Compositions containing paraxanthine and beta-hydroxybutyric acid or precursors for increasing neurological and physiological performance - Patent Application 20070122999

Abstract

Disclosed herein are "paraxanthine-BHB" compositions containing a combination of (1) paraxanthine; (2) a BHB ketone body component, such as a beta-hydroxybutyrate (BHB) salt, BHB ester, or BHB acid; and (3) optionally, a dietary or pharmaceutically acceptable carrier. A BHB precursor, such as 1,3-butanediol, can be used in addition to or in place of BHB. Also disclosed herein are methods of using such compositions to produce desired physiological effects in mammals, such as enhanced cognitive flexibility, improved sustained attention, improved working memory, and neuroprotection. In addition to such improved mental performance, the compositions also advantageously increase resting energy expenditure (resting metabolic rate), primarily through ketosis, and can enhance fat loss, promote muscle formation and maintenance, and modulate somnolence / drowsiness upon entering the ketotic state.

Description

[Background technology]

[0001]

[0001] Energy drinks and similar caffeinated beverages are beverages used by consumers to promote wakefulness, maintain alertness, and enhance mood and cognition. Typical energy drinks sold at gas stations generally contain high levels of caffeine and sugar. Some drinks may also contain vitamins, electrolytes, or amino acids.

[0002] Despite their widespread use, there are several health concerns regarding the consumption of such caffeinated beverages, particularly regarding their effects on the cardiovascular system. Such caffeinated energy drinks have been implicated in increasing heart rate, blood pressure, and even blood thickening. Such beverages may also affect the brain in undesirable ways, such as by increasing stress levels and inducing anxiety, insomnia, gastrointestinal irritation, muscle twitching, and prolonged restlessness.

[0003]

[0003] Such beverages are also associated with an initial boost following ingestion, followed by high levels of fatigue, irritability, and cognitive decline. This energy "crash" can be long-lasting and unpleasant. As the stimulating effects of caffeine wear off, adrenaline, dopamine, and acetylcholine levels begin to decline, and blood sugar levels can fluctuate abnormally, often leaving users feeling even more fatigued, irritable, and unable to concentrate than they were before consuming the beverage. A user's adenosine levels may continue to increase even after caffeine administration. When caffeine is no longer available to block adenosine receptors, stored adenosine can rapidly flood the receptors, causing the perceived crash.

[0004]

[0004] To date, popular caffeinated energy drinks sold at gas stations have generally failed to improve users' overall quality of life and health. Instead, such energy drinks provide a perceived short-term increase in alertness, followed by a subsequent crash that often tends to be unpleasant enough to negate the benefits and essentially make consuming such drinks a negative experience. When used to combat drowsiness while driving, such drinks can induce high levels of stress and possibly contribute to "road rage." For long-distance transport drivers, experiencing a mental and / or physical "crash" can be potentially harmful and even fatal if it leads to a highway accident.

[0005]

[0005] Therefore, there is a continuing need for compositions that can promote a natural, sustained feeling of wakefulness, maintain a natural sense of alertness without jitteriness or elevated heart rate, increase focus, clarity of thought and working memory, enhance mood, and / or enhance cognitive flexibility without producing the typical energy crash and without compromising the user's long-term physiological or mental health.

[0006]

[0006] Ketone bodies are produced from fat and are an alternative calorie source to glucose, especially when glucose is unavailable. During periods of fasting, extreme exercise, and / or low-carbohydrate intake, the body's glucose and glycogen stores can be used and rapidly depleted. If glucose stores are not replenished when they are depleted, the body will metabolically shift to using ketone bodies as its primary source of caloric energy. This metabolic state is called "ketosis."

[0007]

[0007] Ketone bodies can be used as fuel by the body's cells in addition to or instead of glucose to meet the body's energy needs, including the brain and heart. During prolonged fasting, blood ketone levels can increase to 2-3 mmol / L or higher. It is traditionally understood that when blood ketones are elevated above 0.5 mmol / L, the heart, brain, and peripheral tissues use ketone bodies (e.g., beta-hydroxybutyrate and acetoacetate) as their primary caloric energy source. This state is called "ketosis." When blood ketones are between 1.0 mmol / L and 3.0 mmol / L, the state is called "nutritional ketosis."

[0008]

[0008] Upon entering ketosis, or in other words, during ketone metabolism in the liver, the body uses dietary and stored body fat as a primary energy source. Consequently, once in ketosis, controlling dietary fat and maintaining low carbohydrate intake to maintain ketone metabolism can induce body fat loss. During ketosis, the body essentially burns fat as a primary fuel.

[0009]

[0009] Ketone metabolism is associated with several beneficial effects. However, despite the many health benefits of following a ketogenic diet or lifestyle and maintaining nutritional ketosis, significant barriers remain to maintaining and maintaining ketosis. One of these barriers is the difficulty of entering ketosis. The most rapid endogenous method of entering ketosis is through a combination of fasting and high-intensity exercise, which depletes the body's glucose stores and creates a catabolic state. This depletes the body's limited glucose and glycogen stores. This is physically and mentally demanding and extremely difficult, even for the most motivated and trained individuals.

[0010] Additionally, the transition to ketosis is often accompanied by hypoglycemia, which can cause drowsiness and drowsiness in many individuals, resulting in an uncomfortable physiological and psychological state commonly referred to as "low-carb flu" or "keto flu." Many individuals also experience metabolic downregulation as the body enters "energy-conserving" mode. Some suggest that these temporary symptoms can last two to three weeks. During this transition period, consuming any meal or snack containing more than the limiting amount of carbohydrates rapidly halts ketone body production, causing the body to exit ketosis and shift back to glucose as its primary fuel. At this point, the difficult transition to ketosis must begin all over again. Thus, despite the promise of the ketogenic diet for weight loss and other health benefits, serious limitations continue to prevent its full realization. Summary of the Invention [Problem to be solved by the invention]

[0011]

[0011] It would be beneficial to provide a nutritional supplement composition that can address at least some of these unpleasant effects associated with entering a state of ketosis (e.g., minimizing or preventing drowsiness and / or drowsiness, minimizing or preventing the downregulation of typical metabolic rate, etc.). [Means for solving the problem]

[0012]

[0012] Disclosed herein are compositions comprising a combination of (1) paraxanthine; (2) beta-hydroxybutyric acid ("BHB"); and (3) optionally a dietary or pharmaceutically acceptable carrier. For ease of reference, such combination compositions may be referred to herein as "paraxanthine-BHB" or "BHB-paraxanthine." In some embodiments, a BHB precursor, e.g., 1,3-butanediol, may be used in addition to or in place of BHB.

[0013] Also disclosed herein are methods of using such compositions for neuroprotection, improved cognitive flexibility, improved working memory, reduced oxidative stress, minimizing or preventing drowsiness or drowsiness associated with entering nutritional ketosis (e.g., low-carb flu or keto flu), minimizing or preventing the downregulation of metabolic rate normally associated with entering nutritional ketosis, or other benefits. Combining paraxanthine with BHB has been found to synergistically enhance one or more of these functional properties in the user. For example, paraxanthine provides benefits such as improved cognitive flexibility, the ability to achieve sustained attention, improved working memory, and enhanced inhibitory control. When used with BHB, these benefits are synergistically enhanced beyond any such benefits obtained from either paraxanthine or BHB alone, providing additional benefits such as limiting the effects of hypoglycemia upon entering ketosis and maintaining or even increasing metabolic rate upon entering ketosis.

[0014] Such a combination also provides improved results compared to a combination of caffeine and BHB, because paraxanthine and BHB do not exhibit the same undesirable secondary effects associated with caffeine (e.g., subsequent crash, irritability, elevated heart rate, increased susceptibility to mental errors, etc.). For example, providing paraxanthine directly in combination with BHB rather than caffeine largely, if not completely, eliminates the theophylline and theobromine metabolically derived from caffeine use, which are believed to be at least partially responsible for the undesirable secondary effects associated with caffeine use (e.g., irritability, palpitations, increased susceptibility to mental errors, etc.). Additionally, providing BHB in such an environment (i.e., in the presence of paraxanthine and the general absence of theophylline and theobromine) allows BHB, a ketone body capable of providing caloric energy, to be more effectively utilized, enhancing benefits such as improved cognitive flexibility, sustained attention, working memory, and enhanced inhibitory control. The combination of paraxanthine and BHB also advantageously minimizes the drowsiness and drowsiness associated with hypoglycemia when entering ketosis, as well as the typical downregulation of metabolic rate that occurs when entering ketosis.

[0015]

[0015] The combination of paraxanthine and BHB is also beneficial because it allows for a lower dose of paraxanthine to be provided to the user when delivered with BHB, while still providing similar levels of benefit associated with the use of paraxanthine. In other words, when paraxanthine is administered alone, a given dose may be required to achieve specific benefits for improved cognitive flexibility, improved sustained attention, improved working memory, and enhanced inhibitory control, but when combined with BHB, a lower dose of paraxanthine may be sufficient to achieve the same benefit. This is advantageous in reducing the cost of a supplement that can provide a given benefit. Alternatively, greater benefit can be achieved for a similar cost (if BHB is also provided while maintaining the dose of paraxanthine).

[0016]

[0016] The BHB ketone body component provides an exogenous source of ketone bodies that the body can use for energy without significantly "interrupting" the user's fasting (e.g., without causing a significant increase in blood insulin levels), thus eliminating the hard-earned physiological benefits of the fasted state. The ketone body component also benefits users who train during fasting periods, when fat burning is optimized but training can be challenging due to relatively low levels of energy and motivation. The energy provided by the BHB ketone body component can help users train more effectively while minimizing disruption of the fasted state, while the paraxanthine component provides benefits such as improved cognitive flexibility, improved sustained attention, improved working memory, enhanced inhibitory control, and minimized undesirable side effects associated with hypoglycemia and metabolic rate downregulation.

[0017] Ketone body components can also help induce and sustain a state of ketosis in a subject. For example, ketone body components can help the body shift more rapidly to a fat-burning catabolic state. This can be useful during intermittent fasting, where the fat-burning window at the end of the fasting period is relatively short. Similar results can be achieved using 1,3-butanediol, which is readily converted to BHB in the body.

[0018]

[0018] Furthermore, even when a user is not necessarily fasting, supplementation with exogenous ketone bodies can benefit the user by supporting mitochondrial function while preserving blood glucose and glycogen stores, which are therefore still available for the anabolic formation of lean muscle mass as a result of that exercise. This allows glucose, protein, and insulin to work together when needed to build lean muscle mass, rather than being burned as an energy source. Additionally, because excess ketone bodies, unlike sugars, are not converted to fat, ketone bodies do not cause the concomitant accumulation of fat when consuming a normal caloric intake of sugars, protein, and fat.

[0019] Unexpectedly, it has now been discovered that combining BHB and paraxanthine in appropriate amounts and / or ratios results in enhancements in working memory, cognitive flexibility, inhibitory control, and the ability to achieve sustained attention that would not be predicted by the individual effects of these ingredients when used alone. For example, supplementation with a paraxanthine-BHB composition can provide improvements in these desirable functional properties without the secondary effects typically associated with caffeine use (e.g., nervousness, palpitations, and subsequent crashes), even though caffeine is metabolized to paraxanthine. Provision of paraxanthine directly reduces or eliminates the concentration of theophylline and / or theobromine present in the user's bloodstream, ingredients that are associated with these undesirable secondary effects.

[0020]

[0020] Additionally, the rate and consequences of caffeine metabolism vary across the general population. For example, the cytochrome P450 1A2 enzyme is responsible for approximately 95% of all caffeine metabolism, and depending on genetics, some users produce more cytochrome P450 than others. Thus, the general population includes fast, moderate, and slow caffeine metabolizers. Fast metabolizers account for less than half of the population, and fast metabolizers generally derive greater benefits from caffeine than moderate or slow metabolizers. By providing paraxanthine directly, more uniform physiological and neurological responses can be achieved across a wide variety of users, regardless of whether they are fast, moderate, or slow metabolizers of caffeine.

[0021] The paraxanthine-BHB compositions described herein may be provided in single-component or multi-component compositions configured for administration in a variety of forms, for example, by one or more of oral ingestion, intragastric, injection, topical application, inhalation, buccal, rectal, vaginal, or parenteral administration.

[0022] In one embodiment, the BHB includes 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, diglyceride, or triglyceride), such as a medium-chain fatty acid, a short-chain fatty acid, and their esters. Medium-chain fatty acids and their esters can be converted to BHB through lipolysis. As disclosed in U.S. Publication No. 2022 / 0062216, the entire contents of which are incorporated herein by reference, the composition can also optionally comprise beta-hydroxybeta-methylbutyrate (HMB) in combination with BHB.

[0023]

[0024] In one aspect, the composition may be provided in any of a variety of forms, such as a crystal, powder, solid, liquid, solution, suspension, 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.

[0024]

[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 mg, or about 100 mg to about 300 mg, or about 125 mg to about 250 mg of paraxanthine per dose.

[0025]

[0027] In one embodiment, the composition comprises a pharmaceutically or dietarily acceptable carrier (eg, water, ethanol, glycerin, propylene glycol, 1,3-propanediol, fruit juice, or food).

[0026]

[0028] Another exemplary embodiment can include paraxanthine, multiple anions, including a BHB anion, and multiple cations (e.g., alkali metal cations, alkaline earth metal cations, transition metal cations, and / or amino acid cations). Such an embodiment can be referred to as a "mixed salt."

[0027]

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

[0028]

[0030] Embodiments of such methods can include administering multiple doses per day. Exemplary dosages 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).

[0029]

[0031] In one embodiment, the composition is substantially or completely free of caffeine.

[0032] Such methods can result in one or more of the following: improved cognitive flexibility, improved sustained attention, improved working memory, enhanced inhibitory control, reduced drowsiness or drowsiness associated with hypoglycemia during ketosis, and maintained or increased metabolic rate during ketosis.As shown in the accompanying prospective data, improvements in these areas are significantly greater than those achieved by supplementing with caffeine rather than paraxanthine.Other potential benefits may include promoting homeostasis, neuroprotection, memory enhancement, anxiolytic, antidepressant, anti-inflammatory, analgesic, antioxidant, blood pressure modulation, heart rate modulation, or longevity promotion.

[0030]

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

[0034] In one aspect, the method can accelerate the production of endogenous ketones in a user as a result of paraxanthine causing an increase in fat metabolism.

[0031]

[0035] Additional features and advantages will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the aspects disclosed herein. It is to be understood that both the foregoing brief summary and the following detailed description are exemplary and explanatory only and are not restrictive of the aspects disclosed or claimed herein.

[0032]

[0036] Various objects, features, characteristics and advantages of the present invention will become apparent and more readily appreciated from the following description of embodiments, taken in conjunction with the accompanying drawings and claims, all of which form a part of this specification. In the figures, for example, reference numerals and the like may be utilized to refer to corresponding or similar parts in the various figures, although the various elements shown are not necessarily drawn to scale. [Brief explanation of the drawings]

[0033] [Figure 1]

[0037] 1 is a graph showing the relative plasma concentration levels of caffeine and its major metabolites following caffeine administration. [Figure 2]

[0038] FIG. 1 shows a simplified exemplary metabolic pathway for the metabolism of caffeine. [Figure 3]

[0039] 1 is a graph showing the elimination half-life of paraxanthine compared to the elimination half-lives of caffeine, theophylline, and theobromine. [Figure 4]

[0040] 1 is a graph showing predicted results for the Go / No Go Attention and Inhibitory Control Test, showing the percentage of correct responses obtained from different treatments with paraxanthine in combination with BHB, paraxanthine alone, BHB alone, and placebo, indicating that the improvement in percentage of correct responses is predicted to be greater for the combined paraxanthine + BHB treatment than the sum of the BHB and paraxanthine treatments. [Figure 5]

[0041] 1 is a graph showing predicted results for the Go / No Go attention and inhibitory control test, showing predicted mean response times from different treatments: paraxanthine in combination with BHB, paraxanthine alone, BHB alone, and placebo. [Figure 6]

[0042] 1 is a graph showing predicted results for the Vigilance Task Test, showing predicted mean response times from treatment with paraxanthine in combination with BHB compared to different treatments with paraxanthine alone, BHB alone, and placebo. [Figure 7]

[0043] 1 is a graph showing predicted results for the Berg-Washington Card Sorting Task Test, showing the predicted percentage of correct responses resulting from treatment with paraxanthine in combination with BHB compared to different treatments with paraxanthine alone, BHB alone, and placebo. [Figure 8]

[0044] 1 is a graph showing predicted results for the Berg-Washington card sorting task, showing the predicted error rate resulting from treatment with paraxanthine in combination with BHB compared to different treatments: paraxanthine alone, BHB alone, and placebo. [Figure 9]

[0045] 1 is a graph showing predicted results for the Sternberg Test with string length 2. The predicted reaction times obtained from treatment with paraxanthine in combination with BHB are shown compared to different treatments with paraxanthine alone, BHB alone, and placebo. [Figure 10]

[0046] 1 is a graph showing predicted results for the Sternberg test with a string length of 4. The predicted reaction times resulting from treatment with paraxanthine in combination with BHB are shown compared to different treatments with paraxanthine alone, BHB alone, and placebo. [Figure 11]

[0047] 1 is a graph showing predicted results for the Sternberg test with a string length of 6. The predicted reaction times from treatment with paraxanthine in combination with BHB are shown compared to different treatments with paraxanthine alone, BHB alone, and placebo. [Figure 12A]

[0048] Figure 12A is a graph showing predicted results for the Berg-Washington card sorting task test, showing the predicted percentage of correct responses resulting from treatment with paraxanthine in combination with BHB compared to different treatments: paraxanthine alone, BHB alone, caffeine and paraxanthine in combination with BHB, caffeine alone, caffeine in combination with BHB, and placebo. [Figure 12B]

[0049] Figure 12B is a graph showing predicted results for the Berg-Washington card sorting task, showing the predicted error rates resulting from treatment with paraxanthine in combination with BHB compared to different treatments: paraxanthine alone, BHB alone, caffeine and paraxanthine in combination with BHB, caffeine alone, caffeine in combination with BHB, and placebo. [Figure 12C]

[0050] Figure 12C is a graph showing predicted results for the Berg-Washington card sorting task, showing predicted perseverative errors resulting from treatment with paraxanthine in combination with BHB compared to different treatments: paraxanthine alone, BHB alone, caffeine and paraxanthine in combination with BHB, caffeine alone, caffeine in combination with BHB, and placebo. [Figure 12D]

[0051] Figure 12D is a graph showing predicted results for the Berg-Washington card sorting task. The predicted perseverative error (PAR rule) from treatment with paraxanthine in combination with BHB is compared to different treatments: paraxanthine alone, BHB alone, caffeine and paraxanthine in combination with BHB, caffeine alone, caffeine in combination with BHB, and placebo. [Figure 13]

[0052] 1 is a graph showing predicted results for a vigilance task test, showing predicted mean response times from treatment with paraxanthine in combination with BHB compared to different treatments: paraxanthine alone, BHB alone, caffeine and paraxanthine in combination with BHB, caffeine alone, caffeine in combination with BHB, and placebo. [Figure 14A]

[0053] FIG. 14A is a graph showing predicted results on treadmill distance from treatment with paraxanthine in combination with BHB compared to different treatments with paraxanthine alone, BHB alone, and various amino acids and amino acid derivatives. [Figure 14B] FIG. 14B is a graph showing the predicted results on muscle mass from treatment with paraxanthine in combination with BHB compared to different treatments with paraxanthine alone, BHB alone, and various amino acids and amino acid derivatives. [Figure 14C] Figure 14C is a graph showing predicted results on hand grip strength from treatment with paraxanthine in combination with BHB compared to different treatments with paraxanthine alone, BHB alone, and various amino acids and amino acid derivatives. [Figure 15A]

[0054] FIG. 15A is a graph showing predicted results on the Stroop test over a 6-week period from treatment with BHB alone. [Figure 15B] FIG. 15B is a graph showing predicted results on the Stroop test over a 6-week period from treatment with paraxanthine alone. [Figure 15C] FIG. 15C is a graph showing predicted results on the Stroop test over a 6-week period from treatment with paraxanthine in combination with BHB. [Figure 16]

[0055] 1 is a graph showing predicted results on Resting Energy Expenditure from treatment with paraxanthine in combination with BHB compared to different treatments with paraxanthine alone, BHB alone, and placebo. DETAILED DESCRIPTION OF THE INVENTION

[0034] I. Introduction and Definitions

[0056] Disclosed herein are compositions comprising a combination of (1) paraxanthine; (2) beta-hydroxybutyric acid ("BHB"); and (3) optionally, a dietary or pharmaceutically acceptable carrier. Such combination compositions may be referred to herein as "paraxanthine-BHB" or "BHB-paraxanthine." Also disclosed herein are methods of using such compositions for neuroprotection, improved cognitive flexibility, improved working memory, reduced oxidative stress, minimizing or preventing drowsiness or drowsiness associated with entering nutritional ketosis (e.g., low-carb flu or keto flu), minimizing or preventing metabolic rate downregulation typically associated with entering nutritional ketosis, or other benefits. In some embodiments, a BHB precursor, e.g., 1,3-butanediol, may be used in addition to or in place of BHB.

[0035]

[0057] It has been found that combining paraxanthine with BHB synergistically enhances one or more of these functional properties in the user's body.For example, paraxanthine provides benefits such as improved cognitive flexibility, the ability to achieve sustained attention, improved working memory, and enhanced inhibitory control.When used together with BHB, these benefits are synergistically enhanced beyond any such benefits obtained from either paraxanthine or BHB alone, and additional benefits are also obtained, such as limiting the effects of hypoglycemia when entering ketosis, and maintaining or even increasing metabolic rate when entering ketosis.

[0036]

[0058] Such a combination also provides improved results compared to a combination of caffeine and BHB, because paraxanthine and BHB do not exhibit the same undesirable secondary effects associated with caffeine (e.g., subsequent crash, irritability, elevated heart rate, increased susceptibility to mental errors, etc.). For example, providing paraxanthine directly in combination with BHB rather than caffeine largely, if not completely, eliminates the theophylline and theobromine metabolically derived from caffeine use, which are believed to be at least partially responsible for the undesirable secondary effects associated with caffeine use (e.g., irritability, palpitations, increased susceptibility to mental errors, etc.). Additionally, providing BHB in such an environment (i.e., in the presence of paraxanthine and the general absence of theophylline and theobromine) allows BHB, a ketone body capable of providing caloric energy, to be more effectively utilized, enhancing benefits such as improved cognitive flexibility, sustained attention, working memory, and enhanced inhibitory control. The combination of paraxanthine and BHB also advantageously minimizes the drowsiness and drowsiness associated with hypoglycemia when entering ketosis, as well as the typical downregulation of metabolic rate that occurs when entering ketosis.

[0037] A. Ketosis and Ketone Bodies

[0059] As discussed above, ketone bodies are produced from fat and are an alternative source of calories to glucose, especially when glucose is unavailable, such as during periods of fasting, intense exercise, and / or low carbohydrate intake. When the body undergoes a metabolic shift to using ketone bodies as its primary caloric energy source, this state is known as "ketosis." Ketone bodies can be used by the body's cells as fuel in addition to or instead of glucose to meet the body's energy needs, including the brain and heart.

[0038]

[0060] Transitioning to ketosis allows the body to use dietary and stored body fat as a primary energy source during ketone metabolism in the liver. The body first breaks down fat into fatty acids and glycerol. The fatty acids are then converted into acetyl-coenzyme A ("acetyl-CoA") molecules, which are then ultimately converted in the liver via ketogenesis into water-soluble ketone bodies: beta-hydroxybutyrate ("β-hydroxybutyrate" or "BHB"), acetoacetate, and acetone. BHB and acetoacetate are ketone bodies used by the body for energy, while acetone is eliminated as a byproduct of ketogenesis. While BHB is not technically a "ketone," it is still commonly referred to as a "ketone body" in the context of ketosis. Ketone metabolism has several beneficial effects.

[0039] B. Intermittent fasting

[0061] One method of fasting, commonly referred to as "intermittent fasting," has gained popularity in recent years as an alternative to long-term fasting. Intermittent fasting often involves entering a state of ketosis. Because long-term fasting is difficult and not fully sustainable over the long term, intermittent fasting attempts to achieve many of the same benefits of fasting while minimizing its associated drawbacks. Like long-term fasting, intermittent fasting involves entering a catabolic state, but it shortens the daily window during which eating is permitted. For example, in a typical eater, there is approximately 16–18 hours between the time they consume their first and last meal. Intermittent fasting attempts to shorten this eating window. While intermittent fasting regimens vary, they all generally attempt to shorten the eating window from the typical 16–18-hour period to approximately 2–12 hours, more commonly, approximately 4–10 hours.

[0040]

[0062] Intermittent fasting provides similar benefits to long-term fasting and nutritional ketosis. While the fasting periods in intermittent fasting typically don't last long enough for the user to completely deplete glycogen stores, ketosis typically begins to occur to some degree after only about 12 hours of fasting. Thus, intermittent fasting serves to train the body to use fat for energy, even if only for a few hours per day. In other words, as the body becomes accustomed to longer periods between eating windows, it becomes more metabolically flexible and can more efficiently shift toward using fat as a fuel source.

[0041]

[0063] Intermittent fasting is also a popular regimen among athletes, especially those trying to train to achieve fat loss and increase the ratio of lean to fat mass. Many people schedule their training sessions during fasting periods to accelerate or extend their fat-burning window by more rapidly depleting glycogen stores, or to take advantage of the beneficial hormonal profile of fasting. For example, many athletes may schedule their training / workouts near the end of their fast, when glycogen stores are more depleted and the body is more metabolically shifted toward a fat-burning state.

[0042]

[0064] In some embodiments, the method of administering paraxanthine and beta-hydroxybutyric acid (and / or its precursors) comprises administering the composition during a fasting state, for example, during intermittent fasting. The composition provides the individual with more energy, clarity of mind, and other benefits that offset the lack of energy, lack of clarity of mind, and other negative effects of fasting. By combining fasting with the disclosed composition, the benefits provided by fasting can be obtained along with the additional benefits provided by the composition. This can be referred to as "enhanced fasting" or "enhanced intermittent fasting."

[0043] C. beta-hydroxybutyrate and 1,3-butanediol

[0065] The compound "beta-hydroxybutyric acid," also known as β-hydroxybutyric acid, 3-hydroxybutyric acid, βHB, or BHB, is the deprotonated form of beta-hydroxybutyric acid, which is a hydroxycarboxylic acid with the general formula CH3CH2OHCH2COOH. The deprotonated form present at typical biological pH levels is CH3CH2OHCH2COO - Formula I below

[0044] [ka]

[0045] wherein X can be hydrogen, a metal ion, an amino cation, e.g., an amino cation derived from an amino acid, an alkyl group, an alkenyl group, an aryl group, or an acyl group. The general chemical structure of represents a typical BHB compound.

[0046]

[0066] When X is hydrogen, the compound is beta-hydroxybutyric acid. When X is a metal ion or an amino cation, the compound is a beta-hydroxybutyrate salt. When X is an alkyl, alkenyl, aryl, or acyl group, the compound is a beta-hydroxybutyrate ester.

[0047]

[0067] The chemical structure below:

[0048] [ka]

[0049] 1,3-butanediol, which has a chiral center, is readily converted to beta-hydroxybutyric acid in the body and can therefore be used as a precursor to beta-hydroxybutyric acid. Like BHB, 1,3-butanediol also has a chiral center and can be present as R-1,3-butanediol, S-1,3-butanediol, a racemic mixture of R-1,3-butanediol and S-1,3-butanediol, or forms enriched in R-1,3-butanediol or S-1,3-butanediol. It is generally understood that when 1,3-butanediol is converted to BHB, chirality is maintained; thus, R-1,3-butanediol is converted to R-beta-hydroxybutyric acid in the body, and S-1,3-butanediol is converted to S-beta-hydroxybutyric acid.

[0050]

[0068] Beta-hydroxybutyrate (BHB) is utilized by a patient's body as an energy source when a subject has low glucose levels or when the patient is supplemented with a usable form of BHB. As noted above, while BHB is not technically a "ketone," those skilled in the art will recognize that BHB is commonly referred to as a "ketone body" in the context of ketosis due to its close relationship and biological interaction with acetoacetate, a true ketone.

[0051]

[0069] As described, BHB can be provided in any of a variety of forms, such as beta-hydroxybutyric acid, beta-hydroxybutyrate salts, or beta-hydroxybutyrate esters. The compounds can be in any desired physical form, such as crystals, powders, solids, liquids, solutions, suspensions, or gels.

[0052]

[0070] Unless otherwise specified, the term "salt" does not mean or imply any particular physical state, such as a crystal, powder, other solid form, dissolved in water to form a liquid solution, dispersed in a liquid to form a suspension, or a gel. Salts can be formed, for example, in solution by at least partially neutralizing beta-hydroxybutyric acid with a strong or weak base, such as an alkali or alkaline earth metal hydroxide, carbonate, or bicarbonate, a basic amino acid, or the like.

[0053]

[0071] BHB is a chiral compound and can exist as the R-enantiomer or S-enantiomer, a racemic mixture, or a mixture enriched in one enantiomer over the other. Endogenous BHB produced by the body is the R-enantiomer. BHB can be converted by the body to acetoacetate, another ketone body that can be utilized by the body, but it is not chiral; acetoacetate can be converted back to the R-enantiomer of BHB by the body converting it to acetoacetate and then to the R-enantiomer. It is believed that the S-enantiomer of BHB can be converted to the R-enantiomer by first converting it to acetoacetate and then to the R-enantiomer, or the body can utilize acetoacetate directly. The S-enantiomer can also be highly bioactive and has unique pharmacokinetic and pharmacodynamic properties, although the S-enantiomer is produced in very small amounts, if at all, by the body.

[0054]

[0072] In one embodiment, at least a portion of the BHB provided in the paraxanthine-BHB product is provided as the S-enantiomer. Providing at least a portion of the S-enantiomer can provide benefits such as increased attention. For example, increasing the S-enantiomer of BHB can allow for a more significant reduction in the paraxanthine dose provided while providing the same or similar benefits for increased attention, improved working memory, improved cognitive flexibility, inhibitory control, and sustained attention. For example, at least 1%, at least 3%, at least 5%, or at least 10% of the BHB provided may be 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 BHB provided by weight. 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% by weight of the BHB component. The S-enantiomer content of BHB can be within a range having any two of the aforementioned values ​​as endpoints. The R-enantiomer of BHB primarily provides caloric energy, while the S-enantiomer can enhance alertness and other mental clarity attributes. The R-enantiomer 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% by weight of the BHB component. The R-enantiomer of the BHB component can fall within a range having any two of the foregoing values ​​as endpoints.

[0055] D. Acetoacetate

[0073] Acetoacetate (AcAc) is another ketone body that may be included in the formulations of the present invention in addition to BHB. AcAc is a true ketone and is the deprotonated form of acetoacetic acid, a carboxylic acid with the formula CH3COCH2COOH. Thus, the deprotonated form present at typical biological pH levels is CH3COCH2COOH. - As noted above, the body can convert BHB to acetoacetate and vice versa. Like BHB, acetoacetate can be utilized as an energy source when a patient's body is supplemented with a usable form of acetoacetate during ketosis or regardless of the body's energy utilization priority state. Formula II:

[0056] [ka]

[0057] wherein X can be hydrogen, a metal ion, an amino cation, e.g., an amino cation derived from an amino acid, an alkyl, an alkenyl, an aryl, or an acyl. The general chemical structure represents an acetoacetate compound that can be utilized in the disclosed compositions (conformational isomers thereof can also be utilized).

[0058]

[0074] Like BHB, acetoacetate can be utilized by a patient's body as an energy source when glucose levels are low in the subject or when the patient is supplemented with a usable form of acetoacetate. Unlike BHB, acetoacetate is a true "ketone" and, along with BHB, is commonly referred to as a "ketone body" in the context of ketosis.

[0059]

[0075] The beta-hydroxybutyrate and acetoacetate compounds described above may be collectively referred to herein as "ketone bodies," "exogenous ketone bodies," "ketone body components," or "exogenous ketones."

[0060]

[0076] The compositions contemplated herein can also contain ketone body precursors. Suitable ketone body precursors include, but are not limited to, beta-hydroxybeta-methylbutyrate (HMB), 1,3-butanediol, medium-chain fatty acids, and esters of medium-chain fatty acids, such as medium-chain triglycerides. Ketone body compounds and ketone body precursor compounds are described in more detail below. While 1,3-butanediol is readily converted to BHB, HMB undergoes a complex metabolic cascade that may ultimately result in the formation of BHB, but may also be converted to other substances or excreted in urine.

[0061] E. Paraxanthine

[0077] Paraxanthine is a metabolite of caffeine, along with theophylline and theobromine. Upon oral ingestion, caffeine is metabolized by demethylation to primarily the three dimethylxanthines mentioned above. The metabolism of caffeine, and its dimethylxanthine metabolites, is complex.

[0062]

[0078] Immediately after oral ingestion, caffeine is metabolized by hepatic cytochrome P450 to paraxanthine by removal of the methyl group from the N3 position of caffeine. Following formation, paraxanthine can be degraded by demethylation of the N1 position to 7-methylxanthine, which is then demethylated to xanthine or oxidized by CYP2A6 to 1,7-dimethyluric acid. Alternatively, paraxanthine can be degraded via N-acetyltransferase 2 to 5-acetylamino-6-formylamino-3-methyluracil, which can then be nonenzymatically degraded to 5-acetylamino-6-amino-3-methyluracil. Alternatively, paraxanthine can be metabolized by CYP1A2 to form 1-methylxanthine, which can then be metabolized by xanthine oxidase to form 1-methyluric acid.

[0063]

[0079] Like caffeine, paraxanthine is a psychotropic central nervous system (CNS) stimulant. Studies have shown that, like caffeine, simultaneous antagonism of adenosine receptors contributes to paraxanthine's stimulating effects. The binding affinity of paraxanthine to adenosine receptors appears to be similar to or slightly stronger than that of caffeine, but weaker than that of theophylline.

[0064]

[0080] Paraxanthine is a selective inhibitor of cGMP-preferring phosphodiesterase (PDE9) activity and is thought to increase glutamate and dopamine release by enhancing nitric oxide signaling. Activation of the nitric oxide-cGMP pathway may be responsible for some of the behavioral effects of paraxanthine that are distinct from those associated with caffeine.

[0065]

[0081] Paraxanthine is a competitive, non-selective phosphodiesterase inhibitor that also elevates intracellular cAMP, activates PKA, inhibits TNF-alpha and leukotriene synthesis, and reduces inflammation and innate immunity.

[0066]

[0082] Unlike caffeine, paraxanthine acts as an enzymatic effector of Na+ / K+ATPase, thereby contributing to increased potassium ion transport into skeletal muscle tissue. Similarly, this compound also promotes increased calcium ion concentrations in muscles.

[0067]

[0083] The pharmacokinetic parameters for paraxanthine are similar to those for caffeine but significantly different from those for the other major caffeine-derived methylxanthine metabolites in humans, theobromine and theophylline.

[0068]

[0084] Paraxanthine supplementation has been studied for various biological effects, and while positive results have often been noted, paraxanthine is an expensive ingredient to obtain, and its effects usually appear to be relatively minor or somewhat inconsistent. Thus, although paraxanthine supplementation appears to have great potential for achieving various health and / or performance benefits, there is a continuing need to determine biological mechanisms, compositions, and methods that can harness and / or enhance the effects of paraxanthine to levels that can provide significant health and performance benefits.

[0069] F. Stacked Ketone Bodies and Mixed Cation Salts

[0085] Any of the compositions described herein may include other ketone bodies in combination with BHB. Such compositions may include "stacked compositions." The terms "stacked composition," "keto-stack," "stack," "ketone body stack," and variations thereof, are used herein to refer to compositions that include at least two distinct compounds selected from the following: (i) beta-hydroxybutyrate salts; (ii) acetoacetate salts; (iii) beta-hydroxybutyrate esters; (iv) acetoacetate esters; (v) the free acid of beta-hydroxybutyrate (i.e., beta-hydroxybutyric acid); and (vi) the free acid of acetoacetate (i.e., acetoacetic acid), wherein at least one of the compounds in the stack is a BHB compound.

[0070]

[0086] The stacked composition can include a combination of compounds selected from (i) through (vi) such that at least two of the following are present: (A) representing one or more salts; (B) representing one or more esters; and (C) representing one or more free acids, wherein at least one of the salts, esters, or free acids is a BHB compound.

[0071]

[0087] Exemplary salt forms include sodium, potassium, calcium, magnesium, and lithium. Some embodiments include one or more transition metal salts. Suitable transition metal cations for use as part of the 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 that can have a net positive charge, including amino acids or their derivatives / metabolites, such as arginine, lysine, leucine, iso-leucine, histidine, ornithine, creatine, agmatine, L-glutamine, and citrulline.

[0072]

[0088] 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 glycerin, diesters of glycerin, and triesters of glycerin. 1,3-Butanediol is a metabolic precursor of BHB, which can be further utilized in vivo for the production of BHB and / or acetoacetate compounds. The acid form typically has an unpleasant taste, but can be used with an appropriate taste-masking mechanism, such as one or more capsules, tablets, or other boluses.

[0073]

[0089] Each of the different forms (salt, acid, ester) has its own properties and its own potential benefits and limitations. For example, ester forms of beta-hydroxybutyric acid typically have weaker organoleptic properties compared to other forms of beta-hydroxybutyric acid. That is, ester forms of beta-hydroxybutyric acid are often described as having a pungent taste and / or odor.

[0074]

[0090] Salt forms are generally considered to taste better than ester forms. However, administering a clinically or dietarily effective dose of a component in salt form naturally requires administering a relatively high level of the corresponding cation. For example, sodium is often used as a cation in beta-hydroxybutyrate salts, and high levels of sodium are well known to have negative health effects (e.g., increased blood pressure). As a further example, calcium is often used as a cation in HMB salts, and high levels of calcium can also be harmful to health, especially when not balanced with other cations. Although different salts with different cations can be mixed to dilute the effect of a single cation, relying on the use of salts alone can still be difficult to provide an effective amount of BHB or other ketone bodies without disrupting the electrolyte balance in the subject.

[0075]

[0091] The free acid forms of beta-hydroxybutyrate (i.e., beta-hydroxybutyric acid) and acetoacetate (i.e., acetoacetic acid) can be used. However, due to their relatively low pKa values ​​(e.g., beta-hydroxybutyric acid has a pKa of 4.70), these compounds deprotonate and become H at physiological pH. + The resulting excess acidity can have unwanted side effects, including causing or worsening gastrointestinal problems such as ulcers or reflux.

[0076]

[0092] The 1,3-butanediol used in Keto-Stack is neither an acid nor a salt, and is easily converted to beta-hydroxybutyric acid in the body. However, the amount of 1,3-butanediol that can be administered is limited by its ability to produce intoxicating effects, similar to ethanol. Therefore, 1,3-butanediol can be advantageously used in addition to beta-hydroxybutyric acid to obtain additional amounts of beta-hydroxybutyric acid without providing additional electrolytes or acidity. In some cases, it may be desirable to administer 1,3-butanediol at a dose lower than the intoxicating dose, which depends on the user's weight, gender, and other aspects, for example, less than 30 grams, less than 25 grams, or less than 20 grams. However, administering an intoxicating dose (e.g., at least 30 grams, 40 grams, or 50 grams) may be desirable in some cases, such as when a user is at a party and wishes to enjoy the benefits of the disclosed compositions along with a sense of relaxation and increased confidence.

[0077]

[0093] Providing different amounts or ratios of R-beta-hydroxybutyrate and S-beta-hydroxybutyrate can be a form of stacking, as these are different ketone bodies that provide different physiological effects. To increase potency, it may be desirable to provide BHB as pure R-beta-hydroxybutyrate or in a form enriched relative to S-beta-hydroxybutyrate. Alternatively, to reduce potency and increase long-term effects, it may be desirable to provide BHB as pure S-beta-hydroxybutyrate or in a form enriched relative to R-beta-hydroxybutyrate. While administering the endogenous form, R-beta-hydroxybutyrate, can result in a rapid rise in ketosis, administering S-beta-hydroxybutyrate can result in a slower, more sustained ketosis, since it must first be converted to acetoacetate and then, optionally, to R-beta-hydroxybutyrate. As noted above, S-BHB also provides the benefit of increased alertness in addition to its potential as a caloric energy source, compared to R-BHB, which primarily provides caloric energy benefits.

[0078]

[0094] Combining or stacking different salts and / or different forms of BHB and acetoacetate can advantageously limit the onset or severity of these undesirable side effects and / or allow for the administration of higher doses of such components. For example, a mixed salt composition or stacked form containing different cations can deliver the same amount of ketone bodies as a single form without causing the same onset and / or severity of side effects. Similarly, a mixed salt form or stacked form can deliver a greater amount of BHB or acetoacetate before reaching the same onset and / or severity of side effects compared to a single form.

[0079]

[0095] In other words, for a given dose of BHB or acetoacetate, the stacked forms are expected to produce fewer of the following compared to the mono-forms: 1) undesirable organoleptic side effects, 2) electrolyte imbalance side effects, and / or 3) acidity side effects. For example, a mono-form ester may have a dose threshold that a typical user would not exceed due to negative organoleptic side effects, a mono-form salt may have a dose threshold that is limited by recommended dietary restrictions on electrolytes co-administered with the salt, and a mono-form acid may have a dose threshold that a typical user would not exceed due to the adverse effects of acidity. The combined or stacked forms may allow for the supplementation of larger amounts of BHB and / or acetoacetate without exceeding any of the thresholds related to organoleptic, electrolyte, or acidity side effects.

[0080]

[0096] In some embodiments, the composition contains, on a molar basis, 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 other words, at least about 2% of the molecules (BHB and / or acetoacetate) can be provided in each separate form, or at least two forms. More preferably, the composition contains, on a molar basis, 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; 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; 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; 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.

[0081]

[0097] In some embodiments, the composition comprises from about 2% to about 96%, or from about 5% to about 90%, or from about 10% to about 80%, or from about 20% to about 60% on a molar basis of the ester form, from about 2% to about 96%, or from about 5% to about 90%, or from about 10% to about 80%, or from about 20% to about 60% on a molar basis of the salt form, and from about 2% to about 96%, or from about 5% to about 90%, or from about 10% to about 80%, or from about 20% to about 60% on a molar basis of the acid form.

[0082] G. Other Definitions

[0098] As used herein, "subject," "patient," or "user" refers to a mammal, including humans and other primates. A subject may be any mammal in need of metabolic therapy, treatment, or prophylaxis, or any mammal suspected of being in need of metabolic therapy, treatment, or prophylaxis. Prophylaxis means that the regimen is administered to prevent potential onset, such as when a high risk of diabetes or other metabolic disorder is identified. "Patient," "subject," and "user" are used interchangeably herein.

[0083]

[0099] "Ketosis," as used herein, refers to a metabolic state entered during an intermittent fasting period or an extended fasting period (e.g., two or more days). A subject can also be considered in ketosis if the subject has blood ketone levels within the range of about 0.5 mmol / L to about 16 mmol / L. Ketosis can improve mitochondrial function, reduce reactive oxygen species production, decrease inflammation, and increase neurotrophic factor activity. "Ketoadaptation," as used herein, refers to prolonged nutritional ketosis (>1 week) to achieve sustained, non-pathological "mild ketosis" or "therapeutic ketosis," or a metabolic shift in which fat becomes the primary energy source, resulting in the body shifting from a state of adiposity to a state of fat oxidation. It is believed that administration of BHB and other ketone bodies at the doses disclosed herein can provide the same or similar benefits as a state of ketosis, even if the subject does not achieve blood ketone levels high enough to be truly in ketosis.

[0084]

[0100] The terms "administration" or "administering" are used herein to describe the process by which the disclosed compositions are delivered to a subject. "Administration" and "administering" can include any known method or configuration capable of delivering the disclosed compositions to blood, tissues, and / or cells, whether delivered to a targeted area, widely dispersed, or systemically.

[0085]

[0101] The term "unit dose" refers to a dosage form configured to deliver a specified amount or dose of a composition or its components. Exemplary dosage forms include, but are not limited to, tablets, capsules, powders, foodstuffs, food additives, beverages (e.g., flavored, vitamin-enriched, or non-alcoholic), beverage additives (e.g., flavored, vitamin-enriched, or non-alcoholic), candies, lollipops, pastilles, dietary supplements, dietarily acceptable sprays (e.g., flavored mouth sprays), injections (e.g., alcohol-free injections), and suppositories. Such dosage forms can be configured to provide a whole unit dose or a fraction thereof (e.g., 1 / 2, 1 / 3, or 1 / 4 of a unit dose).

[0086]

[0102] Another dosage form that can be used to provide a unit dose of the composition or its components is a unit dose measuring device, such as a cup, spoon, spatula, syringe, dropper, scoop, or suppository injector, configured to hold a metered amount equivalent to a full unit dose or fraction thereof (e.g., 1 / 2, 1 / 3, or 1 / 4 of a unit dose) of the composition. For example, a bulk container, such as a carton, box, can, bottle, bag, pouch, jar, jug, or keg, containing several unit doses of the composition (e.g., 5 to 250 or 10 to 150 unit doses), can be provided to the user along with a unit dose measuring device configured to provide a unit dose, or fraction thereof, of the composition or its components.

[0087]

[0103] Kits used to provide the compositions disclosed herein in bulk form while providing unit doses of the composition can include a bulk container holding a quantity of the composition therein and a unit dose metering device configured to provide a unit dose or fraction thereof of the composition or its components. One or more unit dose metering devices can be located inside the bulk container at the time of sale, attached to the outside of the bulk container, prepackaged with the bulk container in a larger package, or provided by the distributor or manufacturer for use with one or multiple bulk containers.

[0088]

[0104] The kit can also include instructions regarding the size of the unit dose or subportion thereof, as well as the mode and frequency of administration. The instructions may be provided on the bulk container, prepackaged with the bulk container, placed on packaging sold with the bulk container, or provided by the distributor or manufacturer (e.g., on a website, in mailings, in flyers, product brochures, etc.). The instructions for use may include reference to how to properly deliver the unit dose or subportion thereof using the unit dose measuring device. The instructions may additionally or alternatively include reference to a common unit dose measuring device, such as a spoon, spatula, cup, etc., not provided with the bulk container (e.g., in case the provided unit dose measuring device is lost or misplaced). In such cases, the kit can be assembled by the end user by following the instructions provided on or with the bulk container or instructions provided by the distributor regarding how to properly deliver the unit dose or subportion thereof of the product and composition.

[0089] II. Paraxanthine-BHB Composition

[0105] The paraxanthine-BHB compositions described herein can include: (1) paraxanthine; (2) a ketone body (KB) component including beta-hydroxybutyric acid (BHB); and (3) an optional dietary or pharmaceutically acceptable carrier. Additional ketone body components, such as acetoacetate (AcAc), may also be included with (2) KB. In some embodiments, a BHB precursor, such as 1,3-butanediol, can be used in addition to or in place of BHB. Similarly, while 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. Publication No. 2022 / 0062216, which is incorporated by reference.

[0090]

[0106] As described above, paraxanthine-BHB compositions can be formulated with various ratios of paraxanthine to BHB. While the ratio can vary, the dose of BHB will typically be greater than that of paraxanthine because BHB serves as a caloric energy source and paraxanthine is provided for its pharmacokinetic and pharmacodynamic benefits, rather than as caloric energy. For example, the ratio of BHB to paraxanthine may be at least 1:1, 1.25:1, 1.5:1, 2:1, 4:1, 5:1, 6:1, 9:1, or within a range having any two of the aforementioned ratios as endpoints. The ratio can be formulated according to the needs and priorities of a particular application. While BHB provided alone can result in enhanced metabolic activity (e.g., fat loss, anti-inflammatory effects, vasodilation), when provided in combination with paraxanthine, it is believed to provide synergistic results, including, for example, in addition to these enhanced metabolic benefits, neuroprotection, enhanced focus and clarity, improved cognitive flexibility, working memory, improved response time, reduced oxidative stress, modulation of the drowsiness / grogginess typically associated with hypoglycemia upon entering ketosis, and modulation of the downregulation of metabolic rate typical of entering ketosis.

[0091]

[0107] Various additional additives that may be present in the energy formulation include any of those described in U.S. Publication No. 2021 / 026724, which is incorporated by reference.

[0092]

[0108] The paraxanthine-BHB composition may also optionally include one or more supplemental sources of ketone body precursors, such as 1,3-butanediol, fatty acids, and / or esters of fatty acids. 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- and / or long-chain fatty acids and their esters can also be used. In embodiments where used, medium-chain fatty acids have 6-12 carbons, preferably 8-10 carbons. Compositions and methods relating to the combination of BHB and medium-chain fatty acids, or esters thereof, are disclosed in U.S. Patent No. 9,138,420, which is incorporated by reference.

[0093]

[0109] Exemplary medium-chain fatty acids are caproic acid, also known as hexanoic acid, which has 6 carbons, caprylic acid, also known as octanoic acid, which has 8 carbons, capric acid, also known as decanoic acid, which has 10 carbons, and lauric acid, also known as dodecanoic acid, which has 12 carbons. Because MCTs are ketone body precursors, the inclusion of one or more MCTs can provide an additional source for ketone body production that is independent of BHB and any acetoacetate compounds, thereby helping to promote a sustained increase in ketone levels to desired therapeutic levels.

[0094]

[0110] The term "short-chain triglycerides" (SCTs) refers to molecules similar to MCTs but with short-chain fatty acids (less than six carbon atoms in length) attached to a glycerol backbone. The term "long-chain triglycerides" (LCTs) refers to molecules similar to MCTs but with long-chain fatty acids (more than 12 carbon atoms in length) attached to a glycerol backbone.

[0095]

[0111] 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, and isolated decanoic acid, purified or natural medium-chain triglycerides, such as coconut oil, and ester derivatives of medium-chain fatty acids, ethoxylated triglycerides, enone triglyceride derivatives, aldehyde triglyceride derivatives, monoglyceride derivatives, diglyceride derivatives, and triglyceride derivatives, as well as salts of medium-chain triglycerides. Ester derivatives optionally include alkyl ester derivatives, such as methyl, ethyl, propyl, butyl, and hexyl derivatives.

[0096]

[0112] When medium-chain fatty acids, fatty acid esters, or mono-, di-, or triglycerides of medium-chain fatty acids are provided, the compositions are preferably administered so that the weight ratio of ketone bodies (e.g., BHB) to medium-chain fatty acids (or esters thereof) ranges from about 4:1 to about 1:4, or from about 2:1 to about 1:2, or from about 1.5:1 to about 1:1.5. The same ratios can be used when short-chain fatty acids (or esters thereof) or long-chain fatty acids (or esters thereof) are additionally or instead used.

[0097]

[0113] 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 caproic acid, caprylic acid, capric 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.

[0098] III. Therapeutic Efficacy

[0114] Administration of paraxanthine-BHB compositions can provide a variety of beneficial physiological and neurological effects, including one or more of: neuroprotection, enhanced focus and clarity, cognitive flexibility, improved working memory, improved response time, enhanced neurotransmitter signaling via vasodilators (e.g., nitric oxide), modulation of the drowsiness / drowsiness typically associated with hypoglycemia upon entering ketosis, and modulation of the downregulation of metabolic rate typical of entering ketosis. Additional benefits can include, for example, reduced oxidative stress, antioxidant effects, analgesia, anti-inflammatory effects, as well as fat loss, increased appetite suppression and inhibitory control, anxiety modulation, suppression of depressive symptoms, cardiovascular benefits (e.g., vasodilation and blood pressure modulation), and anti-aging / longevity.

[0099]

[0115] Although various different pharmacological and / or physiological variables may be involved, the combination compositions described herein can enable complementary enhancement in several different nervous and physiological systems. Without being bound by any particular theory, it is currently believed that the paraxanthine component functions to provide enhancement similar to that provided by caffeine, while eliminating the undesirable side effects associated with caffeine and reducing or eliminating the differences in how different users metabolize such psychostimulants. In addition, paraxanthine provides benefits not available from caffeine, such as enhanced signaling by vasodilatory neurotransmitters. While some such benefits are known to occur when supplementing with paraxanthine alone, providing paraxanthine together with BHB enhances the benefits provided beyond what would be expected or anticipated based solely on additive effects. In other words, synergistic benefits are obtained from the combination of both paraxanthine and BHB, and these benefits are not obtained from either component alone.

[0100]

[0116] The beneficial therapeutic effects described herein can be achieved or enhanced by the BHB component of the composition when a subject is in or entering ketosis. Many examples can be described as situations in which a subject enters or is in ketosis, such as during fasting, but it is understood that the beneficial effects do not necessarily require the subject to be in such a state. For example, many neurological benefits, such as enhanced focus and clarity, improved cognitive flexibility, improved working memory, improved response time, enhanced signaling by vasodilatory neurotransmitters, and neuroprotection, can be achieved without the subject necessarily being in ketosis. In ketosis, these benefits, as well as modulation of the drowsiness / drowsiness typically associated with entering ketosis, modulation of the metabolic rate downregulation typical of ketosis, fat loss, muscle preservation, etc., can be achieved. In other words, beneficial effects can be achieved as a result of co-administration of the exogenous ketone body components BHB and paraxanthine. These effects may be further enhanced once a subject has entered an active state of ketosis, and the BHB components themselves may assist a subject in entering such a state, although ketosis is not necessarily a prerequisite for realizing the benefits described herein. A. Caffeine vs. Paraxanthine Metabolism

[0117] Figure 1 illustrates exemplary plasma concentration curves for caffeine and its metabolites (paraxanthine, theophylline, and theobromine) following an oral dose of 270 mg of caffeine. Paraxanthine (1,7-dimethylxanthine) accounts for approximately 70-72% of ingested caffeine and approximately 84% of the methylxanthine metabolic by-products. As shown in Figure 2, theophylline and theobromine account for 4% and 12%, respectively, of the methylxanthine metabolic by-products.

[0101]

[0118] Paraxanthine is a natural dietary component and can be found in small amounts in, for example, Theobroma cacao fruit, Coffea arabica, Sinomenium actum, and the stamens of citrus flowers. As shown in Figure 3, paraxanthine has a shorter half-life and faster clearance than caffeine, theophylline, or theobromine. For example, the half-life of paraxanthine is 3.1 hours, significantly shorter than caffeine (4.1 hours) and half or less than half that of theophylline (6.2 hours) and theobromine (7.2 hours). The total plasma clearance of paraxanthine (2.20 mL / min / kg) was greater than that of caffeine (2.07 mL / min / kg) and much greater than that of theophylline (0.93 mL / min / kg) or theobromine (1.2 mL / min / kg).

[0102]

[0119] Paraxanthine offers significant benefits (and minimizes negative side effects) compared to caffeine use. For example, paraxanthine is less toxic than caffeine, less clastogenic than caffeine or theophylline, and less teratogenic than caffeine or theophylline. Like caffeine, paraxanthine is a psychostimulant and central nervous system stimulant. Paraxanthine is thought to act via its adenosine receptor antagonist mechanism. Paraxanthine exerts a stronger locomotor activating effect than caffeine and has a higher binding potency for adenosine A1 and A2a receptors. Blockade of A1 receptors increases neurotransmitter release (e.g., glutamate and dopamine). Advantageously, in addition to being an adenosine receptor antagonist, paraxanthine also enhances signaling by the nitric oxide (vasodilator) neurotransmitter. Caffeine does not offer these benefits. Phosphodiesterase 9 (PDE9) is thought to terminate nitric oxide neurotransmission by metabolizing cGMP back to GMP. Paraxanthine inhibits PDE9, thereby enhancing nitric oxide neurotransmission and dopamine release. As noted, caffeine does not have this effect.

[0103]

[0120] Paraxanthine has stronger neuroprotective properties than caffeine. For example, paraxanthine has been shown to protect dopamine neurons and has strong protective effects against neurodegeneration and loss of synaptic function, whereas caffeine offers only limited protection against these.

[0104]

[0121] Interestingly, paraxanthine has a stronger wake-promoting effect than caffeine and lasts longer. This is interesting considering that paraxanthine has a shorter half-life and faster clearance (paradoxically, paraxanthine has a shorter half-life and faster clearance, but is more potent and lasts longer). As noted, paraxanthine is less toxic than caffeine. For example, higher doses of caffeine (as well as modafinil) induce hypothermia and decreased locomotor activity. Such problems have not been observed with paraxanthine at similar doses.

[0105]

[0122] Importantly, as previously described, human caffeine metabolism varies depending on each individual's genetic characteristics. For example, the enzyme cytochrome P450 1A2 is responsible for approximately 95% of all caffeine metabolism, including the demethylation of caffeine to paraxanthine. Subjects with a homogenous A-type allele of the CYP1A2 gene tend to produce more cytochrome P450 and consequently metabolize caffeine more rapidly. Rapid caffeine metabolizers have consistently experienced higher ergogenic outcomes in some (but not all) studies. The problem is that rapid metabolizers represent less than 50% of the population, meaning the majority of subjects miss out on the benefits that rapid metabolizers achieve from caffeine. Using paraxanthine directly avoids the effects of genetic differences among subjects and allows moderate or slow caffeine metabolizers to more optimally enjoy its benefits.

[0106]

[0123] The use of paraxanthine rather than caffeine provides many benefits, some of which are discussed above. Paraxanthine provides additional organoleptic benefits in that it is less bitter than caffeine and easier to formulate. When used with BHB, even less paraxanthine is needed to achieve a given benefit, further facilitating formulation. Table 1 below shows the results of a taste test evaluating bitterness, which was conducted using a specially trained taste evaluation panel. Each solution was prepared by dissolving 163 mg of the ingredient to be tested for bitterness in 473 mL of water. As a reference point for comparison, caffeine yields a bitterness score of 5.0. Solution L was Liberine, Solution T was Theacrine, Solution M was Methylliberine, and Solution P was a solution of paraxanthine. Paraxanthine, with an average bitterness score of 3.9, yielded significantly less bitterness than caffeine (5.0) and was significantly less bitter than the other ingredients tested.

[0107] [Table 1]

[0108]

[0124] While the above-described effects of paraxanthine are independently desirable, it has surprisingly been found that the combination of paraxanthine and BHB enhances the benefits provided by paraxanthine and reduces the amount of paraxanthine required to achieve a given level of benefit. For example, because the BHB component provides caloric energy without causing an insulin spike and also promotes more efficient use of fat for energy purposes, more energy is available to the subject via available ketone bodies for performing tasks, enhancing cognitive flexibility, enhancing sustained attention, maintaining clarity, and enjoying the benefits of enhanced working memory associated with paraxanthine supplementation. The caloric energy provided by BHB in combination with paraxanthine also modulates the drowsiness / drowsiness typically associated with entering ketosis, while also modulating the downregulation of metabolic rate typically associated with entering ketosis. As shown in the accompanying prospective data, users who supplement with such a combination can maintain or even increase metabolic rate. As shown in the accompanying data, these benefits and the performance of a given subject supplemented with paraxanthine in combination with BHB are significantly enhanced compared to similar subjects supplemented with paraxanthine alone, or BHB alone, or caffeine alone, or a combination of caffeine and BHB.

[0109]

[0125] The following diagram illustrates these expected improvements across various clinical studies. For example, one clinical study compared the results of paraxanthine supplementation in combination with BHB compared to paraxanthine supplementation alone, BHB supplementation alone, and placebo supplementation. Subjects included healthy young adults of both genders who completed four executive function tests assessing working memory, inhibitory control, cognitive flexibility, and sustained attention. Working memory is the ability to mentally hold information and activate it. The ability to remember instructions, generate action plans, and pay attention all depend on working memory. Inhibitory control is the ability to control attention, behavior, thoughts, and emotions rather than acting on impulses or desires. Cognitive flexibility is the ability to change tasks and respond to changing demands, priorities, and perspectives. Sustained attention is the ability to focus on an activity or stimulus for an extended period of time (e.g., 2-3 hours or more). It allows one to focus on an activity for the time it takes to complete it, even in the presence of other distracting stimuli.

[0110]

[0126] Attention and inhibitory control abilities can be measured using a Go / No Go test, which is used to measure participants' abilities for sustained attention and response control. Go / No Go tests are routinely used in the field and are familiar to those skilled in the art. In a Go / No Go test, participants view a 2 × 2 square array. Letters (e.g., P or R) are then presented sequentially, and participants respond to the target letter by pressing the corresponding button on a keyboard. A single letter (P or R) is presented in one of the four squares for 500 milliseconds, followed by a 1500-millisecond interval between stimuli. For the P-Go condition, participants are required to press the P key in response to the letter P and refrain from responding to the letter R. For the R-Reversed condition, participants are required to respond to the letter R and refrain from responding if they see the letter P. The median response time and percentage of correct responses are recorded.

[0111]

[0127] The vigilance task test is another test routinely used in the field and is used to assess participants' ability to sustain attention. The vigilance task test is a sustained attention, reaction time task test that measures the speed at which participants respond to visual stimuli. Subjects respond to a visual stimulus (e.g., a red dot) by pressing a key as soon as it appears on a computer screen. During the test, lights are turned on randomly, e.g., approximately every few seconds. Response speed is measured. Due to the random nature of this test, there is no learning effect. The median response time is recorded.

[0112]

[0128] The Berg-Washington Card Sorting Test (BCST) is a test commonly used in the field to assess cognitive flexibility. The BCST 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 particularly sensitive to subjects' inability to shift sets. Cards with different colors (e.g., red, green, yellow, blue), designs (e.g., circles, triangles, stars, plus signs), and numbers of symbols (e.g., 1-4) are presented on a computer screen. Participants are required to sort the cards by matching the color and / or design and / or number of symbols, although instructions on how to sort the cards may change at different points during the test. The number of correct responses and errors (e.g., perseveration errors, in which participants erroneously continue to sort cards according to the old instructions even after new instructions have been given) are recorded.

[0113]

[0129] The Sternberg test is a commonly used test in the field to assess working memory and the ability to utilize short-term memory. A shorter reaction time indicates that participants can access these working memories more quickly. The Sternberg task test is a widely used paradigm to study short-term / working memory, including cognitive control processes. Participants are asked to memorize a short string of letters or other symbols, and then must respond to whether the string of letters or symbols exists within a longer string of letters or symbols. Reaction times are measured both when the memorized short string exists and when it does not. The median response time is recorded.

[0114]

[0130] In each study, subjects received either paraxanthine and BHB, paraxanthine alone, BHB alone, or a placebo. The dosages were 200 mg paraxanthine and 5 g BHB, 200 mg paraxanthine alone, 5 g BHB alone, or a placebo. The study was double-blind and placebo-controlled. The subjects included 13 healthy young adults (10 men and 3 women), age 24 ± 5 ​​years; height 170.0 ± 11.8 cm; weight 72.9 ± 19.3 kg. Measurements were performed at baseline and 1, 2, 3, 4, 5, and 6 hours after supplementation for the Go / No Go test, vigilance task, Sternberg task, and Berg-Washington card sorting task.

[0115]

[0131] Figures 4 and 5 illustrate the expected results of the Go / No Go test. As shown, paraxanthine supplementation, especially when combined with BHB, results in faster response times. Placebo and BHB alone show a decrease in correct responses over time (see Figure 4), indicating the onset of mental fatigue. Responses charted for placebo are nearly identical to those for BHB alone. Surprisingly, the combination of paraxanthine and BHB shows significant, synergistic improvements in both correct response accuracy and mean response time compared to paraxanthine alone. The combination of BHB and paraxanthine results in a synergistic increase in the ability for sustained attention and response control, as shown by the results of the Go / No Go test.

[0116]

[0132] Figure 6 illustrates the expected results of the vigilance task test. As shown, paraxanthine supplementation, especially when combined with BHB, results in faster response times. In contrast, placebo and BHB alone show significantly slower response times (e.g., especially at 3 and 6 hours from baseline). Surprisingly, the combination of paraxanthine and BHB shows a significant, synergistic improvement in mean response time compared to paraxanthine alone. The combination of paraxanthine and BHB results in a synergistic increase in the ability to sustain attention, as shown by the results of the vigilance task test.

[0117]

[0133] Figures 7-8 illustrate the predicted results of the Berg-Washington card sorting task. As shown, paraxanthine supplementation, especially when combined with BHB, results in a significant increase in the number of correct responses and a decrease in the number of errors. While paraxanthine alone provides some of these benefits, the increase in correct responses and decrease in errors surprisingly increases with the further supplementation of BHB in combination with paraxanthine. This combination of paraxanthine and BHB surprisingly and synergistically increases cognitive flexibility, or the ability to set-shift between old and new rules, as shown by the results of the Berg-Washington card sorting task.

[0118]

[0134] Figures 9-11 illustrate the expected results of the Sternberg test. As shown, paraxanthine supplementation, particularly when combined with BHB, results in a reduction in median response time compared to placebo or supplementation with BHB alone. While paraxanthine alone results in some reduction in reaction time, supplementation with BHB in combination with paraxanthine surprisingly provides faster response times. This combination of paraxanthine and BHB surprisingly and synergistically increases short-term / working memory, particularly memory for longer string lengths, as shown by the results of the Sternberg test.

[0119]

[0135] A key finding in various cognitive studies is that acute paraxanthine and BHB supplementation improves cognition in all three aspects of executive function: cognitive flexibility, short-term memory, and sustained attention. While cognitive improvements are achieved with paraxanthine supplementation alone, when combined with BHB, the improvements are surprisingly and synergistically enhanced. For example, BHB supplementation alone provides little, if any, significant benefit over placebo, but when combined with paraxanthine, improvements are achieved that exceed those achieved with paraxanthine alone. These results are surprising and unexpected, demonstrating a synergistic effect between paraxanthine and BHB.

[0120]

[0136] Additional clinical studies will be conducted to compare the effects achieved by paraxanthine with those of caffeine. Participants will receive 200 mg of paraxanthine, 200 mg of caffeine, 5 g of BHB, 200 mg of paraxanthine + 5 g of BHB, 200 mg of caffeine + 5 g of BHB, 200 mg of paraxanthine + 200 mg of caffeine + 5 g of BHB, or a placebo. The study will be double-blind and placebo-controlled. Subjects will include 12 healthy, trained male runners aged 26 ± 5 years. They will undergo baseline cognitive testing (PRE), ingest the supplements, rest for 60 minutes, and then undergo pre-race cognitive function testing (PRE-EX). They will then run 10 km on a treadmill, followed by post-race cognitive function testing (POST). Cognitive function tests include the Vigilance Task Test (which measures the ability to remain alert) and the Berg-Washington Card Sorting Task (which measures cognitive flexibility).

[0121]

[0137] Expected results from such testing are shown in Figures 12A-12D, where Figure 12A shows the difference in the rate (e.g., percentage) of correct responses on the POST test relative to the PRE test. Figure 12B shows the difference in the rate (e.g., percentage) of errors on the POST test relative to the PRE test. Figure 12C shows the difference in the rate (e.g., percentage) of perseverative errors on the POST test relative to the PRE test. Figure 12D shows the difference in the rate (e.g., percentage) of perseverative errors (PAR rule) on the POST test relative to the PRE test. While paraxanthine alone results in some improvement in correct responses and a reduction in errors, supplementing with BHB in combination with paraxanthine surprisingly produces even more improved results. This combination of paraxanthine and BHB surprisingly and synergistically increases alertness, vigilance, and cognitive flexibility, and reduces mental fatigue. Caffeine supplementation, even when combined with paraxanthine and / or BHB, has been shown to produce weak results. For example, all examples containing caffeine, even when compared with placebo, result in a decrease in correct responses and an increase in errors (i.e., placebo or no supplementation is superior to any supplementation, including caffeine). Thus, in one embodiment, the composition is substantially or completely caffeine-free.

[0122]

[0138] Figure 13 plots predicted response times for the vigilance task test for the same supplementation shown in Figures 12A-12D. As shown, supplementation with paraxanthine alone provides some benefit, but an increased synergistic benefit is provided when paraxanthine + BHB are supplemented. A caffeine-containing supplement can reduce reaction times, as shown, but not to the extent provided by a caffeine-free supplement. Caffeine causes an increase in errors, as shown in Figures 12A-12D.

[0123]

[0139] Such clinical studies show that paraxanthine supplementation, especially when combined with BHB, improves cognition PRE-EX and especially POST-EX, but that caffeine is harmful even in combination with paraxanthine and / or BHB.

[0124]

[0140] Figures 14A-14C show predicted results from a 28-day sports nutrition clinical study in which participants were supplemented with paraxanthine alone (100 mg), BHB alone (5 g), paraxanthine (100 mg) in combination with BHB (5 g), or one of various muscle-building supplements (e.g., L-theanine (50 mg), alpha-GPC (200 mg), or taurine (500 mg)). Participants exercised five days per week over the four-week study. While paraxanthine alone provided some improvements in muscle mass, endurance, and grip strength, supplementation with BHB in combination with paraxanthine surprisingly provided even more improved results. This combination of paraxanthine and BHB surprisingly and synergistically increased muscle mass, muscle endurance, and grip strength. Increased nitric oxide levels and improvements in blood lipid scores (e.g., TG, TC, LDL, HDL) were also observed.

[0125]

[0141] In a study of age-related cognitive decline, predictive results indicate that paraxanthine supplementation in combination with BHB results in improved cognitive performance, improved neurotransmitter levels, improved brain protection, and improved oxidative stress beyond those achieved by paraxanthine or BHB alone. These predictive results are presented in Table 2. As shown, BHB alone provides little, if any, benefit compared to control. When used with paraxanthine, this combination results in synergistic decreases in escape latency and amyloid Aβ1-40 concentrations, while also providing synergistic increases in acetylcholine, dopamine, glutathione, catalase, and BDNF.

[0126] [Table 2]

[0127]

[0142] In the Forced Swim and Cook's Pole Climbing Test in mice, predicted results indicate that paraxanthine supplementation in combination with BHB results in improved active swimming duration and increased climbing test scores beyond those produced by paraxanthine alone, BHB alone, or various other muscle-building supplements tested (e.g., L-theanine, alpha-GPC, and taurine). These predicted results are shown in Table 3. As shown, BHB alone provides little, if any, benefit compared to the control. When used with paraxanthine, this combination results in a synergistic decrease in immobility time and number of climbs in the Cook's Pole Climbing Test, while also resulting in a synergistic increase in locomotion / active swimming time.

[0128] [Table 3]

[0129]

[0143] Figures 15A-15C show predicted results from a clinical trial of the Stroop test. In this study, participants were supplemented with paraxanthine alone (200 mg), BHB alone (5 g), or paraxanthine (200 mg) in combination with BHB (5 g) over a 6-week period. The Stroop effect refers to a delay in reaction time between congruent and incongruent stimuli. The Stroop test is a psychological test known to demonstrate this effect when there is a mismatch between a color name (e.g., "blue," "green," or "red") and its printed color (i.e., the word "red" is printed in blue ink instead of red ink). When asked to identify the color of a word, subjects took longer and were more likely to make errors if the ink color did not match the color name. While paraxanthine alone (Figure 15B) produced some improvement in reaction speed and the number of correct responses in this Stroop test, surprisingly, supplementation with BHB in combination with paraxanthine provided even further improvement (Figure 15C). As shown in Figure 15A, BHB alone provides little, if any, benefit compared to baseline (pre-supplementation). When used with paraxanthine, the combination provides a synergistic improvement in mental acuity.

[0130]

[0144] Figures 16A-16B show predicted results from a clinical trial of resting energy expenditure. In this study, participants were supplemented with paraxanthine alone (100 mg or 300 mg), BHB alone (5 g), or paraxanthine (100 mg or 300 mg) in combination with BHB (5 g) over a 180-day period. Paraxanthine alone resulted in a modest increase in resting energy expenditure (helpful for weight loss), and supplementing with BHB in combination with paraxanthine surprisingly produced even more improved results. As shown, BHB alone provided only a modest benefit. However, when used with paraxanthine, the combination resulted in a synergistic increase in resting metabolic energy expenditure. The presence of BHB's ketone body component makes it more likely that this increase in metabolic rate would occur under conditions of ketosis, where fat is primarily used as a caloric energy source relative to a higher resting metabolic rate.

[0131] IV. Dosage Forms and Administration

[0145] The compositions described herein may be provided in single or multi-component compositions configured for administration in a variety of forms, for example, by one or more of oral ingestion, intragastric, injection, topical application, inhalation, buccal, rectal, vaginal, or parenteral administration.

[0132]

[0146] Non-limiting examples of the aforementioned routes of administration include, but are not limited to, orally ingestible compositions, suppositories (anal or vaginal), transdermal patches, sublingual compositions, subcutaneous administration forms, solids, powders, liquids, gels, tablets, capsules, other dietarily or pharmaceutically acceptable forms, vaporizable cartridges, nebulizer liquids, smokable boluses, intravenous syringes, nasal drops or vapors, pulmonary compositions for inhalation, enemas, rinses, injectable boluses, subdermal implants (e.g., pellets or sticks), and the like.

[0133]

[0147] Inhalation can be achieved using a heated vaporizer (e.g., a vape stick, mod box, e-cigarette, or vape cartridge), smoking a bolus (e.g., using a pipe, water pipe, bong, rolling papers, glass pipe, chillum, one-hitter, shisha, apple pipe, avocado pipe, gas mask, or snorkel device), or a nebulizer.

[0134]

[0148] Edible forms include beverages, sodas, energy shots, sparkling water, beer, wine, spirits, hard seltzer, coconut water, fruit juice, chocolate, fruit chews, oral drops, palm oil, butter, water, milk, cookies, cakes, ice cream, gummy bears, pizza crust, brownies, pastries, yogurt, frozen yogurt, chewable vitamins, candy, protein powders, supplements, supplement powders, ingestible powders, coffee, and tea.

[0135]

[0149] Oral administration / concentrates / extracts include chewing gum, tinctures, oils, sublingual sprays, pills, capsules, fast-dissolving tablets, lozenges, nose drops, eye drops, dabs, shatter, and rosin.

[0136]

[0150] Topical agents include lotions, creams, ointments, balms, transdermal patches, gels, shampoos, conditioners, deodorants, lip balms, lipsticks, and makeup products.

[0137]

[0151] The solid or powder composition may contain one or more additional ingredients configured to reduce the hygroscopicity of the composition. For example, various anti-caking agents, flow agents, and / or moisture absorbers may be included in types and amounts safe for ingestion. Such additional ingredients may include one or more of aluminosilicates, ferrocyanides, carbonates or bicarbonates, silicates (e.g., sodium silicate or calcium silicate), phosphates (e.g., tricalcium phosphate), talcum, powdered cellulose, etc.

[0138]

[0152] In alternative embodiments, the paraxanthine-BHB composition can be provided in the form of a liquid, such as a shot or mouth spray for rapid delivery and absorption, or as a gel. The liquid or gel form can include one or more carriers, such as water, ethanol, glycerin, propylene glycol, 1,3-propanediol, etc., to dissolve or disperse the ingredients. The composition can include flavoring agents to help mask the somewhat unpleasant taste of the BHB compounds. These flavoring agents can include essential oils, such as peppermint, natural and artificial sweeteners, and other flavoring agents known in the art.

[0139]

[0153] The paraxanthine-BHB composition may contain one or more supplements known in the art, such as vitamins, minerals, or herbs. In one embodiment, little, if any, caffeine is present, since caffeine interferes with the effectiveness of paraxanthine, as noted above. For example, if present, caffeine may be present in an amount of less than 10 mg, less than 5 mg, less than 3 mg, or less than 1 mg. The composition may advantageously be substantially or completely free of caffeine.

[0140]

[0154] The paraxanthine-BHB compositions described herein can be provided in a dosage regimen effective to induce and sustain ketosis and / or provide other benefits described herein. For example, the mass of exogenous ketone bodies (e.g., BHB) in a daily dose (for an average adult weighing approximately 175 pounds) can range 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, and can be provided using one or more unit doses. The mass of the paraxanthine component in a daily dose (for an average adult weighing approximately 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. If necessary, the dosage can be adjusted (e.g., linearly) based on the subject's body weight. The paraxanthine component and the BHB ketone body component can be mixed / combined, although in some methods the components can be provided separately. The daily dose(s) can be taken as a single daily dose or multiple doses (e.g., 2, 3, or 4 times daily).

[0141]

[0155] In some embodiments, the compositions comprise a ratio of BHB ketone body components to paraxanthine components ranging from about 1:1 to about 500:1, although greater amounts of BHB ketone body components relative to paraxanthine components are preferred, preferably significantly greater. For example, more preferred ratios of BHB ketone body components to paraxanthine components may range from about 5:1 to about 300:1, about 5:1 to about 100:1, or about 5:1 to about 50:1. The BHB components are present in significantly higher amounts because the BHB components provide a caloric energy source while the paraxanthine serves other purposes (e.g., enhanced cognitive flexibility, increased sustained attention, improved working memory, increased inhibitory control, neuroprotection, etc.). Exemplary weight ratios of BHB ketone body component(s) to paraxanthine component(s) 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 ranges incorporating any of the foregoing endpoints. These and other ratios disclosed herein also generally apply when 1,3-butanediol is used in addition to or instead of BHB.

[0142]

[0156] In preferred embodiments, the paraxanthine-BHB composition is administered one or more unit doses per day via oral administration of the composition 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 of skill in the art.

[0143]

[0157] In some embodiments, multiple doses of the composition are administered. The frequency of administration of the composition may vary depending on any of a variety of factors, such as the timing of treatment since previous treatment, the purpose of treatment, etc. The duration of administration of the composition (e.g., the period during which the agent is administered) may vary depending on any of a variety of factors, including the subject's response, the desired effect of treatment, etc.

[0144]

[0158] The amount of the composition administered may vary according to factors such as the individual's degree of susceptibility, the individual's age, sex, and weight, the individual's idiosyncratic response, etc. A "therapeutically effective amount" is the amount necessary to promote a therapeutically effective result in vivo. According to the present disclosure, an appropriate single dose size is a dose that, when administered one or more times over a suitable period of time (e.g., a daily dose), is capable of preventing or alleviating (reducing or eliminating) symptoms in a patient.

[0145]

[0159] The amount of the composition administered will depend on the potency, absorption, distribution, metabolism, and excretion rate of the composition components, the method of administration, and the specific disorder being treated, as well as other factors known to those skilled in the art. The dosage should be sufficient to affect the desired response, e.g., a therapeutic or prophylactic response for the specific disorder or condition, taking into account the severity of the condition to be alleviated. The compound may be administered once (e.g., once daily) for a given period of time, or in divided doses at intervals of time. It should be understood that dosage can be adjusted according to the individual need and the professional judgment of the person administering or supervising the administration of the composition.

[0146] VII. [Example]

[0147]

[0160] The following is a description of exemplary paraxanthine-BHB compositions useful for enhancing cognitive flexibility, sustained attention, working memory, inhibitory control, and neuroprotection in a subject.

[0148] Example 1

[0161] The paraxanthine-BHB composition is prepared by mixing a BHB ketone body component, including 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 available in an easily administered form, such as a powder mixed with food or beverage as a dietary supplement, in the form of one or more capsules or tablets, or in a liquid form, such as a mouth spray, liquid shot, or beverage. The paraxanthine-BHB composition provides superior results compared to compositions containing caffeine and BHB.

[0149] Example 2

[0162] The paraxanthine-BHB composition is prepared by mixing a BHB ketone body component, including 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 25:1. The paraxanthine-BHB composition is in an easily administered form, such as a powder mixed with food or beverage as a dietary supplement, one or more capsules or tablets, or a liquid form, such as a mouth spray, liquid shot, or beverage. The paraxanthine-BHB composition provides superior results compared to compositions containing caffeine and BHB.

[0150] Example 3

[0163] The paraxanthine-BHB composition is prepared by mixing a BHB ketone body component, including 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 100:1. The paraxanthine-BHB composition is in an easily administered form, such as a powder mixed with food or beverage as a dietary supplement, one or more capsules or tablets, or a liquid form, such as a mouth spray, liquid shot, or beverage. The paraxanthine-BHB composition provides superior results compared to compositions containing caffeine and BHB.

[0151] Example 4

[0164] Modify any of the above examples by substituting a portion of the beta-hydroxybutyrate salt(s) with beta-hydroxybutyric acid.

[0152] Example 5

[0165] Any of the preceding examples is modified by including one or more esters of beta-hydroxybutyric acid.

[0153] Example 6

[0166] Modify any of the above examples by supplementing or substituting at least a portion of the BHB with 1,3-butanediol.

[0154] Example 7

[0167] Modify any of the above examples by substituting a portion of the beta-hydroxybutyrate(s) with one or more of sodium acetoacetate, potassium acetoacetate, magnesium acetoacetate, or calcium acetoacetate.

[0155] Example 8

[0168] Example 6 is modified by replacing a portion of the acetoacetate salt(s) with acetoacetic acid.

[0156] Example 9

[0169] Modify any of the preceding embodiments by providing a dosage form that provides 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 BHB ketone body components.

[0157] Example 10

[0170] Any of the preceding examples is modified by providing a dosage form that provides from about 50 mg to about 500 mg, or from about 50 mg to about 400 mg, or from about 100 mg to about 300 mg of paraxanthine component.

[0158] Example 11

[0171] Modify any of the above examples by including one or more supplements including one or more of: vitamin(s), mineral(s), or herb(s).

[0159] Example 12

[0172] Any of the above examples are modified to include a liquid carrier comprising one or more of water, ethanol, glycerin, propylene glycol, or 1,3-propanediol.

[0160] Example 13

[0173] Modify any of the preceding examples to further include a ketone body precursor selected from 1,3-butanediol, a fatty acid, and / or an ester of a fatty acid, e.g., one or more medium chain fatty acids or one or more medium chain triglycerides (MCTs).

[0161] Example 14

[0174] Any of the above examples are modified to include a short chain fatty acid or ester thereof.

[0162] Example 15

[0175] The composition may be administered in combination 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, e.g., epigallocatechin gallate (EGCG)), green coffee extract, conjugated linoleic acid (CLA), tetradecylthioacetic acid (TTA), Coleus forskohlii (Coleus Any of the foregoing examples may be modified by combining the composition with an active ingredient such as benzoyl peroxide (e.g., forskolin), yohimbine, rauwolscine, capsaicin, raspberry ketones (e.g., 4-(4-hydroxyphenyl)butan-2-one, p-hydroxybenzylacetone), ephedrine, synephrine (e.g., bitter orange extract), octopamine, 1,3-dimethylamylamine, higenamine, fucoxanthin, an acetylcholine modulator, nicotine, coca leaf derivatives, ursolic acid, clenbuterol, noradrenaline reuptake inhibitors (e.g., hordenine, atomoxetine), 7-oxodehydroepiandrosterone (e.g., 7-ketoDHEA), thyroid hormones (e.g., triiodothyronine), or a combination thereof. The resulting composition is expected to provide enhanced lipolysis and / or fat oxidation.

[0163] Example 16

[0176] The compositions may be administered in combination with one or more nootropic supplements, such as tyrosine, L-dopa (i.e., L-3,4-dihydroxyphenylalanine), tryptophan, and 5-hydroxytryptophan (5-HTP), racetams such as piracetam, oxiracetam, and aniracetam, L-theanine, D-serine, phosphatidylserine, tolcapone, uridine, vinpocetine, norepinephrine reuptake inhibitors such as hordenine and atomoxetine, ginseng (Panax ginseng), ginkgo biloba (Ginkgo biloba), Rhodiola rosea (Rhodiola rosea), Polygala tenuifolia (Polygala tenuifolia), Muira puama (Muira puama), California poppy (Eschscholzia californica), Shankhpushpi (Convolvulus Any of the foregoing examples may be modified by combining with herbs such as Centella pluricaulis, Centella asiatica, Evolvulus alsinoides, Bacopa monnieri, Epimedium herbs, Ashwagandha herbs, cyclic adenosine monophosphate (cAMP) modulators such as forskolin, stimulants such as nicotine and amphetamines, cholinergic compounds and / or acetylcholine modulators such as huperzine A, dimethylaminoethanol, choline, and alpha-glycerophosphocholine, and combinations thereof. The resulting combined supplement is expected to provide greater cognitive, attention, and / or mood effects.

[0164] Example 17

[0177] Any of the above examples is modified by the inclusion of a pharmaceutically or dietarily acceptable carrier.

[0165] Example 18

[0178] Modify any of the preceding embodiments by being a dosage form configured for administration by one or more of: oral ingestion, intragastric, injection, topical, inhalation, buccal, rectal, vaginal, or parenteral.

[0166]

[0179] Unless otherwise stated, all percentages, ratios, parts and amounts used and described herein are by weight.

[0180] Numbers, percentages, ratios, or other values ​​set forth herein may include values ​​that are approximations or approximate values ​​of the stated value, as well as other values, as recognized by those skilled in the art. Accordingly, all numerical values ​​may be optionally modified in the claims by including the term "about." Thus, such values ​​may include amounts or conditions near the stated amount or condition that still perform the desired function or achieve the desired result. Accordingly, the stated value should be interpreted to encompass values ​​at least sufficiently near the stated value and / or broadly enough that the stated value can be rounded to the nearest whole number to perform the desired function or achieve the desired result. The stated value will at least include expected variations in typical manufacturing or other processes, and may include values ​​within 10%, 5%, 1%, etc., of the stated value.

[0167]

[0181] The phrase "substantially free of" or similar phrases, as used herein, means that the composition or article preferably contains 0% of the listed ingredient, although it should be recognized that extremely low concentrations may possibly be present, for example, through accidental formation, contamination, or even intentional addition. Such ingredients may be present, if at all, in amounts of 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 may be free or substantially free of any specific ingredient not described herein. For example, if present, caffeine may be present in a provided dose of paraxanthine-BHB supplement at less than 10 mg, less than 5 mg, less than 3 mg, or less than 1 mg.

[0168]

[0182] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects merely as illustrative and not restrictive. The scope of the present invention is therefore indicated by the appended claims rather than the foregoing description. All changes that come within the meaning and range of equivalency of the claims are intended to be embraced within their scope.

Claims

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

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

3. 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. 4. The composition of claim 1, comprising a mixed salt comprising a plurality of cations, including at least one of lithium ions, sodium ions, potassium ions, magnesium ions, calcium ions, and amino acid cations, in combination with a BHB ketone body anion.

5. 5. The composition of claim 1, provided in solid, powder or liquid form.

6. 6. The composition of any one of claims 1 to 5, in a dosage form providing 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 the BHB ketone body component.

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

8. 8. The composition of claim 1, further comprising a pharmaceutically or dietarily acceptable carrier.

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

10. 10. The composition of any one of claims 1 to 9 for use in providing one or more of the following: promoting homeostasis, neuroprotection, brain protection, memory enhancement, enhanced focus and clarity, improved cognitive performance, improved working memory, improved neurotransmitter levels, faster response time, reduced oxidative stress, enhanced inhibitory control (attention control), anxiolytic effects, reduced irritability, antidepressant effects, anti-inflammatory effects, analgesic effects, suppression of depressive symptoms, cardiovascular benefits, blood pressure modulation, heart rate modulation, modulation of drowsiness / drowsiness associated with entering ketosis, modulation of metabolic rate downregulation upon entering ketosis, anti-aging, and reduced energy crash.

11. 10. The composition of any one of claims 1 to 9 for use in the manufacture of a medicament to provide one or more of the following: promoting homeostasis, neuroprotection, brain protection, memory enhancement, enhanced focus and clarity, improved cognitive performance, improved working memory, improved neurotransmitter levels, faster response time, reduced oxidative stress, enhanced inhibitory control (attention control), anxiolytic effects, reduced irritability, antidepressant effects, anti-inflammatory effects, analgesic effects, suppression of depressive symptoms, cardiovascular benefits, blood pressure modulation, heart rate modulation, modulation of hypoglycemia-associated drowsiness / drowsiness upon entering ketosis, modulation of metabolic rate downregulation upon entering ketosis, anti-aging, and reduced energy crash.

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

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

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

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

16. 16. The method of any one of claims 12 to 15, which results in one or more of improved cognitive flexibility, improved sustained attention, improved working memory, enhanced inhibitory control, neuroprotection, memory enhancement, modulation of somnolence / drowsiness upon entering ketosis, or modulation of metabolic rate downregulation while in ketosis.

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

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

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

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

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