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Rapid communication: A Simple, Non-Invasive, Cost-Effective Technique to Monitor Ice Nucleation in GMP Freeze-Drying. 快速交流:一种监测 GMP 冻干过程中冰核形成的简单、无创、经济高效的技术。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-05 DOI: 10.1016/j.xphs.2024.07.011
Jean-René Authelin, Evgenyi Shalaev
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引用次数: 0
Characterization of Oral Drug Absorption from Jelly Formulations: Effects of Membrane Permeability and Intestinal Fluid Volume. 果冻制剂口服药物吸收的特征:膜渗透性和肠液容量的影响。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-04 DOI: 10.1016/j.xphs.2024.07.016
Junko Nakamura, Yukari Kakino, Makoto Kataoka, Shinji Yamashita, Yoshihiro Hishikawa, Keiko Minami

This study aims to clarify the process of oral drug absorption from jelly formulations. Agar and pectin-based jellies containing drugs with different membrane permeability (high: antipyrine [ANT], medium: metoprolol [MET], low: atenolol [ATE]) were prepared and tested for in vitro drug release and in vivo drug absorption in rats. All drugs showed similar release profiles in vitro from both jelly formulations, except for the faster release from pectin jelly at neutral pH. In contrast, in vivo absorption of ATE but not of ANT from jelly formulations was significantly lower than from solution. Absorption of ATE and MET was low from agar jelly after oral administration, whereas additional water intake significantly increased the absorption. The process of drug absorption was described by the compartmental model consisting of jelly, intestinal fluid, and blood compartments. Drugs in the jelly diffuse into the intestinal fluid and then permeate the intestinal membrane. By considering the rate-limiting process, membrane permeability-dependent drug absorption from agar jelly and the effects of water intake were identified. In conclusion, jelly formulations may potentially decrease and delay drug oral absorption, especially of poorly permeable drugs. Intestinal fluid volume is one of the important factors to control the drug absorption.

本研究旨在阐明果冻制剂的口服药物吸收过程。研究人员制备了含有不同膜渗透性药物(高:安替比林[ANT];中:美托洛尔[MET];低:阿替洛尔[ATE])的琼脂果冻和果胶果冻,并在大鼠体内进行了体外药物释放和体内药物吸收试验。除了果胶果冻在中性 pH 值下释放较快外,所有药物在两种果冻配方中的体外释放曲线相似。相比之下,大鼠体内对果冻制剂中 ATE 的吸收率明显低于对溶液中 ANT 的吸收率。口服后,琼脂胶冻对 ATE 和 MET 的吸收率较低,而额外摄入的水分可显著增加吸收率。药物吸收过程由果冻、肠液和血液组成的区室模型来描述。果冻中的药物扩散到肠液中,然后渗透到肠膜上。通过考虑限速过程,确定了琼脂果冻的药物吸收依赖于膜渗透性以及水摄入量的影响。总之,果冻制剂可能会减少和延迟药物的口服吸收,尤其是渗透性差的药物。肠液容量是控制药物吸收的重要因素之一。
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引用次数: 0
Manufacture, characterization, and elucidation of drug release mechanisms of etonogestrel implants based on ethylene vinyl acetate. 基于乙烯-醋酸乙烯酯的依托孕烯植入物的制造、表征和药物释放机制的阐明。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-03 DOI: 10.1016/j.xphs.2024.08.015
Angela Ren, Ziyue Zhong, Yan Wang, Bin Qin, William Smith, Xiaoming Xu, Tony Listro, Feng Zhang

In this work, etonogestrel implants were manufactured using coextrusion. The purpose of the study was to correlate changes in microstructure and transport properties that occurred in etonogestrel implants to drug release mechanisms. The implants consisted of an EVA 28 (28 % vinyl acetate) core containing dispersed and dissolved etonogestrel, and an EVA 15 (15 % vinyl acetate) skin. The drug release was determined to be via diffusion at a controlled rate and governed by implant dimensions. In-vitro release revealed evidence of supersaturation in the implant core and skin, likely from the intense mechanical energy input during the twin-screw manufacturing process. Subsequently during storage under ambient conditions, supersaturation resulted in recrystallization of drug crystals, preferentially in the implant core. Etonogestrel solubility and diffusivity in EVA were determined by permeation experiments and used for release modeling. Drug release from the EVA skin layer deviated from the predicted values due to 1) formation of a drug depletion zone in the core and 2) presence of a stagnant media layer adjacent to the skin. Drug release from implant ends was significantly faster than predicted. Air-filled pores were observed in the implant core using microCT which likely contributed to the faster release from implant ends.

在这项研究中,依托孕烯植入物是采用共挤工艺制造的。研究的目的是将依托孕烯植入物的微观结构和传输特性变化与药物释放机制联系起来。植入物由含有分散和溶解的依托孕烯的 EVA 28(28% 醋酸乙烯酯)内核和 EVA 15(15% 醋酸乙烯酯)外皮组成。经测定,药物释放是通过可控速率的扩散作用进行的,并受植入物尺寸的制约。体外释放显示出植入物核心和表皮过饱和的迹象,这可能是双螺杆制造过程中输入的高强度机械能造成的。随后,在环境条件下储存期间,过饱和导致药物晶体再结晶,并优先出现在植入体核心部位。通过渗透实验确定了依托孕烯在 EVA 中的溶解度和扩散率,并将其用于释放模型的建立。EVA 皮肤层的药物释放偏离了预测值,原因是:1)在核心部位形成了一个药物耗竭区;2)皮肤附近存在一个停滞介质层。植入体末端的药物释放速度明显快于预测值。使用显微 CT 观察到种植体核心部位有充满空气的孔隙,这可能是导致种植体末端药物释放更快的原因。
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引用次数: 0
Early clinical drug product shelf-life setting using accelerated predictive stability and metabolite data for impurity qualification: A case study. 利用加速预测稳定性和代谢物数据进行杂质鉴定,确定早期临床药物产品的保质期:案例研究。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-01 DOI: 10.1016/j.xphs.2024.08.010
Jenny E Ottosson, Angela Ku, Magnus Fransson, Carina Leandersson, Lars Weidolf, Jufang Wu Ludvigsson, Magnus Klarqvist

This case study demonstrates how knowledge of degradation products together with predictions can establish a lean stability strategy using the accelerated predictive stability (APS) principles. Applying all available data for AZD4831, (R)-1-(2-(1-aminoethyl)-4-chlorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrrolo[3,2-d]pyrimidin-4(5H)-one, a reliable predictive model was developed despite minor differences in technical batch tablet compositions. Early forced degradation studies were performed to map potential degradation pathways. The insights from these studies guided the design of an APS study, which in turn inform on a suitable clinical stability program, initial specification and shelf-life. The use of APS predictions of degradants as well as total impurities highlighted at an early stage, when designing the clinical stability program, the opportunity to identify which degradation product that would be shelf-life limiting. Hence, it was possible to guide the development stability activities and set an initial shelf-life of a tablet formulation. The presented study displays the importance of combining several sources of information in drug development, e.g., potential degradation pathways, accelerated stability, stability program design, metabolite data, and specification limits.

本案例研究展示了降解产物知识和预测如何利用加速预测稳定性(APS)原理建立精益稳定性策略。应用 AZD4831((R)-1-(2-(1-氨基乙基)-4-氯苄基)-2-硫酮-2,3-二氢-1H-吡咯并[3,2-d]嘧啶-4(5H)-酮)的所有可用数据,建立了一个可靠的预测模型,尽管技术批次片剂成分略有不同。为绘制潜在降解途径图,进行了早期强制降解研究。这些研究为 APS 研究的设计提供了指导,而 APS 研究又为合适的临床稳定性计划、初始规格和保质期提供了信息。在设计临床稳定性方案的早期阶段,使用 APS 预测降解剂和杂质总量,可以确定哪种降解产物会对货架期产生限制。因此,有可能指导开发稳定性活动并设定片剂制剂的初始保质期。本研究显示了在药物开发过程中结合多种信息来源的重要性,例如潜在降解途径、加速稳定性、稳定性方案设计、代谢物数据和规格限值。
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引用次数: 0
Amorphous Solubility Advantage: Theoretical Considerations, Experimental Methods, and Contemporary Relevance. 无定形溶解度优势:理论思考、实验方法和当代意义。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-01 DOI: 10.1016/j.xphs.2024.08.029
Keisuke Ueda, Dana E Moseson, Lynne S Taylor

Twenty-five years ago, Hancock and Parks asked a provocative question: "what is the true solubility advantage for amorphous pharmaceuticals?" Difficulties in determining the amorphous solubility have since been overcome due to significant advances in theoretical understanding and experimental methods. The amorphous solubility is now understood to be the concentration after the drug undergoes liquid-liquid or liquid-glass phase separation, forming a water-saturated drug-rich phase in metastable equilibrium with an aqueous phase containing molecularly dissolved drug. While crystalline solubility is an essential parameter impacting the absorption of crystalline drug formulations, amorphous solubility is a vital factor for considering absorption from supersaturating formulations. However, the amorphous solubility of drugs is complex, especially in the presence of formulation additives and gastrointestinal components, and concentration-based measurements may not indicate the maximum drug thermodynamic activity. This review discusses the concept of the amorphous solubility advantage, including a historical perspective, theoretical considerations, experimental methods for amorphous solubility measurement, and the contribution of supersaturation and amorphous solubility to drug absorption. Leveraging amorphous solubility and understanding the associated physicochemical principles can lead to more effective development strategies for poorly water-soluble drugs, ultimately benefiting therapeutic outcomes.

25 年前,汉考克和帕克斯提出了一个具有启发性的问题:"无定形药物的真正溶解度优势是什么?此后,由于理论认识和实验方法的重大进步,确定无定形溶解度的困难已被克服。现在,无定形溶解度被理解为药物经历液-液或液-玻璃相分离后的浓度,该分离形成了富含药物的水饱和相,与含有分子溶解药物的水相处于可移动的平衡状态。晶体溶解度是影响晶体药物制剂吸收的重要参数,而无定形溶解度则是考虑过饱和制剂吸收的重要因素。然而,药物的无定形溶解度非常复杂,尤其是在配方添加剂和胃肠道成分存在的情况下,基于浓度的测量可能无法显示药物的最大热力学活性。本综述将讨论无定形溶解度优势的概念,包括历史视角、理论考虑因素、无定形溶解度测量的实验方法,以及过饱和度和无定形溶解度对药物吸收的贡献。利用无定形溶解度并了解相关的物理化学原理,可以为水溶性差的药物制定更有效的开发策略,从而最终改善治疗效果。
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引用次数: 0
Measuring Erosion of Biodegradable Polymers in Brimonidine Drug Delivery Implants by Quantitative Proton NMR Spectroscopy (q-HNMR). 利用定量质子核磁共振波谱(q-HNMR)测量布利莫尼定给药植入物中生物可降解聚合物的侵蚀。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-08-31 DOI: 10.1016/j.xphs.2024.08.028
Hongpeng Wang, Mike Roof, Kyle Burgher, Chiem Pham, Eric R Samuels, Yan He, Huahua Jian, Tao Wang

Erosion of biodegradable polymeric excipients, such as polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA), is generally characterized by microbalance for the remaining mass of PLA and/or PLGA and Gel Permeation Chromatography (GPC) for molecular weight (MW) decrease. For polymer erosion studies of intravitreal sustained release brimonidine implants, however, both microbalance and GPC present several challenges. Mass loss measurement by microbalance does not have specificity for excipient polymers and drug substances. Accuracy of the remaining mass by weighing could also be low due to sample mass loss through retrieval-drying steps, especially at later drug release (DR) time points. When measuring the decrease of polymer MW by GPC, trace amounts of polymeric degradants (oligomers and/or monomers) trapped inside the implants during DR tests may not be measurable due to sensitivity limitations of the GPC detector and column MW range. Previous efforts to measure remained PLGA weight of dexamethasone micro-implants using qNMR with external calibration have been performed, however, these measurements do not account for chemical structure changes (i.e. LA to GA ratio changes from time zero) of PLGA implants during drug release tests. Here, a qNMR method with an internal standard was developed to monitor the following changes in micro-implants during drug release tests: 1. The remaining overall PLA/PLGA mass. 2. The remaining lactic acid (LA), glycolic acid (GA) unit and PLGA's lauryl ester end group percentages. 3. The trace content of PLA/PLGA oligomers as degradants retained in the implants. Unlike microbalance analysis, qNMR has both specificity for drug substance, excipient polymer, and accuracy due to minimal implant loss during sample preparation. Compared to the overall PLA/PLGA remaining mass generally monitored in erosion studies, the percentage of remaining LA, GA, and the ester end group provide more information about the microstructure change (such as hydrophobicity) of PLA/PLGA. Additionally, the qNMR method can complement GPC methods by measuring the change of remaining PLA and PLGA oligomer concentrations in brimonidine implants, with tenfold less sample and no MW cutoff. The qNMR method can be used as a sensitive tool for both polymer excipient characterization and kinetics studies of brimonidine implant erosion.

生物可降解聚合物辅料(如聚乳酸(PLA)和聚乳酸-共-乙醇酸(PLGA))的侵蚀通常是通过微天平来测定聚乳酸和/或聚乳酸-共-乙醇酸的剩余质量,以及通过凝胶渗透色谱法(GPC)来测定分子量(MW)的降低。然而,对于玻璃体内缓释溴莫尼定植入物的聚合物侵蚀研究,微量天平和凝胶渗透色谱法都面临着一些挑战。用微量天平测量质量损失对辅料聚合物和药物物质没有特异性。由于样品在回收-干燥步骤中的质量损失,称量剩余质量的准确性也可能较低,尤其是在较晚的药物释放 (DR) 时间点。在通过 GPC 测量聚合物 MW 的减少时,由于 GPC 检测器和色谱柱 MW 范围的灵敏度限制,可能无法测量 DR 测试期间植入物内部残留的聚合物降解物(低聚物和/或单体)的痕量。以前曾有人使用 qNMR 测量地塞米松微植入物的 PLGA 残余重量并进行外部校准,但这些测量方法并没有考虑到药物释放测试期间 PLGA 植入物的化学结构变化(即 LA 与 GA 的比率从零时开始的变化)。在此,我们开发了一种带有内标的 qNMR 方法,用于监测药物释放测试过程中微型植入物的以下变化:1.剩余的 PLA/PLGA 总质量。2.2. 剩余乳酸(LA)、乙醇酸(GA)单元和 PLGA 的十二烷基酯端基百分比。3.植入物中保留的作为降解物的 PLA/PLGA 低聚物的痕量含量。与微量天平分析不同,qNMR 不仅对药物物质、辅料聚合物具有特异性,而且由于在样品制备过程中植入物损失极少,因此准确性很高。与侵蚀研究中通常监测的 PLA/PLGA 整体剩余质量相比,LA、GA 和酯末端基团的剩余百分比能提供更多有关 PLA/PLGA 微观结构变化(如疏水性)的信息。此外,qNMR 方法还可以补充 GPC 方法,测量溴莫尼定植入物中剩余 PLA 和 PLGA 低聚物浓度的变化,样品量减少十倍,且无截留分子量。qNMR 方法可作为聚合物辅料表征和溴莫尼定植入物侵蚀动力学研究的灵敏工具。
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引用次数: 0
An Unexpected Degradation Pathway of N-Hydroxy-5-Methylfuran-2-Sulfonamide (BMS-986231), a pH Sensitive Prodrug of HNO, in a Prototype Formulation Solution. N-羟基-5-甲基呋喃-2-磺酰胺(BMS-986231)(一种对 pH 值敏感的 HNO 原药)在原型制剂溶液中的意外降解途径。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-08-30 DOI: 10.1016/j.xphs.2024.08.027
Yande Huang, Amy Sarjeant, Roger Sommer, Dhaval Patel, Qinggang Wang, Dilbir Bindra, Scott A Miller

N-hydroxy-5-methylfuran-2-sulfonamide (BMS-986231, Cimlanod) was being developed as a pH-sensitive prodrug of HNO (nitroxyl) for the treatment of acute decompensated heart failure. During a stressed study of Cimlanod in a prototype formulation solution (pH 4.5) at 40°C, a predominant unknown degradant along with three previously identified degradants were observed. The unknown degradant was isolated from the stressed solution via preparative HPLC but totally decomposed during freeze-drying. LC-HRMS analysis of the isolated unknown degradant, prior to freeze-drying, revealed an empirical formula equivalent to the adduct of Cimlanod with SO2 even though SO2 was not added in the prototype formulation solution. The unknown degradant was synthesized from Cimlanod and DABSO ((1,4-diazabiscyclo[2,2,2]octane bis(sulfur dioxide) adduct) and isolated as a crystalline DABCO (1,4-diazabiscyclo[2,2,2]octane) salt for single crystal X-ray structure elucidation. The degradation of Cimlanod increased when the solution was exposed to air, as compared to N2 atmosphere. A plausible mechanism was postulated for the unexpected degradation pathway of Cimlanod. This study provided in-depth stability knowledge of Cimlanod, which will be beneficial to the subsequent stability indicating method development and validation as well as the registrational applications on the content and qualification of impurities in new drug products.

N-羟基-5-甲基呋喃-2-磺酰胺(BMS-986231,Cimlanod)是一种对 pH 值敏感的硝化氢原药,用于治疗急性失代偿性心力衰竭。在对 40°C 下原型制剂溶液(pH 值为 4.5)中的 Cimlanod 进行压力研究期间,观察到了一种主要的未知降解剂和三种先前确定的降解剂。通过制备型 HPLC 从受压溶液中分离出了未知降解剂,但在冷冻干燥过程中完全分解。对冷冻干燥前分离出的未知降解剂进行的 LC-HRMS 分析表明,尽管原型配方溶液中没有添加二氧化硫,但其经验公式相当于辛拉诺与二氧化硫的加合物。未知降解剂是由辛拉诺和 DABSO(1,4-二氮杂双环[2,2,2]辛烷二(二氧化硫)加合物)合成的,并分离出结晶的 DABCO(1,4-二氮杂双环[2,2,2]辛烷)盐,用于单晶 X 射线结构解析。与氮气环境相比,当溶液暴露在空气中时,辛辣诺的降解速度加快。研究人员推测了辛辣诺意外降解的合理机制。这项研究提供了关于辛辣诺稳定性的深入知识,有利于后续稳定性指示方法的开发和验证,以及新药中杂质含量和合格性的注册应用。
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引用次数: 0
Synthesis of Thiomer/Nanoclay Nanocomposites as a Potential Drug Carrier: Evaluation of Mucoadhesive and Controlled Release Properties. 作为潜在药物载体的硫代物/纳米黏土纳米复合材料的合成:黏附性和控释性能评估
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-08-30 DOI: 10.1016/j.xphs.2024.08.030
Alexander Sepúlveda-Córdova, Tomás Fernández-Martínez, Víctor H Campos-Requena

Novel thiomer/nanoclay nanocomposites based on a thiomer and montmorillonite (MMT) were prepared in order to obtain a mucoadhesive material with controlled release properties for its potential use as drug carrier. The thiomer was synthesized by immobilization of L-cysteine in alginate mediated by carbodiimide reaction and further characterized by FT-IR and Ellman's reaction. Nanocomposites with growing concentrations of thiomer and MMT were prepared and analyzed by XRD, TGA and TEM. Rheological behavior of nanocomposite in contact with mucin and intestinal mucus were studied as in vitro and in situ mucoadhesion approach, showing until ∼10-fold increasing in the complex viscosity and ∼27-fold in elastic modulus when the amount of thiomer is increased. Higuchi and Korsmeyer-Peppas kinetic models were evaluated in order to study the release of deltamethrin from nanocomposite films. Release profiles showed a retard in the migration of the drug influenced by the amount of MMT (P < 0.05). Diffusion coefficient (D) showed a significant decrease (P < 0.0001) when concentration of MMT is increased reaching D = 4.18 × 10-7 m2 h-1, which resulted ∼7-fold lower in comparison with formulation without MMT. This hybrid nanocomposite can be projected as a potential mucoadhesive drug carrier with controlled release properties.

为了获得一种具有控释特性的粘液粘附材料并将其用作潜在的药物载体,本研究制备了基于硫代物和蒙脱石(MMT)的新型硫代物/纳米粘土纳米复合材料。硫代物是通过碳二亚胺反应将 L-半胱氨酸固定在海藻酸盐中合成的,并通过傅立叶变换红外光谱和埃尔曼反应对其进行了进一步表征。制备了硫代物和 MMT 浓度不断增加的纳米复合材料,并通过 XRD、TGA 和 TEM 进行了分析。研究了纳米复合材料与粘蛋白和肠粘液接触时的流变学行为,结果表明,当硫单体的用量增加时,复合粘度增加 10 倍,弹性模量增加 27 倍。为了研究溴氰菊酯从纳米复合薄膜中的释放,对 Higuchi 和 Korsmeyer-Peppas 动力学模型进行了评估。释放曲线显示,药物的迁移速度受 MMT 含量的影响而减慢(P < 0.05)。当 MMT 的浓度增加时,扩散系数(D)显著降低(P < 0.0001),达到 D = 4.18 × 10-7 m2 h-1,与不含 MMT 的配方相比降低了 7 倍。这种混合纳米复合材料有望成为一种具有控释特性的粘液粘附药物载体。
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引用次数: 0
Brain Targeting of Venlafaxine via Intranasal Transbilosomes Thermogel for Improved Management of Depressive Disorder. 通过鼻内透纤体热凝胶实现文拉法辛的脑靶向治疗,从而改善抑郁症的治疗。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-08-30 DOI: 10.1016/j.xphs.2024.08.026
Omar A Alsaidan, Mohammed H Elkomy, Randa Mohammed Zaki, Alaa S Tulbah, Rehab Mohammad Yusif, Hussein M Eid

The current research aimed to design and optimize hyaluronic acid-coated transbilosomes containing venlafaxine (VLF-HA-TBLs) for nose-to-brain delivery for improved management of depressive disorder. Venlafaxine-loaded transbilosomes (VLF-TBLs) were developed according to the film hydration procedure, optimized for maximum efficiency using the quality by design-based Box-Behnken design (BBD), and then coated with hyaluronic acid (HA). The optimized VLF-HA-TBLs were subjected to in vitro characterization, integrated into a thermolabile gel, and then exposed to in vivo evaluation studies. The results revealed that the VLF-HA-TBLs formulation exhibited acceptable size (185.6 ± 4.9 nm), surface charge (-39.8 ± 1.7 mV), and entrapment efficiency (69.6 ± 2.6 %). The morphological study revealed that nanovesicles were spherical and displayed a consistent size distribution without particle aggregation. It also showed improved ex vivo nasal diffusion and a prolonged release profile. In addition, the formulated VLF-HA-TBLs were stable under the studied conditions and tolerable when applied intranasally. Compared to the intranasal administration of VLF solution (VLF-SOL), the biodistribution analysis showed that VLF-HA-TBLs delivered intranasally had a relative bioavailability of 441 % in the brain and 288 % in plasma. Moreover, the intranasal delivery of VLF-HA-TBLs demonstrated much higher bioavailability (512 %) in the brain compared to VLF-SOL administered intravenously. Collectively, it could be possible to infer that HA-TBLs might be an effective nanocarrier to administer VLF to the brain via the nasal route.

目前的研究旨在设计和优化含有文拉法辛的透明质酸涂层经纤体(VLF-HA-TBLs),用于鼻脑给药,改善抑郁症的治疗。根据薄膜水合过程开发出了文拉法辛负载型反式螺旋体(VLF-TBLs),并利用基于设计的盒-贝肯设计(BBD)方法对其进行了优化,以实现最高效率,然后在其表面涂上透明质酸(HA)。对优化后的 VLF-HA-TBLs 进行了体外表征,将其整合到热稳定凝胶中,然后进行了体内评估研究。结果表明,VLF-HA-TBLs 制剂具有可接受的尺寸(185.6±4.9 nm)、表面电荷(-39.8±1.7 mV)和夹持效率(69.6±2.6%)。形态学研究显示,纳米微粒呈球形,大小分布一致,无颗粒聚集。它还显示出较好的体内鼻腔扩散性和较长的释放曲线。此外,配制的 VLF-HA-TBLs 在研究条件下是稳定的,鼻内使用时也是可耐受的。与VLF溶液(VLF-SOL)鼻内给药相比,生物分布分析表明,VLF-HA-TBLs鼻内给药在大脑中的相对生物利用率为441%,在血浆中的生物利用率为288%。此外,与静脉注射 VLF-SOL 相比,鼻内给药的 VLF-HA-TBLs 在大脑中的生物利用率要高得多(512%)。综上所述,可以推断HA-TBLs可能是一种有效的纳米载体,可通过鼻腔途径将VLF注入大脑。
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引用次数: 0
A New Ciprofibrate Calcium Salt with Improved Solubility and Intrinsic Dissolution Rate. 一种新的环丙贝特钙盐,其溶解度和内在溶解速率均有所提高。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-08-29 DOI: 10.1016/j.xphs.2024.08.025
Bruno Arantes Borges, Kassius de Souza Reis, Camila Batista Pinto, Javier Ellena, Antônio Carlos Doriguetto, Rudy Bonfilio

Ciprofibrate (CIP) is an active pharmaceutical ingredient (API) classified as class II on the basis of biopharmaceutical classification system (BCS), what indicates that it has low solubility in aqueous solvents. The use of API salts has attracted attention due to their improvements in solubility, tolerability, higher rate and extent of absorption, and faster onset of the therapeutic effect. In this work, a new crystalline CIP monohydrated calcium salt (Ca(CIP)2.H2O) was successfully obtained and its crystal structure determined by single crystal X-ray diffraction analysis (SCXRD). Additionally, Ca(CIP)2.H2O was widely characterized by powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and submitted to solubility, intrinsic dissolution and accelerated stability studies. Ca(CIP)2.H2O exhibited higher solubility and dissolution rate than CIP-free form and was stable up to 6 months at 40 °C (75 %RH). Therefore, Ca(CIP)2.H2O may be a viable alternative for use in solid dosage forms.

环丙贝特(CIP)是一种活性药物成分(API),根据生物制药分类系统(BCS)被归为第二类,这表明它在水性溶剂中的溶解度较低。由于原料药盐具有更好的溶解性、耐受性、更高的吸收率和吸收范围以及更快的治疗效果,其使用已引起人们的关注。在这项研究中,我们成功获得了一种新型结晶的 CIP 一水钙盐 (Ca(CIP)2.H2O),并通过单晶 X 射线衍射分析 (SCXRD) 确定了其晶体结构。此外,还通过粉末 X 射线衍射 (PXRD)、傅立叶变换红外光谱 (FTIR)、差示扫描量热法 (DSC)、热重分析 (TGA) 对 Ca(CIP)2.H2O 进行了广泛表征,并对其进行了溶解度、内在溶解度和加速稳定性研究。与不含 CIP 的形式相比,Ca(CIP)2.H2O 表现出更高的溶解度和溶解速率,并且在 40°C (75%RH)条件下可稳定长达 6 个月。因此,Ca(CIP)2.H2O 可以作为固体制剂的一种可行替代品。
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Journal of pharmaceutical sciences
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