AAPS PharmSciTech最新文献_第9页

Differential Scanning Calorimetry (DSC) in Solid-State Characterization of Solid Dispersions: A Practical Guide 差示扫描量热法（DSC）在固体分散体的固态表征：实用指南

IF 4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2025-11-06 DOI: 10.1208/s12249-025-03240-2

Shunhua Ding, Rishi M. Shah, Hien V. Nguyen, Tushar Saha

Differential Scanning Calorimetry (DSC) is one of the most widely employed and rapid thermal analysis techniques for early-stage solid-state characterization, particularly in the development of solid dispersions. As an indirect method, DSC detects transitions in solid-state properties through heat flow measurements, providing valuable insights into crystallinity, polymorphism, and miscibility. However, the accuracy and interpretation of DSC thermograms are highly sensitive to various experimental parameters, including heating and cooling rates, sample preparation, moisture content, and the thermal history of the material. These variables can introduce artifacts or mask thermal events, leading to misinterpretation of solid-state transitions. This review critically examines key thermodynamic and kinetic factors reported in literature that influence DSC measurements in the context of solid dispersions. Emphasis is placed on the mechanisms by which these variables affect endothermic and exothermic transitions and how such influences can be mitigated through experimental design. Practical recommendations are provided to improve method reliability, including optimal scan rates, sample handling techniques, and the use of complementary analytical tools such as X-ray powder diffraction (XRPD) and Fourier-transform infrared spectroscopy (FTIR) to support DSC findings. The primary objective of this review is to serve as a technical guide for researchers and formulation scientists aiming to generate reproducible and interpretable DSC data for solid dispersion systems. By understanding the limitations and best practices associated with DSC, researchers can enhance the reliability of solid-state characterization and make informed decisions in formulation development.

Graphical Abstract

差示扫描量热法（DSC）是一种应用最广泛的快速热分析技术，用于早期固态表征，特别是在固体分散体的开发中。作为一种间接方法，DSC通过热流测量来检测固态性质的转变，为结晶度、多态性和混相性提供了有价值的见解。然而，DSC热图的准确性和解释对各种实验参数非常敏感，包括加热和冷却速率、样品制备、水分含量和材料的热历史。这些变量可能会引入伪影或掩盖热事件，从而导致对固态转变的误解。这篇综述严格审查了文献中报道的影响固体分散体DSC测量的关键热力学和动力学因素。重点放在这些变量影响吸热和放热转变的机制，以及如何通过实验设计减轻这种影响。提出了提高方法可靠性的实用建议，包括优化扫描速率，样品处理技术，以及使用x射线粉末衍射（XRPD）和傅里叶变换红外光谱（FTIR）等互补分析工具来支持DSC结果。本综述的主要目的是为研究人员和配方科学家提供技术指导，旨在为固体分散体系生成可重复和可解释的DSC数据。通过了解与DSC相关的局限性和最佳实践，研究人员可以提高固态表征的可靠性，并在配方开发中做出明智的决策。图形抽象

{"title":"Differential Scanning Calorimetry (DSC) in Solid-State Characterization of Solid Dispersions: A Practical Guide","authors":"Shunhua Ding, Rishi M. Shah, Hien V. Nguyen, Tushar Saha","doi":"10.1208/s12249-025-03240-2","DOIUrl":"10.1208/s12249-025-03240-2","url":null,"abstract":"<div><p>Differential Scanning Calorimetry (DSC) is one of the most widely employed and rapid thermal analysis techniques for early-stage solid-state characterization, particularly in the development of solid dispersions. As an indirect method, DSC detects transitions in solid-state properties through heat flow measurements, providing valuable insights into crystallinity, polymorphism, and miscibility. However, the accuracy and interpretation of DSC thermograms are highly sensitive to various experimental parameters, including heating and cooling rates, sample preparation, moisture content, and the thermal history of the material. These variables can introduce artifacts or mask thermal events, leading to misinterpretation of solid-state transitions. This review critically examines key thermodynamic and kinetic factors reported in literature that influence DSC measurements in the context of solid dispersions. Emphasis is placed on the mechanisms by which these variables affect endothermic and exothermic transitions and how such influences can be mitigated through experimental design. Practical recommendations are provided to improve method reliability, including optimal scan rates, sample handling techniques, and the use of complementary analytical tools such as X-ray powder diffraction (XRPD) and Fourier-transform infrared spectroscopy (FTIR) to support DSC findings. The primary objective of this review is to serve as a technical guide for researchers and formulation scientists aiming to generate reproducible and interpretable DSC data for solid dispersion systems. By understanding the limitations and best practices associated with DSC, researchers can enhance the reliability of solid-state characterization and make informed decisions in formulation development.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145456521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Influence of pH and Preservative Agents on Physicochemical and Microbiological Stability of a Flexible Dose/Age-Appropriate Formulation of Enalapril Maleate. A Quality by Design‑Based Optimization pH和防腐剂对马来酸依那普利弹性剂量/年龄配方的理化和微生物稳定性的影响。基于设计的质量优化

IF 4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2025-11-06 DOI: 10.1208/s12249-025-03262-w

Mauro Morri, María Alejandra Operto, Rubén Maggio, Darío Leonardi, Silvana Vignaduzzo

Enalapril (ENA) is indicated for the management of heart failure, hypertension, and asymptomatic left ventricular dysfunction, while pediatric patients also benefit from its use in treating hypertension and congestive heart failure. ENA is commercially available as tablets with doses ranging from 2.5 to 20 mg. However, achieving the typical starting dose of 0.1 mg kg⁻¹ day⁻¹ for infants and children can be challenging due to the limitations of available tablet strengths. This limitation is compounded by patients with dysphagia or those who are averse to swallowing tablets. Liquid oral formulations would facilitate adherence to treatment in these patients. The purpose of this study was to develop and optimize an oral liquid scalable-dose formulation of Enalapril Maleate at 2 mg mL⁻¹ following a Quality by Design approach. Quality Target Product Profiles, Critical Process Parameters, and Critical Quality Attributes (CQAs) were identified. CQAs with a higher level were further evaluated through a Design of Experiments (DoE) approach, including pH, physical stability, microbiological quality, and chemical stability. Chemical stability of ENA showed variation depending on the specific formulation conditions and the influence of pH, buffer type, preservative agent, and storage temperature on the stability of the active ingredient was determined by DoE. The final selected formulation: enalapril 2 mg mL⁻¹, pH 3.5, containing 10% v/v glycerin, 10 mM citrate buffer, and 0.2% w/v sodium benzoate, demonstrated to be physically, chemically, and microbiologically stable for at least six months under refrigerated conditions, with drug recoveries exceeding 95%, and a robust Design Space was established for its manufacture and storage.

Graphical Abstract

依那普利（ENA）适用于心力衰竭、高血压和无症状左心室功能障碍的治疗，同时儿科患者也受益于其治疗高血压和充血性心力衰竭。ENA是市售片剂，剂量从2.5毫克到20毫克不等。然而，由于现有片剂强度的限制，婴儿和儿童达到0.1 mg kg - 1 day - 1的典型起始剂量可能具有挑战性。对于吞咽困难或不愿吞咽药片的患者，这种限制更为复杂。液体口服制剂将有助于这些患者坚持治疗。本研究的目的是根据质量设计方法开发和优化2 mg mL - 1马来酸依那普利口服液的可缩放剂量配方。确定了质量目标产品概要、关键工艺参数和关键质量属性（cqa）。通过实验设计（Design of Experiments, DoE）的方法对较高水平的cqa进行进一步评价，包括pH值、物理稳定性、微生物质量和化学稳定性。ENA的化学稳定性随配方条件的不同而变化，通过DoE测定了pH、缓冲液类型、防腐剂和储存温度对活性成分稳定性的影响。最终选定的配方：依那四月2mg mL−1，pH为3.5，含有10% v/v甘油，10mm柠檬酸缓冲液和0.2% w/v苯甲酸钠，在冷藏条件下具有物理、化学和微生物稳定性至少6个月，药物回收率超过95%，并为其生产和储存建立了强大的设计空间。图形抽象

{"title":"The Influence of pH and Preservative Agents on Physicochemical and Microbiological Stability of a Flexible Dose/Age-Appropriate Formulation of Enalapril Maleate. A Quality by Design‑Based Optimization","authors":"Mauro Morri, María Alejandra Operto, Rubén Maggio, Darío Leonardi, Silvana Vignaduzzo","doi":"10.1208/s12249-025-03262-w","DOIUrl":"10.1208/s12249-025-03262-w","url":null,"abstract":"<div><p>Enalapril (ENA) is indicated for the management of heart failure, hypertension, and asymptomatic left ventricular dysfunction, while pediatric patients also benefit from its use in treating hypertension and congestive heart failure. ENA is commercially available as tablets with doses ranging from 2.5 to 20 mg. However, achieving the typical starting dose of 0.1 mg kg<sup>−1</sup> day<sup>−1</sup> for infants and children can be challenging due to the limitations of available tablet strengths. This limitation is compounded by patients with dysphagia or those who are averse to swallowing tablets. Liquid oral formulations would facilitate adherence to treatment in these patients. The purpose of this study was to develop and optimize an oral liquid scalable-dose formulation of Enalapril Maleate at 2 mg mL<sup>−1</sup> following a Quality by Design approach. Quality Target Product Profiles, Critical Process Parameters, and Critical Quality Attributes (CQAs) were identified. CQAs with a higher level were further evaluated through a Design of Experiments (DoE) approach, including pH, physical stability, microbiological quality, and chemical stability. Chemical stability of ENA showed variation depending on the specific formulation conditions and the influence of pH, buffer type, preservative agent, and storage temperature on the stability of the active ingredient was determined by DoE. The final selected formulation: enalapril 2 mg mL<sup>−1</sup>, pH 3.5, containing 10% v/v glycerin, 10 mM citrate buffer, and 0.2% w/v sodium benzoate, demonstrated to be physically, chemically, and microbiologically stable for at least six months under refrigerated conditions, with drug recoveries exceeding 95%, and a robust Design Space was established for its manufacture and storage.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145456354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Co-amorphous Approach for Enhancing Rilpivirine Oral Bioavailability using CYP3A4 Inhibitor as a Co-former 以CYP3A4抑制剂为共聚物提高利匹韦林口服生物利用度的共定形方法。

IF 4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2025-11-05 DOI: 10.1208/s12249-025-03222-4

Ashwini R. Madgulkar, Mangesh R. Bhalekar, Maryam S. Mulla

Rilpivirine, a BCS class II drug, has low water solubility (0.0166 mg/ml) and oral bioavailability of (32%), limiting its HIV treatment delivery. This research aimed to improve rilpivirine's solubility and bioavailability by developing a co-amorphous system (CAMS) using nicotinamide as co-former. Nicotinamide selection was based on knowledge-based methods such as Hansen solubility parameter, Flory–Huggins interaction parameter, and molecular modeling. CAMS was prepared using solvent evaporation and quench cooling at molar ratio of 1:1, 1:2, and 2:1. Phase solubility study showed 1:1 molar ratio was most suitable for complex formation. Fourier transform infrared spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and field-emission scanning electron microscopy confirmed CAMS formation. Saturation solubility studies showed rilpivirine's solubility increased 38-fold in CAMS compared to pure drug. In vitro drug release and ex vivo permeation study demonstrated 2.86- and 2.87-fold enhancement in drug release and permeation. Pharmacokinetic study in Wistar rats showed 2.49-fold improvement in oral bioavailability, attributed to improved dissolution and CYP3A4 enzyme inhibition by nicotinamide. Stability studies confirmed CAMS maintained its amorphous state for over three months, as shown by DSC, PXRD, FE-SEM, solubility and dissolution studies. The CAMS of rilpivirine and nicotinamide, prepared through solvent evaporation at 1:1 molar ratio, enhanced rilpivirine's solubility, dissolution, permeation, and oral bioavailability, offering a promising antiretroviral drug delivery strategy.

Graphical Abstract

利匹韦林（Rilpivirine）是一种BCS II类药物，水溶性低（0.0166 mg/ml），口服生物利用度低（32%），限制了其HIV治疗的递送。本研究以烟酰胺为共聚物，建立了利匹韦林的共晶体系（CAMS），以提高利匹韦林的溶解度和生物利用度。烟酰胺的选择基于基于知识的方法，如Hansen溶解度参数、Flory-Huggins相互作用参数和分子模型。以1:1、1:2、2:1的摩尔比采用溶剂蒸发和淬火冷却法制备CAMS。相溶解度研究表明，1:1的摩尔比最适合络合物的形成。傅里叶变换红外光谱、粉末x射线衍射、差示扫描量热法和场发射扫描电镜证实了CAMS的形成。饱和溶解度研究表明，利匹韦林在CAMS中的溶解度比纯药物增加了38倍。体外释药和体外透性研究表明，其释药和透性分别提高2.86倍和2.87倍。Wistar大鼠的药代动力学研究显示，由于烟酰胺改善了溶出度和抑制CYP3A4酶，口服生物利用度提高了2.49倍。通过DSC、PXRD、FE-SEM、溶解度和溶解度研究，稳定性研究证实CAMS保持了3个多月的非晶态。通过1:1摩尔比的溶剂蒸发制备利匹韦林和烟酰胺的CAMS，增强了利匹韦林的溶解度、溶出度、渗透性和口服生物利用度，提供了一种很有前景的抗逆转录病毒药物递送策略。

{"title":"Co-amorphous Approach for Enhancing Rilpivirine Oral Bioavailability using CYP3A4 Inhibitor as a Co-former","authors":"Ashwini R. Madgulkar, Mangesh R. Bhalekar, Maryam S. Mulla","doi":"10.1208/s12249-025-03222-4","DOIUrl":"10.1208/s12249-025-03222-4","url":null,"abstract":"<div><p>Rilpivirine, a BCS class II drug, has low water solubility (0.0166 mg/ml) and oral bioavailability of (32%), limiting its HIV treatment delivery. This research aimed to improve rilpivirine's solubility and bioavailability by developing a co-amorphous system (CAMS) using nicotinamide as co-former. Nicotinamide selection was based on knowledge-based methods such as Hansen solubility parameter, Flory–Huggins interaction parameter, and molecular modeling. CAMS was prepared using solvent evaporation and quench cooling at molar ratio of 1:1, 1:2, and 2:1. Phase solubility study showed 1:1 molar ratio was most suitable for complex formation. Fourier transform infrared spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and field-emission scanning electron microscopy confirmed CAMS formation. Saturation solubility studies showed rilpivirine's solubility increased 38-fold in CAMS compared to pure drug. <i>In vitro</i> drug release and <i>ex vivo</i> permeation study demonstrated 2.86- and 2.87-fold enhancement in drug release and permeation. Pharmacokinetic study in Wistar rats showed 2.49-fold improvement in oral bioavailability, attributed to improved dissolution and CYP3A4 enzyme inhibition by nicotinamide. Stability studies confirmed CAMS maintained its amorphous state for over three months, as shown by DSC, PXRD, FE-SEM, solubility and dissolution studies. The CAMS of rilpivirine and nicotinamide, prepared through solvent evaporation at 1:1 molar ratio, enhanced rilpivirine's solubility, dissolution, permeation, and oral bioavailability, offering a promising antiretroviral drug delivery strategy.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Strategies to Overcome Challenges in Formulating Tablets from Dried Plant Extracts: a Comprehensive Review 植物提取物制剂中克服挑战的策略：综述。

IF 4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2025-11-04 DOI: 10.1208/s12249-025-03255-9

Ewelyn Cintya Felipe dos Santos, Janaina Carla Barbosa Machado, Magda Rhayanny Assunção Ferreira, Luiz Alberto Lira Soares

Traditional medicinal plant derivatives (such as infusions, decoctions, and extracts) are employed in various therapeutic applications due to their wide chemical diversity and multiple biological effects. However, their therapeutic potential is often limited by challenges in conventional pharmaceutical dosage forms, including poor solubility, stability issues, and difficulties in handling and accurate dosing. To overcome these limitations, drying and tableting emerge as viable alternatives, providing stable, cost-effective, uniform, and scalable dosage forms suitable for large-scale production. Nonetheless, factors such as high hygroscopicity, low flowability, poor compressibility, and reduced bioavailability of the complex dried mixture obtained from plant materials pose challenges for tablet formulation. Given this scenario, this review provides a comprehensive overview of these technological hurdles, and explores strategies to overcome them, including the use of excipients to improve flow, optimization of the drying process, granulation techniques, composite particles, solid dispersions, and liquisolid systems. These strategies have enabled the successful development of various types of tablets, such as immediate-release, orodispersible, mucoadhesive, chewable, and extended-release formulations. Finally, this work highlights current advances and practical applications, offering insights into future innovations in the formulation of tablets containing dried plant extracts, including approaches that could facilitate progress toward continuous manufacturing.

Graphical Abstract

传统药用植物衍生物（如冲剂、煎剂和提取物）由于其广泛的化学多样性和多种生物效应而被用于各种治疗应用。然而，它们的治疗潜力往往受到传统药物剂型的限制，包括溶解度差、稳定性问题以及处理和准确给药的困难。为了克服这些限制，干燥和片剂成为可行的替代方案，提供稳定、经济、均匀和可扩展的剂型，适合大规模生产。然而，从植物材料中获得的复杂干燥混合物的高吸湿性、低流动性、差压缩性和生物利用度降低等因素对片剂配方构成了挑战。鉴于这种情况，本综述提供了这些技术障碍的全面概述，并探讨了克服这些障碍的策略，包括使用赋形剂来改善流动，优化干燥过程，造粒技术，复合颗粒，固体分散体和液-固体系。这些策略使各种类型的片剂得以成功开发，如速释、或分散、黏附、咀嚼和缓释制剂。最后，这项工作强调了当前的进展和实际应用，为含有干燥植物提取物的片剂配方的未来创新提供了见解，包括可以促进连续制造进展的方法。

{"title":"Strategies to Overcome Challenges in Formulating Tablets from Dried Plant Extracts: a Comprehensive Review","authors":"Ewelyn Cintya Felipe dos Santos, Janaina Carla Barbosa Machado, Magda Rhayanny Assunção Ferreira, Luiz Alberto Lira Soares","doi":"10.1208/s12249-025-03255-9","DOIUrl":"10.1208/s12249-025-03255-9","url":null,"abstract":"<div><p>Traditional medicinal plant derivatives (such as infusions, decoctions, and extracts) are employed in various therapeutic applications due to their wide chemical diversity and multiple biological effects. However, their therapeutic potential is often limited by challenges in conventional pharmaceutical dosage forms, including poor solubility, stability issues, and difficulties in handling and accurate dosing. To overcome these limitations, drying and tableting emerge as viable alternatives, providing stable, cost-effective, uniform, and scalable dosage forms suitable for large-scale production. Nonetheless, factors such as high hygroscopicity, low flowability, poor compressibility, and reduced bioavailability of the complex dried mixture obtained from plant materials pose challenges for tablet formulation. Given this scenario, this review provides a comprehensive overview of these technological hurdles, and explores strategies to overcome them, including the use of excipients to improve flow, optimization of the drying process, granulation techniques, composite particles, solid dispersions, and liquisolid systems. These strategies have enabled the successful development of various types of tablets, such as immediate-release, orodispersible, mucoadhesive, chewable, and extended-release formulations. Finally, this work highlights current advances and practical applications, offering insights into future innovations in the formulation of tablets containing dried plant extracts, including approaches that could facilitate progress toward continuous manufacturing.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145443499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dissolvable Microneedles with Their Design, Materials, and Limitations in Translation: a Technical Review 可溶解微针及其设计、材料和翻译的局限性：技术综述。

IF 4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2025-11-03 DOI: 10.1208/s12249-025-03246-w

Kirthana Gopal, Ramsha Khalid, Syed Mahmood

Dissolvable microneedles (DMNs) have emerged as a groundbreaking drug delivery platform, offering a minimally invasive alternative to conventional parenteral and oral administration while enabling precise, pain-free, and patient-friendly therapeutic delivery. This review provides a comprehensive technical overview of the design, materials, and translational challenges of DMN systems. We begin by examining critical design parameters, including microneedle geometry, array configuration, mechanical strength, and drug distribution, that directly influence insertion efficiency, structural integrity, and dissolution kinetics. The role of mathematical modeling in optimizing DMN performance is also explored, offering insights into drug diffusion, structural mechanics, and dissolution kinetics. The materials section highlights the diverse natural and synthetic polymers used in DMN fabrication, along with additives and stabilizers that modulate drug release, improve biocompatibility, and ensure formulation stability. Despite significant advances in preclinical research, the translation of DMNs into clinical and commercial applications remains hindered by several factors, including limitations in drug loading capacity, manufacturing scalability, dose precision, long-term storage stability, and regulatory complexity. We also explore user-centric challenges, including ease of administration, patient compliance, and cost-effectiveness. The final section discusses current strategies to address these barriers, including the use of smart and stimuli-responsive polymers, next-generation microfabrication techniques, and packaging innovations designed to enhance shelf life and user handling. Through this, we aim to provide a critical perspective on the design, materials, and future potential of DMN technology, charting a path toward its successful integration into mainstream healthcare systems.

Graphical Abstract

可溶解微针（DMNs）已经成为一种突破性的给药平台，提供了传统肠外和口服给药的微创替代方案，同时实现了精确、无痛和对患者友好的治疗给药。这篇综述提供了DMN系统的设计、材料和转化挑战的全面技术概述。我们首先检查关键的设计参数，包括微针几何形状、阵列配置、机械强度和药物分布，这些参数直接影响插入效率、结构完整性和溶解动力学。数学建模在优化DMN性能中的作用也进行了探讨，为药物扩散、结构力学和溶解动力学提供了见解。材料部分重点介绍DMN制造中使用的各种天然和合成聚合物，以及调节药物释放、改善生物相容性和确保配方稳定性的添加剂和稳定剂。尽管临床前研究取得了重大进展，但DMNs转化为临床和商业应用仍然受到几个因素的阻碍，包括药物装载能力、制造可扩展性、剂量精度、长期储存稳定性和监管复杂性的限制。我们还探讨了以用户为中心的挑战，包括易于管理、患者依从性和成本效益。最后一节讨论了解决这些障碍的当前策略，包括使用智能和刺激响应聚合物，下一代微加工技术，以及旨在提高保质期和用户处理的包装创新。通过这一点，我们的目标是对DMN技术的设计、材料和未来潜力提供一个关键的视角，为其成功整合到主流医疗保健系统指明一条道路。

{"title":"Dissolvable Microneedles with Their Design, Materials, and Limitations in Translation: a Technical Review","authors":"Kirthana Gopal, Ramsha Khalid, Syed Mahmood","doi":"10.1208/s12249-025-03246-w","DOIUrl":"10.1208/s12249-025-03246-w","url":null,"abstract":"<div><p>Dissolvable microneedles (DMNs) have emerged as a groundbreaking drug delivery platform, offering a minimally invasive alternative to conventional parenteral and oral administration while enabling precise, pain-free, and patient-friendly therapeutic delivery. This review provides a comprehensive technical overview of the design, materials, and translational challenges of DMN systems. We begin by examining critical design parameters, including microneedle geometry, array configuration, mechanical strength, and drug distribution, that directly influence insertion efficiency, structural integrity, and dissolution kinetics. The role of mathematical modeling in optimizing DMN performance is also explored, offering insights into drug diffusion, structural mechanics, and dissolution kinetics. The materials section highlights the diverse natural and synthetic polymers used in DMN fabrication, along with additives and stabilizers that modulate drug release, improve biocompatibility, and ensure formulation stability. Despite significant advances in preclinical research, the translation of DMNs into clinical and commercial applications remains hindered by several factors, including limitations in drug loading capacity, manufacturing scalability, dose precision, long-term storage stability, and regulatory complexity. We also explore user-centric challenges, including ease of administration, patient compliance, and cost-effectiveness. The final section discusses current strategies to address these barriers, including the use of smart and stimuli-responsive polymers, next-generation microfabrication techniques, and packaging innovations designed to enhance shelf life and user handling. Through this, we aim to provide a critical perspective on the design, materials, and future potential of DMN technology, charting a path toward its successful integration into mainstream healthcare systems.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145436780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multistep Machine Learning Pipeline For Polymeric Nanoparticle Design 聚合物纳米颗粒设计的多步机器学习管道

IF 4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2025-10-30 DOI: 10.1208/s12249-025-03248-8

Rodrigo Fonseca Silveira, Ingrid Araujo de Santana, Ana Luiza Lima, Idejan Padilha Gross, Tais Gratieri, Guilherme Gelfuso, Marcilio Cunha-Filho

Integrating machine learning (ML) into nanotechnology represents a promising strategy for rational design and accelerated development of drug delivery systems. However, studies in this field are scarce and face methodological and interpretative problems. This study presents a modular ML pipeline for the predictive modeling of nanoparticles produced via nanoprecipitation using isoniazid as a model drug. The workflow was structured into three sequential steps: (1) binary classification to predict nanoparticle formation, (2) multiclass classification to estimate size ranges, and (3) regression to refine size prediction. Several algorithms were used, including Extreme Gradient Boosting, Random Forest, Artificial Neural Networks (ANN), Generalized Linear Models, and Naive Bayes. A total of 90 formulations were evaluated over three iterative experimental rounds. In each cycle, models were retrained with new data and used to simulate virtual formulations, thereby guiding the selection of experiments to reduce data imbalance and improve prediction accuracy. The ANN algorithm consistently outperformed other models in all steps, achieving an R² > 0.9 in both classification and regression tasks. Classification outputs were used as constraints in the regression phase to improve robustness. The final pipeline demonstrated high predictive performance across a broad size range (75–768 nm), with maximum absolute errors below 40 nm. Validation with new formulations confirmed the model's reliability and generalization capacity. This approach may significantly reduce experimental workload while providing a scalable framework. Overall, the proposed ML-guided strategy supports data-driven decision-making in nanopharmaceutical research, enabling systematic formulation development aligned with Quality-by-Design principles.

Graphical Abstract

将机器学习（ML）集成到纳米技术中代表了一种合理设计和加速药物输送系统开发的有前途的策略。然而，这一领域的研究很少，面临着方法论和解释性问题。本研究提出了一个模块化的ML管道，用于通过纳米沉淀法以异烟肼为模型药物生产纳米颗粒的预测建模。工作流程分为三个连续步骤：(1)二元分类预测纳米颗粒形成，(2)多类分类估计尺寸范围，(3)回归优化尺寸预测。使用了几种算法，包括极端梯度增强、随机森林、人工神经网络（ANN）、广义线性模型和朴素贝叶斯。共有90种配方在三轮迭代实验中进行了评估。在每个周期中，使用新数据对模型进行重新训练，并用于模拟虚拟公式，从而指导实验的选择，以减少数据不平衡，提高预测精度。ANN算法在所有步骤中始终优于其他模型，在分类和回归任务中均达到R2 >； 0.9。分类输出被用作回归阶段的约束，以提高鲁棒性。最终的管道在宽尺寸范围内（75-768 nm）表现出较高的预测性能，最大绝对误差低于40 nm。新公式的验证证实了模型的可靠性和泛化能力。这种方法可以显著减少实验工作量，同时提供可扩展的框架。总的来说，提议的机器学习指导策略支持纳米药物研究中数据驱动的决策，使系统的配方开发与质量设计原则相一致。图形抽象

{"title":"Multistep Machine Learning Pipeline For Polymeric Nanoparticle Design","authors":"Rodrigo Fonseca Silveira, Ingrid Araujo de Santana, Ana Luiza Lima, Idejan Padilha Gross, Tais Gratieri, Guilherme Gelfuso, Marcilio Cunha-Filho","doi":"10.1208/s12249-025-03248-8","DOIUrl":"10.1208/s12249-025-03248-8","url":null,"abstract":"<div><p>Integrating machine learning (ML) into nanotechnology represents a promising strategy for rational design and accelerated development of drug delivery systems. However, studies in this field are scarce and face methodological and interpretative problems. This study presents a modular ML pipeline for the predictive modeling of nanoparticles produced via nanoprecipitation using isoniazid as a model drug. The workflow was structured into three sequential steps: (1) binary classification to predict nanoparticle formation, (2) multiclass classification to estimate size ranges, and (3) regression to refine size prediction. Several algorithms were used, including Extreme Gradient Boosting, Random Forest, Artificial Neural Networks (ANN), Generalized Linear Models, and Naive Bayes. A total of 90 formulations were evaluated over three iterative experimental rounds. In each cycle, models were retrained with new data and used to simulate virtual formulations, thereby guiding the selection of experiments to reduce data imbalance and improve prediction accuracy. The ANN algorithm consistently outperformed other models in all steps, achieving an R<sup>2</sup> > 0.9 in both classification and regression tasks. Classification outputs were used as constraints in the regression phase to improve robustness. The final pipeline demonstrated high predictive performance across a broad size range (75–768 nm), with maximum absolute errors below 40 nm. Validation with new formulations confirmed the model's reliability and generalization capacity. This approach may significantly reduce experimental workload while providing a scalable framework. Overall, the proposed ML-guided strategy supports data-driven decision-making in nanopharmaceutical research, enabling systematic formulation development aligned with Quality-by-Design principles.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145406397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retraction Note: Loteprednol-Loaded Nanoformulations for Corneal Delivery by Quality-by-Design Concepts: Optimization, Characterization, and Anti-inflammatory Activity 缩回注：通过质量设计概念：优化，表征和抗炎活性，用于角膜递送的loteprednol负载纳米配方

IF 4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2025-10-30 DOI: 10.1208/s12249-025-03278-2

Burcu Uner, Samet Ozdemir, Cetin Tas, Melike Uner, Yildiz Ozsoy

引用次数: 0

Retraction Note: Formulation of Metoclopramide Hydrochloride-Loaded Lipid Carriers by QbD Approach for Combating Nausea: Safety and Bioavailability Evaluation in New Zealand Rabbit 撤回注：QbD法制备盐酸甲氧氯普胺脂质载体治疗恶心：新西兰兔的安全性和生物利用度评价

IF 4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2025-10-30 DOI: 10.1208/s12249-025-03281-7

Juste Baranauskaite, Meryem Aydin, Burcu Uner, Cetin Tas

引用次数: 0

Retraction Note: Revolutionizing Lung Cancer Treatment: Innovative CRISPR-Cas9 Delivery Strategies 撤回注：肺癌治疗的革命性变革：创新的CRISPR-Cas9传递策略

IF 4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2025-10-30 DOI: 10.1208/s12249-025-03280-8

Dilpreet Singh

引用次数: 0

Injectables Protein-Based Nanodiscs in Cancer Drug Delivery: From Bench to Clinical Potential 注射蛋白纳米片在癌症药物输送中的应用：从实验到临床潜力

IF 4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2025-10-30 DOI: 10.1208/s12249-025-03247-9

Vimal Patel, Jigar N. Shah, Saloni Dalwadi, Parv Barot, Darshan Vaghela, Megha Patel, Vijaykumar Sutariya

Membrane mimicking protein nanodiscs are nanoscale structures composed of a lipid bilayer and a scaffold protein that forms a circular disc-like structure. These NDs are designed to mimic the natural cell membrane and are used as a platform to study membrane-associated proteins, such as those involved in signal transduction or drug transport. In cancer therapeutics, NDs have been developed as a promising nano-formulation for delivering macromolecules, such as drugs or nucleic acids, to cancer cells. The NDs can be functionalized with targeting ligands, such as antibodies or peptides, to specifically bind to cancer cells and deliver therapeutic payloads. One advantage of ND-based formulations is their ability to protect macromolecules from degradation and enhance their pharmacokinetics and bioavailability. Additionally, the use of NDs as a delivery vehicle allows for the precise control of drug release, which can improve efficacy while reducing toxic side effects. Overall, membrane mimicking protein NDs show great potential as a versatile platform for macromolecular delivery in cancer therapeutics, with the ability to precisely target cancer cells and enhance the therapeutic effect of drugs or nucleic acids. In this review, we discuss the structural components, stability issues, synthetic strategies, limitations, therapeutic advancements, and future challenges associated with the clinical implication of ND’s anti-cancer therapies.

Graphical Abstract

膜模拟蛋白质纳米盘是由脂质双分子层和支架蛋白组成的纳米级结构，形成圆盘状结构。这些NDs被设计成模拟天然细胞膜，并被用作研究膜相关蛋白的平台，例如那些参与信号转导或药物运输的蛋白。在癌症治疗中，ndds已经发展成为一种有前途的纳米制剂，用于向癌细胞输送大分子，如药物或核酸。NDs可以与靶向配体（如抗体或肽）功能化，以特异性结合癌细胞并提供治疗有效载荷。基于nd的制剂的一个优点是它们能够保护大分子免受降解并增强其药代动力学和生物利用度。此外，使用NDs作为递送载体可以精确控制药物释放，这可以提高疗效，同时减少毒副作用。总的来说，膜模拟蛋白NDs作为一种多功能的大分子递送平台在癌症治疗中显示出巨大的潜力，具有精确靶向癌细胞和增强药物或核酸治疗效果的能力。在这篇综述中，我们讨论了ND抗癌治疗的结构组成、稳定性问题、合成策略、局限性、治疗进展以及与临床意义相关的未来挑战。图形抽象

{"title":"Injectables Protein-Based Nanodiscs in Cancer Drug Delivery: From Bench to Clinical Potential","authors":"Vimal Patel, Jigar N. Shah, Saloni Dalwadi, Parv Barot, Darshan Vaghela, Megha Patel, Vijaykumar Sutariya","doi":"10.1208/s12249-025-03247-9","DOIUrl":"10.1208/s12249-025-03247-9","url":null,"abstract":"<div><p>Membrane mimicking protein nanodiscs are nanoscale structures composed of a lipid bilayer and a scaffold protein that forms a circular disc-like structure. These NDs are designed to mimic the natural cell membrane and are used as a platform to study membrane-associated proteins, such as those involved in signal transduction or drug transport. In cancer therapeutics, NDs have been developed as a promising nano-formulation for delivering macromolecules, such as drugs or nucleic acids, to cancer cells. The NDs can be functionalized with targeting ligands, such as antibodies or peptides, to specifically bind to cancer cells and deliver therapeutic payloads. One advantage of ND-based formulations is their ability to protect macromolecules from degradation and enhance their pharmacokinetics and bioavailability. Additionally, the use of NDs as a delivery vehicle allows for the precise control of drug release, which can improve efficacy while reducing toxic side effects. Overall, membrane mimicking protein NDs show great potential as a versatile platform for macromolecular delivery in cancer therapeutics, with the ability to precisely target cancer cells and enhance the therapeutic effect of drugs or nucleic acids. In this review, we discuss the structural components, stability issues, synthetic strategies, limitations, therapeutic advancements, and future challenges associated with the clinical implication of ND’s anti-cancer therapies.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145406398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0