WO2026032974A1 - Formulation de glurate de linaprazan - Google Patents

Formulation de glurate de linaprazan

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Publication number
WO2026032974A1
WO2026032974A1 PCT/EP2025/072496 EP2025072496W WO2026032974A1 WO 2026032974 A1 WO2026032974 A1 WO 2026032974A1 EP 2025072496 W EP2025072496 W EP 2025072496W WO 2026032974 A1 WO2026032974 A1 WO 2026032974A1
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WO
WIPO (PCT)
Prior art keywords
linaprazan
glurate
formulation
formulation according
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/072496
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English (en)
Inventor
Ramesh Kenchappa
Jeffrey Williamson
Karthikeyan Selvaraj
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cinclus Pharma Holding Publ AB
Original Assignee
Cinclus Pharma Holding Publ AB
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Filing date
Publication date
Application filed by Cinclus Pharma Holding Publ AB filed Critical Cinclus Pharma Holding Publ AB
Publication of WO2026032974A1 publication Critical patent/WO2026032974A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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

Definitions

  • the invention relates to an immediate release oral formulation of linaprazan glurate, comprising a therapeutically effective amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, and hydroxypropyl methylcellulose acetate succinate (HPMC-AS).
  • the formulation provides a rapid release of the active ingredient and furthermore improves the bioavailability.
  • the invention also relates to the use of the oral formulation in the treatment or prevention of a gastrointestinal inflammatory or a gastric acid related disease, such as gastroesophageal reflux disease (GERD), erosive gastroesophageal reflux disease (eGERD) or H. pylori infection.
  • Gastroesophageal reflux disease is a digestive disease that affects the lower esophageal sphincter (the ring of muscle between the esophagus and stomach), which causes retrograde flow of gastric content into the esophagus.
  • Symptoms of GERD include dental corrosion, dysphagia, heartburn, acid regurgitation, non-cardiac chest pain, extraesophageal symptoms such as chronic cough, hoarseness, reflux-induced laryngitis and asthma.
  • GERD When left untreated, GERD may result in complications such as esophagitis (inflammation of the esophagus), esophageal stricture, Barrett's esophagus (a condition involving an abnormal (metaplastic) change in the mucosal cells lining the lower portion of the esophagus), dysplasia and cancer (e.g., MALToma or adenocarcinoma).
  • GERD has a high prevalence in North America and Europe, and a lower (yet increasing) prevalence in Asia. It is estimated that 10% to 20% of the Western population is affected by GERD, but a prevalence of up to 28% has been reported in the United States (El-Serag et al., Gut 2014, vol. 63, p. 871-880). Approximately 133 million people of the adult population in the United States and the EU-30 suffer from reflux disease. Symptoms of GERD are typically treated with proton-pump inhibitors (PPIs), Hz receptor blockers or antacids.
  • PPIs proton-pump inhibitors
  • Hz receptor blockers or antacids.
  • P-CABs Potassium-competitive acid blockers
  • H+/K+ ATPase gastric hydrogen potassium pump
  • PPIs typically 1-2 hours vs. 3-5 days.
  • Linaprazan glurate (5- ⁇ 2-[( ⁇ 8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[l,2-a]pyridine-6- yl ⁇ carbonyl)-amino]ethoxy ⁇ -5-oxopentanoic acid; first disclosed in WO 2010/063876) is a P-CAB currently under development for treatment of GERD. It is a prodrug of linaprazan, which was previously studied in Phase I and II studies. While those studies showed that linaprazan was well tolerated, with a fast onset of action and full effect at first dose, linaprazan was quickly eliminated from the body and had too short duration of acid inhibition.
  • linaprazan glurate has a longer half-life in the body and shows total control of the gastric acid production for a longer time compared to linaprazan. It is therefore expected that administration of linaprazan glurate once or twice daily may provide 24h acid control. Indeed, clinical Phase I and II studies have shown that administration of a single dose of linaprazan glurate can maintain the intragastric acidity above pH 4 for 24 hours. Linaprazan glurate is therefore tailored for patients with severe erosive gastroesophageal reflux disease (eGERD).
  • eGERD severe erosive gastroesophageal reflux disease
  • WO 2021/089580 discloses an immediate release oral tablet formulation of linaprazan glurate, which comprises a surfactant, such as sodium dodecyl sulfate (SDS), in an amount of from about 1.0 to about 12.0% (w/w) relative to the amount of the active ingredient.
  • a surfactant such as sodium dodecyl sulfate (SDS)
  • WO 2023/185624 discloses an oral pharmaceutical formulation of linaprazan glurate, comprising a solid dispersion of amorphous linaprazan glurate and a water-soluble, amphiphilic carrier such as vinylcaprolactam or vinyl acetate. Nevertheless, there is a need for further oral formulations of linaprazan glurate that not only rapidly dissolve in the stomach following oral administration but also provide higher bioavailability of the active ingredient.
  • an oral formulation of linaprazan glurate should provide a doseproportional increase in AUC and C ma x, that is not dependent on the pH of the stomach.
  • FIG. 1 shows the X-ray powder diffractogram of crystalline Form A of linaprazan glurate.
  • FIG. 2 shows the X-ray powder diffractogram of crystalline Form 1 of the HCI salt of linaprazan glurate, as obtained from a slurry of the HCI salt in DMF.
  • FIG. 3 shows a plot of the release of linaprazan glurate from tablets of three different feasibility batches over time.
  • FIG. 4 shows a plot of the release of linaprazan glurate from tablets of the optimized formulation over time.
  • FIG. 5 shows a plot of the mean linaprazan plasma concentration over time for treatments A (reference formulation, fasted), B (test formulation, fasted) and C (test formulation, fed).
  • FIG. 6 shows a plot of the mean logarithmic linaprazan plasma concentration over time for treatments A (reference formulation, fasted), B (test formulation, fasted) and C (test formulation, fed).
  • FIG. 7 shows a plot of the mean linaprazan glurate plasma concentration over time for treatments A (reference formulation, fasted), B (test formulation, fasted) and C (test formulation, fed).
  • FIG. 8 shows a plot of the mean logarithmic linaprazan glurate plasma concentration over time for treatments A (reference formulation, fasted), B (test formulation, fasted) and C (test formulation, fed).
  • FIG. 9 shows a 24-hour plot of the mean intragastric pH upon treatment with 25, 50 or 75 mg linaprazan glurate QD at day 1.
  • FIG. 10 shows a 24-hour plot of the mean intragastric pH upon treatment with 25, 50 or 75 mg linaprazan glurate QD at day 14.
  • FIG. 11 shows a 24-hour plot of the mean intragastric pH upon treatment with 25, 50 or 75 mg linaprazan glurate BID at day 1.
  • FIG. 12 shows a 24-hour plot of the mean intragastric pH upon treatment with 25, 50 or 75 mg linaprazan glurate BID at day 14. DETAILED DESCRIPTION OF THE INVENTION
  • Hydroxypropyl methylcellulose acetate succinate (also referred to as hypromellose acetate succinate or HPMC-AS) is a polymer that is commonly used in oral pharmaceutical formulations as a film coating, as well as an enteric coating material for tablets or granules. It is insoluble in gastric fluid but will swell and dissolve rapidly in the upper intestine (Handbook of Pharmaceutical Excipients, 6th edition, Pharmaceutical Press and the American Pharmacists Association, 2009, p. 330-332). HPMC-AS is also known for its properties to enhance solubility and inhibit precipitation to achieve supersaturation of poorly soluble drugs.
  • HPMC-AS has frequently been used in solid dispersions of poorly water-soluble drugs, and in particular in amorphous solid dispersions, i.e., solid dispersions of amorphous drugs (see e.g., Ueda et al., Int. J. Pharm. 2014, vol. 464, p. 205-213; Friesen et al., Mol. Pharmaceutics 2008, vol. 5, p. 1003-1019; Konno et al., Eur. J.
  • the invention relates to an immediate release formulation of linaprazan glurate for oral administration, comprising a therapeutically effective amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, and hydroxypropyl methylcellulose acetate succinate (HPMC-AS).
  • HPMC-AS hydroxypropyl methylcellulose acetate succinate
  • linaprazan glurate is present in crystalline form.
  • linaprazan glurate is present as a crystalline form of the free base of linaprazan glurate.
  • linaprazan glurate is present as a crystalline form of a pharmaceutically acceptable salt of linaprazan glurate.
  • the ratio of the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, to the amount of HPMC-AS is between about 70:30 and about 30:70 (w/w), such as about 65:35, about 60:40, about 55:45, about 50:50, about 45:55, about 40:60, about 35:65 (w/w). In a preferred embodiment, the ratio of the amount of linaprazan glurate or a pharmaceutically acceptable salt thereof, to the amount of HPMC-AS is about 50:50 (w/w).
  • the amount of HPMC-AS in the formulation is from about 15 to about 30% (w/w), such as from about 15 to about 20% (w/w), or such as from about 20 to about 25% (w/w), or such as from about 25 to about 30% (w/w). In some embodiments, the amount of HPMC-AS in the formulation is about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27 , about 28, about 29 or about 30% (w/w).
  • the amount of linaprazan glurate, or a pharmaceutical acceptable salt thereof, in the formulation is from about 15 to about 30% (w/w), such as from about 15 to about 20% (w/w), such as from about 20 to about 25% (w/w), or such as from about 25 to about 30% (w/w). In some embodiments, the amount of linaprazan glurate, or a pharmaceutical acceptable salt thereof, in the formulation is about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25, about 26, about 27 , about 28, about 29 or about 30% (w/w).
  • HPMC-AS is available in several grades, based on the pH at which the polymer starts to dissolve (L - low; M - medium; and H - high) and the predominant particle size of the polymer (F - fine; M - medium; and G - granular).
  • the low, medium and high grades of HPMC-AS have different chemical substitution levels of the acetyl and succinoyl groups, resulting in an opening pH range (the lowest pH at which the polymer starts to dissolve) from 5.5 to 6.5. Accordingly, HPMC-AS LF grade has an opening pH >5.5, HPMC-AS MF grade has an opening pH >6.0, and HPMC-AS HF grade has an opening pH >6.5.
  • the HPMS-AS is HF grade.
  • the formulation may additionally comprise excipients such as fillers, surfactants, disintegrants, lubricants and glidants.
  • suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (such as lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starches and pregelatinized starch.
  • the filler is mannitol.
  • the formulation does not comprise microcrystalline cellulose.
  • the surfactant may be a cationic surfactant, an anionic surfactant or a nonionic surfactant.
  • cationic surfactants include, but are not limited to, cetyltrimethylammonium bromide (cetrimonium bromide) and cetylpyridinium chloride.
  • anionic surfactants include, but are not limited to, sodium dodecyl sulfate (sodium lauryl sulfate) and ammonium dodecyl sulfate (ammonium lauryl sulfate).
  • nonionic surfactants include, but are not limited to, glycerol monooleate, glycerol monostearate, polyoxyl castor oil (Cremophor EL), poloxamers (e.g., poloxamer 407 or 188), polysorbate 80 and sorbitan esters (Tween).
  • the surfactant is a nonionic surfactant.
  • the nonionic surfactant is a poloxamer, more preferably poloxamer 188.
  • suitable disintegrants include, but are not limited to, dry starch, modified starch (such as (partially) pregelatinized starch, sodium starch glycolate and sodium carboxymethyl starch), alginic acid, cellulose derivatives (such as sodium carboxymethylcellulose, hydroxypropyl cellulose, and low substituted hydroxypropyl cellulose (L-HPC)) and cross-linked polymers (such as carmellose, croscarmellose sodium, carmellose calcium and cross-linked PVP (crospovidone)).
  • the disintegrant is croscarmellose sodium.
  • the formulation does not comprise crospovidone.
  • Suitable lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, colloidal anhydrous silica, aqueous silicon dioxide, synthetic magnesium silicate, fine granulated silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (such as carnauba wax), hydrogenated oil, sodium benzoate, polyethylene glycol, and mineral oil.
  • the lubricant is magnesium stearate.
  • the formulation does not comprise sodium stearyl fumarate.
  • glidants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, colloidal anhydrous silica, synthetic magnesium silicate, fine granulated silicon oxide.
  • the glidant is colloidal anhydrous silica.
  • the formulation comprises a therapeutically effective amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, and hydroxypropyl methylcellulose acetate succinate (HPMC-AS), and one or more of a filler, a surfactant, a disintegrant, a lubricant and a glidant.
  • HPMC-AS hydroxypropyl methylcellulose acetate succinate
  • the formulation comprises a therapeutically effective amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, and hydroxypropyl methylcellulose acetate succinate (HPMC-AS), and a filler, a surfactant, a disintegrant, a lubricant and a glidant.
  • the formulation comprises a therapeutically effective amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, and hydroxypropyl methylcellulose acetate succinate (HPMC-AS), mannitol, poloxamer 188, croscarmellose sodium, magnesium stearate, and colloidal anhydrous silica.
  • linaprazan glurate is present as a crystalline anhydrate (i.e., a crystalline form of the free base of linaprazan glurate), such as disclosed in US 2022/0002297.
  • the crystalline anhydrate of linaprazan glurate is Form A, having an X-ray powder diffraction (XRPD) pattern, obtained with CuKal-radiation, with at least peaks at °20 values of 9.9 ⁇ 0.2 and 11.5 ⁇ 0.2.
  • Form A has an X-ray powder diffraction pattern, obtained with CuKal-radiation, with at least peaks at 9.9 ⁇ 0.2 and 11.5 ⁇ 0.2 and one or more of 8.4 ⁇ 0.2, 15.5 ⁇ 0.2 and 16.8 ⁇ 0.2.
  • Form A has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 values of 8.4 ⁇ 0.2, 9.9 ⁇ 0.2, 11.5 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 23.5 ⁇ 0.2, 24.9 ⁇ 0.2 and 25.5 ⁇ 0.2.
  • Form A has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 values of 8.4 ⁇ 0.2, 9.9 ⁇ 0.2, 11.5 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 23.5 ⁇ 0.2, 24.9 ⁇ 0.2 and 25.5 ⁇ 0.2, and one or more of 18.2 ⁇ 0.2, 18.4 ⁇ 0.2, 21.0 ⁇ 0.2, 21.2 ⁇ 0.2 and 23.3 ⁇ 0.2.
  • Form A has an XRPD pattern, obtained with CuKal- radiation, substantially as shown in Figure 1.
  • linaprazan glurate is present as a pharmaceutically acceptable salt of linaprazan glurate, more preferably as a crystalline form of a pharmaceutically acceptable salt of linaprazan glurate.
  • suitable examples of pharmaceutically acceptable salts of linaprazan glurate include, but are not limited to, a hydrochloride salt (WO 2023/079094), a hydrobromide salt (WO 2024/149834), a mesylate salt (WO 2023/079093) or a maleate salt (WO 2004/149833).
  • linaprazan glurate is present as a hydrochloride salt of linaprazan glurate.
  • linaprazan glurate is present as a crystalline hydrochloride salt of linaprazan glurate, such as disclosed in WO 2023/079094. In some embodiments, linaprazan glurate is present as a crystalline anhydrate of the HCI salt of linaprazan glurate.
  • the crystalline anhydrate of the HCI salt of linaprazan glurate is Form 1, having an X-ray powder diffraction (XRPD) pattern, obtained with CuKal-radiation, with at least two peaks at °20 values selected from the list consisting of 9.1 ⁇ 0.2, 13.8 ⁇ 0.2, 14.0 ⁇ 0.2, 20.0 ⁇ 0.2, 22.9 ⁇ 0.2, 23.4 ⁇ 0.2, 24.4 ⁇ 0.2, 24.6 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 values of 20.0 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, with at least four peaks at °20 values selected from the list consisting of 9.1 ⁇ 0.2, 13.8 ⁇ 0.2, 14.0 ⁇ 0.2, 20.0 ⁇ 0.2, 22.9 ⁇ 0.2, 23.4 ⁇ 0.2, 24.4 ⁇ 0.2, 24.6 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal- radiation, with at least peaks at °20 values of 20.0 ⁇ 0.2, 24.4 ⁇ 0.2, 24.6 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal- radiation, with at least peaks at °20 values of 20.0 ⁇ 0.2, 24.4 ⁇ 0.2, 24.6 ⁇ 0.2 and 26.7 ⁇ 0.2, and or more of 9.1 ⁇ 0.2, 13.8 ⁇ 0.2, 14.0 ⁇ 0.2, 22.9 ⁇ 0.2 and 23.4 ⁇ 0.2.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 values of 9.1 ⁇ 0.2, 13.8 ⁇ 0.2, 20.0 ⁇ 0.2, 23.4 ⁇ 0.2, 24.4 ⁇ 0.2, 24.6 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal- radiation, with at least peaks at °20 values of 9.1 ⁇ 0.2, 13.8 ⁇ 0.2, 14.0 ⁇ 0.2, 20.0 ⁇ 0.2, 22.9 ⁇ 0.2, 23.4 ⁇ 0.2, 24.4 ⁇ 0.2, 24.6 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, with at least peaks at °20 values of 9.1 ⁇ 0.2, 13.8 ⁇ 0.2, 14.0 ⁇ 0.2, 20.0 ⁇ 0.2, 22.9 ⁇ 0.2, 23.4 ⁇ 0.2, 24.4 ⁇ 0.2, 24.6 ⁇ 0.2 and 26.7 ⁇ 0.2, and one or more of 16.2 ⁇ 0.2, 18.6 ⁇ 0.2, 22.2 ⁇ 0.2, 25.6 ⁇ 0.2 and 27.9 ⁇ 0.2.
  • Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, substantially as shown in Figure 2.
  • the formulation is in the form of a unit dose.
  • a unit dose form such as a tablet or a capsule, may contain about 10 to about 250 mg of linaprazan glurate, or a pharmaceutically acceptable salt thereof, such as about 10 to about 225 mg, about 10 to about 200 mg, about 10 to about 175 mg, about 10 to about 150 mg, about 10 to about 125 mg, about 10 to about 100 mg, about 10 to about 75 mg, about 10 to about 50 mg, about 10 to about 25 mg, about 25 to about 225 mg, about 25 to about 200 mg, about 25 to about 175 mg, about 25 to about 150 mg, about 25 to about 125 mg, about 25 to about 100 mg, about 25 to about 75 mg, about 25 to about 50 mg, about 50 to about 225 mg, about 50 to about 200 mg, about 50 to about 175 mg, about 50 to about 150 mg, about 50 to about 125 mg, about 50 to about 100 mg, about 50 to about 75 mg, about 75 to about 225 mg, about 75 to about 200 mg, about 75 to
  • a unit dose form such as a tablet or a capsule, contains about 10 to about 20 mg, about 20 to about 30 mg, about 30 to about 40 mg, about 40 to about 50 mg, about 50 to about 60 mg, about 60 to about 70 mg, about 70 to about 80 mg, about 80 to about 90 mg, about 90 to about 100 mg, about 100 to about 110 mg, about 110 to about 120 mg, about 120 to about 130 mg, about 130 to 140 mg, or about 140 to about 150 mg of linaprazan glurate, or a pharmaceutically acceptable salt thereof.
  • a unit dose form such as a tablet or a capsule, contains about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg of linaprazan glurate, or a pharmaceutically acceptable salt thereof.
  • a unit dose form such as a tablet or a capsule, contains about 25 mg of linaprazan glurate, or a pharmaceutically acceptable salt thereof. In another preferred embodiment, a unit dose form, such as a tablet or a capsule, contains about 50 mg of linaprazan glurate, or a pharmaceutically acceptable salt thereof. In another preferred embodiment, a unit dose form, such as a tablet or a capsule, contains about 75 mg of linaprazan glurate, or a pharmaceutically acceptable salt thereof. In yet another preferred embodiment, a unit dose form, such as a tablet or a capsule, contains about 100 mg of linaprazan glurate, or a pharmaceutically acceptable salt thereof.
  • a unit dose of the formulation comprises about 15 to about 30% w/w linaprazan glurate, or a pharmaceutically acceptable salt thereof; about 15 to about 30% w/w HPMC-AS; about 35 to about 60% w/w mannitol; about 4 to about 6% croscarmellose sodium; and from 0 to about 5% w/w of other excipients; wherein the relative amounts of the ingredients add up to 100%.
  • a unit dose of the formulation comprises about 15 to about 20% w/w linaprazan glurate, or a pharmaceutically acceptable salt thereof; about 15 to about 20% w/w HPMC-AS; about 55 to about 60% w/w mannitol; about 4 to about 6% croscarmellose sodium; and from 0 to about 5% w/w of other excipients; wherein the relative amounts of the ingredients add up to 100%.
  • a unit dose of the formulation has the following composition: Table 1. Ingredients per 25 or 100 mg API formulation.
  • the formulation is a capsule containing e.g., a powder or a granulate of a mixture of the active pharmaceutical ingredient (API) and one or more excipients.
  • Such capsules are conventionally made from gelatine, a cellulose based polymer such as hydroxypropyl methylcellulose (hypromellose), or a polysaccharide-based polymer such as pullulan, and easily disintegrate under the acidic conditions in the stomach. The contents of the capsules are thereby quickly released into the stomach.
  • a capsule formulation has the following composition:
  • the formulation is a tablet, more preferably a compressed tablet.
  • Compressed tablets may be prepared by techniques known in the art, such as by direct compression of a powder mixture of the active pharmaceutical ingredient (API) and one or more excipients, or by the compression of a granulate comprising the active pharmaceutical ingredient (API) and one or more excipients.
  • Granulates may be prepared by techniques known in the art, such as by dry granulation of a powder mixture of the active pharmaceutical ingredient (API) and one or more excipients; or by wet granulation of a mixture of the active pharmaceutical ingredient (API), one or more excipients and a suitable solvent such a water, followed by drying of the granulate. Granulates may be compressed as obtained, or may be milled and/or sieved prior to compression, so as to reduce the particle size of the granulate.
  • a tablet of the formulation is prepared by compression of a granulate.
  • the granulate is milled prior to compression.
  • a suitable method for the preparation of tablets of the present formulation is disclosed in the experimental section.
  • a tablet formulation has the following composition:
  • a tablet formulation additionally comprises an outer coating to facilitate swallowing of the formulation.
  • Such coatings typically comprise a water-soluble polymer such as cellulose ether derivates (e.g., methylcellulose or hydroxypropyl methylcellulose (HPMC)), polyvinyl alcohol and polyvinylpyrrolidone, and may comprise further agents such as coloring agents and lubricants.
  • the coating comprises polyvinyl alcohol and/or hydroxypropyl methylcellulose.
  • the coating is Opadry® EZ.
  • the coating is Opadry® TF.
  • the coating may be added to the formulation using conventional techniques known in the art, such as spray drying.
  • the coating may be added to the formulation in an amount up to about 5% of the weight of the uncoated formulation, such as about 1%, about 2%, about 3%, about 4% or about 5% of the weight of the uncoated formulation.
  • the amount of in vitro dissolved active ingredient may be determined e.g., as described in USP ⁇ 711>, and may be expressed as a percentage of the labeled content of the dosage unit.
  • at least 70% of linaprazan glurate is dissolved after 15 minutes in aqueous solution at pH 4.5, for each out of 6 individual dosage units.
  • the formulation disclosed herein has significant advantages. As shown in the experimental section, the formulation is able to provide a rapid release of linaprazan glurate. Clinical trials have also shown that the bioavailability of linaprazan glurate was significantly increased when compared with a previous formulation of the same compound. In particular, the PK data showed that linaprazan plasma exposures increased approximately in proportion to dose with no apparent deviation from timeindependent PK. It was also shown that the pH of the stomach increased with dosing. Additionally, it was found that the intersubject variability in linaprazan exposure was lower than for the previous formulation. PD-data furthermore showed that the formulation is able to provide a rapid increase in gastric pH after the first dose, with a clear dose-response pattern.
  • the oral formulation disclosed herein may be used in the treatment of prevention of a gastrointestinal inflammatory disease or a gastric acid related diseases, such as gastritis, gastroesophageal reflux disease (GERD), erosive gastroesophageal reflux disease (eGERD), non-erosive gastroesophageal reflux disease (NERD), esophagitis, eosinophilic esophagitis (EoE), H.
  • GERD gastroesophageal reflux disease
  • eGERD erosive gastroesophageal reflux disease
  • NERD non-erosive gastroesophageal reflux disease
  • EoE eosinophilic esophagitis
  • the invention relates to the oral formulation disclosed herein for use in the treatment or prevention of a gastrointestinal inflammatory disease or a gastric acid related disease.
  • the invention relates to the use of the oral formulation disclosed herein for the treatment or prevention of a gastrointestinal inflammatory disease or a gastric acid related disease.
  • the invention relates to a method of treating or preventing a gastrointestinal inflammatory disease or a gastric acid related disease in a subject, such as man, comprising administering to the subject in need of such treatment or prevention a therapeutically effective amount of the oral formulation disclosed herein.
  • the gastrointestinal inflammatory or gastric acid related disease is H. pylori infection. In some embodiments, the gastrointestinal inflammatory or gastric acid related disease is gastroesophageal reflux disease (GERD). In some embodiments, the gastrointestinal inflammatory or gastric acid related disease is erosive gastroesophageal reflux disease (eGERD).
  • GGERD gastroesophageal reflux disease
  • eGERD erosive gastroesophageal reflux disease
  • the severity of esophagitis is typically indicated using the Los Angeles (LA) classification of reflux esophagitis, which is based on an endoscopic assessment of the patient.
  • LA grade scoring system divides reflux esophagitis into four categories (LA grade A to D) based on the extent of esophageal mucosal breaks.
  • the mildest form, LA grade A esophagitis is defined as one or more mucosal breaks not longer than 5 mm, that do not extend between the tops of two mucosal folds.
  • LA grade B esophagitis is defined as one or more mucosal breaks longer than 5 mm that do not extend between the tops of two mucosal folds.
  • LA grade C esophagitis is defined as one or more mucosal breaks that are continuous between the tops of two mucosal folds, but which involves less than 75% of the esophageal circumference.
  • the most severe form, LA grade D esophagitis is defined as one or more mucosal breaks involving at least 75% of the esophageal circumference (Lundell et al., Gut 1999, vol. 45, p. 172-180).
  • the GERD or eGERD is LA grade A.
  • the GERD or eGERD is LA grade B.
  • the GERD or eGERD is LA grade C.
  • the GERD or eGERD is LA grade D.
  • the oral formulation is administered once or twice daily in a dose of about 25 to about 100 mg linaprazan glurate, or a pharmaceutically acceptable salt thereof, such as from about 25 to about 75 mg, such as from about 25 to about 50 mg, such as from about 50 to about 100 mg, such as from about 50 to about 75 mg, or such as from about 75 to about 100 mg.
  • the oral formulation is administered once daily in a dose of about 25 mg linaprazan glurate, or a pharmaceutically acceptable salt thereof.
  • the oral formulation is administered twice daily in a dose of about 25 mg linaprazan glurate, or a pharmaceutically acceptable salt thereof.
  • the oral formulation is administered once daily in a dose of about 50 mg linaprazan glurate, or a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation is administered twice daily in a dose of about 50 mg linaprazan glurate, or a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation is administered once daily in a dose of about 75 mg linaprazan glurate, or a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation is administered twice daily in a dose of about 75 mg linaprazan glurate, or a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation is administered once daily in a dose of about 100 mg linaprazan glurate, or a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation is administered twice daily in a dose of about 100 mg linaprazan glurate, or a pharmaceutically acceptable salt thereof.
  • the oral formulation is administered on demand. In some embodiments, the oral formulation is administered for at least 1 week. In some embodiments, the oral formulation is administered for at least 2 weeks. In some embodiments, the oral formulation is administered for at least 3 weeks. In some embodiments, the oral formulation is administered for at least 4 weeks. In some embodiments, the oral formulation is administered for at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks or at least 10 weeks. In some embodiments, the oral formulation is administered for at least 3 months, at least 6 months, at least 9 months or at least 12 months.
  • the oral formulation is administered in a dose of from about 25 to about 100 mg twice daily for 4 weeks.
  • the daily dose can be administered as a single dose or divided into one, two, three or more unit doses.
  • the oral formulation is administered at least 30 minutes prior to meals. In some embodiments, the oral formulation is administered within 30 minutes of the consumption of a meal. Definitions
  • the term "about” refers to a value or parameter herein that includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about 20” includes description of "20". Numeric ranges are inclusive of the numbers defining the range. Generally speaking, the term “about” refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value (e.g., within the 95% confidence interval for the mean) or within 10 percent of the indicated value, whichever is greater.
  • an “effective amount” and “therapeutically effective amount” refer to a sufficient amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, that, following administration to a subject, will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” for therapeutic use is the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, required to provide a clinically significant decrease in disease symptoms.
  • An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • the terms “subject,” “individual,” or “patient,” used interchangeably, refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are suitable for human pharmaceutical use and that are generally safe, non-toxic and neither biologically nor otherwise undesirable.
  • the terms “twice daily” and “BID” (bis in die) refer to administration of a drug at two different times during the day, such as separated by at least about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours.
  • twice daily refers to once in the morning and once in the evening.
  • Administration of two or more unit doses (e.g., pills, tablets or capsules) of a drug at a single time during the day is considered once daily administration, whereas administration of two or more unit doses (e.g., pills, tablets or capsules) of a drug at two different times during the day is considered twice daily administration.
  • crystalline form and “polymorph” refer to crystals of the same molecule that have different physical properties as a result of the order of the molecules in the crystal lattice.
  • Polymorphs of a single compound have one or more different chemical, physical, mechanical, electrical, thermodynamic, and/or biological properties from each other. Differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in composition and product manufacturing), dissolution rates (an important factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water sorption, compaction, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g.
  • a dosage form discolours more rapidly when comprised of one polymorph than when comprised of another polymorph
  • mechanical changes e.g., crystal changes on storage as a kinetically favoured polymorph converts to a thermodynamically more stable polymorph
  • one polymorph is more hygroscopic than the other.
  • solubility/dissolution differences some transitions affect potency and/or toxicity.
  • the physical properties of the crystal may be important in processing; for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities ( i.e., particle shape and size distribution might be different between one polymorph relative to the other).
  • Polymorph does not include amorphous forms of the compound.
  • anhydrate or “anhydrous form” refers to a crystalline form of linaprazan glurate, or a pharmaceutically acceptable salt thereof, that has 0.5% or less by weight water, for example 0.4% or less, or 0.3% or less, or 0.2% or less, or 0.1% or less by weight water.
  • the term “stable” means that the crystalline forms (i.e., polymorphs) do not exhibit a change in one or more of polymorph form (e.g., an increase or decrease of a certain form), appearance, pH, percent impurities, activity (as measured by in vitro assays), or osmolarity over time.
  • the polymorphs provided herein are stable for at least 1, 2, 3 or 4 weeks.
  • the polymorphs do not exhibit a change in one or more of polymorph form (e.g., an increase or decrease of a certain form), appearance, pH, percent impurities, activity (as measured by in vitro assays), or osmolarity over at least 1, 2, 3 or 4 weeks.
  • the polymorphs provided herein are stable for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months.
  • the polymorphs do not exhibit a change in one or more of polymorph form (e.g., an increase or decrease of a certain form), appearance, pH, percent impurities, activity (as measured by in vitro assays), or osmolarity over at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months.
  • the phrase "do not exhibit a change” refers to a change of less than 5% (e.g., less than 4%, less than 3%, less than 2%, less than 1%) as measured for any of the parameters over the relevant time period.
  • pre-blend Approximately 200 g of pre-blend (intra-granular) was manufactured. All the intra-granular ingredients except the disintegrant (croscarmellose sodium or crospovidone) and the lubricant (magnesium stearate or sodium stearyl fumarate) were dispensed, passed through a 20 mesh screen and blended in a 1 liter Diosna high shear granulator bowl for 5 minutes at 400 rpm impeller speed and 600 rpm chopper speed. The high shear blended ingredients and the disintegrant (croscarmellose sodium or crospovidone; passed through a 20 mesh screen) were then combined in a 2 qt. V-shell blender and blended for 10 minutes at 25 rpm (250 revolutions).
  • disintegrant croscarmellose sodium or crospovidone
  • lubricant magnesium stearate or sodium stearyl fumarate
  • the lubricant magnesium stearate or sodium stearyl fumarate; passed through a 40 mesh screen
  • the lubricant was added and mixed with the other ingredients in the blender for 3 minutes at 25 rpm (75 revolutions) to obtain a lubricated pre-blend.
  • Pre-blend (about 195 to 260 g) was loaded on a TFC lab micro roller compactor installed with 'S' rolls (noninterlocking rolls) operated at a roll speed of about 0.9 to 1.6 rpm, screw speed of about 15 to 22 rpm, and roll force of about 5 to 6 Mpa.
  • the collected ribbons were passed through a Co-mil 197 installed with a 0.052" grated screen and then passed through an 18 mesh screen. At the end of comilling and 18 mesh screening, about 140 to 220 g of milled granules were produced.
  • the bulk milled granules were weighed to adjust the weight of the extra-granular ingredients.
  • the filler mannitol or microcrystalline cellulose; passed through a 20 mesh screen
  • the disintegrant croscarmellose sodium or crospovidone; passed through a 20 mesh screen
  • Colloidal silicon dioxide was passed through a 20 mesh screen and blended with the other ingredients for 5 minutes at 25 rpm (125 revolutions).
  • the lubricant magnesium stearate or sodium stearyl fumarate; passed through a 40 mesh screen was added and blended with the other ingredients for 3 minutes at 25 rpm (75 revolutions) to obtain the final blend.
  • Compression was performed using a RIVA Piccola B-10 tablet press, equipped with one set of 0.3060" x 0.6130" capsule shaped tooling.
  • the tablet press was adjusted to get the target weight of 600 mg (+/- 5% range 570.0 mg - 630.0 mg) and the hardness range of 12.0 - 15.0 kP.
  • the press speed was maintained at about 20 rpm. At this setup, compression was completed in about 10 to 15 minutes. Core tablets were submitted for dissolution testing.
  • the release of the active ingredient (linaprazan glurate) from tablets of the three different batches was determined in an in vitro dissolution test, according to USP ⁇ 711>. Briefly, dissolution testing was performed in 900 mL of acetate buffer at pH 4.5 and containing 0.2% SDS, using USP apparatus 2 and paddle rotation at 50 rpm (after 45 min paddle rotation at 250 rpm). The results are shown in table 5 below. A plot of the release of linaprazan glurate from tablets of the three different feasibility batches over time is shown in Figure 3.
  • Pre-blend About 1259 g of pre-blend was prepared. All the intra-granular ingredients except croscarmellose sodium and magnesium stearate were mixed in a 6 L high shear granulator bowl for 5 minutes at 400 rpm impeller and 600 rpm chopper speed. The blend was then mixed with croscarmellose sodium (20 mesh sieved) in an 8 quart V-shell blender for 10 minutes at 25 rpm (250 revolutions). This blend was lubricated with magnesium stearate (40 mesh sieved) for 3 minutes at 25 rpm (75 revolutions).
  • Roller compacted milled granules and fines were weighed to adjust the weight of the extra-granular ingredients. Fines and roller compacted milled granules were transferred to an 8 quart V-shell and blended for 5 minutes at 25 rpm (125 revolutions). Extra-granular mannitol (20 mesh sieved) was transferred to the contents in the V-shell and mixed for 10 minutes at 25 rpm (250 revolutions). The recalculated quantity of croscarmellose sodium was passed through a 20 mesh screen and blended with the contents for 10 minutes at 25 rpm (250 revolutions). Colloidal silicon dioxide was passed through a 20 mesh screen and mixed with the ingredients for 5 minutes at 25 rpm (125 revolutions). Finally, magnesium stearate was passed through a 40 mesh screen and added to the blend and mixed for 3 minutes at 25 rpm (75 revolutions) to obtain the final blend.
  • Compression was performed using a RIVA Piccola B-10 tablet press installed with two sets of 0.3060" x 0.6130" capsule shaped tooling along with the force feeder and 15 mm weight cam. Compression profile was performed at low and high hardness 23argeting 8 kP and 20 kP. Samples were collected at each of these targets and weight, thickness and hardness values were recorded; tablets generated at each hardness were within the 600 mg weight range (+/- 5%) with tablets collected at 7.3 - 10.5 kP and 16.0 - 25.8 kP, respectively, for the compression profile. Compression continued with the remaining blend at the target weight of 600 mg (+/- 5% range 570.0 mg - 630.0 mg) and the hardness range of 12.0 - 15.0 kP.
  • Blend flow from the hopper to the feed frame was consistent, allowing for uniform tablet fill weight. Press speed was maintained at about 23 rpm. At this setup, compression was completed in about 45 minutes, producing about 2150 tablets (about 1296 g). Core tablets were packaged for informal stability testing.
  • the release of the active ingredient (linaprazan glurate) from tablets of the optimized formulation was determined in an in vitro dissolution test, as described in Example 1. The results are shown in table 7 below. A plot of the release of linaprazan glurate from the formulation over time is shown in Figure 4. Table 7. Release of linaprazan glurate from tablet of the optimized formulation.
  • test formulation A single-center, open-label, randomized, single dose, 3-way crossover study in healthy volunteers was performed to evaluate the relative bioavailability of the formulation of example 2 ("test formulation") in comparison with a reference formulation under fasting conditions, and to assess the effect of a high- fat, high-calorie meal on the PK of linaprazan glurate and the active substance linaprazan after the administration of the test formulation.
  • the reference formulation corresponds to the formulation disclosed in WO 2021/089580, and contained 25 mg of crystalline anhydrate of linaprazan glurate (Form A). All tablets were administered orally.
  • Subjects participating in the study were to attend 4 in-person visits to the study clinic, namely a screening visit (Visit 1) followed by 3 treatment visits (Visits 2, 3 and 4).
  • the treatment visits were separated by wash-out periods of a minimum of 5 days, corresponding to approximately 5 half-lives of the active substance linaprazan.
  • the treatment visits were followed by a remote follow-up/end-of- study visit via telephone (Visit 5), 7 days ( ⁇ 2 days) after the final dose.
  • Visit 1 Screening (Visit 1) took place within 28 days prior to the start of treatment and included an eligibility check, collection of demographic and medical history data as well as a review of health status, including a physical examination and collection of ECGs, vital signs and safety laboratory blood samples. Eligible subjects were admitted to the study clinic on Day -1 of Visit 2 and remained at the study clinic until Day 2 (residential period). After admission, each subject's eligibility was confirmed, a physical examination was conducted, and baseline safety laboratory blood samples, 12 lead safety ECGs, and vital signs were collected. Study clinic admission on Visits 3 and 4 followed the same procedure, except for the confirmation of eligibility.
  • Treatment A 100 mg linaprazan glurate reference formulation (4x25 mg oral tablets) in fasting conditions.
  • Treatment B 100 mg linaprazan glurate test formulation (1x100 mg oral tablet) in fasting conditions.
  • Treatment C 100 mg linaprazan glurate test formulation (1x100 mg oral tablet) in fed conditions.
  • subjects Following an overnight fast of at least 10 hours, subjects had to consume a high-fat, high-calorie breakfast meal within 30 minutes, and were administered the IMP 30 minutes after start of the meal together with 240 mL of tap water. Subjects were instructed not to chew or crush the tablets. Water, but no other drinks, were allowed ad libitum, except from 1 hour before dosing to 30 minutes after dosing. No food was allowed for at least 4 hours post-dose.
  • the high-fat, high-calorie breakfast consisted of the following: 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces (113 g) of hash brown potatoes, and 8 ounces (236 mL) of whole milk.
  • This test meal derives approximately 150 kcal from protein, 250 kcal from carbohydrates, and 500-600 kcal from fat.
  • Day 1 On dosing day (Day 1) of Visits 2, 3 and 4, following randomization during Visit 2 and at corresponding time-points during Visits 3 and 4, subjects were administered single doses of investigational medicinal product (IMP) (dosing). Subjects were carefully monitored by clinical staff during and after dosing. Vital signs and 12 lead safety ECGs were assessed at 4 hours post-dose. AEs and the use of concomitant medications was recorded from first dose on Day 1.
  • IMP investigational medicinal product
  • PK blood samples were to be collected pre-dose (within -01:00 hh:mm prior dosing) and at 00:15, 00:30, 01:00, 01:15, 01:30, 02:00, 03:00, 04:00, 06:00, 08:00, 12:00, 14:00, 20:00, 24:00, 36:00, 48:00 and 72:00 hh:mm post-dose.
  • Subjects were temporarily discharged from the study clinic after the 36-hour PK blood sample on Day 2 and returned to the study clinic on the morning of Day 3 and again on the morning of Day 4 for PK blood sampling at 48 and 72 hours post-dose, respectively.
  • formal discharge procedures took place, including safety laboratory, physical examination, vital signs and 12- lead safety ECG assessments as well as the collection of AEs and uses of concomitant medications.
  • a final remote follow-up visit (Visit 5) was conducted via telephone 7 days ( ⁇ 2 days) after the final dose of IMP, or after early withdrawal, to follow-up on AEs and concomitant medications.
  • Visit 5 counted as each subject's end-of-study visit, and the date of last subject's end-of-study visit counted as the overall end-of-study date.
  • Subjects were expected to participate in the study for approximately 49 days. Including the up to 28-day screening period and approximately 3 weeks of treatment and follow-up.
  • the bioavailability of linaprazan was approximately 2-fold higher from the test formulation than from the reference formulation following a dose of 100 mg with geometric LS mean ratio (90% Cl) of 2.00 (1.83-2.16) for AUC inf , 2.12 (1.97-2.30) for AUCi ast and 2.32 (2.09-2.57) for C max .
  • the intersubject variability in linaprazan exposure was lower for the test formulation than for the reference formulation, for C ma x CV was 23% and 50% and for AUCinf CV was 28% and 40% for these two formulations, respectively.
  • the characteristics of the linaprazan glurate plasma concentration time profiles were similar for the test and reference formulations with T ma x at 1 hour after dose and T1/2 of approximately 1 hour.
  • the bioavailability of linaprazan glurate was also higher (approximately 3-fold) from the test formulation than from the reference formulation.
  • the test formulation When administered together with a high-fat, high calorie meal, the test formulation median linaprazan T ma x occurred later (6.00 hours) than following intake in a fasting state (T ma x 3.00 hours) and AUC and C max was reduced as reflected in the geometric LS mean ratio (90% Cl) 0.76 (0.70-0.82) for AUCinf, 0.77 (0.71-0.83) for AUCi as t and 0.45 (0.41-0.50) for C ma x- Linaprazan glurate AUC was approximately 50% lower when the test formulation was administered in the fed condition as compared to intake in a fasted state.
  • Plots of the mean linaprazan and mean logarithmic linaprazan plasma concentrations over time for treatments A (reference formulation, fasted), B (test formulation, fasted) and C (test formulation, fed) are shown in Figures 5 and 6, respectively.
  • Plots of the mean linaprazan glurate and mean logarithmic linaprazan glurate plasma concentrations over time for treatments A, B and C are shown in Figures 7 and 8, respectively.
  • test formulation A Phase 1, single-center, open parallel-group, randomized study was performed to evaluate the PK, PD, safety and tolerability of single and repeated oral doses of the linaprazan glurate formulation of example 2 ("test formulation") at 6 dose groups in healthy male and female subjects.
  • Subjects participating in the study were to attend 7 visits to the clinic, namely a screening visit (Visit 1) followed by 6 visits (Visit 2-7) and a follow-up visit (Visit 8).
  • Visit 2 Visit 5 and Visit 7 were residential stays at the clinic and Visit 3
  • Visit 4 Visit 6 were outpatient visits.
  • the participants were also to 1 be followed by a remote follow-up/end-of-study visit via telephone (Visit 8), 7 days ( ⁇ 2 days) after the final dose.
  • Each subject was expected to participate in the study for a maximum of 52 to 56 days, including the up to 28-day screening period.
  • Screening took place within 28 days prior to the start of treatment and included an eligibility check, collection of demographic and medical history data as well as a review of health status, including a physical examination and collection of ECGs, vital signs and safety laboratory blood samples.
  • each dose group was randomized to a drug holiday period of 2, 4, or 6 days after the end of the 14-day treatment period.
  • a drug holiday period of 2, 4, or 6 days after the end of the 14-day treatment period.
  • one or two doses of linaprazan glurate (QD or BID depending on previous randomization) were administered for further PK evaluation.
  • Eligible subjects were admitted to the clinic on Day -2 of Visit 2 and remained at the study clinic until Day 2 (residential period) up until 24 hours after the first investigational medicinal product (IMP) dose.
  • IMP investigational medicinal product
  • a baseline intragastric pH measurement was recorded for all subjects over the 24-hour period prior to the first IMP dose.
  • the first IMP dose was given in the evening of Day 1 for Dose groups 1 to 3 and in the morning of Day 1 for Dose groups 4 to 6.
  • the intake of food and snacks was standardized on the days of intragastric pH measurements including the baseline recording.
  • measurement of intragastric pH for 24 hours post- dose was performed.
  • Dose groups 4 to 6 the subjects had to fast from >10 hours overnight before the anticipated dosing time on Day 1 until 30 minutes postdose. During fasting, tap water, but no other drinks, was allowed as desired, except for 1 hour before and 30 minutes after dosing.
  • the second daily dose was administered after the evening meal, i.e. in a non-fasted condition. Subjects were fasted for 30 min after intake of the second daily dose. For Dose groups 1 to 3, the subjects were non-fasting and followed a standardized food intake schedule.
  • PK blood samples were collected for 24 hours after the first IMP dose on Day 1 to Day 2.
  • Subjects were to continue to take linaprazan glurate at home from Day 3 to Day 13. Subjects used a paper diary to record drug intake at home.
  • Visit 8 A final remote follow-up visit (Visit 8) was conducted via telephone 7 days ( ⁇ 2 days) after the final dose of IMP, or after early withdrawal, to follow-up on AEs and concomitant medications. Visit 8 was classified as each subject's end-of-study visit, and the date of last subject's end-of-study visit counted as the overall end-of-study date.
  • the PD-data showed that linaprazan glurate achieves a rapid increase in gastric pH after the first dose with a clear dose-response pattern, keeping pH >4 for more than 90% of the time studied from 90 minutes after dosing on Day 1 and >95% of the time studied at Day 14 with the two highest doses studied, 50 mg and 75 mg BID.
  • linaprazan plasma exposures following 25, 50 and 75 mg QD and BID for 14 days increased approximately in proportion to dose with no apparent deviation from time-independent PK.
  • Repeated oral doses of linaprazan glurate 25, 50 and 75 mg QD and BID for 14 days were safe and well tolerated as assessed by AEs, physical examinations, vital signs, ECG and laboratory parameters.

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Abstract

L'invention concerne une formulation orale à libération immédiate de glurate de linaprazan, comprenant une quantité thérapeutiquement efficace de glurate de linaprazan, ou un sel pharmaceutiquement acceptable de celui-ci, et de l'acétate succinate d'hydroxypropylméthylcellulose (HPMC-AS). La formulation assure une libération rapide du principe actif et améliore en outre la biodisponibilité. L'invention concerne également l'utilisation de la formulation orale dans le traitement ou la prévention d'une maladie gastro-intestinale inflammatoire ou liée à l'acide gastrique, telle que la maladie du reflux gastro-œsophagien (RGO), la maladie du reflux gastro-œsophagien érosif (RGO érosif) ou l'infection par H pylori.
PCT/EP2025/072496 2024-08-05 2025-08-05 Formulation de glurate de linaprazan Pending WO2026032974A1 (fr)

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WO2023079094A1 (fr) 2021-11-05 2023-05-11 Cinclus Pharma Holding AB (publ) Polymorphes du sel chlorhydrate de linaprazan glurate
WO2023079093A1 (fr) 2021-11-05 2023-05-11 Cinclus Pharma Holding AB (publ) Polymorphes de sel mésylate de linaprazan glurate
WO2023185624A1 (fr) 2022-03-30 2023-10-05 Guizhou Sinorda Biomedicine Co., Ltd Formulation x842
WO2024149834A1 (fr) 2023-01-11 2024-07-18 Cinclus Pharma Holding AB (publ) Polymorphes de sel de bromhydrate de linaprazan glurate

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Publication number Priority date Publication date Assignee Title
WO2010063876A1 (fr) 2008-12-03 2010-06-10 Dahlstroem Mikael Dérivés d'imidazopyridine inhibant la sécrétion d'acide gastrique
WO2021089580A1 (fr) 2019-11-04 2021-05-14 Cinclus Pharma Ag Formulation orale de x842
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