JP2008266171A - Autoimmune disease amelioration agent, and medicine and food product containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine and food product for ameliorating the symptom of autoimmune diseases by using hyaluronic acid as an active component. <P>SOLUTION: The invention provides a medicine and a food product containing hyaluronic acid having an average molecular weight of ≥500,000 as an active component. The symptom of autoimmune diseases, especially autoimmune skin diseases is ameliorated by inquestion or administration of a medicine containing the hyaluronic acid as an active component or a food product containing the acid. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to pharmaceuticals and foods for alleviating symptoms of autoimmune diseases, particularly autoimmune skin diseases.

  In recent years, the number of patients suffering from autoimmune diseases is increasing due to rapid changes in eating habits and lifestyle habits. An autoimmune disease is a disease caused by an immune response to a self-body component, and is caused by abnormalities in immunocompetent cells such as T cells, B cells, and macrophages. In addition, since many autoimmune disease symptoms are chronic and are refractory, there are many diseases included in specific diseases that are set as public expenditure targets in Japan. Although the treatment method varies depending on the disease, steroids and immunosuppressive agents are used as the first-line drugs in many diseases because immune disorders are the cause of the disease.

  Various autoimmune diseases are known. For example, alopecia areata is an immune abnormality that occurs in the hair growth phase, that is, a disease in which hair roots are damaged by attacking the hair roots as foreign substances, and hair loss occurs. Often associated with immune disease. Alopecia areata is a normal type in which circular hair loss occurs in one or more hairs, a whole head type in which the entire hair is removed, a serpentine type in which the hairline is removed in a band shape, not only hair, but also eyebrows and eyelashes, It can be divided into four types: generalized type, with whiskers and body hair coming off. For the treatment of intractable alopecia areata, topical steroid drugs are generally used, but sufficient effects are often not obtained.

  Systemic lupus erythematosus (SLE) is a type of autoimmune disease in which antibodies are made against its own DNA. Systemic lupus erythematosus is a chronic disease and is classified as one of the collagen diseases. Symptoms of systemic lupus erythematosus are mainly mucocutaneous symptoms, general malaise, fever, and various visceral lesions. Symptoms. Systemic lupus erythematosus often accompanies nephritis and the like. For the treatment of systemic lupus erythematosus, steroids and cyclophosphamide are administered, and plasma exchange and high-dose immunoglobulin are administered depending on the disease state.

In Japanese Patent Publication No. 11-500742, a pharmaceutical preparation of low molecular weight hyaluronic acid is sufficient for patients suffering from undesired T cell activity, such as transplant host disease, transplant rejection and autoimmune diseases having T cell components. Are described. However, Japanese Patent Publication No. 11-500742 discloses that high molecular weight hyaluronic acid has a therapeutic effect on autoimmune diseases caused by abnormalities of macrophages and humoral factors, and has a therapeutic effect on autoimmune diseases associated with skin diseases. That is not described. Japanese Patent Application Laid-Open No. 2006-327958 describes that low molecular weight hyaluronan such as tetrasaccharide is mainly effective for autoimmune diseases, but high molecular weight hyaluronic acid is effective for autoimmune diseases. It is not described that it has a therapeutic effect on autoimmune diseases accompanied by skin diseases.
Special table 11-500742 JP 2006-327958 A

  Accordingly, an object of the present invention is to provide a medicament for alleviating symptoms of autoimmune diseases, particularly autoimmune skin diseases. Another object of the present invention is to provide a food for alleviating symptoms of autoimmune diseases, particularly autoimmune skin diseases.

  The present inventors have found that ingestion of hyaluronic acid, particularly hyaluronic acid having an average molecular weight of 500,000 or more, alleviates symptoms of autoimmune diseases.

  Therefore, this invention provides the pharmaceutical and foodstuff for relieving the symptom of an autoimmune disease characterized by including a hyaluronic acid as an active ingredient. Here, the average molecular weight of hyaluronic acid is preferably 500,000 or more, more preferably 700 to 1,200,000. Examples of the subject autoimmune diseases include skin diseases. Furthermore, this invention provides the said foodstuff which contains a hyaluronic acid as an active ingredient.

  ADVANTAGE OF THE INVENTION According to this invention, since hyaluronic acid itself is a natural substance, the pharmaceutical which does not have a side effect (or few), has high safety | security, and can relieve the symptom of an autoimmune disease can be provided. Moreover, the food / beverage products which contain the hyaluronic acid of this invention as an active ingredient can also be used as an auxiliary | assistant treatment from the point that an autoimmune disease patient can relieve a symptom in daily life.

  In autoimmune diseases, the immune system, which originally plays a role in recognizing and eliminating foreign substances different from self such as bacteria, viruses, and tumors, reacts excessively to its own normal cells and tissues and attacks. It is a general term for diseases that cause symptoms when added. Although many autoimmune diseases are caused by T cell abnormalities, the present invention is particularly directed to autoimmune diseases caused by macrophage and humoral factor abnormalities. The autoimmune diseases targeted by the present invention are particularly accompanied by autoimmune skin diseases, such as skin diseases systemic lupus erythematosus, systemic scleroderma, mixed connective tissue disease, pemphigus, pemphigoid Alopecia areata can be exemplified, and alopecia areata is preferable.

  Hyaluronic acid contained as an active ingredient in pharmaceuticals and foods for alleviating the symptoms of autoimmune disease of the present invention is a high level composed of disaccharide repeating units of D-glucuronic acid and N-acetyl-D-glucosamine. The molecular weight of hyaluronic acid, which is a long-chain polysaccharide of molecules and contained in the pharmaceuticals and foods of the present invention, is preferably an average molecular weight of 500,000 or more, more preferably 700 to 1,200,000. The hyaluronic acid contained in the pharmaceutical product and food of the present invention is not limited to one having a single average molecular weight, and may be a mixture of hyaluronic acids having different average molecular weights.

  The hyaluronic acid contained in the pharmaceuticals and foods of the present invention basically has at least a disaccharide unit in which the 1-position of β-D-glucuronic acid and the 3-position of β-D-N-acetyl-glucosamine- are bonded. One containing two or more sugars and basically composed of β-D-glucuronic acid and β-DN-acetyl-glucosamine-, or a combination of a plurality of disaccharide units, or Sugars to which these elements are bound may be used, and derivatives thereof such as those having a hydrolyzable protecting group such as an acyl group may also be used. The sugar may be an unsaturated sugar, and examples of the unsaturated sugar include non-reducing terminal sugars, usually those having unsaturated carbon atoms between positions 4 and 5 of glucuronic acid.

  The hyaluronic acid of the present invention may be extracted from natural products such as animals (for example, biological tissues such as chicken crown, umbilical cord, skin, joint fluid, etc.), or obtained by culturing microorganisms or animal cells. (For example, fermentation methods using Streptococcus bacteria or the like), chemically or enzymatically synthesized ones, and the like can be used.

  The hyaluronic acid used in the present invention includes a pharmacologically acceptable salt form, and a pharmaceutically acceptable salt thereof can be used as necessary in the preparation. For example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, amine salts such as tri (n-butyl) amine salt, triethylamine salt, pyridine salt and amino acid salt Can do.

  Or various commercially available hyaluronic acid can also be used, for example, what is marketed as a product name hyaluronic-san HA-F (average molecular weight 700-1.2 million, QP Corporation) can be used.

  The present invention also provides a food for alleviating the symptoms of autoimmune disease comprising hyaluronic acid as an active ingredient. The food of the present invention has an effect of alleviating the symptoms of autoimmune disease when an autoimmune disease patient takes the food of the present invention as part of treatment. Moreover, the foodstuff of this application can also be ingested by adding or mixing to a patient's meal.

  Food includes not only solid and semi-solid food products but also so-called beverages that are liquid or highly fluid. For example, the food of the present invention can be contained in any food product such as animal food, vegetable food, processed food, seasoning material, cooking material, taste food, processed food. Moreover, it can be contained in arbitrary drinks, such as water, soft drinks, alcoholic beverages, tea, coffee, liquid food, for example. Specific examples of foods and beverages include, for example, nutritional supplements and supplements. Moreover, it can also be set as a health food paying attention to the function which relieves the symptom of an autoimmune disease. Furthermore, with the approval of the Ministry of Health, Labor and Welfare, it is also possible to sell it as a food for specified health use that can advocate the effect of alleviating symptoms of autoimmune diseases.

  Hyaluronic acid is a biological substance, so even if it is ingested in large amounts, it is considered that there is no side effect or very low, but the amount of hyaluronic acid of the present invention to be ingested as a food and beverage is 1-1000 mg per day, preferably A standard of 15 to 300 mg can be used. Moreover, in the case of the drink containing the hyaluronic acid of the present invention, the hyaluronic acid of the present invention can be contained in the drink in an amount of 0.001 to 1% by weight, preferably 0.01 to 0.5% by weight. In addition, the amount of hyaluronic acid taken as a pharmaceutical can be 10 mg to 10 g, preferably 200 to 1000 mg per day. The number of administrations can be selected once or multiple times per day depending on the symptoms.

  As described above, the food of the present invention can be contained in any food and beverage. In order to alleviate the symptoms of autoimmune diseases, it is desirable to continuously take the hyaluronic acid of the present invention. Therefore, it is desirable to include the food of the present invention in foods and beverages taken on a daily basis.

  The content of the hyaluronic acid of the present invention contained in a pharmaceutical product varies depending on the use and form of the pharmaceutical product, and those skilled in the art can appropriately select an appropriate amount. In addition, the agent of the present invention may contain water, excipients, antioxidants, preservatives, wetting agents, thickeners, buffers, adsorbents, solvents, emulsifiers, stabilizers, surfactants as necessary. Additives such as lubricants, water-soluble polymers, sweeteners, flavoring agents, acidulants, alcohols and the like can be added. The pharmaceutical dosage form is not particularly limited, but for example, oral administration of solid preparations such as tablets, powders, fine granules, granules, capsules, pills, liquids such as liquids, suspensions, syrups, emulsions, etc. Agents.

  The food (foodstuffs and beverages) containing the hyaluronic acid of the present invention can be used as a part of treatment or as an adjunct to treatment by a patient suffering from autoimmune disease for a long period of time by ingesting it comfortably. Mitigation and improvement can be achieved. Moreover, the patient reserve army who is highly likely to suffer from autoimmunity by judging from family history and the like can prevent or delay the onset of these autoimmune diseases by ingesting the food of the present invention. Moreover, the pharmaceutical containing the hyaluronic acid of this invention can relieve the symptom of the autoimmune disease of the said patient, or prevent or delay the onset of the autoimmune disease of the said patient reserve arm by oral administration.

  The present invention will be described in more detail with reference to the following examples. However, the present invention is not intended to be limited thereby.

  MRL mice are pathological model mice that spontaneously develop autoimmune diseases such as rheumatism, and it is known that changes such as hair loss and crusting occur in the skin due to autoimmune diseases. In this test, low molecular weight hyaluronic acid and the hyaluronic acid of the present invention were administered to MRL mice by drinking water, and the effects of low molecular weight hyaluronic acid and the hyaluronic acid of the present invention on the hyaluronic acid molecular weight of the skin were examined.

Eighteen MRL lpr / lpr strain (SPF) female mice (Charles River Japan, Inc.) of 14 weeks of age (weight approximately 27-37 g) were used in the experiment. Mice were raised in a breeding room set at 22 ± 3 ° C. and a relative humidity of 50 ± 20%, and rat-mouse solid material CE-2 (CLEA Japan, Inc.) was given as feed. As shown in Table 1 below, distilled water (Otsuka distilled water, Otsuka Steam Pharmaceutical Co., Ltd.), low molecular weight hyaluronic acid (average molecular weight 200 to 400,000, QP Corporation) or hyaluronic acid of the present invention (HA-F, average) A product obtained by diluting a molecular weight of 70 to 1,200,000, a prototype of QP Corporation with distilled water, was given freely.
These test substances were prepared aseptically using a clean bench at room temperature. For the preparation, it was prepared to a predetermined concentration using distilled water for injection and stored refrigerated until use.

  The dose of low molecular weight hyaluronic acid and HA-F was set to 200 mg / kg / day, which is expected to be effective when administered with drinking water. As a result of preliminary studies, the amount of water consumed per day for mice was 6 ml / animal, and the body weight of MRL mice was about 33 g. Therefore, the concentrations of low molecular weight hyaluronic acid and HA-F were set to 1.1 mg / ml. .

  In addition, it is known that pathological conditions such as lymphadenopathy spontaneously develop in MRL mice. In this example, administration was started from 14 weeks of age, which is the initial stage of the disease state. The dosing period was a 28-day study considered appropriate for evaluating the efficacy of drinking water.

After 28 days of experiment, mouse skin was homogenized in buffer and digested with proteolytic enzymes. The supernatant was electrophoresed, blotted, and stained with hyaluronic acid binding protein. The molecular weight was calculated based on a commercially available hyaluronic acid with a known molecular weight. The results are shown in FIG. In the control distilled water group, the average molecular weight of hyaluronic acid in the skin is about 500,000, compared to an average of about 300,000 in the low molecular weight hyaluronic acid group and an average of about 850,000 in the HA-F group. The molecular weight was about 1.7 times that of the distilled water group and about 2.8 times that of the low molecular weight hyaluronic acid group.
In addition, the periphery of the nose where hair loss was observed in the distilled water group and the low molecular weight hyaluronic acid group was photographed for each of the distilled water group, the low molecular weight hyaluronic acid group, and the HA-F group. The results are shown in FIG.

  As shown in FIG. 2, it was revealed that hair loss due to autoimmune disease confirmed in the distilled water group and the low molecular weight hyaluronic acid group was suppressed by drinking HA-F. It is presumed that administration of high molecular weight hyaluronic acid increased the molecular weight of hyaluronic acid in the skin, which suppressed hair loss, one of the symptoms of autoimmune diseases.

It is a graph which shows the average molecular weight of the hyaluronic acid in the skin of the mouse | mouth which drunk and administered distilled water, low molecular-weight hyaluronic acid, or HA-F. It is the photograph which compared the hair removal around the nose of the mouse | mouth which administered drinking water, distilled water, low molecular-weight hyaluronic acid, or HA-F.

Claims (7)

  An autoimmune disease symptom alleviating agent comprising hyaluronic acid having an average molecular weight of 500,000 or more as an active ingredient.   The average molecular weight of hyaluronic acid is 700-1.2 million, The autoimmune disease symptom alleviating agent according to claim 1.   The autoimmune disease symptom alleviating agent according to claim 1 or 2, wherein the autoimmune disease is associated with a skin disease.   The autoimmune disease symptom alleviating agent according to any one of claims 1 to 3, wherein the skin disease is associated with hair loss.   A pharmaceutical comprising the autoimmune disease symptom alleviating agent according to any one of claims 1 to 4.   The pharmaceutical product according to claim 5, which is taken orally.   A food comprising the autoimmune disease symptom alleviating agent according to any one of claims 1 to 4.