[화학공학] 히알루론산 및 유도체에 관한 연구에 대한 자료입니다

Hyaluronic산(HA), also known as 유리acid, is 한kind 의linear macro분자acidic mucopolysaccharide widely distributed 에서human body 그리고animal body.In 1934, Professor Meyer 의Columbia University isolated 에서히알루론산이vitreous body 의cow's 눈, 그 후 켄델 등은 1937년 발효 국물에서 히알루론산을 추출했다.사람들은 다년간의 연구를 거쳐 히알루론산의 구조, 성질과 기능을 명확히 이해하게 되였고 미용, 건강관리제품, 임상, 의약품 등 여러 분야에 응용되고있다.

히알루론산의 1분포

루 론산is widely distributed 에서nature, 에서이body, more than 50% 루 론의산exists 에서이skin, lungs 그리고intestines. In addition, it is also found in 이interstitial tissues such as synovial fluid, cartilage, umbilical cord 그리고blood vessel wall. In early studies, 이main source 의루 론산was 이umbilical cord. 현재,루 론산can be extracted 에서animal tissues, such as 이corns 의chickens, the vitreous humor 의eye, brain cartilage, joint fluids, or fermented 에 의해bacteria, such as Streptococcus, Pseudomonas aeruginosa, etc. [1]. 이fermentati에method 루 론의산producti에is gradually replacing the tissue extracti에method because 의its 낮은cost, abundant raw materials, easy to produce 에a large scale, 그리고high 분자quality 의the 루 론산obtained.

In recent years, the latest research 에루 론산at home 그리고abroad has focused 에the optimisati에의the fermentati에process as well as the derivatisation 그리고degradation 의hyaluronic 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 산에서other organisms. China's 해양자원은 수량이 많고 값이 싸며 얻기 쉬우며 물고기눈은 어업발전과정의 페기물로서 폐기하면 자원낭비 뿐만 아니라 수체의 부영양화를 형성하기 쉬워 생태환경을 위험에 빠뜨린다.그러나 물고기 눈에서 히알루론산을 원료로 추출하면 쓰레기 이용 및 종합 개발의 효과를 얻을 수 있을 뿐만 아니라 원가를 절감하고 경제 수요를 충족시킬 수 있다.

히알루론산의 구조 및 특성 2

2.1 히알루론산의 구조

루 론산is the only non-sulfur mucopolysaccharide known so far, it is a linear straight chain polysaccharide polymer formed by repeating arrangement 의disaccharide units, D-glucuronic 산그리고N-acetylglucosamine are connected by β-1,3 glycosidic bond in each disaccharide unit, 그리고the disaccharide units are connected by β-1,4 glycosidic bond. The molecule consists 의two monosaccharides in a 1:1 molar ratio [2]. The structure 루 론의acid 에서다른organisational sources is the same, but the length of the sugar chain 그리고the 분자mass are different, the relative molecular mass is generally 105-107, 그리고the number of disaccharide units is 300-1,100 pairs [3].

히알루론산의 성질 2.2

루 론acid is generally a white amorphous solid, colourless 그리고odourless, 와strong 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 을adsorbed water is about 1,000 times its own mass, so it is recognised as a natural moisturising factor [5-6].

히알루론산 3 제조

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 산업 생산without 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.

3.1조직 추출

지상원료 3.1.1

The most commonly used raw material 을tissue extraction is chicken crowns, which is usually crushed directly and then treated 와acetone or ethanol, and then extracted 와sterile water directly or heated.Dong 젊은Kang[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, 와a final yield of 0.6%. Wang Jian et al[8] used domestic crude trypsin enzyme to 추출chicken crowns after grinding, and filtered with 120 mesh filter cloth and diatomaceous earth at 60 ℃, meanwhile, the 미치는 영향secondary enzyme digestion on the purity and molecular mass of hyaluronic acid was also investigated, and the final yield of hyaluronic acid 에서chicken 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 소eyes 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%.

해양생물자원 3.1.2

육상 생물에서 추출한 히알루론산에는 일부 병원성 세균이 포함된 경우가 많아 제품에 안전성에 문제가 생긴다.따라서 현재 연구 열점은 비교적 안전한 수생생물을 원료로 사용하는 것이며, 그 중 가장 널리 사용되고 있는 것은 물고기eye이다.어획물은 수량이 풍부하고 값이 싸며 얻기 쉬워 어업발전과정에 페기물로 되는데 만약 페기하면 자원낭비가 될뿐만아니라 수체의 부영양화를 초래하기 쉬워 생태환경에 해롭다.따라서 히알루론산을 원료로 물고기 눈에서 추출하면 폐기물 이용 및 종합 개발의 효과를 얻을 수 있을 뿐만 아니라 히알루론산 추출 비용을 절감할 수 있다 [10].진나라 Qian'an et al. [11] thawed the 오징어eye and stripped out the vitreous body, put it into acetone degreasing 을24h, dried, crushed, and then extracted with 0.2mol /L 나트륨chloride 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 에서squid 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 사용ultrafiltration and dialysis of the hyaluronic acid extract 에서swordfish. Lu Jiafang [15] used DEAE-Sephadex A-25 column chromatography to purify hyaluronic acid from squid eyes, and eluted with distilled water and 0.95mol/L NaCl solution step by step to obtain two hyaluronic acid fractions, which accounted 을5.22% and 82.37% of the sample volume, respectively.

Besides fish 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 분석showed that the extract was in complete agreement with the scanning pattern of hyaluronic acid standard. Nicola et al[17] obtained hyaluronic acid 을the first time from the molluscbivalvepurple 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 해양resources.

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].

변형 히알루론산의 제조 3.2

조직 추출과 미생물 발효를 통해 얻은 히알루론산은 안정성이 떨어지고, 히알루로니다제와 활성산소에 민감하며, 분해가 쉽고, 체내 유지 시간이 짧으며, 수용액계의 기계적 강도가 부족하여 응용에 큰 제한을 받는 단점이 있으므로 [21] 기계적 강도와 분해 방지특성을 향상시키기 위해 수정해야 한다.

3.2.1 히알루론산을 교반

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 성장of 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 기계strength [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 biocompatibilityof 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 (기본cross-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 개선the mechanical strength of hyaluronic acid and prolongs the sustained release time of proteins[29] .

비가교성 히알루론산 2.2.2

( 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 산or anhydrides, or the carboxyl group reacts with alcohols, phenols, epoxides, or halogenated hydrocarbons to form esterified 파생상품들이다. Vazquez et al[30] permeated 나트륨 hyaluronateinto acid in a cation exchange resin, added tetrabutylammonium hydr산화to 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 copolymerHA-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.

히알루론산 적용 4

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 안과or 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 고분자량 히알루론산 (HMWHA) 활용

관절질환의 치료 4.1.1

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 dys함수of 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 of저분자 질량 히알루론산.

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.

안과 응용 4.1.2

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 세포and accelerate the healing of corneal wounds [39].

또한 분자량이 높은 히알루론산은 수술 후 유착을 방지할 수 있으며 [40~41], 약물을 천천히 풀어주는 효과가 있다 [42].

4.2 저분자량 히알루론산 (LMWHA) 적용

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 셀surface, 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 강화the 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 면역cells, so it is often used as a drug carrier.

4.2.1 히알루론산 나노입자

Choi et al [43] used hyaluronic acid to produce nanoparticles. After systemic administration to mice carrying tumours, the hyaluronic acid 나노 입자could circulate in the blood for 2 days and selectively accumulate at the tumour site. In addition, hyaluronic acid 나노 입자can 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.

히알루론산 변형 지질 운반체 4.2.2

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]은 paclitaxel nanolipid carrier (PTX-NLC)를 제조한 다음, PTX-NLC 표면에 상대 분자량이 300,000과 1,000,000,000인 히알루론산을 전하 흡착법으로 흡착하여 활성 표적 히알루론산-변형된 paclitaxel nanolipid carrier (HA-NLC)를 각각 얻었다.그 결과 비교적 많이 사용하는 것으로 나타났다 low molecular mass hyaluronic acid더 안정적인 캐리어를 생산할 수 있습니다.in vivo 약동학 및 약리학적 연구 결과 HA-NLC는 paclitaxel 주사제인 Taisu ®보다 생체 내 종양 억제 효과가 우수했으며, 생체 내 약물의 유통 시간을 연장시키고 심장 및 신장 독성을 감소시켰다.이와 동시에 종양내 HA-NLC의 총 타겟팅 효율은 약 1.4배 증가하였으며, 종양의 활성 타겟팅이 뚜렷하였다.장원경 [47]은 우선 거대분자 히알루론산을 분해하여 상대분자량이 150,000~200,000인 히알루론산을 얻은 후, 역상증발법으로 히알루론산 리포좀을 제조하고 투과성을 조사하여 리포좀을 매개체로 하는 화장품에 히알루론산이 사용될 수 있는 이론적 근거를 마련하였다.

히알루론산과 약물의 결합 4.2.3

The carboxyl group, ammonia group and reducing end of hyaluronic acid can be amidated and esterified and 결합 되어with 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's 용해도가 증가하였으며, 세포 살균 효과가 우수하고 IC50 값이 원래 약제보다 낮게 나타났다.Galer 등 [49]은 목의 편평세포암 (SCCHN)에 대한 생쥐 종양 모델에서 히알루론산-파클리탁셀 결합법을 사용하였으며, 순수 파클리탁셀 주사에 비해 효과적으로 종양 성장을 억제하고 생쥐의 생존율을 증가시켰다.Ding Baoyue 등 (50)은 히알루론산 (MW = 150 000)을 이용하여 독소루비신 (DOX)과 폴리아미드-아민 결합 화합물을 개질하여 약물 운반 수상의 고분자 나노입자 약물 전달 시스템을 형성하였으며, 독소루비신 용액에 비해 약물의 세포 내 흡수를 크게 증가시킬 수 있고, 동시에 독소루비신의 표적 세포 핵 내 진입도 촉진시켜 치료 효능을 더욱 향상시킬 수 있었다.

히알루론산 나노겔 4.2.4

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 분자 무게of 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 chitosanwith 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.

히알루론산 마이크로스피어 4.2.5

Li Dan et al[53] prepared sodium hyaluronate 유화 교차연결법에 의한 마이크로스피어는 약제방출속도를 감소시키고, 약제방출시간을 연장시켰으며, 마이크로스피어의 불용성 골격을 통해 생체가용성을 향상시켰다.Liang Henglun 등 [54]은 단일 약물 전달체로서의 히알루론산은 다음과 같은 단점이 있다고 결론 내렸다:저분자 질량의 히알루론산은 간에서 쉽게 유지 및 대사되며, 목표 조직에 도달하기 어렵다;고분자량의 히알루론산은 수용체 매개 세포독성의 소실 때문에 활성 표적이 없습니다.따라서 량흥운 등 (54)은 키토산과 결합한 저분자량의 히알루론산 나트륨을 이용하여 평균 228 nm의 입자 크기를 갖는 일종의 히알루론산-키토산 결합 미세구 (DTX-HACTNPs)를 준비하여 약물 히알루론산의 활성 표적 특성을 그대로 유지하면서도 다른 단점을 극복하고자 하였다,그리고 MTTassay를 통해 히알루론산과 결합된 미세구가 비선택성 세포독성을 감소시키고 활성 표적 특성을 통해 약물의 활성 표적 특성을 유지할 수 있음을 입증하였다.

MTT assay showed that the hyaluronic acid-결합 되어drug microspheres could reduce the non-selective cytotoxicity and maintain the antitumour 활동of the drug 을 통해active targeting. Similarly, Zhou Panghu et al[55] showed that hyaluronic acid-chitosan microspheres could significantly inhibit the activity of induciblenitric oxide synthasein osteoarthritic chondrocytes in vitro, avoiding the production of excessive NO, thus inhibiting the destruction of articular cartilage and protecting chondrocytes다.

히알루론산 나노에멀젼 4.2.6

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.

4.2.7기타 신청

Zhang Jinxiang et al.[58] found that small-molecule hyaluronic acid degraded by HMW- HA could 활성화the main immune cells in the liver, the b빛cells, 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 체액 성immune 반응to inactivated HAV antigens, and can therefore also be used as an immune adjuvant [59].

히알루론산 시장 5

With regard to pharmaceutical hyaluronic acid, the number of people suffering from diseases such as 골관절 염of 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 $2012년에만 1300만명.일본에서는 무릎 치료용 히알루론산 시장이 그 이상으로 평가받고 있다$500만, 그리고 새로운 치료 옵션에 대한 수요가 증가하고 있습니다.전 세계 인구의 노령화가 가속화되고 의약에서 히알루론산에 대한 연구가 증가하고 있기 때문에, 히알루론산을 비스테로이드성 항염증제 등으로 사용한다면 [60] 의약에서의 히알루론산 시장 확대에도 도움이 될 것이다.

6 결론

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 낭비is 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.

참조

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