Systems and methods for compartmentalizing components for liquid pharmaceutical formulations - Patents.com

Abstract

1. A compartmentalized component system for a liquid pharmaceutical formulation, said system comprising: Formula I [Formula 1] TIFF2025515160000022.tif25169 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 an alkali metal, where R' is selected from one of H, an alkali metal, C1-C6 alkyl, C6-C12 aryl, or C(O)R''', R'' is selected from one of H, C1-C6 alkyl, or C6-C12 aryl, and R'' is selected from one of H, C1-C20 alkyl, or C6-C12 aryl, and R'' is selected from one of H, C1-C20 alkyl, or C6-C12 aryl, in a first liquid carrier, and a second container is provided with an excipient in a second liquid carrier that is chemically reactive with the cellular energy inhibitor, wherein the first liquid carrier is mixed with the second liquid carrier to form a finished liquid dosage form.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 337,573, filed May 2, 2022, which is incorporated by reference in its entirety herein. [Background technology]

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

[0003] [Figure 1] 1 illustrates a compartmentalized liquid component pharmaceutical system according to an example embodiment. [Figure 2A] 1 illustrates a compartmentalized liquid component pharmaceutical system according to an example embodiment. [Figure 2B] 1 illustrates a compartmentalized liquid component pharmaceutical system according to an example embodiment. [Diagram 3] 1 illustrates a compartmentalized liquid component pharmaceutical system according to an example embodiment. [Figure 4] 1 illustrates a compartmentalized liquid component pharmaceutical system according to an example embodiment. [Diagram 5] 1 illustrates a compartmentalized liquid component pharmaceutical system according to an example embodiment. [Figure 6] 1 illustrates a compartmentalized liquid component pharmaceutical system according to an example embodiment. Summary of the Invention

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

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

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

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

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

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

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

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

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

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

[0014] As used herein, "administration" and "administering" refer to a method of giving a composition to a subject. Administration can be accomplished by a variety of art-known routes, such as enteral, parenteral, transdermal, and the like, including, optionally, combinations thereof. Thus, enteral administration can be accomplished by drinking, swallowing, chewing, or inhaling an oral dosage form containing the active agent or other compound to be delivered. Parenteral administration can be accomplished by injecting the drug composition intravenously, intraarterially, intramuscularly, intrathecally, subcutaneously, and the like. Transdermal administration can be accomplished by applying, sticking, rolling, adhering, injecting, applying pressure, rubbing, and the like, a transdermal formulation onto the skin surface. These and additional administration methods are well known in the art.

[0015] As used herein, "subject" refers to a mammalian animal that can benefit from administration of the pharmaceutical composition or method of the present invention. Examples of subjects include humans and other animals, such as horses, pigs, cows, sheep, goats, dogs (felines), cats (canines), rabbits, rodents, primates, and aquatic mammals. In one embodiment, subject can refer to a human.

[0016] As used herein, "drug," "active agent," "bioactive agent," "pharmaceutical active agent," "therapeutically active agent," "pharmaceutical," and "active pharmaceutical ingredient (API)" may be used interchangeably to refer to an agent or subject that has a specific or selected biological activity that is measurable when administered to a subject in a significant or effective amount. It is to be understood that the term "drug" is expressly included by this definition, as many drugs and prodrugs are known to have specific biological activities. These terminologies are well known in the pharmaceutical and medical fields. Furthermore, when these terms are used or a particular active agent is specifically identified by name or category, it is understood that such reference is intended to include not only the active agent itself, but also pharma- ceutically acceptable salts, or compounds significantly related thereto, including, but not limited to, prodrugs, active metabolites, isomers, and the like. Terms such as "cellular energy inhibitors," "glycolysis inhibitors," and "mitochondrial inhibitors" are considered to be active agents.

[0017] As used herein, the terms "inhibit," "inhibiting," or any other derivative thereof, refer to the process of holding back, suppressing, or restraining so as to block, prevent, limit, or reduce the rate of an action or function. Use of the terms should not be misconstrued to mean only absolute prevention, but can refer to all minor and incremental measures that limit or reduce a function through complete and absolute prevention of the function.

[0018] As used herein, a "cellular energy inhibitor" refers to a compound that inhibits ATP production in a cell. In some instances, the cellular energy inhibitor can inhibit glycolysis, oxidative phosphorylation, or both glycolysis and oxidative phosphorylation in a cell.

[0019] As used herein, "glycolytic inhibitor" refers to a compound that inhibits, reduces, or stops glycolysis in a cell.

[0020] As used herein, "mitochondrial inhibitor" refers to a compound that inhibits, reduces, or stops mitochondrial production of ATP in a cell.

[0021] As used herein, the terms "dosage form," "formulation," and "composition" are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some instances, the terms "dosage form," "formulation," and "composition" may be used to refer to a mixture of one or more active agents with carriers and / or other excipients.

[0022] As used herein, "carrier" or "pharmaceutical acceptable carrier" refers to a substance that can be combined with a drug to achieve a particular dosage formulation for delivery to a subject. In some instances, a carrier may or may not enhance drug delivery. As a general rule, a carrier will not react with a drug in a manner that substantially degrades or adversely affects the drug, although some carriers may react with a drug in such a way that the drug cannot exert a therapeutic effect until it is released from the carrier. Additionally, the carrier, or at least a portion thereof, must be physiologically suitable for administration to a subject along with the drug.

[0023] The term "excipient" as used herein includes, for example, any substance used as a carrier for an active agent in a liquid formulation, such as any substance added to an active agent and / or solid formulation to improve its handling characteristics, enable the resulting composition to be formed into a suitable storage form, facilitate dissolution in liquid, etc. Excipients include, by way of example and not 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.

[0024] The terms "reaction" and "reacting" include any form of chemical change that occurs to a formulation component upon contact with another formulation component, including a reaction that activates one or more molecules or components (e.g., conversion of an activator precursor to an activator), a reaction that degrades at least one component, etc.

[0025] As used herein, "admixed" means that at least two components of the composition can be partially or completely mixed, dispersed, suspended, dissolved or emulsified with each other. In some cases, at least a portion of the drug can be mixed with at least one carrier material.

[0026] An initial overview of the embodiments is provided below, and specific embodiments are described in more detail below. This initial summary is intended to help the reader understand the 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.

[0027] Many liquid formulations may include, inter alia, an active agent dispersed in a liquid carrier, such as a pharmaceutical carrier. However, liquid formulations have several disadvantages. For example, highly reactive molecules tend to react more readily in liquid media. Thus, many active agents lose potency / effectiveness when exposed to highly reactive molecules in liquid media for extended periods of time. Moreover, the volume of a liquid pharmaceutical ingredient can generally be measured more accurately compared to the amount of a dry pharmaceutical ingredient.

[0028] The present disclosure provides compartmentalized systems and methods for keeping pharmaceutical formulation ingredients separate and in separate liquid forms isolated from one another. For example, formulations with ingredients that react with one another can be separated and mixed when needed to make a finished drug product, reducing degradation of the ingredients. As another example, a compartmentalized system holds an active pharmaceutical ingredient (API) in a convenient liquid form ready for use, in a separate container from ingredients that may react with the API. Isolating highly reactive ingredients from the API extends the efficacy of the API, allowing ingredients for a pharmaceutical formulation to be kept in a convenient liquid form for extended periods of time.

[0029] In one example, as shown in Figure 1, a compartmentalized system may include a first container 102 containing an active pharmaceutical ingredient (API) in a first liquid carrier, and a second container 104 containing excipients in a second liquid carrier that are chemically reactive with the API. Upon mixing the first liquid carrier with the second liquid carrier, the API and excipients form a finished drug product in a third container 106. Such a system allows for on-demand mixing of formulation components, not only extending the efficacy of the API, but also reducing waste of the API and excipients. Due to reactivity between the API and excipients, the API generally has a lower chemical stability in the finished liquid dosage form than the API prior to mixing.

[0030] In many cases, a particular formulation may include additional excipients, which may be included in either the first liquid carrier or the second liquid carrier, depending on the reactivity of the excipients in the API or the second liquid carrier with the additional excipients, as the case may be. In one example, FIG. 2A depicts a first container 202 containing an API in a first liquid carrier and a second container 204 containing an excipient in a second liquid carrier that is chemically reactive with the API. The system further includes additional excipients in the first liquid carrier that are unreactive with the API or less reactive with the API than the excipients. Upon mixing the first liquid carrier with the second liquid carrier, the API, the additional excipients, and the excipients form a finished pharmaceutical product in the third container 106. Such a system allows for the formulation components to be mixed on demand, not only extending the efficacy of the API, but also reducing the waste of API and excipients. Due to the reactivity of the API with the excipients, the API generally has a lower chemical stability in the finished liquid dosage form than the API prior to blending.

[0031] In another example, FIG. 2B depicts a first container 208 containing an API in a first liquid carrier and a second container 210 containing excipients and additional excipients in a second liquid carrier. In some cases, one or both excipients in the second container 210 are chemically reactive with the API. In other cases, one or both excipients in the second container 210 are not chemically reactive with the API. In other cases, the additional excipients are not chemically reactive with the API. Upon mixing the first liquid carrier with the second liquid carrier, the API, additional excipients, and the excipients form a finished pharmaceutical product in a third container 212. Such a system allows for on-demand mixing of formulation components, not only extending the efficacy of the API, but also reducing waste of the API and excipients. If the API and excipients are chemically reactive, the API will generally have a lower chemical stability in the finished liquid dosage form than the API prior to mixing.

[0032] The components in the various liquid containers may be prepared by any technique known in the pharmaceutical arts. In one convenient example, the first liquid formulation, the second liquid formulation, or both, can be made by introducing a dissolving tablet (or capsule, effervescent tablet, etc.) into a suitable carrier to form a segregated component, which can be combined with the other components to create the finished pharmaceutical product. Thus, when the tablet is introduced into either liquid carrier, the tablet disintegrates, releasing the API and excipients into the suitable liquid carrier to form the segregated components of the finished pharmaceutical product.

[0033] In one embodiment, the API can be a molecule according to Formula I. [ka] A variety of specific molecules are contemplated, where, for example, X may be, but is not limited to, nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, or amine oxide, etc. Additionally, R may be, but is not limited to, OR', N(R'')2, C(O)R''', C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, alkali metal, etc., where R' represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl, or C(O)R''', R'' represents H, C1-C6 alkyl, or C6-C12 aryl, and R''' represents H, C1-C20 alkyl, or C6-C12 aryl.

[0034] In one example, R in formula (I) can be OH, and X in formula (I) can be nitro, imidazole, halide, sulfonate, carboxylate, alkoxide, or amine oxide, etc. Furthermore, X can be a halide, such as fluoride, bromide, chloride, or iodide, etc. In one example, X can be a sulfonate, such as triflate, mesylate, or tosylate, etc. In another example, X can be an amine oxide. In yet another example, the amine oxide can be dimethylamine oxide.

[0035] In another example, the API may be a 3-halopyruvate, such as 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate, 3-iodopyruvate, or a combination thereof. A general structure showing the halide at the 3-position is represented by Formula II: [ka] In a further non-limiting example, the API can have a bromine at the 3-position as represented by formula III. [ka] In one further non-limiting example, the API can be 3-bromopyruvic acid, as represented by formula IV. [ka] In another further non-limiting example, the API can be 3-bromopyruvate as represented by formula V. [ka]

[0036] Both 3-bromopyruvic acid and 3-bromopyruvate may be referred to herein using the abbreviation 3-BP, which those of skill in the art will readily use to distinguish between the moieties depending on the particular context.

[0037] In some instances, the API may be formulated in a composition with at least one sugar, which may stabilize the API by substantially preventing the API from hydrolysis. In some instances, the composition may include, for example, 3-BP as a cellular energy inhibitor, and at least one sugar, at least two sugars, at least three sugars, etc. In one example, the sugar may include a monosaccharide, a disaccharide, an oligosaccharide, or a combination thereof. Non-limiting examples of monosaccharides may include glucose, fructose, galactose, etc. Non-limiting examples of disaccharides may include sucrose, lactose, maltose, etc. It is noted that for purposes of this disclosure, the term "sugar" may also include oligosaccharides, polysaccharides, polyols, polyhydric alcohols, and similar molecules that function to stabilize 3-BP.

[0038] Sugars can include 3-carbon sugars, 4-carbon sugars, 5-carbon sugars, 6-carbon sugars, 7-carbon sugars, etc., including combinations thereof. In one embodiment, the sugars can be trioses, tetraoses, pentoses, hexoses, heptoses, etc., and combinations thereof, provided that the sugars do not participate in energy metabolism to the extent that they generate energy (i.e., non-metabolizable sugars).

[0039] In one example, the sugar may be gluconic acid. In another example, the sugar may be glucuronic acid. At least one sugar may be a pentose. In one example, at least two sugars may be pentoses. The pentoses may be independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, and the like, or may include combinations thereof. In one example, the at least one sugar may be glycerol. In another example, the sugars may be glycerol, inositol, and sorbitol. Other non-limiting examples of sugars may include ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetraitol, and polyglycitol, and combinations thereof. In one example, the sugars may include glycerol, inositol, sorbitol, mannitol, or any combination thereof. In another example, the sugar can include glycerol, inositol, sorbitol, or any combination thereof. In yet another example, the inositol can be myo-inositol. In another example, the sugar can be a polyhydric alcohol.

[0040] The sugars described herein may be any isomer. In one example, the compositions described herein may include a form of the sugar that has a lower biological activity compared to the isomer. In some cases, the sugar with a lower biological activity may be an L-enantiomer sugar. However, if a D-enantiomer sugar is found to have a lower biological activity compared to the L-enantiomer, the D-enantiomer may be used. In one example, such sugars may function as glycolysis inhibitors.

[0041] In one example, the composition may contain one or more sugars in the range of about 0.5% to about 50.0% by weight, or about 1.0% to about 25.5% by weight. In yet another example, the composition may contain one or more sugars in the range of about 0.2% to about 75.0% by weight, or about 0.5% to about 50.0% by weight. In a further example, the composition may contain one or more sugars in the range of about 0.1% to about 25.0% by weight, or about 0.2% to about 10.0% by weight.

[0042] In some examples, the composition may contain glycerol in the range of about 0.1% to about 5.0% by weight, or about 0.1% to about 3.0% by weight. In another example, the composition may contain inositol in the range of about 0.1% to about 10% by weight, or about 0.1% to about 6% by weight. In a further example, the composition may contain sorbitol in the range of about 0.1% to about 40.0% by weight, or about 0.1% to about 30% by weight. In yet a further example, the composition may contain mannitol in the range of about 0.1% to about 30% by weight, or about 0.1% to about 10% by weight. In addition, each sugar may be added to the formulation or composition in a volume up to the maximum solubility of the sugar. It is also noted that the weight percentages of the components do not include water or other liquid carriers.

[0043] In some examples, the 3-BP composition can include a biological buffer present in an amount sufficient to at least partially deccidify the cellular energy inhibitors and neutralize metabolic by-products of the cellular energy inhibitors. Non-limiting examples of biological buffers can include citrate buffers, phosphate buffers, acetate buffers, and the like, and combinations thereof. In one embodiment, the biological buffer can be a citrate buffer, such as, but not limited to, sodium citrate. In another embodiment, the biological buffer can be a phosphate buffer, such as, but not limited to, sodium phosphate. In one embodiment, the biological buffer can be an acetate buffer, such as, but not limited to, sodium acetate. In yet another embodiment, the biological buffer can include at least two biological buffers, such as, but not limited to, a citrate buffer and an acetate buffer, a citrate buffer and a phosphate buffer, an acetate buffer and a phosphate buffer, or a citrate buffer, a phosphate buffer and an acetate buffer.

[0044] In some examples, the composition may include a biological buffer in the range of about 0.1% to about 15% by weight, or about 2.0% to about 8.0% by weight. Furthermore, the biological buffer may maintain a physiological pH of 4.0 to 8.5. In one embodiment, the biological buffer may maintain a physiological pH of 5.5 to 8.0. In another embodiment, the biological buffer may maintain a physiological pH of 6.8 to 7.8. In yet another embodiment, the biological buffer may maintain a physiological pH of 7.3 to 7.6. It is also noted that the weight percentages of the components do not include water or other liquid carriers.

[0045] In one example, a compartmentalized system and method is provided that keeps 3-BP and excipients separate and in separate liquid forms isolated from one another. For example, because biological buffers may react with 3-BP, the biological buffers may be isolated from 3-BP until they are mixed together to form a finished 3-BP product or a component of a finished 3-BP product. Such isolation can reduce degradation of 3-BP while keeping 3-BP in liquid form, such that the finished 3-BP product is readily available when needed. Isolating the components from one another extends the potency of 3-BP, thereby allowing the components to be kept in a convenient liquid form for extended periods of time.

[0046] In one example, as shown in FIG. 3, a compartmentalized system may include a first container 302 containing 3-BP in a first liquid carrier and a second container 304 containing a biological buffer in a second liquid carrier. Optionally, one or more sugars may be included in the second carrier along with the biological buffer, as shown in second container 304. Upon mixing the first liquid carrier with the second liquid carrier, the 3-BP and biological buffer (and optionally the sugar) form the finished 3-BP product in third container 306. Such a system allows for on-demand mixing of formulation components, not only extending the potency of 3-BP, but also reducing waste of 3-BP and biological buffer. Due to the reactivity of 3-BP with biological buffers, 3-BP generally has a lower chemical stability in the finished liquid dosage form than 3-BP before mixing.

[0047] In another example, FIG. 4 depicts a first container 402 containing 3-BP in a first liquid carrier and a second container 404 containing a biological buffer in a second liquid carrier that is chemically reactive with 3-BP. The system further includes one or more sugars in the first liquid carrier along with 3-BP. Upon mixing the first liquid carrier with the second liquid carrier, the 3-BP, sugar, and biological buffer form a finished 3-BP product in a third container 406. Such a system allows for on-demand mixing of formulation components, not only extending the efficacy of 3-BP, but also reducing waste of 3-BP. Due to the reactivity of 3-BP with excipients, 3-BP generally has a lower chemical stability in the finished liquid dosage form compared to the API prior to mixing.

[0048] In another example, Figure 5 depicts a first container 502 containing 3-BP and a biological buffer in a first liquid carrier, and a second container 504 containing one or more sugars in a second liquid carrier. Upon mixing the first liquid carrier with the second liquid carrier, the 3-BP, sugar, and biological buffer form the finished 3-BP product in a third container 506. Such a system allows for on-demand mixing of the formulation components, not only extending the potency of 3-BP, but also reducing waste of 3-BP. Due to the reactivity of 3-BP with excipients, 3-BP generally has a lower chemical stability in the finished liquid dosage form compared to the API prior to mixing.

[0049] In another example, FIG. 6 depicts a first container 602 containing 3-BP in a first liquid carrier, a second container 604 containing a biological buffer, and a third container 606 containing one or more sugars in a third liquid carrier. Other excipients may be added to one or more of the first through third containers, or other excipients may be in a fourth container with the fourth liquid carrier, etc. Upon mixing the first liquid carrier with the second and third liquid carriers, the 3-BP, biological buffer, and sugar form the finished 3-BP product in the fourth container 608. Such a system allows the formulation components to be mixed on demand, not only extending the potency of 3-BP, but also reducing waste of 3-BP and excipients. Due to the reactivity of 3-BP with the excipients, 3-BP generally has a lower chemical stability in the finished liquid dosage form than 3-BP before mixing.

[0050] In some examples, the 3-BP formulation may include a glycolysis inhibitor, in one non-limiting example, 2-deoxyglucose (2DOG). The 3-BP formulation may include the glycolysis inhibitor in any effective amount. In the various dosage forms described above, the glycolysis inhibitor may be included with the 3-BP, any excipients, or may be in a separate container. The glycolysis inhibitor may be mixed into a biological buffer, provided that it does not react with the biological buffer.

[0051] In addition to the above components, the 3-BP compositions described herein may further comprise a halogenated monocarboxylate compound separate from the cellular energy inhibitor. If the halogenated monocarboxylate compound can act to inhibit glycolysis and / or mitochondrial function, the halogenated monocarboxylate can also be considered a second cellular energy inhibitor. In one embodiment, the halogenated monocarboxylate compound may be a two-carbon halo monocarboxylate compound. The two-carbon halo monocarboxylate compound may be selected from, but is not limited to, 2-fluoroacetate, 2-chloroacetate, 2-bromoacetate, 2-iodoacetate, and the like, including combinations thereof. In one embodiment, the two-carbon halo monocarboxylate compound may be a 2-bromoacetate. In one example, the composition may comprise a two-carbon halo monocarboxylate compound at a concentration of about 0.01 mM to about 5.0 mM. In another example, the composition may contain a monocarboxylate compound halogenated at the 2-carbon position at a concentration of about 0.1 mM to about 0.5 mM.

[0052] Further, the halogenated monocarboxylate compound may be a monocarboxylate compound with a halogenated carbon at the 3-position. In one embodiment, the monocarboxylate compound with a halogenated carbon at the 3-position may be selected from, but is not limited to, 3-fluorolactate, 3-chlorolactate, 3-bromolactate, 3-iodolactate, and the like, including combinations thereof. In another example, the composition may contain a monocarboxylate compound with a halogenated carbon at the 3-position at a concentration of about 0.5 mM to about 250 mM. In one embodiment, the composition may contain a monocarboxylate compound with a halogenated carbon at the 3-position at a concentration of about 10 mM to about 50 mM. In the various dosage forms described above in Figures 4 to 7, the halogenated monocarboxylate compound may be mixed with 3-BP, or may be included in a separate layer or in any of the layers described above, provided that the halogenated monocarboxylate compound is reactively isolated in the storage form.

[0053] In some examples, the 3-BP formulations described herein may further include a mitochondrial inhibitor in addition to the cellular energy inhibitor. The mitochondrial inhibitor may be selected from, but is not limited to, oligomycin, efrapeptin, aurovertin, and the like, and combinations thereof. In another example, the composition may include a mitochondrial inhibitor at a concentration of about 0.001 mM to about 5.0 mM. In one example, the composition may include a mitochondrial inhibitor at a concentration of about 0.01 mM to about 0.5 mM. In the various dosage forms described above, the mitochondrial inhibitor may be included with the 3-BP, any excipients, or may be in a separate container.

[0054] In some instances, the 3-BP formulation may include, but is not limited to, antifungals, antibiotics, glycolysis inhibitors, mitochondrial inhibitors, sugars, and biological buffers. Examples of such agents include, but are not limited to, amphotericin B, efrapeptins, doxorubicin, (2-deoxyglucose (2DOC)), 2-DOG analogs, d-lactic acid, dichloroacetic acid (or a salt form of dichloroacetic acid), oligomycin, oligomycin analogs, glycerol, inositol, sorbitol, glycol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, dulcitol, iditol, isomalt, maltitol, lactitol, polyglycitol, sodium phosphate, sodium citrate, sodium acetate, sodium carbonate, sodium bicarbonate, sodium pyruvate, sodium lactate, oxaloacetate, isocitrate, aconitrate, succinate, fumarate, malate, and dilute saline solutions containing various concentrations of NaCl and water. In addition to the sodium ions associated with the biological buffer, calcium and potassium ions may also be associated with the biological buffer. The various active agents of the composition may include cellular energy inhibitors, glycolysis inhibitors, mitochondrial inhibitors, halogenated monocarboxylate compounds, antifungals, antibiotics, etc. In the various dosage forms, any of the ingredients may be included with 3-BP, optional excipients, or may be in separate containers.

[0055] In some instances, the 3-BP compositions described herein may further comprise a hexokinase inhibitor, which in the various dosage forms described above may be included with the 3-BP, optional excipients, or in a separate container.

[0056] As used herein, "hexokinase 1" or "hexokinase 1 isozyme" refers to any isoform of hexokinase 1 and its naturally known variants, including those provided in SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4, as follows:

[0057] [Table 1] [Table 2] [Table 3] [Table 4] As used herein, "hexokinase 2" or "hexokinase 2 isozyme" refers to any isoform of hexokinase 2 and its naturally occurring variants, including those provided in SEQ ID NO:5, as follows: [Table 5] In some instances, the 3-BP formulations described herein may further comprise a hexokinase inhibitor, which may be any molecule that inhibits hexokinase 1, hexokinase 2, and / or their isoenzymes (collectively referred to herein as "hexokinases").

[0058] As mentioned above, the main source of ATP production occurs in the mitochondria in normal cells. However, in cancer cells, ATP production from glycolysis is significantly upregulated. One of the reasons for this upregulation is that hexokinase molecules bind to and form complexes with mitochondrial voltage dependent anion channels (VDACs) in the ATP synthasome, forming the so-called "ATP synthasome mega complex." The formation of such an ATP synthasome mega complex immortalizes the cancer cells and allows them to continue to use the cellular energy production process for cancer growth. Therefore, hexokinase inhibitors can either block hexokinase from binding to the VADC or displace hexokinase molecules from the VADC of the already formed ATP synthasome mega complex.

[0059] In one example, the hexokinase inhibitor may be within a maximum of 25 amino acid units from the N-terminal region of the hexokinase 2 isozyme or the hexokinase 1 isozyme. In another example, the hexokinase inhibitor may be an amino acid sequence consisting of the 5th to 20th amino acid units, in which the 5th to 20th amino acid sequence is present in the first 25 amino acid unit region starting from the N-terminus of the hexokinase 1 isozyme or the hexokinase 2 isozyme. In one example, the 5th to 20th amino acid sequence may be any 5 to 20 amino acid sequence present in the first 25 amino acid unit region of the N-terminus of hexokinase 11 or hexokinase 2. Such an amino acid sequence can displace hexokinase bound to cells or competitively bind to voltage-dependent anion channels (VDACs) to prevent initial hexokinase binding.

[0060] In another example, the hexokinase inhibitor can include an antibody against a portion of HK1 or HK2, such as, for example, the N-terminal region of the HK1 or HK2 molecule. In one specific example, the hexokinase inhibitor can be an amino acid sequence such as SEQ ID NO:6, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 1), which has the sequence as follows: [Table 6] In another example, a hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 7, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 2), which has the sequence as follows: [Table 7] In yet another example, a hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 8, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 3), which has the sequence as follows: [Table 8] In yet another example, a hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 9, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 1 (isoform 4), which has the sequence as follows: [Table 9] In yet another example, a hexokinase inhibitor may be an amino acid sequence such as SEQ ID NO: 10, which corresponds to the first 25 amino acids from the N-terminus of hexokinase 2, which has the sequence as follows: [Table 10] Additional hexokinase inhibitors may be those disclosed in U.S. Patent No. 5,854,067 (Newgard et al., issued December 29, 1998) and / or U.S. Patent No. 5,891,717 (Newgard et al., issued April 6, 1999), both of which are incorporated by reference in their entireties. Additional hexokinase inhibitors that may be used in the formulation include those disclosed in U.S. Patent Nos. 6,670,330; 6,218,435; 5,824,665; 5,652,273; and 5,643,883; and U.S. Patent Application Publication Nos. 20030072814; 20020077300; and 20020035071, each of which is incorporated by reference in its entirety.

[0061] In some examples, the 3-BP compositions described herein can further include various ingredients, as listed below: In the various dosage forms previously described in Figures 4-7, any of the various ingredients may be mixed with the 3-BP, provided that the ingredient does not react with the 3-BP, or may be included in a separate layer or any of the layers previously described, provided that the ingredient(s) are reactively isolated in the reservoir form.

[0062] In one embodiment, the composition may comprise an amino acid with less biological activity than the isomer to promote the starvation of cancer cells.In one embodiment, the less biologically active amino acid may be a D-amino acid.However, L-amino acid may be used when L-amino acid has less biological activity than D-isomer.

[0063] In one embodiment, the composition may include a DNA replication inhibitor, a DNA binding inhibitor, and / or a DNA transcription inhibitor. In another embodiment, the composition may include an inhibitor of cell cycle, growth, and / or proliferation. In yet another embodiment, the composition may include an inhibitor of a signal transduction pathway. In yet another embodiment, the composition may include an inhibitor of angiogenesis. In yet another embodiment, the composition may include a small RNA that interferes with normal gene regulation, such as antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, small interfering RNA, and the like. In yet another embodiment, the composition may include a nutritional supplement containing vitamin C; vitamins, coenzyme Q10 (CoQ10), flavonoids, free fatty acids, alpha lipoic acid, acai, goji berry (gogi), mango, pomegranate (pomergrante), L-carnitine, selenium, and the like. EXAMPLES

[0064] The following examples relate to particular embodiments and illustrate specific features, elements, or steps that can be used or combined in achieving said embodiments.

[0065] In one example, a compartmentalized component system for a liquid pharmaceutical formulation includes a first container containing an active pharmaceutical ingredient (API) in a first liquid carrier and a second container containing an excipient that is chemically reactive with the API in a second liquid carrier, the first liquid carrier being mixed with the second liquid carrier to form a finished liquid dosage form.

[0066] In another example of a compartmentalized component system for liquid pharmaceutical formulations, the API in the finished liquid dosage form has lower chemical stability compared to the API prior to blending.

[0067] In another example, a compartmentalized component system for a liquid pharmaceutical formulation may further include additional excipients along with the API in the first liquid carrier.

[0068] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the additional excipients do not substantially chemically react with the API.

[0069] In one example, a compartmentalized component system for a liquid pharmaceutical formulation includes a first container containing a cellular energy inhibitor according to formula I in a first liquid carrier, wherein halogen comprises a member selected from the group consisting of fluoro-, chloro-, bromo-, and iodo-, and a second container containing an excipient in a second liquid carrier, wherein the first liquid carrier is mixed with the second liquid carrier to form a finished liquid 3-halopyruvate dosage form. [ka] In another example of a compartmentalized component system for liquid pharmaceutical formulations, the halogen is bromo- and the cellular energy inhibitor is 3-bromopyruvate (3-BP) according to formula (II): [ka] And the finished liquid 3-halopyruvate dosage form is the finished liquid 3-BP dosage form.

[0070] In another example of a compartmentalized component system for liquid pharmaceutical formulations, the excipients in the second carrier are chemically reactive with 3-BP.

[0071] In another example of a compartmentalized component system for liquid pharmaceutical formulations, the 3-BP in the finished liquid 3-BP dosage form has lower chemical stability compared to the 3-BP prior to mixing.

[0072] In another example of a compartmentalized component system for liquid pharmaceutical formulations, the excipient in the second liquid carrier comprises at least one sugar, which stabilizes 3-BP in the finished liquid 3-BP dosage form by substantially preventing 3-BP from hydrolysis.

[0073] In another example of a compartmentalized component system for liquid pharmaceutical formulations, the excipient in the second liquid carrier comprises a biological buffer, said biological buffer being present in an amount sufficient to at least partially deacidify 3-BP in the finished liquid 3-BP dosage form and at least partially neutralize metabolic by-products of 3-BP in the finished liquid 3-BP dosage form.

[0074] In another example of a compartmentalized component system for liquid pharmaceutical formulations, the excipients in the second liquid carrier include a biological buffer, the biological buffer being present in an amount sufficient to at least partially deacidify 3-BP in the finished liquid 3-BP dosage form and at least partially neutralize metabolic by-products of 3-BP in the finished liquid 3-BP dosage form, and at least one sugar, the sugar stabilizing 3-BP in the finished liquid 3-BP dosage form by substantially preventing 3-BP from hydrolyzing.

[0075] In another example, a compartmentalized component system for a liquid pharmaceutical formulation may include additional excipients in a first liquid carrier.

[0076] In another example of a compartmentalized component system for liquid pharmaceutical formulations, the additional excipient in the first liquid carrier comprises a biological buffer, said biological buffer being present in an amount sufficient to at least partially deacidify 3-BP in the finished liquid 3-BP dosage form and at least partially neutralize metabolic by-products of 3-BP in the finished liquid 3-BP dosage form.

[0077] In another example of a compartmentalized component system for liquid pharmaceutical formulations, the additional excipient in the first liquid carrier comprises at least one sugar, which stabilizes 3-BP by substantially preventing the 3-BP from hydrolysis.

[0078] In another example of a compartmentalized component system for liquid pharmaceutical formulations, the additional excipient in the first liquid carrier comprises a biological buffer, said biological buffer being present in an amount sufficient to at least partially deacidify 3-BP in the finished liquid 3-BP dosage form and at least partially neutralize metabolic by-products of 3-BP in the finished liquid 3-BP dosage form.

[0079] In another example, a compartmentalized component system for a liquid pharmaceutical formulation may include a third container containing additional excipients in a third liquid carrier, and the first liquid carrier is mixed with the second liquid carrier and the third liquid carrier to form the finished liquid 3-BP dosage form.

[0080] In another example of a compartmentalized component system for liquid pharmaceutical formulations, the excipient in the second liquid carrier comprises a biological buffer present in an amount sufficient to at least partially deacidify 3-BP in the finished liquid 3-BP dosage form and at least partially neutralize metabolic by-products of 3-BP in the finished liquid 3-BP dosage form, and the additional excipient in the third liquid carrier comprises at least one sugar, which stabilizes 3-BP by substantially preventing 3-BP from hydrolyzing.

[0081] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the at least one sugar may be selected from gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo-inositol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetriitol, polyglycitol, or combinations thereof.

[0082] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the at least one sugar may be a pentose.

[0083] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the at least one sugar may be at least two pentose sugars.

[0084] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the composition may include a second sugar selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xyolitol, dulcitol, ribitol, inositol, myo-inositol, sorbitol, and combinations thereof.

[0085] In another example, a compartmentalized component system for a liquid pharmaceutical formulation may include a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xyolitol, dulcitol, ribitol, inositol, myo-inositol, sorbitol, and combinations thereof.

[0086] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the at least one sugar may include glycerol, myo-inositol, and sorbitol.

[0087] In another example, a compartmentalized component system for a liquid pharmaceutical formulation may contain one or more sugars in the range of about 0.5% to about 50.0% by weight, or about 1.0% to about 25.5% by weight. In yet another example, a composition may contain one or more sugars in the range of about 0.2% to about 75.0% by weight, or about 0.5% to about 50.0% by weight. In a further example, a composition may contain one or more sugars in the range of about 0.1% to about 25.0% by weight, or about 0.2% to about 10.0% by weight.

[0088] In another example, a compartmentalized component system for liquid pharmaceutical formulations may contain glycerol in the range of about 0.1% to about 5.0% by weight, or about 0.1% to about 3.0% by weight. In another example, the composition may contain inositol in the range of about 0.1% to about 10% by weight, or about 0.1% to about 6% by weight. In a further example, the composition may contain sorbitol in the range of about 0.1% to about 40.0% by weight, or about 0.1% to about 30% by weight. In yet a further example, the composition may contain mannitol in the range of about 0.1% to about 30% by weight, or about 0.1% to about 10% by weight. Additionally, each sugar may be added to the formulation or composition in a volume up to the maximum solubility of the sugar.

[0089] In another example, a compartmentalized component system for a liquid pharmaceutical formulation may include d-lactic acid and epinephrine.

[0090] In another example, a compartmentalized component system for a liquid pharmaceutical formulation may include a glycolytic inhibitor, where the glycolytic inhibitor is 2-deoxglucose at a concentration of about 1 mM to about 5 mM.

[0091] In another example, a compartmentalized component system for a liquid pharmaceutical formulation may include 2-deoxglucose, a glycolysis inhibitor.

[0092] In another example, a compartmentalized component system for a liquid pharmaceutical formulation may include 2-deoxglucose at a concentration of about 1 mM to about 5 mM.

[0093] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the biological buffer is selected from one or more of a citrate buffer, a phosphate buffer, and an acetate buffer.

[0094] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the biological buffer is selected from one or more of a citrate buffer, a phosphate buffer, and an acetate buffer.

[0095] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the biological buffer is a citrate buffer.

[0096] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the biological buffer is a phosphate buffer.

[0097] In another example, the compartmentalized component system for liquid pharmaceutical formulations includes phospholipids; liposomes; nanoparticles; immune system modulators and / or immune system boosters including brown rice extracts, muramyl dipeptide including analogs, mushroom extracts, bioflavonoids, vitamin D3 binding protein-derived macrophage activating factor (GcMAF), Nagalase inhibitors, threonine associated with N-acetylgalactosamine, and antibodies against Nagalase; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; cell cycle, growth and / or proliferation inhibitors. The composition may include at least one additive selected from the group consisting of inhibitors of proliferation; inhibitors of signal transduction pathways; inhibitors of angiogenesis; small RNAs that interfere with normal gene regulation, including antisense RNA, microRNA, small hairpin RNA, short hairpin RNA, and small interfering RNA; vitamin C; nutritional supplements including vitamins, coenzyme Q10 (CoQ10), flavonoids, free fatty acids, alpha lipoic acid, acai, goji berry (gogi), mango, pomegranate (pomergrante), L-carnitine, and selenium; amino acids having lower biological activity than their isomers; and mixtures thereof.

[0098] In another example, a compartmentalized component system for a liquid pharmaceutical formulation may include a hexokinase inhibitor.

[0099] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, a hexokinase inhibitor inhibits the binding of hexokinase 1 and / or hexokinase 2 to VDAC.

[0100] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, 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.

[0101] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the composition may include a mitochondrial inhibitor.

[0102] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the mitochondrial inhibitor is selected from oligomycin, efrapeptin, aurovertin, and mixtures thereof, at a concentration of about 0.01 mM to about 0.5 mM.

[0103] In another example of a compartmentalized component system for a liquid pharmaceutical formulation, the mitochondrial inhibitor is at a concentration of about 0.01 mM to about 5.0 mM.

Claims

1. 1. A compartmentalized component system for a liquid pharmaceutical formulation, said system comprising: Formula I 【Chemistry 1】 (In the above formula, R is OR', N(R'') ２ , C(O)R'", C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, C6-C12 heteroaryl, H, or an alkali metal, where R' is selected from one of H, an alkali metal, C1-C6 alkyl, C6-C12 aryl, or C(O)R'", R" is selected from one of H, C1-C6 alkyl, or C6-C12 aryl, and R'" is selected from one of H, C1-C20 alkyl, or C6-C12 aryl. a first container containing a cellular energy inhibitor according to the method of the present invention in a first liquid carrier; and a second container containing an excipient in a second liquid carrier that is chemically reactive with the cellular energy inhibitor; wherein the first liquid carrier is mixed with the second liquid carrier to form a finished liquid dosage form.

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

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

4. The system of claim 1 , wherein the cellular energy inhibitor in the finished liquid dosage form has lower chemical stability compared to the cellular energy inhibitor prior to mixing.

5. The system of claim 1 further comprising an additional excipient in the first liquid carrier.

6. 6. The system of claim 5, wherein the additional excipient is substantially chemically non-reactive with the API.

7. 2. The system of claim 1, wherein the excipient in the second liquid carrier comprises at least one sugar, and the at least one sugar stabilizes the cellular energy inhibitor in the finished liquid dosage form by substantially preventing the cellular energy inhibitor from hydrolysis.

8. 8. The system of claim 7, wherein the at least one sugar is selected from gluconic acid, glucuronic acid, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo inositol, glycerol, ethylene glycol, threitol, arabitol, galactitol, fucitol, iditol, volemitol, maltotriitol, maltotetritoitol, polyglycitol, or combinations thereof.

9. The system of claim 7 , wherein the at least one sugar is a pentose.

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

11. 8. The system of claim 7, wherein the second liquid carrier further comprises a second sugar selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo-inositol, or sorbitol.

12. 8. The system of claim 7, wherein the second liquid carrier further comprises a second sugar and a third sugar independently selected from mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, dulcitol, ribitol, inositol, myo-inositol, sorbitol, or combinations thereof.

13. The system of claim 7 , wherein the at least one sugar may include glycerol, myo-inositol, and sorbitol.

14. 8. The system of claim 7, wherein the at least one sugar is present in a range of about 0.1% to about 25.0% by weight, or about 0.2% to about 10.0% by weight.

15. 8. The system of claim 7, wherein the at least one sugar comprises glycerol in the range of about 0.1% to about 5.0% by weight, or about 0.1% to about 3.0% by weight, inositol in the range of about 0.1% to about 10% by weight, or about 0.1% to about 6% by weight, and sorbitol in the range of about 0.1% to about 40.0% by weight, or about 0.1% to about 30% by weight.

16. 2. The system of claim 1, wherein the excipient in the second liquid carrier comprises a biological buffer, the biological buffer being present in an amount sufficient to at least partially deacidify the cellular energy inhibitor in the finished liquid dosage form and at least partially neutralize metabolic by-products of the cellular energy inhibitor in the finished liquid dosage form.

17. The excipient in the second liquid carrier is a biological buffer, the biological buffer being present in an amount sufficient to at least partially deacidify the cellular energy inhibitor in the finished liquid dosage form and at least partially neutralize metabolic by-products of the cellular energy inhibitor in the finished liquid dosage form; and at least one sugar, said at least one sugar stabilizing said cellular energy inhibitor in said finished liquid dosage form by substantially preventing said cellular energy inhibitor from hydrolysis; The system of claim 1 , comprising:

18. 10. The system of claim 1, further comprising a third container containing an additional excipient in a third liquid carrier, and wherein the finished liquid dosage form is formed by mixing the first liquid carrier with the second liquid carrier and the third liquid carrier.

19. 20. The system of claim 18, wherein the excipient in the second liquid carrier comprises a biological buffer, the biological buffer being present in an amount sufficient to at least partially deacidify the cellular energy inhibitor in the finished liquid dosage form and at least partially neutralize metabolic by-products of the cellular energy inhibitor in the finished liquid dosage form, and the additional excipient in the third liquid carrier comprises at least one sugar, the at least one sugar stabilizing the cellular energy inhibitor by substantially preventing hydrolysis.

20. 20. The system of claim 19, wherein the biological buffer is selected from one or more of a citrate buffer, a phosphate buffer, or an acetate buffer.

21. At least one of the first liquid carrier or the second liquid carrier may further comprise: phospholipids; liposomes; nanoparticles; immune system modulators and / or immune system boosters including brown rice extract, muramyl dipeptide including analogs, mushroom extract, bioflavonoids, vitamin D3 binding protein-derived macrophage activating factor (GcMAF), Nagalase inhibitors, threonine associated with N-acetylgalactosamine, and antibodies against Nagalase; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotide; DNA replication inhibitors; DNA binding inhibitors; DNA transcription inhibitors; cell cycle, growth and / or proliferation inhibitors.

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

22. The system of claim 1 , wherein at least one of the first liquid carrier or the second liquid carrier further comprises a hexokinase inhibitor.

23. The system of claim 22 , wherein the hexokinase inhibitor inhibits binding of hexokinase 1 and / or hexokinase 2 to VDAC.

24. 23. The system of claim 22, wherein at least one of the first liquid carrier or the second liquid carrier further comprises a mitochondrial inhibitor selected from oligomycin, efrapeptin, aurovertin, and mixtures thereof, at a concentration of about 0.01 mM to about 0.5 mM.

25. 2. The system of claim 1, wherein at least one of the first liquid carrier or the second liquid carrier further comprises 2-deoxyglucose at a concentration of about 1 mM to about 5 mM.

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