Therapeutic compositions for animals and related methods

Abstract

Therapeutic products for animals are described and discussed. The therapeutic products for animals can include animal food and a cell energy inhibitor composition combined with the animal food, and the cell energy inhibitor composition includes 3-bromopyruvic acid (3-BP), a 3-BP salt, or a combination thereof, at least one sugar for stabilizing the 3-BP molecule by substantially preventing the hydrolysis of the 3-BP molecule, and a biological buffer present in an amount sufficient to at least partially deacidify and neutralize the metabolic by-products of 3-BP.

Description

Technical Field

[0001] [Cross - Reference to Related Applications] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 391,261, filed on July 21, 2022, which is hereby incorporated by reference in its entirety.

[0002] [Sequence Listing] This application incorporates by reference herein a Sequence Listing in ST.26 XML format named 2553 - 042 - PCT_Sequence_Listing.xml, created on July 21, 2023, and having a size of 14 KB. The sequences contained in the Sequence Listing are viewable over the entire originally filed application.

Background Art

[0003] Pharmaceutical formulations have diverse physical forms and composition formulations depending on the active agent in the formulation, the route of administration, etc. For example, solid pharmaceutical formulations contain an active agent dispersed in a solid pharmaceutical carrier. Similarly, liquid pharmaceutical formulations contain an active agent dispersed in a liquid pharmaceutical carrier. Additional additives can be varied depending on whether the dosage form is liquid or solid, for example.

Brief Description of the Drawings

[0004]

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Best Mode for Carrying Out the Invention

[0005] The following detailed description includes many details for purposes of illustration, but those skilled in the art will understand that many variations and modifications to the following details are possible and are considered to be included herein. Accordingly, the following embodiments are described without losing generality with respect to any of the recited claims and without imposing limitations. It should also be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Also, the same reference numerals in different figures denote the same elements. The numbers shown in the flowcharts and processes are provided for clarity in explaining steps and operations and do not necessarily indicate a particular order or sequence.

[0006] Furthermore, the described features, structures, or characteristics can be combined in any suitable manner in one or more embodiments. In the following description, numerous specific details are provided, such as examples of layouts, distances, network examples, etc., to provide a thorough understanding of the various embodiments. However, those skilled in the relevant art will recognize that such detailed embodiments do not limit the overall concepts described herein, but merely represent them. Those skilled in the relevant art will also recognize that the technology can be implemented without one or more of the specific details, or by other methods, components, compounds, ingredients, etc. In other cases, well-known materials or operations may not be shown or described in detail to avoid obscuring aspects of the present disclosure.

[0007] In this application, terms such as "comprises", "comprising", "containing", and "having" can have the meanings considered to belong to them in the United States Patent Law, can mean "includes", "including", etc., and are generally interpreted as open-ended terms. The terms "consisting of" or "consists of" are closed terms and include only the components, structures, steps, etc. specifically listed together with such terms and those under the United States Patent Law. "Consisting essentially of" or "consists essentially of" has the meaning generally considered to belong to them under the United States Patent Law. In particular, such terms are generally closed terms, except that they can include additional items, materials, components, steps, or elements that do not significantly affect the basic and novel characteristics or functions of the items used together with such terms. For example, trace elements present in a composition but having no effect on the nature or properties of the composition may be tolerated under the term "consisting essentially of" even if not explicitly mentioned in the list of items listed after such term. When using open-ended terms such as "comprising" or "including" in this specification, direct support should be given not only to the term "consisting of" as if explicitly mentioned, but also to the term "consisting essentially of", and vice versa is understood to be the same.

[0008] As used herein, the term "substantially" means the complete or nearly complete scope or degree of an action, characteristic, attribute, state, structure, item, or result. For example, an object that is "substantially" enclosed means that the object is either completely enclosed or nearly completely enclosed. The exact degree of deviation permitted from absolute completeness may vary depending on the particular situation in some cases. However, generally speaking, being close to completion would mean that the overall result would be the same as if absolute and complete completion had been achieved. The use of "substantially" is equally applicable when used in a negative sense to indicate a complete or nearly complete absence of an action, characteristic, attribute, state, structure, item, or result. For example, a composition that is "substantially free of" particles means that the particles are either completely absent or nearly completely absent, and thus exhibits the same effect as if the particles were completely absent. In other words, a composition that is "substantially free of" a component or element may actually contain said item as long as there is no measurable impact thereof.

[0009] As used herein, the term "about" is used to provide flexibility to a given term, metric, value, range endpoint, etc. The degree of flexibility for a particular variable can be readily determined by those skilled in the art. However, unless otherwise specified, the term "about" generally provides a flexibility of less than 0.01%. It should be understood that even when the term "about" is used in conjunction with a particular numerical value herein, support is also provided for the exact numerical value mentioned separately from the term "about".

[0010] As used herein, a plurality of items, structural elements, components, and / or materials may be provided in a common list for convenience. However, such a list should be interpreted as if each member of the list were individually identified as a separate and unique member. Thus, individual members of such a list should not be construed as de facto equivalents of any other member of the same list merely because they are presented in a common group in the absence of an indication to the contrary.

[0011] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. Such a range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also all individual numerical values or sub-ranges contained within that range as if each numerical value and sub-range were explicitly recited. By way of example, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5 but also individual values and sub-ranges within the indicated range. Thus, this numerical range includes individual values such as 2, 3, and 4, sub-ranges such as 1 to 3, 2 to 4, and 3 to 5, and also 1, 1.5, 2, 2.3, 3, 3.8, 4, 4.6, 5, and 5.1 individually. The same principle applies to ranges that recite only one numerical value as a minimum or maximum value. Also, such an interpretation must apply regardless of the width or nature of the range being described.

[0012] References to "an embodiment" throughout this specification mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, appearances of the phrases "an embodiment" or "embodiments" containing various places throughout this specification are not necessarily all referring to the same embodiment or embodiments.

[0013] As used herein, the term "animal" refers to non-human animals such as mammals, birds, marsupials, etc. The term "animal" includes references to domestic animals, pets, exotic animals, racehorses and racing dogs, rabbits, rodents, or any other animal that is cared for by humans or considered to have some value to humans.

[0014] As used herein, the term "subject animal" refers to an animal to which the animal nutritional products of the present disclosure are fed.

[0015] Animals play important roles in the lives of many people, whether they are pets, food sources, means of entertainment, or otherwise. Furthermore, although not all, most animals can become ill with various diseases, nutritional disorders and / or the effects of abandonment, autoimmune diseases, pathogenic infections, cancer, etc. Due to their importance, therapeutic agents for treating such diseases have been developed. Similar to humans, cancer is one disease that can be difficult to treat in animals. The present disclosure provides compositions, systems, and methods that can be used not only to treat many of these diseases but also to act as prophylactic agents against them. Although much of the following describes cancer treatment, this is for convenience only, and it should be understood that any disease afflicting an animal that can be treated or otherwise alleviated according to the present disclosure is within the scope of the present disclosure.

[0016] As a more specific example, the present disclosure provides an animal therapeutic product comprising an animal food and a cell energy inhibitor composition combined with an animal product. Delivery of a therapeutic system to an animal such as a dog can be facilitated by mixing or otherwise combining the therapeutic composition with the animal's food and / or feed. Furthermore, such food-based therapeutic agents provide an easily measurable portion of the therapeutic composition at an appropriate dosage. In other embodiments, the therapeutic system can be delivered to the animal by conventional routes.

[0017] Furthermore, the administration methods can include inter-arterially, intravenously, intraperitoneally, inhalation, intratumorally, orally, topically, and subcutaneously. In one embodiment, the administration can be inter-arterial administration. The composition can also be delivered using a feeding tube. The intratumoral delivery methods can include techniques such as bronchoscopy, endoscopy, and / or colonoscopy, suppositories for any opening, eye drops, nasal drops, and ear drops. In one embodiment, the administration can be by intranasal delivery.

[0018] Intranasal delivery can be used to bypass the blood-brain barrier and can be particularly effective against tumors of the brain and / or spinal cord. In another embodiment, the administration can be by suppository. Suppository administration can be used for tumors in the rectal / anal region. Further, when an intratumoral injection is performed directly into the tumor / intratumorally, ultrasound imaging (or other imaging methods) can be used to assist with this injection. In one embodiment, the administration can be by direct injection, for example, into the prostate. Further, the administration can be by an enema containing the composition described herein into the rectum and / or lower intestine. Chronic perfusion for treating obstructive colon cancer, intestinal cancer, or other obstructive cancers can also be used with the composition described herein. In one embodiment, the administration can be by catheter for treating bladder cancer via the urethra. Further, intravenous delivery can be combined with hemodialysis to destroy metastatic circulating cancer cells outside the blood vessels. Further, intravenous and intraperitoneal administrations can be assisted by utilizing a port system. Further, the present composition can enable immediate release, controlled release, or time-controlled release. In the case of time-controlled release, the present composition can be delivered by implanting wafers, diamond chips, and other implantable devices near or on the tumor site.

[0019] Generally, when an anti-cancer composition is administered intra-arterially or intravenously, the administration can be for a period of about 30 minutes to about 8 hours. In one embodiment, the composition can be administered intra-arterially or intravenously over a period of about 3 hours to about 5 hours. Further, the administration of the anti-cancer composition can be part of an administration regimen. In one embodiment, the administration can include a regimen that lasts from about 1 week to 24 weeks. In another embodiment, the regimen can last from about 4 weeks to 8 weeks or longer.

[0020] Some new targeted therapies and immunotherapies have shown some success, but many cancer and disease types do not respond well to treatment and can cause significant short-term and long-term toxicity in animals. The cell energy inhibitor formulations of the present disclosure effectively treat many of the aforementioned diseases with low toxicity to animals, especially when compared to other treatments. A non-limiting example of a cell energy inhibitor is 3-bromopyruvic acid and its salt 3-bromopyruvate (collectively referred to herein as 3-BP).

[0021] In general, 3-BP is effective in regulating or otherwise eliminating abnormal and / or pathological cells, such as cancer cells and pathogenic bacteria, and therefore can be used as an anticancer, antiviral, antibacterial, antifungal, and antiparasitic agent. For example, 3-BP effectively treats many cancers by targeting the metabolic energy production mechanisms of cancer cells. While the energy metabolism of eukaryotic cells is highly complex, two major cellular energy production mechanisms are glycolysis, which occurs in the cytosol, and oxidative phosphorylation, which occurs in the mitochondria. In the cytosol, glucose is broken down into pyruvate under aerobic conditions and lactate under anaerobic conditions. Under aerobic conditions, glycolysis converts one molecule of glucose into two molecules of pyruvate (pyruvic acid), generating energy in the form of adenosine triphosphate (ATP), a molecule that provides energy to cells. In normal cells, only a small portion of total ATP production comes from glycolysis, while the majority of ATP is produced via oxidative phosphorylation in the mitochondria. On the other hand, cancer cells can experience a marked increase in cytosolic energy production via glycolysis, resulting in a significant increase in ATP production, sometimes by more than 60%.

[0022] Many types of cancer exhibit a marked increase in glycolysis, known as the "Warburg effect," a common metabolic phenotype. Cancer cells exhibiting the Warburg effect consequently increase lactate production, which is transported out of the cell via monocarboxylate transporters (MCTs). MCTs are a family of cell membrane proteins that transport molecules with a single carboxylate group, such as lactate, pyruvate, and ketones, across biological membranes. While normal cells express MCTs, cancer cells express significantly greater numbers of MCTs due to increased glycolysis and the resulting production of lactate.

[0023] The cell energy inhibitor of the present disclosure has a chemical structure sufficiently similar to lactic acid to enter cancer cells via MCT. Such a cell energy inhibitor is taken up by normal cells to a much lesser extent because the number of MSCs is extremely small. Since the cell energy inhibitor is highly reactive, it inactivates the glycolysis system and the oxidative phosphorylation system, thus inhibiting the energy production of cancer cells and rapidly depleting ATP. Without cell energy in the form of ATP, cancer cells begin to die.

[0024] Cancer can be particularly troublesome in canines. This year, over 4 million dogs are diagnosed with cancer, but only about 1 million are receiving treatment. Cancer is a major health problem in dogs, contributing to approximately 30% of the total canine deaths, and is one of the leading causes of death in dogs over 6 years old.

[0025] In the case of pet dogs, the most common treatment options are surgery, radiotherapy, chemotherapy, etc. In the case of sarcoma and anal sac adenocarcinoma, aggressive surgical resection with a wide margin is recommended, but this can lead to permanent wounds or amputations, and in the case of ASAC, it can also lead to fecal incontinence and nerve damage. All of these highly invasive canine cancers generally recur after surgery and metastasize to regional lymph nodes.

[0026] Furthermore, dogs are recommended to receive postoperative radiotherapy for 50 - 40 days, but this is costly and can lead to a shortened lifespan. Standard chemotherapy is generally recommended, but this is because it is ineffective against the disease and tends to cause unfavorable side effects. Similar to elderly humans, anesthesia for surgery and radiotherapy is risky for elderly pets. Despite aggressive treatment, the recurrence rate is high, and the overall survival period is often short, about 6 months to about one and a half years.

[0027] Many cancers afflict dogs, and among the more common types, but not limited to, are canine spindle cell soft sarcoma, anal sac adenocarcinoma, lymphoma, bone tumors, mast cell tumors, oral tumors, nasal tumors, bladder cancer, angiosarcoma, liver cancer, thyroid cancer, stomach cancer, and others.

[0028] Examples of cell energy inhibitors include lactate, iodoacetate, pyruvate, and halopyruvate, including their salts and acids. As noted above, 3-BP is an example of a useful cell energy inhibitor. 3-BP is a small molecule with a chemical structure similar enough to lactate to enter cancer cells through an upregulated MCT transport system. Once inside cancer cells, 3-BP, due to its highly reactive nature, damages the glycolytic and oxidative phosphorylation systems, thus significantly reducing ATP production. This reduction in ATP production subsequently leads to the death of cancer cells. Therefore, 3-BP has a direct therapeutic effect on cancer cells due to its ability to inhibit energy production within cancer cells.

[0029] In one embodiment, the cell energy inhibitor can be a molecule according to Formula I:

Chemical formula

[0030] In some embodiments, the cell energy inhibitor composition can include various excipients, active agents, prodrugs, metabolites, buffers, etc., such as, for example, one or more sugars, polyhydric alcohols, glycolysis inhibitors, biological buffers, etc. In some embodiments, the cell energy inhibitor molecule can be formulated in the composition with at least one sugar that can substantially prevent the hydrolysis of the cell energy inhibitor, thereby stabilizing the cell energy inhibitor.

[0031] In one embodiment, R in formula (I) is OH or O (-) and X in formula (I) can be nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, amine oxide, etc. Further, X can be a halide, for example, fluoride, bromide, chloride, iodide, etc. In one embodiment, X can be a sulfonate, for example, triflate, mesylate, tosylate, etc. In another embodiment, X can be an amine oxide. In yet another embodiment, the amine oxide can be dimethylamine oxide.

[0032] In another embodiment, the cell energy inhibitor can be 3-halopyruvate, for example, 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate, 3-iodopyruvate, or a combination thereof. The general structure showing the halide at the 3-position is represented by formula II.

Chemical formula

[0033] In a further non-limiting embodiment, the cell energy inhibitor can have bromine at the 3-position as shown in formula III.

Chemical formula

[0034] In one further non-limiting embodiment, R of the cell energy inhibitor of formula III is O as shown in formula IV(-) , may be (3-bromopyruvate).

Chemical formula

[0035] In another non-limiting example, R of the cell energy inhibitor of formula III may be OH (3-bromopyruvic acid) as shown in formula V.

Chemical formula

[0036] 3-Bromopyruvate or 3-bromopyruvic acid may be referred to herein as "3-BP", and it should be noted that these two molecules can be used interchangeably unless otherwise clearly indicated in the context.

[0037] Generally, 3-BP can be formulated as any type of dosage form that can be delivered to a subject. Such dosage forms can be enteral, parenteral, transdermal, etc. Enteral dosage forms can be sustained release or immediate release, and include, but are not limited to, tablets, troches, capsules, caplets, encapsulated pellet agents, encapsulated granules, encapsulated powders, gelatin capsules, liquids, syrups, elixirs, suspensions, sprays, aerosols, powders, etc., and combinations thereof. Non-limiting examples of transdermal dosage forms include lotions, gels, creams, pastes, ointments, liquid sprays, liquid drops, powder sprays, wipes, emulsions, aerosols, transmucosal tablets, adhesive devices, adhesive matrix transdermal patches, liquid reservoir transdermal patches, microneedle devices, magnetic devices, etc. Non-limiting examples of parenteral dosage forms include intravenous, subcutaneous, etc.

[0038] In one embodiment, the 3-BP composition of the present disclosure can be formulated in a composition having at least one sugar that can stabilize 3-BP molecules by substantially preventing the hydrolysis of 3-BP molecules. In other embodiments, the 3-BP composition contains multiple sugars to stabilize 3-BP molecules. The multiple sugars can include at least two sugars, at least three sugars, and the like.

[0039] Although various sugars are contemplated, in some embodiments, examples of the sugar can include monosaccharides, disaccharides, oligosaccharides, or combinations thereof. Non-limiting examples of monosaccharides can include glucose, fructose, galactose, and the like. Non-limiting examples of disaccharides can include sucrose, lactose, maltose, and the like. It should be noted that for the purposes of the present disclosure, the term "sugar" can also include similar molecules such as oligosaccharides, polysaccharides, polyols, polyhydric alcohols, and glycerol that function to stabilize 3-BP. Examples of the sugar can include 3-carbon sugars, 4-carbon sugars, 5-carbon sugars, 6-carbon sugars, 7-carbon sugars, and the like, including combinations thereof. In one aspect, the sugar can be non-metabolic.

[0040] In one embodiment, the sugar is gluconic acid. In another embodiment, the sugar is glucuronic acid. In another embodiment, at least one of the sugars is a pentose sugar. In another embodiment, at least two of the sugars are pentose sugars. The pentose sugar can be independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, etc., including combinations thereof. In another embodiment, at least one of the sugars can be glycerol. In another embodiment, the sugars are glycerol, inositol, and sorbitol. Other non-limiting examples of sugars include ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetraitol, and polyglycitols, including combinations thereof. In one embodiment, the sugars include glycerol, inositol, sorbitol, mannitol, or any combination thereof. In another embodiment, the sugars include glycerol, inositol, sorbitol, or any combination thereof. In other embodiments, the sugar is a polyhydric alcohol.

[0041] The sugars described herein may be any isomer. In one embodiment, the compositions described herein can include a form of sugar that has lower biological activity compared to its isomer. In certain cases, the sugar with lower biological activity may be an L-enantiomer sugar. However, if it is found that the D-enantiomer sugar has lower biological activity compared to its L-form, the D-form can be used. In one embodiment, such sugars can function as glycolysis inhibitors.

[0042] In one embodiment, the composition comprises one or more sugars in the range of about 0.5 wt% to about 50.0 wt%, or about 1.0 wt% to about 25.5 wt%. In yet another embodiment, the composition comprises one or more sugars in the range of about 0.2 wt% to about 75.0 wt%, or about 0.5 wt% to about 50.0 wt%. In a further embodiment, the composition comprises one or more sugars in the range of about 0.1 wt% to about 25.0 wt%, about 0.2 wt% to about 10.0 wt%.

[0043] In some embodiments, the composition comprises glycerol in the range of about 0.1 wt% to about 5.0 wt%, or about 0.1 wt% to about 3.0 wt%. In other embodiments, the composition comprises inositol in the range of about 0.1 wt% to about 10 wt%, about 0.1 wt% to about 6 wt%. In a further embodiment, the composition comprises sorbitol in the range of about 0.1 wt% to about 40.0 wt%, or about 0.1 wt% to about 30 wt%. In still a further embodiment, the composition comprises mannitol in the range of about 0.1 wt% to about 30 wt%, or about 0.1 wt% to about 10 wt%. Additionally, each sugar may be added to the formulation or composition in a volume up to the maximum solubility of the sugar. It should also be noted that the weight percentages of the aforementioned components do not include water or other liquid carriers. Further, each sugar can be added to the formulation or composition in a volume up to the maximum solubility of the sugar.

[0044] The 3-BP composition can contain a biological buffer present in an amount sufficient to at least partially deacidify the cell energy inhibitor and neutralize the metabolic by-products of the cell energy inhibitor. Non-limiting examples of biological buffers can include citrate buffers, phosphate buffers, acetate buffers, etc., including combinations thereof. In a specific embodiment, the biological buffer can be a citrate buffer, for example, but not limited to, sodium citrate. In another specific embodiment, the biological buffer can be a phosphate buffer, for example, but not limited to, sodium phosphate. In a specific embodiment, the biological buffer can be an acetate buffer, for example, but not limited to, sodium acetate. In still other embodiments, the biological buffer can include at least two biological buffers, for example, but not limited to, a citrate buffer and an acetate buffer, a citrate buffer and a phosphate buffer, an acetate buffer and a phosphate buffer, or a citrate buffer, a phosphate buffer, and an acetate buffer.

[0045] In some embodiments, the composition can contain a biological buffer at a concentration of about 0.1 mM to about 200 mM. In one embodiment, the composition can contain a biological buffer at a concentration of about 1 mM to about 20 mM. In some embodiments, the composition can contain the biological buffer in the range of about 0.1 wt% to about 15 wt%, or about 2.0 wt% to about 8.0 wt%. Further, the biological buffer can maintain a physiological pH of 4.0 to 8.5. In one embodiment, the biological buffer can maintain a physiological pH of 5.5 to 8.0. In another embodiment, the biological buffer can maintain a physiological pH of 6.8 to 7.8. In still another embodiment, the biological buffer can maintain a physiological pH of 7.3 to 7.6. Also, note that the weight percentages of the components described above do not include water or other liquid carriers.

[0046] In some embodiments, the 3-BP formulations of the present invention may include, but are not limited to, antifungal agents, antibiotics, glycolysis inhibitors, mitochondrial inhibitors, sugars, and biological buffers. Examples of such agents include amphotericin B, efrapeptin, doxorubicin, (2-DG), 2-DG analogs, d-lactic acid, dichloroacetic acid (or salt forms of dichloroacetate), oligomycin, oligomycin analogs, glycerol, inositol, sorbitol, glycol, erythritol, threitol, arabinitol, xylitol, ribitol, mannitol, dulcitol, iditol, isomalt, maltitol, lactitol, polyglycitols, sodium phosphate, sodium citrate, sodium acetate, sodium carbonate, sodium bicarbonate, sodium pyruvate, sodium lactate, oxaloacetate, isocitrate, aconitate, succinate, fumarate, malate, diluted saline having various concentrations of NaCl, and water, among others. In addition to sodium ions associated with these biological buffers, calcium and potassium cations may also be associated with the biological buffers. Various active agents of the composition may include cell energy inhibitors, glycolysis inhibitors, mitochondrial inhibitors, halo monocarboxylate compounds, antifungal agents, antibiotic formulations, and the like. In the various dosage forms described above, any of the above components may be included together with either 3-BP or an excipient, or in a separate container.

[0047] In addition to the foregoing components, the 3-BP composition described herein may further include a halogenated monocarboxylate compound separated from the cell energy inhibitor. When the halogenated monocarboxylate compound can function to inhibit glycolysis and / or mitochondrial function, the halogenated monocarboxylate can be considered a second cell energy inhibitor. In one embodiment, the halogenated monocarboxylate compound may be a (halo two-carbon) monocarboxylate compound in which the carbon at the 2-position is halogenated. The monocarboxylate compound in which the carbon at the 2-position is halogenated may be selected from, but not limited to, 2-fluoroacetate, 2-chloroacetate, 2-bromoacetate, 2-iodoacetate, etc., and combinations thereof are also included. In one embodiment, the monocarboxylate compound in which the carbon at the 2-position is halogenated may be 2-bromoacetate. In one example, the composition may contain the monocarboxylate compound in which the carbon at the 2-position is halogenated at a concentration of about 0.01 mM to about 5.0 mM. In another example, the composition may contain the monocarboxylate compound in which the carbon at the 2-position is halogenated at a concentration of about 0.1 mM to about 0.5 mM.

[0048] Furthermore, the halogenated monocarboxylate compound may be a monocarboxylate compound in which the carbon at the 3-position is halogenated. In one embodiment, the monocarboxylate compound in which the carbon at the 3-position is halogenated may be selected from, but not limited to, 3-fluorolactate, 3-chlorolactate, 3-bromolactate, 3-iodolactate, etc., and combinations thereof are also included. In another example, the composition may contain the monocarboxylate compound in which the carbon at the 3-position is halogenated at a concentration of about 0.5 mM to about 250 mM. In one embodiment, the composition may contain the monocarboxylate compound in which the carbon at the 3-position is halogenated at a concentration of about 10 mM to about 50 mM.

[0049] In some embodiments, the 3-BP formulations described herein may further include a mitochondrial inhibitor in addition to the cell energy inhibitor. The mitochondrial inhibitor may be selected from, but not limited to, oligomycin, efrapeptin, aurovertin, etc., and combinations thereof are also included. In another embodiment, the composition may include the mitochondrial inhibitor at a concentration of about 0.001 mM to about 5.0 mM. In one embodiment, the composition may include the mitochondrial inhibitor at a concentration of about 0.01 mM to about 0.5 mM.

[0050] In some embodiments, the 3-BP composition described herein may further include an antifungal agent and / or an antibacterial agent. In one embodiment, the composition may individually include the antifungal agent and / or the antibacterial agent at a concentration of about 0.01 mM to about 5.0 mM. In another embodiment, the composition may individually include the antifungal agent and / or the antibacterial agent at a concentration of about 0.05 mM to about 0.5 mM.

[0051] In some embodiments, the 3-BP formulation can include a glycolysis inhibitor. Although many suitable glycolysis inhibitors are contemplated, a non-limiting list may include 2-DG, lonidamine, imatinib, oxythiamine, 6-aminonicotinamide, genistein, 5-thioglucose (5-TG), mannoheptulose, α-chlorohydrin, ornidazole, oxalate, glufosfamide, etc., and combinations thereof are also included. The 3-BP formulation can include any effective amount of the glycolysis inhibitor.

[0052] In addition to the above concentrations, the present composition may have various ratios of the components described herein. In one embodiment, the cell energy inhibitor and the biological buffer may be present in a ratio in the range of 1:1 to 1:5 mM. In another embodiment, the cell energy inhibitor and the glycolysis inhibitor may be present in a ratio in the range of 5:1 to 1:1 mM. In yet another embodiment, the cell energy inhibitor and at least one sugar are present in a ratio in the range of 1:1 to 1:5 mM. In yet another embodiment, the cell energy inhibitor and the monocarboxylate compound with a halogenated carbon at the 2-position may be present in a ratio in the range of 20:1 to 4:1 mM. In yet another embodiment, the cell energy inhibitor and the mitochondrial inhibitor may be present in a ratio in the range of 20:1 to 40:1 mM.

[0053] In some examples, the 3-BP composition described herein may further comprise a hexokinase inhibitor. The hexokinase inhibitor may be any molecule that inhibits hexokinase 1, hexokinase 2, and / or its isoenzymes (collectively referred to herein as "hexokinase"). As used herein, "hexokinase 1" or "hexokinase 1 isozyme" refers to any isoform of hexokinase 1 and its naturally known variants, including those provided by SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 4.

Table 1

Table 2

Table 3

Table 4

[0054] As used herein, "hexokinase 2" or "hexokinase 2 isozyme" refers to any isoform of hexokinase 2 and its naturally known variants, including those provided by SEQ ID NO: 5 below. [Table 5]

[0055] As described above, the major source of ATP production occurs in the mitochondria of normal cells. However, in cancer cells, ATP production by glycolysis is significantly upregulated. One reason for this upregulation is that hexokinase molecules bind to the voltage-dependent anion channel (VDAC) in ATP synthasomes to form a complex with it, forming so-called "ATP synthasome mega complexes". When such ATP synthasome mega complexes are formed, cancer cells become immortalized and can continuously use the cell's energy production process for cancer growth. Therefore, hexokinase inhibitors can block hexokinase from binding to VADC or move hexokinase molecules from VADC of pre-formed ATP synthasome mega complexes.

[0056] In one embodiment, the hexokinase inhibitor may be up to 25 amino acid units from the N-terminal region of hexokinase 2 isozyme or hexokinase 1 isozyme. In another embodiment, the hexokinase inhibitor may be an amino acid sequence of 5 to 20 amino acid units, and at this time, the 5 to 20 amino acid sequence is present in the first 25 amino acid unit region starting from the N-terminus of hexokinase 1 isozyme or hexokinase 2 isozyme. In one embodiment, the 5 to 20 amino acid sequence may be any 5 to 20 amino acid sequence present in the first 25 amino acid unit region at the N-terminus of hexokinase 11 (Hexokinase 11) or hexokinase 2. Such an amino acid sequence can replace the hexokinase bound to the cell or competitively bind to the voltage-dependent anion channel (VDAC) to prevent the initial hexokinase binding.

[0057] In other embodiments, the hexokinase inhibitor can include an antibody against a portion of HK1 or HK2, such as the N-terminal region of the HK1 or HK2 molecule. In one specific embodiment, the hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 6 corresponding to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 1) having the following sequence.

Table 6

[0058] In another embodiment, the hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 7 corresponding to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 2) having the following sequence.

Table 7

[0059] In yet another embodiment, the hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 8 corresponding to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 3) having the following sequence.

Table 8

[0060] In yet another embodiment, the hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 9 corresponding to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 4) having the following sequence.

Table 9

[0061] In yet another embodiment, the hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 10 corresponding to the first 25 amino acids from the N-terminus of hexokinase 2 having the following sequence.

Table 10

[0062] Additional hexokinase inhibitors may be the hexokinase inhibitors disclosed in U.S. Patent No. 5,854,067 (issued to Newgard et al. on December 29, 1998) and / or U.S. Patent No. 5,891,717 (issued to Newgard et al. on April 6, 1999), both of which are incorporated herein by reference in their entirety. Additional hexokinase inhibitors that may be used in the present formulation include those disclosed in U.S. Patent No. 6,670,330; U.S. Patent No. 6,218,435; No. 5,824,665; No. 5,652,273; and No. 5,643,883; as well as U.S. Patent Application Publication No. 20030072814; No. 20020077300; and No. 20020035071, the entire texts of the aforementioned patent publications and patent applications are incorporated herein by reference, respectively.

[0063] In one embodiment, the composition can promote the starvation of cancer cells by containing amino acids with lower biological activity compared to isomers. In one aspect, the amino acid with lower biological activity can be a D - amino acid. However, if the L - amino acid has even lower biological activity than the D - form, the L - amino acid may be used.

[0064] In one embodiment, the composition may contain a DNA replication inhibitor, a DNA binding inhibitor, and / or a DNA transcription inhibitor. In another embodiment, the composition may contain an inhibitor related to the cell cycle, growth, and / or proliferation. In yet another embodiment, the composition may contain an inhibitor against a signal transduction pathway. In still another embodiment, the composition may contain an inhibitor of angiogenesis. In still another embodiment, the composition may contain small RNAs that interfere with normal gene regulation, such as antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, small interfering RNA, etc. In still another embodiment, the composition may contain nutritional supplements including vitamin C; vitamins, CoQ10, flavonoids, free fatty acids, alpha - lipoic acid, acai, goji, mango, pomegranate, L - carnitine, selenium, etc.

[0065] In one example, the 3 - composition can contain 3 - BP in an amount of about 0.01 wt% to about 2.0 wt%, about 0.1 wt% to about 1.6 wt%.

[0066] Therapeutic products for animals can be formed in various shapes and sizes, which may, in some cases, depend on the preferences of the animal or the owner. Further, the shape and / or size of the food form may depend on the size and / or structure of the animal's mouth. Non - limiting examples can include food forms such as pate, cubes, spheres, cylinders, disks, flakes, sheets, pellets, bone shapes, flat shapes, etc.

[0067] As described above, the cell energy inhibitor can be associated with animal food ingredients in various ways. In a specific example, an animal therapeutic product can include an animal food ingredient together with a cell energy inhibitor that is packaged and ready to be applied to the animal food ingredient. By separating the animal food ingredient from the cell energy inhibitor, the efficacy of the cell energy inhibitor can be prolonged. In the case of the 3-BP formulation, for example, the 3-BP composition can be packaged such that the animal food ingredient and the 3-BP composition do not contact each other. In one example, the 3-BP composition and the animal food ingredient can be isolated from each other within the same package. To administer the animal therapeutic product to an animal, the owner can open the package, apply the 3-BP composition to the animal food ingredient, and administer the animal nutritional product to the target animal. The components of the 3-BP composition can be pre-mixed together or separately packaged so that they can be mixed by the owner. In some cases, one or more components can be pre-mixed with 3-BP and one or more components can be separately packaged. For example, in a 3-BP composition containing a biological buffer, 3-BP and sugar can be packaged together separately from the biological buffer. Once ready for use, the owner can mix the buffer with the mixture of 3-BP and sugar, apply the e-BP composition to the animal food ingredient, and administer the resulting animal therapeutic product to the target animal.

[0068] In some examples, the 3-BP compositions described herein can further include various components described below. In various dosage forms known to those skilled in the art, any of these various components can be mixed with 3-BP if they are non-reactive with 3-BP, and can be present in a separate layer or any of the layers described above if the components are reactively isolated in the storage form.

[0069] As an example, an animal therapeutic product may include food ingredients that may, in some cases, be appropriate for ingestion and digestion by a given animal of interest, and that may be the majority of food ingredients (or food ingredients that make up the majority by weight of the animal therapeutic product). The animal therapeutic product further includes a cell energy inhibitor associated with the animal food ingredient. The cell energy inhibitor is associated with the animal food ingredient during the manufacture of the animal food ingredient. Various techniques for associating the cell energy inhibitor with the animal food ingredient are contemplated, such as, but not limited to, techniques such as mixing, layering, coating, encapsulating, spraying, atomizing, etc., which may include techniques that combine two or more of the foregoing where appropriate.

[0070] The present disclosure provides animal therapeutic products, animal nutraceuticals for animal products, animal treatment systems, and various methods of use. Without intending to be bound by any scientific theory, such products, nutraceuticals, and systems may be used to treat animals for disease or other ailments, used as adjuvants, used as prophylactics, or combinations thereof. Such effects may further include enhancement of relevant physiological systems such as the immune system.

[0071] As an example, an animal therapeutic product may include food ingredients that may, in some cases, be appropriate for ingestion and digestion by a given animal of interest, and that may be the majority of food ingredients (or food ingredients that make up the majority by weight of the animal therapeutic product). The animal therapeutic product further includes a cell energy inhibitor associated with the animal food ingredient. The cell energy inhibitor is associated with the animal food ingredient during the manufacture of the animal food ingredient. Various techniques for associating the cell energy inhibitor with the animal food ingredient are contemplated, such as, but not limited to, techniques such as mixing, layering, coating, encapsulating, spraying, atomizing, etc., which may include techniques that combine two or more of the foregoing where appropriate.

[0072] In another embodiment, the cell energy inhibitor may be associated with the animal food ingredient at some point along the distribution network from the manufacturer to the animal owner after manufacture of the animal food ingredient, for example, by a supplier or a vendor. Various techniques for associating the cell energy inhibitor with the animal food ingredient by an entity along the distribution network are contemplated, for example, but not limited to, techniques such as mixing, layering, coating, encapsulation, sprinkling, spraying, etc., which may include techniques that combine two or more of the foregoing when appropriate. Note that the associating techniques available to an entity are likely to depend on the sophistication and / or technical resources available to that entity.

[0073] In yet another embodiment, the cell energy inhibitor may be associated with the animal food ingredient at the level of ownership and / or care (hereinafter "ownership") of the subject animal. In such a case, the animal therapeutic product is obtained as a multi-component product by the owner / caregiver (hereinafter, "owner"). Thus, the association between the cell energy inhibitor and the animal food ingredient is affected by the owner physically combining the two components with each other prior to feeding the subject animal. The possible associating techniques will depend on the knowledge and / or technical resources available to the owner, but may potentially include, but are not limited to, mixing, layering, coating, encapsulation, sprinkling, spraying, etc., which may include techniques that combine two or more of the foregoing when appropriate.

[0074] In one embodiment, as shown in FIG. 1, the animal therapeutic product 100 can include an animal food ingredient 102 surrounded by a layer or coating (hereinafter referred to as a "layer") of a cell energy inhibitor 104. Depending on the nature of the cell energy inhibitor and the design of the resulting animal therapeutic product, the layer or coating of the cell energy inhibitor can be a solid layer, a semi-solid layer, etc. The layer can be continuous or discontinuous, and can have a thickness that delivers an appropriate amount of the cell energy inhibitor to the target animal. With respect to continuity, the layer can be a continuous layer extending across one or more sides / surfaces of the animal therapeutic product. A discontinuous layer can be a layer having gaps or substantially thinner portions over at least a portion of its surface. For example, by spraying and light spraying, a discontinuous cell energy inhibitor layer or a layer having discontinuous portions can be formed.

[0075] In another embodiment, as shown in FIG. 2, the animal therapeutic product 200 can include an animal food ingredient 202 surrounded by a plurality of layers 204, 206. Each of the layers 204 and 206 can be a separate component of the cell energy inhibitor, or one of 204 or 206 can contain the cell energy inhibitor and the other can be a separate component or a non-immunogenic component. Depending on the nature of the cell energy inhibitor and the design of the resulting animal therapeutic product, the layer or coating of the cell energy inhibitor can independently be a solid layer, a semi-solid layer, etc.

[0076] In more specific embodiments, the plurality of layers 204 and 206 can be separate components of the cell energy inhibitor. In one such configuration, the outer layer 206 can be a component of the cell energy inhibitor that is reactive with the animal food component 202 and thus separated from the animal food component 202 by another component of the cell energy inhibitor that is non-reactive or less reactive compared to the outer layer component. In another configuration, the components of the cell energy inhibitor may react with each other and thus be maintained separately until degraded by the subject animal. In such cases, a third layer can also be disposed between the two layers 204 and 206 (not shown). In other configurations, the component of the inner layer 204 can be a semi-solid, gel, or liquid, and the component of the outer layer 206 closes in the component of the inner layer 204 in contact with the animal food component 202.

[0077] In another embodiment, as shown in FIG. 3, the animal therapeutic product 300 can include an animal food component 302 in which a cell energy inhibitor 304 is mixed throughout at least a portion of the animal food component 302. The cell energy inhibitor 304 can be uniformly dispersed throughout the animal food component 302, uniformly dispersed throughout a portion of the animal food component, or non-uniformly dispersed throughout a portion of the animal food component 302 or may be non-uniformly dispersed throughout a portion of the animal food component 302. In some cases, the cell energy inhibitor 304 may further not be present in one or more portions of the animal food component 302.

[0078] In yet another embodiment, as shown in FIG. 4, the animal therapeutic product 400 can include an animal food component 402 having a cell energy inhibitor 404 that includes an outer layer 406, where the outer layer is a component of the cell energy inhibitor 404 or a separate component. In one such configuration, the outer layer 406 can be a component of the cell energy inhibitor that is reactive with the animal food component 402 and thus separated from the animal food component 402 by another component of the cell energy inhibitor that is non-reactive or less reactive compared to the outer layer component. In another configuration, the components of the cell energy inhibitor can react with each other and thus be maintained separately until degraded by the subject animal. In such a case, a third layer can also be disposed between the animal food component 404 and the outer layer 406 (not shown). In other configurations, the components of the inner portion 404 can be semi-solid, gel, or liquid, and the components of the outer layer 206 enclose the components of the inner portion 404 in contact with the animal food component 402.

[0079] In a further embodiment, as shown in FIG. 5, the animal therapeutic product 500 can include an animal food component 502 surrounding a cell energy inhibitor 504. In this configuration, the cell energy inhibitor 504 can contact the animal food component 502, or an intervening layer can be disposed therebetween (not shown). In one example, the cell energy inhibitor 504 can be solid or substantially solid. In another example, the cell energy inhibitor 504 can be a semi-solid, gel, or liquid contained by the animal food component 502.

[0080] The shelf life of animal food ingredients and / or 3-BP compositions can be improved by packaging them, in some cases, in a light-shielded, oxygen-free environment. For some components of animal therapeutic products, packaging that substantially excludes moisture can also be beneficial. An example of packaging is Alu-Plastic packaging (e.g., Alu-Plastic blister packs), which can be used to seal components of animal therapeutic products in a substantially oxygen-free environment where light exposure is not harmful to the cell energy inhibitor. However, some cell energy inhibitors may be sensitive to light, and thus packaging that minimizes light exposure can extend the shelf life of this component of animal therapeutic products. 3-BP is an example of a cell energy inhibitor that benefits from an environment without light. Such an environment without light and oxygen can be provided using Alu-Alu packaging (e.g., Alu-Alu blister packs) where layers of aluminum foil cover both sides of the package.

[0081] Furthermore, animal therapeutic products can be packaged to be refrigerated, frozen, or maintained at room temperature. In some cases, the temperature at which an animal therapeutic product is stored can affect its shelf life, which can be important or unimportant to the owner depending on the intended shelf life before use.

[0082] In the embodiments shown in FIGS. 6A and 6B, a package used to contain an animal nutrition product is shown. FIG. 6A shows, for example, a package 602 having a first compartment 604 for containing an animal food ingredient 606. This packaging can be any suitable type of packaging including, for example, Alu-Plastic, Alu-Alu, etc. Package 602 further includes a second compartment 608 that hermetically contains a cell energy inhibitor 610 therein. FIG. 6B shows an embodiment of a package 602 having a first compartment 604 for containing an animal food ingredient 606. The packaging can be any suitable type of packaging including, for example, Alu-Plastic, Alu-Alu, etc. Package 602 further includes a second compartment 612 and a third compartment 614. The second compartment 618 contains one or more components of 3-BP and a cell energy inhibitor, and the third compartment 614 contains one or more components of the cell energy inhibitor, each being hermetically sealed therein separately.

Example

[0083] Example 1: Dog No. 1 A dog with inoperable spontaneous soft tissue sarcoma was treated with a 3-BP composition by both oral and IV routes. The sarcoma initially had a tumor volume of 263.9 cm 3 and was highly angiogenic and invasive. The tumor volume decreased to 69.3 (74%) after 11 intertumoral injections of the 3-BP composition over a 4-month period.

[0084] FIG. 7 shows the course of Dog No. 1 during the treatment period. The image shows the tumor size (cm 3 ) along the y-axis measured at 13 observation days on the x-axis. The data point labels represent the injection amounts of the 3-BP composition. The tumor volume decreased by 97% after the 13th injection.

[0085] Example 2: Dog No. 2 Dog 2 was treated with the 3-BP composition via the oral and intratumoral routes for anal sac adenocarcinoma. This adenocarcinoma was aggressive and doubling every two weeks. The tumor decreased in volume over time as well as with the regular administration of the 3-BP composition, from 67 cm 3 to 4 cm 3 on day 237. Figure 8 shows the tumor size (cm 3 ) along the y-axis measured at 11 observation days on the x-axis. The data point labels represent the infusion amount of the 3-BP composition.

[0086] Example 3: Dog 3 Dog 3 was treated with the 3-BP composition via oral administration for sarcoma. The sarcoma initially had a size of 10×8×5 cm and was a hard, fixed sarcoma on the midline near the chest. The tumor had ruptured as shown in Figure 9A. Dog 3 showed anorexia, lethargy, and depression. Oral administration of 3-BP was started at the initial observation and continued for 4 months. After the first month, the tumor shrank to a size of 5×4×3 cm, showing dramatic improvement (see Figure 9B). As shown in Figure 9C, the tumor softened and the ruptured part was still healing. The vitality and appetite of Dog 3 improved. After using oral 3-BP for 4 months, the tumor no longer existed, and only scar tissue and some extra skill remained after 8 months.

[0087] The following examples relate to specific embodiments and point out specific features, elements, or steps that are used in achieving such embodiments or that can be otherwise combined.

[0088] In one example, the veterinary therapeutic product can include a food component and a cell energy inhibitor combined with the food component. The cell energy inhibitor can be, for example, a 3-halopyruvate molecule according to Formula I

Chemical formula

[0089] In another embodiment, the cell energy inhibitor is a 3-bromopyruvate (3-BP) molecule according to formula (II)

Chemical formula

[0090] In one embodiment, the animal nutrition product is a dog food formulation. Such dog food formulations can include a cell energy inhibitor and a protein. Non-limiting examples of suitable proteins can include meat, appetein, serum, plasma, albumin, globulin, etc., including mixtures thereof. Suitable meat proteins can include, but are not limited to, chicken, fish, beef, lamb, duck, etc., including combinations thereof. Dog food formulations can further include various additional ingredients that can vary depending on a given dog food formulation. Such ingredients can include, but are not limited to, carbohydrates, fruits, vegetables, grains, fatty acids, etc., including combinations thereof.

[0091] In another embodiment, the animal nutrition product is a cat food formulation. Such cat food formulations can include a cell energy inhibitor and a protein such as meat protein, flaxseed meal, etc., including combinations thereof. Meat proteins can include, but are not limited to, any meat protein such as chicken, fish, beef, lamb, duck, etc., including combinations thereof. Cat food formulations can further include various additional ingredients that can vary depending on a given cat food formulation. Such ingredients can include, but are not limited to, carbohydrates, fruits, grains, fatty acids, omega-3 fatty acids, eggs, etc., including combinations thereof.

[0092] In another embodiment, the animal nutrition product is a bird food formulation. Such a bird food formulation can include a cell energy inhibitor and various ingredients such as, for example, seeds, nuts, cracked corn, millet, dried fruits, and combinations thereof.

[0093] In another embodiment, the animal nutrition product is livestock feed. Such a livestock feed formulation can include a cell energy inhibitor and livestock feed ingredients. The livestock feed ingredients can vary widely depending on the owner's preference and the nature of the livestock. General examples of livestock feed ingredients include, but are not limited to, corn, soybean meal, dry and wet distillers grains, bakery meal, corn gluten feed, cottonseed meal, wheat midds, grain sorghum, soybean hulls, oats, fruits, animal protein products, seafood, dairy products, wheat products, and combinations thereof.

[0094] In another embodiment, the animal nutrition product is horse feed. Such a horse feed formulation can include a cell energy inhibitor and horse feed ingredients. The horse feed ingredients can vary widely depending on the owner's preference and the nature of the horse. General examples of horse feed ingredients include, but are not limited to, grains such as oats, barley, corn, rice or wheat, and by-products of these grains such as corn distillers grains, rice bran or wheat midds, pasture hay, weet and oaten hay and chaff, sunflower meal, cottonseed meal, soybean meal, molasses (wheat product) horse feed, horse pellets, fruits, and combinations thereof.

[0095] In one embodiment, at least one sugar can be selected from gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo-inositol, glycerol, ethylene glycol, trehalose, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetraitol, polyglycitols, or combinations thereof.

[0096] In one embodiment, at least one sugar can be a pentose.

[0097] In one embodiment, at least one sugar can be at least two pentoses.

[0098] In one embodiment, the cell energy inhibitor can include a second sugar selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo-inositol, sorbitol, and combinations thereof.

[0099] In one embodiment, the cell energy inhibitor can include a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo-inositol, sorbitol, and combinations thereof.

[0100] In one embodiment, at least one sugar can include glycerol, myo-inositol, and sorbitol.

[0101] In one embodiment, the cell energy inhibitor can include one or more sugars in the range of about 0.5 wt% to about 50.0 wt%, or about 1.0 wt% to about 25.5 wt%. In yet another embodiment, the cell energy inhibitor can include one or more sugars in the range of about 0.2 wt% to about 75.0 wt%, or about 0.5 wt% to about 50.0 wt%. In a further embodiment, the cell energy inhibitor can include one or more sugars in the range of about 0.1 wt% to about 25.0 wt%, about 0.2 wt% to about 10.0 wt%.

[0102] In some embodiments, the cell energy inhibitor can include glycerol in the range of about 0.1 wt% to about 5.0 wt%, or about 0.1 wt% to about 3.0 wt%. In other embodiments, the cell energy inhibitor can include inositol in the range of about 0.1 wt% to about 10 wt%, about 0.1 wt% to about 6 wt%. In a further embodiment, the cell energy inhibitor can include sorbitol in the range of about 0.1 wt% to about 40.0 wt%, or about 0.1 wt% to about 30 wt%. In yet another embodiment, the cell energy inhibitor can include mannitol in the range of about 0.1 wt% to about 30 wt%, or about 0.1 wt% to about 10 wt%. Further, each of the sugars can be added in a volume up to the maximum solubility of the sugar in the formulation or the cell energy inhibitor.

[0103] In one embodiment, the cell energy inhibitor can include d-lactic acid and epinephrine.

[0104] In one embodiment, the cell energy inhibitor can include a biological buffer present in an amount sufficient to at least partially deacidify and neutralize the metabolic by-products of the 3-BP molecule.

[0105] In one embodiment, the biological buffer is selected from one or more of citrate buffer, phosphate buffer, and acetate buffer.

[0106] In one embodiment, the biological buffer is a citrate buffer.

[0107] In one embodiment, the biological buffer is a phosphate buffer.

[0108] In one embodiment, the animal nutrition product is used to treat cancer diseases in animals.

[0109] In another embodiment, the animal therapeutic product is used as an adjuvant for preventing cancer diseases in animals.

[0110] In one embodiment, a method for treating an animal for a disease is provided, which includes delivering to the animal an animal therapeutic product comprising a food component and a cell energy inhibitor combined with the food component, and causing the animal to ingest the animal therapeutic product. The cell energy inhibitor can be, for example, 3-bromopyruvic acid according to formula I and / or its salt 3-bromopyruvate (collectively referred to as 3-BP),

Chemical formula

[0111] In one embodiment, the animal nutrition product is a dog food formulation. Such a dog food formulation can include a cell energy inhibitor and a protein. Non-limiting examples of suitable proteins can include meat, appetein, serum, plasma, albumin, globulin, etc., including mixtures thereof. Suitable meat proteins can include, but are not limited to, chicken, fish, beef, lamb, duck, etc., including combinations thereof. The dog food formulation can further include various additional components that can vary depending on a given dog food formulation. Such components can include, but are not limited to, carbohydrates, fruits, vegetables, grains, fatty acids, etc., including combinations thereof.

[0112] In another embodiment, the animal nutrition product is a cat food formulation. Such a cat food formulation can include a cell energy inhibitor and proteins such as meat proteins, flaxseed meal, and combinations thereof. Examples of meat proteins include, but are not limited to, any meat protein such as chicken, fish, beef, lamb, duck, etc., including combinations thereof. The cat food formulation can further include various additional ingredients that can vary depending on the given cat food formulation. Such ingredients include, but are not limited to, carbohydrates, fruits, grains, fatty acids, omega-3 fatty acids, eggs, etc., including combinations thereof.

[0113] In another embodiment, the animal nutrition product is a bird food formulation. Such a bird food formulation can include a cell energy inhibitor and various ingredients including, for example, seeds, nuts, cracked corn, millet, dried fruits, and combinations thereof.

[0114] In another embodiment, the animal nutrition product is livestock feed. Such a livestock feed formulation can include a cell energy inhibitor and livestock feed ingredients. The livestock feed ingredients can vary greatly depending on the owner's preference and the nature of the livestock. General examples of livestock feed ingredients include, but are not limited to, corn, soybean meal, dried and wet distillers grains, bakery meal, corn gluten feed, cottonseed meal, wheat middlings, grain sorghum, soybean hulls, oats, fruits, animal protein products, seafood, dairy products, wheat products, etc., including combinations thereof.

[0115] In another embodiment, the animal nutrition product is horse feed. Such horse feed formulations can include a cell energy inhibitor and horse feed ingredients. The horse feed ingredients can vary widely depending on the owner's preference and the nature of the horse. General examples of horse feed ingredients include, but are not limited to, grains such as oats, barley, corn, rice or wheat, and by-products of these grains such as corn distillers grains, rice bran or wheat middlings, pasture hay, weet and oaten hay and chaff, sunflower meal, cottonseed meal, soybean meal, molasses (wheat product) horse feed, horse pellets, fruits, etc., including combinations thereof.

[0116] In one embodiment, at least one sugar can be selected from gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, zylitol, ribitol, inositol, myo-inositol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetraitol, polyglycitols, or combinations thereof.

[0117] In one embodiment, at least one sugar can be a pentose sugar.

[0118] In one embodiment, at least one sugar can be at least two pentose sugars.

[0119] In one embodiment, the cell energy inhibitor can include a second sugar selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, zylitol, ribitol, inositol, myo-inositol, sorbitol, and combinations thereof.

[0120] In one embodiment, the cell energy inhibitor can include a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo-inositol, sorbitol, and combinations thereof.

[0121] In one embodiment, at least one sugar can include glycerol, myo-inositol, and sorbitol.

[0122] In one embodiment, the cell energy inhibitor can include one or more sugars in the range of about 0.5 wt% to about 50.0 wt%, or about 1.0 wt% to about 25.5 wt%. In yet another embodiment, the cell energy inhibitor can include one or more sugars in the range of about 0.2 wt% to about 75.0 wt%, or about 0.5 wt% to about 50.0 wt%. In a further embodiment, the cell energy inhibitor can include one or more sugars in the range of about 0.1 wt% to about 25.0 wt%, about 0.2 wt% to about 10.0 wt%.

[0123] In some embodiments, the cell energy inhibitor can include glycerol in the range of about 0.1 wt% to about 5.0 wt%, or about 0.1 wt% to about 3.0 wt%. In other embodiments, the cell energy inhibitor can include inositol in the range of about 0.1 wt% to about 10 wt%, about 0.1 wt% to about 6 wt%. In a further embodiment, the cell energy inhibitor can include sorbitol in the range of about 0.1 wt% to about 40.0 wt%, or about 0.1 wt% to about 30 wt%. In yet another embodiment, the cell energy inhibitor can include mannitol in the range of about 0.1 wt% to about 30 wt%, or about 0.1 wt% to about 10 wt%. Further, each sugar can be added in a volume up to the maximum solubility of the sugar in the formulation or cell energy inhibitor.

[0124] In one embodiment, the cell energy inhibitor can include d-lactic acid and epinephrine.

[0125] In one embodiment, the cell energy inhibitor can include a biological buffer present in an amount sufficient to at least partially deacidify and neutralize the metabolic by-products of the 3-BP molecule.

[0126] In one embodiment, the biological buffer is selected from one or more of a citrate buffer, a phosphate buffer, and an acetate buffer.

[0127] In one embodiment, the biological buffer is a citrate buffer.

[0128] In one embodiment, the biological buffer is a phosphate buffer.

[0129] In one embodiment, the animal nutritional product is used to treat cancer diseases in animals.

[0130] In another embodiment, the animal therapeutic product is delivered to an animal as an adjuvant.

[0131] In another embodiment, the disease is selected from cancer, autoimmune diseases, pathogenic infections, or combinations thereof.

[0132] In yet another embodiment, the disease is selected from canine atopic dermatitis, inflammatory bowel disease, kidney disease, pemphigus foliaceus, atopic dermatitis, lupus, vesicular autoimmune skin disease, immune-mediated polyarthritis and rheumatoid arthritis, or combinations thereof.

[0133] In another embodiment, the disease is cancer selected from sarcoma, canine spindle cell soft tissue sarcoma, bone tumor, anal sac adenocarcinoma, leukemia, lymphoma, myeloma, pancreatic cancer, mast cell tumor, oral tumor, nasal tumor, bladder cancer, angiosarcoma, liver cancer, thyroid cancer, gastric cancer, or combinations thereof.

[0134] In another embodiment, the animal is a canine animal.

[0135] In another embodiment, the animal is selected from livestock or horses.

[0136] [Embodiment] (1) A therapeutic product for animals, animal food, and a cell energy inhibitor composition combined with the animal food, 3-bromopyruvic acid (3-BP), a 3-BP salt, or a combination thereof, and at least one sugar for stabilizing the 3-BP molecule by substantially preventing hydrolysis of the 3-BP molecule, and a biological buffer present in an amount sufficient to at least partially deacidify and neutralize the metabolic by-products of the 3-BP, a cell energy inhibitor composition comprising, and a therapeutic product for animals comprising. (2) The therapeutic product for animals according to Embodiment 1, wherein the at least one sugar is a member selected from the group consisting of gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, glycerol, ethylene glycol, threitol, arabinitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetraitol, polyglycitols, and combinations thereof. (3) The therapeutic product for animals according to Embodiment 1, wherein the cell energy inhibitor composition further comprises a second sugar selected from the group consisting of mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, sorbitol, and combinations thereof. (4) The therapeutic product for animals according to Embodiment 1, wherein the cell energy inhibitor composition further comprises a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, sorbitol, or combinations thereof. (5) The animal therapeutic product according to embodiment 1, wherein the cell energy inhibitor composition further comprises at least one sugar selected from glycerol, inositol, and sorbitol.

[0137] (6) The animal therapeutic product according to embodiment 1, wherein the cell energy inhibitor composition further comprises d-lactic acid and epinephrine. (7) The animal therapeutic product according to embodiment 1, wherein the cell energy inhibitor composition further comprises a glycolysis inhibitor. (8) The animal therapeutic product according to embodiment 9, wherein the glycolysis inhibitor is 2-deoxyglucose at a concentration of about 1 mM to about 5 mM. (9) The animal therapeutic product according to embodiment 1, wherein the biological buffer is selected from citrate buffer, phosphate buffer, and acetate buffer. (10) The animal therapeutic product according to embodiment 1, wherein the biological buffer is citrate buffer.

[0138] (11) The animal therapeutic product according to embodiment 1, wherein the animal food is selected from meat, carbohydrates, fruits, vegetables, grains, fatty acids, eggs, appetein, serum, plasma, albumin, globulin, or a combination thereof. (12) The cell energy inhibitor composition further comprises at least one additive selected from phospholipids; liposomes; nanoparticles; muramyl dipeptides including brown rice extract, analogs thereof, mushroom extracts, bioflavonoids, macrophage activating factor (GcMAF) derived from vitamin D3 binding protein, nagalase inhibitors, threonine associated with N-acetylgalactosamine, and antibodies against nagalase, an immune system modulator and / or an immune booster; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; inhibitors against the cell cycle, growth and / or proliferation; inhibitors against signal transduction pathways; angiogenesis inhibitors; small RNAs that interfere with normal gene regulation including antisense RNAs, microRNAs, small hairpin RNAs, short hairpin RNAs, and small interfering RNAs; vitamin C; dietary supplements including vitamins, CoQ10, flavonoids, free fatty acids, alpha-lipoic acid, acai, goji berry, mango, pomegranate, L-carnitine, selenium; amino acids with lower biological activity compared to their isomers; or combinations thereof, the veterinary therapeutic product according to Embodiment 1. (13) The cell energy inhibitor composition further comprises a hexokinase inhibitor, the veterinary therapeutic product according to Embodiment 1. (14) A method for treating an animal for a disease, providing the veterinary therapeutic product according to Embodiment 1 to an animal having the disease, administering the veterinary therapeutic product to the animal, comprising. (15) The veterinary therapeutic product is provided to the animal as an adjuvant, the method according to Embodiment 14.

[0139] (16) The disease is selected from cancer, autoimmune diseases, pathogenic infections, or combinations thereof, the method according to Embodiment 14. (17) The method according to embodiment 14, wherein the disease is selected from canine atopic dermatitis, inflammatory bowel disease, kidney disease, pemphigus foliaceus, atopic dermatitis, lupus, vesicular autoimmune skin disease, immune-mediated polyarthritis and rheumatoid arthritis, or a combination thereof. (18) The method according to embodiment 14, wherein the disease is cancer selected from sarcoma, canine spindle cell soft tissue sarcoma, bone tumor, anal sac adenocarcinoma, leukemia, lymphoma, myeloma, pancreatic cancer, mast cell tumor, oral tumor, nasal tumor, bladder cancer, angiosarcoma, liver cancer, thyroid cancer, gastric cancer, or a combination thereof. (19) The method according to embodiment 14, wherein the animal is a member of the Canidae family. (20) The method according to embodiment 14, wherein the animal is selected from livestock or horses.

Claims

Claim 1 A therapeutic product for animals, comprising animal food, and a cell energy inhibitor composition combined with the animal food, comprising 3-bromopyruvic acid (3-BP), a 3-BP salt, or a combination thereof, at least one sugar for stabilizing the 3-BP molecule by substantially preventing hydrolysis of the 3-BP molecule, a biological buffer present in an amount sufficient to at least partially deacidify and neutralize the metabolic by-products of the 3-BP, a cell energy inhibitor composition, and a therapeutic product for animals. Claim 2 The therapeutic product for animals according to claim 1, wherein the at least one sugar is a member selected from the group consisting of gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetraitol, polyglycitols, and combinations thereof. Claim 3 The therapeutic product for animals according to claim 1, wherein the cell energy inhibitor composition further comprises a second sugar selected from the group consisting of mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, sorbitol, and combinations thereof. Claim 4 The therapeutic product for animals according to claim 1, wherein the cell energy inhibitor composition further comprises a second sugar and a third sugar independently selected from the group consisting of mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, sorbitol, or combinations thereof. Claim 5 The therapeutic product for animals according to claim 1, wherein the cell energy inhibitor composition further comprises at least one sugar selected from glycerol, inositol, and sorbitol. Claim 6 The therapeutic product for animals according to claim 1, wherein the cell energy inhibitor composition further comprises d-lactic acid and epinephrine. Claim 7 The therapeutic product for animals according to claim 1, wherein the cell energy inhibitor composition further comprises a glycolysis inhibitor. Claim 8 The therapeutic product for animals according to claim 7, wherein the glycolysis inhibitor is 2-deoxyglucose at a concentration of about 1 mM to about 5 mM.

9. The therapeutic product for animals according to claim 1, wherein the biological buffer is selected from citrate buffer, phosphate buffer, and acetate buffer.

10. The therapeutic product for animals according to claim 1, wherein the biological buffer is citrate buffer.

11. The therapeutic product for animals according to claim 1, wherein the animal food is selected from meat, carbohydrates, fruits, vegetables, grains, fatty acids, eggs, appetein, serum, plasma, albumin, globulin, or combinations thereof.

12. The cell energy inhibitor composition further comprises at least one additive selected from phospholipids; liposomes; nanoparticles; brown rice extract, muramyl dipeptide containing analogs, mushroom extract, bioflavonoid, macrophage activating factor (GcMAF) derived from vitamin D3 binding protein, nagalase inhibitor, threonine associated with N-acetylgalactosamine, and antibody against nagalase, an immune system modulator and / or an immune system booster; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitor; DNA binding inhibitor; DNA transcription inhibitor; inhibitor against cell cycle, growth and / or proliferation; inhibitor against signal transduction pathway; inhibitor against angiogenesis; small RNAs that interfere with normal gene regulation including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, small interfering RNA; vitamin C; nutritional supplements containing vitamins, CoQ10, flavonoids, free fatty acids, alpha-lipoic acid, acai, goji berry, mango, pomegranate, L-carnitine, selenium; amino acids with lower biological activity compared to isomers; or combinations thereof. The therapeutic product for animals according to claim 1.

13. The therapeutic product for animals according to claim 1, wherein the cell energy inhibitor composition further comprises a hexokinase inhibitor.

14. A method for treating an animal for a disease, comprising: providing the therapeutic product for animals according to claim 1 to the animal having the disease; administering the therapeutic product for animals to the animal; A method comprising the above steps.

15. The method according to claim 14, wherein the animal therapeutic product is provided to the animal as an adjuvant.

16. The method according to claim 14, wherein the disease is selected from cancer, autoimmune disease, pathogenic infection, or a combination thereof.

17. The method according to claim 14, wherein the disease is selected from canine atopic dermatitis, inflammatory bowel disease, kidney disease, pemphigus foliaceus, atopic dermatitis, lupus, vesicular autoimmune skin disease, immune-mediated polyarthritis and rheumatoid arthritis, or a combination thereof.

18. The method according to claim 14, wherein the disease is cancer selected from sarcoma, canine spindle cell soft tissue sarcoma, bone tumor, anal sac adenocarcinoma, leukemia, lymphoma, myeloma, pancreatic cancer, mast cell tumor, oral tumor, nasal tumor, bladder cancer, angiosarcoma, liver cancer, thyroid cancer, gastric cancer, or a combination thereof.

19. The method according to claim 14, wherein the animal is a member of the Canidae family.

20. The method according to claim 14, wherein the animal is selected from livestock or horses.

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