Compositions comprising paraxanthine and beta-hydroxybutyric acid or precursors for improving neurological and physiological properties

Abstract

Disclosed herein is a "paraxanthine-BHB" composition comprising the following combinations: (1) paraxanthine; (2) a BHB ketone body component, such as a beta-hydroxybutyric acid (BHB) salt, a BHB ester or a BHB acid; and (3) an optionally dietary or pharmaceutically acceptable carrier. In addition to BHB, a BHB precursor, such as 1, 3-butanediol, may also be used, or the BHB may be replaced with the precursor. Also disclosed herein are methods of using such compositions for producing a desired physiological effect in a mammal, such as enhanced cognitive flexibility, improved persistent attention, improved working memory, and neuroprotection. In addition to this improved mental sensitivity profile, the composition may also beneficially increase resting energy consumption (resting metabolic rate), increase fat consumption primarily by ketosis, while promoting muscle formation and maintenance, and modulate sleepiness / dizziness when entering a ketosis state.

Description

BACKGROUND

[0001] Energy drinks and similar caffeinated beverages are consumed by consumers to promote wakefulness, maintain alertness, enhance mood, and enhance cognition. Typical gas station energy drinks often contain a high proportion of caffeine and sugar. Some can also include vitamins, electrolytes, or amino acids.

[0002] Despite their widespread use, there are health concerns associated with consuming such caffeinated beverages, particularly their effects on the cardiovascular system. Such caffeinated energy drinks have been shown to increase heart rate, increase blood pressure, and even thicken the blood. Such beverages can also affect the brain in undesirable ways, such as by elevating stress levels and inducing anxiety, insomnia, gastrointestinal irritation, muscle twitching, and long-term restlessness.

[0003] Such beverages are accompanied by heightened fatigue, irritability, and suboptimal cognitive functioning after the initial boost of drinking. This energy “crash” can last for a long time and is unpleasant. As the stimulating effects of the caffeine wear off, levels of adrenaline, dopamine, and acetylcholine begin to drop, and blood sugar levels can fluctuate erratically, often leaving the user feeling more fatigued, irritable, and inattentive than before the beverage was consumed. After caffeine is taken, the user’s adenosine levels can continue to rise. When the caffeine can no longer block the adenosine receptors, the accumulated adenosine rushes to the receptors in large quantities, which can cause the sensation of a crash.

[0004] To date, the caffeinated energy drinks commonly found at gas stations have generally failed to improve the overall quality of life and well-being of the user. Instead, such energy drinks provide a short-lived boost in alertness, but are accompanied by a subsequent crash that is so unpleasant that it negates the previous benefits, making the consumption of such beverages a negative experience. When used to stay awake while driving, such beverages cause heightened stress and can lead to “road rage.” For long drives, the user’s mental and / or physical “crash” can be detrimental, even deadly if it leads to a highway accident.

[0005] Accordingly, there is a continuing need for compositions that can promote a natural and sustained feeling of wakefulness; maintain a natural sense of alertness without nervousness or a racing heart; improve focus, clarity of thought, and working memory; enhance mood; and / or enhance cognitive flexibility without the typical energy crash and without compromising the long-term physical or mental health of the user.

[0006] Ketones are produced from fat and are an alternative source of calories to glucose, especially when glucose is not available. During periods of fasting, intense exercise, and / or low carbohydrate intake, glucose and glycogen stores in the body are rapidly used and can be quickly depleted. When glucose stores are depleted, and glucose stores are not replenished, the body shifts its metabolism to use ketones as the primary source of thermal energy. This metabolic state is referred to as “ketosis.”

[0007] Ketones can be used by the body’s cells as a supplemental or alternative fuel to glucose to meet the body’s energy demands, including the brain and heart. During prolonged fasting, blood ketone levels can increase to 2-3 mmol / L or more. It is generally accepted that when blood ketones rise above 0.5 mmol / L, the heart, brain, and peripheral tissues use ketones (e.g., beta-hydroxybutyrate and acetoacetate) as the primary source of thermal energy. This condition is referred to as “ketosis.” The condition between 1.0 mmol / L and 3.0 mmol / L is referred to as “nutritional ketosis.”

[0008] During the transition to ketosis, or in other words, during hepatoketogenesis, the body uses dietary and stored body fat as the primary source of energy. Thus, once ketosis has occurred, one can maintain a state of ketogenesis by controlling dietary fat and keeping carbohydrate intake low to induce a reduction in body fat. When in ketosis, the body primarily burns fat as its primary fuel.

[0009] The metabolism of ketones is associated with several beneficial effects. However, despite the many health advantages of pursuing a ketogenic diet or lifestyle and maintaining a state of nutritional ketosis, there are significant barriers to pursuing and maintaining a state of ketogenesis. One of these barriers is the difficulty of shifting into a state of ketogenesis. The fastest endogenous way to enter ketosis is by depleting the body’s glucose stores through fasting combined with high-intensity exercise, thereby entering a catabolic state. This depletes the body’s limited glucose and glycogen stores. This is highly demanding on the body and emotionally taxing, even for the most motivated and disciplined individuals.

[0010] In addition, the transition to ketosis is often accompanied by hypoglycemia, which in many people results in drowsiness and lightheadedness, leading to an uncomfortable physical and mental state often referred to as "low-carb flu" or "ketoflu." Many people also experience a downregulation of metabolism as the body enters "economy mode." Some believe that these transient symptoms can last for two to three weeks. During this transition period, if any meal or snack containing more than the restricted amount of carbohydrates is ingested, ketogenesis is quickly terminated, causing the body to exit the ketotic state and instead utilize glucose as its primary fuel. At this point, the difficult transition into ketosis must begin anew. Thus, despite the potential for weight loss and other health benefits, the serious limitations continue to hinder the full realization of the potential of ketogenic diets.

[0011] It would be beneficial to provide a dietary supplement composition that is capable of addressing at least some of these unpleasant effects associated with entering a ketogenic state (e.g., minimizing or preventing drowsiness and / or lightheadedness, minimizing or preventing the typical downregulation of metabolic rate, etc.). SUMMARY

[0012] Disclosed herein is a composition comprising a combination of: (1) a paraurine; (2) a beta-hydroxybutyrate ("BHB"); and (3) optionally a dietarily or pharmaceutically acceptable carrier. For ease of reference, such combination composition can be referred to herein as a "paraurine-BHB" or "BHB-paraurine." In some embodiments, a BHB precursor, such as 1,3-butanediol, can be used in addition to or in place of BHB.

[0013] Also disclosed herein are methods of using such a combination for neuroprotection, improved cognitive flexibility, improved working memory, reduced oxidative stress, minimizing or preventing drowsiness or lightheadedness associated with entering a nutritional ketotic state (e.g., low-carb flu or ketoflu), minimizing or preventing the downregulation of metabolic rate typically associated with entering a nutritional ketotic state, or other benefits. It has been discovered that the combination of paraurine and BHB produces a synergistic enhancement of one or more of such functional attributes in the user. For example, paraurine provides the benefits of improved cognitive flexibility, the ability to sustain attention, improved working memory, and enhanced inhibitory control. When paired with BHB, these benefits are synergistically enhanced beyond any such benefits provided by paraurine or BHB alone, and additional benefits are provided, such as limiting the effects of hypoglycemia when entering a ketogenic state, maintaining or even increasing metabolic rate when entering a ketogenic state, etc.

[0014] This combination also provides better results than the comparative combination of caffeine plus BHB because the paraxanthine plus BHB does not exhibit the same adverse side effects associated with caffeine (subsequent energy crash, jitters, increased heart rate, increased incidence of thought errors, etc.). For example, by directly providing paraxanthine (rather than caffeine) in combination with BHB, the theobromine and theophylline produced by caffeine metabolism are largely, if not completely, eliminated, and these components are believed to be at least partially responsible for adverse side effects associated with caffeine use (e.g., jitters, increased heart rate, increased thought errors, etc.). Moreover, by providing BHB in such an environment (i.e., in combination with paraxanthine and generally without theobromine and theophylline), BHB (which is a ketone body capable of providing thermal energy) can be more effectively utilized, thereby enhancing benefits such as improved cognitive flexibility, improved sustained attention, improved working memory, and enhanced inhibitory control. The combined use of paraxanthine and BHB also advantageously minimizes the drowsiness and dizziness associated with hypoglycemia upon entering a ketotic state, as well as the typical metabolic rate downshift that occurs upon entering a ketotic state.

[0015] Additionally, the combination of paraxanthine and BHB is beneficial also because when delivered with BHB, the combination allows for a lower dose of paraxanthine to be provided to the user while still providing similar levels of benefits associated with paraxanthine use. In other words, while a given dose of paraxanthine can be required to provide certain benefits associated with improved cognitive flexibility, improved sustained attention, improved working memory, and enhanced inhibitory control when administered alone, a lower dose of paraxanthine can be sufficient to provide similar benefits when combined with BHB. This is advantageous in reducing the cost of the supplement capable of providing a given benefit. Alternatively, greater benefits can be provided at similar costs if the paraxanthine dose is maintained while also providing BHB.

[0016] The BHB ketone body component provides an exogenous source of ketone bodies that can be utilized by the body as energy without significantly causing the user to “break” the fast (e.g., without causing a significant increase in blood insulin levels) and thus lose the physiological benefits of being in a fasted state. The ketone body component is also beneficial for users training during a fast. While this is a period in which fat burning is optimized, it can make training difficult due to relatively low energy and motivation levels. The energy provided by the BHB ketone body component can help the user train more effectively with minimal disruption to the fasted state, while the paraxanthine component provides benefits of improved cognitive flexibility, improved sustained attention, improved working memory, enhanced inhibitory control, and minimization of adverse side effects associated with hypoglycemia and metabolic rate downshift.

[0017] The ketone body components can also help induce and maintain a ketotic state in the subject. For example, the ketone body components can help the body transition more quickly to a fat-burning catabolic state. This is especially useful during intermittent fasting, when the fat-burning window at the end of the fasting period is relatively short. Similar results can be obtained when using 1,3-butanediol, which is readily converted to BHB in the body.

[0018] Further, even if the user is not necessarily in a fasting state, exogenous ketone body supplementation can benefit the user by assisting mitochondrial function while maintaining blood glucose levels and glycogen reserves, which can then still be used for anabolic building of lean muscle as a result of exercise. This allows glucose, protein, and insulin to work together to build lean muscle when needed, rather than being consumed as an energy source. Further, because ketones, unlike sugars, are not converted to fat, excess ketones do not result in the simultaneous accumulation of fat as sugars, proteins, and fats of normal caloric intake are consumed.

[0019] Unexpectedly, it has now been discovered that a combination of BHB and para-xanthine in appropriate amounts and / or ratios provides enhanced working memory, cognitive flexibility, inhibitory control, and the ability to sustain attention that is not predictable based on the individual effects of these components when used alone. For example, supplementing with a para-xanthine-BHB composition can result in improvements in such desirable functional attributes without the side effects (e.g., jitters, heart racing, subsequent energy crash) typically associated with caffeine use, even where caffeine is metabolized to para-xanthine. Providing para-xanthine directly reduces or eliminates the concentration of theophylline and / or theobromine present in the bloodstream of the user, which components are associated with such undesirable side effects.

[0020] Further, most people metabolize caffeine at different rates and with different results. For example, the cytochrome P450 1A2 enzyme is responsible for about 95% of all caffeine metabolism, and some users produce more of the cytochrome P450 enzyme than others, depending on genetics. As a result, the human population includes fast metabolizers, medium metabolizers, and slow metabolizers of caffeine. Fast metabolizers make up less than half of the human population, and fast metabolizers typically get more benefit from caffeine than medium or slow metabolizers. By providing para-xanthine directly, this provides a more consistent physiological and neurological response for a wide variety of users, regardless of whether the user is a fast, medium, or slow metabolizer of caffeine.

[0021] The para-xanthine-BHB compositions described herein can be provided in various forms, such as single- or multi-part compositions, configured for administration by one or more of the following: ingestion, intragastrically, injection, topical application, inhalation, oral mucosal administration, rectal administration, vaginal administration, or parenteral administration.

[0022] In one embodiment, the BHB comprises at least one of a BHB salt, a BHB ester, beta-hydroxybutyric acid, or a BHB precursor (such as 1,3-butanediol).

[0023] In one embodiment, the composition can further comprise at least one fatty acid or ester of a fatty acid (e.g., a monoglyceride, a diglyceride, or a triglyceride), such as a medium chain fatty acid, a short chain fatty acid, and esters thereof. Medium chain fatty acids and esters thereof can be converted to BHB through lipolysis. The composition can optionally comprise beta-hydroxy beta-methylbutyric acid (HMB) in combination with BHB, as disclosed in U.S. Patent Publication No. 2022 / 0062216, the entire contents of which are incorporated herein by reference.

[0024] In one embodiment, the composition can be provided in any of a variety of forms, such as a crystal, a powder, a solid, a liquid, a solution, a suspension, a gel, and the like.

[0025] In one embodiment, the composition is in a dosage form that provides about 0.5 grams to about 50 grams, or about 1 gram to about 40 grams, or about 2 grams to about 30 grams, or about 3 grams to about 25 grams, or about 4 grams to about 20 grams of BHB (or precursor) per dose.

[0026] In one embodiment, the composition is in a dosage form that provides about 25 mg to about 1000 mg, or about 50 mg to about 500 mg, or about 75 mg to about 400 grams, or about 100 mg to about 300 mg, or about 125 mg to about 250 mg of para-xanthine per dose.

[0027] In one embodiment, the composition comprises a pharmaceutically or dietetically acceptable carrier (e.g., water, ethanol, glycerol, propylene glycol, 1,3-propanediol, fruit juice, or a foodstuff).

[0028] Another exemplary embodiment can comprise para-xanthine, a plurality of anions comprising BHB anions, and a plurality of cations (e.g., alkali metal cations, alkaline earth cations, transition metal cations, and / or amino acid cations). Such an embodiment can be referred to as a “mixed salt.”

[0029] An exemplary method can comprise administering para-xanthine, and administering a ketone body component or precursor comprising at least one of a beta-hydroxybutyric acid (BHB) salt, a BHB ester, a BHB acid, or 1,3-butanediol.

[0030] One embodiment of this method can include administering multiple doses per day. Exemplary doses of BHB and paraxanthine can be as described above (e.g., about 0.5-50 grams, or about 1-40 grams, or about 2-30 grams, or about 3-25 grams, or about 4-20 grams of BHB (or precursor); and about 25-1000 mg, or about 50-500 mg, or about 75-400 grams, or about 100-300 mg, or about 125-250 mg of paraxanthine).

[0031] In one embodiment, the compositions of the present application are substantially or completely free of caffeine.

[0032] This method can provide one or more of the following benefits: improved cognitive flexibility, improved sustained attention, improved working memory, enhanced inhibitory control, reduced drowsiness or lightheadedness associated with hypoglycemia upon entering a ketotic state, or even maintenance or increase in metabolic rate upon entering a ketotic state. As shown in the accompanying prospective data, these improvements in aspects are significantly better than those produced when supplementing with caffeine (as opposed to paraxanthine). Other possible benefits can include promoting homeostasis, neuroprotection, enhancing memory, anxiolytic effects, antidepressant effects, anti-inflammatory effects, analgesic effects, antioxidant effects, blood pressure regulation, heart rate regulation, or longevity promotion.

[0033] In one embodiment, BHB increases the pharmacokinetic availability of paraxanthine relative to the pharmacokinetic availability of paraxanthine in the absence of BHB.

[0034] In one embodiment, the method can accelerate the production of endogenous ketones in the user due to increased fat metabolism caused by paraxanthine.

[0035] Additional features and advantages will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following and the accompanying drawings. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments disclosed or claimed herein. BRIEF DESCRIPTION OF DRAWINGS

[0036] Various objects, features, and advantages of the present application will become apparent to those skilled in the art from the following description, which is to be read in connection with the accompanying drawings and appended claims. In the drawings, like reference numerals can be used to denote identical or similar elements involving corresponding or similar portions as can be found in the several figures of the drawings. In which:

[0037] Figure 1 Relative plasma concentration levels of caffeine and its major metabolites associated with caffeine administration are shown;

[0038] Figure 2 A simplified exemplary metabolic pathway of caffeine metabolism is shown;

[0039] Figure 3 A comparison of the elimination half-lives of paraxanthine to caffeine, theophylline, and theobromine is shown;

[0040] Figure 4 Expected results of a Go / No Go attention and inhibitory control test are shown, showing the expected incidence of correct responses resulting from different treatments of paraxanthine in combination with BHB, paraxanthine alone, BHB alone, and placebo, respectively, and showing that the expected effect of paraxanthine in combination with BHB is more significant in increasing the incidence of correct responses than the simple additive effect of BHB alone and paraxanthine alone;

[0041] Figure 5 Expected results of a Go / No Go attention and inhibitory control test are shown, showing the expected mean response time resulting from different treatments of paraxanthine in combination with BHB, paraxanthine alone, BHB alone, and placebo, respectively;

[0042] Figure 6 Expected results of an alertness task test are shown, showing the expected mean response time resulting from different treatments of paraxanthine in combination with BHB, paraxanthine alone as a comparison, BHB alone as a comparison, and placebo;

[0043] Figure 7 Expected results of a Berg-Washington card sorting task test are shown, showing the expected incidence of correct responses resulting from different treatments of paraxanthine in combination with BHB, paraxanthine alone as a comparison, BHB alone as a comparison, and placebo, respectively;

[0044] Figure 8 Expected results of a Berg-Washington card sorting task test are shown, showing the expected incidence of errors resulting from different treatments of paraxanthine in combination with BHB, paraxanthine alone as a comparison, BHB alone as a comparison, and placebo, respectively;

[0045] Figure 9 Expected results of a Sternberg test with letter length of 2 are shown, showing the expected mean reaction time resulting from different treatments of paraxanthine in combination with BHB, paraxanthine alone as a comparison, BHB alone as a comparison, and placebo, respectively;

[0046] Figure 10Expected results for the Sternberg test with letter length of 4 are shown, showing the expected mean reaction time resulting from the different treatments as follows: paraxanthine in combination with BHB, paraxanthine alone as a comparison, BHB alone, and placebo;

[0047] Figure 11 Expected results for the Sternberg test with letter length of 6 are shown, showing the expected mean reaction time resulting from the different treatments as follows: paraxanthine in combination with BHB, paraxanthine alone as a comparison, BHB alone, and placebo;

[0048] Figure 12A Expected results for the Berg-Washington card sorting task test are shown, showing the expected correct response incidence resulting from the different treatments as follows: paraxanthine in combination with BHB, paraxanthine alone as a comparison, BHB alone, caffeine, paraxanthine in combination with BHB, caffeine alone, caffeine in combination with BHB, and placebo;

[0049] Figure 12B Expected results for the Berg-Washington card sorting task test are shown, showing the expected error incidence resulting from the different treatments as follows: paraxanthine in combination with BHB, paraxanthine alone as a comparison, BHB alone, caffeine, paraxanthine in combination with BHB, caffeine alone, caffeine in combination with BHB, and placebo;

[0050] Figure 12C Expected results for the Berg-Washington card sorting task test are shown, showing the expected error incidence resulting from the different treatments as follows: paraxanthine in combination with BHB, paraxanthine alone as a comparison, BHB alone, caffeine, paraxanthine in combination with BHB, caffeine alone, caffeine in combination with BHB, and placebo;

[0051] Figure 12D Expected results for the Berg-Washington card sorting task test are shown, showing the expected persistence error incidence (PAR rule) resulting from the different treatments as follows: paraxanthine in combination with BHB, paraxanthine alone as a comparison, BHB alone, caffeine, paraxanthine in combination with BHB, caffeine alone, caffeine in combination with BHB, and placebo;

[0052] Figure 13Expected results for the Vigilance Task Test are shown, showing the expected average response time resulting from different treatments of: paraurine in combination with BHB, paraurine alone as a comparison, BHB alone, caffeine and paraurine in combination, caffeine alone, caffeine and BHB in combination, and placebo;

[0053] Figures 14A-14C Expected results for treadmill distance (14A), muscle mass (14B), and hand grip strength (14C) are shown, resulting from different treatments of: paraurine in combination with BHB, paraurine alone as a comparison, BHB alone, and various amino acids and amino acid derivatives;

[0054] Figures 15A-15C Expected results for the Stroop Test are shown, resulting from different treatments of: paraurine in combination with BHB, paraurine alone as a comparison, and BHB alone over a period of 6 weeks; and

[0055] Figure 16 Expected results for resting energy expenditure are shown, resulting from different treatments of: paraurine in combination with BHB, paraurine alone as a comparison, BHB alone, and placebo. DETAILED DESCRIPTION

[0056] I. Introduction and Definitions

[0057] Disclosed herein are compositions comprising a combination of: (1) paraurine; (2) beta-hydroxybutyrate (“BHB”); and (3) optionally a dietarily or pharmaceutically acceptable carrier. Such combination compositions can be referred to herein as “paraurine-BHB” or “BHB-paraurine.” Also disclosed herein are methods of using such compositions for neuroprotection, improved cognitive flexibility, improved working memory, reduced oxidative stress, minimization or prevention of drowsiness or lightheadedness associated with entering a state of nutritional ketosis (e.g., low-carb flu or keto flu), minimization or prevention of the downregulation of metabolic rate typically associated with entering a state of nutritional ketosis, or other benefits. In some embodiments, a BHB precursor, such as 1,3-butanediol, can be used in addition to or in place of BHB.

[0058] It has been discovered that the combination of paraxanthine and BHB in a user produces a synergistic enhancement of one or more such functional characteristics. For example, paraxanthine provides benefits of improved cognitive flexibility, ability to sustain attention, improved working memory, and enhanced inhibitory control. When paired with BHB, these benefits are synergistically enhanced beyond any such benefits provided by paraxanthine or BHB alone, and further benefits are provided, such as limiting the effects of hypoglycemia when entering a ketotic state, maintaining or even increasing metabolic rate when entering a ketotic state, etc.

[0059] This combination also provides better results than the comparative combination of caffeine plus BHB, because paraxanthine plus BHB does not exhibit the same adverse side effects associated with caffeine (subsequent energy crash, jitters, increased heart rate, increased incidence of thought errors, etc.). For example, by directly providing paraxanthine (rather than caffeine) in combination with BHB, the theobromine and theophylline produced by caffeine metabolism are largely eliminated, if not completely, and these components are believed to be at least partially responsible for the adverse side effects associated with caffeine use (e.g., jitters, increased heart rate, increased mental errors, etc.). Moreover, by providing BHB in such an environment (i.e., in combination with paraxanthine, and generally without theobromine and theophylline), BHB (which is a ketone body capable of providing thermal energy) can be more effectively utilized, thereby enhancing benefits such as improved cognitive flexibility, improved sustained attention, improved working memory, and enhanced inhibitory control. The combined use of paraxanthine and BHB also advantageously minimizes the drowsiness and lightheadedness associated with hypoglycemia when entering a ketotic state, as well as the typical metabolic rate downshift that occurs when entering a ketotic state.

[0060] A. Ketosis and Ketone Bodies

[0061] As noted above, ketone bodies are produced from fat and are an alternative source of calories to glucose, particularly when glucose is not available, such as during fasting, intense exercise, and / or low carbohydrate intake. When the body’s metabolism shifts to using ketone bodies as the primary source of thermal energy, this is known as “ketosis.” Ketone bodies can be used by the body’s cells as a supplemental or alternative fuel to glucose to meet the body’s energy demands, including the brain and heart.

[0062] During the transition to ketosis, the body uses dietary and stored body fat as the primary energy source during the liver’s process of ketogenesis. The body initially breaks down fat into fatty acids and glycerol. It then converts the fatty acids into acetyl-CoA molecules, which are then ultimately converted into the water-soluble ketone bodies beta-hydroxybutyrate (“beta-hydroxybutyrate” or “BHB”), acetoacetate, and acetone in the liver through ketogenesis. BHB and acetoacetate are the ketone bodies that the body uses to provide energy, while acetone is removed as a byproduct of ketogenesis. Although technically, BHB is not a ketone, it is still commonly referred to as a “ketone body” in the context of ketosis. The metabolism of ketone bodies is associated with a variety of beneficial effects.

[0063] B. Intermittent Fasting

[0064] One method of fasting that has gained popularity in recent years as an alternative to long-term fasting is generally referred to as “intermittent fasting.” Intermittent fasting generally involves entering a state of ketosis. Because long-term fasting is difficult and cannot be sustained completely long-term, intermittent fasting attempts to provide many of the same benefits of fasting while minimizing the associated drawbacks. While intermittent fasting, like long-term fasting, involves entering a catabolic state, intermittent fasting shortens the time of day during which food is allowed. For example, for a person who eats regularly, there are approximately 16-18 hours between the first and last meal. Intermittent fasting attempts to shorten this eating window. Intermittent fasting regimens vary, but generally all attempt to shorten the eating time to approximately 2-12 hours, more commonly approximately 4-10 hours, as opposed to the usual 16-18 hours.

[0065] Intermittent fasting has similar benefits to long-term fasting and nutritional ketosis. Although the fasting period in intermittent fasting generally does not last long enough for the user to completely deplete glycogen stores, ketosis generally begins to some extent after only about 12 hours of fasting. Thus, intermittent fasting can train the body to utilize fat for energy, even if only for a few hours per day. In other words, as the body becomes more accustomed to longer intervals between meals, it will become more metabolically flexible, able to utilize fat as a fuel source more efficiently.

[0066] Intermittent fasting is also a popular method of eating for athletes or those attempting to train specifically to achieve weight loss and achieve a higher lean body to fat mass ratio. Many people schedule training sessions during the fasting period to more quickly deplete glycogen stores, to speed up or lengthen the fat burning window, or to take advantage of the beneficial hormonal profile during fasting. For example, many athletes can schedule training / exercise near the end of the fasting period, when glycogen stores are more depleted and the body’s metabolism is more geared toward fat burning.

[0067] In some embodiments, the method of administering paraprotine and beta-hydroxybutyrate (and / or precursors thereof) includes administering the composition in a fasted state (e.g., during intermittent fasting). The composition will provide the user with more energy, clearer thinking, and other benefits, offsetting the energy deficit, fuzzy thinking, and other negative effects of fasting. By combining fasting with the disclosed composition, the user can obtain the benefits of fasting and the additional benefits provided by the composition. This can be referred to as “enhanced fasting” or “enhanced intermittent fasting.”

[0068] C. Beta-hydroxybutyrate and 1,3-butanediol

[0069] The compound “beta-hydroxybutyrate,” also referred to as beta-hydroxybutyrate, 3-hydroxybutyrate, beta HB, or BHB, is the deprotonated form of the beta-hydroxybutyric acid, a hydroxycarboxylic acid having the general chemical structure CH3CH2OHCH2COOH. At typical biological pH levels, the deprotonated form is CH3CH2OHCH2COO − The general chemical structure of Formula I below represents a typical BHB compound.

[0070]

[0071] Formula I

[0072] wherein X can be hydrogen, a metal ion, an amino cation (e.g., from an amino acid), an alkyl group, an alkenyl group, an aryl group, or an acyl group.

[0073] When X is hydrogen, the compound is beta-hydroxybutyric acid. When X is a metal ion or an amino cation, the compound is beta-hydroxybutyrate. When X is an alkyl group, an alkenyl group, an aryl group, or an acyl group, the compound is beta-hydroxybutyrate ester.

[0074] 1,3-butanediol has the following chemical structure and is readily converted to beta-hydroxybutyrate in the body, and thus can be used as a precursor to beta-hydroxybutyrate:

[0075]

[0076] Like BHB, 1,3-butanediol has a chiral center and can be in the form of R-1,3-butanediol, S-1,3-butanediol, a racemic mixture of R-1,3-butanediol and S-1,3-butanediol, or enriched in R-1,3-butanediol or S-1,3-butanediol. It is generally believed that the chirality is preserved when 1,3-butanediol is converted to BHB, such that R-1,3-butanediol is converted to R-beta-hydroxybutyrate and S-1,3-butanediol is converted to S-beta-hydroxybutyrate in the body.

[0077] Beta-hydroxybutyrate (BHB) is used by the body as a source of energy in the case of low glucose levels in the subject or when the subject’s body is supplemented with BHB in a usable form. As noted above, although BHB is technically not a “ketone,” one skilled in the art will recognize that in the context of ketosis, BHB is commonly referred to as a “ketone body” because of its close relationship and biological interaction with acetoacetate, a true ketone.

[0078] As noted above, BHB can be provided in various forms, e.g., as beta-hydroxybutyric acid, as a beta-hydroxybutyric acid salt, or as a beta-hydroxybutyric acid ester. The foregoing compounds can be in any desired physical form, e.g., crystalline, powder, solid, liquid, solution, suspension, or gel.

[0079] Unless otherwise specified, the term “salt” does not connote or imply any particular physical state, e.g., crystalline, powder, other solid form, nor does it specifically refer to dissolution in water to form a liquid solution, dispersion in a liquid to form a suspension, or gel. The salt can be formed in solution, e.g., by at least partial neutralization of beta-hydroxybutyric acid with a strong or weak base, e.g., an alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate, a basic amino acid, etc.

[0080] BHB is a chiral compound and can exist in the following forms: R- or S-enantiomer, a racemic mixture, or a mixture enriched in one enantiomer relative to the other. Endogenous BHB produced by the body is the R-enantiomer. BHB can be converted by the body to acetoacetate, another ketone body utilized by the body, but which is not chiral, and acetoacetate can be converted back to the R-enantiomer of BHB. It is believed that the S-enantiomer of BHB can be converted to the R-enantiomer by first being converted to acetoacetate and then to the R-enantiomer; or the body can utilize acetoacetate directly. The S-enantiomer can also be biologically active on its own, with unique pharmacokinetic and pharmacodynamic characteristics, although the body produces very little (or even none) of the S-enantiomer.

[0081] In one embodiment, at least a portion of the BHB provided in the paraxanthine-BHB product is provided in the form of the S-enantiomer. Providing at least some of the S-enantiomer can provide the benefit of increased alertness. For example, increasing the S-enantiomer of BHB can reduce the dose of paraxanthine provided more significantly while providing the same or similar benefits of increased alertness, improved working memory, improved cognitive flexibility, inhibitory control, and sustained attention. By way of example, at least 1%, at least 3%, at least 5%, or at least 10% of the BHB provided can be of the S-enantiomer type. The S-enantiomer of BHB can comprise 5% to 95%, 5% to 75%, 5% to 50%, 10% to 50%, 10% to 40%, or 20% to 30% of the weight of the BHB provided. The S-enantiomer of BHB can comprise 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% of the weight of the BHB component. The S-enantiomer of the BHB component can be within a range having any two of the above values as endpoints. The R-enantiomer of BHB can provide thermal energy primarily, while the S-enantiomer can increase alertness and other features of mental clarity. The R-enantiomer of BHB can comprise 1%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% of the weight of the BHB component. The R-enantiomer of the BHB component can be within a range having any two of the above values as endpoints.

[0082] D. Acetoacetate

[0083] Acetoacetate (AcAc) is another ketone that can be included in the formulations of the present application in addition to BHB. AcAc is a true ketone, being the deprotonated form of acetoacetic acid, which is a carboxylic acid having the chemical formula CH3COCH2COOH. Thus, the deprotonated form that exists at typical biological pH levels is CH3COCH2COO − As noted above, the body can convert BHB to acetoacetate and vice versa. Like BHB, acetoacetate can be used as an energy source during ketosis or when the patient's body is supplemented with acetoacetate in a usable form, regardless of the state of the body's energy utilization preferences. The general chemical structure of Formula II represents acetoacetate compounds that can be used in the disclosed compositions (conformational isomers thereof can also be used):

[0084]

[0085] Formula II

[0086] wherein X can be hydrogen, a metal ion, an amino cation (e.g., from an amino acid), an alkyl group, an alkenyl group, an aryl group, or an acyl group.

[0087] Like BHB, acetoacetate can be used by the patient’s body as a source of energy, in situations where the subject’s glucose levels are low or when the patient’s body is supplemented with acetoacetate in a usable form. Unlike BHB, acetoacetate is a true “ketone,” as opposed to being referred to as a “ketone body” in the context of ketosis, along with BHB.

[0088] The above-described beta-hydroxybutyrate and acetoacetate compounds can be collectively referred to herein as “ketone bodies,” “exogenous ketone bodies,” “ketone body components,” or “exogenous ketones.”

[0089] The compositions described herein can also include ketone body precursors. Suitable ketone body precursors include, but are not limited to, beta-hydroxy beta-methylbutyrate (HMB), 1,3-butanediol, medium-chain fatty acids, and esters of medium-chain fatty acids (e.g., medium-chain triglycerides). Ketone body and ketone precursor compounds are described in more detail below. While 1,3-butanediol is readily converted to BHB, HMB is metabolized in a complex cascade that can ultimately result in the formation of BHB, but can also be converted to other substances or excreted in the urine.

[0090] E. Paraxanthine

[0091] Paraxanthine, like theophylline and theobromine, is a metabolic product of caffeine. Upon ingestion, caffeine is primarily metabolized to the three dimethylxanthines described above. The metabolism of caffeine and its dimethylxanthine metabolites is complex.

[0092] Shortly after ingestion, caffeine is metabolized to paraxanthine by liver cytochrome P450 enzymes that remove a methyl group from the N3 position of caffeine. Once formed, paraxanthine can be broken down to 7-methylxanthine by demethylation at the N1 position, which is then demethylated to xanthine or oxidized to 1,7-dimethyluric acid by CYP2A6. In another pathway, paraxanthine is broken down to 5-acetylamino-6-formamino-3-methyluracil by N-acetyltransferase 2, which is then broken down to 5-acetylamino-6-amino-3-methyluracil by non-enzymatic breakdown. In another pathway, paraxanthine is metabolized by CYP1A2 to form 1-methyl-xanthine, which is then metabolized by xanthine oxidase to form 1-methyl-uric acid.

[0093] Like caffeine, theophylline is a psychoactive central nervous system (CNS) stimulant. Studies suggest that, like caffeine, the simultaneous antagonism of adenosine receptors by theophylline is responsible for its stimulant effects. Theophylline appears to have similar or slightly greater binding affinity for adenosine receptors than caffeine, but less than theobromine.

[0094] Theophylline is a selective inhibitor of cGMP-preferential phosphodiesterase (PDE9) activity and is believed to increase glutamate and dopamine release by potentiating nitric oxide signaling. Activation of the nitric oxide-cGMP pathway can be responsible for some of the behavioral effects of theophylline that are distinct from those associated with caffeine.

[0095] Theophylline is also a competitive, non-selective phosphodiesterase inhibitor that increases intracellular cAMP, activates PKA, inhibits TNF-a and leukotriene synthesis, and reduces inflammation and innate immunity.

[0096] Unlike caffeine, theophylline acts as an enzyme effector of Na+ / K+ ATPase. As such, it is responsible for increasing the transport of potassium ions to skeletal muscle tissue. Similarly, the compound also stimulates an increase in calcium ion concentration in muscle.

[0097] Theophylline has similar pharmacokinetic parameters to caffeine, but significantly different pharmacokinetic parameters than theobromine and theobromine (the other major methylxanthine metabolite of caffeine in humans).

[0098] Despite research into the various biological effects of theophylline supplements, and despite the frequent noting of positive results, theophylline is an expensive source of ingredient, and the effects are often relatively small or somewhat inconsistent. Thus, while supplementing with theophylline appears to have great potential for achieving a variety of health and / or performance benefits, there remains a need to identify biological mechanisms, compositions, and methods that are capable of utilizing and / or enhancing the effects of theophylline to levels that can be significantly beneficial to health and performance.

[0099] F. Stacked ketone bodies & mixed cation salts

[0100] Any of the compositions described herein can include other ketone bodies in combination with BHB. Such compositions can include "stacked compositions." The terms "stacked composition," "ketone stack," "stack," "ketone stack," and variants thereof are used herein to refer to a composition comprising at least two independent compounds selected from: (i) a beta-hydroxybutyrate salt; (ii) an acetoacetate salt; (iii) a beta-hydroxybutyrate ester; (iv) an acetoacetate ester; (v) a beta-hydroxybutyric acid free acid (i.e., beta-hydroxybutyric acid); and (vi) an acetoacetic acid free acid (i.e., acetoacetic acid), wherein at least one of the stacks is a BHB compound.

[0101] The stacked composition can include a combination of compounds selected from (i) to (vi) such that there is at least two of (A)-(C), where: (A) represents one or more salts; (B) represents one or more esters; and (C) represents one or more free acids. At least one of the salts, esters, or free acids is a BHB compound.

[0102] Exemplary salt forms include sodium, potassium, calcium, magnesium, and lithium salts. Some embodiments include one or more transition metal salts. Transition metal cations suitable for use as part of a salt include chromium, manganese, cobalt, copper, zinc, iron (e.g., as iron II or iron III cations), molybdenum, and selenium. Other suitable salt forms include cations of organic compounds capable of having a net positive charge, including amino acids or their derivatives / metabolites, such as arginine, lysine, leucine, isoleucine, histidine, ornithine, creatine, agmatine, L-glutamine, and citrulline.

[0103] Suitable ester forms include monoesters of ethanol, monoesters of 1-propanol, monoesters of 1,3-propanediol, diesters of 1,3-propanediol, monoesters of S-1,3-butanediol, monoesters of R-1,3-butanediol, diesters of 1,3-butanediol, monoesters of glycerol, diesters of glycerol, and triesters of glycerol. 1,3-Butanediol is a metabolic BHB precursor that can additionally be used to produce BHB and / or acetoacetic compounds in vivo. Acid forms generally have an unpleasant taste, but can be used with appropriate taste-masking mechanisms, such as one or more capsules, tablets, or other pellets.

[0104] Each different form (salt, acid, ester) has its own characteristics and potential benefits and limitations. For example, ester forms of beta-hydroxybutyric acid generally have worse organoleptic properties relative to other forms of beta-hydroxybutyric acid. That is, ester forms of beta-hydroxybutyric acid are generally described as having a pungent taste and / or odor.

[0105] Salt forms are generally considered to have a better taste than ester forms. However, administration of a clinically or dietetically effective dose of components in salt form necessarily requires administration of relatively high levels of the corresponding cation. For example, sodium is commonly used as the cation in beta-hydroxybutyrate salts, and high levels of sodium have well-known negative health effects (e.g., elevated blood pressure). As a further example, calcium is often used as the cation in HMB salts, and high levels of calcium can also be detrimental to health, particularly when not balanced by other cations. While different salts with different cations can be mixed to dilute the effects of a single cation, it is still difficult to provide effective amounts of BHB or other ketone bodies without disrupting the subject’s electrolyte balance when relying on salts alone.

[0106] The beta-hydroxybutyrate (i.e., beta-hydroxybutyric acid) and acetoacetate (i.e., acetoacetic acid) can be used in the free acid form. However, due to the relatively low pKa values (e.g., pKa of 4.70 for beta-hydroxybutyric acid), these compounds are deprotonated and produce H + The excess acidity that results from this can cause adverse side effects, including causing or exacerbating gastrointestinal issues, such as ulcers or reflux.

[0107] The 1,3-butanediol that can be used in the ketone stack is neither acidic nor a salt, and it is readily converted to beta-hydroxybutyrate in the body. However, the amount of 1,3-butanediol that can be administered is limited by its ability to provide a intoxicating effect (similar to ethanol). Thus, 1,3-butanediol can be used in addition to beta-hydroxybutyrate to advantageously provide additional amounts of beta-hydroxybutyrate without providing additional electrolytes or acidity. In some cases, it can be desirable to administer 1,3-butanediol in a sub-intoxicating dose (which depends on the user's weight, gender, and other aspects), such as less than 30 grams, 25 grams, or 20 grams. Nonetheless, in some cases, it can be desirable to administer an intoxicating dose (e.g., at least 30 grams, 40 grams, or 50 grams), such as when the user is at a party and wishes to obtain the benefits of the disclosed compositions as well as an enhanced feeling of relaxation and confidence.

[0108] Providing different amounts or ratios of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be a form of stacking, as they are different ketone bodies that provide different physiological effects. It can be desirable to provide BHB in pure R-beta-hydroxybutyrate or enriched relative to S-beta-hydroxybutyrate to increase potency. Alternatively, it can be desirable to provide BHB in pure S-beta-hydroxybutyrate or enriched relative to R-beta-hydroxybutyrate to decrease potency and increase long-term effects. Administering endogenous forms of R-beta-hydroxybutyrate can result in a rapid increase in ketosis, whereas administering S-beta-hydroxybutyrate (which must first be converted to acetoacetate and then optionally to R-beta-hydroxybutyrate) can provide a slower and more sustained ketosis. As noted above, S-BHB provides benefits of increased alertness in addition to its potential as a source of thermal energy, as compared to R-BHB, which primarily provides thermal energy benefits.

[0109] Combining or stacking different salt types and / or different forms of BHB and acetoacetate can advantageously limit the occurrence or severity of these adverse side effects, and / or can allow for administration of higher doses of these components. For example, a mixed salt composition comprising different cations or stacked forms can deliver the same amount of ketone body as a single form without causing the same incidence and / or severity of side effects. Likewise, a mixed salt form or stacked form can deliver a greater amount of BHB or acetoacetate salt before reaching a similar incidence and / or severity of side effects as compared to a single form.

[0110] In other words, for a given dose of BHB or acetoacetate, the stacked form is expected to have less 1) undesirable organoleptic side effects, 2) electrolyte imbalance side effects, and / or 3) acidity side effects than the single form. For example, the single form of an ester can have a threshold dose beyond which a typical user will not exceed due to the negative impact on organoleptic properties; the single form of a salt can have a threshold dose limited by the recommended dietary limit for the electrolyte that is administered with the salt; and the single form of an acid can have a threshold dose beyond which a typical user will not exceed due to the negative impact of acidity. The combined or stacked form can allow for supplementation of larger amounts of BHB and / or acetoacetate without exceeding the threshold for any of the organoleptic, electrolyte, or acidity side effects.

[0111] In some embodiments, the composition includes at least about 2% of the ester form, at least about 2% of the salt form, and / or at least about 2% of the free acid form, in moles. In other words, at least about 2% of the molecular number (BHB and / or acetoacetate) can be provided by each individual form or at least two forms. More preferably, the composition includes at least about 5% of the ester form, at least about 5% of the salt form, and / or at least about 5% of the free acid form, in moles, or at least about 10% of the ester form, at least about 10% of the salt form, and at least about 10% of the free acid form, in moles, or at least about 20% of the ester form, at least about 20% of the salt form, and at least about 20% of the free acid form, in moles, or at least about 30% of the ester form, at least about 30% of the salt form, or at least about 30% of the free acid form, in moles.

[0112] In some embodiments, the composition includes about 2% to about 96%, or about 5% to about 90%, or about 10% to about 80%, or about 20% to about 60% of the ester form, in moles, including about 2% to about 96%, or about 5% to about 90%, or about 10% to about 80%, or about 20% to about 60% of the salt form, in moles, and including about 2% to about 96%, or about 5% to about 90%, or about 10% to about 80%, or about 20% to about 60% of the acid form, in moles.

[0113] G. Other Definitions

[0114] As used herein, "subject," "patient," or "user" refers to a mammal, including humans and other primates. The subject can be any mammal in need of metabolic therapy, treatment, or prevention, or any mammal suspected of being in need of metabolic therapy, treatment, or prevention. Prevention refers to taking a series of measures to prevent a condition from occurring, such as a high risk of being diagnosed with diabetes or other metabolic disorder. "Patient," "subject," and "user" are used interchangeably herein.

[0115] “Ketosis” as used herein refers to a metabolic state entered during an intermittent fasting period or longer fast (e.g., 2 days or longer). A subject can also be considered to be in ketosis when the subject’s blood ketone levels are in the range of about 0.5 mmol / L to about 16 mmol / L. Ketosis can improve mitochondrial function, reduce reactive oxygen species production, reduce inflammation, and increase activity of neurotrophins. “Ketoadaptation” as used herein refers to prolonged nutritional ketosis (>1 week) to achieve sustained non-pathological “mild ketosis” or “therapeutic ketosis” or to metabolic changes in which fat becomes the primary energy source, thereby shifting the body from a fat storage state to a fat oxidation state. It is believed that administration of BHB and other ketones at the doses disclosed herein can provide the same or similar benefits as being in a state of ketosis, even if the subject has not reached a blood ketone level high enough to be technically in a state of ketosis.

[0116] The term “administering” is used herein to describe the process of delivering the disclosed compositions to a subject. “Administering” can include any known method or configuration that can deliver the disclosed compositions to the blood, tissues, and / or cells, whether targeted, broadly diffused, or systemic.

[0117] The term “unit dose” refers to a dosage form configured to deliver a particular amount or dose of a composition or component thereof. Example dosage forms include, but are not limited to, tablets, capsules, powders, food items, food additives, beverages (e.g., flavored, vitamin fortified, or non-alcoholic), beverage additives (e.g., flavored, vitamin fortified, or non-alcoholic), confections, straws, lozenges, food supplements, dietarily acceptable sprays (e.g., flavored mouth sprays), injections (e.g., non-alcoholic injections), and suppositories. Such dosage forms can be configured to provide a complete unit dose or a fraction thereof (e.g., ½, 1 / 3, or 1 / 4 of a unit dose).

[0118] Another dosage form that can be used to provide a unit dose of a composition or component thereof is a unit dose measuring device, such as a cup, spoon, spatula, syringe, dropper, scoop, or suppository injection device, configured to hold a measured amount of the composition therein equal to a whole unit dose or a fraction thereof (e.g., ½, 1 / 3, or 1 / 4 of a unit dose). For example, a bulk container of a composition comprising several unit doses (e.g., 5-250 or 10-150 unit doses), such as a carton, box, can, jar, bag, pouch, bottle, jug, or keg, can be provided to a user with a unit dose measuring device configured to provide a unit dose of the composition or component thereof or a fraction thereof.

[0119] A kit for providing a composition as disclosed herein in bulk form can include, while providing unit doses of the composition, a bulk container holding an amount of the composition therein and a unit dose measuring device configured to provide a unit dose or a fraction thereof of the composition or component thereof. The unit dose measuring device(s) can be positioned within the bulk container at the time of sale, attached to the exterior of the bulk container, prepackaged with the bulk container within a larger package, or provided by the seller or manufacturer for use with the bulk container.

[0120] The kit can include instructions regarding the size of the unit dose or fraction thereof and the manner and frequency of administration. The instructions can be provided on the bulk container, prepackaged with the bulk container, placed on packaging materials with which the bulk container is sold, or otherwise provided by the seller or manufacturer (e.g., on a website, in a mailing, in a flyer, in product literature, etc.). The instructions for use can include a reference for how to use the unit dose measuring device to correctly deliver a unit dose or fraction thereof. The instructions can additionally or alternatively include a reference to a common unit dose measuring device, such as a spoon, spatula, cup, etc., that is not provided with the bulk container (e.g., in the event that the provided unit dose measuring device is lost or misplaced). In such cases, the end user can construct the kit by following the instructions provided on or with the bulk container, or otherwise provided by the seller regarding the product and how to correctly deliver a unit dose of the composition or a portion thereof.

[0121] II. Para-xanthine-BHB Compositions

[0122] The para-xanthine-BHB compositions described herein can comprise: (1) a para-xanthine; (2) a ketone body (KB) component comprising beta-hydroxybutyrate (BHB); and (3) optionally a dietarily or pharmaceutically acceptable carrier. Other ketone body components, such as acetoacetate (AcAc), can also be included in the KB of (2). In some embodiments, BHB precursors, such as 1,3-butanediol, can be used in addition to, or in place of, BHB. Similarly, although HMB is not technically a ketone body, it can also be included in the composition, providing the benefits associated with the combination of BHB and HMB (as described in U.S. Patent Publication No. 2022 / 0062216, which is incorporated herein by reference).

[0123] As noted above, the parabanic acid-BHB compositions can be formulated with different ratios of parabanic acid to BHB. While the ratio can vary, because BHB is provided as a source of thermal energy, while parabanic acid is not provided for thermal energy, but for its pharmacokinetic and pharmacodynamic benefits, the dosage of BHB can generally be greater than the dosage of parabanic acid. For example, the ratio of BHB to parabanic acid can be at least 1 : 1, 1.25: 1, 1.5: 1, 2: 1, 4: 1, 5: 1, 6: 1, 9: 1, or can be within a range having any two of the above ratios as endpoints. The ratio can be made according to the needs and preferences of a particular application. While BHB provided alone can provide enhanced metabolic activity (e.g., fat loss, anti-inflammatory, vasodilation), when provided in combination with parabanic acid, it is believed that synergistic results can be provided, including, for example, enhanced such metabolic benefits, but also including neuroprotection, enhanced focus and mental clarity, cognitive flexibility, improved working memory, improved reaction time, reduced oxidative stress, modulation of the drowsiness / dizziness typically associated with hypoglycemia when entering a ketotic state, modulation of the typical downregulation of metabolic rate when entering a ketotic state, etc.

[0124] Different other additives that can be present in the energy formulation include any of those described in U.S. Patent Publication No. 2021 / 026724, which is incorporated by reference herein.

[0125] The parabanic acid-BHB compositions can also optionally include a supplemental source of ketone body precursors, such as one or more of 1,3-butanediol, fatty acids, and / or fatty acid esters. Typical ester forms of fatty acids are monoglycerides, diglycerides, or triglycerides. Preferred forms of fatty acids and their esters are medium chain fatty acids and medium chain triglycerides (MCTs), although short chain and / or long chain fatty acids and their esters can also be used. In embodiments where used, the medium chain fatty acids have 6 to 12 carbons, preferably 8 to 10 carbons. U.S. Patent No. 9, 138,420, which is incorporated by reference herein, discloses compositions and methods involving combinations of BHB with medium chain fatty acids or esters thereof.

[0126] Exemplary medium chain fatty acids are caproic acid, also known as hexanoic acid having 6 carbons, caprylic acid, also known as octanoic acid having 8 carbons, capric acid, also known as decanoic acid having 10 carbons, and lauric acid, also known as dodecanoic acid having 12 carbons. Because MCTs are ketone body precursors, inclusion of one or more MCTs can provide an additional source of ketone body production independent of BHB and any acetoacetate compounds, thereby helping to facilitate sustained elevation of ketone levels to the desired therapeutic levels.

[0127] The term "short-chain triglyceride" (SCT) refers to a molecule similar to an MCT molecule, but with a short-chain fatty acid (less than 6 carbon atoms in length) attached to the glycerol backbone. The term "long-chain triglyceride" (LCT) refers to a molecule similar to an MCT molecule, but with a long-chain fatty acid (more than 12 carbon atoms in length) attached to the glycerol backbone.

[0128] Examples and sources of medium-chain fatty acids or esters thereof (such as medium-chain triglycerides) include coconut oil, coconut milk powder, fractionated coconut oil, palm oil, palm kernel oil, caprylic acid, isolated medium-chain fatty acids (such as isolated hexanoic acid, isolated octanoic acid, isolated decanoic acid), medium-chain triglycerides in purified or natural form (such as coconut oil), as well as ester derivatives of medium-chain fatty acid ethoxylated triglycerides, enone triglyceride derivatives, aldehyde triglyceride derivatives, monoglyceride derivatives, diglyceride derivatives, and triglyceride derivatives, and salts of medium-chain triglycerides. Ester derivatives optionally include alkyl ester derivatives, such as methyl, ethyl, propyl, butyl, hexyl, and the like.

[0129] When providing medium-chain fatty acids, fatty acid esters, or glyceryl mono-, di-, or triglycerides of medium-chain fatty acids, the composition is preferably administered such that the weight ratio of ketone bodies (e.g., BHB) to medium-chain fatty acids (or esters thereof) is about 4: 1 to about 1 :4, or about 2: 1 to about 1 :2, or about 1.5: 1 to about 1 : 1.5. The same ratios can be used when additionally or alternatively using short-chain fatty acids (or esters thereof) or long-chain fatty acids (or esters thereof).

[0130] Examples of short-chain fatty acids include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid. Examples of medium-chain fatty acids include hexanoic acid, octanoic acid, decanoic acid, and lauric acid. Examples of long-chain fatty acids include myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, omega-3 fatty acids, omega-6 fatty acids, omega-7 fatty acids, and omega-9 fatty acids.

[0131] III. Therapeutic Effects

[0132] Administration of the xanthine-BHB composition can provide a variety of beneficial physiological and neurological effects, including one or more of the following: neuroprotection, enhanced attention and thought clarity, cognitive flexibility, improved working memory, improved reaction time, enhanced vasodilator (e.g., nitric oxide) neurotransmitter signaling, modulation of the somnolence / dizziness typically associated with hypoglycemia when entering a ketotic state, and modulation of the typical downregulation of metabolic rate when entering a ketotic state. Other benefits can include, for example, reduced oxidative stress, antioxidant effects, analgesic effects, anti-inflammatory effects, as well as fat reduction, appetite suppression and enhanced inhibitory control, anxiety modulation, suppression of depressive symptoms, cardiovascular benefits (e.g., vasodilation and blood pressure modulation), and anti-aging / longevity.

[0133] While potentially involving a variety of different pharmacological and / or physiological variables, the combination compositions described herein can achieve complementary enhancements of a variety of different neurological and physiological systems. Without being bound to any particular theory, it is presently believed that the role of the paraxanthine component is to provide an enhancement similar to that provided by caffeine, but while eliminating the adverse side effects associated with caffeine and reducing or eliminating the differences in the metabolism of this psychostimulant by different users. In addition, paraxanthine provides benefits that caffeine cannot, such as enhancing vasodilatory neurotransmitter signaling. While it is known that supplementation with paraxanthine alone produces some of these benefits, by providing BHB with the paraxanthine, the benefits provided are enhanced beyond what would be predicted or expected based on additive effects alone. In other words, the combination of paraxanthine and BHB produces synergistic benefits that are not provided by either component alone.

[0134] Due to the BHB component in the composition, the beneficial therapeutic effects described herein can be achieved or enhanced when the subject is in a ketotic state or enters a ketotic state. While many of the examples can be described in the context of a subject entering or being in a ketotic state (e.g., during fasting), it should be understood that achieving the beneficial effects does not necessarily require the subject to be in such a state. For example, various neurological benefits can be provided even if the subject is not necessarily in a ketotic state, such as enhanced attention and mental clarity, improved cognitive flexibility, improved working memory, improved reaction time, enhanced vasodilatory neurotransmitter signaling, and neuroprotection. Such benefits can be provided when in a ketotic state, as well as modulating drowsiness / dizziness typically associated with entering a ketotic state, modulating the metabolic rate down typically under ketotic states, reducing fat, maintaining muscle, etc. In other words, due to the co-administration of the exogenous ketone body component BHB and paraxanthine, beneficial effects can be achieved. These effects can be further enhanced once the subject enters a ketotic active state, and the BHB component itself can help the subject enter such a state, but ketosis is not a requirement for achieving the benefits described herein.

[0135] A. Metabolism of Caffeine and Paraxanthine

[0136] Figure 1 An exemplary plasma concentration profile of caffeine and its metabolites (paraxanthine, theophylline, and theobromine) following oral administration of 270 mg of caffeine is shown. Paraxanthine (1,7-dimethylxanthine) accounts for about 70-72% of the ingested caffeine and about 84% of the methylxanthine metabolic byproducts. As shown, theophylline and theobromine account for 4% and 12% of the methylxanthine metabolic byproducts, respectively. Figure 2

[0137] ​Paraxanthine is a natural dietary component that can be found in small amounts in, for example, the fruit of Theobroma cacao, Coffea arabica, Sinomenium actum, and the stamens of citrus flowers. As shown in Figure 3 Paraxanthine has a shorter half-life and faster clearance rate than caffeine, theophylline, or theobromine. For example, the half-life of paraxanthine is 3.1 hours, which is significantly shorter than caffeine (4.1 hours), and is half or less than theophylline (6.2 hours) and theobromine (7.2 hours). The total plasma clearance rate of paraxanthine (2.20 mL / min / kg) is greater than caffeine (2.07 mL / min / kg), and is much greater than theophylline (0.93 mL / min / kg) or theobromine (1.2 mL / min / kg).

[0138] Paraxanthine offers significant benefits (and minimizes negative side effects) compared to the use of caffeine. For example, paraxanthine is less toxic than caffeine, causes less chromosomal breakage than caffeine or theophylline, and causes less teratogenicity than caffeine or theophylline. Like caffeine, paraxanthine is a psychostimulant and central nervous system stimulant. Paraxanthine is believed to work through the mechanism of an adenosine receptor antagonist. Paraxanthine provides stronger motor activation than caffeine, and has a higher binding capacity to adenosine Al and A2a receptors. Blocking Al receptors increases the release of neurotransmitters (such as glutamate and dopamine). Advantageously, in addition to being an adenosine receptor antagonist, paraxanthine also enhances nitric oxide (a vasodilator) neurotransmitter signaling. Caffeine does not have this benefit. Phosphodiesterase 9 (PDE9) is believed to terminate nitric oxide neurotransmission by metabolizing cGMP back to GMP. Paraxanthine inhibits PDE9, thereby enhancing nitric oxide neurotransmission and dopamine release. As noted above, caffeine does not have this effect.

[0139] Paraxanthine has stronger, more potent neuroprotective effects than caffeine. For example, paraxanthine has been shown to protect dopaminergic neurons and has strong protective effects against neurodegeneration and loss of synaptic function, while caffeine provides only weak protective effects.

[0140] Interestingly, paraxanthine has stronger wakefulness-promoting activity than caffeine, while also being more long-lasting than caffeine. Paraxanthine is of particular interest given its shorter half-life and faster clearance rate (seemingly paradoxical, paraxanthine has a shorter half-life and shorter clearance rate, but is more potent and longer lasting). As noted above, paraxanthine is less toxic than caffeine. For example, increasing doses of caffeine (and modafinil) cause decreased body temperature and motor activity. At similar doses, paraxanthine does not exhibit such problems.

[0141] As mentioned previously, it is important that different people metabolize caffeine differently, depending on their genetic profile. For example, the cytochrome P450 1A2 enzyme is responsible for about 95% of all caffeine metabolism, including the demethylation of caffeine to paraxanthine. Subjects with the CYP1A2 gene homolog A allele tend to produce more cytochrome P450 and therefore metabolize caffeine more quickly. In some, but not all, studies, fast metabolizers of caffeine more consistently experience greater ergogenic outcomes. The problem is that only less than 50% of people are fast metabolizers, meaning that most subjects miss out on the benefits that fast metabolizers gain from caffeine. By using paraxanthine directly, this avoids the effects associated with the genetic differences of subjects, allowing those who are moderate or slow metabolizers of caffeine to benefit better.

[0142] Using paraxanthine instead of caffeine provides a number of benefits, some of which have been mentioned above. Because paraxanthine is less bitter than caffeine, it provides other sensory benefits, making it easier to formulate. When paired with BHB, less paraxanthine is needed to achieve a given benefit, making it even easier to formulate. Table 1 below shows the results of a taste test to evaluate bitterness using a specially trained taste panel. Each solution was prepared by dissolving 163 mg of the component being tested for bitterness in 473 mL of water. As a comparative reference point, caffeine provided a bitterness score of 5.0. Solution L is Liberine, solution T is catechol, solution M is methyl Liberine, and solution P is paraxanthine. Paraxanthine had an average bitterness score of 3.9, which was significantly less bitter than caffeine (5.0) and much less bitter than the other test components.

[0143] Table 1 - Bitterness Score

[0144]

[0145] While the above effects of paraxanthine are desirable when used alone, it was unexpectedly discovered that the combination of paraxanthine and BHB unexpectedly enhanced the benefits provided by paraxanthine and reduced the amount of paraxanthine needed to provide a given level of benefit. For example, because the BHB component both provides thermal energy without triggering an insulin spike and also promotes the more efficient conversion of fat into energy, a subject can obtain greater energy available from the ketones to engage in work, thereby enhancing cognitive flexibility, the ability to sustain attention, maintain mental clarity, and benefit from enhanced working memory associated with supplementation of paraxanthine. The thermal energy provided by BHB in combination with paraxanthine also modulates the drowsiness / dizziness typically associated with entering a ketotic state, while also modulating the typical metabolic rate downshift associated with entering a ketotic state. As shown in the accompanying prospective data, when a user supplements this combination, the metabolic rate can be maintained, or even increased. As shown in the accompanying data, these benefits and performance of a given subject supplementing paraxanthine and BHB in combination are significantly enhanced compared to similar subjects supplementing paraxanthine alone, or BHB alone, or caffeine alone, or a combination of caffeine and BHB.

[0146] The figures below illustrate this expected improvement through various clinical studies. For example, one clinical study compared the results of the following regimens: supplementation with a combination of paraxanthine and BHB, supplementation with paraxanthine alone as a comparison, supplementation with BHB alone as a comparison, and supplementation with a placebo as a comparison. The subjects included a mix of healthy young men and women, and were subjected to four executive function tests to assess working memory, inhibitory control, cognitive flexibility, and sustained attention. Working memory is the ability to hold information in mind and use it. The ability to remember instructions, plan actions, and focus attention all rely on working memory. Inhibitory control is the ability to control attention, behavior, thoughts, and emotions rather than acting on impulse or desire. Cognitive flexibility is the ability to change tasks, adapt to changing demands, changing priorities, and changing perspectives. Sustained attention is the ability to focus on an activity or stimulus for a long period of time, such as 2-3 hours or more. It is what enables us to focus on an activity in the presence of other distracting stimuli for the length of time needed to complete the activity.

[0147] Attention and inhibitory control can be measured using a Go / No Go test, which measures the ability of a participant to sustain attention and response control. The Go / No Go test is routinely used in the art and is familiar to those skilled in the art. In the Go / No Go test, a participant views a 2x2 array of squares, then letters (e.g., P or R) are presented in turn, and the participant responds to the target letter by pressing the corresponding button on the keyboard. Individual letters (P or R) are presented in one of the 4 squares for 500 milliseconds, with a subsequent stimulus interval of 1500 milliseconds. For the P-Go condition, the participant is required to press the P key to respond to the letter P and to forego responding to the letter R. For the R-reverse condition, the participant is required to respond to the letter R and to forego when the letter P is seen. The mean response time is recorded, as well as the percentage of correct answers.

[0148] The Vigilance Task Test is another test routinely used in the art and is used to assess the ability of a participant to sustain attention. The Vigilance Task Test is a sustained attention, reaction time task test that measures the speed of a participant's response to visual stimuli. The subject reacts as quickly as possible by pressing a key when a visual stimulus (e.g., a red dot) appears on a computer screen. The light is turned on randomly, for example, about every few seconds during the test. The response speed is measured. Due to the randomness of the test, there is no learning effect. The mean response time is recorded.

[0149] The Berg-Washington Card Sorting Task (BCST) test is a test routinely used in the art to assess cognitive flexibility. The BCST test focuses on basic cognitive flexibility or set shifting between old and new rules. The test involves reasoning, learning, executive control, and attention shifting. It is highly sensitive to subjects who cannot shift sets. On a computer screen, cards are displayed with different colors (e.g., red, green, yellow, blue), different patterns (e.g., circles, triangles, stars, plus signs), and different number symbols (e.g., 1-4). The participant is asked to sort the cards by matching the color and / or pattern and / or number of symbols, where the instructions on how to sort the cards can change at different times during the test. The number of correct responses and the number of errors (particularly persistent errors, i.e., the participant continues to sort the cards incorrectly according to the old instructions after a new instruction is given) are recorded.

[0150] The Sternberg test is a test routinely used in the art to assess working memory and the ability to utilize short-term memory. Shorter reaction times mean that the participant can access their working memory more quickly. The Sternberg task test is a widely used paradigm for studying short-term / working memory that involves cognitive control processes. Participants are asked to remember a short sequence of letters or other characters, and then the participant must answer whether that sequence of letters or characters appears in a larger sequence of letters or characters. Reaction times are measured when the remembered short sequence is present or absent. The average response time is recorded.

[0151] When each such test was performed, the subject was given paratilline + BHB, paratilline alone, BHB alone, or placebo. The dosage was 200 mg paratilline and 5 g BHB, 200 mg paratilline alone, 5 g BHB alone, or placebo. The tests were performed under double-blind, placebo-controlled conditions. The subjects included 13 healthy young adults (10 males, 3 females), age 24 ± 5 years; height 170.0 ± 11.8 cm; weight 72.9 ± 19.3 kg. Measurements were taken at baseline levels, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours after the supplement was taken for each of the following tests: Go / No Go test, Vigilance Task test, Sternberg Task test, and Berg-Washington Card Sorting Task test.

[0152] Figure 4 and Figure 5 The expected results of the Go / No Go test are shown. As shown, the supplementation of paratilline, especially in combination with BHB, resulted in faster reaction times. Over time, the placebo and BHB alone showed a decrease in correct answers (see Figure 4 ), indicating the onset of mental fatigue. The placebo showed little difference in the graphed responses compared to BHB alone. Unexpectedly, the combination of paratilline with BHB showed a significant synergistic improvement in correct response accuracy and average response time compared to paratilline alone. The results of the Go / No Go test show that the combined use of paratilline and BHB provides a synergistic increase in the ability for sustained attention and response control.

[0153] Figure 6The expected results of the vigilance task test are shown. As shown, supplementation with paraurine, especially in combination with BHB, resulted in faster reaction times. In contrast, placebo and BHB alone showed significantly slower reaction times (e.g., especially at 3 hours and 6 hours from baseline). Unexpectedly, the combination of paraurine and BHB showed a significant synergistic improvement in average response time compared to paraurine alone. As shown by the results of the vigilance task test, the combined use of paraurine and BHB provided a synergistic increase in the ability to sustain attention.

[0154] Figures 7-8 The expected results of the Berg-Washington card sorting task test are shown. As shown, supplementation with paraurine, especially in combination with BHB, resulted in a significant increase in the number of correct responses and a decrease in the number of errors. While paraurine alone provided some such benefits, the increase in correct answers and decrease in errors was unexpectedly increased by further supplementation of BHB in combination with paraurine. As shown by the results of the Berg-Washington card sorting task test, this combination of paraurine and BHB unexpectedly and synergistically increased cognitive flexibility or the ability to set a switch between old and new rules.

[0155] Figures 9-11 The expected results of the Sternberg test are shown. As shown, supplementation with paraurine, especially in combination with BHB, resulted in a decrease in average response time compared to placebo or BHB supplementation alone. While paraurine alone decreased reaction time to some extent, the combination of supplementation of BHB with paraurine unexpectedly provided faster response times. As shown by the results of the Sternberg test, this combination of paraurine and BHB unexpectedly and synergistically increased short-term / working memory, especially for longer letters.

[0156] A key finding from the various cognitive tests is that acute paraurine and BHB supplementation improved cognition in all 3 aspects of executive function: cognitive flexibility, short-term memory, and sustained attention. While paraurine supplementation alone can improve cognitive abilities, this improvement is unexpectedly synergistically enhanced when used in combination with BHB. For example, BHB supplementation alone provided little, if any, benefit compared to placebo, but when combined with paraurine, results were obtained that were superior to paraurine alone. Such results are unexpected and unpredictable, showing a synergy between paraurine and BHB.

[0157] Other clinical studies were conducted to compare the effects achieved by paraxanthine versus caffeine. Participants were given 200 mg paraxanthine, 200 mg caffeine, 5 g BHB, 200 mg paraxanthine + 5 g BHB, 200 mg caffeine + 5 g BHB, 200 mg paraxanthine + 200 mg caffeine + 5 g BHB, or placebo. The tests were conducted under double-blind, placebo-controlled conditions. The subjects included 12 trained, healthy male runners, age 26 ± 5 years. Baseline cognitive tests (PRE) were conducted, the specified supplements were ingested, and after a 60-minute rest, pre-exercise cognitive tests (PRE-EX) were conducted. The subjects then ran 10 km on a treadmill, followed by post-exercise cognitive tests (POST), which included vigilance task tests (measuring the ability to remain highly alert) and Berg-Washington card-sorting task tests (measuring cognitive flexibility).

[0158] The expected results of this test are shown in Figures 12A-12D where Figure 12A the difference in the incidence (e.g., percentage) of correct responses in the POST test versus the PRE test is shown. Figure 12B the difference in the incidence (e.g., percentage) of errors in the POST test versus the PRE test is shown. Figure 12C the difference in the incidence (e.g., percentage) of persistent errors in the POST test versus the PRE test is shown. Figure 12D the difference in the incidence (e.g., percentage) of persistent errors (PAR rule) in the POST test versus the PRE test is shown. While paraxanthine alone provided some improvement in correct responses and reduced errors, the combination of BHB with paraxanthine even unexpectedly provided further improved results. This combination of paraxanthine and BHB unexpectedly and synergistically increased mental clarity, alertness, and cognitive flexibility, while reducing mental fatigue. As shown, the supplementation of caffeine, even in combination with paraxanthine and / or BHB, was not as effective. For example, all of the embodiments including caffeine resulted in a reduction in correct responses and an increase in errors, even compared to placebo (i.e., placebo, or not using a supplement, was superior to using any of the supplements including caffeine). Thus, in one embodiment, the compositions of the present invention are substantially or completely free of caffeine.

[0159] For Figures 12A-12D the same supplements shown in Figure 13Expected response times for alertness task testing were plotted. As shown, supplementation with para-xanthine alone provided some benefit, but when para-xanthine + BHB was supplemented, increased, synergistic benefits were provided. Supplementation with caffeine containing supplements could reduce reaction times as shown, although not to the extent provided by the caffeine free supplements, and caffeine caused increased errors as shown. Figures 12A-12D

[0160] This clinical study shows that supplementation with para-xanthine, particularly in combination with BHB, can improve cognition at PRE-EX, and especially POST-EX; whereas caffeine has a negative impact on cognition even when combined with para-xanthine and / or beta-hydroxybutyrate.

[0161] Figures 14A-14C Expected results from a 28-day sports nutrition clinical study are shown, in which participants supplemented with para-xanthine (100 mg) alone, BHB (5 g) alone, a combination of para-xanthine (100 mg) and BHB (5 g), or one of various mass building supplements (e.g., L-theanine (50 mg), alpha-GPC (200 mg), or taurine (500 mg)). In the 4-week study, participants exercised 5 days per week. While para-xanthine alone provided some improvements in muscle mass, endurance, and grip strength, the combination of BHB with para-xanthine even surprisingly provided further improved results. This combination of para-xanthine and BHB surprisingly and synergistically increased muscle mass, muscle endurance, and grip strength. Increases in nitric oxide levels and improvements in blood lipid scores (e.g., TG, TC, LDL, HDL) were also observed.

[0162] In an age-related cognitive decline study, expected results show that a combination of para-xanthine and BHB provided improved cognitive performance, improved neurotransmitter levels, improved brain protection, and improved oxidative stress, over and above the effects provided by para-xanthine alone or BHB alone. These expected results are shown in Table 2. As shown, BHB alone provided little benefit compared to the control group. When paired with para-xanthine, the combination synergistically decreased escape latency and amyloid Ab1-40 concentration, while synergistically increasing acetylcholine, dopamine, glutathione, catalase, and BDNF.

[0163] Table 2

[0164]

[0165] ​In forced swim and Cook’s Pole pole climb tests in mice, expected results show that the combination of parasympatholamine supplementation with BHB provides improved active swim duration and increases pole climb test scores better than parasympatholamine alone, BHB alone, or various other muscle-building supplements (e.g., L-theanine, alpha-GPC, and taurine) provide. These expected results are shown in Table 3. As shown in the table, BHB alone provides little benefit compared to the control group. When paired with parasympatholamine, the combination provides a synergistic decrease in rest duration and number of climbs in the Cook’s Pole pole climb test, while providing a synergistic increase in activity / active swim duration.

[0166] Table 3

[0167]

[0168] Figures 15A-15C Expected results are shown for a clinical Stroop test study in which participants supplemented with parasympatholamine (200 mg) alone, BHB (5 g) alone, or a combination of parasympatholamine (200 mg) and BHB (5 g) over a 6-week period. The Stroop effect refers to the delay in reaction time between congruent and incongruent stimuli. The Stroop test is a well-known psychological test that demonstrates this effect when the name of a color (e.g., “blue,” “green,” or “red”) does not match the color in which it is printed (i.e., the word “red” is printed in blue ink instead of red ink). When the color of the ink does not match the name of the color, subjects take longer and make more errors when asked to say the color of the word. In this Stroop test, while parasympatholamine alone (200 mg) provides some improvement in reaction speed and number of correct answers, the combination of BHB with parasympatholamine even surprisingly provides further improved results. As shown in Table 4, BHB alone provides little benefit compared to baseline (pre-supplementation). When paired with parasympatholamine, the combination provides a synergistic improvement in mental acuity. Figure 15B Figure 15C Figure 15A

[0169] Figure 16 ​​​A-16B shows the expected results of a clinical resting energy expenditure study where participants were supplemented with: paraurin alone (100 mg or 300 mg), BHB alone (5 g), or a combination of paraurin (100 mg or 300 mg) with BHB (5 g) over a period of 180 days. While paraurin alone provided some increase in resting energy expenditure (which contributes to weight loss), the combination of BHB with paraurin provided even more surprisingly improved results. As shown, BHB alone provided little benefit. However, when paired with paraurin, the combination provided a synergistic increase in resting metabolic energy expenditure. This increase in metabolic rate is also more likely to occur in a ketotic state due to the presence of the BHB ketone body component, where fat is primarily used as the energy source for the increase in resting metabolic rate.

[0170] IV. Dosage Form and Administration

[0171] The compositions described herein can be provided in various forms, such as single- or multi-part compositions, configured for administration by one or more of ingestion, intragastric, injection, topical application, inhalation, buccal mucosal administration, rectal administration, vaginal administration, or parenteral administration.

[0172] Non-limiting examples of the foregoing routes of administration include, but are not limited to, ingestible compositions, suppositories (anal or vaginal), transdermal patches, sublingual compositions, subcutaneous forms, solids, powders, liquids, gels, tablets, capsules, other diet or pharmaceutically acceptable forms, vaporizable cartridges, atomized liquids, smokeable pellets, syringes for intravenous injection, nasal sprays or vapors, inhalable lung compositions, enemas, douches, injectable pellets, subcutaneous implants (e.g., pellets or rods), and the like.

[0173] Inhalation can be performed using a heat vaporizer (e.g., a smoking rod, a mod box, an electronic cigarette, or a suction tube cartridge), a suction pellet (e.g., using a tube, a water pipe, a bong, a rolling paper, a glass tube, a hookah cartridge, a disposable syringe, a hookah bag, an apple tube, an avocado tube, a gas mask, a snorkel device), or a nebulizer.

[0174] Food items include beverages, sodas, energy drinks, sparkling water, beer, wine, liquor, hard seltzer, coconut water, fruit juice, chocolate, fruit chew, oral drops, coconut oil, butter, water, milk, cookies, cakes, ice cream, gummy bears, pizza crust, brownie cake, pastries, yogurt, frozen yogurt, chewable vitamins, candy, protein powder, supplements, supplement powder, consumable powder, coffee, tea, and the like.

[0175] Oral / concentrate / extracts include chewing gum, tinctures, oils, sublingual sprays, pills, capsules, fast-dissolve tablets, lozenges, nasal sprays, eye drops, dabs, shatter, and rosin.

[0176] Topical applications include lotions, creams, ointments, balms, transdermal patches, gels, shampoos, conditioners, deodorants, lipsticks, lip balms, and cosmetics.

[0177] Solid or powder compositions can include one or more additional components configured to reduce the hygroscopicity of the composition. For example, various anti-caking agents, flow agents, and / or hygroscopic agents can be included in types and amounts that are safe for consumption. Such additional components can include one or more of aluminosilicates, ferrocyanides, carbonates or bicarbonates, silicates (e.g., sodium or calcium silicate), phosphates (e.g., tricalcium phosphate), talc, powdered cellulose, and the like.

[0178] In alternative embodiments, the paraxanthine-BHB composition can be provided as a liquid, such as in the form of an injection or oral spray for rapid delivery and absorption, or as a gel. Liquid or gel forms can include one or more carriers, such as water, ethanol, glycerol, propylene glycol, 1,3-propanediol, and the like, in which the components are dissolved or dispersed. The composition can include flavorings that help mask the undesirable taste of the BHB compounds. These flavorings can include essential oils, such as peppermint, natural and artificial sweeteners, and other flavorings known in the art.

[0179] The paraxanthine-BHB composition can include one or more supplements known in the art, such as vitamins, minerals, or herbs. In one embodiment, there is little to no caffeine, if any, as caffeine interferes with the efficacy of paraxanthines, as shown above. For example, if present, caffeine can be present in less than 10 mg, less than 5 mg, less than 3 mg, or less than 1 mg. The composition can advantageously be substantially free or completely free of caffeine.

[0180] The parapallium-BHB compositions described herein can be provided in a dosage regimen effective to induce and maintain ketosis and / or provide other benefits described herein. For example, the mass of exogenous ketones (e.g., BHB) in a daily dose (for an average adult of about 175 pounds) can range from about 0.5 g to about 50 g, or about 1 g to about 40 g, or about 2 g to about 30 g, or about 3 g to about 25 g, or about 4 g to about 20 g, and can be provided using one or more unit doses. The mass of parapallium component in a daily dose (for an average adult of about 175 pounds) can range from about 25 mg to about 1000 mg, about 50 mg to about 500 mg, about 75 mg to about 400 mg, about 100 mg to about 300 mg, or about 125 mg to about 250 mg. As needed, the dosage can be adjusted (e.g., linearly adjusted) based on the subject’s body weight. The parapallium component and BHB ketone component can be mixed / combined, although some approaches can provide these components separately. The daily dose can be taken in a single daily dose or in multiple doses (e.g., 2, 3, or 4 times per day).

[0181] In some embodiments, the compositions include a ratio of BHB ketone component to parapallium component ranging from about 1 : 1 to about 500: 1, although it is preferred that the amount of BHB ketone component be greater, and preferably significantly greater, than the parapallium component. For example, more preferred ratios of BHB ketone component to parapallium component can be about 5: 1 to about 300: 1, about 5: 1 to about 100: 1, or about 5: 1 to about 50: 1. The BHB component is present in a significantly higher amount because it is provided as an energy source, while the parapallium is used for other purposes (e.g., enhanced cognitive flexibility, increased sustained attention, improved working memory, increased inhibitory control, neuroprotection, etc.). Examples of weight ratios of BHB ketone component to parapallium component include 3: 1, 5: 1, 10: 1, 15: 1, 20: 1, 25: 1, 30: 1, 40: 1, 50: 1, 75: 1, 100: 1, 200: 1, 300: 1, 400: 1, and 500: 1, as well as any range having any of the foregoing values as endpoints. These and other ratios disclosed herein will be generally applicable when 1,3-butanediol is used as a supplement or replacement for BHB.

[0182] In a preferred embodiment, one or more unit doses of parapallium-BHB compositions are administered daily by oral administration of the compositions in solid, powdered form, or liquid form, such as a powder mixture (e.g., a powder-filled gelatin capsule), a hard-pressed tablet, or other oral administration routes known to those skilled in the art.

[0183] In some embodiments, multiple doses of the composition are administered. The frequency of administration of the composition can vary depending on any of a variety of factors, such as the length of treatment from prior treatments, the purpose of the treatment, and the like. The duration of administration of the composition (e.g., the period of time over which the agent is administered) can vary according to any of a variety of factors, including the subject’s response, the desired therapeutic effect, and the like.

[0184] The amount of the composition to be administered can vary depending on factors such as the sensitivity of the individual, the age, sex, and weight of the individual, the specific reaction of the individual, and the like. A “therapeutically effective amount” is that amount necessary to promote a therapeutically effective result in vivo. According to the present disclosure, a suitable single dose size is a dose (e.g., a daily dose) that is capable of preventing or alleviating (reducing or eliminating) the symptoms of the patient when administered one or more times over a suitable period of time.

[0185] The amount of the composition administered will depend on the potency, absorption, distribution, metabolism, and excretion rates of the components of the composition, the method of administration, and the particular condition being treated, as well as other factors known to those of skill in the art. The dosage should be sufficient to effect a response, e.g., a therapeutic or prophylactic response against a particular condition or state, taking into account the severity of the condition being alleviated. The compound can be administered once (e.g., once a day) over a given time, or can be divided and administered over a time interval. It will be appreciated that administration can be adjusted according to individual needs and the professional judgment of the person administering or supervising the administration of the composition.

[0186] VII. EXAMPLES

[0187] The following is a description of an exemplary paraxanthine-BHB composition for enhancing cognitive flexibility, sustained attention, working memory, inhibitory control, and neuroprotection in a subject.

[0188] Example 1

[0189] A paraxanthine-BHB composition is prepared by mixing a BHB ketone body component comprising one or more of sodium beta-hydroxybutyrate, potassium beta-hydroxybutyrate, magnesium beta-hydroxybutyrate, or calcium beta-hydroxybutyrate with a paraxanthine component. The weight ratio of the BHB ketone body component to paraxanthine is 5:1. The paraxanthine-BHB composition is in a form that is easy to administer, such as a powder form as a dietary supplement mixed with food or a beverage, a form of one or more capsules or tablets, or a liquid form (e.g., an oral spray, a liquid injection, or a beverage). The paraxanthine-BHB composition provides better results compared to a composition containing caffeine and BHB.

[0190] Example 2

[0191] A paraxanthine-BHB composition is prepared by mixing a BHB ketone body component comprising one or more of sodium beta-hydroxybutyrate, potassium beta-hydroxybutyrate, magnesium beta-hydroxybutyrate, or calcium beta-hydroxybutyrate with a paraxanthine component. The weight ratio of BHB ketone body component to paraxanthine is 25:1. The paraxanthine-BHB composition is in a form that is easy to administer, such as a powder form as a dietary supplement mixed with food or drink, one or more capsules or tablets, or a liquid form (e.g., an oral spray, a liquid injection, or a drink). The paraxanthine-BHB composition provides better results compared to a composition containing caffeine and BHB.

[0192] Example 3

[0193] A paraxanthine-BHB composition is prepared by mixing a BHB ketone body component comprising one or more of sodium beta-hydroxybutyrate, potassium beta-hydroxybutyrate, magnesium beta-hydroxybutyrate, or calcium beta-hydroxybutyrate with a paraxanthine component. The weight ratio of BHB ketone body component to paraxanthine is 100:1. The paraxanthine-BHB composition is in a form that is easy to administer, such as a powder form as a dietary supplement mixed with food or drink, one or more capsules or tablets, or a liquid form (e.g., an oral spray, a liquid injection, or a drink). The paraxanthine-BHB composition provides better results compared to a composition containing caffeine and BHB.

[0194] Example 4

[0195] Any of the foregoing examples are modified by replacing a portion of the beta-hydroxybutyrate salt with beta-hydroxybutyric acid.

[0196] Example 5

[0197] Any of the foregoing examples are modified by including one or more esters of beta-hydroxybutyric acid.

[0198] Example 6

[0199] Any of the foregoing examples are modified by supplementing or replacing at least a portion of the BHB with 1,3-butanediol.

[0200] Example 7

[0201] Any of the foregoing examples are modified by replacing a portion of the beta-hydroxybutyrate salt with one or more of sodium acetoacetate, potassium acetoacetate, magnesium acetoacetate, or calcium acetoacetate.

[0202] Example 8

[0203] Example 6 is modified by replacing a portion of the acetoacetate salt with acetoacetic acid.

[0204] Example 9

[0205] Any of the foregoing embodiments is modified to provide a dosage form of about 0.5 g to about 50 g, or about 1 g to about 40 g, or about 2 g to about 30 g, or about 3 g to about 25 g, or about 4 g to about 20 g of the BHB ketone body component.

[0206] Example 10

[0207] Any of the foregoing embodiments is modified to provide a dosage form of about 50 mg to about 500 mg, or about 50 mg to about 400 mg, or about 100 mg to about 300 mg of the para-xanthine component.

[0208] Example 11

[0209] Any of the foregoing embodiments is modified by including one or more supplements, including one or more of vitamins, minerals, or herbs.

[0210] Example 12

[0211] Any of the foregoing embodiments is modified to further include a liquid carrier comprising one or more of water, ethanol, glycerol, propylene glycol, or 1,3-propanediol.

[0212] Example 13

[0213] Any of the foregoing embodiments is modified to further include a ketone body precursor selected from 1,3-butanediol, a fatty acid, and / or a fatty acid ester, such as one or more medium-chain fatty acids or one or more medium-chain triglycerides (MCTs).

[0214] Example 14

[0215] Any of the foregoing embodiments is modified to include a short-chain fatty acid or ester thereof.

[0216] Example 15

[0217] Any of the foregoing embodiments are modified by combining the composition with one or more fat-burning supplements, such as: green tea, green tea extract (e.g., a composition comprising one or more isolated green tea catechins, such as epigallocatechin gallate (EGCG)), green coffee extract, conjugated linoleic acid (CLA), tetradecylthioacetic acid (TTA), Coleus forskohlii (i.e., forskolin), yohimbine, rauwolscine, capsaicin, raspberry ketone (e.g., 4-(4-hydroxyphenyl)butan-2-one, p-hydroxyphenylpropionone), synephrine (e.g., bitter orange extract), octopamine, 1,3-dimethylpentylamine, norwighamidine, fucoxanthin, acetylcholine modulators, ursolic acid, clenbuterol, norepinephrine reuptake inhibitors (e.g., hordenine, tomoxetine), 7-oxodehydroepiandrosterone (i.e., 7-keto DHEA), thyroid hormones (e.g., triiodothyronine), or combinations thereof. The resulting composition is expected to provide better fat breakdown and / or fat oxidation effects.

[0218] Example 16

[0219] Any of the foregoing embodiments are modified by combining the composition with one or more cognition-enhancing supplements, such as: tyrosine, L-DOPA (i.e., L-3,4-dihydroxyphenylalanine), tryptophan and 5-hydroxytryptophan (5-HTP)), racetams (e.g., piracetam, oxiracetam, and aniracetam), L-theanine, D-serine, phosphatidylserine, tasmar, uridine, vinpocetine, norepinephrine reuptake inhibitors (e.g., hordenine and tomoxetine), ginseng, ginkgo, rhodiola, polygala, paullinia cupana, Eschscholzia californica, basellaceae ipomoea, centella asiatica, tinospora crispa, bacopa monnieri, epimedium, kanna herb, cyclic adenosine monophosphate (cAMP) modulators (e.g., forskolin), stimulants, cholinergic compounds, and / or acetylcholine modulators (e.g., huperzine A, dimethylaminoethanol, choline, and alpha-glycerylphosphorylcholine), and combinations thereof. The resulting combination supplement is expected to provide better cognitive, alertness, and / or mood effects.

[0220] Example 17

[0221] Any of the foregoing embodiments are modified by adding a pharmaceutically- or dietetically-acceptable carrier.

[0222] Example 18

[0223] Any of the foregoing embodiments are modified to be configured as a dosage form for administration by one or more of ingestion, intragastrical, injection, topical, inhalation, buccal, rectal, vaginal, or parenteral.

[0224] All percentages, ratios, parts, and quantities used herein are by weight, unless otherwise specified.

[0225] As those skilled in the art will appreciate, the numerical, percentage, ratio, or other values set forth in the specification can include other values that are about or approximately the value that is stated. All numerical values can be modified by the term "about" whether or not "about" is expressly stated. Such values therefore can include values that are within a reasonable operating range of the value stated. For example, a range of "about 1 to about 5" can include values such as 1.5, 2.5, 3.5, etc. Such values are intended to be within the scope of the application.

[0226] The phrase "substantially free of" or similar phrases as used herein means that the composition or article preferably contains 0% of the component in question, although it is understood that there can be very small concentrations, such as by accidental inclusion, contamination or even by intentional addition. If present, these components can be present at less than 1%, less than 0.5%, less than 0.25%, less than 0.1%, less than 0.05%, less than 0.01%, less than 0.005%, less than 0.001%, or less than 0.0001%. In some embodiments, the compositions or articles described herein can be free or substantially free of any particular component not mentioned in this specification. For example, if present, caffeine can be present in less than 10 mg, less than 5 mg, less than 3 mg, or less than 1 mg in the dose of the paraxanthine-BHB supplement provided.

[0227] The application can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the application is, therefore, indicated by the appended claims, rather than by the foregoing description. All changes that come within the meaning of the equivalences of the claims are to be embraced within their scope.

Claims

1. A composition comprising: a parabromine; and a BHB ketone component comprising at least one of a beta-hydroxybutyrate (BHB) salt, a BHB ester, or beta-hydroxybutyric acid.

2. The composition of claim 1, wherein the BHB ketone component comprises at least one BHB salt and beta-hydroxybutyric acid.

3. The composition of claim 1 or 2, further comprising one or more of 1,3-butanediol, a fatty acid, an ester of a fatty acid, an acetoacetate salt, an acetoacetate ester, or acetoacetic acid, wherein the fatty acid or ester thereof is a medium chain fatty acid or ester thereof, or a short chain fatty acid or ester thereof.

4. The composition of any one of claims 1 to 3, wherein the composition comprises a mixed salt comprising a plurality of cations in combination with the BHB ketone anion, the cations comprising at least one of a lithium ion, a sodium ion, a potassium ion, a magnesium ion, a calcium ion, and an amino acid cation.

5. The composition of any one of claims 1 to 4, wherein the composition is provided in a solid, powder, or liquid form.

6. The composition of any one of claims 1 to 5, wherein the composition is in a dosage form providing from about 0.5 grams to about 50 grams, or from about 1 gram to about 40 grams, or from about 2 grams to about 30 grams, or from about 3 grams to about 25 grams, or from about 4 grams to about 20 grams of the BHB ketone component.

7. The composition of any one of claims 1 to 6, wherein the composition is in a dosage form providing from 50 mg to about 500 mg, or from about 75 mg to about 400 mg, or from about 100 mg to about 300 mg of the parabromine.

8. The composition of any one of claims 1 to 7, further comprising a pharmaceutically or dietetically acceptable carrier.

9. A composition comprising: a parabromine; and 1,3-butanediol.

10. The composition of any one of claims 1 to 9 for use in providing one or more of: in vivo balance promotion, neuroprotection, brain protection, enhanced memory, enhanced focus and clarity of thought, improved cognitive ability, improved working memory, improved neurotransmitter levels, shorter response times, reduced oxidative stress, enhanced inhibitory control (ability to control attention), anxiolytic effects, reduced nervousness, antidepressant effects, anti-inflammatory effects, analgesic effects, depression symptom suppression, cardiovascular benefits, blood pressure regulation, heart rate regulation, regulation of drowsiness / dizziness associated with hypoglycemia when entering a ketotic state, regulation of the downregulation of metabolic rate when entering a ketotic state, anti-aging, and reduced energy crashes.

11. The composition of any one of claims 1 to 9 for use in the manufacture of a medicament for providing one or more of the following benefits: homeostasis promotion, neuroprotection, brain protection, enhanced memory, enhanced focus and clarity of thought, improved cognitive ability, improved working memory, improved neurotransmitter levels, shorter response times, reduced oxidative stress, enhanced inhibitory control (ability to control attention), anxiolytic effects, reduced nervousness, antidepressant effects, anti-inflammatory effects, analgesic effects, depression symptom suppression, cardiovascular benefits, blood pressure regulation, heart rate regulation, regulation of drowsiness / dizziness associated with hypoglycemia upon entering a ketotic state, regulation of the downregulation of metabolic rate upon entering a ketotic state, anti-aging, and reduced energy crashes.

12. A method for improving mental and / or physical performance in a mammal comprising administering to the mammal an effective amount of the composition of any one of claims 1 to 11.

13. The method of claim 12, wherein administering comprises administering a daily dose of about 0.5 g to about 50 g of the ketone body component and a daily dose of about 25 mg to about 1000 mg of the paraxanthine.

14. The method of claim 12 or 13, wherein administering comprises administering to the mammal in a fasted state.

15. The method of any one of claims 12 to 14, wherein administering comprises administering multiple doses per day.

16. The method of any one of claims 12 to 15, wherein the method provides one or more of the following: improved cognitive flexibility, improved sustained attention, improved working memory, enhanced inhibitory control, neuroprotection, memory enhancement, regulation of drowsiness / dizziness upon entering a ketotic state, or regulation of the downregulation of metabolic rate while in a ketotic state.

17. The method of any one of claims 12 to 16, wherein the method improves cognitive flexibility in the mammal.

18. The method of any one of claims 12 to 17, wherein the BHB ketone body component increases the pharmacokinetic utilization of the paraxanthine relative to the pharmacokinetic utilization of the paraxanthine in the absence of the BHB ketone body component.

19. The method of any one of claims 12 to 18, wherein the method accelerates the production of endogenous ketones in the subject by increasing the availability of ketone body precursors.

20. The method of any one of claims 12 to 19, wherein administering comprises one or more of the following: ingestion, intragastric, injection, topical, inhalation, buccal, rectal, vaginal, or parenteral administration.

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