HPLC—UV法同时测定复方坎地沙坦酯片中坎地沙坦酯和氢氯噻嗪的含量

目的:建立同时测定复方坎地沙坦酯片中坎地沙坦酯和氢氯噻嗪含量的HPLC-UV法。方法:采用Phenomenex C_(18)(250mm×4.6mm,5μm)色谱柱,流动相为乙腈-0.1mol·L~(-1)磷酸二氢钠溶液(加0.1%三乙胺,磷酸调pH5.0)(65∶35),流速1.0mL·min~(-1),检测波长262nm,柱温35℃。结果:坎地沙坦酯和氢氯噻嗪分别在1.6～32.0μg·mL~(-1)(r=0.9998)和1.2～23.8μg·mL~(-1)(r=0.9999)浓度范围内线性关系良好;平均回收率(n=9)分别为102.1%和100.7%。结论:本文方法准确、快速,适合于复方坎地沙坦酯片的含量测定。     

坎地沙坦酯治疗轻中度高血压病人的疗效及安全性

目的：评价坎地沙坦酯治疗轻中度高血压病人的疗效及安全性。方法：人选48例轻中度高血压病人，经2周导人期后随机分人试验组和对照组各24例，按双盲、平行临床药理试验方法分别给予坎地沙坦酯8mg和氯沙坦50mg治疗。治疗4周后如不能有效控制血压，则将用药剂量加倍并维持到第8周末。检测病人治疗前、后不同时间的血压，心率，以及血、尿常规，肝、肾功能，并记录服药期间可能发生的不良事件。结果：试验组和对照组降压显效率均为100％，治疗后2周末收缩压(SBP)和舒张压(DBP)均已明显降低。此后血压继续下降，与治疗前相比，用药8周末试验组和对照组SBP分别下降20．3和16．4mmHg，DBP分别下降16．8和16．1mmHg。试验组中有1例病人服药期间出现头痛，1例病人感轻微胸闷和腹胀。两组病人血、尿常规，肝、肾功能均正常。结论：坎地沙坦酯治疗轻中度高血压病人降压效果良好，服用安全。     

HPLC-UV法测定大鼠血浆中坎地沙坦的质量浓度及胃肠道吸收的研究

目的建立灵敏、简便的HPLC-UV法测定大鼠血浆中坎地沙坦的质量浓度,用于研究坎地沙坦酯固体脂质纳米粒在大鼠胃肠道的吸收情况。方法采用Eclipse XCB-C18色谱柱(150 mm×4.6 mm,5μm),流动相为水(体积分数0.1%磷酸,体积分数0.1%三乙胺,pH值2.7)-乙腈(体积比42∶58),流速为1.0 mL·min-1,检测波长为254 nm。结果测定坎地沙坦的线性范围在0.01～1 mg·L-1时,回归方程为A=7.028ρ+4.200×10-2(r=0.999 8);线性范围在0.3～30 mg·L-1时,回归方程为A=0.237ρ+1.00×10-3(r=0.999 2),定量下限达到10μg.L-1。日内、日间RSD值均小于10.0%,提取回收率大于75%。该方法用于评价坎地沙坦酯固体脂质纳米粒及原料药在大鼠胃肠道的吸收。结论该方法灵敏、简单、可靠,可用于测定血浆中坎地沙坦的质量浓度。与原料药相比,坎地沙坦酯固体脂质纳米粒在胃和小肠部位的吸收均有显著提高。     

Pharmacokinetics and haemodynamics of candesartan cilexetil in hypertensive patients on regular haemodialysis

AIMS: The pharmacokinetic profile of candesartan cilexetil might be altered in patients with end-stage renal disease (ESRD). No data are available about the pharmacokinetics and haemodynamics of the angiotensin II receptor antagonist candesartan cilexetil in ESRD patients on regular haemodialysis (HD). METHODS: We performed a repeated dose study (8 mg candesartan cilexetil once daily) in eight male HD patients over a treatment period of 5 days with an additional observation period of 3 days. RESULTS: Pharmacokinetic analysis with nonlinear mixed effects modeling (NONMEM) over the whole treatment period revealed a dependency of the volume of distribution on body weight and of the metabolic clearance on age and body weight in the studied population. No significant drug elimination by HD was observed. The estimated metabolic and intercompartmental clearances were 83 ml min-1 (CV 39%) and 9.9 ml min-1, respectively. The unexplained random variability of the final two compartment model was 30%. In one patient with adult polycystic kidney disease oral clearance decreased during the observation period, attributable to a significant increase in bioavailability. Maximum observed changes in blood pressure were -50/-27+/-14/8 mmHg on day 5 with haemodialysis therapy as compared with changes in blood pressure of -14/-12+/-14/8 mmHg on day 1 without haemodialysis treatment. The observed maximum decrease in systolic blood pressure correlated with the amount of ultrafiltration during the HD session on day 5 (r=0.70, P<0.05). In two patients, one of whom was binephrectomized, severe hypotensive episodes were observed during this HD session. CONCLUSIONS: HD does not influence the elimination kinetics of candesartan. The observed inter- and intraindividual variability of oral clearance and the pronounced influence of HD-induced volume contraction on the haemodynamic effects of candesartan makes it mandatory to carefully monitor HD patients treated with candesartan cilexetil.     

HPLC法测定坎地沙坦酯及其有关物质

目的建立坎地沙坦酯及其有关物质的HPLC测定方法.方法采用C18柱,流动相为磷酸缓冲液(磷酸二氢钾2.72 g溶于1000 mL水中,加磷酸1 mL,混匀后用三乙胺调节pH值为5.8±0.1)-乙腈(48:52);流速为1.0 mL·min-1;检测波长为210 nm.结果坎地沙坦酯浓度在5.0～40.0μg·mL-1时,方法线性关系良好(r＝0.999 8),回收率为99.8%,坎地沙坦酯最低检测浓度为0.025 ng,可检测到十万分之一的有关物质.结论该法简便、专属、重现好,可用于测定坎地沙坦酯的含量及对合成过程中的有关物质进行限量控制.     

高脂高热量饮食对坎地沙坦酯氨氯地平在中国健康人体内药代动力学的影响

目的 探索空腹和高脂高热量饮食情况下坎地沙坦酯氨氯地平片中两制剂在中国健康受试者中的药代动力学特征差异.方法 用单中心、随机、开放、两制剂、单次给药、双周期、交叉的试验设计.空腹或高脂饮食条件下各入组32例中国健康受试者,单次口服坎地沙坦酯氨氯地平片(8 mg/5 mg),给药前后按时间点采集静脉血样.用高效液相色谱串...     

高剂量坎地沙坦西酯16mg治疗轻中度原发性高血压65例临床观察

目的:评价16 mg坎地沙坦西酯治疗轻中度原发性高血压患者的有效性和安全性.方法:采用随机、双盲、平行对照的研究方法,入选患者65例,随机接受坎地沙坦西酯16 mg·d-1(n=33)或8 mg·d-1(n=32)治疗,共8周,并对其中的37例患者于治疗前后进行24 h动态血压监测.结果:治疗8周末,16 mg组和8 mg组的收缩压分别下降(10.9±11.5)mmHg和(11.5±15.1)mmHg,舒张压分别下降(12.9±11.3)mmHg和(10.5±7.8)mmHg;两组的降压总有效率分别为70%和61.3%.动态血压监测显示,16 mg组和8 mg组的收缩压谷峰比值分别为73%和47%,舒张压为65%和47%.两组的不良事件发生率无统计学差异.结论:高剂量坎地沙坦西酯16 mg·d-1治疗轻中度原发性高血压安全有效,患者耐受性好.     

Candesartan cilexetil loaded solid lipid nanoparticles for oral delivery: characterization,pharmacokinetic and pharmacodynamic evaluation

Abstract

Candesartan cilexetil (CC) is used in the treatment of hypertension and heart failure. It has poor aqueous solubility and low oral bioavailability. In this work, CC loaded solid lipid nanoparticles (CC-SLNs) were developed to improve the oral bioavailability. Components of the SLNs include either of trimyristin/tripalmitin/tristearin, and surfactants (Poloxamer 188 and egg lecithin E80). The CC loaded nanoparticles were prepared by hot homogenization followed by ultrasonication method. The physicochemical properties, morphology of CC-SLNs were characterized, the pharmacokinetic and pharmacodynamic behaviour of CC-SLNs were evaluated in rats. Stable CC-SLNs having a mean particle size of 180–220?nm with entrapment efficiency varying in between 91–96% were developed. The physical stability of optimized formulation was studied at refrigerated and room temperature for 3 months. Further, freeze drying was tried for improving the physical stability. DSC and XRD analyses indicated that the drug incorporated into SLN was in amorphous form but not in crystalline state. The SLN-morphology was found to be nearly spherical by electron microscopic studies. Pharmacokinetic results indicated that the oral bioavailability of CC was improved over 2.75-fold after incorporation into SLNs. Pharmacodynamic study of SLNs in hypertensive rats showed a decrease in systolic blood pressure for 48?h, while suspension showed a decrease in systolic blood pressure for only 2?h. Taken together, these effects are due to enhanced bioavailability coupled with sustained action of CC in SLN formulation. Thus, the results conclusively demonstrated the role of CC-SLNs for a significant enhancement in oral bioavailability along with improved pharmacodynamic effect.     

Adaptive Neuro-Fuzzy Modeling of Poorly Soluble Drug Formulations

Purpose The purpose of this study was to evaluate the efficiency of a neuro-fuzzy logic-based methodology to model poorly soluble drug formulations and predict the development of the particle size that has been proven to be an important factor for long-term stability. Methods An adaptive neuro-fuzzy inference system was used to model the natural structures within the data and construct a set of fuzzy rules that can subsequently used as a predictive tool. The model was implemented in Matlab 6.5 and trained using 75% of an experimental data set. Subsequently, the model was evaluated and tested using the remaining 25%, and the predicted values of the particle size were compared to the ones from the experimental data. The produced adaptive neuro-fuzzy inference system-based model consisted of four inputs, i.e., acetone, propylene glycol, POE-5 phytosterol (BPS-5), and hydroxypropylmethylcellulose 90SH-50, with four membership functions each. Moreover, 256 fuzzy rules were employed in the model structure. Results Model training resulted in a root mean square error of 4.5 × 10⁻³, whereas model testing proved its highly predictive efficiency, achieving a correlation coefficient of 0.99 between the actual and the predicted values of the particle size (mean diameter). Conclusions Neuro-fuzzy modeling has been proven to be a realistic and promising tool for predicting the particle size of drug formulations with an easy and fast way, after proper training and testing.     

Effect of cyclodextrins on the solubility and stability of candesartan cilexetil in solution and solid state

Guest-host interactions of candesartan cilexetil (CAND) with cyclodextrins (CyDs) have been investigated using phase solubility diagrams (PSD), X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC) and molecular mechanical modelling (MM). Estimates of the complex formation constant (K(11)) show that the tendency of CAND (pK(a)=6.0) to complex with CyDs follows the order: β-CyD>HP-β-CyD>γ-CyD>α-CyD. Complex formation of CAND with β-CyD (ΔG°=-31.5 kJ/mol) is largely driven by enthalpy change (ΔH°=-32.8 kJ/mol) and slightly retarded by entropy change (ΔS°=-4.6J/mol K). The HPLC results indicate that complex prepared by freeze drying method is chemically not stable due to the formation of amorphous CAND. Also it may suggest formulating CAND with β-CyD by kneading (dispersion) or co-evaporation (real inclusion complex) methods into capsule rather than compressed in tablets, where the compression enhances the instability of CAND. DSC thermograms for CAND/β-CyD complexes proved the formation of inclusion complexes with new solid phase. MM studies indicate the partial penetration of CAND into the β-CyD cavity.     

Enhanced solubility and intestinal absorption of candesartan cilexetil solid dispersions using everted rat intestinal sacs

Objective

Candesartan cilexetil (CAN) is a poor aqueous soluble compound and a P-glycoprotein (P-gp) efflux pump substrate. These key factors are responsible for its incomplete intestinal absorption.

Methods

In this study, we investigated to enhance the absorption of CAN by improving its solubility and inhibiting intestinal P-gp activity. A phase solubility method was used to evaluate the aqueous solubility of CAN in PVP K30 (0.2–2%). Gibbs free energy (ΔGtro) values were all negative. Solubility was enhanced by the freeze drying technique. The in vitro dissolution was evaluated using the USP paddle method. The interaction between drug and carrier was evaluated by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and Differential scanning calorimetry (DSC) studies. Naringin was selected as P-gp inhibitor. Absorption studies were performed using the everted gut sac model from rat jejunum. The drug analysis was performed by HPLC.

Results

FTIR spectra revealed no interaction between drug and PVP K30. From XRD and DSC data, CAN was in the amorphous form, which explains the cumulative release of drug from its prepared systems. We noticed an enhancement of CAN absorption by improving its solubility and inhibiting the P-gp activity. The significant results (p < 0.05) were obtained for freeze dried solid dispersions in the presence of P-gp inhibitor than without naringin (15 mg/kg) with an absorption enhancement of 8-fold.

Conclusion

Naringin, a natural flavonoid, has no undesirable side effects. Therefore, it could be employed as an excipient in the form of solid dispersions to increase CAN intestinal absorption and its oral bioavailability.     

Effects of polysorbate 80 on the in‐vitro precipitation and oral bioavailability of halofantrine from polyethylene glycol 400 formulations in rats

Objectives The aim of this study was to examine the effects of formulations of polysorbate 80 (PS 80) and polyethylene glycol 400 (PEG 400) on the precipitation and oral bioavailability of the hydrophobic drug halofantrine. Methods The in‐vitro dilution profile of the formulations was evaluated in phosphate buffer and in simulated intestinal fluids using a standard dissolution apparatus. The pharmacokinetic profile of the formulations was investigated in fasted rats at two dose levels, 5 and 17.5 mg/kg, with blood sampling by vein puncture in the tail. Key findings The solubility of halofantrine was found to be highest in PS 80, and in co‐mixtures there was a correlation with the content of PS 80. The in‐vitro dilution profile revealed precipitation of halofantrine when dissolved in pure PEG 400, although the precipitation was smaller in the simulated intestinal fluid. Addition of 25% PS 80 to the PEG 400 significantly decreased precipitation. The animals dosed with the PEG 400 formulation had significant lower bioavailability than the PS 80–PEG 400 co‐mixtures, possibly due to halofantrine precipitation in the gastrointestinal tract. Conclusions Addition of PS80 to the formulation increased the bioavailability of halofantrine and the more compound, the more PS80 was needed to prevent precipitation.     

Pharmacokinetics and pharmacodynamics of oral heparin solid dosage form in healthy human subjects

The present investigation determined the molecular structure and the pharmacokinetic and pharmacodynamic profiles of oral unfractionated heparin containing oral absorption enhancer sodium N-[8-(2-hydroxybenzoyl) amino]caprylate, salcaprozate sodium (SNAC) and assessed the safety and tolerability of the orally dosed heparin solid dosage form versus other routes. Sixteen healthy men were included in this single-dose, 3-way crossover, randomized, open-label study. Disaccharide compositional analysis was performed using capillary high-performance liquid chromatography with electrospray ionization mass spectrometry detection. The pharmacodynamics of heparin were obtained from analysis of plasma anti-factor Xa, anti-factor IIa, activated partial thromboplastin time, and total tissue factor pathway inhibitor data. The molecular weight properties and the disaccharide composition of orally administered unfractionated heparin/SNAC and parenterally administered unfractionated heparin are identical and consistent with the starting pharmaceutical standard heparin. Furthermore, the anti-factor Xa/anti-factor IIa ratio achieved is of approximately 1:1. This is the first true pharmacokinetic study to measure the chemical compositions of heparin administered by different routes.     

Novel oral delivery system of indomethacin by solidified mPEG-PDLLA micelles: in vivo study

To administer indomethacin (IND) orally using polymeric micelles, IND loaded solidified polymeric micelles (IND-SPM) were prepared and evaluated for their in vitro and in vivo characteristics. IND and methoxy-poly(ethylene glycol) poly(d, l-lactide) copolymer (mPEG-PDLLA) were dissolved in acetone followed by the addition of an equivalent amount of polyplasdone XL-10 and stirred to obtain a suspension. Afterwards, acetone was completely evaporated. It was found that IND-SPM generates small polymeric micelles of 18.1 nm. Moreover, the solubility of IND at pH 6.8 increased 4.6-folds, and more than 90% of IND in 20 mg of IND-SPM was dissolved in 250 mL SIF pH 6.8 within 30 min. Pharmacokinetic parameters in fasted rats showed that IND-SPM 1:3 resulted in 3-folds increase of AUC and C_max compared to commercial IND. mPEG-PDLLA micelles were found to be efficient carriers for oral administration of IND as solid dosage forms by adsorption on polyplasdone XL-10.     

Effect of bile on the oral absorption of halofantrine in polyethylene glycol 400 and polysorbate 80 formulations dosed to bile duct cannulated rats

Objectives The aim of this study was to examine the effects of bile on the oral absorption of the poorly water‐soluble compound, halofantrine, when administered to rats in vehicles consisting of the co‐solvent polyethylene glycol 400 (PEG 400) alone or in mixtures with the surfactant polysorbate 80 (PS 80) (95 : 5; 85 : 15; 75 : 25 PEG 400 : PS 80). Methods Halofantrine (17.5 mg/kg) was administered to bile duct cannulated (BDC) and sham‐operated rats in a fixed vehicle volume of 5 ml/kg. Key findings The bioavailability of halofantrine was significantly lower in BDC rats when dosed with 0–5% PS 80 in PEG 400 compared with BDC rats dosed with >15% PS 80. Increasing the concentration of PS 80 to 15–100% eliminated this difference. A possible explanation for the lower bioavailability of halofantrine in BDC rats when dosed in pure PEG 400 could be the dilution of the vehicle by intestinal fluids, decreased transit time and precipitation in the gastrointestinal tract upon dilution of PEG 400. Conclusions The addition of PS 80 to the formulation increased its solubilising power upon dilution and may have inhibited precipitation and substituted the absence of bile above a certain level. Adjusting the level of surfactant in drug formulations could therefore be used to minimise variability in the bioavailability from co‐solvent systems based upon differences in bile concentration between individuals.     

3D打印技术在口服固体制剂中的应用与挑战

近年来3D打印技术发展迅速,已被广泛应用于组织工程、牙科、建筑、汽车和航空航天等领域,然而在制药领域,该技术仍处于起步阶段,其潜力尚未得到充分发掘,直到FDA批准第一个3D打印药物才引起科研人员的兴趣。本文介绍了黏合剂沉积法、物料喷射法、挤出法、粉末床熔融法及光聚合法等各种3D打印技术,并尝试对目前使用3D打印技术制备的口服固体剂型(尤其是片剂)进行了全面回顾,突显其在制药领域较好的适用性。与传统制剂技术相比该技术具有明显的优势,其中最突出的是制剂个性化定制以提高依从性,但还需要克服诸多技术挑战,以释放其在制药工业中的真正潜力。     

流池法的研究进展及应用

流池法作为一种溶出度的检查方法,有着广阔的应用前景.目前,流池法在国外被广泛应用,在国内也逐渐成为研究热点.本文结合国内外相关文献资料,对流池法溶出度检查法的研究进展及应用进行综述,进一步为难溶性药物、特殊剂型等提供一种新的体外溶出策略.     

齐墩果酸固体脂质纳米粒口服给药系统的制备与表征(英文)

采用改良的乳化-溶剂挥发法制备齐墩果酸-固体脂质纳米粒(OA-SLNs)并对其性质进行评价。其粒径,zeta电位,包封率和载药率分别为(104.5±11.7)nm,(-25.5±1.8)mV,(94.2±3.9)%,和(4.71±0.15)%。透射电子显微镜下,可见球形实心纳米粒。X-粉末衍射和差示扫描量热(DSC)图谱证实药物分子均匀分散在脂质骨架中。体外释放实验表明,OA-SLNs以每小时4.88%速率缓慢释放药物,符合零级释放动力学模型。OA-SLNs在人工胃液和肠液中具有良好的稳定性。本文研究为OA-SLNs口服给药系统的应用进一步研究提供了可能。     

Supersaturation and crystallization: non-equilibrium dynamics of amorphous solid dispersions for oral drug delivery

Introduction: Amorphous solid dispersions (ASDs) are one of the key formulation technologies that aid the development of poorly soluble candidates. However, their dynamic behaviors, including dissolution and crystallization processes, are still full of mystery. Further understanding of these processes should enhance their wider use.

Areas covered: The first part of this review describes the current understanding of the dissolution of ASDs, where phase separation behavior is frequently involved and attempts to develop appropriate dissolution tests to achieve an in vitro–in vivo correlation are examined. The second part of this review discusses crystallization of the drug molecule with the eventual aim of establishing an accelerated testing protocol for predicting its physical stability.

Expert opinion: The phase separation behavior from the supersaturated state during the dissolution test must be understood, and its relevance to the oral absorption behavior needs to be clarified. Research efforts should focus on the differences between the phase behavior in in vitro and in vivo situations. Initiation time of the crystallization was shown to be predicted only from storage and glass transition temperatures. This finding should encourage the establishment of testing protocol of the physical stability of ASDs.