Formulation of linaprazan glurate

Abstract

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.

Description

[0001] FORMULATION OF LINAPRAZAN GLURATE

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to Swedish application No. 2430394-3, filed August 5, 2024, the disclosure of which is incorporated herein by reference in its entirety.

[0004] TECHNICAL FIELD

[0005] 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.

[0006] BACKGROUND

[0007] Gastroesophageal reflux disease (GERD) 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. 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).

[0008] 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. The global acid reflux market is dominated by PPIs, and it is estimated that more than 20% of all GERD patients take PPIs off-label twice daily to overcome the incomplete symptom relief or supplement their treatment with over-the-counter-remedies. Despite frequent off- label prescription of high dosage PPIs, many patients still suffer from poor symptom control.

[0009] Potassium-competitive acid blockers (P-CABs) present a new mode of action, that may allow full intragastric acid control both day and night. P-CABs competitively inhibit the gastric hydrogen potassium pump (H+ / K+ ATPase) in the parietal cells and have a considerably faster onset to maximum effect than PPIs (typically 1-2 hours vs. 3-5 days). (Anderson et al., Pharmacol. Ther. 2005, vol. 108, p. 294-307). Such acid inhibitory properties are likely to allow for the successful treatment of subjects with erosive GERD and eradication of H. pylori infection.

[0010] 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. In comparison, 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).

[0011] The solubility of the free base of linaprazan glurate is very low. It is practically insoluble in water at pH 6.8, whereas the solubility in water at pH 1.0 has been determined to be as low as about 0.113 mg / mL. This low solubility is problematic for solid oral formulations, and especially for solid immediate release formulations wherein the active ingredient should rapidly dissolve. 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. 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. Preferably, an oral formulation of linaprazan glurate should provide a doseproportional increase in AUC and Cmax, that is not dependent on the pH of the stomach.

[0012] BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 shows the X-ray powder diffractogram of crystalline Form A of linaprazan glurate.

[0014] 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.

[0015] FIG. 3 shows a plot of the release of linaprazan glurate from tablets of three different feasibility batches over time.

[0016] FIG. 4 shows a plot of the release of linaprazan glurate from tablets of the optimized formulation over time.

[0017] 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).

[0018] 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).

[0019] 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).

[0020] 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).

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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

[0025] 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. Through its hydrophobic interactions with such drugs, it prevents the drugs from crystallizing and precipitating in the gastrointestinal tract (Butreddy, Eur. J. Pharm. Biopharm. 2022, vol. 177, p. 289-307). 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. Pharm. Biopharm. 2008, vol. 70, p. 493-499; Konno et al., Pharm. Res. 2008, vol. 25, p. 969-978; Tanno et al., Drug. Dev. Ind. Pharm. 2004, vol. 30, p. 9-17; and Kaur et al., J. Pharm. Sci. 2025, 103894).

[0026] In initial trials to investigate the suitability of HPMC-AS in a spray dried dispersion of linaprazan glurate, it was observed that film casting of a solution of linaprazan glurate and HPMC-AS did not result in a clear film but in recrystallization of the API. The hydrophobic interactions between HPMC-AS and the API were apparently not strong enough to prevent the API from crystallizing. For a variety of different reasons, other polymers did not give satisfactory results either. Surprisingly, however, it was discovered that a compressed tablet comprising linaprazan glurate and HPMC-AS in powder form provided rapid release of linaprazan glurate from the formulation. It was additionally observed that the bioavailability of linaprazan glurate was significantly increased compared with previous formulations of the same compound.

[0027] In a first aspect, therefore, 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).

[0028] In some embodiments, linaprazan glurate, or a pharmaceutically acceptable salt thereof, is present in crystalline form. In a preferred embodiment, linaprazan glurate is present as a crystalline form of the free base of linaprazan glurate. In another preferred embodiment, linaprazan glurate is present as a crystalline form of a pharmaceutically acceptable salt of linaprazan glurate.

[0029] In some embodiments, 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).

[0030] In some embodiments, 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).

[0031] In some embodiments, 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).

[0032] 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. In a preferred embodiment, the HPMS-AS is HF grade.

[0033] The formulation may additionally comprise excipients such as fillers, surfactants, disintegrants, lubricants and glidants. Examples of 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. In a preferred embodiment, the filler is mannitol. In some embodiments, the formulation does not comprise microcrystalline cellulose.

[0034] The surfactant may be a cationic surfactant, an anionic surfactant or a nonionic surfactant. Examples of cationic surfactants include, but are not limited to, cetyltrimethylammonium bromide (cetrimonium bromide) and cetylpyridinium chloride. Examples of anionic surfactants include, but are not limited to, sodium dodecyl sulfate (sodium lauryl sulfate) and ammonium dodecyl sulfate (ammonium lauryl sulfate). Examples of 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). In a preferred embodiment, the surfactant is a nonionic surfactant. In a further preferred embodiment, the nonionic surfactant is a poloxamer, more preferably poloxamer 188.

[0035] Examples of 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)). In a preferred embodiment, the disintegrant is croscarmellose sodium. In some embodiments, the formulation does not comprise crospovidone.

[0036] Examples of 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. In a preferred embodiment, the lubricant is magnesium stearate. In some embodiments, the formulation does not comprise sodium stearyl fumarate.

[0037] Examples of suitable glidants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, colloidal anhydrous silica, synthetic magnesium silicate, fine granulated silicon oxide. In a preferred embodiment, the glidant is colloidal anhydrous silica. In some embodiments, 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. In a preferred embodiment, 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. In a more preferred embodiment, 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.

[0038] In some embodiments, 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. In a particular embodiment, 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. In a more specific embodiment, 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. In a more specific embodiment, 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. In a more specific embodiment, 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. In a particular embodiment, Form A has an XRPD pattern, obtained with CuKal- radiation, substantially as shown in Figure 1.

[0039] In some embodiments, 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). In some embodiments, linaprazan glurate is present as a hydrochloride salt of linaprazan glurate.

[0040] In some embodiments, 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. In a particular embodiment, 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. In a more specific embodiment, 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. In some embodiments, 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. In a more specific embodiment, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, Form 1 of the HCI salt of linaprazan glurate has an XRPD pattern, obtained with CuKal-radiation, substantially as shown in Figure 2.

[0041] In some embodiments, 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 about 175 mg, about 75 to about 150 mg, about 75 to about 125 mg, or about 75 to about 100 mg of linaprazan glurate, or a pharmaceutically acceptable salt thereof. In some embodiments, 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.

[0042] In some embodiments, 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.

[0043] In one preferred embodiment, 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.

[0044] In some embodiments, 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%. In some embodiments, 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%.

[0045] In some embodiments, a unit dose of the formulation has the following composition: Table 1. Ingredients per 25 or 100 mg API formulation.

[0046] * Corrected to the weight of the free base of linaprazan glurate.

[0047] In some embodiments, 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.

[0048] In a particular embodiment, a capsule formulation has the following composition:

[0049] Table 2. Ingredients per 25 or 100 mg API capsule formulation.

[0050] * Corrected to the weight of the free base of linaprazan g urate. In some embodiments, 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.

[0051] In a preferred embodiment, a tablet of the formulation is prepared by compression of a granulate. In a more preferred embodiment, 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.

[0052] In a particular embodiment, a tablet formulation has the following composition:

[0053] Table 3. Ingredients per 25 or 100 mg API compressed tablet

[0054] * Corrected to the weight of the free base of linaprazan glurate. In some embodiments, 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. In a preferred embodiment, the coating comprises polyvinyl alcohol and / or hydroxypropyl methylcellulose. In one preferred embodiment, the coating is Opadry® EZ. In another preferred embodiment, 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.

[0055] The amount of in vitro dissolved active ingredient (linaprazan glurate) 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. In some embodiments, 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. In some embodiments, at least 80% of linaprazan glurate is dissolved after 30 minutes in aqueous solution at pH 4.5, for each out of 6 individual dosage units (i.e., Q. = 75%).

[0056] 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.

[0057] 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. pylori infection, Zollinger-Ellison syndrome, peptic ulcer disease (including gastric ulcers and duodenal ulcers), bleeding gastric ulcer, symptoms of gastroesophageal reflux disease (including heartburn, regurgitation and nausea), gastrinoma, acute upper gastrointestinal bleeding, or damage or bleeding caused by aspirin or NSAIDs. In one aspect, therefore, 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. In another aspect, 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. In yet another aspect, 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.

[0058] In some embodiments, 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).

[0059] 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. The 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). In some embodiments, the GERD or eGERD is LA grade A. In some embodiments, the GERD or eGERD is LA grade B. In some embodiments, the GERD or eGERD is LA grade C. In some embodiments, the GERD or eGERD is LA grade D.

[0060] In some embodiments, 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. In some embodiments, the oral formulation is administered once daily in a dose of about 25 mg linaprazan glurate, or a pharmaceutically acceptable salt thereof. In some embodiments, the oral formulation is administered twice daily in a dose of about 25 mg linaprazan glurate, or a pharmaceutically acceptable salt thereof. In some embodiments, 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.

[0061] In some embodiments, 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.

[0062] In some embodiments, the oral formulation is administered in a dose of from about 25 to about 100 mg twice daily for 4 weeks.

[0063] The daily dose can be administered as a single dose or divided into one, two, three or more unit doses.

[0064] In some embodiments, 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

[0065] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0066] As used herein, 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.

[0067] As used herein, the terms "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. For example, 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.

[0068] As used herein, the terms "treatment," "treat," and "treating" refer 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. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, 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.

[0069] As used herein, 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.

[0070] As used herein, the term "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.

[0071] As used herein, 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. In some embodiments, 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.

[0072] As used herein, the terms "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. differential oxidation, such that a dosage form discolours more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g., crystal changes on storage as a kinetically favoured polymorph converts to a thermodynamically more stable polymorph) or both (e.g., one polymorph is more hygroscopic than the other). As a result of solubility / dissolution differences, some transitions affect potency and / or toxicity. In addition, 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.

[0073] As used herein, the term "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.

[0074] As used herein, 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. In some embodiments, the polymorphs provided herein are stable for at least 1, 2, 3 or 4 weeks. For example, 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. In some embodiments, the polymorphs provided herein are stable for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. For example, 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. In the above, 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.

[0075] Abbreviations

[0076] AE Adverse event

[0077] API Active pharmaceutical ingredient

[0078] AUC Area under the concentration-time curve

[0079] AUCjnf Area under the concentration-time curve from time zero extrapolated to infinity

[0080] AUCiast Area under the concentration-time curve from time zero to time of last measurable observed concentration

[0081] BID Bis in die (twice daily)

[0082] Cl Confidence interval

[0083] Cmax Maximum concentration CV Coefficient of variation

[0084] ECG Electrocardiogram

[0085] LG Linaprazan glurate

[0086] LS mean Least squares mean

[0087] PD Pharmacodynamic

[0088] PK Pharmacokinetic rpm Revolutions per minute

[0089] TI / 2 Terminal elimination half-life

[0090] Tiag Delay between the time of dosing and the time of appearance of plasma concentration

[0091] Tmax Time to Cmax

[0092] QD Quaque die (once daily)

[0093] SD Standard deviation

[0094] The invention will now be described by the following examples which do not limit the invention in any respect. All cited documents and references are incorporated by reference.

[0095] EXAMPLES

[0096] Example 1

[0097] Evaluation of excipients and different feasibility batches

[0098] An excipient compatibility study was performed to study the physical and chemical stability of linaprazan glurate HCI salt in admixture with various excipients commonly used for tablet formulations. Based on those results (data not shown), suitable excipients were selected for a formulation of linaprazan glurate. Three feasibility batches were then prepared, having the compositions as shown in table 4 below.

[0099] Table 4. Ingredients per 100 mg API tablet

[0100] * 107.60 mg linaprazan glurate HCI salt corresponds to 100.00 mg linaprazan glurate.

[0101] 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). Finally, the lubricant (magnesium stearate or sodium stearyl fumarate; passed through a 40 mesh screen) 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.

[0102] Dry granulation

[0103] 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.

[0104] Final blend

[0105] 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) was added to the intra- granular ingredients and blended for 10 to 15 minutes at 25 rpm. The disintegrant (croscarmellose sodium or crospovidone; passed through a 20 mesh screen) was then added and blended with the other ingredients for 10 minutes at 25 rpm (250 revolutions). Colloidal silicon dioxide was passed through a 20 mesh screen and blended with the other ingredients for 5 minutes at 25 rpm (125 revolutions). Finally, 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.

[0106] Compression

[0107] 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.

[0108] Dissolution testing

[0109] 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.

[0110] Table 5. Release of linaprazan glurate from feasibility batches 1-3. * Mean of 6 measured samples.

[0111] Example 2

[0112] Preparation of optimized formulation Tablets comprising 100 mg linaprazan glurate were prepared on a 1.2 kg scale, with the composition as shown in table 6 below.

[0113] Table 6. Ingredients per 100 mg API tablet

[0114] * 107.59 mg linaprazan glurate HCI salt corresponds to 100.00 mg linaprazan glurate

[0115] 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).

[0116] Dry granulation

[0117] Approximately 1200 g of pre-blend was loaded into a TFC-220 roller compactor installed with 'S' rolls (non-interlocking rolls) operated at a roll speed of 2.0 rpm, screw speed of 20.0 rpm, and roll force of 5000 LBF. Ribbons were acceptable but brittle at this setup. Roller compaction lasted 10 minutes. At the end of roller compaction, ribbons were passed through a 20 mesh screen and fines were separated.

[0118] Approximately 22 g of fines (2.0%) was removed from the ribbons. Fines were not reprocessed and were added to the batch during the extra-granular processing step. Ribbons were passed through the Co-mil 197 installed with a 0.040" grater screen (1.0 mm) at 1250 rpm, which produced about 985 g of milled materials.

[0119] Final blend

[0120] 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.

[0121] Compression

[0122] 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.

[0123] Dissolution testing

[0124] 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.

[0125] * Mean of 6 measured samples.

[0126] Example 3

[0127] In vivo comparison of different formulations

[0128] 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.

[0129] Study Design and Treatment

[0130] 54 subjects (healthy male and female) were randomized for an estimated total of 9 evaluable subjects per treatment sequence.

[0131] 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.

[0132] 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.

[0133] On Day 1 (Visit 2), the subjects were randomized to treatment sequences using the following treatment nomenclature:

[0134] • Treatment A: 100 mg linaprazan glurate reference formulation (4x25 mg oral tablets) in fasting conditions.

[0135] • Treatment B: 100 mg linaprazan glurate test formulation (1x100 mg oral tablet) in fasting conditions.

[0136] • Treatment C: 100 mg linaprazan glurate test formulation (1x100 mg oral tablet) in fed conditions.

[0137] The 6 treatment sequences were as follows:

[0138] 1. A B C

[0139] 2. A C B

[0140] 3. B A C

[0141] 4. B C A

[0142] 5. C A B

[0143] 6. C B A

[0144] Fasted conditions (Treatments A and B)

[0145] Following an overnight fast of at least 10 hours, subjects were administered the IMP together with 240 mL of tap water. Subjects were instructed not to chew or crush the tablets. Water, but no other drinks, was 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.

[0146] Fed conditions (Treatment C)

[0147] 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. 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.

[0148] Subjects remained in the study clinic for at least 36 hours for continuous PK blood sampling. 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. On Day 4, 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.

[0149] 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.

[0150] Results

[0151] Following administration of 100 mg of the test formulation there was no or a short Tiagfor linaprazan and median (min-max) Tmax for linaprazan was 3.00 (1.25-4.00) hours. Mean T1 / 2 was 11.66 hours with individual values ranging from 4.98 to 27.93 hours. Following administration of the reference formulation, median (min-max) for linaprazan was 2 (1-6) hours. Mean T1 / 2, which was only possible to calculate in 40 out of 51 subjects, was 18.94 hours with individual values ranging from 3.99 to 67.85 hours. In the other subjects linaprazan concentrations were too variable in the latter part of the curve to estimate T1 / 2, which may not have been related only to the elimination but also some remaining absorption of linaprazan.

[0152] 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 AUCinf, 2.12 (1.97-2.30) for AUCiastand 2.32 (2.09-2.57) for Cmax. The intersubject variability in linaprazan exposure was lower for the test formulation than for the reference formulation, for Cmax CV was 23% and 50% and for AUCinf CV was 28% and 40% for these two formulations, respectively.

[0153] The characteristics of the linaprazan glurate plasma concentration time profiles were similar for the test and reference formulations with Tmax 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.

[0154] When administered together with a high-fat, high calorie meal, the test formulation median linaprazan Tmax occurred later (6.00 hours) than following intake in a fasting state (Tmax 3.00 hours) and AUC and Cmaxwas 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 AUCiast and 0.45 (0.41-0.50) for Cmax- 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.

[0155] 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.

[0156] Example 4

[0157] Study on effect of different doses on stomach pH

[0158] 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.

[0159] Study Design and Treatment

[0160] 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, and 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.

[0161] 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.

[0162] At the start of Visit 2, after all eligibility criteria from the screening visits were confirmed, the subjects were allocated the next available sequential randomization number, stratified by gender, in a preprinted Randomization list.

[0163] Subjects were randomized into one 1 of 6 dose groups as follows:

[0164] • No 1: 25 mg linaprazan glurate (1x25 mg oral tablet) QD for 14 days

[0165] • No 2: 50 mg linaprazan glurate (2x25 mg oral tablet) QD for 14 days

[0166] • No 3: 75 mg linaprazan glurate (3x25 mg oral tablets) QD for 14 days

[0167] • No 4: 25 mg linaprazan glurate (1x25 mg oral tablet) BID for 14 days

[0168] • No 5: 50 mg linaprazan glurate (2x25 mg oral tablet) BID for 14 days

[0169] • No 6: 75 mg linaprazan glurate (3x25 mg oral tablets) BID for 14 days

[0170] In addition, the subjects in each dose group were randomized to a drug holiday period of 2, 4, or 6 days after the end of the 14-day treatment period. On Day 16, 18 or 20, one or two doses of linaprazan glurate (QD or BID depending on previous randomization) were administered for further PK evaluation.

[0171] 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. At 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.

[0172] 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. Following IMP administration on Day 1, measurement of intragastric pH for 24 hours post- dose was performed. For 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.

[0173] PK blood samples were collected for 24 hours after the first IMP dose on Day 1 to Day 2. The subjects left the clinic in the morning of Day 2 (Dose groups 4 to 6) or the evening of Day 2 (Dose groups 1 to 3) after PK sampling up until 24 hours post first dose.

[0174] 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.

[0175] On Day 5 (Visit 3) and Day 10 (Visit 4) subjects returned to the clinic for PK blood sampling (trough plasma concentration). Dose groups 1 to 3 had their sample drawn prior to IMP intake in the evening and Dose groups 4 to 6 had their sample drawn prior to the morning IMP dose.

[0176] Subjects were admitted to the clinic on Day 14 (Visit 5) and remained until Day 15 for PK blood sampling, measurement of intragastric pH and safety assessments. For Dose groups 4 to 6, subjects were required to fast for >10 hours overnight before the anticipated dosing time on Day 14 until 30 minutes post-dose. During fasting, tap water, but no other drink, 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 minutes after intake of the second daily dose. PK blood samples were collected for 24 hours post-dose on Day 14 to Day 15. The measurement of intragastric pH was to start after the last dose of IMP on Day 14 and continue for 48 hours. The last IMP dose was given in the evening of Day 14.

[0177] The subjects remained at the clinic until the morning of Day 16 for PK blood sampling at 36- and 48- hours post-dose, and removal of the pH catheter 48 hours after the last IMP dose. NP0890WQ

[0178] 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.

[0179] Results

[0180] 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.

[0181] Based on PK data, 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.

[0182] The descriptive statistics of the percentage of time with pH >4 (based on 10-minute medians of the pH) for all dose groups are shown in Table 8. 24-Hour plots of the mean intragastric pH upon treatment with 25, 50 or 75 mg linaprazan glurate QD at days 1 and 14 are shown in Figures 9 and 10, respectively. 24-Hour plots of the mean intragastric pH upon treatment with 25, 50 or 75 mg linaprazan glurate BID at days 1 and 14 are shown in Figures 11 and 12, respectively.

[0183] Table 8. Descriptive statistics of percentage of time with pH >4 (PK / PD Analysis Set) - based on 10-minute medians of pH.

Claims

CLAIMS1. 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).

2. The formulation according to claim 1, wherein linaprazan glurate, or a pharmaceutically acceptable salt thereof, is present in crystalline form.

3. The formulation according to claim 1 or 2, wherein 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).

4. The formulation according to any one of claims 1 to 3, wherein 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).

5. The formulation according to any one of claims 1 to 4, wherein the formulation additionally comprises a filler, a surfactant, a disintegrant, a lubricant and a glidant.

6. The formulation according to any one of claims 1 to 5, which is in the form of a unit dose.7 The formulation according to any one of claims 1 to 6, wherein the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in the unit dose is from about 10 to about 150 mg.

8. The formulation according to claim 7, wherein the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in the unit dose is about 25 mg.

9. The formulation according to claim 7, wherein the amount of linaprazan glurate, or a pharmaceutically acceptable salt thereof, in the unit dose is about 50 mg.

10. The formulation according to any one of claims 1 to 9, wherein the formulation is in tablet form.3211. The formulation according to claim 10, wherein the tablet is prepared by compression of a granulate.

12. The formulation according to any one of claims 1 to 11, wherein linaprazan glurate is present as a hydrochloride salt.

13. The formulation according to any one of claims 1 to 11, wherein linaprazan glurate is present as a crystalline hydrochloride salt.

14. The formulation according to claim 13, wherein the crystalline hydrochloride salt of linaprazan glurate is an anhydrate.

15. The formulation according to claim 14, wherein the crystalline hydrochloride salt of linaprazan glurate is Form 1, having an 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.

16. The formulation according to any one of claims 1 to 15, wherein the formulation is a compressed tablet.

17. The formulation according to any one of claims 1 to 16, wherein the formulation additionally comprises an outer coating.

18. The formulation according to claim 17, wherein the outer coating comprises polyvinyl alcohol and / or hydroxypropyl methylcellulose.

19. The formulation according to any one of claims 1 to 18, wherein 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.

20. The formulation according to any one of claims 1 to 18, wherein at least 80% of linaprazan glurate is dissolved after 30 minutes in aqueous solution at pH 4.5, for each out of 6 individual dosage units.3321. The formulation according to any one of claims 1 to 20, for use in the treatment or prevention of a gastrointestinal inflammatory or a gastric acid related disease.

22. The formulation for use according to claim 21, wherein the gastrointestinal inflammatory or gastric acid related disease is gastritis, gastroesophageal reflux disease (GERD), erosive gastroesophageal reflux disease (eGERD), non-erosive gastroesophageal reflux disease (NERD), esophagitis, eosinophilic esophagitis (EoE), H. pylori infection, Zollinger-Ellison syndrome, peptic ulcer disease (including gastric ulcers and duodenal ulcers), bleeding gastric ulcer, symptoms of gastroesophageal reflux disease (including heartburn, regurgitation and nausea), gastrinoma, acute upper gastrointestinal bleeding, or damage or bleeding caused by aspirin or NSAIDs.

23. The formulation for use according to claim 21, wherein the gastrointestinal inflammatory or gastric acid related disease is gastroesophageal reflux disease (GERD), erosive gastroesophageal reflux disease (eGERD) or H. pylori infection.

Images