WO2022173813A1

WO2022173813A1 - Improved bhb-citrate formulations for promoting health

Info

Publication number: WO2022173813A1
Application number: PCT/US2022/015796
Authority: WO
Inventors: Thomas Weimbs; Jacob TORRES
Original assignee: University of California Berkeley; University of California San Diego UCSD
Current assignee: University of California Berkeley; University of California San Diego UCSD
Priority date: 2021-02-09
Filing date: 2022-02-09
Publication date: 2022-08-18
Anticipated expiration: 2023-08-09

Abstract

Formulations of a combination product made up of beta-hydroxybutyrate and citrate. The formulations may be used in methods of promoting health, including promotion of renal health. The formulations enable convenient administration of the beneficial combination product in powdered form for mixing with liquid. The formulations are salt-balanced, and may be free of sodium and/or silicates, and are well tolerated. The formulations may be provided in a container and measuring implement to enable convenient measurement of dosages.

Description

Title: Improved BHB-Citrate Formulations for Promoting Health

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS: This application claims the benefit of priority to United States Provisional Patent Application Serial Number 63/147,747 entitled “BHB-Citrate Formulation for Promoting Health,” filed February 9,

2021, the contents of which are hereby incorporated by reference.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT: This invention was made with government support under grant no. R01 DK109563 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0003] BACKGROUND OF THE INVENTION

[0004] Nutritional ketosis has various therapeutic effects. For example, in the context of renal health, research from several laboratories has established that kidney cells with an ADPKD mutation have a metabolic defect that drives disease progression. These changes in metabolism involve disruption of mitochondrial function, impairment of fatty acid metabolism, and dependence on glycolysis. These cells become dependent on glucose as their energy source and appear to be unable to efficiently utilize other energy carriers such as fatty acids and ketone bodies. These changes in cellular metabolism resemble the “Warburg effect” that has been known in cancer cells for a long time. Research has shown that the induction of nutritional ketosis by time-restricted feeding, fasting, or by using ketogenic diets strongly inhibits renal cyst growth and fibrosis in several different orthologous and non- orthologous animal models of PKD, for example as described in Torres et ak, 2019. Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease, Cell Metabolism 30:1007- 1023.

[0005] These beneficial effects of nutritional ketosis were shown to be mimicked by dietary supplementation with the ketone BHB (Torres et ak, 2019). BHB is the main “ketone body” produced in large amounts by the liver during periods of starvation or fasting. In the absence of starvation or fasting, BHB levels in the blood are very low. While it is possible to raise BHB levels by fasting or by administering specialized ketogenic diets in animal models, this is very difficult to do - especially in the long term - in human patients with renal issues, such as subjects suffering from ADPKD. It is well known that adherence to these strict diets is very low, which makes ketogenic dietary interventions unfeasible as therapeutic interventions for the vast majority of patients. However, most advantageously, exogenous BHB can be ingested to recapitulate a state of ketosis, without the requirement for strict diets.

[0006] Furthermore, as previously disclosed in United States Patent Application Publication Number US20200289444, entitled Methods and Compositions for Supporting Renal Health, the contents of which are hereby incorporated by reference, BHB may be combined with crystal precipitation inhibitors for improved efficacy. In short, this previously filed patent application teaches the use of BHB and other ketonic agents for promoting renal health, for example, in the management and treatment of polycystic kidney disease (PKD). The previous application also discloses that ketonic agents can be combined with crystal precipitation inhibitors such as citrate, for synergistic therapeutic effects.

[0007] Given the effectiveness of the foregoing BHB-citrate combination product, there is a need in the art for refined and improved formulations thereof. There is a need for salt- balanced formulations of the combination product to improve tolerance, especially in subjects with renal issues. There is a need in the art for sodium-free formulations of the combination product to improve tolerance, especially in subjects with renal issues. There is further a need in the art for conveniently formatted formulations that enable facile administration of the combination product at effective and tolerable dosages.

[0008] SUMMARY OF THE INVENTION

[0009] The scope of the invention encompasses what will be referred to herein as the “Combination Product.” The Combination Product is a composition for promoting health, particularly renal health, for example, in relation to renal cystic conditions such as polycystic kidney disease. The Combination Product of the invention is made up of two primary active ingredients: BHB and citrate.

[0010] Disclosed herein are novel implementations of the Combination Product, encompassing specific formulations of the combination products that represent improvements to the art, providing novel formulations of BHB and citrate that may be conveniently orally administered, and which are highly tolerated, particularly by subjects with renal issues, for example by sodium-free formulations, formulations free of silicates, and alkali formulations. Also disclosed herein are associated methods of using the Composition Products of the invention. Also disclosed are novel kits providing Combination Products of the invention and components for convenient administration.

[0011] BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Fig. 1. Fig. 1 depicts BHB effects on renal collagen deposition in SPRD:Han rats when provided in drinking water at varying concentrations: BHB at 40 mM (“Bl”), 80 mM (“B2”), and 160 (“B3”) mM.

[0013] Fig. 2. Fig. 2 depicts citrate effects on renal collagen deposition in SPRD:Han rats when provided in drinking water at varying concentrations: Citrate at 30 mM (“Cl”), 60 mM (“C2”), and 120 mM (“C3”).

[0014] Fig. 3. Fig. 3 depicts combined BHB and citrate effects on renal collagen deposition in SPRD:Han rats when provided in drinking water at varying concentrations: 40 mM BHB/30 mM Citrate (“BC1”); 40 mM BHB/60 mM Citrate (“BC2”); and 80M BHB/60 mM Citrate (“BC3”).

[0015] Fig. 4. Fig. 4 depicts BHB effects on renal cell division in the interstitial and tubule compartments in SPRD:Han rats when provided in drinking water at varying concentrations: BHB at 40 mM (“Bl”), 80 mM (“B2”), and 160 (“B3”) mM.

[0016] Fig. 5. Fig. 5 depicts citrate effects on renal cell division in the interstitial and tubule compartments in SPRD:Han rats when provided in drinking water at varying concentrations: Citrate at 30 mM (“Cl”), 60 mM (“C2”), and 120 mM (“C3”).

[0017] Fig. 6. Fig. 6 depicts combined BHB and citrate effects on renal cell division in the interstitial and tubule compartments in SPRD:Han rats when provided in drinking water at varying concentrations: 40 mM BHB/30 mM Citrate (“BC1”); 40 mM BHB/60 mM Citrate (“BC2”); and 80M BHB/60 mM Citrate (“BC3”).

[0018] Fig. 7. Fig. 7 depicts BHB effects on serum creatinine concentration in SPRD:Han rats when provided in drinking water at varying concentrations: BHB at 40 mM (“Bl”), 80 mM (“B2”), and 160 (“B3”) mM. [0019] Fig. 8. Fig. 8 depicts citrate effects on serum creatinine concentration in SPRD:Han rats when provided in drinking water at varying concentrations: Citrate at 30 mM (“Cl”), 60 mM (“C2”), and 120 mM (“C3”).

[0020] Fig. 9. Fig. 9 depicts combined BHB and citrate effects on serum creatinine concentration in SPRD:Han rats when provided in drinking water at varying concentrations: 40 mM BHB/30 mM Citrate (“BC1”); 40 mM BHB/60 mM Citrate (“BC2”); and 80M BHB/60 mM Citrate (“BC3”).

[0021] DETAILED DESCRIPTION OF THE INVENTION

[0022] A description of the various implementations of the invention follows. The inventions encompass a number of novel compositions, including compositions that may be used as medical foods, dietary supplements, therapeutic agents, and others. The compositions may be employed in methods of promoting health, particularly renal health.

[0021] In the following description, reference may be made to an amount being “about” an enumerated value, for example, “about 50%. ” As used herein, about means the enumerated value and a range of values that are within +/- 10% of the enumerated value.

[0022] Beta-hydroxybutyrate. The first element of the Combination Product is beta hydroxybutyrate (BHB). As known in the art, beta-hydroxybutyric acid, abbreviated BHB, is a ketone that is synthesized in the liver from acetyl-CoA formed from the breakdown of fatty acids via several intermediates and reaction steps. BHB is formed in ketosis or other low glucose conditions. STRUCTURE 1:

[0023] The BHB in the Combination Product may be provided in various forms. The BHB may be provided as BHB. Reference to BHB in the Combination Product will also encompass compositions comprising what is termed herein as a “BHB analog.” The BHB may be provided in a single form, or as a mixture of two or more forms of BHB or BHB analog. [0024] Likewise, analogs of BHB may also be employed in the Combination Products. As used herein, “BHB analog” broadly encompasses any compositions that (1) is converted to BHB in vivo or (2) has structural similarly to BHB and promote like physiological responses as those promoted by BHB.

[0025] In one embodiment, the BHB analog is a precursor of BHB. A BHB precursor is a composition that is converted to BHB in vivo via one or more reactions or intermediates. In one embodiment, the BHB precursor is butyrate. In one embodiment, the BHB precursor is beta-hydroxy beta-methylbutyrate. In one embodiment, the BHB precursor is a ketogenic amino acid or a deaminated keto-analogue of a ketogenic amino acid. In one embodiment, the BHB precursor is acetoacetate (the physiological form of acetoacetic acid). In one embodiment, the BHB precursor is poly-beta-hydroxybutyrate. In one embodiment, the BHB precursor is beta-hydroxybutyryloxy-butyrate.

[0026] In one embodiment, the BHB precursor is 1,3 butanediol, Structure 2:

1,3 butanediol is water soluble and well tolerated by animals, including humans. In the body, it is efficiently converted to BHB by enzymatic and/or chemical action, for example, wherein alcohol dehydrogenase catalyzes metabolism of 1,3 -butanediol to beta- hydroxybutyraldehyde, which is subsequently oxidized to beta-hydroxybutyrate by aldehyde dehydrogenase. Advantageously, 1,3 butane diol is neutral and can be administered directly without the need to formulate as a salt. In one embodiment, the BHB precursor is 1,3- butanediol diacetoacetate. 1,3 -butanediol diacetoacetate is water soluble, well tolerated in animals and converted to BHB in vivo.

[0027] In one embodiment, the BHB analog comprises a BHB precursor comprising a fat molecule which is readily converted to ketones in the body. In one embodiment, the BHB precursor is a medium chain triglyceride (MCT), for example, a triglyceride comprising six to 12 carbon chains. MCTs are more efficiently converted to ketones in vivo than shorter or longer chain fats. Exemplary MCTs include caproic acid (C6), caprylic acid (C8), capric acid (CIO), and 1 auric acid (Cl 2). [0028] The BHB analogs of the invention further encompass esters of BHB, and esters of BHB analogs, wherein the oxygen of the hydroxyl group of the BHB carboxylic acid moiety (carbon 1) is conjugated with a hydroxyl group of another compound. Exemplary esters include methyl, ethyl, propyl (e.g. n-propyl or 2-propyl), butyl (e.g. tert-butyl), pentyl, hydroxylbutyl, hydroxylpropyl, glycerol, citrate, or glycol groups joined to the 1 carbon of BHB. Other exemplary esters are 3-hydroxybutyrate-(R)-l,3-butanediol monoester. Esters of BHB at the 1 carbon eliminate the carboxylic acid group and associated charge. In vivo , these compositions are de-esterified by esterase enzymes, releasing BHB (or the BHB analog or mimic in some cases). Such compositions may have improved solubility, increased membrane permeability, improved stability, more sustained release, and increased tolerance compared to native BHB or BHB analogs. Reference to “BHB” and “BHB analogs” herein will be understood to encompass esters of BHB and esters of BHB precursors and mimic compositions. Esters of the 3 carbon are also within the scope of the invention.

[0029] Various BHB esters are known in the art. Additional BHB esters may include compositions of the formula: STRUCTURE 3

wherein R1 and/or R2 may be an alkyl moiety, for example, comprising one to twelve carbons, for example, methyl, ethyl, propyl (e.g. n-propyl or 2-propyl), butyl (e.g. tert-butyl), pentyl, hydroxylbutyl, hydroxylpropyl, glycerol, citrate, or glycol.

[0030] In some embodiments the BHB analog is a polymer of BHB or a polymer of a BHB analog. One example is polymeric BHB which is a polymeric ester between the carboxyl group of BHB and the hydroxyl group of BHB. Hydrolysis of polymeric BHB, for example in the gastrointestinal tract, either chemically, enzymatically or mediated by microorganisms, may lead to release of monomeric BHB and uptake into circulation.

[0031] In some embodiments, the BHB in the Combination Product of the invention comprises a BHB prodrug, or BHB analog prodrug. A BHB prodrug, or BHB analog prodrug, is a composition comprising a cleavable promoiety conjugated to BHB, or a BHB analog. In the body of a subject to which the prodrug is administered, the promoiety is cleaved by enzymatic or chemical action to release the BHB, or BHB analog. In a primary embodiment, the promoiety is joined to the BHB or BHB analog by ester linkage to the 1 and/or 3 carbon.

[0032] In one embodiment, the BHB analog comprises 3-hydroxybutyl 3-hydroxybutyrate, as described in United States Patent Number 10,051,880, Hydroxybutyrate ester and medical uses thereof, by Clarke and Veech. In one embodiment, the BHB analog comprises R,S-1,3- butanediol acetoacetate, for example, as described in United States Patent Number 9,795,590, Ketone supplements for treatment of angelman syndrome, by Weeber et al. In one embodiment, the BHB analog is an oligomer of (R)-3 -hydroxybutyrate, for example, as described in United States Patent Number 10,559,258, Nutritional supplements and therapeutic compositions comprising (R)-3 -hydroxybutyrate derivatives, by Veech and King. The BHB analog may comprise a composition described in United States Patent Number 10,376,528, Composition comprising ketone body and nicotinamide adenine dinucleotide modulator and methyl donor, by Schmidt or in United States Patent Number 5,693,850, Nutritive water soluble glycerol esters of hydroxy butyric acid, by Birkhahn et al..

[0033] BHB is a chiral composition having two enantiomers: D-P-hydroxybutyric acid (also known as R-P-hydroxybutyric acid) and L-P-hydroxybutyric acid (also known as S-P- hydroxybutyric acid). The D- and L-forms of BHB are determined by the tetrahedral orientation of the hydroxyl group (or oxy group, in BHB esters) on the third carbon of BHB. D-BHB is the most common endogenous form of BHB. L-BHB is only occurring in small amounts in cells, and thus is metabolized or cleared at a slower rate, while retaining key signaling properties of endogenous D-BHB. Reference to “BHB” or a “BHB analog” made herein will be understood to encompass either isoform alone or any mixture of D-BHB and L-BHB isoforms, unless the proportion of the enantiomers is specifically specified. Exemplary mixtures of enantiomers include substantially pure formulations of D-BHB and D-BHB analogs, for example, formulations comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% D-BHB or a D- BHB analog. Likewise, the mixture of enantiomers may comprise a substantially pure formulation of L-BHB or a L-BHB analog, for example, formulations comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% L-BHB or L-BHB analog. In other embodiments, the percentage of D-BHB or D- BHB analog in the mixture may be at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% (racemic mixture), 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

[0034] BHB Salts. In some embodiments, the BHB is provided in the Combination Product in a free acid form. In a primary implementation, the BHB is provided as a salt or a mixture of salts.

[0035] In various implementations, the BHB may be provided as any salt. In various embodiments, the BHB may be provided as any of arginine salts, calcium salts, chromium salts, citrulline salts, cobalt salts, copper salts, creatine salts, glutamine salts, histidine salts, iron salts, isoleucine salts, leucine salts, lithium salts, lysine salts, magnesium salts, manganese salts, molybdenum salts, ornithine salts, potassium salts, selenium salts, sodium salts, zinc salts, and combinations of the foregoing.

[0036] The BHB salts utilized in the Combination Product may be selected in order to impart any number of selected properties, for example, ease of manufacturing and handling, solubility, taste, or a desired physiological effect. For example, in some implementations, the Combination Product is formulated for administration to a subject having a kidney condition. Sodium consumption may be problematic for such individuals as sodium can raise blood pressure, predispose kidney stone formation, or have other detrimental effects on kidney function. Accordingly, in some implementations, sodium salts are not utilized in the Combination Product.

[0037] In some implementations, multiple salts are utilized in order to avoid providing overly high doses of a single mineral.

[0038] In some implementations, calcium and magnesium salts of BHB are utilized. In some implementations, these minerals are selected to mitigate the effects of oxalate and phosphate in diet. Oxalate is found in vegetables such as spinach and phosphate is found in many processed foods and drink. Both oxalate and phosphate can be damaging to the kidneys and high intake can worsen PKD progression. Calcium and magnesium, when ingested with food, are known to bind oxalate and phosphate. Accordingly, in the Combination Product of the invention, calcium salts of BHB and magnesium salts of BHB may be utilized to provide BHB in order to inhibit the absorption of oxalate and/or phosphorous. [0039] In a primary implementation, the BHB is provided as a salt or mixture of the foregoing. In some implementations, the BHB is provided as a calcium salt, e.g. Ca-(BHB)2. In some implementations, the BHB is provided as a magnesium salt, e.g. Mg-(BHB)2. In some implementations, the BHB is provided as a potassium salt, e.g. K-BHB. In some implementations, the BHB is provided as a mixture of two or three of the foregoing, for example, a mixture of a calcium salt and a magnesium salt; a mixture of a calcium salt and a potassium salt; a mixture of a magnesium salt and a potassium salt; or a mixture of a calcium salt, a magnesium salt and a potassium salt.

[0040] In one embodiment, the Combination Product comprises BHB, wherein BHB is provided as a mixture of calcium BHB salt, magnesium BHB salt and potassium BHB salt. Calcium BHB salt, as used herein, refers to Ca-(BHB)2. Magnesium BHB salt, as used herein, refers to Mg-(BHB)2. Potassium BHB salt, as used herein, refers to K-BHB. The proportion of a selected salt in a mixture of salts may be expressed as a weight percentage, wherein the weight percentage is calculated as the mass of the selected salt divided by the total mass of all BHB salt forms in the mixture, multiplied by 100. For example, in a mixture of 1 gram calcium BHB, 1 gram magnesium BHB, and 1 gram potassium BHB, the weight percentage of each BHB salt in the mixture is 33.33%. In one embodiments, the combination product comprises a mixture of calcium-BHB salt, magnesium BHB salt and potassium BHB salt wherein the calcium BHB salt is present at a weight percentage of about 25-35%, the magnesium BHB salt is present at a weight percentage of about 35-45%, and the potassium BHB salt is present at a weight percentage of about 25-35% In one embodiment, the combination product comprises a mixture of calcium-BHB salt, magnesium BHB salt and potassium BHB salt wherein the calcium BHB salt is present at a weight percentage of about 25-30%, the magnesium BHB salt is present at a weight percentage of about 35-40%, and the potassium BHB salt is present at a weight percentage of about 25-30%. In one embodiment, the Combination Product comprises a mixture of calcium-BHB salt, magnesium BHB salt and potassium BHB salt wherein the calcium BHB salt is present at a weight percentage of about 30%, the magnesium BHB salt is present at a weight percentage of about 40%, and the potassium BHB salt is present at a weight percentage of about 30%.

[0041] Citrate. The Combination Product further comprises citrate. The presence of citrate in the combination product imparts positive biological effects, and synergizes the beneficial effects of BHB. For example, subjects with ADPKD have been found to have a deficiency in urinary citrate levels (hypocitraturia) and also to have an abnormally acidic urine pH. A recent study showed that metabolic acidosis (as defined by lower serum bicarbonate) is common in individuals with ADPKD and correlates with a greater risk of worsening kidney function. Metabolic acidosis is well-known to lead to urine acidification which, in turn, causes hypocitraturia because urinary citrate excretion is partially regulated by urine pH.

[0042] Additionally, low urine pH is a well-known risk factor for forming uric acid kidney stones. Hypocitraturia is a well-known risk factor for forming calcium-based kidney stones such as those composed of calcium oxalate. Kidney stones are much more common in ADPKD patients compared with the normal population. Recent research has shown that the concentration of urinary citrate inversely correlates with faster disease progression in individuals with ADPKD (Torres et ah, 2019). Additionally, it was shown that the formation of insoluble microcrystals (such as calcium oxalate and calcium phosphate crystals) in kidney tubules can trigger the formation of renal cysts and leads to accelerated PKD disease progression in animal models (Torres et ah, 2019).

[0043] The foregoing pathologies can be countered by ingestion of citrate. Nutritional supplementation with citrate has two principal effects: (1) it raises the concentration of urinary citrate, and (2) it raises the urine pH. Both effects are well-known to antagonize the precipitation of microcrystals in kidney tubules. Urinary citrate is known to antagonize the formation of calcium-based crystals (e.g. calcium oxalate and calcium phosphate) and may also be effective against the formation of struvite crystals.

[0044] “Citrate,” as referred to herein, encompasses citric acid, citrate ions thereof, and salts and esters of citric acid.

Citric Acid: STRUCTURE 4:

Citrate ion of citric acid: STRUCTURE 5:

[0045] The citrate component of the Combination Product may be provided as a mono-, di- or tri-valent salt of citrate, for example salts of sodium, potassium, magnesium, calcium, other cations, or mixtures of cations. In other implementations, the citrate may be provided as anhydrous citrate. In some implementations, the citrate is provided as citric acid monohydrate or citric acid dihydrate.

[0046] BHBrCitrate Ratio. One aspect of the Combination Product is the relative proportion of BHB to the proportion of citrate in the composition, referred to herein as the BHB:Citrate ratio. This ratio may be expressed as a percentage ratio, i.e. the percentage of the total active ingredient mass (the active ingredients being BHB and citrate) made up by BHB to the percentage of the total mass of the total active ingredient mass made up by citrate. For example, in one embodiment the ratio is expressed as: vl 00

[0047] The Combination Product may comprise a BHB:Citrate ratio from a range of values, for example, being, or being about, a value selected from the following: 90: 10, 89: 11, 88:12, 87:13, 86:14 85:15, 84:16, 83:17, 82:18, 81:19, 80:20, 79:21, 78:22, 77:23, 76:24, 75:25, 74:26, 73:27, 72:28, 71:29, 70:30, 69:31, 68:32, 67:33, 66:34, 65:35, 64:36, 63:37, 62:38,

61:39, 60:40, 59:41, 58:42, 57:43, 56:44, 55:45, 54:46, 53:47, 52:48; 51:49; 50:50, 49:51,

48:52, 47:53, 46:54, 45:55, 44:56, 43:57, 42:58, 41:59, 40:60, 39:61, 38:62, 37:63, 36:64,

35:65, 34:66, 33:67, 32:68, 31:69, 30:70, 29:71, 28:72, 27:73, 26:74, 25:75, 24:76, 23:77,

22:78, 21:79, 20:80, 19:81, 18:82, 17:83, 16:84, 15:85, 14:86, 13:87, 12:88, 11:89 and 10:90.

[0048] In one embodiment the BHB citrate ratio is between 80:20 and 20:80. In one embodiment the BHB citrate ratio is between 50:50 and 70:30. In one embodiment, the BHB citrate ratio is between 55:45 and 65:35. In some embodiments, the BHB: citrate ratio is or is about 60:40. In various implementations, the BHB: citrate ratio is a ratio between 65:35 and 55:45, for example, 65:35, 64:36, 63:37, 62:38, 61:39, 60:40, 59:41, 58:42, 57:43, 56:44 and 55:45.

[0049] For the purposes of this disclosure, when calculating the weight percentage of BHB and citrate in the combination product, only the mass of the active molecule (BHB or citrate) is counted in the calculation, and the mass of counterions will be disregarded. For example, one gram of potassium BHB (K-BHB) salt contains 732 mg BHB (BHB molecular weight = 104.11 g/m, potassium BHB molecular weight = 142.2 g/m), BHB being 73.2% by weight of potassium-BHB, wherein only the mass of the active ingredient BHB is counted for calculation of BHB: Citrate ratio. Likewise, one gram of magnesium BHB salt (Mg-(BHB)2) contains 903 mg BHB, BHB being 90.3% by weight of magnesium BHB (molecular weight of Mg-(BHB)2= 230.5 g/mol), and one gram of calcium BHB salt (Ca-(BHB)2) contains 845 mg BHB, BHB being 84.5% by weight of magnesium BHB (molecular weight of Ca-BHB2= 246.3).

[0050] Table 1 provides exemplary molecular weights and active ingredient percentages.

TABLE 1 Molecular Weight of Exemplary Ingredients and Active Ingredient Fraction.

[0051] ADDITIONAL COMPONENTS AND PROPERTIES.

[0052] Alkaline Load. In some implementations, the Combination Product of the invention may be formulated to deliver an alkali load. As described above, the inclusion of citrate in the Combination Product imparts various benefits, including urine alkalinization. Urine alkalinization inhibits the formation of uric acid crystals and has been shown to facilitate the urinary excretion of uric acid. Individuals with ADPKD have a high incidence of clinical gout (24%) and hyperuricemia (>60%), conditions that are associated with uric acid crystal formation in the kidneys and renal damage. Hyperuricemia correlates with faster disease progression in ADPKD.

[0053] Accordingly, in a primary implementation, the Combination Product is alkaline. The Combination Product may be formulated to deliver 10-100 mEq of alkali load/day, for example, 25-75 mEq of alkali load/day, for example, ~50 mEq of alkali load/day, for example about 25 mEq of alkali load per dosage at a dosing of twice per day.

[0054] Excipients. The combination product of the invention may further comprise additional compositions, including bulking agents or fillers, anti-caking agents, flavoring agents, coloring agents, sweeteners, binders, disintegrants, preservatives, wetting agents, dispersing agents, surfactants, free-flow aids and other compositions known in the art for the formulation of medicaments, food supplements, medical foods, and edible items.

[0055] In one embodiment, the Combination Product will comprise one or more bulking agents. In one embodiment, the one or more bulking agents comprises plant fiber. In one embodiment, the plant fiber is com fiber, for example, FIBER-SOL(TM).

[0056] In some embodiments, the Combination Product will be substantially free of silicates. Silicates are commonly used as anti-caking agents in many edible compositions, however silicates may have detrimental effects on some subjects, for example, negative renal effects. Accordingly, in a primary embodiment, the Combination Product of the is substantially free of silicates, for example, having less than 0.5% by weight total silicates or having less than 10 mg of silicates per dosage.

[0057] In one embodiment, the Combination Product will comprise one or more sweeteners. In various embodiments, the one or more sweeteners comprises a sugar (e.g. fructose, sucrose, mannose, galactose, etc.) , a sugar alcohol (e.g. sorbitol, erythritol, xylitol), a non sugar sweetener, for example, stevia or yacon syrup.

[0058] In some implementations, the Combination Product will comprise one or more flavoring agents. Exemplary flavoring agents include natural and artificial flavoring agents, for example, flavors of lemon, cherry, lime, strawberry, blueberry, cocoa, vanilla, coffee, and other flavors known in the art.

[0059] Additional Active Ingredients. Optionally, additional active agents may be included in the Combination Products of the invention, including nutrients, medicinal compositions, and other compositions of matter having biological activity.

[0060] Combination Product Formulation and Format

[0061] The Combination Product may be provided in any number of formulations and formats. “Format” as used herein, refers to the physical form of the Combination Product. Format may further encompass how the compositions of the invention are packaged and provided to end-users.

[0062] In a primary embodiment, the Combination Product is formulated as a powder, i.e. a composition comprising particles or granules. The powder may comprise granules of a selected size range, for example, a fine powder that can be shaken or stirred with water or other liquid and ingested by drinking.

[0063] In a primary embodiment, the Combination Product is formulated as a soluble powder that can be mixed with liquid. The powder may comprise a water soluble powder, wherein most of all of the components are water soluble and dissolve to form a solution in liquids comprising water. Alternatively, the Combination Product may be formulated as a wettable powder formulation, wherein the composition forms a suspension when mixed with liquids comprising water. [0064] The scope of the invention encompasses kits. The kits of the invention comprise a Combination Product, a container, and, optionally, a measuring implement. In one implementation of the kits of the invention, the Combination Product may comprise a powder, such as a water soluble powder or wettable powder formulation. The contain may comprise a cannister, bottle, box or other packaging item configured to hold a selected amount of Combination Product. The measuring implement may comprise a cup, a scoop, a spoon, or other article of manufacture that enables measurement or dispensation of a single dosage of the Combination Product. For example a scoop may be provided that measures out 1-10 grams of powder per scoop, for example, 5-7 g per scoop, for example, 6.5 grams per scoop. In another embodiment, the powder may be provided in measured doses enclosed in packages, such as paper packets, sachets, stick packs, plastic vials, or other pouches or containers. In one implementation, the kit of the invention comprises a Combination Product in a liquid form and a container configured to hold liquid. The kit may further comprise a measuring implement, such as a cup or bottle cap with one or more graduations that aids in measuring out a single dosage of the Combination Product. In one implementation, the kit comprises a food item comprising a measured dosage or dosages of the Combination Product and a packaging item enclosing the food item.

[0065] In one implementation, the Combination Product is provided in tablets, wherein the active ingredients are combined with binders and fillers to create a discrete tablet or pill, for example, a chewable pill or pill that is swallowed. In one implementation, the powder is provided in capsules, for example, capsules comprising gelatin, cellulose, or other materials known in the art.

[0066] In one implementation, the Combination Product is formulated as a soluble material that is provided dissolved in a beverage, for example, as infused water, sports drinks, energy drinks, teas, fruit juices, or meal replacement beverages.

[0067] In some implementations, the Combination Product is provided as a component of an edible item, for example, being incorporated into gummies, cookies, snack bars, meal replacement bars and other bars, cereals, biscuits, crackers, confectionery items, and probiotic formulations including yogurt, and other food items. [0068] In some implementations, the Combination Product is formulated for use in veterinary subjects, pets, livestock, or other non-human animals and is provided in a form suitable for the selected animal, for example, as chow, feed, treats or snacks, or supplemented pet food.

[0069] EXEMPLARY EMBODIMENTS. The scope of the invention broadly encompasses the various implementations disclosed above. Additionally, the scope of the invention further encompasses the exemplary embodiment described next.

[0070] In one embodiment, the scope of the invention encompasses a Combination Product comprising “Composition 1,” Composition 1 being a composition formulated according to the ingredients and their relative proportions listed in Table 2. The amounts set forth in Table 2 are representative of a single 6.5 g dosage. It will be understood that the amounts may be scaled to any desired total mass, and that equivalents of the ingredients may be employed as well. The scope of the invention further encompasses variants of Composition 1 having different forms of BHB and citrate and varied amounts of secondary ingredients such as flavoring compositions, bulking compositions, sweeteners, etc., as well as additional secondary ingredients.

TABLE 2. Composition 1 Ingredients

[0071] Composition 1 comprises a mixture of calcium BHB salt, magnesium BHB salt, and potassium BHB salt wherein calcium BHB salt is present in the salt mixture at a weight percentage of 28%, magnesium BHB salt is present in the salt mixture at a weight percentage of 40% and potassium BHB salt is present in the salt mixture at a weight percentage of 32%. Composition 1 has a BHB: Citrate ratio of 63:37. The citrate may be provided as any form of citrate. In one embodiment, the citrate is citric acid or citric acid coated with citrate, for example, CITROCOAT N(TM) (Jungbunzlauer AG, Wulzeshofen, Austria).

[0072] In one embodiment the scope of the invention comprises a Combination Product comprising Composition 1, comprising: about 16.5% by weight calcium-BHB; about 23.8% by weight magnesium-BHB; about 19.0 % by weight potassium -BHB; about 28.6% by weight citrate; about 3.23% by weight flavoring composition; about 2.3% by weight sweetener; and about 6.7% by weight filler. [0073] In one embodiment, the sweetener comprises stevia and the filler comprises maltodextrin. In one embodiment, the composition is provided in a dosage of about 6.5 grams.

[0074] In another embodiment, the scope of the invention encompasses a Combination Product comprising “Composition 2,” Composition 2 being a composition formulated according to the ingredients and their relative proportions listed in Table 3. The amounts set forth in Table 3 are representative of a single dosage of 5 grams. It will be understood that the amounts may be scaled to any desired total mass, and that equivalents of the ingredients may be employed as well. The scope of the invention further encompasses variants of Composition 2 having different forms of BHB and citrate and varied amounts of secondary ingredients such as flavoring compositions, bulking compositions, sweeteners, etc. as well as additional secondary ingredients.

[0074] Composition 2 has a BHB:Citrate weight ratio of 60.3:39.7.

TABLE 3. Composition 2 Ingredients

[0075] MANUFACTURE.

In the case of powdered forms of the Combination Product, the Combination Product in powder form may be manufactured by obtaining the individual raw ingredients as powdered products and by blending them together by use of a mixing device such as a dry- blender. The raw ingredients are widely commercially available in powdered form from commercial suppliers. The raw ingredients may be available in different grain sizes, for example, 0.1 micron to 1 mm, for example, 10-100 microns. In some embodiments, it may be advantageous to match ingredients of similar grain sizes to facilitate more efficient and homogeneous blending to achieve uniform distribution of the ingredients. Commonly used types of blenders that can be used for the manufacturing of the powdered Combination Product include batch blenders and continuous mixers, including rotary drum batch mixers, ribbon blenders, V blenders, Twin-Screw Continuous Blenders, Continuous Processors, Cone Screw Blenders. These motorized blenders are most suitable for large-scale manufacturing. Additionally, smaller batches, e.g. test batches, of the Combination Product in powder form may be manufactured manually using smaller, hand-operated blenders. In the case of powdered forms of the Combination Product, the powder may optionally be dried or otherwise treated as known in the art to form a highly dissolvable formulation.

[0076] METHODS OF USE.

[0077] In one aspect, the scope of the invention encompasses a Combination Product disclosed herein, for use in a method promoting health, wherein the method or promoting health comprises administering to a subject a Combination Product. In one implementation, the administration is oral. In one implementation, the oral administration comprises self administration. In one embodiment, the scope of the invention encompasses a Combination Product disclosed herein for use in a method of promoting renal health, wherein the method or promoting health comprises administering to a subject a Combination Product. In one implementation, the administration is oral. In one implementation, the oral administration comprises self-administration

[0078] In a related aspect, the scope of the invention further encompasses a method of using a Combination Product disclosed herein. The method of use comprises administering a biologically effective amount of the Combination Product to a subject to achieve a selected outcome. Administration encompasses self-administration, for example, ingesting the Combination Product of the invention.

[0079] In the methods of the invention, the Combination Product is administered to a subject. The subject may be a human or a non-human animal such as a pet, livestock, test animal, or veterinary subject, including for example, dogs, cats, rodents, non-human primates, cows, pigs, horses, and other species.

[0080] In one implementation, the Combination Product of the invention is utilized as a dietary supplement. In one embodiment, the Combination Products of the invention is utilized as a medical food. In one embodiment, the Combination of the Product is utilized as a therapeutic treatment. In one embodiment, the Combination Product of the invention is used as a nutraceutical. In one embodiment, the Combination Product of the invention is utilized as a preventative treatment.

[0081] In one embodiment, the Combination Product of the invention is utilized for the promotion of health, for example, for achieving any therapeutic effect or outcome with respect to a selected condition, including, for example: a reduction in the severity of symptoms of the condition; the inhibition of pathological processes underlying the condition; the reversal of pathological events or processes of the condition; halting or slowing the progression of the condition; or a reduction in morbidity and/or mortality associated with the condition. Promoting health will further encompass prevention of an enumerated condition. As used herein, prevention will encompass any number of actions with respect to a selected condition, for example: preventing the onset of the condition; reducing the probability of the condition occurring; halting the further progression of the condition, ameliorating underlying physiological parameters that promote the condition, or any other preventative action. Promoting health will further encompass enhancements of target cell or organ function, such as quantitatively or qualitatively improved function, for example, in certain implementations, improved function, restoring normal function, or maintaining function.

[0082] In a primary implementation, the Combination Products of the invention are utilized to support renal health. “Supporting renal health” encompasses, for example, maintaining or enhancing one or more measures of renal function. For example, renal function may be assessed by glomerular filtration rate, creatine clearance rate, urine output, proteinuria, or other measures of renal function known in the art. In one embodiment, supporting renal health in a subject is achieved by ameliorating the subject’s risk, progression, and/or severity of one or more renal conditions. A renal condition, as used herein, may encompass any pathological process, pathological state, disease, or dysfunction of the kidney.

[0083] In various embodiments, the renal condition is a cystic condition. In one embodiment, the cystic condition is polycystic kidney disease (PKD). In various embodiments, supporting renal health and/or treatment of a cystic condition encompasses preventing or ameliorating any pathological effects of renal cysts, reducing or preventing the formation of renal cysts, reducing the number and/or size of renal cysts, slowing the growth rate of renal cysts, or eliminating renal cysts. In one embodiment, the cystic condition is ADPKD. In one embodiment, the polycystic kidney disease is autosomal recessive polycystic kidney disease (ARPKD). In various embodiments, the subject to which the Combination Product is administered is a subject having PKD or at risk of PKD. In some embodiments, the subject at risk of PKD is a subject carrying a mutation in any of PKD 1, PKD2, PKD3, or other genes wherein mutations increase the risk of PKD. In some embodiments, the subject at risk of PKD is a subject with health or demographic factors associated with PKD risk.

[0085] In other embodiments, the renal cystic condition is a condition selected from the group consisting of renal cysts as found in tuberous sclerosis complex, medullary cystic kidney disease, Acquired Cystic Kidney Disease, including acquired simple renal cysts, cystic renal cell carcinoma, and cystic nephroma. [0086] In one embodiment, the renal condition is acute kidney injury (AKI). AKI encompasses kidney dysfunction or failure, and may be caused by many factors or causative agents. AKI manifests as damage to kidneys and impaired kidney functions, including progression along the RIFLE staging criteria known in the art, encompassing risk, injury, failure, loss, and end-stage renal disease. In various embodiments, the subject to which the Combination Products administered is a subject having or at risk of AKI. In various embodiments, a subject at risk of AKI is a subject having systemic disease, trauma, sepsis, renal artery stenosis, renal vein thrombosis, urinary tract obstruction, glomerulonephritis, acute tubular necrosis, acute interstitial nephritis, or liver cirrhosis. In various embodiments, a subject at risk of AKI is a subject having reduced blood flow to kidneys, such as by cardiac dysfunction or failure, surgery, trauma or ischemia. In various embodiments, a subject at risk of having AKI is a subject likely to be exposed to or being exposed to harmful levels of nephrotoxins such as mercury or platinum compounds, radiological contrast agents, and antibiotics. In one embodiment, the subject at risk of AKI is a subject likely to have or scheduled to have surgery, in one embodiment, cardiac surgery. In various embodiments, the Combination Product is administered as a pre-treatment prior to surgery and/or post treatment after surgery in order reduce the risk or severity of AKI and to reduce the risk of developing complications therefrom, including chronic kidney disease.

[0087] In various embodiments, the renal condition is chronic kidney disease (CKD), encompassing any gradual loss or long-term impairment of kidney function. In various embodiments, the subject to which the dietary supplement, medical food or therapeutic composition is administered is a subject having or at risk of CKD. A subject at risk of CKD may be a subject having any known risk factor of CKD including, Type I or Type II diabetes mellitus, prior occurrence of acute kidney injury, glomerulomephritis, high blood pressure, or family history of CKD.

[0088] In various embodiments, the renal condition is a condition selected from the group consisting of: diabetic nephropathy, nephronophthisis, Meckel-Gruber syndrome, Bardet- Biedl syndrome, Joubert syndrome, medullary sponge kidney, multicystic dysplastic kidney, Dent's disease, Glomerulocystic kidney disease, Von Hippel-Lindau Syndrome, and mixed epithelial and stromal tumor of the kidney. [0089] In the methods of the invention, the Combination Product is administered in a biologically effective amount, being an amount sufficient to achieve a measurable biological effect, which such biological effect underlies (or cumulatively leads to) the achievement of a selected outcome, for example, preventing or ameliorating a renal condition.

[0090] In one embodiment, the biologically effective amount of the Combination Product comprises 2-10 g BHB per day in combination with 1 to 6 g citrate per day. In various embodiments, the method encompasses the daily administration of any of about 2.0, 2.25,

2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5.0, 5.25, 5.5, 5.75, 6.0, 6.25, 6.5, 6.75, 7.0,

7.25, 7.5, 8.0, 8.25, 8.5, 8.75, 9.0, 9.25, 9.5, 9.75 or 10.0 g of BHB in combination with any of about 1.0, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5.0, 5.25,

5.5, 5.75, or 6.0 g citrate.

[0091] In one embodiment, the methods of the invention encompass the administration of a dosage comprising about 2.0 to 3.0 g BHB in combination with about 1.25 to 2.0 g citrate. In one embodiment, the methods of the invention encompass the administration of about 2.65 g BHB in combination with about 1.75 g citrate. In one embodiment, two dosages, each of about 2.65 g BHB in combination with about 1.75 g citrate, are administered per day.

[0092] In one embodiment, the methods of the invention encompass the administration of two daily dosages of two doses of the Combination Product of the invention. In one embodiment, each dose comprises, for example, of any of about 1.0, 1.25, 1.5, 1.75, 2.0,

2.25, 2.5, 2.65, 2.75, 3.0, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75 or 5.0 g of BHB in combination with any of about 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, or 4.0 g citrate.

[0093] In one embodiment, the methods of the invention encompass the administration of at least two doses of the Combination Product, wherein each dosage of the Combination Product comprises about 2.0 to 3.0 g BHB in combination with about 1.25 to 2.0 g citrate. In one embodiment, each of the two dosages comprises about 2.65 g BHB in combination with about 1.75 g citrate.

[0094] The foregoing dosages may be administered to an adult human of about 70 kg body mass. The foregoing dosages may be adjusted downward or upward for animals of lower than 70 kg body mass and greater than 70 kg body mass, respectively. Adjustment of dosages may be proportional to body weight or may be calculated based on allometric conversions known in the art.

[0095] In one embodiment, the method of the invention encompasses Composition 1, for use in a method of promoting health in a subject. In one embodiment, the method of the invention encompasses Composition 2, for use in a method of promoting health in a subject. In one embodiment, the scope of the invention encompasses a method of using Composition 1 to promote health in a subject, comprising administering to the subject a therapeutically effective amount of Composition 1. In one embodiment, the scope of the invention encompasses a method of using Composition 2 to promote health in a subject, comprising administering to the subject a therapeutically effective amount of Composition 2.

[0096] EXAMPLES.

[0097] Example 1. Manufacture and Use of Composition 2.

[0098] Composition 1 was prepared by mixing the weighed, powdered raw ingredients in a hand-operated dry blender until homogeneity according to the proportions set forth in Table 2. The resulting blend was then stored at room temperature in a closed container to protect the mixture from moisture in the air. When needed, the appropriate amount of powder was removed, then stirred vigorously in water to obtain a liquid form suitable for ingestion by drinking.

[0099] Example 2. Synergistic Effects of BHB-Citrate Combination Products in Renal Health.

[0100] Brief Summary of Experimental Methods: The following experiments were performed using the SPRD: Han rat model, an established animal model for renal conditions such as polycystic kidney disease and also used as a model for chronic kidney disease. These animals have a mutation in the ANKS6 gene. Homozygous mutant rats experience early death. Heterozygous animals, as used in the studies described herein, experience a slower onset of renal dysfunction and are useful in experiments of progressive renal disease. This model develops cysts beginning at week three which progress in severity until approximately week eight, after which point cyst progression nearly stops and kidney function decline becomes persistent for the remainder of the animal’s life. Male rats progress more severely than female rats, making them more suitable for studying the effects of interventions. SPRD: Han rats serve as an animal model of renal dysfunction, including for polycystic kidney disease, and also for chronic kidney disease. Several aspects of chronic kidney disease are recapitulated in SPRD:Han rats, including fibrosis (collagen deposition) and aberrant cell division in interstitial cells and tubules.

[0101] In the experiments described herein, young male SPRD:Han rats were administered BHB, citrate, or a combination thereof, in drinking water given ad libitum, starting at three weeks of age, until eight weeks of age. The following treatments were administered, wherein rats were provided with BHB, citrate or a combination of the two:

BHB Treatments- BHB at 40 mM (“Bl”), 80 mM (“B2”), and 160 (“B3”) mM;

Citrate Treatments- Citrate at 30 mM (“Cl”), 60 mM (“C2”), and 120 mM (“C3”); and

BHB:Citrate Combination Treatments-

(40 mM BHB/30 mM) Citrate, -42:58 BHB:Citrate (“BC1”);

(40 mM BHB/60 mM Citrate), -26:74 BHB: Citrate (“BC2”); and

(80M BHB/60 mM Citrate), -42:58 BHB:Citrate (“BC3”).

BHB was provided in a mixture of 50% potassium-BHB and 50% sodium-BHB. Citrate was provided in a mixture of 45% tripotassium citrate and 55% citric acid. The control treatment was regular water (“W”). Following the treatments, we harvested the organs from the animals and performed immunostaining, histological and biochemical interrogation.

Collagen deposition was quantified by positive Sirius Red stain. Cell proliferation rates were assessed by Ki67 staining and quantification of Ki67-positive cells versus the total number of cells per given field. Serum creatinine levels, indicative of kidney function, were assessed by Quantichrom’s colorimetric assay for creatinine. Data is presented in Fig. 1-9, wherein * denotes a significant difference at p<0.05, ** indicates significance at p< 001, *** indicates significance at p< 0001, and **** indicates significance at p< 00001. [0102] Results: Collagen Deposition. Renal collagen deposition is associated with fibrosis and kidney dysfunction. In SPRD animals, the deposition of collagen was reduced by both BHB and citrate in a dose dependent manner (Fig. 1 and 4), indicating that each of these agents alone has a therapeutic effect. The strongest inhibition of collagen deposition in the SPRD rats was seen in the combined BHB and citrate treatment (Fig. 3).

[0103] The effect on collagen deposition observed in the lowest treatment group for combined BHB and citrate (40mM BHB and 30mM citrate) produced an effect comparable to the highest dosages of BHB alone at 160mM and 80mM or citrate alone at 120mM, indicating that this combination created a synergistic effect at a lower dosage than for either BHB or citrate alone.

[0104] Results: Cell Proliferation Rate. Aberrant cell proliferation in renal tubule cells and interstitial cells is a hallmark of cyst growth and renal dysfunction in SPRD rats and may be assessed by quantifying expression of the cell cycle marker Ki67.

[0105] For rats treated with BHB alone, no inhibitory effect was observed in interstitial cells and inhibitory effects on tubule Ki67 expression were only significant at the highest dosage of 160 mM (Fig. 4). Citrate had no effect on Ki67 expression in interstitial cells or tubules at any dosage (Fig. 5).

[0106] In contrast, the combination of BHB and citrate at 40 mM BHB/60 mM Citrate (“BC2”) and 80 mM BHB/60 mM Citrate (“BC3”) produced a measurable and significant decrease in tubule proliferation and additionally decreased proliferation in interstitial cells (Fig. 6), whereas neither BHB or citrate alone did. These results demonstrate a substantial synergistic effect between citrate and BHB wherein the combination produces ameliorative effects that the single components do not possess.

[0107] Results: Serum Creatinine. Serum creatinine levels are a well-established indicator of renal function, with elevated levels indicative of impaired renal clearance capacity. Serum creatinine was assessed in treated and control animals for both wild-type rats (WT) and SPRD rats (Cy+). In SPRD rats, BHB alone had a therapeutic effect, reducing serum creatinine (Fig. 7). Likewise, citrate alone reduced creatinine in SPRD animals (Fig. 8).

The combination of BHB and citrate produced similar effects to that of BHB or citrate alone (Fig. 9) in SPRD rats. [0108] Meanwhile, in wild-type rats, neither BHB or citrate alone had any effect on creatinine (Figures 7 and 8). However, a positive effect on creatinine reduction was observed in wild type rats treated with the combination of BHB and citrate at all dosages (Fig. 9) that was not seen in BHB or citrate alone.

[0109] Overall, these results demonstrate that the combination of BHB and Citrate produces synergistic therapeutic effects beyond the effects of each component individually. This provides important unique effects on the kidney that positively impact kidney function, even in non-cystic animals. Practically, these results demonstrate that the product can be effective at smaller consumed doses. For users this means less expense as less product is needed. The ability to achieve therapeutic effects with less product greatly improves tolerance for the product. Both BHB and citrate supplements have gastrointestinal and salt tolerance issues which can here be mitigated by using less, more effective product.

[0110] All patents, patent applications, and publications cited in this specification are herein incorporated by reference to the same extent as if each independent patent application, or publication was specifically and individually indicated to be incorporated by reference. The disclosed embodiments are presented for purposes of illustration and not limitation. While the invention has been described with reference to the described embodiments thereof, it will be appreciated by those of skill in the art that modifications can be made to the structure and elements of the invention without departing from the spirit and scope of the invention as a whole.

Claims

What is claimed is:

Claim 1. A combination product comprising BHB and/or a BHB analog; and citrate.

Claim 2. The combination product of Claim 1, wherein the BHB comprises a mixture of two or more mineral salts of BHB.

Claim 3. The combination product of Claim 2, wherein the mixture of mineral salts of BHB comprises calcium BHB, magnesium BHB, and potassium BHB.

Claim 4. The combination product of Claim 3, wherein the mixture of calcium BHB, magnesium BHB, and potassium BHB comprises 25-35% by weight calcium BHB;

35-45% by weight magnesium BHB; and 25-35% by weight potassium -BHB.

Claim 5. The combination product of Claim 4, wherein the mixture of calcium BHB, magnesium BHB, and potassium BHB comprises about 30% by weight calcium BHB; about 40% by weight magnesium BHB; and about 30% by weight potassium BHB.

Claim 6. The combination product of Claim 1, wherein the composition comprises a BHB:Citrate weight ratio between 50:50 and 70:30.

Claim 7. The combination product of Claim 6, wherein the composition comprises a BHB:Citrate weight ratio between 55:45 and 65:35.

Claim 8. The combination product of Claim 7, wherein the composition comprises a BHB:Citrate weight ratio of about 60:40.

Claim 9. The combination product of Claim 1, wherein the citrate comprises anhydrous citrate, citric acid monohydrate, and/or citric acid dihydrate.

Claim 10. The combination product of Claim 1, wherein the composition is substantially free of sodium.

Claim 11. The combination product of Claim 1, wherein the composition is substantially free of silicates. Claim 12. The combination product of Claim 1, wherein the composition is alkaline.

Claim 13. The combination product of Claim 1, wherein the composition comprises a water soluble powder formulation or wettable powder formulation.

Claim 14. The combination product of Claim 13, wherein the composition is provided with a measuring device that measures a dosage or about 2-4 g BHB and 1.5-2.25 g citrate.

Claim 15. The combination product of Claim 1, wherein the composition is provided dissolved or suspended in a liquid.

Claim 16. The combination product of Claim 1, wherein the composition is provided in a capsule or pill.

Claim 17. The combination product of Claim 1, wherein the composition is provided incorporated with an edible item.

Claim 18. The combination product of Claim 18, wherein the composition is provided in a food item formulated for an animal. Claim 19. The combination product of Claim 19, wherein the composition is formulated for a cat or dog.

Claim 20. The combination product of Claim 1, comprising about 16.5% by weight calcium-BHB; about 23.8% by weight magnesium-BHB; about 19.0 % by weight potassium -BHB; about 28.6% by weight citrate; about 3.23% by weight flavoring composition; about 2.3% by weight sweetener; and about 6.7% by weight filler.

Claim 21. The combination product of Claim 20, wherein the sweetener comprises stevia and the filler comprises maltodextrin.

Claim 22. The combination product of Claim 1, wherein the composition is provided in a dosage of about 6.5 grams.

Claim 23. The combination product of Claim 1, comprising about 18.3% by weight calcium-BHB; about 25.4% by weight magnesium-BHB; about 21.7 % by weight potassium -BHB; and about 34.6% by weight citrate.

Claim 24. The combination product of Claim 1, wherein the composition is provided in a dosage of about 5.0 grams.

Claim 25. The combination product of any of Claims 1-24, for use in a method of promoting health in a subject, the method comprising administration to the subject of a biologically effective amount of the composition.

Claim 26. The combination product of Claim 25, wherein the method of promoting health in a subject the subject is a method of promoting renal health.

Claim 27. The combination product of Claim 26, wherein the subject is a subject having or at risk of having a cystic renal condition.

Claim 28. The combination product of Claim 27, wherein the subject has or it at risk of having polycystic kidney disease.

Claim 29. The combination product of Claim 26, wherein the subject has or it at risk of having chronic kidney disease. Claim 30. The combination product of Claim 25, wherein the method comprises administration of the combination product such that the subject is administered about 1.0 to about 6.0 g BHB per day; and about 1.0 to about 5.0 g citrate per day.

Claim 31. The combination product of Claim 30, wherein the method comprises administration of the combination product such that the subject is administered about 5.3 g BHB per day; and about 3.5 g citrate per day.

Claim 32. The combination product of Claim 30, wherein the composition is administered in two separate dosages per day.

Claim 34. A kit comprising the combination product of any of Claims 1-24; and a container.

Claim 35. The kit of Claim 34, wherein the kit further comprises a measuring implement.