Compositions and methods using a combination of oleuropein and taurine for use in the prevention or treatment of joint disorders

Abstract

The present invention relates to the use of a composition comprising an effective amount of oleuropein and / or its metabolites in combination with taurine and / or functional derivatives for the maintenance of joint health or the prevention or treatment of joint disorders in an individual. In particular, the present invention relates to a composition comprising an effective amount of oleuropein and / or its metabolites in combination with taurine and / or functional derivatives for use in the prevention or treatment of cartilage degeneration in an individual.

Description

[Technical Field]

[0001] The present invention relates to joint health, and in particular to the use of a composition comprising a combination of oleuropein and / or its metabolites and taurine and / or its metabolites for the prevention or treatment of joint disorders or the maintenance of joint health. [Background technology]

[0002] Osteoarthritis (OA) is a highly prevalent disease with significant socioeconomic impacts. Osteoarthritis, a degenerative disease of articular cartilage, is the most common form of arthritis, affecting 10% of the adult population. OA is a major cause of disability and healthcare costs among the elderly worldwide. The primary pathological feature is the progressive degeneration and loss of articular cartilage, accompanied by changes to other joint structures, such as synovial proliferation, sclerosis and thickening of subchondral bone, periarticular osteophyte formation, ligament laxity, and muscle atrophy, all of which contribute to the clinical symptoms of OA. These symptoms include severe pain, stiffness, decreased joint movement, and disability. Because articular cartilage relies solely on its resident chondrocytes to maintain its extracellular matrix, impaired chondrocyte function and survival leads to articular cartilage dysfunction.

[0003] Recent ex vivo studies have reported mitochondrial dysfunction in human OA chondrocytes, and analysis of mitochondrial electron transport chain activity in these cells showed reduced activity of complexes I, II, and III, as well as low ATP production, compared with normal chondrocytes. This mitochondrial dysfunction may affect several pathways involved in cartilage degeneration, including oxidative stress, impaired chondrocyte biosynthesis and proliferation responses, increased cytokine-induced chondrocyte inflammation and matrix catabolism, cartilage matrix mineralization, and increased chondrocyte apoptosis (Blanco et al., "The role of mitochondria in osteoarthritis," Nat. Rev. Rheumatol. 7, 161-169 (2011)).

[0004] Mitochondria are the primary source of aerobic energy production in mammalian cells and also maintain a large Ca2+ gradient across their inner membrane, providing signaling potential for these molecules. Furthermore, mitochondrial Ca2+ may play a role in regulating ATP production in mitochondria and contribute to orchestrating cellular metabolic homeostasis. (Glancy, B. and RS Balaban (2012). "Role of mitochondrial Ca2+ in the regulation of cellular energetics." Biochemistry 51(14):2959-2973)

[0005] Although the number of individuals suffering from OA is increasing, there is still no cure, and current drug therapies are still limited to symptomatic treatments focused on alleviating symptoms. For example, pain and inflammation are treated using analgesics (e.g., acetaminophen) and nonsteroidal anti-inflammatory drugs (NSAIDs). Furthermore, the use of these drugs is often accompanied by side effects such as gastrointestinal or cardiovascular risks. Because current treatments for OA do not prevent or cure OA, chondrocyte apoptosis is an effective target for regulating cartilage degeneration. Summary of the Invention

[0006] The present inventors have surprisingly demonstrated that the combination of oleuropein (or oleuropein aglycone) and taurine synergistically activates mitochondrial function at the cellular level via increasing mitochondrial calcium.

[0007] It is therefore an object of the present invention to provide a composition for use in improving joint health. In particular, it is an object of the present invention to provide a composition that improves joint health by preventing or treating cartilage degeneration and that overcomes the above-mentioned problems of the side effects of the prior art, e.g., gastrointestinal and / or cardiovascular risks.

[0008] Thus, one aspect of the present invention relates to a composition comprising an effective amount of a combination of oleuropein and / or its metabolites and taurine and / or its functional derivatives for use in the prevention or treatment of cartilage degeneration in an individual.

[0009] Another aspect of the invention relates to a method for preparing a composition for use according to the invention.

[0010] In a final aspect, the present invention relates to a kit comprising, in one or more containers, an effective amount of a combination of oleuropein and / or its metabolites and taurine and / or its functional derivatives.

[0011] Additional features and advantages are described herein, and will be apparent from the drawings and detailed description that follow. [Brief explanation of the drawings]

[0012] [Figure 1]Graph showing that taurine supplementation enhances mitochondrial Ca2+ elevation in C2C12-derived myotubes. Statistical evaluation of the effect of taurine on the cumulative mitochondrial calcium elevation evoked by 5 mM caffeine. Taurine was used at the indicated concentrations (μM). Graph shows the average of 28 experiments. Results are expressed as mean ± SEM. * indicates statistically significant difference from control (white) with P<0.05 (one-way ANOVA test). [Figure 2] This graph shows the effect of oleuropein aglycone (3 μM, black), taurine (200 mM, black), and the combination of 3 μM oleuropein aglycone and 200 μM taurine on mitochondrial activation, measured as cumulative mitochondrial calcium elevation in myotubes differentiated from C2C12 cells. Results are expressed as mean ± SEM of n=28 experiments. * indicates statistical significance with P<0.05 (Student's t-test). [Figure 3] This graph shows that oleuropein (3 μM) synergizes with taurine (200 μM) to promote mitochondrial calcium elevation in C2C12 cell-derived myotubes. The graph, derived from the data shown in FIG. 2, compares the theoretical additive effect of taurine supplementation plus oleuropein (aglycone form) supplementation with the measured effect of simultaneous supplementation of the taurine + oleuropein (aglycone) combination on mitochondrial calcium elevation. The theoretical effect is compared to the measured effect to estimate synergy. Data are the average of 28 experiments. Results are expressed as mean ± SEM. * indicates statistical significance for the difference between measured and theoretical mitochondrial calcium values, with P<0.05 (Student's t-test). DETAILED DESCRIPTION OF THE INVENTION

[0013] definition Before discussing the present invention in more detail, the following terms and general technical knowledge will first be defined.

[0014] In the context of the present invention, unless otherwise stated, the percentages referred to are weight / weight percentages.

[0015] The term "and / or" used in the context of "X and / or Y" should be interpreted as "X" or "Y" or "X and Y".

[0016] Numerical ranges used herein are intended to include all numbers and subsets of numbers contained within the range, whether or not expressly disclosed. Furthermore, these numerical ranges should be construed to provide support for claims directed to any number or subset of numbers within the range. For example, a disclosure of 1 to 10 should be construed to correspond to ranges of 1 to 8, 3 to 7, 4 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0017] The terms "prevent" and "prevention" refer to administering a composition disclosed herein to a subject not exhibiting any symptoms of the condition to reduce or prevent the onset of at least one symptom associated with the condition. Furthermore, "prevention" includes reducing the risk, incidence, and / or severity of a condition or disorder.

[0018] 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 the progression of a disease, or provides a nutritional, physiological, or medical benefit to the individual.

[0019] "Animal" includes mammals, including, but not limited to, rodents; aquatic mammals; domestic animals, such as dogs, cats, and other pets; livestock, such as sheep, pigs, cattle, and horses; and humans. When "animal," "mammal," or their plural forms are used, these terms also apply, depending on the context, to any animal in which the effect exhibited or intended by the animal can be exhibited, for example, by the animal benefiting from improved mitochondrial calcium transport. The term "individual" or "subject" is often used herein to refer to a human, although the present disclosure is not so limited. Thus, the term "individual" or "subject" refers to any animal, mammal, or human that can benefit from the methods and compositions disclosed herein.

[0020] The term "pet" refers to any animal that can benefit from or enjoy the compositions provided by the present disclosure. For example, a pet may be an animal such as a bird, bovine, canine, equine, feline, caprine, wolf, murine, ovine, or porcine, although a pet may be any suitable animal. The term "companion animal" refers to a dog or cat.

[0021] A "subject" or "individual" is a mammal, preferably a human. The term "older" in the human context means an age of at least 60 years, preferably greater than 63 years, more preferably greater than 65 years, and most preferably greater than 70 years. The term "older adult" in the human context means a postnatal age of 45 years or greater, preferably greater than 50 years, and more preferably greater than 55 years, and includes elderly people. The term "older adult" in the human context means a postnatal age of 45 years or greater, preferably greater than 50 years, and more preferably greater than 55 years, and includes elderly people.

[0022] An "oral nutritional supplement" or "ONS" is a composition containing at least one macronutrient and / or at least one micronutrient, e.g., in a sterile liquid, semisolid, or powder form, intended to supplement other nutritional intakes, such as those from food. Non-limiting examples of commercially available ONS products include MERITENE®, BOOST®, NUTREN®, and SUSTAGEN®. In some embodiments, an ONS can be a liquid beverage that can be consumed without the addition of additional liquid, e.g., the liquid volume is one serving of the composition.

[0023] "Kit" means that the components of the kit are physically associated in or with one or more containers and are considered a single unit for manufacture, distribution, sale, or use. Containers include, but are not limited to, bags, boxes, cartons, bottles, packaging of any type or design or material, overwrap, shrink wrap, attached components (e.g., stapled or glued), or combinations thereof.

[0024] Unless otherwise specified or clearly implied to the contrary by the recited context, any reference to a single feature or a single limitation of the invention shall include the corresponding multiple features or multiple limitations, and any reference to multiple features or multiple limitations shall include the corresponding single feature or single limitation.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0026] Compositions for use Joint diseases can involve inflammation to varying degrees. In some diseases, such as rheumatoid arthritis (RA), inflammation is a central component. In other diseases, such as OA, inflammation is less prominent. However, all diseases have a catabolic component that destroys articular cartilage.

[0027] The present inventors have shown that providing a combination of oleuropein and / or its metabolites with taurine and / or functional derivatives synergistically improves altered mitochondrial function in, for example, osteoarthritis.

[0028] That is, in a first aspect, the present invention relates to a composition comprising an effective amount of a combination of oleuropein and / or a metabolite thereof and taurine and / or a functional derivative thereof for use in improving joint health, for example for use in the prevention or treatment of cartilage degeneration in an individual.

[0029] In another manner, this aspect of the invention can be described as the use of an effective amount of a combination of oleuropein and / or a metabolite thereof and taurine and / or a functional derivative thereof in the manufacture of a medicament for the prevention or treatment of cartilage degeneration in an individual.

[0030] Use for preventing or treating cartilage degeneration is synonymous with use for inhibiting or reducing cartilage degeneration.

[0031] Accordingly, embodiments of the present invention include compositions comprising an effective amount of a combination of oleuropein and / or its metabolites and taurine and / or its functional derivatives for use in the prevention or treatment of cartilage degeneration.

[0032] A further embodiment of the present invention comprises a composition for use according to the present invention, wherein the composition further comprises calcium.

[0033] Ingredients Key Bioactive Compounds Oleuropein and taurine are the primary bioactive molecules according to the present invention.

[0034] Oleuropein is a polyphenol present in the fruits, roots, stems and more particularly leaves of plants belonging to the Oleaceae family, in particular the olive (Olea europaea).

[0035] In one embodiment, at least a portion of the oleuropein is obtained by extraction, for example, from a plant, such as one or more of the stems, leaves, fruits, or pits of a plant belonging to the Oleaceae family, preferably a plant belonging to the Oleaceae family, such as the olive (olive tree), plants of the genus Ligustrum, plants of the genus Syringa, plants of the genus Fraximus, plants of the genus Jasminum, plants of the genus Osmanthus, etc. Additionally or alternatively, at least a portion of the oleuropein and / or its metabolites can be obtained by chemical synthesis.

[0036] Non-limiting examples of suitable metabolites of oleuropein include oleuropein aglycone, hydroxytyrosol, elenolic acid, homovanillyl alcohol, isohomovanillyl alcohol, glucuronidated forms thereof, sulfated forms thereof, derivatives thereof, and mixtures thereof.

[0037] Taurine, also known as 2-aminoethanesulfonic acid, is an organic acid that occurs naturally in foods, particularly shellfish (e.g., scallops, mussels, clams), as well as dark meat from turkey and chicken, and other meats and eggs.

[0038] Non-limiting examples of suitable functional derivatives of taurine include structural analogs of taurine, its metabolites, or acceptable salts thereof, such as taurolidine, taurultam, taurinamide, 1,4,5-oxathiazinane-4,4-dioxide, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, N-acyltaurine, acetylhomotaurine, N,N-diacetylsalicyloxyethyltaurine, acylmethyltaurine, homotaurine, or salts thereof, as described in "Taurine analogues; a new class of therapeutics: retrospect and prospects," Gupta et al., S. Curr. Med. Chem. 2005;12(17):2021-39.

[0039] An example of a taurine metabolite is hypotaurine.

[0040] The term "acceptable salt" means a salt selected because it is completely harmless insofar as the composition according to the invention is intended to be administered to an individual. Alkali metal or alkaline earth metal salts, in particular magnesium salts, manganese salts, iron(II) salts or zinc salts, are particularly suitable for the present invention in this respect.

[0041] The taurine derivative may also be a natural extract rich in taurine (2-aminoethanesulfonic acid) or its derivatives. According to the present invention, it is preferred to use taurine or an acceptable salt thereof.

[0042] According to a preferred embodiment, taurine and / or hypotaurine are used.

[0043] The effective amount of each of oleuropein and / or its metabolites and taurine and / or its functional derivatives will vary depending on the specific composition, the age and condition of the recipient, and the specific disorder or disease being treated.

[0044] However, in a typical embodiment, an individual can be administered 0.001 mg to 1.0 g / day, preferably 0.01 mg to 0.9 g / day, more preferably 0.1 mg to 750 mg / day, more preferably 0.5 mg to 500 mg / day, and most preferably 1.0 mg to 200 mg / day of oleuropein. Furthermore, the inventors have discovered that the active dose of oleuropein or a derivative in a combination can be reduced for comparable efficacy. In a typical embodiment, taurine, its functional derivatives, and / or acceptable salts thereof are used in a daily dose ranging from 1 to 3,000 mg / day, advantageously from 5 to 2,000 mg / day, and preferably from 10 to 300 mg / day. According to a preferred embodiment, the daily dose is about 50 to 150 mg / day. Doses indicated herein for taurine derivatives or salts thereof are doses in terms of taurine equivalents.

[0045] In some embodiments, the combination of oleuropein or a metabolite and taurine or a functional derivative is administered in a composition further comprising calcium. At least a portion of the calcium may be one or more calcium salts, such as calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluconate, calcium lactate, or mixtures thereof. In general embodiments, an individual is administered 0.1 g to 1.0 g of calcium per day, preferably 125 mg to 950 mg of calcium per day, more preferably 150 mg to 900 mg of calcium per day, more preferably 175 mg to 850 mg of calcium per day, and most preferably 200 mg to 800 mg of calcium per day.

[0046] In an alternative embodiment, the combination of oleuropein and taurine can be administered sequentially in separate compositions, optionally with calcium. The term "sequentially" refers to sequential administration of calcium and oleuropein or at least one of its metabolites, such that at a first time, oleuropein or at least one of its metabolites is administered without calcium, and at a second time (before or after the first time), calcium is administered without the combination of oleuropein and taurine. The time between consecutive administrations can be, for example, one or several seconds, minutes, or hours on the same day; one or several days, or several weeks on the same month; or one or several months on the same year.

[0047] In some embodiments, oleuropein or a metabolite thereof is the only polyphenol in the composition and / or the only polyphenol administered to the individual.

[0048] The composition may comprise an effective amount of at least one of oleuropein or a metabolite thereof and taurine and / or a functional derivative thereof. For example, a single serving or dose of the composition may contain the effective amount, and a package may contain one or more servings or doses. Optionally, the composition may further comprise calcium.

[0049] In another embodiment, oleuropein and / or metabolites may be provided by any of the compositions and methods disclosed in WO 2019 / 092068 and WO 2019 / 092066, entitled "Bioconversion of oleuropein" and "Method of selecting a probiotic," respectively, and WO 2019 / 092069, entitled "Homovanilyl alcohol (HVA), HVA isomers, methods of making compositions comprising such compounds, and methods of using such compounds," each of which is incorporated herein by reference in its entirety.

[0050] Ingredients Additional Bioactive Compounds The composition 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, fibers, probiotics, fatty acids, enzymes, minerals, trace elements and / or vitamins.

[0051] The term "bioactive" in the context of this application means that the compound contributes to the health of an individual or has an effect on the human body beyond satisfying basic nutritional needs.

[0052] The at least one additional bioactive compound may be naturally occurring, i.e., the compound may be obtained from an extract of a plant, animal, fish, fungus, algae, or microbial fermentation. Minerals are also considered naturally occurring within this definition.

[0053] In a preferred embodiment, the enzyme may be a protease, such as trypsin, or an enzyme extract, such as bromelain.

[0054] Nutritional Composition Compositions for use according to the invention may be nutritional or pharmaceutical compositions and may be for human or veterinary use.

[0055] Thus, in a preferred embodiment, the composition for use according to the invention is a nutritional composition.

[0056] By "nutritional composition" is meant, in the context of this application, a composition that is a source of nutrition for an individual.

[0057] The nutritional formulations or compositions of the present invention may be complete or semi-nutritional sources.

[0058] As used herein, "complete nutrition" includes nutritional formulations and compositions that contain sufficient types and levels of macronutrients (protein, fat, and carbohydrates) and sufficient micronutrients to be the sole source of nutrition for the animal to which it is administered, such that the patient can obtain 100% of their nutritional needs from such a complete nutritional composition.

[0059] As used herein, "near-complete nutrition" includes nutritional formulations or compositions that do not contain sufficient levels of macronutrients (protein, fat, and carbohydrates) or enough micronutrients to be the sole source of nutrition for the animal to which it is administered. Partially complete or near-complete nutritional compositions can be used as dietary supplements.

[0060] The combination of oleuropein and taurine can be administered in any composition suitable for human and / or animal consumption. In a preferred embodiment, the combination is administered to an individual orally or enterally (e.g., by tube feeding). For example, the combination can be administered to an individual as a beverage, food product, capsule, tablet, powder, or suspension.

[0061] Non-limiting examples of suitable compositions include food compositions, dietary supplements, dietary supplements (e.g., liquid ONS), complete nutritional compositions, beverages, pharmaceuticals, oral nutritional supplements, medical foods, nutraceuticals, foods for special medical purposes (FSMP), powdered nutritional formulations to be reconstituted with water or milk before ingestion, food additives, medicaments, drinks, pet foods, and combinations thereof.

[0062] Nutritional composition ingredients Protein source In one embodiment, a composition for use according to the present invention comprises a protein source. The protein source may be a food protein, including but not limited to animal protein (e.g., milk protein, meat protein, or egg protein), plant protein (e.g., soy protein, wheat protein, rice protein, and pea protein), or a combination thereof. In one embodiment, the protein is selected from the group consisting of whey, chicken, corn, caseinate, wheat, flax, soy, locust bean, pea, or a combination thereof.

[0063] carbohydrate source In one embodiment, the composition comprises a carbohydrate source. Any suitable carbohydrate may be used in the compositions of the present invention, including, but not limited to, starch, sucrose, lactose, glucose, fructose, corn syrup solids, maltodextrin, modified starch, amylose starch, tapioca starch, maize starch, xylitol, sorbitol, or combinations thereof.

[0064] fat source In one embodiment, the composition includes a fat source. The fat source can include any suitable fat or fat mixture. For example, the fat source can include, but is not limited to, vegetable fats (e.g., olive oil, corn oil, sunflower oil, high oleic sunflower oil, rapeseed oil, canola oil, hazelnut oil, soybean oil, palm oil, coconut oil, blackcurrant seed oil, borage oil, and lecithin), animal fats (e.g., dairy fat), or a combination thereof. The fat source can also be a crude form of the above fats (e.g., polyphenol-containing olive oil).

[0065] Fragrance etc. In addition, compositions for use according to the invention may also contain natural or artificial flavors, for example fruit flavors such as banana, orange, peach, pineapple or raspberry, or other botanical flavors such as vanilla, cocoa, coffee, etc.

[0066] Nutritional Composition Format In addition to the primary bioactive ingredient(s), any additional bioactive ingredient(s), and optionally one or more of a protein source, a carbohydrate source, and a fat source, the nutritional compositions of the present invention may optionally contain any number of additional optional food ingredients, including conventional food additives (artificial or natural), such as, for example, one or more acidulants, additional thickeners, buffers or pH adjusters, chelating agents, colorants, emulsifiers, additives, flavorings, minerals, osmotic agents, pharmaceutically acceptable carriers, preservatives, stabilizers, sugars, sweeteners, quality improvers, and / or vitamins. The optional ingredients can be added in any suitable amount.

[0067] The nutritional compositions of the present invention may be provided in any suitable format.

[0068] Examples of nutritional composition formats in which compositions for use according to the present invention may be supplied include solutions, ready-for-consumption compositions (e.g., ready-to-drink compositions or instant drinks), liquid meals, soft drinks, juices, sports drinks, dairy drinks, milkshakes, yogurt drinks, soups, etc.

[0069] In other embodiments, the nutritional compositions may be provided in the form of a concentrate, powder, or granules (e.g., effervescent granules) that can be diluted with water or other liquids, such as milk or fruit juice, to form a ready-for-consumption composition.

[0070] Further formats of the nutritional compositions include baked goods, dairy products, desserts, confectionery products, cereal bars, and breakfast cereals. Examples of dairy products include milk and dairy products, yogurt and other cultured dairy products, ice cream, and cheese. Examples of baked goods include bread, biscuits, and cakes.

[0071] In one embodiment, the compositions for use according to the invention may also be available in a wide variety of formats designed as animal food, in particular for dogs or cats, whether in wet, semi-moist or dry form, in particular in the form of biscuits.

[0072] Route of administration The nutritional compositions of the present disclosure may be administered by any method suitable for administration to humans, particularly to any part of the digestive tract. Enteral administration, oral administration, and administration through a tube or catheter are all included in the present disclosure. The nutritional compositions of the present invention may also be administered by a method selected from oral, enteral, sublingual, sublabial, buccal, topical, etc.

[0073] The nutritional compositions of the present invention may be administered in any convenient dosage form, including, for example, tablets, capsules, liquids, chewable tablets, softgels, sachets, powders, syrups, suspensions, emulsions, and solutions. In soft capsules, the active ingredient is preferably dissolved or suspended in a suitable liquid, such as fatty oils, paraffin oil, or liquid polyethylene glycol. Optionally, stabilizers may be added.

[0074] When the nutritional composition is administered by tube feeding, the nutritional composition may be used for short-term tube feeding or long-term tube feeding.

[0075] Inhibition or reduction of cartilage degeneration Cartilage degeneration can be the result of pathology (either chronic or acute), trauma, or a combination thereof.

[0076] Cartilage degeneration occurs in both inflammatory-dominant conditions (eg, rheumatoid arthritis) and conditions where inflammation is less prominent (eg, osteoarthritis).

[0077] Trauma can also lead to the initiation of the cartilage degeneration process, for example, ligament tearing in the knee leads to instability of the knee joint and the degeneration process is initiated.

[0078] Trauma in the context of this application refers to physiological damage caused by an external cause, such as a fall or being hit by a car, etc. Trauma can also be the accumulation of small injuries over time, so-called "wear and tear".

[0079] Treating trauma with surgery is often preferred, and in one embodiment, the present invention relates to a method of treatment for treating trauma with surgery and by administering a composition of the present invention.

[0080] Thus, embodiments of the use according to the present invention include use for inhibiting or reducing cartilage degeneration, where cartilage degeneration is the result of pathology or trauma. Examples of conditions that involve cartilage degeneration and for which the compositions of the present invention may therefore be useful include: These include osteoarthritis, rheumatoid arthritis, gout and pseudogout, septic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, Still's disease, psoriasis (psoriatic arthritis), reactive arthritis, Ehlers-Danlos syndrome, hemochromatosis, hepatitis, Lyme disease, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), Henoch-Schönlein purpura, hyperimmunoglobulinemia D with recurrent fever, sarcoidosis, TNF receptor-associated periodic syndrome, Wegener's granulomatosis (and many other vasculitic syndromes), familial Mediterranean fever, and systemic lupus erythematosus.

[0081] In a preferred embodiment, the compositions of the present invention are for use in inhibiting or reducing cartilage degeneration in RA and / or OA.

[0082] In a further preferred embodiment, the compositions of the present invention are for use in inhibiting or reducing cartilage degeneration in OA.

[0083] Furthermore, without wishing to be bound by theory, it has been observed that while inflammation often leads to cartilage degeneration in joints, cartilage degeneration also occurs in situations where the inflammatory component is much less, perhaps even negligible.

[0084] For example, trauma to a joint may be sufficient to initiate cartilage degeneration without the significant inflammatory component present in, for example, RA. Trauma may include, for example, a torn ligament or impact trauma to a joint (e.g., knee, finger).

[0085] In another example, OA is primarily a degenerative joint disease with a lesser inflammatory component.

[0086] Thus, in one embodiment the invention relates to a composition for use according to the invention for inhibiting or reducing cartilage degeneration, wherein the cartilage degeneration occurs in the context of trauma or a pathology with little or no inflammatory component, for example OA.

[0087] Use to combat early degenerative events The hypertrophy suggests catabolic activity of chondrocytes that are not of the normal phenotype.

[0088] Thus, in one embodiment, the present invention relates to a composition according to the invention comprising oleuropein and / or its metabolites in combination with taurine and / or functional derivatives for use in inhibiting or reducing chondrocyte hypertrophy, which is one early event indicative of cartilage degeneration.

[0089] Treatment or prevention of age-related loss of mobility Compositions for use according to the present invention have been shown to inhibit or reduce proteolytic activity.

[0090] Aging leads to cartilage degeneration.

[0091] Thus, the present invention relates to the compositions of the present invention for use in inhibiting or reducing cartilage degeneration associated with aging.

[0092] In another embodiment, the present invention relates to a composition of the present invention for use in inhibiting or reducing collagen degeneration in age-related cartilage degeneration, e.g., for use in inhibiting or preventing collagen II degeneration in age-related cartilage.

[0093] Cartilage degeneration can contribute to joint stiffness and pain, resulting in decreased mobility in patients.

[0094] Compositions for use according to the invention may, in other embodiments, be used to: i) maintain or improve joint function, including cartilage function, during ageing; ii) reduce joint pain, including inflammatory and / or nociceptive pain.

[0095] In a further embodiment, the present invention relates to a composition for use according to the present invention for improving mobility in a subject, such as an adult or elderly mammal.

[0096] Thus, in a preferred embodiment, the compositions according to the invention may be for use to improve the activity and / or mobility of an individual, for example by preventing or treating osteoarthritis and / or by inhibiting or reducing cartilage degeneration.

[0097] Other preferred embodiments relate to compositions for use according to the invention to prevent cartilage degeneration and thus maintain healthy joints, or to maintain or improve mobility, to prevent or reduce joint pain (inflammatory and / or nociceptive pain), In further embodiments, the compositions of the invention may be used to maintain the health of cartilage.

[0098] Subject group The subject group for the composition for use according to the present invention may be any mammal that exhibits cartilage degeneration, for example, due to one or more of the cartilage degeneration-associated pathologies mentioned herein. Cartilage degeneration can be detected by visual means, such as X-ray photography. Alternatively, cartilage degeneration products can be detected in body fluids. For example, one or more collagen II epitopes, such as Coll2-1, Coll2-1 NO2, CTX-II, etc., can be detected in a sample, for example, a plasma sample or a urine sample.

[0099] Another group of subjects may be any mammal that has not yet exhibited cartilage degeneration but is at risk of cartilage degeneration, for example at risk for OA, RA, or any of the conditions associated with cartilage degeneration mentioned herein. In a preferred embodiment, the present invention relates to a composition according to the present invention comprising a combination of oleuropein or a metabolite thereof and taurine or a functional derivative thereof, for use in inhibiting or reducing premature cartilage degeneration, to be administered to this group of subjects.

[0100] Certain embodiments of the present invention relate to compositions for use to improve the activity and / or mobility of an individual, for example, by preventing or treating osteoarthritis and / or by inhibiting or reducing cartilage degeneration in elderly or aging individuals.

[0101] In a further embodiment, the composition for use according to the invention may be for use in a mammal, such as a human, or in a pet, examples of which include cats, dogs, and horses.

[0102] Although the present invention may be useful in many different age groups, in preferred embodiments, the compositions for use in improving mobility according to the present invention are aimed at the geriatric population, particularly healthy aging and / or elderly mammals.

[0103] Method for producing the nutritional composition of the present invention The present invention provides in a further aspect a method for producing a nutritional composition for use according to the invention, comprising the steps of: The present invention relates to a method comprising the steps of providing raw materials for a nutritional composition comprising a combination of oleuropein and / or its metabolites and taurine and / or its functional derivatives, and mixing the raw materials so that the nutritional composition comprises a combination of oleuropein and / or its metabolites and taurine and / or its functional derivatives.

[0104] Pharmaceutical compositions for use In a further embodiment, the present invention relates to a composition for use in inhibiting or preventing cartilage degeneration according to the present invention, which composition is a pharmaceutical composition.

[0105] By pharmaceutical, we mean a composition, as distinct from a nutritional composition, in which the substance is used on or in the body as a medicine to prevent, diagnose, mitigate, treat or cure a disease in a human or animal. In accordance with the present invention, the pharmaceutical can be used to inhibit or reduce cartilage degeneration.

[0106] The medicament may be for human use, or may be a veterinary composition suitable for example for dogs, cats or horses, particularly thoroughbred horses.

[0107] In one preferred embodiment, the pharmaceutical composition of the present invention comprises a combination of oleuropein or a metabolite thereof and taurine or a functional derivative thereof.

[0108] In another preferred embodiment, the pharmaceutical composition of the present invention comprises oleuropein or a metabolite thereof and taurine or a functional derivative thereof.

[0109] The present invention further relates to the use of a pharmaceutical agent according to the invention, as described herein as the use of a composition of the invention.

[0110] A pharmaceutical composition for use according to the present invention comprises a combination of oleuropein or a metabolite thereof and taurine or a functional derivative thereof in combination with at least one additive selected from the group consisting of pharmaceutically acceptable additives. Procedures for preparing pharmaceutical compositions according to the present invention can be easily found by those skilled in the art, for example, in the handbook Remington's Pharmaceutical Sciences, Mid. Publishing Co., Easton, Pa., USA. Physiologically acceptable additives, vehicles, and adjuvants are also described in the handbook "Handbook of Pharmaceutical Excipients, Second Edition, American Pharmaceutical Association, 1994." To formulate pharmaceutical compositions according to the present invention, those skilled in the art will advantageously refer to the latest edition of the European Pharmacopoeia or the United States Pharmacopoeia (USP). In particular, those skilled in the art will advantageously refer to the European Pharmacopoeia, 4th Edition (2002) or the US Pharmacopoeia, USP 25-NF 20th Edition.

[0111] Advantageously, the pharmaceutical composition 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 additive, in particular, the additive is suitable for administering the composition by the oral route, or the additive is suitable for administering the composition by the parenteral route.

[0112] The pharmaceutical compositions for use according to the invention may be available in either solid or liquid form. For oral administration, solid pharmaceutical compositions in the form of tablets, capsules or gelatin capsules will be preferred.

[0113] If in liquid form, the pharmaceutical composition may suitably be in the form of an aqueous or non-aqueous suspension, or in the form of a water-in-oil or oil-in-water emulsion.

[0114] Solid pharmaceutical forms may contain, as vehicles, adjuvants or additives, at least one diluent, one flavoring, one solubilizer, one lubricant, one suspending agent, one binder, one disintegrating agent and one encapsulating agent. Such compounds are, for example, magnesium carbonate, magnesium stearate, talc, lactose, pectin, dextrin, starch, gelatin, cellulose-based materials, cocoa butter, etc. Liquid forms of the compositions may contain water, optionally in admixture with propylene glycol or polyethylene glycol, and may also optionally contain colorants, flavors, stabilizers and thickeners.

[0115] Combination with known treatments In this situation where there are no disease-modifying OA drugs (DMOADs), alternative treatments and prevention of OA may be achieved through nutrition.

[0116] From histological data, it can be seen that oleuropein has a greater effect on OA score than the compound that mainly affects degeneration.Therefore, the effectiveness of oleuropein may be due to the combined effect on inflammation and degeneration.Therefore, in a preferred embodiment, the composition of the present invention that has been shown to inhibit or reduce degeneration can be combined with the treatment for inhibiting or reducing inflammation.

[0117] Treatment method The present invention also relates to a method for preventing or treating cartilage degeneration, such as a pathology resulting in cartilage degeneration or trauma associated with cartilage degeneration, comprising administering an effective amount of a composition according to the present invention to an individual in need thereof. For example, the method comprises administering an effective amount of a composition comprising a combination of oleuropein or a metabolite thereof and taurine or a functional derivative thereof.

[0118] As used herein, an "effective amount" is an amount that prevents a deficiency, treats a disease or medical condition in an individual, or more generally, alleviates symptoms, manages the progression of a disease, or provides a nutritional, physiological, or medical benefit to an individual.

[0119] The effective amount of a composition of the present invention required to achieve a therapeutic effect will, of course, vary depending on the particular composition, the route of administration, the age and condition of the subject, and the particular disorder or disease being treated.

[0120] The present invention further provides a method for preventing or treating a condition involving cartilage degeneration, such as OA or RA, inhibiting or reducing cartilage degeneration, inhibiting or reducing collagen degeneration in cartilage, or inhibiting or reducing collagen II degeneration in cartilage, which method comprises administering to an individual an effective amount of a composition for use according to the present invention.

[0121] In one embodiment, the method of treatment according to the present invention relates to the prevention or treatment of osteoarthritis.

[0122] The method of treatment according to the invention may be in a mammal, such as a human or a pet, such as a dog, cat and / or horse.

[0123] In certain embodiments, the compositions of the invention administered in the treatment method may be one or more nutritional compositions of the invention and / or pharmaceutical compositions of the invention.

[0124] kit The present disclosure also provides a kit comprising a combination of oleuropein and / or its metabolites in combination with taurine and / or functional derivatives in one or more containers. In one embodiment of the kit, the one or more containers include at least one first container that contains oleuropein and / or metabolites separately from taurine and / or functional derivatives contained in at least one second container, and the kit further comprises instructions for combining the oleuropein with taurine to form a unit dosage form.

[0125] In one embodiment of the kit, the combination may be provided together as one or more prepackaged unit dosage forms, for example, as separate containers each containing a dry powder, with each container containing one prepackaged unit dosage form.

[0126] In another embodiment, the kit can include multiple compositions to be mixed together to form one or more of the compositions disclosed herein. For example, the kit can contain two or more dry powders in separate containers related to each other, each containing a portion of the final unit dosage form. As a non-limiting example of such an embodiment, the kit can include one or more first containers containing oleuropein and one or more second containers containing taurine. The contents of one of the first containers can be mixed with one of the second containers to form at least a portion of the unit dosage form of the composition.

[0127] The above dosing examples do not require uninterrupted daily administration. Rather, administration may be interrupted by several short periods, such as a 2-4 day break during the administration period. The ideal duration of administration of the compositions of the present invention can be determined by one of skill in the art.

[0128] Disclosure Combination It should be noted that embodiments and features described in the context of one aspect of the invention also apply to other aspects of the invention.

[0129] Compositions for use according to the invention are described herein in terms of different parameters, e.g., ingredients, form of nutritional composition, use, target population, etc. It should be noted that embodiments and features described in the context of one of the parameters of a 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.

[0130] All patent and non-patent literature cited in this application is incorporated herein by reference in its entirety.

[0131] The invention will now be described in further detail by the following non-limiting examples. [Example]

[0132] The following non-limiting examples provide experimental data supporting the compositions and methods disclosed herein.

[0133] Example 1 To test the effects of oleuropein (or oleuropein aglycone), taurine, and their combination in living cells, we measured mitochondrial calcium elevation in myotubes differentiated from C2C12 cells. C2C12 cells were purchased from ATCC. C2C12 cells were seeded in 96-well plates at a density of 8000 cells / well in DMEM high glucose (Gibco) plus 10% fetal bovine serum. Myotubes were differentiated by growing C2C12 cells in DMEM containing 2% horse serum for 4 days. Mitochondrial calcium measurements were performed using myotubes infected with an adenovirus (Sirion Biotech) expressing the mitochondrially targeted calcium sensor, mitochondrially localized modified aequorin (Montero et al., 2002 Biochem J. 2002 Jul 15;365(Pt 2):451-9). For aequorin reconstitution, 24 h after infection, myotubes were incubated for 2 h at room temperature (22°C) in standard medium (145 mM NaCl, 5 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM glucose, and 10 mM Hepes, pH 7.4) supplemented with 1 μM wild-type coelenterazine. For treatment, compounds were added directly to cell or myotube cultures 2 h prior to measurement. Luminescence was measured using a FLIPR Tetra Aequorin (Molecular Devices). Conversion of luminescence data to calcium concentrations (calibration) was performed using an algorithm as previously described (Montero et al., 2002, Biochem J. 2002 Jul 15;365(Pt 2):451-9). Quantification was performed using a custom module analysis based on Excel (Microsoft) and GraphPad Prism 7.02 (GraphPad) software.

[0134] As shown in Figure 1, taurine increased mitochondrial Ca in C2C12 myotubes. 2+Figure 2 also shows that co-supplementation of oleuropein (aglycone) with taurine results in greater mitochondrial activation (measured as mitochondrial calcium elevation) than the effect of each compound alone. As shown in Figure 3, oleuropein (aglycone) synergizes with taurine to promote mitochondrial calcium elevation during stimulation.

Claims

1. A composition comprising an effective amount of a combination of oleuropein and / or its metabolites and taurine and / or functional derivatives thereof for use in the prevention or treatment of cartilage degeneration in an individual.

2. 2. The composition for use according to claim 1, wherein the metabolite of oleuropein is selected from the group consisting of oleuropein aglycone, hydroxytyrosol, elenolic acid, homovanillyl alcohol, isohomovanillyl alcohol, glucuronidated forms thereof, sulfated forms thereof, derivatives thereof, and mixtures thereof.

3. 3. The composition for use according to claim 1 or 2, wherein the functional derivative of taurine is selected from the group consisting of taurolidine, taurultam, taurinamide and 1,4,5-oxathiazinane-4,4-dioxide, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, N-acyltaurine, acetylhomotaurine, N,N-diacetylsalicyloxyethyltaurine, acylmethyltaurine, homotaurine, and hypotaurine.

4. The composition for use according to any one of claims 1 to 3, further comprising calcium.

5. 5. The composition for use according to any of claims 1 to 4, further comprising at least one compound selected from the group consisting of antioxidants, anti-inflammatory compounds, glycosaminoglycans, prebiotics, fibers, probiotics, fatty acids, enzymes, minerals, trace elements, and / or vitamins.

6. 6. The composition for use according to any one of claims 1 to 5, selected from the group consisting of food compositions, dietary supplements, nutritional compositions, oral nutritional supplements, medical foods, nutraceuticals, beverages, powdered nutritional formulations to be reconstituted with water or milk before ingestion, food additives, foods for special medical purposes (FSMP) medicines, drinks, pet foods, and combinations thereof.

7. The composition for use according to any one of claims 1 to 6, which is in the form of a solid powder, a powder stick, a capsule or a solution.

8. 8. The composition for use according to any one of claims 1 to 7, wherein the use is: i) for maintaining or improving joint function, including cartilage function, during ageing; ii) for reducing joint pain, including inflammatory and / or nociceptive pain.

9. The composition for use according to any one of claims 1 to 8, wherein said use is for improving activity and / or mobility of said individual.

10. The composition for use according to any one of claims 1 to 9, wherein the use is for inhibiting or reducing cartilage degeneration in osteoarthritis.

11. The composition for use according to any one of claims 1 to 10, wherein the individual is a middle-aged or elderly person.

12. 12. A method for producing a nutritional composition for use according to any one of claims 1 to 11, comprising providing and mixing one or more raw materials for the nutritional composition, oleuropein or a metabolite thereof, taurine and / or functional derivatives, and optionally further calcium.

13. A kit comprising, in one or more containers, a combination of oleuropein and / or its metabolites in combination with taurine and / or functional derivatives.

14. 14. The kit of claim 13, wherein the one or more containers include at least one first container that contains the oleuropein and / or metabolites separately from the taurine and / or functional derivatives contained in at least one second container, and the kit further comprises instructions for mixing the oleuropein with the taurine to form a unit dosage form.

15. 15. The kit of claim 13 or 14, wherein the one or more containers each contain a unit dosage form of the combination of oleuropein and / or its metabolites with taurine and / or functional derivatives.

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