Patent 6,765,020

Drug or foods and drink for prevention or treatment of diseases caused by abnormalities in cartilage tissues in which said drugs or foods and drinks have omega-9 unsaturated fatty acid as an active ingredient.

DISCLOSURE OF THE INVENTION

Thus, it is an object of the invention to provide drugs that are useful for prevention or treatment of diseases caused by abnormalities in cartilage tissues, in particular, for prevention of disease associated with cartilage degeneration such as, in particular, arthropathy, osteoarthritis, periarthritis scapulo-humeralis, spondylitis deformans, etc. and that have relatively small side effects, and thus are applicable to chronic disorders, and new foods and drinks having the effect of preventing or alleviating medical conditions caused by abnormalities in cartilage tissues.

Cartilage tissues are avascular, which is extremely uncommon as a tissue derived from a mesenchyma, and even normal cartilage tissues contain lipids (Ann. Rheum. Dis., 24, 123-135, 1965). However, excessive accumulation of lipids may be observed as pathomorphism in lipo-hem arthropathy (J. Bone Joint Surg. [Am] 52, 1147-1158, 1970) and precocious arthropathy (Arthritis Rheum. 24, 965-968, 1981). In addition, correlation of abnormal metabolism of lipids with medical conditions has been reported in osteoarthritis as well (Metabolism, 40, 571-576, 1991).

An appropriate amount of lipids and appropriate composition of fatty acids are considered to be important for maintenance of normal metabolism and functions of chondrocytes based on the reports that administration of lipids into a joint of rabbit can induce experimental osteoarthritis-like arthropathy (J. Anat, 133, 309-314, 1981), and can reduce chondral incorporation of ³⁵ SO₄ in essential fatty acids-deficient Wistar rats (Arthritis Rheum., 14, 379, 1971), and that lipid supply is needed for normal growth of chondrocytes (Exp. Cell. Res., 145, 415-423, 1983).

However, the role of the above changes in lipids in initiation and aggravation processes of arthropathy has not been fully studied, and furthermore it is not clear whether the administration of lipids is effective for treatment of arthropathy, especially, osteoarthritis. On the other hand, omega-9 unsaturated fatty acids are known to be localized in cartilage tissues and its contents decrease with aging (FASEB J., 5,344-353, 1991), and believed to be important for maintenance of functions of chondrocytes. Furthermore, 5,8,11-eicosatrienoic acid has been confirmed to have an anti-inflammatory effect on the rat models of carrageenan-induced edema, but its pharmaceutical actions in arthropathy is little known.

Thus, in order to resolve the above problems, the inventors have carried out studies on various unsaturated fatty acids and consequently found that 5,8,11-eicosatrienoic acid has an action of inhibiting cartilage degeneration and that hence it is very useful for prevention or treatment of diseases caused by abnormalities in cartilage tissues, and we have completed the present invention.

MODE FOR CARRYING OUT THE INVENTION

Omega-9 unsaturated fatty acid, an active ingredient of the present invention, is 5,8,11-eicosatrienoic acid, and 6,9-octadecadienoic acid or 8,11-eicosadienoic acid which can be readily converted to 5,8,11-eicosatrienoic acid thereby showing the effect of 5,8,11-eicosatrienoic acid may be employed. They may be used alone or in combination.

The fatty acids of the present invention may be any of the geometric isomers, the cis-form or the trans-form. But since most of the naturally occurring omega-9 unsaturated fatty acids are in the cis-form, the omega-9 unsaturated fatty acids are preferably in the cis-form when used in foods and drinks of the present invention.

Omega-9 unsaturated fatty acids according to the present invention may be employed in the form of free fatty acids, and also in various forms, for example, pharmaceutically acceptable salts such as sodium salts, potassium salts, lithium salts, or other alkali metal salts, salts of other metals such as zinc salts, calcium salts, magnesium salts, mono-, di-, tri-glycerides, esters of lower alcohols, phospholipids, glycolipids, amides, etc. Especially ethyl esters or triglycerides are preferred. The term "lower alcohol" as used herein means monohydric alcohols having not more than six carbon atoms, such as methanol, ethanol, propanol, isopropanol, butanol, pentanol, hexanol, etc. These may be used alone or in combination.

Sources of omega-9 unsaturated fatty acids used in the present invention may be any source. Thus, they may be those produced by microorganisms capable of producing omega-9 unsaturated fatty acids, animal tissues deficiency of essential fatty acids, and cultured cell of animal deficiency of essential fatty acids, chemically or enzymatically synthesized products, or products extracted, isolated, or purified from natural products for example animal cartilages.

Specific examples of microorganisms capable of producing omega-9 unsaturated fatty acids refer to those microorganisms having the enzymatic activity of .DELTA.5 desaturation and the enzymatic activity of .DELTA.6 desaturation, and having reduced or no enzymatic activity of .DELTA.12 desaturation as set forth in Japanese Unexamined Patent Publication No. 5(1993)-91888. For example, Mortierella alpina SAM1861 (FERM BP-3590) may be used.

Free Omega-9 unsaturated fatty acids and their esters may be extracted, isolated, and purified from the above-mentioned omega-9 unsaturated fatty acids-containing products according to the conventional method. When they are obtained from microorganisms, for example, fats and oils obtained from a cultured cell mass by extraction with an organic solvent such as n-hexane, or supercritical gas extraction with carbon dioxide are subjected to hydrolysis or esterification to prepare a free fatty acid mixture or a fatty acid ester mixture, which is then subjected to urea fractionation, liquid-liquid partition chromatography, column chromatography, etc. to obtain the desired free fatty acids or esters of 6,9-octadecadienoic acid, 8,11-eicosadienoic acid, and 5,8,11-eicosatrienoic acid, etc. at a yield of 80% or higher. More particularly, the extraction, isolation, and purification may be carried out in accordance with the methods as set forth in Japanese Unexamined Patent Publication No. 5(1993)-91888.

The omega-9 unsaturated fatty acids, active ingredient of the present invention, need not be highly purified products, but fats and oils containing omega-9 unsaturated fatty acids (said fats and oils may contain triglycerides, diglycerides, monoglycerides, phospholipids, or glycolipids having omega-9 unsaturated fatty acids, or free omega-9 unsaturated fatty acids or their esters), free fatty acids mixtures containing omega-9 unsaturated fatty acids or fatty acid ester mixtures can be used.

Oils and fats containing omega-9 unsaturated fatty acids may be obtained from a cultured cells of microorganism capable of producing omega-9 unsaturated fatty acids by disrupting the cells and by extraction with an organic solvent such as n-hexane, or supercritical gas extraction with carbon dioxide. Alternatively, they may be obtained from a natural product containing omega-9 unsaturated fatty acids by the conventional method. Hydrolysis and esterification of the thus obtained oils and fats can yield a free fatty acid mixture or fatty acid ester mixtures containing omega-9 unsaturated fatty acids. More particularly, the extraction, isolation, and purification from the cultured cells may be carried out in accordance with the method as set forth in Japanese Unexamined Patent Publication No. 5(1993)-91888.

The fatty acids of the present invention may be used orally or parenterally in the field of drugs, quasi-drugs, cosmetics, health-related foods, functional foods, nutritional supplementary foods, foods for the elderly, and foods and drinks.

Diseases caused by abnormalities in cartilage tissues, the subject of the present invention, include, for example, arthropathy of the joints of knees, elbows, hip, legs, fingers, shoulders, etc., osteoarthritis, gonarthrosis, periarthritis scapulo-humeralis, spondylitis deformans, etc. Various medical conditions caused by these diseases are also the subject of the present invention, and include stiffness of joints, cinealgia, limited range of motion of joints, and swelling of joints known as disease conditions of osteoarthritis, pains, especially, cinealgia, limited range of motion, and hydrarthrosis known as disease conditions of gonarthrosis, trachelodynia, back pain, lumbago, irradiating pains of limbs or sometimes the trunk, radiculopathy or myelopathy such as numbness or weakness, high paralysis, bladder and rectal disturbances, intermittent claudication, or cold sensation known as disease conditions of spondylitis deformans. The fatty acids of the present invention have relatively small side effects due to selective inhibition of cartilage degeneration, thus capable of being applied to chronic conditions.

When the active ingredients of the present invention are employed as pharmaceutical drugs, they may be administered in any form conveniently employed for oral or parenteral administration, such as injections (emulsifiable, suspendable, non-aqueous, etc.), or solid injections emulsified or suspended prior to use, transfusion solutions, powders, granules, tablets, capsules, enteric coated tablets, troches, liquid for internal use, suspensions, emulsions, syrups, liquids for external use, fomentations, nasal drops, inhalants, ointments, lotions, suppositories, enteral nutrients, etc. They may be used either alone or in combinations depending on the disease conditions. These may be prepared according to the conventional methods by adding to the main drug pharmacologically and pharmaceutically acceptable adjuvants for manufacture.

Such adjuvants for manufacture used are suitable components for manufacture selected depending on the route of administration such as preparations for internal use (oral drugs), parenteral preparations (injections), drugs for application to mucosa (buccals, troches, suppositories, etc.), preparations for external use (ointments, patches, etc.), and the like. In the oral drugs and drugs for application to mucosa, for example, components for pharmaceutical manufacture such as excipients (for example, starch, lactose, crystalline cellulose, calcium lactate, magnesium metasilicate aluminate, and anhydrous silicic acid), disintegrators (for example, carboxy methyl cellulose, calcium carboxy methyl cellulose, and sodium alginate), lubricants (for example, magnesium stearate, paraffin sulphate, and talc), binders (for example, dimethyl cellulose, gelatin, and polyvinylpyrrolidone), coating agents (for example, hydroxyethylcellulose), corrigents, coloring agents, flavoring agents, etc. may be used. In the injections, components for pharmaceutical manufacture such as solubilizing agents and solution adjuvants (for example, distilled water for injection, physiological saline, propylene glycol, and glycerin), capable of forming aqueous injections, suspending agents (for example, surfactants such as polysorbate 80, tween 80, etc., and gum arabic solution), pH-adjusting agents (for example, organic acids or their metal salts), stabilizers, etc. may be used. In addition, in the drugs for external use components for pharmaceutical manufacture such as aqueous or non-aqueous solubilizing agents or solution adjuvants (for example, alcohols, and fatty acid esters), adhesives (for example, carboxy vinyl polymers, and polysaccharides), emulsifying agents (for example, surfactants), and the like may be used. Since the fatty acids of the present invention are unsaturated fatty acids, it is preferred that they contain anti-oxidants such as butyrated hydroxy toluene, butyrated hydroxy anisole, propyl gallate, pharmaceutically acceptable quinones, .alpha.-tocopherols, etc. Especially for treatment of arthropathy, osteoarthritis, gonarthrosis, periarthritis scapulo-humeralis, etc., an active ingredient of the present invention may be suspended in an aqueous solvent, its pH is adjusted to be 6.0 to 7.0 and its osmotic pressure ratio vs. 0.9% physiological saline is adjusted to 0.8 to 1.2 to prepare a dosage form for articular cavity administration. As the above aqueous solvent, for example, physiological saline, a 3 to 5% glucose solution, a 3 to 5% xylitol solution, phosphate buffer, etc. may be used.

As a solubilizing agent for preparing injections, for example, nonionic surfactants for pharmaceutical use, etc. may be used. More specifically, it may be prepared by completely mixing an active ingredient of the present invention with half volume of a nonionic surfactant such as POE (60) hydrogenated castor oil or POE sorbitan monooleate, etc. and then by diluting with physiological saline. As needed, isotonicity, oxidation inhibitor (sodium sulfite, sodium bisulfite, etc.), preservatives (benzoic acids, salicylic acid, etc.), soothing agents, etc. may be optionally added.

In the drugs for prevention or treatment of the present invention, active ingredients of the present invention may be blended with drugs such as hyaluronic acid etc. traditionally used for treatment of diseases caused by abnormalities in cartilage tissues, adrenocorticotropic hormone drugs, local anesthetics, antibiotics, etc. may be added.

Though the dose of the active ingredient of the present invention may vary depending on the purpose of administration and the status (sex, age, weight, etc.) of the patient to be administered, the total amount of the omega-9 unsaturated fatty acids of the present invention, when orally administered to an adult, is in the range of 1 to 5,000 mg per day, preferably 1 to 2,000 mg per day, and more preferably 1 to 1,000 mg per day, and when administered parenterally it is in the range of 0.1 to 500 mg per day, preferably 0.1 to 200 mg per day, and more preferably 0.1 to 100 mg per day. The dose may be controlled as appropriate within the above-mentioned range.

For treatment of arthropathy, osteoarthritis, gonarthrosis, periarthritis scapulo-humeralis, in particular, it is injected into articular cavity for an adult in amounts in the range of 0.1 to 500 mg per each administration, preferably 0.1 to 200 mg per each administration, which is administered once every 1 to 7 days. However, in contrast to the commercially available hyaluronic acid preparation of which administration is limited to injection into the articular cavity due to its property as a protecting agent against mechanical stress, the method of administration of the present invention is not limited to injection into the articular cavity but it may be administered in various methods such as oral administration, enteral nutrients, percutaneous absorption, etc., because the fatty acids of the present invention has the activity of inhibiting degeneration of cartilage tissues.

Fatty acids, active ingredients of the present. invention, are known to be synthesized in the body at deficiency state of essential fatty acids. It is evidently superior in safety because its continuously orally administration in an amount of 2 g/day/kg to 7-week old ICR male mice for two weeks did not cause any abnormal conditions.

When the fatty acids of the present invention are used in foods and drinks, they may be in the form of solid or liquid foods or favorite foods.

The foods containing oils and fats include natural foods containing oils and fats such as meat, fish, nuts, etc., foods to which are added oils and fats on cooking such as chinese foods, ramen noodles, soup, etc., foods for which oils and fats are used as a heating medium such as tenpura (deep-fried fish and vegetables), fried foods, fried beancurd, fried rice, doughnuts, fried dough cake, etc., fat and oil foods or processed foods for which oils and fats are added during processing such as butter, margarine, mayonnaise, dressing, chocolate, instant ramen noodles, caramel, biscuits, cookies, cake, ice cream, etc., foods on which oils and fats are sprayed or applied at the finish of processing such as okaki (rice crackers), hard biscuits, anpan (bean-jam buns), etc., but they are not limited to the above, and include, for example, agricultural products such as bread, noodles, rice, confectionery (candy, chewing gum, goumis, tablet candies, and Japanese cake), bean curd and other processed foods thereof etc., fermentation products such as refined sake, medicinal drinks, mirin (sweet sake), cooking vinegar, soy sauce, miso (fermented soy bean paste), etc., dairy products such as yogurt, ham, beacon, sausage, etc., processed marine products such as kamaboko (boiled fish paste), ageten (deep-fried patty of fish paste), hanpen (light, puffy cake made of ground fish), etc., beverages such as fruit juice drinks, soft drinks, sports drinks, alcohol beverages, tea, etc.

Foods and drinks of the present invention are prepared by mixing a given amount of at least one omega-9 unsaturated fatty acid selected from the group consisting of 6,9-octadecadienoic acid, 8,11-eicosadienoic acid, and 5,8,11-eicosatrienoic acid, or extracts containing one of them as a main ingredient, with a source for food and drink containing substantially no omega-9 unsaturated fatty acids, and then by processing it according to the conventional method of manufacture. The amount mixed may vary depending on the forms and property of the food and it is generally 0.001% by weight or more of the total amount of the food, preferably 0.1% by weight or more, and more preferably 1% by weight or more, but is not limited to the above.

The sources for food and drink containing substantially no omega-9 unsaturated fatty acids according to the present invention include those in which the total amount of 6,9-octadecadienoic acid, 8,11-eicosadienoic acid, and 5,8,11-eicosatrienoic acid is less than one mg, and preferably less than two mg, due to the small amount of omega-9 unsaturated fatty acids contained, or those in which the content of 5,8,11-eicosatrienoic acid is less than one mg, and preferably less than two mg as a daily dose of the final product to which the source for food or drink has been added.

In accordance with the present invention, the extracts containing an omega-9 unsaturated fatty acid as a main ingredient include the fats and oils (said fats and pils may contain triglycerides, diglycerides, monoglycerides, phospholipids, and glycolipids having omega-9 unsaturated fatty acids, or free omega-9 unsaturated fatty acids or their esters, etc.) containing omega-9 unsaturated fatty acids obtained from the cultured cells of a microorganism capable of producing omega-9 unsaturated fatty acids by disrupting the cells through extraction with an organic solvent such as n-hexane or through supercritical gas extraction with carbon dioxide, or by extraction from the natural products containing omega-9 unsaturated fatty acids by the conventional methods, mixtures of free fatty acids or mixtures of fatty acid esters containing omega-9 unsaturated fatty acids. The content of the omega-9 unsaturated fatty acids in said extracts is 1% or higher, preferably 5% or higher, and more preferably 10% or higher, and in particular, the content of 5,8,11-eicosatrienoic acids is 1% or higher, preferably 5% or higher, and more preferably 10% or higher.

When used as health-related foods, functional foods, nutritional supplementary foods, and foods for the elderly, their forms may be the above pharmaceutical drug form, or, for example, the processing forms such as natural liquid diets, semi-digested nutritious foods, and chemical defined diets incorporating, in addition to the present fatty acids, for example, proteins (as the protein source, highly nutritious milk protein having balanced amino acid compositions, bean protein, and egg albumin protein are most widely used, but the digests thereof, oligopeptides of egg whites, hydrolyzates of beans, etc. and single amino acids may be used), saccharides, fats, trace metals, vitamins, emulsifying agents, flavors, etc., health-related drinks, capsules, enteral nutrients, etc., but the form of the above foods and drinks are also acceptable.

The health-related foods, functional foods, nutritional supplementary foods, and foods for the elderly can be produced in the form of powders, granules, tablets, capsules, troches, liquid for internal use, suspensions, emulsions, syrups, health-related drinks, natural liquid diets, semi-digested nutritious diets, chemical defined diets, enteral nutrients, etc. using omega-9 unsaturated fatty acids and/or the extract containing omega-9 unsaturated fatty acids as a main ingredient. More specifically, they may be produced in the form of powders, granules, tablets, capsules, troches, liquid for internal use, suspensions, emulsions, syrups, health-related drinks, natural liquid diets, semi-digested nutritious diets, chemical defined diets, enteral nutrients, etc., using oil or fat containing at least 1%, preferably at least 5%, more preferably at least 10% of omega-9-9 unsaturated fatty acids. At this time, any of the elemental diets or any of functional ingredients may be mixed with oils and fats containing omega-9 unsaturated fatty acid of the present invention.

Furthermore, under the supervision of a nutrician based on directions by the physician, the meal prepared on site by adding the fatty acids of the present invention to any foods at the time of cooking of hospital diets can be given to patients with medical conditions caused by abnormalities in cartilage tissues.

The medical conditions according to the present invention caused by abnormalities in cartilage tissues include various medical conditions caused by diseases such as arthropathy of the joints of knees, elbows, hip, legs, fingers, shoulders etc. osteoarthritis, gonarthrosis, periarthritis scapulo-humeralis, spondylitis deformans, etc., and more specifically the medical conditions including stiffness of joints, cinealgia, limited range of motion of joints, and swelling of joints known as disease conditions of osteoarthritis, pains, especially, cinealgia, limited range of motion, and hydrarthrosis known as disease conditions of gonarthrosis, trachelodynia, back pain, lumbago, irradiating pains of limbs or sometimes the trunk, radiculopathy or myelopathy such as numbness or weakness, high paralysis, bladder and rectal disturbances, intermittent claudication, or cold sensation known as disease conditions of spondylitis deformans.

The foods and drinks containing the fatty acids of the present invention are preferably administered orally, for the purpose of preventing or alleviating medical conditions caused by abnormalities in cartilage tissues and maintaining health, in amounts of 1 to 5,000 mg per day of the total amount of the omega-9 unsaturated fatty acids of the present invention, preferably 1 to 2,000 mg per day, and more preferably 1 to 1,000 mg per day.

Claim 1 of 24 Claims

What is claimed is:

1. A method for prevention or treatment of gonarthrosis by inhibiting degeneration of cartilage comprising administering to a subject in need of such treatment an omega-9 unsaturated fatty acid in an amount effective for preventing or treating said disease, wherein the omega-9 unsaturated fatty acid is at least one compound selected from the group consisting of 6,9-octadecadienoic acid, 8,11-eicosadienoic acid and 5,8,11-eicosatrienoic acid.

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