【作者】 接丽莉；

【导师】 杨跃辉；

【作者基本信息】 中国医科大学 ， 药学（专业学位）， 2020， 硕士

【摘要】 目的:结合中国医科大学附属盛京医院患者和儿科医生反映的对于婴幼儿血管瘤的治疗,使用马来酸噻吗洛尔滴眼液外敷的方式,属于超给药途径的超说明书用药为背景。基于婴幼儿血管瘤的疾病特点、马来酸噻吗洛尔的理化性质和婴幼儿皮肤的独特性,以马来酸噻吗洛尔为模型药物制备凝胶剂,开发一种新型制剂,以改善滴眼剂给药不便、疗效不佳的缺点,有效满足临床的实际需求。方法:参照《中国药典》和相关文献,通过紫外分光光度法和高效液相色谱法建立了马来酸噻吗洛尔凝胶剂的含量测定方法;通过处方单因素考察和正交设计试验,筛选出性质稳定、安全无刺激的凝胶剂辅料,确定最优处方与最佳制备工艺;通过透皮扩散试验仪模拟药物的经皮释放,考察凝胶在不同动物皮肤中的渗透性差异,分析其经皮渗透动力学特征;通过对凝胶剂的性状、鉴别、检查和含量测定进行考察,评价其质量;通过影响因素试验、加速试验和长期试验,考察凝胶剂的稳定性。结果:采用紫外分光光度法和高效液相色谱法建立了测定马来酸噻吗洛尔凝胶剂含量的体外分析方法,方法的专属性、精密度和回收率等均符合要求;通过处方单因素考察和正交设计试验,选择出凝胶剂的最优处方(10g):马来酸噻吗洛尔68.34mg、三乙醇胺0.135g、卡波姆940 0.10g、甘油0.50g、丙二醇1.00g、羟苯乙酯0.01g和适量的蒸馏水;凝胶剂在SD大鼠、BALB/c-nu裸鼠和巴马小型猪三种常用皮肤屏障材料中均有部分药物可以抵抗角质层的屏障作用,进入病灶部位发挥药效;经皮透过量存在种属间差异:SD大鼠皮的累积透过量最大,其次是BALB/c-nu裸鼠,巴马小型猪皮最低;凝胶剂在三种动物皮肤中的透皮释放均属于零级动力学过程,即凝胶中的药物释放主要以扩散为主;质量评价结果显示,凝胶剂的质量符合《中国药典》中关于凝胶剂质量标准的要求;稳定性考察结果显示,凝胶剂在长期9个月和加速6个月内的稳定性均较好。结论:成功制备了安全有效、性质稳定的马来酸噻吗洛尔凝胶剂,处方工艺简单,设计合理,稳定性良好,符合凝胶剂的质量要求,适合婴幼儿血管瘤的患者使用,有效解决了滴眼剂给药不便、疗效不佳的问题,满足临床实际需求。更多还原

【Abstract】 Objectives: Combined with the clinician and patient’s reflection on the treatment of infantile hemangiomas,we often use an external application of timolol maleate eye drops,which is off-label drug use.Based on the characteristics of infants hemangiomas,the physical and chemical properties of timolol maleate,and the uniqueness of infant skin,a new preparation named timolol maleate gel was developed,to improve inconvenient and poor effect of eye drops,to meet the actual clinical needs.Methods: Based on the ChP and related literatures,an in vitro analysis method for timolol maleate gel was established by ultraviolet spectrophotometry(UV)and high performance liquid chromatography(HPLC);Through formula single factor investigation and orthogonal design experiment,to find stable and safe gel excipients,to determine the best prescription and process;The transdermal diffusion tester was used to simulate the transdermal release of drugs,to investigate the permeability difference of TM gel in different animal skins,and to analyze the percutaneous kinetics of drugs;Evaluate the quality of TM gel from character,identification,inspection and content determination;The stability of TM gel was investigated through influencing factor experiments,accelerated experiments and long-term experiments.Results: Establishing an in vitro analysis method for timolol maleate gel by UV and HPLC,with excellent specificity,recovery,precision;Through formula single factor investigation and orthogonal design experiment,the best formulation of the gel(10g)was selected: timolol maleate 68.34 mg,carbopol 940 0.10 g,glycerol 0.50 g,propylene glycol1.00 g,phenethyl ester 0.01 g,triethanolamine 0.135 g,appropriate amount of water;The transdermal permeability of TM gel in three commonly used skin barrier materials of rats,nude mice and Bama mini-pigs varies among species: SD rats have the largest skin permeability,followed by nude mice,and pig skins have the lowest,both of them have some drugs to resist the barrier effect of the stratum corneum and enter the lesion site to play a medicinal effect;The in vitro release of the preparation in the skin of the three animals conforms to the zero-order kinetic process,that is,the drug release in the gel is mainly diffusion-based;The quality of TM gel is good and meets the requirements of thegelatin quality standards in the ChP;The results of the stability investigation showed that the stability of the TM gel was good in 6 months of acceleration and 9 months of long-term.Conclusions: The stable,safe and effective TM gel was successfully prepared.The prescription is reasonable,the process is simple,the stability is good,and it meets the quality requirements of the gel in ChP.It is suitable for infant hemangiomas and solves the disadvantages of inconvenient and poor effect of eye drops,meets the actual clinical needs effectively.更多还原