Patent Application
20220313729
The present invention provides compositions comprising stabilized amorphous calcium carbonate as a means for improving athletic performance, such as improving aerobic and anaerobic performance, improving muscle performance, enhancing muscle strength and endurance, and reducing muscle fatigue and time to recovery.
Most athletes, whether professional or recreational, are driven to achieve peak, or at least an increased, athletic performance. This drive is predicated by the desire for self-improvement. Most recreational and professional athletes achieve these goals through a prolonged exercise to improve their athletic performance coupled with proper diet and supplements.
Muscle performance is a general term used to define the collectively muscle power strength and endurance. Muscle fatigue is a common symptom during sport and exercise activities but is also increasingly observed as a secondary outcome in many diseases and health conditions during the performance of everyday activities. Muscle fatigue is often defined as a reversible decline of force production during activity. Muscle fatigue consists of a complex interplay between central and peripheral fatigue. The extent of peripheral muscle fatigue is dependent on several factors.
The most common way to increase muscle performance is training, such as strength training or endurance training. However, this approach is not always sufficient. In such cases, pharmacological treatment, nutritional supplementation, or, sometimes, physical impact such as electrostimulation is used.
US 2015/0250784 describes improving resistance to skeletal muscle fatigue by administering to a person a skeletal muscle troponin activator.
U.S. Pat. No. 9,192,601 describes methods for promoting muscle tone mass or endurance by administering compositions comprising AMPK agonists.
WO 2008/041236 describes treating musculoskeletal disorders by compositions comprising calcium carbonate (CaCO3) finely mixed with an organic matter essentially consisting of chitin and polypeptide (Pp), wherein said specific ratios between CaCO3 and organic matter or said polypeptide is indicated.
WO 2013/088440 disclosed that the bioavailability of amorphous calcium carbonate was significantly higher than the bioavailability 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 the amorphous calcium carbonate is approximately 120 times more soluble than calcite (one of the crystalline forms of calcium carbonate).
Verbitsky et al., (Journal of Applied Physiology, 1997, 83 (2), 333-337) tested the influence of acute ingestion of NaHCO3 on fatigue and recovery of the quadriceps femoris muscle after exercise in six healthy male subjects. As cited in Verbitsky, although previously published work of the effect of NaHCO3 on anaerobic performance shows variable results, there was an agreement that NaHCO3 ingestion of at least 300 mg/kg body mass prolongs high-intensity exercise. Based on the results of the conducted experiments Verbitsky concluded that acute ingestion of 400 mg/kg of NaHCO3 is an effective means for increasing the torques in an isometric contraction, thus reducing muscle fatigue and enhancing recovery.
Zajac et al., (Journal of Sports Science and Medicine (2009) 8, 45-50) showed that oral administration of 300 mg/kg of sodium bicarbonate can increase training intensity and swimming performance.
Requena et al., (Journal of Strength and Conditioning Research, 2005, 19(1), 213-224) reviewed several studies examining the influence of administration of sodium bicarbonate and sodium citrate on human performance. Interestingly, it was shown that when different doses were tested, the significant effect was shown only for doses above 300 mg/kg for sodium bicarbonate. Requena et al. concluded that benefits from the exogenous ingestion of NaHCO3 and Na-citrate are obtained in activities with a duration sufficient to generate a difference in the H+ ion gradient. These activities are very high intensity, recruit fast motor units, and involve large muscle groups.
Lopes-Silva et al (Journal of Sports Sciences, DOI: 10.1080/02640414.2018.1524739) performed a systematic review and meta-analysis on the acute and chronic effects of sodium bicarbonate (NaHCO3) ingestion on Wingate performance. Results of the meta-analysis showed that acute ingestion of NaHCO3 did not improve Wingate test peak or mean power even with high dosage, whereas the chronic ingestion of NaHCO3 did. However, to achieve the improvement the subject had to administer between 300 to 500 mg/kg of NaHCO3.
These studies implied that sodium bicarbonate may be useful for improving athletic performances. However, to get the improvement, the athlete had to administer about 20-35 g/day of NaHCO3, an enormous amount for a daily supplement, that contains several folds of the maximum sodium recommended per day by health authorities. Athletes taking these levels of NaHCO3 have reported adverse effects such as stomach aches and discomfort, nausea, and vomiting.
In a recent meta-analysis review article by Sounders et al (2016), Sounders found that β-alanine supplementation has a significant overall ergogenic effect on exercise. Exercise duration is the greatest influencing factor in the efficacy of β-alanine supplementation. The co-supplementation of β-alanine and sodium bicarbonate resulted in the largest effect sizes, and also resulted in greater gains than β-alanine alone, though the gain seems to be an additive one and not synergistic. There were no conclusions regarding endurance and performance for long periods of activities such as for long-distance runners and swimmers and game players.
There is an unmet need for developing and finding safe and effective means for improving athletic performance and specifically of athletes and subsequently enhancing athletic achievements.
The present invention is based on the surprising finding that the administration of calcium carbonate, which is considered as a poorly soluble substance, can efficiently improve athletic performance. In particular, it is now shown that stabilized amorphous calcium carbonate (ACC) may efficiently increase muscle power, decrease muscle fatigue and therefore improve muscle performance and in general improved athletic performance of people engaged in intense physical activities, especially professional athletes. In one aspect, the present invention provides a method of improving an 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 an 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 athletic performance of a subject.
According to any one of the aspects of the present invention, improving athletic performance comprises improving at least one of the endurance, strength, and recovery from physical activity of a subject. According to some embodiments, improving of athletic performance comprises elongating the duration of physical activities, performing it faster, or both. According to some embodiments, improving athletic performance comprises improving muscle performance. According to some embodiments, improving muscle performance comprises improving at least one of muscle strength, muscle endurance, muscle recovery, reducing muscle fatigue and/or increasing muscle power. According to some embodiments, improving muscle performance improves the athletic performance of a subject. According to any one of the above embodiments, administering comprises administering of 30 to 200 mg/kg/day of stable ACC. According to some embodiments, administering comprises administration of 3000 to 10000 mg/day of ACC. The composition may be administered as one dose or as several divided doses. According to any one of the above embodiments, the composition is formulated as a food supplement that may be in the form of powder, suspension, tablets, or capsules.
According to some embodiments, the subject that may use the composition of the present invention is an athlete, such as a professional and non-professional athlete.
According to any one of the above embodiments, the administration of stabilized ACC is performed by a route selected from sublingual, oral, and both sublingual and oral administration.
The composition of the present invention comprises 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 compound, phosphoric or sulfuric esters of hydroxy carboxylic acids, phosphorylated amino acids, bisphosphonate, organic polyphosphate, hydroxyl bearing organic compounds, derivatives thereof, proteins and any combinations thereof.
It was unexpectedly found according to the teaching of the present invention that stable amorphous calcium carbonate (ACC) may significantly improve the performance of athletes and bring them to better achievements. It was previously shown by the applicant that stable ACC has therapeutic properties in many pathological conditions such as osteoporosis, pain, bone injuries, and even cancer. It was now surprisingly found that stable ACC may help healthy people to improve their athletic performances.
The proof of concept was made on highly professional athletes, for whom it is most difficult to improve performance. The idea behind selecting this group is that if ACC improves the results of highly trained athletes, it will definitely be useful for other non-professionals. Professional athletes chronically suffer from different types of inflammations and injuries due to their extreme activities. Thus, it was important to separate the effect of stabilized ACC administered sublingually and/or orally, on their pathological conditions from the potential effect on their athletic performance. Athletes having pathological conditions were first treated for a medical purpose. After the pathological condition was resolved, they continued taking stabilized ACC to assess any further efficacy for their performance. As seen in the Examples, the athletes using ACC were both cured of their previous pathological conditions and soon after improved their achievements. In some cases, they broke their personal records obtained prior to their medical conditions. Example 3 provides a plurality of examples of professional athletes competing in national and international championships that significantly improved their athletic performances and achievements as a result of taking stabilized amorphous calcium carbonate.
In addition, a controlled experiment was performed, which demonstrated that stabilized amorphous calcium carbonate was more effective in enhancing muscle recovery compared to crystalline calcium carbonate that served as the placebo. Thus, ACC can efficiently improve muscle performance and subsequently athletic performance of professional athletes, and even more, in the case of non-professional ones. Previous studies implied that administering of a very large amount of sodium bicarbonate, which contains several folds of maximum recommended dose of sodium and caused significant side effects, may affect athletic performance. However, the required dose is not bearable by most people. The present invention provides a safe, tolerable method for improving athletic performance.
According to one aspect, the present invention provides a method for improving an 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 an athletic performance of a subject. According to some embodiments, the use is a non-therapeutic use. Thus, according to the aspect, the present invention provides a composition comprising amorphous calcium carbonate (ACC) stabilized by at least one stabilizer for a non-therapeutic use in improving an 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 in improving athletic performance of a subject.
The term “non-therapeutic” as used herein is a concept excluding a medical action aimed to treat a disease, medical or psychological condition, which is a method of surgery, treatment or diagnosis for a human.
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 animals (including bovine, porcine, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats). According to other embodiments, the subject is an animal such as livestock animals or domestic animals. According to some embodiments, the subject is a human subject. According to one embodiment, the subject is a healthy human subject having normal athletic, muscle, 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 a non-therapeutic use in improving an athletic performance of an athlete.
According to the invention, the terms “athlete” and “sportsman” are used herein interchangeably and refer to a person (men or women) performing exercises for training, maintaining health, general health improvement, and for rehabilitation. The term athlete includes people with beginner, intermediate, and expert levels of experience.
According to one embodiment, the athlete is a professional athlete. The term “professional”, “competing sportsmen” or “trained sportsmen” are used herein interchangeably and are taken to mean any person regularly doing physical activity at a professional level, e.g. practicing intense physical activity or sports for at least 3 hours a week for at least two consecutive weeks. The term “professional athlete” encompasses also an athlete that participates in national and international competitions and is daily trained to achieve records at national and international levels. According to some embodiments, the athlete possesses natural or acquired traits, such as strength, agility, and endurance that are necessary for physical exercise or sports, especially those performed in competitive contexts. In some embodiments, the athlete is a non-professional athlete. The terms “non-professional”, “amateur” or “non-competing sportsmen” is taken to mean any person sporadically and non-professionally doing physical exercise.
The term “athletic performance” is used herein to generically refer to any type of athletic activity, event, exercise, training, routine, or the like. This is a complex term that relates to at least one of the following: skills, achievements, strength, endurance, speed, power, and recovery of a subject after performing a physical activity, e.g. an intense physical activity.
The terms “improving athletic performance”, “enhancing athletic performance” or any lingual variations thereof as used herein should be understood to encompass improvement of at least one sport parameter. Non-limiting examples of such improvements are: testosterone elevation, cortisol reduction, fatigue reduction, faster recovery from exercise, reduced muscle soreness, improved endurance, improved muscle strength, improved muscle size, enhanced athletic performance, improved sports-related decision making, improved selective attention of sports-related stimuli, improved concentration during sports events, and improved mental resilience during sports events. According to some embodiments, improving athletic performance comprises elongating the duration of the physical activities, performing it faster and combination thereof. According to some embodiments, improving athletic performance comprises improving endurance, fatigue reduction, faster recovery and any combination thereof. The terms “improving athletic performance” refers to a change in athletic performance, where the change is defined as a difference in the performance between a subject obtaining the administration according to the invention and a subject in similar conditions or the same subject who does not. In some embodiments, the change is detected or measured on the same subject. The change is regarded as an improvement if such change is positive for said subject. Athletic performance exact definition depends on the type of athletic activity. According to some embodiments, improving athletic performance comprises improving athletic achievements.
The term “physical activity” as used herein, refers to any physical exercise, workout, sports, fitness exercise, and, in general, to any bodily movement. The physical activity may be a short term activity and a prolonged activity.
The term “fatigue reduction” or any lingual variations thereof as used herein should be understood to encompass one or more types of general fatigue reduction such as general physical fatigue, general mental fatigue, heart fatigue, lung fatigue, muscle fatigue, aerobic fatigue, anaerobic fatigue, tiredness, exhaustion, weariness, feeling worn-out, asthenia, lassitude, prostration, exercise intolerance, lack of energy and weakness.
The term “faster recovery” or any lingual variations thereof as used herein should be understood to encompass one or more of general recovery following exercise, muscle recovery, heart and/or lung recovery, recovery of gas concentrations in the blood system, mental recovery, restoration of energy, reduction of physical and mental stress, metabolic recovery, immediate recovery, short-term recovery and training recovery.
The terms “enhanced athletic performance”, “improved athletic performance” or any lingual variations thereof as used herein should be understood to encompass one or more of enhanced running endurance, enhanced running speed, enhanced swimming endurance, enhanced swimming speed, enhanced jumping length, enhanced jumping 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 sport's game endurance, and enhanced climbing endurance, and enhanced performance in other similar physical activities.
The term “exercise” as used herein, refers to any form of physical activity. In one embodiment, the exercise enhances 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. Whereas endurance exercise, in particular, aims to increase cardiovascular endurance, strength exercise aims to increase short-term or long-term muscle strength. According to another embodiment, improving athletic performance comprises improving lung performance and endurance. According to another embodiment, improving athletic performance comprises improving of personal records by professional athletes.
According to any aspect of the present invention, improving athletic performance comprises improving at least one of athlete's strength, endurance, recovery, and any combination thereof. According to some embodiment, improving athletic performance comprises improving the subject's athletic achievements. According to some embodiments, improving athletic performance comprises improving the athlete's strength. According to other embodiments, improving athletic performance comprises improving athlete's endurance. According to certain embodiments, improving athletic performance comprises improving athlete's recovery, i.e. reducing the time required for recovery from an exercise. According to one embodiment, improving athletic performance comprises improving aerobic performance. According to another embodiment, improving athletic performance comprises improving cardiovascular performance. According to some embodiments, improving athletic performance comprises improvement anaerobic activity. According to another embodiment, improving athletic performance comprises the improvement of both aerobic and anaerobic activity. According to some embodiments, improving athletic performance comprises the improvement of aerobic capacity and/or aerobic power.
The term “anaerobic exercise” and “anaerobic activity” are used herein interchangeably and refer to exercise that does not increase the body's requirement for oxygen. Typically, anaerobic exercise can be a short-burst, higher-intensity exercise.
The terms “aerobic exercise” and “aerobic activity” refer to exercise that increases the body's requirement for oxygen. Typically, aerobic exercise involves an increased respiratory rate and cardiac rate over an extended period of time. According to any one of the above aspects and embodiments of the present invention, improving athletic performance comprises improving muscle performance. Thus, according to any one of the above aspects and embodiment, the method or the use comprises 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 comprises reducing muscle pain caused by physical training. According to one embodiment, improving muscle performance comprises improving or enhancing muscle endurance. According to another embodiment, improving muscle performance comprises improving or enhancing muscle recovery. According to some embodiments, improving muscle performance comprises improving or enhancing muscle strength. According to another embodiment, improving muscle performance comprises reducing muscle fatigue. According to one embodiment, improving muscle performance comprises increasing muscle power. According to some embodiments, improving muscle performance comprises improvement of joint mobility. According to other embodiments, improving muscle performance comprises reducing muscle pain, in particular, muscle pain resulted from an exercise or physical activity.
According to any one of the above embodiments, improving muscle performance, e.g. improving muscle strength, improving muscle endurance, enhancing muscle recovery reducing muscle fatigue, increasing muscle power and any combination thereof comprises improving muscle during or following physical activity or exercise.
According to another embodiment, improving muscle performance comprises enhancing energy use by a muscle when performing a physical activity or in rest. According to another embodiment, improving muscle performance comprises increasing muscle cell metabolism. Measurement of cell metabolism may be performed by any known method.
The term “muscle function” as used herein, unless otherwise specified, refers to at least one of muscle mass and muscle strength.
The term “muscle endurance” as used herein refers to the ability of muscle groups to perform submaximal contractions for extended periods of time. Muscle endurance may be measured by any known method, e.g. by measuring a fatigue index calculated for example as the percentage of the differences between the total work during the last 10 repetitions and the first 10 repetitions.
The term “muscle strength” as used herein refers to the amount of force a muscle, or muscle groups in sum, can exert. Muscle strength may be evaluated by a variety of methods such as an isokinetic device in clinical trials such as dynamometer, stationary cycles and treat mill, measuring torque (Nm) and angle (degrees), grip strength, one-repetition maximum strength test, time-dependent tests of muscle endurance, time-dependent tests of muscle fatigue, or time-dependent tests of muscle endurance and fatigue, and so forth. For the maximum strength test, peak torque can be defined as the highest value of torque development in one of several repetitions.
The term “peak power” refers to the greatest output or production of work over a given amount of time. The term “mean power” is the average rate of doing work.
The term “muscle fatigue” or “skeletal muscle fatigue” refers to a reduction in contractile capacity following repeat-use and represents a combination of central fatigue (limitations of the central and peripheral nervous system to sustain activity) and peripheral fatigue (intrinsic loss of muscle function such as reduced effectiveness of excitation-contraction coupling). Muscle fatigue can be assessed by the anaerobic fatigue and anaerobic capacity of a Wingate test. The Wingate test is often performed on a cycle ergometer and consists of a set of time pedaling at maximum speed against a constant force. The number of revolutions pedaled for every five seconds interval during the test is count and is used for determining the power and work data. Anaerobic fatigue demonstrates the percentage of power loss from the beginning to the end of the Wingate test. Anaerobic capacity is the total work completed during the test duration.
The term “muscle recovery” as used herein refers to restoring the muscle condition to its original condition before the exercise or to a better condition. As such, “enhancing muscle recovery” refers to reducing or shortening the time required for muscle recovery. Measurable parameters that can indicate a reduction in muscle recovery time may be the reduction of the lactate levels in the blood along time.
The term “muscle” as used herein refers to skeletal muscles as well as other non-skeletal, striated muscles such as a diaphragm, extraocular muscle, and so forth, and a cardiac muscle. Thus, according to some embodiments, the muscle is selected from the group consisting of skeletal, cardiac, and smooth muscle. According to some embodiments, the present invention provides improving skeletal, cardiac, or smooth muscle performance. According to other embodiments, the present invention provides non-therapeutic use of the composition of the present invention for improving skeletal, cardiac, or smooth muscle performance.
The terms “improving muscle performance” and “enhancing muscle performance” are used herein interchangeably and refer to a change in muscle performance, where the change is defined as a difference in muscle performance between a subject obtaining the treatment or administration according to the invention and a subject in similar conditions who does not. In some embodiments, the change is detected or measured on the same subject. The change is regarded as an improvement if such change is positive for said subject. Normally, an improved muscle performance is an increased muscle performance.
It should be clear that improvement of athletic performance in professional athletes may be small if measured as a percent of change but are significant in their absolute value. According to one embodiment, administering stabilized ACC improves professional athletic performance by about 0.5% to about 10%, about 1% to about 8%, or about 2% to about 6%. Athletic performances may be reflected in any measurable values such as speed (of running or swimming), weight (raised), number of sets performed, distance (a person can jump, run or swim), and time the athlete may keep performing the exercise etc.
The rate of improvement of athletic performance of non-professional athletes may be much more significant. According to some embodiments, administering stabilized ACC enhances improves athletic performance by from 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, administering stabilized ACC improves athletic performance by about 5% to 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, administering 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%. Enhancement by 100% means that the parameter, e.g. muscle strength, improving muscle endurance increased 2 times; enhancement by 200% means that the parameter, is increased 3 times, and so on. According to some embodiments, the athletic performance is improved by about 100% to about 500%, about 120% to about 400%, about 150% to about 300%.
According to one embodiment, administering stabilized ACC enhances muscle performance, such as improving muscle strength, force 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, administering stabilized ACC enhances muscle performance, such as improving muscle strength, force and/or endurance, by about 5% to 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, administering stabilized ACC enhances muscle performance, e.g. improving muscle strength, force and/or endurance 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%. Enhancement by 100% means that the parameter, e.g. muscle strength, improving muscle endurance increased 2 times; enhancement by 200% means that the parameter, is increased 3 times, and so on. According to some embodiments, the muscle performance is enhanced by about 100% to about 500%, about 120% to about 400%, about 150% to about 300%. According to some embodiments, enhancing muscle performance comprises reducing muscle fatigue or reducing muscle pain. According to some embodiments, reducing fatigue comprises reducing it 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%. Reducing by 100% means completely reducing the feature. According to some embodiments, administering stabilized ACC improves muscle performance of a professional athlete by about 0.5 to about 10%, about 1% to about 8%, or about 2% to about 6%.
According to any one of the above embodiments, the muscle performance refers to muscle performance of a healthy muscle. Thus, according to any one of the above embodiments, the muscle is a healthy muscle, i.e. muscles of a healthy person.
According to one embodiment, the method of the present invention comprises enhancing the athletic performance of athletes, sportsmen or healthy people. According to another embodiment, the method comprises enhancing muscle performance of athletes, sportsmen or healthy people.
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 of a subject. According to some embodiments, the present invention provides a method for improving muscle performance of a subject comprising administering to said 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 the muscle performance of a subject, such as an athlete. According to some embodiments, the athlete is a professional athlete.
The term “administering” or “administration of” a substance, a compound or a 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 a composition can be administered enterally or parenterally. Enterally refers to administration via the gastrointestinal tract including per os, sublingually or rectally. Parenteral administration includes administration intravenously, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, intranasally, by inhalation, intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or a composition can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other “drug-release” and “controlled-release” devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or composition. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. In some aspects, the administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug or medical food.
According to some embodiments, the administration is an oral administration. According to other embodiments, the administration is a sublingual administration. According to further embodiments, the administration is a combined oral and sublingual administration.
According to certain embodiments, administration, e.g. oral, sublingual, or combined, comprises administering less than 200 mg/kg per day of calcium as stabilized ACC. The dose according to any one of the aspects and embodiments of the present invention refers to the amount of elemental calcium in the 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 administered dose of ACC 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 according to the present invention, e.g. oral, sublingual or combined administration comprising administration of 5 to 150, 10 to 120, 15 to 100, 20 to 80, 30 to 70 or 40 to 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 comprising administration of 5 to 80, 10 to 75, 15 to 70, 20 to 65, 25 to 60, 30 to 55, 35 to 50 or 40 to 45 mg/kg/day of calcium as stabilized ACC. According to some embodiment, administration according to the present invention, e.g. oral, sublingual or combined administration comprising administration of about 10 to about 45, about 15 to about 40, about 20 to about 35 mg/kg/day of calcium as stabilized ACC. According to further embodiment, administration according to the present invention, e.g. oral, sublingual or combined administration comprising administration of 0.1 to 30, 0.2 to 28, 0.3 to 26, 0.5 to 24, 1 to 22, 2 to 20, 3 to 18, 3 to 16, 4 to 15, 5 to 14, 6 to 12, or 8 to 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 comprising administration of 0.2 to 10, 0.5 to 8, 0.8 to 6, 1 to 5, 1.5 to 4, or 2 to 3 mg/kg/day of calcium as stabilized ACC. According to another embodiment, the administration comprises administration of 500 to 8000 mg/day, 800 to 6000, or 100 to 4000 mg/day of ACC. According to some embodiments, the administration comprises administration of from 200 to 3000 mg/day, from 400 to 2500 or from 600 to 2000 mg/day of calcium as stabilized ACC. According to other embodiments, the administration comprises administration of from 800 to 4000 mg/day, from 1000 to 3000 or from 1500 to 2500 mg/day of calcium as stabilized ACC.
According to some embodiments, the administration e.g. oral, sublingual or combined administration, comprises daily administering of about 600 to about 23,500 mg of ACC. According to one embodiment, the administration comprises administering of 600 to 20,000, 800 to 18,000, 1,000 to 15,000, 1,200 to 12,000, 1,500 to 10,000, and 2000 to 8000 mg/day of ACC. According to some embodiments, the administration comprises administering of 1000 to 12000, 2000 to 11000, 3000 to 10000, 3500 to 9000, 4000 to 8000 mg/day of ACC.
According to some embodiments, the administration comprises administering of 10 to 350 mg/kg/day of stabilized ACC. According to some embodiment, the administration comprises administering of 20 to 300, 30 to 250 40 to 200, 50 to 150 or 30 to 120 mg/kg/day of ACC.
According to some embodiments, the administration comprises administration in a single dose or in multiple separated doses. For Example, the daily dose may be separated and administered in 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 separate doses.
According to some embodiments, the administration is short-term administration, e.g. administration for at least 1, 2, 3, 5, or 7 days. According to other embodiments, the administration is for 1, 2, 3, or 4 weeks. According to further embodiments, the administration is for a long term such as for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. According to other embodiments, the administration for one or more years such as 2, 3, 4, 5, or more years.
According to some embodiments, the composition for sublingual administration is in the form of a powder of ACC. The powder for sublingual administration is formed of ACC particles.
The term “particles” as used herein refers to a discrete microparticle or a nanoparticle of ACC stabilized by the stabilizer as defined hereinabove, as well as to the aggregates or agglomerates thereof. According to some embodiments, the particles are primary particles of the stabilized ACC. The basic nanoparticles are in the range of 5 to 500 nm or 10 to 300 nm or 20 to 100 nm. In many cases, these nanoparticles immediately agglomerate and aggregate into much larger secondary particles. These aggregation and agglomeration can be then broken by milling and dissolution techniques into smaller particles. According to other embodiments, the particles are agglomerates or aggregates of the primary particles, i.e. secondary particles. The term “particle size” as used herein refers to a measurement of a representative diameter of the secondary particles such as an aggregate or a broken aggregate in at least one dimension.
The particle size of agglomerates can be tailored into ranges 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, 30 μm or less. According to some embodiments, the particle size is from about 20 to about 500 μm, from about 30 to about 450 μm or from about 50 to about 400 μm.
According to any one of the above embodiments, the ACC is a stabilized ACC, i.e. ACC that maintains amorphous for a long period even in humid conditions or in an aqueous environment
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 herein interchangeably and refer to any molecule, ion or substance that contributes to preserving calcium carbonate in the amorphous state during ACC production, formulating and/or storage. According to the teachings of the present invention, the ACC acts as an active agent conferring improvement in athletic and muscle performance. Any ACC that remains stable may be used according to the teaching of the present invention. Any compound that may stabilize ACC in its amorphous form is suitable for the implementation of the present invention. The terms “stable ACC” and “stabilized ACC” are used herein interchangeably and indicates that calcium carbonate is maintained in its amorphous form for a prolonged period of time having less than or about 30% of conversion to a crystalline form.
The essence of the present invention is in providing ACC to athletes and therefore improving their performances. As long as ACC remains amorphous, this goal is achieved. Many stabilizers were previously shown, e.g. by the Applicant, to effectively stabilize ACC in the amorphous form in aqueous condition. Some of the stabilizers are listed below.
In certain embodiments, the stabilizing agent is a single agent. In other embodiments, the use of several stabilizing agents is encompassed. In some cases, the stabilizers are present within the molecular matrix of the ACC particles. In some cases, they are deposited externally and in other cases, they are both internal or external. The internal stabilizers or combination of stabilizers can be the same or different than the external ones.
ACC Stabilizers
The stabilizer may comprise a molecule having one or more functional groups selected from, but not limited to, hydroxyl, carboxyl, ester, amine, phosphino, phosphono, phosphate, sulfonyl, sulfate or sulfino groups. The hydroxy bearing compounds, combined with the hydroxide, optionally also bear other functions like carboxyl, etc. but with the hydroxyl not being esterified.
According to some embodiments, the stabilizer has low toxicity or no toxicity to mammalian cells or organism, and in particular to a human being. According to some embodiment, the stabilizer is of food, nutraceutical or pharmaceutical grade.
In certain embodiments, the ACC stabilizing agent is independently at each occurrence, an organic acid, phosphorylated, phosphonated, sulfated or sulfonated organic compound, phosphoric or sulfuric ester of a hydroxyl carboxylic acid, an organoamine compound, an organic compound comprising a hydroxyl, an organophosphorous compound or a salt thereof, phosphorylated amino acids and derivatives thereof, a bisphosphonate compound, an organophosphate compound, an organophosphonate compound, an inorganic phosphorous acid, an organic compound having multiple functional groups as defined above, an inorganic phosphate and polyphosphate compound, an organic compound having a polyphosphate chain, an organic surfactant, a bio-essential inorganic ion, or any combination thereof.
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, aconitic acid, and optionally include compounds having at least two carboxylic groups and molecular weight not larger than 250 g/mol, such as citric acid, tartaric acid, malic acid, etc. According to one particular embodiment, the stabilizer is citric acid.
In another embodiment, the phosphoric ester of hydroxyl carboxylic acids is a phosphoenolpyruvate. In another embodiment, the phosphoric or sulfuric esters of hydroxyl carboxylic acids comprise amino acids. Examples of such esters are phosphoserine, phosphothreonine, sulfoserine, sulfothreonine and phosphocreatine.
The hydroxyl bearing compounds combined with hydroxide may comprise, for example, mono-, di- tri-, oligo-, and polysaccharides like sucrose or other polyols like glycerol. The hydroxyl bearing compounds may further comprise hydroxy acids like citric acid, tartaric acid, malic acid, etc., or hydroxyl-bearing amino acids such as serine or threonine. Each possibility represents a separate embodiment, of the present invention.
Some specific unlimited examples for such ACC stabilizers that 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.
According to some embodiments, the stabilizer comprises at least one component selected from phosphoric or sulfuric esters of hydroxyl carboxylic acids, such as phosphoenolpyruvate, phosphoserine, phosphothreonine, sulfoserine or sulfothreonine and hydroxyl bearing organic compounds, selected from mono-, di-, tri-, oligo- and poly-saccharides, for example, sucrose, mannose, glucose.
The hydroxyl bearing compound may further comprise at least one alkali hydroxide, such as sodium hydroxide, potassium hydroxide and the like. The phosphorylated acids may be present in oligopeptides and polypeptides. In other embodiments, of the invention, the stabilizer is an organic acid selected from monocarboxylic acid or multiple carboxylic acid, e.g. dicarboxylic acid or tricarboxylic acid. Each possibility represents a separate embodiment, of the invention. The organic acid may be as defined above.
In some embodiments, of the 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 wherein the 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. The non-limiting examples of stabilizers containing phosphate, phosphite, phosphonate groups and salts or esters thereof include phytic acid, dimethyl phosphate, trimethyl phosphate, sodium pyrophosphate, tetraethyl pyrophosphate, ribulose bisphosphate, etidronic acid and other medical bisphosphonates, 3-phosphoglyceric acid salt, glyceraldehyde 3-phosphate, 1-deoxy-D-xylulose-5-phosphate sodium salt, diethylene triamine pentakis(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)pyruvic acid 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 combinations thereof.
In some embodiments, the stabilizers can be bio-essential inorganic ions including, inter alia, Na, K, Mg, Zn, Fe, P, S, N, P, or S in the phase of oxides, or N as ammonia or nitro groups.
The stabilized ACC may be stabilized by more than one stabilizer, e.g. 2, 3, or more stabilizers. The stabilizers can be added during the synthesis and precipitation of the ACC primary particles and they are defined as “internal stabilizer”. Stabilizers can be added after the synthesis and bind to the external surface of the particles. They are defined as “external stabilizers”. In some embodiments, where both internal and external stabilizers are used the internal stabilizer and the external stabilizer are similar. In other embodiments, the internal stabilizer and the external stabilizer are different stabilizers. The internal and the external stabilizers may be each independently as defined hereinabove and each can be a combination of more than one type of stabilizer.
The stable ACC can comprise more than two stabilizers, wherein one or more stabilizers are added to the ACC during the formation and precipitation of the ACC.
According to some embodiments, the at least one stabilizer is selected from the group consisting of a polyphosphate, bisphosphonate, phosphorylated amino acid, citric acid, and any combination thereof. In some embodiments, more than one stabilizer, e.g. 2, 3, or 4 stabilizers are added.
According to one embodiment, ACC is stabilized by a combination of phosphoserine and citric acid. According to another embodiment, ACC is stabilized by a combination of triphosphate and citric acid.
According to some embodiments, the stabilizer is a polyphosphate or pharmaceutically acceptable salts thereof. According to some embodiments, the polyphosphate is physiologically compatible, water-soluble polyphosphate salt selected from the group consisting of sodium, potassium, and any other essential cation of polyphosphate. In one embodiment, the polyphosphate is organic or inorganic polyphosphate. The term “polyphosphate” as used herein refers to polymeric esters of PO4. According to some embodiments, the polyphosphate is a physiologically compatible water-soluble polyphosphate salt selected from the group consisting of sodium and potassium polyphosphate. In some embodiments, the polyphosphate is an inorganic polyphosphate or pharmaceutically acceptable salts thereof. Not-limiting examples of such salt are Na, K, Mg, Mn, and Zn. According to some embodiments, the inorganic phosphate comprises 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 pyrophosphate or pharmaceutically acceptable salts thereof such as sodium pyrophosphate. According to another embodiment, the stabilizer is triphosphate or pharmaceutically acceptable salts thereof such as sodium triphosphate. The term “triphosphate” and “tripolyphosphate” are used herein interchangeably. According to a further embodiment, the stabilizer is hexametaphosphate or a pharmaceutically acceptable salt thereof such as sodium hexametaphosphate.
According to some embodiments, the stabilizer is a bisphosphonate or pharmaceutically acceptable salts thereof. The non-limiting examples of salt are Na, K, Mg, Mn and Zn.
The term “bisphosphonate” as used herein refers to organic compounds having two phosphonate (PO(OH)2) groups. The term further relates to compounds having a backbone of PO3-organic-PO3. Most typical is a series of bisphosphonates that are 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 a pharmaceutically acceptable salt thereof. According to some embodiments, the stabilizer is an etidronic acid or a pharmaceutically acceptable salt thereof. According to another embodiment, the stabilizer is a zoledronic acid or a pharmaceutically acceptable salt thereof. According to a further embodiment, the stabilizer is a medronic acid or a pharmaceutically acceptable salt thereof. According to certain embodiments, the stabilizer is alendronic acid or a pharmaceutically acceptable salt thereof.
According to certain embodiments, the stabilizer is a phosphorylated amino acid. According to one embodiment, the phosphorylated amino acid is phosphoserine. According to another embodiment, the phosphorylated amino acid is phosphothreonine.
According to some embodiments, the ACC composition comprises a combination of the stabilizers disclosed above.
According to some embodiments, the stabilizer is an inorganic polyphosphate or a bisphosphonate as defined hereinabove, and the molar ratio between P atoms of the stabilizer and 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 embodiment, 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 a particular embodiment, the P:Ca molar ratio is about 1:15 to about 1:5. In another particular embodiment, the P:Ca molar ratio is about 1:25 to about 1:5. According to some embodiments, such inorganic polyphosphate is pyrophosphate, triphosphate, hexametaphosphate or a pharmaceutically acceptable salt thereof. According to another embodiment, the bisphosphonate is alendronic acid, etidronic acid, zoledronic acid or medronic acid and the P:Ca molar ratio is as defined hereinabove.
According to some embodiments, the calcium content (Ca content) of such compositions comprising stabilizers is about 1 wt % to about 39 wt %, about 5 wt % to about 39 wt %, about 10% to about 39 wt %, about 15% to about 39 wt %, about 20 wt % to about 38 wt %, about 25 wt % to about 38 wt %, or about 30 wt % to about 38 wt % of the dry ACC particles The terms “Ca content” and “calcium content” is used herein interchangeably and refer to the content of calcium of the ACC in the final composition.
In certain embodiments, the P:Ca molar ratio is about 1:40 to about 1:1, and the Ca content is about 20 wt % to about 39 wt %. In some embodiments, the molar ratio is 1:28 to about 1:3, and the Ca content is about 30 wt % to about 38 wt % of the dry ACC particles. In another embodiment, the molar ratio is 1:25 to about 1:5, and the Ca content is about 30 wt % to about 36 wt % of the dry ACC particles.
According to some embodiments, the stabilized ACC powder comprises absorbed and adsorbed water, from about 1 wt % to about 18 wt %, from about 4 wt % to about 15 wt %, and from about 6 wt % to about 10 wt %. According to some embodiments, the stabilizer is polyphosphate or bisphosphonate and the molar ratio between P atoms of the stabilizer and Ca atoms of the ACC is about 1:90 to 1:1.
According to some embodiments, the stabilizer is selected from the group consisting of a polyphosphate, phosphorylated amino acid, bisphosphonate, citric acid, tartaric acid and any combination thereof. According to one embodiments, 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 an inorganic polyphosphate.
According to one embodiment, the stabilizer is selected from selected from the group consisting of organic acids, phosphorylated, phosphonated, sulfated or sulfonated organic compound, phosphoric or sulfuric esters of hydroxy carboxylic acids, phosphorylated amino acids, bisphosphonate, organic polyphosphate, hydroxyl bearing organic compounds, derivatives thereof, proteins and any combinations thereof.
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, hexamethaphosphate, ethanol, and any combination thereof.
In most cases, the ACC contains 1 to 20 wt % and preferably no more than 10 wt % of adsorbed water and maintain its stabilization in the presence of a stabilizer and further storage in dry conditions. ACC powder that was used in the examples contained about 6 to 10 wt % of water when formulated. In terms of calcium content, it means that the calcium content in ACC is in a practical range of 28 to 38 wt % of its composition. For practical calculation, the average calcium content is defined as 30 wt % in this application.
The term “pharmaceutical composition” as used herein refers to any composition comprising at least stabilized ACC, and optionally at least one additional pharmaceutically acceptable carriers, stabilizers, and/or bulking agents.
According to any above aspects and embodiments, the composition of the present invention is a food supplement. Thus is 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 a non-therapeutic use. 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 in improving the athletic performance of a subject. According to some embodiments, improving athletic performance comprises improving muscle performance.
Formulations of the composition of the present invention may be adjusted according to the required applications. In particular, the composition may be formulated using a method known in the art to provide a rapid, continuous or delayed release of the active ingredient after administration to mammals. For example, the formulation may be any one selected from plasters, granules, lotions, liniments, lemonades, aromatic waters, powders, syrups, ophthalmic ointments, liquids and solutions, aerosols, extracts, elixirs, ointments, fluidextracts, emulsions, suspensions, decoctions, infusions, ophthalmic solutions, tablets, suppositories, injections, spirits, capsules, creams, troches, tinctures, pastes, pills, and soft or hard gelatin capsules. According to some embodiments, the composition is a powder. According to certain embodiments, the composition is a powder for a sublingual administration. According to other embodiments, the composition is in the form of a tablet or capsules for oral administration. According to some embodiments, the composition for oral administration may be an enteric-coated composition or an enteric capsule.
Formulations can also include excipients for aiding the manufacturing, storage, and efficiency of the administration. Examples are silicon dioxide and microcellulose as anticaking agents, magnesium stearate as a lubricant, and sucralose, mannitol, sorbitol, erythritol, menthol and citric acid as flavoring agents.
According to some embodiments, the composition is a nutraceutical composition. As used herein, the term “nutraceutical composition” refers to a composition suitable for use in human beings or animals, comprising one or more natural products with therapeutic action which provide a health benefit or have been associated with disease prevention or reduction.
The term “food supplement” is used to mean a product containing said composition and intended to supplement the food by providing nutrients that are beneficial to health according to any acceptable directive, such as European directive. For example, a food supplement may be a capsule or a tablet for swallowing, or powder or small vial to mix with food and providing beneficial health effects. The food supplement may be also formulated as a sublingual composition. The food supplement may comprise aside the active agent edible carrier and/or excipients. According to some embodiments, the edible carrier and/or excipient is a pharmaceutically acceptable carrier and/or excipient.
The term “edible carrier” refers to compounds, materials, compositions, and/or dosage forms that are suitable for use in contact with the tissues of a subject. Each carrier must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation. The term “edible carrier” as used herein means a material that can be administered, consumed, digested or passed through the digestive system of an animal or human without any toxic effect. These edible carrier materials can exist as either a solid or liquid at room temperature.
The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein 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 compositions may contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
The terms “pharmaceutically acceptable” and “pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic, or other untoward reactions when administered to an animal, or human, as appropriate.
According to any one of the above embodiments, the composition of the present invention, is formulated in any known form such as powder, suspension, tablet, or capsule.
Having now generally described the invention, the same will be more readily understood through reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.
ACC stabilized by sodium triphosphate and citric acid solid composition was prepared as described in WO2016193982 A1 with water content of from 8-10% as measured by loss when drying. For preparing the powder for sublingual administration, the obtained solid was further milled to the size of below 0.4 millimeter. The powder was mixed with excipients such as: anticaking agent, such as silicon dioxide, lubricant such as magnesium stearate and sweetening and flavoring compounds such as sucralose, mannitol, sorbitol, erythritol, mint and citric acid and used by sublingual administration. The ACC tablet formulation for oral administration was prepared as described in WO 2016/193982, and corresponds with the commercial product Density®, developed and marketed by the applicant.
Aim:
This pilot study aimed at comparing the ability of athletes taking sublingually amorphous calcium carbonate (ACC) and crystalline calcium carbonate (CCC) to perform intense physical activity using the Wingate anaerobic test and lactate measurements before and after the test. The sublingual administration of ACC powder formulation allows to bypass stomach.
Study Procedure
The study was done with two professional cyclists, as a double-blind crossover test, using ACC or CCC (control) as test items. The subjects received the first test item for 3 days, and performed Wingate test. After a cleaning period of 3 days the routine was repeated with the second test item. The efficacy of CCC and ACC on performing Wingate test was evaluated for each cyclist.
Each subject received ACC or CCC formulations in sachets that looked identical from the outside, with the exception of the writing B (for CCC) or D (for ACC). Each sachet contained 250 mg elemental calcium in the form of powder (about 740 mg of ACC). The test item was administered by the sublingual route for 5 minutes. The total daily dose was 2,250 mg elemental calcium as ACC (corresponding to about 6660 mg of ACC). On the day of the Wingate test, the subjects received 2 sachets before the test and 1 sachet afterward. Then, for the next 3 days, they received no treatment (see Table 1).
The ACC powder and tablets that were used in the experiments were primarily prepared for the purpose of calcium supplementation. Hence, their dosage was documented by their exact calcium content. However, the commercial ACC (manufactured by Amorphical) may contain various amounts of strongly adsorbed water, which does not affect its long-term stability. Hence, for calculation purposes based on an average measurements of commercial batches, the ACC amount is calculated in the examples on the approximate basis of 30-35% calcium content of ACC.
Wingate anaerobic test is an anaerobic exercise test, performed on a stationary bicycle that measures peak anaerobic power and anaerobic capacity. The test was performed as follows: after a warmed up the subject cycled for 30 seconds in full power followed by 2 minutes of a rest interval, after which he cycled again for 30 seconds in full power, followed by 2 minutes of rest, and then a third round of cycling for 30 seconds in full power.
Lactate levels were measured using EKF Lactate Scout device prior to performing the Wingate test and tested again 3, 5, 7, 9 and 15 minutes after the test.
The peak power (PP) for each cyclist, as measured during each of the 3 repeats of the Wingate test are presented in
Power=Force(kg)×Distance(m)÷Time(s)
wherein the force is calculated as 7.5% of the athlete mass and the distance is the number of revolutions multiplied by the distance per revolution (in meters).
The results presented in
The Fatigue Index measures the rate at which power declines from peak power to the lowest power (5 last secs) of the same 30 sec test. A higher fatigue index represents lower ability to maintain power, i.e., lower endurance. It is calculated according to the following equation:
As shown in
Lactate measurements (
These results clearly indicate that ACC has a positive effect on the ability of cyclists to maintain high performance as seen by the PP values, which barely declined for both athletes after taking ACC compared to after taking CCC. Examining the fatigue index results reveals that it was much lower after taking ACC than after taking CCC for both cyclists, especially during the last cycling session which is the most tiring session.
Several case studies of athletes are described. The athletes started receiving ACC sublingually due to different physiological conditions such as non-healing fractures, inflammations and persistent pains. Following rapid recovery from the pathological condition(s) (if any present), the athletes kept taking ACC and most began improving their achievements and break their own records. Athletes consumed between 2 and 10 sachets per day, containing ACC powder for sublingual administration, each sachet containing 200 or 250 mg of calcium (corresponding to about 620 and 740 mg of ACC, respectively). The powder for sublingual administration comprised 80-90 wt % of stabilized ACC, anticaking agent, such as silicon dioxide, lubricant such as magnesium stearate and sweetening and flavoring compounds such as sucralose, mannitol, sorbitol, erythritol and citric acid. In some cases, the athletes received oral formulations (tablets), each comprising 200 mg elemental calcium in the form of ACC, in addition to the sublingual doses.
Athlete 1 (Swimmer, Male)
Athlete 1 is a swimmer with international success for over 8 years. He suffered from painful osteolysis of clavicle and was treated with steroid injections for over a year. After 21 days of administering 2400 mg/day of calcium in ACC sublingually (˜7440 mg of ACC), the pain was gone. The athlete continued taking 2000 mg/day of calcium as ACC (˜7000 mg of ACC), and after 60 days from beginning of administration, he set a new national record in 200 m individual medley and in 100 m individual medley. In an international championship. In the 100 m swim he broke his own record by more than half a second After 80 days he achieved additional new personal records including an improvement of his best record in 200 m breaststroke by 1.2 sec.
Athlete 2 (Runner, Male)
Athlete 2, a long-distance runner with national championship records, was diagnosed as suffering from stress fracture of sacrum. After 9 days of treatment with ACC, by administering 1800 mg/day of calcium as ACC (˜5580 mg of ACC) administered sublingually, the pain disappeared. The athlete continued the ACC administration as follows: 200 (˜620) mg calcium as ACC oral tablet twice a day with the addition of 1,500 mg calcium as ACC (˜4440 mg) of the sublingual ACC dose for about 20 additional days, after which he returned to regular training. The athlete indicated that each day he could handle more extensive training without feeling fatigue. The Athlete continued with ˜5680 mg/day of ACC, administered sublingually and orally. After 52 days he broke his personal record in marathon running by reducing more than 4 minutes and did it again after 84 days and 136 days, while participating in international competitions (another time reduction by more than 3 minutes).
Athlete 3 (Crossfit, Female)
Athlete 3, a crossfit athlete with national records, suffered from overly trained knee resulted in swelling. She was previously treated with Etopan (etodolac). Upon ceasing the etodolac treatment she began ACC treatment by sublingual administration of 1500 mg/day of calcium as ACC (˜4440 mg/day of ACC). The swelling and pain were completely gone after two days of treatment. The Athlete continued taking sublingually the same dose of ACC. Within a period of 30-90 days she broke more than 10 personal records as follows (% improvements in parentheses): Snatch from blocks (11.4%), Back Squat (7.8%), Front Squat (5.0%), Jerk 101 Kg (1.0%), P.R. 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%), Press for 2reps (10.0%).
Athlete 4 (Runner, Male)
Athlete 4, a long-distance runner with national records, suffered from hip stress fracture and inflammation of adductor magnus and longus. The Athlete was treated with of 1,500 mg/day of calcium as ACC sublingually (˜4440 mg/day of ACC) for 14 days and increased the dose to 1,750 mg/day afterwards (˜5180 mg/day of ACC). The pain was gradually subdued: 80% of the pain disappeared after 14 day, and completely disappeared after 19 days. The Athlete continued taking sublingually the same dose of ACC. After 54 days he broke 2 records in 20,000 meters running and after another 27 days his record in marathon running improved by more than 2 minutes.
Athlete 5 (Runner, Male)
Athlete 5 was diagnosed as suffering from hamstring tendonitis. The athlete was treated with 1,400/day of calcium as ACC (˜4340 mg/day), sublingually. The Athlete reported gradual calming of pains: After 14 days 50% of the pain disappeared and after 45 days of additional sublingual administration, he reported that 95% of the pain disappeared. The Athlete continued taking the same dose of ACC sublingually. After 56 and 83 days from the beginning of the treatment, the Athlete broke his personal record in 3000 m running by 7 and 6.5 second, respectively.
Athlete 6 (Swimmer, Female)
Athlete 6 reported performance regression for almost 4 years without any injury, most likely due to age-related decline. After 30 days of administering ˜5180 mg/day of ACC sublingually (1750 mg of calcium), the Athlete reported that she felt stronger. After additional 30 days, she broke her personal record at 200 freestyle.
Athlete 7 (Runner, Male)
Athlete 7 suffered from level-3 stress fracture of a tibia. After 14 days of sublingual administration of 2200 mg/day calcium (˜6820 mg/day of ACC), using a combination of sublingual and oral doses, the athlete reported pain disappearance and returned to regular training. The athlete continued taking ˜5680 mg ACC. The athlete reported great feeling during training and performance improvement. After 59 days he broke his personal record in half marathon by more than 9 minutes. After additional 12 days he broke his recent personal record in half marathon by another 3 minutes.
Athlete 8 (Runner, Female)
Athlete 8 suffered from inflammation as a result of a bulging disc, accompanied with a decreased range of muscle motion (muscle stiffness). After 14 days of sublingual administration of 1500 mg/day of calcium as ACC (˜4440 mg/day of ACC) the pain decreased during running. After 30 days the pain dropped from level 10 to 3. The motion range was improved and the athlete reported rapid recovery right after running. She became much more flexible, with higher endurance. Her performance has improved immeasurably. Her recovery from training to training is fantastic. Her heart rate during intense exercise dropped significantly. This recovery changed all her abilities. This has reversed her body's age (at the age of 49) she felt 10 to 15 years younger.
Two commercial media, Dulbecco's phosphate-buffered saline (DPBS) and Gibco Dulbecco's Modified Eagle Medium: Nutrient Mixture F-12 (DMEM/F12), with 10% Fetal Bovine Serum (FBS) were used to evaluate the pH effect of different sources of calcium carbonate. DPBS is Dulbecco's Phosphate Buffered Saline, generally serves as an isotonic saline solution or buffer for washing cells and tissues and intends to provide a buffer system for maintaining cell culture media in the physiological range of 7.2-7.6.
DMEM/F12 is a widely used basal medium for supporting the growth of many different mammalian cells. DMEM/F12 medium+10% FBS was used to maximally mimic the environment of the body fluids.
Three sources of calcium carbonate were used ACC, Sodium bicarbonate (SBC) and Crystalline Calcium Carbonate (CCC).
ACC suspension was prepared by adding 36 ml calcium chloride di-hydrate solution 3.10% w/v mixed with 4 ml water and 10 ml triphosphate solution 0.56% w/v with 40 ml sodium carbonate solution 1.95% to precipitate ACC, followed by addition of 10 ml of stabilizing solution containing triphosphate 0.56% w/v to obtain ACC suspension comprising 10% of sodium triphosphate. The final composition comprised 73.53 mM of CaCO3 in the water suspension.
SBC and CCC were dissolved or dispersed in water such that the concentration of carbonate was equal to that of ACC suspension (73.5 mM CaCO3).
The dispersions or SBC solution of the different carbonate sources were slowly and continuously added to the 2 different media. The addition was done until a pH plateau was accomplished or the level of the solution reached the end of the capacity of the used container (˜130 ml). The results are shown in
As demonstrated in this example, the amount of ACC, needed to reach pH 8, was remarkably lower than the amount of both SBC solution and the CCC suspension. This is in-spite of the lower solubility of ACC relative to SBC. SBC, which is the substance tried previously for improving athlete performance, is not significantly different than the highly insoluble CCC in its capability (very slow) to reach higher pH levels.
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 to 2 different sources of CCC.
The experiment's solution was prepared by mixing 18 ml of a commercial 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 inside a sterile tissue sample cup and a hole was punched out at its top into which a pH probe was inserted. The cup was placed over a magnetic stirrer (JB-10 stirrer, Inesa, China) and during the procedure the solution was constantly stirred. A pH meter (MesuLab, PXSJ-216F ion meter, MRC, Israel) was connected to a PC for continuous measurement of the pH values using REXDC2.0 software.
An amount of 20.5 μl of lactic acid was added to the solution in order to reduce the pH to a slightly acidic pH in the range of 6.8. After a few seconds, 3 ml of various nanometric ACC or CCC suspensions having concentrations of 0.06%, freshly prepared (either in-situ or by suspending pre-made powders) were added to the acidified solution in each of the experiments. The procedure was repeated several times with:
1. ACC stabilized by triphosphate (TP), generated in-situ by mixing 4 solutions (calcium chloride, sodium carbonate and 2 solutions of TP, in an appropriate order.
2. ACC stabilized by triphosphate (TP), generated in-situ by mixing 2 solutions, in an appropriate order.
3. ACC stabilized by triphosphate (TP), generated and dried before its resuspension in water at equivalent weight of the above suspensions.
4. Nanometric crystalline calcium carbonate (CCC) that was prepared similarly to the above ACC but without the stabilizer. The powder was resuspended at the same concentrations as above.
5. Commercial nanometric CCC, suspended at the same concentration of the above solutions.
The results are presented in
The two experiments with the CCC nanoparticles indicates almost no change in the pH. Hence, lower pH levels are required to activate and accelerate their dissolutions.
Although the present invention has been described herein above by way of preferred embodiments thereof, it can be modified, without departing from the spirit and nature of the subject invention as defined in the appended claims.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IL2020/050818 | 7/23/2020 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 62877316 | Jul 2019 | US |
