氯雷他定固体自乳化制剂的体外溶出及体内药动学研究

目的:研究氯雷他定固体自乳化制剂的体外溶出行为及其在比格犬体内的药物动力学。方法:采用HPLC方法测定氯雷他定固体自乳化制剂与市售片剂的体外溶出曲线;采用LC-MS/MS测定市售片剂和氯雷他定固体自乳化制剂在比格犬体内的血药浓度,考察氯雷他定固体自乳化制剂的相对生物利用度。结果:以0.1 mol·L-1盐酸溶液为溶出介质的体外溶出结果表明,氯雷他定固体自乳化胶囊与市售片剂30 min时均可以溶出80%以上;比格犬体内药物动力学研究结果表明,固体自乳化制剂比市售片剂最高血药浓度显著性增加(P0.05),Cmax=1.79μg·L-1,而市售片剂Cmax=0.67μg·L-1;AUC(0~t)提高了149%(P0.05)。结论:固体自乳化制剂可以显著提高氯雷他定的体内吸收。     

雷诺嗪缓释片在比格犬体内的药代动力学

目的:研究雷诺嗪缓释片在比格犬体内的药物代谢动力学,并与参照制剂比较,为其是否具有缓释特征提供依据。方法:首先建立血浆中雷诺嗪浓度的液相色谱-串联质谱联用检测方法,并考察方法的专属性、准确度、日内日间精密度、回收率、线性范围等。采用随机对照试验设计,将12只比格犬随机分为A、B组,每组6只,分别服用1片雷诺嗪缓释片(500 mg/片)和1片参比制剂雷诺嗪片(500 mg/片),均于给药前和给药后不同时间点采集血样,用已建立的液质联用方法检测血样中雷诺嗪的血药浓度,计算2组比格犬的药代动力学参数。结果:受试组和参照组半衰期t1/2分别为13.3±8.3和2.36±0.92 h,峰浓度Cmax分别为923.9±340.5和3205±1314 ng/mL,达峰时间Tmax分别为1.6±0.38和0.88±0.14 h,曲线下面积AUC0~∞分别为6252.1±2860.3和9916±4305(ng·h)/mL,清除率Cl分别为11.3±9.8和6.39±3.95 L/(kg·h)。受试制剂雷诺嗪缓释片和参比制剂雷诺嗪片的药代特征和血药浓度-时间变化趋势明显不同,受试组血药浓度缓慢上升和下降,峰值较低;而参照组血药浓度峰值显著高于受试组,有明显的突释效应。结论:液质联用检测方法准确可靠,适合体内药代动力学研究;与参比制剂雷诺嗪片相比,受试制剂雷诺嗪缓释片符合缓释片的基本药代动力学特点。     

万氏牛黄清心缓释胶囊在比格犬体内药动学研究

目的:研究比格犬单剂量交叉口服万氏牛黄清心缓释胶囊和市售普通丸给药的药动学.方法:采用高效液相色谱法测定10只比格犬单剂量口服万氏牛黄清心pH-依赖型梯度释药胶囊和市售丸后血浆中盐酸小檗碱的血药浓度.血浆样品采用碱化后乙醚萃取浓缩方法制备.以青藤碱为内标物质,流动相采用乙腈-0.1 mol·L-1磷酸二氢钾溶液-磷酸(30:70:0.01),检测波长为262nm,流速为1.0mL·min-1.结果:血浆中内源性物质对盐酸小檗碱及青藤碱的测定无干扰;最低检出限为1.25ng·mL-1;盐酸小檗碱在1.25～250ng·mL-1浓度范围内线性关系良好,r=0.9990;绝对回收率为82.94%～88.36%,方法回收率为89.28%～92.29%;日内精密度RSD≤4.87%、日间精密度RSD≤7.03%.缓释胶囊和普通丸药动学参数AUC0∞分别为668.02和809.95 h·ng·ml-1,MRT分别为5.27和4.34h,缓释胶囊相对于普通丸的生物利用度为84.6%.结论:建立的测定方法处理简单,无干扰,灵敏度高,适合测定中药缓释制剂的药物动力学研究.万氏牛黄清心缓释胶囊具有明显的缓释作用,药物在体内呈梯度释放.     

妇宁康泡腾胶囊的药代动力学研究

目的研究妇宁康泡腾胶囊在家兔体内的药动学特点。方法用HPLC法测定甘草酸在家兔体内48 h血药浓度,采用3P87药动学程序计算药动学参数。结果主要药动学参数为t1/2=8.956 h,Tmax=8.27 h,Cmax=0.4544μg/ml,AUC=37.161。结论该制剂在家兔体内吸收代谢缓慢,其生物半衰期超过8 h。     

定量比格犬血浆中去甲文拉法辛LC-MS/MS方法的建立及比格犬血浆中富马酸去甲文拉法辛药代动力学研究

目的:建立一种快速灵敏的液质联用方法定量比格犬血浆中去甲文拉法辛,并进行比格犬体内富马酸去甲文拉法辛药代动力学研究,同时与琥珀酸去甲文拉法辛比格犬体内药代参数进行对比。方法:样品处理采用叔丁基甲醚进行液液萃取,液相分离采用Agilent Eclipse Plus C18色谱柱(2.1 mm×100 mm,3.5μm),以乙腈-乙酸铵缓冲液(1 mmol/L)(体积比80∶20)进行等度洗脱。采用单次给药和多次给药试验进行比格犬体内药代动力学研究。结果:此方法具有良好的线性、精密度、准确度,定量下限(0.5 ng/mL)高于文献报道。液液萃取的样品提取方法简便,液质联用分析时间相对较短(3 min)。结论:此方法可成功地应用于比格犬血浆中去甲文拉法辛定量分析。比格犬体内富马酸去甲文拉法辛的药代参数(单次给药和多次给药试验)与对照品琥珀酸去甲文拉法辛没有明显的统计学差异。     

LC-MS/MS 法测定人血浆中伊伐布雷定浓度及药动学

目的:建立人血浆中伊伐布雷定的液相色谱-质谱-质谱联用测定方法,研究健康人体药代动力学.方法:以地西泮为内标物,采用液相色谱-质谱-质谱联用法,电喷雾电离源选择性正离子峰检测.测30名健康志愿者单剂量口服盐酸伊伐布雷定片的体内血药浓度,获得药动学参数.结果:伊伐布雷定在0.101-101 ng·mL-1浓度范围内呈良好的线性关系(r=0.998),最低检测浓度为0.101 ng·mL-1.高、中、低浓度的方法提取回收率分别为93.2%、86.6%、87.5%,日内、日间精密度RSD均小于15%.结论:LC-MS/MS方法灵敏度高,专属性强,准确,简便,适用于盐酸伊伐布雷定片的人体药代动力学研究.     

RP-HPLC法测定阿托伐他汀在新西兰兔体内的药代动力学

目的:研究阿托伐他汀片在新西兰兔体内的药代动力学.方法:18只成年健康雄性新西兰兔.随机分为正常对照组、10mg/kg·d阿托伐他汀片组与15 mg/kg·d阿托伐他汀片组,每组6只,采用RP-HPLC法测定血药浓度,计算药代动力学参数.结果:10mg/kg·d组与15 mg/kg·d组的主要药代动力学参数分别为:AUC0～t/μ g·L-1·h为(619.58±215.45)与(1138.34±422.32)、AUC0～∞/μ g·L-1·h为(655.68±242.83)与(1216.57±353.64)、Cmax/μ g·L-1为(455.81±168.52)和(896.53±168.5.8)、MRT0～t/h为(3.68±0.75)与(5.73±0.56)、MRT0～∞/h为(3.83±0.91)与(5.25±0.48)、Tmax/h为(2.51±0.82)与(3.68±0.33)、T1/2/h为(4.22±0.55)与(9.51±0.67).结论:RP-HPLC法适用于阿托伐他汀片动物药代动力学的研究.     

重组人血管内皮抑素在Beagle犬体内的药代动力学研究

研究重组人血管内皮抑素(rhEndostatin)静脉注射后在Beagle犬体内的药代动力学过程,为临床应用提供药代动力学数据。用酶联免疫吸附试验(ELISA)竞争法检测Beagle犬静脉注射rhEndostatin后不同时间的血药浓度,并将血药浓度-时间数据经计算机拟合,计算出相应参数。rhEndostatin静脉注射Beagle犬后,药物的分布半衰期平均为(0.34±0.04)h,消除半衰期为(16.5±1.6)h。血药浓度-时间曲线下面积(AUC)与剂量呈正相关,相关系数为0.999 9。血浆清除率(CLs)均值为(0.123±0.006)l/h,高、中、低剂量CLs基本相同。rhEndostatin在Beagle犬体内的药代动学过程基本符合线性药动学特征,血药浓度-时间曲线符合二房室模型。rhEndostatin在Beagle犬体内药代动力学过程的研究对其进一步开发具有指导价值。     

LC-MS/MS法测定人血浆中伊伐布雷定浓度及药动学

目的：建立人血浆中伊伐布雷定的液相色谱-质谱-质谱联用测定方法,研究健康人体药代动力学。方法：以地西泮为内标物,采用液相色谱-质谱-质谱联用法,电喷雾电离源选择性正离子峰检测。测30名健康志愿者单剂量口服盐酸伊伐布雷定片的体内血药浓度,获得药动学参数。结果：伊伐布雷定在0.101-101 ng·mL-1浓度范围内呈良好的线性关系（r=0.998）,最低检测浓度为0.101 ng·mL-1。高、中、低浓度的方法提取回收率分别为93.2%、86.6%、87.5%,日内、日间精密度RSD均小于15%。结论：LC-MS/MS方法灵敏度高,专属性强,准确,简便,适用于盐酸伊伐布雷定片的人体药代动力学研究。     

LC-MS/MS方法测定比格犬血浆中沙芬酰胺及其代谢物

建立液相色谱-质谱联用/质谱(LC-MS/MS)测定比格犬血浆中沙芬酰胺异构体及其代谢物浓度的方法,在此基础上对沙芬酰胺异构体及其代谢物在比格犬体内的药代动力学进行研究。色谱检测条件方法一为用AS-RH手性柱测定沙芬酰胺异构体;方法二为用XB-C18分析柱测定沙芬酰胺代谢物。质谱条件离子源为APCI源,离子化方式为正离子模式,喷雾电压5 200 V,加热毛细管温度550℃,雾化气(N2)流速75.8 KPa,气帘气(N2)75.8KPa,碰撞气(N2)55.16 KPa,扫描方式为多反应监测(MRM)。建立的LC-MS/MS方法线性范围左旋沙芬酰胺为10~2 000 ng/m L(r=0.999 4),右旋沙芬酰胺为10~2 000 ng/m L(r=0.997 6),沙芬酰胺代谢物为10~1 000 ng/m L(r=0.994 1)。本方法灵敏,快速且稳定,适用于沙芬酰胺异构体及其代谢物药代动力学研究。     

Solid Self-Microemulsifying Formulation for Candesartan Cilexetil

Sparingly, water-soluble drugs such as candesartan cilexetil offer challenges in developing a drug product with adequate bioavailability. The objective of the present study was to develop and characterize self-microemulsifying drug delivery system (SMEDDS) of candesartan cilexetil for filling into hard gelatin capsules. Solubility of candesartan cilexetil was evaluated in various nonaqueous careers that included oils, surfactants, and cosurfactants. Pseudoternary phase diagrams were constructed to identify the self-microemulsification region. Four self-microemulsifying formulations were prepared using mixtures of oils, surfactants, and cosurfactants in various proportions. The self-microemulsification properties, droplet size, and zeta potential of these formulations were studied upon dilution with water. The optimized liquid SMEDDS formulation was converted into free flowing powder by adsorbing onto a solid carrier for encapsulation. The dissolution characteristics of solid intermediates of SMEDDS filled into hard gelatin capsules was investigated and compared with liquid formulation and commercial formulation to ascertain the impact on self-emulsifying properties following conversion. The results indicated that solid intermediates showed comparable rate and extent of drug dissolution in a discriminating dissolution medium as liquid SMEDDS indicating that the self-emulsifying properties of SMEDDS were unaffected following conversion. Also, the rate and extent of drug dissolution for solid intermediates was significantly higher than commercial tablet formulation. The results from this study demonstrate the potential use of SMEDDS as a means of improving solubility, dissolution, and concomitantly the bioavailability.     

Pharmacokinetics of the progesterone-containing vaginal tablet and its use in assisted reproduction

Natural progesterone, which is devoid of androgenic activity, is widely used in assisted reproduction for luteal and pregnancy support. The vaginal route has become the most established way to deliver natural progesterone because it is easily administered, avoids liver first-pass metabolism, and has no systemic side-effects. The vagina has a large potential for absorption, and through the 'uterine first-pass effect' vaginal administration results in higher uterine progesterone concentrations. We have investigated the pharmacokinetics of natural progesterone in the form of a vaginal tablet. A single dose of 100 mg resulted in a mean C(max) of 31.53 +/- 9.15 nmol/l with a T(max) of 6.92 +/- 3.12 h. The terminal half-life was 16.39 +/- 5.25 h. The pharmacokinetic data are discussed in relation to dose, age, and estrogen priming. Single-dose pharmacokinetics of 100 mg of progesterone vaginal tablets and gelatin capsules were evaluated over 24 h. Results indicated a similar mean T(max) of 6.92 +/- 3.12 and 6.23 +/- 6.57 h, respectively. However, a significantly higher C(max) was achieved by the vaginal tablet (31.95 +/- 9.15 and 23.85 +/- 9.57 nmol/l, respectively, P < 0.05). Continuous use of vaginal progesterone did not influence the hormonal, liver, or lipid profiles evaluated. There was no case of endometrial hyperplasia. The vaginal tablet was found to be well-tolerated, safe, and easily administered. In conclusion, progesterone-containing vaginal tablets have good pharmacokinetic properties and should be used for progesterone supplementation in IVF.     

Preparation and <Emphasis Type="Italic">In Vitro</Emphasis>/<Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Puerarin Solid Self-Microemulsifying Drug Delivery System by Spherical Crystallization Technique

The aim of this work was to establish a method for preparing stable and controllable solid self-microemulsifying drug delivery system (S-SMEDDS) by spherical crystallization technique, which was explored for promoting the dissolution, oral bioavailability, and process efficiency. Solubility test, preparation of liquid self-microemulsifying drug delivery system (L-SMEDDS), and the obtained ternary phase diagrams test have been performed to screen and optimize the composition of LSMEDDS. The optimized formulation was used to prepare puerarin solid self-microemulsifying drug delivery system (Pue-SSMEDDS) by spherical crystallization technique. Droplet size and morphological analysis of the optimal Pue-SSMEDDS were determined to evaluate the final formulation. And the Pue-SSMEDDS was also assessed by flowability study, angle of repose, Carr’s index, and flow velocity. Furthermore, the vitro dissolution and pharmacokinetic profile in vivo were analyzed. The study in vitro showed the Pue-SSMEDDS could disperse in the dispersion medium within 60 s and was spherical with the particle size of 19.66 nm and zeta potential of ?28.3 mV. It could keep stable at low temperature and seal condition for 3 months. In vivo pharmacokinetic experiments of rats, the mean plasma concentration of self-microemulsion group was much higher than that of conventional tablets and could play a long-lasting efficacy, while there was no significant difference between the LSMEDDS and S-SMEDDS. The results suggested the potential of S-SMEDDS could improve the oral bioavailability of poorly water-soluble drug, such as puerarin.     

Tablet formulation containing meloxicam and beta-cyclodextrin: mechanical characterization and bioavailability evaluation

The purpose of this research was to evaluate beta-cyclodextrin (beta-CD) as a vehicle, either singly or in blends with lactose (spray-dried or monohydrate), for preparing a meloxicam tablet. Aqueous solubility of meloxicam in presence of beta-CD was investigated. The tablets were prepared by direct compression and wet granulation techniques. The powder blends and the granules were evaluated for angle of repose, bulk density, compressibility index, total porosity, and drug content. The tablets were subjected to thickness, diameter, weight variation test, drug content, hardness, friability, disintegration time, and in vitro dissolution studies. The effect of beta-CD on the bioavailability of meloxicam was also investigated in human volunteers using a balanced 2-way crossover study. Phase-solubility studies indicated an A(L)-type diagram with inclusion complex of 1:1 molar ratio. The powder blends and granules of all formulations showed satisfactory flow properties, compressibility, and drug content. All tablet formulations prepared by direct compression or wet granulation showed acceptable mechanical properties. The dissolution rate of meloxicam was significantly enhanced by inclusion of beta-CD in the formulations up to 30%. The mean pharmacokinetic parameters (C(max), K(e), and area under the curve [AUC](0-infinity)) were significantly increased in presence of beta-CD. These results suggest that beta-CD would facilitate the preparation of meloxicam tablets with acceptable mechanical properties using the direct compression technique as there is no important difference between tablets prepared by direct compression and those prepared by wet granulation. Also, beta-CD is particularly useful for improving the oral bioavailablity of meloxicam.     

Comparative in vitro and in vivo evaluation of matrix,osmotic matrix,and osmotic pump tablets for controlled delivery of diclofenac sodium

The aim of this investigation was preparation and comparative evaluation of fabricated matrix (FM), osmotic matrix (OM), and osmotic pump (OP) tablets for controlled delivery of diclofenac sodium (DS). All formulations were evaluated for various physical parameters, and in vitro studies were performed on USP 24 dissolution apparatus II in pH 7.4 buffer and distilled water. In vivo studies were performed in 6 healthy human volunteers; the drug was assayed in plasma using HPLC, and results were compared with the performance of 2 commercial tablets of DS. Various pharmacokinetic parameters (ie, C_max, T_max, area under the curve [AUC_0–24], and mean residence time) and relative bioavailability were compared. All fabricated formulations showed more prolonged and controlled DS release compared with commercial tablets studied. The OM and OP tablets, however, performed better than the matrix tablets. The rate and extent of drug release from FM1 matrix tablets (single polymer) was significantly different from that of FM2 (admixed polymers). Type of porosigenic agents and osmogens also influenced the drug release. Analysis of in vitro data by regression coefficient analysis revealed zero-order release kinetics for OM and OP tablets, while FM tablets exhibited Higuchi kinetics. In vivo results indicated prolonged blood levels with delayed peak and improved bioavailability for fabricated tablets compared to commercial tablets. It was concluded that the osmotic matrix and osmotic pump tablets could provide more prolonged, controlled, and gastrointestinal environmental-independent DS release that may result in an improved therapeutic efficacy and patient compliance.     

Development,Characterization and Permeability Assessment Based on Caco-2 Monolayers of Self-Microemulsifying Floating Tablets of Tetrahydrocurcumin

Novel self-microemulsifying floating tablets were developed to enhance the dissolution and oral absorption of the poorly water-soluble tetrahydrocurcumin (THC). Their physicochemical properties and THC permeability across Caco-2 cell monolayers were assessed. The self-microemulsifying liquid containing THC was adsorbed onto colloidal silicon dioxide, mixed with HPMC, gas-generating agents (sodium bicarbonate and tartaric acid), lactose and silicified-microcrystalline cellulose and transformed into tablets by direct compression. The use of different types/concentrations of HPMC and sodium bicarbonate in tablet formulations had different effects on the floating characteristics and in vitro THC release. The optimum tablet formulation (F2) provided a short floating lag time (∼23 s) together with a prolonged buoyancy (>12 h). About 72% of THC was released in 12 h with an emulsion droplet size in aqueous media of 33.9 ± 1.0 nm while that of a self-microemulsifying liquid was 29.9 ± 0.3 nm. The tablet formulation was stable under intermediate and accelerated storage conditions for up to 6 months. The THC released from the self-microemulsifying liquid and tablet formulations provided an approximately three- to fivefold greater permeability across the Caco-2 cell monolayers than the unformulated THC and indicated an enhanced absorption of THC by the formulations. The self-microemulsifying floating tablet could provide a dosage form with the potential to improve the oral bioavailability of THC and other hydrophobic compounds.KEY WORDS: Caco-2 cells, controlled release, permeability, self-microemulsifying floating tablets, tetrahydrocurcumin     

Polymeric surfactant based etodolac chewable tablets: formulation and in vivo evaluation

Etodolac (ET) is a nonsteroidal anti-inflammatory drug with proved potential antitumor and uric acid lowering effects. It shows dissolution rate-dependent bioavailability. This work was carried out to improve the dissolution rate of etodolac using three carriers of known potential to improve solubility and hence dissolution rate of poorly soluble drugs through coevaporation technique. The polymeric surfactant inutec, 2-hydroxypropyl-β-cyclodextrin, and tromethamine were used at three different drug/carrier ratios. The dissolution rate of ET at pH 1.2 and 6.8 is improved in all of the solid dispersion systems compared to that of the pure drug and physical mixtures. DSC of coevaporates at 1:5 drug/carrier ratio providing the fastest dissolution rate suggested loss of ET crystallinity which was further confirmed by X-ray diffraction. Inutec-based coevaporate was chosen for the formulation of ET chewable tablets. Chewable tablets (F3) that met the USP monograph specifications for ET tablets, with 86% dissolved amount within 15 min, was chosen for in vivo absorption study in comparison with pure ET-filled hard gelatin capsules. The results showed significantly higher mean C _max and shorter mean T _max (about 2 h earlier) and about 1.32-fold higher mean AUC_0–24 values for the F3 chewable tablets compared to ET-filled capsules.     

Design and Evaluation of Self-Microemulsifying Drug Delivery System (SMEDDS) of Tacrolimus

The objective of present investigation was to formulate self-microemulsifying drug delivery systems (SMEDDS) of tacrolimus (FK 506), a poorly water soluble immunosuppressant that exhibits low and erratic bioavailability. Solubility of FK 506 in various oils, surfactants cosurfactants and buffers was determined. Phase diagrams were constructed at different ratios of surfactant/cosurfactant (K _m ) to determine microemulsion existence region. The effect of oil content, pH of aqueous phase, dilution, and incorporation of drug on mean globule size of resulting microemulsions was studied. The optimized SMEDDS formulation was evaluated for in vitro dissolution profile in comparison to pure drug and marketed formulation (Pangraf capsules). The in vivo immunosuppressant activity of FK 506 SMEDDS was evaluated in comparison to Pangraf capsules. Area of o/w microemulsion region in phase diagram was increased with increase in K _m . The SMEDDS yielded microemulsion with globule size less than 25 nm which was not affected by the pH of dilution medium. The SMEDDS was robust to dilution and did not show any phase separation and drug precipitation even after 24 h. Optimized SMEDDS exhibited superior in vitro dissolution profile as compared to pure drug and Pangraf capsules. Furthermore, FK 506 SMEDDS exhibited significantly higher immunosuppressant activity in mice as compared to Pangraf capsules.     

百令胶囊联合厄贝沙坦片对膜性肾病患者MMP-9, MMP-3和TIMP-1水平的影响

目的:探究百令胶囊联合厄贝沙坦片对膜性肾病患者基质金属蛋白酶-9、3和金属蛋白酶组织抑制物-1影响。方法:收集我院肾内科收治的膜性肾病患者98例,根据随机对照表分为对照组和试验组,每组49例。对照组给予厄贝沙坦片治疗,试验组联合百令胶囊治疗。对比分析两组患者的临床疗效、血清Scr、BUN、UA、Ccr、尿蛋白、MMP-9、MMP-3及TIMP-l水平以及不良反应的发生情况。结果:治疗后,对照组临床总有效率为81.63%,显著低于试验组的95.92%(P0.05)。两组治疗后血清Scr、BUN、UA、MMP-9、MMP-3、TIMP-l水平均显著降低,且试验组显著低于对照组(P0.05),Ccr水平升高,且试验组显著高于对照组(P0.05)。对照组不良反应发生率为10.20%,试验组为6.25%,差异无统计学意义(P0.05)。结论:百令胶囊联合厄贝沙坦片对膜性肾病患者的临床疗效显著,安全性较高,可能与其显著降低MMP-9、MMP-3和TIMP-1水平有关。