Equine esomeprazole formulations and methods of use

Abstract

To provide: formulations that can be relatively simple to administer, and accordingly do not rely on oral administration, which may improve the animal's compliance with the administration, and which may be suitable for equines that are unable to receive oral medications; and to provide methods of use thereof.SOLUTION: The present disclosure relates to formulations of proton pump inhibitors such as omeprazole or esomeprazole, including salts or hydrated salts thereof, such as esomeprazole sodium, esomeprazole magnesium, or esomeprazole magnesium dihydrate, and methods of use in treating ulcers in equines and other veterinary animals. The present disclosure also relates to injectable formulations of proton pump inhibitors such as omeprazole or esomeprazole, including salts or hydrated salts thereof, such as esomeprazole sodium, esomeprazole magnesium, or esomeprazole magnesium dihydrate, having a small particle size, such as a median particle size of less than 10 μm or less than 5 μm.SELECTED DRAWING: Figure 1A

Description

Technical Field

[0001] The present disclosure relates to proton pump inhibitors such as omeprazole or esomeprazole, formulations such as esomeprazole magnesium or esomeprazole magnesium dihydrate, and methods of use in the treatment of gastric ulcers in equine and other veterinary subject animals. The present disclosure also relates to injectable formulations of proton pump inhibitors such as omeprazole or esomeprazole having a small particle size such as a median particle size of less than 10 μm or less than 5 μm, for example esomeprazole magnesium dihydrate.

Background Art

[0002] Modern domesticated equine animals suffer from gastric ulcers at a relatively high rate, and the symptoms of ulcers such as pain and discomfort in the stomach and digestive tract interfere with the animal's healthy living conditions as well as, in the case of equine animals used for sports, the animal's work and training. The relatively high rate of gastric ulcers seen in domesticated equine animals may be due to, for example, the housing and feeding patterns associated with domestication in which the equine animal is not able to constantly forage for food as it would in the wild and is fed at specific times several times a day. These different feeding conditions affect the function and acidity of the stomach and upper intestine and may perhaps make gastric ulcers more common.

[0003] Equine animals, for example, when diagnosed with gastric ulcers by endoscopy, or when presenting symptoms of ulcers such as discomfort, loss of health, and irritability or uneasiness towards training, or when exposed to stressful conditions such as transportation that may cause ulcer-like symptoms or the occurrence of ulcer disease, oral proton pump inhibitor pastes are frequently administered. Common oral proton pump inhibitor pastes for horses are omeprazole pastes sold under the trade names Gastrogard® and Ulcergard®. While these oral paste compositions are effective, they are expensive, the horse must tolerate and ingest the full dose, it is necessary for the animal to be able to receive oral drug treatment (which may not be possible in certain situations), typically daily administration is required, it is difficult to administer accurately, and handling and storage can be cumbersome and difficult.

[0004] In contrast, the present disclosure relates to alternative injectable formulations, such as proton pump inhibitors like omeprazole or esomeprazole (including their salts or hydrates), for example magnesium esomeprazole, which can be administered relatively easily and thus do not rely on oral administration, can improve the animal's compliance with administration, and may be suitable for equine animals that cannot receive oral drug treatment. Further, the formulations herein do not necessarily need to be given daily because their bioavailability can reduce gastric acid levels, and thus promote the healing of damaged mucosal tissue over a longer time between administrations than oral pastes. Thus, when using the formulations herein, in some embodiments, equine animals do not have to tolerate daily oral paste administration but may, for example, only receive an injection once or twice a week.

[0005] Certain injectable pharmaceutical formulations herein also provide specific mixtures of proton pump inhibitors and additives that allow for long-term storage as well as easy administration to equine and other veterinary subject animals, as well as a simpler and less frequent dosing procedure. SUMMARY OF THE INVENTION

[0006] The present disclosure includes pharmaceutical formulations comprising a suspension of a proton pump inhibitor, such as omeprazole or esomeprazole, for example esomeprazole sodium, esomeprazole magnesium, omeprazole magnesium, omeprazole sodium, or another salt or hydrate of omeprazole or esomeprazole, in a mixture of a vegetable oil and caprylic / capric triglyceride. In some embodiments, the pharmaceutical formulation comprises a suspension of esomeprazole in a mixture of a vegetable oil and caprylic / capric triglyceride. In some embodiments, the pharmaceutical formulation comprises a suspension of esomeprazole magnesium salt (such as esomeprazole magnesium dihydrate) in a mixture of a vegetable oil and caprylic / capric triglyceride. In some embodiments, the pharmaceutical formulation comprises a suspension of omeprazole (such as omeprazole magnesium) in a mixture of a vegetable oil and caprylic / capric triglyceride. The vegetable oil can be selected from the group consisting of canola oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil, and any mixture of two or more of canola oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil. In some embodiments, the vegetable oil is cottonseed oil or a mixture of cottonseed oil and another vegetable oil. In some embodiments, the vegetable oil is cottonseed oil.

[0007] In some embodiments, the formulation comprises 15% to 25% weight / weight (w / w) esomeprazole magnesium, such as 18% w / w to 22% w / w esomeprazole magnesium, 19% w / w to 21% w / w esomeprazole magnesium, or 20% w / w esomeprazole or esomeprazole, such as esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate of omeprazole or esomeprazole. In some embodiments, the formulation comprises 15% to 25% weight / weight (w / w) esomeprazole magnesium, such as 18% w / w to 22% w / w esomeprazole magnesium, 19% w / w to 21% w / w esomeprazole magnesium, or 20% w / w esomeprazole magnesium. In some embodiments, esomeprazole magnesium is esomeprazole magnesium dihydrate. In some embodiments, the formulation comprises 15% to 25% weight / weight (w / w) omeprazole magnesium, such as 18% w / w to 22% w / w omeprazole magnesium, 19% w / w to 21% w / w omeprazole magnesium, or 20% w / w omeprazole magnesium. In some embodiments, the formulation comprises 15% to 25% weight / weight (w / w) omeprazole magnesium, such as 18% w / w to 22% w / w omeprazole magnesium, 19% w / w to 21% w / w omeprazole magnesium, or 20% w / w omeprazole magnesium.

[0008] In some embodiments, the formulation comprises 5% w / w to 30% w / w of vegetable oil, such as 5 to 10%, 10 to 15%, 15 to 20%, 20 to 25%, or 25 to 30%. In some embodiments, the formulation comprises 5% w / w to 30% w / w of cottonseed oil, such as 5 to 10%, 10 to 15%, 15 to 20%, 20 to 25%, or 25 to 30%. In some embodiments, the formulation comprises 10 to 15%, 10 to 12%, 13 to 15%, 15 to 17%, 18 to 20%, or 15 to 20% w / w of cottonseed oil. In some embodiments, the formulation comprises 50% w / w to 90% w / w of caprylic / capric triglyceride, such as 50 to 60%, 60 to 70%, 70 to 80%, or 80 to 90%. In some embodiments, the formulation comprises 60 to 70%, 60 to 65%, 65 to 70%, 70 to 80%, 70 to 75%, or 75 to 80% w / w of caprylic / capric triglyceride.

[0009] The formulations herein may also contain at least one preservative, such as butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA) or sodium bisulfite, or a mixture of two or more preservatives. The preservative may comprise a single additional ingredient or two or more additional ingredients. In some embodiments, the preservative comprises butylated hydroxytoluene (BHT). In some embodiments, the preservative comprises 0.05 to 1.0% w / w of BHT. In some embodiments, the preservative comprises 0.05 to 0.15% w / w of BHT. In some embodiments, the preservative comprises 0.1% w / w of BHT. In some embodiments, the preservative comprises 0.1 to 1.0%, 0.1 to 0.2%, 0.1 to 0.5%, 0.5 to 1.0%, 0.05%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0% w / w of BHT or BHA.

[0010] In some cases herein, the formulation can consist essentially of esomeprazole magnesium, cottonseed oil, caprylic / capric triglyceride, and at least one preservative. In some such cases, the formulation consists essentially of a proton pump inhibitor such as omeprazole or esomeprazole, for example esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate of omeprazole or esomeprazole, cottonseed oil, caprylic / capric triglyceride, and at least one preservative such as BHT. In some such cases, the formulation consists essentially of esomeprazole magnesium, cottonseed oil, caprylic / capric triglyceride, and BHT. In some cases herein, the formulation can consist essentially of esomeprazole magnesium dihydrate, cottonseed oil, caprylic / capric triglyceride, and at least one preservative. In some such cases, the formulation consists essentially of esomeprazole magnesium dihydrate, cottonseed oil, caprylic / capric triglyceride, and BHT.

[0011] The formulations of the present specification also include injectable formulations containing 18 - 22% weight / weight (w / w) of a proton pump inhibitor such as omeprazole or esomeprazole, for example sodium esomeprazole, magnesium esomeprazole, or another salt or hydrate of omeprazole or esomeprazole, such as magnesium omeprazole or sodium omeprazole, in a suspension in a mixture of cottonseed oil and caprylic / capric triglyceride, and 0.05 - 1.0% w / w of a preservative. Similarly, formulations consisting essentially of 18 - 22% weight / weight (w / w) of a proton pump inhibitor such as omeprazole or esomeprazole, for example sodium esomeprazole, magnesium esomeprazole, or another salt or hydrate of omeprazole or esomeprazole, such as magnesium omeprazole or sodium omeprazole, in a suspension in a mixture of cottonseed oil and caprylic / capric triglyceride, and 0.05 - 1.0% w / w of a preservative are also included. In some embodiments, magnesium esomeprazole is magnesium esomeprazole dihydrate. In some embodiments, the formulation contains 5 - 30% cottonseed oil, for example 5 - 25%, 10 - 15%, 10 - 12%, 13 - 15%, 15 - 17%, 18 - 20%, 15 - 20%, 20 - 22%, or 20 - 25% w / w of cottonseed oil. In some embodiments, the formulation contains 50% w / w - 90% w / w, for example 60 - 70%, 60 - 65%, 65 - 70%, 70 - 80%, 70 - 75%, 75 - 80%, 80 - 90%, 80 - 85%, or 85 - 90% of caprylic / capric triglyceride.

[0012] In any of the exemplary formulations herein, the caprylic / capric triglyceride may contain 50 - 65% caprylic acid and 30 - 45% capric acid, or it may be Miglyol® 812. In any of the exemplary formulations herein, the caprylic / capric triglyceride may contain 50 - 75% caprylic acid and 22 - 45% capric acid, or it may be Captex® 355. The caprylic / capric triglyceride may be derived from a vegetable oil source and may contain other raw materials such as glycerin, or for example, a small amount of longer-chain fatty acids.

[0013] In some embodiments of the above formulations, the formulation has a median particle size of less than 10 μm, for example less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm. In any of the above embodiments, the above formulation has at least one of the following characteristics: a) The formulation is suitable for intramuscular injection into equines or other animals; b) The formulation is suitable for subcutaneous injection into equines or other animals; c) After storage for 6 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 8 μm; d) After storage for 6 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 5 μm; e) After storage for 6 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 4 μm; f) After storage for 6 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 2.5 μm; g) After storage for 6 months at 2 - 8, 25, or 30 °C, the particle size at the 90th percentile of the particle size distribution curve remains less than 8 μm; h) After storage for 6 months at 2 - 8, 25, or 30 °C, there is no significant change in the viscosity of the formulation; i) The viscosity remains lower than 300 cP, between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP after storage for 6 months at 2 - 8, 25, or 30 °C; j) After 6 months at room temperature (e.g., 25 °C), there is no change in the injectability of the formulation when using a 3 mL 21G × 1 / 2 inch syringe / needle; k) The total proton pump inhibitor impurities remain less than 0.15% after storage for up to 6 months at 2 - 8, 25, or 30 °C; l) After storage for 12 months at 2 - 8 or 25 °C, the median particle size of the formulation remains less than 8 μm; m) After storage for 12 months at 2 - 8 or 25 °C, the median particle size of the formulation remains less than 5 μm; n) After storage for 12 months at 2 - 8 or 25 °C, the median particle size of the formulation remains less than 4 μm; o) After storage for 12 months at 2 - 8 or 25 °C, the median particle size of the formulation remains less than 2.5 μm; p) After storage for 12 months at 2 - 8 or 25 °C, the particle size at the 90th percentile of the particle size distribution curve remains less than 8 μm; q) After storage for 12 months at 2 - 8 or 25 °C, there is no significant change in the viscosity of the formulation; r) The viscosity is lower than 300 cP and remains between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP after storage for 12 months at 2 - 8 or 25 °C; s) After 12 months at room temperature (e.g., 25 °C), there is no change in the injectability of the formulation when using a 3 mL syringe / needle from 21G × 1 / 2 inch to 18G × 1 / 2 inch; t) The total proton pump inhibitor impurities remain less than 0.15% after storage for up to 12 months at 2 - 8 or 25 °C; and / or u) When intramuscularly injected into horses, the average half - life (T 1 / 2 ) of the formulation is in the range of 12 - 24 hours, may have.

[0014] In some embodiments, after 24 months at 2 - 8°C or 25°C or 30°C, the median particle size of the formulation remains less than 10 μm, less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm. In some embodiments, after 24 months at 2 - 8°C or 25°C or 30°C, the formulation remains stable for use.

[0015] Additional embodiments herein include injectable pharmaceutical formulations comprising a proton pump inhibitor such as omeprazole or esomeprazole, for example esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate of omeprazole or esomeprazole, such as esomeprazole magnesium dihydrate or a suspension such as omeprazole magnesium or omeprazole sodium, in an oil and fat containing medium-chain to long-chain fatty acids such as medium-chain to long-chain triglycerides. In some embodiments, the median particle size of the formulation is less than 10 μm, less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm. In other cases, the median particle size can be greater than 10 μm, greater than 8 μm, greater than 5 μm, greater than 4 μm, or greater than 2.5 μm. In some cases, the proton pump inhibitor is micronized either before or after formulation such that the formulation achieves a median particle size of less than 10 μm, less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm. In other cases, micronization is not necessary to achieve this particle size and is thus not performed. In some cases where micronization is performed, after 6 months, the micronization to achieve a median particle size of less than 10 μm, less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm does not affect the stability of the formulation. In other cases, micronization can improve the stability of the formulation. If micronization does not improve the stability of the formulation, micronization may not be performed.

[0016] In some embodiments, the medium-chain to long-chain fatty acids are long-chain triglycerides. In some embodiments, the medium-chain to long-chain fatty acids are a mixture of medium-chain to long-chain triglycerides. In some embodiments, the medium-chain to long-chain triglycerides include vegetable oil. In some embodiments, the vegetable oil is selected from the group consisting of canola oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil, and any mixture of two or more thereof. In some embodiments, the vegetable oil is cottonseed oil or a mixture of cottonseed oil and another vegetable oil. In some embodiments, the medium-chain to long-chain triglycerides include caprylic / capric triglyceride. In some embodiments, the caprylic / capric triglyceride contains 50 to 65% caprylic acid and 30 to 45% capric acid, or the caprylic / capric triglyceride contains Miglyol® 812. In some embodiments, the caprylic / capric triglyceride contains 50 to 75% caprylic acid and 22 to 45% capric acid, or the caprylic / capric triglyceride contains Captex® 355.

[0017] In some embodiments, the above-mentioned formulation contains 50% w / w to 90% w / w, for example 50 - 60%, 60 - 70%, 70 - 80%, or 80 - 90% of caprylic / capric triglyceride. In some embodiments, the formulation contains 60 - 70%, 60 - 65%, 65 - 70%, 70 - 80%, 70 - 75%, or 75 - 80% w / w of caprylic / capric triglyceride. In some embodiments, the formulation contains 15% - 25% weight / weight (w / w) of esomeprazole magnesium dihydrate. In some embodiments, the formulation contains 18% w / w to 22% w / w of esomeprazole magnesium. In some embodiments, the formulation contains 19% w / w to 21% w / w of esomeprazole magnesium. In some embodiments, the formulation contains 20% w / w of esomeprazole magnesium. In some embodiments, the formulation contains 5% w / w to 30% w / w, for example 5 - 10%, 10 - 15%, 15 - 20%, 20 - 25%, or 25 - 30% of vegetable oil. In some embodiments, the formulation contains 5% w / w to 30% w / w, for example 5 - 10%, 10 - 15%, 15 - 20%, 20 - 25%, or 25 - 30% of cottonseed oil. In some embodiments, the formulation contains 10 - 15%, 10 - 12%, 13 - 15%, 15 - 17%, 18 - 20%, or 15 - 20% w / w of cottonseed oil. In some embodiments, the formulation contains 5 - 30% of cottonseed oil, for example 5 - 25%, 10 - 15%, 10 - 12%, 13 - 15%, 15 - 17%, 18 - 20%, 15 - 20%, 20 - 22%, or 20 - 25% w / w of cottonseed oil. In some embodiments, the formulation contains 50% w / w to 90% w / w, for example 60 - 70%, 60 - 65%, 65 - 70%, 70 - 80%, 70 - 75%, 75 - 80%, 80 - 90%, 80 - 85%, or 85 - 90% of caprylic / capric triglyceride.

[0018] The formulations of the present specification may also contain at least one preservative, such as bacteriostatic agents like butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium bisulfite, vitamin C, sodium nitrile, sulfur dioxide, benzoic acid, methyl paraben, propyl paraben, benzyl alcohol, phenol, cresols such as m-cresol, chlorobutanol, or a mixture of two or more preservatives. The preservative may comprise a single additional ingredient or two or more additional ingredients. In some embodiments, the preservative comprises butylated hydroxytoluene (BHT). In some embodiments, the preservative is present in an amount of 0.05 - 1.0% w / w. In some embodiments, the preservative is present at 0.05 - 0.15% w / w. In some embodiments, the preservative is present at 0.1% w / w. In some embodiments, the preservative is present at 0.1 - 1.0%, 0.1 - 0.2%, 0.1 - 0.5%, 0.5 - 1.0%, 0.05%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0% w / w. In some embodiments, the preservative comprises 0.05 - 1.0% w / w of BHT. In some embodiments, the preservative comprises 0.05 - 0.15% w / w of BHT. In some embodiments, the preservative comprises 0.1% w / w of BHT. In some embodiments, the preservative comprises 0.1 - 1.0%, 0.1 - 0.2%, 0.1 - 0.5%, 0.5 - 1.0%, 0.05%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0% w / w of BHT or BHA.

[0019] In some embodiments, the formulation consists essentially of omeprazole or esomeprazole, such as esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate of omeprazole or esomeprazole, medium-chain to long-chain triglycerides, and a preservative. In some embodiments, the formulation consists essentially of esomeprazole magnesium dihydrate, medium-chain to long-chain triglycerides, and a preservative. In some such embodiments, the formulation has at least one of the following characteristics: a) The formulation is suitable for intramuscular injection into equines or other animals; b) The formulation is suitable for subcutaneous injection into equines or other animals; c) After storage for 6 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 8 μm; d) After storage for 6 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 5 μm; e) After storage for 6 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 4 μm; f) After storage for 6 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 2.5 μm; g) After storage for 6 months at 2 - 8, 25, or 30 °C, the particle size at the 90th percentile of the particle size distribution curve remains less than 8 μm; h) After storage for 6 months at 2 - 8, 25, or 30 °C, there is no significant change in the viscosity of the formulation; i) The viscosity remains lower than 300 cP, between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP after storage for 6 months at 2 - 8, 25, or 30 °C; j) After 6 months at room temperature (e.g., 25 °C), there is no change in the injectability of the formulation when using a 3 mL 21G × 1 / 2 inch syringe / needle; k) The total proton pump inhibitor impurities remain less than 0.15% after storage for up to 6 months at 2 - 8, 25, or 30 °C; l) After storage for 12 months at 2 - 8 or 25 °C, the median particle size of the formulation remains less than 8 μm; m) After storage at 2 - 8 or 25 °C for 12 months, the median particle size of the formulation remains less than 5 μm; n) After storage at 2 - 8 or 25 °C for 12 months, the median particle size of the formulation remains less than 4 μm; o) After storage at 2 - 8 or 25 °C for 12 months, the median particle size of the formulation remains less than 2.5 μm; p) After storage at 2 - 8 or 25 °C for 12 months, the particle size at the 90th percentile of the particle size distribution curve remains less than 8 μm; q) After storage at 2 - 8 or 25 °C for 12 months, there is no significant change in the viscosity of the formulation; r) The viscosity is less than 300 cP, and remains between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP after storage at 2 - 8 or 25 °C for 12 months; s) After 12 months at room temperature (e.g., 25 °C), there is no change in the injectability of the formulation when using a 3 mL syringe / needle of 21G × 1 / 2 inch to 18G × 1 / 2 inch; t) The total proton pump inhibitor impurities remain less than 0.15% after storage at 2 - 8 or 25 °C for up to 12 months; and / or u) When intramuscularly injected into horses, the average half - life (T 1 / 2 ) of the formulation is in the range of 12 - 24 hours. It has.

[0020] In some embodiments, after 24 months at 2 - 8 °C or 25 °C or 30 °C, the median particle size of the formulation remains less than 10 μm, less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm. In some embodiments, after 24 months at 2 - 8 °C or 25 °C or 30 °C, the formulation remains stable for use.

[0021] The present disclosure also includes vials containing the formulations herein, which may be suitable for transporting and storing the formulations. The vials herein may be containers of any shape or type and may be designed to allow for easy dispensing of the dosage formulations. The present disclosure also includes devices for intramuscular or subcutaneous injection for administering the formulations herein to equine or other animals. Such devices may contain any of the above-described formulations. Such devices include, for example, syringes equipped with needles for intramuscular injection or intramuscular injection pen devices. In some embodiments, each device contains a complete, single unit dosage of esomeprazole magnesium. Thus, each device is used for a single injection of a unit dosage and may then be discarded.

[0022] The present disclosure also includes a method of preparing the injectable equine pharmaceutical formulation described above. In some embodiments, the method comprises: (a) mixing a vegetable oil or cottonseed oil with a caprylic / capric triglyceride; and (b) adding omeprazole or esomeprazole, such as esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate of omeprazole or esomeprazole, such as omeprazole magnesium or omeprazole sodium, to the mixture of (a) to form a suspension of omeprazole or esomeprazole, such as esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate of omeprazole or esomeprazole, such as omeprazole magnesium or omeprazole sodium, in the mixture, and optionally adding at least one preservative to the mixture of vegetable oil or cottonseed oil and caprylic / capric triglyceride and / or to the suspension. In other embodiments, the method comprises: (a) optionally mixing medium-chain to long-chain triglycerides; (b) adding omeprazole or esomeprazole, such as esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate of omeprazole or esomeprazole, to the product of (a) to form a suspension of omeprazole or esomeprazole, such as esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate of omeprazole or esomeprazole, in the mixture, and optionally adding at least one preservative to the product of (a) or to the suspension of (b).

[0023] The present disclosure also includes the use of the above-described formulation for treating gastric ulcers in animals such as equids. In some embodiments, the treatment method includes administering an effective amount of the above formulation to an animal such as an equid by intramuscular injection or subcutaneous injection at least once a week. In some embodiments, the formulation is administered to provide esomeprazole magnesium between at least 1.5 mg / kg and 5.0 mg / kg per dose at least once a week. In some embodiments, the formulation is administered once, twice, or three times a week. In some embodiments, the formulation is administered at a dose of esomeprazole magnesium of 1.5 mg / kg, 1.75 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, or 5 mg / kg. In some embodiments, the formulation is administered over a period of 4 weeks. In some embodiments, the formulation is administered over a period of 3 weeks. In some embodiments, the formulation is administered according to one of the following regimens: (a) at a dose of 2.0 - 4.0 mg / kg once a week for 3 weeks; (b) at a dose of 2.0 - 4.0 mg / kg once a week for 4 weeks; (c) at a dose of 2.0 - 4.0 mg / kg twice a week for 3 weeks; (d) at a dose of 2.0 - 4.0 mg / kg twice a week for 4 weeks; or (e) any one of (a) - (d), followed by a reduced dose, once or twice a week for at least an additional 1 week. In some embodiments, the first dose or the first two doses or the doses for the first week, two weeks, three weeks, or four weeks are at a higher level (e.g., a "loading dose") than the subsequent doses. In some embodiments, the formulation is administered for a period longer than 4 weeks, and optionally, the dose is reduced after a period of 4 weeks. In some embodiments, the formulation is administered for a period longer than 3 weeks, and optionally, the dose is reduced after a period of 3 weeks. In any of the above dosing regimens, the formulation can be administered by intramuscular injection or subcutaneous injection. In some embodiments, the formulation is administered using the above vial and / or device. In some embodiments, the formulation is administered to an equid. In some embodiments, the equid is suffering from gastric ulcer, equine gastric ulcer syndrome (EGUS), equine squamous gastric disease (ESGD), or equine glandular gastric disease (EGGD).In some embodiments, gastric ulcers are treated. For example, in some embodiments, at least one ulcerative lesion is resolved or reduced in size and / or the number of lesions is reduced.

[0024] The present disclosure also includes injectable pharmaceutical compositions for use in the treatment of ulcers in animals such as equids. In some embodiments, the injectable pharmaceutical formulation is for use in a method of treating ulcers in equids, and the formulation is administered to the equid by intramuscular injection or subcutaneous injection. In some embodiments, the formulation is administered to provide esomeprazole magnesium between at least 1.5 mg / kg and 5.0 mg / kg per dose, at least once a week. In some embodiments, the formulation is administered once, twice, or three times a week. In some embodiments, the formulation is administered once a week. In some embodiments, the formulation is administered twice a week. In some embodiments, the formulation is administered three times a week. In some embodiments, the formulation is administered at a dose of esomeprazole magnesium of 1.5 mg / kg, 1.75 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, or 5 mg / kg. In some embodiments, the formulation is administered over a period of 4 weeks. In some embodiments, the formulation is administered over a period of 3 weeks. In some embodiments, the formulation is administered according to one of the following regimens: (a) at a dose of 2.0 - 4.0 mg / kg, once a week for 3 weeks; (b) at a dose of 2.0 - 4.0 mg / kg, once a week for 4 weeks; (c) at a dose of 2.0 - 4.0 mg / kg, twice a week for 3 weeks; (d) at a dose of 2.0 - 4.0 mg / kg, twice a week for 4 weeks; or (e) any one of the regimens of (a) - (d), followed by a reduced dose, once or twice a week for at least an additional 1 week. In some embodiments, the formulation is administered for a period longer than 4 weeks, and optionally, the dose is reduced after a 4-week period. In some embodiments, the formulation is administered for a period longer than 3 weeks, and optionally, the dose is reduced after a 3-week period. In some embodiments, the formulation is administered by intramuscular injection. In some embodiments, the formulation is administered by subcutaneous injection. In some embodiments, the formulation is administered using the vials and / or devices described herein. In some embodiments, the equid is suffering from equine gastric ulcer syndrome (EGUS), equine squamous glandular disease (ESGD), or equine glandular gastric disease (EGGD).In some embodiments, ulcers are treated by, for example, (a) reducing the size of at least one ulcerative lesion or (b) reducing the number of ulcerative lesions.

[0025] Additional objects of the present disclosure are set forth in the following description, including the figures and claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claims.

[0026] The headings provided herein are not limitations of the various aspects of the disclosure that may be made reference to throughout this specification. Accordingly, the terms defined hereinafter are more fully defined by reference to the entire specification.

[0027] Figures 1A, 1B, and 1C show the effect on intragastric pH in five horses of administration of an exemplary formulation of the present disclosure, as described in the Examples section below. BRIEF DESCRIPTION OF THE DRAWINGS

[0028]

Figure 1A

Figure 1B

Figure 1C

Mode for Carrying Out the Invention

[0029] I. Definitions Unless otherwise defined, scientific and technical terms used in connection with the present invention shall have the meanings commonly understood by those skilled in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include singulars.

[0030] In this application, the use of "or" means "and / or" unless otherwise specified. In the context of multiple dependent claims, the use of "or" refers only to two or more preceding independent or dependent claims in an alternative form. Also, terms such as "element" or "component" include both elements and components containing one unit and elements and components containing two or more sub-units, unless otherwise specified.

[0031] As described herein, any concentration range, percentage range, ratio range or integer range shall be understood to include any integer value within the stated range and, where appropriate, fractions thereof (such as tenths and hundredths of an integer), unless otherwise indicated. Units, prefixes, and symbols are expressed in their internationally approved SI forms. Numerical ranges include the numbers defining the range. It is understood that measured values in this specification, such as weight-for-weight percentages, are approximate values taking into account significant figures and errors associated with the measurement.

[0032] All percentage measurements in this specification are weight-for-weight (w / w) percentages unless expressly stated otherwise.

[0033] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a preparation that is in a form that enables the biological activity of the active ingredient(s) to be effective and that does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered.

[0034] The formulations of the present specification can be administered to animals such as equids and other livestock. The "equid" in the present specification includes domesticated equids of any breed from mini horses and ponies to large draft horses, as well as mustangs, other wild horse breeds, and zebras. The term "equid" also includes equids of all ages from foals to aged horses. Among equids, there are all domesticated horse breeds with many different sizes and weights, such as mini horses, small ponies like Shetland ponies, Welsh ponies, German riding ponies, large ponies like Haflingers and cobs, Arabs, Thoroughbreds, Quarter Horses, a wide range of riding and racing horses such as various types of warmbloods, as well as Andalusians, Lusitanos, Appaloosas, Standardbreds, draft breeds such as Friesians, Belgians, Clydesdales, and crossbreeds between the above-mentioned breeds and other breeds. Other non-equid animals such as donkeys, mules, pigs, llamas, and alpacas can also be treated with the formulations of the present specification. The animals treated in the present specification may sometimes be referred to as "subjects" or "patients".

[0035] "Proton pump inhibitor" refers to a compound that suppresses gastric acid secretion by inhibiting the gastric proton pump H+ / K+ ATPase. Proton pump inhibitors include, for example, omeprazole, esomeprazole, rabeprazole, lansoprazole, tenatoprazole, and their pharmaceutically active stereoisomers such as enantiomers, including, for example, in the form of salts and hydrates. For example, omeprazole, esomeprazole, rabeprazole, lansoprazole, and tenatoprazole can be found as sodium salts or magnesium salts, and in some cases as magnesium hydrate salts.

[0036] "Omeprazole" refers to a compound having the molecular formula C17H18N3O3S and is a racemic mixture of S and R enantiomers. The term omeprazole includes omeprazole in any form, such as any salt or hydrate form. "Esomeprazole" refers to the S enantiomer of omeprazole and has the molecular formula C17H18N3O3S. Esomeprazole can be found in various salt or hydrate forms, including esomeprazole sodium, esomeprazole strontium, and esomeprazole magnesium. "Esomeprazole magnesium", as generally used herein, refers to both esomeprazole magnesium dihydrate and esomeprazole magnesium trihydrate, as well as mixtures of these two hydrate forms, as well as anhydrous esomeprazole magnesium and esomeprazole magnesium monohydrate. Esomeprazole magnesium trihydrate has a molecular weight of 767.2 g / mol and the molecular formula C34H42MgN6O9S2, while esomeprazole magnesium dihydrate has a molecular weight of 749.2 g / mol and the molecular formula C34H40MgN6O8S2. The anhydrous weight of esomeprazole magnesium is 713 g / mol. In these forms, one magnesium ion is coordinated to two esomeprazole molecules. The terms "esomeprazole magnesium dihydrate" or "esomeprazole magnesium trihydrate" are used to refer to specific hydrate forms. These hydrate forms may each contain small amounts of other hydrate forms, for example, as impurities. For example, once esomeprazole magnesium dihydrate is added to make a suspension for a pharmaceutical formulation, its hydrate form may be somewhat modified due to exposure to other additives in the formulation. Other forms of esomeprazole include "esomeprazole sodium", which has a molecular weight of 367.4 g / mol and the molecular formula C17H18NaN3O3S.

[0037] "Medium-chain triglyceride", as used herein, refers to a fatty acid triglyceride ester where the fatty acid is generally in the range of, for example, C6-C12 (the numbers following C represent the number of carbon atoms in the chain). Examples include triglyceride compositions containing fatty acids of lengths C6, C8, C10, and C12, or mixtures of two or more of these. "Long-chain triglyceride", as used herein, refers to a fatty acid triglyceride ester where the fatty acid is generally longer than C12, for example, of lengths C14, C16, C18, and C20, or a mixture of two or more of these. Long-chain triglyceride compositions can also include fatty acids of lengths C22 or C24 or C26. Medium-chain triglyceride compositions can contain low amounts of triglycerides with longer chain lengths, such as less than 20% or less than 10% or less than 5%. Similarly, long-chain triglyceride compositions can contain low amounts of medium-chain triglycerides, such as less than 20% or less than 10% or less than 5%. Compositions containing "medium-chain to long-chain fatty acids" can include mixtures of the above-described medium-chain and / or long-chain fatty acids. Compositions containing "medium-chain to long-chain triglycerides" can include mixtures of triglycerides containing medium-chain and / or long-chain triglycerides. Examples of such compositions include various vegetable and animal oils, as well as products derived from such oils by, for example, subjecting natural oils to various processing or refining steps designed to alter the fatty acid composition.

[0038] "Vegetable oil" refers to fats and oils derived from plant species. Some examples include, for example, canola oil (also known as rapeseed oil), coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil, as well as mixtures of two or more of the above-mentioned fats and oils. Vegetable oils also include, for example, oils derived from plants after processing to modify the fatty acid composition of the oil or to remove or reduce the concentration of certain components, such as fatty acids with shorter chain lengths (e.g., less than C14) or longer chain lengths (e.g., C20 or C22, or C24 or more). Vegetable oils may, in some cases, contain a large amount of C16 and C18 fatty acids, such as at least 80% of fatty acids such as palmitic acid, stearic acid, oleic acid, and linoleic acid (e.g., may mainly contain long-chain fatty acids). "Cottonseed oil" is an oil derived from cottonseed plants. Cottonseed oil generally contains a mixture of fatty acids of palmitic acid, stearic acid, oleic acid, and linoleic acid. Commercially available preparations of cottonseed oil may contain, for example, a mixture of fatty acids of about 20% palmitic acid (C16:0), 2% stearic acid (C18:0), 35% oleic acid (C18:1), and 42% linoleic acid (C18:2).

[0039] "Caprylic / capric triglyceride" is a term used to describe a mixture mainly of triglycerides of C8 and C10 fatty acids. Caprylic / capric triglyceride may, in some embodiments, include compositions containing 50 - 65% caprylic acid (C8) and 30 - 45% capric acid (C10). Caprylic / capric triglyceride may be derived from vegetable oils such as coconut oil and palm kernel oil. Caprylic / capric triglyceride is commercially available, for example, under the names Miglyol® 812 and, for example, Captex® 355.

[0040] For example, when referring to certain types of fatty acids of the present specification such as capric acid, caprylic acid, palmitic acid, or oleic acid, the term includes molecules in any common chemical form, such as free fatty acids, salts of free fatty acids, and fatty acid esters such as monoglycerides, diglycerides, or triglycerides, or phospholipids. For example, fatty acids found in vegetable oils are often in the form of triglycerides. Since individual triglyceride molecules contain three fatty acid chains, a triglyceride molecule can contain one, two, or three different types of fatty acids. Generally, regardless of the form found in the original oil or fat (e.g., as part of a triglyceride or other ester and the point of attachment to the triglyceride), fatty acid analysis is performed to provide the relative amounts of the various types of fatty acids in the oil or fat, for example, by weight percentage.

[0041] Fatty acids found in natural oils are typically in the form of triglycerides. The compositions of the present specification may also contain other raw materials and by-products of vegetable oils such as glycerin. The compositions may not be in purely triglyceride form. For example, a triglyceride composition may also contain monoglycerides and diglycerides as well as other esterified fatty acids. They may also contain other raw materials naturally found in oils and fats such as glycerin.

[0042] "Preservative" includes compounds that are pharmaceutically acceptable as injectable formulations and can help improve the shelf life of the formulation. For example, in some embodiments, the preservative may include antioxidants. In some embodiments, the preservative consists essentially of one or more antioxidants.

[0043] The formulations of the present specification can be administered, for example, by intramuscular injection or subcutaneous injection. "Administration" generally refers herein to the physical introduction of a composition containing a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those of skill in the art. Administration can be carried out, for example, once, multiple times, and / or over one or more extended periods of time.

[0044] "Pharmaceutical formulation" or "therapeutic formulation", as used herein, refers to a composition containing a therapeutic agent such as esomeprazole suitable for pharmaceutical use, for example, for direct administration to an animal or for administration after being reconstituted, diluted, mixed, or dissolved with at least one additional composition, or after being thawed from a frozen state. "Ready-to-use" formulation, as used herein, means a formulation that can be administered directly and thus does not need to be diluted, reconstituted, thawed from a frozen state, dissolved in a solution, or mixed with other ingredients prior to administration.

[0045] In some embodiments herein, the pharmaceutical formulation "does not contain" one or more types of additives or ingredients. The expression "does not contain" means, in this context, that, for example, exclusion ingredients resulting from contaminants or impurities found in other intentionally added ingredients are not present in amounts exceeding trace levels.

[0046] The term "consisting essentially of", when referring to a mixture of ingredients of a formulation herein, means that ingredients other than those expressly listed may be present, but such ingredients are found only in trace amounts or, if otherwise, in sufficiently low amounts such that the basic properties of the formulation, including esomeprazole concentration, viscosity, stability upon storage, osmotic pressure, and pH, are not significantly changed. For example, ingredients such as cottonseed oil and caprylic / capric triglyceride may contain small or trace amounts of other ingredients and by-products due to their origin from natural sources, while esomeprazole may also contain trace levels of various impurities resulting from its synthesis or natural degradation processes.

[0047] "Vial" herein includes any bottle or container of any size or shape suitable for storing the pharmaceutical formulations herein. In some cases, the vial can be used not only for storing the formulation but also for withdrawing a suitable volume of the formulation for injection into a subject. The vial can contain an amount sufficient to provide one or multiple doses of the formulation.

[0048] As used herein, "device" refers to means for intramuscular administration of a formulation and can be of any suitable structure and configuration suitable for intramuscular injection. Examples of "devices" herein include needle-equipped syringes used to deliver the contents of a syringe by intramuscular injection. Other examples include automated infusion devices similar to those used for intramuscular administration of human drugs such as norepinephrine, epinephrine, adrenaline, and insulin.

[0049] As used herein, the term "ulcer" or "gastric ulcer" encompasses ulcerative diseases of the digestive tract such as the stomach and intestine, as well as diseases suspected of being ulcerative. An ulcer can include, for example, an open sore in the back of the stomach or intestine. An ulcer can be diagnosed, for example, by endoscopy, or in some cases, suspected based on the outward behavior of the equine generally associated with ulcers, such as irritability, discomfort, restlessness, and / or uncooperativeness, weight loss, loss of appetite, and a decline in the state of the coat, particularly occurring during riding or training. In some embodiments, the ulcer can be equine gastric ulcer syndrome (EGUS). In some embodiments, the ulcer can be equine squamous gastric disease (ESGD), or equine glandular gastric disease (EGGD).

[0050] "Treatment", as used herein, refers to a therapeutic treatment, for example, to obtain partial or complete resolution of an ulcer, to slow the progression of an ulcer, or to reduce its severity. The term "treatment" also includes reducing the severity of any cosmetic features associated with the ulcer, and / or reducing the frequency, degree, or likelihood of such features, such as irritability, discomfort, restlessness, and / or non - cooperation, particularly during riding or training, weight loss, anorexia, and / or a decline in the condition of the coat, etc. Animals in need of treatment include animals already diagnosed with gastric ulcers, as well as animals that have previously had ulcers and are at risk of recurrence or exacerbation of the cosmetic symptoms of the disorder, and animals at risk of developing ulcers (e.g., animals experiencing stress such as transportation). Treatment of gastric ulcers in animals such as equids may include, for example, reducing the size and / or number of gastric lesions, partially or completely resolving existing lesions, increasing the overall pH of gastric fluid in the subject, as well as reducing symptoms and appearances generally associated with ulcers, such as poor condition (e.g., weight loss and poor quality of the coat), irritability, restlessness, or non - cooperation during riding and training activities, and other cosmetic symptoms of gastric upset.

[0051] The term "effective amount" or "therapeutically effective amount" refers to the amount of a drug that is effective in treating an ulcer in a subject. In certain embodiments, an effective amount refers to the amount effective to achieve a desired therapeutic result, such as alleviating physical or cosmetic symptoms associated with ulcers in equids during dosing and for the required period.

[0052] Additional definitions are provided in the following section.

[0053] II. Pharmaceutical Formulations and Their Preparation The present disclosure relates, inter alia, to an injectable pharmaceutical formulation comprising a proton pump inhibitor, such as omeprazole or esomeprazole, which is suitable for treating other animals such as equines and livestock animals. In some embodiments, the formulation comprises a suspension of a proton pump inhibitor, such as omeprazole or esomeprazole, in a mixture of vegetable oil and caprylic / capric triglyceride. In some embodiments, the proton pump inhibitor can be omeprazole, esomeprazole, rabeprazole, lansoprazole, or tenatoprazole. In some embodiments, the proton pump inhibitor can be in the magnesium salt form of omeprazole, esomeprazole, rabeprazole, lansoprazole, or tenatoprazole.

[0054] In some embodiments, the formulation comprises omeprazole such as a salt or hydrate of omeprazole. Omeprazole may be in different omeprazole forms such as omeprazole magnesium or omeprazole sodium. In some embodiments, the formulation comprises esomeprazole such as a salt or hydrate of esomeprazole. Esomeprazole may be in different esomeprazole forms such as esomeprazole magnesium, or esomeprazole sodium or esomeprazole strontium. In a formulation comprising esomeprazole magnesium, esomeprazole magnesium may be in the form of esomeprazole magnesium dihydrate or trihydrate, or a mixture of these forms. For example, the formulation may be prepared by adding esomeprazole dihydrate, which may have a trace amount of trihydrate, or may slowly convert to the trihydrate form over time in suspension or upon exposure to water. Thus, for example, esomeprazole dihydrate may contain a small amount of esomeprazole trihydrate due to impurities in the product or based on the degree to which the product is exposed to water, and vice versa. Vegetable oil may, in some embodiments, be any one of canola oil (also known as rapeseed oil), coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil, as well as any mixture of two or more of the above-mentioned oils and fats. In some embodiments, the vegetable oil is cottonseed oil or a mixture of cottonseed oil and at least one other vegetable oil.

[0055] In some embodiments, the formulation comprises a proton pump inhibitor such as omeprazole or esomeprazole at 15% to 25% weight / weight (w / w), for example, sodium esomeprazole, magnesium esomeprazole, or another salt or hydrate of omeprazole or esomeprazole, such as magnesium omeprazole or sodium omeprazole. In other embodiments, the formulation comprises a proton pump inhibitor such as omeprazole or esomeprazole at 18% to 22% w / w, for example, sodium esomeprazole, magnesium esomeprazole, or another salt or hydrate of omeprazole or esomeprazole, such as magnesium omeprazole or sodium omeprazole. In some embodiments, the formulation comprises a proton pump inhibitor such as omeprazole or esomeprazole at 19% to 21% w / w, for example, sodium esomeprazole, magnesium esomeprazole, or another salt or hydrate of omeprazole or esomeprazole, such as magnesium omeprazole or sodium omeprazole. In some embodiments, the formulation comprises a proton pump inhibitor such as omeprazole or esomeprazole at 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% w / w, for example, sodium esomeprazole, magnesium esomeprazole, or another salt or hydrate of omeprazole or esomeprazole, such as magnesium omeprazole or sodium omeprazole. In some embodiments, the formulation comprises a proton pump inhibitor such as omeprazole or esomeprazole at 20% w / w, for example, sodium esomeprazole, magnesium esomeprazole, or another salt or hydrate of omeprazole or esomeprazole, such as magnesium omeprazole or sodium omeprazole. In some embodiments, the formulation comprises magnesium esomeprazole or magnesium omeprazole at 15% to 25% weight / weight (w / w). In other embodiments, the formulation comprises magnesium esomeprazole or magnesium omeprazole at 18% w / w to 22% w / w.In some embodiments, the formulation comprises 19% w / w to 21% w / w esomeprazole magnesium or omeprazole magnesium. In some embodiments, the formulation comprises 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% w / w esomeprazole magnesium or omeprazole magnesium. In some embodiments, the formulation comprises 20% w / w esomeprazole magnesium or omeprazole magnesium. In some embodiments, the formulation comprises esomeprazole magnesium that is stable for at least 36 months for pharmaceutical use.

[0056] In some embodiments, the formulation comprises 5 to 30% vegetable oil, such as 5 to 25%, 10 to 15%, 10 to 12%, 13 to 15%, 15 to 17%, 18 to 20%, 15 to 20%, 20 to 22%, 23 to 25%, 20 to 25%, 20 to 30%, or 25 to 30% w / w vegetable oil. In some embodiments, the formulation comprises 5 to 25% w / w vegetable oil. In some embodiments, the formulation comprises 8 to 15% w / w vegetable oil. In some embodiments, the formulation comprises 10 to 15% w / w vegetable oil. In some embodiments, the formulation comprises 10 to 12% w / w vegetable oil. In some embodiments, the formulation comprises 13 to 15% w / w vegetable oil. In some embodiments, the formulation comprises 15 to 17% w / w vegetable oil. In some embodiments, the formulation comprises 18 to 20% w / w vegetable oil. In some embodiments, the formulation comprises 15 to 20% w / w vegetable oil. In some embodiments, the formulation comprises 20 to 22% w / w vegetable oil. In some embodiments, the formulation comprises 23 to 25% w / w vegetable oil. In some embodiments, the formulation comprises 20 to 25% w / w vegetable oil. In some embodiments, the formulation comprises 25 to 30% w / w vegetable oil. In some embodiments, the formulation comprises 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% w / w vegetable oil.

[0057] In some embodiments, the formulation comprises 5-30% cottonseed oil, such as 5-25%, 10-15%, 10-12%, 13-15%, 15-17%, 18-20%, 15-20%, 20-22%, 23-25%, 20-25%, 20-30%, or 25-30% w / w cottonseed oil. In some embodiments, the formulation comprises 5-25% w / w cottonseed oil. In some embodiments, the formulation comprises 8-15% w / w cottonseed oil. In some embodiments, the formulation comprises 10-15% w / w cottonseed oil. In some embodiments, the formulation comprises 10-12% w / w cottonseed oil. In some embodiments, the formulation comprises 13-15% w / w cottonseed oil. In some embodiments, the formulation comprises 15-17% w / w cottonseed oil. In some embodiments, the formulation comprises 18-20% w / w cottonseed oil. In some embodiments, the formulation comprises 15-20% w / w cottonseed oil. In some embodiments, the formulation comprises 20-22% w / w cottonseed oil. In some embodiments, the formulation comprises 23-25% w / w cottonseed oil. In some embodiments, the formulation comprises 20-25% w / w cottonseed oil. In some embodiments, the formulation comprises 25-30% w / w cottonseed oil. In some embodiments, the formulation comprises 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% w / w cottonseed oil.

[0058] In some embodiments, the vegetable oil or cottonseed oil may contain at least 80% or at least 90% C16 and C18 fatty acids. In some embodiments, the vegetable oil or cottonseed oil may contain at least 80% or at least 90% C16:0, C18:0, C18:1, and C18:2 fatty acids. In some embodiments, the vegetable oil or cottonseed oil may contain fatty acids of palmitic acid (C16:0) and / or stearic acid (C18:0), oleic acid (C18:1), and linoleic acid (C18:2), respectively. In some embodiments, the vegetable oil or cottonseed oil may contain fatty acids of palmitic acid (C16:0), stearic acid (C18:0), oleic acid (C18:1), and linoleic acid (C18:2), respectively. In some embodiments, the vegetable oil or cottonseed oil may contain, for example, fatty acids of about 15-25% palmitic acid, 1-5% stearic acid, 30-40% oleic acid, and 35-45% linoleic acid (C18:2). In some embodiments, the vegetable oil or cottonseed oil may contain, for example, a mixture of fatty acids of about 20% palmitic acid (C16:0), 2% stearic acid (C18:0), 35% oleic acid (C18:1), and 42% linoleic acid (C18:2). Since vegetable oils such as cottonseed oil are natural products, in addition to those listed above, other fats and oils, as well as other raw materials, may also be contained, for example, as by-products.

[0059] In some embodiments, the formulation comprises 50% w / w to 90% w / w, such as 50 to 60%, 60 to 70%, 70 to 80%, or 80 to 90% caprylic / capric triglyceride. In some embodiments, the formulation comprises 60 to 70%, 60 to 65%, 65 to 70%, 70 to 80%, 70 to 75%, or 75 to 80% w / w caprylic / capric triglyceride. In some embodiments, the formulation comprises 50% to 60% caprylic / capric triglyceride. In some embodiments, the formulation comprises 60% to 70% caprylic / capric triglyceride. In some embodiments, the formulation comprises 60% to 65% w / w caprylic / capric triglyceride. In some embodiments, the formulation comprises 65% to 70% caprylic / capric triglyceride. In some embodiments, the formulation comprises 70% to 75% caprylic / capric triglyceride. In some embodiments, the formulation comprises 75% to 80% caprylic / capric triglyceride. In some embodiments, the formulation comprises 80% to 90% caprylic / capric triglyceride. In some embodiments, the formulation comprises 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% caprylic / capric triglyceride.

[0060] In some embodiments, capric / caprylic triglyceride contains 50-65% capric acid and 30-45% caprylic acid. In some embodiments, capric / caprylic triglyceride contains 50-75% capric acid and 20-45% caprylic acid. In other embodiments, the mixture is 50-60% capric acid to 30-40% caprylic acid. In some embodiments, capric / caprylic triglyceride is Miglyol® 812, Miglyol® 810, or Captex® 355. Further, capric / caprylic triglyceride is generally derived from vegetable oils or seed oils such as palm seed oil and coconut oil. Thus, capric / caprylic triglyceride may typically contain other ingredients found in such oils and fats, such as glycerin or other non-fatty acid molecules, as well as other fatty acids other than capric acid and caprylic acid, as well as mono-glycerides or di-glycerides of capric acid and caprylic acid or other fatty acids. In some embodiments, capric / caprylic triglyceride also contains other fatty acids such as myristic acid (C14:0), lauric acid (C12:0), and caproic acid (C6:0).

[0061] As described above, when referring to certain types of fatty acids herein, such as, for example, capric acid, caprylic acid, palmitic acid, or oleic acid, or medium-chain or long-chain fatty acids, the term includes any common form of molecule, such as free fatty acids, salts of fatty acids, and fatty acid esters such as monoglycerides, diglycerides, or triglycerides, or phospholipids. For example, fatty acids found in vegetable oils are often in the triglyceride form. However, triglycerides may contain impurities in the form of monoglycerides and diglycerides or other esterified fatty acids, particularly in natural oils.

[0062] Additional embodiments of the present specification include injectable pharmaceutical formulations comprising a suspension of esomeprazole magnesium dihydrate in an oil and fat containing medium-chain to long-chain fatty acids such as medium-chain to long-chain triglycerides. In some embodiments, the median particle size of the formulation is less than 10 μm, such as less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm.

[0063] In some embodiments, the medium-chain to long-chain fatty acids include medium-chain fatty acids. In some embodiments, the medium-chain to long-chain fatty acids include long-chain fatty acids. In some embodiments, the medium-chain to long-chain fatty acids include a mixture of medium-chain fatty acids and long-chain fatty acids. In some embodiments, the medium-chain to long-chain triglycerides include long-chain triglycerides. In some embodiments, the medium-chain to long-chain triglycerides include a mixture of medium-chain triglycerides and long-chain triglycerides.

[0064] In some embodiments, the fatty acid or triglyceride comprises or consists of one or more vegetable oils. In some embodiments, the vegetable oil is selected from the group consisting of canola oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil, and any mixture of two or more of canola oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil, and any mixture of these oils. In some embodiments, the vegetable oil is cottonseed oil or a mixture of cottonseed oil and another vegetable oil. In some embodiments, the medium-chain to long-chain triglycerides include caprylic / capric triglyceride or another product similarly derived from vegetable oil. In some embodiments, the caprylic / capric triglyceride contains 50 - 65% caprylic acid and 30 - 45% capric acid, or the caprylic / capric triglyceride contains Miglyol® 812. In some embodiments, the caprylic / capric triglyceride contains 50 - 75% caprylic acid and 22 - 45% capric acid, or the caprylic / capric triglyceride contains Captex® 355.

[0065] In some embodiments, the above-mentioned formulation contains 50% w / w to 90% w / w, such as 50 to 60%, 60 to 70%, 70 to 80%, or 80 to 90% of caprylic / capric triglyceride. In some embodiments, the formulation contains 60 to 70%, 60 to 65%, 65 to 70%, 70 to 80%, 70 to 75%, or 75 to 80% w / w of caprylic / capric triglyceride. In some embodiments, the formulation contains 15% to 25% weight / weight (w / w) of esomeprazole magnesium dihydrate. In some embodiments, the formulation contains 18% w / w to 22% w / w of esomeprazole magnesium. In some embodiments, the formulation contains 19% w / w to 21% w / w of esomeprazole magnesium. In some embodiments, the formulation contains 20% w / w of esomeprazole magnesium. In some embodiments, the formulation contains 5% w / w to 30% w / w, such as 5 to 10%, 10 to 15%, 15 to 20%, 20 to 25%, or 25 to 30% of vegetable oil. In some embodiments, the formulation contains 5% w / w to 30% w / w, such as 5 to 10%, 10 to 15%, 15 to 20%, 20 to 25%, or 25 to 30% of cottonseed oil. In some embodiments, the formulation contains 10 to 15%, 10 to 12%, 13 to 15%, 15 to 17%, 18 to 20%, or 15 to 20% w / w of cottonseed oil.

[0066] In some embodiments, the formulations herein include proton pump inhibitors, medium- to long-chain triglycerides, caprylic / capric triglycerides, and / or other additives other than vegetable oil raw materials. For example, in some embodiments, the formulation may also include preservatives, such as bacteriostatic agents like butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium bisulfite, vitamin C, sodium nitrile, sulfur dioxide, benzoic acid, methyl paraben, propyl paraben, benzyl alcohol, phenol, cresol such as m-cresol, chlorobutanol, or a mixture of two or more preservatives. In some cases, the preservative may consist essentially of an antioxidant preservative such as BHA and / or BHT. The preservative may include a single additional ingredient or two or more additional ingredients. In some embodiments, the preservative includes butylated hydroxytoluene (BHT). In some embodiments, the preservative is present in an amount of 0.05 - 1.0% w / w. In some embodiments, the preservative is present at 0.05 - 0.15% w / w. In some embodiments, the preservative is present at 0.1% w / w. In some embodiments, the preservative is present at 0.1 - 1.0%, 0.1 - 0.2%, 0.1 - 0.5%, 0.5 - 1.0%, 0.05%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0% w / w. In some embodiments, the preservative includes 0.05 - 1.0% w / w of BHT. In some embodiments, the preservative includes 0.05 - 0.15% w / w of BHT. In some embodiments, the preservative includes 0.1% w / w of BHT. In some embodiments, the preservative includes 0.1 - 1.0%, 0.1 - 0.2%, 0.1 - 0.5%, 0.5 - 1.0%, 0.05%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0% w / w of BHT or BHA.

[0067] In some embodiments, certain combinations of the above-described raw materials may be used. For example, in some embodiments, the formulation consists essentially of a proton pump inhibitor such as omeprazole or esomeprazole, such as sodium esomeprazole, magnesium esomeprazole, or another salt or hydrate of omeprazole or esomeprazole, such as magnesium omeprazole or sodium omeprazole, a vegetable oil such as cottonseed oil, caprylic / capric triglyceride, and a preservative such as BHT or BHA or sodium bisulfite. For example, in some embodiments, the formulation consists essentially of magnesium esomeprazole, a vegetable oil such as cottonseed oil, caprylic / capric triglyceride, and a preservative such as BHT or BHA or sodium bisulfite. In some embodiments, the formulation consists essentially of magnesium omeprazole, a vegetable oil such as cottonseed oil, caprylic / capric triglyceride, and a preservative such as BHT or BHA or sodium bisulfite. In some embodiments, the formulation consists essentially of magnesium esomeprazole dihydrate, a vegetable oil such as cottonseed oil, caprylic / capric triglyceride, and a preservative such as BHT or BHA or sodium bisulfite. In some embodiments, the formulation consists essentially of magnesium esomeprazole dihydrate, medium-chain to long-chain triglycerides, and a preservative. In some embodiments, the formulation does not contain aqueous raw materials such as water or buffer, except for perhaps a small amount of aqueous components that are contaminants of proton pump inhibitors, preservatives, or oil-based additives.

[0068] In some embodiments, the formulation has a median particle size of less than 10 μm, less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm. In some such embodiments, the proton pump inhibitor is micronized before or after addition to the formulation to achieve this median particle size. For example, if a particular proton pump inhibitor species, such as a salt of a particular omeprazole or esomeprazole, exhibits a formulation median particle size that exceeds, for example, 10 μm, in some embodiments it can be micronized to reduce the particle size. In other embodiments, the formulation is not micronized but has a median particle size of less than 10 μm, less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm. For example, some formulations herein can achieve a median particle size of less than 10 μm, less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm without using micronization. In some such cases, the proton pump inhibitor species is a magnesium salt, such as esomeprazole magnesium, such as esomeprazole magnesium dihydrate.

[0069] In some embodiments, the formulation comprises 18 - 22% weight / weight (w / w) of a proton pump inhibitor such as omeprazole or esomeprazole, for example sodium esomeprazole, magnesium esomeprazole, or another salt or hydrate of omeprazole or esomeprazole, such as a magnesium salt, in a suspension in a mixture of cottonseed oil and caprylic / capric triglyceride, and 0.05 - 1.0% w / w of a preservative. In some embodiments, the formulation consists essentially of 18 - 22% weight / weight (w / w) of a proton pump inhibitor such as omeprazole or esomeprazole, for example sodium esomeprazole, magnesium esomeprazole, or another salt or hydrate of omeprazole or esomeprazole, such as magnesium omeprazole or sodium omeprazole, in a suspension in a mixture of a vegetable oil such as cottonseed oil and caprylic / capric triglyceride, and 0.05 - 1.0% w / w of a preservative. In some embodiments, the formulation comprises a suspension of 18 - 22% weight / weight (w / w) of magnesium esomeprazole in a mixture of cottonseed oil and caprylic / capric triglyceride, and 0.05 - 1.0% w / w of a preservative. In some embodiments, the formulation consists essentially of a suspension of 18 - 22% weight / weight (w / w) of magnesium esomeprazole in a mixture of a vegetable oil such as cottonseed oil and caprylic / capric triglyceride, and 0.05 - 1.0% w / w of a preservative. In some such embodiments, the vegetable oil is present at 5 - 30% w / w and the caprylic / capric triglyceride is present at 50 - 90%. In some such embodiments, the vegetable oil is present at 8 - 15% w / w and the caprylic / capric triglyceride is present at 60 - 80%. In some such embodiments, the vegetable oil is present at 5 - 10% w / w and the caprylic / capric triglyceride is present at 70 - 85%. In some such embodiments, the vegetable oil is present at 10 - 15% w / w and the caprylic / capric triglyceride is present at 60 - 75%. In some such embodiments, the vegetable oil is present at 12 - 20% w / w and the caprylic / capric triglyceride is present at 55 - 70%.In some such embodiments, the vegetable oil is present at 15 - 20% w / w and the caprylic / capric triglyceride is present at 55 - 70%. In some such embodiments, the vegetable oil is present at 20 - 25% w / w and the caprylic / capric triglyceride is present at 50 - 65%. In some embodiments, the vegetable oil is any one of canola oil (also known as rapeseed oil), coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil, as well as any mixture of two or more of the above-mentioned oils and fats. In some embodiments, the vegetable oil is cottonseed oil or a mixture of cottonseed oil and at least one other vegetable oil.

[0070] The present disclosure also encompasses a method for preparing the pharmaceutical formulations described herein. An example of the method includes first mixing a vegetable oil and a caprylic / capric triglyceride (or medium-chain to long-chain triglyceride), and then adding it to a proton pump inhibitor to form a suspension. When a preservative is added, the preservative can be added to the oil or oil mixture in the first step, or the preservative can be added to the proton pump inhibitor, or the preservative can be added after the proton pump inhibitor.

[0071] III. Storage Stability and Other Characteristics of the Formulation In some embodiments, the median particle size of the formulation within 24 hours of storage at room temperature after preparation of the formulation is less than 10 μm. In some embodiments, the median particle size of the formulation within 24 hours of storage at room temperature after preparation of the formulation is less than 8 μm. In some embodiments, the median particle size of the formulation within 24 hours of storage at room temperature after preparation of the formulation is less than 5 μm. In some embodiments, the median particle size of the formulation within 24 hours of storage at room temperature after preparation of the formulation is less than 4 μm. In some embodiments, the median particle size of the formulation within 24 hours of storage at room temperature after preparation of the formulation is less than 2.5 μm. In some embodiments, the median particle size of the formulation within 24 hours of storage at room temperature after preparation of the formulation is less than 1 μm. The median particle size of the formulation, when referred to herein, refers to the median particle size of the proton pump inhibitor active ingredient in the formulation. The median particle size can be measured as described in the examples below.

[0072] In some embodiments, the 90th percentile particle size of the particle size distribution curve within 24 hours after preparation of the formulation and stored at room temperature is less than 10 μm. In some embodiments, the 90th percentile particle size of the particle size distribution curve within 24 hours after preparation of the formulation and stored at room temperature is less than 8 μm. In some embodiments, the 90th percentile particle size of the particle size distribution curve within 24 hours after preparation of the formulation and stored at room temperature is less than 7 μm. In some embodiments, the 90th percentile particle size of the particle size distribution curve within 24 hours after preparation of the formulation and stored at room temperature is less than 5 μm.

[0073] In some embodiments, after storage for 4 weeks at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 10 μm. In some embodiments, after storage for 4 weeks at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 8 μm. In some embodiments, after storage for 4 weeks at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 7 μm. In some embodiments, after storage for 4 weeks at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 5 μm. In some embodiments, after storage for 4 weeks at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 2.5 μm. In some embodiments, after storage for 3 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 8 μm. In some embodiments, after storage for 3 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 7 μm. In some embodiments, after storage for 3 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 5 μm. In some embodiments, after storage for 3 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 2.5 μm.

[0074] In some embodiments, after 6 months of storage at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 10 μm. In some embodiments, after 6 months of storage at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 8 μm. In some embodiments, after 6 months of storage at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 7 μm. In some embodiments, after 6 months of storage at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 5 μm. In some embodiments, after 6 months of storage at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 4 μm. In some embodiments, after 6 months of storage at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 2.5 μm.

[0075] In some embodiments, after 3 months of storage at 2 - 8, 25, or 30 °C, the particle size at the 90th percentile of the particle size distribution curve remains less than 10 μm. In some embodiments, after 3 months of storage at 2 - 8, 25, or 30 °C, the particle size at the 90th percentile of the particle size distribution curve remains less than 8 μm. In some embodiments, after 3 months of storage at 2 - 8, 25, or 30 °C, the particle size at the 90th percentile of the particle size distribution curve remains less than 7 μm. In some embodiments, after 6 months of storage at 2 - 8, 25, or 30 °C, the particle size at the 90th percentile of the particle size distribution curve remains less than 6 μm.

[0076] The particle size distribution can be measured, for example, using a Malvern MASTERSIZER 2000 instrument.

[0077] Redispersibility can be measured by determining the viscosity after the storage period and by whether there are significant changes in the viscosity, such as an increase of more than 20%. For example, in the examples of this specification, as further described below, the viscosity was measured using a Brookfield DV3TLVCJ viscometer at 25°C. In some embodiments, there is no change in the redispersibility of the formulation after 4 weeks at 2 - 8, 25, or 30°C. In some embodiments, there is no change in the redispersibility of the formulation after 6 weeks at 2 - 8, 25, or 30°C. In some embodiments, there is no significant change in the viscosity of the formulation after 6 weeks at 2 - 8, 25, or 30°C. In some embodiments, there is no change in the redispersibility of the formulation after 3 months at 2 - 8, 25, or 30°C. In some embodiments, there is no significant change in the viscosity of the formulation after 3 months of storage at 2 - 8, 25, or 30°C. In some embodiments, there is no change in the redispersibility of the formulation after 6 months at 2 - 8, 25, or 30°C. In some embodiments, there is no significant change in the viscosity of the formulation after 6 months of storage at 2 - 8, 25, or 30°C. In some embodiments, there is no change in the redispersibility of the formulation after 12 months at 2 - 8, 25, or 30°C. In some embodiments, there is no significant change in the viscosity of the formulation after 12 months of storage at 2 - 8, 25, or 30°C.

[0078] In some embodiments, the viscosity of the formulation is less than 300 cP at 25°C as measured using a Brookfield DV3%LVCJ viscometer as described in the examples below. In some embodiments, the viscosity remains below 300 cP after 6 months of storage at 2 - 8, 25, or 30°C. In some embodiments, the viscosity remains below 300 cP after 12 months of storage at 2 - 8, or 25°C. In some embodiments, the viscosity remains between 200 and 300 cP after 6 months of storage at 2 - 8, 25, or 30°C. In some embodiments, the viscosity remains between 200 and 300 cP after 12 months of storage at 2 - 8, or 25°C. In some embodiments, the viscosity remains between 225 and 300 cP after 6 months of storage at 2 - 8, 25, or 30°C. In some embodiments, the viscosity remains between 225 and 300 cP after 12 months of storage at 2 - 8, or 25°C. In some embodiments, the viscosity remains between 225 and 280 cP after 6 months of storage at 2 - 8, 25, or 30°C. In some embodiments, the viscosity remains between 225 and 280 cP after 12 months of storage at 2 - 8, or 25°C. In some embodiments, the viscosity remains between 250 and 300 cP after 6 months of storage at 2 - 8, 25, or 30°C. In some embodiments, the viscosity remains between 250 and 300 cP after 12 months of storage at 2 - 8, or 25°C.

[0079] In some embodiments, after 4 weeks at 2 - 8, 25, or 30 °C, there is no change in the injectability of the formulation when using a 3 mL 26G x 1 / 2 inch syringe / needle. In some embodiments, after 6 weeks at 2 - 8, 25, or 30 °C, there is no change in the injectability of the formulation when using a 3 mL 26G x 1 / 2 inch syringe / needle. In some embodiments, after 3 months at room temperature (e.g., 25 °C), there is no change in the injectability of the formulation when using a 3 mL 21G x 1 / 2 inch syringe / needle. In some embodiments, after 6 months at room temperature (e.g., 25 °C), there is no change in the injectability of the formulation when using a 3 mL 21G x 1 / 2 inch syringe / needle. In some embodiments, after 3 months at room temperature (e.g., 25 °C), there is no change in the injectability of the formulation when using a 3 mL 18G x 1 / 2 inch syringe / needle. In some embodiments, after 6 months at room temperature (e.g., 25 °C), there is no change in the injectability of the formulation when using a 3 mL 18G x 1 / 2 inch syringe / needle.

[0080] In some embodiments, the total proton pump inhibitor (e.g., esomeprazole) impurities remain less than 0.15% after storage for up to 6 months at 2 - 8, 25, or 30 °C. The impurities can be measured, for example, by HPLC. In the following examples, the impurities were examined using HPLC on an Agilent 1100 system equipped with a Zorbax SB-C8, 150 x 4.6 mm, 3.5 μm analytical column, using a mobile phase of acetonitrile (72.5:27.5 by volume) from phosphate buffer (pH 7.6), filtered through a 0.8 μm nylon filter, and examined at a flow rate of 1.0 mL / min at room temperature.

[0081] Thus, the formulations herein may have one or more of the following characteristics: a. The formulation is suitable for intramuscular injection into equines or other animals; b. The formulation is suitable for subcutaneous injection into equines or other animals; c. After storage for 6 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 8 μm; d. After storage for 6 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 5 μm; e. After storage for 6 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 4 μm; f. After storage for 6 months at 2 - 8, 25, or 30 °C, the median particle size of the formulation remains less than 2.5 μm; g. After storage for 6 months at 2 - 8, 25, or 30 °C, the particle size at the 90th percentile of the particle size distribution curve remains less than 8 μm; h. In some embodiments, after storage for 6 months at 2 - 8, 25, or 30 °C, there is no significant change in the viscosity of the formulation; i. The viscosity remains lower than 300 cP, between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP after storage for 6 months at 2 - 8, 25, or 30 °C; j. After 6 months at room temperature (e.g., 25 °C), there is no change in the injectability of the formulation when using a 3 mL 21G × 1 / 2 inch syringe / needle; k. The total proton pump inhibitor impurities remain less than 0.15% after storage for up to 6 months at 2 - 8, 25, or 30 °C; l. After storage for 12 months at 2 - 8 or 25 °C, the median particle size of the formulation remains less than 8 μm; m. After storage for 12 months at 2 - 8 or 25 °C, the median particle size of the formulation remains less than 5 μm; n. After storage for 12 months at 2 - 8 or 25 °C, the median particle size of the formulation remains less than 4 μm; o. After storage for 12 months at 2 - 8 or 25 °C, the median particle size of the formulation remains less than 2.5 μm; p. After storage for 12 months at 2 - 8 or 25 °C, the particle size at the 90th percentile of the particle size distribution curve remains less than 8 μm; q. After storage for 12 months at 2 - 8 or 25 °C, there is no significant change in the viscosity of the formulation; r. The viscosity remains lower than 300 cP, between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP after storage for 12 months at 2 - 8 or 25 °C; After 12 months at room temperature (e.g., 25°C), there is no change in the injectability of the formulation using a 3 mL syringe / needle of 21G × 1 / 2 inch to 18G × 1 / 2 inch; t. The total proton pump inhibitor impurities remain less than 0.15% after storage for up to 12 months at 2 - 8, or 25°C; and / or u. When intramuscularly injected into horses, the average half-life (T 1 / 2 ) of the formulation is in the range of 12 - 24 hours.

[0082] In some embodiments, after 24 months at 2 - 8°C or 25°C or 30°C, the median particle size of the formulation remains less than 10 μm, less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm. In some embodiments, after 24 months at 2 - 8°C or 25°C or 30°C, the formulation remains stable for use.

[0083] IV. Container and Administration Method The present disclosure also encompasses vials for storing the formulation. In some embodiments, the vial may also be suitable for containing the formulation to be administered. The vial may be of any shape or size appropriate for holding a veterinary pharmaceutical injectable formulation product.

[0084] The present disclosure also encompasses devices for intramuscular or subcutaneous injection into animals such as equines, containing a suitable amount of the formulation of the present specification for administration. In some embodiments, when it is desired to administer the formulation by intramuscular injection with a syringe, the device may include a syringe and needle for intramuscular injection. In some embodiments, the device may be structurally similar to devices used for intramuscular administration of human pharmaceuticals such as epinephrine or insulin or other animal pharmaceuticals. For example, epinephrine is often administered using an auto-injector device often called an injection pen. A similar pen-type device may also be used herein and is suitable for intramuscular injection into equines or other animals.

[0085] In some embodiments, the device comprises a proton pump inhibitor in a complete single unit dosage amount, such as omeprazole or esomeprazole, such as esomeprazole magnesium, for example, for a horse of average body weight. In other embodiments, the device comprises two or more dosages, such as two dosages, three dosages, or four dosages.

[0086] In some embodiments, the vial or device may also be packaged with instructions for use, for example, to provide dosing instructions for equine and / or other animals.

[0087] V. Methods of Using Pharmaceutical Formulations The present disclosure also encompasses a method of treating gastric ulcers in an animal such as an equine, comprising administering an effective amount of the formulation herein intramuscularly or subcutaneously, for example, from the vial described above and / or using the device described above. In some embodiments, the formulation is an omeprazole formulation such as an omeprazole magnesium formulation. In some embodiments, the formulation is an esomeprazole formulation. In some such embodiments, esomeprazole is esomeprazole magnesium such as esomeprazole magnesium dihydrate. In some embodiments, the method of treatment comprises administering an effective amount of the above formulation to an animal such as an equine by intramuscular injection or subcutaneous injection at least once a week. In some embodiments, the formulation is administered over a period of four weeks. In some embodiments, the formulation is administered over a period of three weeks. In some embodiments, the formulation is administered once, twice, or three times a week.

[0088] In some embodiments, when the formulation comprises esomeprazole magnesium, the formulation is administered to provide esomeprazole magnesium between at least 1.5 mg / kg and 5.0 mg / kg per dose, at least once a week. In some embodiments, the formulation is administered at a dose of esomeprazole magnesium of 1.5 mg / kg, 1.75 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, or 5 mg / kg. In some embodiments, the formulation is according to one of the following regimens: (a) at a dose of 2.0 - 4.0 mg / kg, once a week for 3 weeks; (b) at a dose of 2.0 - 4.0 mg / kg, once a week for 4 weeks; (c) at a dose of 2.0 - 4.0 mg / kg, twice a week for 3 weeks; (d) at a dose of 2.0 - 4.0 mg / kg, twice a week for 4 weeks; or (e) according to any one of (a) - (d), followed by a reduced dose, once or twice a week, for at least an additional 1 week.

[0089] In some embodiments, the first dose or the first two doses or the doses for the first week, two weeks, three weeks, or four weeks are at a higher level (e.g., a "loading dose") than subsequent doses. In some embodiments, the formulation is administered for a period longer than 4 weeks, and optionally, the dose is reduced after a 4 - week period. In some embodiments, the formulation is administered for a period longer than 3 weeks, and optionally, the dose is reduced after a 3 - week period. For example, in some embodiments, the initial dosing level can be selected up to 2 weeks, up to 1 month, or up to 6 weeks, and then either the dose or the dosing frequency can be reduced in subsequent weeks or months.

[0090] In any of the above dosing regimens, the formulation can be administered by intramuscular injection or by subcutaneous injection. In some embodiments, the formulation is administered using the above vial and / or device. In some embodiments, the formulation is administered to equine animals. In some embodiments, the equine animal is suffering from gastric ulcer, equine gastric ulcer syndrome (EGUS), equine squamous gastric disease (ESGD), or equine glandular gastric disease (EGGD). In some embodiments, the gastric ulcer is treated. For example, in some embodiments, at least one ulcerative lesion is resolved or reduced in size and / or the number of lesions is reduced.

[0091] In some embodiments, the subject to be treated is an equine animal. In other embodiments, the subject to be treated is another animal such as a domestic animal or a draft animal. In some embodiments, the other animal is a donkey, a camel, a pig, a llama, or an alpaca. In some embodiments, when a non-equine animal is treated, the esomeprazole dosage can vary up to a dosage equivalent to the dosage administered to such an animal by the oral route. For example, some other animals require a higher or lower dosage of proton pump inhibitor per body weight than that required by equine animals.

[0092] In some embodiments, the formulation is administered at a dosage equal to or greater than a dosage capable of controlling the gastric pH of an equine animal for at least 3 days after dosing, for example, 3 to 5 days after dosing, or 3 days, 4 days, or 5 days after dosing. Gastric pH can be considered to be controlled if it remains at pH 4 or higher for more than 60% of the time.

[0093] In some embodiments, the formulation is administered at a dosage that has resulted in an improvement in an equine clinical trial corresponding to at least a 1-grade reduction in the symptoms of gastric ulcer disease in horses with respect to the following gastric ulcer scoring system of 0-3: 0. Intact mucosal epithelium (may have erythema and / or hyperkeratosis) 1. Small single or small multifocal lesions 2. Large single or large multifocal lesions 3. Extensive (often adherent) lesions with areas of overt deep ulceration.

[0094] In some embodiments, the formulation is administered at a dosage that, in equine clinical trials, resulted in an improvement corresponding to at least a 1-grade reduction in the symptoms of gastric ulceration in horses with respect to the following 0 - 4 gastric ulceration scoring system: 0. The epithelium is intact and there is no appearance of hyperkeratosis 1. The mucosa is intact but there are areas of hyperkeratosis 2. Small single or multifocal lesions 3. Large single or extensive superficial lesions 4. Extensive lesions with areas of overt deep ulceration.

[0095] In some embodiments, the formulation is administered at a dosage that, in equine clinical trials, resulted in both control of gastric pH and at least a 1-grade reduction in the above-described gastric ulceration scoring system.

Examples

[0096] Example 1 An oily suspension containing esomeprazole magnesium dihydrate and esomeprazole sodium An oily suspension containing 20% w / w esomeprazole sodium or esomeprazole magnesium dihydrate was prepared in 50-gram batches using either esomeprazole magnesium dihydrate or esomeprazole sodium (FIS Chemicals) in a mixture of Miglyol® MCT 812 (Cremer) and super-refined cottonseed oil (Croda). The goal was to obtain one homogeneous oily suspension for each esomeprazole species, verify each particle size distribution, and confirm the homogeneity of the formulation after 24 hours of storage at room temperature.

[0097] To prepare the suspension, first MCT 812 and cottonseed oil were mixed together, and then esomeprazole sodium or esomeprazole magnesium was added next. The esomeprazole magnesium formulation was a grayish-white, visually homogeneous viscous oily solution, while the esomeprazole sodium formulation was a white, visually homogeneous, denser viscous oily solution than the esomeprazole magnesium formulation. After 24 hours on the bench top, the appearance of the esomeprazole magnesium formulation did not change, while the esomeprazole sodium formulation appeared denser. In neither formulation was phase separation observed.

[0098] After 24 hours of storage, the particle size distribution (PSD) was performed using a Malvern MASTERSIZER 2000. The measurement range of the instrument was 0.02 - 2000 μm, with a refractive index dispersant of 1.375 - hexanes, an obscuration range of 5 - 20%, a sample / background measurement time = 1, 5000 sample / background measurement snaps, and a manual stirring speed of 2000 rpm.

[0099] The particle size distribution of the esomeprazole magnesium formulation for the 10th - 90th percentile portion of the distribution curve (in μm) was in the range of 0.12 - 4.75 μm (average of 3 measurements). The median particle size (i.e., the 50th percentile of the distribution) was 0.62 μm (average of 3 measurements). The particle size distribution of the esomeprazole sodium formulation for the 10th - 90th percentile portion of the distribution curve was in the range of 6.08 - 50.28 μm (average of 3 measurements), while the median particle size was 22.16 μm (average of 3 measurements).

[0100] Therefore, the cottonseed oil - Miglyol® 812 suspension prepared with esomeprazole magnesium dihydrate had a significantly lower particle size range than the same formulation prepared with esomeprazole sodium. Furthermore, visually, the esomeprazole sodium formulation appeared denser and more paste - like, presumably due to its larger particle size.

[0101] Also, for the sterilized magnesium esomeprazole dihydrate and sodium esomeprazole, both obtained from Shouguang Fukang Pharma, particle size distribution was carried out. The particle size distribution of magnesium esomeprazole for the 10th to 90th percentile part of the distribution curve (in μm) was in the range of 0.22 to 6.57 μm, and the median particle size was 2.01 μm (average of 3 measurements). The particle size distribution of sodium esomeprazole for the 10th to 90th percentile part of the distribution curve was in the range of 8.60 to 36.49 μm, and the median particle size was 18.84 μm (average of 3 measurements).

[0102] Using a Brookfield viscometer (model number.DV3TLVCJ), the viscosity was measured at 25 °C, and the redispersibility was tested by measuring the viscosity of the formulation. A standard solution (S60 standard) having a nominal viscosity of about 100 cP (mPa·s) at 25 °C was used as a reference. The redispersibility of the magnesium esomeprazole formulation was also tested using 26- and 27-gauge needles, and the formulation was found to pass through both types of needles.

[0103] The magnesium esomeprazole formulation was also stored at room temperature for 1 month, and no sedimentation was observed upon visual inspection. To determine sedimentation, after storage, the formulation was manually shaken to uniformly disperse the sediment to form a suspension, and the suspension was allowed to sediment at room temperature under gravity for 1 hour before visually confirming the appearance.

[0104] Example 2 Injection Possibility of Formulation Vehicle and Magnesium Esomeprazole Formulation The injectability of the esomeprazole magnesium formulation of Example 1 was compared with that of the formulation vehicle (i.e., additives only) to determine whether the oil suspension was filterable for sterilization and injectable through a needle using a syringe. Approximately 2 mL of the vehicle or esomeprazole magnesium formulation was transferred to a 3 mL plastic syringe, and a filter (for the vehicle; 0.2 μm hydrophobic filter) or a needle (for the formulation; either 26G × 1 / 2 inch or 27G × 1 / 2 inch) was attached to the syringe, and the contents were extruded into a small vial for visual analysis. The vehicle could pass easily through the 26G × 1 / 2 inch needle with relatively low resistance without clogging and could pass through the 27G × 1 / 2 inch needle without clogging with a resistance slightly greater than that of the 26G × 1 / 2 inch needle, but could still be easily extruded. Using the 26G × 1 / 2 inch needle, the esomeprazole magnesium formulation could pass through without clogging with relatively low resistance. Using the 27G × 1 / 2 inch needle, the formulation could pass through without clogging with a resistance slightly greater than that when using the 26G × 1 / 2 inch needle, but could still be easily extruded.

[0105] Example 3 Stability of Esomeprazole Magnesium Formulation The formulation described in Example 1 was prepared for a stability study and measured during storage for up to 6 weeks at four different temperatures (2 - 8°C, 25°C, 30°C, and 40°C) to determine purity, particle size, redispersibility, and injectability.

[0106] Impurities were filtered through a 0.8 μm nylon filter and examined at a flow rate of 1.0 mL / min at room temperature using HPLC on an Agilent 1100 system equipped with a Zorbax® SB-C8, 150 × 4.6 mm, 3.5 μm analytical column, with a mobile phase gradient from phosphate buffer (pH 7.6) to acetonitrile (72.5:27.5 by volume). The esomeprazole major peak in the HPLC chromatogram of esomeprazole magnesium dihydrate standard was 99.94%, while the esomeprazole major peak remained at least 99.91% after 4 weeks of storage at each temperature. Thus, the total impurities remained below 0.1% after 4 weeks at each temperature. After 6 weeks of storage, the total impurities at 2 - 8, 25, and 30 °C remained below 0.1%, while at 40 °C, the total impurities were 0.12%.

[0107] Resuspendability, as measured by viscosity (see above), showed no change after 4 weeks of storage at each temperature and no significant change after 6 weeks at 2 - 8, 25, or 30 °C. The results after 4 weeks and 6 weeks are as shown in the table below. TIFF2025098044000002.tif87170

[0108] The injectability results after 4 weeks and 6 weeks are as shown in the table below. There were no changes after 4 weeks and 6 weeks at 2 - 8, 25, or 30 °C. The "N / D" median was not determined. TIFF2025098044000003.tif60170

[0109] The particle size distribution remained essentially the same after 4 weeks of storage at each temperature. The particle sizes at the 10th - 90th percentiles were in the range of approximately 0.2 - 7.0 μm after 4 weeks of storage at all four temperatures. The median particle size remained at approximately 1 - 2 μm after 4 weeks of storage at all four temperatures. These results represent the average of three measurements.

[0110] The above results, when summarized, indicate that the formulation is stable at temperatures up to 30°C for at least 6 weeks. The particle size remains substantially unchanged, and the formulation remains injectable while keeping the total impurity level below 0.1%. However, there was a color change in the formulation from grayish white to bright yellow at 30°C. At 40°C, the formulation becomes paste-like after 6 weeks of storage.

[0111] Example 4 Long-term storage of esomeprazole magnesium formulation Next, a batch of the esomeprazole magnesium formulation of Example 1 was prepared and tested for storage over 3-month and 6-month periods at 25°C, 30°C, and 40°C. Assays for purity, particle size distribution, resuspendability, and injectability similar to those in Example 3 above were performed. The results of resuspendability are as shown in the table below. TIFF2025098044000004.tif94170

[0112] The results of injectability are as shown in the table below. TIFF2025098044000005.tif65170

[0113] The particle size ranges from T0 to 6 months at each temperature are as follows. At T0, the particle size range at the 10th to 90th percentile was 0.24 - 6.32 μm, and the median was 1.72 μm (average of 3 measurements). After 6 months at either 25 or 30°C, the particle size range was generally narrower, and as a result, the 10th to 90th percentile range at both temperatures was approximately 2.0 - 7.5 μm, and the median particle size was approximately 3.7 - 3.8 μm. At 40°C, the overall particle size range increased to approximately 4.0 - 18 μm at the 10th to 90th percentile after 6 months.

[0114] After 6 months at either 25 or 30 °C, the total impurities measured by HPLC remained at 0.11% or less, while the impurities in the esomeprazole magnesium dihydrate standard solution were 0.07%. After storage at 40 °C for 6 months, the total impurities measured by HPLC were 0.15%. Based on the above results, the formulation is sufficiently stable after 6 months at either 25 or 30 °C, but storage at 40 °C is not recommended.

[0115] As described in Example 1, but additionally containing 0.1% BHT (butylated hydroxytoluene; Spectrum Chemical) preservative, further formulations of esomeprazole magnesium dihydrate were tested for long-term storage up to 6 months at 2 - 8 °C, 25 °C, and 40 °C. At T0 before storage, the formulation appeared as a grayish-white oily suspension that became uniform when shaken. The formulation at T0 was able to pass through a 3 mL syringe equipped with a 21G × 1 / 2 inch needle without clogging and with relatively low resistance, and was easily resuspendable when shaken. The total impurities were measured at 0.04%, while the impurities in the esomeprazole magnesium standard were measured at 0.07%. The particle size at T0 was in the range of approximately 2.2 - 5.4 μm (10th - 90th percentile), and the median was 3.45 μm.

[0116] After storage for 3 and 6 months at each temperature, the results for appearance, injectability, and resuspendability are as shown in the table below.

[0117] Appearance: TIFF2025098044000006.tif41170

[0118] Injectability: TIFF2025098044000007.tif72170

[0119] Resuspendability: TIFF2025098044000008.tif50170

[0120] The particle size after 3 months at either 2 - 8°C or 25°C remained in the range of about 2.0 - 5.0 μm, similar to the particle size at T0, and the median value was about 3.0 - 3.5 μm. The particle size at 40°C was not determined.

[0121] After 6 months of storage at 2 - 8°C and 25°C, there were 0.11% and 0.13% total impurities respectively.

[0122] After 6 months of storage at 2 - 8°C and 25°C, the viscosity of the formulation measured at 25°C for 5 minutes (as described above) was about 250 - 290 cP. On the other hand, after 9 months of storage, the viscosity measured at 25°C for 5 minutes was about 230 - 245 cP. The viscosity at T0 (measured at 25°C for 5 minutes) was measured and was about 235 - 240 cP.

[0123] After 12 months of storage at 2 - 8°C and 25°C, the particle size of the formulation remained in the range of about 1.5 - 5.0 μm, similar to the particle size at T0 again, and the median value was about 2.5 - 3.0 μm. The particle size at 40°C was not determined. Also, after 9 or 12 months of storage at 2 - 8°C and 25°C, there was no change in redispersibility. After 12 months of storage at 2 - 8°C and 25°C, the viscosity was measured at 25°C for 5 minutes using the S60 standard with a viscosity of about 100 cP on a Brookfield Ametek rheometer DV3T as described above, and remained about 230 - 250 cP. The total impurities remained less than 0.1% in these two temperature ranges after 12 months of storage.

[0124] In conclusion, this formulation was stable for 6 - 12 months at both 2 - 8°C and 25°C; the appearance of the formulation did not change, it was easily injectable and redispersible. The viscosity, like the particle size distribution, remained almost the same as at T0, while the total impurities remained less than 0.15%, increasing only slightly between the two temperatures (from 0.11% to 0.13%), and the standard impurity was 0.07%. After several months at 40°C, the formulation changed color from grayish - white to purple, formed lumps, and could not be redispersed. Therefore, no other tests were performed at 40°C.

[0125] For the formulation containing the preservative, a similar three-month stability test was also carried out at 30°C. After three months at 30°C, the appearance of the formulation did not change, it could be easily injected, and there was no significant change in the impurities, but it was slightly difficult to resuspend and became viscous.

[0126] Example 5 Clinical trial of injectable formulation of esomeprazole magnesium dihydrate A clinical study was conducted in five horses with a suspension of 195.8 mg / mL of esomeprazole magnesium dihydrate containing the BHT preservative (antioxidant) in a mixture of cottonseed oil and Miglyol® 812 additive as described in Example 4, and its effectiveness in controlling the pH of equine gastric juice was determined.

[0127] The general trial protocol was as follows. Five horses equipped with gastric cannulas were acclimatized to the study state. The horses were healthy throughout the acclimatization period. The baseline gastric pH was recorded before product administration. On the second day, each horse was treated intramuscularly with a dose of the product aimed at delivering 1.75 mg of esomeprazole magnesium dihydrate per kg of body weight. After the washout period, the study was repeated using a dose of the product aimed at delivering 4.0 mg of esomeprazole magnesium dihydrate per kg of body weight. The gastric pH was measured after treatment.

[0128] The first five-day treatment period evaluated the effect of the treatment with the amount of formulation aimed at delivering 1.75 mg per kg of body weight on the gastric pH and then rounded up to the next larger 0.2 mL increment. The second five-day treatment period tested the effect of the amount of formulation aimed at delivering a dosage of 4.0 mg / kg of esomeprazole magnesium dihydrate on the gastric pH.

[0129] The product was provided as a sterile suspension.

[0130] The horses were lightweight, saddle-bred, approximately 3 years old, and weighed approximately 378 - 428 kg as estimated from the system, and consisted of castrated males (geldings) and / or non-castrated females (mares). Female candidates were neither pregnant nor lactating. Procedures were performed to avoid or minimize discomfort, distress, or pain to the participating animals.

[0131] Intragastric pH was continuously measured from immediately after treatment until dosing continued the next day. Intragastric pH was measured at baseline and after each of two treatments at different dosages. Control of intragastric pH varied among individual horses as expected. (See Figures 1A, 1B, and 1C.) The products administered at dosages of 1.75 mg / kg and 4.0 mg / kg, respectively, controlled intragastric pH in individual horses for approximately 3 - 5 days. The experimental regimen was considered safe for intramuscular administration to mature horses and did not have any apparent adverse effects on the health of equine animals.

[0132] Example 6 Randomized, placebo-controlled, dose-range, pilot clinical trial to evaluate the efficacy and field safety of an injectable formulation of esomeprazole magnesium dihydrate for the resolution of gastric ulcers in horses A larger clinical study of a suspension of approximately 200 mg / mL of esomeprazole magnesium dihydrate containing a BHT preservative in a mixture of cottonseed oil and Miglyol® 812 additive, as described in Example 4, was performed on 53 horses to test its efficacy in controlling gastric ulcers at specific dosing regimens. The suspension was tested against a control saline solution.

[0133] The study was a multi-site, blinded, placebo-controlled, randomized clinical trial that investigated the efficacy and safety of a product administered intramuscularly to control gastric ulceration in horses. The first efficacy endpoint was the resolution of gastric ulceration in horses, defined as a score of 0 on a 0 - 3 gastric ulcer scoring system. The second efficacy endpoint was the improvement of gastric ulceration in horses, defined as at least a 1-grade decrease on the following 0 - 3 gastric ulcer scoring system: 0. Intact mucosal epithelium (may have erythema and / or hyperkeratosis) 1. Small, single or small, multifocal lesions 2. Large, single or large, multifocal lesions 3. Extensive (often adherent) lesions with areas of obvious deep ulceration.

[0134] A total of 53 horses were randomized to one of four treatment groups (4 mg / kg once weekly, 2 mg / kg once weekly, 2 mg / kg twice weekly, twice-weekly control product). Fourteen horses were treated with the investigational veterinary product (IVP) at 4 mg / kg once weekly, 13 horses were treated with the IVP at 2 mg / kg once weekly, 13 horses were treated with the IVP at 2 mg / kg twice weekly, and 13 horses were treated with twice-weekly control saline (CP). Prohibited medications during the study included drug applications that could change gastric pH. The test animals were at least 1 year old, of either sex, intact or castrated, non-pregnant, non-lactating, and non-breeding, of any breed, and the initial weight range was not specified. All horses were determined to be evaluable for efficacy analysis prior to the unblinded study. Of the 14 horses treated at 4 mg / kg once weekly, 11 (78.6%) had ulcers resolve. Of the 13 horses treated at 2 mg / kg twice weekly, 10 (76.9%) had ulcers resolve. Of the 13 horses treated at 2 mg / kg once weekly, 11 (84.6%) had ulcers resolve. Of the horses in the placebo group, 30.8% had ulcers resolve. All esomeprazole treatment groups showed a statistically significant difference from the control treatment group (analysis by Fisher's exact test). The product also showed good tolerance.

[0135] A baseline gastroscopy was performed to confirm the presence of gastric ulcers and the randomization procedure was completed. The horses were administered a single dose of IVP or cP. Gastroscopy and evaluation were completed again at Visit 2 (Day 14). If the gastroscopy evaluation at Visit 2 was Grade 0, the horse was withdrawn from the study. Horses with a gastroscopy evaluation of Grade 1 or higher at Visit 2 were continued until Visit 3. For the remaining horses, at Visit 3 (Day 21), gastroscopy evaluation and study termination activities were completed. The first efficacy was determined by gastric ulcer resolution (gastroscopy evaluation grade = 0) at the end of the study. The second efficacy was determined by gastric ulcer improvement (at least a one-grade decrease in gastric ulcer grade at the end of the study compared to baseline).

[0136] The intended dose of the product is either 4 mg / kg body weight or 2 mg / kg body weight, calculated in mL based on the starting weight of the horse and the esomeprazole magnesium dihydrate concentration of 200 mg / mL of the formulation, and rounded to the nearest mL. The control saline was provided in a standard volume. The dose was administered using a new 18-gauge, 1.5-inch needle and a 5 - 10 mL sterile syringe. The duration of dosing depended on ulcer resolution and continued for up to 18 days.

[0137] The dosing schedule for each treatment group is as shown in the table below: TIFF2025098044000009.tif70170

[0138] The first measurement variable for efficacy was ulcer resolution (score "0") at the end of the study. The second measurement variable was at least a one-grade improvement in the gastric ulcer score at the end of the study. The results were summarized by frequency and count. An exploratory statistical analysis of IVP vs cP was performed. Horses whose ulcers had resolved by Visit 2 were withdrawn at that visit. Horses that did not withdraw at Visit 2 were withdrawn at Visit 3.

[0139] Fourteen horses treated with 4 mg / kg of IVP received a total of 35 doses. Of the 14 horses treated with 4 mg / kg of IVP once a week, 11 (78.6%) were determined to have improved with treatment. Thirteen horses treated with 2 mg / kg of IVP (either once or twice a week dosing groups) received a total of 103 doses. Of the 13 horses treated with 2 mg / kg of IVP twice a week, 12 (92.3%) were determined to have improved with treatment. Of the 13 horses treated with 2 mg / kg of IVP once a week, 13 (100.0%) were determined to have improved with treatment. Thirteen horses treated with CP received a total of 74 doses. Of the 13 horses treated with CP, 7 (53.8%) were determined to have improved with treatment. By comparison of the confidence intervals, a statistical difference was shown between the twice-weekly 2 mg / kg IVP group and the once-weekly 2 mg / kg IVP group when compared to the CP group.

[0140] Treatment success was defined as the resolution of gastric ulceration (gastric ulcer score = 0). Of the 14 horses treated with 4 mg / kg of IVP once a week, 11 (78.6%) were determined to have treatment success. Of the 13 horses treated with 2 mg / kg of IVP twice a week, 10 (76.9%) were determined to have treatment success. Of the 13 horses treated with 2 mg / kg of IVP once a week, 11 (84.6%) were determined to have treatment success. Of the 13 horses treated with CP, 4 (30.8%) were determined to have treatment success. Therefore, the IVP formulation was effective in controlling gastric ulcers within 3 weeks after the start of the treatment schedule in the treated horses.

[0141] This clinical study in horses demonstrated that an intramuscularly administered esomeprazole magnesium dihydrate formulation is effective in controlling gastric ulcers in horses. Use of the formulation resulted in efficacy shown in 84.6% of the horses treated once a week with 2 mg / kg of esomeprazole magnesium dihydrate. In this study, once-weekly, 2 mg / kg treatment was the most effective. Abnormal clinical signs and adverse events after treatment were mild and transient and resolved shortly after treatment. The product generally showed good tolerance.

[0142] Further details of this study are provided in the table below.

[0143] Details of the horses treated: TIFF2025098044000010.tif234170

[0144] Treatment successful; disappearance of gastric ulcer: TIFF2025098044000011.tif73170

[0145] Treatment improvement; improvement of gastric ulcer: TIFF2025098044000012.tif74170

[0146] Time until the end of the study: TIFF2025098044000013.tif75170

[0147] Example 7 Evaluation of the pharmacokinetic profile of an intramuscular formulation This study evaluated the pharmacokinetics of the proton pump inhibitor, esomeprazole, after multiple intramuscular administrations to horses.

[0148] Eighteen adult horses were randomized into three equal treatment groups and assigned to one of three doses: 2 mg / kg (1x), 6 mg / kg (3x), or 10 mg / kg (5x). The doses were administered intramuscularly. Each horse received the assigned dose three times at 7-day intervals. Blood samples were collected at 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after each administration and then every 48 hours until day 28. Esomeprazole was quantified by LC-MS / MS. The data were analyzed using non-compartmental analysis.

[0149] The maximum concentration (Cmax) of esomeprazole was reached within 1.2 - 2 hours, and the mean half-life was 11.63 - 24.5 hours across all doses and administrations. Linear pharmacokinetics were demonstrated across the three dosing regimens by dose-normalization of Cmax and the area under the curve. After administration of the final dose in the 5-fold group, the drug was detectable for 96 ± 26.29 hours. A single mild and self-resolving injection-site reaction was identified in one horse in the 3-fold group.

[0150] This study demonstrated that intramuscular administration of esomeprazole to horses had good tolerance with three administrations every 7 days at 1-, 3-, and 5-fold doses. Esomeprazole was rapidly absorbed from the injection site, and the extended half-life was 12 - 24 hours. Linear kinetic characteristics were observed across the test doses. These results support extended dosing intervals such as once weekly or longer periods when used in horses for the treatment of gastric ulcers.

Claims

1. 1. An injectable pharmaceutical formulation comprising a suspension of a proton pump inhibitor, such as omeprazole, omeprazole magnesium, omeprazole sodium, esomeprazole, esomeprazole sodium, esomeprazole magnesium, or esomeprazole magnesium dihydrate, in a mixture of vegetable oil and caprylic / capric triglyceride.

2. 2. The formulation of claim 1, wherein the vegetable oil is selected from the group consisting of canola oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil, and mixtures of any two or more of canola oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil.

3. 3. A formulation according to claim 1 or 2, wherein the vegetable oil is cottonseed oil or a mixture of cottonseed oil and another vegetable oil.

4. 4. The formulation of claim 1, 2, or 3, wherein the vegetable oil is cottonseed oil.

5. 5. A formulation according to any one of claims 1 to 4, comprising 15% to 25% weight / weight (w / w) esomeprazole magnesium.

6. 6. The formulation of claim 5, comprising 18% w / w to 22% w / w of esomeprazole magnesium.

7. 7. The formulation of claim 6 comprising 19% w / w to 21% w / w of esomeprazole magnesium.

8. 8. The formulation of claim 7 comprising 20% ​​w / w esomeprazole magnesium.

9. 9. The formulation of any one of claims 1 to 8, wherein the proton pump inhibitor is esomeprazole magnesium dihydrate.

10. 10. A formulation according to any one of claims 1 to 9, comprising 5% w / w to 30% w / w of vegetable oil, such as 5-10%, 10-15%, 15-20%, 20-25% or 25-30%.

11. 9. A formulation according to any one of claims 1 to 8, comprising from 5% w / w to 30% w / w cottonseed oil, for example 5-10%, 10-15%, 15-20%, 20-25% or 25-30%.

12. 12. The formulation of claim 11 comprising 10-15%, 10-12%, 13-15%, 15-17%, 18-20%, or 15-20% w / w cottonseed oil.

13. 13. A formulation according to any one of claims 1 to 12, comprising 50% to 90% w / w caprylic / capric triglyceride, such as 50-60%, 60-70%, 70-80% or 80-90%.

14. 14. A formulation according to claim 13 comprising 60-70%, 60-65%, 65-70%, 70-80%, 70-75% or 75-80% w / w caprylic / capric triglyceride.

15. 14. A formulation according to any one of claims 1 to 13, further comprising at least one preservative, such as butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA) or sodium bisulfite, or a mixture of BHT, BHA and / or sodium bisulfite.

16. 15. The formulation of claim 14, wherein the at least one preservative comprises 0.05-1.0% w / w of butylated hydroxytoluene (BHT).

17. 17. The formulation of any one of claims 1 to 16, consisting essentially of: (a) a proton pump inhibitor, such as omeprazole, esomeprazole, omeprazole magnesium, omeprazole sodium, esomeprazole sodium, esomeprazole magnesium, or esomeprazole magnesium dihydrate; (b) cottonseed oil; (c) caprylic / capric triglyceride; and (d) at least one preservative.

18. 18. The formulation of claim 17, consisting essentially of esomeprazole magnesium, such as esomeprazole magnesium dihydrate, cottonseed oil, caprylic / capric triglyceride, and at least one preservative, such as BHT.

19. 1. An injectable pharmaceutical formulation comprising a 18-22% weight / weight (w / w) suspension of a proton pump inhibitor, such as omeprazole, esomeprazole, omeprazole magnesium, omeprazole sodium, esomeprazole sodium, esomeprazole magnesium, or esomeprazole magnesium dihydrate, in a mixture of cottonseed oil and caprylic / capric triglyceride, and 0.05-1.0% w / w of a preservative.

20. 1. An injectable pharmaceutical formulation consisting essentially of a 18-22% weight / weight (w / w) suspension of a proton pump inhibitor, such as omeprazole, omeprazole magnesium, omeprazole sodium, esomeprazole, esomeprazole sodium, esomeprazole magnesium, or esomeprazole magnesium dihydrate, in a mixture of cottonseed oil and caprylic / capric triglyceride, and 0.05-1.0% w / w of a preservative.

21. 21. The formulation of claim 19 or 20, wherein the proton pump inhibitor is esomeprazole magnesium or esomeprazole magnesium dihydrate.

22. 22. A formulation as claimed in claim 19, 20 or 21 comprising 5 to 30% cottonseed oil, for example 5 to 25%, 10 to 15%, 10 to 12%, 13 to 15%, 15 to 17%, 18 to 20%, 15 to 20%, 20 to 22% or 20 to 25% w / w cottonseed oil.

23. 23. A formulation according to any one of claims 19 to 22 comprising 50% to 90% w / w caprylic / capric triglyceride, such as 60-70%, 60-65%, 65-70%, 70-80%, 70-75%, 75-80%, 80-90%, 80-85% or 85-90%.

24. 24. A formulation according to any one of claims 1 to 23, wherein the caprylic / capric triglyceride comprises 50-65% caprylic acid and 30-45% capric acid, or the caprylic / capric triglyceride comprises Miglyol® 812.

25. 24. A formulation according to any one of claims 1 to 23, wherein the caprylic / capric triglyceride comprises 50-75% caprylic acid and 22-45% capric acid, or the caprylic / capric triglyceride comprises Captex® 355.

26. 26. The formulation of any one of claims 1 to 25, having a median particle size of less than 10 μm, less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm.

27. At least one of the following characteristics: a) the formulation is suitable for intramuscular injection into equines or other animals; b) the formulation is suitable for subcutaneous injection into equines or other animals; c) after 6 months of storage at 2-8, 25, or 30° C., the median particle size of the formulation remains less than 8 μm; d) after 6 months of storage at 2-8, 25, or 30° C., the median particle size of the formulation remains less than 5 μm; e) after 6 months of storage at 2-8, 25, or 30° C., the median particle size of the formulation remains less than 4 μm; f) after 6 months of storage at 2-8, 25, or 30° C., the median particle size of the formulation remains less than 2.5 μm; g) after 6 months of storage at 2-8, 25, or 30° C., the 90th percentile particle size of the particle size distribution curve remains less than 8 μm; h) there is no significant change in the viscosity of the formulation after 6 months of storage at 2-8, 25, or 30°C; i) the viscosity is less than 300 cP, remains between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP; j) after 6 months at room temperature (e.g., 25° C.), there is no change in the injectability of the formulation using a 3 mL 21 G×½ inch to 18 G×½ inch syringe / needle; and / or k) total proton pump inhibitor impurities remain less than 0.15% after up to 6 months of storage at 2-8, 25, or 30° C.; 27. The formulation of any one of claims 1 to 26, having the formula:

28. At least one of the following characteristics: a) after 2-8 or 12 months storage at 25°C, the median particle size of the formulation remains less than 8 μm; b) after 2-8 or 12 months storage at 25°C, the median particle size of the formulation remains less than 5 μm; c) after 2-8 or 12 months storage at 25°C, the median particle size of the formulation remains less than 4 μm; d) after 2-8 or 12 months storage at 25°C, the median particle size of the formulation remains less than 2.5 μm; e) after 2 to 8, or 12 months storage at 25°C, the particle size of the 90th percentile of the particle size distribution curve remains less than 8 μm; f) there is no significant change in the viscosity of the formulation after 2-8, or 12 months of storage at 25°C; g) the viscosity remains less than 300 cP, between 200-300 cP, between 225 and 300 cP, or between 250 and 300 cP after 2-8, or 12 months storage at 25°C; h) after 12 months at room temperature (e.g., 25° C.), there is no change in the injectability of the formulation using a 3 mL 21 G×½ inch to 18 G×½ inch syringe / needle; and / or i) total proton pump inhibitor impurities remain less than 0.15% after 2-8, or up to 12 months storage at 25° C.; 28. The formulation of any one of claims 1 to 27, having the formula:

29. 1. An injectable pharmaceutical formulation comprising a suspension of a proton pump inhibitor, such as omeprazole, esomeprazole, omeprazole magnesium, omeprazole sodium, esomeprazole sodium, esomeprazole magnesium, or esomeprazole magnesium dihydrate, in a medium to long chain triglyceride, wherein the median particle size of the formulation is less than 10 μm, less than 8 μm, less than 5 μm, less than 4 μm, or less than 2.5 μm.

30. 30. The formulation of claim 29, wherein the proton pump inhibitor is esomeprazole magnesium.

31. 31. The formulation of claim 30, wherein the esomeprazole magnesium is esomeprazole magnesium dihydrate.

32. 32. The formulation of any one of claims 29-31, wherein the medium to long chain triglycerides comprise a vegetable oil selected from the group consisting of canola oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil, and mixtures of any two or more of canola oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, and sunflower oil.

33. 33. The formulation of any one of claims 29 to 32, wherein the vegetable oil is cottonseed oil or a mixture of cottonseed oil and another vegetable oil.

34. 34. The formulation of any one of claims 29 to 33, wherein the medium to long chain triglyceride comprises caprylic / capric triglyceride.

35. 35. The formulation of claim 34, wherein the caprylic / capric triglyceride comprises 50-65% caprylic acid and 30-45% capric acid, or the caprylic / capric triglyceride comprises Miglyol® 812.

36. 35. The formulation of claim 34, wherein the caprylic / capric triglyceride comprises 50-75% caprylic acid and 22-45% capric acid, or the caprylic / capric triglyceride comprises Captex® 355.

37. 37. A formulation according to any one of claims 34 to 36, comprising 50% to 90% w / w caprylic / capric triglyceride, such as 50-60%, 60-70%, 70-80% or 80-90%.

38. 38. A formulation according to claim 37 comprising 60-70%, 60-65%, 65-70%, 70-80%, 70-75%, or 75-80% w / w caprylic / capric triglyceride.

39. 39. A formulation according to any one of claims 29 to 38, comprising 15% to 25% weight / weight (w / w) of esomeprazole magnesium dihydrate.

40. 40. The formulation of claim 39, comprising 18% w / w to 22% w / w of esomeprazole magnesium dihydrate.

41. 41. The formulation of claim 40 comprising 19% w / w to 21% w / w of esomeprazole magnesium dihydrate.

42. 42. The formulation of claim 41 comprising 20% ​​w / w esomeprazole magnesium dihydrate.

43. 43. A formulation according to any one of claims 29 to 42, comprising 5% w / w to 30% w / w of vegetable oil, such as 5-10%, 10-15%, 15-20%, 20-25%, or 25-30%.

44. 43. A formulation according to any one of claims 29 to 42, comprising 5% w / w to 30% w / w cottonseed oil, such as 5-10%, 10-15%, 15-20%, 20-25%, or 25-30%.

45. 45. The formulation of claim 44, comprising 10-15%, 10-12%, 13-15%, 15-17%, 18-20%, or 15-20% w / w cottonseed oil.

46. 46. ​​The formulation of any one of claims 29 to 45, further comprising at least one preservative such as butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA) or sodium bisulfite, or a mixture of BHT, BHA and / or sodium bisulfite.

47. 47. The formulation of claim 46, wherein the at least one preservative comprises 0.05-1.0% w / w of butylated hydroxytoluene (BHT).

48. 48. The formulation of claim 46 or 47, consisting essentially of a proton pump inhibitor, a medium to long chain triglyceride, and a preservative.

49. At least one of the following characteristics: a) the formulation is suitable for intramuscular injection into equines or other animals; b) the formulation is suitable for subcutaneous injection into equines or other animals; c) after 6 months of storage at 2-8, 25, or 30° C., the median particle size of the formulation remains less than 8 μm; d) after 6 months of storage at 2-8, 25, or 30° C., the median particle size of the formulation remains less than 5 μm; e) after 6 months of storage at 2-8, 25, or 30° C., the median particle size of the formulation remains less than 4 μm; f) after 6 months of storage at 2-8, 25, or 30° C., the median particle size of the formulation remains less than 2.5 μm; g) after 6 months of storage at 2-8, 25, or 30° C., the 90th percentile particle size of the particle size distribution curve remains less than 8 μm; h) there is no significant change in the viscosity of the formulation after 6 months of storage at 2-8, 25, or 30°C; i) after 6 months at room temperature (e.g., 25° C.), there is no change in the injectability of the formulation using a 3 mL 21 G×½ inch to 18 G×½ inch syringe / needle; and / or j) total proton pump inhibitor impurities remain less than 0.15% after up to 6 months of storage at 2-8, 25, or 30° C.; 49. The formulation of any one of claims 29 to 48, having the formula:

50. 50. A vial comprising the formulation of any one of claims 1 to 49.

51. 50. A device for intramuscular injection into equines comprising a formulation according to any one of claims 1 to 49.

52. 29. A method of preparing the injectable pharmaceutical formulation of any one of claims 1 to 28, comprising: (a) mixing vegetable oil or cottonseed oil with caprylic / capric triglyceride; and (b) adding a proton pump inhibitor to the mixture of (a) to form a suspension of the proton pump inhibitor in the mixture.

53. 53. The method of claim 52, further comprising adding at least one preservative to the mixture of vegetable oil or cottonseed oil and caprylic / capric triglyceride and / or to the suspension.

54. 50. A method of preparing an injectable pharmaceutical formulation according to any one of claims 29 to 49, comprising: (a) optionally blending medium to long chain triglycerides to obtain a product of (a), and (b) adding a proton pump inhibitor to the product of (a) to produce a suspension of the proton pump inhibitor in the blend.

55. 55. The method of claim 54, further comprising adding at least one preservative to the product of (a) and / or to the suspension.

56. 50. A method of treating gastric ulcers in an equine animal comprising administering to the equine animal an effective amount of the formulation of any one of claims 1-49 by intramuscular or subcutaneous injection at least once a week.

57. 54. The method of claim 53, wherein the formulation is administered to provide at least one dose of between 1.5 mg / kg and 5.0 mg / kg of the proton pump inhibitor at least once a week.

58. 58. The method of claim 57, wherein the formulation is administered to provide at least one dose of between 1.5 mg / kg and 5.0 mg / kg esomeprazole magnesium at least once a week.

59. 59. The method of any one of claims 56 to 58, wherein the formulation is administered once, twice or three times per week.

60. 60. The method of claim 59, wherein the formulation is administered once a week.

61. 60. The method of claim 59, wherein the formulation is administered twice a week.

62. 60. The method of claim 59, wherein the formulation is administered three times per week.

63. 63. The method of any one of claims 56 to 62, wherein the formulation is administered at a dose of 1.5 mg / kg, 1.75 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, or 5 mg / kg of the proton pump inhibitor.

64. 64. The method of any one of claims 56 to 63, wherein the formulation is administered for a period of four weeks.

65. 64. The method of any one of claims 56 to 63, wherein the formulation is administered for a period of three weeks.

66. The formulation is one of the following regimens: a. 2.0-4.0 mg / kg, once a week for 3 weeks; b. 2.0-4.0 mg / kg once a week for 4 weeks; c. 2.0-4.0 mg / kg, twice a week for 3 weeks; d. 2.0-4.0 mg / kg, twice weekly for 4 weeks; or e. Any one of the regimens (a)-(d) followed by a reduced dose once or twice weekly for at least an additional week; 66. The method of any one of claims 56 to 65, wherein the method is administered according to

67. 66. The method of any one of claims 56 to 65, wherein the formulation is administered for a period of greater than four weeks, and optionally, the dose is reduced after the four week period.

68. 66. The method of any one of claims 56 to 65, wherein the formulation is administered for a period of more than three weeks, and optionally, the dose is reduced after the three week period.

69. 69. The method of any one of claims 56 to 68, wherein the formulation is administered by intramuscular injection.

70. 69. The method of any one of claims 56 to 68, wherein the formulation is administered by subcutaneous injection.

71. 71. The method of any one of claims 56 to 70, wherein the formulation is administered using a vial of claim 50 and / or a device of claim 51.

72. 72. The method of any one of claims 56 to 71, wherein the equine animal is suffering from Equine Gastric Ulcer Syndrome (EGUS), Equine Squamous Gastric Disease (ESGD), or Equine Glandular Gastropathy (EGGD).

73. 73. The method of any one of claims 56 to 72, wherein the ulcer is treated, such as by (a) reducing the size of at least one ulcerative lesion, or (b) reducing the number of ulcerative lesions.

74. 50. An injectable pharmaceutical formulation according to any one of claims 1 to 49 for use in a method for the treatment of ulcers in an equine animal, administered to the equine animal by intramuscular or subcutaneous injection.

75. 75. The formulation for use of claim 74, administered to provide at least one dose of between 1.5 mg / kg and 5.0 mg / kg of the proton pump inhibitor at least once a week.

76. 75. The formulation for use of claim 74, administered to provide at least one dose of between 1.5 mg / kg and 5.0 mg / kg of esomeprazole magnesium at least once a week.

77. 77. The formulation for use according to claim 74 or 76, which is administered once, twice or three times per week.

78. 78. The formulation for use according to claim 77, which is administered once a week.

79. 78. The formulation for use according to claim 77, which is administered twice weekly.

80. 78. The formulation for use according to claim 77, which is administered three times a week.

81. 81. The formulation for use of any one of claims 74 to 80, administered at a dose of 1.5 mg / kg, 1.75 mg / kg, 2.0 mg / kg, 2.5 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, or 5 mg / kg of esomeprazole magnesium.

82. 82. The formulation for use according to any one of claims 74 to 81, which is administered for a period of four weeks.

83. 82. The formulation for use according to any one of claims 74 to 81, which is administered for a period of three weeks.

84. One of the following regimens: a. 2.0-4.0 mg / kg, once a week for 3 weeks; b. 2.0-4.0 mg / kg once a week for 4 weeks; c. 2.0-4.0 mg / kg, twice a week for 3 weeks; d. 2.0-4.0 mg / kg, twice weekly for 4 weeks; or e. Any one of the regimens (a)-(d) followed by a reduced dose once or twice weekly for at least an additional week; 84. The formulation for use according to any one of claims 74 to 83, wherein the formulation is administered according to

85. 84. The formulation for use according to any one of claims 74 to 83, administered for a period longer than 4 weeks, optionally with the dose being reduced after the 4 week period.

86. 84. The formulation for use according to any one of claims 74 to 83, administered for a period longer than three weeks, optionally with the dose being reduced after the three week period.

87. 85. A formulation for use according to any one of claims 74 to 84, administered by intramuscular injection.

88. 85. A formulation for use according to any one of claims 74 to 84, which is administered by subcutaneous injection.

89. 89. A formulation for use according to any one of claims 74 to 88, administered using a vial according to claim 50 and / or a device according to claim 51.

90. 90. The formulation for use according to any one of claims 74 to 89, wherein the equine animal is afflicted with Equine Gastric Ulcer Syndrome (EGUS), Equine Squamous Gastric Disease (ESGD), or Equine Glandular Gastropathy (EGGD).

91. 91. The formulation for use according to any one of claims 74 to 90, wherein the ulcer is treated such as by (a) reducing the size of at least one ulcerative lesion, or (b) reducing the number of ulcerative lesions.

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