JP2006335694A - Treating agent for osteoarthritis - Google Patents
Treating agent for osteoarthritis Download PDFInfo
- Publication number
- JP2006335694A JP2006335694A JP2005163086A JP2005163086A JP2006335694A JP 2006335694 A JP2006335694 A JP 2006335694A JP 2005163086 A JP2005163086 A JP 2005163086A JP 2005163086 A JP2005163086 A JP 2005163086A JP 2006335694 A JP2006335694 A JP 2006335694A
- Authority
- JP
- Japan
- Prior art keywords
- hyaluronan
- osteoarthritis
- salt
- joint
- administration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
Description
本発明は、ヒアルロナンを有効成分とする変形性関節症治療剤に関する。 The present invention relates to a therapeutic agent for osteoarthritis containing hyaluronan as an active ingredient.
ヒアルロナンは、D−グルクロン酸とN−アセチル−D−グルコサミンとの2糖繰り返し単位から構成されている長鎖の多糖であり、一方、オリゴ糖も知られている。ヒアルロナンは鶏冠、さい体、皮膚、関節液などの生体組織からの抽出液、またはストレプトコッカス属の細菌を用いる発酵法などにより製造され、毒性学的および免疫学的作用が存在しないため、薬剤や化粧品として利用されており、例えばヒアルロナンの関節内注射による関節炎の治療がよく知られている。以下の説明において、4糖のヒアルロナンをHA4と記載する。 Hyaluronan is a long-chain polysaccharide composed of disaccharide repeating units of D-glucuronic acid and N-acetyl-D-glucosamine, while oligosaccharides are also known. Hyaluronan is produced by extraction from biological tissues such as chicken crowns, corpses, skin, joint fluids, or fermentation methods using bacteria of the genus Streptococcus, and has no toxicological or immunological effects. For example, treatment of arthritis by intraarticular injection of hyaluronan is well known. In the following description, the tetrasaccharide hyaluronan is referred to as HA4.
HA4には、臓器保存、肝障害および胃潰瘍に対する治療・抑制効果があることが報告されている(特許文献1参照)。また、HA4には、ストレス蛋白発現増強作用および細胞死抑制作用があることが知られている(非特許文献1参照)。 HA4 has been reported to have therapeutic / suppressive effects on organ preservation, liver damage, and gastric ulcers (see Patent Document 1). Moreover, it is known that HA4 has a stress protein expression enhancing action and a cell death suppressing action (see Non-Patent Document 1).
一方、変形性関節症は、慢性の関節炎を伴う関節疾患で、関節の構成要素の退行変性により、軟骨の破壊と骨、軟骨の増殖性変化を来たす疾患である。また、関節炎(滑膜炎)が上記変化により二次的(続発性)に発生する。初期には痛みは関節を使いすぎた後に生じ、安静でおさまる。進行すると軽い運動や安静時にも痛みを来たし、夜間痛もよく見られる。関節を強く曲げ伸ばしたり、運動時コツコツ音がしたり、関節炎で関節が腫れ関節液が貯留することもある。 On the other hand, osteoarthritis is a joint disease associated with chronic arthritis, and is a disease that causes destruction of cartilage and proliferative changes in bone and cartilage due to degenerative degeneration of joint components. In addition, arthritis (synovitis) occurs secondary (secondary) due to the above change. Initially, the pain occurs after overuse of the joints and calms down. As it progresses, it causes pain during light exercise and rest, and night pain is common. The joint may be bent and stretched strongly, the sound of knacking may be heard during exercise, or the joint may swell due to arthritis and the joint fluid may accumulate.
原因としては、関節構成要素の退行変性(年齢による変化)を基盤として遺伝的要因、加令、肥満、関節不安性症、繰り返しの亜脱臼・脱臼、労働、スポーツなどによる関節への負荷等がその進行に関与している。 Causes include genetic factors, age, obesity, joint anxiety, repeated subluxation / dislocation, labor, and stress on joints due to degenerative degeneration (change with age) of joint components Involved in its progression.
治療としては、初期には、抗炎症薬や痛み止めの薬を服用したり、痛み止めの入った湿布剤やテープなどを塗ったりするとおさまる。膝では大腿四頭筋力の強化訓練が有効である。股関節では外転筋力訓練(横になり足を上に挙上する)が有効である。膝や股関節の変形性関節症では杖の使用も関節への負担がへり有効である。関節内への関節保護剤の注入も有効である。関節内へのステロイドの注入療法は、乱用すると関節破壊を強めることもあり注意を要する。痛みや変形が強い場合、膝や股関節では骨切り術や人工関節などの手術の適応となる。 Treatment can be stopped in the early days by taking anti-inflammatory drugs or pain relieving drugs, or applying a poultice or tape containing pain relievers. In the knee, quadriceps strength training is effective. In the hip joint, abduction muscle strength training (lie down and raise your foot up) is effective. For osteoarthritis of the knee and hip joint, the use of a cane is effective because it places a burden on the joint. Injection of joint protective agents into the joint is also effective. Caution should be exercised when injecting steroids into the joint, as abuse may increase joint destruction. When pain and deformation are strong, knee and hip joints are indicated for surgery such as osteotomy and artificial joints.
本発明は、変形性関節症治療剤を提供することを目的とする。 An object of the present invention is to provide a therapeutic agent for osteoarthritis.
上述した目的を達成した本発明に係る変形性関節症治療剤は、ヒアルロナンを有効成分として含有する。 The therapeutic agent for osteoarthritis according to the present invention that has achieved the above-described object contains hyaluronan as an active ingredient.
本発明に係る薬剤には、ヒアルロナンを有効成分とするものであるから、比較的安価にかつ容易に大量生産できる利点がある。また、ヒアルロナンは毒性や抗原性がほとんどないこと、生体が元来有している治療作用や疾患の防止作用を増強することから副作用の極めて少ない治療剤として期待される。このように、本発明によれば、変形性関節症に有効な新規な薬剤を提供することができる。 Since the drug according to the present invention contains hyaluronan as an active ingredient, it has an advantage that it can be easily mass-produced at a relatively low cost. Hyaluronan is expected to be a therapeutic agent with extremely few side effects because it has little toxicity and antigenicity, and enhances the therapeutic action and disease prevention action inherent in the living body. Thus, according to the present invention, a novel drug effective for osteoarthritis can be provided.
以下、本発明を詳細に説明する。以下の説明において、本発明に係る治療剤を単に薬剤と称する。 Hereinafter, the present invention will be described in detail. In the following description, the therapeutic agent according to the present invention is simply referred to as a drug.
本発明に係る薬剤に含まれるヒアルロナンとしては、基本的にはβ−D−グルクロン酸の1位とβ−D−N−アセチルグルコサミンの3位とが結合した2糖単位を少なくとも1個含む2糖以上のものでかつβ−D−グルクロン酸とβ−D−N−アセチルグルコサミンとから基本的に構成されるものであれば、2糖単位が1個または複数個結合したものにそれらの要素が結合した糖であってもよく、またこれらの誘導体、例えば、アシル基等の加水分解性保護基を有したもの等も使用し得る。該糖は不飽和糖であってもよく、不飽和糖としては、非還元末端糖、通常、グルクロン酸の4,5位炭素間が不飽和のもの等が挙げられる。本発明で使用するヒアルロナンとしては、具体的には動物等の天然物から抽出されたもの、微生物を培養して得られたもの、化学的もしくは酵素的に合成されたものなどいずれも使用することができる。例えば鶏冠、さい体、皮膚、関節液などの生体組織から公知の抽出法と精製法によって得ることができる。またストレプトコッカス属の細菌等を用いた発酵法によっても製造できる。 The hyaluronan contained in the drug according to the present invention basically includes at least one disaccharide unit in which the 1-position of β-D-glucuronic acid and the 3-position of β-D-N-acetylglucosamine are bonded. As long as it is more than sugar and is basically composed of β-D-glucuronic acid and β-DN-acetylglucosamine, those elements are combined with one or more disaccharide units combined. May be used, and derivatives thereof such as those having a hydrolyzable protecting group such as an acyl group can 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. As the hyaluronan used in the present invention, specifically, those extracted from natural products such as animals, those obtained by culturing microorganisms, those synthesized chemically or enzymatically, etc. should be used. Can do. For example, it can be obtained by known extraction and purification methods from biological tissues such as chicken crown, corpse, skin, and joint fluid. It can also be produced by a fermentation method using Streptococcus bacteria or the like.
本発明においては、ヒアルロナンオリゴ糖もヒアルロナンに包含され、上記2糖単位1個からなる2糖およびその誘導体のような低分子量のヒアルロナンから、重量平均分子量400万程度の高分子量のヒアルロナンまで使用することができる。好ましくは組織における浸透性などの点で優れる重量平均分子量380程度〜900,000程度のヒアルロナンが挙げられ、より好ましくは2〜20糖程度のヒアルロナンを挙げることができる。 In the present invention, hyaluronan oligosaccharides are also included in hyaluronan, and use from low molecular weight hyaluronan such as the above-mentioned disaccharide consisting of one disaccharide unit and its derivatives to high molecular weight hyaluronan having a weight average molecular weight of about 4 million. be able to. Preferably, hyaluronan having a weight average molecular weight of about 380 to 900,000, which is excellent in terms of permeability in tissues, and the like, more preferably about 2 to 20 sugars.
ヒアルロナンのうち分子量の低いものは、具体的には、酵素分解法、アルカリ分解法、加熱処理法、超音波処理法(Biochem., 33(1994)p6503-6507)等の公知の方法によってヒアルロナンを低分子化する方法、化学的もしくは酵素的に合成する方法(Glycoconjugate J., (1993)p435-439、WO93/20827) などで製造することが好ましい。例えば酵素分解法としては、ヒアルロナン分解酵素(ヒアルロニダーゼ(睾丸由来)、ヒアルロニダーゼ(Streptomyces由来)、ヒアルロニダーゼSDなど)、コンドロイチナーゼAC、コンドロイチナーゼACII、コンドロイチナーゼACIII 、コンドロイチナーゼABCなどのヒアルロナンを分解する酵素をヒアルロナンに作用させてヒアルロナンオリゴ糖を生成する方法(新生化学実験講座「糖質II−プロテオグリカンとグリコサミノグリカン−」p244-248、1991年発行、東京化学同人 参照)などが挙げられる。 Specifically, hyaluronan having a low molecular weight can be obtained by known methods such as enzymatic decomposition, alkaline decomposition, heat treatment, and ultrasonic treatment (Biochem., 33 (1994) p6503-6507). It is preferably produced by a method of reducing the molecular weight, a method of chemically or enzymatically synthesizing (Glycoconjugate J., (1993) p435-439, WO93 / 20827). For example, hyaluronan degrading enzymes (hyaluronidase (derived from testicles), hyaluronidase (derived from Streptomyces), hyaluronidase SD, etc.), chondroitinase AC, chondroitinase ACII, chondroitinase ACIII, chondroitinase ABC, etc. A method to produce hyaluronan oligosaccharides by causing an enzyme that degrades hyaluronan to produce hyaluronan oligosaccharides (see Shinsei Chemistry Laboratory "Carbohydrate II-Proteoglycans and Glycosaminoglycans" p244-248, published in 1991, Tokyo Chemical Dojin) Can be mentioned.
また、アルカリ分解法としては、例えばヒアルロナンの溶液に1N程度の水酸化ナトリウム等の塩基を加え、数時間加温して、低分子化させた後、塩酸等の酸を加えて中和して、低分子量のヒアルロナンを得る方法などが挙げられる。本発明で用いるヒアルロナンは、塩の形態を包含し、製剤上の必要に応じて、その薬学上許容できる塩を用いることができる。例えばナトリウム塩、カリウム塩などのアルカリ金属塩、カルシウム塩、マグネシウム塩などのアルカリ土類金属塩、トリ(n−ブチル)アミン塩、トリエチルアミン塩、ピリジン塩、アミノ酸塩等のアミン塩などであることができる。 As an alkali decomposition method, for example, a base such as sodium hydroxide of about 1N is added to a hyaluronan solution, heated for several hours to lower the molecular weight, and then neutralized by adding an acid such as hydrochloric acid. And a method for obtaining a low molecular weight hyaluronan. Hyaluronan used in the present invention includes a 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.
本発明の薬剤は、ある分子量のヒアルロナン単独又は種々の分子量のヒアルロナンを組み合わせたものなど特に限定することなく使用できる。本発明の薬剤は、ヒアルロナンを有効成分とするものであり、その有効量をヒトを含む哺乳動物に投与することによって生体に悪影響を与えることなく変形性関節症を改善することができる。 The drug of the present invention can be used without particular limitation, such as hyaluronan having a certain molecular weight alone or a combination of hyaluronan having various molecular weights. The drug of the present invention comprises hyaluronan as an active ingredient, and osteoarthritis can be improved without adversely affecting the living body by administering an effective amount thereof to mammals including humans.
本発明の薬剤は、ヒアルロナン又はその塩を、そのまままたは必要に応じて担体、賦形剤、その他の添加物と共に、経口的あるいは非経口的に投与(関節内投与、静脈内、筋肉内、皮下などの組織内投与(注射)、経腸投与、経皮投与など)するための医薬品として、任意の剤形に製剤化することが可能であり、任意の投与方法で患者に投与される。特に、本発明に係る薬剤は、経口製剤とすることが好ましい。 The agent of the present invention is administered hyaluronan or a salt thereof, as it is or as necessary, with a carrier, excipient, or other additive, orally or parenterally (intra-articular administration, intravenous, intramuscular, subcutaneous). As a pharmaceutical for administration (injection), enteral administration, transdermal administration, etc.), it can be formulated into any dosage form and administered to a patient by any administration method. In particular, the drug according to the present invention is preferably an oral preparation.
経口製剤としては、散剤、顆粒剤、カプセル剤、錠剤等の固形製剤;シロップ剤、エリキシル剤、乳剤等の液状製剤を挙げることができる。散剤は、例えば、乳糖、デンプン、結晶セルロース、乳酸カルシウム、リン酸水素カルシウム、メタケイ酸アルミン酸マグネシウム、無水ケイ酸等の賦形剤と混合して得ることができる。顆粒剤は、上記賦形剤のほか、必要に応じ、例えば白糖、ヒドロキシプロピルセルロース、ポリビニルピロリドン等の結合剤や、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム等の結合剤や、カルボキシメチルロース、カルボキシメチルセルロースカルシウム等の崩壊剤をさらに加え、湿式又は乾式で造粒して得ることができる。錠剤は、上記散剤又は顆粒剤をそのまま、或いはステアリン酸マグネシウム、タルク等の滑沢剤を加えて打錠して得ることができる。また、上記錠剤又は顆粒剤は、ヒドロキシプロピルメチルセルロースフタレート、メタアクリル酸メチルコポリマー等の腸溶性基剤で被覆し、或いはエチルセルロース、カルナウバロウ、硬化油等で被覆し、これらを腸溶性或いは持続性製剤にすることができる。硬カプセル剤は、上記散剤又は顆粒剤を硬カプセルに充填して得ることができる。また軟カプセル剤は、ヒアルロナン又はその塩を、グリセリン、ポリエチレングリコール、ゴマ油、オリーブ油等に混合し、これをゼラチン膜で被覆して得ることができる。シロップ剤は、白糖、ソルビトール、グルセリン等の甘味剤とヒアルロナン又はその塩とを、水に溶解して得ることができる。また、甘味剤及び水のほかに、精油、エタノール等を加えてエリキシル剤とするか、或いはアラビアゴム、トラガカント、ポリソルベート80、カルボキシメチルセルロースナトリウム等を加えて乳剤又は懸濁剤にすることができる。またこれらの液状製剤には必要に応じ、矯味剤、着色剤、保存剤等を加えることができる。 Examples of oral preparations include solid preparations such as powders, granules, capsules and tablets; liquid preparations such as syrups, elixirs and emulsions. The powder can be obtained by mixing with excipients such as lactose, starch, crystalline cellulose, calcium lactate, calcium hydrogen phosphate, magnesium aluminate metasilicate, and silicic anhydride. In addition to the above excipients, the granule is optionally combined with a binder such as sucrose, hydroxypropylcellulose, polyvinylpyrrolidone, a binder such as carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylrose, carboxymethylcellulose calcium, etc. Further, a disintegrant may be added and granulated by wet or dry method. Tablets can be obtained by compressing the powder or granules as described above or by adding a lubricant such as magnesium stearate or talc. The tablet or granule is coated with an enteric base such as hydroxypropyl methylcellulose phthalate or methyl methacrylate copolymer, or coated with ethyl cellulose, carnauba wax, hardened oil, etc. can do. The hard capsule can be obtained by filling the above powder or granule into a hard capsule. Soft capsules can be obtained by mixing hyaluronan or a salt thereof with glycerin, polyethylene glycol, sesame oil, olive oil or the like and coating it with a gelatin film. The syrup can be obtained by dissolving a sweetener such as sucrose, sorbitol, and glycerin and hyaluronan or a salt thereof in water. In addition to sweeteners and water, essential oils, ethanol and the like can be added to make elixirs, or gum arabic, tragacanth, polysorbate 80, sodium carboxymethylcellulose and the like can be added to make emulsions or suspensions. Moreover, a corrigent, a coloring agent, a preservative, etc. can be added to these liquid preparations as needed.
非経口製剤としては、注射剤、直腸投与剤、ペッサリー、皮膚外用剤、吸入剤、エアゾール剤、点眼剤等を挙げることができる。注射剤は、ヒアルロナン又はその塩に塩酸、水酸化ナトリウム、乳酸、乳酸ナトリウム、リン酸一水素ナトリウム、リン酸二水素ナトリウム等のpH調節剤;塩化ナトリウムウム、ブドウ糖等の等張化剤;及び注射用蒸留水を加え、滅菌濾過した後、アンプルに充填して得ることができる。また、更にマンニトール、デキストリン、シクロデキストリン、ゼラチン等を加えて真空凍結乾燥し、用時溶解型の注射剤とすることができる。またヒアルロナン又はその塩にレシチン、ポリソルベート80、ポリオキシエチレン硬化ヒマシ油等の乳化剤を加えた後、水中で乳化された注射用乳剤とすることもできる。 Examples of parenteral preparations include injections, rectal administration agents, pessaries, external preparations for skin, inhalants, aerosols, eye drops and the like. Injections include hyaluronan or salts thereof, pH regulators such as hydrochloric acid, sodium hydroxide, lactic acid, sodium lactate, sodium monohydrogen phosphate, sodium dihydrogen phosphate; isotonic agents such as sodium chloride and glucose; and It can be obtained by adding distilled water for injection, sterilizing and filtering and then filling ampoules. Further, mannitol, dextrin, cyclodextrin, gelatin and the like can be added and lyophilized in a vacuum to obtain an injection that can be dissolved at the time of use. Moreover, after adding an emulsifier, such as lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, to hyaluronan or its salt, it can also be set as the emulsion for injection emulsified in water.
直腸投与剤は、ヒアルロナン又はその塩にカカオ脂肪酸のモノ、ジ又はトリグリセリド、ポリエチレングリコール等の坐剤用基剤を加えた後、加温して溶解し、これを型に流し込んで冷却するか、或いはヒアルロナン又はその塩をポリエチレングリコール、大豆油等に混合した後、ゼラチン膜で被覆して得ることができる。皮膚外用剤は、ヒアルロナン又はその塩に、白色ワセリン、ミツロウ、流動パラフィン、ポリエチレングリコール等を加え、必要に応じて加温し、混練して得ることができる。テープ剤は、ヒアルロナン又はその塩を、ロジン、アクリル酸アルキルエステル重合体等の粘着剤と混練し、これを不織布等に展延して得ることができる。吸入剤は、例えば薬学的に許容される不活性ガス等の噴射剤に、ヒアルロナン又はその塩を溶解又は分散し、これを耐圧容器に充填して得ることができる。 For rectal administration, add a suppository base such as mono-, di- or triglyceride of cacao fatty acid or polyethylene glycol to hyaluronan or a salt thereof, dissolve by heating, and pour it into a mold to cool, Alternatively, hyaluronan or a salt thereof can be mixed with polyethylene glycol, soybean oil or the like and then coated with a gelatin film. The external preparation for skin can be obtained by adding white petrolatum, beeswax, liquid paraffin, polyethylene glycol or the like to hyaluronan or a salt thereof, and heating and kneading as necessary. The tape agent can be obtained by kneading hyaluronan or a salt thereof with a pressure-sensitive adhesive such as rosin or an alkyl acrylate polymer and spreading it on a nonwoven fabric or the like. The inhalant can be obtained by, for example, dissolving or dispersing hyaluronan or a salt thereof in a propellant such as a pharmaceutically acceptable inert gas and filling the pressure-resistant container.
(投与方法)本発明のヒアルロナンを有効成分とする薬剤の投与方法は、特に限定されないが、静脈内投与、経口投与および関節内投与を挙げることができる。 (Administration method) The administration method of the drug comprising the hyaluronan of the present invention as an active ingredient is not particularly limited, and examples thereof include intravenous administration, oral administration and intra-articular administration.
(投与量)投与量は、対象とする疾患、患者の年令、健康状態、体重等に応じ適宜決定するが、一般には0.05〜50mg/kg を1日1回あるはそれ以上に分けて投与する。 (Dosage) The dosage is appropriately determined according to the target disease, the patient's age, health condition, body weight, etc. Generally, 0.05 to 50 mg / kg is divided once or more once a day. To administer.
(毒性)本発明で使用するヒアルロナンは、医薬としての生物活性を示す投与量において細胞毒性はほとんどもしくは全く認められなかった。 (Toxicity) The hyaluronan used in the present invention showed little or no cytotoxicity at doses showing biological activity as a drug.
以下、本発明に係る薬剤を、実施例を用いてより詳細に説明するが、本発明の技術的範囲は以下の実施例に限定されるものではない。 Hereinafter, although the chemical | medical agent which concerns on this invention is demonstrated in detail using an Example, the technical scope of this invention is not limited to a following example.
〔実施例1〕
本実施例では、変形性関節症を自然発症するC57BL/6マウスにHA4を投与し、その効果を検討した。
[Example 1]
In this Example, HA4 was administered to C57BL / 6 mice that spontaneously develop osteoarthritis, and the effects were examined.
変形性関節症モデル動物
20週齢の雄性C57BL/6マウスを日本チャールスリバーより購入し、変形性関節症を発症した個体を使用した。群構成は、陰性対照(生理食塩水)群及びHA4(100mg/10ml/kg)経口投与群とした。
Osteoarthritis model animal 20-week-old male C57BL / 6 mice were purchased from Charles River Japan and individuals who developed osteoarthritis were used. The group composition was a negative control (saline) group and an HA4 (100 mg / 10 ml / kg) oral administration group.
被検物質の投与
本実施例では、10mg/mlのHA4を調整した。具体的に、HA4は、Tawadaらの方法(Tawada A, Masa T, Oonuki Y, Watanabe A, Matsuzaki Y, Asari A. Large-scale preparation, purification, and characterization of hyaluronan oligosaccharides from 4-mers to 52-mers. Glycobiology. 2002; 12(7):421-6.)により調製し、生理食塩水で濃度を調節した。また、対照としては生理食塩水(生食)を調整した。
Administration of test substance In this example, 10 mg / ml HA4 was prepared. Specifically, HA4 is produced by the method of Tawada et al. (Tawada A, Masa T, Oonuki Y, Watanabe A, Matsuzaki Y, Asari A. Large-scale preparation, purification, and characterization of hyaluronan oligosaccharides from 4-mers to 52-mers. Glycobiology. 2002; 12 (7): 421-6.) And the concentration was adjusted with physiological saline. Moreover, physiological saline (saline) was adjusted as a control.
本実施例では、変形関節症を発症したマウスに、経口用ゾンデを用いて1日1回、2週間、被検物質または生理食塩水を経口投与した。 In this example, a test substance or physiological saline was orally administered to mice that developed osteoarthritis once a day for 2 weeks using an oral sonde.
肉眼所見の実施
変形性関節症の治癒効果を肉眼にて判断した。具体的には、各群に属する全ての個体について、膝関節軟骨表面(脛骨および大腿骨)に墨汁を塗布後、ガーゼで拭き取り、墨汁の障害部位に残存する程度を以下のようにブラインドで肉眼的に5段階評価した(表1)。なお、本評価方法については、Chang DG, Iverson EP, Schinagl RM, Sonoda M, Amiel D, Coutts RD, Sah RL. Quantitation and localization of cartilage degeneration following the induction of osteoarthritis in the rabbit knee. Osteoarthritis Cartilage. 1997 Sep;5(5):357-72.参照。
Macroscopic findings The healing effect of osteoarthritis was judged with the naked eye. Specifically, for all individuals belonging to each group, after applying ink ink to the knee joint cartilage surface (tibia and femur), wipe it off with gauze and blindly observe the extent of ink ink remaining at the damaged site as follows. Evaluation was made on a five-point scale (Table 1). For this evaluation method, see Chang DG, Iverson EP, Schinagl RM, Sonoda M, Amiel D, Coutts RD, Sah RL.Quantitation and localization of cartilage degeneration following the induction of osteoarthritis in the rabbit knee. ; 5 (5): 357-72.
結果
変形性関節症の肉眼所見の結果を表2に示す。
Results The results of macroscopic findings of osteoarthritis are shown in Table 2.
本実施例の結果、HA4投与群では、変形性関節症の治療効果を確認することができた。この結果から、ヒアルロナンを有効成分として含有する薬剤が変形関節症を抑制することが実証された。 As a result of this example, it was possible to confirm the therapeutic effect of osteoarthritis in the HA4 administration group. From this result, it was demonstrated that a drug containing hyaluronan as an active ingredient suppresses osteoarthritis.
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WO2008068854A1 (en) * | 2006-12-05 | 2008-06-12 | Glycoscience Laboratories, Inc. | Therapeutic agent for degenerative arthritis |
WO2013125634A1 (en) * | 2012-02-22 | 2013-08-29 | 株式会社ヒアルロン酸研究所 | Tlr4 agent, tissue homeostasis agent, hepatocyte growth factor inducer, tissue repairing agent, and sirtuin inducer having hyaluronic acid fragments as active ingredients thereof |
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WO2008068854A1 (en) * | 2006-12-05 | 2008-06-12 | Glycoscience Laboratories, Inc. | Therapeutic agent for degenerative arthritis |
US8153614B2 (en) | 2006-12-05 | 2012-04-10 | Glycoscience Laboratories, Inc. | Treatment of osteoarthritis |
WO2013125634A1 (en) * | 2012-02-22 | 2013-08-29 | 株式会社ヒアルロン酸研究所 | Tlr4 agent, tissue homeostasis agent, hepatocyte growth factor inducer, tissue repairing agent, and sirtuin inducer having hyaluronic acid fragments as active ingredients thereof |
JPWO2013125634A1 (en) * | 2012-02-22 | 2015-07-30 | 株式会社ヒアルロン酸研究所 | Sirtuin inducer, tissue repair agent, hepatocyte growth factor inducer, tissue homeostasis maintainer, and TLR4 agonist containing hyaluronic acid fragment as an active ingredient |
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