AAPS PharmSciTech最新文献_第7页

Concomitant Delivery of Pirarubicin and Salinomycin Synergistically Enhanced the Efficacy of Cancer Therapy and Reduced the Risk of Cancer Relapse 吡柔比星和盐霉素同时给药可协同增强癌症疗效并降低癌症复发风险

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-09-07 DOI: 10.1208/s12249-024-02918-3

Mohd Anees, Priya Gupta, Harshdeep Kaur, Surender Kharbanda, Harpal Singh

Pirarubicin attracted considerable attention in clinical studies because of its high therapeutic efficacy and reduced toxicity in comparison with other anthracyclines. Nevertheless, ~ 30% patients undergoing PIRA treatment still experience relapse and metastasis. Clinical advancements unveiled that cancer stem cells (CSCs) residing in the tumor constitutes a major factor for such limitations and subsequently are the reason for treatment failure. Consequently, eradicating CSCs alongside bulk tumor is a crucial undertaking to attain utmost therapeutic efficacy of the treatment. Nevertheless, majority of the CSCs inhibitors currently under examination lack specificity, show unsynchronized bioavailability with other primary treatments and exhibit notable toxicity in their therapeutic applications, which is primarily attributable to their inadequate tumor-targeting capabilities. Therefore, we have developed a biodegradable polylactic acid based blend block copolymeric NPs for concomitant delivery of CSCs inhibitor Salinomycin (SAL) & chemotherapeutic drug Pirarubicin (PIRA) with an aim to improve the efficacy of treatment and prevent cancer relapse. Prepared NPs showed < 100 nm size and excellent loading with sustained release for both the drugs. Also, PIRA:SAL co-loaded NPs exhibits synergistically enhanced cytotoxicity against cancer cell as well as CSCs. Most importantly, NPs mediated co-delivery of the drugs showed complete tumor eradication, without any reoccurrence throughout the surveillance period. Additionally, NPs treatment didn’t show any histopathological alteration in vital organs confirming their non-toxic nature. Altogether, present study concludes that the developed PIRA:SAL NPs have excellent efficacy for tumor regression as well as prevention of cancer relapse, hence can be used as a potential combination therapy for cancer treatment.

Graphical abstract

与其他蒽环类药物相比，吡柔比星具有疗效高、毒性低的特点，因此在临床研究中备受关注。然而，约 30% 接受 PIRA 治疗的患者仍会出现复发和转移。临床研究发现，肿瘤中的癌症干细胞（CSCs）是造成这种限制的主要因素，也是治疗失败的原因。因此，要获得最佳疗效，根除肿瘤干细胞是一项至关重要的工作。然而，目前研究的大多数 CSCs 抑制剂缺乏特异性，生物利用度与其他主要治疗方法不同步，在治疗应用中表现出明显的毒性，这主要归因于它们的肿瘤靶向能力不足。因此，我们开发了一种可生物降解的聚乳酸基混合嵌段共聚物 NPs，用于同时递送 CSCs 抑制剂 Salinomycin (SAL) 和化疗药物 Pirarubicin (PIRA)，以提高疗效并防止癌症复发。制备的 NPs 显示

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引用次数: 0

Development and Evaluation of Solidified Supersaturated SNEDDS Loaded with Triple Combination Therapy for Metabolic Syndrome 开发和评估装载三联疗法的固化过饱和 SNEDDS，用于治疗代谢综合征。

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-09-06 DOI: 10.1208/s12249-024-02928-1

Abdelrahman Y. Sherif, Doaa Hasan Alshora, Mohamed Abbas Ibrahim, Adel Jreebi

The present study aimed to develop and optimize solidified supersaturated self-nanoemulsifying drug delivery systems (SNEDDS) for the combined administration of antihypertensive, antihyperglycemic, and antihyperlipidemic drugs to enhance their solubility and dissolution during the treatment of metabolic syndrome. Various SNEDDS formulations were prepared and subjected to pharmaceutical assessment. The solubility of candesartan (CC), glibenclamide (GB), and rosuvastatin (RC) in SNEDDS and supersaturated SNEDDS formulations was evaluated. The optimized formulation was solidified using Syloid adsorbent at different ratios. Pharmaceutical characterization of the formulations included particle size, zeta potential, in-vitro dissolution, PXRD, FTIR, and SEM analysis. The prepared optimized formulation (F₆) was able to form homogeneous nanoemulsion droplets without phase separation, which is composed of Tween 20: PEG-400: Capmul MCM (4: 3: 3). It was mixed with 5% PVP-K30 to prepare a supersaturated liquid SNEDDS formulation (F9). In addition, it was found that the addition of PVP-K30 significantly increased solubility CC and GB from 20.46 ± 0.48 and 6.73 ± 0.05 to 27.67 ± 1.72 and 9.45 ± 0.32 mg/g, respectively. In-vitro dissolution study revealed that liquid and solid SNEDD formulations remarkably improved the dissolution rates of CC, GB, and RC compared to pure drugs. XRPD and FTIR analysis revealed that all drugs present in an amorphous state within prepared solidified supersaturated SNEDDS formulation. SEM images showed that liquid SNEDDS formulation was successfully adsorbed on the surface of Syloid. Overall, optimized F9 and solidified supersaturated SNEDDS formulations showed superior performance in enhancing drug solubility and dissolution rate. The present study revealed that the proposed triple combination therapy of metabolic syndrome holds a promising strategy during the treatment of metabolic syndrome. Further in-vivo studies are required to evaluate the therapeutic efficacy of prepared solidified supersaturated SNEDDS formulation.

Graphical Abstract

本研究旨在开发和优化固化过饱和自纳米乳化给药系统（SNEDDS），用于联合给药抗高血压、抗高血糖和抗高血脂药物，以提高这些药物在治疗代谢综合征期间的溶解度和溶出度。我们制备了各种 SNEDDS 制剂，并对其进行了药物评估。评估了坎地沙坦（CC）、格列本脲（GB）和洛伐他汀（RC）在 SNEDDS 和过饱和 SNEDDS 制剂中的溶解度。优化后的制剂使用 Syloid 吸附剂按不同比例进行固化。制剂的药物表征包括粒度、ZETA电位、体外溶解度、PXRD、FTIR和SEM分析。制备的优化配方（F6）能够形成均匀的纳米乳液液滴，且无相分离现象，其成分为吐温 20：PEG-400：Capmul MCM（4：3：3）。将其与 5% 的 PVP-K30 混合，制备出一种过饱和液体 SNEDDS 配方（F9）。此外，研究还发现，添加 PVP-K30 后，CC 和 GB 的溶解度分别从 20.46 ± 0.48 毫克/克和 6.73 ± 0.05 毫克/克显著提高到 27.67 ± 1.72 毫克/克和 9.45 ± 0.32 毫克/克。体外溶出度研究表明，与纯药相比，液体和固体 SNEDD 制剂显著提高了 CC、GB 和 RC 的溶出率。XRPD 和傅立叶变换红外光谱分析显示，在制备的固态过饱和 SNEDD 配方中，所有药物都呈无定形状态。扫描电镜图像显示，液态 SNEDDS 配方成功吸附在 Syloid 表面。总之，优化的 F9 和固化过饱和 SNEDDS 制剂在提高药物溶解度和溶解速率方面表现优异。本研究表明，所提出的代谢综合征三联疗法是治疗代谢综合征的一种很有前景的策略。要评估固化过饱和 SNEDDS 制剂的疗效，还需要进一步的体内研究。

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引用次数: 0

Skin Penetration and Permeation Properties of Transcutol® in Complex Formulations 复方制剂中 Transcutol® 的皮肤渗透和渗透特性。

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-09-05 DOI: 10.1208/s12249-024-02886-8

Jasmine Musakhanian, David W. Osborne, Jean-David Rodier

Percutaneous delivery is explored as alternative pathway for addressing the drawbacks associated with the oral administration of otherwise efficacious drugs. Short of breaching the skin by physical means, the preference goes to formulation strategies that augment passive diffusion across the skin. One such strategy lies in the use of skin penetration and permeation enhancers notably of hydroxylated solvents like propylene glycol (PG), ethanol (EtOH), and diethylene glycol monoethyl ether (Transcutol^®, TRC). In a previous publication, we focused on the role of Transcutol^® as enhancer in neat or diluted systems. Herein, we explore its’ role in complex formulation systems, including patches, emulsions, vesicles, solid lipid nanoparticles, and micro or nanoemulsions. This review discusses enhancement mechanisms associated with hydroalcoholic solvents in general and TRC in particular, as manifested in multi-component formulation settings alongside other solvents and enhancers. The principles that govern skin penetration and permeation, notably the importance of drug diffusion due to solubilization and thermodynamic activity in the vehicle (formulation), drug solubilization and partitioning in the stratum corneum (SC), and/or solvent drag across the skin into deeper tissue for systemic absorption are discussed. Emphasized also are the interplay between the drug properties, the skin barrier function and the formulation parameters that are key to successful (trans)dermal delivery.

Graphical Abstract

经皮给药是解决口服药物疗效不佳问题的另一种途径。由于无法通过物理方法突破皮肤，人们更倾向于采用能增强皮肤被动扩散的配方策略。其中一种策略就是使用皮肤渗透和渗透促进剂，特别是羟基溶剂，如丙二醇（PG）、乙醇（EtOH）和二甘醇单乙醚（Transcutol®，TRC）。在之前的一篇文章中，我们重点介绍了 Transcutol® 在纯净或稀释体系中作为增强剂的作用。在此，我们将探讨其在复杂配方体系中的作用，包括贴片、乳剂、囊泡、固体脂质纳米颗粒以及微乳或纳米乳剂。本综述讨论了与水醇溶剂尤其是 TRC 相关的增强机制，这些机制在多组分配方中与其他溶剂和增强剂一起发挥作用。本文讨论了皮肤渗透和渗透的基本原理，特别是药物在载体（制剂）中的溶解和热力学活动、药物在角质层（SC）中的溶解和分配以及/或溶剂在皮肤深层组织中的拖曳作用对全身吸收的重要性。此外，还强调了药物特性、皮肤屏障功能和制剂参数之间的相互作用，这些都是成功（经）皮肤给药的关键。

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引用次数: 0

Design and Evaluation of Microemulsion-Based Drug Delivery Systems for Biofilm-Based Infection in Burns 针对烧伤生物膜感染的微乳液给药系统的设计与评估

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-09-05 DOI: 10.1208/s12249-024-02909-4

Avirup Biswas, Jesil Mathew A, Shaila Angela Lewis, Selvaraj Raja, Arpita Paul, Kajal Ghosal, Syed Mahmood, Mohd Danish Ansari

Normal skin is the first line of defense in the human body. A burn injury makes the skin susceptible to bacterial infection, thereby delaying wound healing and ultimately leading to sepsis. The chances of biofilm formation are high in burn wounds due to the presence of avascular necrotic tissue. The most common pathogen to cause burn infection and biofilm is Pseudomonas aeruginosa. The purpose of this study was to create a microemulsion (ME) formulation for topical application to treat bacterial burn infection. In the present study, tea tree oil was used as the oil phase, Tween 80 and transcutol were used as surfactants, and water served as the aqueous phase. Pseudo ternary phase diagrams were used to determine the design space. The ranges of components as suggested by the design were chosen, optimization of the microemulsion was performed, and in vitro drug release was assessed. Based on the characterization studies performed, it was found that the microemulsion were formulated properly, and the particle size obtained was within the desired microemulsion range of 10 to 300 nm. The I release study showed that the microemulsion followed an immediate release profile. The formulation was further tested based on its ability to inhibit biofilm formation and bacterial growth. The prepared microemulsion was capable of inhibiting biofilm formation.

Graphical Abstract

正常皮肤是人体的第一道防线。烧伤使皮肤容易受到细菌感染，从而延迟伤口愈合，最终导致败血症。由于存在无血管坏死组织，烧伤创面形成生物膜的几率很高。引起烧伤感染和生物膜的最常见病原体是铜绿假单胞菌。本研究的目的是创建一种微乳液（ME）配方，用于局部治疗烧伤细菌感染。在本研究中，茶树油被用作油相，吐温 80 和 Transcutol 被用作表面活性剂，水被用作水相。使用伪三元相图来确定设计空间。选择了设计所建议的组分范围，对微乳剂进行了优化，并对体外药物释放进行了评估。根据所进行的表征研究发现，微乳剂的配制是正确的，所获得的粒度在 10 至 300 nm 的理想微乳剂范围内。I 释放研究表明，微乳剂具有立即释放的特性。制剂抑制生物膜形成和细菌生长的能力得到了进一步测试。制备的微乳液能够抑制生物膜的形成。

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引用次数: 0

PLGA Nanoparticles Based Mucoadhesive Nasal In Situ Gel for Enhanced Brain Delivery of Topiramate 基于PLGA纳米颗粒的黏性鼻腔原位凝胶用于增强托吡酯的脑部给药效果

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-09-05 DOI: 10.1208/s12249-024-02917-4

Vidhi Tanna, Amisha Vora, Pranav Shah, Anroop B. Nair, Jigar Shah, Sujata P. Sawarkar

Oral Topiramate therapy is associated with systemic adverse effects including paresthesia,abdominal pain, and fluctuations in plasma levels. The purpose of this research was to develop an intranasal in situ gel based system comprising Topiramate polymeric nanoparticles and evaluate its potential both in vitro and in vivo. Poly (lactic-co-glycolic acid) (PLGA)nanoparticles prepared by nanoprecipitation method were added into the in situ gelling system of Poloxamer 407 and HPMC K4M. Selected formulation (TG5) was evaluated for physicochemical properties, nasal permeation and in vivo pharmacokinetics in rats. PLGAnanoparticles (O1) exhibited low particle size (~ 144.4 nm), good polydispersity index (0.202), negative zeta potential (-12.7 mV), and adequate entrapment efficiency (64.7%). Developed in situ gel showed ideal pH (6.5), good gelling time (35 s), gelling temperature(37℃), suitable viscosity (1335 cP)and drug content of 96.2%. In vitro drug release conformedto Higuchi release kinetics, exhibiting a biphasic pattern of initial burst release and sustained release for 24 h. Oral administration of the drug to Sprague–Dawley rats (G3) showed higher plasma C_max(504 ng/ml, p < 0.0001) when compared to nasal delivery of in situ gel (G4) or solution (G5). Additionally, AUC_0-α of G3 (8786.82 ng/ml*h) was considerably higher than othergroups. Brain uptake data indicates a higher drug level with G4 (112.47 ng /ml) at 12 h when compared to G3. Histopathological examination of groups; G1 (intranasal saline), G2(intranasal placebo), G3, G4, and G5 did not show any lesions of pathological significance. Overall, the experimental results observed were promising and substantiated the potential of developed in situ gel for intranasal delivery.

Graphical Abstract

托吡酯口服治疗与全身不良反应有关，包括麻痹、腹痛和血浆水平波动。本研究旨在开发一种由托吡酯聚合物纳米颗粒组成的鼻内原位凝胶系统，并评估其在体外和体内的潜力。采用纳米沉淀法制备的聚（乳酸-共聚-乙醇酸）（PLGA）纳米粒子被添加到由 Poloxamer 407 和 HPMC K4M 组成的原位凝胶系统中。对所选制剂（TG5）的理化性质、鼻腔渗透性和大鼠体内药代动力学进行了评估。PLGA 纳米粒子（O1）的粒径较小（约 144.4 nm），多分散指数（0.202）良好，ZETA 电位为负值（-12.7 mV），并具有足够的包埋效率（64.7%）。所开发的原位凝胶显示出理想的 pH 值（6.5）、良好的胶凝时间（35 秒）、胶凝温度（37℃）、合适的粘度（1335 cP）和 96.2% 的药物含量。给 Sprague-Dawley 大鼠（G3）口服该药物后，其血浆 Cmax（504 ng/ml，P 0-α，8786.82 ng/ml*h）显著高于其他组别。脑摄取数据表明，与 G3 相比，G4 在 12 小时内的药物水平更高（112.47 纳克/毫升）。对 G1 组（鼻内注射生理盐水）、G2 组（鼻内注射安慰剂）、G3 组、G4 组和 G5 组进行的组织病理学检查未发现任何重要病变。总之，观察到的实验结果很有希望，证明了所开发的原位凝胶在鼻内给药方面的潜力。

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引用次数: 0

Fabrication of Luteolin Nanoemulsion by Box-Behnken Design to Enhance its Oral Absorption Via Lymphatic Transport 利用盒式贝肯设计制造木犀草素纳米乳液，通过淋巴运输增强其口服吸收。

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-09-05 DOI: 10.1208/s12249-024-02898-4

Liangxing Tu, Ju Wang, Yongbing Sun, Yang Wan

Intestinal lymphatic transport offers an alternative and effective way to deliver drugs, such as avoiding first-pass metabolism, enhancing oral bioavailability, and facilitating the treatment of targeted lymphoid-related diseases. However, the clinical use of luteolin (LUT) is limited by its poor water solubility and low bioavailability, and enhancing lymphatic transport by nanoemulsion may be an efficient way to enhance its oral bioavailability. The objective of this work is to prepare the luteolin nanoemulsions (LUT NEs), optimized its preparation parameters by using Box-Behnken design optimization (BBD) and evaluated it in vitro and in vivo. An Caco-2 / Raji B cell co-incubation monolayer model was established to simulate the M-cell pathway, and the differences in the transmembrane transport of LUT and NEs were compared. Cycloheximide (CHX) was utilized to establish rat chylomicron (CM) blocking model, and for investigating the influence of pharmacokinetic parameters in rats thereafter. The results showed that LUT NEs have good stability, the particle sizes were about 23.87 ± 0.57 nm. Compared with LUT suspension, The P_app of LUT NEs was enhanced for 3.5-folds, the oral bioavailability was increased by about 2.97-folds. In addition, after binding with chylomicron, the oral bioavailability of LUT NEs was decreased for about 30% (AUC _0–∞ (μg/L*h): 5.356 ± 1.144 vs 3.753 ± 0.188). These results demonstrated that NEs could enhance the oral absorption of luteolin via lymphatic transport routes.

Graphical Abstract

肠道淋巴转运提供了另一种有效的给药方式，如避免首过代谢、提高口服生物利用度和促进靶向淋巴相关疾病的治疗。然而，由于叶黄素（LUT）的水溶性差、生物利用度低，其临床应用受到限制，而通过纳米乳液增强淋巴转运可能是提高其口服生物利用度的有效方法。本研究的目的是制备木犀草素纳米乳剂（LUT NEs），并通过盒-贝肯优化设计（BBD）对其制备参数进行优化，同时对其进行体外和体内评估。建立了 Caco-2 / Raji B 细胞共孵育单层模型来模拟 M 细胞通路，并比较了 LUT 和 NEs 跨膜转运的差异。利用环己亚胺（CHX）建立大鼠乳糜微粒（CM）阻断模型，并研究其后药代动力学参数对大鼠的影响。结果表明，LUT NEs 具有良好的稳定性，粒径约为 23.87 ± 0.57 nm。与 LUT 悬浮液相比，LUT NEs 的 Papp 提高了 3.5 倍，口服生物利用度提高了约 2.97 倍。此外，与乳糜微粒结合后，LUT NEs 的口服生物利用度降低了约 30%（AUC 0-∞ (μg/L*h)：5.356 ± 1.144 vs 3.753 ± 0.188）。这些结果表明，NEs 可通过淋巴转运途径促进叶黄素的口服吸收。

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引用次数: 0

A Comparative Mathematical Analysis of Drug Release from Lipid-Based Nanoparticles 脂质纳米颗粒药物释放的比较数学分析

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-09-05 DOI: 10.1208/s12249-024-02922-7

Pedram Porbaha, Ramin Ansari, Mohammad Reza Kiafar, Rahman Bashiry, Mohammad Mehdi Khazaei, Amirhossein Dadbakhsh, Amir Azadi

Mathematical modeling of drug release from drug delivery systems is crucial for understanding and optimizing formulations. This research provides a comparative mathematical analysis of drug release from lipid-based nanoparticles. Drug release profiles from various types of lipid nanoparticles, including liposomes, nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), and nano/micro-emulsions (NEMs/MEMs), were extracted from the literature and used to assess the suitability of eight conventional mathematical release models. For each dataset, several metrics were calculated, including the coefficient of determination (R²), adjusted R², the number of errors below certain thresholds (5%, 10%, 12%, and 20%), Akaike information criterion (AIC), regression sum square (RSS), regression mean square (RMS), residual sum of square (rSS), and residual mean square (rMS). The Korsmeyer-Peppas model ranked highest among the evaluated models, with the highest adjusted R² values of 0.95 for NLCs and 0.93 for other liposomal drug delivery systems. The Weibull model ranked second, with adjusted R² values of 0.92 for liposomal systems, 0.94 for SLNs, and 0.82 for NEMs/MEMs. Thus, these two models appear to be more effective in forecasting and characterizing the release of lipid nanoparticle drugs, potentially making them more suitable for upcoming research endeavors.

Graphical Abstract

药物从给药系统中释放的数学模型对于理解和优化配方至关重要。本研究对基于脂质的纳米颗粒的药物释放进行了比较数学分析。研究人员从文献中提取了各种类型脂质纳米颗粒的药物释放曲线，包括脂质体、纳米结构脂质载体（NLCs）、固体脂质纳米颗粒（SLNs）和纳米/微乳（NEMs/MEMs），并用这些曲线评估了八个传统释放数学模型的适用性。对每个数据集都计算了几个指标，包括判定系数 (R2)、调整后的 R2、低于特定阈值（5%、10%、12% 和 20%）的误差数、阿凯克信息准则 (AIC)、回归平方和 (RSS)、回归均方 (RMS)、残差平方和 (rSS) 和残差均方 (rMS)。在评估的模型中，Korsmeyer-Peppas 模型的调整 R2 值最高，NLC 为 0.95，其他脂质体给药系统为 0.93。Weibull 模型排名第二，脂质体系统的调整 R2 值为 0.92，SLN 为 0.94，NEMs/MEMs 为 0.82。因此，这两个模型在预测和表征脂质纳米粒子药物释放方面似乎更有效，可能更适合即将开展的研究工作。

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引用次数: 0

Breaking Barriers in Alzheimer’s Disease: the Role of Advanced Drug Delivery Systems 打破阿尔茨海默病的障碍：先进给药系统的作用。

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-09-05 DOI: 10.1208/s12249-024-02923-6

Devank Shekho, Ritika Mishra, Raj Kamal, Rohit Bhatia, Ankit Awasthi

Alzheimer’s disease (AD), characterized by cognitive impairment, brain plaques, and tangles, is a global health concern affecting millions. It involves the build-up of amyloid-β (Aβ) and tau proteins, the formation of neuritic plaques and neurofibrillary tangles, cholinergic system dysfunction, genetic variations, and mitochondrial dysfunction. Various signaling pathways and metabolic processes are implicated in AD, along with numerous biomarkers used for diagnosis, risk assessment, and research. Despite these, there is no cure or effective treatment for AD. It is critically important to address this immediately to develop novel drug delivery systems (NDDS) capable of targeting the brain and delivering therapeutic agents to modulate the pathological processes of AD. This review summarizes AD, its pathogenesis, related signaling pathways, biomarkers, conventional treatments, the need for NDDS, and their application in AD treatment. It also covers preclinical, clinical, and ongoing trials, patents, and marketed AD formulations.

Graphical Abstract

阿尔茨海默病（AD）以认知障碍、脑斑块和纠结为特征，是影响数百万人的全球性健康问题。它涉及淀粉样蛋白-β（Aβ）和 tau 蛋白的堆积、神经uritic 斑块和神经纤维缠结的形成、胆碱能系统功能障碍、基因变异和线粒体功能障碍。各种信号通路和代谢过程都与注意力缺失症有关，同时还有许多生物标志物用于诊断、风险评估和研究。尽管如此，目前仍无法治愈或有效治疗注意力缺失症。当务之急是立即解决这一问题，开发出新型给药系统 (NDDS)，能够以大脑为靶点，输送治疗药物以调节注意力缺失症的病理过程。本综述概述了AD、其发病机制、相关信号通路、生物标志物、传统治疗方法、对NDDS的需求及其在AD治疗中的应用。它还涵盖了临床前、临床和正在进行的试验、专利和已上市的 AD 制剂。

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引用次数: 0

Design and Evaluation of Inorganic/Organic Hybrid Bio-composite for Site-Specific Oral Delivery of Darifenacin 设计和评估无机/有机混合生物复合材料用于达非那新的特定部位口服给药

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-09-05 DOI: 10.1208/s12249-024-02916-5

Wafa Ishaq, Attia Afzal, Muhammad Farooq, Muhammad Sarfraz, Sherjeel Adnan, Hammad Ahmed, Muhammad Waqas, Zainab Safdar

Benign hyperplasia (BHP) is a common disorder that affects men over the age of 60 years. Transurethral resection of the prostate (TURP) is the gold standard for operative treatment, but a range of drugs are also available to improve quality of life and to reduce BHP-associated urinary tract infections and complications. Darifenacin, an anti-muscarinic agent, has been found effective for relieving symptoms of overactive bladder associated with BHP, but the drug has poor solubility and bioavailability, which are major challenges in product development. An inorganic/organic bio-composite with gastric pH-resistant property was synthesized for the targeted oral delivery of Darifenacin to the lower gastrointestinal tract (GIT). This development was accomplished through co-precipitation of calcium carbonate in quince seed-based mucilage. The FTIR, XRD, DSC, and TGA results showed good drug-polymer compatibility, and the SEM images showed calcite formation in the quince hydrogel system. After 72 h, the drug release of 34% and 75% were observed in acidic (0.1N HCl) and 6.8 pH phosphate buffer, respectively. A restricted/less drug was permeated through gastric membrane (21.8%) as compared to permeation through intestinal membrane (65%.) The developed composite showed significant reduction in testosterone-induced prostatic hyperplasia (2.39 ± 0.12***) as compared to untreated diseased animal group. No sign of organ toxicity was observed against all the developed composites. In this study, we developed an inorganic–organic composite system that is highly biocompatible and effective for targeting the lower GIT, thereby avoiding the first-pass metabolism of darifenacin.

Graphical Abstract

良性前列腺增生（BHP）是影响 60 岁以上男性的常见疾病。经尿道前列腺切除术（TURP）是手术治疗的金标准，但也有一系列药物可改善生活质量，减少与 BHP 相关的尿路感染和并发症。达非那新是一种抗迷走神经抑制剂，对缓解必威体育：相关的膀胱过度活动症状有效，但该药物的溶解性和生物利用度较差，这是产品开发的主要挑战。为了将达非那新口服给药靶向输送到下胃肠道（GIT），我们合成了一种具有抗胃 pH 性能的无机/有机生物复合材料。这一开发是通过在榅桲籽粘液中共沉淀碳酸钙实现的。傅立叶变换红外光谱（FTIR）、X射线衍射（XRD）、DSC和TGA结果表明药物与聚合物具有良好的相容性，扫描电镜图像显示榅桲水凝胶体系中形成了方解石。72 小时后，在酸性（0.1N HCl）和 pH 值为 6.8 的磷酸盐缓冲液中观察到的药物释放率分别为 34% 和 75%。与通过肠膜渗透（65%）相比，通过胃膜渗透（21.8%）的药物受到了限制/减少。所有开发的复合材料均未观察到器官毒性迹象。在这项研究中，我们开发了一种无机-有机复合系统，它具有高度的生物相容性，可有效靶向下消化道，从而避免达非那新的首过代谢。

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引用次数: 0

Oral Bioavailability Enhancement of Poorly Soluble Drug by Amorphous Solid Dispersion Using Sucrose Acetate Isobutyrate 使用异丁酸蔗糖醋酸酯的无定形固体分散体提高难溶性药物的口服生物利用度

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-09-05 DOI: 10.1208/s12249-024-02924-5

Eman M. Mohamed, Sathish Dharani, Tahir Khuroo, Mohammad T. H. Nutan, Phillip Cook, Rajendran Arunagiri, Mansoor A. Khan, Ziyaur Rahman

The focus of the present work was to develop amorphous solid dispersion (ASD) formulation of aprepitant (APT) using sucrose acetate isobutyrate (SAIB) excipient, evaluate for physicochemical attributes, stability, and bioavailability, and compared with hydroxypropyl methylcellulose (HPMC) based formulation. Various formulations of APT were prepared by solvent evaporation method and characterized for physiochemical and in-vivo performance attributes such as dissolution, drug phase, stability, and bioavailability. X-ray powder diffraction indicated crystalline drug conversion into amorphous phase. Dissolution varied as a function of drug:SAIB:excipient proportion. The dissolution was more than 80% in the optimized formulation (F10) and comparable to HPMC based formulation (F13). Stability of F10 and F13 formulations stored at 25 C/60% and 40°C/75% RH for three months were comparable. Both ASD formulations (F10 and F13) were bioequivalent as indicated by the pharmacokinetic parameters C_max and AUC_0-∞. C_max and AUC_0-∞ of F10 and F13 formulations were 2.52 ± 0.39, and 2.74 ± 0.32 μg/ml, and 26.59 ± 0.39, and 24.79 ± 6.02 μg/ml.h, respectively. Furthermore, the bioavailability of ASD formulation was more than twofold of the formulation containing crystalline phase of the drug. In conclusion, stability and oral bioavailability of SAIB based ASD formulation is comparable to HPMC-based formulation of poorly soluble drugs.

Graphical Abstract

本研究的重点是使用蔗糖醋酸异丁酸酯（SAIB）赋形剂开发阿瑞匹坦（APT）的无定形固体分散体（ASD）制剂，评估其理化属性、稳定性和生物利用度，并与基于羟丙基甲基纤维素（HPMC）的制剂进行比较。通过溶剂蒸发法制备了各种 APT 制剂，并对其溶解度、药相、稳定性和生物利用度等理化和体内性能属性进行了表征。X 射线粉末衍射表明结晶药物转化为无定形相。溶解度随药物：SAIB：辅料比例的变化而变化。优化配方（F10）的溶出率超过 80%，与基于 HPMC 的配方（F13）相当。F10 和 F13 制剂在 25°C/60% 和 40°C/75% 相对湿度条件下储存三个月的稳定性相当。根据药代动力学参数 Cmax 和 AUC0-∞，两种 ASD 制剂（F10 和 F13）具有生物等效性。F10 和 F13 制剂的 Cmax 和 AUC0-∞ 分别为 2.52 ± 0.39 和 2.74 ± 0.32 μg/ml，以及 26.59 ± 0.39 和 24.79 ± 6.02 μg/ml.h。此外，ASD 制剂的生物利用度是含结晶相药物制剂的两倍多。总之，基于 SAIB 的 ASD 制剂的稳定性和口服生物利用度与基于 HPMC 的难溶性药物制剂相当。

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引用次数: 0