克拉霉素脂肪乳剂在大鼠体内药动学和组织分布研究

目的研究克拉霉素脂肪乳剂在大鼠体内药动学和组织中的分布情况,并与克拉霉素注射液相比。方法通过高压均质方法制备克拉霉素脂肪乳剂,通过微生物管碟法测定克拉霉素在大鼠体内血药浓度和组织中药物浓度。结果克拉霉素脂肪乳剂和克拉霉素注射液药-时曲线相似并均符合二室模型,两种剂型的AUC0-t分别为(66.76±16.34)和(59.00±11.20)μg·h/ml。大鼠单剂量静脉注射37.5mg/kg克拉霉素脂肪乳剂和溶液剂后,测定各时间点各组织中药物浓度,以肺为最高。与溶液剂相比,脂肪乳剂提高了脾、肺、肝、肾和脑的药物分布。结论克拉霉素脂肪乳剂与克拉霉素溶液剂血药浓度相似,但脂肪乳剂明显改变了克拉霉素体内组织分布,说明更有助于治疗局部脏器感染。     

水飞蓟宾脂质微球的制备及在大鼠体内的药物动力学考察

目的制备水飞蓟宾脂质微球并对其理化性质及大鼠体内药物动力学特征进行考察,为水飞蓟宾的临床应用提供理论依据。方法采用高压均质法制备水飞蓟宾脂质微球;分别采用动态光散射法、超速离心法考察制剂的粒径、zeta电位及药物的相分布;以自制水飞蓟宾溶液剂作为参比制剂,采用HPLC法考察大鼠体内药物动力学。结果制剂平均粒径约为192.4 nm,zeta电位为-24.56 mV,约77.5%的药物分布在油水界面膜上;40℃加速实验10 d,药物的相分布无变化;4℃留样观察6个月内稳定;水飞蓟宾脂质微球和溶液剂的药时过程均符合双隔室模型;非隔室模型分析结果表明,脂质微球和溶液剂的AUC0-t分别为(1.90±0.29)、(2.07±0.44)mg.h.L-1,两制剂药-时曲线相似。结论所制备的水飞蓟宾脂质微球性质稳定,大部分药物分布在油水界面膜上;脂质微球未改变药物在大鼠体内的药物动力学特征。     

依托泊苷静脉注射亚微乳的制备及其体内外评价依托泊苷静脉注射亚微乳的制备及其体内外评价

本文旨在制备依托泊苷静脉注射亚微乳(ESE)并考察其体内外性质。采用高压均质法制备载药亚微乳，单因素试验考察处方工艺中影响制剂质量的因素，激光散射法和超滤离心法测定其粒径、zeta电位和包封率；长期留样观察其物理稳定性，恒温加速试验-威布尔分布拟合法考察其化学稳定性；以依托泊苷溶液为参比制剂，考察其在大鼠体内药代动力学行为。测得亚微乳平均粒径(189.9±54.6)nm，zeta电位-32.6 mV，包封率91.7%。4 ℃长期留样9个月物理稳定性无显著变化，加速试验预测4 ℃有效期(T_0.9)约为665 d。亚微乳和溶液在大鼠体内药代动力学曲线均符合双隔室模型，药时曲线下面积(AUC_0-t)分别为(18.30±8.74)和(19.32±6.45)μg·h·mL^-1。结果表明ESE避免了有机增溶剂的使用，物理化学稳定性较溶液显著提高，且未改变体内药代动力学行为。     

水飞蓟宾纳米混悬剂的制备及大鼠体内药动学研究

目的:探讨静脉注射用水飞蓟宾纳米混悬剂的制备,并评价其大鼠静注给药后的药动学。方法:通过对水飞蓟宾纳米混悬剂理化性质及稳定性的评价,考察水飞蓟宾纳米混悬剂的制备方法、处方工艺,并以溶液剂为参照考察其在大鼠体内的药动学行为。结果:水飞蓟宾纳米混悬剂的平均粒径是(268.90±9.20)nm,多分散性为0.22±0.12。水飞蓟宾溶液剂及纳米混悬剂的药时曲线下面积分别为(34.92±0.98)μg·h·mL-1和(57.12±3.20)μg·h·mL-1,消除半衰期(t1/2)分别为(3.05±0.06)h和(6.14±0.42)h。结论:制备的水飞蓟宾纳米混悬剂理化性质比较稳定,与溶?液剂相比,延长了药物在体内的驻留时间,具有一定的缓释效果。     

血液微渗析技术研究酮洛芬在大鼠体内的药代动力学

目的考察酮洛芬微渗析体内外回收率及影响因素，研究酮洛芬静脉给药后非结合型药物在大鼠体内的药代动力学。方法大鼠颈静脉插入探针后，依次用不同浓度的灌注液对探针进行灌注，测定酮洛芬体内回收率及非结合型酮洛芬在大鼠体内的药代动力学。以高效液相色谱法测定微渗析液中药物浓度。体外回收率的测定采用浓差法。结果增量法及减量法测定的回收率一致。以浓差法测定的体外回收率为28.75%；反渗析法测定体内回收率为(40.3±2.7)%。酮洛芬静脉给药后非结合型药物的T_1/2，AUC和CL分别为(181±16) min，(112±27) μg·min·mL^-1和(0.22±0.05) min^-1。结论血液微渗析技术可用于研究非结合型酮洛芬在大鼠体内的药代动力学。     

紫杉醇纳米乳剂的体内外考察

目的考察紫杉醇纳米乳剂的形态、粒径分布及急性过敏反应,研究紫杉醇注射剂及自制紫杉醇纳米乳剂在大鼠体内的药代动力学。 方法用HPLC法测定大鼠体内紫杉醇含量。数据用3P87处理,得到各主要药代动力学参数。 结果纳米乳剂平均粒径为17.2 nm。纳米乳剂急性过敏反应为阴性,而市售紫杉醇注射液急性过敏反应为阳性。血浆中杂质及制剂中辅料不干扰紫杉醇的测定。大鼠iv自制紫杉醇纳米乳剂及紫杉醇注射液后的药-时曲线均符合二室模型。数据用3P87处理,得到各主要药代动力学参数。纳米乳剂及注射液的k₁₀分别为0.57,1.29·h^-1,k₁₂分别为1.44,1.27·h^-1,k₂₁分别为3.08,0.51·h^-1,AUC分别为34.98,21.85 mg·h·L^-1。结论紫杉醇纳米乳剂较紫杉醇注射液毒性降低,可在一定程度上延长药物在大鼠体内的循环时间。     

克拉霉素黏附微球在低pH值溶液中的稳定性

目的 考察克拉霉素在不同pH值条件下的稳定性及微球对药物的稳定作用. 方法 使用乳化 溶剂挥发法制备克拉霉素生物黏附微球（Cla-Ec-Cb）. 以高效液相色谱法测定Cla-Ec-Cb中克拉霉素及克拉霉素原料药在不同低pH值条件下稳定性. 结果 克拉霉素原料药在pH值为1,2,3的盐酸溶液中的半衰期分别为（5.93±0.16）,（74.52±3.23）,（869.58±5.82） min; Cla-Ec-Cb微球中克拉霉素能保持相对稳定. 结论 克拉霉素在低pH值溶液中不稳定,将其制备成黏附微球对克拉霉素具有一定的保护作用.     

坎地沙坦酯脂质体冻干粉的制备及在大鼠体内药动学研究

目的 制备并评价泊洛沙姆407修饰的坎地沙坦酯脂质体（CC/PLip）,考察其口服给药后在大鼠体内药动学过程。方法 用薄膜分散法制备CC/PLip,经冷冻干燥制成冻干粉。动态光散射（DLS）测定其zeta电位和粒径,透射电镜（TEM）观察其形态,超滤离心法测定包封率;采用口服给药,观察肠道粘膜渗透行为,分析药物在大鼠体内的药代动力学参数。结果 泊洛沙姆407修饰的坎地沙坦酯脂质体呈现球形,粒径为（182.67±4.10）nm,Zeta电位为（-8.98±0.19）mV,包封率为98.94%±0.60%;体外释放试验结果表明其具有明显的缓释效果;肠道粘膜渗透试验表明CC/PLip在小肠易被吸收;药动学实验中,参比坎地沙坦酯片和CC/PLip的AUC_0→48h分别为（13 112.6±5 343.7）ng·h·mL^-1、（19 522.8±3 973.7）ng·h·mL^-1;C_max分别为（656.8±345.0）ng·mL^-1、（1 199.1±330.7）ng·mL^-1;T_max分别为（7.3±3.0）h、（2.7±1.4）h。结论 CC/PLip包封率较高,粒径较小,具有缓释效果,能提高在小肠的吸收,可显著提高在大鼠体内的生物利用度。     

塞来昔布纳米混悬剂的制备及大鼠体内药动学研究

摘 要 目的： 制备塞来昔布纳米混悬剂（CXB NSs）,并考察大鼠灌胃给药后体内药动学特征。方法: 采用反溶剂沉淀 高压均质法制备CXB-NSs,并考察其粒度分布,多聚分散系数和Zeta电位。将12只Wistar大鼠随机分为CXB NSs组和CXB混悬液组,灌胃给药剂量均为100 mg·kg^-1,采用高效液相色谱法测定大鼠血浆中的CXB浓度,用3P97软件计算相应的药动学参数。结果: CXB NSs平均粒径为(442.5±61.9) nm,多聚分散系数为0.312±0.057,Zeta电位为(-31.6±3.9) mV。CXB NSs和CXB混悬液在大鼠体内的AUC(0-t)分别为(5.13±0.77)和(13.51±3.18) mg·L^-1·h;t1/2分别为(12.31±1.91)和(12.73±1.83) h;Tmax 分别为(2.48±0.37)和(1.41±0.27) h;Cmax分别为(0.94±0.31)和(2.38±0.25) mg·L^-1。结论:CXB NSs能显著提高药物在大鼠体内的生物利用度。     

五味子醇甲在大鼠肝微粒体内的代谢动力学和性别差异

体外研究五味子醇甲(schizandrin，SZ)在大鼠肝微粒体内的代谢动力学和性别差异。制备正常雌、雄大鼠肝微粒体，与SZ共同温孵，以高效液相色谱法测定SZ及其代谢产物。SZ在雄鼠肝微粒体内代谢反应的最大速率V_max、米氏常数K_m和清除率Cl_int分别为(21.88±2.30) μmol·L^-1·min^-1·mg^-1(protein)，(389.00±46.26) μmol·L^-1和(0.056 3±0.000 7) min·mg^-1(protein)；在雌鼠肝微粒体内代谢反应的最大速率V_max、米氏常数K_m和清除率Clint_{分别为(0.61±0.07) μmol·L^-1·min^-1·mg^-1(protein)，(72.64±13.61) μmol·L^-1和(0.008 4±0.000 8) min·mg^-1(protein)，雌、雄鼠肝微粒体内SZ的主要代谢物不同，分别为7,8-顺二羟基五味子醇甲(M1)和7,8-顺二羟基-2-去甲基五味子醇甲(M2b)。酮康唑、奎尼丁和奥芬得林对SZ的在雌、雄大鼠肝微粒体内代谢均有不同程度的抑制作用，西咪替丁对其在雄鼠肝微粒体内的代谢也有一定的抑制作用。SZ在雌、雄大鼠肝微粒体中代谢动力学及代谢产物存在明显的性别差异，这种差异可能主要是由CYP3A和CYP2C11在大鼠肝微粒体内的性别差异引起的。}     

Formulation and evaluation of less-painful clarithromycin lipid microspheres

Lipid microspheres (LMs) have recently been use as drug carriers for intravenous use due to its low toxicity, good physiological tolerance and the reduction of the drug related side-effect. In this study, clarithromycin was incorporated in LMs, in an attempt to reduce the pain caused by intravenous use. The composition of the drug loaded LMs was clarithromycin 0.5%, oil phase 10%, soybean phospholipid 2%, egg lecithin 0.5%, Sodium oleate 0.1%. Clarithromycin LMs was prepared by high pressure homogenization method at 80 MPa for 8-10 cycles. The mean particle size and surface charge of LMs were 208.7+/-7.8 nm and -23.6+/-2.3 mv respectively. Clarithromycin entrapment efficiency in LMs was 66.4%. Drug loaded LMs was stable during the storage time at 6+/-2 degrees C for 9 month, and the particle size and zeta-potential did not change significantly. Drug concentration in LMs was 5 mg/mL, and there was no drug degradation during long term storage. Animal tests (rat paw lick test and rabbit ear vein irritation test) were used to evaluate the pain reduction of clarithromycin LMs compared with that of clarithromycin aqueous solution. These results suggest that the LM system is a promising option to replace clarithromycin aqueous solutions as an intravenous treatment.     

Optimization of tocol emulsions for the intravenous delivery of clarithromycin

In the present study, novel less-painful tocol emulsions for the intravenous delivery of clarithromycin were prepared and optimized. The therapeutically effective concentration of clarithromycin, 5mg/ml, was achieved using tocopherol succinate (TS) combined with oleic acid as lipophilic counterions. The possibility of employing the microdialysis technique to investigate the distribution of the drug in emulsions was explored. A three-level three-factorial Box-Behnken experimental design was utilized to conduct the experiments. The effects of selected variables, tocopherol succinate/oleic acid relation, poloxamer 188 content and 0.1M NaOH amount, on three considered responses were investigated. The particle size, zeta potential and the oil phase distribution of clarithromycin for the optimized formulation were observed to be 138.5 nm, -32.16 mV and 97.28%, respectively. The emulsions prepared with the optimized formula demonstrated good physical stability during storage at 4 degrees C and room temperature. The histopathological examination for rabbit ear vein irritation test indicated that the irritation of clarithromycin could be eliminated by formulating the drug in a tocol emulsion.     

盐酸吡硫醇无痛型注射液的制备

目的研制盐酸吡硫醇无痛型注射液以降低或消除其静注时产生的刺激性。方法利用二价金属离子对盐酸吡硫醇结构的掩蔽作用,制成无痛型注射液。采用小鼠抓挠试验、大鼠舔足试验和大鼠尾静脉刺激性试验等动物试验模型对无痛型注射液的减少刺激性的效果进行评价。结果3种动物试验模型显示分别采用Ca2+和Mg2+做掩蔽剂,两者与盐酸吡硫醇最佳摩尔比为1∶2时,减痛效果最好,刺激性可以降低50%以上。结论二价金属离子Ca2+和Mg2+均对盐酸吡硫醇中巯基起掩蔽作用,可降低盐酸吡硫醇的刺激性。     

A lipid microsphere vehicle for vinorelbine: Stability, safety and pharmacokinetics

A lipid microsphere vehicle for vinorelbine (VRL) was designed to reduce the severe venous irritation caused by the aqueous intravenous formulation of VRL. Lipid microspheres (LMs) were prepared by high pressure homogenization. The physical stability was monitored by the appearance, particle size and zeta potential changes while the chemical stability was achieved by using effective antioxidants and monitored by long-term investigations. Safety tests were performed by testing rabbit ear vein irritation and a guinea pig hypersensitivity reaction. A pharmacokinetic study was performed by determining the drug levels in plasma up to 24h after intravenous administration of VRL-loaded LMs and conventional VRL aqueous injection separately. The VRL-loaded LMs had a particle size of 180.5+/-35.2nm with a 90% cumulative distribution less than 244.1nm, while the drug entrapment efficiency was 96.8%, and it remained stable for 12 months at 6+/-2 degrees C. The VRL-loaded LMs were less irritating and toxic than the conventional VRL aqueous injection. The pharmacokinetic profiles were similar and the values of AUC(0-t) were very close for the two formulations. A stable and easily mass-produced VRL-loaded LM preparation has been developed. It produces less venous irritation and is less toxic but has similar pharmacokinetics in vivo to the VRL aqueous injection currently commercially available.     

盐酸克林霉素注射液部分安全性试验

目的 评价盐酸克林霉素注射液注射给药的安全性.方法 采用家兔耳缘静脉血管刺激性试验、肌肉刺激性试验、体外溶血性试验、豚鼠全身主动过敏试验和大鼠被动皮肤过敏试验等方法进行研究.结果 盐酸克林霉素注射液静脉滴注对给药部位血管无明显刺激作用,肌内注射给药对注射部位有一定的刺激性;豚鼠全身主动过敏反应和大鼠被动皮肤过敏反应为阴性;对家兔红细胞无溶血和凝集作用.结论 试验所用的盐酸克林霉素注射液临床静脉滴注给药安全性较好,肌内注射给药对注射部位具有刺激性.     

茴拉西坦亚微乳处方及制备工艺考察

目的制备茴拉西坦亚微乳,并进行质量评价。方法采用组织捣碎-高压均质工艺制备茴拉西坦亚微乳,正交试验优化处方,单因素考察制备工艺,并测定所制乳剂zeta电位、粒径、pH值及药物含量。结果茴拉西坦亚微乳最佳处方和工艺为注射用中链油125 g.L-1、大豆磷脂和pluronicF68总量为30 g.L-1、大豆磷脂和pluronic F68的质量比为1∶4,56 MPa均质5次;所得乳剂zeta电位为-30.8 mV,粒径为(149±21)nm,pH值为6.0,茴拉西坦含量为1.5 g.L-1。结论所得乳剂理化性质良好,符合静脉注射要求。     

前列地尔脂质体的制备及刺激性考察

目的 :制备前列地尔脂质体以减少其静脉注射的刺激性。方法 :采用逆相蒸发法制备前列地尔脂质体 ,用超滤膜测定脂质体的包封率及其释放、马尔文粒径仪测定平均粒径 ;并通过动物实验比较静脉注射的刺激性。结果 :前列地尔脂质体的包封率可达到 94 % ,超声后和高压匀质后的粒径为(732±s 35 )nm和 (6 7± 7)nm ,刺激性得到显著改善。结论 :前列地尔脂质体可以显著降低静脉注射引起的刺激性。     

Characteristics and evaluation of an injectable clarithromycin lipid-based complex in vitro and in vivo

Abstract

The purpose of this paper is to prepare a less-irritating and lipid-based clarithromycin complex (LCC) by the route of intravenous administration qualified with high drug-loading and fine particle size. The LCC was prepared by the injection of organic solvent phase (containing clarithromycin, sodium cholesterol sulfate and phospholipid at a molar ratio of 1:1:1.5) into the Tris buffer solution (0.05?M, pH 7.2) at 40?°C, and then was concentrated by ultrafiltration to remove the organic solvent. The technique of lyophilization was applied to obtain the LCC lyophilized products. Evaluation of the injectable LCC was performed by particle sizes analysis, transmission electron microscope, entrapment efficiency, stability and irritation tests. The LCC possessed a log-normal size distribution with an average size of 75.4?nm. The drug entrapment efficiency was above 97.0%, which was influenced by the amount of phospholipid, pH value of the media and ionic strength of aqueous suspension. The results of stability and irritation tests proved that LCC had more stability and less irritation. This unique LCC formulation may be applied to the human by the route of injection with less or no irritation. LCC could be an appropriate candidate for intravenous preparation and has a great potential for clinical and industrial-scale production.     

Highly efficient and lowly toxic docetaxel nanoemulsions for intravenous injection to animals

Hypersensitivity many occur with commercial docetaxel injections containing Tween 80 and ethanol. An alternative formulation of docetaxel, an oil-in-water nanoemulsion was prepared using the high-pressure homogenization method. It was composed of medium-chain triglyceride, oleic acid, egg lecithin, and poloxamer. These ingredients are known as safe agents for intravenous (i.v.) injection. The nanoemulsion had a small size of 169 nm, and a high surface charge with the zeta potential of -33.9 mV. It maintained well stable even under high centrifugation. Acute toxicity of i.v. injection, erythrocyte hemolysis experiment, and rabbit ear vein irritation test showed no toxicity for the docetaxel nanoemulsion. The docetaxel nanoemulsion led to a larger apparent distribution volume and area under curve than the docetaxel injection after i.v. administration to rats. The histopathological test of tumor further demonstrated the highly anticancer efficiency of the docetaxel nanoemulsion. Thus, the nanoemulsion is a promising delivery system for docetaxel with highly anticancer efficiency and low toxicity.