ES2374482B1 - COMPOSITION FOR REDUCTION OF SYMPTOMS ASSOCIATED WITH MENOPAUSE. - Google Patents

Abstract

Composition for the reduction of symptoms associated with menopause. # The present invention is directed to a composition comprising rosemary and vitamin E, for the purpose of providing improved nutritional supplements, as well as the use of said composition for the reduction of inflammatory processes and lipid peroxidation, associated with the typical menopause disorders.

Description

Composition for the reduction of symptoms associated with menopause.

Field of the Invention

The present invention is directed to new compositions, with the purpose of providing improved nutritional supplements, as well as the use of said composition for the reduction of inflammatory processes and lipid peroxidation associated with menopause.

Background of the invention

Menopause corresponds to the transition from the reproductive state to the non-reproductive state in a woman's life and is characterized by the interruption of menstruation. However, menopause has come to mean much more than simply the loss of reproductive capacity, since it is associated with a large number of acute and chronic conditions. Menopausal syndrome consists of a variety of symptoms that are the result of hormonal imbalance and nutritional deficiency in women, such as sweating and vasomotor instability that affects approximately 75% of women. Psychological and emotional symptoms of fatigue, insomnia, irritability and nervousness are also common. Other common symptoms include nausea, constipation, diarrhea and myalgia (The Merck Manual, 1793. 16th Ed. 1992). The hormonal changes that occur during menopause cause various clinical manifestations that affect the health and well-being of women. In addition to those mentioned above, there are alterations of the genito-urinary system, osteoporosis and cardiovascular manifestations that increase the risk of suffering a cerebrovascular accident or myocardial infarction. Even being of varying intensity, it is convenient to treat these clinical manifestations, especially those that can evolve into chronic serious diseases or significantly affect the quality of life of women.

The treatment of menopause-associated disorders is carried out by hormone replacement therapies based on estrogen administration. However, these treatments are not without risks and contraindications, which include risk of certain cancers, such as breast cancer, as well as endometrial cancer. In recent years, the use of phytoestrogens that offer positive benefits with fewer risks and contraindications has generated much interest. Among the different kinds of phytoestrogens, the iso fl avonas of soy and red clover are the ones that provide the best results, according to the studies carried out so far (Lan Yeb et al., Molecular and Cellular Endocrinology (2009) 302: 73-80 ; Chanteranne, B. et al., Clin Interv Aging (2008) 3: 711-718).

Iso fl avonas are substances of plant origin that can act as estrogens. They are found mainly in soybeans and their therapeutic capacity is greater than that of other phytoestrogenic substances such as lignans. However, the effects of iso fl avonas are less than those of estrogen hormones. Iso-fluvones and phytoestrogens exert a stabilizing effect when the level of estrogen is low, for example during menopause. Iso-fluvones can also reduce the effect of estrogen on skin cells and layers when hormone levels are high, and then, essentially, reduce the risk of estrogen-linked cancers. The double activity of the iso fl avonas, acting as estrogenic and antiestrogenic, confers on the iso fl avonas a series of qualities that allow regulating the hormonal balance in women, preventing osteoporosis and acting as potent antioxidants that protect against the development of breast cancer. In the nutritional aspect, it has been observed that the mentioned diseases are infrequent in the countries where soy is consumed. The use of iso fl avones to treat menopause-associated disorders requires their combination with vitamins and minerals to enhance their effect.

There are a large number of publications on products to improve menopausal disorders based on the use of iso-fluvones, such as WO 2000/007566, WO 1993/023069, WO 1989/005655.

According to numerous studies, high diets in β-Carotene, a precursor to vitamin A, decrease the incidence of respiratory and digestive cancer, although they indicate the need for more clinical studies. (Harrison. Internal Medicine 16th Edition, 2005: 408).

The absorption and synthesis of vitamin D3 (cholecalciferol) by the skin decrease with age (Harrison. Internal Medicine 16th Ed 2005: 2247). Therefore, the diet with this vitamin is supplemented, for the prevention of possible diseases, and at higher doses for the treatment of osteoporosis. Other benefits for weakness / muscle pain (Level of evidence B), breast cancer prevention (level C), diabetes (C), hypertension (C), depression (C) have been described. It is prescribed almost systematically to all menopausal women worldwide (400 IU / day = 5 mg) together with Calcium (800-1200 mg / day). The 800 IU dose is considered necessary for an effective prevention of your deficiency (Harrison, ad supra). The most effective way to ensure adequate levels of vitamin D3 is to ingest a daily multivitamin (Inst Nal Health, USA Sept 2005).

Vitamin B9, also called folic acid, decreases hyperhomocysteinemia (one of the main cardiovascular risk factors). Although this protection is discussed, a recent study provides acceptable evidence of this (Yang. Circulation, March 2006; 113 (10): 1335-43). Another study suggests that it can improve endothelial function and lipid profile (Paradisi et al. Human reprod 2004; 19: 1031). Other trials showed that vitamin B9 conferred protection against stroke (He et al. Stroke 2004; 35: 169). Its deficiency affects megaloblastic anemia and psychomotor disorders, so it is advisable to maintain a good level of vitamin B9 throughout the woman's life.

The vitamin complex B1, B6 and B12 is involved in numerous neurotropic, blood, organic functions, etc. The isolated properties of each of these vitamins are analyzed apart from the properties attributed to all three. Along with folates, vitamin B12 is attributed some protection against depression (Tolmunen et al, Psichother Psichosom 2004; 73: 334).

Vitamin B1 or Thiamine is a water-soluble vitamin, whose phosphate derivatives are involved in many cellular processes. No adverse reactions have been described by supplementation nor with the therapeutic doses that are much higher (up to 300 mg / day) (Martindale 34th ed 2005).

Vitamin B6 or Pyridoxine is a water-soluble vitamin, whose severe deficiency is rare and is manifested by neuropathies. Its mild deficiency produces alterations in the epithelia, hyperhomocysteinemia (with increased cardiovascular risk), microcytic anemia, depression etc. There are no adverse reactions from supplementing said vitamin (Favier et al. J Ginecol Obstet Bio Repro 1997; 26: 102), although it should be borne in mind that the maximum tolerated dose is 100 mg / day (Martindale 34th Ed 2005).

Vitamin B2 or Ribo fl avina is important for the metabolism of fats, carbohydrates and proteins. Its deficit is clinically similar to the vitamins of group B: mouth and skin ulcers, corneal vascularization, anemia and neurological and psychic disorders.

Vitamin B3 or Nicotinamide is a water-soluble vitamin, whose severe deficiency (known as pellagra) is quite rare. Its mild deficiency is similar to that of other vitamins of group B and can be seen as cutaneous and mucous alterations (mouth ulcers, etc). With the administration of nicotinamide, the adverse effects of nicotinic acid are not observed.

Vitamin B5 or pantothenic acid is a water-soluble vitamin required for life, that is, it is an essential nutrient, since it is critical for the metabolism and synthesis of carbohydrates, proteins and fats. Its deficit (which is exceptional), could lead to laxity, headaches, nausea etc.

Vitamin B7 or biotin is necessary for cell growth, the production of fatty acids and the metabolism of fats and amino acids. It is normally recommended to strengthen nails and hair. His deficiency (which is very rare), includes dermatitis, seborrhea, muscle pain and alopecia. It is not known that there is toxicity or overdose of said vitamin.

In recent years, scientific advances have shown the healthy properties of omega-3 polyunsaturated fatty acids. Some of the effects of these fatty acids, specifically docosahexanoic acid (DHA), are the improvement of menopause-associated disorders (Fernandes, et al. Front Biosci 2008, 1; 13. 4015). It also acts on the cardiovascular system because it regulates the levels of triglycerides and VLDL (very low density lipoproteins) in the plasma, because it inhibits the hepatic synthesis of triglycerides and VLDL. On the other hand, it also increases HDL levels, increases arterial vasodilation, reduces moderate arterial hypertension, decreases the risk of thrombosis and prevents arrhythmia (Stark et al. Am J Clin Nutr. 2000, 72. 389). In addition, DHA is essential for optimal nerve communication. Some epidemiological studies have shown a relationship between depression and DHA, in the sense that this fatty acid helps reduce depression (Fernandes G et al., Prostaglandins, Leukotrienes and Essential Fatty Acids (2003) 68: 361-372; Simopoulos AP et al. Am Nutr Metab 1999, 43: 127-130). Therefore, DHA has been used for the preparation of some compositions for the treatment of menopause, such as in WO 2004/004638, which describes a composition for the improvement of certain inflammatory symptoms related to menopause, among other disorders . Said composition comprises a tocopherol and an omega-3 polyunsaturated fatty acid (such as DHA) or omega-9.

The Rosmarinus of fi cinalis or rosemary is a species of the genus Rosmarinus whose natural habitat is the Mediterranean region, southern Europe, northern Africa and also Asia Minor. In Spain it is located in most of Catalonia, up to the Pyrenees in Aragon and Navarra, Castilla-La Mancha, Castilla y León, La Rioja, Madrid, Murcia, Extremadura, in the mountainous areas of the Valencian Community, Andalusia and the Balearic Islands . It is very rare in points north or northwest of the peninsula. The rosemary is a woody shrub with evergreen leaves, it can reach 2 meters in height. We find it green all year round, with blurred young stems and old reddish stalks and with cracked bark. The leaves, small and very abundant, have a linear shape. They are opposite, sessile, whole, with the edges down and a dark green color, while on the other hand they have a whitish color and are covered with hairiness. In the zone of union of the leaf with the stem the fl oriferous corsages are born.

The antioxidant properties of spices have been known since the early 1950s (Chipault J.R. et al. 1952; Food Res. 17, 46). In 1955 it was discovered that rosemary was one of those with the greatest activity (Rae M. et al. 1955; Rev. Fr. Corps Gras 2, 796). The compounds responsible for it are well determined, for example, in 1966 carnosol was isolated (Briescorn CH et al. 1966; J. Org. Chem. 29, 2293) and the antioxidant properties of the plant were attributed to this phenolic diterpene . Its structure and that of carnosic acid were con fi rmed in 1982 (Wu JW et al. 1982; JAOCS 59, 339) and in that same year other components of rosemary were identified, such as rosmanol and rosmarinic acid (Inatani R. et al. 1982; Agric. Biol. Chem. 46, 1666). Then the rosmadial (Inatani R. et al., 1983, Agric. Biol. Chem. 47, 521), epirosmanol and isorosmanol (Nakatani N. et al. 1984; Agric. Biol. Chem. 48, 2081) rosmaridiphenol and rosmariquinone (Houlihan CM et al. 1985; JAOCS 62, 1985). In addition to the above compounds, it is known that rosemary leaves also contain fl avonoids with antioxidant activity (Okamura N. et al. 1994; Phytochem. 37, 1463). In general terms, at the individual level, the highest antioxidant activity corresponds to carnosic acid, followed by carnosol, rosmarinic acid, rosmanol and rosmadial (Cuvelier M.E. et al. 1996; JAOCS 73, 645). Carnosol is the component that has generally been detected as a majority, reaching many times 90% of the extracts. Actually, along with other phenolic compounds found in rosemary, the oxidation of carnosic acid during extraction operations.

The phenolic diterpenes of rosemary act as primary antioxidants (Basaga H. et al. 1997, Lebensm. Wiss. Technol. 30: 105; Frankel E.N. et al. 1996; J. Agric. Food Chem. 44, 131). In addition, these products have been shown to have an activity similar to superoxide dismutase (Seok J.K. et al. 1995, Biosci. Biotechnol. Biochem.

59: 822) and synergistic effects with the enzymes glutathione reductase and NADPH-quinone reductase, regenerating them and increasing the free radical blocking effect they exert. These synergies with the aforementioned enzymes are attributed to the protective effects against carcinogens in the lung, liver and stomach, which have been shown in mice in recent years (Singletary KW et al. 1997, Plant Foods for Human Nutrition 50: 47 ). The mechanism of action of antioxidants against peroxidation of lipoproteins in blood is also known, which is key in the development of atherosclerosis (Pinchuk I. et al. 2002, Progress in Lipid Research 41: 279).

The phytochemicals contained in the antioxidant extract of rosemary have important biological activities. The supercritical rosemary extract is an extract enriched in different diterpenic polyphenols, such as carnosic acid, carnosol, romarinic acid that is obtained from the Rosmarinus Of fi cinalis plant. There are scientific articles that refer to the anti-inflammatory and antioxidant properties of the plant and its extracts (Jindal A et al. 2006, J Environ Pathol Toxicol Oncol; 25 (4): 633-642; Soyal D et al. Phytomedicine 2007; 14 (10): 701-705; Peng CH et al. Biosc Biotechnol Biochem 2007; 71 (9): 2223-2232).

Fluid extraction under supercritical conditions is an advantageous alternative to solvent extraction to obtain antioxidants from natural sources. Supercritical fluids behave like a liquid in the extraction process and therefore facilitates the dissolution of solutes, at the same time, their behavior as a gas allows easy separation of the matrix. This entails a faster, more efficient and selective extraction process than in the case of liquid-liquid extraction. In addition, "green solvents" such as CO2 can be used avoiding the use of the usual chlorinated solvents of liquid-liquid extractions. The extraction under mild and non-oxidizing conditions allows to obtain high quality products with their natural properties intact and free of solvent residues. The case of oleoresins, which generally can be divided into the same supercritical extraction process, results in products with different functionalities. Numerous applications have been found to extract lipped plants (rosemary, thyme, oregano, sage, etc.) (Nguyen U. et al. 1994, Supercritical Fluid Processing of Foods and Biomaterials, Ed. SSH Rizvi. Chapman & Hall, London p.103). In these cases, by extracting with supercritical fluids (SFE), an oleoresin easily obtained in two products is obtained: an essential oil, usually with aromatic and antimicrobial functionalities, and an antioxidant. At present it is well known that the natural antioxidants obtained by SFE have a higher activity than those extracted with solvents. Djarmati et al. (Djarmati Z. et al., 1991, JAOCS 68, 731) demonstrated that sage antioxidant extracts obtained by extraction with supercritical CO2 were more effective than Butyl Hydroxytoluene (BHT). More recently it has been confirmed that the same applies to black pepper extracts (Tipsrisukond N. et al. 1998, J. Agric. Food Chem. 46: 4329).

Vitamin E in its natural state has eight different forms of isomers, of which four are tocopherols (alpha α, beta β, gamma γ and delta δ forms) and the corresponding tocotrienols. All isomers have aromatic rings with a hydroxyl group which can donate a hydrogen atom to reduce free radicals of the materials that make up the water-repellent biological membranes of cell walls. Each of the forms has its own biological activity. Vitamin E or tocopherol alfa is a fat-soluble vitamin that acts as an antioxidant at the level of heme pigment synthesis, an essential part of red blood cell hemoglobin. It is found in many foods, mainly of plant origin, especially those with green leaves (broccoli, spinach), seeds, including soybeans, wheat germ and brewer's yeast; It can also be found in animal foods such as egg yolk. The health benefits of vitamin E are many, for example in the circulatory system, it has antioxidant properties, eye properties and acts to prevent Parkinson's disease.

There are many articles in reference to vitamin E as an antioxidant and anti-inflammatory. Studies in humans demonstrate the action of vitamin E as an important immunomodulator, enhancing the immune system (peripheral mononuclear cells) in healthy elderly individuals (Meydani, SN et al. 1990, Am. J. Clin. Nutr. 52 (3), 557-563). Because aging is associated with an increase in oxidative stress and a loss of immune function, in the elderly population there is an increase in infections, autoimmune disorders and degenerative diseases associated with chronic inflammation such as atherosclerosis, cancer or neurodegenerative diseases such as Alzheimer's disease (Fulop, T. et al. 2006. Aging Dev. 127 (6), 526-537). Studies in the elderly indicate that the effects of vitamin E for long periods of time have fewer respiratory tract infections than those that were not treated with vitamin E (Graat, JM et al. 2002. Jama 288 (6), 715-721) Certain effects on the symptoms caused by allergic rhinitis have also been described, reducing the inflammatory effects on the upper respiratory tract (Shahar, E. et al. 2004, Ann. Allergy Asthma Immunol. 92 (6), 654-658).

The prevention of cardiovascular diseases has been one of the main areas of study of vitamin E, although the attribution of the cause of these diseases is a consequence of the oxidation of circulating lipoproteins and their interaction with vascular function and inflammation. There are numerous in vitro studies where vitamin E is able to reverse the oxidation of lipoproteins (Libby, P., 2002. Nature 420 (6917), 868-874).

There is multiple scientific evidence of the involvement of oxidation and inflammation processes in the origin of cardiovascular diseases associated with menopause. Therefore, it is important to enhance the anti-inflammatory and antioxidant effects of the compositions to be used in menopause. There are a large number of patents and research articles dealing with antioxidant and anti-inflammatory products, such as the review by Reiter et al. (Reiter et al. Mol. Aspects Med. 2007; 28: 668-91), which describes the anti-inflammatory properties of tocopherols or vitamin E. There are, for example, compositions directed at the specific inhibition of COX-2 and 5 -LOX (WO 2008/120220), but nevertheless, said composition does not include compounds extracted from rosemary or vitamin E. Other existing compositions are shown in WO 2004/004638, wherein a composition comprising a tocopherol and an acid is described. Polyunsaturated fatty omega-3 (such as DHA) or omega-9 for the improvement of certain inflammatory symptoms related to menopause, among other disorders.

The greatest challenge of preventive and therapeutic treatments based on the administration of drugs is to achieve a high efficiency in the intervention on the molecular mechanisms to which they are directed, with the greatest possible safety and comfort for the patient. In this sense, the use of products from natural sources with a long tradition of use, such as rosemary and vitamin E, are generally recognized as safe and their acceptance is greater by consumers. Therefore, they constitute a particularly favorable alternative to synthetic drugs. Natural products are always extracts or fractions of raw materials of plant or animal origin. When these extracts or fractions are obtained through clean physical technologies, the safety and acceptability is even greater.

Therefore, although there are several compositions described for the reduction of inflammatory processes and lipid peroxidation, associated with menopause, there is still a need for improved compositions for the effective reduction of said disorders, in which the effect is greater than those described.

Compendium of the invention

In a first aspect, the present invention relates to an oral composition comprising vitamin E and Rosmarinus of fi cinalis, with the proviso that said composition is not a pharmaceutical composition.

In another aspect, the invention relates to a nutritional supplement comprising a composition that includes vitamin E and Rosmarinus of fi cinalis and a food grade vehicle.

In another aspect, the invention relates to a composition comprising vitamin E and Rosmarinus of fi cinalis for use in disorders that occur with an increase in inflammatory processes or disorders that result in an increase in lipid peroxidation.

In a final aspect, the invention relates to the use of a composition comprising vitamin E and Rosmarinus of fi cinalis in the preparation of a medicament for disorders that occur with an increase in inflammatory processes or disorders that lead to an increase in lipid peroxidation.

Detailed description of the invention

The authors of the present invention have observed that, surprisingly, a new composition comprising Rosmarinus of fi cinalis and vitamin E can be used for the reduction of inflammatory processes or for the reduction of lipid peroxidation. Specifically, said composition has an unexpected synergistic effect with respect to both ingredients administered separately, as shown in Examples 1 and 2.

Therefore, in a first aspect, the invention relates to an oral composition, hereinafter a composition of the invention, comprising vitamin E and Rosmarinus of fi cinalis, with the proviso that said composition is not a pharmaceutical composition.

As used in the present invention, the terms "Rosmarinus of fi cinalis" and "rosemary" are interchangeable. Said composition comprises an extract of rosemary obtained from the in fl orescences and upper parts, such as the leaves of the bush. Rosemary extract can be obtained by conventional conventional methods known to those skilled in the art. Among the different methods of rosemary extraction, solvent extraction, pressing extraction and extraction with supercritical fluids are used. In the case of solvent extraction, the material must previously be ground, macerated or chopped, to allow greater contact area between the solid and the solvent. To achieve better efficiency in the operation, it is convenient to carry out the process in continuous motion. It is preferably performed at ambient temperature and pressure. The process can be executed in batch (batch) or continuously (such as percolation, leaching and soxhlet extraction). The most commonly used solvents are ethanol, methanol, isopropanol, hexane, cyclohexane, toluene, xylene, ligroin, ethyl ether, isopropyl ether, ethyl acetate, acetone, chloroform, etc. The next step is to separate the solvent from the extract by evaporation, distillation under vacuum, molecular distillation or by extraction by supercritical fluids. The resulting extract, green and highly viscous, is usually subjected to concentration by molecular distillation. A second method is the extraction by pressing, where the plant material is subjected to pressure, either in batch type presses or in continuous form, within these the following high or low-pressure worm equipment, extractor can be used expeller, centrifugal extractor, decanter extractor and press rollers. As for the extraction under supercritical conditions, the critical point corresponds to the conditions of temperature and pressure, for a gas or a vapor, above which the substance can no longer be "liquefied" by pressure increase. Additionally, the properties of the liquid and / or vapor phase are the same, that is, there is no visible or measurable differentiation between gas and liquid. The substance most used for extraction under supercritical conditions is carbon dioxide (CO2), which under these conditions has low viscosity, low surface tension, high diffusion coefficient (10 times more than a normal liquid), which leads to a high contact with the surface of the material and can penetrate small pores and slits of the material, which ensures good extraction efficiency in a short time. In the final part of the process there is a total removal of the solvent and it is carried out at a low temperature, the loss of volatile substances is reduced and the formation of strange flavors and odors is avoided. The critical temperature and pressure for CO2 are 73 bar pressure and 31ºC temperature. It is possible to work with high CO2 (P 150 bar; T 50ºC) or low density (P 90 bar; T 30ºC). In a preferred embodiment, the extraction of rosemary is carried out by extraction under supercritical conditions using CO2.

Plant extracts obtained by supercritical fluids maintain a more or less constant composition. Despite this, due to the plant variability, the chemical composition of the extracts may vary. Some of the major compounds that are always present in the extracts obtained from Rosmarinus of fi cinalis are, for example, but not limited to, rosmanol, carnosol, carnosic acid, rosmarinic acid, methyl carnosate, fl avonoids such as genkwanin, escutellarein and other compounds such as Verbenone, camphor, borneol and 1,8-cineole. On the other hand, within the plant extracts not all the compounds present have the same activity. In rosemary extracts, the antioxidant compounds that have shown the greatest potential are carnosic acid, carnosol and rosmarinic acid. Therefore, in a preferred embodiment of the composition of the invention, rosemary extract contains at least carnosic acid, carnosol and rosmarinic acid.

Vitamin E, as used herein, can be any of the existing isoforms of said vitamin E, ie the four forms of tocopherols (alpha α, beta β, gamma γ and delta δ forms) and the corresponding tocotrienols . It can also refer to a liposoluble (tocopheryl acetate), water-soluble (tocopheryl phosphate) form. Other possible synthetically derived vitamin E derivatives are also included, such as α-tocopherol acetate and di-α-tocopherol and mixed tocopherols obtained by distillation of vegetable fatty fruits or tocotrienols. Vitamin E is commonly obtained from commercial suppliers, such as Calbiochem®, Sigma-Aldrich®, etc.

The oral composition of the invention is not a pharmaceutical composition. As used in the present invention, a pharmaceutical composition comprises a pharmaceutically effective amount of the ingredients of the composition and at least one pharmaceutically acceptable excipient.

The term "vehicle" refers to a diluent, adjuvant, excipient or vehicle with which the active substance is administered. Such carriers or vehicles may be sterile liquids, such as water and oils, including those derived from petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Preferably, water or saline solutions of aqueous solution and aqueous solutions of dextrose and glycerol are used as carriers, particularly for injectable solutions, also buffers, isotonic agents or agents that can increase solubility. The composition of the invention may additionally comprise a vehicle suitable for oral administration.

The composition of the invention may also comprise vitamin Rosmarinus of fi cinalis vitamin E, docosahexanoic acid or DHA. Additionally, it can comprise an ingredient selected from iso-fluvones, a vitamin and a trace element, wherein the vitamin can be selected from the group of vitamin A, vitamin D3, vitamin B9, vitamin B6, vitamin B12, vitamin C, vitamin B1, vitamin B2, Vitamin B3, Vitamin B5, Vitamin B7 and Vitamin K and the trace element can be selected from the group of calcium, iron, zinc, magnesium, phosphorus, copper, iodine and selenium. In a preferred embodiment, the iso-fluvones are daidzein, glycitein or genistein. The following Table 1 shows the preferred amounts of each of said ingredients:

As used in this description, the term "vitamin" refers to organic compounds required by an organism as nutrients in small amounts, that is, they cannot be synthesized in sufficient amounts by an organism and must be obtained in the diet. Examples of vitamins include, without limitation, thiamine (B1), ribo fl avina (B2), nicotinic acid (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folic acid (B9), vitamin B (B1 , B2, B3, B5, B6, B7, B9 and B12), lipoic acid, ascorbic acid (vitamin C), vitamin A, vitamin D (D1 to D5), vitamin E and vitamin K. The term vitamin also includes choline, carnitine, and alpha, beta and gamma-carotenes.

The term "trace element" refers herein to chemical elements required by organisms in small amounts, other than carbon, hydrogen, nitrogen and oxygen and obtained by diet. Examples of trace elements include, without limitation, calcium, iron, zinc, magnesium, phosphorus, copper, iodine, selenium, chromium, potassium, chlorine, similar chemical elements, and mixtures thereof.

In a preferred embodiment, the composition of the invention is presented in the form of gelatin capsules.

For the purposes of the present invention, "suitable vehicle for oral administration" means any product that can be used for oral administration that can be used to accompany the extract of Rosmarinus of fi cinalis and vitamin E, so as to lead to Perform its function in a safe and effective way.

The composition of the invention can be administered orally. Solid dosage forms for oral administration may include conventional capsules, sustained-release capsules, conventional tablets, sustained-release tablets, chewable tablets, sublingual tablets, effervescent tablets, pills, suspensions, powders, granules and gels. In such solid dosage forms, the active compounds may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets, effervescent tablets and pills, the dosage forms may also comprise buffering agents. Soft gelatin capsules can be prepared to contain a mixture of the active compounds or compositions of the invention and vegetable oil. Hard gelatin capsules may contain granules of the active compound in combination with a solid, powdery carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives and gelatin. Tablets and pills can be prepared with enteric coatings. A review of the various forms of administration of active ingredients, of the excipients to be used and their manufacturing procedures can be found in the Treaty of Farmacia Galenica, C. Faulí i Trillo, Luzán 5, S.A. de Ediciones, 1993. In a preferred embodiment, the administration form are gelatin capsules, preferably soft gelatin, which comprise, in addition to the composition of the invention, water, gelatin, glycerin and vegetable oil. In a preferred embodiment, the vegetable oil is virgin olive oil.

The components of the composition of the invention are present in an amount effective to achieve the desired effect, that is, to reduce the inflammatory processes and / or reduce lipid peroxidation. In a preferred embodiment, rosemary extract accounts for between 10% and 90% and vitamin E between 10% and 90% of the total composition of the invention. In another preferred embodiment, the weight ratio between rosemary and vitamin E is preferably 1: 5 to 5: 1. Even more preferably, said ratio of Rosmarinus of fi cinalis extract and vitamin E is 1: 2 to 2: 1.

In general, the effective amount of the composition of the invention to be administered will depend, among other factors, on the individual to be treated, on the severity of the disorder suffered by said individual, etc. For this reason, the doses mentioned in this invention should be considered only as guidelines for the person skilled in the art, and he must adjust the doses according to the variables mentioned above. In a preferred embodiment, said recommended dose is 1-3 soft gelatin capsules daily.

Finally, the composition of the invention can be part of an enriched food product. Examples of these compositions may be, among others, a dairy product or derivative thereof such as a milkshake, cheese, milk, including flavored and fermented milk, a yogurt, etc .; a juice, a floury product or derivative thereof such as a cake, a bread, a cookie; an oil, a candy, such as chewing gum, candy, etc., products based on fermented cereals, liquid suspensions, dry oral supplements, non-dry oral supplements, etc.

In a second aspect the invention relates to a nutritional supplement, hereinafter nutritional supplement of the invention, comprising a composition that includes vitamin E and Rosmarinus of fi cinalis and a food grade vehicle.

For the purposes of the present invention, "nutritional supplement" means any dietary intake that is consumed orally and that contains one or more nutrients intended to supplement the diet or to remedy a deficiency. These nutrients are often absent from the diet or are present at low concentrations. Generally nutritional supplements are distributed in the form of different presentations, such as tablets, capsules, soft capsules, liquids (syrups or drinks) and powders. Said nutritional supplement may contain conventional excipients, such as binders, diluents, disintegrants, lubricants, humectants, etc., and may be prepared by conventional methods. Examples of nutritional supplements can be, among others, liquid suspensions, dry oral supplements, non-dry oral supplements, etc.

For the purposes of the present invention, "food grade vehicle" means any product that can be used in human or animal feed. The choice of the appropriate vehicle for oral administration for each case is made by a person skilled in the art from conventional vehicles existing in the state of the art.

The components of the nutritional supplement of the invention are present in an effective amount so that the desired effect is achieved. In a particular embodiment, said effect is the reduction of inflammatory processes and / or the reduction of lipid peroxidation. In a preferred embodiment, the extract of Rosmarinus of fi cinalis accounts for between 10% and 90% and vitamin E between 10% and 90% of the total composition. In a particular embodiment, the weight ratio between Rosmarinus of fi cinalis and vitamin E is 1: 5 to 5: 1. Even more preferably, said ratio is from 1: 2 to 2: 1.

The nutritional supplement of the invention may also comprise vitamin Rosmarinus of fi cinalis vitamin E, docosahexanoic acid or DHA. Additionally, it can comprise an ingredient selected from iso-fluvones, a vitamin and a trace element, wherein the vitamin is selected from the group of vitamin A, vitamin D3, vitamin B9, vitamin B6, vitamin B12, vitamin C, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B7 and vitamin Kyeloligoelement is selected from the group of calcium, iron, zinc, magnesium, phosphorus, copper, iodine and selenium. Preferred amounts of each of the components of the nutritional supplement of the invention are found in Table 1, as well as the details of the components.

The nutritional supplement of the invention can be administered orally. Solid dosage forms for oral administration may include conventional capsules, sustained-release capsules, conventional tablets, sustained-release tablets, chewable tablets, sublingual tablets, effervescent tablets, pills, suspensions, powders, granules and gels. In such solid dosage forms, the active compounds may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets, effervescent tablets and pills, the dosage forms may also comprise buffering agents. Soft gelatin capsules can be prepared to contain a mixture of the active compounds or compositions of the invention and vegetable oil. Hard gelatin capsules may contain granules of the active compound in combination with a solid, powdery carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives and gelatin. Tablets and pills can be prepared with enteric coatings. A review of the various forms of administration of active ingredients, of the excipients to be used and their manufacturing procedures can be found in the Treaty of Farmacia Galenica, C. Faulí i Trillo, Luzán 5, S.A. de Ediciones, 1993. In a preferred embodiment, the administration form are gelatin capsules, preferably soft gelatin, which comprise, in addition to the composition of the invention, water, gelatin, glycerin and vegetable oil. In a preferred embodiment, the vegetable oil is virgin olive oil. Said capsules contain between 25 and 3000 mg of the composition that includes Vitamin Eyextract of Rosmarinus of fi cinalis, additionally comprising, among other ingredients, water, gelatin, glycerin and vegetable oil. In a particular embodiment, the total amount of Rosmarinus of fi cinalis extract employed is between 100-500 mg, while the total amount of vitamin E is between 5-15 mg.

The composition of the invention can be used for the treatment of disorders that occur with an increase in inflammatory processes and / or with an increase in lipid peroxidation. Thus, in one aspect the invention relates to the composition of the invention, which comprises rosemary and vitamin E for use in disorders that occur with an increase in inflammatory processes or disorders that occur with an increase in lipid peroxidation.

In another aspect, the invention relates to the use of the composition of the invention, which comprises rosemary and vitamin E in the preparation of a medicament for disorders that occur with an increase in inflammatory processes and / or disorders that occur with an increase in the lipid peroxidation.

The term "inflammatory process", as used in the present invention, refers to a nonspecific response to environmental aggressions, and is generated by inflammatory agents. The inflammatory response occurs only in vascularized connective tissues and arises with the defensive purpose of isolating and destroying the harmful agent, as well as repairing the damaged tissue or organ. It is therefore considered a mechanism of innate, stereotyped immunity, in contrast to the adaptive immune reaction, specific for each type of infectious agent. The fundamental action of cytokines is the regulation of the mechanism of inflammation. The main pro-inflammatory cytokines that act in the nonspecific or inflammatory response are: Interleukin 1 (IL-1), Tumor Necrosis Factor Alpha (TNF-α), Interleukin 8 (IL8), Interleukin 12 (IL-12), Interleukin 16 (IL-16) and Interferons. IL-6 and IL-12, in addition, act on specific immunity: IL-6 is an autocrine factor of B7 lymphocytes while IL-12 stimulates cytotoxic cellular immunity. In addition to inflammatory cytokines, other markers of the inflammatory systemic response have been identified, including, for example, C-reactive protein (CRP) (Ridker et al. NEJM 342 (12): 836-43, 2000), certain cell adhesion molecules , such as SICAM-1 (US 6049147) and B61 (US 5688656). Other markers associated with inflammation include leukotriene, thromboxane, isoprostane and soluble TNF receptors.

Disorders involving increased inflammatory processes include, but are not limited to allergies, myopathies, different types of cancer, acne, asthma, chronic prostatitis, glomerolonephritis, hypersensitivity, interstitial cystitis, atherosclerosis, osteoarthritis, multiple sclerosis, Guillain-Barre syndrome , Crohn's disease, ulcerative colitis, psoriasis, graft rejection disease, systemic lupus erythematosus, obesity and insulin-dependent diabetes mellitus. Likewise, the composition of the invention could be used to treat other disorders associated with high levels of proinflammatory cytokines, such as in response to infectious agents and in a large number of autoimmune diseases, such as rheumatoid arthritis, toxic shock syndrome, diabetes. , etc. In a particular embodiment, said inflammatory processes are related to menopause.

In said disorders that involve inflammatory processes, the composition of the invention is capable of decreasing in fl ammation, specifically decreasing proinflammatory cytokines, preferably TNFalfa and IL-6 cytokines.

In order to determine if there has been a reduction in inflammatory processes, the expression of some of the compounds mentioned above is measured. In a preferred embodiment, proinflammatory cytokines are measured. Therefore, one skilled in the art knows that if a decrease in the expression of proinflammatory cytokines is detected, it implies an anti-inflammatory effect and therefore, a positive effect of the composition of the invention.

As used in the present invention, the term "lipid peroxidation" refers to the oxidative degradation of lipids. It is the process through which free radicals capture electrons from lipids in cell membranes. This process is initiated by a chain reaction mechanism of a free radical. In most cases it affects polyunsaturated fatty acids, because they contain multiple double bonds between which are methylene groups (-CH2-) that have particularly reactive hydrogens. Lipid peroxidation is a well-known mechanism of cellular damage in animals, and is therefore sometimes used as an indicator of oxidative stress and a biomarker of environmental pollution. After the decomposition of the polyunsaturated fatty acids of the biological membranes, among others, malonyldialdehyde (MDA) and 4-hydroxyalkene (4-HNE) are generated as the end products of the reaction. Thanks to its determination, lipid peroxidation and, therefore, oxidative stress in organisms can be quantified. Disorders associated with an increase in lipid peroxidation include, but are not limited to liver diseases (such as hepatitis, cirrhosis, liver cancer), Alzheimer's, different types of cancer, AIDS, intestinal ischemia, Crohn's disease, ulcerative colitis, etc. The determination of lipid peroxidation levels in the invention is carried out by conventional methods known to a person skilled in the art.

In a particular embodiment, inflammatory processes and lipid peroxidation are related to the typical symptoms of menopause. The term "menopause," as used herein, refers to the transition from a woman's reproductive stage to the non-reproductive stage. Such symptoms include but are not limited to one or more symptoms commonly experienced by women during periods associated with hormonal fluctuations, such as menopause, such as dysmenorrhea, retention of fluid in the body, fatigue, dizziness, headaches, sweating. sudden, insomnia, nausea, diarrhea, constipation, heart palpitations, abdominal cramps, mood swings, irascibility, violent tendencies, anxiety, nervousness, tension, difficulty in concentration, depression, forgetfulness, increased appetite, backaches, osteoporosis and increased emotional sensitivity.

The following examples serve to illustrate the invention and should not be considered as limiting the scope thereof.

Example 1

Effect of the administration of the composition of rosemary and vitamin E on the digestive system

The rosemary extract is obtained in an extractor for supercritical fluids using CO2 as an extractant. Rosemary leaves dried in darkness and subjected to cryogenic grinding are extracted by CO2 percolation at a pressure between 100 and 300 bars and a temperature between 40 and 60 ° C. The amount of CO2 used is between 10 and 40 kg per kg of dried and ground rosemary. The extract obtained is divided in line into two different separators mounted in series with independent temperature and pressure control. The first separator works at 30 ° C and at a pressure between 30 and 60% of the extraction, and the second separator works at 30 ° C and at a pressure between 30 and 60% of that of the first separator. Once the active ingredients of rosemary are dissolved in CO2, decompression is carried out at atmospheric pressure of the solution so that the CO2 gasifies and is eliminated spontaneously. If the decompression is carried out up to 50 bar, the CO2 does not gasify but is separated from the active ingredients extracted from the rosemary and can be recirculated for use.

To assess the anti-inflammatory and antioxidant effect of the composition of vitamin E rosemary extract in digestive tissue, a radiation damage model was designed in young adult Wistar rats (n = 10 per group) to which a single dose of 6Gy (total body) radiation using an electron accelerator (SLI) with a rate of 2Gy / min. During the seven days prior to radiation, rosemary extract (140 mg) and / or vitamin E (140 mg) was administered - per kg of weight and day (n = 10 per group).

After radiation, samples of intestinal mucosa and liver were obtained at 2 and 72 hours post-radiation and the action of treatment with rosemary extract and / or vitamin-E was evaluated at 2 hours and 72 hours after radiation damage on the expression of the proinflammatory cytokines TNF-alpha and IL-6, as well as on lipid peroxidation (MDA / mg of total protein) in the tissues, compared to a control group subjected to the same gamma radiation but without having been given the treatment with supercritical extract of rosemary and vitamin-E. In all animals, treatment with rosemary extract and / or vitamin E was maintained until slaughter.

The expression of TNF-alpha and IL-6 pro-inflammatory cytokines was determined, as well as lipid peroxidation (malonyldialdehyde / mg total protein) in tissues. The expression of CX-CR4 / SDF1 Alpha chemokines in the organs indicated by RT-PCR, which measures mRNA levels, was also analyzed. All these results can be seen in Table 1. The proliferative response in tissues was assessed by studying immunoreactivity for Ki-67 and PCNA, markers of cell proliferation in histological sections of the intestine.

TABLE 1

Levels of the chemokine SDF1-α / CXCR4, and proinflammatory cytokines in the liver and intestine

Statistical significance: aP <0.001 versus bP control <0.01 versus cP control <0.02 versus dP control <0.05 versus control, n.s. not significant.

The results in intestine and liver indicate a clear anti-inflammatory action of both rosemary extract and vitamin E. Both in liver and intestine it is observed that each compound reduces the concentration of proinflammatory cytokines minimizing tissue damage. The administration of both compounds makes the effects of each of the compounds potentiated causing an increase in the anti-inflammatory response.

TABLE 2

Levels of lipid peroxidation in liver and intestine

bP <0.01 versus control; n.s. not significant.

The results of lipid peroxidation (shown in Table 2) in intestine and liver show a clear antioxidant effect of the elements of the composition. Both compounds reduce lipid peroxidation by endorsing the antioxidant effect. The effects obtained are synergistic since they are obtained with greater intensity when combining rosemary extract and vitamin E than when these products are administered independently.

These results indicate that the cytoprotective effect of the application of the combination of the two compounds is much more intense than if only one of them was administered.

Example 2

Effect of the administration of the composition of rosemary and vitamin E on the nervous system

To assess the anti-inflammatory and antioxidant effect on the nervous system of the vitamin E composition together with rosemary extract, a damage model was designed in young adult Wistar rats irradiated by an electron accelerator (SLI) with a total dose of 6 Gy and a dose rate of 2Gy / minute. For seven days prior to radiation, supercritical rosemary extract (140 mg) and / or vitamin E (140 mg) per kg of weight per day was administered orally (n = 10 per group). After obtaining the samples of nerve tissue (hippocampus) at 2 and 72 hours after transduction, chemokine expression (SDF1-alpha-CXCR4) was analyzed by RT-PCR, which measures mRNA levels, IL-1β expression and peroxidation lipid (MDA / mg total protein).

TABLE 4

Proinflammatory cytokine levels, lipid peroxidation and chemokine SDF1-α / CXCR4, in the nervous system (hippocampus)

Statistical significance: aP <0.001 versus bP control <0.01 versus cP control <0.02 versus dP control <0.05 versus control.

The results obtained in the hippocampus indicate a clear action of the composition to reduce lipid peroxidation, both by administering rosemary and vitamin E separately than when co-administered. This action is observed both by the anti-inflammatory action that it demonstrates by the reduction that it exerts on the expression of proinflammatory cytokines after exposure to radiation, and by the antioxidant action that the compounds exert when analyzing lipid peroxidation. Despite these independent effects, the effects are synergistic as they are obtained with greater intensity when combining rosemary extract and vitamin E than when these products are administered separately.

Claims (24)

one.

Oral composition comprising vitamin E and Rosmarinus of fi cinalis, with the proviso that said composition is not a pharmaceutical composition.

2.

Composition according to claim 1 wherein Rosmarinus of fi cinalis accounts for between 10% and 90% and vitamin E between 10% and 90% of the total composition.

3.

Composition according to claim 1 or 2 wherein the ratio of Rosmarinus of fi cinalis and vitamin E is from 1: 5 to 5: 1.

Four.

Composition according to any of claims 1 to 3, wherein the ratio of Rosmarinus of fi cinalis and vitamin E is 1: 2 to 2: 1.

5.

Composition according to any of claims 1-4 which further comprises docosahexanoic acid.

6.

Composition according to any one of claims 1 to 5 which additionally comprises at least one ingredient selected from iso-fluvones, a vitamin and a trace element.

7.

Composition according to any of claims 1-6, wherein the vitamin is selected from vitamin A, vitamin D3, vitamin B9, vitamin B6, vitamin B12, vitamin C, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B7 and vitamin K.

8.

Composition according to any one of claims 1 to 7, wherein the trace element is selected from calcium, iron, zinc, magnesium, phosphorus, copper, iodine and selenium.

9.

Composition according to any of the preceding claims which is presented in the form of gelatin capsules.

10.

Nutritional supplement comprising a composition according to any one of claims 1 to 9 and a food grade vehicle.

eleven.

Nutritional supplement according to claim 10 wherein the Rosmarinus of fi cinalis accounts for between 10% and 90% and vitamin E between 10% and 90% of the total composition.

12.

Nutritional supplement according to claim 10 or 11 wherein the ratio of Rosmarinus of fi cinalis and vitamin E is from 1: 5 to 5: 1.

13.

Nutritional supplement according to any of claims 10 to 12, wherein the ratio of Rosmarinus of fi cinalis and vitamin E is 1: 2 to 2: 1.

14.

Nutritional supplement according to any of claims 10 to 13 further comprising docosahexanoic acid.

fifteen.

Nutritional supplement according to any of claims 10 to 14, wherein the vitamin is selected from vitamin A, vitamin D3, vitamin B9, vitamin B6, vitamin B12, vitamin C, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B7 and vitamin K.

16.

Nutritional supplement according to any of claims 10 to 15, wherein the metal is selected from calcium, iron, zinc, magnesium, phosphorus, copper, iodine and selenium.

17.

Nutritional supplement according to any of the preceding claims which is presented in the form of gelatin capsules for oral administration.

18.

Composition according to any one of claims 1 to 9 comprising vitamin E and Rosmarinus of fi cinalis for use in disorders that occur with an increase in inflammatory processes or disorders that occur with an increase in lipid peroxidation.

19.

Use of a composition according to any one of claims 1 to 9 comprising vitamin E and Rosmarinus of fi cinalis in the preparation of a medicament for disorders that occur with an increase in inflammatory processes or disorders that occur with an increase in lipid peroxidation.

twenty.

Use according to claim 19 wherein the inflammatory process or lipid peroxidation are related to menopause.

twenty-one.

Use according to any of claims 19 or 20 wherein the reduction of the inflammatory process implies reduction of the proinflammatory cytokines.

22

Use according to claim 21 wherein the reduction of proinflammatory cytokines occurs in the digestive system affected by inflammation.

2. 3.

Use according to claim 21 wherein the reduction of proinflammatory cytokines occurs in the nervous system affected by inflammation.

SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201031225 SPAIN Date of submission of the application: 05.08.2010 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: See Additional Sheet RELEVANT DOCUMENTS

Category

Documents cited Claims Affected

X

US 6352712 B1 (LUKACZER, D. O. et al.) 05.03.2002, 1,6-8,10,15,16

column 5, lines 39-45; column 6, lines 47-60; column 8, lines 2-5; column 9, Table 4;

column 13, Table 9.

X

US2007141170 A1 (LANG, J. C.) 06.21.2007, 1,5-10,14-17

page 2, [0023]; page 3, [0026] - [0027]; pages 5-6, [0044] - [0064]; pages 8-11, examples 1-11;

claims 1,3-13.

Y

6-8.15-17

X

WO 2009120091 A1 (PHARMALOGICA AS) 01.10.2009, 1,4,6-8,18,19

pages 7-8, Example 2; claims 22,23,25,27.

X

WO 2007141764 A1 (THE IAMS COMPANY) 13.12.2007, 1,2,5-7,10,11

pages 5.12-14.17; claims 3,4,7.

Y

2,3,5,1-14-14

X

WO 2010083206 A1 (THE PROCTER & GAMBLE COMPANY) 07.27.2010, 1.4-6

pages 2,4,5,8; page 10, Table IV; page 11, Table V; claims 1-3,5,8.

Y

4,10,11,14

X

WO 2009136410 A2 (NISARGA BIOTECH PVT. LTD.) 12.11.2009, 1,9,10

pages 11,12,20,21; claim 2,4-7,16.

Y

1,3,4,12,13

X

EP 1902631 A2 (INSTITUT NATIONAL DE RECHERCHE AGRONOMIQUE) 26.03.2008, 1.10

page 2, [0007] - [0013]; page 3, [0017], [0019], [0024], [0025], [0029]; page 4, [0031]; page 6,

[0052], [0053]; claims 2,4,5.

Y

1,2,18-23

Y

US2007253941 A1 (NAIDU et al.) 01.11.2007, 6-9.15-23

page 3, [0031]; page 4, [0048] - [0050], [0062]; pages 6-7, [0090]; examples 5,9,18,20,23;

claims 14,16-18,38-40.55.

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 02.12.2011

Examiner A. Sukhwani Page 1/5

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201031225 CLASSIFICATION OBJECT OF THE APPLICATION  A23L1 / 30 (2006.01) A23L1 / 302 (2006.01) A61K36 / 53 (2006.01) A61K31 / 355 (2006.01) Minimum documentation sought (classification system followed by classification symbols) A23L, A61K Electronic databases consulted during the search (name of the database and, if possible, search terms used) INVENTIONS, EPODOC, WPI, X-FULL State of the Art Report Page 2/5  WRITTEN OPINION Application number: 201031225 Date of Written Opinion: 02.12.2011 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 3, 12, 13, 20-23 1, 2, 4-11, 14-19 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1 -23 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published.  Considerations:  The present invention aims at an oral composition comprising vitamin E and Rosmarinus officinalis with the proviso that said composition is not a pharmaceutical composition (reiv. 1), wherein Rosmarinus officinalis accounts for between 10 and 90% and the vitamin E between 10 and 90% of the total composition (reiv. 2). Composition where the ratio of Rosmarinus officinalis and vitamin E is 1: 5 to 5: 1 (reiv. 3), or 1: 2 to 2: 1 (reiv. 4).  The composition further comprises docosahexanoic acid (reiv. 5) and at least one ingredient selected from Isoflavones, a vitamin and a trace element (reiv. 6). The vitamin is selected from vitamin A, vitamin D3, vitamin B9, B6, B12, C, B1, B2, B3, B5, B7 and vitamin K (reiv. 7). The trace element is selected from calcium, iron, zinc, magnesium, phosphorus, copper, iodine, selenium (reiv. 8). The composition is presented in the form of gelatin capsules (reiv. 9). The nutritional supplement comprising the claimed composition and a food grade vehicle (reiv. 10), where Rosmarinus officinalis is between 10 and 90% and vitamin E between 10 and 90% of the food is also protected. total composition (reiv. 11), where the ratio of Rosmarinus officinalis and vitamin E is 1: 5 to 5: 1 (reiv. 12), or 1: 2 to 2: 1 (reiv. 13). The nutritional supplement further comprises docosahexanoic acid (reiv. 14) and vitamins and trace elements according to claims 7 and 8 (reivs. 15, 16), and is presented in the form of gelatin capsules for oral administration (reiv. 17).  The composition comprising vitamin E and Rosmarinus officinalis is used in disorders that occur with an increase in inflammatory processes or disorders that occur with an increase in lipid peroxidation (reiv. 18) and for the preparation of a medicament for said disorders (reiv. 19 ) related to menopause (reiv. 20) so that the reduction of the inflammatory process involves reduction of proinflammatory cytokines (reiv. 21) in the digestive system affected by inflammation (reiv. 22) or in the nervous system affected by inflammation (reiv . 2. 3). State of the Art Report Page 3/5  WRITTEN OPINION Application number: 201031225 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

US 6352712 B1 (LUKACZER, D. O. et al.) 05.03.2002

D02

2007141170 A1 (LANG, J. C.) 06.21.2007

D03

WO 2009120091 A1 (PHARMALOGICA AS) 01.10.2009

D04

WO 2007141764 A1 (THE IAMS COMPANY) 13.12.2007

D05

WO 2010083206 A1 (THE PROCTER & GAMBLE COMPANY) 07.22.2010

D06

WO 2009136410 A2 (NISARGA BIOTECH PVT. LTD.) 12.11.2009

D07

EP 1902631 A2 (INSTITUT NATIONAL DE RECHERCHE AGRONOMIQUE) 03.23.2008

D08

US 2007253941 A1 (NAIDU et al.) 01.11.2007

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement  NOVELTY  The documents cited D01 to D07 are very relevant because they refer to oral compositions comprising rosemary (Rosmarinus officinalis) and vitamin E, the majority being used as food supplements. Indeed,

-

D01 refers to a dietary supplement comprising rosemary and vitamin E (column 5, lines 39-45; column 6, lines 47-60), in addition to other vitamins and trace elements such as vitamin A, B vitamins, calcium, zinc, selenium, copper , magnesium, phosphorus, iodine (column 9, Table 4: column 13, Table 9), which can be supplied in capsules (column 8, lines 2-5) anticipating the technical characteristics of claims 1, 6-8, 10, 15.16.

-

D02 also discloses nutritional supplements containing vitamin E and rosemary (page 3, [0026], [0027]; page 6, [0055]), in addition to DHA, group B vitamins, vitamin D (page 5, [0044] - [0053]), minerals such as calcium, iodine, magnesium, phosphorus, selenium (page 6, [0056] - [0064]). Various examples with vitamin E, rosemary and these components are given in Examples 1-11 (pages 8-11, claims 1, 3-13), and also that it can be supplied in gelatin capsules (page 2, [0023]) , anticipating the technical characteristics of claims 1, 5-10, 14-17

-

D03 refers to a beverage formula comprising rosemary extract, vitamin E, vitamin C, selenium among other components, where the amount of rosemary extract is twice that of vitamin E (pages 7-8, Example 2). The beverage can be used for the prevention and / or prophylaxis of diseases associated with high oxidative stress and inflammatory and cardiovascular disorders (claims 22, 23, 25, 27), anticipating the technical characteristics of claims 1, 4, 6-8, 18, 19.

-

D04 discloses the use of polyphenols to promote eye health such as rosemary extract that can be in the composition between 0.01 to 90% (pages 4-5; claims 3, 4). In addition to other compounds, the composition comprises an antioxidant such as vitamin E present in 0.01 to 10% (pages 12-13), in addition to other vitamins (claim 7). He reports that polyphenols with their antioxidant activity prevent oxidative stress and anti-inflammatory effect (page 5) in anticipation of the technical characteristics of claims 1, 2, 5-7, 10, 11.

-

D05 refers to an antioxidant composition to improve the oxidative stability of concentrated fish oil comprising among others DHA, vitamin E and rosemary extract, where tocopherols may be present from 0.1 to 0.2% and the extract of rosemary between 0.05 to 0.1% (page 2, 4, 5, 8), various examples are contemplated in which the amount of tocopherols is twice that of rosemary extract (page 10, Table IV; page 11, Table V), in addition to being present docosahexanoic acid (DHA) (claims 1-3, 5, 8) anticipating the technical characteristics of claims 1, 4-6.

-

D06 refers to an herbal composition that is supplied as a food supplement in gelatin capsules and comprises, among other extracts, rosemary extract and vitamin E in an amount that varies between Rosmarinus 0.10% and vitamin E from 0 to 2% (claim 2), in these margins the premises of claims 3, 4, 12, 13 are covered. The 10: 1 ratio is also contemplated (pages 11, 12, 20, 21: claims 5-7) or the amount may be greater of vitamin E of 2-6% versus rosemary extract of 0.3 to 0.6% (claim 4), the composition of herbs is effective in reducing oxidative stress (reiv. 16), anticipating the technical characteristics of claims 1, 9, 10.

State of the Art Report Page 4/5  WRITTEN OPINION Application number: 201031225

-

D07 refers to a natural antioxidant additive of plant origin to be supplied as a food supplement where it is reported that effectively limiting lipid oxidation is not sufficient only with vitamin E, but must be accompanied with plant extracts (page 2, [0007] - [0013]); of the extracts cited (page 3, [0017], at least the rosemary extract must be present (page 3, [0019]), the majority extract being (p. 3, [0024], [0025]) to be administered with vitamin E (page 3, [0029]) Rosemary may represent 70 to 95% of the antioxidant additive (claims 1, 2, 4, 5), anticipating the technical characteristics of claims 1, 10

Therefore, it is inferred that the technical characteristics of claims 1, 2, 4-11, 14-19 are anticipated in the cited documents. Therefore, in view of the documents cited D01 to D07, it can be concluded that claims 1, 2, 4-11, 14-19 are novel in accordance with Article 6 LP 11/86.  INVENTIVE ACTIVITY The composition object of the invention comprising vitamin E and Rosmarinus officinalis (rosemary) that is not pharmaceutical composition is very evident to the person skilled in the art since this composition is widely disclosed as a nutritional supplement in the cited documents.  Indeed, documents D01 to D07, in addition to anticipating the novelty of many of the claims, affect the inventive activity of all claims, since the oral composition that is not a pharmaceutical composition is already disclosed in these cited documents.  But in addition, document D08 is also relevant for the study of inventive activity. So,

-

D08 refers to compositions with antioxidants such as vitamin E, rosemary extract, carnosol, carnosic acid with DHA for perimenopausal symptoms (page 3, [0031]; page 4, [0048] - [0050], [0062]); pages 6-7, [0090]; other vitamins, minerals are contemplated in examples 5, 9, 18, 20, 23 and claims 14, 16-18, 38-40, 55).

It does not represent any inventive effort for the person skilled in the art to prepare a composition with vitamin E and Rosmarinus officinalis (rosemary) that is not a pharmaceutical composition but a nutritional supplement since it is known that to limit lipid oxidation the presence of vitamin E is required and rosemary extract (D07), non-pharmaceutical compositions that contain vitamin E and rosemary and that are used in nutritional supplements are widely disclosed in the cited documents, thus the addition of docosahexanoic acid (D02, D05), vitamins and minerals ( D01, D02) is widely known in the state of the art, as is the use in inflammatory processes related to menopause (D08). The other technical characteristics such as the ratio of each component that are equal, double, fivefold are obvious since many ranges and ratios of vitamin E and rosemary are disclosed, from equal to double one, ten times more than one, etc. . and that the inflammation is in the digestive or nervous system, is evident to the person skilled in the art. Therefore, in view of documents D01 to D08, it can be concluded that claims 1–23 lack inventive activity according to Article 8 LP 11/86. State of the Art Report Page 5/5