Drug release from lipid liquid crystalline phases: relation with phase behavior

Introduction: We studied the release of propranolol hydrochloride (PHCl), a water-soluble amphiphilic drug, from monoolein (MO)/water and phytantriol/water systems. Methods: We related the dissolution profiles with phase behavior and viscosity of the different liquid crystalline phases. Diolein has been added aiming to stabilize the cubic phases and thus preventing formation of less viscous (lamellar) phases. Results: Formulations display first-order release rates and diffusion release mechanism. Some formulations (mostly MO) were close to zero-order release in the first 120 minutes. Discussion: Release mechanism can be influenced by phase changes during dissolution. Conclusions: Both MO and phytantriol show good potential to be used for propranolol hydrochloride sustained drug release.     

Formulation,characterization and clinical evaluation of propranolol hydrochloride gel for transdermal treatment of superficial infantile hemangioma

The objective of the present study is to formulate and characterize propranolol hydrochloride (PPL?·?HCl) gel, and to evaluate the efficacy of this formulation in transdermal treatment for superficial infantile hemangioma (IH). The transdermal PPL?·?HCl gel was prepared by a direct swelling method, which chose hydroxypropyl methylcellulose (HPMC) as the matrix and used terpenes plus alcohols as permeation enhancer. Permeation studies of PPL?·?HCl were carried out with modified Franz diffusion cells through piglet skin. Our results pointed to that among all studied permeation enhancers, farnesol plus isopropanol was the most effective combination (Q_24, 6027.4?±?563.1?μg/cm², ER, 6.8), which was significantly higher than that of control gel (p?相似文献   

In vitro release of propranolol from oil/water microemuisions

Oil/water (o/w) microemulsions containing propranolol were studied. Isopropylmyristate was used as the oil, Tween 60 as a surfactant, butanol as a co-surfactant and a buffer of pH 6.5 for the continuous phase. The lipophilicity of propranolol was enhanced by formation of lipophilic ion-pairs to obtain a disperse phase that could act as a reservoir; octanoic acid was used as counter-ion. The diffusion rates of propranolol from microemulsions through a hydrophilic membrane decreased as the concentration of octanoic acid increased. The apparent permeability constant, determined at the beginning of the experiment, was 2.9 × 10⁻⁹ cm s⁻¹ for propranolol alone and diminished until 3.5 × 10⁻¹⁰ cm s⁻¹ in the presence of octanoic acid, at a concentration of 16.4 times that of propranolol.     

Drug-Delivery by Ion-Exchange: Part IIII: Interaction of Ester Pro-Drugs of Propranolol with Cationic Exchange Resins

Abstract

The interaction of a series of O-n-acyl propranolol prodrugs with strong cation exchange resins is reported and various variables which control loading and release profiles have been investigated. pH has little practical effect on the loading efficiency under the conditions used but standardisation of experimental details for the measurement of in vitro liberation profiles must be undertaken. In particular, stirring speeds of 200-300 rpm were necessary to ensure the independence of release profile and agitation. Additionally, the dissolution medium may not provide sink conditions throughout the full dissolution process if pH variation does not take into account solubility differences between analogues. Ionic strength also influences release rates and attempts to examine the effects of pH must also control this variable. The proportion of cross-linking agent in the resin plays an important role. Increasing the cross-linking delays considerably the release of drug from the matrix and is a useful parameter in optimising controlled delivery. The loading efficiency of the resin is reduced, however, as the cations are excluded from parts of the resin due to a reduction in pore diameter. In contrast, the particle size of the resin has little influence upon loading efficiencies but larger particles significantly delay the release of drug. The effect of 0-n-acyl chain-length on the loading and release profiles was determined by molecular size. As groups increased in size the loading was inhibited and release rates were reduced. Again, this enables some control of release profiles but the approach is most suitable for drugs which are active at low doses which allow full use of these variations without the necessity for large amounts of resin in the delivery system.     

Drug-Delivery by Ion-Exchange: Part II: Physico-Chemical Properties of Ester Pro-Drugs of Propranolol

Abstract

The pKa values, solubilities and partition coefficients of a series of O-n-acyl propranolol pro-drugs have been estimated. The direct measurement of solubilities is limited by the instability of the esters and pK values are difficult to estimate by potentiometric titration due to low solubilities. Titrations in a range of aqueous methanolic solutions provide an estimate of the pK_a while titration under non-logarithmic conditions, when excess, undissolved base is present in the system, allows the determination of solubility.     

On the Influence of Crosslinker on Template Complexation in Molecularly Imprinted Polymers: A Computational Study of Prepolymerization Mixture Events with Correlations to Template-Polymer Recognition Behavior and NMR Spectroscopic Studies

Aspects of the molecular-level basis for the function of ethylene glycol dimethacrylate and trimethylolproprane trimethacrylate crosslinked methacrylic acid copolymers molecularly imprinted with (S)-propranolol have been studied using a series of all-component and all-atom molecular dynamics studies of the corresponding prepolymerization systems. The crosslinking agents were observed to contribute to template complexation, and the results were contrasted with previously reported template-recognition behavior of the corresponding polymers. Differences in the extent to which the two crosslinkers interacted with the functional monomer were identified, and correlations were made to polymer-ligand recognition behavior and the results of nuclear magnetic resonance spectroscopic studies studies. This study demonstrates the importance of considering the functional monomer–crosslinker interaction when designing molecularly imprinted polymers, and highlights the often neglected general contribution of crosslinker to determining the nature of molecularly imprinted polymer-template selectivity.     

液相色谱-串联质谱法测定乳制品中盐酸普萘洛尔残留量

目的 建立了乳制品中盐酸普萘洛尔残留的液相色谱-串联质谱检测方法(liquid chromatography- tandem mass spectrometry, LC-MS/MS)。方法 乳制品用乙腈提取, 提取液用甲酸酸化后, 经正己烷去除油脂以及N-丙基乙二胺净化, 微孔滤膜过滤后进样。C8柱分离后采用多反应监测(multiple reaction monitoring, MRM)模式进行检测, 外标法定量。结果 目标化合物在1.56~25.0 μg/L范围内线性关系良好, 相关系数(r2)大于0.999。固体乳制品中盐酸普萘洛尔的定量限(limit of quantitation, LOQ)和检出限(limit of detection, LOD)分别为2.00 μg/kg、1.00 μg/kg; 液体乳制品中盐酸普萘洛尔的定量限(LOQ)和检出限(LOD)分别为0.40 μg/L、0.20 μg/L; 不同加标浓度样品(LOQ、2LOQ、10LOQ)的平均回收率为93.4%~108%, 相对标准偏差(relative standard deviations, RSDs)为2.90%~5.80%。35份市售乳制品中均未检出盐酸普萘洛尔残留。结论 该方法简便、快速、准确, 精密度、检出限等参数均能满足相关的技术规范的要求, 可用于市售乳制品的检测。     

Impairment of Hypoxia-Induced CA IX by Beta-Blocker Propranolol—Impact on Progression and Metastatic Potential of Colorectal Cancer Cells

The coexistence of cancer and other concomitant diseases is very frequent and has substantial implications for treatment decisions and outcomes. Beta-blockers, agents that block the beta-adrenergic receptors, have been related also to cancers. In the model of multicellular spheroids formed by colorectal cancer cells we described a crosstalk between beta-blockade by propranolol and tumour microenvironment. Non-selective beta-blocker propranolol decreased ability of tumour cells to adapt to hypoxia by reducing levels of HIF1α and carbonic anhydrase IX in 3D spheroids. We indicated a double action of propranolol in the tumour microenvironment by inhibiting the stability of HIF1α, thus mediating decrease of CA IX expression and, at the same time, by its possible effect on CA IX activity by decreasing the activity of protein kinase A (PKA). Moreover, the inhibition of β-adrenoreceptors by propranolol enhanced apoptosis, decreased number of mitochondria and lowered the amount of proteins involved in oxidative phosphorylation (V-ATP5A, IV-COX2, III-UQCRC2, II-SDHB, I-NDUFB8). Propranolol reduced metastatic potential, viability and proliferation of colorectal cancer cells cultivated in multicellular spheroids. To choose the right treatment strategy, it is extremely important to know how the treatment of concomitant diseases affects the superior microenvironment that is directly related to the efficiency of anti-cancer therapy     

口服普奈洛尔治疗婴儿血管瘤59例疗效分析

目的：探讨口服普奈洛尔治疗婴幼儿血管瘤的疗效和安全性。方法：选取符合纳入标准的婴儿血管瘤59例,采用普奈洛尔2mg/kg.d,分2次口服,治疗开始前3天每天监测血压和心率,每月来医院随访照相并进行血管瘤严重程度视觉评分以评估疗效,同时常规体检包括血压、心率、血糖,并记录不良反应。结果：59例婴儿血管瘤中男21例,女38例,平均年龄5.08月。其中草莓状血管瘤4例,海绵状血管瘤8例,混合型血管瘤47例。病变位于四肢10例,躯干7例,头颈32例,其中口鼻周8例,眼周1例,溃疡型2例。大多数病例于服药48小时后皮损颜色变暗、皮温降低,随后瘤体开始逐渐缩小。治疗4周、8周时严重程度评分已降至5分、4分,表示瘤体平均消退达到50%、60%。普奈洛尔对草莓状、海绵状及混合型血管瘤的疗效无显著差异。此外,不同性别、起始治疗月龄、不同部位之间疗效无显著差异（P〉O.05）。生长于眼周、口鼻周及溃疡型的血管瘤同样对普奈洛尔治疗有效。治疗中未发现有症状的低血压、低血糖,1例发生腹泻,11例患儿出现睡眠改变,其中9例表现为夜惊,2例表现为睡眠增加。结论：2mg/kg.d普奈洛尔口服治疗婴儿血管瘤疗效显著,副作用小,可望成为血管瘤的一线治疗新方法。     

双波长叠加紫外分光光度法测定盐酸普萘洛尔的含量

建立双波长叠加紫外分光光度法测定盐酸普萘洛尔的含量。盐酸普萘洛尔在290 nm和320 nm波长处有吸收峰,采用290 nm和320 nm作为测定波长,以两波长处吸光度值之和作为定量指标。研究发现盐酸普萘洛尔在2.04～51.0μg· mL-1浓度范围内与两峰处吸光度值之和呈良好线性关系（r＝0.9999）,方法检测限为0.5μg· mL-1,表观摩尔吸收系数为6.708×103 L· mol -1· cm-1,测定灵敏度较最大吸收波长处提高了32.6％。结果表明双波长叠加紫外分光光度法简便,灵敏,快速,可用于样品中盐酸普萘洛尔的含量测定。