紫杉醇注射液配套输液器中邻苯二甲酸二辛酯的溶出性考察

目的:考察紫杉醇注射液配套输液器及聚氯乙烯(PVC)输液器中邻苯二甲酸二辛酯(DEHP)的溶出情况,评价紫杉醇临床用输液器的安全性。方法:收集重庆市9家"三甲"医院紫杉醇包装中配备的输液器,模拟临床紫杉醇输注的浓度、时间,用8种(其中7种为配套输液器)不同输液器滴注3h,用高效液相色谱法测定收集液中DEHP的峰面积,计算含量;并考察时间对DEHP溶出的影响。结果:紫杉醇通过8种输液器的DEHP溶出总量分别为1408、9393、6576·5、2412·6、8194·4、0、8477·2、8037·4μg;输注时间越长,DEHP溶出越多。结论:目前临床使用的紫杉醇配套输液器绝大部分为PVC输液器,由于DEHP溶出后可直接进入人体,不能保证紫杉醇的用药安全,故应高度重视其危害性。     

表面活性剂对两性霉素B溶解行为的影响

目的:研究不同表面活性剂对两性霉素B溶解行为的影响。方法:选用非离子表面活性剂司盘-20、吐温-40、吐温-60、吐温-80、泊洛沙姆188,阳离子表面活性剂十六烷基三甲基氯化铵,阴离子表面活性剂十二烷基磺酸钠、脱氧胆酸钠及两性离子表面活性剂卵磷脂,配成系列浓度的表面活性剂溶液,通过紫外分光光度法,以最大增溶百分比为指标考察其对两性霉素B溶解度的影响。结果:在0.2～4mg·mL-1浓度范围内,各表面活性剂最大增溶百分比司盘-20为1365.44%(4mg·mL-1)、吐温-40为353.46%(0.8mg·mL-1)、吐温-60为1165.30%(4mg·mL-1)、吐温-80为973.46%(0.4mg·mL-1)、泊洛沙姆188为1527.95%(4mg·mL-1)、十二烷基磺酸钠为1199.16%(4mg·mL-1)、脱氧胆酸钠为88.62%(4mg·mL-1)、十六烷基三甲基氯化铵为1671.68%(4mg·mL-1)、卵磷脂为314.36%(4mg·mL-1)。结论:本试验中,表面活性剂司盘-20、吐温-60、吐温-80、泊洛沙姆188、十二烷基磺酸钠、脱氧胆酸钠、十六烷基三甲基氯化铵对两性霉素B具有显著的增溶效果;而吐温-40、脱氧胆酸钠、卵磷脂增溶效果不明显。     

超低密度聚乙烯输液器与聚氯乙烯输液器的溶出物比较

目的:测定输液器溶出物(增塑剂DEHP).方法:用乙醇水溶液在(25±1)℃水浴1 h条件下浸泡输液器碎片所得溶出物溶液,以分光光度法测定增塑剂溶出量.结果:溶出物溶液与增塑剂溶液在250～300 nm波长范围内吸收光谱相同,且在272 nm波长处有最大吸收,增塑剂的线性回归方程为Y=0.003 3X-0.0209,r=0.9999.结论:普通输液器增塑剂很容易被乙醇液溶出(5批溶出量平均为170雌/mL),而超低密度聚乙烯输液器能很好地满足含有乙醇或蓖麻油的注射液(如紫杉醇注射液)对输液器具的要求.     

PVC软输液袋对紫杉醇稳定性的影响及其中DEHP溶出量考察

目的考察聚氯乙烯(PVC)软输液袋对紫杉醇稳定性的影响及其中增塑剂邻苯二甲酸二(2-乙基)己酯(DEHP)的溶出情况。方法模拟临床使用紫杉醇的条件,用高效液相色谱法测定整个使用过程中紫杉醇的浓度变化和DEHP的溶出量。结果紫杉醇浓度随时间的延长而下降,DEHP的溶出量随温度的升高和时间的延长而增大。结论目前临床使用的紫杉醇配套输液袋绝大多数为PVC袋,由于紫杉醇浓度下降且溶出的DEHP可直接进入人体,不能保证用药安全,故应高度重视PVC软输液袋的危害性。     

紫杉醇新剂型的研究进展

紫杉醇是一种广谱、高效的抗肿瘤药物,但由于其水溶性差,临床上应用的注射剂加入聚氧乙烯蓖麻油以增加紫杉醇的水溶性,但聚氧乙烯蓖麻油在体内会产生严重的毒副作用.为了解决紫杉醇注射剂中聚氧乙烯蓖麻油的毒性问题,开发紫杉醇新剂型是近年来新药研发的热点之一.该文综述了近年来研发的一些紫杉醇新剂型,如乳剂、胶束、环糊精包合物、脂质体、微球、纳米粒和药物释放支架等,并对其可行性进行了分析.     

表面活性剂对山楂叶总黄酮中牡荆素-2″-O-鼠李糖苷的肠道吸收促进作用

目的:考察非离子表面活性剂对山楂叶总黄酮中主要活性成分牡荆素-2″-O-鼠李糖苷在大鼠肠道的吸收促进作用。方法:配制含表面活性剂聚山梨酯-80(吐温-80)、聚氧乙烯氢化蓖麻油(RH40)和泊洛沙姆(F68)的山楂叶总黄酮溶液,分别在大鼠肠道上段(十二指肠和空肠)和下段(回肠和结肠)循环灌流,采用HPLC法测定溶液中牡荆素-2″-O-鼠李糖苷的浓度,计算吸收率。结果:加入3种表面活性剂后,牡荆素-2″-O-鼠李糖苷在大鼠肠内的吸收均显著增加(P<0.05),比不加表面活性剂时提高50%以上。且随表面活性剂的浓度从0.01%提高到0.1%,牡荆素-2″-O-鼠李糖苷在大鼠肠道上段和下段的吸收均显著增加。在表面活性剂的浓度较低(0.01%)时,吐温-80对药物的吸收促进作用强于RH40和F68。结论:表面活性剂吐温-80,RH40和F68均可促进山楂叶总黄酮中牡荆素-2″-O-鼠李糖在大鼠肠道上段和下段的吸收。     

黄豆苷元半固体骨架型胶囊处方的初步研究

目的:采用半固体骨架技术提高黄豆苷元的体外溶出度。方法:采用熔融法制备黄豆苷元半固体骨架胶囊,比较不同载体材料聚氧乙烯(40)硬脂酸酯(S-40)、泊洛沙姆、聚乙二醇(PEG)4000,不同含药量(2%、4%、6%),表面活性剂吐温-80不同用量(15%、20%、25%、30%)对其体外溶出度的影响并与市售胶囊进行比较。结果:上述3种影响因素中溶出度较优的选择为采用S-40为载体,含药量为2%,吐温-80用量20%。所制胶囊体外溶出速率快于市售胶囊。结论:半固体骨架技术能够提高难溶性药物黄豆苷元的体外溶出度。     

克林霉素磷酸酯注射液对一次性输液器中邻苯二甲酸二（2-乙基）己酯的溶出研究

摘要：目的:考察克林霉素磷酸酯注射液对一次性使用输液器中苯二甲酸二（2-乙基）己酯（DEHP）的溶出规律。方法:模拟临床使用克林霉素磷酸酯注射液经一次性输液器静脉滴注,UPLC-MS/MS法测定流出液中DEHP的溶出量。同时考察药物浓度和滴注时间对于DEHP溶出的影响,确定克林霉素磷酸酯注射液促进DEHP溶出的因素。结果:克林霉素磷酸酯注射液中的苯甲醇是促进一次性输液器中DEHP溶出的主要因素,并且随着苯甲醇浓度升高和滴注时间的延长,DEHP的溶出量相应增加。结论:苯甲醇促进了一次性输液器中DEHP的溶出,溶出量与苯甲醇浓度和滴注时间呈正相关。     

聚氧乙烯蓖麻油及其安全性研究进展

聚氧乙烯蓖麻油属于非离子型表面活性剂,是药物制剂中常用的辅料。主要应用于口服、局部和注射给药剂型中,其作用主要作为难溶性药物的乳化剂与增溶剂。由于在临床应用中出现了较多不良反应如急性超敏反应、神经毒性等,限制了其使用的广度与深度。本文综述了聚氧乙烯蓖麻油CrEL在药剂学中的最新应用,药理活性与安全性研究概况。为合理的使用与研究含有聚氧乙烯蓖麻油的制剂提供依据。     

表面活性剂对肿瘤细胞多药耐药逆转作用的体外筛选

目的:从表面活性剂中筛选出能逆转肿瘤细胞多药耐药(MDR)的耐药逆转剂。方法:用MTT法筛选出对多药耐药的细胞系K562／A02耐药的抗肿瘤药物,选择并确定表面活性剂没有细胞毒性的浓度,以维拉帕米作阳性对照,检测不同的表面活性剂在不同的浓度下逆转多药耐药的细胞系K562／A02对不同抗肿瘤药物耐药的能力。结果:硬脂酸聚氧乙烯、泊洛沙姆、蓖麻油聚氧乙烯醚、吐温-60、辛基酚聚氧乙烯醚等几种非离子表面活性剂均能降低抗肿瘤药物阿霉素、柔红霉素、长春新碱、依托泊苷、三尖杉酯碱对K562／A02细胞的IC50。结论:具有一定化学结构的非离子表面活性剂能逆转多药耐药的细胞系K562／A02的耐药性,作为药用辅料在逆转肿瘤多药耐药上将会有广阔的应用前景。     

The extraction of diethylhexylphthalate (DEHP) from polyvinyl chloride components of intravenous infusion containers and administration sets by paclitaxel injection

Paclitaxel injection (Taxol^TM) contains cremophor and ethanol in equal proportions, two agents known to leach diethylhexylphthalate (DEHP) from polyvinyl chloride (PVC) infusion bags and administration sets. The manufacturers of paclitaxel therefore recommend the use of glass, polypropylene or polyolefin containers for storage. This recommendation poses a number of practical problems since the availability of these other types of containers is severely limited and as such staff may be unfamiliar in their handling. The aim of this study was to investigate the extent of DEHP extraction by paclitaxel injection contained in PVC infusion bags and administered by either PVC or non-PVC sets in a bid to verify the manufacturers' recommendations to avoid using PVC containers. The results indicated that during a 3 h infusion period, increasing amounts of DEHP were leached into the paclitaxel vehicle from both the PVC infusion bags and the standard PVC sets. The amounts of DEHP extracted depended on the concentration of the paclitaxel vehicle, the length of contact between the injection vehicle and the container and the type of administration set used. DEHP concentration was at its lowest when a non-PVC set was used to administer the infusate. The addition of 300 and 600 mg paclitaxel to the infusate, administered by non-PVC sets, led to no significant increase in DEHP extraction. Comparative total amounts of DEHP extracted for each dose were 10.0 and 30.3 mg for the paclitaxel vehicle infusion through non-PVC sets and 13 and 30.5 mg respectively for the formulated drug plus vehicle. These amounts of DEHP are substantially less than those delivered during a blood transfusion. Furthermore, the possibility of chronic exposure to DEHP from paclitaxel administered under these conditions is negligible in patients receiving the drug on four to six occasions. The study concludes that there is only minimal risk of DEHP exposure from paclitaxel infusion contained in PVC bags and administered through non-PVC administration sets.     

PVC与TPE输液器对3种药物的吸附研究

目的:考察聚氯乙烯(PVC)与聚烯烃热塑弹性体(TPE)输液器对3种药物的吸附性,为临床输液器的选择提供参考。方法:分别将硝酸甘油、硝酸异山梨酯、单硝酸异山梨酯3种药物配成临床用输注浓度,经2个不同厂家的PVC输液器(PVC1、PVC2)、TPE输液器流出,测定不同流出时间流出液的峰面积,并与0时比较。结果:在输注终点时,TPE输液器对硝酸甘油、硝酸异山梨酯、单硝酸异山梨酯的吸附率分别为2.5%、0.06%、0.24%;PVC1、PVC2对3种药物的最大吸附率分别为30.98%、16.52%、13.85%和37.13%、16.14%、15.60%。2种材质输液器的吸附作用比较具有统计学差异(P<0.05)。结论:TPE输液器对所试验的3种药物几乎无吸附作用,PVC输液器对部分药物有明显的吸附作用,应引起临床重视。     

Stability,compatibility and plasticizer extraction of miconazole injection added to infusion solutions and stored in PVC containers

The stability of miconazole in various diluents and polyvinyl chloride (PVC) containers was determined and the release of diethylhexyl phthalate (DEHP) from PVC bags into intravenous infusions of miconazole was measured. An injection formulation (80 ml) containing a 1% solution of miconazole with 11.5% of Cremophor EL was added to 250-ml PVC infusion bags containing 5% glucose injection or 0.9% sodium chloride injection, to give an initial nominal miconazole concentration of 2.42 mg ml⁻¹, the mean concentration commonly used in clinical practice. Samples were assayed by stability-indicating high-performance liquid chromatography (HPLC) and the clarity was determined visually. Experiments were conducted to determine whether the stability and compatibility of miconazole would be compromised, and whether DEHP would be leached from PVC bags and PVC administration sets during storage and simulated infusion.There was no substantial loss of miconazole over 2 h simulated infusion irrespective of the diluent, and over 24 h storage irrespective of temperature (2–6°C and 22–26°C). All the solutions initially appeared slightly hazy. Leaching of DEHP was also detected during simulated delivery using PVC bags and PVC administration sets. There was a substantial difference between the amounts of DEHP released from PVC bags and from administration sets, and also between the amounts released in solutions stored in PVC bags at 2 6°C and 22–26°C over 24 h.At the dilution studied, miconazole was visually and chemically stable for up to 24 h. The storage of miconazole solutions in PVC bags seems to be limited by the leaching of DEHP rather than by degradation. To minimize patient exposure to DEHP, miconazole solutions should be infused immediately after their preparation in PVC bags.     

Investigation of the release behavior of DEHP from infusion sets by paclitaxel-loaded polymeric micelles

The current clinical formulation of paclitaxel (Taxol) contains 1:1 blend of Cremophor EL (polyethoxylated castor oil) and dehydrated ethanol. Cremophor EL and dehydrated ethanol are well known to leach di-(2-ethylhexyl) phthalate (DEHP) from polyvinyl chloride (PVC) infusion bags and PVC administration sets. DEHP is a possible hepatotoxin, carcinogen, teratogen and mutagen. Long-term exposure to DEHP may cause health risks. As an alternative formulation for paclitaxel, paclitaxel-loaded polymeric micelles (PLPM), made of monomethoxy poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PDLLA) diblock copolymer, has demonstrated clear advantages over Taxol in pharmacokinetics and therapeutic index. Paclitaxel in either PLPM or Taxol formulations, diluted in 0.9% sodium chloride injection, was stable in the PVC infusion bags. The PLPM formulation significantly reduced the amount of DEHP extracted from PVC infusion bags and PVC administration sets. For PLPM diluted in 0.9% sodium chloride injection, the total amount of DEHP delivered over the simulated infusion period was 0.7 mg for 3h and 2.0 mg for 24 h, which was less than 2.9% of the DEHP extracted by Taxol. These results confirmed that there is negligible risk of DEHP exposure from diluted PLPM i.v. infusion using PVC infusion bags and PVC administration sets.     

The amount of the loss of cyclosporine A dose correlated with the amount of leaching di (2-ethylhexyl) phthalate from polyvinyl chloride infusion tube

An interaction between cyclosporine A (CyA) injection and infusion tubes were examined. We used polyvinyl chloride (PVC) and polybutadiene (PB) tubes. CyA injection (Sandimmun) was diluted (0.495 mg CyA/ml) with saline and dripped through infusion tubes. The amounts of unsolved substances, loss of CyA dose and leached di (2-ethylhexyl) phthalate (DEHP) during the drip study were compared. CyA was not lost into the PB tube and no DEHP was leached. Therefore, using PVC tube, 11.9 mg of CyA were lost with in 24 h after the beginning of the administration, and the concentration of leached DEHP amounted to 93.6 micrograms/ml at 12 h. We also investigated the effects of the component of the einfusion solution on the loss of CyA into PVC tube using saline, electrolyte maintenance solution, 5% glucose and 10% maltose. Sugar-containing solutions were found to have less effects than other solutions on the loss of CyA dose and DEHP leaching. The leaching of DEHP may be a major factor for the generation of unsolved substances and the loss of CyA dose. In the clinical use of CyA injection, PB tube is the best selection and the sugar-containing solution is a second selection when PB infusion tubes are hard to obtain.     

Leaching of diethylhexyl phthalate from multilayer tubing into etoposide infusion solutions.

PURPOSE: The extent of leaching of diethylhexyl phthalate (DEHP) from various polyvinyl chloride (PVC), polyethylene (PE), coextruded (PVC and PE), and triple-layered (PVC, ethyl vinyl acetate, and PE) i.v. extension tubing into etoposide infusion solutions was studied. METHODS: Different lengths of tubing (25, 50, and 80 cm) were tested in two types of experiments: (1) static, in which the etoposide solution was left in contact inside the tubing for various times and then removed, and chromatography was used to quantify the DEHP content of the effluate, and (2) dynamic, in which infusion was simulated using syringe reservoirs, and three flow rates were tested to assess the effect of flow rate on the quantities of DEHP leached. RESULTS: The static study showed that large quantities of DEHP were leached from all tubing types except the PE tubing. The dynamic study confirmed that leaching occurred, although the values were below the threshold limit of 5 microg/mL. The values varied depending on flow rate, tubing length, and etoposide concentration. The coextruded and triple-layered i.v. tubing did not provide the inertness and safety they are intended to have, as DEHP not only leached out but did so in quantities almost equivalent to those found with tubing made of PVC only. CONCLUSION: DEHP leached rapidly from PVC, coextruded, and triple-layered i.v. tubing into etoposide infusion solution. The quantity of DEHP found in the infusion solution was influenced by the length of the tubing and concentration of etoposide.     

Investigation of the release behavior of diethylhexyl phthalate from the polyvinyl-chloride tubing for intravenous administration

The release behavior of diethylhexyl phthalate (DEHP) from a polyvinyl-chloride (PVC) tube, which is part of an intravenous administration set, was investigated with the coexistence of polysorbate 80 (Tween 80) in various solutions such as physiological saline (PS), distilled water for injection (DWI) and glucose solution (TZ). The cumulative amount of DEHP released after 5 h was in the following order; PS, DWI>50% TZ. From a comparison of the amount of released DEHP and the critical micelle concentration (CMC) of various solutions, the lower the CMC of the solution, the higher the amount of DEHP released from the PVC tubing. When the concentration of Tween 80 was kept constant at 1 mg/ml, the cumulative amount of DEHP released with a flow rate 90 ml/h was higher than that at 60 ml/h. These results suggest that the release of DEHP from the PVC tubing is closely correlated with the interaction of Tween 80 and DEHP such as the formation of micelles, the collision of micelles against the surface of the PVC tubing and the diffusion properties of DEHP and/or Tween 80 in the liquid medium.     

Characterisation and evaluation of novel surfactant bacterial anti-adherent coatings for endotracheal tubes designed for the prevention of ventilator-associated pneumonia

It is accepted that ventilator-associated pneumonia is a frequent cause of morbidity and mortality in intensive care patients. This study describes the physicochemical properties of novel surfactant coatings of the endotracheal tube and the resistance to microbial adherence of surfactant coated endotracheal tube polyvinylchloride (PVC). Organic solutions of surfactants containing a range of ratios of cholesterol and lecithin (0:100, 25:75, 50:50, 75:25, dissolved in dichloromethane) were prepared and coated onto endotracheal tube PVC using a multiple dip-coating process. Using modulated temperature differential scanning calorimetry it was confirmed that the binary surfactant systems existed as physical mixtures. The surface properties of both surfactant-coated and uncoated PVC, following treatment with either pooled human saliva or phosphate-buffered saline (PBS), were characterised using dynamic contact angle analysis. Following treatment with saliva, the contact angles of PVC decreased; however, those of the coated biomaterials were unaffected, indicating different rates and extents of macromolecular adsorption from saliva onto the coated and uncoated PVC. The advancing and receding contact angles of the surfactant-coated PVC were unaffected by sonication, thereby providing evidence of the durability of the coatings. The cell surface hydrophobicity and zeta potentials of isolates of Staphylococcus aureus and Pseudomonas aeruginosa, following treatment with either saliva or PBS, and their adherence to uncoated and surfactant-coated PVC (that had been pre-treated with saliva) were examined. Adherence of S. aureus and Ps. aeruginosa to surfactant-coated PVC at each successive time period (0.5, 1, 2, 4, 8 h) was significantly lower than to uncoated PVC, the extent of the reduction frequently exceeding 90%. Interestingly, the microbial anti-adherent properties of the coatings were dependent on the lecithin content. Based on the impressive microbial anti-adherence properties and durability of the surfactant coating on PVC following dip coatings, it is proposed that these systems may usefully reduce the incidence of ventilator-associated pneumonia when employed as luminal coatings of the endotracheal tube.