Classifications

• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

• the present invention relates to pharmaceutical compositions comprising 2- ⁇ 4-[N-(5,6- diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy ⁇ -N-(methylsulfonyl)acetamide (selexipag, NS-304, ACT-293987; hereinafter COMPOUND) which are suitable for oral administration (p.o.).
• Selexipag was shown to be beneficial in the treatment of pulmonary arterial hypertension for adults.
• 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
• 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).
• Adverse effects associated with PGI2 agonists are also addressed by a particular up- titration schedule.
• the recommended starting dose of oral selexipag for adults is 200 micrograms given twice daily.
• the dose is then increased in increments of 200 micrograms twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 micrograms twice daily. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose.
• Selexipag is a selective IP-receptor agonist for oral use with proven efficacy and safety in adults with PAH. To date, selexipag is the only IP-receptor agonist approved globally for long-term treatment across WHO FC ll-lll and primarily in combination with current first-line oral PAH-specific medicines, in adult patients in need of additional therapy because of insufficient disease control. Selexipag represents an important additional treatment option for these patients.
• Patients with hepatic impairment or patients experiencing drug drug interaction with CYP 2C8 inhibitors may also benefit from a dose adaptation to their condition. Preferably, these patients are adult.
• the present invention provides a means for treating pediatric patients with e.g. PAH, which is effective and safe for children with different age classes, such as 3 2 to ⁇ 6 years of age, 3 6 to ⁇ 12 years of age and 3 12 to ⁇ 18 years of age.
• the present invention provides a means for treating patients with e.g. PAH, suffering from hepatic impairment or experiencing drug drug interaction with CYP 2C8 inhibitors.
• a first embodiment relates to a pharmaceutical composition
• a pharmaceutical composition comprising the compound of formula (I) in the amount of 80 to 170 meg or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof.
• the pharmaceutical composition comprises the compound of formula (I) in the amount of 80 to 160 meg, more preferably in the amount of 90 to 110 ug meg and 140 to 160 meg, and most preferably in the amount of 93 to 107 meg and 143 to 157 meg, e.g. 100 meg with a tolerance of ⁇ 7% and 150 meg with a tolerance of ⁇ 7%. Thereby, the tolerance is applied to a group of 20 tablets.
• a further embodiment relates to the composition according to embodiment 1), further comprising one or more selected from the group consisting of: a) a filler; b) a disintegrant; c) a binder; and d) a lubricant.
• Fillers also referred to as bulking agents or diluents, have several functions, such as diluting the active ingredient within the pharmaceutical composition, they may ensure long-term stabilization or can confer a therapeutic enhancement such as facilitating drug absorption, or enhancing solubility. They may also be useful in the manufacturing process, to aid in the handling of the active substance.
• a disintegrant expands when wet, causing the tablet to break apart, for instance in specific segments of the digestion process, releasing the active ingredient for absorption.
• Binders hold the ingredients in a tablet together. They ensure that tablets and granules can be formed with required mechanical strength.
• Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall.
• a further embodiment relates to the pharmaceutical composition according to embodiment 2), wherein the filler, if present, is one or more selected from the group consisting of: D- mannitol, maize starch, lactose, pregelatinized starch, dibasic calcium phosphate dihydrate (CaHP04 * 2H20), microcrystalline cellulose, and maltodextrin; preferred fillers are D-mannitol and maize starch; the disintegrant, if present, is one or more selected from the group consisting of: low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, and cross-linked polyvinylpyrrolidone; a preferred disintegrant is low substituted hydroxypropyl cellulose; the binder, if present, is one or more selected from the group consisting of: hydroxypropyl cellulose, sucrose, gelatin, starch, pregelatinized starch, alginic acid, sodium alginate, methyl cellulose, ethyl
• a preferred disintegrant is low substituted hydroxypropyl cellulose (L-HPC); lUPAC name: Cellulose, 2-hydroxypropyl ether (low substituted). Particularly preferred is L-HPC with a hydroxypropoxyl content of 7 to 13 %, in particular about 10 to 13 % (in accordance with USP/NF method).
• a preferred binder is hydroxypropyl cellulose (HPC), which is soluble in water due to its large amount of hydroxypropoxyl groups in the cellulose backbone.
• HPC hydroxypropyl cellulose
• lUPAC name Cellulose, 2-hydroxypropyl ether.
• Particularly preferred is a viscosity (mPa*s) in 2% aqueous solution at 20°C of 2.0 to 6.0, preferably 2.0 to 5.9, particularly preferred 2.0 to 2.9.
• the molecular weight (GPC method) is preferably from 34000 to 110000, more preferably from 40000 to 100000, most preferably 40000 ( ⁇ 15 %, preferably ⁇ 10 %).
• a further embodiment relates to the pharmaceutical composition according to any one of embodiments 1) to 3), which comprises
• D-mannitol and maize starch low substituted hydroxypropyl cellulose; hydroxypropyl cellulose; and magnesium stearate.
• a further embodiment relates to the pharmaceutical composition according to any one of embodiments 2) to 4), wherein
• the filler is comprised in an amount from 11.5 to 145.0 mg, preferably from 12.0 to 45.0 mg, for example from 12.0 to 35.0 mg;
• the disintegrant is comprised in an amount from 0.6 to 8.5 mg, preferably from 0.6 to 2.5 mg, for example from 0.7 to 2.0 mg;
• the binder is comprised in an amount from 0.5 to 6.5 mg, preferably from 0.5 to 2.0 mg, for example from 0.5 to 1.5 mg;
• the lubricant is comprised in an amount from 0.2 to 2.5 mg, preferably from 0.2 to 0.7 mg, for example from 0.2 to 0.5 mg.
• a further embodiment relates to the pharmaceutical composition according to any one of embodiments 1) to 5), which comprises
• D-mannitol in an amount from 7.0 to 90.0 mg, preferably from 7.0 to 25.0 mg, for example 7.0 to 20 mg; maize starch in an amount from 4.5 to 60.0 mg, preferably from 4.5 to 20.0 mg, for example from 4.5 to 15.0 mg; low substituted hydroxypropyl cellulose in an amount from 0.6 to 9.0 mg, preferably from 0.6 to 3.0 mg, for example from 0.7 to 1.8 mg; hydroxypropyl cellulose in an amount from 0.5 to 6.5 mg, preferably from 0.5 to 2.0 mg, for example from 0.5 to 1.5 mg; and magnesium stearate is comprised in an amount from 0.2 to 2.5 mg, preferably from 0.2 to 0.7 mg, for example from 0.2 to 0.5 mg.
• a further embodiment relates to the pharmaceutical composition according to any one of embodiments 1) to 6), which is in the form of a tablet or a capsule.
• the pharmaceutical composition is in the form of a tablet.
• the tablets may vary in shape and be, for example, round, oval, oblong, cylindrical, clover-shaped or any other suitable shape. Preferably, the tablets are round.
• Procedures which may be used may be conventional or known in the art or based on such procedures e.g. those described in L. Lachman et al. , The Theory and Practice of Industrial Pharmacy, 3rd Ed., 1986; H. Sucker et al., Pharmazeutician Technologie, Thieme, 1991; Hagers Handbuch der pharmazeutician für für Science, 13th Ed., (Mack Publ., Co., 1970) or later editions.
• a further embodiment relates to the pharmaceutical composition according to embodiment 7), wherein the tablet is coated, the coating material comprising one or more selected from the group consisting of a plasticizer, a film former and a pigment.
• the tablet is film coated.
• film formers are hypromellose, cellulose acetate phthalate (CAP), acrylate polymers, hydroxypropyl methyl cellulose phthalate (HPMCP) or polyvinyl acetate phthalate (PVAP). It is to be noted that the present list is not limiting.
• a preferred film former is hypromellose (INN), also known as hydroxypropyl methylcellulose (HPMC).
• Plasticizers are added to the polymers used as film forming agents in order to make the polymer pliable and soft, enhancing the flexibility and plasticity of the films. They play a vital role in the formulations like gastro-retentive films, ocular films, transdermal films, buccal films, oro-dispersible films and are added to these products to reduce the glass transition temperature facilitating the thermal stability of the drug and other ingredients.
• the plasticizer is a hydrophilic plasticizer.
• hydrophilic plasticizer are glycerine, polyethylene glycols, polyethylene glycol monomethyl ether, propylene glycol, sorbitol sorbitan solution and triethyl citrate. Preferred is propylene glycol.
• a glidant is a substance to be added to improve the powder flow and to reduce the friction or cohesion between particles.
• Common examples are magnesium stearate, Aerosil (colloidal silicon dioxide), starch and talc. Preferred concentrations of the glidant is 5- 10%.
• a preferable coating method used herein is aquatic coating.
• Preferred pigments are titanium dioxide, or iron dioxide in any colour.
• polishing agents may be applied, such as carnauba wax, beeswax or paraffin. Carnauba wax is preferred.
• compositions as defined in embodiment 1) to 9) may additionally comprise further conventional ingredients and/ or additives, which may be used alone or in combination.
• a further preferred excipient is talc, which functions as glidant.
• a further embodiment relates to the pharmaceutical composition according to any embodiment from 7) to 9), wherein the tablet is a mini-tablet with a diameter of 1.5 to 4 mm, preferably 2.5 to 4 mm, more preferably 2.7 to 3.5 mm, most preferably 3 mm ⁇ 0.3 mm.
• the pharmaceutical composition according to the preceding embodiments which is preferably a mini-tablet, has a weight of 12 to less than 50 mg, preferably of 12 to 47 mg.
• composition according to the preceding embodiments is considered “stable”, if during a certain period of time 70%, preferably 80%, more preferably 90% and most preferably 95% of the initial content of compound of formula I, or pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof, is maintained over said period of time.
• the stability of the pharmaceutical composition may be tested in conventional manner, e.g. by measurement of compound of formula I and its degradation products, dissolution, friability, disintegration time, appearance and/or microscopy, e.g. after storage at 25 °C and 60% relative humidity, 30°C and 75% relative humidity and/or storage at 40 °C and 75% relative humidity for defined periods of time.
• the solid compositions of this invention will be stable for at least 6 or 12 months when kept at a temperature of 5 to 50°C. More preferably, they will be stable for at least 6 or 12 months when kept at a temperature of 15 to 45°C. Most preferred, they will be stable for at least 12 or 36 months when kept at a temperature of 25 to 40°C
• the pharmaceutical compositions are stable over a certain period of time such as 1 year, and preferably 2 years. More preferably, the pharmaceutical compositions are stable for 3 to 5 years.
• the mini-tablet according to the invention exhibits particular stability.
• composition is interchangeable with the term “formulation”, or “composition”.
• composition according to the preceding embodiments may be used as a medicament, preferably for oral administration.
• the pharmaceutical composition according to the preceding embodiments may be used as a pediatric medicament.
• the pediatric patients are from 3 2 years to ⁇ 18 years old.
• composition according to the preceding embodiments may further be used in patients with hepatic impairment or patients experiencing drug drug interaction with CYP 2C8 inhibitors such as clopidogrel.
• the pharmaceutical composition may also be used for patients which do not tolerate the starting dose of 200 meg.
• the pharmaceutical composition according to the preceding embodiments is suitable for use in the prevention and/or treatment of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pressure ulcer (bedsore), hypertension, pulmonary hypertension, pulmonary arterial 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 angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute-phase cerebral thrombosis, pulmonary embolism), transient ischemic attack (TIA), diabetic neuropathy,
• hepatocirrhosis hepatocirrhosis, viral hepatitis, chronic pancreatitis and scirrhous stomachic cancer
• 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,
• the pharmaceutical composition according to any one of the preceding embodiments may be used in the prevention or treatment of ulcer, digital ulcer, diabetic gangrene, diabetic foot ulcer, pulmonary hypertension, pulmonary arterial hypertension, 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, or respiratory diseases.
• the pharmaceutical composition according to any one of the preceding embodiments may be used in the prevention or treatment of pulmonary arterial hypertension (PAH).
• PAH pulmonary arterial hypertension
• composition according to any one of the preceding embodiments may be used for the manufacture of a medicament, in particular for a medicament for preventing and/or treating the above-referenced indications.
• the present invention also relates to a method for preventing and/or treating the diseases of embodiment 13).
• a further embodiment of the present invention relates to a process for manufacturing the pharmaceutical composition according to any one of embodiments 1 to 9, comprising the steps of
• step (b) adding a filler and a disintegrant to the blend of step (a) and mixing it;
• step (c) wet-granulating the blend received from step (b) with a solution comprising the binder
• step (d) drying and milling the granulate of step (c);
• the tablet cores are film-coated, dried and polished.
• the tablets are film- coated.
• IP receptor Prostacyclin receptor also termed prostaglandin 12 receptor meg microgram
• the film-coated tablet shown in Table 2 and 3 is a mini-tablet having a diameter of approximately 3 mm, which makes it easy to swallow for children.
• Maize starch and low-substituted hydroxypropylcellulose are then added to the blender. The mixture is blended. iii) Wet granulation
• the blend is transferred into a fluid bed granulator/dryer and a solution of hydroxypropylcellulose in water is sprayed, maintaining the product at a temperature of approximately 30-35 °C. iv) Drying and milling
• the granulate is lubricated with magnesium stearate in a suitable blender. vi) Compression
• the film-coated tablets are polished using carnauba wax. ix) Packaging
• the film-coated tablets are packed in high-density polyethylene bottles with child-resistant polypropylene caps, and containing one desiccant.

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• 2020
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