ヒアルロン酸とその誘導体の研究

Hyaluronic酸(HA), also known as ガラスacid, is のkind のlinear macro分子acidic mucopolysaccharide widely distributed でhuman body とanimal body.In 1934, Professor Meyer のColumbia University isolated ヒアルロン酸からのvitreous body のcow's eye、そしてkendellらは1937年に発酵スープからヒアルロン酸を抽出した。長年の研究により、ヒアルロン酸の構造、特性、機能が明確に理解され、美容、ヘルスケア、臨床、医薬品など多くの分野で応用されています。

1ヒアルロン酸の分布

ヒアルロン酸is widely distributed でnature, でのbody, more than 50% ヒアルロンの酸exists でのskin, lungs とintestines. In addition, it is also found in のinterstitial tissues such as synovial fluid, cartilage, umbilical cord とblood vessel wall. In early studies, のmain source のヒアルロン酸was のumbilical cord. 現在、ヒアルロン酸can be extracted からanimal tissues, such as のcorns のchickens, the vitreous humor のeye, brain cartilage, joint fluids, or fermented によってbacteria, such as Streptococcus, Pseudomonas aeruginosa, etc. [1]. のfermentatiにmethod ヒアルロンの酸productiにis gradually replacing the tissue extractiにmethod because のits 低cost, abundant raw materials, easy to produce にa large scale, とhigh 分子quality のthe ヒアルロン酸obtained.

In recent years, the latest research にヒアルロン酸at home とabroad has focused にthe optimisatiにのthe fermentatiにprocess as well as the derivatisation とdegradation のhyaluronic acid. However, the fermentation technology in China is not mature, so tissue extraction still has an irreplaceable role. At the same time, people are also trying to find hyaluronic 酸からother organisms. China'の海洋資源は、安価で入手しやすい量が大きい、と魚の目は、廃棄された場合、資源の廃棄物だけでなく、水の富栄養化を形成しやすいだけでなく、漁業開発プロセスの廃棄物である生態環境を危険にさらす。しかし、魚の目からヒアルロン酸を抽出する原料は、廃棄物の利用と総合的な開発の効果を達成するだけでなく、コストを削減し、経済的な需要を満たすことができます。

2ヒアルロン酸の構造と性質

2.1ヒアルロン酸の構造

ヒアルロン酸is the only non-sulfur mucopolysaccharide known so far, it is a linear straight chain polysaccharide polymer formed by repeating arrangement のdisaccharide units, D-glucuronic 酸とN-acetylglucosamine are connected by β-1,3 glycosidic bond in each disaccharide unit, とthe disaccharide units are connected by β-1,4 glycosidic bond. The molecule consists のtwo monosaccharides in a 1:1 molar ratio [2]. The structure ヒアルロンのacid から異なるorganisational sources is the same, but the length of the sugar chain とthe 分子mass are different, the relative molecular mass is generally 105-107, とthe number of disaccharide units is 300-1,100 pairs [3].

2.2ヒアルロン酸の性質

ヒアルロンacid is generally a white amorphous solid, colourless とodourless, とstrong hygroscopicity, very soluble in water, insoluble in organic solvents. Hyaluronic acid forms a rigid spiral column of 200nm in space, and the inner side of the column is strongly hydrophilic due to hydroxyl groups; at the same time, due to the continuous directional arrangement of hydroxyl groups, it forms a highly hydrophobic region on the molecular chain of hyaluronic acid[4]. At the same time, due to the continuous orientation of the hydroxyl groups, highly hydrophobic regions are formed in the molecular chain of hyaluronic acid [4]. Hyaluronic acid has a very strong water-absorbing capacity, good osmotic pressure and viscoelasticity in aqueous solution, and its affinity ためadsorbed water is about 1,000 times its own mass, so it is recognised as a natural moisturising factor [5-6].

3ヒアルロン酸の準備

Hyaluronic acid can be prepared by tissue extraction or fermentation. Fermentation is not limited by the source of hyaluronic acid, has high yield and low cost, and is easy to form large-scale 産業生産without the risk of contamination by pathogenic viruses of animal origin, so it has gradually become a hot research topic. However, the fermentation method is limited by high equipment requirements, high investment in the early stage, large volume of fermentation broth and large amount of bacteria and their metabolites, and so on, and the processing volume and complexity of hyaluronic acid isolation are higher than that of the tissue extraction method.

3.1組織抽出

3.1.1地球の原材料

The most commonly used raw material ためtissue extraction is chicken crowns, which is usually crushed directly and then treated とacetone or ethanol, and then extracted とsterile water directly or heated.Dong 若いKang[7] cut frozen chicken crowns into pieces and repeated acetone precipitation several times, and after drying, they obtained 80g of chicken crowns dried powder, and 500mg of hyaluronic acid was extracted, とa final yield of 0.6%. Wang Jian et al[8] used domestic crude trypsin enzyme to 抽出chicken crowns after grinding, and filtered with 120 mesh filter cloth and diatomaceous earth at 60 ℃, meanwhile, the 効果secondary enzyme digestion on the purity and molecular mass of hyaluronic acid was also investigated, and the final yield of hyaluronic acid からchicken crowns was 0.4%~0.6%.

The vitreous body of the eye is another major source of hyaluronic acid, and in the early stage, the eyeballs of terrestrial organisms such as cows and sheep were mainly used as the main raw material. Guo Yutao et al[9] used the vitreous body of 牛eyes as raw material, peeled off the outer skin, removed the lens, and obtained the vitreous body fluid. After a series of separation and purification process, the final hyaluronic acid recovery rate of 79.5%.

3.1.2海洋生物資源

陸上生物から抽出されたヒアルロン酸には病原性細菌が含まれていることが多く、製品の安全性に問題があります。したがって、現在の研究のホットスポットは、原料として比較的安全な水生生物を使用することであり、その中で最も広く使用されているのはフィッシュアイです。鱼眼レンズ過程で廃棄物漁業としての発展を豊富にありしかも必要な、安価で入手しやすいが、廃棄されたりすれば、資源だけでなく無駄に、水の富栄養化の原因にもなりやすい体に有害だという生態環境などの分野に充てる。したがって、魚の目からヒアルロン酸を抽出することで、廃棄物利用と総合開発の効果が得られるだけでなく、ヒアルロン酸抽出のコストを下げることができる[10]。秦Qian'an et al. [11] thawed the イカeye and stripped out the vitreous body, put it into acetone degreasing ため24h, dried, crushed, and then extracted with 0.2mol /L ナトリウムchloride solution. After neutral protease digestion, the final hyaluronic acid yield reached 85.7% and the protein removal rate reached 91.1%.

Yao Meiqin et al.[12] investigated the effect of protein removal by Sevage method, isoelectric point precipitation (IEP) and trichloroacetic acid (TCA) after obtaining the crude extract of hyaluronic acid からsquid eyes, and the protein content of IEP method contained the least amount of protein, and the protein content of the final product was 3.06%, with the total yield of hyaluronic acid of 2.96%. Amagai et al.[13] obtained high purity hyaluronic acid by repeated CPCprecipitation-dissolution and alcohol precipitation with 95% ethanol solution containing 10% potassium acetate.Muradoa et al.[14] obtained hyaluronic acid with molecular mass of 2,000 kDa and purity of 99.4% by 使用ultrafiltration and dialysis of the hyaluronic acid extract からswordfish. Lu Jiafang [15] used DEAE-Sephadex A-25 column chromatography to purify hyaluronic acid からsquid eyes, and eluted with distilled water and 0.95mol/L NaCl solution step by step to obtain two hyaluronic acid fractions, which accounted ため5.22% and 82.37% of the sample volume, respectively.

Besides 魚eyes, other aquatic organisms are also rich in hyaluronic acid. Sun Zhihua et al.[16] studied the extraction of hyaluronic acid from the mucus of loach, and the results showed that the extract contained hexanedioic acid and aminocaproic acid, and the infrared spectroscopy 分析showed that the extract was in complete agreement with the scanning pattern of hyaluronic acid standard. Nicola et al[17] obtained hyaluronic acid ためthe first time from the mollusc二枚貝purple mussel, and the purity of hyaluronic acid reached 97% after degreasing, enzyme digestion and anion-exchange resin, etc. Giji[18] extracted hyaluronic acid with a molecular mass of 1,365 kDa from the liver of stingray, and the analytical results showed that it was of high purity and good antioxidant activity. In recent years, with the increasing market demand for hyaluronic acid, the production of hyaluronic acid from aquatic organisms has gradually become an important issue in the rational development of 海洋resources.

In addition to cockles, fish eyes and loaches, hyaluronic acid has also been extracted from pig skin, forest frog skin and egg shell membrane [19-20].

3.2修飾されたヒアルロン酸の調製

によって取得されたヒアルロン酸共組織抽出処理および微生物発酵は時代に1、贫乏人の弊害安定hyaluronidaseとフリーラジカル感度は退化しやすい保持時間に余裕が無いの体内で、確信で機械実力不足などが、システムアプリケーションを制限しており、な情報を口に改善が必要だ機械力それに特性をanti-degradationて[21]ます。

3.2.1架橋ヒアルロン酸

The cross-linking of hyaluronic acid refers to the intermolecular cross-linking reaction between hyaluronic acid and cross-linking agent with relevant functional groups, or the intramolecular cross-linking reaction with cross-linking agent as catalyst, to obtain the molecular mesh structure with different cross-linking degree, which results in the 成長of molecular chain of hyaluronic acid, the increase of average molecular mass, the enhancement of viscous-elasticity, the relative weakening of water solubility, and the enhancement of 機械strength [22-23]. Commonly used cross-linking methods include hydrazide cross-linking, disulfide cross-linking, polyethylene glycol cross-linking, aldehyde cross-linking and carbodiimide cross-linking.

( 1) Hydrazide cross-linking: Hydrazide compounds can be used as cross-linking agents to modify flowable gels into brittle and mechanically hard gels, and the most commonly used cross-linking agent is adipic dihydrazide (ADH), which is used to produce stable HA-ADHderivatives of hyaluronic acid in the presence of a large amount of adipic dihydrazide. Xu et al. [24] prepared HA-ADH gel films by chemically modifying hyaluronic acid molecules using ADH as a cross-linking agent. The crosslinked film was obviously dissolved in the buffer, and the solubility was lower than that before crosslinking, and the stability was improved.

(2) Carbodiimide cross-linking: Carbodiimide (EDC) can react with the carboxyl group of hyaluronic acid in acidic solution to form N-acyl urea compounds, and then add with different carbodiimides to form cross-linking derivatives with good stability, high rigidity, high biodensity, and high hyaluronic acid enzyme degradation resistance [25]. Lai et al.[26] investigated the 生体適合性of EDC-crosslinked hyaluronic acid gel in the anterior chamber of the mouse eye, and the results showed that compared with glutaraldehyde-crosslinked membranes, these gel membranes were more biocompatible with the eye and had a higher tensile resistance.

(3) Sulfone cross-linking: The rapid cross-linking of divinyl sulfone (DVS) with the hydroxyl group of hyaluronic acid at room temperature resulted in gels with different properties. The cross-linking degree of the gel can be changed by controlling the concentration of hyaluronic acid, molecular mass, HA/DVS value and pH of the reaction medium. Wang Yanguo et al[27] obtained DVS-HA gels by cross-linking DVS at room temperature, and used ethanol precipitation to remove the residual DVS, and finally made cross-linked hyaluronic acid dry powder.

(4) Photocrosslinking: Photocrosslinking has the advantages of fast reaction, good reproducibility and non-toxic solvent, which is very suitable for the preparation of hyaluronic acid hydrogel. Luo Chunhong et al.[28] used glycidyl methacrylate (GMA) to chemically modify hyaluronic acid, and then crosslinked it to form hydrogel under radiation. The results showed that by increasing the degree of GMA substitution of hyaluronic acid, the cross-linking density of hydrogel could be increased, which led to smaller pore sizes, improved mechanical properties, and slower degradation rate of the gel. In the further study, Luo Chunhong constructed a self-reinforced double cross-linked hyaluronic acid hydrogel. Firstly, hyaluronic acid microsphereswith different cross-linking densities were prepared by reversed-phase microemulsion polymerisation (小学校cross-linking), and then modified with glycidyl methacrylate (GMA) to introduce reactive double bonds, and then the GMA-modified hyaluronic acid molecular chain was used as the base phase and the modified microspheres as the reinforcing phase, and then cross-linking was performed twice under ultraviolet radiation, resulting in a self-reinforced double-cross-linking hyaluronic acid hydrogel with double-cross-linking structure. This kind of hydrogel 改善the mechanical strength of hyaluronic acid and prolongs the sustained release time of proteins[29] .

2.2.2非架橋型ヒアルロン酸

( 1) Esterification: Esterification of hyaluronic acid includes hydroxyl and carboxyl modification, i.e., the hydroxyl group in the structure of hyaluronic acid undergoes esterification with 酸or anhydrides, or the carboxyl group reacts with alcohols, phenols, epoxides, or halogenated hydrocarbons to form esterified 派生 Vazquez et al[30] permeated hyaluronateナトリウムinto acid in a cation exchange resin, added tetrabutylammonium hydr酸化to neutrality, freeze-dried the hyaluronic acid, dissolved it in anhydrous dimethylsulfoxide (DMSO), and added p-chloromethylstyrene to obtain the ester compound HA-VB. This compound can be further cross-linked under the action of ultraviolet light.

(2) Graft modification: The grafting reaction of hyaluronic acid involves the grafting of small molecules or polymers onto the main chain of hyaluronic acid. Oldinski et al[31-32] prepared a biomaterial for bone tissue repair by graft copolymerisation of hyaluronic acid with high density polyethylene (HDPE). Palumbo et al. [33] prepared low molecular mass tetrabutylammonium salt of hyaluronic acid (HA-TBA), and then reacted it with NHS-activated polylactic acid (PLA-NHS) in dimethylsulfoxide to obtain the graft 共HA-PLA.

(3) Hydrophobic modification: Hyaluronic acid is highly hydrophilic, often exists in the form of sodium salt, and is insoluble in most organic solvents, so it is difficult to modify or combine it with many hydrophobic substances.Pravata et al.[34] modified sodium hyaluronate with cetylammonium bromide (CTA-Br) to obtain hydrophobic CTA-HA, and then grafted poly(lactic acid) (COL-OLA), which was chloride terminated, to NHS activated polylactic acid (PLA-NHS) in dimethylsulfoxide. (Then COL-OLA was grafted onto CTA-HA in dimethylsulfoxide to obtain the degradable derivative CTA-HAOLA, which can be further self-assembled in aqueous solution to form a hydrogel.

4ヒアルロン酸の応用

It is well known that hyaluronic acid has been widely used in cosmetics, ophthalmology and joint surgery due to its unique physicochemical properties. It is worth noting that the effect of hyaluronic acid is closely related to its molecular mass, which varies according to the purpose of use. High molecular mass hyaluronic acid has a good moisturising and lubricating effect and is mostly used in 眼科or joint surgery; medium molecular mass hyaluronic acid has a good slow-release effect and is often used in cosmetics and post-surgical anti-adhesion; and small molecular mass hyaluronic acid has anti-tumour, immunomodulatory, and angiogenesis-promoting effects [35].

4.1高分子ヒアルロン酸(hmwha)の応用

4.1.1関節疾患の治療

Hyaluronic acid is the main component of articular cartilage and synovial fluid. In osteoarthritis, rheumatoid arthritis, and other infectious and non-infectious arthritis, the concentration and molecular mass of hyaluronic acid in the synovial fluid are reduced, and the cartilage is degraded and destroyed, which leads to physiological dys機能of the joints [36]. Therefore, in the treatment of joint diseases, hyaluronic acid can be supplemented to restore the lubrication function of synovial fluid and promote joint repair, and the effect of high molecular mass hyaluronic acid is better than that of低分子量ヒアルロン酸.

According to Ji[37] , regular intra-articular injections of 1% exogenous high molecular mass hyaluronic acid can not only increase the content of hyaluronic acid in the intra-articular cavity, but also act as a synovial fluid to protect articular cartilage from wear and tear and slow down the degeneration of articular cartilage. Fu Lifeng [38] compared the efficacy of Synvisc (欣维可) and Hyalgan (海尔根) with relative molecular mass of 6 × 106-7 × 106 on rabbit knee osteoarthritis, and the results showed that the degree of damage to the knee cartilage in the Synvisc group was lower than that in the Hyalgan group. The results showed that the degree of cartilage damage in the knee joint of the Synvisc group was lower than that of the Hyalgan group, and the protective effect of Synvisc was stronger and the therapeutic effect was better.

4.1.2眼科アプリケーション

The reticular structure of hyaluronic acid varies according to its molecular mass. Compared with hyaluronic acid of low molecular mass, hyaluronic acid of high molecular mass forms a more complete reticular structure, so its viscoelasticity is higher, hydrophilicity and lubrication are better, and it can stabilise the tear film, prevent the cornea from drying out, reduce the friction of ocular tissues, and alleviate the dry eye syndrome. It can stabilise the tear film, prevent corneal dryness, reduce the friction of ocular tissues and alleviate dry eye. When it is combined with fibronectin, it can promote the connection and extension of corneal epithelial 細胞and accelerate the healing of corneal wounds [39].

さらに、高分子ヒアルロン酸は術後の癒着を防ぐことができ[40-41]、薬剤の緩徐な放出を防ぐ効果がある[42]。

4.2低分子ヒアルロン酸(lmwha)の応用

Currently, hyaluronic acid and its derivatives as a drug delivery system is a hot research topic, which is based on the fact that hyaluronic acid can bind to some specific receptors on the セルsurface, so its use as a drug carrier can improve the targeting of drugs, and at the same time prolong the duration of action of the drug in vivo, improve bioavailability, and 強化the therapeutic efficacy. Compared with high molecular mass hyaluronic acid, low molecular mass hyaluronic acid has the properties of low viscosity, anti-tumour and activation of 免疫cells, so it is often used as a drug carrier.

4.2.1ヒアルロン酸ナノ粒子

Choi et al [43] used hyaluronic acid to produce nanoparticles. After systemic administration to mice carrying tumours, the hyaluronic acid ナノ粒子could circulate in the blood for 2 days and selectively accumulate at the tumour site. In addition, hyaluronic acid ナノ粒子can be modified with hydrophobicity, or made into novel copolymersand graft derivatives to change the particle size and drug loading capacity and improve the targeting ability. It was shown in [44] that after systemic administration of hyaluronic acid nanoparticles, they usually accumulate in the liver first, but polyethylene glycolated hyaluronic acid nanoparticles can effectively reduce this phenomenon, and at the same time, their circulation time in the blood was significantly increased, and their accumulation effect in the tumour site was 1.6 times more than that of the unmodified hyaluronic acid nanoparticles.

4.2.2ヒアルロン酸修飾脂質キャリア

Liposome is a widely used carrier in drug delivery system, which has slow release, targeting and biocompatibility. If attached with glycoconjugates such as hyaluronic acid, they can reach the target more effectively, but the attached hyaluronic acid must be low molecular mass hyaluronic acid and its oligosaccharides, because high molecular mass hyaluronic acid has high viscosity, which affects the rheological properties of the drug [45].

yang xiaoyan[46]は、パクリタキセルナノリピドキャリア(ptx-nlc)を調製し、次いで、相対分子量30万と10億のヒアルロン酸をptx-nlc表面に電荷吸着して、それぞれ活性標的型ヒアルロン酸修飾パクリタキセルナノリピドキャリア(ha-nlc)を得た。結果は、比較的の使用を示した low molecular mass hyaluronic acidより安定した輸送体を作り出すことができますin vivo薬物動態および薬物動態試験では、ha-nlcは、パクリタキセル注射taisu®よりもin vivoでの腫瘍抑制効果が良好であり、薬物の循環時間を延長し、心臓および腎毒性を減少させた。同時に、ha-nlcの腫瘍における総ターゲティング効率は約1.4倍に向上し、腫瘍に対する積極的なターゲティングが明らかになった。張Wenqiang[47]まず変性高分子ヒアルロン酸とヒアルロン酸取得とは別に比較的分子大量15万~ 20万にもなるので、ヒアルロン酸を準備しliposome reversed-phase蒸着法、通気捜査、ヒアルロン酸理論的根拠を提供会社の「化粧品する際に使用される搬送波としてliposomeに使用する。

4.2.3ヒアルロン酸と薬剤の結合

The carboxyl group, ammonia group and reducing end of hyaluronic acid can be amidated and esterified and 結合with antitumor drugs to form a drug coupling body, which can prolong the retention time of the former drug in the body and enhance the water solubility of the drug and the targeting of the tumour. Xin Dingtui [48] designed a new type of anticancer drug paclitaxel precursor system using low molecular mass hyaluronic acid as the carrier. Leucine, phenylalanine and valine were used as linker arms to bind with the drug molecules, and then linked with hyaluronic acid with a molecular mass of 9,800 Da, which resulted in a large increase in the molecular mass of the original drug, and thus the water solubility was affected, and paclitaxel'の溶解度は、良好な細胞殺滅効果と元の薬剤よりも低いic50値で、増加しました。galerら[49]は、頸部扁平上皮がん(scchn)のマウス腫瘍モデルにヒアルロン酸-パクリタキセル結合を用いたが、これは腫瘍の成長を効果的に阻害し、純粋なパクリタキセル注入よりもマウスの生存率を向上させた。「チーンBaoyueらです【50】昔、ヒアルロン酸(メラティ= 150万)を修正するdoxorubicin (t)とpolyamide-amine結合化合物を形成するdrug-carrying樹状高分子nanocarrierシステムをが大幅にする可能性が細胞内の麻薬doxorubicin解決策に比べの取り込みを同時にに推進するdoxorubicin条を、既に生成されて、手綱核の対象細胞治療効果を向上させる可能性も少なくない。

4.2.4ヒアルロン酸ナノゲル

Nanogels are usually hydrogel particles composed of chemically or physically crosslinked polymer networks, which can be used as a new type of drug carriers due to their high loading capacity and stability. Jieying Ding [51] investigated the effect of the molecular mass of hyaluronic acid on the sulfhydrylated hyaluronic acid in the preparation of sulfhydrylated hyaluronic acid-poly(vinyl alcohol) multilayered hydrogel film carriers. The results showed that the total sulfhydryl groups and disulfide bonds attached to the hyaluronic acid chain decreased with the increase of molecular mass, which could be attributed to the fact that the higher 分子量of hyaluronic acid and the longer molecular chain made it more difficult for the free sulfhydryl groups to form disulfide bonds.Duceppe et al.[52] used *アミン・with ultra-low molecular mass to make a new type of nanogel with hyaluronic acid. Duceppe et al. [52] used ultra-low molecular mass chitosan and hyaluronic acid to make a new type of nanogel. When chitosan and hyaluronic acid were mixed in a 4:1 ratio with a molecular mass of 5 kDa and 64 kDa respectively, a gel with an average size of 146 nm was obtained. Further studies showed that the transfection rate of DNA-encapsulated chitosan-hyaluronic acid gel could be increased from 0.7% to 25% under the same condition.

4.2.5ヒアルロン酸マイクロスフィア

Li Dan et al[53] prepared sodium hyaluronate 薬剤の放出速度を低下させる乳化架橋法によるマイクロスフィアの不溶性骨格による薬剤の放出時間の延長と生物学的利用能の向上。liang henglunらは、ヒアルロン酸を単一の薬剤担体として、以下の欠点があると結論付けている。低分子量ヒアルロン酸は肝臓に保持され、代謝されやすく、目的の組織に到達するのが難しい。高分子量ヒアルロン酸は、受容体を介した細胞毒性が失われるため、活性的な標的を持たない。そこで、liang henglunらは、低分子ヒアルロン酸ナトリウムとキトサンを結合させ、平均粒子サイズ228 nmのヒアルロン酸-キトサン結合微小球(dtx-hactnp)を調製した。そして、mttアッセイは、ヒアルロン酸結合マイクロスフィアが非選択的細胞毒性を減少させ、薬剤の活性的な標的化特性を活性的な標的化特性によって維持できることを示した。

MTTassay showed that the hyaluronic acid-結合drug microspheres could reduce the non-selective cytotoxicity and maintain the antitumour 活動of the drug を通じてactive targeting. Similarly, Zhou Panghu et al[55] showed that hyaluronic acid-chitosan microspheres could significantly inhibit the activity of induciblenitric oxide シンターゼin osteoarthritic chondrocytes in vitro, avoiding the production of excessive NO, thus inhibiting the destruction of articular cartilage and protecting 自分の軟骨細胞。

4.2.6ヒアルロン酸ナノエマルジョン

Nanoemulsions are good carriers for transdermal drug delivery because of their small particle size, high transdermal permeability and high drug-carrying capacity. Gao Yuanyuan et al.[56] used hyaluronic acid with a molecular mass of 10-110 K as a carrier, and prepared a 10,11- methylenedioxycamptothecin (MD-CPT) encapsulated hyaluronic acid nanocarrier (HA-GMS) by microemulsion method, which had a significantly higher transdermal efficiency and improved drug efficacy compared with MD-CPT ethanol solution. Kong et al.[57] prepared O/W/S nanoemulsions by modifying hyaluronic acid, in which dichloromethane was the oil phase, HA-GMA was the aqueous phase, and Tween-80 and Spectra-20 were used as surfactants. The nano-emulsions had low protein dispersion, uniform distribution, and the smallest particle size was 39.7 nm, which was a good carrier for lipophilic drugs.

4.2.7他のアプリケーション

Zhang Jinxiang et al.[58] found that small-molecule hyaluronic acid degraded by HMW- HA could 発動the main immune cells in the liver, the b光cells, and promote the secretion of pro-inflammatory factors, which triggered the inflammatory response, while the high molecular mass of hyaluronic acid did not have this function. Low molecular mass hyaluronic acid can also act as an endogenous danger signalling molecule to enhance the humoralimmune 応答to inactivated HAV antigens, and can therefore also be used as an immune adjuvant [59].

5ヒアルロン酸市場

With regard to pharmaceutical hyaluronic acid, the number of people suffering from diseases such as 退行性関節炎of the knee has increased by 4 million from 2000 to 2010, which has led to a rapid growth in the demand for hyaluronic acid as a viscoelastic supplement. In Canada, the orthopaedic market spent $2012年だけで1300万人。日本では、膝の治療のためのヒアルロン酸の市場は、以上の価値があります$新しい治療法の需要が高まっています世界人口の高齢化が加速し、ヒアルロン酸の医学分野での研究が増加していることから、ヒアルロン酸を非ステロイド性抗炎症薬などとして使用することは、ヒアルロン酸の医学分野での市場拡大にも役立つと考えられます[60]。

6結論

With the improvement of living standards, health is becoming more and more important to people, and the development potential of hyaluronic acid market in China is increasing. China has a long coastline and rich marine resources, but a large amount of 浪費is generated in the production and processing process every year, which is not only a waste of resources, but also a great pressure on the environment. The use of cheap and easily available marine resources to extract hyaluronic acid not only reduces the production cost, but also reduces the impact of processing waste on the environment, and opens the way for the development of high value-added products.

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