Amorphous calcium carbonate for improving athletic performance

Abstract

The present invention provides a method for enhancing and improving athletic performance in both professional and non-professional athletes by administering a composition comprising stabilized amorphous calcium carbonate. Enhanced athletic performance results from, among other things, enhanced muscle performance, enhanced recovery and endurance.

Description

[Technical Field]

[0001] The present invention provides compositions comprising stabilized amorphous calcium carbonate as a means for improving athletic performance, including improving aerobic and anaerobic performance, improving muscle performance, increasing muscle strength and endurance, and reducing muscle fatigue and time to recovery. [Background technology]

[0002] Most athletes, whether professional or recreational, are driven to achieve peak or at least improved athletic performance. This drive is based on a desire for self-improvement. Most recreational and professional athletes achieve these goals through prolonged exercise to improve athletic performance combined with proper diet and supplementation.

[0003] Muscle performance is a general term used to define overall muscle power, strength, and endurance. Muscle fatigue is a common symptom during sports and athletic activities, but is increasingly observed during the performance of everyday activities as a secondary consequence of many diseases and health conditions. Muscle fatigue is often defined as a reversible decrease in force production during activity. Muscle fatigue consists of a complex interplay of central and peripheral fatigue. The degree of peripheral muscle fatigue depends on several factors.

[0004] The most common way to improve muscle performance is through training, such as strength and endurance training. However, this approach is not always sufficient. In such cases, pharmacological treatments, nutritional supplements, or sometimes physical impulses such as electrical stimulation are used.

[0005] US2015 / 0250784 describes improving resistance to skeletal muscle fatigue by administering a skeletal muscle troponin activator to humans.

[0006] US 9,192,601 describes a method for promoting muscle tone or endurance by administering a composition comprising an AMPK agonist.

[0007] WO2008 / 041236 describes the treatment of musculoskeletal disorders with a composition comprising calcium carbonate (CaCO3) finely mixed with organic matter consisting essentially of chitin and polypeptides (PP). 、 The specific ratio between CaCO3 and the organic matter or polypeptide of interest is indicated.

[0008] WO2013 / 088440 discloses that the bioavailability of amorphous calcium carbonate is significantly higher than that of crystalline calcium carbonate. Meiron (Journal of Bone and Mineral Research, Vol. 26, No. 2, 2011, pp. 364-372) reached a similar observation and further stated that amorphous calcium carbonate is approximately 120 times more soluble than calcite (a crystalline form of calcium carbonate).

[0009] Verbitsky et al. (Journal of Applied Physiology, 1997, 83(2), 333-337) tested the effect of acute NaHCO3 ingestion on post-exercise fatigue and recovery in the quadriceps femoris muscles of six healthy male subjects. As cited by Verbitsky, previously published studies of the effect of NaHCO3 on anaerobic performance have shown mixed results, but there is consensus that ingestion of at least 300 mg / kg body weight of NaHCO3 prolongs high-intensity exercise. Based on the results of the experiments conducted, Verbitsky concluded that acute ingestion of 400 mg / kg of NaHCO3 is thus an effective means of increasing torque in isometric contractions, thus reducing muscle fatigue and improving recovery.

[0010] Zajac et al. (Journal of Sports Science and Medicine (2009) 8, 45-50) showed that oral administration of 300 mg / kg sodium bicarbonate can improve training intensity and swimming performance.

[0011] Requena et al. (Journal of Strength and Conditioning Research, 2005, 19(1), 213-224) reviewed several studies examining the effects of sodium bicarbonate and sodium citrate administration on human performance. Interestingly, when various doses were tested, only sodium bicarbonate at doses above 300 mg / kg was shown to have a significant effect. Requena et al. found that the benefits of exogenous intake of NaHCO3 and sodium citrate were not significant in H + We conclude that activities of sufficient duration to produce differences in ion gradients can be achieved. These activities are very intense, recruit fast motor units, and involve large muscle groups.

[0012] Lopes-Silva et al. (Journal of Sports Sciences, DOI: 10.1080 / 02640414.2018.1524739) conducted a systematic review and meta-analysis of the acute and chronic effects of sodium bicarbonate (NaHCO3) intake on Wingate performance. The meta-analysis found that acute NaHCO3 intake, even at high doses, did not improve Wingate test peak or mean power output, whereas chronic NaHCO3 intake did. However, to achieve improvement, subjects had to receive 300–500 mg / kg NaHCO3.

[0013] These studies suggest that sodium bicarbonate may help improve athletic performance. However, to obtain this improvement, athletes needed to receive a huge daily supplemental dose of approximately 20–35 g / day of NaHCO3, containing several times the maximum sodium recommended by health authorities. Athletes taking these levels of NaHCO3 reported side effects such as stomach pain and discomfort, nausea, and vomiting.

[0014] In a recent meta-analysis review by Sounders et al. (2016), Sounders found that beta-alanine supplementation had a significant overall ergogenic effect on exercise. Exercise duration was the greatest factor affecting the effectiveness of beta-alanine supplementation. Co-supplementation with beta-alanine and sodium bicarbonate produced the largest effect size and also produced greater increases than beta-alanine alone, but the increases appeared to be additive, not synergistic. No conclusions were reached regarding endurance and performance in long-term activities such as long-distance runners and swimmers, as well as game athletes.

[0015] There is an unmet need to develop and find safe and effective means to improve athletic performance, particularly in athletes, and to enhance subsequent athletic outcomes. Summary of the Invention

[0016] The present invention is based on the surprising discovery that athletic performance can be effectively improved by administering calcium carbonate, which is considered a poorly soluble substance. In particular, stabilized amorphous calcium carbonate (ACC) has been shown to efficiently increase muscle power and reduce muscle fatigue, thus improving muscle performance and potentially improving the athletic performance of people engaged in strenuous physical activity in general, and professional athletes in particular. In one aspect, the present invention provides a method for improving the athletic performance of a subject, comprising administering to said subject a composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer. In another aspect, the present invention provides a non-therapeutic use of a composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer in improving the athletic performance of a subject. According to another aspect, the present invention provides a composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer for non-therapeutic use in improving the athletic performance of a subject.

[0017] According to any one of the aspects of the present invention, improving athletic performance includes improving at least one of the subject's endurance, strength, and recovery from physical activity. According to some embodiments, improving athletic performance includes extending the duration of physical activity, performing it faster, or both. According to some embodiments, improving athletic performance includes improving muscle performance. According to some embodiments, improving muscle performance includes improving at least one of muscle strength, muscle endurance, muscle recovery, reduced muscle fatigue, and / or increased muscle power. According to some embodiments, improving muscle performance improves the subject's athletic performance. According to any one of the above embodiments, administration includes stable administration of ACC at 30-200 mg / kg / day. According to some embodiments, administration includes administration of ACC at 3000-10000 mg / day. The composition can be administered as a single dose or in several divided doses. According to any one of the above embodiments, the composition is formulated as a food supplement, which can be in the form of a powder, suspension, tablet, or capsule.

[0018] According to some embodiments, subjects to whom the compositions of the present invention can be used are athletes, including professional and non-professional athletes.

[0019] According to any one of the above embodiments, administration of the stabilized ACC is carried out by a route selected from sublingual, oral, and both sublingual and oral administration.

[0020] The compositions of the present invention comprise ACC stabilized by at least one stabilizer. According to some embodiments, the stabilizer is selected from the group consisting of organic acids, phosphorylated, phosphonated, sulfated, or sulfonated organic compounds, phosphate or sulfate esters of hydroxycarboxylic acids, phosphorylated amino acids, bisphosphonates, organic polysulfonates, hydroxyl-containing organic compounds, derivatives thereof, proteins, and any combination thereof. [Brief explanation of the drawings]

[0021] [Figure 1] The protocol design of the Wingate test performed on each subject and the measurements taken are shown (WAnT - Wingate test, HR - heart rate, RPE - rate of perceived exertion, La - lactate). [Figure 2] The peak and average power output of two cyclists are shown in Figure 2A. Cyclist 1: Peak power output (Figure 2A) and average power output (Figure 2B). Cyclist 2: Peak power output (Figure 2C) and average power output (Figure 2D). B represents CCC administration, and D represents ACC administration. Plac represents CCC administration as a placebo control. [Figure 3] Figure 3 shows the calculated fatigue index for cyclist 1 (Figure 3A) and cyclist 2 (Figure 3B). [Figure 4] Blood lactate levels for cyclist 1 (Figure 4A) and cyclist 2 (Figure 4B) are shown. B (triangles) represent administration of CCC, and D (circles) represent administration of ACC. [Figure 5] 10 shows an outline of the titration procedure for DMEM / F12 using various carbonate sources. [Figure 6] outlines the titration procedure for DPBS using different types of carbonate sources. [Figure 7] The effect of various CaCO3 sources on the pH of lactate-supplemented media shows a decrease in pH to about 6.8. DETAILED DESCRIPTION OF THE INVENTION

[0022] In accordance with the teachings of the present invention, it has been unexpectedly discovered that stable amorphous calcium carbonate (ACC) can significantly improve athletic performance and lead athletes to better outcomes. Applicant has previously shown that stable ACC has therapeutic properties in many pathological conditions, such as osteoporosis, pain, bone injury, and even cancer. It has also been surprisingly discovered that stable ACC can be useful in improving athletic performance in healthy individuals.

[0023] Proof of concept was conducted on highly professional athletes, for whom performance improvement is the most challenging. The idea behind selecting this group was that if ACC improves the results of highly trained athletes, it would undoubtedly be useful for other non-professionals. Professional athletes chronically suffer from various types of inflammation and injuries due to their extreme activities. Therefore, it was important to separate the effects of sublingually and / or orally administered stabilized ACC on pathological conditions from potential effects on athletic performance. Athletes with pathological conditions were initially treated for medical purposes. After the pathological conditions resolved, they continued taking stabilized ACC, and further efficacy on their performance was evaluated. As seen in the examples, athletes using ACC recovered from their previous pathological conditions and immediately improved their performance thereafter. In some cases, they even beat personal records achieved before the condition. Example 3 presents multiple examples of professional athletes competing in national and international championships who significantly improved their athletic performance and outcomes as a result of taking stabilized amorphous calcium carbonate.

[0024] Additionally, controlled experiments demonstrated that stabilized amorphous calcium carbonate was more effective at promoting muscle recovery than crystalline calcium carbonate used as a placebo. Therefore, ACC can effectively improve muscle performance and subsequent athletic performance in professional athletes, and even more so in non-professional athletes. Previous studies have suggested that the administration of very large amounts of sodium bicarbonate, which contain several times the maximum recommended sodium dose and cause significant side effects, may affect athletic performance. However, the required doses are intolerable to most people. The present invention provides a safe and tolerable method for improving athletic performance.

[0025] According to one aspect, the present invention provides a method for improving the athletic performance of a subject, comprising administering to said subject a composition comprising amorphous calcium carbonate stabilized by at least one stabilizer. According to another aspect, the present invention provides a composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer for use in improving the athletic performance of a subject. According to some embodiments, the use is non-therapeutic. Thus, according to one aspect, the present invention provides a composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer for non-therapeutic use in improving the athletic performance of a subject. According to some embodiments, the present invention provides a non-therapeutic use of a composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer to improve the athletic performance of a subject.

[0026] The term "non-therapeutic" as used herein refers to methods of human surgery, therapy, or diagnosis, excluding medical actions intended to treat a disease, medical, or psychological condition.

[0027] The terms "subject" or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock (including cows, pigs, etc.), pets (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats). According to other embodiments, the subject is an animal, such as a livestock or farm animal. According to some embodiments, the subject is a human subject. According to one embodiment, the subject is a healthy human subject with normal motor, muscular, and cardiovascular performance. According to some embodiments, the subject is a human subject. According to some embodiments, the subject is an athlete. Thus, in some embodiments, the present invention provides a composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer for non-therapeutic use in improving athletic performance in athletes.

[0028] In accordance with the present invention, the terms "athlete" and "sportsperson" are used interchangeably herein and refer to a person (male or female) who exercises for training, maintaining fitness, improving general health, and rehabilitation. The term athlete includes people with beginner, intermediate, and advanced levels of experience.

[0029] According to one embodiment, the athlete is a professional athlete. The terms "professional," "competitive sportsman," or "trained sportsman" are used interchangeably herein and are intended to mean any person who regularly engages in physical activity at a professional level, for example, a person who engages in strenuous physical activity or sport for at least three hours per week for at least two consecutive weeks. The term "professional athlete" also includes athletes who participate in national and international competitions and train daily to achieve records at the national and international levels. According to some embodiments, an athlete possesses natural or acquired characteristics, such as strength, agility, and endurance, required for physical activity or sport, especially one performed in a competitive setting. In some embodiments, the athlete is a non-professional athlete. The terms "non-professional," "amateur," or "non-competitive sportsman" are intended to mean a person who engages in physical activity sporadically and non-professionally.

[0030] The term "athletic performance" is used herein to refer collectively to any type of athletic activity, event, exercise, training, routine, etc. It is a compound term relating to at least one of the following: skill, performance, strength, endurance, speed, work rate, and recovery of a subject after engaging in physical activity, e.g., strenuous physical activity.

[0031] As used herein, the terms "improved athletic performance," "enhanced athletic performance," or linguistic variations thereof, should be understood to encompass an improvement in at least one sports parameter. Non-limiting examples of such improvements include increased steroids, decreased cortisol, decreased fatigue, faster recovery from exercise, decreased muscle soreness, improved endurance, improved muscle strength, improved muscle size, enhanced athletic performance, improved sports-related decision-making, improved selective attention to sports-related stimuli, improved concentration during a sports event, and improved mental resilience during a sports event. According to some embodiments, improved athletic performance includes extending the duration of physical activity, performing it faster, and combinations thereof. According to some embodiments, improved athletic performance includes improving endurance, reduced fatigue, faster recovery, and any combination thereof. The term "improved athletic performance" refers to a change in athletic performance, where the change is defined as the difference in performance between a subject receiving administration according to the present invention and a subject with a similar condition or a subject not receiving administration according to the present invention. In some embodiments, the change is detected or measured in the same subject. If such a change is positive for the subject, the change is considered an improvement. The exact definition of athletic performance varies depending on the type of athletic activity. According to some embodiments, improving athletic performance includes improving athletic performance.

[0032] As used herein, the term "physical activity" refers to any physical exercise, training, sport, fitness exercise, and generally any physical movement. Physical activity can be short-term or long-term activity.

[0033] As used herein, the term "fatigue relief" or linguistic variations thereof should be understood to encompass relief of one or more types of general fatigue, such as general physical fatigue, general mental fatigue, cardiac fatigue, pulmonary fatigue, muscular fatigue, aerobic fatigue, anaerobic fatigue, tiredness, exhaustion, weariness, feeling worn-out, asthenia, lethargy, weakness, exercise intolerance, lack of energy, weakness, and the like.

[0034] As used herein, the term "faster recovery" or linguistic variations thereof should be understood to encompass one or more of general recovery after exercise, muscle recovery, cardiac and / or pulmonary recovery, blood system gas concentration recovery, mental recovery, energy recovery, physical and mental stress reduction, metabolic recovery, immediate recovery, short-term recovery, and training recovery.

[0035] As used herein, the terms "enhanced athletic performance," "improved athletic performance," or linguistic variations thereof, should be understood to encompass one or more of enhanced running endurance, enhanced running speed, enhanced swimming endurance, enhanced swimming speed, enhanced jump length, enhanced jump height, enhanced cycling endurance, enhanced cycling speed, enhanced throwing distance, enhanced weightlifting, enhanced rowing endurance, enhanced rowing speed, enhanced walking endurance, enhanced walking speed, enhanced sports game endurance, and enhanced climbing endurance, and enhanced performance in other similar physical activities.

[0036] As used herein, the term "exercise" refers to any form of physical activity. In one embodiment, exercise improves or maintains physical fitness. The term "exercise" may refer to strength exercise and endurance exercise. The terms "endurance exercise" and "strength exercise" are well known in the art. In particular, endurance exercise aims to increase cardiovascular endurance, while strength exercise aims to increase short- or long-term muscle strength. According to another embodiment, improving athletic performance includes improving pulmonary capacity and endurance. According to another embodiment, improving athletic performance includes improving personal records by professional athletes.

[0037] According to any aspect of the present invention, improving athletic performance includes improving at least one of an athlete's strength, endurance, recovery, and any combination thereof. According to some embodiments, improving athletic performance includes improving a subject's athletic performance. According to some embodiments, improving athletic performance includes improving an athlete's strength. According to other embodiments, improving athletic performance includes improving an athlete's endurance. According to particular embodiments, improving athletic performance includes improving an athlete's recovery, i.e., reducing the time required to recover from exercise. According to one embodiment, improving athletic performance includes improving aerobic performance. According to another embodiment, improving athletic performance includes improving cardiovascular performance. According to some embodiments, improving athletic performance includes improving anaerobic activity. According to another embodiment, improving athletic performance includes improving both aerobic and anaerobic activity. According to some embodiments, improving athletic performance includes improving aerobic capacity and / or aerobic power.

[0038] The terms "anaerobic exercise" and "anaerobic activity" are used interchangeably herein and refer to exercise that does not increase the body's oxygen demand. Anaerobic exercise typically involves short bursts of high-intensity exercise.

[0039] The terms "aerobic exercise" and "aerobic activity" refer to exercise that increases the body's oxygen demand. Typically, aerobic exercise may involve increased respiratory and heart rates over a prolonged period of time. According to any one of the above aspects and embodiments of the present invention, improving exercise capacity includes improving muscle performance. Thus, according to any one of the above aspects and embodiments, the method or use includes improving muscle performance. According to some embodiments, improving muscle performance is selected from improving muscle strength, improving muscle endurance, enhancing muscle recovery, increasing muscle power, reducing muscle fatigue, and any combination thereof. According to some embodiments, improving muscle performance includes reducing muscle soreness caused by physical training. According to one embodiment, improving muscle performance includes improving or enhancing muscle endurance. According to another embodiment, improving muscle performance includes improving or enhancing muscle recovery. According to some embodiments, improving muscle performance includes improving or enhancing muscle strength. According to another embodiment, improving muscle performance includes reducing muscle fatigue. According to one embodiment, improving muscle performance includes increasing muscle power. According to some embodiments, improving muscle performance includes improving joint mobility. According to other embodiments, improving muscle performance includes reducing muscle pain, particularly muscle pain resulting from exercise or physical activity.

[0040] According to any of the above embodiments, improving muscle performance, such as improving muscle strength, improving muscle endurance, enhancing muscle recovery, reducing muscle fatigue, increasing muscle power, and any combination thereof, includes improving muscle during or after physical activity or exercise.

[0041] According to another embodiment, improving muscle performance comprises enhancing energy use by muscles when performing physical activity or at rest. According to another embodiment, improving muscle performance comprises increasing muscle cell metabolism. Measuring cellular metabolism can be performed by any known method.

[0042] As used herein, the term "muscle function" refers to at least one of muscle mass and muscle strength, unless otherwise specified.

[0043] As used herein, the term "muscular endurance" refers to the ability of a muscle group to perform a submaximal contraction for an extended period of time. Muscular endurance can be measured in any known manner, such as by measuring a fatigue index calculated as a percentage of the difference between the total work of the last 10 repetitions and the first 10 repetitions.

[0044] As used herein, the term "muscle strength" refers to the amount of force a muscle, or group of muscles, can exert collectively. Muscle strength can be assessed in a variety of ways, including by dynamometers, isokinetic devices such as stationary cycles and therapeutic mills, torque (Nm) and angle (degrees) measurements, grip strength, and clinical trials such as single-repetition maximal strength tests, time-dependent tests of muscular endurance, time-dependent tests of muscular fatigue, or time-dependent tests of muscular endurance and fatigue. For maximal strength tests, peak torque can be defined as the maximum torque generated in one of several repetitions.

[0045] The term "peak power" refers to the maximum output or work production in a particular time. The term "average power" is the average rate at which work is done.

[0046] The terms "muscle fatigue" or "skeletal muscle fatigue" refer to a decrease in contractile capacity after repeated use and represent a combination of central fatigue (limitations of the central and peripheral nervous systems to maintain activity) and peripheral fatigue (loss of intrinsic muscle function, such as a decrease in the efficacy of excitation-contraction coupling). Muscle fatigue can be assessed by the anaerobic fatigue and anaerobic capacity of the Wingate test. The Wingate test, often performed on a cycle ergometer, consists of a series of periods of pedaling at maximum speed against a constant force. The number of revolutions pedaled at each 5-second interval during the test is counted and used to determine power and work rate data. Anaerobic fatigue represents the percentage loss of power from the beginning to the end of the Wingate test. Anaerobic capacity is the total amount of work completed during the test period.

[0047] As used herein, the term "muscle recovery" refers to restoring muscle condition to its original or better state before exercise. Thus, "enhancing muscle recovery" refers to reducing or shortening the time required for muscle recovery. A measurable parameter that can indicate a reduction in muscle recovery time can be a decrease in blood lactate levels over time.

[0048] The term "muscle" as used herein refers to skeletal muscle, as well as other non-skeletal striated muscles such as the diaphragm and extraocular muscles, and cardiac muscle. Thus, according to some embodiments, the muscle is selected from the group consisting of skeletal muscle, cardiac muscle, and smooth muscle. According to some embodiments, the present invention provides for improving the performance of skeletal muscle, cardiac muscle, or smooth muscle. According to other embodiments, the present invention provides for the non-therapeutic use of the composition of the present invention for improving the performance of skeletal muscle, cardiac muscle, or smooth muscle.

[0049] The terms "improved muscle strength" and "enhanced muscle strength" are used interchangeably herein and refer to a change in muscle performance, where the change is defined as the difference in muscle performance between a subject treated or administered according to the present invention and a similarly affected subject not treated or administered. In some embodiments, the change is detected or measured in the same subject. If such a change is positive for the subject, the change is considered an improvement. Typically, improved muscle performance is increased muscle performance.

[0050] While improvements in athletic performance in professional athletes may be small when measured as a percentage change, they are clearly significant in absolute terms. According to one embodiment, administering stabilized ACC improves athletic performance in professional athletes by about 0.5% to about 10%, about 1% to about 8%, or about 2% to about 6%. Athletic performance can be reflected in any measurable value, such as speed (running or swimming), weight (lifted), number of sets performed, distance (a person can jump, run, or swim), and the length of time an athlete can sustain an exercise.

[0051] The improvement in athletic performance in non-professional athletes can be even more significant. According to some embodiments, administration of a stabilized ACC enhancer improves athletic performance by about 10% to about 600%, about 20% to about 500%, about 30% to about 400%, about 40% to about 300%, about 50% to about 200%, about 60% to about 150%, or about 70% to about 100%. According to some embodiments, stabilized ACC improves athletic performance by about 5% to about 50%, about 7% to about 40%, about 10% to about 30%, about 15% to about 25%, or about 5% to about 20%. According to other embodiments, administration of stabilized ACC improves athletic performance by about 10% to about 100%, about 20% to about 90%, about 30% to about 80%, about 40% to about 70%, or about 50% to about 60%. A 100% enhancement means a two-fold increase in the improvement of a parameter, e.g., muscle strength, muscle endurance, a 200% enhancement means a three-fold increase in the parameter, etc. According to some embodiments, athletic performance is improved by about 100% to about 500%, about 120% to about 400%, about 150% to about 300%.

[0052] According to one embodiment, administration of stabilized ACC enhances muscle performance, e.g., improving muscle strength, power, and / or endurance, by about 10% to about 600%, about 20% to about 500%, about 30% to about 400%, about 40% to about 300%, about 50% to about 200%, about 60% to about 150%, or about 70% to about 100%. According to some embodiments, administration of stabilized ACC enhances muscle performance, e.g., improving muscle strength, power, and / or endurance, by about 5% to about 50%, about 7% to about 40%, about 10% to about 30%, about 15% to about 25%, or about 5% to about 20%. According to another embodiment, administration of stabilized ACC enhances muscle performance by about 10% to about 100%, about 20% to about 90%, about 30% to about 80%, about 40% to about 70%, or about 50% to about 60%, e.g., improving muscle strength, power, and / or endurance. A 100% enhancement represents a two-fold increase in the improvement of a parameter, e.g., muscle strength, muscle endurance, etc., a 200% enhancement represents a three-fold increase in the parameter, etc. According to some embodiments, muscle performance is enhanced by about 100% to about 500%, about 120% to about 400%, or about 150% to about 300%. According to some embodiments, the enhancement of muscle performance includes a reduction in muscle fatigue or a reduction in muscle soreness. According to some embodiments, reducing fatigue includes reducing fatigue by about 5% to about 100%, about 10% to about 90%, about 20% to about 80%, about 30% to about 70%, or about 40% to about 60%. A 100% reduction means a complete reduction in the characteristic. According to some embodiments, administering stabilized ACC improves muscle performance in professional athletes by about 0.5% to about 10%, about 1% to about 8%, or about 2% to about 6%.

[0053] According to any one of the above embodiments, muscle performance refers to muscle performance of healthy muscles. Thus, according to any one of the above embodiments, the muscles are healthy muscles, i.e., muscles of a healthy person.

[0054] According to one embodiment, the method of the present invention comprises increasing athletic performance in athletes, sportsmen, or healthy individuals. According to another embodiment, the method comprises improving muscle performance in athletes, sportsmen, or healthy individuals.

[0055] According to some embodiments, the present invention provides a composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer for non-therapeutic use in improving muscle performance in a subject. According to some embodiments, the present invention provides a method for improving muscle performance in a subject, comprising administering to the subject a composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer. According to some embodiments, the present invention provides a non-therapeutic use of a composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer in improving muscle performance in a subject, such as an athlete. According to some embodiments, the athlete is a professional athlete.

[0056] The term "administration" or "administration of" a substance, compound, or composition to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or composition can be administered enterally or parenterally. Enteral refers to administration via the gastrointestinal tract, including orally, sublingually, or rectally. Parenteral administration includes intravenous, intradermal, intramuscular, intraperitoneal, subcutaneous, ocular, sublingual, intranasal, inhalation, intraspinal, intracerebral, and transdermal (e.g., via absorption through the skin duct) administration. A compound or composition can also be suitably introduced via rechargeable or biodegradable polymeric devices or other "drug release" and "controlled release" devices, e.g., patches and pumps, or formulations that provide extended, slow, or controlled release of the compound or composition. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended periods. In some aspects, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug or medical food.

[0057] According to some embodiments, the administration is oral. According to other embodiments, the administration is sublingual. According to further embodiments, the administration is a combination of oral and sublingual administration.

[0058] According to certain embodiments, administration, e.g., oral administration, sublingual administration, or a combination thereof, comprises administering less than 200 mg / kg of calcium per day as stabilized ACC. Dosage, according to any one of the aspects and embodiments of the present invention, refers to the amount of elemental calcium in ACC. According to one embodiment, the method of the present invention comprises administering less than 150 mg / kg / day or less than 100 mg / kg / day of calcium as stabilized ACC. According to another embodiment, the ACC dosage is less than 50 mg / kg / day, less than 30 mg / kg / day, or less than 20 mg / kg / day of calcium as stabilized ACC. According to some embodiments, administration, e.g., oral, sublingual, or a combination thereof, according to the present invention comprises administering 5-150, 10-120, 15-100, 20-80, 30-70, or 40-60 mg / kg / day of calcium as stabilized ACC. According to certain embodiments, administration according to the present invention, e.g., oral, sublingual, or combined administration, comprises 5-80, 10-75, 15-70, 20-65, 25-60, 30-55, 35-50, or 40-45 mg / kg / day of calcium as stabilized ACC. According to some embodiments, administration according to the present invention, e.g., oral, sublingual, or combined administration, comprises about 10-45, about 15-40, or about 20-35 mg / kg / day of calcium as stabilized ACC. According to further embodiments, administration according to the present invention, e.g., oral, sublingual, or combined administration, comprises 0.1-30, 0.2-28, 0.3-26, 0.5-24, 1-22, 2-20, 3-18, 3-16, 4-15, 5-14, 6-12, or 8-10 mg / kg / day of calcium as stabilized ACC. According to some embodiments, administration according to the present invention, e.g., oral, sublingual, or combined administration, comprises administration of 0.2-10, 0.5-8, 0.8-6, 1-5, 1.5-4, or 2-3 mg / kg / day of calcium as stabilized ACC. According to other embodiments, administration comprises administration of 500-8000 mg / day, 800-6000, or 100-4000 mg / day of ACC. According to some embodiments, administration comprises administration of 200-3000 mg / day, 400-2500, or 600-2000 mg / day of calcium as stabilized ACC.According to other embodiments, administration comprises administration of 800-4000 mg / day, 1000-3000, or 1500-2500 mg / day of calcium as stabilized ACC.

[0059] According to some embodiments, administration, e.g., oral administration, sublingual administration, or combined administration, comprises daily administration of about 600 to about 23,500 mg of ACC. According to one embodiment, administration comprises administration of 600 to 20,000, 800 to 18,000, 1,000 to 15,000, 1,200 to 12,000, 1,500 to 10,000, or 2,000 to 8,000 mg / day of ACC. According to some embodiments, administration comprises administration of 1,000 to 12,000, 2,000 to 11,000, 3,000 to 10,000, 3,500 to 9,000, or 4,000 to 8,000 mg / day of ACC.

[0060] According to some embodiments, the administration comprises administering 10-350 mg / kg / day of stabilized ACC. According to some embodiments, the administration comprises administering 20-300, 30-250, 40-200, 50-150, or 30-120 mg / kg / day of ACC.

[0061] According to some embodiments, administration comprises administration in a single dose or in multiple separate doses, for example, the daily dose can be divided into 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 separate doses.

[0062] According to some embodiments, administration is short-term, e.g., for at least 1, 2, 3, 5, or 7 days. According to other embodiments, administration is for 1, 2, 3, or 4 weeks. According to further embodiments, administration is long-term, such as for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. According to other embodiments, administration is for one year or more, such as for 2, 3, 4, 5, or more years.

[0063] According to some embodiments, the composition for sublingual administration is in the form of a powder of ACC. The powder for sublingual administration is composed of ACC particles.

[0064] The term "particle" as used herein refers to individual microparticles or nanoparticles of ACC stabilized by the stabilizer defined above, as well as their aggregates or agglomerates. According to some embodiments, the particles are primary particles of stabilized ACC. The basic nanoparticles range from 5 to 500 nm, 10 to 300 nm, or 20 to 100 nm. Often, these nanoparticles quickly agglomerate and aggregate into much larger secondary particles. These aggregates and agglomerates can then be broken down into smaller particles by grinding and dissolution techniques. According to other embodiments, the particles are agglomerates or aggregates of primary particles, i.e., secondary particles. As used herein, the term "particle size" refers to a measurement of the representative diameter of secondary particles, such as aggregates or broken agglomerates, in at least one dimension.

[0065] The particle size of the agglomerates can be adjusted to a range by a combination of milling and sieving techniques. In some embodiments, at least 70% of the processed particles of the composition have a particle size of 600 μm or less. In other embodiments, at least 80%, at least 85%, at least 90%, or at least 95% of the particles of the composition have a particle size of 600 μm or less. In some embodiments, at least 80%, at least 85%, at least 90%, or at least 95% of the particles of the composition have a particle size of 500 μm or less. In some embodiments, at least 80%, at least 85%, at least 90%, or at least 95% of the particles of the composition have a particle size of 400 μm or less. In some embodiments, at least 80%, at least 85%, at least 90%, or at least 95% of the particles of the composition have a particle size of 300 μm or less. In some embodiments, at least 80%, at least 85%, at least 90%, or at least 95% of the particles of the composition have a particle size of 200 μm or less. In some embodiments, at least 80%, at least 85%, at least 90%, or at least 95% of the particles of the composition have a particle size of 100 μm or less. In some embodiments, at least 80%, at least 85%, at least 90%, or at least 95% of the particles of the composition have a particle size of 70, 50, or 30 μm or less. According to some embodiments, the particle size is about 20 to about 500 μm, about 30 to about 450 μm, or about 50 to about 400 μm.

[0066] According to any one of the above embodiments, the ACC is a stabilized ACC, i.e., an ACC that remains amorphous for extended periods of time even in humid conditions or in an aqueous environment.

[0067] According to any one of the above embodiments, the ACC is stabilized by at least one stabilizer. The terms "stabilizing agent" and "stabilizer" are used interchangeably herein and refer to any molecule, ion, or substance that contributes to preserving calcium carbonate in an amorphous state during the manufacture, formulation, and / or storage of the ACC. According to the teachings of the present invention, the ACC acts as an active agent that provides improved exercise and muscle performance. According to the teachings of the present invention, any ACC that maintains stability can be used. Any compound that can stabilize ACC in its amorphous form is suitable for the practice of the present invention. The terms "stable ACC" and "stabilized ACC" are used interchangeably herein and refer to calcium carbonate that is maintained in an amorphous form for an extended period of time with less than about 30% or about 30% conversion to crystalline form.

[0068] The essence of the present invention is to provide athletes with ACC, thereby improving their performance. This goal is achieved as long as the ACC remains amorphous. Many stabilizers have previously been shown, for example by the applicant, to effectively stabilize the amorphous form of ACC under aqueous conditions. Some of these stabilizers are listed below.

[0069] In certain embodiments, the stabilizer is a single agent. In other embodiments, the use of several stabilizers is encompassed. In some cases, the stabilizer is present within the molecular matrix of the ACC particle. In some cases, the stabilizer is stored externally, and in other cases, they are both internal and external. The internal stabilizer or combination of stabilizers may be the same or different from the external stabilizer.

[0070] ACC stabilizer The stabilizer may include, but is not limited to, molecules having one or more functional groups selected from hydroxyl, carboxyl, ester, amine, phosphino, phosphono, phosphate, sulfonyl, sulfate, or sulfino groups. The hydroxy-containing compound in combination with the hydroxide optionally also has other functional groups, such as carboxyl, but the hydroxyl is not esterified.

[0071] According to some embodiments, the stabilizer has low or no toxicity to mammalian cells or organisms, particularly humans. According to some embodiments, the stabilizer is food, dietary supplement, or pharmaceutical grade.

[0072] In certain embodiments, the ACC stabilizer is, independently in each occurrence, an organic acid, a phosphorylated, phosphonated, sulfated or sulfonated organic compound, a phosphoric or sulfate ester of a hydroxyl carboxylic acid, an organic amine compound, a hydroxyl-containing organic compound, an organic phosphorus compound or a salt thereof, a phosphorylated amino acid and its derivatives, a bisphosphonate compound, an organic phosphate compound, an organic phosphonate compound, an inorganic phosphoric acid, an organic compound with multiple functional groups as defined above, an inorganic phosphate and polyphosphate compound, an organic compound having a polyphosphate chain, an organic surfactant, a bioessential inorganic ion, or any combination thereof.

[0073] According to some embodiments, the stabilizer is an organic acid. According to certain embodiments, the organic acid is selected from ascorbic acid, citric acid, lactic acid, acetic acid, oxalic acid, malonic acid, glutaconic acid, succinic acid, maleic acid, lactic acid, and aconitic acid, and optionally contains a compound having at least two carboxyl groups and a molecular weight of 250 g / mol or less, such as citric acid, tartaric acid, and malic acid. According to one particular embodiment, the stabilizer is citric acid.

[0074] In another embodiment, the phosphate ester of a hydroxyl carboxylic acid is phosphoenolpyruvic acid. In another embodiment, the phosphate or sulfate ester of a hydroxyl carboxylic acid comprises an amino acid. Examples of such esters are phosphoserine, phosphothreonine, sulfoserine, sulfothreonine, and phosphocreatine.

[0075] The hydroxyl-containing compounds combined with the hydroxides can include, for example, mono-, di-, tri-, oligo-, and polysaccharides such as sucrose or other polyols such as glycerol. The hydroxyl-containing compounds can further include hydroxy acids such as citric acid, tartaric acid, malic acid, etc., or hydroxyl-containing amino acids such as serine or threonine. Each possibility represents a separate embodiment of the present invention.

[0076] Some specific, non-limiting examples of such ACC stabilizers include phytic acid, citric acid, sodium pyrophosphate dibasic, adenosine 5'-monophosphate (AMP) sodium salt, adenosine 5'-diphosphate (ADP) sodium salt and adenosine 5'-triphosphate (ATP) disodium salt hydrate, phosphoserine, phosphorylated amino acids, food-grade surfactants, sodium stearoyl lactylate, and combinations thereof.

[0077] According to some embodiments, the stabilizer comprises at least one component selected from phosphate or sulfate esters of hydroxyl carboxylic acids, such as phosphoenolpyruvate, phosphoserine, phosphothreonine, sulfoserine, or sulfothreonine, and a hydroxyl-containing organic compound selected from mono-, di-, tri-, oligo-, and polysaccharides, e.g., sucrose, mannose, glucose.

[0078] The hydroxyl-containing compound may further comprise at least one alkali hydroxide, such as sodium hydroxide or potassium hydroxide. Phosphorylated acids may be present in oligopeptides and polypeptides. In other embodiments of the present invention, the stabilizer is an organic acid selected from monocarboxylic or multicarboxylic acids, such as dicarboxylic or tricarboxylic acids. Each possibility represents a separate embodiment of the present invention. The organic acid may be as defined above.

[0079] In some embodiments of the present invention, the ACC stabilizer is selected from phosphorylated amino acids, polyols, and combinations thereof. In some embodiments, the stable ACC comprises a phosphorylated compound as a stabilizer, where phosphorylation is performed on the hydroxyl group of an organic compound. In some embodiments, the stable ACC comprises a stabilizer selected from the group consisting of citric acid, phosphoserine, phosphothreonine, and combinations thereof. Non-limiting examples of stabilizers containing phosphate, phosphite, phosphonate groups and their salts or esters include phytic acid, dimethyl phosphate, trimethyl phosphate, sodium pyrophosphate, tetraethyl pyrophosphate, ribulose bisphosphate, etidronic acid and other medical bisphosphonates, 3-phosphoglyceric acid, glyceraldehyde 3-phosphate, 1-deoxy-D-xylulose-5-phosphate sodium salt, diethylenetriaminepentakis(methylphosphonic acid), nitrilotri(methylphosphonic acid), 5-phospho-D-ribose 1-diphosphate pentasodium salt, adenosine 5'-diphosphate sodium salt, adenosine 5'-triphosphate disodium salt hydrate. , α-D-galactosamine 1-phosphate, 2-phospho-L-ascorbic acid trisodium salt, α-D-galactose 1-phosphate dipotassium salt pentahydrate, α-D-galactosamine 1-phosphate, O-phosphorylethanolamine, disodium salt hydrate, 2,3-diphospho-D-glyceric acid pentasodium salt, phospho(enol)pyruvate monosodium salt hydrate, D-glyceraldehyde 3-phosphate, sn-glycerol 3-phosphate lithium salt, D-(-)-3-phosphoglyceric acid disodium salt, D-glucose 6-phosphate sodium salt, phosphatidic acid, ibandronate sodium salt, phosphonoacetic acid, DL-2-amino-3-phosphonopropionic acid, or a combination thereof.

[0080] In some embodiments, the stabilizer may be a bioessential inorganic ion, including, inter alia, Na, K, Mg, Zn, Fe, P, S, N, P, or S in the oxide phase, or N as an ammonia or nitro group.

[0081] Stabilized ACC may be stabilized by multiple stabilizers, for example, two, three, or more stabilizers. Stabilizers can be added during the synthesis and precipitation of ACC primary particles and are defined as "internal stabilizers." Stabilizers can be added after synthesis and attached to the outer surface of the particles and are defined as "external stabilizers." In some embodiments where both internal and external stabilizers are used, the internal and external stabilizers are similar. In other embodiments, the internal and external stabilizers are different stabilizers. The internal and external stabilizers may be independent, as defined above, or each may be a combination of multiple types of stabilizers.

[0082] A stable ACC can include three or more stabilizers, one or more of which are added to the ACC during its formation and precipitation.

[0083] According to some embodiments, at least one stabilizer is selected from the group consisting of polyphosphates, bisphosphonates, phosphorylated amino acids, citric acid, and any combination thereof. In some embodiments, multiple stabilizers are added, for example, two, three, or four stabilizers.

[0084] According to one embodiment, ACC is stabilized by a combination of phosphoserine and citrate. According to another embodiment, ACC is stabilized by a combination of triphosphate and citrate.

[0085] According to some embodiments, the stabilizer is a polyphosphate or a pharmaceutically acceptable salt thereof. According to some embodiments, the polypolyphosphate is a physiologically compatible, water-soluble polyphosphate selected from the group consisting of sodium, potassium, and any other essential cation of polyphosphate. In one embodiment, the polyphosphate is an organic or inorganic polyphosphate. As used herein, the term "polyphosphate" refers to a polymeric ester of PO4. According to some embodiments, the polypolyphosphate is a physiologically compatible, water-soluble polyphosphate selected from the group consisting of sodium polyphosphate and potassium polyphosphate. In some embodiments, the polyphosphate is an inorganic polyphosphate or a pharmaceutically acceptable salt thereof. Non-limiting examples of such salts are Na, K, Mg, Mn, and Zn. According to some embodiments, the inorganic polyphosphate contains 2 to 10 phosphate groups, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 phosphate groups. According to some embodiments, the inorganic polyphosphate is selected from pyrophosphate, triphosphate, and hexametaphosphate. According to one embodiment, the stabilizer is polyphosphate or a pharmaceutically acceptable salt thereof, such as sodium pyrophosphate. According to another embodiment, the stabilizer is triphosphate or a pharmaceutically acceptable salt thereof, such as sodium triphosphate. The terms "triphosphate" and "tripolyphosphate" are used interchangeably herein. According to a further embodiment, the stabilizer is hexametaphosphate or a pharmaceutically acceptable salt thereof, such as sodium hexametaphosphate.

[0086] According to some embodiments, the stabilizer is a bisphosphonate or a pharmaceutically acceptable salt thereof. Non-limiting examples of salts are Na, K, Mg, Mn, and Zn.

[0087] The term "bisphosphonate" as used herein refers to an organic compound having two phosphonate (PO(OH)2) groups. This term further relates to compounds having a PO3-organo-PO3 backbone. Most typically, there is a series of bisphosphonates used as pharmaceuticals for treating osteoporosis. According to some embodiments, the bisphosphonate is selected from the group consisting of etidronic acid, zoledronic acid, medronic acid, alendronic acid, and pharmaceutically acceptable salts thereof. According to some embodiments, the stabilizer is etidronic acid or a pharmaceutically acceptable salt thereof. According to another embodiment, the stabilizer is zoledronic acid or a pharmaceutically acceptable salt thereof. According to further embodiments, the stabilizer is medronic acid or a pharmaceutically acceptable salt thereof. According to certain embodiments, the stabilizer is alendronic acid or a pharmaceutically acceptable salt thereof.

[0088] In certain embodiments, the stabilizer is a phosphorylated amino acid. In one embodiment, the phosphorylated amino acid is phosphoserine. In another embodiment, the phosphorylated amino acid is phosphothreonine.

[0089] According to some embodiments, the ACC composition comprises a combination of the stabilizers disclosed above.

[0090] According to some embodiments, the stabilizer is an inorganic polyphosphate or bisphosphonate as defined above, and the molar ratio between the P atoms of the stabilizer and the Ca atoms of the ACC (P:Ca molar ratio) is about 1:90 to 1:1. In one embodiment, the P:Ca molar ratio is about 1:40 to about 1:1. In a further embodiment, the P:Ca molar ratio is about 1:35 to about 1:2. In certain embodiments, the P:Ca molar ratio is about 1:30 to about 1:3. In certain embodiments, the P:Ca molar ratio is about 1:28 to about 1:3. In other embodiments, the P:Ca molar ratio is about 1:25 to about 1:4. In further embodiments, the P:Ca molar ratio is about 1:20 to about 1:5. In another embodiment, the P:Ca molar ratio is about 1:20 to about 1:6. In certain embodiments, the P:Ca molar ratio is about 1:15 to about 1:5. In another specific embodiment, the P:Ca molar ratio is about 1:25 to about 1:5. According to some embodiments, the inorganic polyphosphate is pyrophosphate, triphosphate, hexametaphosphate, or a pharmaceutically acceptable salt thereof. According to another embodiment, the bisphosphonate is alendronate, etidronate, zoledronic acid, or medronate, and the P:Ca molar ratio is as defined above.

[0091] According to some embodiments, the calcium content (Ca content) of such compositions containing a stabilizer is about 1% to about 39%, about 5% to about 39%, about 10% to about 39%, about 15% to about 39%, about 20% to about 38%, about 25% to about 38%, or about 30% to about 38% by weight of the dry ACC particles. The terms "Ca content" and "calcium content" are used interchangeably herein and refer to the calcium content of the ACC in the final composition.

[0092] In certain embodiments, the P:Ca molar ratio is about 1:40 to about 1:1, and the Ca content is about 20% to about 39% by weight. In some embodiments, the molar ratio is 1:28 to about 1:3, and the Ca content is about 30% to about 38% by weight of the dry ACC particles. In other embodiments, the molar ratio is 1:25 to about 1:5, and the Ca content is about 30% to about 36% by weight of the dry ACC particles.

[0093] According to some embodiments, the stabilized ACC powder contains about 1% to about 18%, about 4% to about 15%, and about 6% to about 10% absorbed and adsorbed water by weight. According to some embodiments, the stabilizer is a polyphosphate or bisphosphonate, and the molar ratio of P atoms of the stabilizer to Ca atoms of the ACC is about 1:90 to 1:1.

[0094] According to some embodiments, the stabilizer is selected from the group consisting of polyphosphate, phosphorylated amino acid, bisphosphonate, citric acid, tartaric acid, and any combination thereof. According to one embodiment, the polyphosphate is selected from the group consisting of triphosphate, pyrophosphate, and hexametaphosphate, the phosphorylated amino acid is phosphoserine or phosphothreonine, and the bisphosphonate is selected from the group consisting of alendronate, etidronic acid, zoledronic acid, and medronic acid. According to some embodiments, the polyphosphate is inorganic polyphosphate.

[0095] According to one embodiment, the stabilizer is selected from the group consisting of organic acids, phosphorylated, phosphonated, sulfated or sulfonated organic compounds, phosphoric or sulfate esters of hydroxycarboxylic acids, phosphorylated amino acids, bisphosphonates, organic polyphosphates, hydroxyl-containing organic compounds, derivatives thereof, proteins and any combination thereof.

[0096] According to another embodiment, the stabilizer is selected from the group consisting of phosphoserine, adenosine triphosphate, adenosine diphosphate, phytic acid, citric acid, etidronic acid, pyrophosphate, polyphosphate, inorganic triphosphate, hexametaphosphate, ethanol, and any combination thereof.

[0097] In most cases, ACC contains 1-20 wt% adsorbed water, preferably less than 10 wt%, and remains stable in the presence of stabilizers and further stored under dry conditions. The ACC powder used in the examples contained approximately 6-10 wt% water when formulated. Regarding calcium content, this means that the calcium content of ACC is in the practical range of 28-38 wt% of its composition. For practical calculations, the average calcium content is defined as 30 wt% in this application.

[0098] As used herein, the term "pharmaceutical composition" refers to any composition comprising at least stabilized ACC, and optionally at least one additional pharmaceutically acceptable carrier, stabilizer, and / or bulking agent.

[0099] According to any of the above aspects and embodiments, the composition of the present invention is a food supplement.Therefore, in some embodiments, the present invention provides a food supplement comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer for use in improving the athletic performance of a subject. According to some embodiments, the use is non-therapeutic. In some embodiments, the present invention provides a non-therapeutic use of a food supplement comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer for improving the athletic performance of a subject. According to some embodiments, improving athletic performance includes improving muscle performance.

[0100] The formulation of the compositions of the present invention can be tailored to suit the intended use. In particular, the compositions can be formulated using methods known in the art to provide rapid, continuous, or delayed release of the active ingredient after administration to a mammal. For example, the formulation can be any one selected from plasters, granules, lotions, liniments, lemonades, flavored waters, powders, syrups, eye ointments, liquids and solutions, aerosols, extracts, elixirs, ointments, liquid extracts, emulsions, suspensions, decoctions, infusions, eye drops, tablets, injectables, injections, spirits, capsules, creams, lozenges, colorings, pastes, pills, and soft or hard gelatin capsules. In some embodiments, the composition is a powder. In certain embodiments, the composition is a powder for sublingual administration. In other embodiments, the composition is in the form of a tablet or capsule for oral administration. In some embodiments, the composition for oral administration can be an enterically coated composition or an enteric-coated capsule.

[0101] The formulation may also include excipients to aid in manufacturing, storage, and efficacy of the medication. Examples include silicon dioxide and microcellulose as anti-caking agents, magnesium stearate as a lubricant, and sucralose, mannitol, sorbitol, erythritol, menthol, and citric acid as flavoring agents.

[0102] According to some embodiments, the composition is a dietary supplement composition.As used herein, the term "dietary supplement composition" refers to a composition suitable for human or animal use, which comprises one or more natural products that provide health benefits or have therapeutic effects related to the prevention or alleviation of disease.

[0103] The term "food supplement" is used to refer to a product containing the composition, which is intended to supplement food by providing nutrients beneficial to health in accordance with acceptable directives, such as European directives. For example, the food supplement may be a capsule or tablet for swallowing, or a powder or small vial for mixing with food to provide beneficial health effects. The food supplement may also be formulated as a sublingual composition. The food supplement may include, in addition to an active agent, an edible carrier and / or excipient. According to some embodiments, the edible carrier and / or excipient is a pharmaceutically acceptable carrier and / or excipient.

[0104] The term "edible carrier" refers to a compound, material, composition, and / or dosage form suitable for use in contact with the tissue of a subject. Each carrier must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation. As used herein, the term "edible carrier" refers to a material that can be administered to, consumed, digested, or passed through the digestive system of an animal or human without toxic effects. These edible carrier materials can exist as either a solid or a liquid at room temperature.

[0105] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to any and all solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, surfactants, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also include other active compounds that provide supplementary, additional, or enhanced therapeutic functions.

[0106] The terms "pharmaceutically acceptable" and "pharmacologically acceptable" include molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or human, as appropriate.

[0107] According to any one of the above embodiments, the composition of the present invention is formulated in any known form, such as a powder, suspension, tablet, or capsule.

[0108] Having now generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are not intended to limit the invention. [Example]

[0109] Example 1 - Preparation of a sublingual composition containing stabilized ACC ACC stabilized with sodium triphosphate and citric acid solid compositions was prepared with a moisture content of 8-10% (measured by loss on drying) as described in WO 2016 / 193982 A1. To prepare a powder for sublingual administration, the resulting solid was further milled to a size of less than 0.4 mm. The powder was mixed with excipients such as anti-caking agents (e.g., silicon dioxide), lubricants (e.g., magnesium stearate), and sweeteners and flavorings (e.g., sucralose, mannitol, sorbitol, erythritol, mint, and citric acid) and administered sublingually. An ACC tablet formulation for oral administration was prepared as described in WO 2016 / 193982 and corresponds to the commercial product Density®, developed and marketed by the applicant.

[0110] Example 2. The effect of ACC on athlete performance and recovery target: This pilot study aimed to compare the ability of athletes taking sublingual amorphous calcium carbonate (ACC) and crystalline calcium carbonate (CCC) to perform strenuous physical activity using the Wingate anaerobic test and pre- and post-test lactate measurements. Sublingual administration of the ACC powder formulation allows for bypassing the stomach.

[0111] Study Procedures The study was conducted in two professional cyclists as a double-blind crossover study using either the ACC or the CCC (control) as the test item. Subjects received the first test item for three days and performed the Wingate test. After a three-day washout period, the routine was repeated with the second test item. The effectiveness of the CCC and ACC in performing the Wingate test was evaluated for each cyclist.

[0112] Each subject received their ACC or CCC regimen in sachets that appeared identical from the outside, except for the lettering B (for CCC) or D (for ACC). Each sachet contained 250 mg of elemental calcium in powder form (approximately 740 mg of ACC). The test item was administered sublingually over 5 minutes. The total daily dose was 2,250 mg of elemental calcium as ACC (equivalent to approximately 6,660 mg of ACC). On the day of the Wingate test, subjects received two sachets before the test and one sachet after the test. Then, for the next three days, they received no treatment (see Table 1).

[0113] The ACC powder and tablets used in the experiments were primarily prepared for calcium supplementation. Therefore, their dosages were described by their exact calcium content. However, commercially available ACC (manufactured by Amorphical) may contain varying amounts of strongly adsorbed water, which does not affect long-term stability. Therefore, for calculation purposes based on the average measurements of commercial batches, the ACC dosage in this example is calculated approximately based on the calcium content of ACC, which is 30-35%.

[0114] [Table 1] The Wingate anaerobic test is an anaerobic exercise test performed on a stationary bicycle that measures peak anaerobic power and aerobic capacity. The test was performed as follows: after a warm-up, subjects cycled at full power for 30 seconds, followed by a 2-minute rest period, then cycled again at full power for 30 seconds, followed by a 2-minute rest period, followed by 30 seconds at full power (third round). Figure 1 shows the test design for each subject.

[0115] Lactate levels were measured using an EKF Lactate Scout device before performing the Wingate test and again at 3, 5, 7, 9, and 15 minutes after the test.

[0116] The peak power (PP) for each cyclist, measured during each of the three repetitions of the Wingate test, is shown in Figure 2. Power is measured according to the following formula: Power = force (kg) x distance (m) ÷ time (s) Here, force is calculated as 7.5% of the athlete's mass, and distance is the number of revolutions multiplied by the distance per revolution (in metres).

[0117] Figure 3 shows the Fatigue Index (FI) calculated for each cyclist. This index corresponds to anaerobic capacity or endurance.

[0118] The results shown in Figure 2C indicate that subject #2's performance improved when he took ACC at maximum intensity, and this was maintained over the next two cycles compared to when he took CCC. Figure 2A shows that subject #1's initial performance was better with CCC than with ACC. However, he was able to maintain a much higher performance with ACC in subsequent cycles, far superior to CCC. This observation is further strengthened by the fatigue index shown in Figure 3.

[0119] The fatigue index measures the rate at which power declines from peak power to minimum power (the last 5 seconds) during the same 30-second test. The higher the fatigue index, the lower the ability to maintain power, i.e., the lower the endurance. It is calculated according to the following formula:

number

[0120] As shown in Figure 3A, cyclist #1 showed the same fatigue index in the first cycling session for ACC and CCC, and also showed comparable fatigue indices after the second cycling session. However, in the third cycling session, the index after using ACC was much lower than after using CCC. For cyclist #2, ACC showed a decrease in fatigue index in both the second and third cycling sessions after taking ACC compared to taking CCC.

[0121] Lactate measurements (Figure 4) indicate that cyclist #1 had an improved ability to remove lactate from the blood after consuming ACC compared to CCC (as indicated by lower lactate levels in Figure 4A). A similar trend was observed in cyclist #2 (Figure 4A-B). This evidence corresponds to faster recovery and therefore improved performance.

[0122] These results clearly demonstrate that ACC has a positive effect on cyclists' ability to maintain high performance, as evidenced by the PP values, which were significantly lower in both athletes after taking ACC compared to after taking CCC. Examining the fatigue index results, it can be seen that they were much lower after taking ACC than after taking CCC in both cyclists, especially during the final cycling session, which was the most exhausting session.

[0123] Example 3. Case studies of highly trained and / or top-performing athletes Several case studies of athletes are described. Athletes began receiving ACC sublingually for various physiological conditions, such as non-healing fractures, inflammation, and persistent pain. Following rapid recovery from pathological conditions (if any), athletes continued taking ACC, and most began to improve their performance and break their own records. Athletes consumed 2–10 sachets per day containing sublingual ACC powder, each containing 200 or 250 mg of calcium (equivalent to approximately 620 and 740 mg of ACC, respectively). The sublingual powder consisted of 80–90 wt% stabilized ACC, an anticaking agent such as silicon dioxide, a lubricant such as magnesium stearate, and sweeteners and flavorings such as sucralose, mannitol, sorbitol, erythritol, and citric acid. In some cases, athletes received oral formulations (tablets), each containing 200 mg of elemental calcium in the form of ACC, in addition to the sublingual dosage.

[0124] Athlete 1 (male swimmer) Athlete 1 has been a successful international swimmer for over eight years. He suffered from painful osteolysis of his collarbone and was treated with steroid injections for over a year. After 21 days of sublingual administration of 2400 mg / day of calcium in ACC (approximately 7440 mg of ACC), the pain resolved. The athlete continued to take 2000 mg / day of calcium in ACC (approximately 7000 mg of ACC), and 60 days after starting treatment, he set new national records in the 200-m individual medley and 100-m individual medley at the International Championships. In the 100-m swim, he broke his own record by more than half a second, and 80 days later, he achieved additional new personal records in the 200-m breaststroke, including a 1.2-second improvement in his best time.

[0125] Athlete 2 (runner, male) Athlete 2, a national championship-winning long-distance runner, was diagnosed with a sacral stress fracture. After nine days of treatment with ACC, pain disappeared with the administration of 1800 mg / day of calcium as sublingual ACC (approximately 5580 mg ACC). The athlete continued his ACC regimen with 200 mg (approximately 620 mg) of calcium twice daily as an oral ACC tablet, along with an additional 1500 mg of calcium as a sublingual ACC dose (approximately 4440 mg) for approximately 20 more days, after which he returned to his normal training regimen. The athlete demonstrated that he could handle more extensive training without experiencing fatigue daily. The athlete continued with approximately 5680 mg / day of ACC administered sublingually and orally. After 52 days, he improved his personal record in a marathon run by more than four minutes, and again improved his record (by more than three minutes) 84 and 136 days later while competing in an international competition.

[0126] Athlete 3 (CrossFit, Female) Athlete 3, a national record-holding CrossFit athlete, suffered from an overtrained knee that caused swelling. She had previously been treated with Etopan (etodolac). Upon discontinuing etodolac treatment, she began ACC treatment with 1500 mg / day of calcium (approximately 4440 mg / day of ACC) administered sublingually. The swelling and pain completely resolved within two days of treatment. The athlete continued to take the same dose of ACC sublingually. Between 30 and 90 days, she broke over 10 personal records (% improvement in parentheses): snatch from blocks (11.4%), back squat (7.8%), front squat (5.0%), jerk 101kg (1.0%), PR clean 2 front squat (5.9), clean + front squat (11.8%), hang power clean (6.3%), power snatch (2.9%), snatch + overhead squat (6.7%), snatch (0.6%), 2-rep press (10.0%).

[0127] Athlete 4 (runner, male) Athlete 4, a national record-holding long-distance runner, suffered from a stress fracture of the hip joint and inflammation of the adductor magnus and adductor longus muscles. The athlete was treated with 1,500 mg / day of calcium as ACC sublingually (approximately 4440 mg / day ACC) for 14 days, after which the dose was increased to 1,750 mg / day (approximately 5180 mg / day ACC). The pain gradually subsided, with 80% of the pain disappearing after 14 days and completely disappearing after 19 days. The athlete continued to take the same dose of ACC sublingually. After 54 days, he broke two records in the 20,000-meter run, and after another 27 days, his time in the marathon improved by more than two minutes.

[0128] Athlete 5 (runner, male) Athlete 5 was diagnosed with knee tendonitis. The athlete was treated with 1,400 mg / day of calcium (approximately 4340 mg / day) as ACC sublingually. The athlete reported that the pain gradually subsided. After 14 days, 50% of the pain had disappeared, and after 45 additional days of sublingual administration, he reported that the pain had disappeared by 95%. The athlete continued to take the same dose of ACC sublingually. 56 and 83 days after the start of treatment, the athlete improved his personal best times in the 3000 meter run by 7 and 6.5 seconds, respectively.

[0129] Athlete 6 (Swimmer, Female) Athlete 6 reported a decline in performance for nearly four years without injury, likely due to age-related decline. After 30 days of sublingual administration of approximately 5180 mg / day of ACC (1750 mg of calcium), the athlete reported feeling stronger. After another 30 days, she broke her personal record in the 200 freestyle.

[0130] Athlete 7 (runner, male) Athlete 7 suffered a level 3 stress fracture of the tibia. After 14 days of sublingual administration of 2200 mg / day of calcium (approximately 6820 mg / day of ACC) using a combination of sublingual and oral administration, the athlete reported resolution of pain and returned to normal training. The athlete continued taking approximately 5680 mg of ACC. The athlete reported feeling great and performance improvement in training. After 59 days, he improved his personal record in the half marathon by more than 9 minutes. After another 12 days, he broke his recent personal record in the half marathon by another 3 minutes.

[0131] Athlete 8 (Runner, Female) Athlete 8 suffered from inflammation and reduced muscle range of motion (muscle stiffness) as a result of a bulging disc. After 14 days of sublingual administration of 1500 mg / day of calcium as ACC (approximately 4440 mg / day of ACC), pain decreased while running. After 30 days, pain dropped from a level 10 to a level 3. Range of motion improved, and the athlete reported rapid recovery immediately after running. She became more flexible and her endurance improved. Her performance improved immeasurably. Her recovery from each workout was excellent. Her heart rate during intense exercise dropped significantly. This recovery transformed her entire performance. This reversed her perceived physical age (at 49 years old) and she felt 10 to 15 years younger.

[0132] Example 4 - Effect of different sources of calcium carbonate on the pH of the medium Two commercially available media, Dulbecco's Phosphate Buffered Saline (DPBS) and Gibco's Dulbecco's Modified Eagle's Medium, Nutrient Mixture F-12 (DMEM / F12) supplemented with 10% fetal bovine serum (FBS), were used to evaluate the pH effects of various sources of calcium carbonate. DPBS is Dulbecco's Phosphate Buffered Saline, which generally serves as an isotonic saline or buffer for washing cells and tissues and is intended to provide a buffer system for maintaining cell culture media in the physiological range of 7.2–7.6.

[0133] DMEM / F12 is a widely used basal medium to support the growth of many different mammalian cells. DMEM / F12 medium + 10% FBS was used to best mimic the body fluid environment.

[0134] Three sources of calcium carbonate were used: ACC, sodium bicarbonate (SBC), and crystalline calcium carbonate (CCC).

[0135] The ACC suspension was prepared by adding 10 ml of 0.56% w / v triphosphate solution containing 36 ml of 3.10% w / v calcium chloride dihydrate solution and 40 ml of 1.95% sodium carbonate solution mixed with 4 ml of water to the ACC, followed by 10 ml of 0.56% w / v triphosphate stabilization solution to obtain an ACC suspension containing 10% sodium triphosphate. The final composition contained 73.53 mM CaCO3 in a water suspension.

[0136] SBC and CCC were dissolved or dispersed in water so that the carbonate concentration was equal to that of the ACC suspension (73.5 mM CaCO3).

[0137] Dispersions of different carbonate sources or SBC solutions were slowly and continuously added to two different media. The additions were continued until a pH plateau was achieved or the solution level reached the end of the container's capacity (approximately 130 ml). The results are shown in Figures 5 and 6 and Table 2. [Table 2]

[0138] As shown in this example, the amount of ACC required to reach a pH of 8 was significantly less than that of both the SBC solution and the CCC suspension. This is despite the lower solubility of ACC relative to SBC. SBC, a substance previously tried to improve athletic performance, is not significantly different from the highly insoluble CCC in its ability to reach higher pH levels (very slowly).

[0139] Example 5. Comparative Effects of Nanometer-Sized ACC and Nanometer-Sized CCC's Ability to Restore pH After Acidification of a Buffer System In this experiment, the ability of ACC formulated with different stabilizers to affect the pH of medium supplemented with 10% (v / v) serum was evaluated in comparison with two different CCC sources.

[0140] The experimental solution was prepared by mixing 18 ml of commercial culture medium (DMEM / F12, Biological Industries, Beit Haemek, Israel) and 2 ml of fetal bovine serum (FBS, Biological Industries, Beit Haemek, Israel). The solution was placed in a sterile tissue sample cup, and a hole was drilled in the top to insert a pH probe. The cup was placed on a magnetic stirrer (JB-10 stirrer, Inesa, China), and the solution was constantly stirred during the procedure. A pH meter (MesuLab, PXSJ-216F ion meter, MRC, Israel) was connected to a PC and the pH value was continuously measured using REXDC 2.0 software.

[0141] A volume of 20.5 μl of lactic acid was added to the solution to lower the pH to a slightly acidic pH in the range of 6.8. After a few seconds, 3 ml of freshly prepared (in situ or by suspending pre-made powder) suspensions of various nanometer-sized ACC or CCC at a concentration of 0.06% were added to each experimental acidified solution. The procedure was repeated several times as follows: 1. Triphosphate (TP)-stabilized ACC is produced in situ by mixing four solutions (calcium chloride, sodium carbonate, and two solutions of TP) in the appropriate order. 2. Triphosphate (TP)-stabilized ACC is produced in situ by mixing two solutions in the appropriate order. 3. Triphosphate (TP) stabilized ACC is produced, dried, and then resuspended in water at a weight equivalent to the suspension above. 4. Nanometer-sized crystalline calcium carbonate (CCC) prepared similarly to the ACC above, but without the stabilizer. The powder was resuspended at the same concentration as above. 5. Commercially available nanometer-sized CCC suspended at the same concentration as the above solution.

[0142] The results are shown in Figure 7, which shows the effect of various ACC and CCC suspensions added to media containing 10% serum. Initially, the pH was lowered to approximately 6.8 by adding lactic acid. After the addition of all three ACC suspensions, in experiments 1, 2, and 3, the pH suddenly and significantly increased to levels of 7.9, 7.8, and 7.3, respectively, due to partial ACC dissolution (i.e., a factor of 5–10). + (A sudden drop in concentration). The pH increase then continues at a much slower rate and stops after approximately 500 seconds at pHs of 8.2, 8.1, and 7.6, respectively. Note that the ACC in Run 4 is less reactive than the in situ suspension due to excessive agglomeration, but its reactivity with acidic ions is improved by an order of magnitude.

[0143] Two experiments with CCC nanoparticles show little change in pH, therefore lower pH levels are required to activate and accelerate their dissolution.

[0144] While the present invention has been described hereinabove in its preferred embodiments, modifications can be made thereto without departing from the spirit and nature of the invention as defined in the appended claims.

Claims

1. 1. A composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer for non-therapeutic use in improving athletic performance in a subject, wherein said improving athletic performance comprises improving muscle performance; The composition is administered by sublingual administration or a combination of sublingual and oral administration.

2. 10. The composition of claim 1, wherein improving athletic performance further comprises improving at least one of muscle strength, endurance, athletic performance, and reducing time to recovery.

3. 3. The composition of claim 2, wherein improving athletic performance further comprises improving aerobic activity, anaerobic activity, or both.

4. 2. The composition of claim 1, wherein the improved muscle performance comprises at least one improvement selected from the group consisting of improved muscle strength, improved muscle endurance, increased muscle power, reduced muscle fatigue, improved physical mobility, reduced muscle recovery time, or any combination thereof.

5. A composition described in any one of claims 1 to 4, wherein the improvement in muscle performance is an improvement in the performance of healthy muscles.

6. A composition described in any one of claims 1 to 5, wherein the improvement in muscle performance is an improvement in the performance of a muscle selected from the group consisting of skeletal muscle, cardiac muscle, and smooth muscle.

7. 5. The composition of claim 4, wherein the improved physical mobility includes improved joint mobility and flexibility.

8. 10. The composition of claim 2 or 4, wherein recovery comprises recovery from strenuous physical activity.

9. The composition of claim 8, wherein the vigorous physical activity is short-term or long-term activity.

10. 1. A composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer for non-therapeutic use in improving athletic performance in a subject, wherein the subject is an athlete, the composition being administered by sublingual administration or a combination of sublingual and oral administration.

11. 11. The composition of claim 10, wherein improving athletic performance comprises improving at least one of muscle strength, endurance, athletic performance, reducing time to recovery, and / or improving aerobic activity, anaerobic activity, or both.

12. The composition of any one of claims 1 to 11, wherein the non-therapeutic use comprises administration of 5 to 200 mg / kg / day of stabilized ACC.

13. 13. The composition of claim 12, wherein the administration comprises a single dose or multiple divided doses, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 doses per day.

14. The composition according to any one of claims 1 to 13, wherein the composition for sublingual administration is a powder composition comprising secondary particles of ACC having a size of less than 500 µm.

15. 15. The composition of any one of claims 1 to 14, wherein the stabilizer is selected from the group consisting of polyphosphates, organic acids, phosphorylated amino acids, phosphorylated, phosphonated, sulfated or sulfonated organic compounds, phosphorus or sulfate esters of hydroxycarboxylic acids, bisphosphonates, organic polyphosphates, polyphosphates, hydroxyl-containing organic compounds, derivatives thereof, proteins and any combination thereof.

16. 16. The composition of claim 15, wherein the stabilizer is selected from the group consisting of triphosphate or its salt, phosphoserine, citric acid, sodium triphosphate and citric acid, adenosine triphosphate, adenosine diphosphate, phytic acid, etidronic acid, pyrophosphate, polyphosphate, hexametaphosphate, ethanol, and any combination thereof.

17. The composition of any one of claims 1 to 16, wherein the composition is formulated as a food supplement.

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