AAPS PharmSciTech最新文献_第3页

Demystifying the Potential of Embelin-Loaded Nanoformulations: a Comprehensive Review 解密栓皮肽载体纳米制剂的潜力：全面综述

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-10-21 DOI: 10.1208/s12249-024-02968-7

Layba Noor, Abdul Hafeez, Md. Azizur Rahman, Km Khushboo Vishwakarma, Archita Kapoor, Nargis Ara, Rabia Aqeel

Phytoconstituent based therapies have the potential to reduce the adverse effects and enhance overall patient compliance for different diseased conditions. Embelin (EMB) is a natural compound extracted from Embelia ribes that has demonstrated high therapeutic potential, particularly as anti-inflammatory and anticancer therapeutic applications. However, its poor water solubility and low oral bioavailability limitations make it challenging to use in biomedical applications. Nanostructure-based novel formulations have shown the potential to improve physicochemical and biological characteristics of active pharmaceutical ingredients obtained from plants. Different nanoformulations that have been utilized to encapsulate/entrap EMB for various therapeutic applications are nanoliposomes, nanostructured lipid carriers, niosomes, polymeric nanoparticles, nanosuspensions, phytosomes, self nanoemulsifying drug delivery system, silver nanoparticles, microparticles, solid lipid nanoparticle, gold nanoparticles and nanomicelles. The common methods reported for the preparation of EMB nanoformulations are thin film hydration, nanoprecipitation, ethanol injection, emulsification followed by sonication. The size of nanoformulations ranged in between 50 and 345 nm. In this review, the mentioned EMB loaded nanocarriers are methodically discussed for size, shape, drug entrapment, zeta potential, in vitro release & permeation and in vivo studies. Potential of EMB with other drugs (dual drug approach) incorporated in nanocarriers are also discussed (physicochemical and preclinical characteristics). Patents related to EMB nanoformulations are also presented which showed the clinical translation of this bioactive for future utilization in different indications.

Graphical Abstract

以植物成分为基础的疗法有可能减少不良反应，提高患者对不同疾病的总体依从性。恩贝林（EMB）是一种从恩贝利中提取的天然化合物，已被证明具有很高的治疗潜力，特别是在抗炎和抗癌治疗方面的应用。然而，由于其水溶性差、口服生物利用度低等限制，使其在生物医学应用中面临挑战。基于纳米结构的新型制剂已显示出改善从植物中提取的活性药物成分的理化和生物特性的潜力。不同的纳米制剂已被用来封装/诱捕 EMB，用于各种治疗应用，这些制剂包括纳米脂质体、纳米结构脂质载体、niosomes、聚合物纳米颗粒、纳米悬浮剂、植物载体、自纳米乳化给药系统、银纳米颗粒、微粒、固体脂质纳米颗粒、金纳米颗粒和纳米细胞。据报道，制备 EMB 纳米制剂的常用方法有薄膜水合法、纳米沉淀法、乙醇注射法、超声乳化法。纳米制剂的尺寸在 50 至 345 纳米之间。在这篇综述中，将对上述 EMB 负载纳米载体的尺寸、形状、药物夹持、ZETA 电位、体外释放&amp、渗透和体内研究进行系统讨论。此外，还讨论了 EMB 与其他药物（双药疗法）结合到纳米载体中的潜力（物理化学和临床前特性）。此外，还介绍了与 EMB 纳米制剂有关的专利，这些专利显示了这种生物活性物质未来在不同适应症中的临床应用。

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引用次数: 0

Effect of Liquid Load Level and Binder Type on the Tabletability of Mesoporous Silica Based Liquisolids 液体装载量和粘合剂类型对介孔二氧化硅基胶凝剂片剂性的影响

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-10-21 DOI: 10.1208/s12249-024-02958-9

Jan Appelhaus, Kristina E. Steffens, Karl G. Wagner

Mesoporous silica offers an easy way to transform liquids into solids, due to their high loading capacity for liquid or dissolved active ingredients and the resulting enhanced dissolution properties. However, the compression of both unloaded and loaded mesoporous silica bulk material into tablets is challenging, due to poor/non-existing binding capacity. This becomes critical when high drug loads are to be achieved and the fraction of additional excipients in the final tablet formulation needs to be kept at a minimum. Our study aimed to investigate the mechanism of compression and tabletability dependent on the Liquid Load Level of the silica and type of filler/binder in binary tabletting mixtures. To this end, Vivapur® 101, FlowLac® 90, Pearlitol® 200 SD and tricalcium citrate tetrahydrate were selected and mixed with Syloid® XDP 3050 at various Liquid Load Levels. Compaction characteristics were analysed using the StylOne® Classic 105 ML compaction simulator. Additionally, the Overall Liquid Load (OLL) was defined as a new critical quality attribute for liquisolid tablets. The Overall Liquid Load allows straightforward, formulation-relevant comparisons between various fillers/binders, liquid components, and silica types. Results indicate strong binding capacity and high plasticity of the fillers/binders as key components for successful high liquid load silica tablet formulation. A volumetric combination of 30% Vivapur® 101 and 70% 0.75 mL/g loaded Syloid® XDP 3050 proved to be the most effective mixture, achieving an Overall Liquid Load of 36–41% [v/v] and maintaining a tensile strength of 1.5 N/mm² with various liquid vehicles.

Graphical Abstract

介孔二氧化硅对液体或溶解的活性成分具有很高的负载能力，并能提高溶解性能，因此是一种将液体转化为固体的简便方法。然而，由于结合能力差/不存在结合能力，将未负载和负载介孔二氧化硅散装材料压缩成片剂具有挑战性。当需要实现高药物载量，并且需要将最终片剂配方中的额外辅料成分保持在最低水平时，这一点就变得至关重要。我们的研究旨在探究二元压片混合物中二氧化硅的液体负荷水平和填料/粘合剂类型对压缩和压片性的影响机制。为此，我们选择了 Vivapur® 101、FlowLac® 90、Pearlitol® 200 SD 和柠檬酸三钙（四水合物），并在不同的液体负载水平下与 Syloid® XDP 3050 混合。使用 StylOne® Classic 105 ML 压实模拟器分析了压实特性。此外，总体液体负荷（OLL）被定义为液态固体片剂的新关键质量属性。通过总液体负荷，可以对各种填料/粘合剂、液体成分和二氧化硅类型进行直接的、与配方相关的比较。结果表明，填料/粘合剂的强结合能力和高可塑性是成功配制高液体负荷二氧化硅片剂的关键因素。30% Vivapur® 101 和 70% 0.75 mL/g 负载 Syloid® XDP 3050 的体积组合被证明是最有效的混合物，可实现 36-41% [v/v] 的总体液体负载，并在使用各种液体载体时保持 1.5 N/mm2 的拉伸强度。

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引用次数: 0

Paroxetine Loaded Nanostructured Lipid Carriers Based In-situ Gel for Brain Delivery via Nasal Route for Enhanced Anti-Depressant Effect: In Vitro Prospect and In Vivo Efficacy 基于纳米结构脂质载体的帕罗西汀负载原位凝胶通过鼻腔途径给药大脑以增强抗抑郁效果：体外前景和体内疗效

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-10-21 DOI: 10.1208/s12249-024-02954-z

Kiran Akbar, Masood Ur Rehman, Fawad Ali Shah, Sidra Younas, Jamelah S. Al-Otaibi, Haroon Khan

This study focused on developing a thermosensitive gel with nanostructured lipid carriers (NLCs) loaded with paroxetine (PAR) to enhance the treatment and management of depression via nasal administration. Micro emulsion technique was utilized for the PAR-NLCs preparation. The acetyl alcohol and oleic acid were used in the ratio of 76:24. In the NLCs Tween 40, Span40 and Myrj 52 were used as a surfactant. The NLCs were then added into Poloxamer mixture to get thermosensitive NLCs based gel. Characterization, in vitro and in vivo studies were performed to check the efficiency of formulation in drug delivery. The entrapment efficiency of optimized PAR-NLCs was about 90%. The particle size, zeta potential and PDI were 155 ± 1.4 nm, -25.9 ± 0.5 mV, and 0.12 ± 0.01 respectively. The optimized gel showed a gelling temperature of 31.50 ± 0.50°C and a gelling time of 1 ± 0.12 s with a pH of 6, suitable for nasal administration. The in vitro release assay of PAR-NLC-gel showed a cumulative release of about 59% in the first 6 h after comparison with PAR-NLCs which showed almost 100%release. In vivo studies included forced swim test and tail suspension tests showed significant potential for treating depression when compared to PAR-NLCs. PAR-NLCs and NLCs based gel enhanced the tissue architecture and suppressed the expression of TNF-α in brain cortex from histological and immunohistochemical analysis. PAR- NLCs gel-based delivery system can prove to be an effective delivery system for brain targeting through nose for the better management of depression.

Graphical Abstract

本研究的重点是开发一种载入帕罗西汀（PAR）的纳米结构脂质载体（NLCs）热敏凝胶，通过鼻腔给药加强抑郁症的治疗和管理。制备 PAR-NLCs 时采用了微乳化技术。乙醇和油酸的比例为 76:24。在 NLCs 中使用 Tween 40、Span40 和 Myrj 52 作为表面活性剂。然后将 NLCs 加入 Poloxamer 混合物中，得到基于 NLCs 的热敏凝胶。为了检测配方的给药效率，对其进行了表征、体外和体内研究。优化后的 PAR-NLCs 的夹持效率约为 90%。粒度、ZETA电位和PDI分别为155 ± 1.4 nm、-25.9 ± 0.5 mV和0.12 ± 0.01。优化凝胶的胶凝温度为 31.50 ± 0.50°C，胶凝时间为 1 ± 0.12 秒，pH 值为 6，适合鼻腔给药。PAR-NLC凝胶的体外释放试验显示，与PAR-NLCs相比，PAR-NLCs在前6小时的累积释放率约为59%，而PAR-NLCs的释放率几乎为100%。包括强迫游泳试验和尾悬试验在内的体内研究表明，与 PAR-NLCs 相比，PAR-NLCs 具有治疗抑郁症的显著潜力。通过组织学和免疫组化分析，PAR-NLCs 和基于 NLCs 的凝胶增强了组织结构，抑制了 TNF-α 在大脑皮层的表达。基于PAR-NLCs凝胶的递送系统可被证明是一种通过鼻腔靶向大脑的有效递送系统，能更好地治疗抑郁症。

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引用次数: 0

Systematic Approach in the Development of Chitosan Functionalized Iloperidone Nanoemulsions for Transnasal Delivery, In Vitro and In Vivo Studies 开发用于经鼻给药的壳聚糖功能化伊洛哌酮纳米乳剂的系统方法、体外和体内研究

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-10-21 DOI: 10.1208/s12249-024-02964-x

Niserga D. Sawant, Pratima A. Tatke, Namita D. Desai

Iloperidone, a second-generation USFDA approved antipsychotic and BCS class II drug shows poor oral bioavailability of 28%. The present research deals with optimization of transnasal nanoemulsions of Iloperidone using Design Expert (Version 11) and further surface functionalization with chitosan for potentiating nose to brain delivery. Chitosan functionalized transnasal Iloperidone nanoemulsions were developed using oleic acid, charge inducer, Tween 80, Transcutol HP and chitosan using ultrasonication technique and evaluated. Droplet size, polydispersity index and zeta potential of Iloperidone nanoemulsions was found to be 173 ± 0.5 nm, 0.413 ± 0.2 and − 22.5 ± 0.1 mV while that of chitosan functionalized Iloperidone nanoemulsions was 146.4 ± 0.5 nm, 0.291 ± 0.02 and + 23.6 ± 0.3 mV respectively. Ninhydrin assay, TEM and FTIR studies confirmed surface functionalization of Iloperidone nanoemulsion droplets with chitosan. In vitro release of Iloperidone from nanoemulsions and chitosan functionalized nanoemulsions was 90.41 ± 2.1% and 72.02 ± 0.21% while ex vivo permeation of Iloperidone across goat nasal mucosa was 1270.58 ± 0.023 μg/cm² and 1096.13 ± 0.043 μg/cm² respectively at the end of 8 h. Studies in RPMI 2650 nasal and Neuro2A brain cell line lines indicated safety of chitosan functionalized transnasal Iloperidone nanoemulsions. Studies in Wistar rats showed increased cataleptic effects, reduced cognitive impairment and anxiety-related behaviour with greater brain accumulation indicating promising potential of this approach in nose to brain drug delivery.

伊洛哌酮是美国食品及药物管理局（USFDA）批准的第二代抗精神病药物，也是 BCS 二级药物，其口服生物利用度较低，仅为 28%。本研究利用 Design Expert（第 11 版）对伊哌利酮经鼻纳米乳剂进行了优化，并使用壳聚糖进一步进行表面功能化，以增强从鼻腔到大脑的给药效果。使用油酸、电荷诱导剂、吐温 80、Transcutol HP 和壳聚糖，利用超声波技术开发了壳聚糖功能化的经鼻伊洛哌酮纳米乳剂，并进行了评估。伊洛哌酮纳米乳液的液滴尺寸、多分散指数和 zeta 电位分别为 173 ± 0.5 nm、0.413 ± 0.2 和 - 22.5 ± 0.1 mV，而壳聚糖功能化伊洛哌酮纳米乳液的液滴尺寸、多分散指数和 zeta 电位分别为 146.4 ± 0.5 nm、0.291 ± 0.02 和 + 23.6 ± 0.3 mV。茚三酮测定、TEM 和傅立叶变换红外光谱研究证实了壳聚糖对伊洛哌酮纳米乳液液滴的表面功能化作用。伊洛哌酮从纳米乳液和壳聚糖功能化纳米乳液中的体外释放率分别为 90.41 ± 2.1% 和 72.02 ± 0.21%，而伊洛哌酮在山羊鼻粘膜中的体外渗透率为 1270.58 ± 0.在 RPMI 2650 鼻腔和 Neuro2A 脑细胞系中进行的研究表明，壳聚糖功能化伊洛哌酮纳米乳剂具有安全性。在 Wistar 大鼠身上进行的研究显示，催眠效果增强，认知障碍和焦虑相关行为减少，脑内蓄积量增加，表明这种方法在鼻脑给药方面具有广阔的前景。

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引用次数: 0

Self-Nanoemulsifying/ Self-Assembled Cubic Nanoparticles Lyophilized Tablet: A Novel Biphasic Release Approach to Enhance the Bioavailability of a Lipophilic Drug 自纳米乳化/自组装立方纳米颗粒冻干片剂：提高亲脂性药物生物利用度的新型双相释放方法

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-10-21 DOI: 10.1208/s12249-024-02952-1

Michael M. Farag, Wessam El-Sebaie, Emad B. Basalious, Omaima N. El-Gazayerly

This study aimed to prepare a combined self-nanoemulsifying and self-assembled cubic nanoparticles (SNE/SAC) lyophilized tablet eliciting biphasic release pattern escorted with enhanced bioavailability for drugs hampered with slow dissolution and poor absorption. The antimuscarinic Darifenacin hydrobromide (DRF) was selected as a model drug used to treat overactive bladder-associated nocturia. The DRF-SNE/SAC lyophilized tablet was prepared so that upon reconstitution a mixture of DRF-loaded cubic nanoparticles and nanoemulsion dispersion is obtained. The nanoemulsion portion is responsible for the fast release followed by controlled release of the remaining dose loaded in cubic nanoparticles. A comparative pharmacokinetic study adopting randomized crossover design in male albino rabbits versus marketed product Frequefenacine® tablet was performed. Half of the dose (52.05% ± 4.21%) was rapidly released in the first 4 h followed by sustained release of the remaining drug where (90.16% ± 8.85%) was released in 24 h. The tested system showed 2.45 folds higher % relative bioavailability and 1.57 folds higher C_max with 1.62 longer residence time relative to reference product. The results endow the ability of the developed DRF-SNE/SAC lyophilized tablet to be considered as a propitious approach for the treatment of overactive bladder-associated nocturia without midnight dose administration.

Graphical Abstract

本研究旨在制备一种自纳米乳化和自组装立方纳米颗粒（SNE/SAC）相结合的冻干片剂，这种片剂具有双相释放模式，并能提高溶解缓慢和吸收不良药物的生物利用度。抗马司卡因药物氢溴酸达非那新（DRF）被选为治疗膀胱过度活动相关性夜尿症的模型药物。制备 DRF-SNE/SAC 冻干片剂的目的是在复溶后获得 DRF 负载立方纳米颗粒和纳米乳液分散体的混合物。纳米乳液部分负责快速释放，然后控制立方纳米颗粒中剩余剂量的释放。研究人员采用随机交叉设计，在雄性白化兔体内进行了一项药代动力学对比研究。一半的剂量（52.05% ± 4.21%）在最初的 4 小时内迅速释放，剩余的药物（90.16% ± 8.85%）在 24 小时内持续释放。与参考产品相比，受试系统的相对生物利用率提高了 2.45 倍，Cmax 提高了 1.57 倍，停留时间延长了 1.62 倍。这些结果表明，所开发的 DRF-SNE/SAC 冻干片剂可被视为治疗膀胱过度活动症相关夜尿的一种有效方法，且无需午夜给药。图解摘要

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引用次数: 0

Development of a Single Vial Mass Flow Rate Monitor to Assess Pharmaceutical Freeze Drying Heterogeneity 开发用于评估药品冷冻干燥异质性的单瓶质量流量监测器

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-10-17 DOI: 10.1208/s12249-024-02961-0

Tiffany Yu, Richard Marx, Michael Hinds, Nicholas Schott, Emily Gong, Seongkyu Yoon, William Kessler

During pharmaceutical lyophilization processes, inter-vial drying heterogeneity remains a significant obstacle. Due to differences in heat and mass transfer based on vial position within the freeze drier, edge vials freeze differently, are typically warmer and dry faster than center vials. This vial position-dependent heterogeneity within the freeze dryer leads to tradeoffs during process development. During primary drying, process developers must be careful to avoid shelf temperatures that would result in overheating of edge vials causing the product sublimation interface temperature to rise above the critical (collapse) temperature. However, at lower shelf temperatures, center vials require longer to complete primary drying, risking collapse or melt-back due to incomplete drying. Both situations may result in poor product quality affecting drug stability, activity, and reconstitution times. We present a new approach for monitoring vial location-specific water vapor mass flow based on Tunable Diode Laser Absorption Spectroscopy (TDLAS). The single vial monitor enables measurement of the gas flow velocity, water vapor temperature, and gas concentration from the sublimating ice, enabling the calculation of the mass flow rate which can be used in combination with a heat and mass transfer model to determine vial heat transfer coefficients and product resistance to drying. These parameters can in turn be used for robust and rapid process development and control.

Graphical Abstract

在药物冻干过程中，药瓶间的干燥异质性仍然是一个重大障碍。由于冷冻干燥机中的药瓶位置不同，传热和传质也不同，因此边缘药瓶的冷冻方式不同，温度通常较高，干燥速度也比中心药瓶快。冷冻干燥机内这种与药瓶位置有关的异质性导致工艺开发过程中的取舍。在初级干燥过程中，工艺开发人员必须注意避免货架温度过高导致边缘小瓶过热，从而使产品升华界面温度高于临界（塌陷）温度。然而，在较低的货架温度下，中心瓶需要更长的时间才能完成初级干燥，从而有可能因干燥不完全而导致塌陷或回熔。这两种情况都可能导致产品质量不佳，影响药物稳定性、活性和复溶时间。我们提出了一种基于可调谐二极管激光吸收光谱（TDLAS）的监测药瓶特定位置水蒸气质量流量的新方法。单瓶监测器可测量升华冰的气体流速、水蒸气温度和气体浓度，从而计算出质量流量，结合传热和传质模型，可确定小瓶传热系数和产品抗干燥性。这些参数反过来又可用于稳健、快速的工艺开发和控制。

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引用次数: 0

Discriminative Power of the Flow through Cell Dissolution Tester in Predicting the In Vivo Performance of Pentoxifylline SR Product under Fed and Fasting Conditions 流过细胞溶出度测试仪在预测五氧去氧肾上腺素 SR 产品在进食和禁食条件下的体内表现方面的鉴别力

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-10-15 DOI: 10.1208/s12249-024-02956-x

Nesrin F. Taha, Laila H. Emara

This study explored, for the first time the role of different designs of the Flow-Through-Cell (FTC, USP IV) dissolution Tester in predicting the in-vivo performance of Pentoxifylline (PTX) sustained-release (SR) market product, under fed & fasting conditions. Release studies of Trental^® SR 400 mg (Sanofi, Egypt), were carried-out in the FTC under different conditions, including: different volumes / compositions of release media, variable FTC flow patterns as well as applying open / closed loop configuration setups. Pharmacokinetic (PK) data, obtained from literature, were converted to in-vivo fraction-absorbed [F_A] using Wagner-Nelson (WN) method. A 1:1 IVIVC was investigated by comparing PTX fraction-dissolved [F_D] under different FTC release designs versus calculated [F_A]. Predicted PK parameters were evaluated, and compared with actual data, with estimation of prediction-error (PE%). The suggested FTC design; a closed-loop setup, with turbulent-flow pattern of the dissolution medium; provided the most acceptable PTX release according to USP labeled limits (USP 27). Also, results showed that PTX release was pronouncedly increased in a finite-volume of gradient-buffer system rather than water, which guarantee complete resemblance to GIT environment. This release design presented the most predictive IVIVC model with PTX in-vivo performance under fasting / fed states, with acceptable PE% values in terms of C_max and AUCs. A suggested FTC design is proposed as an alternative dissolution model in the official USP-monograph for PTX SR products.

Graphical Abstract

本研究首次探讨了在进食和amp; 禁食条件下，不同设计的流通细胞（FTC，USP IV）溶出试验机在预测市场上的戊唑醇缓释（PTX）产品体内性能方面的作用。Trental® SR 400 毫克（赛诺菲，埃及）的释放研究是在 FTC 中不同条件下进行的，包括：不同体积/成分的释放介质、不同的 FTC 流动模式以及开环/闭环配置设置。采用瓦格纳-尼尔森（WN）法将从文献中获得的药代动力学（PK）数据转换为体内吸收率[FA]。通过比较不同 FTC 释放设计下 PTX 的溶出分数[FD]与计算出的[FA]，研究了 1:1 IVIVC。对预测的 PK 参数进行了评估，并与实际数据进行了比较，同时估算了预测误差（PE%）。建议采用的 FTC 设计是闭环设置，溶解介质为湍流模式；根据美国药典（USP）标注的限值（USP 27），该设计提供了最可接受的 PTX 释放量。此外，结果表明，PTX 释放量在有限体积的梯度缓冲体系中比在水中明显增加，这保证了与胃肠道环境的完全相似性。这种释放设计是最能预测 PTX 在空腹/进食状态下体内表现的 IVIVC 模型，在 Cmax 和 AUC 方面具有可接受的 PE% 值。建议将 FTC 设计作为 PTX SR 产品 USP 正式处方集的替代溶出模型。

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引用次数: 0

Effect of Fluid Paraffin on the Formulation Properties of Pressure Sensitive Adhesive Formulations Containing Diclofenac Sodium 液体石蜡对含双氯芬酸钠的压敏胶配方性能的影响

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-10-15 DOI: 10.1208/s12249-024-02959-8

Kaede Osanai, Shunsuke Aoki, Chihiro Otsuka, Hirotaka Watanabe, Haruhiko Hikichi, Takayuki Terukina, Hiromu Kondo

Understanding the relationship between the release characteristics of the active ingredient in the tape formulation and the pharmaceutical characteristics of the adhesive layer can optimize therapeutic efficacy and improve patient adherence. This study aimed to clarify the effect of liquid paraffine (LP)/styrene–isoprene-styrene (SIS) triblock copolymer ratio on pressure-sensitive adhesive (PSA) formulation properties, such as adhesive properties and drug release, with a certain amount of diclofenac sodium (DFS) and tackifier. The effects of changes in PSA composition in DFS-containing tape formulations on adhesive and drug release properties were evaluated. The viscoelasticity results showed rigid gel-like behavior at low angular frequencies regardless of the LP/SIS ratio, and deformable gel-like behavior at high angular frequencies, with a maximum plasticizing effect of LP up to an LP/SIS ratio of 3.7. The peel adhesion test results showed that peel adhesion was not affected, but indicated a decreasing trend by increasing the LP/SIS ratio in the presence of DFS. Drug release test results showed that DFS release increased up to 24 h for LP/SIS ratios of up to 3.7, but decreased when the LP/SIS ratio was 6. The results of the drug permeation tests were similar to those of the drug release tests. In conclusion, it is possible to change the drug release properties by changing the amount of LP in the tape formulation; however, no definitive correlation was found between the adhesive and drug release properties.

Graphical Abstract

了解胶带配方中活性成分的释放特性与粘合剂层的药物特性之间的关系可以优化疗效并提高患者的依从性。本研究旨在阐明液态石蜡（LP）/苯乙烯-异戊二烯-苯乙烯（SIS）三嵌段共聚物配比对含有一定量双氯芬酸钠（DFS）和增粘剂的压敏胶（PSA）配方性能（如粘合性能和药物释放）的影响。评估了含 DFS 胶带配方中 PSA 成分的变化对粘合性能和药物释放性能的影响。粘弹性结果表明，无论 LP/SIS 比为多少，在低角频率下都表现为刚性凝胶状，而在高角频率下则表现为可变形凝胶状，LP 的最大塑化效果可达 LP/SIS 比 3.7。剥离粘附力测试结果表明，剥离粘附力未受影响，但在有 DFS 的情况下，随着 LP/SIS 比的增加，剥离粘附力呈下降趋势。药物释放测试结果表明，当 LP/SIS 比率为 3.7 时，DFS 的释放时间最长可达 24 小时，但当 LP/SIS 比率为 6 时，DFS 的释放时间则有所减少。总之，可以通过改变胶带配方中的 LP 含量来改变药物释放性能；但在粘合剂和药物释放性能之间没有发现明确的相关性。

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引用次数: 0

Moxifloxacin HCl -loaded Cellulose Acetate Butylate In Situ Forming Gel for Periodontitis Treatment 用于治疗牙周炎的盐酸莫西沙星醋酸纤维素丁酯原位成形凝胶

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-10-14 DOI: 10.1208/s12249-024-02960-1

Warakon Thammasut, Catleya Rojviriya, Pornsit Chaiya, Thawatchai Phaechamud, Sucharat Limsitthichaikoon

Periodontitis presents significant treatment challenges due to its complexity and potential complications. In response, an in situ forming gel (ISG) loaded with moxifloxacin HCl (Mx) and cellulose acetate butyrate (CAB) was developed for targeted periodontitis therapy. Mx-loaded 10–45% CAB-based ISGs were developed, and their physicochemical properties such as rheology, viscosity, contact angle, gel morphology and gel formation, interface interaction were investigated. Moreover, the formulation performance studies including drug release and kinetics, in vitro degradation, and antimicrobial activities were also evaluated. The Mx-loaded ISGs containing 25–45% CAB demonstrated rapid matrix formation in both macroscopic and microscopic examinations and presented plastic deformation matrix. Tracking with sodium fluorescein and Nile red fluorescence probes indicated delayed solvent movement owing to CAB matrix formation. Adequate CAB content sustained Mx release for one week, following Peppas-Sahlin model and indicating a predominantly Fickian diffusion mechanism. Higher CAB content likely contributed to a denser matrix structure, leading to a slower in vitro degradation rate. Synchrotron radiation X-ray tomographic and SEM imaging provided insights into the CAB matrix structure and porous network formation. These ISG formulations effectively inhibited Staphylococcus aureus, Escherichia coli, Candida albicans, and Porphyromonas gingivalis. The Mx-loaded 40% CAB-based ISG shows promise as a dosage form for treating periodontitis. Further clinical trials are necessary to ensure the safety of this new ISG formulation, despite existing safety data for other medicinal uses of CAB.

牙周炎因其复杂性和潜在并发症给治疗带来了巨大挑战。为此，我们开发了一种负载盐酸莫西沙星（Mx）和醋酸丁酸纤维素（CAB）的原位成型凝胶（ISG），用于牙周炎的靶向治疗。研究人员开发了含盐酸莫西沙星（Mx）和醋酸纤维素丁酸酯（CAB）的 ISG，并对其流变学、粘度、接触角、凝胶形态和凝胶形成、界面相互作用等理化性质进行了研究。此外，还评估了药物释放和动力学、体外降解和抗菌活性等制剂性能研究。含有 25-45% CAB 的 Mx 负载 ISGs 在宏观和微观检查中都显示出基质的快速形成，并呈现出塑性变形基质。荧光素钠和尼罗河红荧光探针的跟踪显示，CAB基质的形成延迟了溶剂的移动。根据 Peppas-Sahlin 模型，充足的 CAB 含量可使 Mx 的释放持续一周，这表明主要是一种 Fickian 扩散机制。CAB 含量越高，基质结构越致密，体外降解速度越慢。同步辐射 X 射线断层扫描和扫描电子显微镜成像深入揭示了 CAB 的基质结构和多孔网络的形成。这些 ISG 配方能有效抑制金黄色葡萄球菌、大肠杆菌、白色念珠菌和牙龈卟啉单胞菌。以 Mx 为载体、40% CAB 为基质的 ISG 作为治疗牙周炎的剂型前景广阔。尽管已有 CAB 其他药用用途的安全数据，但仍有必要进行进一步的临床试验，以确保这种新型 ISG 制剂的安全性。

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引用次数: 0

Surfactant-Assisted Wet Granulation-Based Matrix Tablets without Exceptional Additives: Prolonging Systemic Exposure of Model BCS Class II Ketoprofen 无特殊添加剂的表面活性剂辅助湿法造粒基质片剂：延长模型 BCS II 级酮洛芬的全身暴露时间

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-10-14 DOI: 10.1208/s12249-024-02966-9

Rahat Shamim, Sana Shafique, Khalid Hussain, Nasir Abbas, Sana Ijaz, Nadeem Irfan Bukhari

The present study was aimed to ameliorate the issue of solubility and thereby, bioavailability of ketoprofen, a BCS Class II drug. The sustained release matrix tablets (MT) were prepared using surfactant-assisted wet granulation (SAWG) with 1–5% of different surfactants. The tablet characteristics were within the compendial limits. The selected sustained release-compliant matrix tablet formulation containing granules prepared using 3% Soluplus® (MT2) released the drug by swelling-erosion. In human volunteers, MT2 attained the maximum plasma concentration (C_max) of 5.72µg /ml ± 0.30 h, time to C_max (T_max) of 5.56 ± 0.30 h and maintained the plasma concentration above its minimum effective concentration (MEC), 0.7 µg.ml⁻¹ till 24h. A control formulation, prepared from granules without surfactant (MT16), promptly attained C_max of 9.62 ± 0.76 µg/ml within 1h but rapidly declined to below MEC in 8h. Area under the curve from initial point to infinity (AUC_0-∞) of MT2 (78.65 ± 7.64 µg.h.ml⁻¹) was 2.29 folds higher than 34.39 ± 3.06 µg.h.ml⁻¹ of MT16. With decreased C_max, increased AUC_0-∞, delayed T_max and retained ketoprofen concentration above MEC for longer time, MT2 corresponded with the in-vitro sustained drug release characteristic. There is a likelihood of administration of once-a-day single dose of MT2 without plasma fluctuations, expected from two doses of MT16. SAWG helped developing a swellable-erodible sustained release matrix tablet formulation of ketoprofen with the desired biopharmaceutical and pharmacokinetics properties, merely by addition of Soluplus® in granules and without incorporation of any special ingredients or the major manipulation of the formulative ingredients in the formulation.

Graphical Abstract

本研究旨在改善BCS二类药物酮洛芬的溶解度问题，从而提高其生物利用度。本研究采用表面活性剂辅助湿法制粒法（SAWG）制备了含有 1-5% 不同表面活性剂的缓释基质片（MT）。片剂特性符合药典限制。所选的符合缓释标准的基质片剂含有使用 3% Soluplus® 制备的颗粒（MT2），通过膨胀-侵蚀释放药物。在人体志愿者体内，MT2 的最大血浆浓度（Cmax）为 5.72µg /ml ± 0.30 小时，达到 Cmax 的时间（Tmax）为 5.56 ± 0.30 小时，并将血浆浓度维持在最低有效浓度（MEC）（0.7 µg.ml-1）以上直至 24 小时。由不含表面活性剂的颗粒制备的对照制剂（MT16）在 1 小时内迅速达到 9.62 ± 0.76 µg/ml 的 Cmax，但在 8 小时内迅速降至 MEC 以下。MT2 从起始点到无穷远的曲线下面积（AUC0-∞）（78.65 ± 7.64 µg.h.ml-1）比 MT16 的 34.39 ± 3.06 µg.h.ml-1 高 2.29 倍。MT2 的 Cmax 值降低，AUC0-∞ 值升高，Tmax 值延迟，酮洛芬浓度高于 MEC 的时间延长，符合体外持续释药的特点。MT2 每日单次给药可能不会出现 MT16 两次给药时出现的血浆波动。SAWG 帮助开发了一种具有理想生物制药和药代动力学特性的酮洛芬可膨胀缓释基质片剂，只需在颗粒剂中添加 Soluplus®，而无需加入任何特殊成分或对制剂中的配方成分进行重大调整。

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引用次数: 0