Compositions comprising a combination of taurine and vitamin b9 and their use in the treatment of bone disorders

Abstract

The present invention relates to bone health and in particular to use of a composition comprising a combination of taurine and vitamin B9 for prevention or treatment of bone disorders or maintenance of bone health. The present invention also relates to compositions and methods for enhancing bone quality, bone growth and / or bone strength.

Description

[0001] Compositions and methods using a combination of taurine and vitamin B9 for use in bone disorders

[0002] Technical field of the invention

[0003] The present invention relates to bone health and in particular to use of a composition comprising a combination of taurine and vitamin B9 for prevention or treatment of bone disorders or maintenance of bone health. The present invention also relates to compositions and methods for enhancing bone quality, bone growth and / or bone strength.

[0004] Background of the invention

[0005] Bone is a tissue that undergoes constant remodelling as a result of the destruction and de novo synthesis of bone tissue in a complex process involving two main types of cells, the osteoblasts which produce new bone tissue and the osteoclasts which destroy bone, respectively. The osteoblasts, the cells responsible for bone formation, differentiate from precursor cells and express and secrete many enzymes and many structural proteins of the bone matrix, including collagen type I, osteocalcin, osteopontin and alkaline phosphatase. The osteoclasts are multinucleated cells which are responsible for bone loss in a process generally designated bone resorption.

[0006] In a healthy adult, human or animal, the joint action of the osteoblasts and osteoclasts makes possible the maintenance of the bone mass over time and simultaneously ensures remodelling of bone tissue by resorption and de novo synthesis of bone.

[0007] However, in some conditions or diseases, an imbalance in the process of bone remodelling is produced that may culminate in a loss of bone which proceeds at a more rapid rate than the rate of formation. Although this imbalance exists to a certain extent in most individuals as they age, it is much more severe and may occur at a younger age individuals. Thus, in human and other mammals a great variety of disorders are related to abnormal metabolism of bone resorption and bone formation, leading to an imbalance in metabolism or bone remodelling.

[0008] Of the pathological disorders related to an imbalance in bone metabolism, particular mention may be made of the disorders or diseases such as Paget's disease, bone loss or osteolysis observed close to a prosthesis, metastatic bone diseases, hypercalcemia due to a cancer, multiple myelomas and periodontal diseases. Some of the disorders or diseases of bone metabolism may be caused by long-term immobilisation, for example long-term hospitalisation or even after a period of weightlessness.

[0009] Studies reveal differences in bone processes between animal and human, in particular, animals can exhibit bone changes, however, they may not develop osteoporosis, which is commonly developed in human (Ruff Christopher B. et al. 2020 Skeletal ageing in Virunga mountain gorillas Phil. Trans. R. Soc.)

[0010] In human and animals, there are many conditions characterised by the need to increase bone formation. For example, in the case of bone fractures, it is necessary to stimulate bone growth in order to accelerate complete repair of the bone. This need is also present in the periodontal diseases, the metastatic diseases of bone, the osteolytic diseases and the conditions under which repair of the connective tissue is required, for example for the cicatrisation or regeneration of defects or traumatisms of cartilage. The stimulation of bone growth is also required in the case of primary and secondary hyperparathyroidism, as well as in bone conditions associated with diabetes, or associated with glucocorticoids.

[0011] Although there exists to-day a large variety of active compounds for stimulating bone formation and / or inhibiting bone resorption, there is a constant need for new active compounds, in particular owing to the limited success of the current treatments.

[0012] Furthermore, in view of the chronic character of some conditions caused by an imbalance in bone metabolism, there is a need for new active compounds which it will be possible to use in the long term in human and animals, and which are likely to be available in the form of a food additive, for example in the form of a nutritional composition.

[0013] Summary of the invention

[0014] The inventors have surprisingly demonstrated that a combination of taurine and vitamin B9 acts synergistically on mitochondrial calcium elevation in SW1353 cells.

[0015] Mitochondrial calcium plays a role in the regulation of ATP generation and contributes to the orchestration of cellular metabolic homeostasis (Glancy, B. and R. S. Balaban (2012). "Role of mitochondrial Ca2+ in the regulation of cellular energetics." Biochemistry 51(14): 2959-2973). In bone tissue and cells, it plays a central role in bone formation (Sautchuk and Eliseev, Bone Report, Cell energy metabolism and bone formation (2022), 27: 16: 101594).

[0016] Thus, an object of the present invention therefore relates to providing compositions for use in improving bone health, and solves the above mentioned problems of the prior art with regards to possibility to use in the long term without side effects.

[0017] Thus, one aspect of the invention relates to a composition comprising an effective amount of a combination of taurine and vitamin B9 for use to prevent or treat bone disorders or maintenance of bone health in an individual.

[0018] In an embodiment, the amount of taurine in the composition is higher than the amount of vitamin B9.

[0019] Another aspect of the present invention relates to a method of manufacturing a composition for use according to the invention.

[0020] In a last aspect, the present invention relates to a kit comprising an effective amount of a combination of taurine and vitamin B9 in one or more containers. Additional features and advantages are described herein and will be apparent from the following Figures and Detailed Description.

[0021] Brief description of the figures

[0022] FIG. 1 is a graph showing that the effect of the combination of taurine with vitamin B9 is greater than the effect of taurine or vitamin B9 alone on mitochondrial Ca2+ rise in SW1353 cells. The bar chart shows the effect of taurine (500 pM, black), vitamin B9 (250 pM, gray) and the combination of 500 pM taurine + 250 pM vitamin B9 (ratio taurine / vitamin B9 = 2 / 1) on the integrated mitochondrial calcium rise, evoked by 100 pM histamine. Results are expressed as mean + / - SEM from n = 16 experiments. * indicates statistically significant difference of the measured vs. theoretical difference in mitochondrial calcium at P < 0.05 (one-way ANOVA test).

[0023] FIG. 2 is a graph showing that taurine synergies with vitamin B9 to activate mitochondrial Ca2+ rise, during SW1353 cells stimulation, when the dose of taurine is higher than the dose of vitamin B9. The data of Fig. 1 were used to determine, in the Fig. 2, the expected theoretical effect (sum between taurine effect and vitamin B9 effect) and the real measured effect of the combination (taurine + vitamin B9) and to extrapolate the synergism. Results are expressed as mean + / - SEM from n = 16 experiments per condition. * indicates statistically significant difference of the measured vs. theoretical difference in mitochondrial calcium at P < 0.05 (Student's t-test).

[0024] FIG. 3 is a graph showing that taurine with vitamin B9 activates mitochondrial Ca2+ rise, during SW1353 cells stimulation, when the dose of taurine is lower than the dose of vitamin B9. The effect of Taurine (75 pM), vitamin B9 (2 mM) and the combination of 75 pM taurine + 2 mM vitamin B6 (ratio taurine / vitamin B9 = 1 / 27) were measured as described in FIG.l and the extrapolation of the theoretical effect (sum between taurine effect and vitamin B9 effect) and the real measured effect of the combination (taurine + vitamin B9) were determined as explained in FIG. 2 and were represented in this figure. Results are expressed as mean + / - SEM from n = 16 experiments per condition. * indicates statistically significant difference of the measured vs. theoretical difference in mitochondrial calcium at P < 0.05 (Student's t-test).

[0025] Detailed description of the invention

[0026] Definitions

[0027] Prior to discussing the present invention in further details, the following terms and conventions will first be defined:

[0028] In the context of the present invention, mentioned percentages are weight / weight percentages unless otherwise stated.

[0029] The term "and / or" used in the context of the "X and / or Y" should be interpreted as "X", or "Y", or "X and Y".

[0030] Numerical ranges as used herein are intended to include every number and subset of numbers contained within that range, whether specifically disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 1 to 8, from 3 to 7, from 4 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

[0031] The terms "prevent" and "prevention" mean to administer a composition as disclosed herein to a subject is not showing any symptoms of the condition to reduce or prevent development of at least one symptom associated with the condition. Furthermore, "prevention" includes reduction of risk, incidence and / or severity of a condition or disorder.

[0032] As used herein, an "effective amount" is an amount that treats or prevents a deficiency, treats or prevents a disease or medical condition in an individual, or, more generally, reduces symptoms, manages progression of the disease, or provides a nutritional, physiological, or medical benefit to the individual. "Animal" includes, but is not limited to, mammals, which includes but is not limited to rodents; aquatic mammals; domestic animals such as dogs, cats and other pets; farm animals such as sheep, pigs, cows and horses; and humans. Where "animal," "mammal" or a plural thereof is used, these terms also apply to any animal that is capable of the effect exhibited or intended to be exhibited by the context of the passage, e.g., an animal benefitting from improved mitochondrial calcium import. While the term "individual" or "subject" is often used herein to refer to a human, the present disclosure is not so limited. Accordingly, the term "individual" or "subject" refers to any animal, mammal or human that can benefit from the methods and compositions disclosed herein.

[0033] The term "pet" means any animal which could benefit from or enjoy the compositions provided by the present disclosure. For example, the pet can be an avian, bovine, canine, equine, feline, hircine, lupine, murine, ovine, or porcine animal, but the pet can be any suitable animal. The term "companion animal" means a dog or a cat.

[0034] A "subject" or "individual" is a mammal, preferably a human, that includes an elderly human, an older human, an older adult, am adult or a child, an animal, an older adult or ageing animal, a pet, an old pet.

[0035] The term "elderly" in the context of a human means an age from birth of at least 60 years, preferably above 63 years, more preferably above 65 years, and most preferably above 70 years. The term "older adult" in the context of a human means an age from birth of at least 45 years, preferably above 50 years, more preferably above 55 years, and includes elderly individuals. The term "older adult" in the context of a human means an age from birth of at least 45 years, preferably above 50 years, more preferably above 55 years, and includes elderly individuals.

[0036] For animals, an "older adult" or "ageing individual" has exceeded 50% of the average lifespan for its particular species and / or breed within a species. An animal is considered "elderly" if it has surpassed 66% of the average expected lifespan, preferably if it has surpassed the 75% of the average expected lifespan, more preferably if it has surpassed 80% of the average expected lifespan. For example, an elderly cat or dog has an age from birth of at least about 7 years.

[0037] An "oral nutrition supplement" or "ONS" is a composition comprising at least one macronutrient and / or at least one micronutrient, for example in a form of sterile liquids, semi-solids or powders, and intended to supplement other nutritional intake such as that from food. Non-limiting examples of commercially available ONS products include MERITENE®, BOOST®, NUTREN® and SUSTAGEN®. In some embodiments, an ONS can be a beverage in liquid form that can be consumed without further addition of liquid, for example an amount of the liquid that is one serving of the composition.

[0038] A "kit" means that the components of the kit are physically associated in or with one or more containers and considered a unit for manufacture, distribution, sale, or use. Containers include, but are not limited to, bags, boxes, cartons, bottles, packages of any type or design or material, over- wrap, shrink-wrap, affixed components (e.g., stapled, adhered, or the like), or combinations thereof.

[0039] All references to singular characteristics or limitations of the present invention shall include the corresponding plural characteristic or limitation, and vice versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made.

[0040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0041] Composition for use The present inventors have shown that the provision of a combination of taurine and vitamin B9 synergistically improves mitochondrial calcium uptake which is altered in bone disorders.

[0042] Thus, the invention in a first aspect relates to a composition comprising an effective amount of a combination of taurine and vitamin B9 for use to improve bone health, for example to prevent or treat bone disorders or maintain bone health in an individual.

[0043] In an embodiment, the amount of taurine in the composition is higher than the amount of vitamin B9.

[0044] In an embodiment, the said composition is for use in i) stimulating bone formation and / or inhibiting bone resorption; ii) improving bone quality; iii) preventing or treating disorders linked to an imbalance in the relationship between bone formation and bone resorption.

[0045] By "stimulation of bone formation" is meant according to the invention, the capacity of the combination of taurine and vitamin B9 of the present invention to induce an increase of the bone density at a given dose.

[0046] The specialist skilled in the art may also have recourse to any of the other tests, such as the measurement of the resistance of bone to rupture or also to the measurement of alkaline phosphatase activity and the measurement of the accumulation of calcium in the osteoblast cells.

[0047] By "inhibition of bone resorption" is meant according to the invention inhibition of the destructive activity of bone tissue by the osteoclast cells. In order to verify that the supply of the composition in human or animals inhibits bone resorption, the specialist skilled in the art can measure the urinary excretion of desoxypyridinoline, a diminution of the expression of desoxypyridinoline being the reflection of inhibition of bone resorption. The supply of the composition according to the invention to an animal organism induces simultaneously a stimulation of bone formation and inhibition of bone resorption, the overall increase of bone mineralisation, and hence of the bone density, being the result of the induction of these two mechanisms.

[0048] The composition according to the present invention is also designed for individuals presenting symptoms of bone deficit or likely to suffer from bone deficit, i.e. from an imbalance in the relationship between bone formation and bone resorption which, if it continues, induces a diminution of the bone mass. A composition according to the invention is also designed for individuals presenting symptoms of bone deficit resulting from a fracture, an operation or also a dental disease.

[0049] In an embodiment, the composition for use according to present invention is designed to treat a bone deficit resulting from a fracture.

[0050] In particular the composition is designed to prevent or treat diseases selected from Paget's disease, bone loss or osteolysis observed close to a prosthesis, metastatic bone diseases, hypercalcemia due to a cancer, multiple myelomas, periodontal diseases.

[0051] As has already been mentioned above, many disorders linked to an imbalance of bone metabolism develop gradually over a long period of time and require chronic treatments. Their prevention or their treatment can hence be carried out by means of a regular supply of the composition according to the present invention, preferably in the form of a nutritional composition.

[0052] Similarly, a regular nutritional supply of the composition according to the present invention to young growing individuals, humans or animals, is such as to make possible the production of a high bone density and an elevated peak bone mass by stimulation of bone formation when these individuals attain adult age. A regular nutritional supply of the composition according to the present inventionis also useful for preventing the bone loss that occurs with ageing and / or to protect bone cells during bone aging.

[0053] In another embodiment, the said composition is designed to stimulate bone formation in young individuals in the growth phase.

[0054] A composition such as defined above is also designed to promote bone quality, bone growth in order to obtain individuals possessing high bone density and, if possible, concomitantly a high peak bone mass. In particular, a composition according to the invention is useful during the growth phase of human as well as other mammals, in particular of pedigree dogs, and also racehorses.

[0055] As used herein "bone quality" may refer to aspects of bone composition and structure that contribute to bone strength independently of bone mineral density. These include bone turnover, microarchitecture, mineralisation, microdamage and the composition of bone matrix and mineral. Methods to measure bone quality are known in the art.

[0056] As used herein, "promoting bone growth and / or strength" may refer to the support of normal bone growth and / or strength. Supporting normal bone growth and / or strength may result in normal bone anatomy and physiology. Suitable methods and parameters to determine bone growth and bone strength will be known to the skilled person (see e.g. Donnelly, E., 2011. Clinical Orthopaedics and Related Research, 469(8), pp.2128-2138). Suitably, normal bone growth and / or strength may be determined using one or more bone parameter selected from: trabecular bone volume fraction (BV / TV), bone mineral density (BMD), bone mineral content (BMC), cortical bone volume (Ct.BV), medio-lateral diameter, antero-posterior diameter, bone ultimate force (FMax), and bone stiffness. In some embodiments, normal bone growth and / or strength is determined using one or more bone parameter selected from: bone mineral density (BMD), trabecular bone volume fraction (BV / TV), cortical bone volume (Ct.BV), and bone ultimate force (FMax). Suitable methods to determine these parameters will be available to the skilled person. In another manner, this aspect of the invention may be described as the use of an effective amount of a combination of taurine and vitamin B9 in the manufacture of a medicament for the prevention or treatment of bone disorders or maintenance of bone health in an individual.

[0057] Embodiments of the invention thus include a composition comprising an effective amount of a combination of taurine and vitamin B9 for use to prevent or treat bone disorders or for maintenance of bone health in an individual.

[0058] Further embodiments of the invention include a composition for use according to the invention, wherein the composition further comprises at least one of vitamin B3, vitamin B6 and / or vitamin B12.

[0059] Ingredients- main bioactive compounds

[0060] The taurine and vitamin B9 are the main bioactive molecules according to present invention.

[0061] Taurine

[0062] Taurine also known as 2-aminoethanesulfonic acid is an organic acid that occurs naturally in food, especially in shellfish (eg, scallops, mussels, clams) and in the dark meat of turkey and chicken, as well as in other meats and eggs.

[0063] In an embodiment, the daily doses for a human 60 kg subject are from about 400 mg to about 6000 mg per day of taurine or a functional derivative thereof.

[0064] In an embodiment, taurine is administered to an individual in an amount of at least about 50 mg, or 70 mg, or 100 mg, or 120 mg, or 150 mg, or 200 mg, or 300 mg, or 400 mg, or 500 mg, or 600 mg, or 800 mg, or 1000 mg, or 2000 mg, or 3000 mg per day. In an embodiment, the daily doses for children are from are from about 1.7 mg to about 41.7 mg per kg of body weight, preferably 8.3 mg per kg of body weight.

[0065] In another embodiment the daily amount of taurine is administered to an animal or a pet in an amount of the equivalent conversion from the human dose to the animal dose based on body surface, as per FDA guidelines (Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016 Mar;7(2):27-31. doi: 10.4103 / 0976- 0105.177703. PMID: 27057123; PMCID: PMC4804402).

[0066] In an embodiment, taurine is administered to a dog in the daily amount of from about 5 mg to about 150 mg per kg of body weight.

[0067] In an embodiment, taurine is administered to a cat in the daily amount of from about 10 mg to 150 mg per kg of body weight.

[0068] In an embodiment, taurine is administered to small breed dogs in an amount of about 6 mg / day to 1000 mg / day, preferably about 20 mg / day to 800 mg / day, more preferably about 40 mg / day to 600 mg / day.

[0069] In an embodiment, taurine is administered to medium breed dogs in an amount of about 20 mg / day to 4000 mg / day, preferably about 40 mg / day to 3000 mg / day, more preferably about 80 mg / day to 2000 mg / day.

[0070] In an embodiment, taurine is administered to large breed dogs in an amount of about 40 mg / day to 8000 mg / day, preferably about 80 mg / day to 6000 mg / day, more preferably about 100 mg / day to 4000 mg / day

[0071] In an embodiment, taurine is administered to small breed cats in an amount of about 5 mg / day to 1200 mg / day, preferably about 10 mg / day to 750 mg / day, more preferably about 15 mg / day to 600 mg / day. In an embodiment, taurine is administered to medium breed cats in an amount of about 10 mg / day to 1500 mg / day, preferably about 15 mg / day to 900 mg / day, more preferably about 25 mg / day to 750 mg / day.

[0072] In an embodiment, taurine is administered to large breed cats in an amount of about 20 mg / day to 3000 mg / day, preferably about 30 mg / day to 2000 mg / day, more preferably about 40 mg / day to 1000 mg / day

[0073] In general embodiment, taurine in dog foods ranges from 100 mg to 6000 mg / kg diet. Yet, taurine in cats foods ranges from about 1000 mg to 6000 mg / kg diet.

[0074] Moreover, the inventors found that the active dose of taurine or derivative in the combination, may be lowered for an equal efficacy.

[0075] "Vitamin" includes such compounds obtained naturally from plant and animal foods or synthetically made, pro-vitamins, derivatives thereof, and analogs thereof.

[0076] Vitamin B9, also known as folate or folic acid, is not produced in the body, making it an essential nutrient. Folate naturally occurs in vegetables (especially dark green leafy vegetables), fruits and fruit juices, nuts, beans, peas, seafood, eggs, dairy products, meat, poultry, and grains.

[0077] Thus, in an embodiment, the vitamin B9 is folate.

[0078] In an embodiment, the vitamin B9 is folic acid.

[0079] The vitamin B9 may be from any suitable source and may be isolated and / or chemically synthesized.

[0080] The effective amount of each of the taurine and vitamin B9 varies with the particular composition, the age and condition of the recipient, and the particular disorder or disease being treated. In an embodiment, Vitamin B9 is administered to a human in the amount of from about 0.02 mg to about 4.29 mg per day, preferably from 0.2 mg to 1.2 mg per day.

[0081] In an embodiment, vitamin B9 is administered to small breed dogs: in an amount of about 0.001 mg / day to 30 mg / day, preferably about 0.0015 mg / day to 20 mg / day, more preferably about 0.002 mg / day to 15 mg / day.

[0082] In an embodiment, vitamin B9 is administered to medium breed dogs in an amount of about 0.01 mg / day to 50 mg / day, preferably about 0.015 mg / day to 40 mg / day, more preferably about 0.02 mg / day to 30 mg / day.

[0083] In an embodiment, vitamin B9 is administered to large breed dogs in an amount of about 0.03 mg / day to 150 mg / day, preferably about 0.04 mg / day to 125 mg / day, more preferably about 0.06 mg / day to 100 mg / day

[0084] In an embodiment, vitamin B9 is administered to small breed cats in an amount of about 0.05 mg / day to 10 mg / day, preferably about 0.10 mg / day to 7.5 mg / day, more preferably about 0.15 mg / day to 6.0 mg / day.

[0085] In an embodiment, vitamin B9 is administered to medium breed cats in an amount of about 0.10 mg / day to 15 mg / day, preferably about 0.2 mg / day to 10 mg / day, more preferably about 0.25 mg / day to 7.5 mg / day.

[0086] In an embodiment, vitamin B9 is administered to large breed cats in an amount of about 0.1 mg / day to 20 mg / day, preferably about 0.25 mg / day to 15 mg / day, more preferably about 0.3 mg / day to 10 mg / day.

[0087] In an embodiment, vitamin B9 is contained in a dog food in an amount of from about 0.216 mg to about 11 mg per kg of dry matter.

[0088] In an embodiment, vitamin B9 is contained in a cat food in an amount of from about 0.8 mg to about 40 mg per kg of dry matter. In an embodiment, vitamin B9 is administered to a dog in an amount of from about 0.002 to 0.25 mg per kg of body weight.

[0089] In an embodiment, vitamin B9 is administered to a cat in an amount of from about 0.01 to 1 mg per kg of body weight.

[0090] In some embodiments, the taurine and the vitamin B9 are the only components administered to the individual.

[0091] In an embodiment, the amount of taurine in the composition is higher than the amount of vitamin B9.

[0092] In an embodiment, the composition for use according to the present invention consists essentially of a combination of taurine and vitamin B9.

[0093] In an embodiment, the composition for use according to the present invention consists of a combination of taurine and vitamin B9.

[0094] A single serving or dose of the composition can comprise the effective amount of taurine and vitamin B9 , and a package can contain one or more of the servings or doses.

[0095] Ingredients- further bioactive compound

[0096] The compositions for use according to the invention may also comprise at least one further bioactive compound selected from the group consisting of antioxidants, anti-inflammatory compounds, glycosaminoglycans, prebiotics, fibres, probiotics, fatty acids, enzymes, minerals, trace elements and / or vitamins.

[0097] The term "bioactive" in the context of the present application means that the compound contributes to the health of an individual, or has an effect on the human body, beyond that of meeting basic nutritional need.

[0098] The at least one further bioactive compound may be from a natural source. Thus the compounds may be from extracts of plants, animals, fish, fungi, algae, microbial fermentation. Minerals are considered as from natural source also within this definition.

[0099] In a preferred embodiment, enzymes may be proteases such as trypsin, or enzyme extracts such as bromelain, for example.

[0100] Optionally the composition can further comprise one or more vitamin B selected from vitamin B3, vitamin B6, vitamin B12.

[0101] Non-limiting examples of suitable B vitamins include Vitamin Bl (thiamine), Vitamin B2 (riboflavin), Vitamin B5 (pantothenic acid), Vitamin B3 (nicotinic acid or niacin, nicotinamide or niacinamide), Vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), Vitamin B7 (biotin) and Vitamin B12 (various cobalamins; commonly cyanocobalamin, adenosylcobalamin in vitamin supplements) and combinations thereof.

[0102] Nutritional compositions

[0103] The compositions for use according to the invention may be nutritional compositions or pharmaceutical compositions, and may be for human or veterinary use.

[0104] Thus, in preferred embodiments, the composition for use according to the invention is a nutritional composition.

[0105] By "nutritional composition" is meant in the context of the present application a composition which is a source of nutrition to an individual.

[0106] The nutritional products or compositions of the invention may be a source of complete nutrition or may be a source of incomplete nutrition.

[0107] As used herein, "complete nutrition" includes nutritional products and compositions that contain sufficient types and levels of macronutrients (protein, fats and carbohydrates) and micronutrients to be sufficient to be a sole source of nutrition for the animal to which it is being administered to. Patients can receive 100% of their nutritional requirements from such complete nutritional compositions.

[0108] As used herein, "incomplete nutrition" includes nutritional products or compositions that do not contain sufficient levels of macronutrients (protein, fats and carbohydrates) or micronutrients to be sufficient to be a sole source of nutrition for the animal to which it is being administered to. Partial or incomplete nutritional compositions can be used as a nutritional supplement.

[0109] The combination of taurine and vitamin B9 can be administered in any composition that is suitable for human and / or animal consumption. In a preferred embodiment, it is administered to the individual orally or enterally (e.g. tube feeding). For example, it can be administered to the individual in a beverage, a food product, a capsule, a tablet, a powder or a suspension.

[0110] Non-limiting examples of suitable compositions for the include food compositions, dietary supplements, dietary supplements (e.g., liquid ONS), complete nutritional compositions, beverages, pharmaceuticals, oral nutritional supplement, medical food, nutraceuticals, food for special medical purpose (FSMP), powdered nutritional products to be reconstituted in water or milk before consumption, food additives, medicaments, drinks, petfood, and combinations thereof.

[0111] For pet food compositions, they may supply the necessary dietary requirements for an animal, animal treats (e.g., biscuits), or dietary supplements. The compositions may be a dry composition (e.g., kibble), semi-moist composition, wet composition, or any mixture thereof.

[0112] In another embodiment, the composition is a dietary supplement such as a gravy, drinking water, beverage, yogurt, powder, granule, paste, suspension, chew, morsel, treat, snack, pellet, pill, capsule, tablet, or any other suitable delivery form. The dietary supplement is to be administered to the animal in small amounts, or in the alternative, can be diluted before administration to an animal. The dietary supplement may require admixing or can be admixed with water or other diluent prior to administration to the animal.

[0113] Nutritional composition ingredients

[0114] Protein source

[0115] In an embodiment, the compositions for use according to the invention include a source of protein. The protein source may be dietary protein including, but not limited to animal protein (such as milk protein, meat protein or egg protein), vegetable protein (such as soy protein, wheat protein, rice protein, and pea protein), or combinations thereof. In an embodiment, the protein is selected from the group consisting of whey, chicken, corn, caseinate, wheat, flax, soy, carob, pea or combinations thereof.

[0116] Carbohydrate source

[0117] In an embodiment, the compositions include a source of carbohydrates. Any suitable carbohydrate may be used in the present compositions including, but not limited to, starch, sucrose, lactose, glucose, fructose, corn syrup solids, maltodextrin, modified starch, amylose starch, tapioca starch, corn starch, xylitol, sorbitol or combinations thereof.

[0118] Fat source

[0119] In an embodiment, the compositions include a source of fat. The source of fat may include any suitable fat or fat mixture. For example, the fat source may include, but is not limited to, vegetable fat (such as olive oil, corn oil, sunflower oil, high-oleic sunflower, rapeseed oil, canola oil, hazelnut oil, soy oil, palm oil, coconut oil, blackcurrant seed oil, borage oil, lecithins, and the like), animal fats (such as milk fat), or combinations thereof. The source of fat may also be less refined versions of the fats listed above (e.g., olive oil for polyphenol content).

[0120] Flavourings etc.

[0121] In addition, compositions for use according to the invention may also comprise natural or artificial flavours, for example fruit flavours like banana, orange, peach, pineapple or raspberry or other plant flavours like vanilla, cocoa, coffee, etc.

[0122] Nutritional composition formats

[0123] The nutritional compositions may include, besides the main bioactive components and any further bioactive components, and optionally one or more of a protein, carbohydrate and fat source, any number of optional additional food ingredients, including conventional food additives (synthetic or natural), for example one or more acidulants, additional thickeners, buffers or agents for pH adjustment, chelating agents, colorants, emulsifiers, excipient, flavor agent, mineral, osmotic agents, a pharmaceutically acceptable carrier, preservatives, stabilizers, sugar, sweeteners, texturizers, and / or vitamins. The optional ingredients can be added in any suitable amount.

[0124] The nutritional composition may be provided in any suitable format.

[0125] Examples of nutritional composition formats in which the composition for use according to the invention may be provided include solutions, ready-for- consumption compositions (e.g. ready-to-drink compositions or instant drinks), liquid comestibles, soft drinks, juice, sports drinks, milk drinks, milkshakes, yogurt drinks, soup, etc.

[0126] In a other embodiments, the nutritional compositions may be provided in the form of a concentrate, a powder, or granules (e.g. effervescent granules), which are diluted with water or other liquid, such as milk or fruit juice, to yield the ready-for-consumption composition. Further nutritional composition formats include, baked products, dairy products, desserts, confectionery products, cereal bars, and breakfast cereals. Examples of dairy products include milk and milk drinks, yoghurts and other cultured milk products, ice creams and cheeses. Examples of baked products include bread, biscuits and cakes.

[0127] In one embodiment, the composition for use according to the invention may also be available in a great variety of formats designed as animal foods, in particular for the dog or the cat, whether in a wet form, semi-wet form or dry form, in particular in the form of biscuits.

[0128] In an embodiment, the composition is in the form of an effervescent tablet.

[0129] Routes of administration

[0130] The nutritional compositions of the present disclosure may be administered by any means suitable for human or animal administration, and in particular for administration in any part of the gastrointestinal tract. Enteral administration, oral administration, and administration through a tube or catheter are all covered by the present disclosure. The nutritional compositions may also be administered by means selected from oral, rectal, sublingual, sublabial, buccal, topical, etc.

[0131] The nutritional compositions may be administered in any known form including, for example, tablets, capsules, liquids, chewables, soft gels, sachets, powders, syrups, liquid suspensions, emulsions and solutions in convenient dosage forms. In soft capsules, the active ingredients are preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols. Optionally, stabilizers may be added.

[0132] If the nutritional compositions are administered by tube feeding, the nutritional compositions may be used for short term or long term tube feeding. The composition of the invention can be administered at least one day per week, preferably at least two days per week, more preferably at least three or four days per week (e.g., every other day), most preferably at least five days per week, six days per week, or seven days per week. The time period of administration can be at least one week, preferably at least one month, more preferably at least two months, most preferably at least three months, for example at least four months. In an embodiment, dosing is at least daily; for example, a subject may receive one or more doses daily. In some embodiments, the administration continues for the remaining life of the individual. In other embodiments, the administration occurs until no detectable symptoms of the condition remain. In specific embodiments, the administration occurs until a detectable improvement of at least one symptom occurs and, in further cases, continues to remain ameliorated.

[0133] The ideal duration of the administration of the composition can be determined by those of skill in the art.

[0134] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.

[0135] Individual

[0136] The individual may be any suitable individual. Suitably, the individual may be a mammal. In preferred embodiments, the individual is a human. In other embodiments, the individual is an animal, preferably wherein the animal is a pet. A pet may be an animal selected from dogs, cats, birds, fish, rodents such as mice, rats, and guinea pigs, rabbits, etc. In some embodiments, the pet is a small dog breed. In some embodiments, the pet is a large dog breed. Though the invention may be useful in many various age groups, in a preferred embodiment the invention is targeted to ageing population, in particular healthy aging and / or elderly mammals. The elderly mammals include elderly human, old animals or pets, such as old cats, old dogs, old horses.

[0137] In another embodiment, the individual is menopausal or perimenopausal individual, in particular menouposal or perimenopausal woman.

[0138] In some embodiments, the individual is a juvenile, an adolescent, a child.

[0139] In some embodiments, the individual suffered from and / or is suffering from stunted growth. The definition of stunting may refer to the "height for age" value to be less than two standard deviations of the WHO Child Growth Standards median (see e.g. De Onis, M. and Branca, F., 2016. Maternal & child nutrition, 12, pp.12-26).

[0140] In some embodiments, the individual suffered from and / or is suffering from faltering growth. The term "faltering growth" may describe a pattern of slower weight gain than expected for age and sex in children and other adolescents (see e.g. King, C. and Davis, T., 2010. European journal of clinical nutrition, 64(1), pp.Sll-S13). In some embodiments, the individual suffered from and / or is suffering from growth stunting and / or faltering growth because of malnutrition or experienced disease such as anorexia, Crohn's disease and / or celiac disease. In some embodiments, the individual suffered from and / or is suffering from growth stunting and / or faltering growth because of treatment with drugs leading to malabsorption, anorexia and / or metabolic bone disease, such as chemotherapy drugs and / or corticosteroids.

[0141] Method of manufacturing a nutritional composition of the invention

[0142] The invention relates in a further aspect to a method for manufacturing a nutritional composition for use according to the invention, said method comprising the step of: - providing ingredients for a nutritional composition comprising a combination of taurine and vitamin B9, and mixing, such that the nutritional composition comprises the combination of taurine and vitamin B9.

[0143] Pharmaceutical composition for use.

[0144] In a further embodiment, the invention relates to a composition for use to prevent or treat bone disorders or maintain bone health according to the invention, wherein the composition is a pharmaceutical composition.

[0145] By pharmaceutical means a composition, other than a nutritional composition, wherein a substance is used on or in the body to prevent, diagnose, alleviate, treat, or cure a disease in humans or animals in medicine. According to the present invention, the pharmaceutical may be used for preventing or treating bone disorders or maintaining bone health.

[0146] The pharmaceutical may be for use by a human. It may alternatively be a veterinary composition, for example suited for a dog, cat, or horse, in particular a thoroughbred horse.

[0147] In one preferred embodiment, the pharmaceutical composition of the invention comprises a combination of taurine and vitamin B9 or derivative.

[0148] The invention further relates to uses of the pharmaceutical according to the invention, as described herein as use of the compositions of the invention.

[0149] A pharmaceutical composition for use according to the invention comprising a combination of taurine and vitamin B9 or derivative in combination with at least one excipient selected from the group constituted by the pharmaceutically acceptable excipients. Procedures for the preparation of pharmaceutical compositions according to the invention can easily be found by the specialist skilled in the art, for example in the handbook Remington's Pharmaceutical Sciences, Mid. Publishing Co, Easton, Pa., USA. Physiologically acceptable excipients, vehicles and adjuvants are also described in the handbook entitled "Handbook of Pharmaceutical Excipients, Second edition, American Pharmaceutical Association, 1994. In order to formulate a pharmaceutical composition according to the invention, the specialist skilled in the art will advantageously be able to refer to the latest edition of the European Pharmacopoeia or the Pharmacopoeia of the United States of America (USP). The specialist skilled in the art will in particular be able advantageously to refer to the fourth edition "2002" of the European Pharmacopoeia or also to the edition USP 25-NF 20 of the American Pharmacopoeia (U.S. Pharmacopoeia).

[0150] Advantageously, a pharmaceutical composition such as defined above is suitable for oral, parenteral or intravenous administration. When the pharmaceutical composition for use according to the invention comprises at least one pharmaceutically or physiologically acceptable excipient, it is in particular an excipient appropriate for administration of the composition by the oral route or an excipient suitable for administration of the composition by the parenteral route.

[0151] A pharmaceutical composition for use according to the invention is available indifferently in a solid or liquid form. For oral administration, a solid pharmaceutical composition in the form of tablets, capsules or gelatine capsules will be preferred.

[0152] In liquid form, a pharmaceutical composition in the form of an aqueous or non-aqueous suspension, or also in the form of a water-in-oil or oil-in-water emulsion will be preferred.

[0153] Solid pharmaceutical forms may comprise, as vehicles, adjuvants or excipients, at least one diluent, one flavour, one solubilising agent, one lubricant, one suspension agent, one binder, one disintegrating agent and one encapsulating agent. Such compounds are for example magnesium carbonate, magnesium stearate, talc, lactose, pectin, dextrin, starch, gelatine, cellulosic materials, cocoa butter, etc. The compositions in liquid form may also comprise water, possibly as a mixture with propylene glycol or polyethylene glycol, and possibly also colouring agents, flavours, stabilisers and thickening agents.

[0154] Kit

[0155] The present disclosure also provides a kit comprising a combination of a combination of taurine and vitamin B9 in one or more containers. In an embodiment of the kit, the one or more containers comprise at least one first container that stores the taurine separately from the vitamin B9, which is stored in at least one second container, and the kit further comprises instructions for admixing the taurine with the vitamin B9 into a unit dosage form.

[0156] In an embodiment of the kit, the combination can be provided together in one or more prepackaged unit dosage forms, for example in separate containers that each contain a dried powder such that each container contains one prepackaged unit dosage form.

[0157] In another embodiment, the kit can comprise a plurality of compositions for admixing together to form one or more of the compositions disclosed herein. For example, the kit can contain two or more dried powders in separate containers relative to each other, the separate powders each containing a portion of the final unit dosage form. As a non-limiting example of such an embodiment, the kit can contain one or more first containers that house the taurine and can also contain one or more second containers that house the vitamin B9. The content of one of the first containers can be admixed with one of the second containers to form at least a portion of the unit dosage form of the composition.

[0158] The above examples of administration do not require continuous daily administration with no interruptions. Instead, there may be some short breaks in the administration, such as a break of two to four days during the period of administration. The ideal duration of the administration of the composition can be determined by those of skill in the art.

[0159] Combination of disclosures

[0160] It should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention.

[0161] The compositions for use according to the invention are herein described in different parameters, such as the ingredients, nutritional composition formats, uses, target groups etc. It should be noted that embodiments and features described in the context of one of the parameters of the composition for use according to the invention, may also be combined with other embodiments and features described in the context of another parameter, unless expressly stated otherwise.

[0162] All patent and non-patent references cited in the present application, are hereby incorporated by reference in their entirety.

[0163] The invention will now be described in further details in the following nonlimiting examples.

[0164] EXAMPLES

[0165] The following non-limiting examples present experimental data supporting the compositions and methods disclosed herein.

[0166] Example 1

[0167] To test the effect of taurine, vitamin B9 and their combination in living cells, the inventors measured mitochondrial calcium elevation in SW1353 cells. SW1353 cells were purchased from ATCC. SW1353 cells were seeded in 96-well plates at a density of 10 000 cells per well in 100mm dishes. Cells were cultured in minimal essential medium (DMEM, Gibco), high glucose, with 10% fetal calf serum and 1% Penicillin -Streptomycin. Mitochondrial calcium measurements were carried out using Hela cells infected with the adenovirus (from Sirion biotech) expressing the mitochondrially targeted calcium sensor mitochondrial mutated aequorin (Montero et al., 2004). For aequorin reconstitution, 24 hours after infection, cells were incubated for 2 h at room temperature (22 ±°C) in standard medium (145 mM NaCI, 5 mM KCI, 1 mM MgC , 1 mM CaC , 10 mM glucose and 10 mM Hepes, pH 7.4) with 1 pM wild-type coelenterazine.For treatment, compounds were directly added to the cell culture or myotubes cultures 2 hours before measurements. Luminescence was measured at the FLIPR. Tetra Aequorin (Molecular Devices). Mitochondrial calcium rise was obtained by stimulating the cells with 100 |_iM histamine. Calibration of the luminescence data into calcium concentration was carried out using an algorithm, as described previously (Alvarez & Montero, 2002). Custom module analysis based on Excel (Microsoft) and GhaphPad Prism 7.02 (GraphPad) software was used for quantification.

[0168] Results:

[0169] As shown in FIG. 1 the effect of the combination of taurine with vitamin B9 is greater than the effect of taurine or vitamin B9 alone on mitochondrial Ca2 + activation in SW1353 chondrocyte cells. As shown in FIG. 2, taurine synergies with vitamin B9 to activate mitochondrial Ca2+ rise, during SW1353 chondrocyte cells stimulation, when the dose of taurine is higher than the dose of vitamin B9. FIG. 3 shows that taurine with vitamin B9 activates mitochondrial Ca2+ rise, during SW1353 cells stimulation, when the dose of taurine is lower than the dose of vitamin B9.

Claims

28Claims1. Composition comprising an effective amount of a combination of taurine and vitamin B9 for use to prevent or treat bone disorders or maintain bone health in an individual.

2. The composition for use according to claim 1, wherein the amount of taurine in the composition is higher than the amount of vitamin B9.

3. The composition for use according to Claim 1, wherein the vitamin B9 is folate.

4. The composition for use according to Claim 1, wherein the vitamin B9 is folic acid.

5. The composition for use according to any of the preceding claims, wherein the individual is a human or an animal, preferably wherein the animal is a pet.

6. The composition for use according to any of the preceding claims, wherein the composition is selected from the group consisting of food compositions, dietary supplements, nutritional compositions, oral nutritional supplement, medical food, nutraceuticals, beverages, powdered nutritional products to be reconstituted in water or milk before consumption, food additives, food for special medical purpose (FSMP) medicaments, drinks, petfood, and combinations thereof.

7. The composition for use according to any of the preceding claims, wherein the composition is in a form of a solid powder, a powdered stick, a capsule or a solution.

8. The composition for use according to any of the preceding claims, wherein the use is for i) stimulating bone formation and / or inhibiting bone resorption; ii) improving bone quality; iii) preventing or treating disorderslinked to an imbalance in the relationship between bone formation and bone resorption.

9. The composition for use according to any preceding claim, characterised in that said composition is designed to prevent the bone loss which occurs with aging and / or to protect bone cells during bone aging.

10. The composition for use according to any preceding claim, characterised in that said composition is designed to treat a bone deficit resulting from a fracture.

11. The composition for use according to any preceding claim, characterised in that said composition is designed to prevent or treat diseases selected from Paget's disease, bone loss or osteolysis observed close to a prosthesis, metastatic bone diseases, hypercalcemia due to a cancer, multiple myelomas, periodontal diseases.

12. The composition for use according to any preceding claim, wherein the individual suffered from and / or is suffering from stunted growth and / or faltering growth.

13. The composition for use according to any of the preceding claims, wherein it further comprises at least one of vitamin B3, vitamin B6 and / or vitamin B12.

14. The composition for use according to any of the preceding claims, wherein the composition further comprises at least one compound selected from the group consisting of antioxidants, anti-inflammatory compounds, glycosaminoglycans, prebiotics, fibres, probiotics, fatty acids, enzymes, minerals, trace elements and / or vitamins.

15. The composition for use according to any of claims 1 to 12, wherein it consists essentially of a combination of taurine and vitamin B9.

16. The composition for use according to any of claims 1 to 12, wherein it consists of a combination of taurine and vitamin B9.

17. A method of manufacturing a nutritional composition for use according to any of the preceding claims, comprising the steps of providing one or more ingredients for a nutritional composition, taurine and vitamin B9.

18. A kit comprising a combination of a combination of taurine and vitamin B9 in one or more containers.

19. The kit according to claim 18, wherein the one or more containers comprise at least one first container that stores the taurine separately from the vitamin B9, which is stored in at least one second container, and the kit further comprises instructions for admixing taurine with vitamin B9 into a unit dosage form.

20. The kit according to claim 18 or 19, wherein the one or more containers each comprise a unit dosage form of a combination of the taurine and vitamin B9.

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