EPR Studies on Film Formation of Colloidal Dispersions, 1. Site Selectivity and Techniques

For the first time, electron paramagnetic resonance (EPR) spectroscopy of spin probes is applied to the characterisation of colloidal polymer dispersions and of films obtained from them. The different domains of the dispersions and films can be selectively addressed by simply adding various, readily available spin probes to the initial dispersions. Evidence for the localisation of these probes is obtained from the comparison of their rotational correlation times or rotational diffusion tensors, from the observation of local order in the case of surfactant probes, and from the variation of fluorine matrix hyperfine couplings in the case of probes in poly(fluoroalkyl acrylates). The introduced methodology forms the basis for a new approach to studies of film formation, film annealing, and film rewetting by spin probe EPR.     

Diptool—A Novel Numerical Tool for Membrane Interactions Analysis,Applying to Antimicrobial Detergents and Drug Delivery Aids

The widespread problem of resistance development in bacteria has become a critical issue for modern medicine. To limit that phenomenon, many compounds have been extensively studied. Among them were derivatives of available drugs, but also alternative novel detergents such as Gemini surfactants. Over the last decade, they have been massively synthesized and studied to obtain the most effective antimicrobial agents, as well as the most selective aids for nanoparticles drug delivery. Various protocols and distinct bacterial strains used in Minimal Inhibitory Concentration experimental studies prevented performance benchmarking of different surfactant classes over these last years. Motivated by this limitation, we designed a theoretical methodology implemented in custom fast screening software to assess the surfactant activity on model lipid membranes. Experimentally based QSAR (quantitative structure-activity relationship) prediction delivered a set of parameters underlying the Diptool software engine for high-throughput agent-membrane interactions analysis. We validated our software by comparing score energy profiles with Gibbs free energy from the Adaptive Biasing Force approach on octenidine and chlorhexidine, popular antimicrobials. Results from Diptool can reflect the molecule behavior in the lipid membrane and correctly predict free energy of translocation much faster than classic molecular dynamics. This opens a new venue for searching novel classes of detergents with sharp biologic activity.     

Comparison of rapid bolus instillation with simplified slow administration of surfactant in lung lavaged rats

The aim of this study was to compare the effects of modified porcine surfactant (Curosurf®) given either by a simplified slow delivery technique or by the standard bolus method, on pulmonary gas exchange, lung mechanics, and surfactant distribution in rats with respiratory failure produced by lung lavage. Twelve rats with respiratory failure induced by lung lavage received 200 mg·kg⁻¹ body weight (b.w.) of tagged porcine surfactant, either by the standard bolus delivery technique or by a simplified 1-min intratracheal infusion method, not requiring interruption of mechanical ventilation. Cardiovascular parameters, arterial blood gases, and pulmonary mechanics were measured repeatedly. Surfactant distribution was also measured by dye-tagged microbeadspheres. After surfactant administration, there were no overall major differences between groups in mean heart rate, blood pressure, arterial blood gases, dynamic lung compliance, respiratory system resistance, and pulmonary distribution of exogenous surfactant. However, after 180 min pulmonary gas exchange was better and compliance higher in the bolus than the 1-min infusion group. A transient decrease in blood pressure and heart rate was observed in the bolus group; this side effect was not seen in animals treated with the simplified 1-min infusion method. We conclude that in rats subjected to lung lavage, the infusion of porcine surfactant by a simplified 1-min procedure produced similar short-term effects compared to the same dose of surfactant given by the bolus method. We speculate that tracheal bolus dosing is highly effective and might be the preferable delivery method for porcine surfactant. Dosing by the simplified method described appears less effective, but since no significant differences were observed, and since it produced less acute adverse effects, it could be used when clinical circumstances preclude rapid delivery. Pediatr Pulmonol. 1998; 26:129–134. © 1998 Wiley-Liss, Inc.     

Low-frequency sonophoresis: application to the transdermal delivery of macromolecules and hydrophilic drugs

Importance of the field: Transdermal delivery of macromolecules provides an attractive alternative route of drug administration when compared to oral delivery and hypodermic injection because of its ability to bypass the harsh gastrointestinal tract and deliver therapeutics non-invasively. However, the barrier properties of the skin only allow small, hydrophobic permeants to traverse the skin passively, greatly limiting the number of molecules that can be delivered via this route. The use of low-frequency ultrasound for the transdermal delivery of drugs, referred to as low-frequency sonophoresis (LFS), has been shown to increase skin permeability to a wide range of therapeutic compounds, including both hydrophilic molecules and macromolecules. Recent research has demonstrated the feasibility of delivering proteins, hormones, vaccines, liposomes and other nanoparticles through LFS-treated skin. In vivo studies have also established that LFS can act as a physical immunization adjuvant. LFS technology is already clinically available for use with topical anesthetics, with other technologies currently under investigation.

Areas covered in this review: This review provides an overview of mechanisms associated with LFS-mediated transdermal delivery, followed by an in-depth discussion of the current applications of LFS technology for the delivery of hydrophilic drugs and macromolecules, including its use in clinical applications.

What the reader will gain: The reader will gain an insight into the field of LFS-mediated transdermal drug delivery, including how the use of this technology can improve on more traditional drug delivery methods.

Take home message: Ultrasound technology has the potential to impact many more transdermal delivery platforms in the future due to its unique ability to enhance skin permeability in a controlled manner.     

Reversed-phase high-performance liquid chromatographic method for the assay of 1,4-dioxane in sulphated polyoxyethylene alcohol surfactants

A rapid high-performance liquid chromatographic method has been developed for the assay of 1,4-dioxane in ethoxylated fatty alcohol sulphates. After solid-phase extraction using Bakerbond C₁₈ cartridges, samples were directly analysed on a LiChrospher CH-8 reversed-phase column with UV detection at 200 nm and an acetonitrile-water eluent. Recovery of 1,4-dioxane from the surfactant matrix was 95.7% in the 40 to 120 μg g⁻¹ range. The minimum quantifiable amount was 18 μg g⁻¹. The procedure is simple, reproducible, specific and suitable for routine analyses of commercial surfactants.     

Differential Effects of Anionic,Cationic, Nonionic,and Physiologic Surfactants on the Dissociation, α-Chymotryptic Degradation,and Enteral Absorption of Insulin Hexamers

Various surfactants were investigated to compare their effects on insulin dissociation, -chymotryptic degradation, and rat enteral absorption. With a circular dichroism technique, sodium dodecyl sulfate (SDS) at a 5 mM concentration was found to completely dissociate procine-zinc insulin hexamers (0.5 mg/ml) into monomers. The catalytic activity of -chymotrypsin (0.5 µM) was also abolished by 5 mM SDS. When insulin was injected into the distal jejunum/ proximal ileum segment of the rat, 5 mM SDS greatly enhanced its pharmacological availability, from a negligible value to 2.8%. Being a cationic surfactant, hexadecyl trimethylammonium bromide (CTAB) also efficiently dissociated insulin hexamers at concentrations of 1–5 mM. However, extensive charge–charge interaction was observed below a CTAB concentration of 0.6 mM, leading to insulin precipitation at a molar CTAB:insulin ratio of 1:1 to 2:1. An -chymotryptic degradation study also revealed near-complete dissociation of insulin hexamers at 1 mM CTAB. Above 1 mM, however, CTAB acted as an enzyme inhibitor, most likely by means of charge repulsion. Enteral absorption studies showed a much lower pharmacological availability, only 0.29%. Nonionic surfactants such as Tween 80 and polyoxyethylene 9 lauryl ether were ineffective in dissociating insulin hexamers. Tween 80, at 5 mM, neither significantly altered the -chymotryptic degradation pattern nor enhanced the enteral absorption of insulin. The relative effectiveness of different species of bile salts on insulin hexamer dissociation appeared to be similar. Sodium glycocholate at a 30 mM concentration also significantly increased insulin pharmacological availability, to 2.3%. A morphological study did not reveal any significant alteration of the rat intestinal mucosal integrity after exposure to 5 mM SDS for 30 min. The results further emphasize the importance of the degree of insulin aggregation on its enteral transport.     

复合乳化剂对微乳成乳区域的影响

[目的]研究复合乳化剂对O/W微乳成乳区域的影响,为微乳的处方筛选提供依据。[方法]选用磷脂（PC）和泊洛沙姆188（F68）为复合乳化剂,甘油为助乳化剂,分别选取不同的乳化剂/助乳化剂（Km值）和F68/PC的不同比例绘制三元相图;对比相同条件下以磷脂为乳化剂,甘油为助乳化剂,油酸乙酯为油相所得相图的微乳区域面积,考察复合乳化剂对O/W微乳成乳区域的影响。[结果]以磷脂和F68为复合乳化剂的三元相图的成乳区域较单乳化剂的成乳区域明显增大。当Km=1∶1,成乳区域较大,在实验取值范围内随着Km的增大或减小微乳区域随之减小,随着复合乳化剂中F68的比例的增大,微乳区域 随之变大。当Km=1∶1且F68∶PC=2∶1时,所得的成乳区域最大。[结论]较单乳化剂复合乳化剂可显著增大O/W微乳的成乳区域,对于寻找可形成稳定O/W微乳的处方有积极的意义。     

庆大霉素-肺表面活性物质磷脂乳剂气道滴入治疗大鼠克雷白杆菌性肺炎

目的　了解庆大霉素 肺表面活性物质磷脂乳剂气道滴入给药在大鼠细菌性肺炎早期的疗效。方法　将肺炎克雷白杆菌经大鼠气道滴入 ,经气道给予庆大霉素 肺表面活性物质磷脂乳剂 ;观察肺通气换气功能、肺病理形态、肺组织及循环血液中细菌数量变化及庆大霉素浓度。结果　庆大霉素磷脂乳剂气道内给药可改善氧合 ,减少肺内细菌数量 ,减轻肺部炎症病变。与静脉内用药相比 ,可获得较高的组织内药物浓度 ,并对肺通气换气功能无不良影响。结论　庆大霉素磷脂乳剂气道给药可有效治疗实验性细菌性肺炎 ,但不对肺呼吸力学产生不良影响     

单独使用沐舒坦对大鼠胎肺表面活性物质及胎肺形态发育的影响

目的研究单独使用沐舒坦对大鼠胎肺表面活性物质及胎肺形态发育的影响。方法选择健康清洁级妊娠的SD大鼠18只分为3组,沐舒坦治疗组、地塞米松治疗组和对照组各6只。各组大鼠于妊娠第16、17、18天尾静脉分别注射沐舒坦75mg／kg(按成人15mg／kg计算),地塞米松0．8mg／kg(按成人0．2mg／kg计算),生理盐水2ml／只。于妊娠第19天剖宫取出胎肺,通过光镜图像分析和电镜技术观察胎肺的形态结构,并测定胎肺的磷脂含量。结果在光镜下,沐舒坦和地塞米松治疗组的肺泡扩张比对照组明显,肺泡腔结构大且较规则;呼吸膜周径比对照组大;肺泡间质比对照组薄(P<0．01),但沐舒坦组与地塞米松组之间无差异(P>0．05)。电镜下,两个治疗组的板层小体数量明显多于对照组,且板层小体深染、致密。而对照组肺内难见板层小体,胞浆内糖原沉积却非常丰富。此外,沐舒坦治疗组肺磷脂含量为(0．72±0．06)mmol／g湿肺,地塞米松治疗组为(0．73±0．19)mmol／g湿肺,对照组为(0．62±0．09)mmol／g湿肺,沐舒坦、地塞米松治疗组与对照组比较,差异有统计学意义(P<0．01),沐舒坦治疗组与地塞米松治疗组两者之间无统计学差异(P>0．05)。结论单独使用沐舒坦能促进胎肺发育,效果类似于地塞米松。沐舒坦可能成为临床上用于产前促胎肺成熟的一种更好的选择。     

表面活性剂对姜黄素类成分水溶性与抗肝纤维化作用的影响

目的研究以3种食品级表面活性剂为增溶剂增加姜黄素类成分的水溶性,并研究表面活性剂对姜黄素类成分结构、稳定性及体内抗肝纤维化作用的影响。方法采用高速分散法制备姜黄素类成分与表面活性剂的配比溶液,通过LC-MS/MS对配比溶液中姜黄素类成分进行定性分析,建立HPLC-DAD指纹图谱,进行定量分析;进一步通过肝纤维化大鼠模型评估不同质量浓度姜黄素配比溶液的抗肝纤维化作用。结果羟乙基纤维素、明胶、蔗糖酯加入的质量比为3∶5∶40,高速分散机转速为6 000 r/min时,姜黄素类成分的水溶性最大为1.387 mg/m L;LC-MS/MS分析表明,姜黄素类成分结构未改变;指纹图谱表明,有18批次样品相似度大于99%;且不同批次样品中姜黄素、脱甲氧基姜黄素、双脱甲氧基姜黄素含量稳定,RSD分别为1.60%、2.24%、3.74%;抗肝纤维化动物实验表明,游离药物混悬液组大鼠天冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)水平分别为(64.1±20.3)、(45.1±13.9)U/L,而姜黄素配比溶液组为(19.4±8.7)、(11.8±4.9)U/L。结论姜黄素类成分经表面活性剂配比增溶后水溶性较游离状态(2.677μg/m L)提高了517倍,重复试验表明姜黄素类成分的化学结构与含量均稳定;增溶后的姜黄素类成分显示出更好的抗肝纤维化效果。