Chitosan/pectin polyelectrolyte complexes: Selection of suitable preparative conditions for colon-specific delivery of vancomycin

The influence of polyelectrolyte complexes composed of chitosan and pectin on the release behaviour of vancomycin has been investigated. Polyelectrolyte complexes between chitosan and pectin were prepared in various pH regions and at different molar ratios by mixing solutions of pectin and chitosan with the same ionic strength. The precipitates were collected by spray-drying and tablets were obtained with the different complexes and vancomycin. FT-IR spectra and TGA thermograms were analysed to study the degree of interactive strength between polyions. In vitro swelling, mucoadhesion and release tests were performed in order to investigate the chitosan/pectin complex ability in the delivery of vancomycin in the gastro-intestinal tract. The results confirmed the formation of polyelectrolyte complexes between pectin and chitosan at pH values in the vicinity of the pK_a interval of the two polymers. Chitosan/pectin complexes showed a pH-sensitive swelling ability and drug release behaviour suggesting their possible use for colon-specific localization of vancomycin. Among the different complexes, chitosan/pectin complex prepared in molar ratio of 1:9 showed the highest mucoadhesive properties and a pH-dependent swelling sensitivity suitable for colon-delivery. Moreover, the particular composition of these complexes improved vancomycin availability at alkaline pH on the bases of an enzyme-dependent degradation as confirmed from release studies performed in presence of beta-glucosidase.     

注射用盐酸万古霉素配伍禁忌的文献分析

目的研究注射用盐酸万古霉素的配伍问题。方法检索、分析近年来有关注射用盐酸万古霉素配伍禁忌的国内医药文献。结果注射用盐酸万古霉素与头孢哌酮钠舒巴坦钠、头孢匹胺钠等多种药物存在配伍禁忌。结论应避免将注射用盐酸万古霉素与头孢哌酮钠舒巴坦钠、头孢匹胺钠等药物配伍。     

替考拉宁与盐酸万古霉素致严重水疱型药疹

1例74岁男性患者,因直肠癌根治术后出现咳嗽、咯痰、发热约1个月,先后给予拉氧头孢钠、比阿培南、莫西沙星、替考拉宁、盐酸万古霉素、利柰唑胺和达托霉素治疗。在应用替考拉宁12d后换用莫西沙星,应用莫西沙星的第4天,患者四肢及躯干部位出现充血性皮疹伴瘙痒感。停用莫西沙星、改用盐酸万古霉素并给予抗过敏对症治疗后患者皮疹好转。应用盐酸万古霉素第8天,患者四肢再次出现红疹,停用盐酸万古霉素并换用替考拉宁。应用替考拉宁第5天患者皮疹加重,部分皮疹表面出现水泡并连接成片,换用利奈唑胺并继续抗过敏治疗,陈旧水泡逐渐吸收,未再出现新发水疱。考虑可能为替考拉宁引起的迟发型过敏反应,不排除还存在与盐酸万古霉素交叉过敏的可能。     

国产注射用盐酸万古霉素的质量评价

目的 评价国产注射用盐酸万古霉素的质量。方法 按国家标准检验与探索性研究项结合,对抽验样品进行检验,对检验结果进行统计与分析。结果 共抽取样品26批,按国家标准检验合格率为100%。探索性研究中对盐酸万古霉素的有关物质来源进行了研究,建议对有关物质中工艺杂质与降解杂质应分别进行控制;利用模拟预测技术建立万古霉素药动学模型,探讨万古霉素B含量与临床有效性的相互关系。根据现行盐酸万古霉素说明书中的剂量与用法,成年健康人群中万古霉素血药浓度无法在全部给药时间内满足《中国万古霉素治疗药物监测指南》推荐的最低治疗浓度要求。提高盐酸万古霉素中含量及万古霉素B的限度,可以有效的提高本品的临床有效性水平。建议现行标准提高万古霉素含量与万古霉素B的限度水平。结论 目前国内注射用盐酸万古霉素总体质量较好,现行标准有待进一步提高。     

Liposomes as delivery systems for nasal vaccination: strategies and outcomes

Importance of the field: Among the particulate systems that have been envisaged in vaccine delivery, liposomes are very attractive. These phospholipid vesicles can indeed deliver a wide range of molecules. They have been shown to enhance considerably the immunogenicity of weak protein antigens or synthetic peptides. Also, they offer a wide range of pharmaceutical options for the design of vaccines. In the past decade, the nasal mucosa has emerged as an effective route for vaccine delivery, together with the opportunity to develop non-invasive approaches in vaccination.

Areas covered in this review: This review focuses on the recent strategies and outcomes that have been developed around the use of liposomes in nasal vaccination.

What the reader will gain: The various formulation parameters, including lipid composition, size, charge and mucoadhesiveness, that have been investigated in the design of liposomal vaccine candidates dedicated to nasal vaccination are outlined. Also, an overview of the immunological and protective responses obtained with the developed formulations is presented.

Take home message: This review illustrates the high potential of liposomes as nasal vaccine delivery systems.     

Stability-indicating spectrofluorimetric method with enhanced sensitivity for determination of vancomycin hydrochloride in pharmaceuticals and spiked human plasma: Application to degradation kinetics

Based on investigating the relative fluorescence intensity of vancomycin hydrochloride (VCM) in methanol, a simple, highly sensitive, time-saving and specific spectrofluorimetric method was developed and validated. VCM fluorescence was measured at 335 nm when excited at 268 nm. Excellent linearity is obeyed in the concentration range 1–100 ng/mL with a detection limit of 5.94 pg/mL, a quantitation limit of 18.03 pg/mL and a very good correlation coefficient (r = 0.9999). Our method was applied to analyze VCM in pharmaceuticals as well as spiked human plasma. Moreover, VCM stability was studied when exposed to various degradation conditions such as oxidative, alkaline as well as acidic stress. Acidic and alkaline degradation kinetics of VCM was studied for the first time. The degradation follows pseudo-first-order kinetics. The apparent rate constants and half-life times were calculated. The Arrhenius equation was assessed and the activation energies of the degradation were also calculated. The developed method can be easily applied in quality control laboratories due to its sensitivity, specificity, simplicity and low cost.     

Chitosan based micro- and nanoparticles for colon-targeted delivery of vancomycin prepared by alternative processing methods

The aim of this work was to prepare chitosan (CH) based particulate formulations for colon delivery of vancomycin (VM). Chitosan microparticles (MPs) and nanoparticles (NPs) loaded with VM were prepared using different CH/tripolyphosphate (TPP) molar ratios and different technological processes. In particular, nanoparticles were prepared by ionic gelation and freeze-drying to recover these particles, or, alternatively, by spray-drying method. Microparticles were prepared using a different spray-dryer. Micro- and nanoparticles were characterized in terms of size distributions by photon correlation spectroscopy (PCS), while encapsulation and drug loading efficiencies were studied using a dialysis method. Fourier Transform Infrared Spectroscopy (FT-IR) was employed to determine the surface composition of the micro- and nanoparticles respectively, and the morphologies of the developed systems were studied by scanning electron microscopy (SEM). Water uptake as well as drug release profiles were also measured. Antibacterial activity against Staphylococcus aureus, a Gram-positive model strain, was evaluated. FT-IR results suggested an electrostatic interaction between VM and CH/TPP particles. Moreover, the particles were found to hold a positive zeta-potential, indicating the presence of CH on the particle surfaces. Particle size and encapsulation efficiency were mainly influenced by the different manufacturing processes employed. Nanoparticles obtained by spray-drying showed the best results in terms of water uptake and drug release rate. Moreover, they showed a good bactericidal activity against S. aureus.     

Novel PEG-grafted nanostructured lipid carrier for systematic delivery of a poorly soluble anti-leukemia agent Tamibarotene: characterization and evaluation

Abstract

Tamibarotene (Am80), a poorly water-soluble drug for the treatment of acute promyelocytic leukemia (APL), loaded nanostructured lipid carrier (Am80-NLC) was developed and characterized previously. The purpose of the present work was to develop PEGylated nanostructured lipid carrier (PEG-NLC) for intravenous delivery of Am80, with the aim to further extend the circulation in blood and decrease the adverse events. Am80-loaded PEG-NLC (Am80-PEG-NLC) modified with PEG-40 stearate (PEG40-SA, molecular weight 2000?Da) was formulated by the method of melt-emulsification and low temperature-solidification technique. Am80-NLC was developed as well as control. Based on the optimized results of single-factor screening experiment, the average drug entrapment efficiency, the mean particle size, and zeta potential of Am80-NLC and Am80-PEG-NLC were found to be 89.8–94.3%, 178.9–201.6?nm, and ?37.74 to ?20.1?mV, respectively. In vitro drug release of Am80-NLC and Am80-PEG-NLC possessed a sustained release characteristic and their release behavior was in accordance with the Ritger–Peppas equation. In vivo, after intravenous (i.v.) injection to rats, the mean residence time (MRT) of Am80-PEG-NLC group was significantly prolonged and the AUC value was improved as well compared with the Am80-NLC group. Furthermore, the biodistribution in mice showed that Am80-PEG-NLC preferentially decreased the accumulation of Am80 in kidney and increased the drug concentration in brain after i.v. injection. In conclusion, Am80-PEG-NLC may be a potential delivery system for Am80 in the treatment of APL.     

Novel two-chain fatty acid-based lipids for development of vancomycin pH-responsive liposomes against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA)

Abstract

The development of bacterial resistance against antibiotics is attributed to poor localisation of lethal antibiotic dose at the infection site. This study reports on the synthesis and use of novel two-chain fatty acid-based lipids (FAL) containing amino acid head groups in the formulation of pH-responsive liposomes for the targeted delivery of vancomycin (VAN). The formulated liposomes were characterised for their size, polydispersity index (PDI), surface charge and morphology. The drug-loading capacity, drug release, cell viability, and in vitro and in vivo efficacy of the formulations were investigated. A sustained VAN release profile was observed and in vitro antibacterial studies against S. aureus and MRSA showed superior and prolonged activity over 72?h at both pH 7.4 and 6.0. Enhanced antibacterial activity at pH 6.0 was observed for the DOAPA-VAN-Lipo and DLAPA-VAN-Lipo formulations. Flow cytometry studies indicated a high killing rate of MRSA cells using DOAPA-VN-Lipo (71.98%) and DLAPA-VN-Lipo (73.32%). In vivo studies showed reduced MRSA recovered from mice treated with formulations by four- and two-folds lower than bare VN treated mice, respectively. The targeted delivery of VAN can be improved by novel pH-responsive liposomes from the two-chain (FAL) designed in this study.     

Pharmacokinetics and nephrotoxicity of aristolochic acid in rabbits

Aristolochic acids (AAs) which exist in plants of the genus Aristolochia are the toxins responsible for aristolochic acid nephropathy (AAN). To investigate the pharmacokinetics and nephrotoxicity of AAs, rabbits were used in this study. The plasma concentrations of the main components of AAs, aristolochic acid I (AA I) and aristolochic acid II (AA II), were determined by a validated high-performance liquid chromatographic method. After intravenous administration of different doses (0.25, 0.5, 1.0, and 2.0 mg/kg) of aristolochic acid sodium (AANa) to 4 respective groups of rabbits (n=6 for each dose), linear relationships between the doses of AA I and AA II and the area under the plasma concentration curve (AUC) were found to exist (p<0.001). AANa was also given in escalating doses (0.5, 1.0, and 2.0 mg/kg) to the same rabbits at 7-day intervals. The clearance rates of both AA I and AA II significantly decreased with the escalating dose (p<0.001). A nonlinear relationship between the dose and AUC was obtained. Kidney specimens of rabbits were obtained to observe morphological changes on days 1 and 7 after AANa administration. The renal lesions caused by AAs consisted of progressive and dose-dependent tubular damage. However, no remarkable changes in the morphology of glomeruli were observed.     

万古霉素治疗革兰阳性球菌血流感染患者的血药浓度监测

目的了解本院革兰阳性球菌血流感染患者万古霉素的临床应用及血清谷浓度的监测。方法采用荧光偏振免疫偏振法测定万古霉素血清谷浓度,并结合住院患者的临床资料(基础疾病、病原学结果、万古霉素血清谷浓度、疗效、肾功能情况等),对血流感染革兰阳性球菌并应用万古霉素的25例患者进行回顾性分析。结果血流感染耐甲氧西林金黄色葡萄球菌(MRSA)11例(44.0%),屎肠球菌14例(56.0%);临床治愈率32.0%。25例患者共进行万古霉素血清谷浓度测定38例次,血清谷浓度范围2.99~39.1μg/mL,均值(14.96±7.83)μg/mL,其中达到靶浓度15~20μg/mL者8例(21.0%)。临床治愈组与临床无效组万古霉素血清谷浓度分别为(14.69±7.20)、(15.13±8.53)μg/mL(P=0.85)。肾毒性发生6例(24.0%),APACHEⅡ评分均值17分,均为临床无效组。11例MRSA血流感染中,1例万古霉素最低抑菌浓度(MIC)值为2 mg/L,其余万古霉素MIC值均为1 mg/L;临床治愈组万古霉素曲线下面积(AUC)与MIC浓度比值(AUC/MIC)为209±114。结论按照指南的标准,25例血流感染患者万古霉素血清谷浓度达标率低,需加强对这一类患者血清谷浓度的监测力度,并随时调整用药,给出个体化的用药方案。     

Polymer based solutions of bupranolol hydrochloride for intranasal systemic delivery

The present study was aimed at developing intranasal polymer based solutions as alternative route for systemic delivery of Bupranolol hydrochloride (BPH). It is a potent β-blocker drug which upon oral administration undergoes extremely high hepatic first-pass metabolism (>90% in humans). The polymeric solutions were prepared using varying concentrations of polymers like sodium alginate, chitosan, sodium carboxymethylcellulose, methylcellulose (MC), polyvinyl alcohol, carbopol, hydroxypropyl MC, and hydroxypropyl cellulose. The prepared formulations were evaluated in terms of pH of the solution, angular viscosity, drug content, gel strength, gelation temperature, in vitro drug release, in vivo pharmacodynamic studies, histopathological, and stability studies. Except MC based solutions, a biphasic pattern of drug release was obtained in all other cases. Nasal administration of selected batches of polymeric solutions were found to be nontoxic and were able to improve drug bioavailability when compared to oral, nasal, and intravenous solution administrations of BPH.     

Olive oil and clove oil-based nanoemulsion for topical delivery of terbinafine hydrochloride: in vitro and ex vivo evaluation

In this article, formulation studies for terbinafine hydrochloride nanoemulsions, prepared by high-energy ultrasonication technique, are described. Pseudo-ternary phase diagram was constructed in order to find out the optimal ratios of oil and surfactant/co-solvent mixture for nanoemulsion production. Clove and olive oils were selected as oil phase. Based on the droplet size evaluation, maximum nanoemulsion region were determined for formulation development. Further characterization included polydispersity index (PDI), zeta potential, Fourier transform infrared (FT-IR) spectroscopy, morphology, pH, viscosity, refractive index, ex vivo skin permeation, skin irritation, and histopathological examination. Droplet sizes of optimized formulations were in colloidal range. PDI values below 0.35 indicated considerably homogeneous nanoemulsions. Zeta potential values were from 13.2 to 18.1 mV indicating good stability, which was also confirmed by dispersion stability studies. Ex vivo permeation studies revealed almost total skin permeation of terbinafine hydrochloride from the nanoemulsions (96–98%) in 6 hours whereas commercial product reached only 57% permeation at the same time. Maximum drug amounts were seen in epidermis and dermis layers. Skin irritation and histopathological examination demonstrated dermatologically safe formulations. In conclusion, olive oil and clove oil-based nanoemulsion systems have potential to serve as promising carriers for topical terbinafine hydrochloride delivery.     

盐酸多柔比星脂质体的制备及体外质量评价

目的：制备盐酸多柔比星脂质体并进行体外质量评价,以期实现自制脂质体质量与市售盐酸多柔比星脂质体注射液Doxil一致,并为其生物体内等效及产业化提供研究基础。方法：采用乙醇注入法结合硫酸铵梯度法制备盐酸多柔比星脂质体,以包封率为评价指标通过单因素筛选和正交试验优化制备工艺,以市售Doxil为参比制剂,对比最优工艺制得的脂质体与市售Doxil的微观结构、粒径大小及分布、Zeta电位、相变温度、包封率等理化指标,考察最优工艺制得的脂质体与市售Doxil在加速条件的体外释放及储存条件下稳定性情况。结果：自制盐酸多柔比星脂质体最优制备工艺为高速剪切速率13 000 r·min^-1,挤出3次,载药孵育温度65℃,载药孵育时间60 min,最优工艺制得的脂质体与市售Doxil外观均为椭圆形,平均粒径分别为（90.81±0.58） nm （n=3）和（89.05±0.66） nm （n=3）,分布较为均匀,Zeta电位分别为（-41.9±1.8） mV （n=3）和（-44.9±4.2） mV （n=3）,相变温度范围相同,包封率分别为98.0%和97.9%,体外释放较为一致,稳定性好。结论：采用最优工艺制备的盐酸多柔比星脂质体制备工艺可行,与市售Doxil相比,理化指标及体外释放无明显差异,自制脂质体体外质量良好,符合实验预期。     

自溶性微针的制备及其对盐酸青藤碱凝胶透皮性能的影响

目的：优选出自溶性微针的处方工艺,并考察所制备的微针对盐酸青藤碱凝胶透皮性能的影响。方法采用浇注法制备自溶性微针,穿刺试验考察其机械性能,并采用改良Franz扩散池考察自溶性微针预处理皮肤,对盐酸青藤碱凝胶透皮性能的影响。结果采用浇注法制备自溶性微针,其最佳处方为：基质材料硫酸软骨素和聚乙烯吡咯烷酮（PVP）按照1∶1的比例混合,加入重量比60％的水;所制得的微针针形完整、机械强度良好,能够很好的穿刺铝箔和大鼠皮肤;体外透皮实验显示,自溶性微针使得盐酸青藤碱凝胶的累积渗透量增加了3．62倍。结论优选的自溶性微针的处方与制备工艺简单、可行,可显著提高盐酸青藤碱凝胶的透皮性能,为载药微针的进一步研究提供参考依据。     

盐酸多西环素脂质体凝胶剂的制备与评价

以薄膜-振荡分散法制备盐酸多西环素脂质体，再以卡波姆为基质制备脂质体凝胶剂。比较了制品及普通凝胶剂对离体鼠皮的经皮渗透作用。结果表明，制品平均粒径为200～300nm，包封率为80．1％。体外透皮实验中，脂质体凝胶剂24h的药物浓度为156，7μg／ml，明显高于普通凝胶剂（83．3μg／m1）。     

Inhalational System for Etoposide Liposomes: Formulation Development and In Vitro Deposition

Etoposide is a semisynthetic compound, widely used in treatment of non small cell lung cancer. However, frequent dosing and adverse effects remain a major concern in the use of etoposide. Liposomal systems for pulmonary drug delivery have been particularly attractive because of their compatibility with lung surfactant components. In the present investigation, pulmonary liposomal delivery system of etoposide was prepared by film hydration method. Various parameters were optimized with respect to entrapment efficiency as well as particle size of etoposide liposomes. For better shelf life of etoposide liposomes, freeze drying using trehalose as cryoprotectant was carried out. The liposomes were characterized for entrapment efficiency, particle size, surface topography, and in vitro drug release was carried out in simulated lung fluid at 37° at pH 7.4. The respirable or fine particle fraction was determined by using twin stage impinger. The stability study of freeze dried as well as aqueous liposomal systems was carried out at 2-8° and at ambient temperature (28±4°). The freeze dried liposomes showed better fine particle fraction and drug content over the period of six months at ambient as well as at 2-8° storage condition compared to aqueous dispersion of liposomes.     

pH敏感型盐酸左氧氟沙星眼用即型凝胶的制备及其体外释放考察

目的研制具有缓释作用的pH敏感型盐酸左氧氟沙星眼用即型凝胶。方法以卡波普为凝胶基质,以羟丙甲基纤维素为增稠剂,以溶液的粘度、即型凝胶形成能力及盐酸左氧氟沙星含量为评价指标,确定制备处方和工艺,并以优选处方进行体外释放考察。结果经实验,其优选处方为盐酸左氧氟沙星0.1 g,羟丙甲基纤维素E 50 LV 2.0 g,卡波普9 400.3g,磷酸氢二钠0.35 g,磷酸二氢钠0.45 g,氯化钠0.50 g,尼泊金乙酯0.03 g,加水共制成100 ml。体外释放结果显示其释药平缓,具有较好的缓释特征。结论优选处方工艺稳定,质量控制方法可靠,适用于pH敏感型盐酸左氧氟沙星眼用即型凝胶的制备和评价。     

Liposomes for targeted delivery of antithrombotic drugs

Background: Targeted delivery of antithrombotic (thrombolytic) drugs is expected to increase their efficacy and decrease side effects, especially in the case of thrombolytic enzymes. Liposomes, phospholipid nanosized bubbles with a bilayered membrane structure, have drawn a lot of interest as pharmaceutical carriers for drugs and genes. In particular, several attempts have been made to use liposomes as vehicles for antithrombotic agents. Objective: This review analyzes the available data on the application of liposomes, including liposomes targeted by specific ligands, for the delivery of antithrombotic/thrombolytic agents in order to increase their efficacy and decrease side effects. Methods: The papers published on the subject of liposomes loaded with antithrombotic agents, mainly over the last 10 – 15 years, will be discussed. Conclusion: Liposomes loaded with various antithrombotic drugs, though they have been the subject of a significant number of experimental papers, can hardly be considered as real candidates for clinical application in the near future.     

应用盐酸利托君治疗先兆早产的疗效观察

目的：观察盐酸利托君治疗先兆早产的临床效果。方法：对本院妇产科150例有先兆早产症状的孕妇应用盐酸利托君治疗。结果：150例均取得了很好的疗效,总有效率为100％;有22例出现药物不良反应,不良反应发生率为14．7％,无一例发生肺水肿、心功能衰竭及其他严重并发症。结论：盐酸利托君是治疗先兆早产的一种安全有效的药物,但要注意合理应用,以减少不良反应的发生。