Liquid dispersible halogenated pyruvate formulations and related methods

Abstract

Described is an anti-cancer formulation comprising a dry liquid dispersible composition of a cellular energy inhibitor in combination with a reactive ingredient and a pharmaceutically acceptable carrier wherein the cellular energy inhibitor has the structure according to Formula I; wherein R is selected from one of OR ', N (R '') 2, C (0) R''', C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H or alkali metal, where R 'is selected from one of H, alkali metal, C1-C6 alkyl, C6-C12 aryl or C (0) R ''', where R'' is selected from one of H, C1-C6 alkyl or C6-C12 aryl, and where R '''is selected from one of H, C1-C20 alkyl or C6-C12 aryl.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 328,197, filed on April 6, 2022, the entire contents of which are incorporated herein by reference. Background Art

[0003] Pharmaceutical formulations have a variety of physical forms and combination formulations, depending on the active agent in the formulation, the route of administration, etc. For example, a solid pharmaceutical formulation includes an active agent dispersed in a solid pharmaceutical carrier. Similarly, a liquid pharmaceutical formulation includes an active agent dispersed in a liquid pharmaceutical carrier. Additional additives may vary depending on whether the dosage form is, for example, liquid or solid. General categories include diluents, disintegrants, binders, adhesives, wetting agents, lubricants, glidants, dyes, flavoring agents, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0004] Figure 1 shows a dry liquid dispersible formulation according to example embodiments;

[0005] Figure 2 shows a dry liquid dispersible formulation according to example embodiments;

[0006] Figure 3 shows a dry liquid dispersible formulation according to example embodiments;

[0007] Figure 4 shows a dry liquid dispersible formulation according to example embodiments;

[0008] Figure 5 shows a dry liquid dispersible formulation according to example embodiments;

[0009] Figure 6 shows a dry liquid dispersible formulation according to example embodiments;

[0010] Figure 7 shows a dry liquid dispersible formulation according to example embodiments;

[0011] Fig. 8A shows a dry liquid dispersible formulation according to example embodiments;

[0012] Figure 8B shows a dry liquid dispersible formulation according to example embodiments;

[0013] Fig. 9 shows a dry liquid dispersible formulation according to example embodiments;

[0014] Fig.10 shows a dry liquid dispersible formulation according to example embodiments; and

[0015] Fig.11 Stability data over time at storage temperature for dry liquid dispersible formulations according to example embodiments are shown. DETAILED DESCRIPTION

[0016] Although the following detailed description contains many features for illustration, it will be understood by those of ordinary skill in the art that many changes and modifications may be made to the following details and are considered to be included herein. Therefore, the elaboration of the following embodiments does not cause any general loss to any claims proposed, nor does it impose limitations thereon. It should also be understood that the terms used herein are only used to describe specific embodiments and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure belongs. In addition, the same reference numerals appearing in different figures represent the same elements. The numbers provided in the flow charts and processes are for the purpose of clearly illustrating the steps and operations and do not necessarily represent a specific order or sequence.

[0017] In addition, the 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 layout examples, distance examples, network examples, etc., to provide a thorough understanding of various embodiments. However, those skilled in the relevant art will recognize that these detailed embodiments do not limit the overall concepts explained herein, but are merely representative thereof. Those skilled in the relevant art will also recognize that the technology may be practiced without one or more specific details, or may be practiced using 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 various aspects of the present disclosure.

[0018] In this application, the words "comprises," "comprising," "containing," and "having" have the meanings ascribed to them by patent law, may also refer to words such as "includes," "including," and are generally interpreted as open-ended terms. The terms "consisting of" or "consists of" are closed terms that include only the components, structures, steps, or the like specifically listed with such terms and that are consistent with patent law. "Consisting essentially of" or "consists essentially of" have the meanings generally ascribed to them by patent law. In particular, these terms are generally closed terms, with the exception that the inclusion of additional items, materials, components, steps, or elements that do not materially affect the basic and novel characteristics or functions of the items with which they are associated is permitted. For example, trace elements present in a composition that do not affect the properties or characteristics of the composition are permitted if present under the phrase "consisting essentially of," even if not explicitly listed in the list of items using such terminology. When open-ended terms such as "comprising" or "including" are used in this written description, they should be understood to also directly support the terms "consisting essentially of" and "consisting of," as if explicitly stated, and vice versa.

[0019] As used herein, the term "substantially" refers to the complete or nearly complete range or degree of an action, characteristic, attribute, state, structure, item, or result. For example, an object that is "substantially" closed means that the object is completely closed or almost completely closed. In some cases, the exact degree of deviation from absolute completeness may depend on the specific context. However, in general, the degree of near completion should be the same as the overall result of absolute and complete completion. When "substantially" is used in a negative sense to refer to the complete absence or near complete absence of an action, characteristic, attribute, state, structure, item, or result, its usage also applies. For example, a composition that is "substantially free of" particles is either completely free of particles or almost completely free of particles, and its effect is the same as that of completely free of particles. In other words, a composition that is "substantially free of" a certain component or element may actually still contain the item as long as there is no measurable effect.

[0020] As used herein, the term "about" means to provide flexibility for a given term, measurement, value, range end point, etc. One of ordinary skill in the art can easily determine the degree of flexibility for a particular variable. However, unless otherwise indicated, the term "about" generally provides less than 0.01% flexibility. It should be understood that even if the term "about" is used in this specification in relation to a specific numerical value, support for an exact numerical value other than "about" is provided.

[0021] As used herein, for convenience, a plurality of items, structural elements, combination elements and / or materials may be presented in the form of a general list. However, such lists should be understood as if each member of the list is individually identified as a separate and unique member. Therefore, no single member in such a list should be understood as a de facto equivalent of any other member in the same list unless otherwise stated.

[0022] Concentration, quantity and other numerical data can be represented or presented in range format.It should be understood that the use of this range format is only for convenience and simplicity, and therefore should be flexibly interpreted as not only including the numerical value clearly stated as the range limit, but also including all single numerical values ​​or sub-ranges contained in the range, just as each numerical value and sub-range are clearly stated.As an illustration, the numerical range of "about 1 to about 5 (about 1 to about 5)" should be interpreted as not only including the numerical value of about 1 to about 5 clearly listed, but also including each numerical value and sub-range in the specified range.Therefore, the numerical range includes single values ​​such as 2, 3 and 4 and sub-ranges such as from 1 to 3, from 2 to 4 and from 3 to 5, and single values ​​such as 1, 1.5, 2, 2.3, 3, 3.8, 4, 4.6, 5 and 5.1.This principle is also applicable to the scope of only listing one numerical value as the minimum or maximum value.In addition, no matter how wide or narrow the range is or how the characteristics described are, this explanation should be applicable.

[0023] The "example" mentioned throughout this specification means that a particular feature, structure or characteristic associated with the example is included in at least one embodiment. Therefore, phrases including "an example" or "an embodiment" appearing in various places in this specification do not necessarily refer to the same example or embodiment.

[0024] The terms "first," "second," "third," "fourth," and the like, if any, in the specification and claims are used to distinguish between similar elements and not necessarily to describe a particular order or timing. It should be understood that the terms so used are interchangeable where appropriate, such that, for example, the embodiments described herein are capable of operating in an order other than that illustrated or otherwise described herein. Similarly, if the methods described herein include a series of steps, the order in which the steps are described herein is not necessarily the only order in which the steps may be performed, and certain of the steps described may be omitted and / or certain other steps not described herein may be added to the method.

[0025] The formulations of the present invention may include pharmaceutically acceptable carriers and other ingredients determined by the specific needs of a particular dosage formulation. Such ingredients are well known to those of ordinary skill in the art. See, e.g., Gennaro, A. Remington: The Science and Practice of Pharmacy , 19th edition (1995), the entire contents of which are incorporated by reference.

[0026] As used herein, "subject" refers to a mammal that can benefit from administering the pharmaceutical composition or method of the present invention. Examples of subjects include humans and other animals, such as horses, pigs, cattle, sheep, goats, dogs (canines), cats (felines), rabbits, rodents, primates, and aquatic mammals. In one embodiment, the subject may refer to a human.

[0027] As used herein, "drug", "active agent", "bioactive agent", "pharmaceutically active agent", "therapeutically active agent" and "pharmaceutical" are used interchangeably to refer to an agent or substance that has a specified or selected physiological activity that can be measured when administered to a subject in a significant or effective amount. It should be understood that this definition explicitly includes the term "drug" because many drugs and prodrugs are known to have specific physiological activities. These technical terms are well known in the pharmaceutical and medical arts. In addition, when these terms are used, or when a specific active agent is specifically indicated by name or class, it should be understood that such description is intended to include the active agent itself, as well as pharmaceutically acceptable salts, or compounds significantly related thereto, including but not limited to prodrugs, active metabolites, isomers, etc. The terms "cellular energy inhibitor", "glycolysis inhibitor", "mitochondrial inhibitor", etc. are all considered active agents.

[0028] As used herein, the term "inhibit," "inhibiting," or any other derivative thereof, refers to the process of restraining, stopping, or constraining to block, prevent, limit, or reduce the rate of an action or function. The use of this term should not be misunderstood as merely absolute prevention, but can refer to any small incremental step that limits or reduces a function by completely and absolutely preventing it.

[0029] As used herein, "cellular energy inhibitor" refers to a compound that inhibits the production of ATP in a cell. In some examples, the cellular energy inhibitor can inhibit glycolysis, oxidative phosphorylation, or glycolysis and oxidative phosphorylation in a cell.

[0030] As used herein, "glycolysis inhibitor" refers to a compound that inhibits, reduces or stops glycolysis in a cell.

[0031] As used herein, "mitochondria inhibitor" refers to a compound that inhibits, reduces or stops the production of ATP by mitochondria in a cell.

[0032] As used herein, the terms "dosage form", "formulation" and "composition" are used interchangeably to 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 a carrier and / or other excipients.

[0033] As used herein, "carrier" or "pharmaceutically acceptable carrier" refers to a substance that can be combined with a drug to achieve a specific dosage formulation for delivery to a subject. In some instances, the carrier may or may not enhance the effect of drug administration. As a general rule, the carrier will not react with the drug in a manner that severely degrades the drug or has other adverse effects on the drug, but some carriers may react with the drug so that the drug cannot exert its therapeutic effect before being released from the carrier. In addition, the carrier or at least a portion thereof must be physiologically suitable for administration into the subject together with the drug.

[0034] The term "excipient" herein includes, for example, any substance used as a carrier for an active agent in a liquid formulation, any substance added to an active agent and / or a solid formulation, for example, to improve its handling characteristics, to form the resulting composition into a suitable storage form, to promote disintegration in a liquid, etc. Excipients may include, by way of example and without limitation, diluents, disintegrants, binders, adhesives, wetting agents, lubricants, glidants, dyes, and any other substance other than the active ingredient conventionally used in the preparation of liquid or solid formulations.

[0035] 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 in at least one carrier substance.

[0036] The following provides a preliminary overview of the embodiments, and then further describes the specific embodiments in detail. This preliminary overview is intended to help readers understand the present disclosure more quickly, but is not intended to identify key or essential technical features, nor is it intended to limit the scope of the claimed subject matter.

[0037] Detailed description

[0038] Many liquid preparations can include an activating agent dispersed in a liquid carrier such as, for example, a buffer solution or the like. However, liquid preparations have several disadvantages. For example, liquid preparations may be inconvenient to store and transport, partly because their liquid volume increases. In addition, many activating agents are more likely to react with liquid carriers or other excipients in a liquid state, thereby possibly reducing the effectiveness / effect of the liquid preparation.

[0039] One solution to these problems is to keep the active agent and possible other excipients as dry ingredients (i.e., "dry form") for ease of transport and storage. When a liquid formulation is desired, the dry ingredients can be mixed with a liquid carrier. In this way, the total volume of the shipping portion of the formulation can be minimized while maintaining the potency of the active agent. It may be convenient to include at least some of the liquid formulation ingredients in dry form. For example, including a buffer in dry form can greatly facilitate the process of mixing the dry form ingredients with a liquid carrier prior to use, particularly if the dry form is contained in a premix container and only needs to be added to an appropriate volume of liquid carrier. However, many active agents react with other ingredients such as buffers that are present in dry form.

[0040] The present disclosure provides preparations and systems with storage forms and usage forms. As used herein, "usage form" refers to a liquid preparation prepared for use, such as, for example, can be administered to a subject at any time. On the other hand, storage form refers to a preparation that is not ready for use. This storage form includes at least two ingredients, wherein at least one formulation ingredient is condensed into a powder, compressed powder, solid or the like. The storage form can additionally include all formulation ingredients condensed into a powder, compressed powder, solid or the like. In some instances, the storage form can include two or more formulation ingredients that can react with each other immediately or over a period of time.

[0041] The present disclosure also provides methods for treating various diseases associated with mitochondrial dysfunction, including but not limited to metabolic diseases, neurodegenerative diseases, chronic inflammatory diseases, aging diseases, photoaging, hyperproliferative diseases including psoriasis and cancer, etc.

[0042] The terms "reaction" and "reaction" include any form of chemical change that occurs when a formulation component comes into contact with another formulation component, including a reaction that activates one or more molecules or components (e.g., a precursor of an active agent is converted to an active agent), a reaction that degrades at least one component, or the like.

[0043] In some cases, the use form is a liquid formulation comprising an active agent and a reactive component, and the reactive component reacts with the active agent when in the storage form. The storage form is a concentrated formulation of the active agent and the reactive component, which is formulated to reduce or eliminate the reactivity between the active agent and the reactive component. Therefore, this storage form can be stored for a long time until ready for use by mixing the concentrated formulation of the storage form with an appropriate liquid carrier (e.g., water) to produce a use form (i.e., a liquid formulation).

[0044] The storage form of the present disclosure may vary depending on the nature of the intended liquid formulation, active agent, excipients, any reactive components, etc. Such storage forms may be anhydrous or dry.

[0045] Various techniques can be used to reduce or eliminate the reactivity of the active agent and the reactive component in the storage form. In a non-limiting example of the storage form of the present disclosure, the active ingredient is mixed with the reactive component and stored in a manner that reduces the reaction between the active agent and the reactive component. In such an example, the active agent and the reactive component can be mixed together in the storage form, which can include storage at a specific temperature, packaging and storage in an oxygen-free and / or non-humid environment, etc. In some cases, the storage form is only used in a time window in which the reaction degree of the two can be accepted.

[0046] In another example, in the storage form, the mutually reactive first component and the second reactive component can be isolated from each other by a reaction isolation barrier. Figure 1In the embodiment, a tablet 100 including a first component 102 and a second component 104 is shown, wherein the first component and the second component react with each other. In order to avoid such reactivity in the storage form, the first component 102 and the second component 104 can be isolated from each other by a reaction isolation barrier 106. In this way, the reaction isolation barrier 106 isolates the first reactive component 102 from the second reactive component 104 in terms of reaction. In some examples, the reaction isolation barrier can be composed of a decomposable material that disintegrates when it contacts a liquid carrier. When the tablet 100 enters the liquid, the second reactive component 104 disintegrates and / or dissolves into the liquid, and then the reaction isolation barrier 106 disintegrates and / or dissolves, which releases the active agent 102 into the liquid to form a liquid preparation in a use form. In some examples, the first component 102 can be in the form of a gel or concentrated liquid. In another example, a tablet is considered, wherein the second component is located in the center of the tablet, which is surrounded by the reaction isolation barrier, and the reaction isolation barrier is surrounded by the first component.

[0047] exist Figure 1 In a more specific example, the tablet 100 may include an active agent 102, a reactive component 104, and a reactive isolation barrier 106 placed between the active agent 102 and the reactive component 104. Therefore, the reactive isolation barrier 106 isolates the active agent 102 from the reactive component 104 in the reaction. When the tablet 100 enters the liquid, the reactive component 104 disintegrates and / or dissolves into the liquid, followed by the reactive isolation barrier 106 disintegrates and / or dissolves, and then the active agent 102 disintegrates and / or dissolves to form a liquid preparation in a use form. In some examples, the active agent 102 may be in the form of a gel or concentrated liquid. In another example, a tablet is considered, in which the reactive component is located in the center of the tablet, which is surrounded by the reactive isolation barrier, and the reactive isolation barrier is surrounded by the active agent.

[0048] The reaction isolation barrier can be any pharmaceutically acceptable material layer, and it can isolate the active agent from the reactant in the reaction. In some instances, the reaction isolation barrier can be or include molecules, compounds, etc. that are the expected components of the produced liquid preparation. For example, the decomposable material can be or include an excipient that does not react with or does not substantially react with the active agent in the storage form. In other instances, the reaction isolation barrier can be molecules, compounds, etc. that provide unexpected beneficial effects for the liquid preparation. In still other instances, the reaction isolation barrier can be molecules, compounds, etc. that have no effect or no substantial effect on the liquid preparation.

[0049] As another example, Figure 2A tablet 200 is shown that includes an active agent 202, a reactive component 204, and an internal reactive isolation barrier 206 disposed between the active agent 202 and the reactive component 204. Thus, the internal reactive isolation barrier 206 reactively isolates the active agent 202 from the reactive component 204. The tablet additionally includes an external reactive isolation barrier 208 that provides a protective layer for the reactive component 204, at least in one aspect.

[0050] The external reaction isolation barrier 208 may be the same material as the internal reaction isolation barrier 206, or may be a different material from the internal reaction isolation barrier 206. It is also contemplated that the external reaction isolation barrier 208 may include the same material as the internal reaction isolation barrier 206, and a different material that is not present in the internal reaction isolation barrier 206. In other examples, the internal reaction isolation barrier 206 may include the same material as the external reaction isolation barrier 208, and a different material that is not present in the external reaction isolation barrier 208.

[0051] When tablet 200 is introduced into a liquid, external reaction isolation barrier 208 disintegrates and / or dissolves into the liquid, thereby exposing reaction component 204. Once exposed to the liquid, reaction component 204 disintegrates and / or dissolves into the liquid, followed by internal reaction isolation barrier 206 and active agent 202 also disintegrating and / or dissolving to form a liquid formulation in a use form. In some instances, active agent 202 may be in the form of a gel or concentrated liquid. In another example, consider a tablet in which the reaction component is located in the center of the tablet, which is surrounded by a reaction isolation barrier, which in turn is surrounded by the active agent and the external reaction isolation barrier. It should be noted that the active agent and reaction component may be present in any of the above-mentioned regions / barriers, as long as the active agent is isolated from the reaction component in the reaction.

[0052] In yet other instances, Figure 3A solid formulation 300 is shown, which includes a plurality of active agent particles 302 dispersed in a reactive component 304, wherein each active agent particle 302 is surrounded by an internal reaction isolation barrier 306 to reactively isolate the active agent in each active agent particle 302 from the reactive component 304. In some examples, the solid formulation 300 may additionally include an external reaction isolation barrier 308 to provide a protective layer around the reactive component 304, at least in one aspect. The external reaction isolation barrier 308 may be the same material as the internal reaction isolation barrier 306, or may be a different material from the internal reaction isolation barrier 306. It is also contemplated that the external reaction isolation barrier 308 may include the same material as the internal reaction isolation barrier 306, as well as a different material that is not present in the internal reaction isolation barrier 306. In other examples, the internal reaction isolation barrier 306 may include the same material as the external reaction isolation barrier 308, as well as a different material that is not present in the external reaction isolation barrier 308.

[0053] In one example, the reactive component 304 can be in the form of a solid tablet. In another example, the reactive component 304 can be in the form of a powder. In a specific example of such a powder form, the external reaction isolation barrier 308 can contain the reactive component 304 in a discrete dosage form. When the formulation is introduced into a liquid, the external reaction isolation barrier 308 will dissolve or otherwise decompose into the liquid, thereby exposing the powder reactive component 304. Once exposed to the liquid, the reactive component 304 and the internal reaction isolation barrier 306 surrounding each active agent particle 302 will dissolve or otherwise decompose into the liquid, thereby exposing the active agent, which will dissolve or decompose to form a liquid formulation in a use form. Due to the faster diffusion rate of the liquid through the powder reactive component 304 and the greatly increased surface area of ​​the reaction isolation barrier and the active agent portion in the storage form, this dosage form generates a liquid formulation much faster than a tablet. In an example without an external reaction isolation barrier, the reactive component 304 containing multiple active agent particles 302 can be used as a powder.

[0054] In another example, a solid formulation is considered to have a plurality of reactive component particles dispersed in an active agent, wherein each reactive component particle is surrounded by an internal reaction isolation barrier to isolate the reactive component particles from the active agent in a reaction. It should also be noted that the active agent and the reactive component can be present in any of the above-mentioned regions / barriers, as long as the active agent is isolated from the reactive component in a reaction.

[0055] In some cases, the present storage forms may include a pharmaceutically acceptable diluent, for example, as a filler to increase weight, improve content uniformity, etc. Suitable diluents include, alone or in combination, and are not limited to, lactose; anhydrous lactose; lactose monohydrate; starch; directly compressible starch; hydrolyzed starch; partially pregelatinized starch; sodium starch glycolate; mannitol; sorbitol; xylitol; dextrose monohydrate; calcium phosphate dihydrate; sucrose diluents; confectioner's sugar; calcium sulfate monohydrate; calcium sulfate dihydrate NF; calcium lactate trihydrate granules; dextran; glucose; cyclohexanehexol; hydrolyzed grain solids; amylase; powdered cellulose; calcium carbonate; glycine; bentonite; polyvinyl pyrrolidone; clay; cellulose; purified cellulose; methylcellulose; sodium carboxymethylcellulose, carboxymethylcellulose; microcrystalline cellulose; alginate; pregelatinized corn starch; crospovidone; gum; agar; guar gum; locust bean; karaya; pectin; tragacanth gum, etc. The use of extragranular microcrystalline cellulose (i.e., microcrystalline cellulose added to the wet granular composition after the drying step) can, for example, be used to increase hardness and / or disintegration time. Many diluents provide storage forms with suitable disintegration rates, stability, pre-compression flowability, and / or drying characteristics. Diluents can also provide a high-density matrix that aids disintegration during granulation (when wet granulation is employed), thereby improving the flow characteristics of the mixture.

[0056] In some cases, the present storage form may include a pharmaceutically acceptable binder or adhesive. Such binders and adhesives can provide sufficient cohesion for the tableted powder to improve processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate. Suitable binders and adhesives include, alone or in combination, and are not limited to: acacia; tragacanth; sucrose; gelatin; glucose; starch; cellulosic materials such as, but not limited to cellulose, microcrystalline cellulose, cellulose ethers, hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose; ethyl cellulose; alginic acid and alginates; magnesium aluminum silicate; polyethylene glycol; guar gum; polysaccharide acids; bentonite; polyvinyl pyrrolidone; polymethacrylates; hydroxypropyl methylcellulose; hydroxypropyl cellulose; pregelatinized starch; sugars and suitable derivatives; disaccharides; sucrose; lactose; polysaccharides and suitable derivatives; sugar alcohols, such as, but not limited to xylitol, sorbitol or mannitol; proteins; gelatin, etc.

[0057] Solution binders can be dissolved in the solvent used in the wet granulation process. Examples of solution binders include gelatin, cellulose, cellulose derivatives, polyvinyl pyrrolidone, starch, sucrose, polyethylene glycol, etc. Dry binders can be added to the powder mixture after the wet granulation step or as part of the direct powder compression formulation. Examples of dry binders include cellulose, methylcellulose, polyvinyl pyrrolidone, polyethylene glycol, etc.

[0058] The amount of binding agent and / or adhesive can be any amount sufficient to achieve the desired result. In one example, binding agent and / or adhesive can account for about 0.5% to about 25% of the total weight of the storage form. In another example, binding agent and / or adhesive can account for about 0.75% to about 15% of the total weight of the storage form. In another example, binding agent and / or adhesive can account for about 1% to about 10% of the total weight of the storage form. As a specific example, polyvinyl pyrrolidone can be used to give the powder mixture of active agent and other excipients cohesive properties to granulate. The amount of polyvinyl pyrrolidone can be any amount sufficient to achieve the desired result. In one example, polyvinyl pyrrolidone can account for about 0.5% to about 10% of the total weight of the storage form. In another example, polyvinyl pyrrolidone can account for about 0.5% to about 7% of the total weight of the storage form. In another example, polyvinyl pyrrolidone can account for about 0.5% to about 5% of the total weight of the composition.

[0059] In some cases, the storage form may include a pharmaceutically acceptable disintegrant to facilitate disintegration of the storage form into a liquid formulation when an appropriate solvent is added. Suitable disintegrants include, alone or in combination, and are not limited to starches such as corn starch, rice starch, sodium starch glycolate, etc.; cross-linked N-vinyl-2-pyrrolidone (CLPVP); alginic acid or alginates; microcrystalline cellulose; hydroxypropyl cellulose and other celluloses; cross-linked sodium carboxymethyl cellulose, such as cross-linked sodium carboxymethyl cellulose; polyvinyl polypyrrolidone; crospovidone; polacrilin potassium, etc. In one example, the disintegrant can be a gas-generating disintegrant, such as but not limited to sodium bicarbonate; potassium bicarbonate; acidic sodium carbonate; citric acid; tartaric acid, etc.

[0060] The amount of disintegrant can be any amount sufficient to achieve the desired result, and can be added in any appropriate step during the preparation of the storage form, and in some cases can be added before granulation or in the lubrication step before compression. In one example, the disintegrant can account for about 0.2% to about 30% of the total weight of the composition. In another example, the disintegrant can account for about 0.2% to about 10% of the total weight of the composition. In another example, the disintegrant can account for about 0.2% to about 5% of the total weight of the composition. In some cases, the disintegrant can be mixed with the active agent before granulation. In some cases, the disintegrant can be divided into two parts: one part is added to the powder formulation before granulation, and the rest is added before compression after mixing with the lubricant. In this way, the part with the lubricant can quickly decompose the tablet particles, and the disintegrant mixed with the active ingredient can disintegrate the particles into smaller particles.

[0061] In one example, the storage form of the preparation can be an effervescent preparation, such as effervescent tablets, effervescent powders, etc. Effervescent tablets can be coated or uncoated, depending on the design of the tablet. Any effervescent material compatible with the preparation and capable of reacting in the presence of water to release the gas that is conducive to the disintegration of the storage form can be applicable. In one example, the effervescent material can react in the presence of water to release carbon dioxide. In some non-limiting examples, the effervescent material can include acidic substances, such as citric acid, tartaric acid, malic acid, fumaric acid, adipic acid or any other suitable acid, including its anhydride and salt. In other non-limiting examples, the effervescent material can include citric acid, tartaric acid or malic acid, including its anhydride and salt. In further examples, the effervescent material can include carbonate, bicarbonate or similar substances. More specific examples can include potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, arginine carbonate, etc.

[0062] In some cases, the present storage form may include a pharmaceutically acceptable tablet coating to protect the tablet ingredients from deterioration due to moisture in the air. Non-limiting examples of such coatings may include cellulose ether hydroxypropyl methylcellulose (HPMC) films, various synthetic polymers, shellac, corn protein zein, other polysaccharides, etc.

[0063] In some examples, the active agents of the present disclosure can inhibit the energy in certain cells to treat various diseases. In a specific example, the active agent can be a cell energy inhibitor according to formula I:

[0064]

[0065] Various specific molecules can be considered, where, for example, without limitation, X can be nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, amine oxide, etc. In addition, R can 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.

[0066] In one example, R of formula (I) can be OH, and X of formula (I) can be nitro, imidazole, halide, sulfonate, carboxylate, alkoxy, aminooxy, etc. In addition, X can be halide, such as fluoro, bromo, chloro, iodo, etc. In one example, X can be sulfonate, such as, for example, trifluoromethanesulfonate, mesylate, toluenesulfonate, etc. In another example, X can be aminooxy. In yet another example, aminooxy can be dimethylaminooxy.

[0067] In another example, the cellular energy inhibitor can be a 3-halopyruvate, such as, for example, 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate, 3-iodopyruvate, or a combination thereof. Formula II shows the general structure with a halide at the 3-position.

[0068]

[0069] In a further non-limiting example, the cellular energy inhibitor can have a bromine at the 3-position, as shown in Formula III.

[0070]

[0071] In a further non-limiting example, the cellular energy inhibitor can be 3-bromopyruvate (3-BP), as shown in Formula IV.

[0072]

[0073] In another non-limiting example, the cellular energy inhibitor can be 3-bromopyruvate, as shown in Formula V.

[0074]

[0075] In some instances, the cell energy inhibitor can be formulated into a composition containing at least one sugar, which can stabilize the cell energy inhibitor by substantially preventing the inhibitor from hydrolyzing. In some instances, the composition can include 3-BP and at least one sugar, at least two sugars, at least three sugars, etc. In one example, the sugar can include monosaccharides, disaccharides, oligosaccharides, or a combination thereof. Non-limiting examples of monosaccharides can include glucose, fructose, galactose, etc. Non-limiting examples of disaccharides can include sucrose, lactose, maltose, etc. It is worth noting that, for the purposes of this disclosure, the term "sugar" can also include oligosaccharides, polysaccharides, polyols, polyols, and similar molecules with stable 3-BP functions.

[0076] Sugar can include 3-carbon sugar, 4-carbon sugar, 5-carbon sugar, 6-carbon sugar, 7-carbon sugar etc., including combinations thereof. In one aspect, sugar can be 3-carbon sugar, 4-carbon sugar, 5-carbon sugar, 6-carbon sugar, 7-carbon sugar etc., including combinations thereof, as long as sugar does not participate in energy metabolism to the extent of producing energy (i.e., non-metabolizable sugar).

[0077] In one example, sugar can be gluconic acid. In another example, sugar can be glucuronic acid. At least one sugar can be five-carbon sugar. In one example, at least two sugars can be five-carbon sugar. Five-carbon sugar can be independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, cyclohexane hexaol, inositol, etc., including combinations thereof. In one example, at least one sugar can be glycerol. In another example, sugar can be glycerol, cyclohexane hexaol and sorbitol. Other non-limiting examples of sugar can include ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, heptane heptol, maltotriitol, maltotetraitol and polysaccharide alcohol, including combinations thereof. In one example, sugar can include glycerol, cyclohexane hexaol, inositol, sorbitol, mannitol or any combination thereof. In another example, sugar can include glycerol, cyclohexane hexaol, sorbitol or any combination thereof. In yet another example, the cyclohexane hexol can be inositol. In other examples, the sugar can be a polyol. In another example, the sugar can include a heptasaccharide, such as, for example but not limited to, a cyclodextrin, such as β-cyclodextrin.

[0078] Sugars described herein can be in any isomeric form. In one example, the compositions described herein can include sugar forms that are less biologically active than their isomers. In one case, the sugar with lower biological activity can be an L-enantiomeric sugar. However, if it is found that the biological activity of the D-enantiomeric sugar is lower than its L form, the D form can be used. In one example, this sugar can act as a glycolysis inhibitor.

[0079] In one example, the composition may include one or more sugars ranging from about 0.5wt% to about 50.0wt% or from about 1.0wt% to about 25.5wt%. In yet another example, the composition may include one or more sugars ranging from about 0.2wt% to about 75.0wt% or from about 0.5wt% to about 50.0wt%. In a further example, the composition may include one or more sugars ranging from about 0.1wt% to about 25.0wt%, from about 0.2wt% to about 10.0wt%.

[0080] In some examples, the composition may include glycerol ranging from about 0.1wt% to about 5.0wt% or from about 0.1wt% to about 3.0wt%. In other examples, the composition may include inositol ranging from about 0.1wt% to about 10wt%, from about 0.1wt% to about 6wt%. In a further example, the composition may include sorbitol ranging from about 0.1wt% to about 40.0wt% or from about 0.1wt% to about 30wt%. In a further example, the composition may include mannitol ranging from about 0.1wt% to about 30wt% or from about 0.1wt% to about 10wt%. In addition, the amount of each sugar added may reach the volume of the maximum solubility of the sugar in the formulation or composition. It should also be noted that the wt% of the above ingredients does not contain water or other liquid carriers.

[0081] In some examples, the 3-BP composition may include a biological buffer, which is present in an amount sufficient to at least partially deacidify the cell energy inhibitor and neutralize the metabolic byproducts of the cell energy inhibitor. Non-limiting examples of biological buffers may include citrate buffers, phosphate buffers, acetate buffers, etc., including combinations thereof. In a specific example, the biological buffer may be a citrate buffer, such as but not limited to sodium citrate. In another specific example, the biological buffer may be a phosphate buffer, such as but not limited to sodium phosphate. In a specific example, the biological buffer may be an acetate buffer, such as but not limited to sodium acetate. In yet other examples, the biological buffer may 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.

[0082] In some examples, the composition can include a biological buffer ranging from about 0.1 wt % to about 15 wt % or from about 2.0 wt % to about 8.0 wt %. In addition, 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 should also be noted that the wt % of the above ingredients do not contain water or other liquid carriers.

[0083] In one example, 3-BP can be mixed with a biological buffer without a reaction isolation barrier between the two. In addition, other ingredients, such as sugars, can be mixed with 3-BP and biological buffers. In some examples, the mixed solid formulation can include an outer protective coating. In other examples, the mixed solid formulation lacks an outer protective coating.

[0084] In one example, 3-BP can be included in a storage form with a biological buffer, which are reactively isolated from each other by a reactive isolation barrier. For example, Figure 4 A tablet 400 is shown that includes a 3-BP 402, a biological buffer 404, and a reaction isolation barrier 406 disposed between the 3-BP 402 and the biological buffer 404. Thus, the reaction isolation barrier 406 isolates the 3-BP 402 from the biological buffer 404 in a reaction manner. When the tablet 400 is introduced into a liquid, the biological buffer 404 dissolves or otherwise disintegrates into the liquid, followed by the reaction isolation barrier 406 dissolving or disintegrating, and then the 3-BP 402 dissolving or disintegrating to form a liquid formulation in a use form. In another example, the tablet is considered to have a biological buffer in the center of the tablet, which is surrounded by a reaction isolation barrier, which is in turn surrounded by the 3-BP.

[0085] The reaction isolation barrier can be any pharmaceutically acceptable material layer that can isolate 3-BP from the biological buffer in the reaction. In some examples, the reaction isolation barrier can be a molecule, compound, etc. that is the expected component of the liquid preparation produced. For example, the decomposable material can be or can include an excipient that does not react with 3BP or does not substantially react with 3BP. In other examples, the reaction isolation barrier can be a molecule, compound, etc. that provides an unexpected beneficial effect for the liquid preparation. In still other examples, the reaction isolation barrier can be a molecule, compound, etc. that has no effect or no substantial effect on the liquid preparation.

[0086] In a specific example, the reaction isolation barrier includes at least one sugar, at least two sugars, at least three sugars, etc. in the desired 3-BP liquid formulation. In another example, sugar can be mixed with 3-BP. In another example, sugar can be mixed with biological buffer. In another example, sugar can be added to the liquid formulation after the storage form disintegrates, or sugar can be added to the liquid before the storage form disintegrates.

[0087] As another example, Figure 5A tablet 500 is shown, including a 3-BP 502, a biological buffer 504, and an internal reaction isolation barrier 506 disposed between the 3-BP 502 and the biological buffer 504. Thus, the internal reaction isolation barrier 506 reactively isolates the 3-BP 502 from the biological buffer 504. The tablet additionally includes an external reaction isolation barrier 508, which provides a protective coating for the biological buffer 504 in at least one aspect. The external reaction isolation barrier 508 can be the same material as the internal reaction isolation barrier 506, or it can be a different material than the internal reaction isolation barrier 506. It is also contemplated that the external reaction isolation barrier 508 can include the same material as the internal reaction isolation barrier 506 and a different material that is not present in the internal reaction isolation barrier 506. In other examples, the internal reaction isolation barrier 506 can include the same material as the external reaction isolation barrier 508 and a different material that is not present in the external reaction isolation barrier 508. When the tablet 500 is introduced into a liquid, the external reaction isolation barrier 508 dissolves or otherwise decomposes into the liquid, thereby exposing the biological buffer 504. Once exposed to the liquid, the biological buffer 504 will dissolve or otherwise decompose into the liquid, followed by the internal reaction isolation barrier 506 and 3-BP 502 to form a liquid formulation in a use form. In some examples, 3-BP 502 can be in the form of a gel or concentrated liquid. In another example, a tablet is considered to have a biological buffer in the center of the tablet, which is surrounded by a reaction isolation barrier, and further surrounded by 3-BP, which is in turn surrounded by an outer reaction isolation barrier.

[0088] In a specific example, the internal reaction isolation barrier, the external reaction isolation barrier or both can include at least one sugar, at least two sugars, at least three sugars, etc. in the desired 3-BP liquid preparation. In another example, sugar can be mixed with 3-BP. In yet another example, sugar can be mixed with biological buffer. In addition, it is also considered that the internal reaction isolation barrier and / or the external reaction isolation barrier can include one or more sugars. In some examples, the one or more sugars in each reaction isolation barrier can be the same, different or various mixtures thereof. In yet another example, sugar can be added to the liquid preparation after the storage form disintegrates, or it can be added to the liquid before the storage form disintegrates.

[0089] As yet another example, Figure 6A solid dosage form 600 is shown that includes a plurality of 3-BP particles 602 dispersed in a biological buffer 604, wherein each 3-BP particle 602 is surrounded by an internal reaction 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 dosage form 600 may additionally include an external reaction isolation barrier 608 to provide a protective coating around the biological buffer 604 in at least one aspect.

[0090] External reaction isolation barrier 608 may be the same material as internal reaction isolation barrier 606 or a different material than internal reaction isolation barrier 606. It is additionally contemplated that external reaction isolation barrier 608 may include the same material as internal reaction isolation barrier 606, as well as a different material that is not present in internal reaction isolation barrier 606. In other examples, internal reaction isolation barrier 606 may include the same material as external reaction isolation barrier 608, as well as a different material that is not present in external reaction isolation barrier 608.

[0091] In one example, the biological buffer 604 can be in the form of a solid tablet. In another example, the biological buffer 604 can be in the form of a powder. In a specific example of such a powder form, the external reaction isolation barrier 608 can contain the biological buffer 604 in a discrete dosage form similar to a capsule. When the capsule is introduced into the liquid, the external reaction isolation barrier 608 will dissolve or otherwise decompose into the liquid, thereby exposing the powdered biological buffer 604. Once exposed to the liquid, the biological buffer 604 and the reaction isolation barrier 606 surrounding each 3-BP particle 602 will dissolve or otherwise decompose into the liquid, thereby exposing the 3-BP, which will dissolve or decompose to form a liquid preparation in a use form. Since the liquid can diffuse through the powdered active ingredient 604 more quickly, and the surface area of ​​the reaction isolation barrier and the active agent portion in the storage form is greatly increased, this dosage form can generate a liquid preparation faster than a tablet form. In the absence of an external reaction isolation barrier, the active ingredient 604 containing multiple 3-BP particles 602 can be used as a powder. In yet another example, the powder can be a compressed powder or a solid.

[0092] In addition to providing a reaction isolation barrier between regions, mutually reactive components in the storage form can also come into direct contact along a common boundary. Thus, by confining reactivity to a small proportion of the storage form, i.e., along the common boundary, reactivity between the active agent and the reactive component can be minimized. Figure 7In one example shown, active agent 702 is surrounded by active component 740. Although a reaction between active agent 702 and reactant 704 can occur, such reaction is confined to common boundary 706. In addition to the described arrangement of components, an active component surrounded by an active agent is additionally contemplated.

[0093] Fig. 8A and 8B Examples are shown with different component areas placed next to each other. For example, Fig. 8A A storage form is shown having three components 802, 804, and 806 arranged side by side. Thus, any reaction that occurs between these components is confined to the common boundary between them. Figure 8B A similar storage format arrangement is shown having two components 802 and 806.

[0094] In another example, the storage form can be contained in a capsule, such as but not limited to a solid compacted form or a powdered form. Fig. 9 A capsule 904 is shown containing a mixture 902 of a cell energy inhibitor or a cell energy inhibitor precursor together with at least one other excipient in the form of a powder, a compact, etc. In some cases, the capsule storage form can be directly introduced into a liquid carrier to form a use form. In other cases, the capsule can be opened and its contents poured into a liquid carrier to form a use form. The capsule can be Fig.10 An example of a capsule 1008 is shown containing a storage form having three partitioned components 1002, 1004, and 1006.

[0095] The various components of the composition in the storage form may also react when exposed to oxygen and other reactive elements / molecules in the air, including moisture in some cases. Therefore, in one technique, reactivity can be minimized or prevented by vacuum packaging the storage form. In another technique, reactivity can be minimized or prevented by packaging the storage form in an inert gas. Although the solid form can be packaged in any form, such as bottles, tubes, bags, etc., one convenient packaging form is blister packaging. Blister packaging allows the solid form to be each independent storage dosage form without exposing the remaining dose in the blister pack to the air / humidity of the local environment when used.

[0096] In a specific example, the reaction isolation barrier can include at least one sugar, at least two sugars, at least three sugars, etc. in the desired 3-BP liquid formulation. In another example, the sugar can be mixed with the 3-BP. In yet another example, the sugar can be mixed with a biological buffer. It is additionally considered that the reaction isolation barrier and / or the external reaction isolation barrier can include one or more sugars, which can be the same, different, or various mixtures of sugars in a single barrier or each barrier. In yet another example, the sugar can be added to the liquid formulation after the storage form disintegrates, or it can be added to the liquid before the storage form disintegrates.

[0097] In one embodiment, the storage form may include a powder mixture of at least 3-BP, at least one buffer, at least one sugar and an excipient. Such a mixed powder storage form has a higher stability, especially compared to a liquid use form with similar ingredients. In such a mixed powder formulation, 3-BP exhibits only slight degradation, for example after being placed at -20°C for 24 weeks or more.

[0098] As an example, over time, the stability of the 3-BP mixed powder formulation increases with changes in storage temperature, especially when stored in an inner packaging material and an outer packaging material. For example, the inner packaging material may include a polyethylene bag and the outer primary packaging material may include an aluminum bag. Table 1 shows an example of the change of a 3-BP mixed powder formulation over time at different storage temperatures, wherein the 3-BP mixed powder formulation includes 3-BP, sodium citrate, sodium phosphate, inositol, sorbitol, glycerol, microcrystalline cellulose, colloidal silicon dioxide and stearic acid. Table 1 shows an example of the change of a 3-BP mixed powder formulation over time at different storage temperatures, wherein the 3-BP mixed powder formulation includes 3-BP, sodium citrate, sodium phosphate, inositol, sorbitol, microcrystalline cellulose, colloidal silicon dioxide and stearic acid. Appearance, total 3-BP and total impurity tests are indicators of the degradation of 3-BP in the 3-BP mixed powder formulation over time and at different temperatures from room temperature to -20°C.

[0099] Table 1: Stability of 3-BP mixed powder formulations containing glycerol

[0100]

[0101] Table 2: Stability of 3-BP mixed powder formulations without glycerol

[0102]

[0103] Look again Fig.11 , both 3-BP formulations (with and without glycerol) showed no significant degradation within 24 weeks at -20°C, gradual degradation within 12 weeks at 5°C, and significant degradation within 8 weeks. Fig.11The determinations noted in the table are the % w / w of 3-BP determined by HPLC. In one example, at least 85% w / w of 3-BP remains in the formulation after 24 weeks at -20°C; in another example, at least 90% w / w of 3-BP remains in the formulation after 24 weeks at -20°C. In another example, at least 95% w / w of 3-BP remains in the formulation after 24 weeks at -20°C.

[0104] In some examples, the 3-BP composition may include a glycolysis inhibitor, a non-limiting example of which may include 2-deoxyglucose (2DOG). The 3-BP formulation may include any effective amount of a glycolysis inhibitor. Figure 4-6 In the various dosage forms described, the glycolytic inhibitor may be mixed with the 3-BP or may be present in a separate layer or in any of the above layers, provided that the glycolytic inhibitor is isolated from any components of the reservoir that react with it, such as a biological buffer. As long as it does not react with the biological buffer, the glycolytic inhibitor may be mixed therein.

[0105] In addition to the above components, the 3-BP composition described herein may further include a halogenated monocarboxylate compound separated from a cell energy inhibitor. In the case where the halogenated monocarboxylate compound can inhibit glycolysis and / or mitochondrial function, the halogenated monocarboxylate can be considered as a second cell energy inhibitor. In one embodiment, the halogenated monocarboxylate compound can be a halogenated dicarbon monocarboxylate compound. The halogenated dicarbon monocarboxylate compound can be selected from, but not limited to, 2-fluoroacetate, 2-chloroacetate, 2-bromoacetate, 2-iodoacetate, etc., including combinations thereof. In one embodiment, the halogenated dicarbon monocarboxylate compound can be 2-bromoacetate. In an example, the composition may include a halogenated dicarbon monocarboxylate compound having a concentration of from about 0.01mM to about 5.0mM. In another example, the composition may include a halogenated dicarbon monocarboxylate compound having a concentration of from about 0.1mM to about 0.5mM.

[0106] In addition, the halogenated monocarboxylate compound can be a halogenated tricarbon monocarboxylate compound. In one embodiment, the halogenated tricarbon monocarboxylate compound can be selected from but not limited to 3-fluorolactate, 3-chlorolactate, 3-bromolactate, 3-iodolactate, etc., including combinations thereof. In another example, the composition can include a halogenated tricarbon monocarboxylate compound at a concentration of from about 0.5 mM to about 250 mM. In one embodiment, the composition can include a halogenated tricarbon monocarboxylate compound at a concentration of from about 10 mM to about 50 mM. Figure 4-7 In the various dosage forms described above, the halogenated monocarboxylate compound may be mixed with the 3-BP or may be present in a separate layer or in any of the above layers, as long as the halogenated monocarboxylate compound is reactively isolated in the stored form.

[0107] In some examples, the 3-BP composition described herein may further comprise a mitochondrial inhibitor in addition to a cellular energy inhibitor. The mitochondrial inhibitor may be selected from, but not limited to, oligomycin, efiprin, auroverticin, and the like, including combinations thereof. In another example, the composition may include a mitochondrial inhibitor at a concentration of from about 0.001 mM to about 5.0 mM. In one example, the composition may include a mitochondrial inhibitor at a concentration of from about 0.01 mM to about 0.5 mM. Figure 4-7 In the various dosage forms described above, the mitochondrial inhibitor may be mixed with the 3-BP or may be present in a separate layer or in any of the above layers, provided that the mitochondrial inhibitor is reactively sequestered in the storage form.

[0108] In some instances, the present 3-BP composition may include, but is not limited to, antifungal agents, antibiotics, glycolysis inhibitors, mitochondrial inhibitors, sugars, and biological buffers. Examples of such agents include, but are not limited to, amphotericin B, efiprin, doxorubicin, (2DOG), 2DOG analogs, d-lactic acid, dichloroacetic acid (or dichloroacetate form), oligomycin, oligomycin analogs, glycerol, cyclohexane hexol, sorbitol, ethylene glycol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, dulcitol, iditol, isomalt, maltitol, lactitol, polysaccharide alcohol, sodium phosphate, sodium citrate, sodium acetate, sodium carbonate, sodium bicarbonate, sodium pyruvate, sodium lactate, oxaloacetate, isocitrate, aconitate, succinate, fumarate, malate, dilute saline and water of different concentrations of NaCl. In addition to the sodium ions accompanying these biological buffers, calcium and potassium cations may also accompany the biological buffers. The various active agents of the composition may include cellular energy inhibitors, glycolysis inhibitors, mitochondrial inhibitors, halogenated monocarboxylate compounds, antifungal agents, antibiotic agents, etc. Figure 4-7 In the various dosage forms described above, any of the above ingredients may be mixed with 3-BP, or present in a separate layer or in any of the above layers, provided that the added ingredient is reactively isolated in the storage form.

[0109] In some examples, the 3-BP compositions described herein may further include a hexokinase inhibitor. Figure 4-7 In the various dosage forms described above, the hexokinase inhibitor may be mixed with the 3-BP, or present in a separate layer or in any of the above layers, provided that the hexokinase inhibitor is reactively isolated in the storage form.

[0110] As used herein, "hexokinase 1" or "hexokinase 1 isozyme" refers to any isozyme 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:

[0111]

[0112] (SEQ ID NO:1)

[0113]

[0114]

[0115] (SEQ ID NO:2)

[0116]

[0117] (SEQ ID NO:3)

[0118]

[0119] (SEQ ID NO:4)

[0120] As used herein, "hexokinase 2" or "hexokinase 2 isozyme"

[0121] Refers to any isozyme of hexokinase 2 and its naturally-known variants, including those provided in SEQ ID NO:5 as follows:

[0122]

[0123] (SEQ ID NO:5)

[0124] In some examples, the 3-BP compositions described herein may further include a hexokinase inhibitor. The hexokinase inhibitor may be any molecule that inhibits hexokinase 1, hexokinase 2, and / or any isozymes thereof (collectively referred to herein as "hexokinase").

[0125] As already described, the main source of ATP production is the mitochondria in normal cells. However, in cancer cells, the production of ATP from glycolysis is significantly upregulated. One of the reasons for this upregulation is due to the binding and formation of a complex between hexokinase molecules and the mitochondrial voltage-dependent anion channel (VDAC) on the ATP synthasesome, thereby forming the so-called "ATP synthasome mega complexes". The formation of such ATP synthasome mega complexes can immortalize cancer cells, allowing the cell's energy production process to continue for the growth of cancer cells. Therefore, hexokinase inhibitors can prevent hexokinase from binding to VADC or displace hexokinase molecules from VADC of an already formed ATP synthasome mega complex.

[0126] In one example, the hexokinase inhibitor can be up to 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 can be an amino acid sequence of 5 to 20 amino acid units, wherein the 5 to 20 amino acid sequence is present in the first 25 amino acid unit region starting from the N-terminus of the hexokinase 1 isozyme or the hexokinase 2 isozyme. In one example, the 5 to 20 amino acid sequence can be any 5 to 20 amino acid sequence present in the first 25 amino acid unit region of the N-terminus of hexokinase 1 or hexokinase 2. These amino acid sequences can replace the hexokinase bound to the cell, or competitively bind to the voltage-dependent anion channel (VDAC), thereby preventing the binding of the initiating hexokinase.

[0127] In other examples, the hexokinase inhibitor may include antibodies against a portion of HK1 or HK2, such as, for example, the N-terminal region of both molecules. In a specific example, the hexokinase inhibitor may be an amino acid sequence, such as SEQ ID NO: 6, corresponding to the first 25 amino acids at the N-terminus of hexokinase 1 (isoform 1), the sequence of which is as follows:

[0128] 1MIAAQLLAYY FTELKDDQVK KIDKY(SEQ ID NO:6)

[0129] In another example, the hexokinase inhibitor can be the amino acid sequence in SEQ ID NO: 7, corresponding to the first 25 amino acids at the N-terminus of hexokinase 1 (isoform 2), and its sequence is as follows:

[0130] 1MDCEHSLSLP CRGAEAWEIG IDKYL(SEQ ID NO:7)

[0131] In yet another example, the hexokinase inhibitor can be the amino acid sequence in SEQ ID NO: 8, corresponding to the first 25 amino acids at the N-terminus of hexokinase 1 (isoform 3), the sequence of which is as follows:

[0132] 1MGQICQRESA TAAEKPKLHL LAESE(SEQ ID NO:8)

[0133] In yet another example, the hexokinase inhibitor can be the amino acid sequence in SEQ ID NO: 9, corresponding to the first 25 amino acids at the N-terminus of hexokinase 1 (isoform 4), having the following sequence:

[0134] 1MAKRALDFIDKYLYAMRLSDETLI(SEQ ID NO:9)

[0135] In yet another example, the hexokinase inhibitor may be the amino acid sequence in SEQ ID NO: 10, corresponding to the first 25 amino acids at the N-terminus of hexokinase 2, having the following sequence:

[0136] MIASHLLAYF FTELNHDQVQ KVDQY(SEQ ID NO:10)

[0137] Other hexokinase inhibitors may be those disclosed in U.S. Pat. No. 5,854,067 (Newgard et al., issued Dec. 29, 1998) and / or U.S. Pat. No. 5,891,717 (Newgard et al., issued Apr. 6, 1999), both of which are incorporated by reference in their entirety. Other hexokinase inhibitors useful in the present formulations include those disclosed in U.S. Pat. No. 6,670,330; U.S. Pat. No. 6,218,435; 5,824,665; 5,652,273; and 5,643,883; and U.S. Patent Application Publication Nos. 20030072814; 20020077300; and 20020035071, the entire contents of which are incorporated by reference in their entirety.

[0138] In some examples, the 3-BP composition described herein may further include various ingredients described below. Figure 4-7 In the various dosage forms described above, any of these different ingredients may be mixed with 3-BP, provided that they do not react with 3-BP, or be present in a separate layer or any of the above layers, provided that these ingredients are reactively isolated in the storage form.

[0139] In one embodiment, the present composition can include an amino acid with lower biological activity compared to its isomer to promote cancer cell starvation. In one aspect, the amino acid with lower biological activity can be a D-amino acid. However, if the L-amino acid has lower biological activity than the D-form, the L-amino acid can also be used.

[0140] In one embodiment, the present composition may include a DNA replication inhibitor; a DNA binding inhibitor; and / or a DNA transcription inhibitor. In another embodiment, the present composition may include an inhibitor of the cell cycle, growth and / or proliferation. In yet another embodiment, the present composition may include an inhibitor of a signal transduction pathway. In yet another embodiment, the present composition may include an inhibitor of angiogenesis. In yet another embodiment, the present composition may include a small RNA that interferes with normal gene control, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, small interfering RNA, etc. In yet another embodiment, the present composition may include vitamin C; nutritional supplements including vitamins, CoQ10, flavonoids, free fatty acids, alpha-lipoic acid, acai, wolfberry, mango, pomegranate, L-carnitine, selenium, etc.

[0141] In addition to the active agent, the storage form of the composition can also include a pharmaceutically acceptable carrier. The carrier can be a single composition or a mixture of compositions. In addition, the form of the carrier can be an encapsulation coating, an absorbent, a coating material, a controlled release device, a release modifier, a surfactant or a combination thereof. In some aspects, the carrier can account for about 0.01wt% to about 99wt% of the total composition. In one embodiment, the carrier can account for about 1wt% to about 95wt% of the total preparation. In another embodiment, the carrier can account for about 5wt% to about 80wt%. In a further embodiment, the carrier can account for about 10wt% to about 60wt%. In one embodiment, the carrier can be mixed with an active agent. In another embodiment, the carrier can adsorb, carry or encapsulate at least part of the active agent.

[0142] Non-limiting examples of compounds that can be used as at least part of the carrier include, but are not limited to, cetyl alcohol and its esters; stearic acid and its glycerides; polyoxyethylene alkyl ethers; polyethylene glycol; polyethylene glycol glycerides; polyoxyethylene alkylphenols; polyethylene glycol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; proteins; polyoxyethylene glycerides; polyoxyethylene sterols, their derivatives and analogs; 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; sucrose glycerides; waxes, shellac, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0143] Non-limiting examples of release modifiers include, but are not limited to, polyethylene glycol having a weight average molecular weight of about 1000 or more, carbomer, methyl methacrylate copolymers, methacrylate copolymers, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose acetate phthalate, ethyl cellulose, methyl cellulose and derivatives thereof; ion exchange resins; monoesters, diesters, triesters of fatty acids and glycerol; tocopherol and its esters; sucrose fatty acid esters; polyvinyl pyrrolidone; xanthan gum; hexadecanol; waxes; oils, proteins, alginates, polyethylene polymers, gelatin, organic acids and their derivatives and combinations thereof.

[0144] In one embodiment, the carrier may include at least one of cellulose; carbomer; methacrylate; dextrin; gum; inorganic carbonate or calcium salt or magnesium salt or both; fatty acid ester; gelatin; lactose; maltose; monoglyceride, diglyceride or triglyceride; oil; polyethylene glycol; polyethylene oxide copolymer; protein; resin; shellac; silicate; starch; stearic acid sugar; partially or fully hydrogenated vegetable oil; wax and combinations thereof.

[0145] In yet another embodiment, the carrier may include at least one of cellulose; carbomer; methacrylate; inorganic carbonate or calcium salt; inorganic carbonate or magnesium salt; fatty acid; fatty acid ester; gelatin; lactose; polyethylene glycol; polyoxyethylene copolymer; silicate; partially or fully hydrogenated vegetable oil and combinations thereof.

[0146] In still further embodiments, the carrier may include at least one of microcrystalline cellulose; hydroxypropyl methylcellulose; ethyl cellulose; silicon dioxide; colloidal silicon dioxide; magnesium aluminum silicate; lactose; xanthan gum; stearic acid; glyceryl distearate; hydrogenated vegetable oils, and combinations thereof.

[0147] In another example, the 3-BP preparations of the present disclosure may include various additives, including but not limited to: fillers, such as lactose, starch, sugar, cellulose, calcium salts, silicon oxides, metal silicates, etc.; disintegrants, such as glycolic acid starch, lauryl sulfate, pregelatinized starch, cross-linked carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, etc.; binders, such as pyrrolidone, methacrylate, vinyl acetate, gum, acacia; tragacanth; kaolin; carrageenan alginate, gelatin, etc.; co-solvents , such as alcohol, polyethylene glycol with an average molecular weight of less than 1000, propylene glycol, etc.; surface tension modifiers, such as hydrophilic or amphoteric surfactants; masking agents; sweeteners; microencapsulation agents; processing aids, such as lubricants, glidants, talc, stearates, lecithin, etc.; polymer coating agents; plasticizers; buffers; organic acids; antioxidants; flavors; pigments; alkalizers; humectants; sorbitol; mannitol; osmotic salts; proteins; resins; desiccant agents; hygroscopic agents; desiccants and combinations thereof.

[0148] Example

[0149] The following examples relate to specific embodiments and indicate specific features, elements or steps that may be used or otherwise combined in implementing such embodiments.

[0150] In one embodiment, the liquid dispersible solid formulation may include an active agent, a reactive component dispersed in a pharmaceutically acceptable carrier, and a reaction isolation barrier placed between the active agent and the reactive component to exclude chemical contact between the two, thereby stabilizing the active agent.

[0151] In one embodiment, the reaction isolation barrier is a reaction isolation barrier layer surrounding the active agent.

[0152] In one embodiment, the reaction barrier layer is a reaction barrier coating around the active agent.

[0153] In one embodiment, the reactive component is a reactive component coating surrounding a reactive isolation barrier coating.

[0154] In one embodiment, the liquid dispersible formulation further comprises a decomposable protective coating surrounding the reactive ingredient coating.

[0155] In one embodiment, the reactive component is a reactive component powder surrounding a reactive isolation barrier coating.

[0156] In one embodiment, the active agent is a plurality of active agent particles, each particle comprising a reactive isolation barrier coating, wherein the plurality of active agent particles are dispersed in a reactive component powder.

[0157] In one embodiment, the active agent is encapsulated in a reaction isolating barrier layer.

[0158] In one embodiment, the reactive component is a biological buffer selected from the group consisting of citrate, succinate, malate, ethylenediaminetetraacetate, histidine, acetate, adipate, aconitate, ascorbate, benzoate, carbonate, bicarbonate, maleate, glutamate, phosphate, tartrate, and combinations thereof.

[0159] In one embodiment, the biological buffer is a component selected from the group consisting of citrate, acetate, phosphate, and combinations thereof.

[0160] In one embodiment, the reaction isolation barrier comprises 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.

[0161] In one embodiment, the anti-cancer liquid dispersible formulation may include a cellular energy inhibitor dispersed in a pharmaceutically acceptable carrier, a reactive component, and a reactive isolation barrier placed between the active agent and the reactive component to exclude chemical contact between the two, thereby stabilizing the active agent, wherein the cellular energy inhibitor has a structure according to Formula I:

[0162]

[0163] Wherein X is selected from: nitro, imidazole, halide, sulfonate, carboxylate, alkoxy and amineoxy; and R is selected from: 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.

[0164] In one embodiment, the liquid dispersible formulation may further include at least one sugar that stabilizes the cellular energy inhibitor by substantially preventing hydrolysis of the inhibitor.

[0165] In one embodiment, the reactive component is a biological buffer and is present in an amount sufficient to at least partially deacidify the cellular energetic inhibitor and neutralize metabolic byproducts of the cellular energetic inhibitor.

[0166] In one embodiment, the cellular energy inhibitor is a 3-halopyruvate selected from the group consisting of 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate, 3-iodopyruvate, and combinations thereof.

[0167] In one embodiment, the cellular energy inhibitor is 3-bromopyruvate.

[0168] In one embodiment, at least one sugar can be selected from gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, cyclohexanehexol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, heptanoate, maltotriitol, maltotetraitol, polysaccharide alcohol or a combination thereof.

[0169] In one embodiment, at least one sugar may be a pentose sugar.

[0170] In one embodiment, at least one sugar may be at least two pentose sugars.

[0171] In one embodiment, the composition may include a second sugar selected from the group consisting of mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, cyclohexanehexol, sorbitol, and combinations thereof.

[0172] In one embodiment, the composition may include a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, cyclohexanehexol, sorbitol, and combinations thereof.

[0173] In one embodiment, the at least one sugar may include glycerol, cyclohexane hexasol, and sorbitol.

[0174] In one embodiment, the composition includes glycerol ranging from about 0.1 wt % to about 3 wt %, inositol ranging from about 1 wt % to about 5 wt %, sorbitol ranging from about 30 wt % to about 50 wt %.

[0175] In one embodiment, the composition may include d-lactic acid and epinephrine.

[0176] In one embodiment, the composition can include a glycolysis inhibitor, and wherein the glycolysis inhibitor is 2-deoxyglucose at a concentration of from about 1 mM to about 5 mM.

[0177] In one embodiment, the composition may include the glycolysis inhibitor 2-deoxyglucose.

[0178] In one embodiment, the composition can include 2-deoxyglucose at a concentration of from about 1 mM to about 5 mM.

[0179] In one embodiment, the biological buffer is selected from one or more of a citrate buffer, a phosphate buffer, and an acetate buffer.

[0180] In one embodiment, the biological buffer is a citrate buffer.

[0181] In one embodiment, the biological buffer is a phosphate buffer.

[0182] In one embodiment, the composition may include at least one additive selected from phospholipids; liposomes; nanoparticles; immune system modulators and / or immune system enhancers, including brown rice extract, muramyl dipeptides, including analogs, mushroom extracts, bioflavonoids, vitamin D3 binding protein-derived macrophage activating factor (GcMAF), nagalase inhibitors, threonine attached to N-acetylgalactosamine and anti-nagalase antibodies; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; cell cycle, growth and / or proliferation inhibitors; signal transduction pathway inhibitors; angiogenesis inhibitors; small RNAs that interfere with normal gene control, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, small interfering RNA; vitamin C; nutritional supplements, including vitamins, CoQ10, flavonoids, free fatty acids, alpha-lipoic acid, acai berry, wolfberry, mango, pomegranate, L-carnitine, selenium; amino acids with lower biological activity than their isomers; and mixtures thereof.

[0183] In one embodiment, the composition may include a hexokinase inhibitor.

[0184] In one embodiment, the hexokinase inhibitor inhibits the binding of hexokinase 1 and / or hexokinase 2 to VDAC.

[0185] In one embodiment, 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.

[0186] In one embodiment, the composition may include a mitochondrial inhibitor.

[0187] In one embodiment, the mitochondrial inhibitor is selected from oligomycin, efiprin, auroverticin, and mixtures thereof; and the concentration is from about 0.01 mM to about 0.5 mM.

[0188] In one embodiment, the concentration of the mitochondrial inhibitor is from about 0.01 mM to about 0.5 mM.

[0189] In one embodiment, the reaction isolation barrier is a reaction isolation barrier layer around 3-bromopyruvic acid.

[0190] In one embodiment, the reaction isolation barrier layer is a reaction isolation barrier coating around the 3-bromopyruvate salt.

[0191] In one embodiment, the reactive component is a biological buffer coating surrounding a reactive isolating barrier coating.

[0192] In one embodiment, the liquid dispersible formulation further comprises a degradable protective coating surrounding the bio-buffering coating.

[0193] In one embodiment, the biological buffer is a biological buffer powder surrounding a reaction isolation barrier coating.

[0194] In one embodiment, the 3-bromopyruvate salt is a plurality of 3-bromopyruvate particles, each particle comprising a reaction isolation barrier coating, wherein the plurality of 3-bromopyruvate particles are dispersed in a biological buffer powder.

[0195] In one embodiment, 3-bromopyruvic acid is encapsulated in a reaction isolation barrier.

[0196] In one embodiment, the reaction isolation barrier comprises 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.

[0197] In one embodiment, the anticancer liquid dispersible formulation may include a cellular energy inhibitor mixed with a reactive component dispersed in a pharmaceutically acceptable carrier, wherein the cellular energy inhibitor has a structure according to Formula I

[0198]

[0199] Wherein X is selected from: nitro, imidazole, halide, sulfonate, carboxylate, alkoxy and amineoxy; and R is selected from: 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.

[0200] In one embodiment, the liquid dispersible formulation may further include at least one sugar that stabilizes the cellular energy inhibitor by substantially preventing hydrolysis of the inhibitor.

[0201] In one embodiment, the reactive component is a biological buffer and is present in an amount sufficient to at least partially deacidify the cellular energetic inhibitor and neutralize metabolic byproducts of the cellular energetic inhibitor.

[0202] In one embodiment, the cellular energy inhibitor is a 3-halopyruvate selected from the group consisting of 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate, 3-iodopyruvate, and combinations thereof.

[0203] In one embodiment, the cellular energy inhibitor is 3-bromopyruvate.

[0204] In one embodiment, at least one sugar can be selected from gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, cyclohexanehexol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, heptanoate, maltotriitol, maltotetraitol, polysaccharide alcohol or a combination thereof.

[0205] In one embodiment, at least one sugar may be a pentose sugar.

[0206] In one embodiment, at least one sugar may be at least two pentose sugars.

[0207] In one embodiment, the composition may include a second sugar selected from the group consisting of mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, cyclohexanehexol, inositol, sorbitol, and combinations thereof.

[0208] In one embodiment, the composition may include a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, cyclohexanehexol, inositol, sorbitol, and combinations thereof.

[0209] In one embodiment, the composition may include one or more sugars ranging from about 0.5wt% to about 50.0wt% or from about 1.0wt% to about 25.5wt%. In another embodiment, the composition may include one or more sugars ranging from about 0.2wt% to about 75.0wt% or from about 0.5wt% to about 50.0wt%. In a further embodiment, the composition may include one or more sugars ranging from about 0.1wt% to about 25.0wt%, from about 0.2wt% to about 10.0wt%.

[0210] In some embodiments, the composition may include glycerol ranging from about 0.1wt% to about 5.0wt% or from about 0.1wt% to about 3.0wt%. In other embodiments, the composition may include inositol ranging from about 0.1wt% to about 10wt%, from about 0.1wt% to about 6wt%. In further embodiments, the composition may include sorbitol ranging from about 0.1wt% to about 40.0wt% or from about 0.1wt% to about 30wt%. In still further embodiments, the composition may include mannitol ranging from about 0.1wt% to about 30wt% or from about 0.1wt% to about 10wt%. In addition, the addition amount of each sugar may reach the maximum solubility of the sugar in the formulation or composition.

[0211] In one embodiment, the composition may include d-lactic acid and epinephrine.

[0212] In one embodiment, the composition can include a glycolysis inhibitor, and wherein the glycolysis inhibitor is 2-deoxyglucose at a concentration of from about 1 mM to about 5 mM.

[0213] In one embodiment, the composition may include the glycolysis inhibitor 2-deoxyglucose.

[0214] In one embodiment, the composition can include 2-deoxyglucose at a concentration of from about 1 mM to about 5 mM.

[0215] In one embodiment, the biological buffer is selected from one or more of a citrate buffer, a phosphate buffer, and an acetate buffer.

[0216] In one embodiment, the biological buffer is a citrate buffer.

[0217] In one embodiment, the biological buffer is a phosphate buffer.

[0218] In one embodiment, the composition may include at least one additive selected from phospholipids; liposomes; nanoparticles; immune system modulators and / or immune system enhancers, including brown rice extract, muramyl dipeptides, including analogs, mushroom extracts, bioflavonoids, vitamin D3 binding protein-derived macrophage activating factor (GcMAF), nagaase inhibitors, threonine attached to N-acetylgalactosamine and anti-nagaase antibodies; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; cell cycle, growth and / or proliferation inhibitors; signal transduction pathway inhibitors; angiogenesis inhibitors; small RNAs that interfere with normal gene control, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, small interfering RNA; vitamin C; nutritional supplements, including vitamins, CoQ10, flavonoids, free fatty acids, alpha-lipoic acid, acai berry, wolfberry, mango, pomegranate, L-carnitine, selenium; amino acids with lower biological activity than their isomers; and mixtures thereof.

[0219] In one embodiment, the composition may include a hexokinase inhibitor.

[0220] In one embodiment, the hexokinase inhibitor inhibits the binding of hexokinase 1 and / or hexokinase 2 to VDAC.

[0221] In one embodiment, 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.

[0222] In one embodiment, the composition may include a mitochondrial inhibitor.

[0223] In one embodiment, the mitochondrial inhibitor is selected from oligomycin, efiprin, auroverticin, and mixtures thereof; and the concentration is from about 0.01 mM to about 0.5 mM.

[0224] In one embodiment, the concentration of the mitochondrial inhibitor is from about 0.01 mM to about 0.5 mM.

[0225] In one embodiment, the liquid dispersible formulation further comprises a decomposable protective coating.

[0226] In one embodiment, the 3-bromopyruvate is a plurality of 3-bromopyruvate microparticles dispersed in a biological buffer powder.

Claims

1. An anticancer preparation comprising: A dry liquid dispersible composition of a cellular energy inhibitor mixed with a reactive ingredient and a pharmaceutically acceptable carrier, wherein the cellular energy inhibitor has a structure according to Formula I wherein 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 alkali metal, wherein R' is selected from one of H, alkali metal, C1-C6 alkyl, C6-C12 aryl or C(O)R"', Wherein R" is selected from one of H, C1-C6 alkyl or C6-C12 aryl, And wherein R'' is selected from one of H, C1-C20 alkyl or C6-C12 aryl.

2. The formulation of claim 1, wherein the cellular energy inhibitor has a structure according to Formula II 3. The formulation of claim 1, wherein the cellular energy inhibitor has a structure according to Formula III 4. The formulation of claim 1, wherein the dry liquid dispersible composition further comprises at least one sugar that stabilizes the cellular energy inhibitor by substantially preventing hydrolysis of the cellular energy inhibitor.

5. The formulation 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, cyclohexanehexol, inositol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, heptanoate, maltotriitol, maltotetraitol, polysaccharide alcohol, or a combination thereof.

6. The formulation of claim 4, wherein the at least one sugar is a pentose sugar.

7. The formulation of claim 4, wherein the at least one sugar is at least two pentose sugars.

8. The formulation 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, cyclohexanehexol, inositol or sorbitol.

9. The formulation 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, cyclohexanehexol, inositol, sorbitol, or a combination thereof.

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

11. The formulation of claim 4, wherein the dry liquid dispersible composition comprises glycerin ranging from about 0.1 wt% to about 5.0 wt% or from about 0.1 wt% to about 3.0 wt%.

12. The formulation of claim 4, wherein the dry liquid dispersible composition comprises inositol ranging from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 6 wt%.

13. The formulation of claim 4, wherein the dry liquid dispersible composition comprises sorbitol in a range from about 0.1 wt% to about 40.0 wt% or from about 0.1 wt% to about 30 wt%.

14. The formulation of claim 4, wherein the dry liquid dispersible composition comprises mannitol ranging from about 0.1 wt% to about 30 wt% or from about 0.1 wt% to about 10 wt%.

15. The formulation of claim 4, wherein the dry liquid dispersible composition comprises the at least one sugar in an amount ranging from about 0.5 wt% to about 50.0 wt%, from about 1.0 wt% to about 25.5 wt%, from about 0.1 wt% to about 25.0 wt%, or from about 0.2 wt% to about 10.0 wt%.

16. The formulation of claim 1, wherein the reactive component is a biological buffering agent present in an amount sufficient to at least partially deacidify the cellular energetic inhibitor and neutralize metabolic byproducts of the cellular energetic inhibitor.

17. The formulation 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 formulation of claim 1, further comprising 2-deoxyglucose at a concentration of from about 1 mM to about 5 mM.

19. The formulation of claim 1, further comprising at least one additive selected from phospholipids; liposomes; nanoparticles; immune system modulators and / or immune system enhancers, including brown rice extract, muramyl dipeptides, including analogs, mushroom extracts, bioflavonoids, vitamin D3 binding protein-derived macrophage activating factor (GcMAF), nagaase inhibitors, threonine attached to N-acetylgalactosamine, and anti-nagaase antibodies; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; cell cycle, growth and / or proliferation inhibitors; signal transduction pathway inhibitors; angiogenesis inhibitors; small RNAs that interfere with normal gene control, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, small interfering RNA; vitamin C; nutritional supplements, including vitamins, CoQ10, flavonoids, free fatty acids, alpha-lipoic acid, acai berry, wolfberry, mango, pomegranate, L-carnitine, selenium; amino acids that are less biologically active than their isomers; or Its combination.

20. The preparation according to claim 1, further comprising a hexokinase inhibitor which inhibits the binding of hexokinase 1 and / or hexokinase 2 to VDAC.

21. The formulation of claim 20, wherein the hexokinase inhibitor has 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.

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

23. The formulation of claim 22, wherein the mitochondrial inhibitor is selected from oligomycin, efipristin, aureobasidin, or a mixture thereof.

24. The formulation of claim 1, further comprising d-lactic acid and / or epinephrine.

25. The formulation of claim 1, wherein the dry liquid dispersible composition has stability such that at least 90% w / w of 3-BP remains in the dry liquid dispersible composition after 24 weeks at -20°C.

26. A liquid dispersible solid formulation comprising: a pharmaceutically acceptable carrier; a cellular energy inhibitor dispersed in the pharmaceutically acceptable carrier; Reactive ingredients; and a reactive isolation barrier placed between the cellular energy inhibitor and the reactive component to prevent chemical contact between the two, thereby stabilizing the cellular energy inhibitor; wherein the cellular energy inhibitor has a structure according to Formula I wherein 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 alkali metal, wherein R' is selected from one of H, alkali metal, C1-C6 alkyl, C6-C12 aryl or C(O)R"', Wherein R" is selected from one of H, C1-C6 alkyl or C6-C12 aryl, And wherein R'' is selected from one of H, C1-C20 alkyl or C6-C12 aryl.

27. The formulation of claim 26, wherein the reaction isolation barrier is a coating around the cellular energy inhibitor.

28. The formulation of claim 26, wherein the reactive component is a coating around the reactive isolation barrier.

29. The formulation of claim 28, further comprising a decomposable protective coating around the reactive component.

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

31. The formulation of claim 30, wherein the cellular energy inhibitor is a plurality of cellular energy inhibitor microparticles, each microparticle being coated with a reactive isolation barrier, wherein the plurality of active cellular energy inhibitor microparticles are dispersed in a reactive ingredient powder.

32. The formulation of claim 26, wherein the reactive component is a biological buffer selected from citrate, succinate, malate, oxalate, histidine, acetate, adipate, aconitate, ascorbate, benzoate, carbonate, bicarbonate, maleate, glutamate, phosphate, tartrate, or a combination thereof.

33. The formulation of claim 26, wherein the reaction isolation barrier comprises a disintegrant selected from starch, sodium starch glycolate, clay, cellulose, methylcellulose, carboxymethylcellulose, alginate, pregelatinized corn starch, crospovidone, gums, or combinations thereof.

34. The formulation of claim 26, further comprising at least one sugar that stabilizes the cellular energetic inhibitor by substantially preventing hydrolysis of the cellular energetic inhibitor.

35. The 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, cyclohexanehexol, inositol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, heptanoate, maltotriitol, maltotetraitol, polysaccharide alcohol, or a combination thereof.

36. The formulation of claim 34, wherein the at least one sugar is a pentose sugar.

37. The formulation of claim 34, wherein the at least one sugar is at least two pentose sugars.

38. The formulation of claim 33, further comprising a second sugar selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, cyclohexanehexasol, inositol, or sorbitol.

39. The formulation of claim 34, further comprising a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, cyclohexanehexasol, inositol, sorbitol, or a combination thereof.

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

41. The formulation of claim 34, further comprising glycerin ranging from about 0.1 wt% to about 5.0 wt% or from about 0.1 wt% to about 3.0 wt%.

42. The formulation of claim 34, further comprising inositol ranging from about 0.1 wt% to about 10 wt% or from about 0.1 wt% to about 6 wt%.

43. The formulation of claim 34, further comprising sorbitol ranging from about 0.1 wt% to about 40.0 wt% or from about 0.1 wt% to about 30 wt%.

44. The formulation of claim 34, further comprising mannitol ranging from about 0.1 wt% to about 30 wt% or from about 0.1 wt% to about 10 wt%.

45. The formulation of claim 34, further comprising the at least one sugar ranging from about 0.5 wt% to about 50.0 wt%, from about 1.0 wt% to about 25.5 wt%, from about 0.1 wt% to about 25.0 wt%, or from about 0.2 wt% to about 10.0 wt%.

46. ​​The formulation of claim 26, wherein the reactive component is a biological buffer present in an amount sufficient to at least partially deacidify the cellular energetic inhibitor and neutralize metabolic byproducts of the cellular energetic inhibitor.

47. The 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. The formulation of claim 26, further comprising 2-deoxyglucose at a concentration of from about 1 mM to about 5 mM.

49. The formulation of claim 26, further comprising at least one additive selected from phospholipids; liposomes; nanoparticles; immune system modulators and / or immune system enhancers, including brown rice extract, muramyl dipeptides, including analogs, mushroom extracts, bioflavonoids, vitamin D3 binding protein-derived macrophage activating factor (GcMAF), nagaase inhibitors, threonine attached to N-acetylgalactosamine, and anti-nagaase antibodies; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; cell cycle, growth and / or proliferation inhibitors; signal transduction pathway inhibitors; angiogenesis inhibitors; small RNAs that interfere with normal gene control, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, small interfering RNA; vitamin C; nutritional supplements, including vitamins, CoQ10, flavonoids, free fatty acids, alpha-lipoic acid, acai berry, wolfberry, mango, pomegranate, L-carnitine, selenium; amino acids with lower biological activity than their isomers; or combinations thereof.

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

51. The formulation of claim 50, wherein the hexokinase inhibitor has 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.

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

53. The formulation of claim 52, wherein the mitochondrial inhibitor is selected from oligomycin, efipristin, aureobasidin, or a mixture thereof.

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

Images