LIQUID DISPERSABLE HALOPYRUVATE FORMULATIONS AND RELATED METHODS

Abstract

The present invention describes an anti-cancer drug comprising a dry liquid dispersion composition consisting of a cellular energy inhibitor mixed with a highly reactive component and a pharma- ceutical acceptable carrier, wherein the cellular energy inhibitor has the formula (I): [C1] JPEG2025511977000025.jpg29170 wherein in said formula (I), R is selected from one of OR', N(R'')2, C(O)R''', C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, or an alkali metal; R' is selected from one of H, an alkali metal, C1-C6 alkyl, C6-C12 aryl, or C(O)R'''; R'' is selected from one of H, C1-C6 alkyl, or C6-C12 aryl; and R''' is selected from H, C1-C20 alkyl, or C6-C12 aryl.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 328,197, filed April 6, 2022, which is incorporated by reference in its entirety herein. [Background technology]

[0002] Pharmaceutical formulations have a variety of physical forms and compositional formulations depending on the active agent in the formulation, the route of administration, etc. For example, a solid pharmaceutical formulation contains an active agent dispersed in a solid pharmaceutical carrier. Similarly, a liquid pharmaceutical formulation contains an active agent dispersed in a liquid pharmaceutical carrier. Additional additives can vary, for example, depending on whether the dosage form is liquid or solid. Common categories include diluents, disintegrants, binders, adhesives, wetting agents, lubricants, glidants, dyes, and flavorings, to name a few. [Brief description of the drawings]

[0003] [Figure 1] 1 illustrates a dry liquid dispersible formulation according to an example embodiment. [Diagram 2] 1 illustrates a dry liquid dispersible formulation according to an example embodiment. [Diagram 3] 1 illustrates a dry liquid dispersible formulation according to an example embodiment. [Figure 4] 1 illustrates a dry liquid dispersible formulation according to an example embodiment. [Diagram 5] 1 illustrates a dry liquid dispersible formulation according to an example embodiment. [Figure 6] 1 illustrates a dry liquid dispersible formulation according to an example embodiment. [Figure 7] 1 illustrates a dry liquid dispersible formulation according to an example embodiment. [Figure 8A] 1 illustrates a dry liquid dispersible formulation according to an example embodiment. [Figure 8B] 1 illustrates a dry liquid dispersible formulation according to an example embodiment. [Figure 9]1 illustrates a dry liquid dispersible formulation according to an example embodiment. [Figure 10] 1 illustrates a dry liquid dispersible formulation according to an example embodiment. [Figure 11] 1 shows stability data over time by storage temperature for a dry liquid dispersible formulation according to an example embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0004] Although the following detailed description contains many details for the purpose of illustration, those skilled in the art will understand that many variations and modifications to the following details are possible and can be considered to be included in the present application. Thus, the following embodiments are described without loss of generality and without limitation to any claims described herein. It should also be understood that the terms used herein are for the purpose of describing specific 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 those skilled in the art to which this disclosure belongs. Also, the same reference numerals appearing in different drawings refer to the same elements. The numbers shown in the flowcharts and processes are provided to clearly explain the steps and operations and do not necessarily indicate a particular order or sequence.

[0005] Furthermore, the described features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. In the following description, many specific details are provided, such as examples of layouts, distances, and networks, to provide a thorough understanding of various embodiments. However, those skilled in the relevant art will recognize that such detailed embodiments are not limiting of the overall concepts described herein, but are merely representative thereof. Those skilled in the relevant art will also recognize that the technology can be practiced without one or more specific details, or with other methods, components, layouts, etc. In other cases, well-known structures, materials, or operations may not be shown or described in detail to avoid obscuring aspects of the present disclosure.

[0006] In this application, the terms "comprise," "comprising," "containing," "having," and the like, may have the meaning given to them in U.S. patent law, and may mean "include," "including," and the like, and are generally construed as open-ended terms. The terms "consisting of" or "consists of" are closed terms and include only those components, structures, steps, and the like specifically recited with the term, and those prescribed by U.S. patent law. "consisting essentially of" or "consists essentially of" have the meaning generally given to them by U.S. patent law. In particular, the terms are generally closed terms, except that they may include additional items, materials, components, steps, or elements that do not materially affect the basic and novel characteristics or function of the item with which such term is used. For example, trace elements that are present in the composition but do not affect the properties or characteristics of the composition may be permitted when the term "consisting essentially of" is present even if they are not explicitly mentioned in the list of items enumerated with such term. When open-ended terms such as "comprising" or "including" are used herein, it is understood that direct support should be given to the words "consisting essentially of" as well as the words "consisting of" as if they were explicitly mentioned, and vice versa.

[0007] The term "substantially" as used herein means a complete or nearly complete extent or degree of an action, property, attribute, state, structure, item, or result. For example, a "substantially" enclosed object means that the object is completely enclosed or nearly completely enclosed. The exact degree of deviation permitted from absolute completeness may vary, depending on the particular situation. Generally, however, near completion would result in the same overall result as if absolute and complete completion had been obtained. The use of "substantially" may equally be applied when used in a negative sense to indicate a complete or nearly complete lack of an action, property, attribute, state, structure, item, or result. For example, a composition that is "substantially free" of particles will have the same effect as if it were completely free of particles, either because of the complete lack of particles or because of the nearly complete lack of particles. In other words, a composition that is "substantially free" of a component or element may actually contain said item, so long as there is no measurable effect.

[0008] The term "about" as used herein is used to provide flexibility to a given term, metric, value, range endpoint, etc. The degree of flexibility for a particular variable can be easily determined by one of ordinary skill in the art. However, unless otherwise specified, the term "about" generally provides less than 0.01% flexibility. Even when the term "about" is used herein in conjunction with a specific numerical value, it should be understood that support is also provided for the exact numerical value stated apart from the term "about."

[0009] As used herein, a plurality of items, structural elements, components, and / or materials may be provided in a common list for convenience. However, such list should be construed as though each member of the list is individually identified as an individual and unique member. Thus, the individual members of such lists should not be construed as being de facto equivalents to any other members of the same list merely by virtue of being displayed in a common grouping, unless otherwise indicated.

[0010] Concentrations, amounts, and other numerical data may be expressed or provided in a range format herein. It should be understood that such range formats are used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values ​​expressly recited as the limits of the range, but also all individual numerical values ​​or sub-ranges (sub-ranges) contained within the range, as if each numerical value and sub-range were expressly recited. As an example, a numerical range of "about 1 to about 5" should be interpreted not only to include the values ​​of about 1 to about 5 expressly recited, but also to include the individual values ​​and sub-ranges within the stated range. Thus, this numerical range includes individual values ​​such as 2, 3, and 4, and subranges such as 1 to 3, 2 to 4, and 3 to 5, as well as 1, 1.5, 2, 2.3, 3, 3.8, 4, 4.6, 5, and 5.1 individually. Such same principles apply to ranges that recite only one numerical value as a minimum or maximum value. Moreover, such interpretation should be applied regardless of the breadth or characteristics of the range being described.

[0011] References throughout this specification to "an example" mean that the particular feature, structure, or characteristic described in connection with the example is included in at least one embodiment. Thus, the appearances of phrases including "an example" or "an embodiment" in various places throughout this specification do not necessarily all refer to the same example or embodiment.

[0012] Terms such as "first," "second," "third," and "fourth," etc. in the specification and claims, when present, are used to distinguish between similar elements and are not necessarily used to describe a particular order or chronology. It is to be understood that the terms so used may be interchanged under appropriate circumstances such that the embodiments described herein may, for example, be operated in orders other than those illustrated or described herein. Similarly, when a method is described herein as including a series of steps, the order of such steps presented herein is not necessarily the only order in which such steps may be performed, and certain steps described may be omitted and / or certain other steps not described herein may be added to the method.

[0013] The formulations of the present invention may include pharma- ceutically acceptable carriers and other ingredients as determined by the specific needs of a particular administration formulation. Such ingredients are well known to those skilled in the art. See, for example, Gennaro, A. Remington, The Science and Practice of Pharmacy, 19th ed. (1995), the entire contents of which are incorporated by reference.

[0014] As used herein, "subject" refers to a mammalian animal that can benefit from the administration of the pharmaceutical composition or method of the present invention. Examples of subjects include humans and other animals, such as horses, pigs, cows, sheep, goats, dogs (felines), cats (canines), rabbits, rodents, primates, and aquatic mammals. In one embodiment, subject can refer to a human.

[0015] As used herein, "drug," "active agent," "bioactive agent," "pharmaceutical agent," "therapeutically active agent," and "pharmaceutical" may be used interchangeably to refer to an agent or subject that has a specific or selected bioactivity that is measurable when administered to a subject in a significant or effective amount. It is to be understood that the term "drug" is expressly included in this definition, as many drugs and prodrugs are known to have specific bioactivities. These terminologies are well known in the pharmaceutical and medical fields. Furthermore, when these terms are used or a particular active agent is specifically identified by name or category, it is understood that such reference is intended to include not only the active agent itself, but also pharma- ceutically acceptable salts, or compounds significantly related thereto, including, but not limited to, prodrugs, active metabolites, isomers, and the like. Terms such as "cellular energy inhibitors," "glycolysis inhibitors," and "mitochondrial inhibitors" are considered to be active agents.

[0016] As used herein, the terms "inhibit," "inhibiting," or any other derivative thereof, refer to the process of holding back, suppressing, or restraining in order to block, prevent, limit, or reduce the rate of an action or function. Use of the terms should not be misconstrued to mean only absolute prevention, but can refer to all minor and incremental measures that limit or reduce a function through complete and absolute prevention of the function.

[0017] As used herein, a "cellular energy inhibitor" refers to a compound that inhibits ATP production in a cell. In some instances, the cellular energy inhibitor can inhibit glycolysis, oxidative phosphorylation, or both glycolysis and oxidative phosphorylation in a cell.

[0018] As used herein, "glycolytic inhibitor" refers to a compound that inhibits, reduces, or stops glycolysis in a cell.

[0019] As used herein, "mitochondrial inhibitor" refers to a compound that inhibits, reduces, or stops mitochondrial production of ATP in a cell.

[0020] As used herein, "dosage form," "formulation," and "composition" are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some instances, the terms "dosage form," "formulation," and "composition" may be used to refer to a mixture of one or more active agents with carriers and / or other excipients.

[0021] As used herein, "carrier" or "pharmaceutical acceptable carrier" refers to a substance that can be combined with a drug to achieve a particular dosage formulation for delivery to a subject. In some instances, a carrier may or may not enhance drug delivery. Generally, a carrier will not react with a drug in a manner that substantially degrades the drug or adversely affects other drugs, although some carriers may react with a drug such that the drug cannot exert a therapeutic effect until it is released from the carrier. Additionally, the carrier, or at least a portion thereof, must be physiologically suitable for administration to a subject along with the drug.

[0022] The term "excipient" as used herein includes any substance used as a carrier for an active agent, e.g., in a liquid formulation, added to an active agent and / or solid formulation, e.g., to improve its handling characteristics, to enable the resulting composition to be formed into a suitable storage form, to facilitate dissolution into a liquid, etc. Excipients include, by way of example and not limitation, diluents, disintegrants, binders, adhesives, wetting agents, lubricants, glidants, dyes, and other substances other than the active ingredient conventionally used in the preparation of liquid or solid formulations.

[0023] As used herein, "admixed" means that at least two components of the composition can be partially or completely mixed, dispersed, suspended, dissolved or emulsified with each other. In some cases, at least a portion of the drug can be mixed with at least one carrier material.

[0024] An initial overview of the embodiments is provided below, followed by a more detailed description of certain embodiments. This initial summary is intended to aid the reader in understanding the disclosure more quickly, and is not intended to identify key or essential technical features, nor is it intended to limit the scope of the claimed subject matter.

[0025] Many liquid formulations can include active agents dispersed in liquid carriers, such as buffers. However, liquid formulations have some disadvantages. For example, liquid formulations can be inconvenient to store and transport, in part due to their large liquid volume. Moreover, many active agents react more easily with liquid carriers or other excipients in liquid form, potentially reducing the efficacy / effectiveness of liquid formulations.

[0026] One solution to such problems can be to keep the active agent and potentially other excipients in dry components (i.e., "dry form") for transport and storage. When a liquid formulation is required, the dry components can be mixed with a liquid carrier. In this manner, the volume of the transport portion of the formulation is minimized while preserving the efficacy of the active agent. It can be advantageous to include at least certain liquid formulation components in dry form. For example, a buffering agent included in a dry form can greatly facilitate the process of mixing the dry form component with the liquid carrier prior to use, particularly if the dry form is in a premix container, which can be simply added to an appropriate volume of the liquid carrier. However, many active agents can react with other components included in the dry form, such as buffering agents.

[0027] The present disclosure provides formulations and systems having storage and application forms. As used herein, "application form" refers to a liquid formulation that is prepared for use, such as ready for administration to a subject. A storage form, on the other hand, refers to a formulation that is not ready for use. Such a storage form includes at least two components, where at least one formulation component is concentrated into a powder, compressed powder, solid, etc. A storage form can also include all formulation components concentrated into a powder, compressed powder, solid, etc. In some examples, a storage form can include two or more formulation components that react with each other either immediately or over a period of time.

[0028] The present disclosure further provides methods for treating various diseases associated with mitochondrial dysfunction, including, but not limited to, metabolic disorders, neurodegenerative diseases, chronic inflammatory diseases, age-related diseases, photoaging, psoriasis, and hyperproliferative diseases including cancer.

[0029] The terms "reaction" and "reacting" include any form of chemical change that occurs in a formulation component upon contact with another formulation component, including a reaction that activates one or more molecules or components (e.g., conversion of an activator precursor to an activator), a reaction that degrades at least one component, etc.

[0030] In some cases, the application form is a liquid formulation that includes an active agent and a reactive component that is prone to react with the active agent when in the storage form. The storage form is a concentrated formulation of the active agent and the reactive component that is formulated to reduce or eliminate the reactivity between the active agent and the reactive component. Thus, the storage form can be stored for an extended period of time until the application form (i.e., liquid formulation) is generated by mixing the concentrated formulation of the storage form with a suitable liquid carrier (e.g., water) when ready for use.

[0031] The storage form of the present disclosure can vary depending on the nature of the desired liquid formulation, the active agent, excipients, any reactive ingredients, etc. The storage form can be anhydrous or dry.

[0032] Various techniques can be used to reduce or eliminate reactivity between the active agent and the reactive ingredient in the storage form. In some non-limiting examples of storage forms of the present disclosure, the active ingredient is mixed with the reactive ingredient and stored in a manner that reduces the reaction between the active agent and the reactive ingredient. In such examples, the active agent and the reactive ingredient may be mixed in the storage form, including storage at a specific temperature, packaging and storage in an oxygen-free and / or anhydrous environment, etc. In some cases, the storage form may only be used within a time window in which the reaction rate between the two is within an acceptable range.

[0033] In another example, a first component and a second reactive component that react with each other can be separated from each other in the storage form by a reactive isolation barrier. For example, FIG. 1 shows a tablet 100 including a first component 102 and a second component 104, where the first component and the second component react with each other. To avoid said reaction in the storage form, the first component 102 and the second component 104 can be reactively separated from each other by a reactive isolation barrier 106. Thus, the reactive isolation barrier 106 reactively isolates the first reactive component 102 from the second reactive component 104. In some examples, the reactive isolation barrier can be composed of a degradable material that degrades upon contact with a liquid carrier. When the tablet 100 is introduced into a liquid, the second reactive component 104 degrades and / or dissolves in the liquid, and then the reactive isolation barrier 106 degrades and / or dissolves, releasing the active agent 102 into the liquid to form a liquid formulation in the application form. In some examples, the first component 102 may be a gel or a thickened liquid. Another example is a tablet that may have the second component in the center of the tablet, surrounded by a reactive isolation barrier, which is then surrounded by the first component.

[0034] In a more specific example of FIG. 1, the tablet 100 may include an active agent 102, a reactive component 104, and a reactive isolation barrier 106 disposed between the active agent 102 and the reactive component 104. The reactive isolation barrier 106 thus reactively isolates the active agent 102 from the reactive component 104. When the tablet 100 is introduced into a liquid, the reactive component 104 disintegrates and / or dissolves in the liquid, followed by the disintegration and / or dissolution of the reactive isolation barrier 106 and then the active agent 102, forming a liquid formulation in a form for use. In some examples, the active agent 102 may be a gel or concentrated liquid. In another example, a tablet may be considered that has a reactive component in the center of the tablet, surrounded by a reactive isolation barrier, which is then surrounded by the active agent.

[0035] The reactive isolation barrier may be any pharma- ceutically acceptable layer of material that can reactively isolate the active agent from highly reactive substances. In some instances, the reactive isolation barrier may be or include a molecule, compound, etc. that is an intended component of the resulting liquid formulation. For example, the degradable material may be or include an excipient that does not react or does not substantially react with the active agent in the storage form. In other instances, the reactive isolation barrier may be a molecule, compound, etc. that provides an unexpected beneficial effect to the liquid formulation. In yet other instances, the reactive isolation barrier may be a molecule, compound, etc. that provides no effect or no substantial effect to the liquid formulation.

[0036] 2 shows a tablet 200 including an active agent 202, a reactive component 204, and an inner reactive isolation barrier 206 disposed between the active agent 202 and the reactive component 204. The inner reactive isolation barrier 206 thus reactively isolates the active agent 202 from the reactive component 204. The tablet also includes, in at least one embodiment, an outer reactive isolation barrier 208 to provide a protective coating around the reactive component 204.

[0037] The outer reactive isolation barrier 208 may be the same material as the inner reactive isolation barrier 206 or a different material than the inner reactive isolation barrier 206. It is also contemplated that the outer reactive isolation barrier 208 may include the same material as the inner reactive isolation barrier 206 along with other materials not included in the inner reactive isolation barrier 206. In other examples, the inner reactive isolation barrier 206 may include the same material as the outer reactive isolation barrier 208 along with other materials not included in the outer reactive isolation barrier 208.

[0038] When the tablet 200 is introduced into a liquid, the outer reactive isolation barrier 208 degrades and / or dissolves in the liquid, exposing the reactive component 204. Upon exposure to the liquid, the reactive component 204 degrades and / or dissolves in the liquid, followed by the decomposition and / or dissolution of the inner reactive isolation barrier 206 and then the active agent 202, forming a liquid formulation in a usable form. In some examples, the active agent 202 may be a gel or concentrated liquid. Another example is a tablet that has a reactive component in the center of the tablet, surrounded by a reactive isolation barrier, which is in turn surrounded by the active agent and an outer reactive isolation barrier. Additionally, the active agent and reactive component may be contained in any of the above regions / barriers, so long as the active agent is reactively isolated from the reactive component.

[0039] In yet another example, FIG. 3 illustrates a solid dosage form 300 including a plurality of active agent particles 302 dispersed in a highly reactive component 304, where each active agent particle 302 is surrounded by an inner reactive isolation barrier 306 to reactively isolate the active agent in each active agent particle 302 from the highly reactive component 304. In some examples, the solid dosage form 300 can further include an outer reactive isolation barrier 308 to provide a protective coating around the highly reactive component 304, at least in one embodiment. The outer reactive isolation barrier 308 can be the same material as the inner reactive isolation barrier 306 or a different material than the inner reactive isolation barrier 306. It is also contemplated that the outer reactive isolation barrier 308 can include the same material as the inner reactive isolation barrier 306, along with other materials not included in the inner reactive isolation barrier 306. In other examples, the inner reactive isolation barrier 306 can include the same material as the outer reactive isolation barrier 308, along with other materials not included in the outer reactive isolation barrier 308.

[0040] In one example, the reactive component 304 may be in the form of a solid tablet. In another example, the reactive component 304 may be in the form of a powder. In one embodiment of such a powder form, the outer reactive isolation barrier 308 may contain the reactive component 304 in a separate dosage form. When the tablet is introduced into a liquid, the outer reactive isolation barrier 308 dissolves or decomposes in the liquid, thereby exposing the powdered reactive component 304. Upon contact with the liquid, the reactive component 304 and the inner reactive isolation barrier 306 surrounding each active agent particle 302 dissolve or decompose in the liquid, thereby exposing the active agent, which then dissolves or decomposes to form a liquid formulation in the form of application. Such a dosage form may generate a liquid formulation much more quickly than a tablet form due to the liquid dispersing more quickly throughout the powdered reactive component 304 and the much larger surface area of ​​the reactive isolation barrier and active agent portion in the reservoir form. In an example where there is no outer reactive isolation barrier, the reactive component 304 containing multiple active agent particles 302 may be applied as a powder.

[0041] In another example, a solid dosage form may be considered to have a plurality of reactive component particles dispersed in an active agent, where each reactive component particle is surrounded by an inner reactive isolation barrier, thereby reactively isolating the reactive component particle from the active agent. It is further noted that the active agent and reactive component may be contained within any of the above regions / barriers, so long as the active agent is reactively isolated from the reactive component.

[0042] In some cases, the storage form may include a pharma- ceutically acceptable diluent, e.g., as a bulking agent to add weight, improve content uniformity, etc. Suitable diluents, individually or in combination, include, but are not limited to, lactose, lactose anhydrous, lactose monohydrate; starch, directly compressible starch, hydrolyzed starch, partially pregelatinized starch, sodium starch glycolate; mannitol, sorbitol, xylitol, dextrose monohydrate, dibasic calcium phosphate dihydrate, sucrose-based diluents, powdered sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate NF, calcium lactate trihydrate granules, dextrins, glyceryl stearate ... dextrates, dextrose, inositol, hydrolyzed cereal solids, amylase, powdered cellulose, calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, clay, cellulose, purified cellulose, methylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, microcrystalline cellulose, alginates, pregelatinized corn starch, crospovidone, gums, agar, guar gum, locust bean gum, karaya gum; pectin, tragacanth, and the like. For example, the use of additional granular microcrystalline cellulose (i.e., microcrystalline cellulose added to the wet granulation composition after the drying step) may be used to increase hardness and / or extend disintegration time. Many diluents provide storage forms with suitable disintegration rates, stability, pre-compression flowability, and / or drying characteristics. Diluents may also provide a high density matrix that promotes densification during granulation (where wet granulation is employed) and thus increases the flowability of the mixture.

[0043] In some cases, the depot form may contain pharma- ceutically acceptable binders or adhesives that can provide sufficient cohesion to the powder to tablet it, improving processing operations such as sizing, lubrication, compression and packaging, yet still allow the tablet to disintegrate. Suitable binders and adhesives include, individually or in combination, and without limitation, acacia, tragacanth, sucrose, gelatin, glucose, starch; cellulosic materials, such as, but not limited to, cellulose, microcrystalline cellulose, cellulose ethers, hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose; ethylcellulose, alginic acid and alginates; magnesium aluminum silicate; polyethylene glycol, guar gum; polysaccharide acids; bentonite, polyvinylpyrrolidone, polymethacrylates, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pregelatinized starch; monosaccharides and suitable derivatives; disaccharides, sucrose, lactose; polysaccharides and suitable derivatives; sugar alcohols, such as, but not limited to, xylitol, sorbitol or mannitol; proteins; gelatin, and the like.

[0044] Liquid binders may be dissolved in the solvent used in the wet granulation process. Examples of liquid binders include gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose, polyethylene glycol, etc. Dry binders may be added to the powder mixture either after the wet granulation step or as part of a direct powder compression formulation. Examples of dry binders include cellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol, etc.

[0045] The binder and / or adhesive may be included in any amount sufficient to achieve the desired result. In one example, the binder and / or adhesive may comprise about 0.5% to about 25% of the total weight of the storage form. In another example, the binder and / or adhesive may comprise about 0.75% to about 15% of the total weight of the storage form. In yet another example, the binder and / or adhesive may comprise about 1% to about 10% of the total weight of the storage form. In one specific example, polyvinylpyrrolidone may be used to impart cohesive properties to a powder mixture of active agent and other excipients for granulation. The polyvinylpyrrolidone may be included in any amount sufficient to achieve the desired result. In one example, the polyvinylpyrrolidone may comprise about 0.5% to about 10% of the total weight of the storage form. In another example, the polyvinylpyrrolidone may comprise about 0.5% to about 7% of the total weight of the storage form. In yet another example, the polyvinylpyrrolidone may comprise about 0.5% to about 5% of the total weight of the composition.

[0046] In some cases, the storage form may contain a pharma- ceutically acceptable disintegrant to facilitate the disintegration of the storage form and convert it into a liquid formulation when added to a suitable solvent. Suitable disintegrants include, individually or in combination, and are not limited to, starches, such as corn starch, rice starch, sodium starch glycolate, and the like; cross-linked N-vinyl basic-2-pyrrolidone (CLPVP); alginic acid or alginates; microcrystalline cellulose; hydroxycellulose and other celluloses; cross-linked sodium carboxymethylcellulose, such as croscarmellose sodium; polyvinylpyrrolidone; crospovidone; polacrilin potassium, and the like. In one example, the disintegrant may be a gas-generating disintegrant, such as, but not limited to, sodium bicarbonate, potassium bicarbonate, sodium acid carbonate, citric acid, tartaric acid, and the like.

[0047] Disintegrants may be included in any amount sufficient to achieve the desired results and may be added at any suitable step during the preparation of the storage form, optionally during the lubrication step before granulation or compression. In one example, the disintegrant may comprise about 0.2% to about 30% of the total weight of the composition. In another example, the disintegrant may comprise about 0.2% to about 10% of the total weight of the composition. In yet another example, the disintegrant may comprise about 0.2% to about 5% of the total weight of the composition. In some cases, the disintegrant may be mixed with the active agent before granulation. In some cases, the disintegrant may be divided into two parts, one part is added to the powder formulation before granulation, and the remaining part is mixed with the lubricant and added before compression. In this way, the part added to the lubricant will rapidly break down the tablet granules, and the disintegrant mixed with the active ingredient will break down the granules into smaller particles.

[0048] In one example, the depot formulation may be an effervescent formulation, such as effervescent tablets, effervescent powders, etc. The effervescent tablets may be coated or uncoated depending on the tablet format. Any effervescent material compatible with the formulation and capable of reacting in the presence of water to release a gas that promotes the decomposition of the depot form may be suitable for use. In one example, the effervescent material may react in the presence of water to release carbon dioxide. In one non-limiting example, the effervescent material may include an acidic substance, such as citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, or any other suitable acid, including anhydrides and salts thereof. In other non-limiting examples, the effervescent material may include citric acid, tartaric acid, or malic acid, including anhydrides and salts thereof. In further examples, the effervescent material may include carbonates, bicarbonates, etc. Further examples may include potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, arginine carbonate, etc.

[0049] In some cases, the storage forms may include a pharma- ceutically acceptable tablet coating to protect the tablet ingredients from deterioration due to atmospheric moisture, non-limiting examples of such coatings include films of the cellulose ether hydroxypropyl methylcellulose (HPMC), various synthetic polymers, shellac, corn protein zein, and other polysaccharides.

[0050] In some instances, the active agents of the present disclosure can treat various ailments by suppressing energy within certain cells. In one embodiment, the active agent can be a cellular energy inhibitor according to Formula I. [ka] A variety of specific molecules are contemplated, where, for example, X may be, but is not limited to, nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, or amine oxide, etc. Additionally, R may be, but is not limited to, OR', N(R'')2, C(O)R''', C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, alkali metal, etc., where R' represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl, or C(O)R''', R'' represents H, C1-C6 alkyl, or C6-C12 aryl, and R''' represents H, C1-C20 alkyl, or C6-C12 aryl.

[0051] In one example, R in formula (I) can be OH, and X in formula (I) can be nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, or amine oxide, etc. Furthermore, X can be a halide, such as fluoride, bromide, chloride, or iodide, etc. In one example, X can be a sulfonate, such as triflate, mesylate, or tosylate, etc. In another example, X can be an amine oxide. In yet another example, the amine oxide can be dimethylamine oxide.

[0052] In another example, the cellular energy inhibitor can be a 3-halopyruvate, such as 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate, 3-iodopyruvate, or a combination thereof. A general formula showing a halide at the 3-position is represented by Formula II. [ka] In a further non-limiting example, the cellular energy inhibitor can have a bromine at the 3 position, as represented by formula III. [ka] In one further non-limiting example, the cellular energy inhibitor can be 3-bromopyruvic acid (3-BP), as represented by formula IV. [ka] In another further non-limiting example, the cellular energy inhibitor can be 3-bromopyruvate, as represented by Formula V. [ka]

[0053] In some instances, the cellular energy inhibitor may be formulated in a composition with at least one sugar, which may stabilize the cellular energy inhibitor by substantially preventing the inhibitor from hydrolyzing. In some instances, the composition may include 3-BP and at least one sugar, at least two sugars, at least three sugars, etc. In one example, the sugar may include a monosaccharide, a disaccharide, an oligosaccharide, or a combination thereof. Non-limiting examples of monosaccharides may include glucose, fructose, galactose, etc. Non-limiting examples of disaccharides may include sucrose, lactose, maltose, etc. It is noted that for purposes of this disclosure, the term "sugar" may also include oligosaccharides, polysaccharides, polyols, polyhydric alcohols, and similar molecules that function to stabilize 3-BP.

[0054] Sugars can include 3-carbon sugars, 4-carbon sugars, 5-carbon sugars, 6-carbon sugars, 7-carbon sugars, etc., including combinations thereof. In one embodiment, the sugars can be trioses, tetraoses, pentoses, hexoses, heptoses, etc., and combinations thereof, provided that the sugars do not participate in energy metabolism to the extent that they generate energy (i.e., non-metabolizable sugars).

[0055] In one example, the sugar may be gluconic acid. In another example, the sugar may be glucuronic acid. At least one sugar may be a pentose. In one example, at least two sugars may be pentoses. The pentoses may be independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo-inositol, and the like, or combinations thereof. In one example, the at least one sugar may be glycerol. In another example, the sugars may be glycerol, inositol, and sorbitol. Other non-limiting examples of sugars may include ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetraitol, and polyglycitol, and combinations thereof. In one example, the sugar can include glycerol, inositol, myo-inositol, sorbitol, mannitol, or any combination thereof. In another example, the sugar can include glycerol, inositol, sorbitol, or any combination thereof. In yet another example, the inositol can be myo-inositol. In another example, the sugar can be a polyhydric alcohol. In another example, the sugar can include a heptasaccharide, such as, but not limited to, a cyclodextrin, such as β-cyclodextrin.

[0056] The sugars described herein may be in any isomeric form. In one example, the compositions described herein may include a form of the sugar that has a lower biological activity compared to the isomer of the sugar. In some cases, the sugar with a lower biological activity may be the L-enantiomer of the sugar. However, if the D-enantiomer of the sugar is known to have a lower biological activity compared to the L-enantiomer, the D-enantiomer may be used. In one example, such sugars may function as glycolysis inhibitors.

[0057] In one example, the composition may contain one or more sugars in a range of about 0.5% to about 50.0% by weight, or about 1.0% to about 25.5% by weight. In another example, the composition may contain one or more sugars in a range of about 0.2% to about 75.0% by weight, or about 0.5% to about 50.0% by weight. In a further example, the composition may contain one or more sugars in a range of about 0.1% to about 25.0% by weight, or about 0.2% to about 10.0% by weight.

[0058] In some examples, the composition may contain glycerol in the range of about 0.1% to about 5.0% by weight, or about 0.1% to about 3.0% by weight. In another example, the composition may contain inositol in the range of about 0.1% to about 10% by weight, or about 0.1% to about 6% by weight. In a further example, the composition may contain sorbitol in the range of about 0.1% to about 40.0% by weight, or about 0.1% to about 30% by weight. In yet a further example, the composition may contain mannitol in the range of about 0.1% to about 30% by weight, or about 0.1% to about 10% by weight. In addition, each sugar may be added to the formulation or composition in a volume up to the maximum solubility of the sugar. It is also noted that the weight percentages of the components above do not include water or other liquid carriers.

[0059] In some examples, the 3-BP composition can include a biological buffer present in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize the metabolic by-products of the cellular energy inhibitor. Non-limiting examples of biological buffers can include citrate buffer, phosphate buffer, acetate buffer, and the like, or combinations thereof. In one embodiment, the biological buffer can be a citrate buffer, such as, but not limited to, sodium citrate. In another embodiment, the biological buffer can be a phosphate buffer, such as, but not limited to, sodium phosphate. In one embodiment, the biological buffer can be an acetate buffer, such as, but not limited to, sodium acetate. In yet another embodiment, the biological buffer can include at least two biological buffers, such as, 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.

[0060] In some examples, the composition can include a biological buffer in the range of about 0.1% to about 15% by weight, or about 2.0% to about 8.0% by weight. Furthermore, 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 yet another embodiment, the biological buffer can maintain a physiological pH of 7.3 to 7.6. It is also noted that the weight percentages of the components do not include water or other liquid carriers.

[0061] In one example, 3-BP may be mixed with a biological buffer without a reactive isolation barrier between them. Additionally, other ingredients, such as, for example, sugar(s), may also be mixed with 3-BP and the biological buffer. In some examples, the mixed solid formulation may include an outer protective coating. In another example, the mixed solid formulation is free of an outer protective coating.

[0062] In one example, 3-BP may be included with a biological buffer in a storage form, which are reactively isolated from each other by a reactive isolation barrier. For example, FIG. 4 shows a tablet 400 that includes 3-BP 402, a biological buffer 404, and a reactive isolation barrier 406 disposed between 3-BP 402 and biological buffer 404. Thus, reactive isolation barrier 406 reactively isolates 3-BP 402 from biological buffer 404. When tablet 400 is introduced into a liquid, biological buffer 404 dissolves or disintegrates in the liquid, and then reactive isolation barrier 406 and then 3-BP 402 dissolve or disintegrate to form a liquid formulation in a usage form. In another example, a tablet is contemplated that has a biological buffer in the center of the tablet, which is surrounded by a reactive isolation barrier, which is then surrounded by 3-BP.

[0063] The reactive isolation barrier may be any pharma- ceutically acceptable layer of material capable of reactively isolating 3-BP from a biological buffer. In some instances, the reactive isolation barrier may be a molecule, compound, etc. that is an intended component of the resulting liquid formulation. For example, the degradable material may be or may include an excipient that does not react or does not substantially react with 3-BP. In other instances, the reactive isolation barrier may be a molecule, compound, etc. that provides an unexpected beneficial effect to the liquid formulation. In yet other instances, the reactive isolation barrier may be a molecule, compound, etc. that provides no effect or no substantial effect to the liquid formulation.

[0064] In one embodiment, the reactive isolation barrier comprises at least one sugar, at least two sugars, at least three sugars, etc., of the desired 3-BP liquid formulation. In another example, the sugar may be mixed with the 3-BP. In yet another example, the sugar may be mixed with a biological buffer. In yet another example, the sugar may be added to the liquid formulation after degradation of the storage form or to the liquid prior to degradation of the storage form.

[0065] As another example, FIG. 5 shows a tablet 500 including 3-BP 502, a biological buffer 504, and an inner reactive isolation barrier 506 disposed between the 3-BP 502 and the biological buffer 504. The inner reactive isolation barrier 506 thus reactively isolates the 3-BP 502 from the biological buffer 504. The tablet also includes, at least in one embodiment, an outer reactive isolation barrier 508 to provide a protective coating around the biological buffer 504. The outer reactive isolation barrier 508 may be the same material as the inner reactive isolation barrier 506 or a different material than the inner reactive isolation barrier 506. Moreover, it is contemplated that the outer reactive isolation barrier 508 may include the same material as the inner reactive isolation barrier 506 along with another material not included in the inner reactive isolation barrier 506. In other examples, the inner reactive isolation barrier 506 may include the same material as the outer reactive isolation barrier 508 along with another material not included in the outer reactive isolation barrier 508. When tablet 500 is introduced into a liquid, outer reactive isolation barrier 508 dissolves or degrades in the liquid, exposing biological buffer 504. When exposed to liquid, biological buffer 504 dissolves or dissolves in the liquid, followed by dissolution or degradation of inner reactive isolation barrier 506 and 3-BP 502, forming a liquid formulation for use. In some examples, 3-BP 502 may be a gel or concentrated liquid. Another example is a tablet that has a biological buffer in the center of the tablet, surrounded by a reactive isolation barrier, which is further surrounded by 3-B, which is then surrounded by an outer reactive isolation barrier.

[0066] In one embodiment, the inner reactive isolation barrier, the outer reactive isolation barrier, or both of said isolation barriers may include at least one sugar, at least two sugars, at least three sugars, etc., of the desired 3-BP liquid formulation. In another example, the sugar may be mixed with 3-BP. In yet another example, the sugar may be mixed with a biological buffer. It is also contemplated that the inner reactive isolation barrier and / or the outer reactive isolation barrier may also include one or more sugars. In some examples, the one or more sugars in each reactive isolation barrier may be the same, different, or various mixtures thereof. In yet another example, the sugar may be added to the liquid formulation after degradation of the storage form or to the liquid before degradation of the storage form.

[0067] 6 illustrates a solid formulation 600 including a plurality of 3-BP particles 602 dispersed in a biological buffer 604, where each 3-BP particle 602 is surrounded by an inner reactive isolation barrier 606 to reactively isolate the active agent in each 3-BP particle 602 from the biological buffer 604. In some examples, the solid formulation 600 can further include an outer reactive isolation barrier 608 to provide a protective coating around the biological buffer 604, at least in one embodiment.

[0068] The outer reactive isolation barrier 608 may be the same material as the inner reactive isolation barrier 606 or a different material than the inner reactive isolation barrier 606. It is also contemplated that the outer reactive isolation barrier 608 may include the same material as the inner reactive isolation barrier 606 along with another material not included in the inner reactive isolation barrier 606. In other examples, the inner reactive isolation barrier 606 may include the same material as the outer reactive isolation barrier 608 along with another material not included in the outer reactive isolation barrier 608.

[0069] In one example, the biological buffer 604 may be in a solid tablet form. In another example, the biological buffer 604 may be in a powder form. In one embodiment of such a powder form, the outer reactive isolation barrier 608 may contain the biological buffer 604 in a separate dosage form similar to a capsule. When the capsule is introduced into a liquid, the outer reactive isolation barrier 608 dissolves or degrades in the liquid, exposing the powdered biological buffer 604. When exposed to a liquid, the biological buffer 604 and the reactive isolation barrier 606 surrounding each 3-BP particle 602 dissolve or degrade in the liquid, exposing the 3-BP, which then dissolves or degrades to form the liquid formulation in the form of use. Such a dosage form may generate a liquid formulation much more quickly than a tablet form due to the liquid dispersing more quickly throughout the powdered reactive ingredient 604 and the very large surface area of ​​the reactive isolation barrier and active agent moieties in the reservoir form. In an example where there is no outer reactive isolation barrier, the reactive ingredient 604 may be utilized as a powder including a plurality of 3-BP particles 602. In yet another example, the powder may be a compressed powder or solid.

[0070] In addition to providing reactive isolation barriers between regions, components that react with each other within the storage form may be in direct contact along a common boundary between the components. Thus, reactivity between the active agent and the highly reactive component is minimized by confining reactivity to a proportionately smaller region of the storage form, i.e., along a common boundary. In one example shown in FIG. 7, the active agent 702 is surrounded by the highly reactive component 740. Reaction may occur between the active agent 702 and the highly reactive material 704, but is confined to the common boundary 706. In addition to the above component arrangements, it is contemplated that the highly reactive component may also be surrounded by the active agent.

[0071] Figures 8A and 8B show examples with distinct component regions located adjacent to one another. For example, Figure 8A shows a storage form with three components 802, 804, and 806 located side-by-side. Any reactivity occurring between the three components is therefore restricted to the common boundary between them. Figure 8B shows a similar storage form with two components 802 and 806.

[0072] In another example, the storage form may be contained within a capsule, for example, but not limited to, in either a solid compressed form or a powder form. FIG. 9 shows a capsule 904 containing a mixture of cellular energy inhibitors or cellular energy inhibitor precursors 902 in powder form, compressed form, etc., along with at least one other excipient. In some cases, the capsule storage form may be directly introduced into a liquid carrier to form a use form. In other cases, the capsule may be opened and its contents poured into a liquid carrier to form a use form. The capsule may be FIG. 10, which shows an example of a capsule 1008 containing a storage form having three compartments 1002, 1004, and 1006.

[0073] Various components of the composition in the storage form may also react when exposed to other reactive elements / molecules in the air, including oxygen and possibly moisture. Therefore, in one approach, reactivity may be minimized or avoided by vacuum-packing the storage form. In another approach, reactivity may be minimized or avoided by packaging the storage form in an inert gas. The solid forms are packaged in packaging forms, such as bottles, tubes, pouches, etc., one convenient packaging form is a blister pack. The blister pack allows the solid forms to be in separate single-dose storage forms, allowing the single doses remaining in the blister pack to be used in the local environment without exposure to air / moisture.

[0074] In one embodiment, the reactive isolation barrier may include at least one sugar, at least two sugars, at least three sugars, etc., of the desired 3-BP liquid formulation. In another example, the sugar may be mixed with the 3-BP. In yet another example, the sugar may be mixed with a biological buffer. It is also contemplated that the reactive isolation barrier and / or the outer reactive isolation barrier may include one or more sugars, either the same sugar or different sugars or various sugar mixtures, within a single barrier or within each barrier. In yet another example, the sugar may be added to the liquid formulation after degradation of the storage form or to the liquid prior to degradation of the storage form.

[0075] In one embodiment, the storage form may comprise a powder mixture of at least 3-BP, at least one buffer, at least one sugar, and excipients. Such mixed powder storage forms have a long-term stability profile, especially when compared to liquid application forms with similar components. 3-BP in such mixed powder formulations shows only slight degradation after 24 weeks, for example, at -20°C.

[0076] As an example, the stability of the 3-BP mixed powder formulation increases over time depending on the storage temperature, especially when stored in the inner packaging material and the outer packaging material. For example, the inner packaging material can be a polyethylene pouch, and the outer packaging material can be an aluminum pouch. Table 1 shows an example of a 3-BP mixed powder formulation over time at different storage temperatures, the 3-BP mixed powder formulation including 3-BP, sodium citrate, sodium phosphate, myo-inositol, sorbitol, glycerol, microcrystalline cellulose, colloidal silicon dioxide, and stearic acid. Table 1 also shows an example of a 3-BP mixed powder formulation over time at different storage temperatures, the 3-BP mixed powder formulation including 3-BP, sodium citrate, sodium phosphate, myo-inositol, sorbitol, microcrystalline cellulose, colloidal silicon dioxide, and stearic acid. Analytical results for appearance, total 3-BP, and total impurities show degradation of 3-BP over time in 3-BP mixed powder formulations at various temperatures ranging from room temperature to -20°C.

[0077] [Table 1]

[0078] [Table 2]

[0079] With reference to FIG. 11, 3-BP formulations (both with and without glycerol) show little degradation at −20° C. for 24 weeks, gradual degradation over 12 weeks at 5° C., and significant degradation over 8 weeks. The analytical results displayed in FIG. 11 are the weight percent of 3-BP as determined by HPLC. In one example, at least 85% by weight of 3-BP remains in the formulation after 24 weeks at −20° C. In another example, at least 90% by weight of 3-BP remains in the formulation after 24 weeks at −20° C. In yet another example, at least 95% by weight of 3-BP remains in the formulation after 24 weeks at −20° C.

[0080] In some examples, the 3-BP composition may include a glycolytic inhibitor, in one non-limiting example, 2-deoxyglucose (2DOG). The 3-BP formulation may include any effective amount of a glycolytic inhibitor. In the various dosage forms described above in Figures 4-6, the glycolytic inhibitor may be mixed with the 3-BP or may be included in a separate layer or any of the layers described above, provided that the glycolytic inhibitor is isolated from any components during storage, e.g., that react with the biological buffer. The glycolytic inhibitor may be mixed into the biological buffer, provided that it does not react with the biological buffer.

[0081] In addition to the above components, the 3-BP compositions described herein may further comprise a halogenated monocarboxylate compound separate from the cellular energy inhibitor. If the halogenated monocarboxylate compound acts to inhibit glycolysis and / or mitochondrial function, the halogenated monocarboxylate may also be considered a second cellular energy inhibitor. In one embodiment, the halogenated monocarboxylate compound may be a halo two-carbon monocarboxylate compound. The two-carbon halogenated monocarboxylate compound may be selected from, but is not limited to, 2-fluoroacetate, 2-chloroacetate, 2-bromoacetate, 2-iodoacetate, and the like, including combinations thereof. In one embodiment, the two-carbon halogenated monocarboxylate compound may be a 2-bromoacetate. In one example, the composition may comprise a concentration of about 0.01 mM to about 5.0 mM of the two-carbon halogenated monocarboxylate compound. In another example, the composition may include a monocarboxylate compound halogenated at the 2-carbon position at a concentration of about 0.1 mM to about 0.5 mM.

[0082] Further, the halogenated monocarboxylate compound may be a monocarboxylate compound having a halogenated carbon at the 3-position. The monocarboxylate compound having a halogenated carbon at the 3-position may be selected from, but is not limited to, 3-fluoroacetate, 3-chloroacetate, 3-bromoacetate, 3-iodoacetate, and the like, including combinations thereof. In another example, the composition may contain a monocarboxylate compound having a halogenated carbon at the 3-position at a concentration of about 0.5 mM to about 250 mM. In one example, the composition may contain a monocarboxylate compound having a halogenated carbon at the 3-position at a concentration of about 10 mM to about 50 mM. In the various dosage forms described above in Figures 4 to 7, the halogenated monocarboxylate compound may be mixed with 3-BP or may be included in a separate layer or any of the layers described above, provided that the halogenated monocarboxylate compound is reactively isolated in the reservoir form.

[0083] In some examples, the 3-BP compositions described herein may further include a mitochondrial inhibitor in addition to a cellular energy inhibitor. The mitochondrial inhibitor may be selected from, but is not limited to, oligomycin, efrapeptin, aurovertin, and the like, including combinations thereof. In another example, the composition may include a mitochondrial inhibitor at a concentration of about 0.001 mM to about 5.0 mM. In one example, the composition may include a mitochondrial inhibitor at a concentration of about 0.01 mM to about 0.5 mM. Of the various dosage forms previously described in Figures 4-7, the mitochondrial inhibitor may be mixed with the 3-BP or may be included in a separate layer or any of the previously described layers, provided that the mitochondrial inhibitor is reactively sequestered in the reservoir form.

[0084] In some examples, the 3-BP composition may include, but is not limited to, antifungals, antibiotics, glycolysis inhibitors, mitochondrial inhibitors, sugars, and biological buffers. Examples of such agents include, but are not limited to, amphotericin B, efrapeptins, doxorubicin, (2-deoxyglucose (2DOC)), 2-DOG analogs, d-lactic acid, dichloroacetic acid (or a salt form of dichloroacetic acid), oligomycin, oligomycin analogs, glycerol, inositol, sorbitol, glycol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, dulcitol, iditol, isomalt, maltitol, lactitol, polyglycitol, sodium phosphate, sodium citrate, sodium acetate, sodium carbonate, sodium bicarbonate, sodium pyruvate, sodium lactate, oxaloacetate, isocitrate, aconitrate, succinate, fumarate, malate, and dilute saline solutions containing various concentrations of NaCl and water. In addition to the sodium ions associated with the biological buffer, calcium and potassium ions may also be associated with the biological buffer. The various active agents of the composition may include cellular energy inhibitors, glycolysis inhibitors, mitochondrial inhibitors, halogenated monocarboxylate compounds, antifungal agents, antibiotic agents, and the like. In the various dosage forms previously described in Figures 4-7, any of the above ingredients may be mixed with 3-BP or may be included in a separate layer or any of the layers previously described, so long as the additional ingredient(s) are reactively sequestered in the reservoir form.

[0085] In some instances, the 3-BP compositions described herein may further comprise a hexokinase inhibitor. In the various dosage forms previously described in Figures 4-7, the hexokinase inhibitor may be mixed with the 3-BP or may be included in a separate layer or any of the layers previously described, so long as the hexokinase inhibitor is reactively sequestered in the reservoir form.

[0086] As used herein, "hexokinase 1" or "hexokinase 1 isozyme" refers to any isoform of hexokinase 1 and its naturally known variants, including those provided in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, as follows: [Table 3] [Table 4] [Table 5] [Table 6] As used herein, "hexokinase 2" or "hexokinase 2 isozyme" refers to any isoform of hexokinase 2 and its naturally known variants, including those provided in SEQ ID NO:5, as follows: [Table 7] In some instances, the 3-BP compositions described herein may further comprise a hexokinase inhibitor, which may be any molecule that inhibits hexokinase 1, hexokinase 2, and / or their isozymes (collectively referred to herein as "hexokinases").

[0087] As mentioned above, the main source of ATP production occurs in the mitochondria in normal cells. However, in cancer cells, ATP production from glycolysis is significantly upregulated. One of the reasons for this upregulation is that hexokinase molecules bind to and form complexes with mitochondrial voltage dependent anion channels (VDACs) in the ATP synthasome, forming the so-called "ATP synthasome mega complex." The formation of such an ATP synthasome mega complex allows the cancer cells to immortalize and continue to use the cellular energy production process for cancer growth. Therefore, hexokinase inhibitors can block hexokinase from binding to VADC or displace hexokinase molecules from the VADC of the already formed ATP synthasome mega complex.

[0088] In one example, the hexokinase inhibitor may be within a maximum of 25 amino acid units from the N-terminal region of the hexokinase 2 isozyme or the hexokinase 1 isozyme. In another example, the hexokinase inhibitor may be an amino acid sequence consisting of the 5th to 20th amino acid units, in which the 5th to 20th amino acid sequence is present in the first 25 amino acid unit region of the N-terminus of the hexokinase 1 isozyme or the hexokinase 2 isozyme. In one example, the 5th to 20th amino acid sequence may be any 5 to 20 amino acid sequence present in the first 25 amino acid unit region of the N-terminus of hexokinase 11 or hexokinase 2. Such an amino acid sequence can displace hexokinase bound to cells or competitively bind to a voltage-dependent anion channel (VDAC) to prevent initial hexokinase binding.

[0089] In another example, 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 example, the hexokinase inhibitor can be an amino acid sequence such as SEQ ID NO:6, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 1), which has the sequence as follows: [Table 8] In another example, a hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 7, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 2), which has the sequence as follows: [Table 9] In yet another example, a hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 8, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 3), which has the sequence as follows: [Table 10] In yet another example, a hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 9, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 4), which has the sequence as follows: [Table 11] In yet another example, a hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 10, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 2, which has the sequence as follows: [Table 12] Additional hexokinase inhibitors may be those disclosed in U.S. Patent No. 5,854,067 (Newgard et al., issued December 29, 1998) and / or U.S. Patent No. 5,891,717 (Newgard et al., issued April 6, 1999), both of which are incorporated by reference in their entirety. Additional hexokinase inhibitors that may be used in the 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; and U.S. Patent Application Publication Nos. 20030072814; 20020077300; and 20020035071; each of the aforementioned patent publications and patent applications is incorporated by reference in its entirety herein.

[0090] In some examples, the 3-BP compositions described herein can further include various ingredients, as listed below: In the various dosage forms previously described in Figures 4-7, any of the various ingredients may be mixed with the 3-BP, provided that the ingredient does not react with the 3-BP, or may be included in a separate layer or any of the layers previously described, provided that the ingredient(s) are reactively isolated in the reservoir form.

[0091] In one embodiment, the composition may comprise an amino acid with lower biological activity than the isomer, thereby promoting the starvation of cancer cells.In one embodiment, the amino acid with lower biological activity may be D-amino acid.On the other hand, when L-amino acid has lower biological activity than D-amino acid, L-amino acid may be used.

[0092] In one embodiment, the composition may include a DNA replication inhibitor, a DNA binding inhibitor, and / or a DNA transcription inhibitor. In another embodiment, the composition may include an inhibitor of cell cycle, growth, and / or replication. In yet another embodiment, the composition may include an inhibitor of a signal transduction pathway. In yet another embodiment, the composition may include an inhibitor of angiogenesis. In yet another embodiment, the composition may include a small RNA that interferes with normal gene regulation, such as antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, small interfering RNA, and the like. In yet another embodiment, the composition may include a nutritional supplement containing vitamin C; vitamins, coenzyme Q10 (CoQ10), flavonoids, free fatty acids, alpha lipoic acid, acai, goji berry (gogi), mango, pomegranate (pomergrante), L-carnitine, selenium, and the like.

[0093] In addition to the active agent, the storage form of the composition may further include a pharma- ceutically acceptable carrier. The carrier may be a single composition or a mixture of compositions. Moreover, the carrier may be in the form of an encapsulating coating, an absorbent, a coating material, a controlled release device, a release modifying agent, a surfactant, or a combination thereof. In some aspects, the carrier may comprise about 0.01% to about 99% by weight of the total composition. In one embodiment, the carrier may comprise about 1% to about 95% by weight of the total formulation. In another embodiment, the carrier may comprise about 5% to about 80% by weight. In yet a further embodiment, the carrier may comprise about 10% to about 60% by weight. In one embodiment, the carrier may be mixed with the active agent. In another embodiment, the carrier may also adsorb, entrap, or encapsulate at least a portion of the active agent.

[0094] Non-limiting examples of compounds that can be used as at least a portion of the carrier include, but are not limited to, cetyl alcohol and esters thereof; stearic acid and glycerol esters thereof, polyoxyethylene alkyl ethers; polyethylene glycols; polyglycolyzed glycerides; polyoxyethylene alkylphenols; polyethylene glycol fatty acid esters; polyoxyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; proteins; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; tocopherol derivatives, sugar esters; sugar ethers; sucroglycerides; waxes, shellacs, pharma- ceutically acceptable salts thereof, and mixtures thereof.

[0095] Non-limiting examples of release modifying agents include, but are not limited to, polyethylene glycols having a weight average molecular weight of about 1000 or greater, carbomers, methyl methacrylate copolymers, methacrylate copolymers, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose acetate phthalate, ethyl cellulose, methyl cellulose and derivatives thereof; ion-exchange resins; mono-, di-, and tri-esters of fatty acids and glycerol; tocopherol and its esters; sucrose esters with fatty acids; polyvinylpyrrolidone; xanthan gum; cetyl alcohol; waxes; fats and oils, proteins, alginates, polyvinyl polymers, gelatin, organic acids, and derivatives thereof, and combinations thereof.

[0096] In one embodiment, the carrier may comprise at least one of cellulose; carbomer; methacrylate; dextrin; gum; inorganic carbonate ester or salt of calcium or magnesium or both; fatty acid ester; gelatin; lactose; maltose; mono-, di-, or triglyceride; oil; polyethylene glycol; polyethylene oxide copolymer; protein; resin; shellac; silicate; starch; sugar stearates; partially or fully hydrogenated vegetable oils; wax; and combinations thereof.

[0097] In yet another embodiment, the carrier may comprise at least one of cellulose; carbomer; methacrylate; inorganic carbonate ester or calcium salt; inorganic carbonate ester or magnesium salt; fatty acid; fatty acid ester; gelatin; lactose; polyethylene glycol; polyethylene oxide copolymer; silicate; partially or fully hydrogenated vegetable oil, and combinations thereof.

[0098] In yet another embodiment, the carrier may comprise at least one of microcrystalline cellulose; hydroxypropyl methylcellulose; ethyl cellulose; silicon dioxide; colloidal silicon dioxide; magnesium aluminosilicate; lactose; xanthan gum; stearic acid; glyceryl distearate; hydrogenated vegetable oils; and combinations thereof.

[0099] In another example, the 3-BP formulations of the present disclosure may include various additives, including, but not limited to, fillers such as lactose, starch, sugars, cellulose, calcium salts, silicon oxide, and metallosilicates; disintegrants such as starch glycolates, lauryl sulfate, pregelatinized starch, croscarmelose, and crospovidone; pyrrolidones, methacrylates, vinyl acetate, gums, acacia; tragacanth; kaolin; binders such as carrageenan alginates, and gelatin; cosolvents such as alcohols, polyethylene glycols having an average molecular weight less than 1000, and propylene glycol; surface tension modifiers such as hydrophilic or amphiphlic surfactants; taste-masking agents such as sorbitol, ... agents); sweeteners; microencapsulating agents; lubricants, glidants, processing aids such as talc, stearates, and lecithin; polymeric coating agents; plasticizers; buffering agents; organic acids; antioxidants; flavors; colors; alkalizing agents; humectants; sorbitol; mannitol; osmotic salts; proteins; resins; moisture repelling agents; moisture absorbents; desiccants; and combinations thereof. EXAMPLES

[0100] The following examples relate to particular embodiments and illustrate specific features, elements, or steps that can be used or combined in achieving said embodiments.

[0101] In one example, a liquid dispersible solid dosage form may include an active agent dispersed in a pharma- ceutically acceptable carrier, a highly reactive component, and a reactive isolation barrier disposed between the active agent and the highly reactive component such that the active agent is stabilized and no chemical contact occurs between them.

[0102] In one example, the reactive isolation barrier is a reactive isolation barrier layer that surrounds the active agent.

[0103] In one example, the reactive isolation barrier layer is a reactive isolation barrier coating that surrounds the active agent.

[0104] In one example, the highly reactive component is a highly reactive component coating that surrounds a reactive isolation barrier coating.

[0105] In one example, the liquid dispersible formulation further comprises a degradable protective coating surrounding the highly reactive ingredient coating.

[0106] In one example, the reactive component is a reactive component powder that surrounds a reactive isolation barrier coating.

[0107] In one example, the active agent is a plurality of active agent particles, each including a reactive isolating barrier coating, where the plurality of active agent particles are dispersed among the highly reactive component particles.

[0108] In one example, the active agent is encapsulated with a reactive isolating barrier layer.

[0109] In one example, the highly reactive component is a biological buffer selected from the group consisting of citrate, succinate, malate, edetate, histidine, acetate, adipate, aconitate, ascorbate, benzoate, carbonate, bicarbonate, maleate, glutamate, phosphate, tartrate, and combinations thereof.

[0110] In one example, the biological buffer is a member selected from the group consisting of citrate, acetate, phosphate, and combinations thereof.

[0111] In one example, the reactive isolation barrier includes a disintegrant selected from the group consisting of starch, sodium starch glycolate, clay, cellulose, methylcellulose, carboxymethylcellulose, alginates, pregelatinized corn starch, crospovidone, gums, and combinations thereof.

[0112] In one example, the liquid dispersible anticancer drug may include a cellular energy inhibitor dispersed in a pharma- ceutically acceptable carrier, a highly reactive component, and a reactive isolation barrier disposed between the active agent and the highly reactive component such that the active agent is stabilized and no chemical contact occurs therebetween, wherein the cellular energy inhibitor has a structure according to Formula I. [ka] In the formula, X is selected from the group consisting of nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, and amine oxide, and R is selected from the group consisting of OR', N(R'')2, C(O)R''', C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, and alkali metal, where R' represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl, or C(O)R''', R'' represents H, C1-C6 alkyl, or C6-C12 aryl, and R''' represents H, C1-C20 alkyl, or C6-C12 aryl.

[0113] In some instances, the liquid dispersible formulation may further comprise at least one sugar, which stabilizes the cellular energy inhibitor by substantially protecting the cellular energy inhibitor from hydrolysis.

[0114] In some instances, the highly reactive component is a biological buffer, and the biological buffer is present in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic by-products of the cellular energy inhibitor.

[0115] In one example, the cellular energy inhibitor is a 3-halopyruvate selected from 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate, 3-iodopyruvate, or a combination thereof.

[0116] In one example, the cellular energy inhibitor is 3-bromopyruvate.

[0117] In one example, the at least one sugar may be selected from gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetriitol, polyglycitol, or combinations thereof.

[0118] In one example, the at least one sugar can be a pentose.

[0119] In one example, the at least one sugar may be at least two pentose sugars.

[0120] In one example, the composition may include a second sugar selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xyolitol, dulcitol, ribitol, inositol, sorbitol, and combinations thereof.

[0121] In one example, the composition may include a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xyolitol, dulcitol, ribitol, inositol, sorbitol, and combinations thereof.

[0122] In one example, the at least one sugar may include glycerol, inositol, and sorbitol.

[0123] In one example, the composition comprises glycerol in the range of about 0.1% to about 3% by weight, inositol in the range of about 1% to about 5% by weight, and sorbitol in the range of about 30% to about 50% by weight.

[0124] In one example, the composition may include d-lactic acid and epinephrine.

[0125] In one example, the composition can include a glycolysis inhibitor, where the glycolysis inhibitor is 2-deoxyglucose at a concentration of about 1 mM to about 5 mM.

[0126] In one example, the composition may include the glycolysis inhibitor 2-deoxglucose.

[0127] In one example, the composition may contain 2-deoxyglucose at a concentration of about 1 mM to about 5 mM.

[0128] In one example, the biological buffer is selected from one or more of a citrate buffer, a phosphate buffer, and an acetate buffer.

[0129] In one example, the biological buffer is a citrate buffer.

[0130] In one example, the biological buffer is a phosphate buffer.

[0131] In one example, the composition comprises: phospholipids; liposomes; nanoparticles; immune system modulators and / or immune system boosters including brown rice extracts, muramyl dipeptide including analogs, mushroom extracts, bioflavonoids, vitamin D3 binding protein-derived macrophage activating factor (GcMAF), Nagalase inhibitors, threonine associated with N-acetylgalactosamine, and antibodies against Nagalase; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; inhibitors of cell cycle, growth and / or proliferation. the at least one additive selected from the group consisting of agents; inhibitors of signal transduction pathways; inhibitors of angiogenesis; small RNAs that interfere with normal gene regulation, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, and small interfering RNA; vitamin C; nutritional supplements including vitamins, coenzyme Q10 (CoQ10), flavonoids, free fatty acids, alpha lipoic acid, acai, goji berry (gogi), mango, pomegranate (pomergrante), L-carnitine, and selenium; amino acids having lower biological activity than their isomers; and mixtures thereof.

[0132] In one example, the composition can include a hexokinase inhibitor.

[0133] In one example, the hexokinase inhibitor inhibits the binding of hexokinase 1 and / or hexokinase 2 to VDAC.

[0134] In one example, the hexokinase inhibitor is an amino acid sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10.

[0135] In one example, the composition can include a mitochondrial inhibitor.

[0136] In one example, the mitochondrial inhibitor is selected from oligomycin, efrapeptin, aurovertin, and mixtures thereof, and is present at a concentration of about 0.01 mM to about 0.5 mM.

[0137] In one example, the mitochondrial inhibitor is present at a concentration of about 0.01 mM to about 0.5 mM.

[0138] In one example, the reactive isolation barrier is a reactive isolation barrier layer surrounding 3-bromopyruvic acid.

[0139] In one example, the reactive isolation barrier layer is a reactive isolation barrier coating surrounding 3-bromopyruvic acid.

[0140] In one example, the highly reactive component is a physiological buffer coating that surrounds a reactive isolation barrier coating.

[0141] In one example, the liquid dispersion formulation further comprises a degradable protective coating surrounding the physiological buffer coating.

[0142] In one example, the biological buffer is a physiological buffer powder that surrounds the reactive isolation barrier coating.

[0143] In one example, the 3-bromopyruvic acid is a plurality of 3-bromopyruvic acid particles, each of which comprises a reactive isolation barrier coating, wherein the plurality of 3-bromopyruvic acid particles are dispersed in a physiological buffer particle.

[0144] In one example, 3-bromopyruvic acid is encapsulated within a reactive isolating barrier layer.

[0145] In one example, the reactive isolation barrier includes a disintegrant selected from the group consisting of starch, sodium starch glycolate, clay, cellulose, methylcellulose, carboxymethylcellulose, alginates, pregelatinized corn starch, crospovidone, gums, and combinations thereof.

[0146] In one example, the liquid dispersible anticancer drug may include a cellular energy inhibitor mixed with a highly reactive component dispersed in a pharma- ceutically acceptable carrier, where the cellular energy inhibitor has a structure according to Formula I. [ka] wherein X is selected from the group consisting of nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, and amine oxide; and R is selected from the group consisting of OR', N(R'')2, C(O)R''', C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, and alkali metal; wherein R' represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl, or C(O)R''', R'' represents H, C1-C6 alkyl, or C6-C12 aryl, and R''' represents H, C1-C20 alkyl, or C6-C12 aryl.

[0147] In some instances, the liquid dispersible formulation may further comprise at least one sugar, which stabilizes the cellular energy inhibitor by substantially protecting the cellular energy inhibitor from hydrolysis.

[0148] In some instances, the highly reactive component is a biological buffer, and the biological buffer is present in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic by-products of the cellular energy inhibitor.

[0149] In one example, the cellular energy inhibitor is a 3-halopyruvate selected from 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate, 3-iodopyruvate, or a combination thereof.

[0150] In one example, the cellular energy inhibitor is 3-bromopyruvate.

[0151] In one example, the at least one sugar may be selected from gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo-inositol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetriitol, polyglycitol, or combinations thereof.

[0152] In one example, the at least one sugar can be a pentose.

[0153] In one example, the at least one sugar may be at least two pentose sugars.

[0154] In one example, the composition may include a second sugar selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xyolitol, dulcitol, ribitol, inositol, myo-inositol, sorbitol, and combinations thereof.

[0155] In one example, the composition may include a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xyolitol, dulcitol, ribitol, inositol, myo-inositol, sorbitol, and combinations thereof.

[0156] In one example, the at least one sugar may include glycerol, myo-inositol, and sorbitol.

[0157] In one example, the composition may contain one or more sugars in a range of about 0.5% to about 50.0% by weight, or about 1.0% to about 25.5% by weight. In yet another example, the composition may contain one or more sugars in a range of about 0.2% to about 75.0% by weight, or about 0.5% to about 50.0% by weight. In a further example, the composition may contain one or more sugars in a range of about 0.1% to about 25.0% by weight, or about 0.2% to about 10.0% by weight.

[0158] In some examples, the composition may contain glycerol in the range of about 0.1% to about 5.0% by weight, or about 0.1% to about 3.0% by weight. In another example, the composition may contain inositol in the range of about 0.1% to about 10% by weight, or about 0.1% to about 6% by weight. In a further example, the composition may contain sorbitol in the range of about 0.1% to about 40.0% by weight, or about 0.1% to about 30% by weight. In yet a further example, the composition may contain mannitol in the range of about 0.1% to about 30% by weight, or about 0.1% to about 10% by weight. Additionally, each sugar may be added to the formulation or composition in a volume up to the maximum solubility of the sugar.

[0159] In one example, the composition may include d-lactic acid and epinephrine.

[0160] In one example, the composition can include a glycolysis inhibitor, where the glycolysis inhibitor is 2-deoxyglucose at a concentration of about 1 mM to about 5 mM.

[0161] In one example, the composition may include the glycolysis inhibitor 2-deoxglucose.

[0162] In one example, the composition may contain 2-deoxyglucose at a concentration of about 1 mM to about 5 mM.

[0163] In one example, the biological buffer is selected from one or more of a citrate buffer, a phosphate buffer, and an acetate buffer.

[0164] In one example, the biological buffer is a citrate buffer.

[0165] In one example, the biological buffer is a phosphate buffer.

[0166] In one example, the composition comprises: phospholipids; liposomes; nanoparticles; immune system modulators and / or immune system boosters including brown rice extracts, muramyl dipeptide including analogs, mushroom extracts, bioflavonoids, vitamin D3 binding protein-derived macrophage activating factor (GcMAF), Nagalase inhibitors, threonine associated with N-acetylgalactosamine, and antibodies against Nagalase; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; inhibitors of cell cycle, growth and / or proliferation. The composition may include at least one additive selected from the group consisting of inhibitors of signal transduction pathways; inhibitors of angiogenesis; small RNAs that interfere with normal gene regulation, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, and small interfering RNA; vitamin C; nutritional supplements including vitamins, coenzyme Q10 (CoQ10), flavonoids, free fatty acids, alpha lipoic acid, acai, goji berry (gogi), mango, pomegranate (pomergrante), L-carnitine, and selenium; amino acids having lower biological activity than their isomers; and mixtures thereof.

[0167] In one example, the composition can include a hexokinase inhibitor.

[0168] In one example, the hexokinase inhibitor inhibits the binding of hexokinase 1 and / or hexokinase 2 to VDAC.

[0169] In one example, the hexokinase inhibitor is an amino acid sequence selected from the group consisting of SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10.

[0170] In one example, the composition can include a mitochondrial inhibitor.

[0171] In one example, the mitochondrial inhibitor is selected from oligomycin, efrapeptin, aurovertin, and mixtures thereof, and is present at a concentration of about 0.01 mM to about 0.5 mM.

[0172] In one example, the mitochondrial inhibitor is present at a concentration of about 0.01 mM to about 0.5 mM.

[0173] In one example, the liquid dispersible formulation further comprises a degradable protective coating.

[0174] In one example, the 3-bromopyruvic acid is a plurality of 3-bromopyruvic acid particles dispersed in physiological buffer particles.

Claims

1. 1. An anti-cancer drug, the anti-cancer drug comprising a dry liquid dispersible composition comprised of a cellular energy inhibitor mixed with a highly reactive component and a pharma- ceutically acceptable carrier, wherein the cellular energy inhibitor has a structure according to Formula I: 【Chemistry 1】 In the above formula, R is OR', N(R'') ２ , C(O)R''', C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, or an alkali metal, R' is selected from one of H, an alkali metal, C1-C6 alkyl, C6-C12 aryl, or C(O)R''', R'' is selected from one of H, C1-C6 alkyl, or C6-C12 aryl, and R''' is selected from H, C1-C20 alkyl, or C6-C12 aryl.

2. The cellular energy inhibitor has formula II: 【Chemistry 2】 The anticancer agent of claim 1 having a structure according to

3. The cellular energy inhibitor has formula III: 【Chemistry 3】 The anticancer agent of claim 1 having a structure according to

4. The anticancer agent of claim 1, wherein the dry liquid dispersible composition further comprises at least one sugar, which stabilizes the cellular energy inhibitor by substantially preventing the cellular energy inhibitor from hydrolysis.

5. 5. The anticancer agent of claim 4, wherein the at least one sugar is selected from gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo inositol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetritoitol, polyglycitol, or a combination thereof.

6. The anticancer agent according to claim 4 , wherein the at least one sugar is a pentose.

7. The anticancer agent according to claim 4 , wherein the at least one type of sugar is at least two types of pentose.

8. 5. The anticancer agent of claim 4, wherein the dry liquid dispersible composition further comprises a second sugar selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myoinositol, or sorbitol.

9. 5. The anti-cancer agent of claim 4, wherein the dry liquid dispersible composition further comprises a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo-inositol, sorbitol, or combinations thereof.

10. The anticancer agent of claim 4 , wherein the at least one sugar comprises glycerol, myo-inositol, and sorbitol.

11. 5. The anti-cancer agent of claim 4, wherein the dry liquid dispersible composition comprises glycerol in the range of about 0.1% to about 5.0% by weight, or about 0.1% to about 3.0% by weight.

12. 5. The anti-cancer agent of claim 4, wherein the dry liquid dispersible composition comprises inositol in the range of about 0.1% to about 10% by weight, or about 0.1% to about 6% by weight.

13. 5. The anti-cancer agent of claim 4, wherein the dry liquid dispersible composition comprises sorbitol in the range of about 0.1% to about 40.0% by weight, or about 0.1% to about 30% by weight.

14. 5. The anti-cancer agent of claim 4, wherein the dry liquid dispersible composition comprises mannitol in the range of about 0.1% to about 30% by weight, or about 0.1% to about 10% by weight.

15. 5. The anti-cancer agent of claim 4, wherein the dry liquid dispersible composition comprises at least one sugar in the range of about 0.5% to about 50.0% by weight, about 1.0% to about 25.5% by weight, about 0.1% to about 25.0% by weight, or about 0.2% to about 10.0% by weight.

16. The anticancer drug of claim 1 , wherein the highly reactive component is a biological buffer in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic by-products of the cellular energy inhibitor.

17. The anticancer agent of claim 1 , wherein the biological buffer is selected from one or more of a citrate buffer, a phosphate buffer, or an acetate buffer.

18. The anticancer agent according to claim 1, further comprising 2-deoxyglucose at a concentration of about 1 mM to about 5 mM.

19. Additionally, immune system modulators and / or immune system boosters, including phospholipids; liposomes; nanoparticles; brown rice extracts, muramyl dipeptides including analogs, mushroom extracts, bioflavonoids, vitamin D3 binding protein-derived macrophage activating factor (GcMAF), Nagalase inhibitors, threonine associated with N-acetylgalactosamine, and antibodies against Nagalase; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; inhibitors of cell cycle, growth and / or proliferation; inhibitors of signal transduction pathways.

2. The anticancer agent of claim 1, comprising at least one additive selected from the group consisting of inhibitors of cytotoxic pathways; inhibitors of angiogenesis; small RNAs that disrupt normal gene regulation, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, and small interfering RNA; vitamin C; nutritional supplements including vitamins, coenzyme Q10 (CoQ10), flavonoids, free fatty acids, alpha lipoic acid, acai, goji berry (gogi), mango, pomegranate (pomergrante), L-carnitine, and selenium; amino acids having lower biological activity than their isomers; or mixtures thereof.

20. The anticancer agent according to claim 1, further comprising a hexokinase inhibitor that inhibits binding of hexokinase 1 and / or hexokinase 2 to VADC.

21. The anticancer agent of claim 20, wherein the hexokinase inhibitor has an amino acid sequence selected from SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:

10.

22. The anticancer agent of claim 1, further comprising a mitochondrial inhibitor at a concentration of about 0.01 mM to about 0.5 mM.

23. The anticancer agent of claim 22, wherein the mitochondrial inhibitor is selected from oligomycin, efrapeptin, aurovertin, or a mixture thereof.

24. The anticancer agent according to claim 1, further comprising d-lactic acid and / or epinephrine.

25. 2. The anticancer agent according to claim 1, wherein the dry liquid dispersible composition has such stability that at least 30% by weight of 3-BP remains in the dry liquid dispersible composition after 24 weeks at -20°C.

26. A liquid dispersible solid formulation, comprising: A pharma- ceutically acceptable carrier; a cellular energy inhibitor dispersed in said pharma- ceutical acceptable carrier; Highly reactive components, disposed between the cellular energy inhibitor and the highly reactive component; a reactive isolation barrier that prevents chemical contact between the cellular energy inhibitors such that the cellular energy inhibitors are stabilized; the cellular energy inhibitor having a structure according to formula I, 【Chemistry 4】 In the above formula, R is OR', N(R'') ２ , C(O)R''', C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, or an alkali metal, where R' is selected from one of H, an alkali metal, C1-C6 alkyl, C6-C12 aryl, or C(O)R''', where R'' is selected from one of H, C1-C6 alkyl, or C6-C12 aryl, and R''' is selected from H, C1-C20 alkyl, or C6-C12 aryl.

27. 27. The liquid dispersible solid formulation of claim 26, wherein the reactive isolation barrier is a coating surrounding the cellular energy inhibitor.

28. 27. The liquid dispersible solid dosage form of claim 26, wherein the highly reactive component is a coating surrounding the reactive isolation barrier.

29. 30. The liquid dispersible solid formulation of claim 28, further comprising a degradable protective coating surrounding said highly reactive component.

30. 30. The liquid dispersible solid formulation of claim 28, wherein the highly reactive component is a powder surrounding the reactive isolation barrier.

31. 31. The liquid dispersible solid formulation of claim 30, wherein the cellular energy inhibitor is a plurality of cellular energy inhibitor particles, each coated with a reactive isolation barrier, wherein the plurality of active cellular energy inhibitor particles are dispersed in the highly reactive component powder.

32. 27. The liquid dispersible solid formulation of claim 26, wherein the highly reactive component is a biological buffer selected from citrate, succinate, malate, edetate, histidine, acetate, adipate, aconitate, ascorbate, benzoate, carbonate, bicarbonate, maleate, glutamate, phosphate, tartrate, or combinations thereof.

33. 27. The liquid dispersible solid formulation of claim 26, wherein the reactive isolation barrier comprises a disintegrant selected from starch, sodium starch glycolate, clay, cellulose, methylcellulose, carboxymethylcellulose, alginate, pregelatinized corn starch, crospovidone, gum, or combinations thereof.

34. 27. The liquid dispersible solid formulation of claim 26, further comprising at least one sugar, wherein the sugar stabilizes the cellular energy inhibitor by substantially preventing the cellular energy inhibitor from hydrolysis.

35. 35. The liquid dispersible solid formulation of claim 34, wherein the at least one sugar is selected from gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo inositol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetritoitol, polyglycitol, or combinations thereof.

36. 35. The liquid dispersible solid formulation of claim 34, wherein said at least one sugar is a pentose.

37. 35. The liquid dispersible solid formulation of claim 34, wherein said at least one sugar is at least two pentose sugars.

38. 34. The liquid dispersible solid formulation of claim 33, further comprising a second sugar selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo-inositol, or sorbitol.

39. 35. The liquid dispersible solid formulation of claim 34, further comprising a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xyolitol, dulcitol, ribitol, inositol, myo-inositol, sorbitol, or combinations thereof.

40. 35. The liquid dispersible solid formulation of claim 34, wherein the at least one sugar comprises glycerol, myo-inositol, and sorbitol.

41. 35. The liquid dispersible solid formulation of claim 34, further comprising glycerol in the range of from about 0.1% to about 5.0% by weight, or from about 0.1% to about 3.0% by weight.

42. 35. The liquid dispersible solid formulation of claim 34, further comprising inositol in the range of from about 0.1% to about 10% by weight, or from about 0.1% to about 6% by weight.

43. 35. The liquid dispersible solid formulation of claim 34, further comprising sorbitol in the range of from about 0.1% to about 40.0% by weight, or from about 0.1% to about 30% by weight.

44. 35. The liquid dispersible solid formulation of claim 34, further comprising mannitol in the range of from about 0.1% to about 30% by weight, or from about 0.1% to about 10% by weight.

45. 35. The liquid dispersible solid formulation of claim 34, further comprising the at least one sugar in the range of from about 0.5% to about 50.0% by weight, from about 1.0% to about 25.5% by weight, from about 0.1% to about 25.0% by weight, or from about 0.2% to about 10.0% by weight.

46. 27. The liquid dispersible solid formulation of claim 26, wherein the highly reactive component is a biological buffer in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic by-products of the cellular energy inhibitor.

47. 27. The liquid dispersible solid formulation of claim 26, wherein the biological buffer is selected from one or more of a citrate buffer, a phosphate buffer, or an acetate buffer.

48. 27. The liquid dispersible solid formulation of claim 26, further comprising 2-deoxyglucose at a concentration of about 1 mM to about 5 mM.

49. Additionally, immune system modulators and / or immune system boosters, including phospholipids; liposomes; nanoparticles; brown rice extracts, muramyl dipeptide including analogs, mushroom extracts, bioflavonoids, vitamin D3 binding protein-derived macrophage activating factor (GcMAF), Nagalase inhibitors, threonine associated with N-acetylgalactosamine, and antibodies against Nagalase; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; inhibitors against cell cycle, growth and / or proliferation; inhibitors against signal transduction pathways.

27. The liquid dispersible solid formulation of claim 26, comprising at least one additive selected from the group consisting of: an inhibitor of angiogenesis; a small RNA that interferes with normal gene regulation, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, and small interfering RNA; vitamin C; a nutritional supplement including vitamins, coenzyme Q10 (CoQ10), flavonoids, free fatty acids, alpha lipoic acid, acai, goji berry (gogi), mango, pomegranate (pomergrante), L-carnitine, and selenium; an amino acid that has a lower biological activity than its isomer; or a mixture thereof.

50. 27. The liquid dispersible solid formulation of claim 26, further comprising a hexokinase inhibitor that inhibits the binding of hexokinase 1 and / or hexokinase 2 to VDAC.

51. 51. The liquid dispersible solid formulation of claim 50, wherein the hexokinase inhibitor has an amino acid sequence selected from SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:

10.

52. 27. The liquid dispersible solid formulation of claim 26, further comprising a mitochondrial inhibitor at a concentration of about 0.01 mM to about 0.5 mM.

53. 53. The liquid dispersible solid formulation of claim 52, wherein the mitochondrial inhibitor is selected from oligomycin, efrapeptin, aurovertin, or a mixture thereof.

54. 27. The liquid dispersible solid formulation of claim 26, further comprising d-lactic acid and / or epinephrine.

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