted to, silica, silicates, and a combination of two or more thereof.
  • the silicon-based inorganic adsorbent is selected from the group consisting of silicas and combinations of two or more thereof; or from the group consisting of silicates and combinations of two or more thereof; or from the group consisting of at least one silica and at least one silicate.
  • silicate as used in this context of the present invention refers to naturally occurring or synthesized compounds containing an anionic silicon compound, preferably an oxide.
  • silicates include, but are not restricted to, nesosilicates comprising the structure unit [S1O4] 4" , sorosilicates comprising the structure unit [S12O7] 6" , cyclosilicates comprising the structure unit [Si n 03n] 2n ⁇ , single chain inosilicates comprising the structure unit [Si n 03n] 2n ⁇ , double chain inosilicates comprising the structure unit [Si4nOii n ] 6n ⁇ , phyllosilicates comprising the structure unit [SinOsn] 2 "-, or tectosilicates with a 3D framework comprising the structure unit [Al x Si y 02(x+ y )] x" .
  • silica refers to naturally occurring or synthesized silica. Examples of such silica include, but are not restricted to fumed silica, precipitated silica, gel silica, colloidal silica.
  • Silicon-based inorganic compounds are preferred which have a pH in a defined range, preferably a pH of at least 6.0. More preferably, the at least one silicon-based compound has a pH in the range of from 6.0 to 9.0, more preferably in the range of from 6.5 to 8.5, more preferably in the range of from 7.0 to 8.0.
  • the solid dispersion of the present invention contains at least one silicon-based inorganic adsorbent having a pH in the above -defined preferred ranges and at least one silicon-based inorganic adsorbent having a pH outside these ranges.
  • all silicon-based inorganic adsorbents comprised in the solid composition of the present invention have a pH in the above-defined preferred ranges.
  • the solid dispersion according to the present invention can also comprise at least one hydrophilic, organic polymer and at least one silicon-based inorganic compound. Generally, it is possible that the solid dispersion contains at least one hydrophilic, organic polymer and at least one silicon-based inorganic adsorbent.
  • the weight ratio of selexipag and the pharmaceutically acceptable excipient is from 1.0 : 0.5 to 1.0 : 8.0, such as 1.0 : 0.5 to 1.0 : 5.0, for example 1.0 : 0.5 to 1.0 : 3.0.
  • the weight ratio is calculated based on the total amount of selexipag present in said solid dispersion and based on the total amount of the pharmaceutically acceptable excipients present in said solid dispersion, i.e. if two or more pharmaceutically acceptable excipients are present in the solid dispersion of the present invention, the combined weight of these is taken for the calculation of the weight ratio.
  • a preferred weight ratio is from 1.0 : 0.5 to 1.0 : 2.0.
  • the solid dispersion of the present invention is a solid dispersion wherein amorphous selexipag is chemically stable.
  • amorphous selexipag present in the solid dispersion of the present invention shows very little degradation upon storage under stress conditions, i.e. when stored at a relative humidity of 70 % at 40 °C for 14 days, preferably after storage for 50 days.
  • the at least one pharmaceutically acceptable excipient used as matrix component is at least one hydrophilic, polymer, preferably consists of at least one, more preferably one, hydrophilic, organic polymer.
  • the present invention also relates to a solid dispersion comprising amorphous selexipag according to formula (I) and at least one pharmaceutically acceptable excipient wherein at least 99 weight-% of the selexipag comprised in the solid dispersion are present in amorphous form, at least 99 weight-% of the solid dispersion consist of the selexipag and the at least one pharmaceutically acceptable excipient, and wherein the at least one pharmaceutically acceptable excipient is a hydrophilic, organic polymer.
  • hydrophilic, organic polymers include, but are not restricted to, polysaccharides, preferably cellulose derivatives, polyvinylpyrrolidones, polyethylene glycols, polyethylene glycol based copolymers, polyacrylic acids, salts of polyacrylic acids, polyvinyl alcohols, polyacrylamide copolymers, methacrylic acid copolymers, methacrylate copolymers, pectines, chitin derivatives, chitosan derivatives, polyphosphates, polyoxazolines, polyvinyl caprolactam-polyvinyl acetate -polyethylene glycol copolymers, and mixtures or combinations of two or more thereof.
  • polysaccharides and derivatives of polysaccharides are preferred.
  • the polysaccharides can be homoglycans or heteroglycans. Further, the polysaccharides can be naturally occurring compounds or synthesized compounds.
  • compounds are preferred which are derivatized at one or more hydroxyl groups of the monosaccharide units of the polysaccharides.
  • Polysaccharides and derivatives of polysaccharides include, but are not restricted to, cellulose and cellulose derivatives, such as alkylcellulose, such as methylcellulose, ethylcellulose, or propylcellulose; hydroxyalkylcellulose, such as hydroxymethylcellulose, hydroxyethylcellulose, or hydroxypropylcellulose; hydroxyalkylalkylcellulose, such as hydroxyethylmethylcellulose (HEMC), or hydroxypropylmethylcellulose (HPMC); carboxyalkylcellulose, such as carboxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxyethylcarboxymethylcellulose (HECMC); sodium carboxymethylcellulose, cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose acetate (HPMCA), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and a mixture or combination of two or more thereof.
  • alkylcellulose such as
  • the at least one hydrophilic, organic polymer comprises, preferably consists of a cellulose derivative selected from the group consisting of hydroxyalkylalkylcelluloses derivatives and a mixture of two or more thereof. More preferably, the at least one hydrophilic, polymer comprises, more preferably consists of, hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate (HPMCAS) or the mixtures thereof. Most preferably, the at least one hydrophilic, polymer comprises, more preferably consists of, hydroxypropylmethylcellulose acetate succinate (HPMCAS).
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • the average molecular weight (M w ) of the cellulose derivative is in the range of from 7 to 225 kDa, more preferably in the range of from 7 to 100 kDa, more preferably in the range of from 7 to 30 kDa.
  • the solid composition contains two or more cellulose derivative, preferably two or more hydroxyalkylalkylcellulose derivatives, more preferably two or more hydroxypropylmethylcellulose derivatives, which differ only in the average molecular weight M w .
  • the degree of substitution of methoxy groups (DSM) of the cellulose derivative is in the range of from 0.3 to 2.8, more preferably in the range of from 0.6 to 2.5, more preferably in the range of from 1.0 to 2.3, more preferably in the range of from 1.3 to 2.0.
  • the solid composition contains two or more cellulose derivative, preferably two or more hydroxyalkylalkylcellulose derivatives, more preferably two or more hydroxypropylmethylcellulose derivatives, which differ only in the degree of substitution.
  • the parameter DSM describes the average number of methoxy substitutions per anhydroglucose unit of a given hydroxyalkylalkylcellulose derivative.
  • the solid dispersion contains two or more cellulose derivatives, preferably two or more hydroxyalkylalkylcellulose derivatives, more preferably two or more hydroxypropylmethylcellulose derivatives, which differ in the degree of substitution of methoxy groups and the average molecular weight M w .
  • the present invention also relates to a solid dispersion comprising amorphous selexipag according to formula (I) and at least one pharmaceutically acceptable excipient, wherein at least 99 weight-% of the selexipag comprised in the solid dispersion are present in amorphous form, at least 99 weight-% of the solid dispersion consist of the selexipag and the at least one pharmaceutically acceptable excipient, and wherein the at least one pharmaceutically acceptable excipient is a cellulose derivative selected from the group consisting of hydro xyalkylalkylcellulose derivatives and a mixture of two or more thereof, the cellulose derivative preferably comprising, more preferably consisting of, hydroxypropylmethylcellulose acetate succinate (HPMCAS).
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • polyethyleneglycol- polyvinyl caprolactam- polyvinyl acetate grafted copolymer is preferred.
  • Polyethyleneglycol- polyvinyl caprolactam- polyvinyl acetate grafted copolymer is commercially available as Soluplus ® from BASF.
  • the at least one pharmaceutically acceptable excipient used as matrix component is a silicon-based inorganic compound, preferably consists of at least one, more preferably one silicon-based inorganic compound.
  • the present invention also relates to a solid dispersion comprising amorphous selexipag according to formula (I) and at least one pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient is a silicon-based inorganic compound, and wherein at least 99 weight-% of the selexipag comprised in the solid dispersion are present in amorphous form, at least 99 weight-% of the solid dispersion consist of the selexipag and the at least one silicon-based inorganic compound.
  • the present invention also relates to a solid composition
  • a solid composition comprising amorphous selexipag according to formula (I) and at least one pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient is a silicon-based inorganic compound, and wherein at least 99 weight-% of the selexipag comprised in the solid dispersion are present in amorphous form, at least 99 weight-% of the solid dispersion consist of the selexipag and the at least one silicon-based inorganic compound, and wherein the pH of the silicon-based inorganic compound is in the range of from 6.0 to 9.0, preferably in the range of from 6.5 to 8.5, more preferably in the range of from 7.0 to 8.0.
  • the bulk density of the at least one silicon-based inorganic compound is in the range of from 10 to 500 g ml, preferably in the range of from 30 to 400 g/ml, more preferably in the range of from 50 to 300 g/ml.
  • the solid dispersion of the present invention contains at least one silicon-based inorganic compound having a bulk density in the above-defined preferred ranges and at least one silicon-based inorganic compound having a bulk density outside these ranges.
  • all silicon-based inorganic compounds comprised in the solid composition of the present invention have a bulk density in the above -defined preferred ranges.
  • the silicon-based inorganic compound is silica.
  • the silica is preferably selected from the group consisting of fumed silica, precipitated silica, gel silica, colloidal silica, and a combination of two or more thereof, such as a combination of fumed silica and precipitated silica or a combination of fumed silica and colloidal silica or a combination of fumed silica and gel silica or a combination of precipitated silica and gel silica or a combination of precipitated silica and colloidal silica or a combination of gel silica and colloidal silica or a combination of fumed silica and precipitated silica and gel silica or a combination or fumed silica and gel silica and colloidal silica or a combination of precipitated silica and gel silica and colloidal silica or a combination of fumed silica and colloidal silica or a combination of fumed silica and colloidal silica or a
  • the silicon-based compound is a silicate.
  • the silicate is preferably an aluminosilicate which, more preferably, additionally contains at least one alkali metal element selected from the group consisting of Li, Na, K, b, Cs and a combination of two or more thereof, preferably from the group consisting of Li, Na, K, and a combination of two or more thereof, more preferably from the group consisting of Na, K, and a combination of two or more thereof, and/or at least one alkaline earth metal element selected from the group consisting of Mg, Ca, Sr, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, and a combination of two or more thereof.
  • the silicate is an alumino silicate which additionally contains at least one alkaline earth metal element selected from the group consisting of Mg, Ca, Sr, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, Ba, and a combination of two or more thereof, preferably from the group consisting of Mg, Ca, and a combination of two or more thereof. More preferably, the silicate is an aluminosilicate, which additionally contains Mg. Preferred silicates include, but are not restricted to, the commercially available compounds Neusilin ® UFL2, Neusilin ® US2, both from Fuji Chemical Industry Co., Ltd.
  • the present invention also relates to the solid dispersion as described above, wherein the at least one silicon- based inorganic compound is selected from the group consisting of silica, silicates, and a combination of two or more thereof, wherein the silica is preferably selected from the group consisting of fumed silica, precipitated silica, gel silica, colloidal silica, and a combination of two or more thereof, and wherein the silicates are preferably aluminosilicates, preferably comprising at least one alkali metal element and/or at least one alkaline earth metal element, more preferably at least one alkaline earth metal element, more preferably magnesium.
  • the silica and/or the silicate can be present in crystalline or amorphous form.
  • at least 90 weight - %, more preferably at least 95 weight-%, more preferably at least 99 weight-% of the at least one silicon-based inorganic compound are present in amorphous form.
  • at least 99.5 weight-%, more preferably at least 99.9 weight-%, more preferably at least 99.99 weight-% of the at least one silicon-based inorganic compound are present in amorphous form.
  • the present invention also relates to a process for preparing a solid dispersion comprising amorphous selexipag and at least one pharmaceutically acceptable excipient, wherein the at least one pharmaceutically acceptable excipient is (i) a polymer, or (ii) a silicon-based inorganic adsorbent, the process comprising:
  • Selexipag may be provided by any method known to the person skilled in the art, such as, e.g., the methods described in EP 2447254 Al.
  • Selexipag may be provided in any form, such as in crystalline, in amorphous form, or in a mixture of thereof.
  • selexipag in step (a) is provided in amorphous form such as described in EP 2447254 Al, table 4, solvent 30.
  • selexipag provided in step (a) may also be present in crystalline form I, II or III or as a mixture of two or more thereof, for example as a mixture of form II and form III.
  • selexipag is provided as a crystalline solvate with a solvation partner, which is an aromatic hydrocarbon, preferably selected from toluene, chlorobenzene and o-xylene.
  • a crystalline solvate of selexipag and an aromatic hydrocarbon is thus a preferred intermediate for the production of the solid dispersion of the present invention.
  • a toluene solvate of selexipag is a preferred intermediate for the production of the solid dispersion of the present invention.
  • a crystalline chlorobenzene solvate of selexipag is a preferred intermediate for the production of the solid dispersion of the present invention.
  • a crystalline o-xylene solvate of selexipag is a preferred intermediate for the production of the solid dispersion of the present invention.
  • the invention therefore also relates to these solvates of selexipag with aromatic hydrocarbons.
  • the invention also relates to the preparation of solvates of selexipag with aromatic hydrocarbons.
  • the invention further relates to the use of crystalline solvates of selexipag with aromatic hydrocarbons for the preparation of amorphous selexipag.
  • the present invention also relates to a process for preparing a solid dispersion and a solid dispersion obtained or obtainable by the above-described method, wherein in step (a) crystalline selexipag, preferably a crystalline solvate of selexipag with aromatic hydrocarbons or crystalline selexipag in polymorphic form I or II or III, or a mixture of two or more of these crystalline forms, more preferably crystalline selexipag in polymorphic form II or III or as a mixture of thereof, is provided.
  • selexipag in step (a) is provided in amorphous form.
  • selexipag is preferably dissolved or dispersed together with the at least one pharmaceutically acceptable excipient as matrix compound in a suitable solvent.
  • excipient a polymer, or (ii) a silicon-based inorganic adsorbent can be used. Both components may be dissolved or dispersed together or subsequently.
  • a suitable solvent refers to a solvent or solvent mixture in which both selexipag and the at least one pharmaceutically acceptable excipient have adequate solubility or may be suitably dispersed.
  • the term "adequate solubility” is denoted to mean a solubility at room temperature of selexipag of greater than about 10 mg/ml.
  • the pharmaceutically acceptable excipient is an organic polymer, preferably a hydrophilic organic polymer
  • selexipag and the organic polymer may require different solvents to obtain the desired solubility.
  • a mixture of solvents can then be used.
  • selexipag may be dissolved in at least one solvent to give a mixture comprising the at least one solvent and selexipag.
  • the organic polymer may be dissolved in at least one further solvent to give a mixture comprising the polymer and the at least one further solvent. Both mixtures may then be mixed together.
  • Selexipag and organic polymer may be dissolved or dispersed, together or subsequently, in the suitable solvent (including solvent mixtures).
  • suitable solvents include, but are not limited to, water, C 1 -C3 ketones, C 1 -C2 halogenated hydrocarbons, C3-C4 alcohols, C2-C6 ethers, C3-C5 esters, and a combination of two or more thereof, more preferably from the group consisting of C 1 -C3 ketones, and a combination of two or more thereof. More preferably, the solvent comprises, and for example consists of, dichloromethane, chloroform, ethanol, methanol, THF, methyl THF, 2-propanol, ethyl acetate, acetone, water or mixtures of two or more thereof.
  • the solvent comprises, and for example consists of, dichloromethane, THF, methyl THF, acetone, or mixtures of two or more thereof.
  • the solvent is ethanol.
  • the solvent is acetone.
  • the solution obtained in step (b) may be directly used in step (c) of the method according to the invention.
  • the solution formed is purified before used in step (c).
  • the term "purified" in this context means e.g. that non-dissolved particles, such as non-dissolved organic polymer and/or non-dissolved selexipag, may be removed by suitable methods known to those skilled in the art such as centrifugation, filtration, ultrafiltration or the like.
  • the solution in step (b) is filtrated prior to step (c).
  • the present invention also relates to a process, as described above, the process comprising
  • step (b) dissolving selexipag provided in step (a) and the at least one organic polymer in a solvent to form a solution, then optionally filtrating the solution, and
  • suitable methods can be applied.
  • the dissolution process can be influenced by choosing suitable temperatures, by stirring, and/or by subjecting the respective mixtures to sonication, wherein these methods can be applied during the entire or one or more parts of the mixing process.
  • the solution of selexipag and the at least one organic polymer in the at least one solvent is prepared at a temperature in the range of from 10 to 40 °C, more preferably in the range of from 15 to 35 °C, more preferably in the range of from 20 to 30 °C, preferably at ambient pressure.
  • the process comprises dispersing the at least one silicon-based inorganic compound in a solution comprising the dissolved selexipag.
  • the at least one suitable solvent is selected from the group consisting of water, C 1 -C3 ketones, C 1 -C2 halogenated hydrocarbons, C3 -C4 alcohols, C2-C6 ethers, C3 -C5 esters, and a combination of two or more thereof, more preferably from the group consisting of C1-C3 ketones or C1-C2 halogenated hydrocarbons, and a combination of two or more thereof.
  • the solvent comprise dichloromethane or acetone. More preferably, the solvent is dichloromethane or acetone.
  • the finally obtained mixture is a mixture wherein the at least one silicon-based inorganic compound is dispersed in a solution of the selexipag in the at least one solvent, which mixture can be subjected to the subsequent step (c).
  • the weight ratio of selexipag plus the at least one silicon-based inorganic compound, preferably selexipag plus the at least one silica, relative to the at least one solvent, preferably dichloromethane or acetone is in the range of from 0.01 : 1 to 0.4 : 1 , preferably in the range of from 0.02 : 1 to 0.3 : 1, more preferably in the range of from 0.05 : 1 to 0.3 : 1.
  • suitable methods can be applied.
  • the dissolution process can be influenced by choosing suitable temperatures, by stirring, and/or by subjecting the respective mixtures to sonication, wherein these methods can be applied during the entire or one or more parts of the mixing process.
  • the dispersion of the at least one silicon-based inorganic compound preferably selected from the group consisting of silica, silicates, and a combination of two or more thereof, in the solution of selexipag in the at least one solvent, is prepared at a temperature in the range of from 10 to 40 °C, more preferably in the range of from 15 to 35 °C, more preferably in the range of from 20 to 30 °C, preferably at ambient pressure.
  • step (c) of the above described method at least part, preferably essentially all, of the solvent is removed.
  • "Essentially all” is denoted to mean that at least 95 % by weight, more preferably at least 96 % by weight, more preferably at least 97 % by weight, more preferably at least 98 % by weight, more preferably at least 99 % by weight, more preferably at least 99.9 % by weight, more preferably all of the solvent present in the solution according to step (b) is removed in step (c).
  • the solid dispersion obtained or obtainable by this process thus comprises less than 5 % by weight, more preferably less than 4 % by weight, more preferably less than 3 % by weight, more preferably less than 2 % by weight, more preferably less than 1 % by weight, more preferably less than 0.1 % by weight, based on the total weight of the solid dispersion, of the solvent. Most preferably, all of the solvent present in the solution is removed to give the solid dispersion.
  • the removal of the solvent may be carried out by any suitable method known to those skilled in the art such as evaporation, spray drying, lyophilization, melt extrusion, drum drying, freeze -drying or other solvent removal processes.
  • the solvent is removed by spray drying or evaporation.
  • Spray drying is a process well known to those skilled in the art for preparing solid dispersions. In such a spray drying process, the solution is pumped through an atomizer into a drying chamber thereby removing the solvent to form the solid dispersion.
  • a drying process uses hot gases, such as air, nitrogen, nitrogen-enriched air or argon, to dry the particles.
  • the solution can be atomized by conventional means well known in the art, such as a two-fluid sonication nozzle and a two-fluid non-sonication nozzle.
  • the solvent is removed by evaporation, such as by evaporation under reduced pressure.
  • the pressure in step (c) is in the range of from 50 to 450 mbar, more preferably in the range of from 50 to 250 mbar, more preferably in the range of from 50 to 200 mbar.
  • the temperature during evaporation may be varied or held essentially constant and is preferably in the range of from 20 to 40 °C, more preferably in the range of from 25 to 40 °C, and most preferably in the range of from 30 to 40 °C.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a solid dispersion as described above or a solid dispersion obtained or obtainable by the above -described method.
  • the pharmaceutical composition preferably comprises the solid dispersion as key ingredient together with at least one further excipient in addition to the at least one matrix compound present in the solid dispersion.
  • the pharmaceutical compositions comprising solid dispersion of the present invention exhibit good pharmaceutical properties, such as stability and dissolution.
  • the pharmaceutical composition of the present invention comprising solid dispersion of selexipag and a polymer selected from a cellulose derivative exhibit excellent dissolution profile. The best dissolution profile was obtained using HPMCAS as polymer.
  • dissolution of pharmaceutical composition comprising solid dispersion of selexipag and HPMCAS was not only faster in comparison to the pharmaceutical composition comprising solid dispersion of selexipag and Soluplus, but also provided a higher total dissolution of 90 % or more.
  • the at least one further excipient may be included in the solid dispersion or may be subsequently added to or mixed with the dispersion.
  • the pharmaceutical composition comprises no further selexipag in addition to the selexipag present in the solid dispersion.
  • Suitable pharmaceutical excipient include, but are not limited to, carriers, fillers, diluents, lubricants, sweeteners, stabilizing agents, solubilizing agents, antioxidants and preservatives, flavoring agents, binders, colorants, osmotic agents, preservatives, buffers, surfactants, granulating and disintegrating agents and combinations thereof.
  • diluents include, but are not limited to, calcium carbonate, sodium carbonate, lactose, calcium phosphate, microcrystalline cellulose, mannitol, starch, sodium phosphate or the like.
  • Examples for granulating and disintegrating agents are corn starch, alginic acid, sodium starch glycolate, crospovidone, croscarmellose sodium and the like.
  • the pharmaceutical composition of the present invention may optionally comprise one or more surfactants, which may be ionic or non-ionic surfactants.
  • the surfactants can increase the rate of dissolution by facilitating wetting, thereby increasing the maximum concentration of dissolved drug.
  • the surfactants may also facilitate the formulation process.
  • Surfactants may also stabilize the amorphous dispersions by inhibiting crystallization or precipitation of the drug by interacting with the dissolved drug by such mechanisms as complexation, formation of inclusion complexes, formation of micelles, and adsorption to the surface of the solid drug.
  • Suitable surfactants include cationic, anionic, and non-ionic surfactants.
  • fatty acids and alkyl sulfonates include for example fatty acids and alkyl sulfonates; cationic surfactants such as benzalkonium chloride; anionic surfactants, such as dioctyl sodium sulfosuccinate and sodium lauryl sulfate (sodium dodecyl sulfate); sorbitan fatty acid esters; Vitamin E TPGS; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene castor oils and hydrogenated castor oils such as Cremophor RH-40 and Cremopher EL; Liposorb P-20, Capmul POE-0, and natural surfactants such as lecithin and other phospholipids and mono- and diglycerides.
  • cationic surfactants such as benzalkonium chloride
  • anionic surfactants such as dioctyl sodium sulfosuccinate and sodium lauryl sulfate (sodium dodecyl sul
  • the present invention also relates to a pharmaceutical composition as described above, wherein the composition comprises one or more surfactants selected from the group consisting of anionic surfactants and non-ionic surfactants.
  • the pharmaceutical composition comprises one or more surfactants selected from sodium dodecyl sulfate and one or more non-ionic surfactants selected from (a) sorbitan fatty acid esters, (b) polyoxyethylene sorbitan fatty acid esters, (c) polyoxyethylene castor oils, (d) polyoxyethylene hydrogenated castor oils, and (e) vitamin E TPGS; and mixtures thereof.
  • surfactants selected from sodium dodecyl sulfate
  • non-ionic surfactants selected from (a) sorbitan fatty acid esters, (b) polyoxyethylene sorbitan fatty acid esters, (c) polyoxyethylene castor oils, (d) polyoxyethylene hydrogenated castor oils, and (e) vitamin E TPGS; and mixtures thereof.
  • Examples of carriers include, without limitation, solvents, saline, buffered saline, dextrose, water, glycerol, ethanol, propylene glycol, polysorbate 80 (Tween-80TM), poly(ethylene)glycol 300 and 400 (PEG 300 and 400), PEGylated castor oil (e.g. Cremophor EL), poloxamer 407 and 188, hydrophobic carriers, fat emulsions, lipids, PEGylated phopholids, polymer matrices, biocompatible polymers, lipospheres, vesicles, particles, and liposomes, or combinations thereof.
  • solvents saline, buffered saline, dextrose, water, glycerol, ethanol, propylene glycol, polysorbate 80 (Tween-80TM), poly(ethylene)glycol 300 and 400 (PEG 300 and 400), PEGylated castor oil (e.g. Cremophor EL
  • osmotic agents examples include sodium chloride, glycerol, sorbitol, xylitol, glucose, or combinations thereof.
  • Binders can include acacia gum, starch, gelatin, sucrose, polyvinylpyrrolidone (Providone), sorbitol, tragacanth methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, or combinations thereof.
  • fillers can include calcium phosphate, glycine, lactose, maize-starch, sorbitol, sucrose, or combinations thereof.
  • lubricants include magnesium stearate or other metallic stearates, stearic acid, polyethylene glycol, waxes, oils, silica and colloical silica, silicon fluid, talc, or combinations thereof.
  • flavoring agent those flavoring agents approved by the FDA for use in sweets and pharmaceuticals, foods, candies and beverages or the like are preferred.
  • these flavoring agents impart flavors such as grape, cherry, citrus, peach, strawberry, bubble gum, peppermint or others.
  • Peppermint, methyl salicylate, orange flavoring and the like are mentioned by way of examples.
  • the pharmaceutical composition of the present invention preferably contains a therapeutically effective amount of selexipag.
  • therapeutically effective amount refers to an amount of selexipag present in the solid dispersion or pharmaceutical composition being administered that is sufficient to prevent the development of, or alleviate to some extent one or more of the symptoms of the pulmonary arterial hypertension.
  • a pharmaceutical composition of the present invention can be a tablet, for example a tablet prepared from 1 -5 mg solid dispersion, 80-120 mg lactose or mannitol as a filler suitable for direct tableting, 5-15 mg HPMC low viscosity or PVP25 as binder, 5-15 mg acdisol, primojel or PVPP as disintegrant, and 1-2 mg Mg stearate as lubricant, These ingredients may be mixed, tableted and optionally film-coated with a standard film known in the art.
  • the pharmaceutical composition of the present invention is preferably administered orally to patients, which include, but is not limited to, mammals, for example humans, in the form of, for example, a tablet, pills, granules or the like. It is also apparent that the pharmaceutical composition of the present invention can be administered with other therapeutic and/or prophylactic agents and/or medications that are not medically incompatible therewith.
  • the solid dispersion described above may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with the solid dispersion of the present invention.
  • the present invention relates to a process for the preparation of the pharmaceutical composition, said process comprising the steps of a) dissolving or dispersing selexipag and the at least one pharmaceutically acceptable excipient selected from (i) a polymer, or (ii) a silicon-based inorganic adsorbent in a solvent to form a mixture,
  • step c) spraying the mixture of step a) on the surface of the pharmaceutically acceptable excipient of step b), d) granulating the mixtures obtained in step c) to obtain granules,
  • step d) drying the granules obtained in step d) to remove solvent.
  • said process of the present invention provides several advantages.
  • a high surface area is provided that allows for homogenous distribution of selexipag in the final pharmaceutical composition.
  • said process allows for preparation of the pharmaceutical composition having good pharmaceutical properties, such as physical and chemical stability, dissolution and content uniformity, hence providing good bioavailability.
  • Exhibiting good content uniformity is in particular important for the pharmaceutical compositions comprising low dose of selexipag, such as 50 ⁇ g, 100 ⁇ g, 200 ⁇ g, 300 ⁇ g, 400 ⁇ g, 500 ⁇ g, 600 ⁇ g, 700 ⁇ g, 800 ⁇ g, 900 ⁇ g, 1000 ⁇ g, 1100 ⁇ g, 1200 ⁇ g, 1400 ⁇ g or 1600 ⁇ g.
  • the test for determining content uniformity is defined in Ph. Eur. section 2.9.40 and/or USP ⁇ 905>. According to the method described the values of content uniformity below 15 are considered as passing the test.
  • the polymer (i) of step a) of the process of the present is selected from a cellulose derivative, more preferably is HPC or HPMCAS, most preferably is HPMCAS.
  • step c) spraying the mixture of step a) on the surface of the pharmaceutically acceptable excipient of step b), d) granulating the mixture obtained in step c) to obtain granules,
  • step d) drying the granules obtained in step d) to remove solvent.
  • the one or more additional pharmaceutically acceptable excipient provided in step b) of the process of the present invention can be selected from carriers, fillers, diluents, lubricants, sweeteners, stabilizing agents, solubilizing agents, antioxidants and preservatives, flavoring agents, binders, colorants, osmotic agents, preservatives, buffers, surfactants, granulating and disintegrating agents and combinations thereof as described above.
  • the additional pharmaceutically acceptable excipient provided is selected from carriers, fillers, diluents and binders, and the mixtures thereof.
  • the additional excipient is selected from mannitol, microcrystalline cellulose, starch, corn starch, and the mixtures thereof.
  • step c) and step d) of the process for preparation of the pharmaceutical composition are performed simultaneously.
  • steps c) and d) of said process are performed by using fluid bed granulation equipment.
  • the process of the present invention further comprises a step f), wherein one or more further pharmaceutically acceptable excipient is added to the granules obtained in step e) to obtain the final blend.
  • Said one or more further pharmaceutically acceptable excipient can be selected from any excipients as described above.
  • one or more further pharmaceutically acceptable excipient is selected from lubricants, disintegrants, and the mixtures thereof.
  • lubricants such as stearates and disintegrants, such as low- substituted hydroxypropylcellulose, sodium starch glycolate, crospovidone, croscarmellose sodium, and the mixtures thereof.
  • the further pharmaceutically acceptable excipient is selected from the mixture of magnesium stearate and low-substituted hydroxypropylcellulose or a mixture of magnesium stearate and crospovidone.
  • the process of the present invention further comprises a step of compression of the granules obtained in step e) or the final blend obtained in step f) into tablets. Any conventional method can be used for the compression step.
  • Suitable material used film coating are polymeric coating agents, pigments, plasticizers, solubilizing agents, and the like.
  • Suitable coating agents include
  • hydroxypropylmethylcellulose hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, and the like, preferably hydroxypropylmethylcellulose.
  • Plasticizers such as polyethylene glycol, diethyl citrate and trietyl citrate may be included in the film coating composition.
  • polyethylene glycol is used as plasticizer.
  • Suitable solubilizing agents include polyoxyethylene sorbitan fatty acid esters particularly polysorbate 80.
  • Suitable pigments include titanium dioxide and various iron oxides.
  • the ingredients of the coating compositions are dispersed in a suitable solvent, preferably water. The coating composition can be applied to the tablets using conventional pan coating or spray coating techniques.
  • composition comprising a solid dispersion of the present invention is obtainable by the process as described above.
  • the solid dispersion, described above, or the pharmaceutical composition described above is useful in a method of providing an agonistic effect on the PGI2 receptor.
  • the present invention also describes the solid dispersion, described above, or a pharmaceutical composition, as described above for use as agonists of PGI2 receptor activity.
  • the solid dispersion, described above, or the pharmaceutical composition, described above is used for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with the PGI 2 receptor, in particular for the treatment of pulmonary hypertension, in particular pulmonary arterial hypertension.
  • the solid dispersion, described above, or the pharmaceutical composition, described above is used for treating or preventing pulmonary hypertension, in particular pulmonary arterial hypertension.
  • treatment and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms.
  • the dosage of selexipag in the compositions of this invention may be varied, however, it is necessary that the amount of selexipag be such that a suitable dosage form is obtained.
  • the dosage regimen will be determined by the attending physician and other clinical factors. It is well known in the medical art that the dosage for anyone patient depends upon many factors including the patient's size, body surface area, age, sex, time and route of administration, general health and other drugs being administered concurrently. Efficacy can be monitored by periodic assessment. Selexipag may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
  • a typical dosage can be, for example, in the range of 10( ⁇ g to 160( ⁇ g, such as 20( ⁇ g, 30( ⁇ g, 40( ⁇ g, 500 ⁇ 3 ⁇ 4 60( ⁇ g, 700 ⁇ 3 ⁇ 4 80( ⁇ g, 900 ⁇ 3 ⁇ 4 100( ⁇ g, 110( ⁇ g, 120( ⁇ g, 140( ⁇ g or 160( ⁇ g.
  • the present invention also relates to the use of (i) a polymer, or (ii) a silicon-based inorganic adsorbent for stabilizing amorphous selexipag.
  • Crystalline solvate of selexipag with aromatic hydrocarbon can be provided in step (a) for the preparation of amorphous solid dispersion of selexipag.
  • the present invention also relates to a process for the preparation of crystalline solvates of selexipag with aromatic hydrocarbon, the process comprising the steps of:
  • the organic solvent in step (i) is preferably selected from aromatic hydrocarbons, preferably from chlorobenzene, toluene and xylene, more preferably from chlorobenzene, toluene and o-xylene.
  • seed crystals may be added in step (ii).
  • the seed crystals are prepared with the same solvent as the one used in step (i) of the process. In particular, the seed crystals are prepared using the same process steps as the solvates of the present invention.
  • the seed crystals are typically added in an amount of 0.1 wt% to 10 wt%, preferably in an amount of 0.5 wt% to 7.0 wt%, most preferably 1.0 wt.% 5.0 wt%, on the basis of the total amount of the starting material used in step (i).
  • step (iii) the solution is cooled to a temperature in the range of from -5 to -20 °C and kept at this temperature, typically for a period of time of from 2 to 24 hours, under stirring condition or without stirring, in order to promote crystallization.
  • isolation in step (iv) may be performed by using procedures known in the art, such as by filtration, centrifugation, or evaporation of solvent.
  • the isolated crystals may optionally be dried in step (v), e.g. under reduced pressure, typically at room temperature, or heated up to a temperature between 25 °C and 40 °C or the crystals may directly be used in further processes, such as the preparation of amorphous solid dispersion of selexipag or isolated crystals may be used as seed crystals for the preparation of a solvate of selexipag.
  • the present invention also refers to new crystalline forms of selexipag.
  • the present invention refers to new crystalline solvates of selexipag.
  • These new solvate forms are preferably prepared from aromatic hydrocarbons, preferably from chlorobenzene, toluene and xylene, more preferably from chlorobenzene, toluene and o-xylene.
  • the solvate of selexipag of the present invention may be characterized by a stoichiometric composition of the solvates, i.e. number of solvent molecules per selexipag molecule as follows: o-Xylene solvate (prepared according to Example 2 herein): 1.0 mol ( ⁇ 0.2 mol) of o-xylene,
  • Chlorobenzene solvate (prepared at -10 °C under stirring, according to Example 3-1 herein): 1.0 mol ( ⁇ 0.2 mol) of chlorobenzene,
  • Chlorobenzene solvate (prepared at -18 °C without stirring, according to Example 3-2 herein): 1.0 mol ( ⁇ 0.2 mol) of chlorobenzene,
  • Toluene solvate (prepared according to Example 4 herein): 1.0 mol ( ⁇ 0.2 mol) of toluene.
  • the present invention refers to an o-xylene solvate of selexipag, having a characteristic powder X-ray diffractogram (PX D) pattern with reflections at 2-theta values of 5.7 ⁇ 0.2, 13.3 ⁇ 0.2, 17.7 ⁇ 0.2, 19.2 ⁇ 0.2 and 20.7 ⁇ 0.2° 2-Theta, when measured at a temperature in the range of from 15 to 25°C with Cu- Kalphal,2 radiation having a wavelength of 0.15419 nm.
  • Thermogravimetric analysis (TGA) of o-xylene solvate of selexipag indicates a total weight loss between 45 °C and 220 °C of about 17.0%. (1.0 mole equivalent of o-xylene corresponds to about 17.6%).
  • the present invention refers to a chlorobenzene solvate of selexipag, prepared under stirring conditions at a temperature of -10 °C, having a characteristic powder X-ray diffractogram (PXRD) pattern with reflections at 2-theta values of 6.2 ⁇ 0.2, 10.5 ⁇ 0.2, 13.9 ⁇ 0.2, 18.8 ⁇ 0.2 and 19.3 ⁇ 0.2° 2-Theta, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphal ,2 radiation having a wavelength of 0.15419 nm.
  • PXRD powder X-ray diffractogram
  • the present invention refers to a chlorobenzene solvate of selexipag, prepared at a temperature of -18 °C without stirring, having a characteristic powder X-ray diffractogram (PXRD) pattern with reflections at 2-theta values of 6.7 ⁇ 0.2, 17.0 ⁇ 0.2, 17.9 ⁇ 0.2, 19.4 ⁇ 0.2 and 24.5 ⁇ 0.2° 2-Theta, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphal,2 radiation having a wavelength of 0.15419 nm.
  • PXRD powder X-ray diffractogram
  • the present invention refers to a toluene solvate of selexipag, having a characteristic powder X-ray diffractogram (PXRD) pattern with reflections at 2-theta values of 5.8 ⁇ 0.2, 13.4 ⁇ 0.2, 17.9 ⁇ 0.2, 19.6 ⁇ 0.2, and 20.9 ⁇ 0.2° 2-Theta, when measured at a temperature in the range of from 15 to 25 °C with Cu-Kalphal, 2 radiation having a wavelength of 0.15419 nm.
  • TGA of toluene solvate of selexipag indicates a total weight loss between 40 °C and 240 °C of about 15.0%. (1.0 mole equivalent of toluene corresponds to about 15.6%).
  • Powder X-ray diffraction was performed with a PANalytical X'Pert PRO diffractometer equipped with a theta/theta coupled goniometer in transmission geometry, radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state PIXcel detector.
  • Diffractograms were recorded at a tube voltage of 45 kV and a tube current of 40 mA, applying a stepsize of 0.013° 2-Theta with 40s per step (255 channels) in the angular range of 2° to 40° 2- Theta at ambient conditions.
  • a typical precision of the 2-Theta values is in the range of ⁇ 0.2° 2-Theta.
  • a diffraction peak that appears for example at 9.0 ° 2-theta (for crystalline form II of selexipag) can appear between 8.8 and 9.2 ° 2-theta on most X-ray diffractometers under standard conditions.
  • DSC was performed on a Mettler Polymer DSC R instrument. The sample was heated in a 40 microL aluminum pan with pierced aluminum lid from 25 to 250 °C at a rate of 10 K/min. Nitrogen (purge rate 50 mL/min) was used as purge gas.
  • TGA was performed on a Mettler TGA/DSC 1 instrument.
  • the sample was heated in a 100 microL aluminum pan closed with an aluminum lid. The lid was automatically pierced at the beginning of the measurement.
  • the sample was heated from 25 to 250 °C at a rate of 10 K/min. Nitrogen (purge rate 50 mL/min) was used as purge gas.
  • Moisture stability at accelerated stress conditions was performed in a Memmert constant climate chamber HPP110. 30-50 mg of a given solid composition prepared according to the Examples and Comparative Example herein were exposed to an atmosphere having a relative humidity of 75 ⁇ 0.5 % and a temperature of 40 ⁇ 0.5 °C for a period of time as indicated in Tables 5-7 below and analyzed via PXRD as described above.
  • the dissolution profiles were determined and calculated using HPLC-based method.
  • the dissolution experiments were performed in 0.05 M KH2PO4 buffer pH 6.8 using USP II apparatus (volume: 900 mL, stirring speed 50 rpm at temperature of 37 °C ⁇ 0.5 °C).
  • HPLC at wavelength of 210 nm was used to determine the amount [%] of selexipag dissolved in the test medium. The dissolution was measured at time points of 5, 10, 15, 30 and 45 minutes.
  • Example 1A Preparation of an amorphous solid dispersion comprising selexipag and HPMCAS
  • the solvent was removed on a rotary evaporator (bath temperature: 40 °C, final vacuum: 20 mbar) and the remaining solid was dried under vacuum (30 mbar) for two hours at 40 °C followed by 15 to 18 hours of drying under vacuum (30 mbar) at room temperature, yielding an amorphous solid dispersion of selexipag.
  • FIG. 3 Representative PXRD pattern of the solid dispersion after its preparation is shown in Figure 3, the PXRD pattern of the solid dispersion after 6 weeks upon storage at a temperature of 40 °C and a relative humidity of 75% is shown in Figure 4.
  • Figures 3 and 4 show that the selexipag comprised in the solid dispersion was in amorphous form and did not crystallize during the moisture stability test.
  • Chlorobenze solvate of selexipag (224 mg, prepared according to Example 3 herein) and HPMCAS (211 mg) were dissolved in dichloromethane (5 mL). The solvent was removed on a rotary evaporator (bath temperature: 40 °C, final vacuum: 20 mbar) and the remaining solid was dried under vacuum (30 mbar) for two hours at 40 °C followed by 18 hours of drying under vacuum (30 mbar) at room temperature, yielding an amorphous solid dispersion of selexipag. The resulting solid dispersion was subjected to a moisture stability test as described in Example part herein.
  • the PXRD pattern of the solid dispersion after its preparation was essentially identical to the one shown in Figure 3
  • the PXRD pattern of the solid dispersion after 6 weeks upon storage at a temperature of 40 °C and a relative humidity of 75% was essentially identical to the one shown in Figure 4.
  • Selexipag comprised in the solid dispersion was in amorphous form and did not crystallize during the moisture stability test.
  • o-Xylene solvate of selexipag (202 mg, prepared according to prepared according to Example 2 herein) and HPMCAS (207 mg) were dissolved in dichloromethane (5 mL). The solvent was removed on a rotary evaporator (bath temperature: 40 °C, final vacuum: 20 mbar) and the remaining solid was dried under vacuum (30 mbar) for two hours at 40 °C followed by 18 hours of drying under vacuum (30 mbar) at room temperature, yielding an amorphous solid dispersion of selexipag.
  • Toluene solvate of selexipag (240 mg, prepared according to prepared according to Example 4 herein) and HPMCAS (200 mg) were dissolved in dichloromethane (5 mL). The solvent was removed on a rotary evaporator (bath temperature: 40 °C, final vacuum: 20 mbar) and the remaining solid was dried under vacuum (30 mbar) for two hours at 40 °C followed by 17 hours of drying under vacuum (30 mbar) at room temperature, yielding an amorphous solid dispersion of selexipag.
  • Example IB Preparation of a composition comprising an amorphous solid dispersion comprising selexipag and hydroxypropylcellulose (HPC)
  • Example 1C Preparation of a composition comprising an amorphous solid dispersion comprising selexipag and HPMCAS
  • selexipag prepared according to the procedure disclosed in example 84 of WO 2002/088084 Al
  • acetone approximately 35 mg
  • Mannitol and corn starch were mixed together.
  • the API-HPMCAS-solvent-solution was sprayed onto the mixture of mannitol and corn starch using a fluid bed granulation equipment. The obtained granules were dried.
  • Low-substituted hydroxypropylcellulose (L-HPC) and magnesium stearate were added to the granules.
  • the final blend was compressed into tablets of a total weight of 135.00 mg. Tablets were coated with a coating solution.
  • selexipag prepared according to the procedure disclosed in example 84 of WO 2002/088084 Al
  • acetone approximately 35 mg
  • Mannitol and corn starch were mixed together.
  • the API-HPMCAS-solvent-solution was sprayed onto the mixture of mannitol and corn starch using a fluid bed granulation equipment. The obtained granules were dried.
  • Low-substituted hydroxypropylcellulose (L-HPC) and magnesium stearate were added to the granules.
  • the final blend was compressed into tablets of a total weight of 135.00 mg. Tablets were coated with a coating solution.
  • Comparative Example 1 Preparation of a composition comprising an amorphous solid dispersion comprising selexipag and Polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer (Soluplus ® BASF)
  • selexipag prepared according to the procedure disclosed in example 84 of WO 2002/088084 Al
  • acetone approximately 35 mg
  • the API-Soluplus®-solvent-solution was sprayed onto the mixture of mannitol and corn starch using a fluid bed granulation equipment. The obtained granules were dried. Low-substituted hydroxypropylcellulose (L-HPC) and magnesium stearate were added to the granules. The final blend was compressed into tablets of a total weight of 135.00 mg. Tablets were coated with a coating solution.
  • L-HPC Low-substituted hydroxypropylcellulose
  • magnesium stearate magnesium stearate
  • Amorphous selexipag (314 mg, for example prepared according to the procedure described in comparative example 1 herein) was dissolved in 2.0 mL o-xylene at room temperature.
  • the obtained clear solution was cooled to a temperature of about -9 ° C and stirred at this temperature for 20 hours in order to promote crystallization.
  • additional 2.0 mL o-xylene were added after crystallization took place.
  • the obtained solid was collected by filtration and dried at room temperature under vacuum (about 30 mbar) for 18 hours to yield 301 mg selexipag o-xylene solvate.
  • Table 1 Peak list of the PXRD pattern of the crystalline selexipag o-xylene solvate prepared according to Example 2 (relative peak intensities can vary due to e.g. inter-apparatus variability, sample crystallinity, sample preparation, etc.)
  • DSC curve shows a first endo therm with an onset temperature of about 65 °C (peak maximum at about 69 °C), corresponding to sample desolvation. Further heating leads to sample conversion to crystalline form I of selexipag. Melting endotherm of form I is then observed with an onset temperature of about 134 °C (peak maximum at about 137 °C).
  • TGA curve indicates a total weight loss between 45 °C and 220 °C of about 17.0%. (1.0 mole equivalent of o- xylene corresponds to about 17.6%).
  • Amorphous selexipag (302 mg, for example prepared according to the procedure described in comparative example 1 herein) was dissolved in 1.5 mL chlorobenzene at room temperature. The obtained clear solution was cooled to a temperature of about -10 °C and stirred at this temperature for 20 hours in order to promote crystallization. The obtained solid was collected by filtration and dried at room temperature under vacuum (about 30 mbar) for 18 hours to yield 262 mg selexipag chlorobenzene solvate.
  • Table 2 Peak list of the PXRD pattern of the crystalline selexipag chlorobenzene solvate prepared according to Example 3-1 (relative peak intensities can vary due to e.g. inter-apparatus variability, sample crystallinity, sample preparation, etc.)
  • DSC curve shows a first endo therm with an onset temperature of about 66 °C (peak maximum at about 69 °C), corresponding to sample desolvation. Further heating leads to sample conversion to crystalline form I of selexipag. Melting endotherm of form I is then observed with an onset temperature of about 134 °C (peak maximum at about 139 °C).
  • TGA TGA curve of chlorobenzene solvate of selexipag, prepared under stirring conditions at a temperature of -10 °C, indicates a total weight loss between 45 °C and 240 °C of about 18.0%. (1.0 mole equivalent of chlorobenzene corresponds to about 18.5%).
  • Amorphous selexipag (308 mg, for example prepared according to the procedure described in comparative example 1 herein) was dissolved in 1.5 mL chlorobenzene at room temperature. The obtained clear solution was cooled to a temperature of about -18 °C and let stand at this temperature without stirring for 24 hours in order to promote crystallization. The obtained solid was collected by filtration and dried at room temperature under vacuum (about 30 mbar) for 18 hours to yield 266 mg selexipag chlorobenzene solvate.
  • Table 3 Peak list of the PXRD pattern of the crystalline selexipag chlorobenzene solvate prepared according to Example 3-2 (relative peak intensities can vary due to e.g. inter-apparatus variability, sample crystallinity, sample preparation, etc.)
  • DSC curve shows a first endo therm with an onset temperature of about 61 °C (peak maximum at about 64 °C), corresponding to sample desolvation. Further heating leads to sample conversion to crystalline form I of selexipag. Melting endo therm of form I is then observed with an onset temperature of about 137 °C (peak maximum at about 139 °C).
  • TGA TGA curve of chlorobenzene solvate of selexipag, prepared at a temperature of -18°C without stirring, indicates a total weight loss between 50 °C and 220 °C of about 17.8%. (1.0 mole equivalent of chlorobenzene corresponds to about 18.5%).
  • Amorphous selexipag (305 mg, for example prepared according to the procedure described in comparative example 1 herein) was dissolved in 2.0 mL toluene at room temperature. The obtained clear solution was cooled to a temperature of about -10 °C and stirred at this temperature for 20 hours in order to promote crystallization. To allow better stirring of the slurry, additional 1.0 mL toluene was added after crystallization took place. The obtained solid was collected by filtration and dried at room temperature under vacuum (about 30 mbar) for 18 hours to yield 322 mg selexipag toluene solvate.
  • Table 4 Peak list of the PX D pattern of the crystalline selexipag toluene solvate prepared according to Example 4 (relative peak intensities can vary due to e.g. inter-apparatus variability, sample crystallinity, sample preparation, etc.)
  • DSC curve shows a first endo therm with an onset temperature of about 69 °C (peak maximum at about 72 °C), corresponding to sample desolvation. Further heating leads to sample conversion to crystalline form I of selexipag. Melting endo therm of form I is then observed with an onset temperature of about 137 °C (peak maximum at about 141 °C).
  • TGA curve indicates a total weight loss between 40 °C and 240 °C of about 15.0%. (1.0 mole equivalent of toluene corresponds to about 15.6%).
  • Comparative example 2 Physical stability of amorphous selexipag at accelerated stress conditions
  • Example 5 Physical stability of solid dispersions with amorphous selexipag and various polymers at accelerated stress conditions
  • Example 6 Physical stability of solid dispersions with amorphous selexipag and various silicon-based carriers at accelerated stress conditions

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Abstract

La présente invention concerne une dispersion solide amorphe comprenant du selexipag et des procédés pour la préparer. L'invention concerne également une composition pharmaceutique comprenant une quantité efficace de ladite dispersion solide amorphe et au moins un autre composé pharmaceutiquement acceptable. La composition pharmaceutique de la présente invention peut être utilisée comme médicament en particulier pour le traitement de l'hypertension artérielle pulmonaire.
PCT/EP2017/050572 2016-01-15 2017-01-12 Composition pharmaceutique de selexipag WO2017121806A1 (fr)

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WO2018015974A1 (fr) * 2016-07-20 2018-01-25 Mylan Laboratories Limited Formes polymorphes de sélexipag et dispersion solide amorphe de sélexipag
WO2018078383A1 (fr) * 2016-10-27 2018-05-03 Cipla Limited Composition pharmaceutique comprenant du selexipag amorphe
WO2019098300A1 (fr) * 2017-11-16 2019-05-23 日本新薬株式会社 Formulation à libération contrôlée
WO2019157337A1 (fr) * 2018-02-08 2019-08-15 Pulmokine, Inc. Formulations d'inhibiteurs de kinase et de prostanoïdes
US10407396B2 (en) 2017-11-16 2019-09-10 Apotex Inc. Crystalline form of selexipag
EP3705115A1 (fr) 2019-03-07 2020-09-09 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition contenant du selexipag
CN112055591A (zh) * 2018-02-21 2020-12-08 日本新药株式会社 粒状组合物、粒状组合物的制造方法及粒状组合物的溶出性改善方法
WO2020255157A1 (fr) * 2019-06-20 2020-12-24 Aizant Drug Research Solutions Private Limited Forme posologique solide stable de sélexipag et son procédé de préparation
WO2021152060A1 (fr) * 2020-01-31 2021-08-05 Actelion Pharmaceuticals Ltd Composition de sélexipag à libération contrôlée
WO2023195955A1 (fr) * 2022-04-05 2023-10-12 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Comprimé revêtu d'un film comprenant du sélexi̇pag et son procédé de préparation
WO2023195956A1 (fr) * 2022-04-05 2023-10-12 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Comprimé revêtu d'un film comprenant du sélexi̇pag et au moins une charge

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EP2893922A1 (fr) * 2014-01-10 2015-07-15 Heart Biotech Pharma Limited Formulations pharmaceutiques pour le traitement de l'hypertension artérielle pulmonaire
WO2016193994A1 (fr) * 2015-05-29 2016-12-08 Megafine Pharma (P) Ltd. Selexipag amorphe et son procédé de préparation
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018015974A1 (fr) * 2016-07-20 2018-01-25 Mylan Laboratories Limited Formes polymorphes de sélexipag et dispersion solide amorphe de sélexipag
WO2018078383A1 (fr) * 2016-10-27 2018-05-03 Cipla Limited Composition pharmaceutique comprenant du selexipag amorphe
JPWO2019098300A1 (ja) * 2017-11-16 2020-11-19 日本新薬株式会社 放出制御製剤
WO2019098300A1 (fr) * 2017-11-16 2019-05-23 日本新薬株式会社 Formulation à libération contrôlée
US10407396B2 (en) 2017-11-16 2019-09-10 Apotex Inc. Crystalline form of selexipag
US11382912B2 (en) 2017-11-16 2022-07-12 Nippon Shinyaku Co., Ltd. Controlled-release preparation
WO2019157337A1 (fr) * 2018-02-08 2019-08-15 Pulmokine, Inc. Formulations d'inhibiteurs de kinase et de prostanoïdes
CN112055591A (zh) * 2018-02-21 2020-12-08 日本新药株式会社 粒状组合物、粒状组合物的制造方法及粒状组合物的溶出性改善方法
EP3756670A4 (fr) * 2018-02-21 2021-11-03 Nippon Shinyaku Co., Ltd. Composition granulaire, procédé de production d'une composition granulaire et procédé d'amélioration de la propriété d'élution d'une composition granulaire
EP3705115A1 (fr) 2019-03-07 2020-09-09 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition contenant du selexipag
WO2020255157A1 (fr) * 2019-06-20 2020-12-24 Aizant Drug Research Solutions Private Limited Forme posologique solide stable de sélexipag et son procédé de préparation
WO2021152060A1 (fr) * 2020-01-31 2021-08-05 Actelion Pharmaceuticals Ltd Composition de sélexipag à libération contrôlée
WO2023195955A1 (fr) * 2022-04-05 2023-10-12 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Comprimé revêtu d'un film comprenant du sélexi̇pag et son procédé de préparation
WO2023195956A1 (fr) * 2022-04-05 2023-10-12 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Comprimé revêtu d'un film comprenant du sélexi̇pag et au moins une charge

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