Therapeutic blood acid transition compositions and methods

Abstract

Disclosed herein is a composition for intravenous injection into a body tissue of an individual comprising an acid having a pKa of less than 3.0 and a conjugated base having therapeutically beneficial properties. The compositions have utility in methods of converting blood acid for various therapeutic purposes.

Description

Background Technology

[0001] The acid-base state of the bloodstream is primarily controlled by the total acid production of cells and is balanced with renal and respiratory processes to correct blood acidity. For example, physical exercise is a process that deprives cells of oxygen, inducing anaerobic metabolism and producing lactic acid (H+, lactate). When acid flows from acid-producing cells into the bloodstream, the blood acidity temporarily shifts, becoming more acidic. During and after such exercise, renal and respiratory processes respond to attempt to maintain and eventually restore physiologically normal blood acidity levels. Specifically, renal processes extract H+ into urine while retaining HCO3- in the blood, while carbonic anhydrase works in conjunction with respiratory processes to enzymatically convert excess H+ and HCO3- into H2O and CO2, with the excess CO2 exhaled from the lungs and H+ stored as water. Through these processes, the bloodstream is first regulated to acidity, then returns to alkalinity, exhibiting a slight alkalinity relative to physiological normality—a phenomenon known as "alkaline rebound"; it then stabilizes again, returning to physiological normality. During exercise-induced acid-base imbalance, oxygen levels fluctuate due to increased cellular oxygen demand and reduced oxygen-carrying capacity of hemoglobin in the presence of H+ (since H+ can directly replace O2 on hemoglobin).

[0002] Given that acid shifts and subsequent alkaline rebounds are natural and common processes, it is not surprising that they also have physiological implications. For example, increases / decreases in the H+ and HCO3- gradient between the bloodstream and the intracellular environment affect electrolyte inflow and outflow from cells, decreases / increases in oxygen status affect various metabolic processes, decreases in O2 stimulate erythropoietin to maintain erythrocytes, and various aspects of immune responses, cell maintenance, growth, and healing are also triggered by changes in pH and O2 levels.

[0003] While many therapies aim to increase oxygen and reduce blood acidity, there are related treatments (such as those described in U.S. Patent No. 11,344,529 and U.S. Patent Publication No. 2020 / 0390743, the disclosures of each of which are incorporated herein by reference in their entirety for all purposes) that introduce the use of acidic solutions to shift blood flow towards acidity as a key element of the therapy, with renal and respiratory compensation expected to subsequently restore alkaline conditions. Thus, elements of such therapies (referred herein to as “pharmaceutical-induced exercise”) are proposed to induce acid-base and corresponding oxygen state changes to deliver therapeutic benefits. It should be noted that this type of stimulation differs from physiological exercise because lactate levels are not expected to increase as a result of the therapy unless lactate is specifically added to the formulation. U.S. Patent No. 11,344,529 additionally specifically endorses the use of hydrochloric acid, ascorbic acid, dehydroascorbic acid, acetic acid, citric acid, lactic acid, phosphoric acid, and combinations of two or more thereof administered via IV. Studies further indicate that various vitamins, electrolytes, antioxidants, amino acids, and other pharmaceutical products may also be included for different therapeutic goals. Finally, the study introduces the common expectation of using pH buffers to buffer pH for compatibility with infusion without undue irritation to veins, arteries, or other tissues. While the study represents an important first step in the field of acid-shifting therapy, the proposed formulation does not address optimization from a drug volume perspective. Summary of the Invention

[0004] This document discloses methods and compositions for converting blood acidity for therapeutic purposes while additionally presenting a therapeutic conjugate base. The method includes administering a therapeutically effective amount of a therapeutic composition comprising: an intravenous buffer solution comprising at least one pharmaceutical-grade acid with a pKa < 3.0, the at least one pharmaceutical-grade acid having a therapeutic conjugate base; and at least one pharmaceutical-grade pH buffer in a sterile aqueous solution. For this purpose, a therapeutically effective amount of the therapeutic composition comprising: an intravenous buffer solution comprising at least one pharmaceutical-grade acid, the at least one pharmaceutical-grade acid containing at least one therapeutic conjugate base; and at least one pharmaceutical-grade pH buffer in a sterile aqueous solution can be administered. As used in this specification and the appended claims, the term "therapeutically effective amount" means an amount sufficient to achieve such treatment when administered to a human or veterinary subject to treat a disease or medical condition, including: delaying or preventing the onset of a disease, symptom, or illness; slowing or stopping the progression, aggravation, or worsening of one or more symptoms of a disease, symptom, or illness; improving the symptoms of a disease, symptom, or illness; reducing the severity of a disease, symptom, or illness; and / or curing a disease, symptom, or illness. The therapeutically effective dose will vary depending on the subject, the disease, condition, or symptom being treated, the stage of the disease, condition, or symptom being treated, the severity of the disease, condition, or symptom being treated, and the method of administration, all of which can be routinely determined by a person skilled in the art. Pharmaceutical-grade acids may include hydroiodic acid, perchloric acid, chloric acid, sulfuric acid, nitric acid, folic acid, sulfurous acid, sulfuric acid, glutamate, and pyruvate, or combinations of two or more thereof. Therapeutic conjugate bases may include iodine, perchlorate, chlorate, sulfate, nitrate, folic acid, bisulfite, glutamate, and pyruvate, or combinations of two or more thereof, or their ionized or radioactive forms. When administered to a subject, the concentration of the pharmaceutical-grade acid and pharmaceutical-grade pH buffer in the buffer solution may be sufficient to provide a total acid content of 60 mmol / L to 3,000 mmol / L. When administered to a subject, the pharmaceutical-grade acid and one or more pharmaceutical-grade pH buffers may be selected to provide a buffer solution pH between 1.8 and 8.6.

[0005] In some implementations, the buffer solution is administered in an amount sufficient to lower the physiological blood flow pH of the subject by 0.01 to 1.1.

[0006] In some implementations, the buffer solution may be administered in an amount sufficient to lower the physiological blood flow pH of the subject by 0.15 to 0.75.

[0007] In some implementations, the concentrations of acid and buffer can provide the buffer solution with sufficient buffering capacity to maintain a decrease in the physiological blood flow pH of the subject for 1 minute to 1 week.

[0008] Therapeutic intentions may include managing diabetes, insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoproteinemia, cancer, sepsis, wound care, wound management, reduction of vascular plaque, management of radiation exposure, enhancement of glutathione status, enhancement of sulfur-based metabolism, and / or infectious diseases.

[0009] In some embodiments, the composition further includes one or more ion sources selected from the following: magnesium ion source, potassium ion source, calcium ion source, zinc ion source, copper ion source, selenium ion source, chromium ion source, cobalt ion source, iodine ion source, manganese ion source, and molybdenum ion source.

[0010] In some embodiments, the composition further includes one or more vitamins selected from the following: B vitamins, vitamin C, and vitamin K.

[0011] In some embodiments, the composition further includes: an antioxidant defense compound, comprising one or more non-enzymatic compounds selected from tocopherol (aTCP), coenzyme Q10 (Q), taurine, cytochrome c (C), and glutathione (GSH); and an enzyme component, comprising manganese superoxide dismutase (MnSOD), catalase (Cat), glutathione peroxidase (GPX), phospholipid peroxidase glutathione peroxidase (PGPX), glutathione reductase (GR); peroxorubicin (PRX3 / 5), glutathione reductase (GRX2), thioredoxin (TRX2), thioredoxin reductase (TRXR2), and combinations of two or more thereof.

[0012] In some embodiments, the composition further includes one or more essential amino acids selected from the following: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, and combinations of two or more thereof.

[0013] In some embodiments, the composition further includes one or more non-essential amino acids selected from the following: tyrosine, glycine, arginine, glutamine, glutamic acid, cysteine, serine, proline, alanine, asparagine, aspartic acid, and combinations of two or more thereof.

[0014] The composition can be formulated into hypotonic, isotonic, or hypertonic forms. It can be administered by intravenous, bolus, transdermal, oral, ocular / ophthalmic, suppository, oral, or inhalation methods.

[0015] The compound can be administered by infusion over a period of about 1 minute to about 1 hour, and can be repeated as needed over a period of about 1 day to about 1 year.

[0016] In some implementations, one or more base conversion solutions are used before or after one or more acid conversion solutions.

[0017] In some implementations, one or more base conversion solutions are applied alternately between one or more acid conversion solutions.

[0018] In some implementations, one or more acid-converting solutions are applied alternately between one or more base-converting solutions.

[0019] The compound can be administered to a variety of subjects, including human or veterinary subjects or their cultures.

[0020] This article provides a pharmaceutical composition for intravenous delivery to mammals, comprising: an intravenous buffer solution comprising at least one pharmaceutical-grade acid, the at least one pharmaceutical-grade acid containing at least one therapeutic conjugate base; and at least one pharmaceutical-grade pH buffer in a sterile aqueous solution.

[0021] In some embodiments, pharmaceutical-grade acids include acids selected from the following: hydroiodic acid, perchloric acid, chloric acid, sulfuric acid, nitric acid, folic acid, sulfurous acid, sulfuric acid, glutamic acid, and pyruvic acid, or combinations of two or more thereof.

[0022] In some embodiments, the therapeutic conjugate base includes a base selected from iodine, perchlorate, chlorate, sulfate, nitrate, folic acid, bisulfite, glutamate, and pyruvate, or a combination of two or more thereof, or an ionized or radioactive form thereof.

[0023] In some embodiments, when applied, the concentrations of the pharmaceutical-grade acid and the pharmaceutical-grade pH buffer in the buffer solution are sufficient to provide a total acid content of 60 mmol / L to 3,000 mmol / L; and wherein, when applied, the selected pharmaceutical-grade acid and pharmaceutical-grade pH buffer provide a buffer solution pH between 1.8 and 8.6. Attached Figure Description

[0024] Figure 1 A diagram illustrating an acid transition that can be produced by the embodiments disclosed herein is shown.

[0025] Figure 2 A solution for therapeutic use at a target osmotic pressure, according to an embodiment disclosed herein, is shown. The hypotonic solution has a lower osmotic pressure (solute concentration) compared to the target solution, while the hypertonic solution has a higher osmotic pressure.

[0026] Figure 3An example of using acid conversion to simultaneously target an indication acting by including a therapeutic base, according to an embodiment disclosed herein, is shown. Packaging efficiency at the target osmotic pressure is formulated using an acid containing a therapeutic base (rather than by pairing an acid and / or base with an excipient).

[0027] Figure 4 A graph showing the total titratable acid (mol H+ / L) at a given volume under a target osmotic pressure is presented. It can be seen that the total titratable acid is greater when prepared using an acid containing a therapeutic base (rather than by pairing the acid and / or base with an excipient).

[0028] Figure 5 An example of an acid-conversion solution and associated calculations according to the embodiments disclosed herein is shown. Detailed Implementation

[0029] like Figure 1 As shown, it is believed that acute acid shifts in the bloodstream impair acid expulsion from cells to promote the recovery of intracellular metabolism. This is relevant because, in cases of chronic metabolic acid production and acid expulsion from cells, net ion exchange can reduce intracellular buffer storage while increasing intracellular calcium. With increased intracellular calcium, this creates a feedback loop that selectively inhibits the electron transport chain (ETC) to reduce oxidative phosphorylation and net adenosine triphosphate (ATP) production. The reduction in ATP further impairs the function of sarcoplasmic reticulum calcium ATPase (SERCA), which regulates intracellular Ca2+ by concentrating Ca2+ in the endoplasmic reticulum reservoir. Finally, decreased ETC activity also reduces H+ to H2O conversion, which further increases metabolic acid production.

[0030] If acid is introduced into the bloodstream, for example via an acid-converting drug according to the embodiments disclosed herein, the sodium-hydrogen exchanger becomes stagnant to directly reduce sodium uptake and thus reduce calcium uptake via the Na / Ca exchanger. Intracellular hydrogen levels can increase, while H+ efflux is impaired, which can increase the chemiosmotic gradient and acutely increase available ATP. It is also recognized that more acidic intracellular conditions stimulate cardiolipin remodeling and mitochondrial fusion and repair processes. Higher ATP levels can also increase the role of Na / K ATPases in potassium inflow, while increasing blood sodium levels to stimulate HCO3 / Na cotransport, thereby inflowing HCO3- buffers. Blood sodium can then act via the sodium-calcium exchanger to reduce intracellular calcium. Increased ATP can additionally restore the function of SERCA, which in turn reduces intracellular Ca+2 by concentrating Ca+2 in the endoplasmic reticulum reservoir. Finally, the decrease in Ca+2 concentration can reduce feedback to authorize the restoration of ETC activity, thereby promoting H+ to H2O conversion while increasing metabolic output.

[0031] Oxygen delivery is also expected to be acutely affected by this process. As blood acidity increases, the efficiency of hemoglobin transport of O2 decreases because H+ competes for these same sites. Therefore, O2 delivery may be acutely reduced. Although ATP production through the oxidation process may be reduced, the increase in blood acidity and the corresponding increase in intracellular acidity are expected to increase the chemiosmotic gradient to increase ATP from oxidative phosphorylation. Simultaneously, the reduction in O2-based metabolism is expected to reduce oxidative stress and net reactive oxygen species (ROS) levels, where the reduction in ROS is expected to further provide feedback to restore ETC activity, thereby increasing future metabolism toward the production of more ATP, at which point more metabolic H+ is converted to H2O via the ETC. This will therefore reduce the outflow of metabolic acid from cells. Post-infusion, renal and respiratory compensation is expected to achieve alkaline rebound, which will enhance O2 delivery because there are fewer H+ competing with O2 for sites on hemoglobin. This process of reducing ROS by reducing O2 supply to restore ETC function has been considered a potential mechanism for reducing post-hypoxia reperfusion injury in studies. These form the basis for the proposed acid-shifting therapy.

[0032] The disclosed formulations are intended for intravenous or intra-arterial infusion, or for other means of delivery within a subject, minimizing the packaging or infusion volume. For therapeutic compositions used in drug-induced exercise involving acid shift, acids with low pKa (or pKa1 or pKa2) (e.g., below pH 3.0) will be particularly valuable because they provide a means of concentrating H+ in the packaging compared to weaker acids. Furthermore, it is recognized that several acids with low pKa also possess conjugate bases, which have therapeutically useful properties. For example, the following compounds are considered to have therapeutic value as conjugate bases and can exist as acids exhibiting one or more pKa < 3.0: iodine, perchlorate, chlorate, sulfate, nitrate, folate, bisulfite, glutamate, and pyruvate, see the table below:

[0033] Table 1: Therapeutic conjugate bases and associated acids with pKa < 3.0

[0034]

[0035] While acid-converting infusion drugs can be formulated by combining a balanced solution containing a therapeutic base with a composition utilizing an acid and an excipient base, such compositions would require increased dilution (and therefore increased volume) to achieve a given osmotic pressure target. This approach increases the package size and infusion volume of the drug product. The acid choice that maintains a minimum package or infusion volume while achieving the target osmotic pressure can be an acid that inherently contains a therapeutic base. For example, if glutamate administration is desired during acid conversion, glutamate would achieve the minimum infusion volume at a given osmotic pressure compared to a composition consisting of a base-excipient acid (such as HCl) and an auxiliary supplement glutamate. If the target molar dose of glutamate is less than the molar H+ (pH) target, a suitable base-excipient acid, combined with a balanced solution of glutamate at a pKa(1) pH level, can be used to achieve the final H+ and glutamate targets at the minimum volume. If the target molar dose of glutamate is equal to the target molar H+ (pH), then only the equilibration solution of glutamate at the pKa (1) pH level is needed to achieve the H+ and glutamate targets in the minimum volume. If the target molar dose of glutamate is greater than the target molar H+ (pH), then the equilibration solution of glutamate at the pKa (1) pH level can be combined with glutamate to achieve the final H+ and glutamate targets in the minimum volume.

[0036] In further context regarding drug design utilizing pKa, the pKa value is the pH at which half of the acid molecules are protonated and half are deprotonated. When the pH is below the pKa value, a higher fraction of the acid molecules are protonated. Alternatively, when the pH is below the pKa value, a higher fraction of the acid molecules are deprotonated. For example, if an acid has a pKa of 4.5 and the solution has a pH of 2, most acid molecules will be protonated (HA), and a very small fraction will be deprotonated (A-). Therefore, utilizing acids in forms above or below their pKa is an alternative means of adjusting the ratio of H+ to A- present in a drug product. Equilibrium mechanisms can be considered to ensure that the acid does not transform into other forms, such as carbonic acid, which can convert H+ to H2O and reduce the net presentation of H+.

[0037] For the selected therapeutic conjugate bases, examples of acid transition selection with pKa < 3.0 are presented below, along with recognized potential applications of interest:

[0038] Ordinary iodine (hydroiodic acid, a strong acid, pKa1<1)

[0039] a. Supports the production of thyroid hormones to overcome hypothyroidism (not suitable for hyperthyroidism)

[0040] b. Treatment and prevention of some goiters, i.e., thyroid enlargement.

[0041] c. Neurodevelopment during pregnancy to support fetal brain development.

[0042] d. Neurodevelopment during lactation to support the baby's brain development.

[0043] e. Neurodevelopment during childhood to support brain development.

[0044] f. Treatment of fibrocystic breast disease, a non-cancerous condition most common in women of reproductive age, characterized by painful breast lumps.

[0045] g. Protection against nuclear fallout; in this case, iodide protects the thyroid gland, which may otherwise be vulnerable to radiation damage.

[0046] Perchlorate (perchloric acid, pKa<1)

[0047] h. Perchlorate is a potent inhibitor of osteoclast function and exerts its effects by influencing intracellular [Ca2+], thereby affecting the degree of cell contraction in osteoporosis.

[0048] Chlorate (chloric acid, pKa < 1)

[0049] i. Chlorate infusion reduces fecal excretion of E. coli.

[0050] Radioactive iodine (hydroiodic acid, a strong acid, pKa1<1)

[0051] j. Hyperthyroidism can be managed by using radioactive iodine to destroy excess thyroid cells.

[0052] k. Treatment options for thyroid cancer to destroy thyroid cancer cells.

[0053] Sulfates (sulfuric acid, strong acid, pKa1<1, pKa2=1.92) and / or bisulfites (sulfurous acid, pKa1=1.18)

[0054] 1. Sulfates and sulfites, which are oxidized to sulfates to promote the synthesis of sulfur-containing amino acids (SAAs), such as methionine, cysteine, cystine, homocysteine, and taurine. Therefore, they have particular potential applications for vegetarians, athletes, children, or people with HIV due to the increased risk of SAA deficiency.

[0055] m. Promotes the synthesis of secondary sulfur-containing compounds (SAAs) in the body: S-adenosylmethionine (SAMe), glutathione (GSH), N-acetylcysteine ​​(NAC), dimethyl sulfoxide (DMSO), glucosamine, and chondroitin sulfate, which have clinical applications in the treatment of several conditions, such as depression, fibromyalgia, arthritis, interstitial cystitis, sports injuries, congestive heart failure, diabetes, cancer, and AIDS.

[0056] Nitrates (nitric acid, strong acid, pKa < 1)

[0057] n. Nitrates are used to convert to NO under hypoxic conditions (such as local ischemia) via low pH or the action of xanthine oxidoreductase.

[0058] o. Nitrates, as diuretics, enhance the excretion of urinary chloride and sodium, resulting in a net loss of salt and water caused by increased glomerular filtration without a corresponding increase in tubular reabsorption.

[0059] Folic acid (pKa1=1.63, pKa2=2.71)

[0060] p. To treat or prevent specific anemias caused by poor diet, pregnancy, alcoholism, liver disease, specific gastrointestinal problems, kidney dialysis, or other conditions by promoting red blood cell growth.

[0061] q. Preventing spinal cord birth defects by promoting normal cell growth.

[0062] Glutamate (glutamate, pKa=2.19)

[0063] r. promotes learning and memory by interacting with four different receptors, thus successfully and rapidly transmitting messages between nerve cells.

[0064] s. When glucose levels are low, such as during hypoglycemic symptoms, it serves as an energy source for brain cells.

[0065] t. The sleep-wake cycle has an effect because glutamate levels are higher when awake and during the rapid eye movement (REM) stage of sleep.

[0066] u. Provides a glutamate pool to work synergistically with the storage of cysteine ​​and glycine, thereby restoring glutathione; used to reduce oxidative stress, maintain redox balance, enhance metabolic detoxification, and regulate the immune system. Various chronic, age-related diseases (such as those associated with neurodegeneration, mitochondrial dysfunction, and even cancer) are associated with insufficient or absent glutathione levels.

[0067] Pyruvate (pyruvate, pKa=2.49)

[0068] v. Pyruvate directly supports impaired central carbon metabolism and acts as an important H2O2 scavenger for Lyme disease / pathogenic spirochetes.

[0069] w. Pyruvate supplementation, as an ergonomic aid, can improve work output.

[0070] x. Pyruvate supplementation promotes weight loss or reduces circulating glucose by providing energy that bypasses the body's ability to store glucose as body fat.

[0071] In addition to delivering acid shifts under the presence of a conjugate base that is therapeutically beneficial, the composition may also benefit from the presence of components that address other needs or deficiencies. For example, the therapeutic acid shift composition can be further enhanced by adding vitamins, mineral electrolytes, antioxidants, amino acids, pain management medications, or other pharmaceutical products, including B vitamins, vitamin C, and / or vitamin K.

[0072] In addition to components added for therapeutic purposes, potential components are also expected to be included to act as conjugate bases or “buffers.” Specifically, these buffering components will aim to support pH adjustment to a specific pH range at application to deliver acid-shifting stimulation in a manner compatible with tissue physiology, in the presence of other therapeutically beneficial components. For example, the ideal pH range for intravenous care is typically between 6.5 and 8.0 to avoid irritation in veins and arteries. In intramuscular injections, a pH range between 2 and 11 is generally considered, while in subcutaneous injections, the range can be between 4 and 9. In dermal applications, the skin’s natural “acidic outer membrane” is recognized to be between 4.4 and 6.0, therefore topical creams are typically formulated in a pH range between 4 and 6. In other tissue compartments, such as the vagina, a lower pH may be appropriate, as the common pH of vaginal secretions is between 3.8 and 5.0. In the pancreas, the pH of pancreatic juice is between 7.8 and 8.8. Therefore, acid-shifting formulations can be designed to cause a variety of pH values ​​to vary across a range below 2.0 (e.g., in muscle) and below 8.8 (e.g., in the pancreas) upon “application.” Thus, a pH range of 1.8 to 8.6 is expected to be potentially useful for acid-shifting purposes. In each application, the component can be optimized based on its ability to buffer and improve acid stability (e.g., quasi-equilibrium) during application.

[0073] For the purpose of enhancing the stability of the composition at or near a specific pH for administration, a wide selection of buffering compounds can be utilized, each of which may be more or less suitable at a given pH. For example, in the pH range of 1.8 to 3.0, buffering substances (such as phosphates) can be used alone or in combination with therapeutic conjugate buffers (such as folate, bisulfite, sulfate, glutamate, or pyruvate). In the pH range of 3.0 to 5.0, conventional buffering substances (such as citrate, lactate, ascorbate, or acetate) can be used alone or in combination with therapeutic conjugate buffers (such as nitrite, glutamate, or folate). In the pH range of 5.0 to 7.0, conventional buffering substances (such as citrate, acetate, or bicarbonate) can be used alone or in combination with therapeutic conjugate buffers (such as folate or bisulfite). In the pH range greater than 7.0, conventional buffering substances (such as phosphates and ascorbate) can be used alone or in combination with therapeutic conjugate buffers (such as glutamate). Therefore, many alternative buffer options can be considered to achieve the target pH application, including those from a group of so-called therapeutic conjugate bases / therapeutic buffers for acid transition, as listed in Table 2. Such therapeutic buffer options may be desirable when the solution requires a larger fraction of therapeutic base relative to the proton (H+) fraction, and when the pKa of the buffer is close to the target pH at application.

[0074] Table 2: Buffering capacity of recognized therapeutic conjugate bases expected to achieve acid transition within the target pH application window of 1.8 to 11.5

[0075]

[0076] In contrast to pH, which measures the concentration of free protons in a solution, titratable acidity measures the sum of free protons and undissociated acids in a solution. For definitional purposes, titratable acidity is defined herein as the sum of free protons and undissociated acids in a solution between the pH at administration and the final pH (7.4). For a specific formulation to achieve acid conversion, it should contain a total titratable acid content suitable for the therapeutic target of acid conversion relative to adjacent compartments, tissues, cells, or organelles. To distinguish from incidentally present acids in a pharmaceutical product that are not designed for acid conversion, levels greater than 60 mmol / L have previously been defined, such as in U.S. Patent No. 11,344,529. The level distinguishes between “incidentally present acids” in a pharmaceutical product and acids intentionally included for the purpose of achieving the acid conversion effect. Essentially, formulations intended to deliver high titratable acid content require additional considerations, as discussed in the context of buffering, to meet the pH target at administration. For this purpose, unless acid conversion is intentionally part of the drug design, it is expected that the drug design will not exceed 60 mmol / L of titratable acidity.

[0077] The total amount of acid introduced into the bloodstream and the fraction extracted through renal and respiratory processes can vary depending on individual factors such as diet, metabolism, and overall health. On average, the human body produces approximately 50 to 100 milliequivalents (mEq) of acid daily, primarily due to metabolic processes. The renal system (especially the kidneys) extracts about 80% of the produced acid into 800 to 2000 ml of urine daily. The remaining 20% ​​of the acid is removed by the respiratory system, mainly through the exhalation of carbon dioxide (CO2), which works synergistically with water (H2O, where H+ combines with O-2) to maintain balance with carbonic acid (H2CO3) in the bloodstream.

[0078] Titratable acidity of urine can be defined as the amount of acid eliminated per liter of urine, or alternatively, as the amount of base required to adjust the urine pH level back to the original plasma pH level (~7.4 in mammalian species). Therefore, under normal conditions, the titratable acidity of typical mammalian urine varies between ~20 and 50 mmol / L, reaching up to 60 mmol / L upon ingestion of acid-producing foods and up to 80 mmol / L during fasting. Thus, a therapeutic composition using a 60 mmol / L titratable acid content contains as much or more acid as ordinary urine. Furthermore, an infusion of 500 ml of a 60 mmol / L solution corresponds to approximately one-quarter of the acid load excreted daily through renal and respiratory processes. Therefore, even solutions with a minimum titratable acidity of 60 mmol / L can be expected to have physiological effects.

[0079] The upper limit of the total titratable acid content is limited only by the concentration potential of the acid itself. For example, considering a formulation based solely on a strong acid (such as 1 M (mol / L) or hydroiodic acid at pH=0), the initial titratable acid content is 1 M or 1,000 mmol / L because hydroiodic acid is fully ionized at pH 0. Since the pKa value of hydroiodic acid is <1 (~-9.4), the [I-] / [HI] ratio is ~1 at physiological pH 7.4, resulting in a final titratable acid content of ~1 mmol / L. Therefore, the change in total titratable acid content is 999 mmol / L. Recognizing this, for the purpose of parametric description, it is recommended to use 3,000 mmol / L as the practical limit.

[0080] The pH of the applied formulation can be lower than that of the target compartment, whether the target is blood flow, interstitial space, intracellular space, or other locations. Using a substance that is alkaline relative to the compartment of interest before or after acid-conversion administration may also be valuable in order to chemically force a “basic displacement” or “basic rebound.” Acid-base oscillations can also be induced by alternately applying acid-conversion and alkaline-conversion solutions relative to the compartment of interest. Given that ion exchange processes between blood flow and intracellular space, interstitial space and intracellular space, and intracellular space and organelles typically exhibit directionally defined frequency response characteristics, the principle of resonance can be used to modulate specific damped or exaggerated responses to induced ion exchange.

[0081] The conjugate base provides therapeutically beneficial properties with an acid with a pKa less than 3.0 (“therapeutic acid”), reducing the packaging and infusion volume of the therapeutic acid conversion composition. Compositions can be developed with a target molar amount of acid less than, equal to, or greater than the target molar amount of the conjugate base. Additionally, various acids with a therapeutically beneficial conjugate base and a pKa < 3.0 are also utilized simultaneously. These cases are described below, and are further influenced by the use of acids at pH levels above and below the relevant pKa. After mixing to achieve the target molar ratio of the components, the solution can be diluted to achieve a hypotonic (human reference: <270 Osm / L), isotonic (human reference: 270–310 Osm / L), or modified with excipients (such as NaCl) to achieve a hypertonic (human reference: >310 Osm / L) target osmotic pressure.

[0082] Compositions involving a single therapeutic acid can be readily designed using the Henderson-Hasselbach equation, which relates the pH of the solution and the ratio of the molar amounts of the conjugate base and acid in the context of their pKa:

[0083] pH = pKa + log (conjugate base / acid)

[0084] Acids that do not contain the target therapeutic conjugate base (such as hydrochloric acid) can be prepared at pH 2.19 and combined with an additional glutamate (such as monosodium glutamate) in a molar equilibrium solution to achieve the target glutamate to H+ ratio. Such solutions will require additional dilution and therefore additional volume compared to solutions that utilize the therapeutic acid in some portions.

[0085] When the target molar amount of acid is less than the target molar amount of conjugate base, the equilibrium solution of the therapeutic acid can be prepared with a pH higher than the relevant pKa and / or must be combined with the equilibrium solution of the therapeutic salt. For example:

[0086] A therapeutic acid-shifting composition containing 1 mol of H+ per 2 mol of glutamate (pKa=2.19) can be formulated at the following target pH:

[0087] pH = pKa + log (conjugate base / acid) = 2.19 + log (2 / 1) = 2.49

[0088] Alternatively, depending on material availability, glutamic acid can be formulated at pH 2.19, and additional molar amounts of glutamate (such as monosodium glutamate) can be added to increase the glutamate ratio without increasing H+.

[0089] Alternatively, for comparative purposes, an acid that does not contain the target therapeutic conjugate base (such as hydrochloric acid) can be prepared at pH 2.49 and combined with an additional molar equilibrium solution of a glutamate (such as monosodium glutamate) to achieve the target glutamate to H+ ratio. Such a solution will require additional dilution and therefore additional volume compared to solutions that utilize the therapeutic acid in some portions.

[0090] When the target molar amount of acid is equal to the target molar amount of conjugate base, the equilibrium solution of the therapeutic acid can be prepared with a pH at the relevant pKa.

[0091] A therapeutic acid-shifting composition having 1 mol H+ per mol of glutamate (pKa=2.19) can be formulated at the following target pH:

[0092] pH = pKa + log (conjugate base / acid) = 2.19 + log (1 / 1) = 2.19

[0093] Alternatively, depending on material availability, glutamic acid can be formulated at a pH below 2.19, with additional molar amounts of glutamate (such as monosodium glutamate) added to increase the glutamate ratio to equal the net H+ content.

[0094] Alternatively, for comparison purposes, an acid that does not contain the target therapeutic conjugate base (such as hydrochloric acid) can be prepared at pH 2.19 and combined with an additional glutamate (such as monosodium glutamate) in a molar equilibrium solution to achieve the target glutamate to H+ ratio. Such a solution will require additional dilution and therefore additional volume compared to solutions that utilize the therapeutic acid in some portions.

[0095] When the target molar amount of acid is greater than the target molar amount of the conjugate base, the equilibrium solution of the therapeutic acid can be prepared to have a pH lower than the relevant pKa. A therapeutic acid-conversion composition with 2 mol H+ per mol of glutamate (pKa = 2.19) can be prepared at the following target pH:

[0096] pH = pKa + log(conjugate base / acid) = 2.19 + log(1 / 2) = 1.89

[0097] Alternatively, depending on material availability, glutamic acid can be formulated at a higher pH, such as pKa = 2.19, while additional molar amounts of a conjugated excipient acid (such as HCl) can be added to increase the H+ ratio relative to glutamate.

[0098] Alternatively, for comparative purposes, an acid that does not contain the target therapeutic conjugate base (such as hydrochloric acid) can be prepared at pH 1.89 and combined with an additional molar equilibrium solution of a glutamate (such as monosodium glutamate) to achieve the target glutamate to H+ ratio. Such a solution would require additional dilution and therefore additional volume compared to solutions that utilize the therapeutic acid in some portions.

[0099] A composition involving multiple therapeutic conjugate bases has a total target molar acidity equal to the sum of equal portions of the two conjugate bases. In this case, the two therapeutic acids can be combined in an appropriate ratio, such as by formulation to each have a pH at its respective pKa.

[0100] A therapeutic acid-shifting composition containing 2 mol H+ per mol of glutamate (pKa = 2.19) and 1 mol of pyruvate (pKa = 2.49) can be formulated at target pH levels of 2.19 and 2.49, respectively. The H+ concentration of each acid (equal to the conjugate base concentration at pKa) can then be calculated to identify the appropriate mixing ratio to obtain the target result. This can be readily determined using the standard relationship between pH and concentration.

[0101] [H+] = 10 -pH

[0102] Therefore, the target mixing ratio will be:

[0103] [H+] GA / [H+] PA = 10 -2.49 / 10 -2.19 = 0.00645 / 0.00323 = 2.0

[0104] Because when mixed at pH=pKa, the concentration of glutamate is twice that of pyruvate, each part of glutamate needs to be mixed with two parts of pyruvate to achieve a 2:1:1 ratio of H+:glutamate:pyruvate.

[0105] Alternatively, depending on material availability, glutamate and / or pyruvate can be formulated at pH levels below, equal to, or above their respective pKa values. In this case, additional molar amounts of glutamate, pyruvate, or an acid with an excipient conjugate base may be required to achieve a 2:1:1 H+:glutamate:pyruvate ratio, where additional excipient concentration is present. In such cases, a small fraction of the excipient will require a moderate level of additional dilution to achieve the target osmotic pressure.

[0106] Alternatively, for comparison purposes, acids that do not contain the target therapeutic conjugate base (such as hydrochloric acid) can be combined with an additional molar equilibrium solution of glutamate and pyruvate. However, this will require additional dilution and therefore additional volume compared to a solution that utilizes one or more therapeutic acids in some portions. Such methods may require up to twice the dilution for a solution that utilizes at least one therapeutic acid in some portions, and therefore require up to twice the volume.

[0107] In some embodiments disclosed herein, it may be preferred that the selected pharmaceutical-grade acid and / or buffer provide a buffer solution pH between 1.8 and 8.6 when administered to a subject. Generally, the target pH for therapeutic administration of the acidic solution should be selected based on the pH tolerance of the surrounding tissues and the desired gradient effect. Methods for stabilizing the acid at the target pH after identifying the pH of interest are well-established. This involves selecting a buffer substance that is physiologically tolerable and / or beneficial and whose pKa value is close to the desired pH at the time of administration. In simple systems involving a single buffer substance, the Henderson-Hasselbalch equation can be rearranged to define the target ratio of base to acid, where the amounts are expressed in units such as M or mM:

[0108] Base / Acid = 10 ^ (pH - pKa)

[0109] As an example, a solution targeting a final pH of 1.8, as disclosed herein, can use a glutamate buffer with a pKa of 2.2. Glutamate is physiologically tolerable and is further considered a therapeutic agent. The appropriate amount of glutamate buffer can be defined if the target acid concentration and therapeutic volume are specified, as illustrated in Table 3.

[0110] Similarly, solutions targeting a final pH of 8.6 can utilize carbonate buffers because of their pKa of 10.3 and their physiological tolerability. If the target acid concentration and treatment volume are defined, the appropriate amount of carbonate buffer can be determined, as illustrated in Table 3.

[0111] Table 3

[0112] Example of buffer material selection for stabilizing 0.5 M / L

[0113] Sulfuric acid at pH 1.8

[0114]

[0115] Example of buffer material selection for stabilizing 0.5 M / L

[0116] Sulfuric acid at pH 8.6

[0117]

[0118] In some implementations, the buffer solution may be administered in an amount sufficient to lower the physiological blood flow pH of the subject by 0.01 to 1.1. The Henderson-Hasselbalch relationship can also be used to design compositions to achieve various pH shift outcomes. In practice, the degree of blood shift depends on the volume of acid-shifting drug administered, the concentrations of the acid and buffer components in the drug and in the blood, dilution from a coexisting source (such as saline), the rate of administration, and the extent of renal and respiratory responses elicited in the patient. If drug delivery is relatively rapid relative to renal and respiratory compensation processes (e.g., measured in seconds or minutes), a corresponding blood pH shift can be expected.

[0119] In simple terms, a buffer is a base that stabilizes hydrogen (acid) at a given pH by associating with hydrogen (acid). The choice of buffer or base for a given application is based on its pKa (or acid dissociation constant). This affects the strength of the acid in a solution containing the buffer. Specifically, pKa represents the dissociation of half of the acid molecule into its conjugate base and hydrogen ions (H+). + The pKa indicates the pH at which an acid contributes protons (H+) in an aqueous solution. In other words, pKa indicates the amount of protons an acid contributes in an aqueous solution. + The tendency to...

[0120] To extend shelf life, acidic medications may require extended storage periods. While it is generally desirable to administer solutions with a pH > 6.0 to avoid intravenous irritation, the acid must be in equilibrium with H₂O and CO₂, in which case it is in the form of carbonic acid with a pKa of 6.4.

[0121] CO2 + H2O ⇌ H+ + HCO3-

[0122] This means that packaging acids near pH 6.4 requires handling gas phase pressure. As an alternative, the drug can be mixed in two parts. One part can utilize a low pKa buffer (such as a therapeutic base with pKa < 3) and be formulated at a low pH (e.g., 2 to 3). This arrangement allows the drug part to be storage-stable without significant gas-phase interactions. It can then be mixed with a second part, including a buffer (such as bicarbonate), to achieve a pH > 6.0 for administration prior to application. Although the solution is also susceptible to carbonic acid instability "at the time of mixing," incidental CO2 escape can be minimized during administration by using a closed container and by minimizing the time between mixing and use.

[0123] Recognizing these factors, the knowledge of acids and buffering substances can be used to calculate the total acid content in the acid-converting solution required to exert an acid-converting effect in blood, as disclosed herein. First, let's discuss blood and plasma, where the primary buffering substances are:

[0124] 1. Bicarbonate (HCO3-): This is the most important buffer substance in the blood and is responsible for about 60% to 70% of the blood's buffering capacity.

[0125] 2. Proteins: Hemoglobin in red blood cells accounts for about 20% to 30% of the blood buffer, while other plasma proteins account for the remaining 5% to 7%.

[0126] 3. Phosphate buffers: These include approximately 1% to 3% of blood flow buffers, thus playing a minor role in the blood but being more important in the renal system.

[0127] 4. Organic acids: such as lactic acid, which can change with metabolic activities and can also play a role.

[0128] For illustrative purposes, it can be assumed that bicarbonate contributes 65% of the total buffering capacity, and further, the total effective buffering capacity in the blood can be approximated by scaling the amount of bicarbonate by 100% / 65%. The average concentration of bicarbonate (HCO3-) in the bloodstream typically ranges from 22 to 29 mmol / L, and the average blood volume of an adult is approximately 5 liters, but this can vary based on several factors such as age, sex, body size, and general health. The net blood conversion effect can be estimated considering the relatively rapid rate of administration to the patient, allowing for negligible renal and respiratory compensation.

[0129] For example, if a small amount of blood flow shift is desired, the acid-shifting solution (AS) can be prepared using a 0.5M sulfuric acid solution. For a patient with a blood volume of 5 liters, a normal high bicarbonate level of 29 mmol / L, and a total buffer storage equivalent to 44.6 mM HCO3-, a 1.2 ml infusion volume containing 0.6 mM acid will achieve a blood acid shift of 0.01 pH. For an infusion procedure achieving pH 6.5, the composition can be stabilized with a 0.76 mM bicarbonate buffer before administration. This scenario assumes that a 100 ml saline supplement can also be administered. Figure 5 Further details of these examples are shown in the figure.

[0130] Alternatively, if a significant blood flow conversion is required, an acid-converting solution (AS) can be designed using a 2.0M sulfuric acid solution. If we assume the patient has lost only 4 liters of blood volume, with a normal low bicarbonate level of 22 mmol / L and containing the equivalent of 13.5 mM HCO3- in total buffer, then a 343 ml infusion volume containing 686 mM of acid will achieve a blood acid conversion to pH 1.1. If the infusion procedure expects a pH of 6.2, the composition can be stabilized with a 43.3 mM bicarbonate buffer prior to administration. This scenario assumes that an additional 657 ml of saline supplement can also be administered.

[0131] Recognizing that the costs associated with delivering care can be substantial, one goal may be to improve health in as many ways as possible during a given intervention, such as infusion. Furthermore, various ions are typically administered to address a wide range of deficiencies and medical conditions. Therefore, acid-shifting formulations as disclosed herein can also deliver additional benefits by including selected ions such as, but not limited to, magnesium, potassium, calcium, zinc, copper, selenium, chromium, cobalt, iodine, manganese, and molybdenum. These ions are considered useful therapeutic options because they play important roles in a variety of physiological processes and metabolic functions. Several examples are provided below illustrating how each ion can increase net benefit when included as part of an acid-shifting formulation as disclosed herein; however, it should be understood that these ions may also be used for other reasons.

[0132] Magnesium (Mg) 2+ It participates in over 300 enzymatic reactions, including energy production, protein synthesis, and DNA replication. It supports muscle and nerve function, regulates blood pressure, and maintains healthy immune function.

[0133] Potassium (K) + Kjeldahl (KK) is essential for maintaining cell function, fluid homeostasis, and transmitting nerve impulses. It regulates heart rhythm, supports muscle contraction, and helps prevent hypokalemia (low potassium levels).

[0134] Calcium (Ca 2+ It is essential for bone and teeth structure, blood clotting, muscle contraction, and neurotransmitter release. It helps prevent osteoporosis, supports cardiovascular health, and contributes to muscle function.

[0135] Zinc (Zn) 2+ It is essential for immune function, wound healing, DNA synthesis, and protein production. It supports the immune system, promotes skin health, and contributes to cell division and growth.

[0136] Copper (Cu) 2+ It participates in iron metabolism, red blood cell formation, and maintains nerve cells and the immune system. It supports cardiovascular health, helps with collagen formation, and acts as an antioxidant.

[0137] Selenium (Se): Essential for antioxidant defense, thyroid hormone metabolism, and immune function. It protects cells from oxidative damage, supports thyroid function, and enhances the immune response.

[0138] Chromium (Cr) 3+ It enhances the action of insulin and plays a role in the metabolism of carbohydrates, fats, and proteins. It helps regulate blood sugar levels and supports weight management and metabolism.

[0139] Cobalt (Co) 2+ Vitamin B12 is a component of vitamin B12 and is essential for red blood cell production and nerve function. It helps prevent vitamin B12 deficiency, supports nerve function, and contributes to DNA synthesis.

[0140] Iodine (I - ): Essential for the synthesis of thyroid hormones, which regulate metabolism, growth, and development. Thyroid hormones prevent thyroid conditions (such as goiter and hypothyroidism), support metabolic rate, and promote healthy growth.

[0141] Manganese (Mn) 2+ It participates in bone formation, blood clotting, and antioxidant defense. It contributes to bone health, aids in the metabolism of amino acids, cholesterol, and carbohydrates, and protects against oxidative stress.

[0142] Molybdenum (Mo): A cofactor of enzymes involved in sulfur and amino acid metabolism. It supports detoxification processes, aids in the metabolism of drugs and toxins, and prevents molybdenum deficiency.

[0143] Each of these ions contributes to important biochemical pathways and physiological functions, making their adequate supply essential for maintaining health and preventing deficiencies. Therefore, infusion of these ions may be particularly beneficial in clinical settings where deficiencies or imbalances may occur due to disease, malnutrition, or specific medical conditions; however, they can also be used in other settings to produce positive effects.

[0144] It is also recognized that antioxidants and enzyme components may be valuable because they play a crucial role in protecting cells from oxidative damage, maintaining redox balance, and supporting overall cellular health. Specifically, tocopherol (aTCP), coenzyme Q10 (Q), taurine, cytochrome c (C), and glutathione (GSH), as well as enzyme components (including manganese superoxide dismutase (MnSOD), catalase (Cat), glutathione peroxidase (GPX), phospholipid peroxidase glutathione peroxidase (PGPX), glutathione reductase (GR); peroxorubicin (PRX3 / 5), glutathione reductase (GRX2), thioredoxin (TRX2), and thioredoxin reductase (TRXR2)) are considered useful therapeutic options due to their important roles in various physiological processes and metabolic functions. Some examples are provided below illustrating how each component can contribute to net benefit when included as part of an acid-shifting formulation as disclosed herein; however, it should be understood that other benefits may also arise from the use of these components, and their uses are not limited to these specific examples.

[0145] Antioxidants:

[0146] Tocopherol (vitamin E, aTCP): A fat-soluble antioxidant that protects cell membranes from oxidative damage by neutralizing free radicals. It reduces the risk of chronic diseases, supports immune function, and promotes skin health.

[0147] Coenzyme Q10 (Q): A component of the electron transport chain in mitochondria, it is essential for ATP production and acts as an antioxidant. It supports heart health, enhances energy production, and protects cells from oxidative stress.

[0148] Taurine: An amino acid with antioxidant properties, it participates in bile salt formation, cell membrane stability, and osmotic pressure regulation. It protects against cell damage, supports cardiovascular health, and contributes to nerve function.

[0149] Cytochrome c (C): A component of the electron transport chain in mitochondria, involved in ATP production and apoptosis regulation. It enhances cellular energy production and helps regulate cell death processes.

[0150] Glutathione (GSH): A tripeptide that acts as a major intracellular antioxidant, participating in detoxification and maintaining redox balance. It protects cells from oxidative damage, supports immune function, and detoxifies harmful substances.

[0151] Enzyme antioxidants:

[0152] Manganese superoxide dismutase (MnSOD): An enzyme that converts superoxide radicals into hydrogen peroxide and oxygen, protecting mitochondria from oxidative damage. It reduces oxidative stress, supports mitochondrial function, and prevents cell damage.

[0153] Catalase (Cat): An enzyme that converts hydrogen peroxide into water and oxygen, reducing oxidative stress. It protects cells from hydrogen peroxide toxicity and supports overall cellular health.

[0154] Glutathione peroxidase (GPX): An enzyme that uses glutathione to reduce hydrogen peroxide and lipid peroxides, protecting cells from oxidative damage. It maintains cellular redox balance and prevents oxidative damage to lipids, proteins, and DNA.

[0155] Phospholipid peroxidase (PGPX): A specific form of GPX that protects cell membranes from lipid peroxidation. It maintains membrane integrity and prevents oxidative damage to phospholipids.

[0156] Glutathione reductase (GR): An enzyme that regenerates GSH from its oxidized form (GSSG), maintaining glutathione levels in cells. It supports continuous cellular detoxification and antioxidant defense.

[0157] Peroxorubicins (PRX3 / 5): a class of enzymes that reduce peroxides and protect cells from oxidative damage. They prevent oxidative stress, support mitochondrial function, and maintain redox balance.

[0158] Glutathione reductase (GRX2): An enzyme that catalyzes the reduction of disulfide bonds in proteins, maintaining redox homeostasis. It protects proteins from oxidative damage and supports cellular redox regulation.

[0159] Thioredoxin 2 (TRX2): A protein involved in redox signaling and the reduction of oxidative proteins, maintaining redox homeostasis. It regulates cell growth and apoptosis and protects against oxidative stress.

[0160] Thioredoxin reductase (TRXR2): An enzyme that regenerates reduced thioredoxin from its oxidized form, supporting cellular redox homeostasis. It maintains cellular redox homeostasis and protects against oxidative stress.

[0161] It is also recognized that non-essential amino acids can be valuable supplements because they are essential for protein synthesis, metabolism, immune function, tissue repair and growth, cognitive function, detoxification, and antioxidant defense. Even though the body can synthesize them, supplementation can be valuable under various circumstances. Specifically, tyrosine, glycine, arginine, glutamine, glutamic acid, cysteine, serine, proline, alanine, asparagine, and aspartic acid are considered therapeutic options of interest due to their important roles in various physiological processes and metabolic functions. Some examples are provided below to illustrate how each of these components can contribute to the net benefit of acid-shifting preparations as disclosed herein; however, it should be understood that other benefits may also arise from the use of these components, and their uses are not limited to these specific examples.

[0162] 1. Tyrosine: An amino acid involved in the synthesis of neurotransmitters such as dopamine, norepinephrine, and epinephrine. It supports cognitive function, mood regulation, and hormone production.

[0163] 2. Glycine: The simplest amino acid, it plays a crucial role in the synthesis of proteins, collagen, and neurotransmitters. It supports muscle growth, improves sleep quality, and helps maintain healthy skin and joints.

[0164] 3. Arginine: An amino acid involved in the production of nitric oxide, which helps relax blood vessels and improve circulation. Supports cardiovascular health, immune function, and wound healing.

[0165] 4. Glutamine: The most abundant amino acid in the blood, it is essential for maintaining the health of the intestinal lining and immune system. Supports gut health, immune function, and muscle recovery.

[0166] 5. Glutamate: An amino acid that acts as a neurotransmitter in the brain and is a precursor to glutamine. It supports cognitive function, energy production, and detoxification processes.

[0167] 6. Cysteine: A sulfur-containing amino acid involved in the synthesis of glutathione, a major antioxidant. Glutathione supports detoxification, immune function, and the health of skin, hair, and nails.

[0168] 7. Serine: An amino acid involved in the synthesis of proteins, enzymes, and neurotransmitters. It supports cognitive function, immune responses, and the metabolism of fats and fatty acids.

[0169] 8. Proline: An amino acid essential for collagen synthesis, which is crucial for the structure of skin, bones, and connective tissue. It supports wound healing, skin health, and joint function.

[0170] 9. Alanine: An amino acid involved in glucose metabolism and energy production. It supports muscle performance, immune function, and regulation of blood sugar levels.

[0171] 10. Asparagine: An amino acid involved in protein synthesis and ammonia metabolism. It supports nervous system function, protein synthesis, and detoxification processes.

[0172] 11. Aspartic acid: An amino acid involved in the citric acid cycle and the synthesis of other amino acids. It supports energy production, neurotransmitter regulation, and liver detoxification.

[0173] Therapeutic amounts of the disclosed compositions can be administered via routes including, but not limited to, intravenous, intramuscular, or parenteral, oral, ocular, topical, inhalation or otherwise nebulized, mucosal, and transdermal administration. The disclosed compositions can also be formulated for intravenous, bolus, transdermal, oral, ocular, suppository, oral, ocular, or inhalation delivery. For intravenous or parenteral administration (i.e., injection or infusion), the composition may also contain suitable pharmaceutical diluents and carriers, such as water, saline, glucose solution, fructose solution, ethanol, or oils of animal, plant, or synthetic origin. It may also contain preservatives and buffering substances known in the art. When a therapeutic amount is administered via intravenous, transdermal, or subcutaneous injection, the solution may also contain components for adjusting pH, tonicity, stability, etc., all of which fall within the scope of the art. For topical application, the composition may be formulated as, for example, a liquid, gel, paste, or cream. In some embodiments, the composition may be applied via a topical patch. For ocular application, the composition may be formulated as, for example, liquid eye drops, or as a gel, paste, or cream to be applied to the surface of the eye and / or surrounding tissues. For ocular application, the composition may be formulated as, for example, ear drops. Other formulations, combinations with other compositions, application techniques, etc., are described in U.S. Patent Publication No. 2020 / 0390743 and U.S. Patent No. 11,344,529, the entire disclosure of which is incorporated herein by reference.

[0174] For purposes of explanation, the foregoing description has been described with reference to specific embodiments. However, the above illustrative discussion is not intended to be exhaustive or to limit the embodiments of the disclosed subject matter to the precise form disclosed. Many modifications and variations are possible in light of the foregoing teachings. These embodiments were chosen and described to explain the principles of the embodiments of the disclosed subject matter and their practical application, thereby enabling those skilled in the art to utilize these embodiments and various embodiments with various modifications that may be adapted to the particular intended use. Furthermore, specific examples of components that may be used as part of or in conjunction with the compounds and techniques disclosed herein are provided as illustrative examples and do not limit the scope or content of the embodiments disclosed herein.

[0175] The above description includes several exemplary implementations. However, those skilled in the art will understand that the invention disclosed herein is not limited to the described implementations and can be practiced with modifications and variations within the spirit and scope of the appended claims. Therefore, this specification is illustrative and not restrictive.

Claims

1. A method for converting blood acid for therapeutic purposes while presenting a therapeutic conjugate base, the method comprising: The composition is administered to a subject in a therapeutically effective amount, the composition comprising at least one pharmaceutical-grade pH buffer selected from a buffer solution and a sterile aqueous solution, the buffer solution having at least one pharmaceutical-grade acid, the at least one pharmaceutical-grade acid comprising at least one therapeutic conjugate base. The pharmaceutical-grade acids mentioned above include acids selected from the group consisting of: hydroiodic acid, perchloric acid, chloric acid, sulfuric acid, nitric acid, folic acid, sulfurous acid, sulfuric acid, glutamic acid, and pyruvic acid, or combinations of two or more thereof. The therapeutic conjugate bases described herein include bases selected from the group consisting of: iodine, perchlorate, chlorate, sulfate, nitrate, folate, bisulfite, glutamate, and pyruvate, or combinations of two or more thereof, or their ionized or radioactive forms. When administered to a subject, the concentrations of the pharmaceutical-grade acid and the pharmaceutical-grade pH buffer in the buffer solution are sufficient to provide a total acid content of 60 mmol / L to 3,000 mmol / L. When administered to a subject, the selected pharmaceutical-grade acid and one or more pharmaceutical-grade pH buffers provide a buffer solution pH between 1.8 and 8.

6.

2. The method of claim 1, wherein the buffer solution is administered in an amount sufficient to lower the physiological blood flow pH of the subject by 0.01 to 1.

1.

3. The method of claim 1, wherein the buffer solution is administered in an amount sufficient to lower the physiological blood flow pH of the subject by 0.15 to 0.

75.

4. The method of claim 1, wherein the concentrations of the acid and the buffer solution provide sufficient buffering capacity to maintain a decrease in the physiological blood flow pH of the subject for between 1 minute and 1 week.

5. The method of claim 1, wherein the therapeutic intent is to treat diabetes, insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoproteinemia, cancer, sepsis, wound care, wound management, reduction of vascular plaque, treatment of radiation exposure, enhancement of glutathione status, enhancement of sulfur-based metabolism, and / or infectious diseases.

6. The method according to claim 1, wherein the composition further comprises one or more ion sources selected from the group consisting of: magnesium ion source, potassium ion source, calcium ion source, zinc ion source, copper ion source, selenium ion source, chromium ion source, cobalt ion source, iodine ion source, manganese ion source and molybdenum ion source.

7. The method of claim 1, wherein the composition further comprises one or more vitamins selected from the group consisting of: B vitamins, vitamin C, and vitamin K.

8. The method of claim 1, wherein the composition further comprises: Antioxidant defense compounds, said antioxidant defense compounds comprising one or more non-enzymatic compounds selected from the group consisting of tocopherol (aTCP), coenzyme Q10 (Q), taurine, cytochrome c (C), and glutathione (GSH); and enzyme components, said enzyme components comprising manganese superoxide dismutase (MnSOD), catalase (Cat), glutathione peroxidase (GPX), phospholipid peroxidase glutathione peroxidase (PGPX), glutathione reductase (GR), peroxorubicin (PRX3 / 5), glutathione reductase (GRX2), thioredoxin (TRX2), thioredoxin reductase (TRXR2), and combinations of two or more thereof.

9. The method of claim 1, wherein the composition further comprises one or more essential amino acids selected from the group consisting of histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, and combinations of two or more thereof.

10. The method of claim 1, wherein the composition further comprises one or more non-essential amino acids selected from the group consisting of: tyrosine, glycine, arginine, glutamine, glutamic acid, cysteine, serine, proline, alanine, asparagine, aspartic acid, and combinations of two or more thereof.

11. The method of claim 1, wherein the composition is formulated as hypotonic, isotonic, or hypertonic.

12. The method of claim 1, wherein the composition is administered by intravenous, bolus, transdermal, oral, ocular, suppository, oral, or inhalation.

13. The method of claim 1, wherein the administration comprises introducing the composition by infusion over a period of about 1 minute to about 1 hour, and repeating the infusion as needed over a period of about 1 day to about 1 year.

14. The method of claim 1, wherein one or more base conversion solutions are used before or after the one or more acid conversion solutions.

15. The method of claim 1, wherein one or more base conversion solutions are applied alternately between one or more acid conversion solutions.

16. The method of claim 1, wherein one or more acid conversion solutions are applied alternately between one or more base conversion solutions.

17. The method of claim 1, wherein the subject is a human or veterinary subject or a culture thereof.

18. A pharmaceutical composition for intravenous delivery to mammals, said pharmaceutical composition comprising: An intravenous buffer solution comprising at least one pharmaceutical-grade acid, wherein the at least one pharmaceutical-grade acid comprises at least one therapeutic conjugate base; and At least one pharmaceutical-grade pH buffer in a sterile aqueous solution.

19. The pharmaceutical composition of claim 18, wherein the pharmaceutical grade acid comprises an acid selected from the group consisting of hydroiodic acid, perchloric acid, chloric acid, sulfuric acid, nitric acid, folic acid, sulfurous acid, sulfuric acid, glutamic acid and pyruvic acid, or a combination of two or more thereof.

20. The pharmaceutical composition of claim 18, wherein the therapeutic conjugate base comprises a base selected from the group consisting of iodine, perchlorate, chlorate, sulfate, nitrate, folic acid, bisulfite, glutamate, and pyruvate, or a combination of two or more thereof, or an ionized or radioactive form thereof.

21. The pharmaceutical composition of claim 18, wherein, when administered, the concentrations of the pharmaceutical-grade acid and the pharmaceutical-grade pH buffer in the buffer solution are sufficient to provide a total acid content of 60 mmol / L to 3,000 mmol / L; and wherein, when administered, the selected pharmaceutical-grade acid and the pharmaceutical-grade pH buffer provide a buffer solution pH between 1.8 and 8.6.

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