鼻腔给药系统的新剂型——淀粉微球

目的：分析探讨鼻腔给药系统－－淀粉微球剂,方法：对淀粉微球剂的制备及体内外的研究及影响其吸收的因素进行综述,结果：其制备简单,DSM能促进药的吸收。结论：鼻腔给药系统为一种新的制剂,随着研究的深入,其临床应用将更加安全可靠。     

靶向微球给药系统质量评价

靶向微球给药系统的研究,是药物新制剂研究的前沿热点之一,本文从载体材料、形态及表面性质、药物含量、释药和体内过程等五个方面对其质量评价进行了讨论。     

鼻腔给药新剂型

鼻腔给药具有吸收迅速、完全,能避免肝脏首过效应等优点。但大分子药物难以通过鼻粘膜吸收,需使用吸收促进剂。所以,许多新剂型如微球、环糊精、脂质体、乳剂等已被用于开发生物利用度高、刺激性小、无毒副作用的鼻腔给药系统。本文拟就此做一报道。１　微球（ｍｉｃｒｏｓｐｈｅｒｅｓ）微球是用白蛋白、明胶、聚丙交酯、淀粉等材料制成的球型载体给药系统。应用较多的是可降解淀粉微球,白蛋白微球。所载药物已有多肽类,如胰岛素、人生长激素（ｈＧＨ）、降钙素、去氨加压素以及普萘洛尔、庆大霉素、甲氧氯普胺等。１．１　提高生物利…     

蛋白多肽类药物微球鼻腔给药的研究进展

<正>鼻腔给药是指在鼻腔内使用,发挥局部和全身作用的给药系统。鼻腔给药可避开"首过效应",药物吸收迅速,可提高生物利用度,部分药物生物利用度可接近于静脉给药,是一种非侵入性给药方式,使用     

褪黑激素明胶微球的鼻腔给药

目的　制备经鼻粘膜给药的褪黑激素明胶微球,以提高其生物利用度。方法　用乳化交联技术制备褪黑激素明胶微球,用放射性核素^99mTc标记,用γ射线闪烁显像技术考察微球在鼻粘膜滞留时间,用HPLC法测定药物的体内吸收。结果　褪黑激素明胶微球粒径在30～70 μm,平均粒径为50.2 μm,褪黑激素含量为13.48%。与滴鼻液相比,明胶微球在鼻粘膜滞留时间明显延长。褪黑激素明胶微球的绝对生物利用度为87.47%。结论　鼻粘膜给药明胶微球,能避免肝脏首过作用,延长药物在鼻粘膜滞留时间,提高药物吸收,有很好的应用前景。     

胰岛素鼻腔给药研究进展

根据胰岛索(INS)是目前治疗胰岛素依赖型糖尿病(IDDM)的主要药物,属多肽类药物.分子量大,半衰期短,脂溶性差,不易透过生物膜,长期以来一直以注射给药为主,不仅用药不便而且会出现注射部位炎症,硬结等不良反应及耐药性,为此,国内外学者一直致力于INS非注射给药剂型的开发与研制.如鼻腔给药途径,现综述如下.     

胰岛素经鼻腔和肺部给药研究进展

胰岛素作为治疗胰岛素依赖型糖尿病的主要药物,长期以来一直注射给药,给患者造成许多痛苦和不便。因此,国内外医药界一直在致力于有效、安全、方便的胰岛素非注射给药途径的研究,例如口服、鼻腔、颊部、肺部、眼部、透皮及直肠途径以及笔式注射器和输入泵等装置的研究都有一定进展,有些已经应用于临床。     

胰岛素鼻腔给药制剂的试验研究

目的:将胰岛素制成一个较稳定的鼻腔给药制剂,为临床提供一个初步可行的用药依据。方法:采用LGY(国外药物透皮扩散室)扩散小室法,用人的胎盘膜模拟鼻黏膜先在体外做累积溶出度试验,再用大白兔做效用试验,验证制剂的可行性及试用性,并采用不同pH值、不同温度控制制剂的稳定性,观察其最稳定的保存时间及温度。结果:本课题采用了氮酮、油酸、丙二醇为联合促透剂,聚乙二醇为基质及稳定剂,以丙三醇为保湿剂,形成一个较稳定的新制剂;本制剂的平均回收率为63.53%,体外累积溶出度6 h,达高峰为42.31%,其制剂在pH 4.0时较稳定,保存温度为2℃,放置1个月后其含量为66.59%;在动物药效试验中,皮下注射组血糖值在给药后1 h降至最低,8 h基本恢复正常;而试验组给药后2 h降至最低,维持较低血糖值的时间比皮下注射组相对较长。结论:体外试验及动物试验表明,胰岛素在促透剂的作用下可以透过鼻黏膜,但所需的剂量较大,经济上损耗大,有待于今后进一步研究。     

胰岛素鼻腔给药新剂型研究进展

鼻腔给药是胰岛素皮下注射最有前景的替代途径之一,而黏膜吸附性制剂代表了胰岛素经鼻制剂的发展方向,主要包括凝胶、微球/微粒、脂质体、纳米粒等剂型.本文对国内外近年来各种剂型的胰岛素经鼻制剂的研究概况进行了综述.     

胰岛素肠溶微球口服的实验研究

目的 :研制一种可供口服的胰岛素肠溶微球。方法 :采用相分离法制备胰岛素丙烯酸树脂微球 ;建立放射性免疫法测定微球包封率 ;利用体外实验法考察微球的抗酸及肠溶能力 ;将不同处方的微球给大鼠灌胃 ,测定其血糖变化。结果 :制得微球粒径分布在 2～ 7μm ;包封率 95 .17% ;在人工胃液中 2h有少于 14%的胰岛素释放 ;在人工肠液中 1h内胰岛素的释放度达 96 % ;微球可使大鼠产生明显的降血糖效果。结论 :胰岛素口服肠溶微球是一类具有发展前景的制剂。     

神经毒素纳米粒的制备及大鼠鼻腔给药的药动学研究

以PLGA为载体,采用复乳-溶剂挥发法制备神经毒素（1）纳米粒,考察其形态、粒径、ζ电位、包封率和载药量。并以大鼠为动物模型,评价1纳米粒溶液肌注及鼻腔给药和1溶液肌注的药动学行为。与1溶液相比,1纳米粒肌注能缩短达峰时间,升高AUC值,延长体循环时间。1纳米粒经鼻腔给药,效果优于肌注。     

前列地尔脂微球载体制剂不同给药方式导致静脉炎发生情况的系统评价

目的 使用meta分析系统评价前列地尔脂微球载体制剂不同给药方式导致静脉炎发生率的差异及临床上常见超说明书给药途径的合理性,为临床应用提供循证参考。方法 检索中国知网、维普、万方、中国生物医学文献数据库、Embase、Pubmed、Cochrane Library,收集与前列地尔脂微球载体制剂不同给药方式导致静脉炎发生差异的相关研究文献,制定筛选条件并筛选文献,并按照Cochrane系统评价员手册评价质量后,采用RevMan 5.2统计软件将提取的有效数据进行meta分析。结果 共纳入23项随机对照试验（randomized cotrolled trial,RCT）研究,涉及3 165例患者。按给药方式进行meta分析,前列地尔脂微球载体制剂采用静脉注射方式较小壶静滴方式更易增加静脉炎发生率[RR=1.92,95%CI（1.17,3.17）,P=0.01];采用静脉注射方式和超说明书给药方式导致静脉炎的发生率无差异[RR=1.35,95%CI（0.69,2.64）,P=0.38];采用小壶静滴方式和超说明书给药方式导致静脉炎的发生率无差异[RR=0.52,95%CI（0.17,1.62）,P=0.26];采用静脉滴注较静脉泵入致静脉炎的发生率降低[RR=0.46,95%CI（0.31,0.67）,P<0.000 1]。按给药工具进行meta分析,采用普通输液器致静脉炎发生率显著高于采用精细过滤输液器[RR=0.18,95%CI（0.13,0.25）,P<0.000 01],差异均有统计学意义。按给药速度进行meta分析,前列地尔脂微球载体制剂以慢速静注给药静脉炎发生率显著高于快速静注给药[RR=0.37,95%CI（0.21,0.67）,P=0.001 0]。结论 前列地尔脂微球载体制剂快速给药或使用精细过滤输液器致静脉炎发生率较低,静脉注射较小壶静滴致静脉炎发生率较高,静脉泵入较静脉滴注致静脉炎发生率较高。按说明书给药方式与超说明书给药方式导致静脉炎的发生率无差异。     

加入不同吸收促进剂的盐酸氯胺酮鼻黏膜给药处方药效学研究

目的:以吸收促进剂为主要因素筛选具有良好麻醉效果的盐酸氯胺酮鼻黏膜给药处方。方法:以盐酸氯胺酮注射液为基本处方,添加各种鼻黏膜吸收促进剂/增黏剂(包括0.5%、1%、2%月桂氮酮,乙二胺四乙酸二钠,卡波姆,2-羟丙基-β-环糊精,羧甲基纤维素)配成不同处方滴鼻剂,对家兔进行鼻腔给药,以麻醉诱导期表现以及各项麻醉指标作为评价指标,对其麻醉效果进行比较。结果:以10mg·kg-1给药剂量的盐酸氯胺酮注射液加入1%月桂氮酮的处方麻醉效果较好,具有较长的麻醉时间,肌肉松弛时长(21.4±7.1)min,眼睑反射消失时长(11.4±4.6)min,痛觉消失时长(15.6±5.7)min,翻正反射消失时长(12.0±4.8)min。结论:以1%月桂氮酮作为吸收促进剂的盐酸氯胺酮鼻黏膜处方较好。     

胰岛素口服制剂的研究进展

综述了近年来国内外关于胰岛素口服剂型的制剂技术发展和生物利用度提高情况，特别对胰岛素纳米微粒，微乳，复乳、脂质体以及结肠定位给药制剂的进展进行了分析。指出目前研究中尚待解决的问题。     

药物的鼻腔黏膜吸收

鼻腔给药具有诸多优点，如能够避免肝脏的首过效应和胃肠道的降解，提高化学药物和肽类药物的生物利用度；增加药物向脑内递释，提高脑部疾病的治疗效果；具有特有的免疫性质等。介绍药物鼻腔黏膜吸收的特点和影响因素，综述鼻腔给药制剂的研究方法和研制情况，旨为该领域研究提供参考。     

Formulating Insulin for Oral Administration: Preparation of Hyaluronan-Insulin Complex

PURPOSE: To investigate the behaviour of peptides and hyaluronan in strong acid solutions containing electrolytes in the preparation of a new formulation of insulin, hyaluronan-insulin complex, and to evaluate the in vivo oral activity of the formulation. METHODS: Individual processing parameters in the preparation of the insulin complex were first refined, and two formulations were subsequently investigated. The chemical structure, particle size and hydrophilic/hydrophobic properties of the insulin complex in these formulations were studied using light scattering techniques, amino acid analysis, atomic force microscopy and cryo-transmission electron microscopy. The in vivo activity of oral hyaluronan-insulin complex was then evaluated by measuring the decrease in blood glucose concentrations in streptozotocin diabetic rats. RESULTS: Five of seven batches of the two insulin complex formulations fit the baseline criteria for approval of the new formulation. The formulation consists of a transparent aqua sol containing a solid hydrophobic phase as precipitate. Glucose-lowering activity was demonstrated after oral administration of the insulin complex'to diabetic rats. CONCLUSION: A new insulin formulation, a hyaluronan-insulin complex, has been developed and oral activity has been demonstrated.     

Nasal Absorption in the Rat. III. Effect of Lysophospholipids on Insulin Absorption and Nasal Histology

The intranasal absorption enhancing and histological effects of a range of lysophospholipids has been investigated in the rat. Blood glucose levels fell rapidly following the administration of insulin (8 IU/kg) in combination with lysophosphatidylcholines (LPC; 0.625% w/v) which had ten or more carbon groups in their fatty acid chain. The effect of the LPC-caproyl (C6) was comparable to that of an unenhanced insulin formulation; the enhancing effect of LPC-decanoyl (C10) was similar to that of an LPC-palmitoyl/stearoyl (C16/C18) for similar concentrations. The effect of LPC-decanoyl was reduced with concentration but was still significant at 0.2% w/v (5mM). Lysophosphatidylglycerol (LPG) had a marked insulin absorption enhancing effect even at 0.0625% w/v. The histological effects of LPC-caproyl were similar to those of an unenhanced insulin formulation, while co-administration of LPC-decanoyl resulted in evidence of epithelial interaction. LPG (0.5% w/v) resulted in similar histological changes as LPC (0.625% w/v) (1), but at 0.0625% w/v no significant changes in epithelial integrity were observed. The length of the fatty acid residue of lysophospholipids was identified as an important factor for intranasal absorption enhancing activity. The nature of the polar head group may also have an influence. Increased insulin absorption was not necessarily accompanied by severe disruption of the nasal epithelium. Careful selection of lysophospholipid type and concentration may enable therapeutic drug levels to be achieved via the nasal route without prohibitive toxic effects.     

Pharmacokinetic and Pharmacodynamic Properties of Insulin Aspart and Human Insulin

The preferred approach to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of insulin analogues is the euglycemic glucose clamp. Currently, non-compartmental data analytical approaches are used to analyze data. The purpose of the present study is to propose a novel compartmental-model for analysis of data from glucose clamp studies. Data used in this trial only involved 18 of the 20 originally treated subjects. Data was obtained from a crossover trial where 18 healthy subjects each received a single subcutaneous (sc) dose of 1.2 nmol/kg (body weight) insulin aspart (IAsp) or 1.2 nmol/kg human insulin (HI) during a euglycemic glucose clamp after overnight fast. Serum insulin and glucose concentrations were measured and the glucose infusion rate (GIR) was adjusted after dosing, to maintain blood glucose near basal levels. Individual model parameters were estimated for IAsp, HI, and the corresponding glucose and GIR data. We found statistically significant differences between most of the HI and IAsp pharmacokinetic parameters, including the sigmoidicity of the time course of absorption (1.5 for HI vs. 2.1 for IAsp (unit less), P=0.0005, Wilcoxon Signed-rank test), elimination rate constant (0.010 min^–1 for HI vs. 0.016 min^–1 for IAsp (P=0.002)). The PD model parameters were mostly not different, except for the rate of insulin action (0.012 min^–1 for HI vs. 0.017 min^–1 for IAsp (P=0.03)). The model may provide a framework to account for different PK properties when estimating the PD properties of insulin and insulin analogues in glucose clamp experiments.     

克拉霉素微球的制备及其评价

以聚丙烯酸树脂肠溶Ⅱ号为囊材,采用相分离-凝聚法制备了克拉霉素微球,该法微球得率为90.5±2.0％(n=3),所得微球粒径为155.1±26.39μm(n=1000),载药量为75％,克拉霉素微球在蒸馏水中几乎不溶出,而在pH6.8磷酸盐缓冲溶液中30min溶出80％以上。