Compositions Comprising Cetyl Fatty Acids and Their Use in Treating Arthritis and Inflammatory Joint Conditions

Abstract

The present invention relates to a composition comprising a mixture of at least one cetylated fatty acid or a mixture of cetylated fatty acids and, optionally, a reduced weight percentage of an antioxidant, for use in a method for treating arthritis, inflammatory joint pain, and musculoskeletal pain. Furthermore, the present invention relates to a composition comprising a mixture of at least one cetylated fatty acid or a mixture of cetylated fatty acids and, optionally, an antioxidant, for use in a method for treating gastric mucosa and regulating blood glucose levels. Finally, the present invention relates to a method for producing at least one cetylated fatty acid or a mixture of cetylated fatty acids, and a method for producing a composition comprising a cetylated fatty acid and an antioxidant.

Description

[Technical field]

[0001] The present invention relates to a composition comprising or alternatively consisting of at least one cetylated fatty acid or a mixture of cetylated fatty acids and a reduced weight percentage of an antioxidant (e.g., LIPOCET). TM ). Furthermore, the present invention relates to a composition comprising or alternatively consisting of at least one cetylated fatty acid or a mixture of cetylated fatty acids and, optionally, an antioxidant, for use in a therapeutic method for protecting the gastric mucosa and regulating blood glucose levels. Finally, the present invention relates to a method for producing at least one cetylated fatty acid or a mixture of cetylated fatty acids and for producing a composition comprising a cetylated fatty acid and an antioxidant. [Background technology]

[0002] In the prior art, compositions containing mixtures of cetylated fatty acids and their use in the treatment of arthritis and joint inflammation are known. For example, patent documents WO 2004 / 084829 and WO 2017 / 029580 disclose compositions containing cetylated fatty acids and, optionally, a mixture of tocopherols, such as antioxidants, in a weight percentage of awt%, including 1 wt% to 5 wt% relative to the total weight.

[0003] The article "Effect of a dietary supplement in combination with exercise and diet on adipocytokines and obesity in overweight women" by MARENS.FRAGALA et al. (EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY, Springer, Berlin, Germany, Vol. 105, No. 5) aimed to investigate whether administering a mixture of modified cellulose and cetylated fatty acids (TrisynexR capsules, Imagenetix) to subjects during an 8-week weight loss plan (diet and physical exercise) would result in greater weight and fat loss compared to physical exercise alone and diet alone. Fasting blood insulin levels were reduced, but no differences were observed between the treatment groups with and without cetylated fatty acids and modified cellulose.

[0004] WO 00 / 64436 relates to a composition for use in treating pain, diseases and symptoms of primary biliary cirrhosis, autoimmune hepatitis or insulin-dependent diabetes by administering cetyl myristolinate (cetylated myristoleic acid). Example 1 describes an enteric capsule containing 400 mg cetyl myristolinate, 550 mg extra virgin olive oil and 50 mg lecithin. WO 2017 / 029580 relates to a mixture containing cetyl myristate (cetylated myristic acid) and cetyl oleate (cetylated oleic acid) for treating cardiovascular disorders. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2004 / 084829 [Patent Document 2] International Publication No. 00 / 64436 [Patent Document 3] International Publication No. 2017 / 029580 [Non-patent literature]

[0006] [Non-Patent Document 1] EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY Summary of the Invention [Problem to be solved by the invention]

[0007] The technical problem addressed and solved by the present invention is to provide an improved composition comprising cetylated fatty acids with respect to known compositions, which is effective in the treatment of arthritis, inflammatory joint and musculoskeletal disorders, as well as in protecting the gastric mucosa and regulating blood glucose levels, has no side effects, is well tolerated, is stable over time with respect to the action of oxidizing agents, and is economically advantageous in terms of production. [Means for solving the problem]

[0008] In order to solve the above technical problems, the present invention provides a composition (pharmaceutical composition, composition for medical devices, novel food (food or food for special medical purposes (FSMP) or medical food), dietary supplement or cosmetic composition, i.e. the composition of the present invention) (e.g. LIPOCET TM ) is provided. Effect of the Invention

[0009] The presence of antioxidants makes the compositions of the present invention stable over time, on the premise that the potency of the active ingredient (cetylated fatty acid) remains almost unchanged over time and protects the cetylated fatty acid from the action of oxidizing agents.The presence of antioxidants therefore makes the compositions of the present invention advantageous in terms of efficacy, transport, storage, and storage time and form, from the first moment the package containing the compositions of the present invention is opened.

[0010] Furthermore, because the compositions of the present invention contain a lower weight percentage of antioxidants compared to compositions based on conventional cetylated fatty acids, they are economically advantageous for large-scale production (i.e., less antioxidant is required) and are well tolerated when administered to, for example, pediatric subjects.

[0011] The above-mentioned composition of the present invention (e.g., LIPOCET TM ) can effectively and rapidly treat symptoms or disorders of joint and / or muscle diseases, such as the diseases, conditions or disorders listed herein below in (i)-(vi).

[0012] Furthermore, the above-mentioned compositions of the present invention can (ii) protect the gastric mucosa, (i.ii) treat diabetes, and (i.iii) treat diseases and / or disorders other than diabetes resulting from or associated with high blood sugar levels.

[0013] Finally, the present invention relates to a first method for producing at least one cetylated fatty acid or a mixture of cetylated fatty acids as described above, and to a composition of the present invention (e.g., LIPOCET) comprising at least one cetylated fatty acid or a mixture of cetylated fatty acids (produced by the first method) and an antioxidant. TM A second method for producing a polystyrene (PS) is provided.

[0014] The above method is easy to apply and economically advantageous.

[0015] Furthermore, the above first process advantageously allows complete conversion of the acid and excellent yields of ester production under simple and economical operating conditions, due to the combination of application of an inert gas flow throughout the entire duration of the ester formation step and application of a vacuum program in the reactor chamber only during the last part of the ester formation step.

[0016] Finally, the first process ensures the production of cetylated fatty acids which are essentially free of traces of catalyst and therefore safe from a health point of view and well tolerated by the subjects to whom they are administered.

[0017] These and other objects which will become apparent from the following detailed description are achieved by the compositions, mixtures and methods of the present invention by virtue of the technical features set out in the claims.

[0018] As a result of intensive research, the applicant has discovered innovative compositions (e.g., LIPOCET TM ), their use in therapeutic and non-therapeutic treatment methods, and methods for their preparation. [Brief description of the drawings]

[0019] [Figure 1] , [Diagram 2] and [Diagram 3] (a) Shown is a plant for carrying out a first process for producing at least one cetylated fatty acid or a mixture of cetylated fatty acids. [Figure 4A] , [Figure 4B] and [Figure 4C] 1 shows an assay of IL6 in cell cultures using the composition of Experimental Example 3. [Figure 5A] , [Figure 5B] and [Figure 5C] 1 shows an assay of LTC4 in cell cultures using the composition according to Experimental Example 3. [Figure 6A] , [Figure 6B] and [Figure 6C] 1 shows an assay of PGE2 in cell cultures using the composition according to Experimental Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Forming an object of the present invention are compositions (in short, compositions of the invention) comprising (I) and, optionally, (II) (e.g. LIPOCET TM ) where (I) is (a) at least one cetylated fatty acid (or a mixture of cetylated fatty acids) having a carbon number ranging from C6 to C21, preferably C8 to C18, more preferably C14 to C18, and which may be saturated or unsaturated, and, optionally, % based on the total weight of the composition, preferably 0.005wt% to 0.1wt%, more preferably 0.01wt% to 0.08wt%; and (b) at least one antioxidant, (II) is at least one food or pharmaceutical grade additive and / or excipient.

[0021] The compositions of the present invention can be used as pharmaceutical compositions, compositions for medical devices, novel foods (foods or beverages or foods / beverages for special medical purposes (FSMP), or medical foods) (e.g., LIPOCET TM ) or a novel food supplement or composition or a dietary supplement or cosmetic composition.

[0022] In one preferred embodiment, the composition of the invention comprises: (a) at least one cetylated fatty acid (or a mixture of cetylated fatty acids), wherein the fatty acid is C6 to C21, C8 to C18, or C14 to C18 and is saturated or unsaturated; and (I) a mixture comprising or alternatively consisting of 0.001 wt% to 0.5 wt%, or 0.001 wt% to 0.4 wt%, or 0.001 wt% to 0.3 wt%, or 0.001 wt% to 0.2 wt%, or 0.001 wt% to 0.1 wt%, or 0.005 wt% to 0.1 wt%, or 0.01 wt% to 0.08 wt%, of the (b) at least one antioxidant, based on the total weight of the composition.

[0023] The (a) at least one cetylated fatty acid (or mixture of cetylated fatty acids) is cetyl alcohol (1-hexadecanol, CH 3 (CH2 ) 15 OH) or a mixture of fatty acids esterified with cetyl alcohol.

[0024] Preferably, the fatty acid of the (a) at least one cetylated fatty acid is selected from the group comprising or alternatively consisting of lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, eicosanoic acid and mixtures thereof, more preferably, said (a) at least one cetylated fatty acid is a mixture of cetylated fatty acids comprising or alternatively consisting of a mixture of cetylated myristic acid and cetylated oleic acid, even more preferably, said (a) at least one cetylated fatty acid is a mixture of cetylated fatty acids comprising or alternatively consisting of cetylated myristic acid, cetylated oleic acid, cetylated linoleic acid and cetylated palmitic acid.

[0025] (a), (b) and (c) LIPOCET T (According to any of the described embodiments) M According to one embodiment of the composition of the invention comprising: 30% to 55%, preferably 35% to 50%, more preferably about 41% of (a1) myristic acid; (a2) oleic acid, 35% to 60%, preferably 40% to 55%, more preferably about 46%; (a3) linoleic acid at 3% to 12%, preferably 5% to 10%, more preferably 8%; 1% to 8%, preferably 2% to 6%, more preferably 3% of (a4) palmitic acid; and / or alternatively consisting of 1% to 4%, preferably 1.5% to 3%, more preferably 1.8% of various fatty acids (a5 to a9) (not myristoleic acid), where % is wt% based on the total weight of the fatty acids (a1) to (a9).

[0026] In one embodiment, (a) above comprises a mixture of cetylated myristic acid and cetylated oleic acid, but does not comprise cetylated myristoleic acid, particularly when the compositions of the invention are used in methods for treating arthritis, inflammatory joint pain, and musculoskeletal pain.

[0027] In a further embodiment, (a) above comprises a mixture of cetylated myristic acid and cetylated oleic acid, which may include cetylated myristic acid, particularly when the composition of the present invention is used in a therapeutic method for protecting the gastric mucosa and regulating blood sugar levels.

[0028] Myristic acid is a derivative of tetradecanoic acid (CH 3 (CH 2 ) 12 Myristic acid is a saturated fatty acid with 14 carbon atoms present in milk derivatives (butter, cream, cheese), coconut oil, palm kernel oil and some spices (nutmeg). The myristic acid used in the present invention can be selected, for example, from those having at least 99% myristic acid (CAS 544-63-8) (EINECS 208-875-2) with a percent composition (%, GLC) of less than 1% lauric acid C12:0, more than 99% myristic acid C14:0 and less than 1% palmitic acid C16:0.

[0029] Oleic acid is a monounsaturated carboxylic acid with 18 carbon atoms and is the most abundant component of vegetable oils. 3 (CH 2 ) 7 CHCH(CH 2 ) 7 COOH).

[0030] The oleic acid used in the present invention may be selected from those having at least 78% oleic acid (CAS112-80-1) (EINECS204-007-1), for example, with a percentage composition (%, GLC) of 0.5% or less [lauric acid + myristic acid] C12:0 + C14:0, 78% or more oleic acid C18:1, 15% or less linoleic acid C18:2, and 1% or less other C18:3.

[0031] The cetyl alcohol (1-hexadecanol) used in the present invention may be selected, for example, from those having CAS 36653-82-4 (EINECS 253-149-0).

[0032] Advantageously, when (a) comprises or consists of a mixture of cetylated myristic acid and cetylated oleic acid, the molar ratio of cetylated myristic acid to cetylated oleic acid is between 4:1 and 1:1, preferably between 3:1 and 1.5:1, more preferably (2.0±0.2):1.

[0033] In one preferred embodiment, the composition of the invention comprises: (a) a mixture of cetylated myristic acid and cetylated oleic acid, preferably in a molar ratio of 4:1 to 1:1 or 3:1 to 1.5:1, preferably (2.0±0.2):1; and (I) a mixture comprising or alternatively consisting of (b) 0.001 wt% to 0.5 wt%, or 0.001 wt% to 0.3 wt%, or 0.001 wt% to 0.2 wt%, or 0.001 wt% to 0.1 wt%, or 0.005 wt% to 0.1 wt%, or preferably 0.01 wt% to 0.08 wt%, based on the total weight of the composition.

[0034] The antioxidant included in the composition of the present invention together with (a), and optionally together with (c), may be any antioxidant that the skilled artisan would consider suitable for use in a pharmaceutical composition, a medical device composition, a novel food (foodstuff), a food supplement or a cosmetic composition for the purposes reported herein.

[0035] Antioxidants are often added to foods, mainly fat-containing foods, to retard the onset of rancidity in the presence of oxygen. Natural antioxidants include, for example, flavonoids, polyphenols, ascorbic acid (vitamin C), and tocopherols (vitamin E). Synthetic antioxidants include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and ethoxyquinoline.

[0036] Preferably, said (b) at least one antioxidant is selected from the group comprising or alternatively consisting of t-butylhydroquinone (TBHQ), AperoxidRTLA (as defined in the present invention), tocopherol (e.g. tocopherol acetate) or mixtures of tocopherols, natural rosemary extract, wheat germ oil, butylhydroxytoluene and mixtures thereof, more preferably (b) is t-butylhydroquinone (TBHQ).

[0037] t-Butylhydroquinone (TBHQ or tertiary butylhydroquinone) is used in the food industry as a preservative for unsaturated vegetable oils and many edible animal fats. TBHQ has an acceptable daily intake (ADI) of 0.7 mg / kg of body weight and is therefore used as a food additive in the European Union, where it is identified by the code E319.

[0038] Aperoxid RTLA® is the trade name of an antioxidant effective in eliminating the phenomenon of fatty acid rancidity, used, for example, in the cosmetics field. Aperoxid RTLA is a mixture containing 10-15% tocopherol ((±) tocopherol), >50% lecithin, 8-10% ascorbyl palmitate (ester formed by ascorbic acid and palmitic acid to produce fat-soluble vitamin C) and <1% citric acid (INCI names Lecithin, Tocopherol (±) Tocopherol), Ascorbyl Palmitate, Citric Acid, CAS numbers 8002-43-5, 10191-41-0, 137-66-6, 77-92-9).

[0039] In one preferred embodiment, the composition of the invention comprises: (a) at least one cetylated fatty acid (or a mixture of cetylated fatty acids), wherein the fatty acid is C6 to C21, C8 to C18, or C14 to C18 and is saturated or unsaturated; and (b) t-butylhydroquinone (TBHQ) in an amount of 0.001 wt% to 0.5 wt%, or 0.001 wt% to 0.3 wt%, or 0.001 wt% to 0.2 wt%, or 0.001 wt% to 0.1 wt%, or 0.005 wt% to 0.1 wt%, or 0.01 wt% to 0.08 wt%, based on the total weight of the composition.

[0040] In one preferred embodiment, the composition of the invention comprises: (a) a mixture of cetylated myristic acid and cetylated oleic acid, preferably in a molar ratio of 4:1 to 1:1, 3:1 to 1.5:1, or (2.0±0.2):1; and (b) t-butylhydroquinone (TBHQ) in an amount of 0.001 wt% to 0.5 wt%, or 0.001 wt% to 0.3 wt%, or 0.001 wt% to 0.2 wt%, or 0.001 wt% to 0.1 wt%, or 0.005 wt% to 0.1 wt%, or 0.01 wt% to 0.08 wt%, based on the total weight of the composition.

[0041] In one more preferred embodiment, the composition of the invention comprises: (a) a mixture of cetylated myristic acid and cetylated oleic acid in a molar ratio of 3:1 to 1.5:1, preferably (2.0±0.2):1; (b) 0.01 wt % to 0.08 wt % of t-butylhydroquinone (TBHQ), based on the total weight of the composition; and (I) a mixture comprising or alternatively consisting of them.

[0042] In a further embodiment, the (I) mixture of the present invention further comprises, in addition to (a) and optionally (b), (c) a vegetable oil.

[0043] Preferably, the (c) vegetable oil is any vegetable oil or corn oil and mixtures thereof, selected from the group consisting of or including olive oil, sunflower oil, corn oil or mixtures thereof, with a high oleic acid content. Advantageously, (c) is olive oil. The content of oleic acid and / or olein in the oil is 55%-95% by weight, preferably 60%-90%, more preferably 65%-85%, for example 70%-80%.

[0044] (a) at least one cetylated fatty acid (or a mixture of cetylated fatty acids), preferably a mixture of cetylated myristic acid and cetylated oleic acid, the weight percentage of which is 50 wt% to 90 wt%, preferably 60 wt% to 85 wt%, more preferably 70 wt% to 80 wt%, based on the total weight of the composition; (b) at least one antioxidant, preferably t-butylhydroquinone (TBHQ), in an awt% range of 0.001 wt% to 0.5 wt%, or 0.001 to 0.3 wt%, or 0.001 wt% to 0.2 wt%, or 0.001 wt% to 0.1 wt%, preferably 0.005 wt% to 0.1 wt%, and more preferably 0.01 wt% to 0.08 wt%, based on the total weight of the composition; and (c) the vegetable oil, preferably olive oil, having a weight percentage of 9.5 wt% to 50 wt%, preferably 14.5 wt% to 40 wt%, more preferably 19.5 wt% to 30 wt%, based on the total weight of the composition, or alternatively consisting of the same.

[0045] In one preferred embodiment, the mixture (I) of the present invention comprises: (a) a mixture of cetylated myristic acid and cetylated oleic acid, the molar ratio of which is 4:1 to 1:1 or 3:1 to 1.5:1, preferably (2.0±0.2):1, and the weight percentage of the total weight of the composition is 60 wt% to 85 wt%, preferably 70 wt% to 80 wt%, inclusive; (b) t-butylhydroquinone (TBHQ) in an awt% range of 0.005 wt% to 0.1 wt%, preferably 0.01 wt% to 0.08 wt%, based on the total weight of the composition; (c) olive oil, the weight percentage of which is between 14.5wt% and 40wt%, preferably between 19.5wt% and 30wt%, based on the total weight of the composition;

[0046] In one more preferred embodiment, the mixture (I) of the present invention comprises: (a) a mixture of cetylated myristic acid and cetylated oleic acid in a molar ratio of (2.0±0.2):1 and a weight percentage of 70 wt% to 80 wt% (awt%); (b) t-butylhydroquinone (TBHQ) in an amount of 0.01 wt% to 0.08 wt%, based on the total weight of the composition; (c) olive oil, the weight percentage of which is 19.5 wt% to 30 wt% based on the total weight of the composition, and

[0047] Forming an object of the present invention are the compositions of the invention reported herein (e.g. LIPOCET TM ) comprising (I) the mixture of the present invention comprising or alternatively consisting of (a), (b), and optionally (c) (as above), and optionally (II) at least one food or pharmaceutical grade additive and / or excipient, for use as a medicament when administered in a therapeutically effective amount to a subject in need thereof.

[0048] Forming an object of the present invention are compositions according to the invention, e.g. LIPOCET TM), comprising (a), (b) and optionally (c) (in accordance with all embodiments described herein) for use in a method for the preventive and / or curative and / or symptomatic treatment of a disease, condition or disorder such as (i) inflammatory and non-inflammatory rheumatoid arthritis, particularly knee osteoarthritis, (ii) inflammatory conditions of the joint other than rheumatoid arthritis, (iii) psoriasis, lupus, periodontal disease or cardiovascular or heart disease, (iv) sports-related injuries, e.g., post-traumatic osteoarticular and musculoskeletal conditions including groin pain syndrome or athletic pubalgia (groin pain syndrome refers to chronic pain in the abdominal and groin area), (v) degenerative joint diseases, preferably knee osteoarthritis, knee osteoarthritis, hip osteoarthritis, and / or hip osteoarthritis, and / or (vi) tendon- and muscle-related inflammatory / traumatic conditions.

[0049] Preferably, the composition of the invention used in the method for treating the diseases or disorders identified above (i) to (vi) comprises: (a) a mixture of cetylated myristic acid and cetylated oleic acid in a molar ratio of 3:1 to 1.5:1, preferably (2.0±0.2):1; (b) 0.01 wt % to 0.08 wt % of t-butylhydroquinone (TBHQ), based on the total weight of the composition; and (I) a mixture comprising or alternatively consisting of them.

[0050] Preferably, the composition of the invention used in the method for treating the diseases or disorders identified above (i) to (vi) comprises: (a) a mixture of cetylated myristic acid and cetylated oleic acid in a molar ratio of (2.0±0.2):1 and a weight percentage of 70 wt% to 80 wt% (awt%); (b) t-butylhydroquinone (TBHQ) in an amount of 0.01 wt% to 0.08 wt%, based on the total weight of the composition; (c) olive oil, the weight percentage of which is from 19.5 wt% to 30 wt% based on the total weight of the composition; and (I) a mixture comprising or alternatively consisting of them.

[0051] The composition of the present invention used in the method for treating the diseases, symptoms or disorders listed in (i) to (vi) above is preferably administered to the subject via a topical or transdermal route, more preferably via a topical route. Advantageously, the cetylated fatty acids (a1) to (a7) contained in the mixture (a) have a molecular weight of 420 Da to 510 Da. Due to this molecular weight range, the mixture (a), and thus the composition of the present invention, can effectively overcome the stratum corneum barrier (skin), facilitating absorption via a topical route.

[0052] Alternatively, the compositions of the present invention used in the method of treating a disease, condition or disorder listed under (i) to (vi) above are preferably administered to the subject via the oral route.

[0053] Forming an object of the present invention are compositions according to the invention, e.g. TM ), which, when administered to a subject in need thereof, comprises (a), (b) and, optionally, (c) (in accordance with all embodiments described herein) for use in a method for the preventive and / or curative and / or symptomatic treatment of (ii) conditions and / or disorders caused by or associated with damage to the gastric mucosa (treatment to protect the gastric mucosa), (i.ii) diabetes and disorders or symptoms caused by or associated with diabetes, and (i.iii) diseases and / or disorders other than diabetes caused by or associated with high blood glucose levels.

[0054] The above (ii) symptoms or disorders resulting from or associated with damage to the gastric mucosa (protection of the gastric mucosa) include or are alternatively selected from the group consisting of peptic ulcer, gastroesophageal reflux (GERD), and heartburn.

[0055] Advantageously, it has been observed in vivo in rats that the use of the composition of the present invention provides effective and sustained protection of the gastric mucosa. The gastric mucosa is known to exert a barrier effect and consists of a mucosal layer of about 0.2 mm that covers the gastric mucosa. The purpose of this barrier is to protect the gastric epithelium from the damaging effects of HCI produced by the gastric parietal cells. This is due to the production of high molecular weight (and therefore highly viscous) mucoprotein droplets and the production of bicarbonate by the gastric mucosal cells.

[0056] Thus, forming an object of the present invention are compositions (see Table 2 or Samples 2 to 6) for use in a method for the treatment (prophylactically and / or curatively) of disorders or conditions resulting from or associated with damage to the gastric mucosa, including or alternatively selected from the group consisting of peptic ulcer, gastroesophageal reflux (GERD), heartburn.

[0057] The above (i.iii) non-diabetic diseases and / or disorders resulting from or associated with high blood glucose levels include or are alternatively selected from the group consisting of hyperglycemia, chronic liver disease, and obesity.

[0058] Advantageously, it has been discovered that administration of a composition of the present invention, e.g., Sample 4, in high doses, e.g., greater than 1600 mg / kg, to rats in vivo results in a statistically significant reduction in blood glucose levels in the treated rats.

[0059] Thus, forming an object of the present invention are compositions (see Table 2 or Samples 2-6) for use in methods for treating diabetes or diseases and / or disorders other than diabetes resulting from or related to blood glucose levels, such as hyperglycemia, chronic liver disease and obesity.

[0060] The composition of the present invention used in the method for treating a disease, condition or disorder listed under (ii) to (i.iii) above is preferably administered to the subject via the oral route.

[0061] Preferably, the composition of the present invention used in the method for treating the diseases or disorders identified above (ii) to (i.iii) comprises: (a) a mixture of cetylated myristic acid and cetylated oleic acid, preferably in a molar ratio of 4:1 to 1:1 or 3:1 to 1.5:1, preferably (2.0±0.2):1; (b) 0.01 wt % to 0.08 wt % of t-butylhydroquinone (TBHQ), based on the total weight of the composition; and (I) a mixture comprising or alternatively consisting of them.

[0062] The compositions of the present invention may be formulated in liquid forms such as solutions, two-phase liquid systems, emulsions, suspensions, syrups, sprays, ointments, oils or beverages, or alternatively in semi-solid forms such as gels, soft gels, creams, foams, or alternatively in solid forms such as powders, sprayable powders (spray dried), granules, microgranules, flakes, agglomerates, orally soluble sticks, tablets, effervescent tablets, capsules, suppositories, bars or food products, and equivalent forms known to those skilled in the art.

[0063] For example, the composition of the present invention can be formulated for oral use in a capsule (e.g., LIPOCET) that contains (a) a mixture of cetylated fatty acids according to the present invention, (b) at least one antioxidant according to the present invention based on %, and excipients such as gelatin, glycerin, and / or preservatives. TM In one embodiment, the composition is in the form of a 300 mg capsule of bovine gelatin.

[0064] Advantageously, when the composition of the invention is used for oral application, it is formulated in solid or liquid form, more preferably in the form of a capsule or oil or powder or sprayable powder (spray dried) or sprayable liquid or beverage or food.

[0065] Advantageously, when the compositions of the present invention are used for topical application, they are formulated in a semi-solid form, more preferably in the form of a cream or gel.

[0066] Advantageously, when the compositions of the invention are used for transdermal applications, they are formulated in semi-solid form, suitable for administration by a patch.

[0067] Forming an object of the present invention is a method for treating a disease, condition or disorder as listed in (i) to (vi) above by administering, preferably via topical or transdermal or oral route, an effective amount of one of the compositions of the present invention comprising (a) or (a) and (b) or (a) and (b) and (c) according to the present invention to a subject in need thereof, or alternatively a method for treating a disease, condition or disorder as listed in (ii) to (i.iii) above by preferably oral administration.

[0068] Appropriate assays for the compositions of the invention will depend, for example, on the condition to be treated / prevented, the severity and course of the condition, the fact that the composition is being administered for prophylactic or therapeutic purposes, prior treatment, the patient's medical history and response to the composition, and the discretion of the treating physician.

[0069] When the composition of the present invention is administered by a topical route, the amount of the composition administered is about 1-15 mg / kg, preferably 3-10 mg / kg, more preferably 5-8 mg / kg of the subject's body weight per day. Furthermore, the composition of the present invention, for example, a cream or gel, is applied via a topical route to an area within a range of 1 cm to 25 cm in diameter of the area to be treated (e.g., 3 cm on the finger, 20 cm on the back), depending on the anatomical area in question.

[0070] When the composition of the present invention is administered orally, the amount of the composition administered is approximately 100 mg / kg to 5000 mg / kg, preferably 200 mg / kg to 4500 mg / kg, and more preferably 300 mg / kg to 4000 mg / kg of the subject's body weight per day.

[0071] The compositions of the present invention are suitably administered to a subject in one or several treatments.

[0072] The compositions of the invention may be administered as single agents or in combination (as co-adjuvants) with other compositions or therapies useful for the preventive and / or curative and / or symptomatic treatment of the diseases, conditions and / or disorders listed in (i)-(vi) and / or (ii)-(i.iii) as described herein.

[0073] Forming an object of the present invention is the non-therapeutic use of a composition of the invention comprising (a) or (a) and (b) or (a) and (b) and (c) for protecting the gastric mucosa, said composition preferably being formulated for oral use.

[0074] The composition of the present invention protects the gastric mucosa from damage, and thus can prevent the occurrence of disorders related to the stomach region, such as peptic ulcers, gastroesophageal reflux (GERD), heartburn, etc.

[0075] In the context of the present invention, the expression "subject" is used to denote a human subject or an animal subject (e.g. a pet such as a dog or cat or other mammal). Preferably, the compositions of the present invention are used in a method of treatment of a human subject.

[0076] The expression "therapeutic method" in the context of the present invention is used to indicate an action including the administration of a substance, a mixture of substances or a combination thereof, aimed at eliminating, alleviating / preventing a pathology or disease and its symptoms or disorders.

[0077] The expression "medical device" in the context of the present invention is used in accordance with the meaning established by Italian Legislative Decree No. 46 of 24 February 1997 (or in accordance with the new Medical Devices Regulation (EU) 2017 / 745 (MDR)), i.e. it denotes a substance or another product designated by its manufacturer for use in humans, alone or in combination, for the diagnosis, prevention, control, treatment or mitigation of diseases, which product does not exert its primary action in or on the human body as designated, and does not use pharmacological or immunological means, nor metabolic processes, although its function can be cross-assisted by such means.

[0078] The compositions of the present invention optionally include (II) at least one food or pharmaceutical grade additive and / or excipient, such as a substance lacking therapeutic activity suitable for pharmaceutical or food use, such as diluents, solvents (e.g., water, glycerin, ethyl alcohol), solubilizers, thickeners, sweeteners, anti-caking agents, flavor enhancers, colorants, lubricants, surfactants, antimicrobial agents, antioxidants, preservatives, pH stabilizing buffers, acidifiers, and all auxiliary substances known to those skilled in the art.

[0079] The composition of the present invention may further comprise, in addition to the above (a), (b) and, if necessary, (c), other active ingredients, such as anti-inflammatory active ingredients, probiotics, antacids, products for the treatment of joint and / or muscle disorders, vitamins of group B and E, mineral salts, analgesics, folic acid, menthol, glucosamine, chondroitin, methylsulfonylmethane (MSM), essential oils, etc.

[0080] Unless otherwise specified, a statement that a composition "comprises" one or more ingredients or substances means that other ingredients or substances may be present in addition to the ingredient or substances specifically named.

[0081] Unless otherwise specified, a statement that a composition comprises a component in an amount in the range "x to y" is used to indicate that the component may be present in the composition in any amount that is not specified but is within that range, including the extremes of that range.

[0082] Forming an object of the present invention is a first process for producing (a) at least one cetylated fatty acid (or a mixture of cetylated fatty acids) as defined herein, comprising the steps of: (I) contacting at least one fatty acid, cetyl alcohol and a catalyst, preferably a metal catalyst, in the absence of a solvent in chamber 3 of reactor 2 to obtain a reaction mixture 15; The container 3 is saturated with an inert gas, the container 3 is brought to a pressure P1 of about 1 atmosphere, and the inert gas flow is passed through the container 3 at a rate of preferably 5 m 3 / h~0.05m 3 / h, more preferably 0.5m 3 / h through chamber 3; (III) applying a first heat lamp to the reaction mixture 15 in the presence of a pressure P1 of about 1 atmosphere and a flow of inert gas until a temperature T1 of 120° C. to 200° C., preferably 145° C. to 175° C., more preferably 160° C. is reached to initiate the esterification reaction with the initial formation of the cetylated fatty acid or mixture of cetylated fatty acids and water of esterification; Step (IV) of maintaining the reaction mixture 15 at the temperature T1 and pressure P1 with stirring for 10 minutes to 2 hours, preferably 30 minutes to 1.5 hours, more preferably 1 hour; (V) applying a second heat lamp to the reaction mixture 15 in the presence of a pressure P1 of about 1 atmosphere and a flow of inert gas until a temperature T2 of 201° C. to 260° C., preferably 210° C. to 240° C., more preferably 220° C., is reached to continue the esterification reaction with further formation of the cetylated fatty acid or mixture of cetylated fatty acids and water of esterification; Step (VI) of stirring and maintaining the reaction mixture 15 for 4 hours to 12 hours, preferably 6 hours to 10 hours, more preferably 8 hours, under the conditions of the temperature T2, the pressure P1, and an inert gas flow, preferably until the acidity value measured by the AOCS official method Cd3d-63 becomes stable over time and reaches 5 mgKOH / g to 8 mgKOH / g; A step (VII) of reducing the reaction pressure by applying a vacuum program in the chamber 3 until a reduced pressure P2 of 100 mbar to 10 mbar, preferably 80 mbar to 30 mbar, more preferably 50 mbar is reached; and (VIII) holding the reaction mixture 15 under stirring in the presence of the reduced pressure P2 and an inert gas flow, preferably for 30 minutes to 4 hours, preferably 1 hour to 2 hours, more preferably 2 hours, until an acidity value of 4.5 mg KOH / g to 3.5 mg KOH / g, preferably 4 mg KOH / g, as measured by AOCS official method Cd3d-63, is reached, to completely form the at least one crude cetylated fatty acid or mixture of crude cetylated fatty acids (MI) ( FIG. 1 ).

[0083] By applying an inert gas flow during part or the entire duration of the ester formation step in combination with a vacuum program in the reactor chamber only during the last part of the ester formation step, the first method advantageously allows the removal of esterification water and a high and complete conversion of fatty acids to esters. The first method is easy to apply and economically advantageous since it does not require the application of a vacuum program during the entire duration of the esterification reaction.

[0084] In one embodiment (FR1) of the first method, the at least one fatty acid is selected from the group comprising or alternatively consisting of lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, eicosanoic acid and mixtures thereof, preferably myristic acid, oleic acid and mixtures of myristic acid and oleic acid, more preferably mixtures of myristic acid and oleic acid, and even more preferably mixtures of myristic acid and oleic acid, with the proviso that said mixture does not include myristoleic acid.

[0085] In one embodiment of the first method (FR2), the inert gas flow is applied above the reaction mixture 15 by means of a blowing means 7 placed in the volume of the chamber 3 (FIG. 1).

[0086] In one embodiment of the first process (FR3), the esterified water withdrawn from chamber 3 during the esterification reaction by applying an inert gas flow and vacuum program is passed through a vertical condenser 16 and then condensed in a horizontal condenser 11 and collected in a vessel 13 (Figures 2 and 3).

[0087] In one embodiment of the first method (FR4), the horizontal condenser 11 is maintained at a temperature between 10°C and 40°C and is connected to the vessel 3 by a vertical condenser 16 maintained at a temperature between 70°C and 90°C (Figure 3).

[0088] In one embodiment (FR5) of the first method, in addition to steps (I) to (VIII), the first method further comprises a step (IX) of filtering the at least one crude cetylated fatty acid or mixture of crude cetylated fatty acids (MI) obtained from step (VIII) onto bleaching earth and / or filtering earth in a filter press 23 (FIG. 3) to obtain at least one filtered cetylated fatty acid or mixture of filtered cetylated fatty acids (Mf), in which a metal catalyst is substantially absent or present in an amount of less than 2 wt.%, preferably in an amount of 0.01 wt.% to 1.5 wt.%, more preferably in an amount of 0.05 wt.% to 1 wt.%, for example 0.5 wt.%, based on the weight of the filtered cetylated fatty acid or mixture of filtered cetylated fatty acids (Mf).

[0089] The metal catalyst (metal in zero oxidation state), preferably metallic zinc, is preferably used in powder form, preferably metallic zinc in powder form. The amount of catalyst added is in the range of 0.01 wt% to 0.5 wt%, preferably 0.05 wt% to 0.25 wt%, more preferably 0.1 wt%, based on the total weight of the reaction reagent (i.e., fatty acid or fatty acid + cetyl alcohol mixture).

[0090] In one embodiment (FR6) of the first method, in addition to steps (I) to (IX), the first method further comprises a step (X) (deodorization step) of treating the at least one filtered cetylated fatty acid or the mixture of filtered cetylated fatty acids (Mf) in a reactor 27 at a temperature T3 of 150° C. to 200° C., preferably 165° C. to 180° C., more preferably 180° C., and a reduced pressure P3 of 1 mbar to 20 mbar, preferably 3 mbar to 5 mbar, and in the presence of a water vapor flow, for 1 hour to 5 hours, preferably 2 hours to 3 hours (FIG. 3) to obtain at least one purified cetylated fatty acid or the mixture of purified cetylated fatty acids (Mf).

[0091] Forming an object of the present invention is a second process for the preparation of an inventive composition comprising said (a) at least one cetylated fatty acid (or a mixture of cetylated fatty acids) as defined herein, comprising the steps of: (a) filtering said at least one filtered cetylated fatty acid (Mf) obtained according to embodiment FR5 in combination with any one of embodiments FR1 to FR4, or alternatively (b) filtering said at least one purified cetylated fatty acid (MF) obtained according to embodiment FR6 in combination with any one of embodiments FR1 to FR5; and (c) filtering said at least one purified cetylated fatty acid (MF) obtained according to embodiment FR6 in combination with any one of embodiments FR1 to FR5. The composition further comprises a step (XI) of mixing (b) at least one antioxidant (as defined in the fine print), wherein the (b) at least one antioxidant is mixed in a weight percentage, awt%, including 0.001 wt% to 0.5 wt%, or 0.001 wt% to 0.4 wt%, or 0.001 wt% to 0.3 wt%, or 0.001 wt% to 0.2 wt%, or 0.001 wt% to 0.1 wt%, preferably 0.005 wt% to 0.1 wt%, and more preferably 0.01 wt% to 0.08 wt%, based on the total weight of the composition (the composition of the present invention).

[0092] In one preferred embodiment, the second method for producing the composition of the present invention comprises the step of mixing said at least one filtered cetylated fatty acid (Mf) or at least one purified cetylated fatty acid (MF) comprising or alternatively consisting of a mixture of cetylated myristic acid and cetylated oleic acid, preferably in a molar ratio of 4:1 to 1:1, or 3:1 to 1.5:1, or (2.0±0.2):1, and 2.) The at least one antioxidant is t-butylhydroquinone (TBHQ) in an awt% range of 0.001 wt% to 0.5 wt%, or 0.001 to 0.4 wt%, or 0.001 to 0.3 wt%, or 0.001 wt% to 0.2 wt%, or 0.001 wt% to 0.1 wt%, preferably 0.005 wt% to 0.1 wt%, and more preferably 0.01 wt% to 0.08 wt%, based on the total weight of the composition.

[0093] In one embodiment, the at least one filtered cetylated fatty acid (or mixture of cetylated fatty acids) (Mf), preferably a mixture of filtered cetylated myristic acid and cetylated oleic acid, is added with the (c) vegetable oil (as defined in the present invention), preferably olive oil or corn oil, prior to carrying out the deodorization step.

[0094] In one embodiment, prior to the deodorization step (X), the at least one filtered cetylated fatty acid (Mf), preferably a mixture of filtered cetylated myristic acid and cetylated oleic acid, is subjected to a step (XII) of adding the (c) vegetable oil, preferably olive oil or corn oil, to the (Mf) to form a mixture comprising (Mf) and (c), which is then subjected to the deodorization step (X).

[0095] In one preferred embodiment, the deodorization step (X) of the first process to obtain at least one purified cetylated fatty acid (MF), preferably a mixture of purified myristic acid and cetylated oleic acid, and the step (XI) of the second process of mixing said at least one purified cetylated fatty acid (MF) with at least one antioxidant, preferably TBHQ, and, optionally, the step (XII) of adding (c) a vegetable oil to the at least one filtered cetylated fatty acid (Mf), are carried out in the same reactor.

[0096] Essentially, the method of the present invention can be roughly summarized by the following embodiments. 1, MI (Process I~VIII) → Mf (Process IX) → MF (Process X) + (b) (Process XI) + (c) (Process XII) 2, MI (Process I~VIII) → Mf (Process IX) + (c) (Process XII) → MF (Process X) + (b) (Process XI) 3. MI (Process I~VIII) → Mf (Process IX) + (b) (Process XI) → MF (Process X) + (c) (Process XII)

[0097] The (a) at least one cetylated fatty acid (or mixture of cetylated fatty acids) is cetyl alcohol (1-hexadecanol, CH 3 (CH 2 ) 15 OH) are fatty acids esterified with

[0098] Preferably, the fatty acid of said (a) at least one cetylated fatty acid is selected from the group comprising or alternatively consisting of (a1) myristic acid, (a2) oleic acid, (a3) ​​linoleic acid, (a4) palmitic acid, (a5) lauric acid, (a6) palmitoleic acid, (a7) stearic acid, (a8) eicosanoic acid, (a9) eicosenoic acid and mixtures thereof, more preferably, said (a) at least one cetylated fatty acid is a mixture of cetylated fatty acids comprising or alternatively consisting of cetylated myristic acid, cetylated oleic acid, cetylated linoleic acid and cetylated palmitic acid, and even more preferably, said (a) comprises or alternatively consists of a mixture of cetylated myristic acid and cetylated oleic acid.

[0099] (a), (b) (at least one antioxidant) and (c) (e.g., LIPOCET TM According to one embodiment of the composition of the invention (any one of the described embodiments), the fatty acid profile comprises: 30% to 55%, preferably 35% to 50%, more preferably 40% to 45%, for example 41% or 42% or 43% or 44% of (a1) myristic acid; (a2) oleic acid of 35% to 60%, preferably 40% to 55%, more preferably 45% to 50%, for example 46% or 47% or 48% or 49%, (a3) linoleic acid at 3% to 12%, preferably 5% to 10%, more preferably 6% to 9%, for example 7% or 8% or 8.5%; and (a4) palmitic acid, comprising or alternatively consisting of 1% to 8%, preferably 2% to 6%, more preferably 3% to 5%, for example 3.5% or 4% or 4.5%.

[0100] Furthermore, the above (a)+(b)+(c) may be combined with one or more of the above (a1) to (a4), 0.1% to 0.3%, for example 0.2%, of (a5) lauric acid; 0.3% to 0.5%, for example 0.4%, of (a6) palmitoleic acid; 0.7% to 0.9%, for example 0.8%, of (a7) stearic acid; 0.05% to 0.15%, e.g. 0.1% (a8) eicosanoic acid and 0.2% to 0.4%, for example 0.3%, of (a9) eicosenoic acid.

[0101] The total amount of the above (a5) to (a9) is preferably 1 wt % to 4 wt %, more preferably 1.5 wt % to 3 wt %, and even more preferably 2 wt % to 2.5 wt %, for example 1.8 wt %.

[0102] Chromatographic separation of the mixture (a)+(b)+(c) gives 60%-80%, preferably 65%-75% (by weight) of wax fraction (a1)-(a9), and the remaining part is a glyceride fraction. The chain length distribution type in the wax fraction is 60%-70% for C30, 1%-3% for C32, and 25%-35% for C34. In the wax fraction, the amount of myristic acid is 60wt%-70wt%, and the amount of oleic acid is 25wt%-35wt%.

[0103] An embodiment of the mixture (a)+(b)+(c) will be described below.

[0104] Sample 2, a composition according to the present invention, a mixture of cetylated myristic acid and cetylated oleic acid having a myristic:oleic molar ratio of about 2.1:1 (about 75 wt % based on the total weight of the sample); Olive oil or corn oil (approximately 25 wt% based on the total weight of the sample) t-Butylhydroquinone (TBHQ) (0.02 wt% based on the total weight of the sample), and optionally excipients and / or additives.

[0105] Sample 3, a composition according to the present invention, a mixture containing primarily cetylated myristic acid and cetylated oleic acid (approximately 75 wt % based on the total weight of the sample) with a myristic:oleic molar ratio of approximately 2.1:1; Olive oil or corn oil (approximately 25 wt% based on the total weight of the sample), AperoxidRTLA (0.05 wt% based on the total weight of the sample) and, if necessary, and excipients and / or additives.

[0106] Sample 4, the composition, a mixture containing primarily cetylated myristic acid and cetylated oleic acid (approximately 75 wt % based on the total weight of the sample) with a myristic:oleic molar ratio of approximately 2.1:1; Olive oil or corn oil (approximately 25 wt% based on the total weight of the sample), Mixture of tocopherols or tocopherol acetate (0.001-0.3 wt%), if necessary, and excipients and / or additives.

[0107] Sample 5, a composition according to the present invention, A mixture of (a1)+(a2)+(a3) in which the molar ratio of (a1):(a2):(a3) is 4:4:1 (approximately 80 wt % based on the total weight of the sample), Olive oil or corn oil (approximately 20 wt% based on the total weight of the sample), a mixture of tocopherol acetate and wheat germ oil in a weight ratio of 1:25, and optionally and excipients and / or additives.

[0108] Sample 6, a composition according to the present invention, A mixture of (a1)+(a2)+(a3)+(a4) in which the molar ratio of (a1):(a2):(a3):(a4) is 4:4:1:0.5 (approximately 85 wt % based on the total weight of the sample), Olive oil or corn oil (approximately 15 wt% based on the total weight of the sample), a mixture of tocopherol acetate and wheat germ oil in a weight ratio of 1:25, and optionally and excipients and / or additives.

[0109] An embodiment (An) relating to the first object of the present invention will be described below.

[0110] An1 A composition comprising (I) and, optionally, (II), (I) is (a) at least one cetylated fatty acid having a carbon number in the range of C6 to C21 and being a saturated or unsaturated fatty acid; (b) at least one antioxidant, the weight percentage of which is in the range of 0.001 wt % to 0.5 wt % relative to the total weight of the composition; and (II) is at least one food or pharmaceutical grade additive and / or excipient.

[0111] An2 The composition according to An1, wherein the fatty acid of the (a) at least one cetylated fatty acid is selected from the group consisting of myristic acid, oleic acid, and mixtures thereof; Preferably, (a) comprises or alternatively consists of a mixture of cetylated myristic acid and cetylated oleic acid.

[0112] An3 In the composition according to An1 or An2, the at least one antioxidant (b) is selected from the group consisting of or includes t-butylhydroquinone (TBHQ), a mixture containing tocopherol, lecithin, ascorbyl palmitate and citric acid (AperoxidRTLA), a mixture of tocopherols, and natural rosemary extract, and preferably (b) is t-butylhydroquinone (TBHQ).

[0113] An4 In the composition according to any one of An1 to An3, the (b) at least one antioxidant is present in a weight percentage ranging from 0.005 wt% to 0.1 wt%, preferably from 0.01 wt% to 0.08 wt%, relative to the total weight of the composition.

[0114] An5: In the composition according to any one of An1 to An4, (a) comprises or alternatively consists of a mixture of cetylated myristic acid and cetylated oleic acid, the molar ratio of said cetylated myristic acid to cetylated oleic acid being in the range of 4:1 to 1:1, preferably 3:1 to 1.5:1, more preferably (2.0±0.2):1; and The above (b) is t-butylhydroquinone (TBHQ) and is present in a weight percentage ranging from 0.001 wt % to 0.5 wt %, preferably from 0.005 wt % to 0.1 wt %, and more preferably from 0.01 wt % to 0.08 wt %, based on the total weight of the composition.

[0115] An6 In the composition described in any one of An1 to An5, in addition to (a) and (b), the composition further contains (c) a vegetable oil, preferably the vegetable oil includes or is alternatively selected from the group consisting of olive oil and sunflower oil having a high olein content.

[0116] An7 The composition according to any one of An1 to An6, (a) at least one cetylated fatty acid, preferably a mixture of cetylated myristic acid and cetylated oleic acid, the weight percentage of which is in the range of 50 wt% to 90 wt%, preferably 60 wt% to 85 wt%, more preferably 70 wt% to 80 wt%, based on the total weight of the composition; the (b) antioxidant, preferably t-butylhydroquinone (TBHQ), in a weight percentage range of 0.001 wt % to 0.5 wt %, preferably 0.005 wt % to 0.1 wt %, more preferably 0.01 wt % to 0.08 wt %, relative to the total weight of the composition; and (c) the vegetable oil, preferably olive oil, in a weight percentage range of 9.5 wt% to 50 wt%, preferably 14.5 wt% to 40 wt%, more preferably 19.5 wt% to 30 wt%, based on the total weight of the composition.

[0117] An8: The composition according to any one of An1 to An7 is used as a medicine.

[0118] An9 The composition for use described in An8 is used in a method for the preventive and / or curative and / or symptomatic treatment of (i) inflammatory and non-inflammatory rheumatoid arthritis, in particular knee osteoarthritis, (ii) inflammatory conditions of the joints other than rheumatoid arthritis, (iii) psoriasis, lupus, periodontal disease or cardiovascular or heart disease, (iv) post-traumatic bone-articular and musculoskeletal conditions including sports-related injuries, (v) degenerative joint diseases, preferably arthropathy, knee osteoarthritis, hip osteoarthritis, and / or (vi) tendon- and muscle-related inflammatory / traumatic conditions, by administration to a subject in need thereof.

[0119] The composition for use according to An10 An8 or An9 is formulated for topical or transdermal application, preferably for topical application.

[0120] Hereinafter, an embodiment (Bn) relating to the second object of the present invention will be described.

[0121] The Bn1 composition is (a) a mixture (I) comprising or alternatively consisting of at least one cetylated fatty acid, and, optionally, (II) at least one pharmaceutical or food grade additive and / or excipient; The composition, when administered to a subject in need thereof, (ii) disorders or conditions resulting from and / or associated with damage to the gastric mucosa, including or alternatively selected from the group consisting of peptic ulcer, gastroesophageal reflux (GERD), and heartburn; (i.ii) diabetes mellitus; and (i.iii) diseases and / or disorders other than diabetes resulting from or associated with high blood glucose levels, including or alternatively selected from the group consisting of hyperglycemia, chronic liver disease, and obesity.

[0122] Bn2 In the composition for use described in Bn1, (a) said fatty acid of at least one cetylated fatty acid is selected from the group comprising or alternatively consisting of lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, eicosanoic acid and mixtures thereof, preferably myristic acid, oleic acid or cetylated myristic acid and cetylated oleic acid.

[0123] Bn3 In the composition for use described in Bn2, the molar ratio of cetylated myristic acid to cetylated oleic acid in the mixture of cetylated myristic acid and cetylated oleic acid is in the range of 4:1 to 1:1, preferably 3:1 to 1.5:1, and more preferably (2.0±0.2):1.

[0124] Bn4 In the composition for use according to any one of Bn1 to Bn3, the mixture (I) containing the (a) further contains (b) at least one antioxidant.

[0125] Bn5 In the composition for use according to Bn4, the at least one antioxidant (b) is selected from the group consisting of or includes t-butylhydroquinone (TBHQ), a mixture containing tocopherol, lecithin, ascorbyl palmitate and citric acid (AperoxidRTLA), a mixture of tocopherols and natural rosemary extract, preferably (b) is t-butylhydroquinone (TBHQ).

[0126] Bn6 In a composition for use according to Bn4 or Bn5, the (b) at least one antioxidant is present in a weight percentage ranging from 0.001 wt% to 0.5 wt%, preferably from 0.005 wt% to 0.1 wt%, more preferably from 0.01 wt% to 0.08 wt%, relative to the total weight of the composition.

[0127] Bn7 In the composition for use according to any one of Bn1 to Bn6, the mixture (I) is a mixture of cetylated myristic acid and cetylated oleic acid, the molar ratio of which is preferably in the range of 4:1 to 1:1, more preferably 3:1 to 1.5:1, and more preferably (2.0±0.2):1; and (b) t-butylhydroquinone (TBHQ) preferably present in a weight percentage ranging from 0.001 wt % to 0.5 wt %, preferably from 0.005 wt % to 0.1 wt %, more preferably from 0.01 wt % to 0.08 wt %, relative to the total weight of the composition.

[0128] Bn8 In the composition described in any one of Bn1 to Bn7, in addition to (a) and (b), (c) a vegetable oil is further contained, preferably the vegetable oil is selected from the group including or alternatively consisting of olive oil and sunflower oil having a high olein content and mixtures thereof.

[0129] Bn9 The composition for use according to any one of Bn1 to Bn8 is formulated for oral use.

[0130] Bn10 The composition according to any one of Bn1 to Bn9 is used as a coadjuvant for one or more compositions used in the preventive and / or curative treatment of (ii), (i.ii) or (i.iii).

[0131] An embodiment (Cn) relating to the third object of the present invention will be described below.

[0132] Cn1 (a) A method for producing at least one cetylated fatty acid or a mixture of cetylated fatty acids, comprising the steps of: (I) contacting at least one fatty acid, cetyl alcohol and a metal catalyst in the absence of a solvent in chamber 3 of a reactor (2) to obtain a reaction mixture 15; (II) saturating the container 3 with an inert gas, bringing the container 3 to a pressure P1 of about 1 atmosphere and applying a flow of said inert gas through said chamber 3; (III) applying a first heat lamp to the reaction mixture 15 in the presence of a pressure P1 of about 1 atmosphere and a flow of inert gas until a temperature T1 of 120° C. to 200° C. is reached to initiate an esterification reaction with the initial formation of the cetylated fatty acid or mixture of cetylated fatty acids and water of esterification; Step (IV) of maintaining the reaction mixture 15 at the temperature T1 and pressure P1 for 10 minutes to 2 hours while stirring; (V) applying a second heat lamp to the reaction mixture 15 in the presence of a pressure P1 of about 1 atmosphere and a flow of inert gas until a temperature T2 of 201° C. to 260° C. is reached to continue the esterification reaction with further formation of the cetylated fatty acid or mixture of cetylated fatty acids and water of esterification; Step (VI) of maintaining the reaction mixture 15 under stirring at the temperature T2 and pressure P1 and in the presence of an inert gas flow for 4 to 12 hours; A step (VII) of reducing the reaction pressure by applying a vacuum program in the chamber 3 until a reduced pressure P2 of 100 mbar to 10 mbar is reached; and (VIII) maintaining the reaction mixture 15 under stirring in the presence of the reduced pressure P2 and inert gas flow for 30 minutes to 4 hours to completely form the at least one crude cetylated fatty acid (MI) or a mixture of crude cetylated fatty acids.

[0133] Cn2: In the method according to Cn1, The step (VI) of stirring and holding the reaction mixture 15 for 6 to 12 hours at the temperature T2 and pressure P1, and in the presence of an inert gas flow, is carried out until the acidity value of the reaction mixture 15, as measured by the AOCS official method Cd3d-63, becomes stable over time and reaches 5 mgKOH / g to 8 mgKOH / g; and The step (VIII) of holding the reaction mixture 15 under stirring in the presence of the reduced pressure P2 and the inert gas flow for 30 minutes to 4 hours to completely form the at least one crude cetylated fatty acid or mixture of crude cetylated fatty acids (MI) is carried out until the acidity value of the reaction mixture 15 reaches 4.5 mg KOH / g to 3.5 mg KOH / g as measured by AOCS official method Cd3d-63.

[0134] Cn3: The method according to Cn1 or Cn2, wherein the at least one fatty acid is selected from the group comprising or alternatively consisting of lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, eicosanoic acid, and mixtures thereof; Preferably, it is selected from myristic acid, oleic acid, and a mixture of myristic acid and oleic acid.

[0135] Cn4: The method according to any one of Cn1 to Cn3, wherein said inert gas flow is applied above the reaction mixture (15) by means of a blowing means (7) arranged in the volume of the chamber (3).

[0136] Cn5: In the method according to any one of Cn1 to Cn4, the esterified water withdrawn from the chamber 3 during the esterification reaction by applying an inert gas flow and a vacuum program is passed through a vertical condenser 16 and then condensed in a horizontal condenser 11 and collected in a container (13).

[0137] Cn6 The method according to any one of Cn1 to Cn5 further comprises a step (IX) (filtration step) of filtering the at least one unrefined cetylated fatty acid (MI) obtained from step (VIII) onto bleaching earth and / or filtering earth in a filter press 23 to obtain at least one filtered cetylated fatty acid (Mf), wherein a metal catalyst is absent or is present in an amount of less than 2 wt. % relative to the weight of the filtered cetylated fatty acid or mixture of filtered cetylated fatty acids (Mf).

[0138] Cn7 The method according to any one of Cn1 to Cn6 further comprises, after step (IX), a step (X) (deodorization step) of treating the at least one filtered cetylated fatty acid (Mf) in a reactor 27 at a temperature T3 of 150°C to 200°C and a reduced pressure P3 of 1 mbar to 20 mbar, and in the presence of a water vapor flow, for 1 hour to 5 hours to obtain at least one purified cetylated fatty acid (MF).

[0139] Cn8 The above (a) method for producing a composition comprising at least one cetylated fatty acid comprises mixing the at least one filtered cetylated fatty acid (Mf) obtained according to any one of the embodiments Cn1 to Cn6, or alternatively the at least one purified cetylated fatty acid (MF) obtained according to any one of the embodiments Cn1 to Cn7, with at least one antioxidant, wherein the at least one antioxidant is mixed in a weight percentage of awt% comprised between 0.001 wt% and 0.5 wt%, preferably between 0.005 wt% and 0.1 wt%, more preferably between 0.01 wt% and 0.08 wt% based on the total weight of the composition.

[0140] Cn9: A method for producing a composition according to Cn8, wherein the at least one filtered cetylated fatty acid (Mf) or the at least one purified cetylated fatty acid (MF) comprises or alternatively consists of a mixture of cetylated myristic acid and cetylated oleic acid, and the at least one antioxidant is t-butylhydroquinone (TBHQ).

[0141] Cn10 In a method for producing a composition according to Cn8 or Cn9, prior to step (X), the at least one filtered cetylated fatty acid (Mf), preferably a mixture of filtered cetylated myristic acid and cetylated oleic acid obtained from step (IX), is subjected to a step (XII) of adding a vegetable oil, preferably olive oil, to the at least one filtered cetylated fatty acid (Mf) to form a mixture comprising (Mf) and the vegetable oil, which mixture is then subjected to step (X). [Experimental Example 1]

[0142] In Experimental Example 1, the stability of the compositions of the present invention with or without antioxidants was analyzed. Using the same method as described below, tests were performed on the compositions shown in Table 2 and Samples 1, 2, and 3. In particular, tests on Samples 2 and 3 (invention) and Sample 1 (comparative sample) are reported as non-limiting examples, since the stability results obtained with the compositions shown in Table 2 are comparable to Samples 2 and 3 due to the presence of at least one antioxidant in the tested compositions.

[0143] material Premise: The weight percentages (wt%) of samples 1, 2, and 3 refer to the total weight of the sample.

[0144] Sample 1, (Comparative Composition) The composition comprises: a mixture containing primarily cetylated myristic acid and cetylated oleic acid (approximately 75 wt % based on the total weight of the sample) with a myristic:oleic molar ratio of approximately 2.1:1; and olive oil or corn oil (approximately 25 wt % based on the total weight of the sample).

[0145] Sample 1 does not contain an antioxidant.

[0146] Sample 2 The composition according to the present invention comprises a mixture containing primarily cetylated myristic acid and cetylated oleic acid (approximately 75 wt % based on the total weight of the sample) with a myristic:oleic molar ratio of approximately 2.1:1; Olive oil or corn oil (approximately 25 wt% based on the total weight of the sample), t-Butylhydroquinone (TBHQ) (0.02 wt% based on the total weight of the sample) and, if necessary, and excipients and / or additives.

[0147] Sample 3 The composition according to the present invention comprises a mixture containing primarily cetylated myristic acid and cetylated oleic acid (approximately 75 wt % based on the total weight of the sample) with a myristic:oleic molar ratio of approximately 2.1:1; Olive oil or corn oil (approximately 25 wt% based on the total weight of the sample), AperoxidRTLA (0.05 wt% based on the total weight of the sample) and, if necessary, and excipients and / or additives.

[0148] methodology After time T0, samples 1, 2, and 3 were stored at a controlled temperature of 18°C ​​and approximately every 40-45 days (i.e., T1, T2, T3, T4), a portion of each sample was taken and the peroxide value (PV) and Kreis test were measured.

[0149] Peroxide Value The peroxide value (PV) was measured by standard methods according to the ISO 3960 method (4th edition 2007-07-15, amended 2009-05-15, edited by Technical Committee ISO / TC34 / SC), as is well known to those skilled in the art.

[0150] The above test is a typical analytical chemistry method for determining the degree of rancidity of edible oils. The test quantitatively measures the peroxide value (PV), which is an indicator of the amount of primary autoxidation products of fatty acids.

[0151] In this method (simply), the oil sample is dissolved in isooctane and glacial acetic acid (glacial acetic acid:isooctane=6:4 v / v) and potassium iodide is added. The iodine released from the peroxide is converted to iodine by the addition of starch indicator and sodium thiosulfate standard solution (0.01N Na 2 S 2 O 3 The titration end point is determined (visually) by iodometric titration.

[0152] PV is expressed in mEq of oxygen per kg of oil.

[0153] Considering that the measurement of the peroxide value (PV) is a highly empirical procedure, ISO03960:2007 sets the sample mass at 5 g when the PV is greater than 1 and at 10 g when the PV is less than or equal to 1, and limits the application of this method to animal and vegetable fats and oils with a peroxide value of 0 mEq to 30 mEq of active oxygen per kg.

[0154] Kreis test The Kreis test is performed by standard methods known to those skilled in the art.

[0155] The Kreis test is a classical chemical test for qualitatively determining the degree of rancidity of edible oils. This test is used to detect secondary autoxidation products of fatty acids.

[0156] Indeed, the sensory properties of rancid and rancid fats correlate significantly with the presence of carbonyl products formed by the interaction of oxygen with unsaturated fatty acids.

[0157] Phloroglucinol (1,3,5-triphenol or symmetric triphenol) has the basic formula C 6 H 6 O 3 It is a chemical compound with a phenolic group, and from its aqueous solution it forms a dihydrate (C 6 H 6 O 3 2H 2 O).

[0158] The Kreis test is based on the condensation reaction of carbonyl compounds (arising from the rancidity of fats) with phloroglucinol in the presence of HCl, which produces red compounds. It is a qualitative method, and the color of the bottom layer is due to the presence of KMnO 4 If it is stronger than a 0.0012% solution of the compound, it is considered positive, and if it is the other way around, it is considered negative.

[0159] Kreis test method 1. 10 ml of oil and 10 ml of concentrated HCl were stirred for 30 seconds.

[0160] 2.10 ml of the reagent was added and stirred for 30 seconds with a 0.1% solution of phloroglucinol in ethyl ether.

[0161] After layering, the color of the lower acid layer was observed as follows: Negative reaction: brown coloration or fading, Positive reaction: pink or red coloration (spoiled oil)

[0162] result As shown in Table 1, Samples 2 and 3 (compositions of the present invention containing antioxidants) exhibit significantly lower peroxide values ​​(PV) than Sample 1 (composition without antioxidants) at times T3 (i.e., after about 150 days) and T4 (i.e., after about 210 days).

[0163] Furthermore, with regard to the Kreis test, samples 2 and 3 are negative at times T3 and T4, whereas sample 1 is positive.

[0164] [Table 1]

[0165] In Experimental Example 2, an in vivo toxicity test was carried out on the compound according to the present invention (Sample 4).

[0166] The in vivo test is a 14-day oral toxicity study for the compounds of the present invention in CrLCD Sprague-Dawley (SD) rats.

[0167] Compounds to be tested Sample 4, the composition, a mixture containing primarily cetylated myristic acid and cetylated oleic acid (approximately 75 wt % based on the total weight of the sample) with a myristic:oleic molar ratio of approximately 2.1:1; Olive oil or corn oil (approximately 25 wt% based on the total weight of the sample), and (b) at least one antioxidant, such as a mixture of tocopherols or tocopherol acetate, the weight percentage being between 0.001 wt% and 0.3 wt%, including awt% (based on the total weight of the sample).

[0168] The test system consisted of 60 Sprague-Dawley rats (30 males and 30 females) aged 7 weeks at the start of treatment.

[0169] Size groups are 5 male and 5 female rats per group.

[0170] Assay levels are 0-1600-1900-2200-2600-4500 mg / kg body weight.

[0171] The dosage was 10 ml / kg body weight.

[0172] Treatment mixtures were prepared weekly and kept at 4°C.

[0173] The treatment regimen was daily for 14 consecutive days.

[0174] For the treatment procedure, the daily dose was divided into two equal subfractions and administered to each fasted rat, 60 minutes apart.

[0175] Observations were made for mortality (daily), clinical signs (daily), body weight (twice weekly), food consumption (twice weekly), hematology (sacrifice), clinical chemistry (sacrifice), urinalysis (sacrifice), gross lesions, and histology (when required).

[0176] For statistics, data were analyzed using ANOVA followed by post-hoc Dunnett's test with JMP statistical detection software.

[0177] result Statistically significant dose-dependent differences related to blood glucose levels were recorded in the high dose test group, which was significantly lower (p<0.05) compared to the control group (there is an inverse relationship between the administered dose of the compound of the present invention and blood glucose levels). Surprisingly, it was discovered that administration of the composition of, for example, sample 4 at the highest dose to rats resulted in a statistically significant reduction in blood glucose levels in the treated rats. This shows that the composition of the present invention can be effectively applied / used in a method for treating subjects suffering from diabetes or diseases and / or disorders other than diabetes that are derived from or related to high blood glucose levels, such as in the case of hyperglycemia, chronic liver disease, and obesity.

[0178] Complete hematology showed no treatment-related differences between groups, and no clinical signs were observed over the 14-day treatment period.

[0179] No abnormalities were recorded in the white blood cell counts and urinalysis between the experimental groups.

[0180] Body weight gain and food intake were similar in all groups, and no behavioral abnormalities were observed over the course of the rat treatment.

[0181] No abnormalities were noted at autopsy level and all organs and tissues of the various organs showed normal appearance, size, colour and position.

[0182] Thus, Sample 4 (a compound according to the invention) was well tolerated at all doses tested, with statistically significant lower blood glucose levels in the high dose rat group (with an inverse dose-effect relationship).

[0183] Surprisingly, in the present in vivo rat test, an effective and durable gastric mucosa protection was visually observed. The gastric mucosa is known to exert a barrier effect and consists of a mucosal layer of about 0.2 mm that covers the gastric mucosa. The purpose of this barrier is to protect the gastric epithelium from the damaging effects of HCI produced by the gastric parietal cells. This is derived from the production of high molecular weight (and therefore highly viscous) mucoprotein droplets and the production of bicarbonate by the gastric mucosal cells. Thus, the compositions of the present invention (see Table 2), such as Samples 2-6, have been found to be effectively applied / used in a method for treating (prophylactically and / or curatively) disorders or symptoms resulting from or associated with damage to the gastric mucosa, including or alternatively selected from the group consisting of peptic ulcer, gastroesophageal reflux (GERD), heartburn.

[0184] The in vivo toxicity test described above was repeated for 90 days. The results were comparable to those obtained for 14 days. In particular, it was surprisingly observed that the rats tested at a dose of 4500 mg / kg body weight (the highest dose that did not produce toxic effects) maintained and retained good thyroid function without any changes in feeding and social behavior. [Experimental Example 3]

[0185] In vitro efficacy testing - an in vitro evaluation of the anti-inflammatory activity of the products of the invention and comparative products on cell cultures was carried out.

[0186] 1. Test Plan The test described in Example 3 was aimed at evaluating the ability of the test product to modulate inflammatory mechanisms induced in human tendon cell cultures in an in vitro system (ZEN BIO TEN-F, Lot # TENM012214F). The test for anti-inflammatory activity was carried out through the assay and respective activity of several inflammatory markers, in particular the proinflammatory cytokine IL6, the main enzyme involved in the inflammatory cascade from arachidonic acid, as well as prostaglandin E2 (PGE2) and leukotriene C4 (LTC4), which are downstream products of cyclooxygenase and lipoxygenase, using ELISA methods.

[0187] 2. Test products For cream products Cn (compositions according to the invention, see C1-C6 in Table 2), the concentrations are 0.050%, 0.025% and 0.010%.

[0188] For Arnica 5.5% cream, the concentrations are 0.070%, 0.035%, and 0.014%.

[0189] For glucosamine 5.5% cream, the concentrations are 0.070%, 0.035%, and 0.014%.

[0190] The test products were all creams based on glycerin and / or glycerol monostearate.

[0191] The products according to the present invention (cream products Cn) tested in the in vitro anti-inflammatory activity evaluation test described above have the following compositions (C1 to C6) shown in Table 2. Products C1 to C6 according to the present invention all gave similar experimental results. Therefore, only the data for cream product C1, which represents products C2 to C6, is shown below.

[0192] [Table 2]

[0193] ( * ) A mixture of cetylated fatty acids in vegetable oils (olive oil, corn oil or sunflower oil) is cetylated, 30% to 55%, preferably 35% to 50%, more preferably about 41% of (a1) myristic acid; (a2) oleic acid, 35% to 60%, preferably 40% to 55%, more preferably about 46%; 3% to 12%, preferably 5% to 10%, more preferably about 8% (a3) ​​linoleic acid; 1% to 8%, preferably 2% to 6%, more preferably about 3% of (a4) palmitic acid; and, alternatively, consisting of 1% to 4%, preferably 1.5% to 3%, more preferably about 1.8% of (a5 to a9) various fatty acids (not myristoleic acid), where the % is in wt% based on the total weight of the mixture of cetylated fatty acids and the weight ratio (a):(c) is 4:1 or 3:1 or 2:1 or 1:1.

[0194] Prior to efficacy testing, samples were prepared in culture medium starting at a dilution ratio of 0.05 g in 1 ml of culture medium.

[0195] A preliminary cytotoxicity test was conducted on the product to select the optimal concentration for the final test. After evaluating the results of the cytotoxicity test, the above-mentioned concentrations were selected to conduct the anti-inflammatory activity test.

[0196] 3. Method In the study, human tendon cell cultures (ZEN BIO TEN-F, Lot # TENM012214F) were treated for 48 hours with Interleukin-1 beta (IL-1β, 10 ng / ml, dose selected after range finding studies) and drugs involved in the inflammatory symptoms of tendinopathy, together with the products tested at three concentrations selected from non-cytotoxic products after preliminary cytotoxicity studies. At the end of the monitored experimental period, the levels of inflammatory markers of interest in the culture medium were measured by ELISA. The results were compared with respect to negative control cultures (untreated, CTR-) and positive control cultures (treated with IL-1β, CTR+).

[0197] In summary, the experimental protocol is: Untreated cell cultures (negative control, CTR-), cell cultures in which inflammatory events were experimentally induced (positive control, CTR+), and Inflammatory events are experimentally induced and assayed for three pro-inflammatory markers (IL6, LTC4 and PGE2) in cell cultures treated simultaneously with the products under test.

[0198] 4. Assay of Inflammatory Markers (IL6, PGE2, and LTC4) Culture media of cells treated with control and tested products (paragraph 2) were used for the determination of the inflammatory markers IL6, PGE2 and LTC4 using the ELISA method.

[0199] For this purpose, a commercially available kit was used that relies on competitive binding between an antigen (in this case the cytokine of interest) and its primary antibody. The immune complex (antigen-antibody) was recognized by a secondary antibody conjugated to peroxidase. Addition of a peroxidase substrate resulted in a color reaction with an intensity proportional to the amount of immune complex present and therefore to the amount of cytokine bound. Quantitative analysis utilized a standard curve constructed with known and increasing concentrations of a standard cytokine.

[0200] 5.Results The following table and graphs show the results obtained in this study.

[0201] The results are presented as the amount of cytokines released into the medium over the experimental period (mean ± standard deviation) and the mean % variation compared to the control.

[0202] IL6 assay results Treatment of cell cultures with the test products (paragraph 2) showed a reduction in the levels of IL6 released by the cells after experimental induction of inflammation (tables 3-5 and figures 4A, 4B and 4C). The test samples more or less significantly modulate and inhibit the release of the pro-inflammatory cytokines monitored during inflammation. All graphs (figures 4A, 4B and 4C) show a more or less clear dose-dependent trend, with the highest tested concentrations of the assay being lower than IL6.

[0203] 5.I. Assay of IL6 in CTR- and CTR+ cell cultures and treated with cream product C1 according to the invention (Table 2). The results are expressed as mean content ± standard deviation (expressed in ng / l) and mean % variation compared to the control (Table 3 and Figure 4A).

[0204] [Table 3]

[0205] 5.II. Assay of IL6 in CTR-, CTR+ cell cultures and treated with Arnica cream 5.5% is described. The results are expressed as the mean content ± standard deviation (expressed in ng / l) and the mean % variation compared to the control (Table 4 and Figure 4B).

[0206] [Table 4]

[0207] 5.III. Assay of IL6 in CTR-, CTR+ cell cultures and treated with glucosamine cream 5.5% is described. The results are expressed as the mean content ± standard deviation (expressed in ng / l) and the mean % variation compared to the control (Table 5 and Figure 4C).

[0208] [Table 5]

[0209] LTC4 assay results Treatment of cell cultures with the test products (paragraph 2) showed a reduction in the levels of LTC4 released from the cells after experimental induction of inflammation (tables 6-8 and figures 5A, 5B and 5C). The test samples more or less significantly modulate and inhibit the release of the proinflammatory markers monitored during inflammation. All graphs (figures 5A, 5B and 5C) show a more or less clear dose-dependent trend, with the highest concentrations of the assay tested being lower than LTC4.

[0210] 5.IV. Assay of LTC4 in CTR-, CTR+ cell cultures and treated with cream product C1 according to the invention (Table 2). The results are expressed as mean content ± standard deviation (expressed in ng / l) and mean % variation compared to the control (Table 6 and Figure 5A).

[0211] [Table 6]

[0212] 5.V. Assay of LTC4 in CTR-, CTR+ cell cultures and treated with Arnica cream 5.5% is described. The results are expressed as mean content ± standard deviation (expressed in ng / l) and mean % variation compared to the control (Table 7 and Figure 5B).

[0213] [Table 7]

[0214] 5.VI. Assay of LTC4 in CTR-, CTR+ cell cultures and treated with glucosamine cream 5.5% is described. The results are expressed as mean content ± standard deviation (expressed in ng / l) and mean % variation compared to the control (Table 8 and Figure 5C).

[0215] [Table 8]

[0216] PGE2 assay results Treatment of cell cultures with the test products (paragraph 2) showed a reduction in the levels of PGE2 released from the cells after experimental induction of inflammation (tables 9-11 and figures 6A, 6B and 6C). The test products more or less significantly modulate and inhibit the release of the proinflammatory markers monitored during inflammation. All graphs (figures 6A, 6B and 6C) show a more or less clear dose-dependent trend, with the highest concentrations of the assay tested being lower than PGE2.

[0217] 5.VII. Assay of PGE2 in CTR-, CTR+ cell cultures and treated with cream product C1 according to the invention (Table 2). The results are expressed as mean content ± standard deviation (expressed in ng / l) and mean % variation compared to the control (Table 9 and Figure 6A).

[0218] [Table 9]

[0219] 5.VIII. Assay of PGE2 in CTR-, CTR+ cell cultures and treated with Arnica cream 5.5% is described. The results are expressed as the mean content ± standard deviation (expressed in ng / l) and the mean % variation compared to the control (Table 10 and Figure 6B).

[0220] [Table 10]

[0221] 5.IX. Assay of PGE2 in CTR-, CTR+ cell cultures and treated with glucosamine cream 5.5% is described. The results are expressed as the mean content ± standard deviation (expressed in ng / l) and the mean % variation compared to the control (Table 11 and Figure 6C).

[0222] [Table 11]

[0223] 6. Conclusion Considering the results obtained and presented in this report and referring to the applied experimental model, all the tested products were able to modulate the inflammatory mechanisms induced in the cell cultures, thereby reducing the levels of the monitored proinflammatory markers, thus demonstrating anti-inflammatory activity. In particular, it was demonstrated that cream product C1 and cream products C2 to C6 according to the invention are able to reduce the levels of IL-6, PGE2 and LTC4, thus modulating the different amplification mechanisms of the inflammatory cascade. [Explanation of symbols]

[0224] 2,27 Reactor 3. Chamber 7. Air Blowing Means 11 Horizontal condenser 13 Container 15 Reaction mixture 16 Vertical Condenser 23 Filter Press

Claims

1. A composition comprising (I) and optionally (II), wherein (I) is (a) at least one cetylated fatty acid having 6 to 21 carbon atoms and being a saturated or unsaturated fatty acid, (b) at least one antioxidant having a weight percentage of 0.001 wt% to 0.3 wt% based on the total weight of the composition, (c) a vegetable oil, and is a mixture, and (II) is at least one food or pharmaceutical grade additive and / or excipient, said (a) is a mixture of cetylated fatty acids containing cetylated myristic acid and cetylated oleic acid, and the molar ratio of said cetylated myristic acid to cetylated oleic acid is 4:1 to 1:1, said (b) at least one antioxidant is selected from t-butylhydroquinone (TBHQ), a mixture (AperoxidRTLA) containing tocopherol, lecithin, ascorbyl palmitate and citric acid, a mixture of tocopherol or tocopherols, natural rosemary extract, butylated hydroxytoluene, and mixtures thereof, the composition.

2. The composition according to claim 1, wherein the mixture of cetylated fatty acids further comprises cetylated linoleic acid and cetylated palmitic acid.

3. The composition according to any one of claims 1 or 2, wherein said (b) at least one antioxidant is present in a weight percentage in the range of 0.001 wt% to 0.1 wt% based on the total weight of the composition.

4. Said (a) at least one cetylated fatty acid, having a weight percentage in the range of 50 wt% to 90 wt% based on the total weight of the composition, Said (b) antioxidant, having a weight percentage in the range of 0.001 wt% to 0.3 wt% based on the total weight of the composition, Said (c) vegetable oil, having a weight percentage in the range of 9.5 wt% to 50 wt% based on the total weight of the composition, the composition according to any one of claims 1 to 3.

5. The composition according to any one of claims 1 to 4, for use as a medicament.

6. A composition for use according to claim 5, which is used for prophylactically and / or curatively and / or symptomatically treating (i) inflammatory and non-inflammatory rheumatoid arthritis, particularly osteoarthritis of the knee, (ii) inflammatory symptoms of joints other than rheumatoid arthritis, (iii) psoriasis, lupus, periodontal disease or cardiovascular disease or heart disease, (iv) post-traumatic osteoarticular and musculoskeletal diseases including sports-related trauma and athletic pubalgia, (v) degenerative joint diseases, and / or (vi) tendon and muscle-related inflammatory / traumatic symptoms by administering to a subject in need thereof.

7. A composition according to any one of claims 1 to 6, formulated for oral use.

8. A composition according to any one of claims 1 to 6, formulated for topical or transdermal use.

9. A composition according to any one of claims 1 to 7, which is a novel food or beverage or dietary supplement, or a food or beverage or dietary supplement.

10. A composition according to any one of claims 1 to 8, which is a pharmaceutical composition or a composition for medical devices.

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