JP2009102278A - Knee joint pain reliever - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a knee joint pain reliever capable of expecting the moderation of knee joint pain by taking it orally, without performing a physical treatment or a surgical operation. <P>SOLUTION: This knee joint pain reliever of oral use includes hyaluronic acid having 600,000 to 1,600,000 average molecular weight or its salt as an active ingredient, and further an oral medicinal composition or a foodstuff composition containing the knee joint pain reliever is also provided. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a knee joint pain relieving agent containing hyaluronic acid or a salt thereof, and an oral pharmaceutical composition and food composition containing the knee joint pain relieving agent.

  An increasing number of people complain of knee joint pain due to aging and obesity. There are various causes of knee joint pain, but in particular, cartilage that cushions the knee joint is worn down, inflammation occurs in the knee, and degenerative knee joint disease in which the joint deforms as it progresses becomes serious.

  Degenerative knee joint disease initially causes pain at the beginning of the knee movement, such as when standing up, and when this progresses, pain also appears during walking on the flat ground or at night, and severely restricts life and daily activities. It will be received.

  Treatment of degenerative knee joint diseases includes taking anti-inflammatory analgesics to suppress inflammation pain or injecting sodium hyaluronate into the joint. In addition, physical therapy such as muscle strength and thermotherapy is taken. However, if remission cannot be expected by such conservative treatment, surgical procedures such as osteotomy and artificial joint replacement are taken. Both have a great mental and physical burden on the patient.

  Therefore, it is expected that the pain of the knee osteoarthritis can be alleviated or reduced by oral intake of pharmaceuticals and foods. Patent Document 1 (USP 6607745) alleviates joint pain and other pain associated with degenerative knee joint disease by oral contact with hyaluronic acid or a salt thereof, or a degradation product thereof at 0.1 to 400 μg / kg body weight. A method is described. However, the molecular weight of effective hyaluronic acid or a salt thereof, and the therapeutic results when ingesting the hyaluronic acid or a salt thereof are not clearly described.

United States Patent: 6607745

  The present invention is intended to solve the problems of the background art, and contains an oral knee joint pain relieving agent for alleviating knee joint pain represented by degenerative knee joint disease and the knee joint pain relieving agent. It is an object of the present invention to provide an oral pharmaceutical composition and a food composition and to provide a method for alleviating knee joint pain.

  The present inventor observed a change in subjective symptoms with medical indicators by orally ingesting a predetermined amount of hyaluronic acid or a salt thereof having a specific molecular weight band to a subject complaining of knee joint pain. Decreased significantly in weeks. Furthermore, the present invention has been completed by finding that it improves even in daily living conditions, normal activities, and health conditions.

  That is, the present invention relates to an oral knee joint pain relieving agent containing hyaluronic acid having a specific molecular weight band or a salt thereof as an active ingredient, an oral pharmaceutical composition containing the same, a food composition, and the hyaluronic acid or Provided is a method for alleviating knee joint pain by ingesting a predetermined amount of the salt.

  According to the oral knee joint pain relieving agent of the present invention, hyaluronic acid having a specific molecular weight band or a salt thereof as an active ingredient is contained as a pharmaceutical composition or a food composition, and a predetermined amount thereof is taken orally. This can alleviate knee joint pain and improve daily life and activities.

  The knee joint pain relieving agent of the present invention contains hyaluronic acid or a salt thereof having an average molecular weight of 600,000 to 1.6 million. Here, hyaluronic acid is a polymer compound classified into a polysaccharide having disaccharides of glucuronic acid and N-acetylglucosamine as repeating structural units. If the average molecular weight of hyaluronic acid is too small or too large, the effects of the invention are hardly obtained, and preferably 600,000 to 1,500,000, more preferably 600,000 to 1,200,000.

  The average molecular weight of hyaluronic acid used in the present invention is defined as a value obtained by the following method, although the amount of sample collected varies depending on the molecular weight.

  That is, about 0.05 g when the molecular weight of hyaluronic acid is about 800,000 to 1.6 million, and about 0.1 g of hyaluronic acid when the molecular weight of hyaluronic acid is about 600,000 to 800,000, Dissolve in a 2 mol / l sodium chloride solution to make exactly 100 ml and accurately measure 8 ml, 12 ml, and 16 ml of this solution, and add 0.2 mol / l sodium chloride solution to each to make exactly 20 ml. The solution obtained is used as a sample solution. This sample solution and 0.2 mol / l sodium chloride solution were measured at 30.0 ± 0.1 ° C. according to the viscosity measurement method (first method capillary viscometry method) of the Japanese Pharmacopoeia (14th revision) general test method. The specific viscosity is measured by (Equation (1)), and the reduced viscosity at each concentration is calculated (Equation (2)). Draw a graph with the reduced viscosity on the vertical axis and the concentration (g / 100 ml) of the product converted to dry matter on the horizontal axis, and obtain the intrinsic viscosity from the intersection of the straight line connecting each point and the vertical axis. The intrinsic viscosity obtained here is substituted into Laurent's formula (formula (3)) to calculate the average molecular weight.

  Examples of the salt of hyaluronic acid include sodium salt, potassium salt, calcium salt, zinc salt, magnesium salt, ammonium salt and the like. The salt of hyaluronic acid can be produced by a known method.

  There is no restriction | limiting in particular in the usage form of the knee joint pain relieving agent of this invention, It can be set as usage forms, such as a powder form, a granular form, a high concentration liquid, and a low concentration liquid. In view of the stability of the molecular weight of hyaluronic acid or a salt thereof, a dry form is preferable to a liquid form. Moreover, the compounding quantity of the hyaluronic acid or its salt of a knee joint pain relieving agent can be suitably determined according to a usage form and the addition amount to a pharmaceutical composition or a food composition.

  The knee joint pain relieving agent can be blended with a bulking agent, a binder, a lubricant, a preservative, an antioxidant, a fragrance, a sweetener, an acidulant, an excipient, and the like, if necessary. . In addition, vitamins such as vitamin C, vitamin B2, vitamin B12, and vitamin E, various nutritional components such as nutritional components such as nucleic acid, chondroitin sulfate, and collagen, and mineral components such as iron and zinc can also be blended.

  The hyaluronic acid used in the present invention can be a commercially available product, but can also be produced according to the following production methods 1 and 2.

<Production method 1 (extraction from chicken crown)>
First, the chicken crown is heat-treated. This is because the protein contained in the chicken crown is heat denatured or the enzyme is deactivated. Any method may be used for the heat treatment, but it can be efficiently performed by immersing the chicken crown in hot water. The heating temperature and time are not particularly limited as long as the protein in the chicken crown is thermally denatured or the enzyme is deactivated. When the heating method using hot water is adopted, hot water at 60 to 100 ° C. It is good to immerse the raw material in it for 20 to 90 minutes.

  In addition, when using a frozen chicken crown, the chicken crown may be heated as it is, but it is preferable that a frozen chicken crown is put in running water or the like and then slowly thawed, and then heat-treated to obtain a certain quality.

  Next, the heat-treated chicken crown is made into a paste. This pasting improves the yield of hyaluronic acid. Prior to pasting, if the chicken crown after heat treatment is cut into thin pieces with a shredder, or shredded with a chopper for grinding meat, etc., it becomes easy to make a paste. As an example of pasting, if approximately 1 to 5 times the amount of fresh water is added to the chicken crown and homogenized with a homogenizer for 10 to 60 minutes, the chicken crown is crushed and finely divided, and can be finished into a paste. In addition, you may use a high-speed stirrer and a crusher other than a homogenizer for pasting.

  Next, acid agents such as hydrochloric acid and sulfuric acid, and alkali agents such as sodium hydroxide and potassium hydroxide are added to pasted chicken crowns to reduce the molecular weight of hyaluronic acid by acid treatment or alkali treatment. The average molecular weight of the acid is adjusted to 600,000 to 1,600,000, preferably 600,000 to 1,200,000. As an adjustment method, the concentration of the acid agent or alkali agent, the amount added, and the treatment time may be appropriately combined so that the hyaluronic acid after treatment has a desired molecular weight. It is preferable because the molecular weight can be easily controlled. If an example by an alkali treatment is shown, after adding about 1-5% of alkaline aqueous solution of 10-30% concentration with respect to a chicken crown, and treating at 25-70 degreeC for about 15-90 minutes, Neutralize with hydrochloric acid to adjust the molecular weight.

  Next, a protease is added to the raw material whose molecular weight has been adjusted, and protease treatment is performed. Any proteolytic enzyme can be used as long as it is commercially available, and examples thereof include pepsin, trypsin, papain, promeline and the like. The amount of the protease added is suitably 0.01 to 1% with respect to the chicken crown. In addition, the temperature and time of protease treatment are suitably in the range of 35 to 65 ° C. and 1 to 10 hours.

  Finally, hyaluronic acid is fractionated from the obtained protease-treated product to obtain crude hyaluronic acid, and then purified by purifying this hyaluronic acid, having a purity of 90% or more and an average molecular weight of 600,000 to 1.6 million Is obtained.

  Here, the fractionation and purification of hyaluronic acid can be performed according to a conventional method. For example, first, the protease-treated raw material is filtered to remove solids to obtain a filtrate containing crude hyaluronic acid. Prior to filtration, activated carbon may be added to the protease-treated product for the purpose of deodorization / decolorization or removal of some protein degradation products. And after melt | dissolving salt in the obtained filtrate, ethanol is added and hyaluronic acid is precipitated, and a deposit is fractionated. Thereafter, hydrous ethanol having an ethanol concentration of about 80 to 95% by volume is added to the precipitate, washed with a homogenizer, and the precipitate is collected. Hyaluronic acid used in the present invention can be obtained by repeating this washing with hydrous ethanol about 2 to 10 times and drying the collected precipitate.

<Production Method 2 (Microbial Fermentation Method)>
Hyaluronic acid-producing Streptococcus microorganism (Streptococcus
Activated carbon is added to the culture solution of Zooepidemicus to deodorize and decolorize, followed by filtration. Sodium chloride is dissolved in the obtained filtrate, ethanol is added to precipitate hyaluronic acid, and the precipitate is collected. Thereafter, hydrous ethanol having an ethanol concentration of about 80 to 95% by volume is added to the precipitate, washed with a homogenizer, and the precipitate is collected. Hyaluronic acid (average molecular weight of 60 to 1,600,000) that can be used in the present invention can be obtained by repeating the washing with hydrous ethanol about 2 to 10 times and drying the collected precipitate.

  In addition, the purity of hyaluronic acid used in the present invention may be a level that can be used in food, and preferably 90% or more. The purity is defined as a value obtained by removing impurities other than hyaluronic acid from 100% in terms of dry matter. Here, examples of the impurities include protein degradation products, fat (crude fat), chondroitin sulfate, and the like. Specifically, the purity of hyaluronic acid using chicken crown as a raw material can be obtained by the following formula (4).

  In the formula (4), the proteolysate (%) is a value obtained by the Lowry method, and the crude fat (%) is a new food analysis method (published by Korin Co., Ltd.) “Chapter 1 General components and related components. “1-4 lipids, 1-4-2 ether extraction method” and chondroitin sulfate (%) are values obtained by the method described below.

  First, hyaluronic acid is dried, and 50 mg of it is precisely weighed and dissolved by adding purified water to make exactly 100 ml as a test solution. Take 4 ml of the test solution in a test tube and add 1 ml of 0.5 mol / l sulfuric acid. Then, 0.2 ml of 0.04 mol / l cetyltrimethylammonium bromide was added to the solution obtained by heating in a water bath for 10 minutes and then cooling, and the mixture was allowed to stand at room temperature for 1 hour. Absorbance at a length of 10 mm and a wavelength of 660 nm is measured.

  Next, the obtained absorbance data is applied to a calibration curve for chondroitin sulfate to determine the amount (%) of chondroitin sulfate in purified hyaluronic acid. Here, the calibration curve is obtained by drying (depressurization, phosphorus pentoxide, 60 ° C., 5 hours) of chondroitin sulfate A sodium salt (SG (Special Grade), manufactured by Seikagaku Corporation) derived from whale cartilage. Precisely weigh and dissolve in purified water, and prepare solutions containing 10 μg, 20 μg, 30 μg, and 40 μg of chondroitin sulfate A sodium salt in 1 ml, respectively. For each 4 ml of solution, 1 ml of sulfuric acid with a concentration of 0.5 ml / l After mixing, 0.2 ml of 0.04 mol / l cetyltrimethylammonium bromide was added and mixed. After standing at room temperature for 1 hour, the absorbance was measured in the same manner. It was prepared by plotting a sulfate A sodium salt solution (μg / ml) on the horizontal axis.

  The oral knee pain relieving agent of the present invention described above can be preferably applied to an oral pharmaceutical composition or food composition for the purpose of reducing knee joint pain. That is, this pharmaceutical composition can take a dry form such as a powder, granule, tablet, capsule, or a liquid form such as a liquid, syrup, or suspension. In addition, in food compositions, supplements based on powders, granules, tablets and capsules, or blended into various processed foods such as beverages, confectionery, block foods for nutritional supplements, jelly foods, seasonings, etc. can do. In order to expect the effect of the present invention, it is necessary to take it continuously every day. Therefore, if it is in the form of a pharmaceutical composition or a food composition, a supplement according to the form of the pharmaceutical is preferable. In addition, in the processed food, it is preferable to avoid foods that have undergone a heating step or those that have acidic and alkaline pH from the viewpoint of the stability of the molecular weight of hyaluronic acid or a salt thereof.

  The amount of hyaluronic acid or a salt thereof contained in the oral pharmaceutical composition or food composition is not particularly limited. From the therapeutic results described below, the equivalent amount of hyaluronic acid or a salt thereof is 120 mg or more per day. In view of the fact that good results have been obtained with the intake of 240 mg, it is preferable that the amount is designed so that this amount can be easily continued every day. Specifically, for example, in the case of a soft capsule, by taking 40 to 120 mg per capsule, the daily intake is 1 to 6 soft capsules, which is reasonable. When blended as a food composition, if the blended amount per meal is too low, it is necessary to consume a large amount every day in order to take a predetermined amount, which is severe for the patient. In addition, if the food to be blended is highly palatable, the daily intake may not be determined, and the effect may be hindered.

  Further, the amount of intake of the oral knee joint pain relieving agent of the present invention or the oral pharmaceutical composition and food composition containing the oral knee pain relieving agent is one day in the examples described later from the effectiveness of knee joint pain alleviation. It is preferable to take 60 to 300 mg from the body weight and the degree of pain of the person who ingests because the effect is shown by ingestion of 120 mg or 240 mg per person.

  The oral pharmaceutical composition or food composition described above is formulated according to a conventional method so that the knee joint pain relieving agent containing hyaluronic acid or a salt thereof having an average molecular weight of 600,000 to 1,600,000 as an active ingredient is at an appropriate concentration. Can be manufactured.

  Hereinafter, the effect of the present invention will be described in detail with reference to examples.

<Summary>
Hereinafter, as shown in detail, hyaluronic acid having an average molecular weight of 600,000 to 1,200,000 is orally administered in the form of soft capsules to 15 men and women with subjective symptoms of knee joint pain, 240 mg per day, before ingestion, for 4 weeks Thereafter, the course after 8 weeks was investigated in accordance with the JKOM knee joint pain questionnaire and the criteria for treatment of degenerative knee disease (JOA).

1. Test article and ingestion According to production method 2, hyaluronic acid having an average molecular weight of 600,000 to 1,200,000 was obtained, and a soft capsule was prepared so as to obtain 48 mg per grain. 5 soft capsules (240 mg as hyaluronic acid) were taken as daily intake.

2. Subjects and Number of Subjects 15 subjects who were Japanese men and women aged over 50 years old and under 70 years of age and who were aware of knee joint pain at rest and during exercise were subjects. However, the knee joint disease treatment outcome criteria (JOA) score is low, and Kellgren-Lawrence is a disease classification of knee osteoarthritis (one of the methods for evaluating knee osteoarthritis by X-ray Grades of 0 to 4 were classified according to the degree of progression of symptoms at joint sites), and grades of 1 to 3 were selected on either leg.

3. Evaluation Method and Evaluation Results According to the following method, evaluation was performed before ingestion, 4 weeks after ingestion, and 8 weeks after ingestion.
3.1. JKOM Knee Joint Pain Questionnaire Judgment Criteria 1 of JKOM Knee Joint Pain Questionnaire 1: Evaluation was made based on the degree of knee pain (VAS: visual analog scale) and the change in the total value of criteria 2-5.

<Criteria 1: Knee pain level>
Assuming that “no pain” is 1 and “the most severe pain experienced so far” is 40, the degree of pain is totaled with a score of 40 levels.

<Total value of criteria 2-5>
According to Table 1, the total score (100 perfect score) of 25 questions of 4 items of 2-5 is calculated.

３．２．ＪＫＯＭ膝関節痛アンケート調査結果
表２の通り、判定基準１（膝の痛みの程度）および判定基準２〜５の合計値のいずれも、摂取８週間後は、危険率１％未満で有意に低下した。

3.2. JKOM Knee Joint Pain Survey Results As shown in Table 2, both the criteria 1 (the degree of knee pain) and the sum of criteria 2 to 5 are significantly reduced at a risk rate of less than 1% after 8 weeks of ingestion. did.

３．３．変形性膝関節疾患治療成績判定基準(JOA)によるアンケート調査
表３に示す、変形性膝関節疾患治療成績判定基準(JOA)による４項目のスコアの合計値の変化により、評価を行った。

3.3. Questionnaire survey based on criteria for treating knee joint disease treatment results (JOA) Table 3 was evaluated based on changes in the total score of four items according to criteria for treating knee joint disease treatment results (JOA).

３．４．変形性膝関節疾患治療成績判定基準(JOA)によるアンケート調査結果

表４の通り、変形性膝関節疾患治療成績判定基準(JOA)によるスコアの合計値は、摂取８週間後、危険率１％未満で有意に低下した。

3.4. Questionnaire survey results based on the JOA treatment outcome criteria

As shown in Table 4, the total score according to JOA treatment score criteria (JOA) significantly decreased at a risk rate of less than 1% after 8 weeks of ingestion.

Thus, as a result of oral administration of 240 mg a day in the form of a soft capsule to 15 men and women with subjective symptoms of knee joint pain, hyaluronic acid having an average molecular weight of 600,000 to 1,200,000, JKOM knee joint pain after 8 weeks The total value of the evaluation and the knee joint disease treatment outcome criteria (JOA) scores both improved significantly with a risk rate of less than 1%.
Therefore, it was confirmed that knee joint pain can be alleviated by orally ingesting a supplement containing hyaluronic acid having an average molecular weight of 600,000 to 1,200,000 as an active ingredient.

Furthermore, as a result of oral administration of hyaluronic acid having an average molecular weight of 800,000 to 1,600,000 according to production method 2 to 120 other men and women with subjective symptoms of knee joint pain, 120 mg per day in the form of soft capsules, The total score of the JKOM knee joint pain evaluation after 8 weeks was significantly improved at a risk rate of less than 1%.
In this study, questionnaire survey based on JOA treatment outcome criteria (JOA) was not conducted, but hyaluronic acid with an average molecular weight of 800,000 to 1.6 million, as in the previous study, has a knee joint pain alleviating effect. I was able to confirm.

  The oral knee joint pain relieving agent of the present invention contains hyaluronic acid having an average molecular weight of 600,000 to 1,600,000 or a salt thereof as a main component, and 120 to 240 mg per day is orally administered to a patient complaining of knee joint pain for 8 weeks. Ingestion alleviated knee joint pain, and as a result, the total value of JKOM knee joint pain assessment and knee joint disease treatment outcome criteria (JOA) scores both improved significantly with a risk rate of less than 1% . Therefore, this knee joint pain relieving agent and the oral pharmaceutical composition and food composition containing the same are effective in alleviating knee joint pain.

Claims (5)

  An oral knee joint pain relieving agent comprising hyaluronic acid having an average molecular weight of 600,000 to 1.6 million or a salt thereof as an active ingredient.   The knee joint pain relieving agent according to claim 1, wherein the knee joint pain is caused by degenerative knee joint disease.   An oral pharmaceutical composition comprising the knee joint pain relieving agent according to claim 1 or 2.   A food composition containing the knee joint pain relieving agent according to claim 1 or 2. A method of relieving knee joint pain by orally ingesting 60 to 300 mg of hyaluronic acid or a salt thereof having an average molecular weight of 600,000 to 1.6 million per day.