Esomeprazole formulations for equine animals and methods of use

Abstract

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 the treatment of ulcers in equine and other veterinary subjects. The 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.

Description

[Technical field]

[0001] The present disclosure relates to formulations of proton pump inhibitors, such as omeprazole or esomeprazole, e.g., esomeprazole magnesium or esomeprazole magnesium dihydrate, and methods of use in the treatment of gastric ulcers in equine and other veterinary subjects. The present disclosure also relates to injectable formulations of proton pump inhibitors, such as omeprazole or esomeprazole, e.g., esomeprazole magnesium, esomeprazole magnesium dihydrate, having small particle sizes, e.g., median particle sizes of less than 10 μm or less than 5 μm. [Background technology]

[0002] Modern domesticated equines suffer from a relatively high rate of gastric ulcers, and ulcer symptoms, such as stomach and digestive pain and upset, can interfere with the animal's healthy living conditions, as well as, in the case of sporting equines, the animal's work and training. The relatively high rate of gastric ulcers seen in domesticated equines may be due, for example, to the stabling and feeding patterns associated with domestication, whereby equines are fed at specific times several times throughout the day, rather than being able to constantly forage for food, as they would be in the wild. These different feeding conditions may affect the function and acidity of the stomach and upper intestine, possibly making gastric ulcers more common.

[0003] Equines are frequently administered oral proton pump inhibitor pastes when diagnosed with gastric ulcers, for example, by endoscopy, or when they exhibit symptoms of ulcers, such as discomfort, loss of well-being, and irritability or anxiety to training, or when they are exposed to stressful conditions, such as transportation, that may cause ulcer-like symptoms or the development of ulcer disease. A common oral proton pump inhibitor paste for horses is omeprazole paste, sold under the trade names Gastrogard® and Ulcergard®. While effective, these oral paste compositions are expensive, require the horse to tolerate and ingest the full dose, require the animal to be able to receive oral medication (which may not be possible in some situations), are difficult to administer accurately since they typically require daily administration, and can be cumbersome and difficult to handle and store.

[0004] The present disclosure, in contrast, relates to alternative injectable formulations of proton pump inhibitors such as omeprazole or esomeprazole (including their salts or hydrated salts), e.g. esomeprazole magnesium, which can be administered relatively easily and therefore do not rely on oral administration, can improve animal compliance to administration, and can be suitable for equines that cannot receive oral drug therapy. Furthermore, the formulations herein do not necessarily need to be given daily, as their bioavailability can reduce stomach acid levels, thus promoting healing of damaged mucosal tissues at longer times between doses than oral pastes. Thus, with the formulations herein, equines, in some embodiments, only need to receive injections, for example, once or twice a week, rather than having to endure daily oral paste administration.

[0005] The particular injectable pharmaceutical formulations herein also provide a particular mixture of proton pump inhibitors and excipients that allows for long-term storage and easy administration to equine and other veterinary subjects, as well as simpler and less frequent administration procedures. Summary of the Invention

[0006] The present disclosure includes pharmaceutical formulations that include a suspension of a proton pump inhibitor, such as omeprazole or esomeprazole, such as esomeprazole sodium, esomeprazole magnesium, omeprazole magnesium, omeprazole sodium, or another salt or hydrate salt of omeprazole or esomeprazole, in a mixture of vegetable oil and caprylic / capric triglyceride. In some embodiments, the pharmaceutical formulation includes a suspension of esomeprazole in a mixture of vegetable oil and caprylic / capric triglyceride. In some embodiments, the pharmaceutical formulation includes a suspension of esomeprazole magnesium salt (e.g., esomeprazole magnesium dihydrate) in a mixture of vegetable oil and caprylic / capric triglyceride. In some embodiments, the pharmaceutical formulation includes a suspension of omeprazole (e.g., omeprazole magnesium) in a mixture of vegetable oil and caprylic / capric triglyceride. The vegetable oil may 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 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.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 omeprazole or esomeprazole, such as esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate salt 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, the 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, e.g., 5-10%, 10-15%, 15-20%, 20-25%, or 25-30%. In some embodiments, the formulation comprises 5% w / w to 30% w / w of cottonseed oil, e.g., 5-10%, 10-15%, 15-20%, 20-25%, or 25-30%. In some embodiments, the formulation comprises 10-15%, 10-12%, 13-15%, 15-17%, 18-20%, or 15-20% w / w of cottonseed oil. In some embodiments, the formulation comprises 50% w / w to 90% w / w of caprylic / capric triglyceride, e.g., 50-60%, 60-70%, 70-80%, or 80-90%. In some embodiments, the formulation comprises 60-70%, 60-65%, 65-70%, 70-80%, 70-75%, or 75-80% w / w 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 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 includes 0.05-1.0% w / w BHT. In some embodiments, the preservative includes 0.05-0.15% w / w BHT. In some embodiments, the preservative includes 0.1% w / w 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 BHT or BHA.

[0010] In some cases herein, the formulation can be essentially composed of esomeprazole magnesium, cottonseed oil, caprylic / capric triglyceride, and at least one preservative.In some such cases, the formulation can be essentially composed of a proton pump inhibitor such as omeprazole or esomeprazole, such as 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 can be essentially composed of esomeprazole magnesium, cottonseed oil, caprylic / capric triglyceride, and BHT.In some cases herein, the formulation can be essentially composed 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 herein also include an injectable preparation comprising a suspension of 18-22% weight / weight (w / w) of a proton pump inhibitor such as omeprazole or esomeprazole, e.g., esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate salt of omeprazole or esomeprazole, e.g., omeprazole magnesium or omeprazole sodium, in a mixture of cottonseed oil and caprylic / capric triglyceride, and 0.05-1.0% w / w of a preservative. The present invention also includes formulations consisting essentially of a suspension of 18-22% weight / weight (w / w) of a proton pump inhibitor such as omeprazole or esomeprazole, e.g., esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate salt of omeprazole or esomeprazole, e.g., omeprazole magnesium or omeprazole sodium, in a mixture of cottonseed oil and caprylic / capric triglyceride, and 0.05-1.0% w / w of a preservative. In some embodiments, the esomeprazole magnesium is esomeprazole magnesium dihydrate. In some embodiments, the formulation comprises 5-30% cottonseed oil, e.g., 5-25%, 10-15%, 10-12%, 13-15%, 15-17%, 18-20%, 15-20%, 20-22%, or 20-25% w / w cottonseed oil. In some embodiments, the formulation comprises 50% w / w 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%.

[0012] In any of the exemplary formulations herein, the caprylic / capric triglyceride may comprise 50-65% caprylic acid and 30-45% capric acid, or may be Miglyol® 812. In any of the exemplary formulations herein, the caprylic / capric triglyceride may comprise 50-75% caprylic acid and 22-45% capric acid, or may be Captex® 355. Caprylic / capric triglycerides may be derived from vegetable oil sources and may contain other ingredients such as glycerin, for example, or small amounts 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, such as 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 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 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 to 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 remains less than 300 cP, between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP after 6 months of storage 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 using a 3mL 21G x 1 / 2 inch syringe / needle; k) the total proton pump inhibitor impurities remain less than 0.15% after up to 6 months of storage at 2-8, 25, or 30° C.; l) after 12 months of storage at 2-8 or 25°C, the median particle size of the formulation remains less than 8 μm; m) after 12 months of storage at 2-8 or 25°C, the median particle size of the formulation remains less than 5 μm; n) after 2-8 or 12 months of storage at 25°C, the median particle size of the formulation remains less than 4 μm; o) after 2-8 or 12 months of storage at 25°C, the median particle size of the formulation remains less than 2.5 μm; p) after 2 to 8, or 12 months of storage at 25°C, the particle size of the 90th percentile of the particle size distribution curve remains less than 8 µm; q) there is no significant change in the viscosity of the formulation after storage for 2 to 8 or 12 months at 25°C; r) the viscosity remains less than 300 cP, between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP after 2-8, or 12 months storage at 25°C; s) 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 x 1 / 2 inch to 18 G x 1 / 2 inch syringe / needle; t) the total proton pump inhibitor impurities remain less than 0.15% after 2-8, or up to 12 months of storage at 25°C; and / or u) The mean half-life (T 1 / 2 ) ranges from 12 to 24 hours, may have:

[0014] In some embodiments, 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 after 24 months at 2-8° C. or 25° C. or 30° C. 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 an injectable pharmaceutical formulation comprising a suspension of a proton pump inhibitor such as omeprazole or esomeprazole, e.g. esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate of omeprazole or esomeprazole, e.g. esomeprazole magnesium dihydrate, or e.g. omeprazole magnesium or omeprazole sodium, in an oil or fat containing medium to long chain fatty acids, such as medium 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 may 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, so 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 therefore is not performed. In some cases where micronization is performed, 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 after 6 months does not affect the stability of the formulation. In other cases, micronization may 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 to long chain fatty acid is a long chain triglyceride. In some embodiments, the medium to long chain fatty acid is a mixture of medium to long chain triglycerides. In some embodiments, the medium to long chain triglycerides comprise a 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 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. In some embodiments, the vegetable oil is cottonseed oil or a mixture of cottonseed oil and another vegetable oil. In some embodiments, the medium to long chain triglycerides comprise caprylic / capric triglycerides. In some embodiments, the caprylic / capric triglyceride comprises 50-65% caprylic acid and 30-45% capric acid, or the caprylic / capric triglyceride comprises Miglyol® 812. In some embodiments, the caprylic / capric triglyceride comprises 50-75% caprylic acid and 22-45% capric acid, or the caprylic / capric triglyceride comprises Captex® 355.

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

[0018] The formulations herein may also contain at least one preservative, such as a bacterial growth inhibitor such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium bisulfite, vitamin C, sodium nitrile, sulfur dioxide, benzoic acid, methylparaben, propylparaben, benzyl alcohol, phenol, cresols such as m-cresol, chlorobutanol, or a mixture of two or more preservatives. 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 comprises 0.05-1.0% w / w BHT. In some embodiments, the preservative comprises 0.05-0.15% w / w BHT. In some embodiments, the preservative comprises 0.1% w / w 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 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, a medium to long chain triglyceride, and a preservative. In some embodiments, the formulation consists essentially of esomeprazole magnesium dihydrate, a medium to long chain triglyceride, 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 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 to 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 remains less than 300 cP, between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP after 6 months of storage 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 using a 3mL 21G x 1 / 2 inch syringe / needle; k) the total proton pump inhibitor impurities remain less than 0.15% after up to 6 months of storage at 2-8, 25, or 30° C.; l) after 12 months of storage at 2-8 or 25°C, the median particle size of the formulation remains less than 8 μm; m) after 12 months of storage at 2-8 or 25°C, the median particle size of the formulation remains less than 5 μm; n) after 2-8 or 12 months of storage at 25°C, the median particle size of the formulation remains less than 4 μm; o) after 2-8 or 12 months of storage at 25°C, the median particle size of the formulation remains less than 2.5 μm; p) after 2 to 8, or 12 months of storage at 25°C, the particle size of the 90th percentile of the particle size distribution curve remains less than 8 µm; q) there is no significant change in the viscosity of the formulation after storage for 2 to 8 or 12 months at 25°C; r) the viscosity remains less than 300 cP, between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP after 2-8, or 12 months storage at 25°C; s) 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 x 1 / 2 inch to 18 G x 1 / 2 inch syringe / needle; t) the total proton pump inhibitor impurities remain less than 0.15% after 2-8, or up to 12 months of storage at 25°C; and / or u) The mean half-life (T 1 / 2 ) ranges from 12 to 24 hours, has.

[0020] In some embodiments, 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 after 24 months at 2-8° C. or 25° C. or 30° C. 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 of any shape or type of container and may be designed to allow easy dispensing of the formulation for administration. The present disclosure also includes intramuscular or subcutaneous injection devices for administering the formulations herein to equines or other animals. Such devices may contain any of the above-mentioned formulations. Such devices include, for example, syringes with needles for intramuscular injection or injection pen devices for intramuscular injection. In some embodiments, each device contains a complete, single unit dose of esomeprazole magnesium. Thus, each device may be used for a single injection of the unit dose and then discarded.

[0022] The present disclosure also includes a method of preparing the above injectable equine pharmaceutical formulation. In some embodiments, the method includes: (a) mixing vegetable oil or cottonseed oil with caprylic / capric triglyceride; (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 generate 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 another embodiment, the method comprises: (a) optionally blending medium to long chain triglycerides; (b) adding omeprazole or esomeprazole, e.g., esomeprazole sodium, esomeprazole magnesium, or another salt or hydrated salt of omeprazole or esomeprazole, to the product of (a) to produce a suspension of omeprazole or esomeprazole, e.g., esomeprazole sodium, esomeprazole magnesium, or another salt or hydrated salt of omeprazole or esomeprazole, e.g., omeprazole magnesium or omeprazole sodium, in the blend; 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 formulations described above to treat gastric ulcers in animals, such as horses. In some embodiments, the method of treatment includes administering an effective amount of the formulation to an animal, such as an horse, by intramuscular or subcutaneous injection at least once a week. In some embodiments, the formulation is administered to provide at least one dose of esomeprazole magnesium between 1.5 mg / kg and 5.0 mg / kg 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 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. In some embodiments, the formulation is administered for 4 weeks. In some embodiments, the formulation is administered for 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 per week for 3 weeks; (b) at a dose of 2.0-4.0 mg / kg, once per week for 4 weeks; (c) at a dose of 2.0-4.0 mg / kg, twice per week for 3 weeks; (d) at a dose of 2.0-4.0 mg / kg, twice per week for 4 weeks; or (e) any one of (a)-(d), followed by a reduced dose once or twice per week for at least an additional week. In some embodiments, the first dose or the first two doses, or the dose for the first week, two weeks, three weeks, or four weeks, is at a higher level (e.g., a "loading dose") than subsequent doses. In some embodiments, the formulation is administered for a period longer than four weeks, and optionally the dose is reduced after the four week period. In some embodiments, the formulation is administered for a period longer than three weeks, and optionally the dose is reduced after the three week period. In any of the above dosing regimens, the formulation may be administered by intramuscular injection or by subcutaneous injection. In some embodiments, the formulation is administered using the vials and / or devices described above. In some embodiments, the formulation is administered to an equine. In some embodiments, the equine suffers from gastric ulcers, equine gastric ulcer syndrome (EGUS), equine squamous gastric disease (ESGD), or equine glandular gastric disease (EGGD).In some embodiments, the gastric ulcer is treated, eg, 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 an injectable pharmaceutical composition for use in treating ulcers in animals, such as horses. In some embodiments, the injectable pharmaceutical formulation is for use in a method for treating ulcers in an equine animal, where the formulation is administered to the equine animal by intramuscular or subcutaneous injection. In some embodiments, the formulation is administered to provide at least one dose of esomeprazole magnesium between 1.5 mg / kg and 5.0 mg / kg 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 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. In some embodiments, the formulation is administered for 4 weeks. In some embodiments, the formulation is administered for 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 per week for 3 weeks; (b) at a dose of 2.0-4.0 mg / kg, once per week for 4 weeks; (c) at a dose of 2.0-4.0 mg / kg, twice per week for 3 weeks; (d) at a dose of 2.0-4.0 mg / kg, twice per week for 4 weeks; or (e) any one of the regimens (a)-(d), followed by a reduced dose, once or twice per week for at least an additional week. In some embodiments, the formulation is administered for a period of greater than 4 weeks, and optionally the dose is reduced after the 4 week period. In some embodiments, the formulation is administered for a period of greater than 3 weeks, and optionally the dose is reduced after the 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 a vial and / or device described herein. In some embodiments, the equine animal is afflicted with Equine Gastric Ulcer Syndrome (EGUS), Equine Squamous Gastric Disease (ESGD), or Equine Glandular Gastropathy (EGGD).In some embodiments, 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.

[0025] Additional objects of the present disclosure are set forth in the following description, including the drawings 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 scope of the claims.

[0026] The headings provided herein are not limitations on the various aspects of this disclosure which can be made by reference to the specification in its entirety, and therefore the terms defined hereinafter are more fully defined by reference to the specification in its entirety.

[0027] 1A, 1B, and 1C show the effect of administration of an exemplary formulation of the present disclosure on intragastric pH in five horses, as described in the Examples section below. [Brief description of the drawings]

[0028] [Figure 1A] FIG. 1 is a graph showing the percentage of time the pH was 4 or greater immediately prior to (day 0), on the day of injection (day 1), or after (days 2-6) intramuscular injection of esomeprazole magnesium at a dose of 1.75 mg / kg contained in a formulation described herein. [Figure 1B] FIG. 1A is a graph showing the percentage of time the pH was 4 or greater immediately prior to (day 0), on the day of injection (day 1), or after (days 2-6) a second intramuscular injection of esomeprazole magnesium at a 4.0 mg / kg dose contained in a formulation described herein. The 4.0 mg / kg injection was administered approximately 2 weeks after the initial 1.75 mg / kg injection. The numbers below the graphs in FIGS. 1A and 1B represent the numbers assigned to the five horses used in the study. [Figure 1C] 1A and 1B, which provide the average of each curve, with "Phase I" representing the 1.75 mg / kg dose shown in FIG. 1A and "Phase II" representing the 4.0 mg / kg dose shown in FIG. 1B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0030] In this application, the use of "or" means "and / or" unless expressly stated otherwise. In the context of a multiple dependent claim, the use of "or" refers to two or more preceding independent or dependent claims in the alternative only. Also, terms such as "element" or "component" encompass both elements and components comprising a single unit and elements and components comprising two or more subunits, unless expressly stated otherwise.

[0031] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the stated range, and fractions thereof, where appropriate (such as tenths and hundredths of integers), unless otherwise indicated. Units, prefixes, and symbols are expressed in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers that define the range. Measurements herein, such as weight-to-weight percentages, are understood to be approximations taking into account significant digits and errors associated with the measurements.

[0032] All percentage measurements herein are weight to 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 allows 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 herein may be administered to animals such as equines and other livestock. As used herein, "equines" includes any breed of domestic horses, from miniature horses and small ponies to large draft horses, as well as mustangs, other wild horse breeds, and zebras. The term equines also includes equines of any age, from foals to senior horses. Equines include all domesticated horse breeds, which come in many different sizes and weights, including a wide range of riding and racing horses, such as miniature horses, small ponies such as Shetland ponies, Welsh ponies, German riding ponies, large ponies such as Haflingers, and cobs, Arabian, thoroughbreds, quarter horses, and various types of Warmbloods, as well as draft breeds such as Andalusians, Lusitanos, Appaloosas, Standardbreds, Friesians, Belgians, Clydesdales, and crosses between the above breeds and other breeds. Other non-equine animals, such as donkeys, mules, pigs, llamas, and alpacas, may also be treated with the formulations herein. Animals treated herein may sometimes be referred to as "subjects" or "patients."

[0035] "Proton pump inhibitor" refers to a compound that inhibits gastric proton pump H+ / K+ ATPase, thereby suppressing gastric acid secretion.Proton pump inhibitors include, for example, omeprazole, esomeprazole, rabeprazole, lansoprazole, tenatoprazole, including their pharma- ceutically effective stereoisomers, such as enantiomers, including, for example, salts and hydrated forms.For example, omeprazole, esomeprazole, rabeprazole, lansoprazole, and tenatoprazole can be found as sodium salt or magnesium salt, and in some cases as hydrated magnesium salt.

[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 any form of omeprazole, 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 used generally 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 monohydrate esomeprazole magnesium. Esomeprazole magnesium trihydrate has a molecular weight of 767.2 g / mol and a molecular formula of C34H42MgN6O9S2, while esomeprazole magnesium dihydrate has a molecular weight of 749.2 g / mol and a molecular formula of C34H40MgN6O8S2. The anhydrous weight of esomeprazole magnesium is 713 g / mol. In these forms, one magnesium ion is coordinated with two esomeprazole molecules. The term "esomeprazole magnesium dihydrate" or "esomeprazole magnesium trihydrate" is used to refer to a specific hydrate form. Each of these hydrate forms may contain small amounts of other hydrate forms, for example, as impurities. For example, once esomeprazole magnesium dihydrate is added to make a suspension for pharmaceutical formulation, it may occur that the hydrate form is 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 a molecular formula of C17H18NaN3O3S.

[0037] "Medium chain triglyceride", as used herein, refers to fatty acid triglyceride esters in which the fatty acids generally range from, for example, C6 to C12 (the number following the C represents the number of carbon atoms in the chain). Examples include triglyceride compositions that include fatty acids of length C6, C8, C10, and C12, or mixtures of two or more thereof. "Long chain triglyceride", as used herein, refers to fatty acid triglyceride esters in which the fatty acids are generally longer than C12, for example, C14, C16, C18, and C20, or mixtures of two or more thereof. Long chain triglyceride compositions may also include fatty acids of length C22 or C24 or C26. Medium chain triglyceride compositions may include low amounts, for example, less than 20%, or less than 10%, or less than 5%, of longer chain triglycerides. Similarly, a long chain triglyceride composition may contain low amounts of medium chain triglycerides, such as less than 20% or less than 10% or less than 5%. A composition containing "medium to long chain fatty acids" may contain a mixture of fatty acids containing medium and / or long chains as described above. A composition containing "medium to long chain triglycerides" may contain a mixture of triglycerides containing medium and / or long chain triglycerides. Examples of such compositions include various vegetable and animal oils, as well as products derived from such fats and oils, for example, by subjecting the 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 oil also includes fats and oils derived from plants after processing, such as modifying the fatty acid composition of the fats and oils or removing or reducing the concentration of certain components, such as fatty acids with shorter chain length (e.g., less than C14) or longer chain length (e.g., C20 or C22, or C24 or more). Vegetable oils may contain, in some cases, at least 80% of C16 and C18 fatty acids (e.g., may contain primarily long-chain fatty acids), such as C16 and C18 fatty acids such as palmitic, stearic, oleic, and linoleic fatty acids. "Cottonseed oil" is fat and oil derived from cottonseed plants. Cottonseed oil generally contains a mixture of palmitic, stearic, oleic, and linoleic fatty acids. Commercial preparations of cottonseed oil may contain, for example, a mixture of approximately 20% palmitic (C16:0), 2% stearic (C18:0), 35% oleic (C18:1), and 42% linoleic (C18:2) fatty acids.

[0039] "Caprylic / capric triglyceride" is a term used to describe a mixture of primarily C8 and C10 fatty acid triglycerides. Caprylic / capric triglyceride may, in some embodiments, comprise a composition comprising 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 seed oil. Caprylic / capric triglyceride is commercially available, for example, under the names Miglyol® 812 and Captex® 355.

[0040] When referring to a particular type of fatty acid herein, for example, capric acid, caprylic acid, palmitic acid, or oleic acid, the term includes any common chemical form of the molecule, for example, free fatty acid, salt of free fatty acid, and fatty acid ester, such as monoglyceride, diglyceride, or triglyceride, or phospholipid. For example, fatty acids found in vegetable oils are often in triglyceride form. Since each triglyceride molecule contains three fatty acid chains, triglyceride molecules may contain one, two, or three different types of fatty acids. Generally, fatty acid analysis is performed to provide the relative amount, for example by weight percentage, of each type of fatty acid in the oil, regardless of the form in which it is found in the original oil (for example, as part of a triglyceride or other ester, and the point of attachment to the triglyceride).

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

[0042] "Preservatives" include compounds that are pharma- ceutically acceptable for injectable formulations and can help improve the shelf life of the formulation. For example, preservatives can, in some embodiments, include antioxidants. In some embodiments, preservatives consist essentially of one or more antioxidants.

[0043] The formulations herein can be administered, for example, by intramuscular or subcutaneous injection. "Administration" herein more generally refers to the physical introduction of a composition containing a therapeutic agent into a subject, using any of a variety of methods and delivery systems known to those skilled in the art. Administration can be performed, 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 that is suitable for pharmaceutical use, such as, for example, administration directly to an animal, or after being reconstituted, diluted, mixed or dissolved with at least one additional composition, or after being thawed from a frozen state. A "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 solution, or mixed with other ingredients prior to administration.

[0045] In some embodiments herein, the pharmaceutical formulation is "free" of one or more types of additives or ingredients. "Free" in this context means that the excluded ingredients are not present beyond trace levels, for example due to contaminants or impurities found in other ingredients that have been intentionally added.

[0046] The term "consisting essentially of," when referring to a mixture of ingredients in the formulations herein, indicates that ingredients other than those explicitly listed may be present, but that such ingredients are found only in trace amounts, or otherwise in amounts low enough that they do not significantly alter the basic properties of the formulation, including esomeprazole concentration, viscosity, storage stability, osmolality, and pH. For example, ingredients such as cottonseed oil and caprylic / capric triglyceride are derived from natural sources and may contain small or trace amounts of other ingredients and by-products, while esomeprazole may also contain trace levels of various impurities resulting from its synthesis or natural degradation processes.

[0047] "Vial" as used 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 storage of the formulation, but also to extract a suitable volume of the formulation for injection into a subject. The vial can contain a sufficient amount to provide one or more doses of the formulation.

[0048] A "device" herein refers to a means for administering a formulation intramuscularly and may be of any suitable structure and configuration suitable for intramuscular injection. Examples of a "device" herein include a syringe equipped with a needle used to deliver the contents of the syringe by intramuscular injection. Other examples include automatic injection devices similar to those used to administer human drugs such as norepinephrine, epinephrine, adrenaline, and insulin intramuscularly.

[0049] The term "ulcer" or "gastric ulcer" as used herein includes ulcerative disease of the digestive tract, such as the stomach and intestines, as well as suspected ulcerative disease. An ulcer may include, for example, an open wound in the stomach or intestinal lining. An ulcer may be diagnosed, for example, by endoscopy, or may be suspected in some cases based on the outward behavior of the equine animal that is commonly associated with an ulcer, such as irritability, discomfort, anxiety, and / or uncooperativeness, weight loss, poor appetite, and poor coat condition, particularly during riding or training. In some embodiments, the ulcer may be Equine Gastric Ulcer Syndrome (EGUS). In some embodiments, the ulcer may be Equine Squamous Gastropathy (ESGD) or Equine Glandular Gastropathy (EGGD).

[0050] "Treatment" as used herein refers to therapeutic treatment, for example to obtain partial or complete resolution of an ulcer, slow the progression of an ulcer, or reduce its severity. The term "treatment" also includes reducing the severity and / or frequency, extent, or likelihood of any appearance characteristic associated with an ulcer, such as irritability, discomfort, anxiety, and / or uncooperativeness, weight loss, anorexia, and poor coat condition, particularly during riding or training. Animals in need of treatment include animals already diagnosed with a gastric ulcer, as well as animals that have previously had an ulcer and are at risk of recurrence or worsening of the appearance symptoms of the disorder, and animals at risk of developing an ulcer (e.g., animals experiencing stress such as transportation). Treatment of gastric ulcers in animals, such as horses, can include, for example, reducing the size and / or number of gastric lesions, partially or completely dissipating existing lesions, increasing the overall pH of the gastric fluids in a subject, as well as reducing symptoms and appearances commonly associated with ulcers, such as poor condition (e.g., weight loss and poor coat quality), irritability, anxiety, or uncooperativeness during riding and training activities, and other outward symptoms of gastric upset.

[0051] The term "effective amount" or "therapeutically effective amount" refers to an amount of drug effective to treat an ulcer in a subject. In some embodiments, an effective amount refers to an amount effective, at the time of administration and for the period of time necessary, to achieve a desired therapeutic result, such as relieving the physical or cosmetic symptoms associated with an ulcer in an equine animal.

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

[0053] II. Pharmaceutical Formulations and Their Preparation The present disclosure relates to an injectable pharmaceutical formulation comprising a proton pump inhibitor, such as omeprazole or esomeprazole, suitable for treating, inter alia, equines and other animals, such as 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 the magnesium salt form of omeprazole, esomeprazole, rabeprazole, lansoprazole, or tenatoprazole.

[0054] In some embodiments, the formulation comprises omeprazole, such as a salt or hydrated salt of omeprazole. Omeprazole may be omeprazole magnesium, or a different omeprazole form, such as omeprazole sodium. In some embodiments, the formulation comprises esomeprazole, such as a salt or hydrated salt of esomeprazole. Esomeprazole may be esomeprazole magnesium, or a different esomeprazole form, such as esomeprazole sodium or esomeprazole strontium. In the formulation comprising esomeprazole magnesium, esomeprazole magnesium may be esomeprazole magnesium dihydrate or trihydrate form, or may be a mixture of these forms. For example, the formulation may be prepared by adding esomeprazole dihydrate, but the dihydrate may have a trace amount of trihydrate, or may slowly convert to the trihydrate form over time in suspension or when exposed 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 extent to which the product has been exposed to water, and vice versa.In some embodiments, the vegetable oil may 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 a mixture of any two or more of the above-mentioned oils.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 15%-25% weight / weight (w / w) of a proton pump inhibitor such as omeprazole or esomeprazole, e.g., esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate salt of omeprazole or esomeprazole, e.g., omeprazole magnesium or omeprazole sodium, etc. In other embodiments, the formulation comprises 18%-22% w / w of a proton pump inhibitor such as omeprazole or esomeprazole, e.g., esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate salt of omeprazole or esomeprazole, e.g., omeprazole magnesium or omeprazole sodium. In some embodiments, the formulation comprises 19%-21% w / w of a proton pump inhibitor such as omeprazole or esomeprazole, e.g., esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate salt of omeprazole or esomeprazole, e.g., omeprazole magnesium or omeprazole sodium. In some embodiments, the formulation comprises 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% w / w of a proton pump inhibitor such as omeprazole or esomeprazole, e.g., esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate salt of omeprazole or esomeprazole, e.g., omeprazole magnesium or omeprazole sodium. In some embodiments, the formulation comprises 20% w / w of a proton pump inhibitor such as omeprazole or esomeprazole, e.g., esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate salt of omeprazole or esomeprazole, e.g., omeprazole magnesium or omeprazole sodium. In some embodiments, the formulation comprises 15% to 25% weight / weight (w / w) of esomeprazole magnesium or omeprazole magnesium. In other embodiments, the formulation comprises 18% w / w to 22% w / w of esomeprazole magnesium or omeprazole magnesium.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 pharmaceutical use for at least 36 months.

[0056] In some embodiments, the formulation comprises 5-30% vegetable 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 vegetable oil. In some embodiments, the formulation comprises 5-25% w / w vegetable oil. In some embodiments, the formulation comprises 8-15% w / w vegetable oil. In some embodiments, the formulation comprises 10-15% w / w vegetable oil. In some embodiments, the formulation comprises 10-12% w / w vegetable oil. In some embodiments, the formulation comprises 13-15% w / w vegetable oil. In some embodiments, the formulation comprises 15-17% w / w vegetable oil. In some embodiments, the formulation comprises 18-20% w / w vegetable oil. In some embodiments, the formulation comprises 15-20% w / w vegetable oil. In some embodiments, the formulation comprises 20-22% w / w vegetable oil. In some embodiments, the formulation comprises 23-25% w / w vegetable oil. In some embodiments, the formulation comprises 20-25% w / w vegetable oil. In some embodiments, the formulation comprises 25-30% 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, e.g., 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 and C18:0, C18:1, and C18:2 fatty acids. In some embodiments, the vegetable oil or cottonseed oil may contain 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 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, about 15-25% palmitic acid, 1-5% stearic acid, 30-40% oleic acid, and 35-45% linoleic acid (C18:2) fatty acids. In some embodiments, the vegetable oil or cottonseed oil may contain, for example, a mixture of about 20% palmitic acid (C16:0), 2% stearic acid (C18:0), 35% oleic acid (C18:1), and 42% linoleic acid (C18:2) fatty acids. Because vegetable oils such as cottonseed oil are natural products, they may contain other fats and oils in addition to those listed above, as well as other raw materials, for example as by-products.

[0059] In some embodiments, the formulation comprises 50% w / w to 90% w / w, e.g., 50-60%, 60-70%, 70-80%, or 80-90% caprylic / capric triglyceride. In some embodiments, the formulation comprises 60-70%, 60-65%, 65-70%, 70-80%, 70-75%, or 75-80% 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%-70% caprylic / capric triglyceride. In some embodiments, the formulation comprises 70%-75% caprylic / capric triglyceride. In some embodiments, the formulation comprises 75%-80% caprylic / capric triglyceride. In some embodiments, the formulation comprises 80%-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, the caprylic / capric triglyceride comprises 50-65% caprylic acid and 30-45% capric acid. In some embodiments, the caprylic / capric triglyceride comprises 50-75% caprylic acid and 20-45% capric acid. In other embodiments, the mixture is 50-60% caprylic acid to 30-40% capric acid. In some embodiments, the caprylic / capric triglyceride is Miglyol® 812, Miglyol® 810, or Captex® 355. Additionally, caprylic / capric triglycerides are typically derived from vegetable or plant oils such as palm seed oil and coconut oil. Thus, caprylic / capric triglycerides may contain other ingredients typically found in such fats and oils, such as glycerin or other non-fatty acid molecules, as well as other fatty acids other than capric and caprylic acids, as well as mono- or di-glycerides of capric and caprylic acids or other fatty acids. In some embodiments, caprylic / capric triglycerides also contain other fatty acids such as myristic acid (C14:0), lauric acid (C12:0) and caproic acid (C6:0).

[0061] As mentioned above, when referring to a specific type of fatty acid herein, such as capric acid, caprylic acid, palmitic acid, or oleic acid, or medium or long chain fatty acid, the term includes any common form of molecule, such as free fatty acid, fatty acid salt, and fatty acid ester, such as monoglyceride, diglyceride, or triglyceride, or phospholipid.For example, fatty acids found in vegetable oils are often in triglyceride form.However, triglycerides may contain impurities, such as monoglycerides and diglycerides or other ester fatty acid forms, especially in natural oils.

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

[0063] In some embodiments, the medium to long chain fatty acids include medium chain fatty acids. In some embodiments, the medium to long chain fatty acids include long chain fatty acids. In some embodiments, the medium to long chain fatty acids include a mixture of medium and long chain fatty acids. In some embodiments, the medium to long chain triglycerides include long chain triglycerides. In some embodiments, the medium to long chain triglycerides include a mixture of medium 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 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, and mixtures of any of these fats and 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 to long chain triglyceride comprises caprylic / capric triglyceride or another product similarly derived from vegetable oil. In some embodiments, the caprylic / capric triglyceride comprises 50-65% caprylic acid and 30-45% capric acid, or the caprylic / capric triglyceride comprises Miglyol® 812. In some embodiments, the caprylic / capric triglyceride comprises 50-75% caprylic acid and 22-45% capric acid, or the caprylic / capric triglyceride comprises Captex® 355.

[0065] In some embodiments, the formulation comprises 50% w / w to 90% w / w of caprylic / capric triglyceride, such as 50-60%, 60-70%, 70-80%, or 80-90%. In some embodiments, the formulation comprises 60-70%, 60-65%, 65-70%, 70-80%, 70-75%, or 75-80% w / w of caprylic / capric triglyceride. In some embodiments, the formulation comprises 15% to 25% weight / weight (w / w) of esomeprazole magnesium dihydrate. In some embodiments, the formulation comprises 18% w / w to 22% w / w of esomeprazole magnesium. In some embodiments, the formulation comprises 19% w / w to 21% w / w of esomeprazole magnesium. In some embodiments, the formulation comprises 20% w / w of esomeprazole magnesium. In some embodiments, the formulation comprises 5% w / w to 30% w / w of vegetable oil, e.g., 5-10%, 10-15%, 15-20%, 20-25%, or 25-30%. In some embodiments, the formulation comprises 5% w / w to 30% w / w of cottonseed oil, e.g., 5-10%, 10-15%, 15-20%, 20-25%, or 25-30%. In some embodiments, the formulation comprises 10-15%, 10-12%, 13-15%, 15-17%, 18-20%, or 15-20% 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 the vegetable oil source. For example, in some embodiments, the formulations also include a preservative, such as, for example, a bacterial growth inhibitor such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium bisulfite, vitamin C, sodium nitrile, sulfur dioxide, benzoic acid, methylparaben, propylparaben, benzyl alcohol, phenol, cresols 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, for example, 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 comprises 0.05-1.0% w / w BHT. In some embodiments, the preservative comprises 0.05-0.15% w / w BHT. In some embodiments, the preservative comprises 0.1% w / w BHT, hi 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 BHT or BHA.

[0067] In some embodiments, a particular combination of the above-mentioned ingredients may be used. For example, in some embodiments, the formulation consists essentially of a proton pump inhibitor such as omeprazole or esomeprazole, e.g. esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate of omeprazole or esomeprazole, e.g. omeprazole magnesium or omeprazole sodium, 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 esomeprazole magnesium, 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 omeprazole magnesium, 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 esomeprazole magnesium 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 esomeprazole magnesium dihydrate, a medium to long chain triglyceride, and a preservative. In some embodiments, the formulation does not contain aqueous ingredients such as water or buffers, except for possibly small amounts 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 particular omeprazole or esomeprazole salt, exhibits a formulation median particle size, such as greater than 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, certain 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 the use of 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 a 18-22% weight / weight (w / w) suspension of a proton pump inhibitor such as omeprazole or esomeprazole, e.g., esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate salt of omeprazole or esomeprazole, e.g., the magnesium salt, 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 a proton pump inhibitor such as omeprazole or esomeprazole, e.g., esomeprazole sodium, esomeprazole magnesium, or another salt or hydrate of omeprazole or esomeprazole, e.g., omeprazole magnesium or omeprazole sodium, in a mixture of a vegetable oil, e.g., 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 esomeprazole magnesium 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 esomeprazole magnesium at 18-22% weight / weight (w / w) in a mixture of 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 a mixture of any two or more of the aforementioned oils. 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 method includes first mixing vegetable oil with caprylic / capric triglyceride (or medium to long chain triglyceride), then adding the proton pump inhibitor to produce a suspension. If 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 stored at room temperature for 24 hours after preparation is less than 10 μm. In some embodiments, the median particle size of the formulation stored at room temperature for 24 hours after preparation is less than 8 μm. In some embodiments, the median particle size of the formulation stored at room temperature for 24 hours after preparation is less than 5 μm. In some embodiments, the median particle size of the formulation stored at room temperature for 24 hours after preparation is less than 4 μm. In some embodiments, the median particle size of the formulation stored at room temperature for 24 hours after preparation is less than 2.5 μm. In some embodiments, the median particle size of the formulation stored at room temperature for 24 hours after preparation is less than 1 μm. The median particle size of the formulation, as 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 after preparation of the formulation and storage at room temperature for 24 hours is less than 10 μm. In some embodiments, the 90th percentile particle size of the particle size distribution curve after preparation of the formulation and storage at room temperature for 24 hours is less than 8 μm. In some embodiments, the 90th percentile particle size of the particle size distribution curve after preparation of the formulation and storage at room temperature for 24 hours is less than 7 μm. In some embodiments, the 90th percentile particle size of the particle size distribution curve after preparation of the formulation and storage at room temperature for 24 hours is less than 5 μm.

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

[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 90th percentile particle size 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 90th percentile particle size 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 90th percentile particle size 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 90th percentile particle size of the particle size distribution curve remains less than 6 μm.

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

[0077] Resuspension properties may be measured by determining the viscosity after a storage period and whether there is a significant change in viscosity, e.g., an increase of more than 20%. For example, in the examples herein, the viscosity was measured using a Brookfield DV3TLVCJ viscometer at 25°C, as further described below. In some embodiments, there is no change in the resuspension properties of the formulation after 4 weeks at 2-8, 25, or 30°C. In some embodiments, there is no change in the resuspension properties 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 resuspension properties 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 resuspension properties 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 significant change in the resuspension properties of the formulation after 12 months of storage 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 at 25° C., 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, there is no change in the injectability of the formulation using a 3 mL 26G x 1 / 2 inch syringe / needle after 4 weeks at 2-8, 25, or 30°C. In some embodiments, there is no change in the injectability of the formulation using a 3 mL 26G x 1 / 2 inch syringe / needle after 6 weeks at 2-8, 25, or 30°C. In some embodiments, there is no change in the injectability of the formulation using a 3 mL 21G x 1 / 2 inch syringe / needle after 3 months at room temperature (e.g., 25°C). In some embodiments, there is no change in the injectability of the formulation using a 3 mL 21G x 1 / 2 inch syringe / needle after 6 months at room temperature (e.g., 25°C). In some embodiments, there is no change in the injectability of the formulation using a 3 mL 18G x 1 / 2 inch syringe / needle after 3 months at room temperature (e.g., 25°C). In some embodiments, after 6 months at room temperature (e.g., 25° C.), there is no change in the injectability of the formulation using a 3 mL 18G×½ inch syringe / needle.

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

[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 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. in some embodiments, there is no significant change in viscosity of the formulation after 6 months of storage at 2-8, 25, or 30° C.; i. the viscosity remains less than 300 cP, between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP after 6 months of storage 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 using a 3 mL 21 G×½ inch syringe / needle; 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.; l. After 12 months of storage at 2-8 or 25°C, the median particle size of the formulation remains less than 8 μm; m.2-8 or after 12 months of storage at 25°C, the median particle size of the formulation remains less than 5 μm; n.2-8 or after 12 months of storage at 25°C, the median particle size of the formulation remains less than 4 μm; o. After 12 months of storage at 2-8 or 25°C, the median particle size of the formulation remains less than 2.5 μm; p.2-8, or after 12 months of storage at 25°C, the particle size of the 90th percentile of the particle size distribution curve remains less than 8 μm; q.2-8, or after 12 months of storage at 25°C, there is no significant change in the viscosity of the formulation; r. the viscosity remains less than 300 cP, between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP after 2-8, or 12 months storage at 25°C; s. after 12 months at room temperature (e.g., 25° C.), there is no change in injectability of the formulation using a 3 mL 21 G×½ inch to 18 G×½ inch syringe / needle; t. the total proton pump inhibitor impurities remain less than 0.15% after 2-8, or up to 12 months of storage at 25°C; and / or u. The mean half-life (T 1 / 2 ) ranges from 12 to 24 hours.

[0082] In some embodiments, 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 after 24 months at 2-8° C. or 25° C. or 30° C. In some embodiments, after 24 months at 2-8° C. or 25° C. or 30° C., the formulation remains stable for use.

[0083] IV. Containers and Methods of Administration 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 suitable for holding a veterinary pharmaceutical injectable formulation product.

[0084] The present disclosure also encompasses a device for intramuscular or subcutaneous injection into animals, such as equines, containing a suitable amount of the formulation herein for administration. In some embodiments, if 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 to administer human or other veterinary medicines, such as epinephrine or insulin, intramuscularly. For example, epinephrine is often administered using an automatic injection device, often referred to as an injection pen. Similar pen-type devices may also be used herein and are suitable for intramuscular injection into equines or other animals.

[0085] In some embodiments, the device includes a complete single unit dosage of a proton pump inhibitor, such as omeprazole or esomeprazole, e.g., esomeprazole magnesium, for an average weight horse, hi other embodiments, the device includes two or more doses, e.g., two doses, three doses, or four doses.

[0086] In some embodiments, the vial or device may also be packaged with instructions for use, for example, to provide administration instructions for equines 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 a formulation herein, intramuscularly or subcutaneously, for example from a vial as described above and / or using a device as 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, the esomeprazole is esomeprazole magnesium, such as esomeprazole magnesium dihydrate. In some embodiments, the method of treatment comprises administering an effective amount of the formulation to an animal, such as an equine, by intramuscular or subcutaneous injection at least once a week. In some embodiments, the formulation is administered for four weeks. In some embodiments, the formulation is administered for 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 at least one dose of between 1.5 mg / kg and 5.0 mg / kg esomeprazole magnesium at least once a week, hi some embodiments, 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 esomeprazole magnesium. 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 per week for three weeks; (b) at a dose of 2.0-4.0 mg / kg, once per week for four weeks; (c) at a dose of 2.0-4.0 mg / kg, twice per week for three weeks; (d) at a dose of 2.0-4.0 mg / kg, twice per week for four weeks; or (e) any one of (a)-(d), followed by a reduced dose once or twice per week for at least an additional week.

[0089] In some embodiments, the first dose or the first two doses, or the first week, two weeks, three weeks, or four weeks dose, are at a higher level (e.g., a "loading dose") than subsequent doses. In some embodiments, the formulation is administered for a period of more than four weeks, and optionally, the dose is reduced after the four week period. In some embodiments, the formulation is administered for a period of more than three weeks, and optionally, the dose is reduced after the three week period. For example, in some embodiments, an initial dosage level can be selected for up to two weeks, up to one month, or up to six weeks, and then either the dosage or the dosage frequency can be reduced in the following weeks or months.

[0090] In any of the above dosing regimens, the formulation may be administered by intramuscular injection or by subcutaneous injection. In some embodiments, the formulation is administered using the vial and / or device described above. In some embodiments, the formulation is administered to an equine. In some embodiments, the equine is afflicted with a 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 livestock animal or a working animal. In some embodiments, the other animal is a donkey, mule, pig, llama, or alpaca. In some embodiments, when a non-equine animal is treated, the esomeprazole dosage can vary up to a dosage equivalent to that given to such an animal by oral route. For example, some other animals require a higher or lower dosage of the proton pump inhibitor per body weight than equine animals require.

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

[0093] In some embodiments, the formulation is administered at a dosage that, in equine clinical trials, resulted in an improvement in symptoms of gastric ulceration in horses equivalent to a reduction of at least one grade on the following gastric ulceration scoring system of 0 to 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 consolidating) lesions with areas of obvious deep ulceration.

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

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

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

[0097] To prepare the suspension, MCT 812 and cottonseed oil were mixed together first, then esomeprazole sodium or esomeprazole magnesium was added next. The esomeprazole magnesium formulation was an off-white, visually homogeneous viscous oily solution, while the esomeprazole sodium formulation was a white, visually homogeneous, thicker viscous oily solution than the esomeprazole magnesium formulation. After 24 hours on the benchtop, the appearance of the esomeprazole magnesium formulation did not change, while the esomeprazole sodium formulation appeared thicker. No phase separation was observed in either formulation.

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

[0099] The particle size distribution of esomeprazole magnesium formulations for the 10th to 90th percentile part of the distribution curve (in μm) ranged from 0.12 to 4.75 μm (average of three measurements). The median particle size (i.e., the 50th percentile of the distribution) was 0.62 μm (average of three measurements). The particle size distribution of esomeprazole sodium formulations for the 10th to 90th percentile part of the distribution curve ranged from 6.08 to 50.28 μm (average of three measurements), while the median particle size was 22.16 μm (average of three measurements).

[0100] Thus, the cottonseed oil-Miglyol® 812 suspensions prepared with esomeprazole magnesium dihydrate have a significantly lower particle size range than the same formulations prepared with esomeprazole sodium. Furthermore, upon visual inspection, the esomeprazole sodium formulations appeared thicker and more paste-like, likely due to the larger particle size.

[0101] Particle size distributions were also performed on sterile esomeprazole magnesium dihydrate and esomeprazole sodium, both obtained from Shouguang Fukang Pharma. The particle size distribution of esomeprazole magnesium for the 10th to 90th percentile portion of the distribution curve (in μm) ranged from 0.22 to 6.57 μm with a median particle size of 2.01 μm (average of three measurements). The particle size distribution of esomeprazole sodium for the 10th to 90th percentile portion of the distribution curve ranged from 8.60 to 36.49 μm with a median particle size of 18.84 μm (average of three measurements).

[0102] Resuspension was tested by measuring the viscosity of the formulation using a Brookfield Viscometer (Model no. DV3TLVCJ) at 25° C. A standard solution (S60 standard) having a nominal viscosity of approximately 100 cP (mPa·sec) at 25° C. was used as a reference. The resuspensionability of the esomeprazole magnesium formulation was also tested using 26 and 27 gauge needles and the formulation was found to pass through both types of needles.

[0103] Esomeprazole magnesium formulations were also stored at room temperature for one month with no observed settling upon visual inspection. To determine settling, after storage, the formulations were manually shaken to homogenously disperse any sediment into a suspension, and the suspension was allowed to settle under gravity at room temperature for one hour before visually inspecting the appearance.

[0104] Example 2 Formulation vehicles and injectability of esomeprazole magnesium formulations The injectability of the esomeprazole magnesium formulation of Example 1 compared to the formulation vehicle (i.e., excipients only) was compared to determine whether the oil suspension could be filtered for sterility and injected through a needle using a syringe. Approximately 2 mL of vehicle or esomeprazole magnesium formulation was transferred to a 3 mL plastic syringe, a filter (for vehicle; 0.2 μm hydrophobic filter) or a needle (for formulation; either 26G×½ inch or 27G×½ inch) was attached to the syringe, and the contents were pushed into a small vial for visual analysis. The vehicle could be easily passed through the 26G×½ inch needle with relatively low resistance without clogging, and through the 27G×½ inch needle with slightly more resistance than the 26G×½ inch needle without clogging, but still could be easily pushed out. Through the 26G×½ inch needle, the esomeprazole magnesium formulation could be passed through relatively low resistance without clogging. Using a 27G x 1 / 2 inch needle, the formulation could be passed without clogging and with slightly more resistance than using a 26G x 1 / 2 inch needle, but could still be easily pushed out.

[0105] Example 3 Stability of esomeprazole magnesium formulations The formulation described in Example 1 was prepared for a stability study and measured at four different temperatures (2-8° C., 25° C., 30° C., and 40° C.) and upon storage for up to six weeks to determine purity, particle size, resuspension, and injection force.

[0106] Impurities were examined 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 of phosphate buffer (pH 7.6) to acetonitrile (72.5:27.5 by volume), filtered through a 0.8 μm nylon filter, at room temperature, at a flow rate of 1.0 mL / min. 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 less than 0.1% after 4 weeks at each temperature. After 6 weeks of storage, the total impurities at 2-8, 25, and 30° C. remained less than 0.1%, while at 40° C., the total impurities were 0.12%.

[0107] Resuspension properties, 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 and 6 weeks are shown in the table below. TIFF0007645861000001.tif87170

[0108] Injectability results after 4 and 6 weeks are shown in the table below. There was no change after 4 and 6 weeks at 2-8, 25, or 30° C. The median "N / D" was not determined. TIFF0007645861000002.tif60170

[0109] The particle size distribution remained essentially the same after four weeks of storage at each temperature. The 10th to 90th percentile particle sizes ranged from approximately 0.2 to 7.0 μm after four weeks of storage at all four temperatures. The median particle size remained approximately 1 to 2 μm after four weeks of storage at all four temperatures. These results represent the average of triplicate measurements.

[0110] The above results, taken together, show that the formulation is stable for at least 6 weeks at temperatures up to 30° C. The particle size does not change substantially and the formulation remains injectable while keeping the total impurity level below 0.1%. However, the formulation did undergo a color change from off-white to light yellow at 30° C. At 40° C., the formulation becomes paste-like after 6 weeks when stored.

[0111] Example 4 Long-term storage of esomeprazole magnesium preparations Batches of the esomeprazole magnesium formulation of Example 1 were then prepared and tested for storage over periods of 3 and 6 months at 25° C., 30° C., and 40° C. Purity, particle size distribution, resuspendability, and injectability assays were performed similar to those in Example 3 above. The resuspendability results are shown in the table below. TIFF0007645861000003.tif94170

[0112] The injectability results are shown in the table below. TIFF0007645861000004.tif65170

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

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

[0115] Further formulations of esomeprazole magnesium dihydrate as described in Example 1, but additionally containing 0.1% BHT (butylated hydroxytoluene; Spectrum Chemical) preservative, were tested for long-term storage up to 6 months at 2-8°C, 25°C, and 40°C. At TO, prior to storage, the formulation appears as an off-white oily suspension that becomes homogenous upon shaking. The formulation at TO could be passed through a 3 mL syringe with a 21G x 1 / 2 inch needle without clogging and with relatively low resistance, and was easily resuspended upon shaking. Total impurities were measured to be 0.04%, while the impurities of the esomeprazole magnesium standard were measured to be 0.07%. Particle size at TO ranged from about 2.2 to 5.4 μm (10th to 90th percentiles) with a median of 3.45 μm.

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

[0117] exterior: TIFF0007645861000005.tif41170

[0118] Injectability: TIFF0007645861000006.tif72170

[0119] Resuspension: TIFF0007645861000007.tif50170

[0120] 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 TO, with a median of about 3.0-3.5 μm. 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 for 5 minutes at 25°C (as above) was approximately 250-290 cP, while after 9 months of storage the viscosity was measured for 5 minutes at 25°C and was approximately 230-245 cP. The viscosity at T0 (5 minutes at 25°C) was measured to be approximately 235-240 cP.

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

[0124] In conclusion, the formulation was stable for 6-12 months at both 2-8°C and 25°C; the appearance of the formulation did not change and it was easily injected and resuspended. The viscosity as well as the particle size distribution remained almost the same as at TO, while the total impurities remained below 0.15% and only increased slightly between the two temperatures (from 0.11% to 0.13%), with the standard impurity at 0.07%. After several months at 40°C, the formulation changed color from off-white to purple, formed clumps and could not be resuspended. Therefore, no further testing at 40°C was performed.

[0125] A similar 3-month stability study was also performed on the preservative-containing formulation at 30° C. After 3 months at 30° C., the formulation remained unchanged in appearance, could be easily injected, and did not show any significant change in impurities, but was slightly difficult to resuspend and had become viscous.

[0126] Example 5 Clinical Trial of Esomeprazole Magnesium Dihydrate Injectable Formulation A clinical study in five horses of a suspension of 195.8 mg / mL esomeprazole magnesium dihydrate with BHT preservative (antioxidant) in a mixture of cottonseed oil and Miglyol® 812 additive, as described in Example 4, was conducted to determine its effectiveness in controlling the pH of gastric fluids in horses.

[0127] The general study protocol was as follows: Five horses with gastric cannulas were acclimated to the study conditions. The horses were healthy throughout the acclimation period. Baseline gastric pH measurements were recorded prior to product administration. On day 2, each horse was treated intramuscularly with a dose of product intended to deliver 1.75 mg esomeprazole magnesium dihydrate per kg body weight. After a washout period, the study was repeated with a dose of product intended to deliver 4.0 mg esomeprazole magnesium dihydrate per kg body weight. Gastric pH was measured after treatment.

[0128] The first 5-day treatment period assessed the effect on intragastric pH of treatment with an amount of formulation intended to deliver 1.75 mg / kg body weight, rounded up to the next highest 0.2 mL increment. The second 5-day treatment period tested the effect on intragastric pH of an amount of formulation intended to deliver a dosage of 4.0 mg / kg esomeprazole magnesium dihydrate.

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

[0130] Horses consisted of light, saddle-bred horses, approximately 3 years old, weighing approximately 378-428 kg based on body size, and consisted of castrated males (geldings) and / or intact females (mares). Female candidates were neither pregnant nor lactating. Procedures were performed to avoid or minimize discomfort, distress, or pain for the participating animals.

[0131] Gastric pH was measured immediately after treatment and continuously until the next day's subsequent administration of medication. Gastric pH was measured at baseline and after each of the two treatments at different dosages. Gastric pH control varied between 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 gastric pH in individual horses for approximately 3-5 days. The experimental regimen had no apparent adverse effects on equine health and was considered safe for intramuscular administration to mature horses.

[0132] Example 6 A Randomized, Placebo-Controlled, Dose-Ranging, 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 esomeprazole magnesium dihydrate with BHT preservative in a mixture of cottonseed oil and Miglyol® 812 additive, as described in Example 4, was performed in 53 horses to test the effectiveness in controlling gastric ulcers at a specific dosing regimen. The suspension was tested against a control saline solution.

[0133] The study was a multicenter, blinded, placebo-controlled, randomized clinical trial that investigated the efficacy and safety of a product administered intramuscularly to control gastric ulcer disease in horses. The primary efficacy endpoint was resolution of gastric ulcer disease in horses, defined as a score of 0 on a gastric ulcer disease scoring system of 0 to 3. The secondary efficacy endpoint was improvement of gastric ulcer disease in horses, defined as a reduction of at least 1 grade on a gastric ulcer disease scoring system of 0 to 3 as follows: 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 consolidating) lesions with areas of obvious deep ulceration.

[0134] A total of 53 horses were randomized to one of four treatment groups (4 mg / kg weekly, 2 mg / kg weekly, 2 mg / kg twice weekly, and control product twice weekly). Fourteen horses were treated with 4 mg / kg veterinary test drug (IVP) once weekly, 13 horses were treated with 2 mg / kg IVP once weekly, 13 horses were treated with 2 mg / kg IVP twice weekly, and 13 horses were treated with control saline (CP) twice weekly. Prohibited medications during the study included medications that may alter intragastric pH. Test animals were at least 1 year old, any sex, intact or neutered, non-pregnant, non-lactating, and non-breeding, of any breed, and initial weight range was not specified. All horses were determined to be evaluable for efficacy analyses prior to the open-label study. Of 14 horses treated with 4 mg / kg weekly, 11 (78.6%) had resolved ulcers. Of 13 horses treated with 2 mg / kg twice weekly, 10 (76.9%) had resolved ulcers. Of 13 horses treated with 2 mg / kg once weekly, 11 (84.6%) had resolved ulcers. Of the placebo horses, 30.8% had resolved ulcers. All esomeprazole treatment groups showed statistically significant differences from the control treatment group (analysis by Fisher's exact test). The product was also well tolerated.

[0135] A baseline gastroscopy was performed to confirm the presence of gastric ulcers and to complete the randomization procedure. Horses received 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 terminated from the study. Horses with a gastroscopy evaluation at Visit 2 of Grade 1 or higher continued through Visit 3. For the remaining horses, a gastroscopy evaluation and end-of-study activities were completed at Visit 3 (Day 21). Primary efficacy was determined by gastric ulcer resolution at the end of the study (gastroscopy evaluation grade = 0). Secondary efficacy was determined by gastric ulcer improvement (a reduction of at least 1 in gastric ulcer grade at the end of the study compared to baseline).

[0136] The intended dose of the product was either 4 mg / kg body weight or 2 mg / kg body weight, calculated in mL based on the horse's starting weight and the formulation's esomeprazole magnesium dihydrate concentration of 200 mg / mL, rounded to the nearest mL. Control saline was provided in standard volumes. Doses were administered using a new 18-gauge, 1.5-inch needle and a 5- to 10-mL sterile syringe. Duration of administration was dependent on resolution of the ulcer and continued for a maximum of 18 days.

[0137] The dosing schedule for each treatment group is shown in the table below: TIFF0007645861000008.tif70170

[0138] The primary efficacy variable measured was ulcer resolution (score "0") at the end of the study. The secondary variable measured was an improvement of at least 1 in gastric ulcer score at the end of the study. Results were summarized by frequency and count. Exploratory statistical analyses for cP of IVP were performed. Horses with ulcer resolution by Visit 2 were terminated at that visit. Horses not terminated at Visit 2 were terminated at Visit 3.

[0139] The 14 horses treated with 4 mg / kg IVP received a total of 35 doses. Of the 14 horses treated with 4 mg / kg IVP once a week, 11 (78.6%) were judged to be improved. The 13 horses treated with 2 mg / kg IVP (either once a week or twice a week) received a total of 103 doses. Of the 13 horses treated with 2 mg / kg IVP twice a week, 12 (92.3%) were judged to be improved. Of the 13 horses treated with 2 mg / kg IVP once a week, 13 (100.0%) were judged to be improved. The 13 horses treated with CP received a total of 74 doses. Of the 13 horses treated with CP, 7 (53.8%) were judged to be improved. Comparison of confidence intervals showed a statistical difference between the twice weekly 2 mg / kg IVP group and the once weekly 2 mg / kg IVP group when compared with the CP group.

[0140] Treatment success was defined as resolution of gastric ulcer disease (gastric ulcer score = 0). Of 14 horses treated with 4 mg / kg IVP once weekly, 11 (78.6%) were judged to be treatment successful. Of 13 horses treated with 2 mg / kg IVP twice weekly, 10 (76.9%) were judged to be treatment successful. Of 13 horses treated with 2 mg / kg IVP once weekly, 11 (84.6%) were judged to be treatment successful. Of 13 horses treated with CP, 4 (30.8%) were judged to be treatment successful. Thus, the IVP formulation was effective in controlling gastric ulcers in treated horses within 3 weeks of initiation of the treatment schedule.

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

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

[0143] Details of treated horses: TIFF0007645861000009.tif234170

[0144] Successful treatment; resolution of gastric ulcer disease: TIFF0007645861000010.tif73170

[0145] Treatment improvement; Improvement of gastric ulcer disease: TIFF0007645861000011.tif74170

[0146] Time to completion of study: TIFF0007645861000012.tif75170

[0147] Example 7 Evaluation of the pharmacokinetic profile of the intramuscular formulation This study evaluated the pharmacokinetics of the proton pump inhibitor, esomeprazole, following multiple intramuscular administration 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). Doses were administered intramuscularly. Each horse received its assigned dose three times, 7 days apart. Blood samples were collected 1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours after each dose, and then every 48 hours until day 28. Esomeprazole was quantified by LC-MS / MS. Data were subjected to noncompartmental analysis.

[0149] Maximum concentrations (Cmax) of esomeprazole were reached within 1.2 to 2 hours, with mean half-lives ranging from 11.63 to 24.5 hours across all doses and administrations. Dose normalization of Cmax and area under the curve demonstrated linear pharmacokinetics across the three dosing regimens. Drug was detectable for 96 ± 26.29 hours following administration of the final dose in the 5x group. A single mild, self-resolving, injection site reaction was noted in one horse in the 3x group.

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

Claims

1. An injectable pharmaceutical formulation comprising a suspension of a proton pump inhibitor selected from the group consisting of esomeprazole, esomeprazole sodium, esomeprazole magnesium, and esomeprazole magnesium dihydrate in a mixture of cottonseed oil and caprylic / capric triglyceride, wherein the formulation comprises 15% to 25% weight / weight (w / w) of esomeprazole, esomeprazole sodium, esomeprazole magnesium, or esomeprazole magnesium dihydrate, 5% w / w to 30% w / w cottonseed oil, and 50% w / w to 90% w / w of caprylic / capric triglyceride, such that the injectable pharmaceutical formulation is stable for at least six months.

2. 2. The formulation of claim 1 comprising 18% w / w to 22% w / w of esomeprazole magnesium.

3. 3. The formulation of claim 2 comprising 19% w / w to 21% w / w of esomeprazole magnesium.

4. 4. The formulation of claim 3 comprising 20% ​​w / w esomeprazole magnesium.

5. 2. The formulation of claim 1, wherein the proton pump inhibitor is esomeprazole magnesium dihydrate.

6. 6. A formulation according to any one of claims 1 to 5, comprising 10-15%, 10-12%, 13-15%, 15-17%, 18-20%, or 15-20% w / w cottonseed oil.

7. 7. A formulation according to any one of claims 1 to 6 comprising 60-70%, 60-65%, 65-70%, 70-80%, 70-75% or 75-80% w / w caprylic / capric triglyceride.

8. The formulation of claim 1, further comprising at least one preservative selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium bisulfite, and mixtures thereof.

9. The formulation of claim 8, comprising 0.05 to 1.0% w / w butylated hydroxytoluene (BHT).

10. 10. The formulation of any one of claims 1 to 9, consisting essentially of: (a) a proton pump inhibitor selected from the group consisting of esomeprazole, esomeprazole sodium, esomeprazole magnesium, and esomeprazole magnesium dihydrate; (b) cottonseed oil; (c) caprylic / capric triglyceride; and (d) at least one preservative selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium bisulfite, and mixtures thereof.

11. 11. The formulation of claim 10, consisting essentially of esomeprazole magnesium dihydrate, cottonseed oil, caprylic / capric triglyceride, and BHT.

12. 12. A formulation according to any one of claims 1 to 11, wherein the caprylic / capric triglyceride comprises 50-65% caprylic acid and 30-45% capric acid.

13. A formulation according to any one of claims 1 to 11, wherein the caprylic / capric triglyceride comprises 50-75% caprylic acid and 22-45% capric acid.

14. 14. The formulation of any one of claims 1 to 13, 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.

15. 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) after 6 months of storage at 2-8, 25, or 30°C, the viscosity of the formulation remains less than 300 cP, between 200 and 300 cP, between 225 and 300 cP, or between 250 and 300 cP; 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.; 15. The formulation of claim 1, having the formula:

16. 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) after 2-8, or 12 months of storage at 25°C, the viscosity of the formulation remains less than 300 cP, between 200-300 cP, between 225 and 300 cP, or between 250 and 300 cP; g) after 12 months at room temperature (e.g., 25° C.), there is no change in the injectability of the formulation using a 3 mL 21G×½ inch to 18G×½ inch syringe / needle; and / or h) total proton pump inhibitor impurities remain less than 0.15% after 2-8, or up to 12 months storage at 25° C.; 16. The formulation of claim 1 , having the formula:

17. A vial comprising a formulation according to any one of claims 1 to 16.

18. 17. A device for intramuscular injection into equines comprising a formulation according to any one of claims 1 to 16.

19. 17. A method of preparing the injectable pharmaceutical formulation of any one of claims 1 to 16, comprising: (a) mixing cottonseed oil and 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.

20. 20. The method of claim 19, further comprising adding at least one preservative to the mixture of cottonseed oil and caprylic / capric triglyceride and / or to the suspension.

21. 20. A method of treating gastric ulcers in an equine animal comprising administering to the equine animal an effective amount of a formulation as defined in any one of claims 1 to 16 by intramuscular or subcutaneous injection at least once a week.

22. 22. The method of claim 21, 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.

23. 23. The method of claim 22, 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.

24. 24. The method of any one of claims 21 to 23, wherein the formulation is administered once, twice or three times per week.

25. 25. The method of claim 24, wherein the formulation is administered once a week.

26. 25. The method of claim 24, wherein the formulation is administered twice a week.

27. 25. The method of claim 24, wherein the formulation is administered three times per week.

28. 28. The method of any one of claims 21 to 27, 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.

29. 29. The method of any one of claims 21 to 28, wherein the formulation is administered for a period of four weeks.

30. 29. The method of any one of claims 21 to 28, wherein the formulation is administered for a period of three weeks.

31. 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; 31. The method of any one of claims 21 to 30, wherein the method is administered according to

32. 31. The method of any one of claims 21 to 30, wherein the formulation is administered for a period of more than four weeks, and optionally the dose is reduced after the four week period.

33. 31. The method of any one of claims 21 to 30, wherein the formulation is administered for a period of more than three weeks, and optionally the dose is reduced after the three week period.

34. 34. The method of any one of claims 21 to 33, wherein the formulation is administered by intramuscular injection.

35. 34. The method of any one of claims 21 to 33, wherein the formulation is administered by subcutaneous injection.

36. 36. The method of any one of claims 21 to 35, wherein the formulation is administered using a vial according to claim 17 and / or a device according to claim 18.

37. 37. The method of any one of claims 21 to 36, wherein the equine animal is afflicted with Equine Gastric Ulcer Syndrome (EGUS), Equine Squamous Gastric Disease (ESGD), or Equine Glandular Gastropathy (EGGD).

38. 38. The method of any one of claims 21 to 37, wherein the ulcer is treated by (a) reducing the size of at least one ulcerative lesion, or (b) reducing the number of ulcerative lesions.

39. 20. An injectable pharmaceutical formulation according to any one of claims 1 to 16 for use in a method for the treatment of ulcers in an equine animal, administered to the equine animal by intramuscular or subcutaneous injection.

40. 40. The formulation for use of claim 39, 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.

41. 40. The formulation for use according to claim 39, 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.

42. 42. The formulation for use according to claim 39 or 41, which is administered once, twice or three times per week.

43. 43. The formulation for use according to claim 42, which is administered once a week.

44. 43. The formulation for use according to claim 42, which is administered twice weekly.

45. 43. The formulation for use according to claim 42, administered three times per week.

46. 46. ​​The formulation for use according to any one of claims 39 to 45, 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.

47. 47. A formulation for use according to any one of claims 39 to 46, administered for a period of four weeks.

48. 47. A formulation for use according to any one of claims 39 to 46, administered for a period of three weeks.

49. 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; 49. The formulation for use according to any one of claims 39 to 48, wherein the formulation is administered according to

50. 49. The formulation for use according to any one of claims 39 to 48, which is administered for a period of more than four weeks, and optionally the dose is reduced after the four week period.

51. 49. The formulation for use according to any one of claims 39 to 48, which is administered for a period longer than three weeks, and optionally the dose is reduced after the three week period.

52. 50. The formulation for use according to any one of claims 39 to 49, which is administered by intramuscular injection.

53. 50. The formulation for use according to any one of claims 39 to 49, which is administered by subcutaneous injection.

54. 54. A formulation for use according to any one of claims 39 to 53, administered using a vial according to claim 17 and / or a device according to claim 18.

55. 55. The formulation for use according to any one of claims 39 to 54, wherein the equine animal is afflicted with Equine Gastric Ulcer Syndrome (EGUS), Equine Squamous Gastric Disease (ESGD), or Equine Glandular Gastropathy (EGGD).

56. 56. The formulation for use according to any one of claims 39 to 55, wherein the ulcer is treated by (a) reducing the size of at least one ulcerative lesion, or (b) reducing the number of ulcerative lesions.

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