Polyoxyethylated nonionic surfactants and their applications in topical ocular drug delivery

Topical dosing of ophthalmic drugs to the eye is a widely accepted route of administration because of convenience, ease of use, and non-invasiveness. However, it has been well recognized that topical ocular delivery endures a low bioavailability due to the anatomical and physiological constraints of the eye which limit drug absorption from the pre-corneal surface. Nonionic surfactants as versatile functional agents in topical ocular drug delivery systems are uniquely suited to meet the challenges through their potential ability to increase bioavailability by increasing drug solubility, prolonging pre-corneal retention, and enhancing permeability. This review attempts to place in perspective the importance of polyoxyethylated nonionic surfactants in the design and development of topical ocular drug delivery systems by assessing their compatibility with common ophthalmic inactive ingredients, their impact on product stability, and their roles in facilitating ocular drugs to reach the target sites.     

Role of benzyl alcohol in the prevention of heat-induced aggregation and inactivation of hen egg white lysozyme

The aim of the study was to investigate the stability of a model protein, lysozyme, in the presence of the commonly used preservative benzyl alcohol. Techniques including lytic assay, size exclusion chromatography, circular dichroism, differential scanning calorimetry, native polyacrylamide gel electrophoresis and dynamic light scattering were used to study the overall stability of lysozyme in the presence of benzyl alcohol. The stability of lysozyme against thermal stress was higher in the presence of benzyl alcohol. In the presence of 0.5%, 0.9% and 2% v/v benzyl alcohol, the enzyme showed 33%, 42% and 75% residual activity, respectively, when exposed to 75 °C for 2 h, as compared to the 22% activity of control sample. A gradual increase in the size of aggregates was observed for the control sample relative to the samples containing benzyl alcohol, as a result of loss of monomer concentration. The effect was found to be concentration-dependent with 2% benzyl alcohol showing maximum prevention of heat-induced unfolding and aggregation. This effect is remarkable since the thermal transition temperature of the enzyme decreases in the presence of benzyl alcohol. Benzyl alcohol favours the thermal denaturation of lysozyme but stabilizes the lysozyme against the heat-induced aggregation.     

Concerning the stability of benzyl alcohol: formation of benzaldehyde dibenzyl acetal under aerobic conditions

An impurity in benzyl alcohol was identified as benzaldehyde dibenzyl acetal (BDBA). The component BDBA is reversibly formed by the reaction of benzyl alcohol with benzaldehyde, an oxidative degradation product of benzyl alcohol. Whereas, BDBA is a known chemical entity, it is not typically controlled in commercial benzyl alcohol since it cannot be formed in the absence of benzaldehyde, which is itself generally controlled. However, once commercial benzyl alcohol is exposed to the atmosphere, formation of BDBA is possible. The synthesis and characterization of BDBA is reported. The ability of BDBA to react with alcohols to form other types of acetals, and the impact of low levels of BDBA on the quantitative analysis of pharmaceutical products, are considered.     

高效液相色谱法测定盐酸苯海拉明注射液中苯甲醇含量

目的 采用高效液相色谱法建立测定盐酸苯海拉明注射液中苯甲醇的方法.方法 色谱柱Agilent氰基柱（250mm×4.6mm,5μm）,流动相为乙腈-20mM乙酸铵（用甲酸调pH值至6.5）（50：50）,检测波长为257nm.结果 苯甲醇浓度在0.625～3.75μL·mL-1范围内与峰面积呈良好的线性关系,r为1.000;苯甲醇加样回收率的平均值为100.3%,RSD=1.4%.结论 本方法简便、准确可靠,适用于盐酸苯海拉明注射液中苯甲醇的质量控制.     

A new validated method for the simultaneous determination of benzocaine, propylparaben and benzyl alcohol in a bioadhesive gel by HPLC

A new HPLC-RP method has been developed and validated for the simultaneous determination of benzocaine, two preservatives (propylparaben (nipasol) and benzyl alcohol) and degradation products of benzocaine in a semisolid pharmaceutical dosage form (benzocaine gel). The method uses a Nucleosil 120 C18 column and gradient elution. The mobile phase consisted of a mixture of methanol and glacial acetic acid (10%, v/v) at different proportion according to a time-schedule programme, pumped at a flow rate of 2.0 ml min⁻¹. The DAD detector was set at 258 nm. The validation study was carried out fulfilling the ICH guidelines in order to prove that the new analytical method, meets the reliability characteristics, and these characteristics showed the capacity of analytical method to keep, throughout the time, the fundamental criteria for validation: selectivity, linearity, precision, accuracy and sensitivity. The method was applied during the quality control of benzocaine gel in order to quantify the drug (benzocaine), preservatives and degraded products and proved to be suitable for rapid and reliable quality control method.     

Effects of nonionic surfactants on the physical stability of immunoglobulin G in aqueous solution during mechanical agitation

The objective of this study was to evaluate the influence of nonionic surfactants in the presence of glycine and sodium chloride on the physical stability of immunoglobulin G (IgG) in aqueous solution. Among surfactants suitable for parenteral preparation, Polysorbate 80 (Tween 80) and Polyoxyl 35 Castor Oil (Cremophor EL) were selected. The physical stability of IgG in the absence and in the presence of excipients was investigated in aqueous solution during mechanical agitation (concentration of IgG 15%; pH 7.1; temperature 6 +/- 2 degrees C). Suitable concentrations of Tween 80 and Cremophor EL were experimentally determined by surface tension measurements at 6 +/- 2 degrees C. Glycine and sodium chloride were used in different concentrations. The influence of the excipients on the physical stability of IgG in solution has been examined by surface tension measurements, protein content assay (Kjeldahl and HPLC) and differential scanning calorimetry (DSC). Based on the results of the investigations, it was found that Tween 80 and Cremophor EL, used in experimentally determined critical micelle concentration (cmc), decreased the physical stability of IgG in solution. Tween 80 and Cremophor EL in the presence of glycine (1.5 g/l) could stabilize the IgG in solution during mechanical agitation. The comparison of the effects of Tween 80 and Cremophor EL on the physical stability of IgG, showed that Tween 80 had better stabilization effects on IgG in solution under the experimental conditions selected.     

Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers

The objectives of this study were (1) to investigate the transporter inhibition activity of three nonionic surfactants on P-glycoprotein, the human intestinal peptide transporter, and the monocarboxylic acid transporter in Caco-2 cell monolayers, and (2) to evaluate the role of membrane fluidity and protein kinase C in surfactant-induced transporter inhibition. All three surfactants inhibited P-glycoprotein (P-gp). Over a range from 0 to 1 mM, Tween 80 and Cremophor EL increased apical-to-basolateral permeability (AP-BL) and decreased basolateral-to-apical (BL-AP) permeability of the P-gp substrate rhodamine 123. Vitamin E TPGS’s effect was equally large, but essentially only reduced the BL-AP permeability of rhodamine 123, and did so at a vitamin E TPGS concentration of only 0.025 mM. These P-gp inhibition effects would appear to be related to these excipients’ modulation of membrane fluidity, where Tween 80 and Cremophor EL fluidized cell lipid bilayers, while vitamin E TPGS rigidized lipid bilayers. However, among the three surfactants, only Tween 80 inhibited the peptide transporter, as measured by glycyl sarcosine permeability. Likewise, only Cremophor EL inhibited the monocarboxylic acid transporter, as measured by benzoic acid permeability. Nevertheless, at least one of these three surfactants inhibited each P-gp, the human intestinal peptide transporter, and the monocarboxylic acid transporter. A common functional feature of these three surfactants was their ability to modulate fluidity, although results indicate that even strong membrane fluidity modulation alone was not sufficient to reduce transporter activity. N-octyl glucoside, a nonionic surfactant that did not modulate membrane fluidity, did not affect transporter functioning. Protein kinase C inhibitors failed to affect rhodamine 123 and glycyl sarcosine permeability, suggesting protein kinase C inhibition was not the mechanism of transporter inhibition. These results suggest that surfactants can inhibit multiple transporters but that changes in membrane fluidity may not be a generalized mechanism to reduce transporter activity.     

Effect of rifampicin on the pharmacokinetics of itraconazole in normal volunteers and AIDS patients

Objective: To investigate the effects of rifampicin on the pharmacokinetics of itraconazole in humans. Methods: Our study was conducted with six healthy normal volunteers and three AIDS patients. All subjects received a 200 mg single dose of oral itraconazole on day 1 and day 15 and 600 mg of oral rifampicin once daily from day 2 to day 15. Itraconazole pharmacokinetics studies were carried out on day 1 (phase 1) and day 15 (phase 2). The limit of detection for itraconazole concentration was 16 ng · ml^–1. Results: Concentrations itraconazole were higher when it was administered alone than when it was administered with rifampicin. Coadministration of rifampicin resulted in undetectable levels of itraconazole in all subjects except one normal volunteer. The mean AUC_0–24 was 3.28 vs 0.39 μg · h · ml⁻¹ in phase 1 and 2, respectively, in healthy normal volunteers. Therefore, the estimated minimum decrease of the mean AUC_0–24 of itraconazole in phase 2 was approximately 88% compared with phase 1. The mean AUC_0–24 was 1.07 vs 0.38 μg · h · ml^–1 in phase 1 and 2, respectively, in AIDS patients. Therefore, the estimated minimum decrease of the mean AUC_0–24 of itraconazole in phase 2 was approximately 64% compared with phase 1. Conclusion: Rifampicin has a very strong inducing effect on the metabolism of itraconazole, so that these two drugs should not be administered concomitantly. Received: 2 September 1997/Accepted in revised form: 16 December 1997     

伊曲康唑分散片人体药动学及生物等效性研究

目的:研究伊曲康唑分散片和伊曲康唑胶囊在正常人体的药动学与生物等效性.方法:18名健康男性志愿受试者随机交叉口服0.2g单剂量伊曲康唑分散片受试制荆和伊曲康唑胶囊参比制剂后,采用高效液相色谱法测定伊曲康唑的血浆药物浓度,采用方差分析及t检验判定其生物等效性.结果:两种制剂均符合一级吸收开放性一室模型,伊曲康唑分散片和伊曲康唑胶囊主要药代动力学参数AUC0→72分别为(2 221.9±762.9)和(2 311.9±844.4)ng/(h·mL),AUC0→∞分别为(2 374.2±790.8)和(2 473.3±878.9)ng/(h·mL),Cmax分别为(179.8±56.8)和(174.1±64.1)ng/mL,Tmax分别为(3.6±1.0)和(4.1±1.3)h,t1/2分别为(16.5±4.2)和(17.5±3.1)h.伊曲康唑分散片的相对生物利用度为(97.8±14.0)%.结论:伊曲康唑分散片和伊曲康唑胶囊为生物等效制剂.     

HPLC法测定小鼠血浆和组织中伊曲康唑的含量

目的建立高效液相色谱法测定小鼠血浆和组织中伊曲康唑的含量.方法采用色谱柱:Diamosil C18(4.6mm×150mm,5μm);流动相:甲醇-水(84∶16,V/V);流速:1.0mL·min-1;检测波长:262nm;柱温:室温;进样量:20μL,按伊曲康唑峰计理论塔板数不小于3000,来测定小鼠血浆和各组织中伊曲康唑的含量.结果小鼠血浆和各组织器官日内精密度和日间精密度RSD均小于4%;小鼠血浆方法回收率大于97%,RSD均小于3%;小鼠各组织器官方法回收率均大于95%,RSD均小于4%;可满足生物样品分析方法的要求.结论建立的HPLC法测定血浆和组织伊曲康唑的浓度,方法简便,准确,内源性物质不干扰测定,适合于大批量生物样本中伊曲康唑含量的测定.     

伊曲康唑凝胶剂的研制及在儿童甲癣的初步应用

目的研制伊曲康唑凝胶剂并观察其治疗儿童甲癣的疗效。方法卡伯姆加入适量甘油研匀后,加入蒸馏水,制成4%胶液,放置过夜。伊曲康唑胶囊内药倒入适量95%乙醇研匀后,再加入到卡伯姆胶液中。将三乙醇胺加适量蒸馏水搅拌后,加入到卡伯姆胶液中,搅拌直至呈凝胶状。将噻酮加入适量丙二醇研匀后,加到凝胶中。最后加蒸馏水至70 g,即制成白色细腻均匀的伊曲康唑凝胶剂。按要求将伊曲康唑凝胶剂外用治疗甲癣患儿。结果治疗3个月后,治愈率为66.7%,总有效率为100%。结论伊曲康唑胶囊可以制备成伊曲康唑凝胶剂,并能有效治疗儿童甲癣。     

高效液相色谱法测定药用辅料苯甲醇中苯甲酸和苯甲醛含量

目的建立HPLC法同时测定药用辅料苯甲醇中苯甲酸和苯甲醛的含量。方法采用Acclaim 120 C18柱(4.6 mm×250 mm,5μm),流动相为乙腈-0.02%甲酸(用氨水调至p H=4.5)(30:70),流速为1.0 m L·min-1,检测波长为230 nm,柱温为35℃,进样量为20μL。结果苯甲酸在0.500 6¹5.02μg·m L-1内与峰面积线性关系良好,平均回收率均>100%,RSD均<1.3%(n=3);苯甲醛在0.505 215.02μg·m L-1内与峰面积线性关系良好,平均回收率均>100%,RSD均<1.3%(n=3);苯甲醛在0.505 2¹5.16μg·m L-1内与峰面积的线性关系良好,平均回收率均>108%,RSD均<0.15%(n=3)。结论本方法准确度高、重现性好,可用于苯甲醇中苯甲酸和苯甲醛的含量测定。     

HPLC法测定人血浆中伊曲康唑的含量及其药代动力学研究

目的建立HPLC法测定人血浆中伊曲康唑含量方法及药代动力学特征的研究。方法选取20名健康受试者高脂饮食后随机交叉口服受试制剂和参比制剂伊曲康唑片100mg。采用HPLC-UV法测定伊曲康唑的血药浓度。结果受试制剂的相对生物利用度为(99.7±9.2)%。结论伊曲康唑的药代动力学特征较明显,表明两制剂具有生物等效性。     

Amphiphilic association of ibuprofen and two nonionic cellulose derivatives in aqueous solution

The aqueous interaction of the sodium salt of ibuprofen with the cellulose ethers ethyl hydroxyethyl cellulose, EHEC, and hydroxypropyl methyl cellulose, HPMC, has been investigated in the concentration range 0-500 mM ibuprofen and 0.1-1% (w/w) polymer, by cloud point, capillary viscometry, equilibrium dialysis, and fluorescence probe techniques. Ibuprofen forms micelles in pure water, with the critical micelle concentration, cmc, at 180 mM. A combination of time-resolved and static fluorescence quenching shows that micelle-like ibuprofen aggregates are formed in the solution. The average aggregation number of pure ibuprofen micelles in water is about 40. In the presence of EHEC or HPMC the aggregation numbers decrease. The interaction of ibuprofen with cellulose ethers is similar to the normally accepted model for polymer-surfactant interaction, although more complex. Ibuprofen adsorbs to the polymer in the form of mixed polymer-drug micelles, noncooperatively up to cmc and cooperatively when cmc is passed. The interaction starts below 50 mM ibuprofen as monitored by the fluorescent probes pyrene and 1,3-di(1-pyrenyl)propane, P3P, with a maximum in microviscosity below cmc, corresponding to polymer-dense mixed micelles. The study illustrates the importance of a precise apprehension of the aggregation behavior as a background for transport studies in drug-polymer systems.     

伊曲康唑白蛋白纳米粒混悬液的制备与体外评价

目的 制备伊曲康唑白蛋白纳米粒混悬液,并优化其处方和制备工艺,同时对所优化的白蛋白纳米粒混悬液进行评价。方法 采用单因素实验法筛选超高压微射流技术制备伊曲康唑白蛋白纳米粒混悬液的处方和制备工艺,考察了白蛋白纳米粒混悬液的外观形态、粒径分布等理化性质以及体外释药情况。结果 制备的伊曲康唑白蛋白纳米粒混悬液呈圆整的球形或类球形分布,平均粒径为(108.1±32.8)nm,PdI为0.205,Zeta电位为(-47.6±1.7)mV;伊曲康唑白蛋白纳米粒在0.5%聚山梨酯-80磷酸盐缓冲液(pH7.4)中24h累积释放73.5%。结论 采用超高压微射流技术制备伊曲康唑白蛋白纳米粒混悬液,工艺简便可行,重现性好,有望工业化生产。     

卡泊芬净和伊曲康唑治疗侵袭性肺部真菌感染的回顾性分析

目的：比较卡泊芬净和伊曲康唑治疗侵袭性肺部真菌感染（IPFI）的有效性和安全性。方法：回顾性分析本院2010年9月-2011年8月入住呼吸科并诊断为IPFI的患者病例,记录患者一般情况、身体体征和临床表现的变化过程及不良反应,比较临床疗效和不良反应的发生情况,并进行统计分析。结果：卡泊芬净组36例,有效率为58_3％,伊曲康唑组31例,有效率为38．7％,两组有效率比较差异有统计学意义（P〈0．05）;卡泊芬净组和伊曲康唑组不良反应发生率分别为22．2％和54．8％;卡泊芬净组和伊曲康唑组因毒性反应停药的病例数分剐为0例和4例,差异存在统计学意义（P〈0．05）。结论：治疗侵袭性肺部真菌感染时,卡泊芬净比伊曲康唑具有更好的疗效且副作用小,需合理使用以减少耐药菌株的产生。     

Time-dependent conversion of benzyl alcohol to benzaldehyde and benzoic acid in aqueous solutions

The oxidative reaction: benzyl alcohol-benzaldehyde-benzoic acid was investigated in time in aqueous solutions of benzyl alcohol widely used as a preservative in medicine and cosmetology. The solutions of benzyl alcohol were stored at concentrations from 0.005 to 2.09 mg/ml for a long time under different conditions. The presence of benzaldehyde and benzoic acid in these solutions was controlled by liquid chromatography on silica sorbent in water. The content of benzoic acid and potentially toxic benzaldehyde in solutions depending on the initial concentration of benzyl alcohol, on time, and on storage conditions was evaluated quantitatively.     

The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healthy volunteers

Rationale and objective Bromazepam, an anti-anxiety agent, has been reported to be metabolized by cytochrome P ₄₅₀ (CYP). However, the enzyme responsible for the metabolism of bromazepam has yet to be determined. The purpose of this study was to examine whether the inhibition of CYP3A4 produced by itraconazole alters the pharmacokinetics and pharmacodynamics of bromazepam.Methods Eight healthy male volunteers participated in this randomized double-blind crossover study. The subjects received a 6-day treatment of itraconazole (200 mg daily) or its placebo. On day 4 of the treatment, each subject received a single oral dose of bromazepam (3 mg). Blood samplings for drug assay were performed up to 70 h after bromazepam administration. The time course of the pharmacodynamic effects of bromazepam on the central nervous system was assessed using a subjective rating of sedation, continuous number addition test and electroencephalography up to 21.5 h after bromazepam administration.Results Itraconazole caused no significant changes in the pharmacokinetics and pharmacodynamics of bromazepam. The mean (±SD) values of area under the plasma concentration–time curve and elimination half-life for placebo versus itraconazole were 1328±330 ng h/ml versus 1445±419 ng h/ml and 32.1±9.3 h versus 31.1±8.4 h, respectively.Conclusion The pharmacokinetics and pharmacodynamics of bromazepam were not affected by itraconazole, suggesting that CYP3A4 is not involved in the metabolism of bromazepam to a major extent. It is likely that bromazepam can be used in the usual doses for patients receiving itraconazole or other CYP3A4 inhibitors.     

伊曲康唑固体分散体制备及体外溶出实验

目的:运用固体分散体技术提高难溶性药物伊曲康唑的溶解度及体外溶出速率.方法:选用聚乙烯吡咯烷酮(PVPK30)为载体,采用喷雾干燥法制备伊曲康唑固体分散体,通过差热分析及X射线衍射对固体分散体进行鉴定,比较考察伊曲康唑及其物理混合物和固体分散体的溶出特性.结果:差热分析、X射线衍射图谱表明药物以无定形状态分散于载体中;体外溶出结果表明固体分散体能显著增加药物在水及人工胃液中的溶出度(45 min时1:4固体分散体体外溶出度为伊曲康唑的11.5倍.1:4固体分散体在0.1 mo1·L-1盐酸中溶解度是伊曲康唑的67倍).结论:伊曲康唑固体分散体能明显提高伊曲康唑的溶解度及体外溶出速率.     

An assessment of the ecological effects of a C9--11 linear alcohol ethoxylate surfactant in stream mesocosm experiments

The responses of stream mesocosm communities to a linear alcohol ethoxylate (LAE) surfactant were studied to (i) assess the relationship between laboratory and field-scale tests; (ii) develop NOECs for responding taxa; and (iii) provide data to develop an aquatic risk assessment for alcohol ethoxylates. The LAE was a mixture of C9--11 linear alcohols with an average of six ethylene oxide (EO) units per mole of alcohol. Twelve stream mesocosms were used to test the effects of five concentrations of the LAE on periphyton, aquatic macrophytes, invertebrates and fish during a 30-day exposure. Vascular plants were unaffected at 11.4 mg L–1, the highest surfactant concentration tested, but various periphyton parameters were altered at lower concentrations. The effects on periphyton were attributed to grazing by resident invertebrates. Invertebrate densities were affected at LAE concentrations above 2.0 mg L–1. Fathead minnows were particularly sensitive to LAE with a NOEC of 0.73 mg L–1 for egg production and larval survival. Bluegill were less sensitive than fathead minnows, with a NOEC for survival and growth of 5.7 mg L–1. The stream mesocosm results for fish and invertebrates were similar to those obtained using laboratory single-species tests