【作者】 刘佳；

【导师】 柳文洁；

【作者基本信息】 中南大学 ， 药剂学， 2023， 硕士

【摘要】 目的:实验室制备可溶微针(DMNs)一般采用两步模板法,即第一步使用含药基质溶液制备DMNs针头,第二步使用不含药基质溶液制备DMNs背衬。在DMNs制备过程中针头和背衬之间存在药物浓度差,药物分子会从高浓度区域往低浓度区域迁移,造成DMNs针头的载药量和给药量不确定等问题。该情况在制备小分子药物DMNs更为常见。本研究旨在通过抑制小分子药物在DMNs中扩散,改善DMNs中药物分布,使药物更多集中于DMNs的针头,减少药物扩散至背衬层造成的药物浪费,精准控制DMNs针头的载药量和给药量。方法:首先以盐酸利多卡因(Lido)为小分子模型药物,进行DMNs的成型性研究。通过比较不同的入模方法、不同的基质材料和基质材料的不同浓度,筛选了成膜性、平整度、气泡量和含针率良好的DMNs处方,用于搭载Lido。后续建立并验证了Lido含量测定的高效液相色谱(HPLC)方法。本课题基于粘度增大会阻碍溶液流动和相分离阻碍不同相之间的迁移扩散这两原理分别抑制Lido在Lido DMNs中的扩散。(1)粘度实质是阻碍液体流动的力,粘度大则溶液流动困难。本研究通过调整制备Lido DMNs的溶剂和探索Lido DMNs针头的最佳干燥时间,增大针头及背衬溶液的粘度,从而减少Lido从针头迁移至背衬的扩散通量。后续计算Lido DMNs针头理论载药量、使用流变仪测定溶液粘度、测定Lido DMNs针头Lido含量、使用罗丹明B(RB)颜色表征DMNs药物分布情况、使用力学试验机测试微针机械强度、研究DMNs的穿刺和渗透能力。(2)相分离实质是不同物质的相互聚集和分离,阻碍不同相之间的迁移扩散。本研究使用水不溶性材料聚苯乙烯(PS)作为Lido DMNs背衬材料,使得针头溶液和背衬溶液出现相分离,从而抑制Lido从针头扩散至背衬。后续测定Lido DMNs针头Lido含量、使用RB颜色表征DMNs药物分布情况、使用力学试验机测试微针机械强度、研究DMNs的穿刺、渗透和释放能力。结果:通过评价DMNs处方的成膜性、平整度、气泡量、含针率四个指标,综合选择真空入模法和40%聚乙烯吡咯烷酮(PVP)用于制备Lido DMNs。成功建立Lido含量测定的HPLC方法,测得制备的Lido DMNs针头载药量为10.39±1.11μg。通过调整溶剂和干燥Lido DMNs针头,Lido DMNs中药物扩散比例从98.33%降低至73.93%,RB在该处方下颜色更多地集中于DMNs针头,Lido DMN的力学试验表明其机械性能良好,Lido DMN的体外皮肤穿刺、渗透实验表明其能够刺破皮肤角质层并经皮释放药物。使用PS作为Lido DMNs的背衬,Lido DMNs中药物扩散比例从98.33%降至23.52%,RB在该处方下颜色集中于DMN针头,Lido DMN的力学试验表明其机械性能良好,Lido DMN的体外皮肤穿刺、渗透和释放实验表明其能够刺破角质层并经皮释放药物。体外药物释放表明该处方优于Lido贴剂,能够减少药物浪费。结论:本研究基于粘度增大会阻碍溶液流动这一原理,构建的Lido DMNs对制备过程中药物扩散有些许抑制效果。后续结合前述研究中Lido DMNs针头的制备工艺和干燥时间,基于相分离阻碍不同相之间的迁移扩散这一原理,构建的Lido DMN成功抑制了Lido从针头扩散至背衬,改善了Lido在Lido DMN中的药物分布。该方法简单易行,制备的DMNs机械性能良好,有利于精准控制DMNs的载药量和给药量,可以作为一种通用型的载药平台,可推广至其他药物,最大化DMNs的治疗效果,促进DMNs在临床的广泛应用。图25幅,表12个,参考文献68篇更多还原

【Abstract】 Objective: The laboratory preparation of dissolving microneedles(DMNs)typically involves a two-step casting method.The first step is to fill the mold cavities with a drug-containing matrix solution to form the DMN needles,while the second step is to create the drug-free backing with a separate matrix solution.However,this process creates a concentration gradient between the drug-containing needles and the drug-free backing,which can lead to uncertainty in drug loading and administration dosage,particularly for small molecule drugs in DMNs.The objective of this research is to improve drug distribution in DMNs by inhibiting the diffusion of small molecule drugs within the needles.The approach aims to increase drug loading on the needles,minimize drug waste caused by diffusion to the backing,and enable precise control of drug loading and administration dosage of DMNs needles.Method: Initially,lidocaine hydrochloride(Lido)was used as a small molecule model drug to investigate the formability of DMNs.Through comparison of different molding methods,matrix materials,and concentrations of matrix materials,optimal DMNs formulations were selected for Lido loading based on film formation,flatness,air bubbles,and needle content.Subsequently,a high performance liquid chromatography(HPLC)method was established and validated to determine Lido content.Our study is based on the principle that an increase in viscosity impedes solution flow and hinders migration and diffusion between different phases.To inhibit Lido diffusion in Lido DMNs,we used two approaches.Firstly,we increased the viscosity of the needle and backing solution by modifying the solvent and optimal drying time for Lido DMNs needles,which effectively reduced Lido diffusion from the needle to the backing.We validated this hypothesis through theoretical drug loading calculations,rheometer-measured solution viscosity,Lido content determination,Rhodamine B(RB)colored characterization of DMNs drug distribution,and mechanical testing machines to assess the puncture and penetration capabilities of DMNs.Secondly,we employed phase separation to impede Lido diffusion by changing the physical conditions of the system to adjust substance interaction and effect the aggregation and separation of different substances.By using the water-insoluble material polystyrene(PS)as Lido DMNs backing material,the needle and backing solution were separated,effectively limiting Lido diffusion from the needle to the backing.We validated this hypothesis through Lido content determination in the needles,RB color characterization of DMNs drug distribution,and mechanical testing machines to evaluate the puncture,penetration,and release capabilities of DMNs.Results: By evaluating the film-forming property,smoothness,bubble volume,and needle content of DMNs formulations,we determined that the optimal parameters for preparing Lido DMNs were the vacuum method and 40% polyvinylpyrrolidone(PVP).We then established a HPLC method to determine the Lido content of the prepared Lido DMNs needles,which showed a drug loading of 10.39 ± 1.11 μg.After adjusting the solvent and drying time for the Lido DMNs needles,we successfully reduced the drug diffusion ratio from 98.33% to 73.93%,as indicated by a more concentrated RB color on the DMNs needles.The mechanical properties of Lido DMN were also found to be satisfactory,and in vitro skin puncture and penetration experiments demonstrated its ability to permeate the stratum corneum and deliver drugs transdermally.Furthermore,employing PS as the backing material for Lido DMNs was shown to decrease the proportion of drug diffusion from the needle to the backing from 98.33% to 23.52%,with a more concentrated RB color on the DMN needle.Mechanical testing revealed that the mechanical properties of Lido DMN remained satisfactory,and in vitro drug release studies showed that the formulation outperformed Lido patch and was capable of reducing drug waste.Conclusion: In this study,we applied the principle that heightened viscosity obstructs solution flow to construct Lido DMNs,resulting in a modest inhibitory impact on drug diffusion during the preparation process.Building on previous studies regarding the preparation process and drying time of Lido DMNs needles,we effectively employed the principle of phase separation to hinder Lido diffusion from the needle to the backing,leading to improved drug distribution within the DMN.This method is uncomplicated and generates DMNs with favorable mechanical properties,enabling precise regulation of drug loading and dosage.Our findings imply that this approach could function as a universal drug loading platform and be expanded to other drugs,potentially amplifying the therapeutic efficacy of DMNs and promoting the widespread use of DMNs in clinical practice.更多还原