异亚丙基莽草酸脂质体体外评价及鼻腔给药后药物动力学研究

目的:制备脑缺血再灌注损伤的保护药物异亚丙基莽草酸脂质体,并对其体外特性及鼻腔给药后的药物动力学进行研究,探讨鼻腔给药的可行性。方法:脂质体采用薄膜分散-探针超声法制备,采用纳米粒度分析仪对其粒径分布进行测定,包封率通过超滤法测得;选择羊鼻中膈黏膜作为模型,进行体外黏膜透过性试验;体内过程考察选择大鼠作为试验动物,通过鼻腔给药,考察其药物动力学过程。结果:在选定的处方和工艺条件下,制得的脂质体外观均匀,平均粒径约（244.1±44.7）nm,包封率为（96.83±1.04）%,制剂总含量14,68 mg·ml^-1;体外透膜试验中,异亚丙基莽草酸脂质体4 h的透过率约90%左右;大鼠鼻腔给药后,5～10 min即达到最高血药浓度,生物利用度为92,64%。结论:异亚丙基莽草酸脂质体透膜和吸收性能良好,可以用于鼻腔途径给药。     

柔红霉素长循环脂质体的药剂学性质及大鼠体内药代动力学研究

目的研究柔红霉素长循环脂质体的药剂学性质及大鼠体内药代动力学。方法考察柔红霉素长循环脂质体的形态和粒径分布、包封率和加速实验稳定性;建立脂质体中柔红霉素含量测定的可见分光光度法和HPLC方法;考察脂质体在Hepes缓冲液(pH 7.5)和大鼠血清中的体外释放行为。考察脂质体在大鼠体内的药代动力学行为。结果制备的柔红霉素长循环脂质体包封率高(>85%)、稳定性好,平均粒径为56.3 nm,体外释放慢;长循环脂质体的T_1/2α和AUC分别是注射剂的17.6和96倍。结论制备的长循环脂质体包封率较高,药剂学性质稳定,在大鼠体内的药代动力学参数优于注射剂,能达到长循环目的。     

羟基喜树碱包衣纳米脂质体的制备及体外释药研究

目的:进行羟基喜树碱氯化壳聚糖包衣纳米脂质体(Nanoliposome,N-liposome)的制备及体外释药考察,以提高包封率和稳定性.方法:采用薄膜分散法制备羟基喜树碱脂质体并用氯化壳聚糖包衣,经高压均质机多次乳匀得到纳米脂质体(＜100nm),用激光粒度分析仪测定其zeta电位、粒径大小及分布,用不同冻干保护剂进行冷冻干燥,用透析法考察药物体外释药性质.结果:包衣纳米脂质体zeta电位为 55.1mV,平均粒径(ZAve)为91.9 nm,粒径分布为20～120 nm;以15%(W/V)的海藻糖做冻干保护剂的脂质体冻干前后粒径变化最小,再水化后平均粒径为98.2 nm,包封率为(61.2±1.2)%(n=3);氯化壳聚糖包衣脂质体外释药曲线符合Higuchi方程(Q=0.055 0.0228t1/2).结论:本试验制备的羟基喜树碱包衣纳米脂质体具有包封率高,稳定性好,大小均匀,以及体外能显著延缓药物的释放的性质.     

洛莫司汀-碘海醇复方脂质体的制备及包封率测定

目的:制备洛莫司汀-碘海醇复方脂质体,并考察其质量、测定其包封率。方法:以逆相蒸发法制备复方脂质体;以磷脂种类(A)、磷脂与胆固醇质量比(B)、脂质质量浓度(C)为因素,以两主药的包封率为评价指标,采用正交设计法优化处方;以两主药的包封率及脂质体的粒径和Zeta电位为指标进行验证试验。结果:优化处方结果显示,A为大豆磷脂80,B为2∶1,C为33mg/ml。验证试验结果显示,洛莫司汀包封率约为75.7%,碘海醇包封率约为65.7%;脂质体粒径约为236.5 nm,Zeta电位约为-42.2mV。结论:采用该处方与工艺可成功制备包封率较高的洛莫司汀-碘海醇复方脂质体,质量符合要求。     

9-硝基喜树碱半固体脂质纳米粒的制备及大鼠的药动学研究

采用高温乳化蒸发-低温固化法制备9-硝基喜树碱(1)半固体脂质纳米粒,并考察其形态、粒径、包封率、z电位及大鼠静脉给药后体内药物动力学行为。结果表明,1半固体脂质纳米粒为圆形,具有明显可见的亲水性聚乙二醇“外壳”,粒径为223.3～249.1nm,包封率为77.9%～83.5%,z电位为-28.4～-22.2mV。分别用1半固体脂质纳米粒和溶液对大鼠静脉给药,体内药物动力学参数分别为:t1/2 (14.9±0.3)h和(1.2±0.6)h,AUC0～t(486±37)mg·h·L-1和(117±64)mg·h·L-1,MRT (19.3±0.7)h和(1.7±1.0)h。表明1半固体脂质纳米粒可延长体循环时间,提高生物利用度。     

全反式维甲酸前体脂质体的制备及体外评价

目的:制备维甲酸前体脂质体,并对其体外性质进行考察。方法:采用乙醇注入结合冷冻干燥法制备前体脂质体;微柱离心-高效液相色谱法测定脂质体的包封率;并进一步对其粒径、Zeta电位、血浆释放率及乙醇残留量进行测定。结果:所制备的前体脂质体包封率为95.2%,Zeta电位为-(28.4±17.5)mV,粒径为(170±29)nm,乙醇残留量为3.98%。结论:乙醇注入结合冷冻干燥法制备的维甲酸前体脂质体包封率高,粒径均匀,稳定性好。     

乙醇注入法制备柚皮素脂质体及其质量评价

目的制备柚皮素脂质体,优化其处方和工艺,并对其相关性能进行评价。方法采用乙醇注入法制备柚皮素脂质体,通过正交设计优化处方工艺;利用马尔文动态光散射粒径测定仪测定其zeta电位和粒径,采用微型凝胶柱离心法分离游离药物和脂质体,HPLC法测定脂质体中柚皮素的包封率。结果确定最佳处方为:磷脂的质量浓度为0.006 g·m L~(-1),胆固醇与磷脂的质量比为1∶3,药脂比为1∶20,缓冲液p H值为7.40,类脂溶液的溶解温度设定为55℃,类脂溶液的溶解时间为25 min。制得的柚皮素脂质体包封率为(80.44±0.98)%,平均粒径为(223±11)nm,Zeta电位为(-35.9±5)m V。结论乙醇注入法制备柚皮素脂质体工艺简单可行,所制备的柚皮素脂质体包封率高、粒径较小、稳定性好。     

三七总皂苷口服脂质体的制备及大鼠体内药动学研究

目的制备三七总皂苷(TPNS)口服胆盐脂质体,考察其药剂学特征及在大鼠体内的药动学行为。方法薄膜分散法制备TPNS胆盐脂质体,对其外观形态、粒径分布、包封率进行评价,并以注射用血栓通和血栓通胶囊为参比制剂,将18只大鼠随机分成血栓通胶囊灌胃组、TPNS脂质体灌胃组和血栓通溶液尾静脉注射组进行药动学行为考察。结果制备的TPNS脂质体呈类球形结构,粒径为(163.0±5.28)nm,包封率为(80.6±2.14)%,3组实验的AUC_(0~t)分别为865.39、1442.79和2124.38h·μg·mL~(-1),自制TPNS脂质体相对于血栓通胶囊的生物利用度为166.72%。结论 TPNS胆盐脂质体外观良好,包封率较高,能显著提高TPNS口服给药的生物利用度。     

两性霉素B脂质体的制备及药动学

目的:制备两性霉素B脂质体并对其药动学进行研究。方法:采用有机溶剂注入法制备两性霉素B脂质体,用微射流进行整粒,用动态光散射法测定粒径,采用Ultrafree-CL离心超滤管分离游离两性霉素B(F-AMB)与复合两性霉素B(L-AMB)检测包封率,用Wistar大鼠进行药动学研究。结果:两性霉素B脂质体平均粒径为(115±20)nm;包封率>99.9%;大鼠静脉注射,实验药与Amphotec的Cmax,AUC0~168 h和AUC0~∞无显著性差异(P>0.05)。结论:采用有机溶剂注入法制备两性霉素B脂质体具有较高包封率,在大鼠体内的药动学特征与Amphotec一致。     

甘草次酸介导pH敏感主动靶向长循环阿霉素脂质体的制备及其药物动力学

目的制备甘草次酸(glycyrrhetinic acid,GA)介导的pH敏感主动靶向长循环阿霉素(doxorubicin,DOX)脂质体(liposomes,LP)(GA-PEG2000-N=CH-DOXLP)并测定其在大鼠体内药物动力学参数。方法采用薄膜分散法制备甘草次酸介导pH敏感主动靶向长循环阿霉素脂质;采用阳离子交换树脂-微柱离心法测定脂质体的包封率和载药量;动态激光散射法测定脂质体的粒径、粒径分布和Zeta电位;透射电镜观察脂质体形态;透析法测定脂质体在不同pH条件下的体外释放;荧光分光光度法测定阿霉素血浆药物浓度,得到药-时曲线并计算药物动力学参数。结果甘草次酸介导的脂质体(GA-PEG2000-N=CH-DOXLP)和普通脂质体(DOXLP)的粒径分别为(135.5±2.6)nm和(105.6±4.0)nm;包封率分别为(53.8±5.8)%和(52.9±3.5)%,载药量质量分数分别为(2.35±0.16)%和(2.39±0.26)%;Zeta电位分别为-(5.19±0.73)mV和-(1.53±0.57)mV;GAPEG2000-N=CH-DOXLP的AUC(0-72)分别是DOXLP的2.33倍和DOX溶液的5.62倍。结论所制备的甘草次酸修饰的pH敏感主动靶向长循环脂质体制剂学性质稳定并能显著延长其在大鼠体内的循环时间。     

Estimation of the absolute bioavailability of rivastigmine in patients with mild to moderate dementia of the Alzheimer's type

OBJECTIVE: To investigate the bioavailability of rivastigmine, an approved therapy for patients with mild to moderate dementia of the Alzheimer's type, at the highest approved single dose of 6 mg. DESIGN AND SETTING: Randomised, two-period crossover, single-centre, non-blinded, inpatient study.Patients and participants: Eleven patients (five females and six males) with mean age 69.5 years. METHODS: The 6 mg oral dose was compared with a 2 mg intravenous dose of rivastigmine infused over a 1-hour period. Plasma concentrations of rivastigmine and its metabolite NAP 226-90 were measured with a gas chromatographic/mass spectrometric method. RESULTS: Following oral administration of a single 6 mg capsule, rivastigmine is rapidly absorbed with an average time to peak plasma concentration of about 1 hour and an average peak concentration of about 25.6 g/L. By a noncompartmental approach, the absolute bioavailability of the 6 mg oral dose of rivastigmine was 71.7% when compared with a 2mg intravenous infusion normalised for dose. By using a population pharmacokinetic model with Michaelis-Menten elimination, absolute bioavailability was estimated at 60.2%. The average terminal elimination half-life of rivastigmine ranged from 1.4 to 1.7 hours for both treatments. Plasma concentrations of the major metabolite, NAP 226-90, formed by the hydrolysis of rivastigmine by cholinesterase are lower than those of the parent compound following oral and intravenous administration. CONCLUSION: A noncompartmental approach and a compartmental approach based on a population pharmacokinetic model with Michaelis-Menten elimination yielded comparable values, 71.7% and 60.2% respectively, for the absolute bioavailability of a single 6 mg oral dose of rivastigmine. Comparison with previous studies confirmed that the oral form of the drug exhibits increased bioavailability with increasing dose, consistent with its nonlinear pharmacokinetics..     

Steady-state pharmacokinetics of rivastigmine in patients with mild to moderate Alzheimer's disease not affected by co-administration of memantine: an open-label, crossover, single-centre study

BACKGROUND AND OBJECTIVE: It has been shown that combining memantine and a cholinesterase inhibitor, which each affect different neurotransmitter systems, may offer further improvements in efficacy over either treatment alone in patients with Alzheimer's disease. The present study was conducted to determine if memantine has any effects on the steady-state pharmacokinetics of rivastigmine in patients with mild to moderate Alzheimer's disease. METHODS: Rivastigmine-treated Alzheimer's disease patients who had been maintained on a fixed regimen of twice-daily rivastigmine for >or=2 months were eligible to enter the study. Sixteen patients (seven males and nine females, age range 64-88 years, weight range 51.8-104 kg) were enrolled in this open-label, crossover study, which consisted of a 28-day screening period, a 36-hour baseline period, and a 35-day combination treatment phase. The patients spent the baseline period and day 35 at the study centre, where plasma samples for pharmacokinetic evaluation were taken at specified time intervals over a 10-hour time period. In addition, 10-hour (evening pre-dose) memantine plasma samples were taken on days 21, 34 and 35. RESULTS: The combination of memantine (10 mg twice daily) with rivastigmine (1.5-6 mg twice daily) was safe and well tolerated. At each dose level of rivastigmine, the area under the concentration-time curve (AUC) values of rivastigmine and its metabolite as well as the metabolite-to-parent AUC ratios were unaffected by co-administration of memantine, confirming the absence of a meaningful pharmacokinetic drug-drug interaction. CONCLUSION: Under the study conditions, the extent of systemic exposure to rivastigmine and its metabolite NAP226-90 at steady state did not appear to be affected by concomitant administration of memantine.     

Preparation of silymarin proliposome: a new way to increase oral bioavailability of silymarin in beagle dogs

The aim of the present study was to find a method to increase oral bioavailability of silymarin, that is to say, by the preparation of silymarin proliposome and to compare the pharmacokinetic characteristics and bioavailability after oral administration of silymarin proliposome and silymarin in beagle dogs. Silymarin proliposome was prepared by the film-deposition on carriers. After the proliposome was contacted with water, the silymarin liposome suspensions formed automatically. The tests of physicochemical properties including SEM, TEM, encapsulation efficiency, dissolution studies, particle size of the reconstituted liposome and stability of the silymarin proliposome were determined by laser-particle-sizer, HPLC, etc. The concentrations of silymarin in plasma of beagle dogs and its pharmacokinetic behaviors after oral administration of silymarin liposome suspensions and silymarin were studied by RP-HPLC. The pharmacokinetic parameters were computed by software program 3p97. The encapsulation efficiency of silymarin liposome could be more than 90%, with an average particle size of about 196.4 nm and the proliposome appeared a very stability at 40 degrees C during 3 months. It was found that mean plasma concentration-time curves of silymarin after oral administration of liposome suspensions and silymarin in beagle dogs were both in accordance with open two-compartments model and first-order absorption. Pharmacokinetic parameters of silymarin proliposome and silymarin in beagle dogs were Tmax both 30 min; Cmax 472.62 and 89.78 ng mL(-1); and AUC0-infinity 2606.21 and 697 ng mL(-1)h, respectively. The high bioavailability of silymarin proliposome could be obtained by oral administration. Silymarin proliposome was stable and did enchance the gastrointestinal absorption of silymarin.     

Pharmacokinetic-pharmacodynamic modeling of rivastigmine, a cholinesterase inhibitor, in patients with Alzheimer's disease

Rivastigmine is a cholinersterase inhibitor approved recently for the treatment of Alzheimer's disease (AD). The objective of this study is to characterize the pharmacokinetics-pharmacodynamics of rivastigmine in patients with AD. Eighteen AD patients received doses ranging from 1 to 6 mg bid for about 11 weeks. Rivastigmine and its active (major) metabolite (ZNS 114-666, also called NAP 226-90), plasma, and cerebrospinal fluid (CSF) concentrations were determined together with the AChE activity and computerized neuropsychological test battery (CNTB) scores. Nonlinear mixed-effects modeling of pharmacokinetic and pharmacodynamic data was conducted using NONMEM. Rivastigmine and its metabolite exhibited dose-disproportional pharmacokinetics. The apparent clearance and volume of distribution (plasma) of rivastigmine were estimated to be 120 L/h and 236 L, respectively. The relative bioavailability at the 6 mg dose was about 140%. The metabolite had a clearance of about 100 L/h and a volume of distribution of 256 L. The kinetics of the parent and metabolite in CSF showed an equilibration half-life of about 0.2 and 0.5 hours, respectively. The metabolite levels in CSF correlated very well with the acetylcholinesterase inhibition, with a ZNS 114-666 concentration of about 5.4 microg/L required for half-maximal inhibition of acetylcholinesterase activity. No statistically significant correlation of the CNTB scores with enzyme inhibition, parent or metabolite concentration (plasma/CSF), or rivastigmine dose could be established. The PK-PD model presented in this study can provide valuable information to optimize the drug development of rivastigmine and other related compounds and also in rationalizing dosing recommendations.     

Bioequivalence evaluation of two brands of rivastigmine of different salt forms, an acetylcholinesterase inhibitor for the treatment of Alzheimer's disease, in healthy Beagle dogs

The bioequivalence of two brands of rivastigmine capsules, of different salt forms, was demonstrated in six healthy beagle dogs after a single oral dose in a randomized cross-over study. Reference (Rivastigmine hydrochloride, Sunve, CN) and test (Rivastigmine tartrate, Novartis, CH) products were administered to fasting beagles on two treatment days separated by a two-day washout period; blood samples were collected at specified time intervals, and the plasma was separated and analyzed for rivastigmine using a validated GC-MS method. The pharmacokinetic parameters AUC(0-t), AUC(0-infinity), C(max), T(max) and t1/2 were compared statistically to evaluate bioequivalence between the two brands, using the statistical modules recommended by the State Food and Drug Administration (SFDA) of China. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable ranges for bioequivalence. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetic profiles and that Sanwei's Rivastigmine hydrochloride was bioequivalent to Rivastigmine tartrate of Novartis, CH.     

Pharmacokinetics of a rivastigmine transdermal patch formulation in healthy volunteers: relative effects of body site application

A patch formulation of rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, is under development. The current objective was to evaluate the pharmacokinetic profile and patch adhesiveness following application at the upper back, chest, abdomen, thigh, and upper arm. In a single-dose, open-label, crossover study with 40 (42.5% men) healthy subjects, a 10-cm(2) patch containing 18 mg rivastigmine was applied to each body site. Median t(max) was 16 hours for all sites except the thigh (22 hours). Exposure levels and C(max) were highest at the upper back, chest, and upper arm sites. Adhesiveness was greatest when applied to the thigh, followed by the abdomen, upper arm, chest, and upper back, although no statistically significant correlations with pharmacokinetic parameters were found, except at the chest (P=.02). Pharmacokinetic profiles and adhesiveness of the upper back, chest, and upper arm, coupled with low rates of erythema at these sites, suggest their suitability for clinical use.     

Rivastigmine exposure provided by a transdermal patch versus capsules

ABSTRACT

Objectives: The rivastigmine transdermal patch is the first transdermal treatment for Alzheimer's disease (AD) and dementia associated with Parkinson's disease. The objective of this study was to evaluate the pharmacokinetics of rivastigmine following transdermal delivery by a patch versus oral delivery with conventional capsules in a population of AD patients.

Methods: Both non-compartmental and compartmental analyses were performed on the same database showing relatively large inter-patient variations in pharmacokinetic parameters (up to 73% for the capsule group). The compartmental analysis provided model-based predictions of pharmacokinetic parameters, with the aim of comparing the two modes of administration when adjusting for confounding factors such as patient body weight and gender.

Results: According to both non-compartmental and compartmental analyses, the patch provided significantly lower peak rivastigmine plasma concentrations (C_max) and slower times to C_max (t_max), compared with capsules. However, drug exposure (area under the curve; AUC) was not significantly different between the 4.6?mg/24 hour (5?cm²) patch and 3?mg BID (6?mg/day) capsule doses, or between the 9.5?mg/24 hour (10?cm²) patch and 6?mg BID (12?mg/day) capsule doses, according to both analyses. This suggests comparable exposure from these two rivastigmine delivery systems.

Conclusion: The analyses were consistent with previous reports of a markedly less fluctuating, more continuous drug delivery with the rivastigmine patch. This characteristic delivery profile is associated with similar efficacy yet improved tolerability, compared with capsules.     

水飞蓟素前体脂质体的制备和大鼠药代动力学的研究水飞蓟素前体脂质体的制备和大鼠药代动力学的研究

目的为了提高水飞蓟素的口服生物利用度，研制水飞蓟素前体脂质体并对其理化性质进行考察；研究水飞蓟素前体脂质体的大鼠体内生物利用度。方法采用薄膜载体沉积法制备水飞蓟素前体脂质体，通过研究水合后脂质体的包封率、粒径、稳定性来考察其理化性质；将水飞蓟素前体脂质体在体外进行水合，再给予大鼠灌胃，用RP-HPLC法测定不同时间血浆中总的和游离的水飞蓟素的浓度，通过3P97程序计算药代动力学参数。结果用该法制得的前体脂质体包封率可达90%以上，平均粒径为238.8 nm，稳定性较好；药代动力学研究表明水飞蓟素脂质体在体内吸收较快，生物利用度较高。结论采用薄膜载体沉积法制备水飞蓟素前体脂质体，制备工艺简单，易于工业化生产；将水飞蓟素制备成前体脂质体提高了水飞蓟素的生物利用度。     

人血浆中卡巴拉汀及其代谢物NAP226-90的LC-MS/MS测定研究

目的：建立LC-MS/MS法同时检测卡巴拉汀及其代谢物NAP226-90血药浓度。方法：血浆经甲基叔丁基醚-二氯甲烷提取预处理,用Phenomenex-curocil PFP（250 mm×4.6 mm,5μm）色谱柱,0.1%甲酸0.05%甲酸铵溶液-0.1%甲酸0.05%甲酸铵甲醇为流动相,梯度洗脱分离,ESI正离子化三重四极杆质谱MRM测定,检测反应离子对：卡巴拉汀m/z 251.0→206.0、NAP226-90 m/z 166.0→121.0、内标（美托洛尔）m/z 268.4→74.3。结果：卡巴拉汀及NAP226-90血药浓度在0.2～30 ng·mL-1范围内均线性关系良好,定量下限均为0.2 ng·mL-1,经方法学验证符合生物样品测定要求。结论：建立的LC-MS/MS方法可用于重酒石酸卡巴拉汀胶囊人体药动学研究。     

Fluorimetric determination of rivastigmine in rat plasma by a reverse phase--high performance liquid chromatographic method. Application to a pharmacokinetic study

A sensitive and selective high performance liquid chromatographic (HPLC) method was developed and validated for the rapid quantification of rivastigmine (CAS 123441-03-2) in micro quantity in rat plasma samples. The chromatographic separation was achieved with a reverse phase monomeric column C18 (4.6 x 250 mm, 5 microm) and the mobile phase consisted of acetonitrile and 20 mmol/L phosphate buffer pH 3.0 (25:75) with a flow rate of 1 mL/min. The effluents were measured by fluorimetric detection with excitation and emission wavelengths at 220 nm and 293 nm, respectively. The calibration curve was linear (r2 > 0.99) ranging from 25-3000 ng/mL and the lower limit of quantification was 25 ng/mL. The method was validated with excellent sensitivity, selectivity, accuracy, precision, recovery and stability. The method has been successfully applied in a pharmacokinetic study of rivastigmine in rats.