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    • 专利摘要:
    Compositions for muscle health. The present invention relates to a composition comprising glucosamine hydrochloride, magnesium malate and glucuronolactone and/or glucuronic acid. It can also contain malic acid. It also refers to the new composition for use in the treatment or prevention of diseases, conditions, dysfunctions, alterations or muscular discomfort, as well as in the increase of endurance, performance, strength or muscle mass. The composition may be in the form of a pharmaceutical composition, food supplement, functional food or medical food. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2631353A1
    申请号:ES201630232
    申请日:2016-02-29
    公开日:2017-08-30
    发明作者:José ESCAICH FERRER；Ana María TORRENT GIBERT；Ramón Ruhí Roura；Josep Vergés Milano；Eulalia Montell Bonaventura；José VIÑA RIBES；María Carmen GÓMEZ CABRERA
    申请人:Bioiberica SA；
    IPC主号:
    专利说明:

    Compositions for muscle health
    5 Technical sector of the inventionThe present invention relates to a new composition. Similarly, it refers to thenew composition for use in the treatment or prevention of diseases,conditions, dysfunctions, alterations or muscular discomforts, as well as in the increase ofendurance, performance, strength or muscle mass. The composition may be in shape.
    10 of pharmaceutical composition, food supplement, functional food or medical food.
    Prior art
    An imbalance between reactive oxygen species and antioxidant levels in the
    15 organism leads to a state of oxidative stress. Physical activity generates free radicals due to increased metabolism and great stress on muscle fibers. With aging there is also a reduction in antioxidant levels and this is a factor that triggers atrophy and loss of muscle mass and strength.
    20 Cellular oxidative stress has negative effects on the health of the muscles and performance in athletes because it causes damage at the level of proteins, lipids and DNA and alters the functions of muscle cells inducing muscle pain, weakness and fatigue. Antioxidant supplementation helps athletes maintain optimal health which is crucial for maximum performance (J.Finaud et al. Sports Med. 25 36 (4), 327-358 (2006)).
    With age there is an increase in oxidation damage in mitochondrial DNA that can be counteracted by antioxidant supplementation. Aging is also associated with a lower renewal of mitochondria (M.C. Gómez et al.
    30 Clin. Chem. Lab. Med. 50 (8), 1287-1295 (2012); F. Sanchís-Gomar et al. Exp. Gerontol. 46, 967-969 (2011)). In addition, sports performance depends on the ergogenic ability of the athlete, that is, on the ability to generate energy and delay the onset of fatigue. These processes are closely linked to mitochondrial energy functionality (C. de Teresa Galván et al. Rev. Andal. Med. Sport 1 (2), 61-72 (2008)).
    35 Oxidative stress and mitochondrial dysfunction are important factors in atrophy


    muscle, sarcopenia and other diseases or muscular conditions (Y.C. Jang et al. FASEB J. 24, 1376-1390 (2010)).
    Muscular atrophy is the wear or loss of muscle tissue, thus losing muscle strength. Sarcopenia is a syndrome that is characterized by a gradual and widespread loss of skeletal muscle mass and poor muscle function (less strength or lower performance). It has been described that the prevalence of sarcopenia in people 60-70 years old is 5-13% and in people over 80 years old it can be 50% (AJ Cruz-Jentoft et al Age and Ageing 39, 412- 423 (2010)). Muscle weakness and impaired muscle function that result from sarcopenia are also major components of geriatric frailty syndrome. Fragility is a condition associated with aging, comorbidity and disability.
    Cachexia is a state of extreme malnutrition, with almost total loss of body fat and intense muscular atrophy, caused by diseases such as tuberculosis, cancer or AIDS.
    Fibromyalgia is characterized by widespread chronic pain, fatigue, memory problems and changes in mood. Extreme fatigue is present in all the activities carried out by people with fibromyalgia, so their daily tasks are inevitably difficult. Fibromyalgia affects between 2% and 5% of the population of different countries, and women are more likely to suffer from it.
    Deferred myalgia, also known as muscle soreness, is a late-onset muscle pain (DMAT) or late-onset post-stress muscle pain (DOMPAT), in English DOMS (delayed onset muscular soreness), accompanied by muscle inflammation. There are several hypotheses about the origin of deferred myalgia, with the breakage of muscle fibers during exercise being the most accepted by the scientific community as the cause of pain and inflammation.
    Muscle tension corresponds to a muscle tone that is too high. The most frequent causes of muscle tensions are a bad position, muscle injuries (muscle pull, fibrillation tear, muscle tear), lack of hydration and mineral salts, and lack of training before playing sports.
    A muscle spasm or cramp is an involuntary contraction of a muscle or group of


    They, who are in mild or intense pain, and who can make these muscles harden or bulge. It can occur due to insufficient oxygenation of the muscles or the loss of fluids and mineral salts as a result of prolonged effort, sudden movements or cold. Muscle contracture is also a painful and involuntary shortening of a muscle, but it is more durable (it can last from days to months) and less painful than a muscle cramp. Possible causes of a contracture are nervous tension, poor postures, excessive exercise, fibromyalgia, psycho-emotional problems, and other pathologies that cause muscle blockage.
    A muscle strain occurs when a muscle is subjected to an exaggerated stretch and there is a tear. This painful injury, also called muscle pull, can be caused by physical activity or excessive exertion, inadequate warm-up before performing physical activity or poor flexibility.
    The cells have developed a complex antioxidant system to prevent excessive accumulation of reactive oxygen species. This system is composed of antioxidant enzymes and non-enzymatic antioxidants that react with reactive oxygen species. Under normal physiological conditions there is a balance between endogenous antioxidants and reactive oxygen species. However, the alteration of said balance produces a state of oxidative stress. Glutathione in its reduced form (GSH) is a non-enzymatic antioxidant that helps protect cells from reactive oxygen species such as free radicals and peroxides. GSH can react directly with free radicals, or it can reduce peroxides through glutathione peroxidase, oxidizing to GSSG. The proportion of oxidized glutathione (GSSG) to reduced glutathione (GSH) within cells is used as a measure of cellular toxicity. A substance or composition that reduces the GSSG / GSH ratio will have a good protective effect against oxidative stress, which will result in good muscle health and can be used in Sports Nutrition and Nutrition in general, Sports Medicine, Geriatrics, Traumatology and Rehabilitation. In fact, in elderly people with knee or hip osteoarthritis it is common to detect muscle weakness already in very early stages. It is important to treat muscle weakness in patients at risk of suffering from osteoarthritis, or with osteoarthritis, as it could delay the onset of the disease and affect its progression (M. Fransen et al, Cochrane Database Syst. Rev. (3): CD004286).
    It has been described that the intake of certain substances (for example, astaxanthin, fermented milk) improves muscle damage of late onset, after exercise, increasing 10


    the antioxidant capacity of muscles (W. Aoi et al. Journal of Nutritional Biochemistry 18, 140-145 (2007); W. Aoi et al. Antioxid Redox Signal 5, 139-144 (2003)).
    It has also been described that the administration of melatonin exerts a reduction in oxidative stress caused by intense physical exercise (C. de Teresa Galván et al. Rev. Andal. Med. Sport 1 (2), 61-72 (2008); KV Kumar et al. 34, 256-259 (2002)).
    The amino sugar sugar glucosamine (2-amino-2-deoxy-D-glucose) is an intermediate substrate used by articular cartilage in the synthesis of glycosaminoglycans and proteoglycans. It is present as a natural compound in almost all human tissues. In particular, the use of glucosamine hydrochloride in the treatment of osteoarthritis is important (H. Nakamura et al. Clin. Exp. Rheumatol. 22 (3), 293-299, (2004); WB Zhang et al. Zhonghua Wai Ke Za Zhi 45 (14), 998-1001 (2007)). On the other hand, although its use has been described, as a component of a beverage, to limit muscle sores that appear after a physical exercise (US patent application 2007/0292483), some researchers doubt its effectiveness in preventing or promoting recovery from fatigue or muscle damage after physical exercise (W. Aoi et al., Nutrition Journal 5 (15), doi: 10.1186 / 1475-2891-515 (2006)).
    L-malic acid, also called L-hydroxybutanedioic acid or Lhydroxysuccinic acid, is a main part of the Krebs cycle, participating in the process of obtaining ATP (adenosine triphosphate). It is believed that deficiency of malic acid in tissues may be one of the factors for fibromyalgia. Magnesium malate is the magnesium salt of malic acid.
    Glucuronolactone (D-glucurono-γ-lactone) is the γ-lactone of D-glucuronic acid. It is present both in the human body and in various foods such as legumes and red wine. It is described that within the human body it participates in detoxification processes. Glucuronolactone is an ingredient in some energy drinks, in which it is in equilibrium with glucuronic acid.
    To date, the combination of the components of the compositions of the present invention has not been described.
    In view of the above, providing new compositions that reduce or inhibit cellular oxidative stress, and that are therefore useful in the treatment or prevention of


    diseases, conditions, dysfunctions, alterations or muscle discomforts, as well as in increasing endurance, performance, strength or muscle mass, is a subject of great interest both in the therapeutic field and in the field of food supplements, functional foods or medical foods.
    Explanation of the invention.
    The present inventors have found that the compositions of the present invention, defined below, are new, reduce cellular oxidative stress, exerting an antioxidant effect, which is also synergistic, and increase the number of muscle mitochondria. Therefore, the compositions of the present invention can be used in the treatment
    or prevention of sarcopenia, muscular atrophy, cachexia, fibromyalgia, muscle injury, muscle fragility syndrome, muscle tension, muscle fatigue, muscle spasm, muscle contracture or deferred myalgia. They can also be used in the form of a food supplement, functional food or medical food to increase muscle endurance, increase performance in athletes, increase or maintain muscle strength, increase or maintain muscle mass, reduce or prevent muscle stiffness, reduce muscle tension, reduce or prevent muscle fatigue, reduce or prevent muscle spasm, reduce muscle contracture, reduce or prevent muscle strain, reduce fibromyalgia, reduce muscle fragility syndrome, reduce muscle recovery time, reduce muscle recovery time from a muscle injury, reduce sarcopenia, reduce muscle atrophy or reduce cachexia. All the diseases, conditions, dysfunctions, alterations or discomforts mentioned in the present invention are related to each other, since they have in common that they manifest in the musculature, and in addition, that in order to treat or alleviate them it is necessary to act on oxidative stress and mitochondrial function
    Accordingly, the present invention relates to a composition comprising glucosamine hydrochloride, magnesium malate and glucuronolactone and / or glucuronic acid.
    In a preferred embodiment, the composition comprises glucosamine hydrochloride, magnesium malate and glucuronolactone. Preferably said composition is in solid form.
    In another preferred embodiment, the composition comprises glucosamine hydrochloride, magnesium malate and glucuronic acid.
    In another preferred embodiment, the composition comprises glucosamine hydrochloride, malate


    of magnesium, glucuronolactone and glucuronic acid.
    In another preferred embodiment, the composition further comprises malic acid.
    In another preferred embodiment, glucosamine hydrochloride and magnesium malate are present in a weight ratio of glucosamine hydrochloride to magnesium malate between 1: 1 and 1: 6, preferably between 1: 1 and 1: 4. More preferably the weight ratio is 1: 2.17.
    In another equally preferred embodiment, glucosamine hydrochloride and glucuronolactone and / or glucuronic acid are present in a weight ratio of glucosamine hydrochloride to glucuronolactone and / or glucuronic acid between 1: 0.1 and 1: 1, preferably comprised between 1: 0.1 and 1: 0.6. More preferably the weight ratio is 1: 0.4.
    Preferably, glucosamine hydrochloride, magnesium malate and glucuronolactone and / or glucuronic acid are present in a weight ratio of glucosamine hydrochloride to magnesium malate to glucuronolactone and / or glucuronic acid between 1: 1: 0.1 and 1: 6: 1, preferably between 1: 1: 0.1 and 1: 4: 0.6. The weight ratio of glucosamine hydrochloride to magnesium malate to glucuronolactone and / or especially preferred glucuronic acid is 1: 2.17: 0.40.
    In another equally preferred embodiment, glucosamine hydrochloride and malic acid are present in a weight ratio of glucosamine hydrochloride to malic acid between 1: 0.1 and 1: 5, preferably between 1: 0.1 and 1: one. More preferably the weight ratio is 1: 0.6.
    Preferably, glucosamine hydrochloride, magnesium malate, glucuronolactone and / or glucuronic acid and malic acid are present in a weight ratio of glucosamine hydrochloride to magnesium malate to glucuronolactone and / or glucuronic acid to malic acid between 1: 1: 0.1: 0.1 and 1: 6: 1: 5, preferably between 1: 1: 0.1: 0.1 and 1: 4: 0.6: 1. The weight ratio of glucosamine hydrochloride to magnesium malate to glucuronolactone and / or glucuronic acid to especially preferred malic acid is 1: 2.17: 0.40: 0.60.
    The present invention also relates to a food supplement, a functional food or a medical food comprising the composition, defined above, and at least one nutritional additive.


    Likewise, the present invention also relates to a pharmaceutical composition comprising the composition, defined above, and at least one pharmaceutically acceptable excipient.
    Likewise, the present invention also relates to a composition, defined above, for use as a medicament or medical food.
    The present invention also relates to a composition, defined above, for use in the treatment or prevention of sarcopenia, muscular atrophy, cachexia, fibromyalgia, muscle injury, muscle fragility syndrome, muscle tension, muscle fatigue, muscle spasm, muscle contracture or deferred myalgia in a mammal.
    Likewise, the present invention also relates to a medical food containing a composition, defined above, for use in increasing muscular endurance, increasing performance in athletes, increasing or maintaining muscle strength, increasing
    or maintain muscle mass, reduce or prevent muscle soreness, reduce muscle tension, reduce or prevent muscle fatigue, reduce or prevent muscle spasm, reduce muscle contracture, reduce or prevent muscle strain, reduce fibromyalgia, reduce Muscle fragility syndrome, reduce muscle recovery time, reduce recovery time from a muscle injury, reduce sarcopenia, reduce muscle atrophy or reduce cachexia in a mammal.
    The present invention also relates to the use of a composition, defined above, for the preparation of a medicament for the treatment or prevention of sarcopenia, muscular atrophy, cachexia, fibromyalgia, muscle injury, muscle fragility syndrome, muscle tension, muscle fatigue, muscle spasm, muscle contracture or deferred myalgia in a mammal. Preferably, the use is for the treatment or prevention of muscular atrophy.
    Likewise, the present invention also relates to the use of a composition defined above, for the preparation of a food supplement, a functional food or a medical food, to increase muscular endurance, increase performance in athletes, increase or maintain muscle strength. , increase or maintain muscle mass, reduce or prevent muscle soreness, reduce muscle tension, reduce or prevent muscle fatigue, reduce or prevent muscle spasm, reduce muscle contracture, reduce or prevent muscle strain, reduce fibromyalgia, reduce the


    Muscle fragility syndrome, reduce muscle recovery time, reduce recovery time from a muscle injury, reduce sarcopenia, reduce muscle atrophy or reduce cachexia in a mammal.
    Likewise, the present invention also relates to the use of a composition, definedpreviously, as a food supplement, a functional food or a fooddoctor, to increase muscular endurance, increase performance in athletes,increase or maintain muscle strength, increase or maintain muscle mass, reduce orprevent muscle soreness, reduce muscle tension, reduce or prevent fatigue
    10 muscle, reduce or prevent muscle spasm, reduce muscle contracture, reduce or prevent muscle strain, reduce fibromyalgia, reduce muscle fragility syndrome, reduce muscle recovery time, reduce recovery time from muscle injury, reduce sarcopenia, reduce muscle atrophy or reduce cachexia in a mammal.
    15 Preferably, the use is to increase muscular endurance. Equally preferred is the use to increase performance in athletes.
    Preferably, the reduction of the muscular recovery time takes place after a physical activity or a muscular injury.
    Preferably, the mammal is a human.
    The present invention also relates to the use of a composition, defined above, as an ergogenic agent.
    Preferably, the magnesium malate is magnesium malate trihydrate, but when the weight ratios between the components of the compositions of the invention are described, the water molecules are not counted. For example, when the relationship in
    30 weight glucosamine hydrochloride to magnesium malate is 1: 1, we refer to 1 magnesium malate, not 1 magnesium malate trihydrate.
    In the present invention, the term "comprises" should be construed so that it also includes the case of "consists solely of" and that of "consists essentially of".
    In the present invention, the abbreviation GSH refers to glutathione in its reduced form, and the abbreviation GSSG refers to the oxidized form of glutathione.


    In the present invention the following terms have the indicated meaning: "Functional food" refers to a food that, apart from its basic nutritional role from the material and energy point of view, is capable of providing a health benefit by containing one or more biologically active components or a combination of biologically active components. Functional food is part of an individual's diet.
    "Food supplement" refers to a diet supplement that contains in concentrated form one or more nutrients or other biologically active components with a nutritional or physiological effect beneficial to health. It is administered in the form of tablets, capsules or in any other dosage form.
    "Medical food" refers to a food administered to a patient under the instructions and supervision of a doctor. Said food is specific to the nutritional requirements of a patient who has a certain disease, malaise or disorder. It is used in the United States and usually comes in the form of food, although it can also be found in dosed form. In Europe the equivalent of “medical food” is “dietary food for special medical uses”, which is a food intended for a special diet, which has been specially prepared or formulated to fully or partially meet the nutritional needs of patients whose ability to ingesting, digesting, absorbing, metabolizing or excreting normal foods or certain nutrients thereof or metabolites is limited or deficient, or is altered, or that need other clinically determined nutrients, whose dietary treatment cannot be carried out only by modifying the normal diet, with other foods intended for a special diet, or by both. It can be in dosed form or not.
    An ergogenic agent is that substance that improves performance in athletes. The compositions of the present invention act as ergogenic agents.
    The components of the compositions of the present invention glucosamine hydrochloride, magnesium malate, glucuronolactone, glucuronic acid and malic acid are commercial products.
    Glucosamine hydrochloride (2-amino-2-deoxy-D-glucose hydrochloride), whose structure is shown below, is available from Bioibérica S.A. (www.bioiberica.com; code


    Product: F1590):
    Magnesium malate (magnesium salt of DL-malic acid), whose structure is shown below, is available from Jost Chemicals Co. (product code (trihydrate): 2557):
    20 Glucuronolactone (D-glucurono-γ-lactone) is available from Merck (product code: 841864) or Sigma-Aldrich (product code: 851450). The compound may exist in the form of monocyclic aldehyde:
    or in the form of bicyclic hemiacetal (lactol):


    When glucuronolactone is in solution, it is in equilibrium with glucuronic acid, so when a composition of the invention is in aqueous solution, part of the glucuronolactone is transformed into glucuronic acid. It is known that at room temperature an aqueous solution of glucuronolactone reaches an equilibrium of about 20% lactone and 80% acid in two months (The Merck Index, Twelfth Edition, 4476, page 760, year 1996).
    Glucuronic acid (D-glucuronic acid), whose structure is shown below, is available in Sigma (product code: G 5269):
    DL-malic acid, whose structure is shown below, is available from Bartek Ingredients Inc. (product code: 296):
    The compositions of the present invention can be prepared by mixing their components in the desired proportions. For example, if it is desired to prepare a composition of the present invention in a solid state, its components can be mixed in a solid state and subsequently sieved and homogenized the mixture.
    To use the compositions of the present invention in the treatment, prophylaxis or


    prevention of sarcopenia, muscular atrophy, cachexia, fibromyalgia, muscle injury, muscle fragility syndrome, muscle tension, muscle fatigue, muscle spasm, muscle contracture or deferred myalgia in a mammal, are formulated in appropriate pharmaceutical compositions, using techniques and excipients or conventional vehicles, such as those described in Remington: The Science and Practice of Pharmacy 2000, edited by Lippincott Williams and Wilkins, 20th edition, Philadelphia. The pharmaceutical compositions comprise a therapeutically effective amount of a composition of the present invention and at least one pharmaceutically acceptable excipient for administration to the patient. Said pharmaceutical compositions can be administered to the patient in required doses. The administration of the pharmaceutical compositions can be carried out by different routes, for example, oral, intravenous, subcutaneous, intramuscular, sublingual, intradermal, nasal or topical. The pharmaceutical compositions of the invention include a therapeutically effective amount of a composition of the present invention, said amount depending on many factors, such as, for example, the physical condition of the patient, age, sex, route of administration, frequency of administration or severity of the illness. Furthermore, it will be understood that said dosage of the composition of the invention can be administered in single or multiple dose units to provide the desired therapeutic effects.
    The pharmaceutical compositions of the invention will generally be in solid, liquid or gel form. Pharmaceutical preparations in solid form that can be prepared in accordance with the present invention include powders, mini-granules (pellets), tablets, dispersible granules, capsules, seals, tablets, lyophilisates and suppositories. Liquid form preparations include solutions, suspensions, emulsions, syrups, elixirs, drinkable vials and herbal teas. Also contemplated are preparations of solid forms that are to be converted, immediately before being used, into preparations in liquid form. Such liquid forms include solutions, suspensions and emulsions.
    To use the compositions of the present invention to increase muscular endurance, increase performance in athletes, increase or maintain muscle strength, increase or maintain muscle mass, reduce or prevent muscle sores, reduce muscle tension, reduce or prevent muscle fatigue, reduce or prevent muscle spasm, reduce muscle contracture, reduce or prevent muscle strain, reduce fibromyalgia, reduce muscle fragility syndrome, reduce muscle recovery time, reduce recovery time from muscle injury, reduce the


    sarcopenia, reduce muscular atrophy or reduce cachexia in a mammal, food supplements or dietary foods are prepared for special medical uses in dosed forms containing a composition of the invention and additives used in nutrition, or functional foods are prepared, adding the Compositions of the invention to foods that are part of the diet, or medical foods or dietary foods for special medical uses in non-dosed forms containing a composition of the invention and nutrients or foods are prepared. The food supplement may be in the form of tablets, capsules, solutions, suspensions or sachets. The functional food may be in the form of yogurts, milk, fermented milk, fruit juices, vegetable juices, soups, creams, dehydrated foods, cookies or baby foods. The dietary food for special medical uses may be in the form of tablets, capsules, solutions, suspensions or sachets or also as food for the special feeding of patients. Medical food is usually presented in the form of food for patient feeding, although it can also be found in dosed form.
    Pharmaceutical compositions, food supplements, functional foods
    or the medical foods of the present invention may also contain vitamins and / or minerals. Vitamins are selected from the group consisting of vitamin C, vitamin E, vitamin A, folic acid, niacin, pantothenic acid, vitamin B2, vitamin B6, vitamin B12, vitamin D and biotin. The minerals, in the form of salt, are selected from the group consisting of iodine, iron, phosphorus, potassium, selenium, zinc, copper, manganese and magnesium.
    In accordance with the present invention, the compositions of the invention have been found to have advantages, such as: (i) reducing oxidative stress (the composition of the invention containing a combination of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid (C) is more effective in reducing oxidative stress than glucosamine hydrochloride (D), magnesium malate (A) and a combination of glucosamine hydrochloride, glucuronolactone and malic acid (B)); (ii) present synergy of action (the composition of the invention containing a combination of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid has a beneficial synergistic effect on oxidative stress); (iii) increase muscle performance and endurance (the administration of a composition of the invention allows animals to increase their running time, as well as the maximum speed achieved, parameters related to muscle performance and endurance; (iv)


    increase the number of mitochondria at the muscular level (the administration of a composition of the invention produces an increase in cytochrome C levels, which is a representative indicator of the number of mitochondria at the muscular level); (v) reduce the levels of oxidized (carbonylated) proteins of the soleus muscle; (vi) do not cause damage
    5 tissues and (vii) are not dopants (none of their components are on the agency listWorld Anti-Doping WADA (World Anti-Doping Agency)).
    Brief Description of the Figures
    Figure 1 shows the running time in minutes of mice that were administered
    Water or a composition of the invention. The race time was determined in a stress test, which consisted of letting them run until exhaustion.
    Figure 2 shows the maximum speed in m.min-1 achieved by mice that were given water or a composition of the invention. The running speed was determined in
    15 a stress test, which consisted of letting them run until exhaustion.
    Figure 3 shows the ratio of oxidized glutathione (GSSG) to reduced glutathione (GSH) in the blood of resting or depleted mice due to exercise, to which water or a composition of the invention was administered for one week.
    Figure 4 shows the running time in minutes of mice at rest or with physical training for 8 weeks, to which water or a composition of the invention was administered daily. The running time was determined in an aerobic endurance test, which consisted of letting them run until exhaustion at a speed
    25 which was 75% of the maximum speed reached in the stress test.
    Figure 5 shows the levels of cytochrome C protein (indicator of the number of mitochondria at the muscular level) in the gastrocnemius muscle of mice at rest or with physical training for 8 weeks, to which water or a
    Composition of the invention daily.
    Figure 6 shows the levels of carbonylated (oxidized) proteins in the sole muscle of mice with physical training for 8 weeks, to which water or a composition of the invention was administered daily.
    35 Figure 7 shows a synergy study. The oxidized glutathione ratio is represented


    (GSSG) at reduced glutathione (GSH) in the blood of resting or depleted mice due to exercise, which were administered for a week water or a composition of the invention containing a combination of glucosamine hydrochloride, magnesium malate , glucuronolactone and malic acid (C), or magnesium malate (A) or a combination of glucosamine hydrochloride, glucuronolactone and malic acid (B).
    Figure 8 shows a comparative study of efficacy. The ratio of oxidized glutathione (GSSG) to reduced glutathione (GSH) in the blood of depleted mice due to exercise, which was administered for a week water or a composition of the invention containing a combination of glucosamine hydrochloride, is represented. magnesium malate, glucuronolactone and malic acid (C), or glucosamine hydrochloride (D).
    Detailed description of the preferred embodiments:
    The following examples are by way of illustration, and do not represent a limitation of the scope of the present invention.
    Example 1: Tablets of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid
    The tablets were prepared following conventional procedures.
    Content of active ingredients per tablet:
    Glucosamine hydrochloride 166.50 mg
    Magnesium Malate Trihydrate 469.50 mg (362.50 mg magnesium malate)
    Glucuronolactone 66.50 mg
    Malic acid 106.50 mg
    Example 2: Effect of a composition of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid on running time, running speed and oxidative stress in mice
    The objective of the study was, on the one hand, to determine the effect of a composition of the invention on the running time and the maximum speed reached, parameters related to muscular endurance and performance in athletes. On the other hand, the study would allow us to determine the ability of a composition of the invention to counteract oxidative stress.
    GSH is an endogenous antioxidant that helps protect cells from reactive species 16


    of oxygen such as free radicals and peroxides. The proportion of oxidized glutathione(GSSG) at reduced glutathione (GSH) within cells is used as a measure of thecellular toxicity A composition that reduces the GSSG / GSH ratio will have a goodprotective effect against oxidative stress, which will result in good muscle health.Therefore, said composition will be useful in the treatment or prevention of diseases,conditions, dysfunctions, alterations or muscle discomfort.
    Materials and methodsA total of 36 mice of strain C57BL / 6 were divided into 4 experimental groups:Rest Group + Water (n = 9): Animals at rest and without treatment.Rest Group + Composition (n = 9): Animals at rest and treated with the composition.Group Exercise + Water (n = 9): Animals exhausted by exercise and without treatment.Group Exercise + Composition (n = 9): Animals depleted by exercise and treated withcomposition.
    The groups without treatment are called placebo groups and the groups with treatment are the treated groups.
    The composition of the invention contained in solid state a combination of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid, in a weight ratio of glucosamine hydrochloride to magnesium malate to glucuronolactone to malic acid of 1: 2.17: 0 , 40: 0.60.
    The amount of composition administered was 0.5 g of composition per kg of animal weight.
    The animals of the Exercise Groups were accustomed for 1 week to the type of exercise that was performed in the stress test. The corresponding treatments (treated groups) or only water (placebo groups) were administered daily in the drinking water for a week before the stress test, which consisted of letting the animals run until exhaustion. Animals are considered exhausted when they are unable to continue running.
    2A) Determination of the effect on running time and running speed:
    The running time was determined by letting each animal run on the treadmill until exhaustion and the running speed is the maximum speed reached in this test.


    Results As can be seen in Figure 1, the group of mice treated daily with the composition of the invention at a dose of 0.5 g.kg-1 weight showed a statistically significant increase (p <0.01) of time in the order of 40% compared to the placebo group (animals exhausted by exercise and without treatment).
    As can be seen in Figure 2, daily administration of the composition of the invention at a dose of 0.5 g.kg-1 of weight produced a statistically significant increase (p <0.05) of the order of 24% of the maximum speed achieved with respect to the placebo group (animals exhausted by exercise and without treatment).
    2B) Determination of the effect on oxidative stress:
    The animals were sacrificed immediately after the cervical dislocation exercise protocol and blood samples were taken for analysis of the GSSG / GSH ratio and evaluation of the effect on oxidative stress.
    Results The results set out in Figure 3 demonstrate that the administration of the composition of the invention for one week to resting animals produced an order of 85% reduction in the degree of oxidative stress (p <0.01) with respect to the Group placebo, which was given only water (Rest Group + Water).
    As can be seen in Figure 3, the practice of exercise produced a significant increase in the GSSG / GSH ratio that was statistically significantly offset (p <0.01) by daily administration of the composition of the invention. The decrease in the degree of oxidative stress of the treated Group (Exercise + Composition Group) was of the order of 90% with respect to the placebo Group, which was administered only water (Exercise + Water Group).
    The results of the present Example show that the composition of the invention is capable of reducing oxidative stress, so it will be useful in the treatment or prevention of diseases, conditions, dysfunctions, alterations or muscle discomforts cited in the present invention. It has also been shown that the composition of the present invention increases muscular endurance.
    Example 3: Effect of a composition of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid on running time in a study


    aerobic endurance after 8 weeks of training
    Aerobic endurance is the ability of the human body to develop a reduced or medium intensity effort for a long time. This capacity depends on the management of oxygen: that is, on the balance that the subject manages to perform between the need for oxygen due to the activity and the consumption that it actually performs. A person with good aerobic endurance can tolerate the fatigue generated by the exercise, managing to maintain the rhythm and intensity for a considerable time. Who has a high aerobic endurance, thus, does not experience a significant drop in physical performance even when the minutes pass. Athletes who run long distances, such as marathoners, need great aerobic endurance to sustain the effort demanded by these competitions.
    The objective was to study the effect of oral administration of a composition of the invention on aerobic resistance in mice trained for 8 weeks.
    Materials and methodsA total of 36 mice of strain C57BL / 6 were divided into 4 experimental groups:Rest Group + Water (n = 9): Animals at rest and without treatment.Rest Group + Composition (n = 9): Animals at rest and treated with the composition.Group Exercise + Water (n = 9): Trained and untreated animals.Group Exercise + Composition (n = 9): Animals trained and treated with the composition.
    The groups without treatment are called placebo groups and the groups with treatment are the treated groups.
    The composition of the invention contained in solid state a combination of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid, in a weight ratio of glucosamine hydrochloride to magnesium malate to glucuronolactone to malic acid of 1: 2.17: 0 , 40: 0.60.
    The amount of composition administered was 0.5 g of composition per kg of animal weight.
    The corresponding treatments (treated groups) or only water (placebo groups) were administered daily in the drinking water. All the animals of the Rest Groups (Rest Group + Water and Rest Group + Composition) were used to the treadmill 2 times a week for 15 minutes. The running speed in these groups


    It was too low and insufficient to produce adaptations. The animals of the Exercise groups (Exercise + Water Group and Exercise + Composition Group) exercised on the treadmill, 5 days a week, for 8 weeks. Before starting the training protocol, as well as after 8 weeks of exercise, 2 stress tests were performed: the maximum speed test reached and the aerobic endurance test. The aerobic endurance test consisted of calculating the speed corresponding to 75% of the maximum speed reached and letting the animal run at this speed until exhaustion. After 24 hours since the last stress test, all animals were sacrificed and the soleus muscle, the gastrocnemius muscle and blood samples were removed. The tissues were frozen at -80 ° C until use.
    Results As can be seen in Figure 4, animals at rest and administered with the composition of the invention for 8 weeks (Rest Group + Composition) experienced an increase (p <0.01) in running time of more than 100 % with respect to the corresponding placebo Group (Rest Group + Water). The treated and trained Group animals (Exercise + Composition Group) increased their aerobic resistance (p <0.01) of the order of 50%, compared to the animals in the placebo and trained group (Exercise Group
    + Water)
    Example 4: Effect of a composition of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid on the values of Cytochrome C in the gastrocnemius muscle of mice
    It is known that with age there is an increase in oxidation damage in mitochondrial DNA. Cytochrome C is a small protein that functions as an electron transporter between respiratory complexes III and IV, and is located in the inner mitochondrial membrane. Cytochrome C levels are a representative indicator of the number of mitochondria at the muscular level. It is known that mitochondrial dysfunction and oxidative stress are important factors in muscular atrophy, sarcopenia and other diseases or muscular conditions. Therefore, it is important that in the treatment of diseases, conditions, dysfunctions, alterations or muscular discomfort there is an increase in the number of muscle mitochondria.
    Materials and methods The frozen gastrocnemius muscle was used at -80 ° C of Example 3. The determination of cytochrome C levels in gastrocnemius muscle was carried out by the Western Blot technique. An electrophoresis with Polyacrylamide gel was performed


    SDS Once the electrophoretic displacement was completed, the gel was transferred to a PVDF (Polyvinylidene Di-fluoride) membrane by electrotransfer. Next, the membranes were incubated with blocking buffer, primary and secondary antibody and exposed in the Image Quant LAS4000 system for visualization. The results were quantified using the "Image Gauge" program.
    Results As can be seen in Figure 5, administration of the composition of the invention to the animals at rest produced a statistically significant increase (p <0.05) of the order of 58% of the number of mitochondria. The animals in the treated and trained group (Exercise + Composition Group) showed a statistically significant increase (p <0.05) in the number of mitochondria on the order of 54%, compared to the placebo Group (Exercise + Water Group).
    Example 5: Effect of a composition of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid on the level of carbonylated (oxidized) proteins in the mouse muscle.
    Oxidative stress has negative effects on muscle health and performance because it produces damage at the level of proteins, lipids, DNA and alters the functions of muscle cells inducing muscle pain, weakness and fatigue. In addition, oxidative stress causes damage also at the mitochondrial level reducing its ability to generate energy. As a result of reduced mitochondrial function, the muscles receive less energy and this causes muscle fatigue and muscle atrophy due to age. It is important that in the treatment of diseases, conditions, dysfunctions, alterations or muscle discomforts there is a decrease in oxidized (carbonylated) proteins.
    Materials and methods To measure the effect on the oxidation of proteins, the frozen soleus muscle of the groups of Example 3 that exercised was used, since it is known that intense sport produces a high degree of oxidation.
    The determination of levels of carbonylated proteins in soleus muscle was carried out by the Western Blot technique, under the same procedure used in Example 4.
    Results As can be seen in Figure 6, in the animals of the treated and trained Group (Exercise + Composition Group) there was a statistically significant reduction


    (p <0.05) of the order of 23% of the levels of carbonylated proteins in the soleus muscle, compared with the placebo Group (Exercise + Water Group).
    Example 6: In vivo synergy study of a composition of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid
    The objective of the study was to determine if there was a synergistic effect between the components ofthe composition of the invention C. For this, the efficiencies of the composition were comparedof the invention (C), of magnesium malate (A) and of a hydrochloride composition ofglucosamine, glucuronolactone and malic acid (B) on oxidative stress.
    The efficacy of the composition of the invention C was also compared in the same study.(glucosamine hydrochloride + magnesium malate + glucuronolactone + malic acid) with theefficacy of glucosamine hydrochloride (D).
    Materials and methodsIn the study the effect of:
    A: magnesium malate trihydrate
    B: glucosamine hydrochloride + glucuronolactone + malic acid
    C: composition of the invention (glucosamine hydrochloride + magnesium malate +glucuronolactone + malic acid)
    D: glucosamine hydrochlorideA total of 54 mice were divided into 6 experimental groups:Rest Group + Water (n = 9): Animals at rest and without treatment.Group Exercise + Water (n = 9): Animals exhausted by exercise and without treatment.Group Exercise + A (n = 9): Animals depleted by exercise and treated with compound A(0.29 g.kg-1 weight).Group Exercise + B (n = 9): Animals exhausted by exercise and treated with the compositionB (0.21 g.kg-1 weight).Group Exercise + C (n = 9): Animals exhausted by exercise and treated with the compositionof the invention C (0.5 g.kg-1 weight).Exercise + D Group (n = 9): Animals depleted by exercise and treated with compound D(0.1 g.kg-1 weight).
    The composition of the invention C contained in solid state a combination of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid, in a weight ratio of glucosamine hydrochloride to magnesium malate to glucuronolactone to malic acid of 1: 2.17: 0.40: 0.60.


    Composition B contained in the solid state a combination of glucosamine hydrochloride, glucuronolactone and malic acid, in a weight ratio of glucosamine hydrochloride to glucuronolactone to malic acid of 1: 0.40: 0.60.
    The corresponding treatments (treated groups) or water (placebo groups) were administered daily for one week before taking the stress test. The animals were sacrificed immediately after the cervical dislocation exercise protocol and blood samples were taken for analysis of the GSSG / GSH ratio and evaluation of the effect on oxidative stress.
    Results As can be seen in Figure 7, there was no effect of reducing the ratio (GSSG / GSH) x 100 when compound A and composition B were administered separately to animals that exercised. In contrast, the administration of the composition of the invention C to animals that exercised led to an increase of about 56% of the antioxidant capacity, as reflected in the ratio (GSSG / GSH) x 100 (p <0.05), if we compare it with the corresponding placebo group (Exercise + Water). Therefore, there is a synergistic effect between the components of the composition of the invention C when co-administered.
    On the other hand, as can be seen in Figure 8, there are no statistically significant differences between the group that was administered glucosamine hydrochloride (Exercise + D) and the placebo Group (Exercise + Water). On the other hand, the administration of the composition of the invention (Exercise + C) caused an increase in the antioxidant capacity of the order of 56%, having found statistically significant differences (p <0.05) between the group to which the glucosamine hydrochloride (Exercise + D) and the group to which the composition of the invention C (Exercise + C) was administered.
    Example 7: Determination of tissue damage in mice by administering a composition of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid
    After administration to mice of a composition of the invention containing a combination of glucosamine hydrochloride, magnesium malate, glucuronolactone and malic acid, in a weight ratio of glucosamine hydrochloride to magnesium malate to glucuronolactone to malic acid of 1: 2.17: 0.40: 0.60, the veterinarian ruled out tissue damage from his observations at the macroscopic level.

    权利要求:
    Claims (8)
    [1]
    1.-A composition comprising glucosamine hydrochloride, magnesium malate, malic acid and glucuronolactone and / or glucuronic acid.
    52. The composition according to claim 1, comprising glucosamine hydrochloride,magnesium malate, malic acid and glucuronolactone.
    [3]
    3. The composition according to claim 1, comprising glucosamine hydrochloride, magnesium malate, malic acid and glucuronic acid.
    [4]
    4. The composition according to claim 1, comprising glucosamine hydrochloride, magnesium malate, malic acid, glucuronolactone and glucuronic acid.
    The composition according to any one of claims 1 to 4, wherein the glucosamine hydrochloride and magnesium malate are present in a weight ratio of glucosamine hydrochloride to magnesium malate comprised between 1: 1 and 1 : 6.
    [6]
    6. The composition according to any one of claims 1 to 5, wherein the hydrochloride
    20 glucosamine and glucuronolactone and / or glucuronic acid are present in a weight ratio of glucosamine hydrochloride to glucuronolactone and / or glucuronic acid between 1: 0.1 and 1: 1.
    [7]
    7. The composition according to any one of claims 1 to 6, wherein the hydrochloride
    Glucosamine and malic acid are present in a weight ratio of glucosamine hydrochloride to malic acid between 1: 0.1 and 1: 5.
    [8]
    8. A food supplement, a functional food or a medical food comprising the composition defined in any one of claims 1 to 7, and at least one additive
    30 nutritional.
    [9]
    9. A pharmaceutical composition comprising the composition defined in any one of claims 1 to 7, and at least one pharmaceutically acceptable excipient.
    10. Use of a composition defined in any one of claims 1 to 7, for the preparation of a medicament for the treatment or prevention of sarcopenia, muscular atrophy, cachexia, fibromyalgia, muscle injury, muscle fragility syndrome, tension

    muscle, muscle fatigue, muscle spasm, muscle contracture or deferred myalgia in a mammal.
    [11]
    11. Use of a composition defined in any one of claims 1 to 7, for the
    5 preparation of a food supplement, a functional food or a medical food, to increase muscular endurance, increase performance in athletes, increase or maintain muscle strength, increase or maintain muscle mass, reduce or prevent muscle stiffness, reduce muscle tension, reduce or prevent muscle fatigue, reduce
    or prevent muscle spasm, reduce muscle contracture, reduce or prevent a
    10 muscle strain, reduce fibromyalgia, reduce muscle fragility syndrome, reduce muscle recovery time, reduce recovery time from muscle injury, reduce sarcopenia, reduce muscle atrophy or reduce cachexia in a mammal.

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