Patent Description:
Conventional oral dosing of animals also suffers from a variety of disadvantages. For example, the animal can spit out the formulation, resulting in a loss of the full dosage. Also, if administered by intubation, the bioavailability can vary considerably due to the inherent and unique characteristics of each animal's digestive system, i.e., the amount of food in the animal's stomach, the length of time since its last feeding, and the animal's levels of digestive enzymes, which may vary due to other environmental conditions, etc. Also, the active ingredient in the oral formulation is sometimes unstable. In some cases the active ingredient in an oral formulation may be unstable because of the pH and/or digestive materials present in an animal's stomach. Moreover, administering conventional oral dosages forms to an animal, e.g., a horse, creates the risk of inadvertently dosing the human administrator with the drug substance.

Another disadvantage of many oral and injectable formulations is that those formulations require administering a relatively high mass percentage ("mass%") of inactive material to the animal. For example, many oral and injectable formulations comprise significant amounts of carriers and/or excipients that provide no direct benefit to the animal. Many care providers generally agree that animals should not consume unnecessary pharmaceutical substances. Accordingly, it would be advantageous to minimize the amount of non-therapeutic materials administered to an animal when providing the pharmaceutically active substance. For example, when providing omeprazole to an animal in need thereof, many conventional formulations comprise more than <NUM>% of an inactive substance having no therapeutic effect. Conventional oral formulations of omeprazole may also often suffer from the disadvantageous correlation between bioavailability and the contents of the animal's stomach. For example, bioavailability may be lessened on account of the animal havig food present in its stomach.

Fast release pharmaceutical formulations have been disclosed in the art. These may include multi-particulate fast disintegrating tablets as disclosed, for instance in <CIT>; the so-called rapidly dispersing "<NUM>-D platform", disclosed in <CIT>; and pectin-based dissolvable films, such as disclosed in <CIT>. Immediate release compositions are disclosed <CIT>. Each of these disclosures is incorporated herein by reference.

Still, there exists a need in the art to provide improved therapeutic methods for animals (for example humans, equines, bovines, ovines, canines, felines and porcines) which obviate many of the disadvantages and side effects of the commonly used injectable and oral formulations.

There is also a need in the art to provide methods for the treatment of humans, equines, bovines, canines, felines, ovines, and porcines equines with drug products which give an earlier onset of action, reduce the number and severity of side effects, lessen the risk of infection at injection sites, and mitigate the bioavailability issues incident to administering the drug via absorption within the digestive tract of the animal.

There is a still another need in the art to provide methods which enable treatment of the animal patient that provide more reliable and predictable clearance from the animal.

The invention disclosed here answers one or more of these needs discussed above. The features, objects, and advantages of the disclosed invention will be apparent to those skilled in the art from the description of the invention, and from the claims.

The invention relates to pharmaceutical compositions for direct systemic introduction (DSI), which are also known as DSI pharmaceutical compositions as defined in the appended claims. DSI pharmaceutical compositions may generally be used in both as human pharmaceutical compositions and veterinary pharmaceutical compositions. Various DSI pharmaceutical compositions are described herein.

In one embodiment, the invention relates to a pharmaceutical composition for direct system introduction for use in treating or preventing gastric ulcers, duodenal ulcers, Zollinger-Ellison syndrome, laryngopharyngeal reflux, dyspepsia, peptic ulcer disease, gastritis, or gastroesophageal reflux in an animal needing treatment, comprising about <NUM>-<NUM> mass% bovine gelatin, about <NUM>-<NUM> mass% mannitol, about <NUM>-<NUM> mass% of a surfactant, about <NUM>-<NUM> mass% of a flavorant, and about <NUM>-<NUM> mass% of an active pharmaceutical ingredient. The pharmaceutical composition may in some embodiments comprise about <NUM>-<NUM> mass% bovine gelatin, about <NUM>-<NUM> mass% mannitol, and about <NUM>-<NUM> mass percent of a surfactant. Alternatively, the pharmaceutical composition may comprise about <NUM>-<NUM> mass% bovine gelatin, about <NUM>-<NUM> mass% mannitol, and about <NUM>-<NUM> mass% of a surfactant. Omeprazole is one active pharmaceutical ingredient that may be formulated in a pharmaceutical composition of the invention.

Another embodiment of the invention relates to a DSI pharmaceutical composition , such as described herein, having a disintegration time of <NUM> seconds or less in deionized water maintained at <NUM> ± <NUM>. A DSI pharmaceutical composition of the invention may in some embodiments have a disintegration time of <NUM> seconds or less in deionized water maintained at <NUM> ± <NUM>.

The invention also describes a method of delivering an active pharmaceutical ingredient to an animal comprising the step of placing a DSI pharmaceutical composition of the invention into a mucosal cavity of an animal to be treated with the active pharmaceutical ingredient. The invention also describes various methods of treatment administering an active pharmaceutical ingredient in this manner.

Disclosed herein are pharmaceutical compositions and methods for treating animals, for example humans, equines, bovines, canines, felines, ovines, and porcines. Various methods comprise administering an active pharmaceutical ingredient, also known as a therapeutic agent, into the bloodstream of the animal by introducing it transdermally across the animal's non-keratinous fibers, e.g., via the oral cavity, anal cavity, vaginal cavity, nasal cavity, gingival mucosa, lingual mucosa, palatal mucosa, pharyngeal mucosa, sublingual mucosa, and/or non-gastric mucosa. In various instances, a majority of the formulation may be absorbed prior to reaching the gastric mucosa. In certain cases, the formulation may be adapted for animals, for example humans, equines, bovines, canines, felines, ovines, and porcines to dissolve in a relatively short period of time, e.g., <NUM> seconds or less.

Administering a DSI pharmaceutical composition of the invention may in some cases provide for faster onset of the therapy, diminished occurrences of the side-effects due to nonuniformity of bioavailability of the active pharmaceutical ingredient, and/or more accurate dosing. In at least some instances, these features result in dose lowering. Further, in at least some instances, such administration may result in a greater portion of the therapeutic agent actually being directly introduced systemically into the circulatory system for its therapeutic effect. For example, in the case of omeprazole, the DSI pharmaceutical compositions disclosed herein provide an advantage because the bioavailability of omeprazole is not limited by the presence of matter (e.g., food) in the animal's stomach. For example, the disclosed methods of administering the active pharmaceutical ingredient omeprazole do not require fasting the animals prior to administering omeprazole. And the bioavailability of omeprazole is not compromised by the contents of the animal's stomach.

Also disclosed herein are methods for the treatment and control of various diseases afflicting animals, for example equines, bovines, canines, felines, ovines, and porcines, with improved safety for the both the animal and the person administering the therapeutic agent. In at least certain exemplary embodiments, the compositions and methods are useful for administration to humans. For example, disclosed herein are methods of treating gastroesophageal reflux disease, gastritis, peptic ulcer disease, dyspepsia, laryngopharyngeal reflux, Zollinger-Ellison syndrome, duodenal ulcers and/or preventing gastric ulcers (e.g., gastric ulcers associated with NSAID therapy or Chrohn's disease) and/or controlling the production of digestive fluids (e.g., gastric acids) and/or normalizing the pH of an animal's stomach comprising administering a DSI compound comprising one or more proton pump inhibitors (e.g., omeprazole and/or any of its stereoisomers).

Administering therapeutic agents to the animal without needles, via the non-keratinous tissues into a mucosal cavity, e.g., the oral cavity, anal cavity, vaginal cavity, nasal cavity, gingival mucosa, lingual mucosa, palatal mucosa, pharyngeal mucosa, sublingual mucosa, and/or non-gastric mucosa results in rapid onset of activity, more accurate dosing, lowered dosing, an absence or diminishment of side-effects, and greater safety to both the animal and the administrator of the formulation. In some cases the therapeutic agents may be administered via the animal's oral cavity, anal cavity, vaginal cavity, nasal cavity, gingival mucosa, lingual mucosa, palatal mucosa, pharyngeal mucosa, sublingual mucosa, and/or non-gastric mucosa.

As used herein, the term "oral cavity" means that portion of the alimentary canal from the orifice conventionally referred to as the mouth, including, for example the area distally from the mouth to the esophagus and all tissues including, for example under the tongue (sublingual), on the top of the tongue, and/or between the cheek and gums (buccal), the mucal membranes, epithelium, and gums.

As used herein, the term "non-gastric mucosa" refers to the pre-gastric mucosal cells, e.g., oral mucosa, including the mucous membrane beneath the tongue, and/or the buccal mucosa at the inside of the cheek and gum and absorption sites in the esopaghus.

As used herein, the term "pre-gastric" refers to all parts of the alimentary canal beginning at the mouth and continuing to the juncture with the first secretory stomach.

As used herein, "Direct Systemic Introduction" ("DSI"), means administering one or more therapeutically active agent directly to the circulatory system of an animal via a formulation administered and absorbed across non-keratinous fibers, e.g., the oral cavity and/or the non-gastric mucosa. DSI may, in at least some embodiments, provide relatively high systemic concentrations of the active agents, e.g. by allowing agents to pass directly into the systemic circulation avoiding the destructive activities in the digestive tract by gastric breakdown, metabolism in the wall of the GI tract and first pass metabolism by the liver. Administering a DSI pharmaceutical composition comprises in one instance contacting the animal's first secretory stomach with less than about <NUM>% of the DSI pharmaceutical composition administered to the animal.

DSI may result in higher systemic availability of therapeutic agents in the animal for their desired therapeutic effects vis-á-vis products formulated in conventional oral delivery systems. DSI provides advantages over traditional oral, intravenous, intramuscular, and subcutaneous routes of administration, in that more of the drug may be available systemically for its desired therapeutic effects. For example, in equines, DSI can provide more rapid metabolic clearance of the drug, resulting in a shortened withdrawal time to clear the animal for performance racing. See, e.g., "<NPL>, which discusses the necessary withdrawal times for performance animals.

A DSI pharmaceutical composition of the invention disintegrates quickly in water. A DSI pharmaceutical composition of the invention generally has a disintegration time of <NUM> seconds or less in deionized water maintained at <NUM> ± <NUM>. A DSI pharmaceutical composition of the invention may have a disintegration time of <NUM> seconds or less in deionized water maintained at <NUM> ± <NUM>.

The rapid dissolution of the DSI pharmaceutical compositions disclosed herein allows them to also dissolve rapidly when in contact with an animal's non-keratinous fibers/mucosal cavity, for example, the oral cavity and/or the non-gastric mucosa. In some embodiments, the formulations contemplated herein will dissolve when in contact with the animal's non-keratinous fibers, e.g., the oral cavity and/or the non-gastric mucosa in about <NUM> seconds or less. In some embodiments, the DSI pharmaceutical composition will dissolve in about <NUM> seconds or less, such as in about <NUM> seconds or less, about <NUM> seconds or less, about <NUM> seconds or less, about <NUM> seconds or less, about <NUM> seconds or less or about <NUM> seconds or less. In some embodiments, the DSI pharmaceutical composition dissolves in less than about <NUM> seconds.

A further benefit of the DSI dosing of an animal is that the person administering may be able to more quickly titrate an appropriate dosage for the level and severity of the condition of the animal. Using typical routes of administration, due to metabolic disposition and the overall health of the animal, it may take a practitioner a period of several days to achieve an appropriate dose to treat and control a condition. One advantage of a DSI pharmaceutical composition is that the practitioner may reliably assume therapeutic effects within a short period of time, and adjust the level of administration of the drug, as needed.

In at least some embodiments, DSI pharmaceutical compositions permit a shorter withdrawal time from treatment than with some conventional oral dosing regimens. By way of example only, typically, an equine patient will need to be withdrawn from many medications for periods ranging from <NUM>-<NUM> hours prior to performance racing. This results in interruption of the therapy, and can lead to a worsening of the existing disease, or at the least, a slower recovery than if the withdrawal had not occurred. In many cases using DSI therapy, however, the equine patient may only need to discontinue the therapy for a period as short as <NUM>-<NUM> hours or not at all, depending upon the particular therapeutic agent being utilized in the methods of the present disclosure.

In at least one exemplary case, the methods herein are administered to the circulatory system of the animal via a DSI pharmaceutical composition administered and absorbed via the non-keratinous fibers/mucosal cavity, such as in the oral cavity and/or the non-gastric mucosa, adapted for humans, equines, bovines, canines, felines, ovines, and porcines, resulting in rapid absorption of the active ingredient and faster clearance. Due to both administration and absorption to the oral cavity and/or the non-gastric mucosa, the resultant effect is DSI.

In some embodiments, the oral dissolution of the disclosed DSI pharmaceutical compositions occurs without the addition of non-biological liquids or accelerants. For example, the DSI pharmaceutical compositions may disintegrate rapidly upon contact with the animal's biological fibers and/or biological fluids. In some embodiments, the DSI pharmaceutical compositions may be administered without the need for any additional sources of accelerant, dissolving agent, or contemporaneous drink.

The DSI pharmaceutical composition comprise an omeprazole (a proton pump inhibitor) as the active pharmaceutical ingredient. As used in this application, the term "proton-pump inhibitor" (sometimes abbreviated "PPI") generally refers to a group of drugs that provide pronounced and long-lasting reduction of gastric acid production. Without being bound by any theory, proton pump inhibitors are believed to act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (often described in terms of "the H+/K+ ATPase" or "gastric proton pump") of the gastric parietal cells. As used in this disclosure, the term proton pump inhibitor includes but is not limited to omeprazole, lansoprazole, rabeprazole, pantoprazole, dexlansoprazole, esomeprazole, etc..

In one embodiment, the DSI pharmaceutical composition comprises omeprazole. In one embodiment, the DSI pharmaceutical composition comprises micronized omeprazole. As used herein, the term "micronized" means having an average particle diameter of between about <NUM> × <NUM>-<NUM> to about <NUM> x <NUM>-<NUM> meters. For example, in some embodiments the disclosed DSI pharmaceutical compositions comprising omeprazole are formulated with micronized omeprazole having an average particle diameter of about <NUM> to about <NUM> microns.

In one embodiment, the DSI pharmaceutical composition comprises both an omeprazole and an H2 blocker (also known as an H2 receptor antagonist). In one embodiment, the DSI pharmaceutical composition comprises omeprazole and at least one compound chosen from famotidine, cimetidine, ranitidine, and nizatidine.

One embodiment of the invention provides DSI pharmaceutical compositions as defined herein, comprising greater than about <NUM> mass% of an omeprazole. In one embodiment, the DSI pharmaceutical composition comprises greater than about <NUM> mass% of omeprazole as an active pharmaceutical ingredient. In another embodiment, the DSI pharmaceutical composition comprises greater than about <NUM> mass% of an active pharmaceutical ingredient. In other embodiments, the DSI pharmaceutical composition comprises about <NUM>-<NUM> mass% of an omeprazole or about <NUM>-<NUM> mass% of anomeprazole.

More specifically, a DSI pharmaceutical composition for use in treating or preventing gastric ulcers, duodenal ulcers, Zollinger-Ellison syndrome, laryngopharyngeal reflux, dyspepsia, peptic ulcer disease, gastritis, or gastroesophageal reflux in an animal needing treatment as defined in the appended claimscontains about <NUM>-<NUM> mass% bovine gelatin, <NUM>-<NUM> mass% mannitol, about <NUM>-<NUM> mass% of a surfactant, about <NUM>-<NUM> mass% of a flavorant and about <NUM>-<NUM> mass% of an omeprazole. A preferred DSI formulation contains about <NUM>-<NUM> or <NUM>-<NUM> mass% bovine gelatin, about <NUM>-<NUM> or <NUM>-<NUM> mass% mannitol, about <NUM>-<NUM> mass% of a surfactant, about <NUM>-<NUM> mass% of a flavorant and about <NUM>-<NUM> mass% of an omeprazole. Also disclosed herein are products produced by the above-described methods. In one example, the product produced comprises about <NUM> mass% omeprazole.

The methods of treatment described herein comprise administering the active ingredient (e.g., omeprazole) in a dehydrated form, such that the active ingredient is rapidly and efficiently delivered to the animal's circulatory system upon contact with the animal's natural biological fluids.

In one embodiment, the DSI pharmaceutical composition provides a Tmax of less than about <NUM> minutes. In another embodiment, the DSI pharmaceutical composition provides a Tmax of less than about <NUM> minutes. In another embodiment, the DSI pharmaceutical composition provides a Tmax of less than about <NUM> minutes. In another embodiment, the DSI pharmaceutical composition provides a Tmax of less than about <NUM> minutes. In another embodiment, the DSI pharmaceutical composition provides a Tmax of less than about <NUM> minutes. In another embodiment, the DSI pharmaceutical composition provides a Tmax of less than about <NUM> minutes. In another embodiment, the DSI pharmaceutical composition provides a Tmax of less than about <NUM> minutes. In another embodiment, the DSI pharmaceutical composition provides a Tmax of less than about <NUM> minutes. In another embodiment, the DSI pharmaceutical composition provides a Tmax of less than about <NUM> minutes.

In one instance, administering a DSI pharmaceutical composition as disclosed herein provides a first Tmax and a second Tmax. As used herein the term "first Tmax" refers to the first relative maximum for the blood concentration of the active pharmaceutical ingredient following administering a DSI pharmaceutical composition comprising that active pharmaceutical ingredient. As used herein the term "second Tmax" refers to the second relative maximum for the blood concentration of the active pharmaceutical ingredient following administering a DSI pharmaceutical composition comprising that active pharmaceutical ingredient. The first Tmax occurs when a portion of the DSI pharmaceutical composition is absorbed via the non-keratinous fibers or in a mucosal cavity, for example in the mouth. The second Tmax then may occur as the remainder of the DSI pharmaceutical composition is absorbed via the gastro-intestinal (GI) tract. In one instance, the first Tmax is less than about <NUM> minutes. In another instance, the first Tmax is less than about <NUM> minutes. In another instance, the first Tmax is less than about <NUM> minutes. In another instance, the first Tmax is less than about <NUM> minutes. In another instance, the first Tmax is less than about <NUM> minutes. In another instance, the first Tmax is less than about <NUM> minutes. In one instance, the second Tmax is less than about <NUM> minutes. In another instance, the second Tmax is less than about <NUM> minutes. In another instance, the second Tmax is less than about <NUM> minutes. In another instance, the second Tmax is less than about <NUM> minutes. In another instance, the second Tmax is less than about <NUM> minutes. In another instance, the second Tmax is less than about <NUM> minutes.

In one instance, when the active pharmaceutical ingredient is omeprazole, one dose of a DSI pharmaceutical composition provides a first Tmax and a second Tmax. In another instance, one dose of an omeprazole DSI pharmaceutical composition provides a first Tmax and a second Tmax. In another instance, a dose of an omeprazole DSI pharmaceutical composition provides a first Tmax between about <NUM>-<NUM> minutes and a second Tmax between about <NUM>-<NUM> minutes.

Disclosed herein are methods of controlling the production of digestive fluids, comprising administering an above-described the DSI pharmaceutical composition comprising omeprazole to an animal in need of treatment. In one instance, the animal is an equine. In another instance, the animal is a human. In one instance, the method controlling the production of digestive fluids comprises administering to the said animal a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration. In another instance, the administering a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration are achieved by administering one dose of omeprazole.

Disclosed herein are methods of treating or preventing gastric ulcers in an animal needing treatment, comprising administering an above-described the DSI pharmaceutical composition comprising omeprazole to an animal in need of treatment. In one instance, the animal is an equine. In another instance, the animal is a human. In one instance, the method of treating or preventing gastric ulcers in an animal needing treatment comprises administering to the said animal a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration. In another instance, the administering a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration are achieved by administering one dose of omeprazole.

Disclosed herein are methods of treating or preventing duodenal ulcers in an animal needing treatment, comprising administering an above-described the DSI pharmaceutical composition comprising omeprazole to an animal in need of treatment. In one instance, the animal is an equine. In another instance, the animal is a human. In one instance, the method of treating or preventing duodenal ulcers in an animal needing treatment comprises administering to the said animal a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration. In one instance, the administering a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration are achieved by administering one dose of omeprazole.

Disclosed herein are methods of treating or preventing Zollinger-Ellison syndrome in an animal needing treatment, comprising administering an above-described the DSI pharmaceutical composition comprising omeprazole to an animal in need of treatment. In one instance, the animal is an equine. In another instance, the animal is a human. In one instance, the method of treating or preventing Zollinger-Ellison syndrome an animal needing treatment comprises administering to the said animal a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration. In one instance, the administering a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration are achieved by administering one dose of omeprazole.

Disclosed herein are methods of treating or preventing laryngopharyngeal reflux in an animal needing treatment, comprising administering an above-described the DSI pharmaceutical composition comprising omeprazole to an animal in need of treatment. In one instance, the animal is an equine. In another instance, the animal is a human. In one instance, the method of treating or preventing laryngopharyngeal reflux in an animal needing treatment comprises administering to the said animal a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration. In one instance, the administering a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration are achieved by administering one dose of omeprazole.

Disclosed herein are methods of treating or preventing dyspepsia in an animal needing treatment, comprising administering an above-described the DSI pharmaceutical composition comprising omeprazole to an animal in need of treatment. In one instance, the animal is an equine. In another instance, the animal is a human. In one instance, the method of treating or preventing dyspepsia in an animal needing treatment comprises administering to the said animal a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration. In one instance, the administering a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration are achieved by administering one dose of omeprazole.

Disclosed herein are methods of treating or preventing peptic ulcer disease in an animal needing treatment, comprising administering an above-described the DSI pharmaceutical composition comprising omeprazole to an animal in need of treatment. In one instance, the animal is an equine. In another instance, the animal is a human. In one instance, the method of treating or preventing peptic ulcer disease in an animal needing treatment comprises administering to the said animal a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration. In one instance, the administering a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration is achieved by administering one dose of omeprazole.

Disclosed herein are methods of treating or preventing gastritis in an animal needing treatment, comprising administering an above-described the DSI pharmaceutical composition comprising omeprazole to an animal in need of treatment. In one instance, the animal is an equine. In another instance, the animal is a human. In one instance, the method of treating or preventing gastritis in an animal needing treatment comprises administering to the said animal a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration. In one instance, the administering of a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration is achieved by administering one dose of omeprazole.

Disclosed herein are methods of treating or preventing gastroesophageal reflux disease in an animal needing treatment, comprising administering an above-described the DSI pharmaceutical composition comprising omeprazole to an animal in need of treatment. In one instance, the animal is an equine. In another instance, the animal is a human. In one instance, the method of treating or preventing gastroesophageal reflux disease in an animal needing treatment comprises administering to the said animal a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration. In one instance, the administering a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration is achieved by administering one dose of omeprazole.

Disclosed herein are methods of raising the pH in an animal's stomach comprising administering an above-described DSI pharmaceutical composition comprising omeprazole to the animal. In one instance, the animal is an equine. In another instance, the animal is a human. In one instance, the method of raising the pH of an animal's stomach comprises administering to the said animal a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration. In one instance, the animal is an equine. In another instance, the animal is a human. In one instance, the administering a first peak in blood omeprazole concentration and a second peak in blood omeprazole concentration is achieved by administering one dose of an omeprazole DSI pharmaceutical composition.

Disclosed herein are methods of making a DSI pharmaceutical composition comprising combining one or more active pharmaceutical ingredient(s) with one or more pharmaceutically inactive compound(s) to form a pre-formulation, freezing the pre-formulation, reducing the pressure surrounding the pre-formulation, and lyophilizing the pre-formulation. In one instance, the method comprises combining one or more active pharmaceutical ingredients with bovine gelatin and water to form a pre-formulation, freezing the pre-formulation, reducing the pressure surrounding the pre-formulation, and lyophilizing the pre-formulation to form a DSI pharmaceutical composition. In one instance, the method comprises combining one or more active pharmaceutical ingredients with bovine gelatin and water and also adding at least one compound chosen from mannitol, sucralose, a flavorant and a surfactant. In one instance, the method comprises combining omeprazole with bovine gelatin, mannitol and water to form a pre-formulation, adjusting the pH of that formulation to a basic pH (e.g., between about <NUM> to <NUM>, between about <NUM> to <NUM>, or between about <NUM> to <NUM> and preferably between about <NUM>-<NUM>, or <NUM>), freezing the pre-formulation, then reducing the pressure surrounding the pre-formulation and lyophilizing the pre-formulation to form a DSI pharmaceutical composition. The preformulation may also optionally contain a pharmaceutically acceptable surfactant, a flavorant and other additives and excipients known in the pharmaceutical and veterinary arts. The components of the pre-formulation may be dissolved together in a single solution or prepared as separate solutions that are then combined to make the pre-formulation.

In one instance, the pre-formulation comprises omeprazole, bovine gelatin, mannitol, and water in about the following relative proportions by mass: <NUM>:<NUM>:<NUM>:<NUM>, respectively. For example, an omeprazole preformulation may contain about <NUM>-<NUM> mass% bovine gelatin, <NUM>-<NUM> mass% mannitol, about <NUM>-<NUM> mass% of a surfactant, about <NUM>-<NUM> mass% of a flavorant, about <NUM>-<NUM> mass% of omeprazole and about <NUM>-<NUM> mass% deionized (DI) water. A preferred prefomulation contains about <NUM>-<NUM> mass% bovine gelatin, <NUM>-<NUM> mass% mannitol, about <NUM>-<NUM> mass% of a surfactant, about <NUM>-<NUM> mass% of a flavorant, about <NUM>-<NUM> mass% of omeprazole and about <NUM>-<NUM> mass% DI water. The amount of omeprazole in a DSI pharmaceutical composition of the invention many range from about <NUM> to <NUM>, preferably from about <NUM> to <NUM>, or be about <NUM>. In one instance, the DSI pharmaceutical composition produced by the above method has a mass% of omeprazole of between about <NUM> mass% - about <NUM> mass% omeprazole.

As mentioned above, pharmaceutically acceptable surfactants may be included in a DSI pharmaceutical composition of the invention. Exemplary surfactants include, but are not limited to, sodium lauryl sulfate (SLS), sodium docusate and PEG. For DSI pharmaceutical compositions with omeprazole an anionic surfactant such as sodium docusate is generally preferred. The surfactant aids in releasing the composition from a bubble pack, e.g., preventing it from sticking to the package surface. Mixtures of surfactants may be used in a DSI pharmaceutical composition of the invention.

Any flavorant used in pharmaceutical or veterinary formulations may be used. A mint flavor is one example. Fruit flavorants, such as citrus or cherry, are another example.

Advantageously, in at least some embodiments, DSI pharmaceutical compositions according to the disclosure may ensure complete and accurate dosing with less stress for both the animal and the animal handler. Further, the methods of the disclosure may allow for higher concentrations of active ingredients, thereby minimizing the need for multiple dosing.

Effective amounts may vary according to various factors, such as, but not limited to, the general health of the animal, the degree or severity of the particular disease under treatment, the age of the animal, the organs infected or infested, and the like. In at least one instanceof the therapeutic methods disclosed herein, the amount of the DSI pharmaceutical composition is sufficient to provide therapeutic levels of the active ingredient as quickly as possible.

In one example, the active ingredient is omeprazole, the amount of said DSI pharmaceutical composition administered is that sufficient to provide about <NUM>/kg to about <NUM>/kg of active ingredient per body weight of the animal and about <NUM>/kg to about <NUM>/kg, about <NUM>/kg of active ingredient per body weight of the animal, with an approximate amount of about <NUM> - <NUM> omeprazole/dose, about <NUM> - <NUM> omeprazole/dose about <NUM> - <NUM> omeprazole/dose or about <NUM> - <NUM> omeprazole/dose, depending factors such as whether a low dose formulation or high dose formulation is needed and upon the animal being treated. For example, in humans omeprazole is administered in doses of <NUM>, <NUM>, <NUM>, and <NUM>.

In another instance, the method disclosed herein comprises administering less than about <NUM> of omeprazole to the animal per day. In some instances, the methods disclosed herein comprise administering between about <NUM> to about <NUM> of omeprazole per day or between about <NUM> to about <NUM> of omeprazole per day. In some instances, the methods disclosed herein comprise administering between about <NUM> to about <NUM> of omeprazole per day.

In some instancess, the methods and compositions of this disclosure comprise controlling the pH of an animal's stomach. For example, this disclosure includes methods of controlling the pH of an animal's stomach comprising administering omeprazole to an animal. As used herein the term controlling means maintaining a pH range that is healthy for the animal; maintaining does not necessarily include raising or lowering the pH to achieve the said healthy pH range.

In a further exemplary embodiment, the active ingredient is omeprazole and the amount of the DSI pharmaceutical composition administered is sufficient to provide omeprazole at a pH of greater than about <NUM>. In other exemplary embodiments, omeprazole is administered to the animal's non-keratinous fibers at a pH of about <NUM>.

Animals suitable for treatment in the disclosed methods include homeothermic animals, for example, humans, equine, bovine, ovine, porcine, caprine, canine, feline or the like animals. For example, the disclosed methods would provide a benefit to any animal for whom the metabolic disposition of an active pharmaceutical ingredient is found problematic, or for which initial dose titration may pose risks, or which is otherwise undesirable.

The above disclosed doses and dosage ranges are not intended to be limiting. A practitioner skilled in the art may likewise administer suitable DSI pharmaceutical compositions (e.g., immediate or rapid release formulation) in single or divided doses, according to the desired therapeutic effect. Thus, in certain clinical situations it may be desirable to administer compositions to give initial high levels of the active ingredient, followed by lower dose maintenance doses.

The preparation and characterization of DSI pharmaceutical compositions of the invention are described below. The DSI pharmaceutical compositions described below were characterized using the following tests:.

DSI pharmaceutical compositions of the invention were prepared using omeprazole as the active pharmaceutical ingredient (API). The ingredients used to manufacture the DSI pharmaceutical compositions are listed in Table <NUM>. Omeprazole was sourced from Srini Pharmaceuticals Limited, India, and all other materials were supplied by Catalent Pharmaceutical Solutions, LLC.

The DSI pharmaceutical composition was manufactured using the process described below. A <NUM> omeprazole DSI pharmaceutical composition was prepared. Table <NUM> lists the amount of each ingredient used.

Batches of DSI pharmaceutical compositions containing <NUM> of omeprazole using the manufacturing process above with the batch variations described in Table <NUM>. Units from each batch were characterized by Appearance, Load to Fracture and Disintegration Time. The results are reported in Tables <NUM>-<NUM>, respectively.

A Design of Experiments (DOE) study was performed by manufacturing and testing nine batches on a <NUM> gram wet mass scale. The DOE study, using a <NUM> level, <NUM> factor design (<NUM> experiments), varied three parameters: the amount of bovine gelatin, the amount of mannitol and the shelf temperature. A centerpoint experiment was added to the design for a total of <NUM> experiments. Table <NUM> describes the DOE study parameters in terms of the wet mass percent of bovine gelatin and mannitol and drying temperature.

The manufacturing process of Example <NUM> was used with the following process parameters: (i) the freezing step was at -<NUM> setpoint with a <NUM>. 3minute cycle; (ii) in the freeze-drying, the unit loading was at -<NUM> with a ramp rate of <NUM>-<NUM>/min to reach primary drying set-point/375mTorr; (iii) the primary drying was at -<NUM>, <NUM> or <NUM> shelf-temperature (these are the Low-Mid-High variables for the DOE) using constant vacuum of 375mTorr and a time of <NUM> hours; and (iv) the secondary drying was at a ramp rate of <NUM>-<NUM>/min to <NUM>. The DOE outputs were three sets of physical data: Appearance (Table <NUM>), Load to Fracture (Table <NUM>) and Disintegration Time (Table <NUM>).

The center-point batch (Experiment <NUM>) yielded optimal physical data, with an Appearance rating of <NUM>/<NUM> and <NUM> second disintegration time. The DOE study did not yield data supporting a formulation change from the center-point batch. However, data analysis using Minitab® software (version <NUM>) did identify a number of significant interactions. A single value of "Desirability" was determined based on the study outputs which are displayed on <FIG> (fixed shelf temp. of <NUM>), <FIG> (fixed shelf temp. of <NUM>) and <FIG> (fixed shelf temp. of -<NUM>). This DOE study did show that (i) overall, changes in gelatin concentration have a much greater effect on desirability of the DIS pharmaceutical composition of omeprazole than changes in mannitol concentration; and (ii) low level freeze drying (shelf) temperature is most favorable, yielding the best desirability scores and also an apparent robust knowledge space at the centerpoint.

Two batches of DSI pharmaceutical compositions of omeprazole, <NUM> unit, were manufactured using the method of Example <NUM> but at different pH of <NUM> and <NUM>. The tablets were packaged in Marvel Seal <NUM> aluminum sachets with <NUM> trays of <NUM> tablets each (<NUM> tablets). The DSI pharmaceutical compositions were placed on accelerated conditions to generate stability data. As is known in the art, omeprazole under certain aqueous conditions is chemically unstable. The DSI pharmaceutical compositions were stored at <NUM>/<NUM>%RH and <NUM>/<NUM>%RH storage conditions and tested on an initial (T=<NUM>), one month (T=<NUM>) and three month (T=<NUM>) time points. The testing included content uniformity (at initial time point (T=<NUM>) only) in compliance with USP <<NUM>>, Appearance, Assay, Disintegration and Load-to-fracture. The data for each batch <NUM>-<NUM> and <NUM>-<NUM> is reported in Tables <NUM>, <NUM> and <NUM>, respectively.

In the compositions and methods described herein, where a particular compound is recited, applicants contemplate isolated enantiomers and mixtures thereof in any proportions. For example, where the compound omeprazole is used, it should be understood that applicants contemplate either pure isomer and/or any mixture thereof.

It is to be understood that the foregoing description is exemplary and explanatory only.

Claim 1:
A pharmaceutical composition for direct systemic introduction (DSI) for use in treating or preventing gastric ulcers, duodenal ulcers, Zollinger-Ellison syndrome, laryngopharyngeal reflux, dyspepsia, peptic ulcer disease, gastritis, or gastroesophageal reflux in an animal needing treatment,
wherein the pharmaceutical composition for DSI comprises:
about <NUM>-<NUM> mass% bovine gelatin,
about <NUM>-<NUM> mass% mannitol,
about <NUM>-<NUM> mass% of a surfactant,
about <NUM>-<NUM> mass% of a flavorant, and
about <NUM>-<NUM> mass% of a proton pump inhibitor selected from omeprazole or
esomeprazole.