ヒアルロン酸は安全ですか?

ヒアルロン酸ha(略称ha)は、haとしても知られ、高分子量の直鎖多糖である。1934年には、meyerとpalmer[1]が、牛のガラス組織からヒアルロン酸とそのナトリウム塩を初めて単離しました#目39;する。後に、ヒアルロン酸とその反イオンから形成されたイオン対または塩は、まとめてヒアルロン酸(ヒアルロン酸)と呼ばれるようになった。(1-3)-2-アセトアミド-2-デオキシ- d-グルコース(1-4)- d- d-グルクロン酸の2糖繰り返し単位からなる直鎖ムコ多糖である。分子量は、ソースと調製方法にもよるが、一般的に5万から800万の範囲である。ヒアルロン酸は、関節、硝子体、滑液、臍帯、軟骨、皮膚、cockscombs、a群およびc群溶血連鎖球菌、およびワディントンガムなどの結合組織に存在し、靭性、構造の支持、細胞の代謝調節などの重要な機能を果たしています。

1. ヒアルロン酸の物理的、化学的性質と生理学的機能

1.1ヒアルロン酸の保湿特性

ヒアルロン酸は保水性ポリマーですそれは自然に人間の皮膚にあります。n-アセチルグルコサミンとグルクロン酸の2糖単位が交互に変化することで形成される。溶液中のヒアルロン酸分子の非常に伸びた不規則なコイル状の構造は、それが広い領域を占有することを可能にし、分子鎖が絡み合って連続的なネットワーク構造を形成している。水分子は極性結合と水素結合を介して水分子と直接相互作用し、ヒアルロン酸をスポンジ分子のように作用させ、自身の重さの何千倍もの水分を吸収し、保持します。国際的に最高の保湿剤[2]として認められており、「天然保湿因子」(nmf)として知られています。結合組織におけるヒアルロン酸の保水量は約80 ml/gです。他の天然または合成ポリマーよりも高い保水性を有します。何人かの学者[3]は、ヒアルロン酸の保水性をソルビトールやポリエチレングリコール4000のそれと比較した。その結果(ヒアルロン酸分子量3000 kd)、ソルビトール、ポリエチレングリコール4000 24hの保水率はそれぞれ87.1、32.4、10.5であった。ヒアルロン酸の保水は、その最も重要な生理機能の一つです。 

1.2ヒアルロン酸はプロテオグリカンポリマーの形成に関与している

Under physiological conditions, hyaluronic acid is covalently linked to core proteins in concert with other glycosaminoglycans (such as chondroitin sulfate and keratan sulfate) to form proteoglycan polymers. These giant polymers occupy a large water pressure domain, and can reduce in volume under external pressure. After the pressure is released, they expand to their original volume, thereby maintaining the shape and volume of the tissue and ensuring its reversible compressive resistance. Proteoglycans (PGs) in different tissues have their own special functions. For example, the proteoglycans distributed in connective tissue bind water through amino sugars. This hyaluronic acid-protein-water gel binds cells together, enables normal cell metabolism and tissue water retention, and protects cells from pathogenic bacteria to prevent infection. and gives the skin a certain elasticity. In cartilage, it determines the volume of cartilage and the final shape of the skeleton. In the aorta, it is essential for the optical physiology of the eye together with the vitreous body. In the ovary, PG (without hyaluronic acid) is synthesized regularly with the periodic growth of follicles. The heparan sulfate proteoglycan on the plasma membrane of human liver cells plays an important role in the interaction between cells and the interaction between cells and the matrix.

1.3ヒアルロン酸:細胞生物学への影響

Toole et al. demonstrated that hyaluronic acid is highly abundant during embryogenesis and morphogenesis, and that during differentiation, hyaluronidase removes this hyaluronic acid, producing a differentiated matrix, such as proteoglycans and collagens [4]. The role of hyaluronic acid during differentiation is to cause isotonic tissue edema, which leads to the opening of channels required for cell migration; to assist in the separation and transposition of mesenchymal cells released from the epithelium; and to change the shape and structure of organs.

1.4免疫細胞におけるヒアルロン酸の役割

Domestic and foreign studies have confirmed that hyaluronic acid has a certain effect on macrophages, granulocytes, lymphocytes, natural killer (NK) cells, etc. Hyaluronic acid at low concentrations has a mild effect on the function of phagocytes and NK cells, but inhibits the transformation of lymphocytes and the formation of E rosettes. Hyaluronic acid at higher concentrations has a significant inhibitory effect on the function of lymphocytes, NK cells and phagocytes, and there is a dose-effect relationship.

The extracellular coat (Coat) formed by hyaluronic acid acts as a barrier against cytotoxic lysis. For example, the glycosaminoglycan coat of glioma cells can enhance their resistance to immune killing cells; the hyaluronic acid coat adhering to the cells can block lymphocyte-mediated cell lysis. In addition, this hyaluronic acid coat can prevent viral invasion (such as the invasion of the Newcastle disease virus into human synoviocytes), and interfere with the function of intercellular lectins and lectin receptors.

1.5創傷治癒に対するヒアルロン酸の効果

ヒアルロン酸は、創傷治癒を促進することができます。局所ヒアルロン酸濃度は、創傷の初期段階で著しく上昇し、さまざまな炎症細胞に調節効果をもたらします。高濃度、高分子ヒアルロン酸は、治癒促進効果が高く、コラーゲンの合成を調節し、繊維の活性を調節し、抗炎症作用があります。一方、低分子ヒアルロン酸は血管新生を促進します。創傷中のヒアルロン酸は酵素によって低分子ヒアルロン酸に分解され、それが創傷治癒を促進します。

2ヒアルロン酸の応用

2.1化粧品におけるヒアルロン酸

2.1.1ヒアルロン酸とリン脂質が乳化剤を形成する[5]

In the absence of other emulsifiers, the addition of hyaluronic acid and phospholipids to an oil-water mixture can form a stable emulsion. This natural emulsifier composed of hyaluronic acid and phospholipids is characterized by both emulsifying and moisturizing properties. It is a safe and effective emulsifier that cannot be matched by other synthetic surfactants and can be used in the preparation of skin creams, lotions, facial cleansers, etc.

2.1.2ヒアルロン酸とポリオキシエチレンは増粘剤を形成する[6]

Polyoxyethylene (molecular weight 100-5000kD) is a commonly used thickener in cosmetics, and hyaluronic acid (molecular weight 3000kD) solution also has a high viscosity. The viscosity of the two combined is much greater than the sum of their individual viscosities. Therefore, hyaluronic acid-polyoxyethylene solution is an excellent thickener with good moisturizing properties, and can be used in cosmetics such as creams and lotions.

2.1.3香り固定剤としてのヒアルロン酸[7]

According to the characteristics of hyaluronic acid, which has the function of molecular encapsulation of various substances, it is used in fragrance products. Hyaluronic acid, as a fixative combined with fragrance, can slow down the volatilization rate of the fragrance and make the fragrance last longer. It is suitable for perfumes, skin care creams, emollients, deodorants, etc. Hyaluronic acid has two advantages in addition to fixing the fragrance: first, it reduces the adverse irritant effect of the fragrance on sensitive skin and reduces allergic reactions; second, it prevents adverse chemical reactions between certain fragrances and skin secretions and prevents the formation of odors.

2.2臨床診断におけるヒアルロン酸の値

Hyaluronic acid levels are significantly elevated in many diseases. Clinically, measuring the serum hyaluronic acid level can reflect changes in various diseases. Studies have shown that changes in serum hyaluronic acid levels are closely related to the course of liver disease and the degree of liver cell damage. In recent years, domestic and foreign scholars have confirmed that the serum hyaluronic acid of patients with liver cirrhosis is significantly elevated, and the degree of elevation of hyaluronic acid is positively correlated with the degree of liver cirrhosis. Therefore, serum hyaluronic acid can be used as a reliable indicator for the diagnosis of liver cirrhosis. Presig believes that this indicator is significantly superior to previous indicators for diagnosing liver cirrhosis (such as the albumin/globulin ratio, pro-collagen III peptide, etc.), and can better reflect the degree of liver cirrhosis than liver puncture and biopsy.

2.3純粋なヒアルロン酸製品の臨床的価値

In the 1980s, Balazs and others developed a cross-linked hyaluronic acid derivative, hylan, and explored its physiological properties and clinical applications. It was found that hylan has the same biocompatibility as natural hyaluronic acid, inspiring people to clinically prevent adhesion after trauma or surgery and repair soft tissues [8].

2.3.1眼科手術におけるヒアルロン酸[9,10]

Hyaluronic acid gel and its high elasticity can be used in a variety of ophthalmic microsurgery. It has been recognized that hyaluronic acid gel is essential in ophthalmic microsurgery. Hyaluronic acid gel is now widely used as an essential filler in various ophthalmic surgeries such as extracapsular cataract extraction, intraocular lens implantation, retinal detachment surgery and corneal transplantation. In addition, hyaluronic acid can also be used for eye canal reopening and dry eye syndrome. Extensive clinical applications over the past 20 years have shown that the role of hyaluronic acid viscoelastic substances in ophthalmic microsurgery is not simply to provide operating space, but also to provide viscoelasticity without a lining, tissue separation, soft tissue restoration, viscous occlusion, viscous bleeding, viscoelastic buffering and viscoelastic fixation, which can greatly reduce surgical trauma, reduce the degree of postoperative inflammatory response, reduce surgical complications, and achieve the goal of improving vision.

2.3.2骨および関節疾患の治療におけるヒアルロン酸

The lubricating and cushioning effect of hyaluronic acid has led to its use in the treatment of osteoarthritis, periarthritis of the shoulder and rheumatoid arthritis. Hyaluronic acid gel is used for intra-articular injections to treat osteoarthritis. Not only does it overcome the side effects of previous hormone treatments, but its short- and long-term effects are also superior to those of hormones, making it the material of choice for treating osteoarthritis. At the 18th International Anti-Rheumatic Federation meeting in July 1993, hyaluronic acid was considered to have a disease-repairing effect on osteoarthritis and is a disease-repairing osteoarthritis treatment [11]. In fact, since hyaluronic acid injections for osteoarthritis were marketed in Italy in 1987, intra-articular injections have been marketed in many countries, and clinical trials are also being conducted in the UK and the US. Japan Bio-Chem&#変形性関節症に対するヒアルロン酸注射は症状を64.1%改善し、1993年の売上高は271億円に達した[12]。

2.3.3ヒアルロン酸の鼓膜修復への応用[13]

Tympanic membrane perforation is a common clinical condition caused by acute and chronic otitis media, trauma, etc. Surgical repair of the tympanic membrane often causes changes in the structure of the original tympanic membrane after surgery, affecting the degree of hearing recovery. This is mainly related to the formation of scar tissue and the use of graft materials. In recent years, domestic and foreign research on the application of medical sodium hyaluronate in tympanic membrane repair has achieved gratifying results. Summary: A large number of clinical results show that hyaluronic acid treatment for tympanic membrane perforations is feasible, without any side effects, and is a good means of treating small dry tympanic membrane perforations.

2.3.4ヒアルロン酸:産婦人科における臨床応用

(1) a:腹腔鏡検査後のアプリケーション,子宮鏡検査や他の子宮内手術

It is known in medical practice that hyaluronic acid is present in the peritoneal fluid, uterine cavity fluid and fallopian tube fluid. The use of hysteroscopy and laparoscopy can cause the loss or dilution of components of the abdominal or uterine cavity fluid, and temporary real space gaps in hyaluronic acid may also occur. Local trauma, bleeding and exudation during surgery can disrupt the internal environment of the uterus, affecting the function of the female reproductive tract and mucosa to varying degrees. The interaction of these factors can lead to impaired organ function or infertility and other consequences. Hylan B gel is a highly viscoelastic. A non-permeable derivative, its polysaccharide chains are cross-linked by divinyl sulfone, making it a good soft tissue filling material. Therefore, in laparoscopic and hysteroscopic use, Hylan B gel can be used as an operating medium for the lens to separate tissues and expose the field of view, which not only accelerates the repair of the damaged surface and the amount of synthesis, but also does not affect the surgical field of view, facilitating operation and reducing the possibility of postoperative complications such as blockages and adhesions. [14]

(2)ヒアルロン酸を用いた術後の癒着防止

In 1971, Balazs et al. reported the role of hyaluronic acid in preventing adhesion formation between tendons and sheaths, conjunctiva and iris. They found that high viscoelastic, high molecular weight hyaluronic acid solutions and hyaluronic acid membranes can reduce the incidence of adhesion formation, and have no adverse effect on wound healing. A large number of animal experiments and clinical applications have shown that hyaluronic acid is a safe and effective substance for preventing and reducing adhesion caused by surgery.

(3)膣内ヒアルロン酸

Hyaluronic acid is secreted and distributed in the fallopian tubes and guiding tissues of mammals, as well as between the epithelial cells of the mucous membrane. Experiments have found that low-density areas of vigorous cell proliferation are always accompanied by increased synthesis of hyaluronic acid. Hyaluronic acid and its derivatives act as a medium for controlled drug release. Therefore, in clinical use of vaginal medication, the moisturizing and lubricating properties, viscoelasticity, and characteristics of hyaluronic acid as a drug carrier can be utilized. Hyaluronic acid can both increase the self-cleaning and lubricating effects that have been disrupted in the vagina, allowing the local epithelial cells to recover, while also slowly releasing the drug it is carrying into the vagina, where it can exert a pharmacological effect for a long time, restore the vagina to its normal state, and heal the original disease.

(4)ヒアルロン酸製剤の延長使用

Wound healing is a process involving multiple cells and their products that work together to rebuild and regenerate the extracellular matrix. Current research has confirmed that hyaluronic acid plays an important role in the process of wound healing. With the development of fetal surgery, a glycoprotein called hyaluronic acid stimulatory factor has received increasing attention. It can significantly increase the hyaluronic acid content in the wound matrix, thereby regulating collagen synthesis. This is considered to be an important factor in the fetal wound healing process without scarring.

2.4ヒアルロン酸の安全性に関する議論

The hyaluronic acid in the preparation is the same as the endogenous hyaluronic acid, which is non-toxic, non-antigenic, and not likely to cause a foreign body reaction. Clinical applications have shown that hyaluronic acid has good safety, and most of them indicate that hyaluronic acid is well tolerated, with an adverse reaction rate of 0% to 10%. Japan has conducted comprehensive preclinical and clinical safety experiments on hyaluronic acid preparations, which have proven their safety and efficacy in clinical use. Common adverse reactions are mostly mild to moderate pain or swelling at the administration site or injection site, as well as symptoms such as headache or fever in individual patients. Adverse reactions often occur within 1 to 2 days of administration, and patients can generally tolerate them without treatment, and they will disappear on their own after 2 days. Obstetrics and gynecology, especially when used in the vagina, has very low absorption, and hyaluronic acid has even fewer adverse reactions. Currently, hyaluronic acid macromolecular cross-linked membrane agents and compound preparations with other anti-adhesion drugs are being studied for their potential in anti-adhesion due to their good safety and controlled-release effects.

3 .ヒアルロン酸の生産

3.1動物の臓器からの抽出

Hyaluronic acid is mainly extracted from umbilical cords, cockscombs, vitreous bodies of cattle and sheep eyes, and whale cartilage. These animal tissue sources are difficult and expensive to obtain, and the hyaluronic acid content in the tissue is very low, resulting in a low yield of product. During the extraction process, large amounts of organic solvents and enzymes must be used, and the process is complex and involves many operating units, which greatly increases the cost of hyaluronic acid and makes it difficult to produce it on a large scale. Foreign companies that use this method include Kabi, Fidia, Gen-zyme, Sweden'sのpヒアルロン酸症と日本's Biochemical Industry Company. The level of research in China is relatively low, and hyaluronic acid production is still in the organ extraction stage, with the main raw materials being umbilical cords and cockscombs. The Shanghai University Journal reported a method for extracting hyaluronic acid from pig skin, and the molecular weight of the resulting hyaluronic acid is about 106. Currently, companies that use this method to produce hyaluronic acid include Shandong Freda Pharmaceutical Company and Shaanxi Pharmaceutical Industry Research Institute.

3.2微生物発酵法

As early as 1937, Kendall et al. [15] discovered that streptococci could produce hyaluronic acid, and many people have conducted research on this. Shiseido of Japan first reported the use of streptococci to produce hyaluronic acid in 1985. China is currently developing this method, and Yan Jialin of Zhengzhou Animal Husbandry Engineering College and others have used hyaluronic acid-deficient streptococci to ferment and produce hyaluronic acid that meets cosmetic requirements. Strains with high fermentation yields are generally obtained by mutagenesis. A Japanese patent reports a method of mutagenesis using NTG (N-methyl-N-nitro-nitrosoguanidine), and a two-step mutagenesis treatment is used to obtain a variant that does not produce hyaluronic acid.

The fermentation rate is as high as 6.7 g/l, and the molecular weight is ≥10×105. The fermentation yield of the original strain without mutagenesis is only 2 g/l, and the molecular weight is 3×105 to 6×105. The mutagenesis rates of the two-step treatment are 4×10-6 and 5×10-5, respectively. In other words, it takes hundreds of thousands or even millions of bacteria to obtain a desired variant, and the amount of work involved is imaginable. A new fermentation process for producing hyaluronic acid has also been developed in China, using hyaluronic acid-producing bacteria obtained by gamma irradiation combined with magnetic field mutagenesis. The results passed the national-level achievement appraisal organized by the Ministry of Chemical Industry on July 29, 1998, and the conclusion was that the technical level has reached the international advanced level. The fermentation level of hyaluronic acid is 4-6.5 g/l. According to literature, the current international fermentation level of hyaluronic acid is 6.5 g/l at the highest.

3.3動物胎児の細胞分離法

アメリカのバイオテクノロジー企業であるgenzymeは、1994年にこの問題を重要なテーマにし、現在の動物の臓器から抽出する方法を置き換えようと試みた。つまり、動物の細胞培養では、ある種の細胞を大量に増殖させて特定の物質を抽出することが重要なバイオテクノロジーの分野である[16]。しかし、現在のところ、この方法の文書や報告例はありません。

参照:

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[2]呉Dongruます。炭水化物の生化学[m]。北京:高等教育出版社、1987年:627。

永井[3]正義です。化粧品の成分。^ a b c d e『人事興信録』第62版、8203頁。

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【7】Bracke) Jwマリオット・ホテル。ヒアルロン酸/ヒアルロン酸tasedフレグランス製品,wo 85/04803, 1985。

【8】侯俊基、張天民、牛貴珍。中国生化薬学会誌[j]。^『官報』第2626号、大正5年。

【9】周立斌、張大琴。中国生化薬学会誌[j]。1998年(5):289。

【10】張延氷、天yeqing。中国生化薬学会誌[j]。1998年(5):288。

【11】李衛平、劉尚立、林道賢。中国生化薬学会誌[j]。1998年(5):252-254。

[12]羅Ruiming。寧夏農業学院[j]誌。2001年(平成13年)2月1日- 62-64号。

[13] pienordio dj, larsen ne, denlinger jl, et al。軟部組織増強材料としてのhylan b gel (hylaform) [a]。クライン。え~。臨床実践における組織増強:手順と技術[c]。『マルセル・デッカー』新潮社、1998年。269-291。

【14】楊小紅、凌peixue、王鳳山。中国生化薬学会誌[j]。^『官報』第2019号、大正8年5月8日。

【15】ケンダル号PE。a群のstrcptococcusのmucoid株によって作られた、血清学的に不活性なポリサックヒアルロン酸酸体[j]。^ a b c d e f g h i j biol chem, 1937(118): 61-69。

慈円[16]徐。江蘇食品発酵[j]。1996年(平成8年)(1)-)。