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北京大学学报（医学版） ›› 2019, Vol. 51 ›› Issue (5): 907-912. doi: 10.19723/j.issn.1671-167X.2019.05.019

• 论著 • 上一篇    下一篇

阿司匹林缓释微球的制备及体外缓释效果评估

陈英1,刘中宁1,李波2,△(),姜婷1,△()   

  1. 1. 北京大学口腔医学院·口腔医院,修复科　国家口腔疾病临床医学研究中心　口腔数字化医疗技术和材料国家工程实验室　口腔数字医学北京市重点实验室,北京　100081
    2. 重庆科技学院纳微复合材料与器件重庆市重点实验室,重庆　401331
  • 收稿日期:2017-09-28 出版日期:2019-10-18 发布日期:2019-10-24
  • 通讯作者: 李波,姜婷 E-mail:15011229485@139.com;Leewave@126.com
  • 基金资助:
    国家自然科学基金青年项目(81400498);国家自然科学基金面上项目(81771045);重庆市基础与前沿研究计划(CSTC2016JCYJA0541);重庆市教委科学技术研究项目(KJ1601301)

Preparation of aspirin sustained-release microsphere and its in vitro releasing

Ying CHEN1,Zhong-ning LIU1,Bo LI2,△(),Ting JIANG1,△()   

  1. 1. Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China
    2. Chongqing Key Laboratory of Nano/Micro Composite Materials and Devices, Chongqing University of Science and Technology, Chongqing 401331, China
  • Received:2017-09-28 Online:2019-10-18 Published:2019-10-24
  • Contact: Bo LI,Ting JIANG E-mail:15011229485@139.com;Leewave@126.com
  • Supported by:
    Supported by the Youth Program of National Natural Science Foundation of China(81400498);the General Program of National Natural Science Foundation of China(81771045);the Natural Science Key Foundation Project of Chongqing(CSTC2016JCYJA0541);and the Scientific and Technological Research Program of Chongqing Municipal Education Commission(KJ1601301)

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摘要：

目的:阿司匹林(acetylsalicylic acid, aspirin)作为经典非甾体抗炎药,已被证实具有抗炎、调节免疫和促矿化作用,但是如何实现长期缓释aspirin并实现促进骨再生仍有待研究。本研究拟构建微球缓释体系,实现aspirin药物长期稳定缓慢释放,从而实现更为理想的成骨效果。方法:(1)合成制备三种缓释微球支架:① 单纯物理浸提法合成硅酸钙(calcium silicate, CaSiO3)负载aspirin微球(CaSiO3+aspirin),② 水包油(oil/water, O/W)乳化法制备聚乳酸羟基乙酸(poly lactic-co-glycolic acid, PLGA)负载aspirin微球(PLGA+aspirin),③ O/W乳化法制备PLGA复合CaSiO3负载aspirin微球(PLGA+CaSiO3+aspirin),并通过调整PLGA与CaSiO3的比例,得到材料的最佳形貌。(2)缓释效果评价:用分光光度计测第1、2、4、6、9、13、17、21、24、30、36、45天微球浸提液的aspirin浓度,计算微球的aspirin载药率,绘制三种缓释微球支架的aspirin累积释放曲线并评价其缓释效果。结果:(1)环境扫描电镜下观察,三种微球支架表面结构规整,粒径均匀,但PLGA+aspirin组微球存在少量团聚现象,CaSiO3+aspirin组部分微球破裂,PLGA+CaSiO3+aspirin组微球均匀分布于CaSiO3粉末上。(2)三组的载药率分别为(1.06±0.04)%、(7.05±0.06)%和(6.75±0.18)%。(3)95%药物缓释时间分别为3 d、24 d和36 d,PLGA+CaSiO3+aspirin微球支架释放时间显著长于其余两组,且释放速率更为稳定。结论:PLGA+CaSiO3+aspirin复合微球支架具有较理想的阿司匹林缓释效果,该复合微球有望成为理想的成骨材料。

关键词: 阿司匹林, 缓释微球, 抗炎, 成骨

Abstract:

Objective: It has been proven that acetylsalicylic acid (aspirin), as a kind of classical non-steroidal anti-inflammatory drug, not only has the effect of anti-inflammatory, but also has the function of immunity regulation and mineralization. However, it needs further investigation to study how to delay release of aspirin for a long time and enable to promote bone regeneration. Herein, we demonstrated that the long-term delayed release pattern of aspirin through the construction of microsphere scaffolds is promising to achieve the excellent bone regeneration. Methods: Here we synthesized three kinds of scaffolds as follows: (1) aspirin loaded calcium silicate (CaSiO3) microsphere (CaSiO3-aspirin) via simple immersion; (2) aspirin loaded polylactic-co-glycolic acid (PLGA) microsphere (PLGA-aspirin) via oil/water (O/W) emulsion; (3) aspirin loaded PLGA-CaSiO3 scaffold (PLGA-CaSiO3-aspirin) via O/W emulsion, optimal morphology and structure of PLGA-CaSiO3-aspirin scaffold was acquired through modulating the ratio between PLGA and CaSiO3. Furthermore, spectrophotometer was used to monitor the concentration of the extract of the three scaffolds for different releasing time, including 1, 2, 4, 6, 9, 13, 17, 21, 24, 30, 36, and 45 days, aspirin loading efficiency and its accumulation releasing curves were both achieved according to the concentration of aspirin. Their sustained release effects of aspirin were evaluated eventually. Results: Environmental scanning electron microscope (ESEM) results showed that the surface structure of the three kinds of scaffolds were smooth and had uniform size distribution. In addition, a small amount of PLGA-aspirin microspheres occurred to aggregation, while a small amount of CaSiO3-aspirin microspheres were broken. Moreover, the PLGA-aspirin microspheres in the PLGA-CaSiO3-aspirin scaffolds were uniformly adhered to the surface of CaSiO3 microspheres. The aspirin loadings of CaSiO3-aspirin, PLGA-aspirin, and PLGA-CaSiO3-aspirin were (1.06±0.04)%, (7.05±0.06)%, and (6.75±0.18)%, respectively. In addition, their corresponding time for releasing 95% of aspirin was 3, 24, and 36 days, respectively. The releasing time of PLGA-CaSiO3-aspirin was longer than that of the others and the releasing rate was more stable. Conclusion: The microsphere scaffold of PLGA-CaSiO3-aspirin composites has excellent delayed-release effect on aspirin, which is promising for using as osteogenic materials.

Key words: Aspirin, Sustained-release microsphere, Anti-inflammatory, Osteogenesis

中图分类号: 

  • R944

表1

三种缓释微球支架合成组分比例"

Scaffold Aspirin (w/v) PLGA (w/v) PVA (w/v) CaSiO3 (w/v)
CaSiO3+aspirin 1% 0 0 10%
PLGA+aspirin 1% 10% 2% 0
PLGA+CaSiO3+aspirin 1% 10% 2% 10%-20%

图1

三种微球扫描电镜图及粒径分布图"

图2

阿司匹林标准曲线(A)和三种微球支架的载药率(B)"

图3

阿司匹林三种微球支架的累积释放曲线"

[1] Carbone LD, Tylavsky FA, Cauley JA , et al. Association between bone mineral density and the use of nonsteroidal anti-inflammatory drugs and aspirin: impact of cyclooxygenase selectivity[J]. J Bone Miner Res, 2003,18(10):1795-1802.
[2] Kwon MS, Shim EJ, Seo YJ , et al. Effect of aspirin and aceta-minophen on proinflammatory cytokine-induced pain behavior in mice[J]. Pharmacology, 2005,74(3):152-156.
[3] Li YF, Fang XQ, Jiang T . Minimally traumatic alveolar ridge augmentation with a tunnel injectable thermo-sensitive alginate scaffold[J]. J Appl Oral Sci, 2015,23(2):215-223.
[4] Fang XQ, Lei L, Jiang T , et al. Injectable thermosensitive alginate/β-tricalcium phosphate/aspirin hydrogels for bone augmentation[J]. J Biomed Mater Res Part B, 2018,106(5):1739-1751.
[5] Kim YH, Tabata Y . Dual-controlled release system of drugs for bone regeneration[J]. Adv Drug Deliver Rev, 2015,94(1):28-40.
[6] Pakulska MM, Miersch S, Shoichet MS , et al. Designer protein delivery: From natural to engineered affinity-controlled release systems[J]. Science, 2016, 351(6279): aac4750.
[7] Tang Y, Singh J . Controlled delivery of aspirin: Effect of aspirin on polymer degradation and in vitro release from PLGA based phase sensitive systems[J]. Int J Pharm, 2008,357(1-2):119-125.
[8] 张安阳, 范田园 . 运用人工神经网络和响应曲面法体外优化阿司匹林海藻酸钙胃漂浮微球[J]. 北京大学学报(医学版), 2010,42(2):197-201.
[9] Vasudev SC, Chandy T, Sharma CP . Development of chitosan/polyethylene vinyl acetate co-matrix: controlled release of aspirin- heparin for preventing cardiovascular thrombosis[J]. Biomaterials, 1997,18(5):375-381.
[10] Xu SF, Lin KL, Wang Z , et al. Reconstruction of calvarial defect of rabbits using porous calcium silicate bioactive ceramics[J]. Biomaterials, 2008,29(17):2588-2596.
[11] Wang C, Lin KL, Chang J , et al. Osteogenesis and angiogenesis induced by porous b-CaSiO3/PDLGA composite scaffold via activation of AMPK/ERK1/2 and PI3K/Akt pathways[J]. Biomaterials, 2013,34(1):64-77.
[12] Lin TH, Pajarinen J, Lu L , et al. NF-κB as a therapeutic target in inflammatory-associated bone diseases[J]. Adv Protein Chem Struct Biol, 2017,107:117-154.
[13] Yamaza T, Miura Y, Bi Y , et al. Pharmacologic stem cell based intervention as a new approach to osteoporosis treatment in rodents[J]. PLoS One, 2008,3(7):e2615.
[14] Yun YR, Jang JH, Jeon E , et al. Administration of growth factors for bone regeneration[J]. Regen Med, 2012,7(3):369-385.
[15] White AP, Vaccaro AR, Hall JA , et al. Clinical applications of BMP-7/OP-1 in fractures, nonunions and spinal fusion[J]. Int Orthop, 2007,31(6):735-741.
[16] Street J, Bao M, deGuzman L, et al. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover[J]. Proc Natl Acad Sci USA, 2002,99(15):9656-9661.
[17] Almubarak S, Nethercott H, Freeberg M , et al. Tissue engineering strategies for promoting vascularized bone regeneration[J]. Bone, 2016,83:197-209.
[18] Zeng YP, Yang C, Li Y , et al. Aspirin inhibits osteoclastogenesis by suppressing the activation of NF-кB andMAPKs in RANKL-induced RAW264.7 cells[J]. Mol Med Rep, 2016,14(3):1957-1962.
[19] Liu Y, Wang L, Kikuiri T , et al. Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α[J]. Nat Med, 2011,17(12):1594-1601.
[20] Park JI, Venteicher AS, Hong JY , et al. Telomerase modulates Wnt signalling by association with target gene chromatin[J]. Nature, 2009,460(7251):66-72.
[21] Chin KY . A Review on the relationship between aspirin and bone health[J]. J Osteoporos, 2017,2017:3710959.
[22] Marco B, Francesca U, Fabiana Q , et al. Controlled drug delivery in tissue engineering[J]. Adv Drug Deliver Rev, 2008,60(2):229-242.
[23] Lin KL, Xia LG, Li HY . Enhanced osteoporotic bone regeneration by strontium-substituted calcium silicate bioactive ceramics[J]. Biomaterials, 2013,34(38):10028-10042.
[24] Hong MH, Choi HJ, Ko YM , et al. Engineered microstructure granules for tailored drug release rate[J]. Biotechnol Bioeng, 2015,112(9):1936-1947.
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ISSN 1671-167X
CN 11-4691/R
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