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US-12622900-B2 - Methods and compositions for treating gastric ulcers

US12622900B2US 12622900 B2US12622900 B2US 12622900B2US-12622900-B2

Abstract

A method of treating and/or preventing gastric ulcers, said method comprising administering by injection a therapeutically effective amount of a composition comprising: c) a first agent selected from the group consisting of: a medium chain triglyceride and a long chain triglyceride; and d) a second agent comprising a proton pump inhibitor or pharmaceutically or veterinary acceptable salt, wherein the composition is adapted for sustained release of a therapeutically effective amount of the proton pump inhibitor to a subject in need thereof.

Inventors

  • Nicholas Bova
  • Sanjay Garg
  • Stephen Page

Assignees

  • Luoda Pharma Limited

Dates

Publication Date
20260512
Application Date
20220316
Priority Date
20151208

Claims (17)

  1. 1 . A method of treating and/or preventing gastric ulcers, said method comprising administering by injection a therapeutically effective amount of a non-aqueous liquid composition comprising: a) from 10 to 90% w/v of a first agent that is a medium chain triglyceride having a viscosity at 20° C. of between 20 and 70 mPa·s and that has at least two fatty acids with aliphatic tails of 6-12 carbon atoms; and b) from 1 mg/mL to 500 mg/mL of a second agent that is a proton pump inhibitor or pharmaceutically or veterinary acceptable salt, wherein the proton pump inhibitor is omeprazole, wherein: the gastric ulcer is selected from the group consisting of stomach ulcer, duodenal ulcer, oesophageal ulcer, dyspepsia, peptic ulcer disease, gastroesophageal reflux disease (GORD), laryngopharyngeal reflux, erosive esophagitis, peptic ulcer, and Zollinger-Ellison syndrome; the composition is adapted for sustained release of a therapeutically effective amount of the proton pump inhibitor to a subject in need thereof; the method results in the sustained release of a therapeutically effective amount of the proton pump inhibitor over a period of at least 2 days; and the composition is stable for at least 1 month.
  2. 2 . The method of claim 1 , wherein the concentration of the first agent is from 60-80% w/v.
  3. 3 . The method of claim 1 , wherein the proton pump inhibitor omeprazole-includes any pharmaceutical or veterinary analogs, enantiomers and polymorphs thereof and any pharmaceutical or veterinary equivalent salts thereof.
  4. 4 . The method of claim 1 , wherein the concentration of proton pump inhibitor in the composition is from 50 mg/mL to 200 mg/mL.
  5. 5 . The method of claim 1 , wherein the composition further comprises a stabiliser.
  6. 6 . The method of claim 5 , wherein the stabiliser is chosen from the list comprising: a) an alkaline agent; b) an amino acid; and/or c) a basic amino acid.
  7. 7 . The method of claim 5 , wherein the stabiliser is L-arginine.
  8. 8 . The method of claim 1 , wherein the composition is administered using a method selected from the group consisting of intramuscularly, subcutaneously, and intraperitoneally.
  9. 9 . The method of claim 1 , wherein the method results in the sustained release of a therapeutically effective amount of the proton pump inhibitor over a period of time selected from the group consisting of 2-6 days, 1-3 weeks, and 1-6 months.
  10. 10 . The method of claim 1 , wherein the method provides a minimum effective amount of the proton pump inhibitor in the subject's blood stream over a period of time selected from the group consisting of 3-6 days; 1-3 weeks; and 1-6 months.
  11. 11 . The method of claim 1 , wherein the composition is administered using a dosing regimen selected from the group consisting of every 1-7 days.
  12. 12 . The method of claim 1 wherein the composition is stable for a time period of at least 2-6 months or 12 months.
  13. 13 . The method of claim 12 wherein the composition is stable for at least 12 months.
  14. 14 . The method of claim 1 , wherein the method results in the sustained release of a therapeutically effective amount of the proton pump inhibitor over a period of at least 5 days.
  15. 15 . The method of claim 1 , said method comprising administering by intramuscular injection a therapeutically effective amount of a non-aqueous liquid composition comprising: a) from 10 to 90% w/v of a first agent that is a medium chain triglyceride having a viscosity at 20° C. of between 20 and 70 mPa·s and that has at least two fatty acids with aliphatic tails of 6-12 carbon atoms; and b) from 50 mg/mL to 200 mg/ml of a second agent that is a proton pump inhibitor or pharmaceutically or veterinary acceptable salt, wherein the proton pump inhibitor is omeprazole; and c) a stabiliser comprising L-arginine wherein: the gastric ulcer is selected from the group consisting of stomach ulcer, duodenal ulcer, oesophageal ulcer, dyspepsia, peptic ulcer disease, gastroesophageal reflux disease (GORD), laryngopharyngeal reflux, erosive esophagitis, peptic ulcer, and Zollinger-Ellison syndrome; the composition is adapted for sustained release of a therapeutically effective amount of the proton pump inhibitor to a subject in need thereof; the sustained release of the therapeutically effective amount of the proton pump inhibitor is over a period of time selected from the group consisting of 2-6 days, 1-3 weeks, and 1-6 months; and/or the minimum effective amount of the proton pump inhibitor in the subject's blood stream is sustained over a period of time selected from the group consisting of 2-6 days, 1-3 weeks, and 1-6 months.
  16. 16 . The method of claim 1 , wherein the composition is administered every 1-3 weeks.
  17. 17 . The method of claim 1 , wherein the composition is administered every 1-6 months.

Description

TECHNICAL FIELD This invention relates to methods and compositions for the treatment and prevention of gastric ulcers in a subject. BACKGROUND ART Equine Gastric Ulcer Syndrome (EGUS) describes the erosive and ulcerative diseases of the equine stomach which include both Equine Squamous Gastric Disease (ESGD) and Equine Glandular Gastric Disease (EGGD), terms that refer to the anatomical region of the stomach affected, which, in the case of EGGD, includes the cardia, fundus, antrum and pylorus. EGUS prevalence has been shown to vary with breed, type of use, level of training, with different prevalence of ESGD and EGGD. Horses involved in training and racing are highly prone to developing EGUS, with greater than 80% of competing racehorses and high level endurance horses suffering from ESGD. Even in horses that rarely compete and are used mainly in their home environment, the prevalence of ESGD is around 11%. Ulcerative disease of the glandular stomach (EGGD) is not as well studied, but frequencies between 17 and 33% have been reported in endurance horses, 56-64% in leisure horses, and 47-65% in thoroughbred racehorses. A variety of management factors contribute to the development of ESGD. All of these factors share the common trait that they increase the exposure of the squamous mucosa of the stomach to acid. In vitro experiments clearly show that squamous mucosal cells are susceptible to hydrochloric acid (HCl) and volatile fatty acid (VFA) injury in a pH, dose and time dependent manner. Damage of the outer cell barrier is induced by HCl. Damaged cells allow diffusion of acid into the squamous cells of the stratum spinosum ultimately resulting in ulceration. The risk of EGUS is closely related to diet, especially the consumption of feeds rich in starch (for example, grain). Starches and sugars are fermented by gut bacteria to produce a variety of acids (including volatile fatty acids and lactic acid) that act together with HCL to produce ulceration. Current therapeutic strategies follow the mantra “no acid, no ulcer” and focus on neutralising existing gastric acid or blocking new gastric acid secretion to increase stomach pH. Suppression of gastric acid production can be achieved by using proton pump inhibitors such as rabeprazole, lansoprazole, dexlansoprazole, tenatoprazole, omeprazole and esomeprazole. The treatment of EGUS requires commitment to long term daily treatment and is difficult, particularly when horses are involved in performance, racing, eventing and other work. EGUS can be treated by protecting the damaged gastric mucosa with mucosal protectants such as sucralfate (which is given orally) and misoprostol (which is given by injection), by neutralising gastric acid with antacids such as magnesium hydroxide, or by suppressing acid production by the oral use of proton pump inhibitors (PPI) or histamine type 2 (H2) receptor antagonists such as ranitidine. Each of the current treatments has significant shortcomings. Mucosal protectants must be continuously present and available at all sites of ulceration to allow ulcers to heal. This requires high doses of the mucosal protectant and frequent administration, at last four times daily for both sucralfate and misoprostol. Similarly, antacids must be present constantly in the stomach and in sufficient quantity to neutralise the significant quantity of continuously produced gastric HCl. The most effective approaches are those which suppress acid production. The H2 receptor antagonists act to block one stimulus of acid production in parietal cells via competitive inhibition of H2 receptors. Acid suppression requires the H2 receptor antagonist to be constantly circulating at a concentration sufficient to block the H2 receptors and recommended dosage regimens include oral treatment every 8 hours. However, other stimulatory pathways for acid production by parietal cells are not inhibited by H2 blockers. Consequently H2 receptor antagonists do not provide reliable acid suppression. The proton pump inhibitors such as omeprazole irreversibly inhibit the H+, K+ ATPase pump in gastric parietal cells leading to prolonged acid suppression irrespective of the stimulus for acid production. However, currently available PPIs must be given orally at least once daily and their bioavailability is dependent on the diet of the recipient horse. Furthermore, they require approximately five days of daily oral administration to reach their maximum degree of acid suppression which is generally less than total acid suppression. The duration of acid suppression within each day that is necessary to enable healing of EGUS has not been definitively determined. However, based on experience of ulcer healing in humans, it is generally considered that healing of equine gastric ulcers requires the presence of a gastric pH of at least 4 for a minimum of 16 hours each day. Published clinical studies have shown that oral omeprazole preparations may only provide 12 hours of adequate gastric