Oral formulation of X842

Abstract

The present invention relates to an immediate release oral formulation of X842 containing only limited amounts of surfactant. The present invention also relates to the use of the oral formulation in the treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases, particularly erosive gastroesophageal reflux disease (eGERD).

Description

[Technical field]

[0001] The present invention relates to an immediate release oral formulation of X842 that contains only limited amounts of surfactants. The present invention also relates to the use of the oral formulation in the treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases, particularly erosive gastroesophageal reflux disease (eGERD). [Background technology]

[0002] The compound 5-{2-[({8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}carbonyl)-amino]ethoxy}-5-oxopentanoic acid (X842; structure shown below) is disclosed in WO2010 / 063876. It is a potassium ion-competitive acid blocker (P-CAB) that activates the gastric hydrogen potassium pump (H + / K + X842 competitively inhibits the ATPase of the stomach. Therefore, X842 can be used to control gastric acid secretion in the stomach.

[0003] [ka]

[0004] X842 is a prodrug of linaprazan, which is disclosed in WO99 / 55706 and has already been studied in phase I and II trials. These studies showed that linaprazan was well tolerated, had a fast onset of action, and was sufficiently effective at the first dose. However, linaprazan was quickly eliminated from the body, and the duration of acid suppression was too short. In comparison, X842 has a long half-life in the body and shows complete control of gastric acid production for a longer time compared to linaprazan. Clinical phase I trials showed that administration of a single dose of X842 can maintain intragastric acidity above pH 4 for 24 hours. Therefore, X842 is suitable for patients presenting with severe erosive gastroesophageal reflux disease (eGERD).

[0005] The solubility of X842 is very low. X842 is particularly insoluble in water at pH 6.8, but its solubility in water at pH 1.0 is similarly low, determined to be about 0.113 mg / mL. This low solubility is problematic for solid oral formulations, especially solid immediate release formulations, where the active ingredient should only dissolve in a short time. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO2010 / 063876 [Patent Document 2] WO99 / 55706 Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, there is a need for a formulation of X842 that dissolves rapidly in the stomach after oral administration. Such a formulation should be suitable for eradicating H. pylori and treating acid reflux disease, especially severe erosive gastroesophageal reflux disease. It would be desirable if such a formulation could be administered once daily. [Means for solving the problem]

[0008] It has been discovered that solid formulations of X842 can dissolve rapidly in aqueous solution when the formulation contains a limited amount of a pharma- ceutically acceptable surfactant. Thus, in a first aspect, the present invention provides an oral formulation of X842 for immediate release, comprising: a) a therapeutically effective amount of X842; and b) a surfactant in an amount of about 12.0% (w / w) or less relative to the amount of X842 The present invention relates to an oral formulation comprising:

[0009] The surfactant may be a cationic surfactant, anionic surfactant or non-ionic 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 non-ionic surfactants include, but are not limited to, glycerol monooleate, glycerol monostearate, polyoxyl castor oil (Cremophore EL), poloxamer (e.g., poloxamer 407 or 188), polysorbate 80 and sorbitan esters (Tween). In a preferred embodiment, the surfactant is an anionic surfactant. In a further preferred embodiment, the anionic surfactant is sodium dodecyl sulfate.

[0010] The surfactant may be present in the formulation in an amount of from about 1.0% (w / w) relative to the amount of X842, such as from about 2.0 to about 12.0% (w / w), such as from about 4.0 to about 12.0% (w / w), such as from about 6.0 to about 12.0% (w / w), such as from about 8.0 to about 12.0% (w / w), or such as from about 10.0 to about 12.0% (w / w) relative to the amount of X842. It is preferred that the amount of surfactant in the formulation is as low as possible. Thus, in another embodiment, the formulation comprises from about 1.0 to about 11.0% (w / w), such as from about 1.0 to about 10.0% (w / w), such as from about 1.0 to about 9.0% (w / w), such as from about 1.0 to about 8.0% (w / w), or such as from about 1.0 to about 7.0% (w / w) of surfactant relative to the amount of X842. In another embodiment, the formulation comprises about 2.0 to about 11.0% (w / w) of surfactant relative to the amount of X842, such as about 2.0 to about 10.0% (w / w), for example about 2.0 to about 9.0% (w / w), such as about 2.0 to about 8.0% (w / w), or such as about 2.0 to about 7.0% (w / w). In yet another embodiment, the formulation comprises about 4.0 to about 11.0% (w / w), such as about 4.0 to about 10.0% (w / w), for example about 4.0 to about 9.0% (w / w), such as about 4.0 to about 8.0% (w / w), or such as about 4.0 to about 7.0% (w / w) of surfactant relative to the amount of X842.

[0011] In some embodiments, the formulation comprises a surfactant in an amount of about 11.0% (w / w) or less relative to the amount of X842. In some embodiments, the formulation comprises a surfactant in an amount of about 10.0% (w / w) or less relative to the amount of X842. In some embodiments, the formulation comprises a surfactant in an amount of about 9.0% (w / w) or less relative to the amount of X842. In some embodiments, the formulation comprises a surfactant in an amount of about 8.0% (w / w) or less relative to the amount of X842.

[0012] The oral formulation may further comprise one or more pharma- ceutically acceptable additives selected from the group consisting of a filler, a disintegrant, and a lubricant.

[0013] Examples of suitable excipients include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starch, and pregelatinized starch. In certain embodiments, the excipient is lactose, e.g., lactose monohydrate.

[0014] Examples of suitable disintegrants include, but are not limited to, dry starch, modified starches (e.g. (partially) pregelatinized starch, sodium starch glycolate and sodium carboxymethyl starch), alginic acid, cellulose derivatives (e.g. sodium carboxymethylcellulose, hydroxypropylcellulose, and low-substituted hydroxypropylcellulose (L-HPC)) and crosslinked polymers (e.g. carmellose, croscarmellose sodium, carmellose calcium and crosslinked PVP (crospovidone)). In a particular embodiment, the disintegrant is croscarmellose sodium.

[0015] 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, micronized silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (e.g., carnauba wax), hydrogenated oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil. In certain embodiments, the lubricant is sodium stearyl fumarate.

[0016] In another embodiment, the oral formulation comprises: a) a therapeutically effective amount of X842; b) an anionic surfactant in an amount of about 12.0% (w / w) or less relative to the amount of X842; and c) at least one excipient; d) at least one disintegrant; and e) at least one lubricant Includes.

[0017] In another embodiment, the oral formulation comprises: a) a therapeutically effective amount of X842; b) sodium dodecyl sulfate in an amount of about 12.0% (w / w) or less relative to the amount of X842; c) lactose monohydrate; d) croscarmellose sodium; and e) Sodium stearyl fumarate Includes.

[0018] In one embodiment, the oral formulation further comprises a glidant.Suitable glidant examples include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, colloidal anhydrous silica, synthetic magnesium silicate, and micronized silicon oxide.In one particular embodiment, the glidant is colloidal anhydrous silica.

[0019] In another embodiment, the formulation does not include microcrystalline cellulose.

[0020] The components of the formulation are preferably mixed into a homogenous mixture and then formulated as tablets or capsules. The homogenous mixture of components may be compressed into tablets using conventional techniques, for example, a rotary tablet press. Alternatively, the mixture may be moistened by adding a liquid, for example, water and / or a suitable organic solvent (e.g., ethanol or isopropanol), followed by granulation and drying. The resulting granules may then be compressed into tablets using conventional techniques. Capsules may contain a powder mixture of the components or small multiparticulates (e.g., granules, extruded pellets, or mini tablets). In a preferred embodiment, the formulation is in the form of a tablet.

[0021] The amount of X842 to be administered will vary depending on the patient to be treated and may be changed to about 0.5 mg / kg to about 5 mg / kg body weight per day, for example, about 1.0 mg / kg per day, or about 1.5 mg / kg per day, or about 2.0 mg / kg per day, or about 2.5 mg / kg per day. The amount of X842 to be administered will depend on the severity of the disease, the age and weight of the patient, and other factors normally considered by the attending physician when determining the appropriate dosage level for the patient.

[0022] In one embodiment, the unit dose of the formulation contains about 25 to about 250 mg of X842, for example about 50 to about 250 mg of X842, for example about 50 to about 200 mg of X842, or for example about 50 to 150 mg of X842. For example, the unit dose of the formulation may contain about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg of X842. The daily dose may be administered as a single dose or divided into two, three or more unit doses.

[0023] The presence of a small amount of surfactant (e.g., anionic surfactant, e.g., sodium dodecyl sulfate) in the oral formulation allows the active ingredient (X842) to dissolve quickly in an aqueous environment, e.g., in gastric contents. The dissolution rate of X842 can be easily determined in vitro using methods based on the European Pharmacopoeia 9.0, monograph 2.9.3, e.g., as described in the experimental section. Thus, in one embodiment, the formulation disclosed herein exhibits at least 70% dissolution within 30 minutes, as measured using the European Pharmacopoeia 2.9.3 dissolution apparatus 2 (paddle). In a more preferred embodiment, the formulation exhibits at least 85% dissolution within 10 minutes, as measured using the European Pharmacopoeia 2.9.3 dissolution apparatus 2 (paddle). In another preferred embodiment, the formulation exhibits at least 95% dissolution within 15 minutes, as measured using the European Pharmacopoeia 2.9.3 dissolution apparatus 2 (paddle).

[0024] After absorption into the bloodstream, X842 is rapidly metabolized to linaprazan, the active metabolite of X842. The plasma concentration of X842 is very small and difficult to determine, but the plasma concentration of linaprazan may be determined instead. Phase I studies have shown that a particular dose of X842 should be capable of maintaining an intragastric pH of greater than 4 for 24 hours after administration. This corresponds to a minimum plasma concentration (C) of linaprazan of at least about 240 nmol / L after 22 hours. min ) is required. At such a dose, administration of the formulation once a day would be sufficient. As a result, in another embodiment, the present invention provides a formulation as disclosed herein, which provides a linaprazan C concentration in a human of at least about 240 nmol / L 22 hours after administration of the oral formulation to said human. min In a preferred embodiment, the present invention relates to a formulation as disclosed herein, wherein a unit dose of the formulation provides a linaprazan C concentration in a human of at least about 240 nmol / L 22 hours after administration of the oral formulation to said human. min The present invention relates to a formulation which

[0025] In certain embodiments, the formulation has the following composition:

[0026] [Table 1]

[0027] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of X842 sufficient to alleviate to some extent one or more of the symptoms of the disease or condition being treated after administration to a subject. The result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or other desired changes in a biological system. For example, an "effective amount" for therapeutic use is the amount of X842 required to cause a clinically significant reduction in disease symptoms. The appropriate "effective" amount in any individual case will be determined using any suitable technique, such as a dose escalation study.

[0028] As used herein, the term "about" refers to a value or parameter herein, including (and describing) embodiments directed to the value or parameter itself. For example, a statement referring to "about 20" includes the statement "20." Numerical ranges include the numbers that define the range. In general, the term "about" refers to the indicated value of the variable, and all values ​​of the variable that are within the experimental error of the indicated value (e.g., within a 95% confidence interval about the mean) or within 10 percent of the indicated value, whichever is greater.

[0029] The oral formulations disclosed herein may be used in the treatment or prevention of diseases or conditions in which inhibition of gastric acid secretion is necessary or desirable, for example, in the eradication of Helicobacter pylori. Examples of such diseases and conditions include gastrointestinal inflammatory diseases and gastric acid-related diseases, such as gastritis, gastroesophageal reflux disease (GERD), erosive gastroesophageal reflux disease (eGERD), Helicobacter pylori infection, Zollinger-Ellison syndrome, peptic ulcer disease (including gastric ulcer and duodenal ulcer), bleeding gastric ulcer, symptoms of gastroesophageal reflux disease (including heartburn, reflux, and nausea), gastrinoma, and acute upper gastrointestinal bleeding. Thus, in one aspect, the present invention relates to the oral formulations disclosed herein for use in the treatment or prevention of gastrointestinal inflammatory diseases or gastric acid-related diseases. In another aspect, the present invention relates to the use of the oral formulations disclosed herein for the treatment or prevention of gastrointestinal inflammatory diseases or gastric acid-related diseases. In yet another aspect, the present invention relates to a method of treating or preventing a gastrointestinal inflammatory disease or a gastric acid-related disease in a subject, e.g., a human, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of an oral formulation disclosed herein. In certain embodiments, the treatment of GERD is an on-demand treatment of GERD.

[0030] The present invention is further illustrated by the following examples, which are not intended to limit the invention in any way. EXAMPLES

[0031] Example 1 Preparation of formulations Tablets containing 50 mg of X842 were prepared on a 2 kg scale using the amounts shown in the table below.

[0032] [Table 2]

[0033] The colloidal anhydrous silica and X842 were premixed and sieved through a stainless steel mesh into the mixing vessel. The lactose monohydrate, croscarmellose sodium and sodium dodecyl sulfate were sieved through a stainless steel mesh and added to the mixing vessel. Mixing was carried out in the mixing vessel for approximately 20 minutes.

[0034] Sodium stearyl fumarate was premixed with a small portion of the powder blend, passed through a stainless steel mesh, and added to the mixing vessel. Mixing was carried out in the mixing vessel for approximately 5 minutes.

[0035] The powder blend was then compressed into round 550 mg tablets in a rotary tablet press. The compressed tablets were packaged in plastic bottles and labeled.

[0036] Example 2 Dissolution Test The dissolution profile for the tablets of Example 1 was determined using dissolution apparatus 2 (paddle) as described in European Pharmacopoeia 9.0, monograph 2.9.3. One tablet was added to a vessel containing 900 mL of acetate buffer (pH 4.5) containing 0.2% SDS, and the contents were stirred at 37±0.5° C. Samples of the solution were removed at different time points and the amount of X842 dissolved was quantified at 302 nm using a UV spectrophotometer. Each experiment was repeated six times and the average value was calculated. The dissolution profile for the tablets of Example 1 is shown in the table below.

[0037] [Table 3]

[0038] Example 3 Stability testing Batches of X842 tablets were stored in open HDPE bottles at 25° C. and 60% relative humidity, or in HDPE bottles capped with LDPE / HDPE caps at either 25° C. and 60% relative humidity (long-term storage conditions) or 40° C. and 75% relative humidity (accelerated conditions). The amounts of X842, decomposition products, and water, as well as the dissolution characteristics, will be determined at selected time intervals.

Claims

1. 1. An oral formulation of X842 for immediate release, comprising: a) a therapeutically effective amount of X842, and b) sodium dodecyl sulfate in an amount of about 8.0 to about 12.0% (w / w) relative to the amount of X842; 13. An oral formulation comprising:

2. The oral formulation of claim 1, comprising about 10.0 to about 12.0% (w / w) sodium dodecyl sulfate relative to the amount of X842.

3. 3. The oral formulation of claim 1 or 2, comprising about 11.0% (w / w) sodium dodecyl sulfate relative to the amount of X842.

4. 4. The oral formulation of claim 1, further comprising one or more additives selected from the group consisting of excipients, disintegrants, and lubricants.

5. 5. The oral formulation of any one of claims 1 to 4, comprising an excipient that is lactose monohydrate.

6. 6. The oral formulation of any one of claims 1 to 5, comprising a disintegrant which is croscarmellose sodium.

7. 7. The oral formulation of any one of claims 1 to 6, comprising a lubricant which is sodium stearyl fumarate.

8. 8. The oral formulation according to any one of claims 1 to 7, a) a therapeutically effective amount of X842; b) sodium dodecyl sulfate in an amount of about 8.0 to about 12.0% (w / w) relative to the amount of X842; c) lactose monohydrate; d) croscarmellose sodium; and e) Sodium stearyl fumarate 13. An oral formulation comprising:

9. 9. The oral formulation of claim 1, further comprising a glidant.

10. 10. The oral formulation of any one of claims 1 to 9, which does not contain microcrystalline cellulose.

11. 11. The oral formulation of any one of claims 1 to 10, exhibiting at least 70% dissolution within 30 minutes as measured using European Pharmacopoeia 2.9.3 dissolution apparatus 2 (paddles).

12. 12. An oral formulation according to any one of claims 1 to 11, exhibiting at least 85% dissolution within 10 minutes as measured using European Pharmacopoeia 2.9.3 dissolution apparatus 2 (paddles).

13. 13. An oral formulation according to any one of claims 1 to 12, exhibiting at least 95% dissolution within 15 minutes as measured using European Pharmacopoeia 2.9.3 dissolution apparatus 2 (paddles).

14. A unit dose of the formulation has a linaprazan C concentration of at least about 240 nmol / L in a human 22 hours after administration of the oral formulation to the human. min 14. The oral formulation of claim 1, wherein

15. 15. An oral formulation according to any one of claims 1 to 14 for use in the treatment or prevention of a gastrointestinal inflammatory disease or a gastric acid related disease.

16. 15. The oral formulation of any one of claims 1 to 14 for use in the treatment or prevention of gastritis, gastroesophageal reflux disease (GERD), erosive gastroesophageal reflux disease (eGERD), Helicobacter pylori infection, Zollinger-Ellison syndrome, peptic ulcer disease (including gastric ulcers and duodenal ulcers), bleeding gastric ulcers, symptoms of gastroesophageal reflux disease (including heartburn, reflux, and nausea), gastrinoma and acute upper gastrointestinal bleeding.

Images