目的 为改善艾塞那肽(exenatide,EX)注射液稳定性差、体内半衰期短和患者依从性差等缺点,本研究构建了EX温敏型凝胶纳米粒鼻腔给药系统。方法 将聚乳酸-羟基乙酸共聚物[poly(lactic-co-glycolic acid),PLGA]纳米粒与泊洛沙姆(poloxamer)温敏凝胶相结合,以聚多巴胺(polydopamine, PDA)包被EX PLGA纳米粒,并制备温敏型凝胶(EX-NPS-GEL)。对其形态、载药量、相变温度、流变学、药物释放进行考察,并以2型糖尿病balb/c小鼠为模型,考察EX-NPS-GEL鼻腔给药后的降糖效果、血药浓度以及鼻粘膜刺激性。结果 EX-NPS-GEL可长时间滞留在鼻黏膜处,有效延长动物体内降血糖时间,提高血药浓度。结论 为EX治疗糖尿病提供了一种新的给药方式,提升了药物效果,缓解患者用药痛苦,为蛋白多肽类药物鼻腔递送的开发提供一定的启发和支持。
Abstract
OBJECTIVE To construct a temperature sensitivegel nanoparticle nasal drug deliverysystem and improve the shortcomings of exenatide (EX) injection, such as poor stability, short half life in vivo, and poor patient compliance. METHODS Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were combined with poloxamer temperature-sensitive gel, and EX was coated with polydopamine (PDA) peptide (PLGA) nanoparticles and prepared into temperature-sensitive gel (EX-NPS-GEL). The morphology, drug loading, phase transition temperature, rheology, and drug release of EX-NPS-GEL were investigated, and hypoglycemic test, blood drug concentration test and nasal mucosal irritation test were carried out in type 2 diabetes balb/c model mice. RESULTS EX-NPS-GEL can be retained in the nasal mucosa for a long time, effectively prolonging the time of lowering blood sugar in the animal body and increasing the blood drug concentration. CONCLUSION It provides a new way of administration for the treatment of diabetes, improves the effect of drugs, relieves the pain of patients with medication, and provides certain inspiration and support for the development of protein peptide drugs for nasal delivery.
关键词
艾塞那肽 /
PLGA纳米粒 /
聚多巴胺 /
温敏凝胶 /
鼻喷剂
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Key words
exenatide /
PLGA nanoparticle /
polydopamine /
temperature sensitive gel /
nasal spray
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中图分类号：
R944
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参考文献
[1] LIA T, SOUDRY-KOCHAV I, NATALYA N, et al. Pharmacodynamical effects of orally administered exenatide nanoparticles embedded in gastro-resistant microparticles[J]. Eur J Pharm Biopharm, 2018, 133(12):214-223.
[2] ILTZ J L, BAKER D E, SETTER S M, et al. Exenatide: An incretin mimetic for the treatment of type 2 diabetes mellitus[J]. Clin Therapeu, 2004, 5(5):652-665.
[3] ZHENG M M, ZHONG X, DU Y J, et al. Effect of exenatide on early type 2 diabetic nephropathy[J]. Anhui Med(安徽医药), 2019, 23(7):1448-1451.
[4] MATO Y L. Nasal route for vaccine and drug delivery: Features and current opportunities[J]. Int J Pharm, 2019, 57(12):801-813.
[5] GARNPIMOL C. Chapter 3: Nasal delivery of peptides and proteins with chitosan and related mucoadhesive polymers[J]. Peptide Protein Deliv, 2011, 3(56):47-68.
[6] WHITLOCK R H, HOUGEN I. A Safety Comparison of Metformin vs Sulfonylurea Initiation in Patients With Type 2 Diabetes and Chronic Kidney Disease: A Retrospective Cohort Study[J]. Mayo Clin Proc, 2014, 1(2):90-100.
[7] YARSHOSAZ J, SADRAI H, ALINAGA RI R. Nasal delivery of insulin using chitosan mic rospheres[J]. Microencapsual, 2014, 21(7):761-774.
[8] SHAH V, SHARMA M, PANDYA R, et al. Quality by design approach for an in situ gelling microemulsion of Lorazepam via intranasal route[J]. Mater Sci Eng, 2017, 751(6):1231-1241.
[9] YANG H J, PARK I S, NA K. Biocompatible microspheres based on acetylated polysaccharide prepared from water-in-oil-in-water (W1/O/W2) double-emulsion method for delivery of type Ⅱ diabetic drug (exenatide)[J]. Physicochem Eng, 2009, 340(5): 115-120.
[10] FORNAGUERA C, FEINER-GRACIA N, CALDERÓ G, et al. PLGA nanoparticles from nano-emulsion templating as imaging agents: Versatile technology to obtain nanoparticles loaded with fluorescent dyes[J]. Colloids Surf B: Biointerfaces, 2016, 147(11): 201-209.
[11] LI Y J, SHI S Y, CAO H B, et al. Improvement of the antifouling performance and stability of an anion exchange membrane by surface modification with graphene oxide (GO) and polydopamine (PDA)[J]. J Membrane Sci, 2018, 15(11): 44-53.
[12] SOUDRY-KOCHAVI L, NARAYKIN N, NASSAR T, et al. Improved oral absorption of exenatide using an original nanoencapsulation and microencapsulation approach[J]. J Controll Release, 2015, 10(11): 202-210.
[13] LI X G, LI L, WANG X P, et al. Application of model-based methods to characterize exenatide-loaded double-walled microspheres: In vivo release, pharmacokinetic/ pharmacodynamic model, and in vitro and in vivo correlation[J]. J Pharm Sci, 2012, 10(10): 3946-3961.
[14] SOLIAMA N, KARIM A, ULLIAH K, et al. Poloxamer-based in situ gelling thermoresponsive systems for ocular drug delivery applications[J]. Drug Discov Today, 2019, 24(8): 1575-1586.
[15] NANDINI H S, RAMACHANDRA P. Antidiabetic, antihyperlipidemic and antioxidant effect of Vincamine, in streptozotocin-induced diabetic rats[J]. Eur J Pharmacol, 2019, 15 (1): 233-239.
[16] TANAKA H, YAMASHITA T, YONEDA M, et al. Characteristics of bone strength and metabolism in type 2 diabetic model tsumura, suzuki, obese diabetes mice[J]. Bone Rep, 2018, 9 (12): 74-83.
[17] LIANG C, GAO L, LIU Y, et al. MiR-451 antagonist protects against cardiac fibrosis in streptozotocin-induced diabetic mouse heart[J]. Life Sci, 2019, 41(5): 12-22.
[18] APUHAN T, TERZI E H, KÜKNER A, et al. Histopathological evaluation of the effect of intranasal phototherapy on nasal mucosa in rabbits[J]. J Photochem Photobiol B: Biology, 2019, 105 (10): 94-97.
[19] GUO J F, XU M T, TAO Y J, et al. The effect of temperature-dependent viscosity on entropy generation in curved square microchannel[J]. Chem Eng Proc: Proc Intensification, 2012, 52 (2): 85-91.
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