AAPS PHARMSCITECH 是一份经过同行评审的在线期刊，致力于为那些对药物剂型和递送系统的研究、开发和评估感兴趣的药物科学家和工程师提供服务，包括来自生物技术的药物和与商业化有关的制造科学这种剂型。由于其电子性质，AAPS PHARMSCITECH 渴望利用不断发展的电子技术来实现更快、更多样化的信息传递机制。欢迎提交不请自来的专家评论和研究文章。

AAPS PharmSciTech is a peer-reviewed online journal dedicated to serving pharmaceutical scientists and engineers interested in the research, development, and evaluation of drug formulations and delivery systems, including those related to biotechnology and manufacturing sciences associated with commercialization. Due to its electronic nature, AAPS PharmSciTech aims to leverage evolving electronic technologies to facilitate faster and more diverse information dissemination. We welcome unsolicited expert reviews and research articles.

AAPS PharmSciTech 是一本经过同行评审的在线期刊，专注于药物剂型和递送系统的研究、开发与评估，服务于药物科学家和工程师，尤其是涉及生物技术药物和商业化制造科学的领域。由于其电子出版的特性，AAPS PharmSciTech 希望利用不断发展的电子技术，实现更快速和多样化的信息传播。我们欢迎专家提交评论和研究文章。

AAPS PharmSciTech

Poorly soluble weak bases form a significant proportion of the drugs available in the market thereby making it imperative to understand their absorption behavior. This work aims to mechanistically understand the oral absorption behavior for a weakly basic drug, Irbesartan (IRB), by investigating its pH dependent solubility, supersaturation, and precipitation behavior. Simulations performed using the equilibrium solubility could not accurately predict oral absorption. A multi-compartmental biorelevant dissolution testing model was used to evaluate dissolution in the stomach and duodenal compartment and mimic oral drug administration. This model exhibited sustained intestinal supersaturation (2–4-fold) even upon varying flow rates (4 mL/min, 7 mL/min, and mono-exponential transfer) from gastric to intestinal compartment. Simulation of oral absorption using GastroPlus™ and dissolution data collectively predicted plasma exposure with higher accuracy (% prediction error values within ± 15%), thereby indicating that multi-compartment dissolution testing enabled an improved prediction for oral pharmacokinetics of Irbesartan. Additionally, precipitates obtained in the intestinal compartment were characterized to determine the factors underlying intestinal supersaturation of Irbesartan. The solid form of these precipitates was amorphous with considerable particle size reduction. This indicated that following gastric transit, precipitate formation in the amorphous form coupled with an approximately 10 times particle size reduction could be potential factors leading to the generation and sustenance of intestinal drug supersaturation.

Navpreet Kaur

Poonam Singh Thakur

Ganesh Shete

Rahul Gangwal

Abhay T. Sangamwar

Arvind Kumar Bansal

Understanding the Oral Absorption of Irbesartan Using Biorelevant Dissolution Testing and PBPK Modeling

使用生物相关溶出测试和PBPK建模理解厄贝沙坦的口服吸收

In early drug development, the selection of a formulation platform and decisions on formulation strategies have to be made within a short timeframe and often with minimal use of the active pharmaceutical ingredient (API). The current work evaluated the various physicochemical parameters required to improve the prediction accuracy of simulation software for immediate release tablets in early drug development. DDDPlus™ was used in simulating dissolution test profiles of immediate release tablets of ritonavir and all simulations were compared with experimental results. The minimum data requirements to make useful predictions were assessed using the ADMET predictor (part of DDDPlus) and Chemicalize (an online resource). A surfactant model was developed to estimate the solubility enhancement in media containing surfactant and the software’s transfer model based on the USP two-tiered dissolution test was assessed. One measured data point was shown to be sufficient to make predictive simulations in DDDPlus. At pH 2.0, the software overestimated drug release while at pH 1.0 and 6.8, simulations were close to the measured values. A surfactant solubility model established with measured data gave good dissolution predictions. The transfer model uses a single-vessel model and was unable to predict the two in vivo environments separately. For weak bases like ritonavir, a minimum of three solubility data points is recommended for in silico predictions in buffered media. A surfactant solubility model is useful when predicting dissolution behavior in surfactant media and in silico predictions need measured solubility data to be predictive.

Juliet Obianuju Njoku

Daniela Amaral Silva

Dwaipayan Mukherjee

Gregory K. Webster

Raimar Löbenberg

In silico Tools at Early Stage of Pharmaceutical Development: Data Needs and Software Capabilities

药物开发早期阶段的计算机工具：数据需求与软件功能

Tetramethylpyrazine (TMP) was extracted from Ligusticum chuanxiong hort. The compound is known to have a variety of medicinal functions; in particular, it is used for the treatment of cerebral ischemic diseases. TMP-loaded hydrogels offer an excellent preparation with the capacity to bypass the blood-brain barrier, allowing treatment of the brain through intranasal administration. We prepared TMP-loaded hydrogels using carbomer 940 and evaluated the release of TMP from the hydrogel. We determined the release rate using Franz-type diffusion cell experiments with a subcutaneous-mucous-membrane model and also by a molecular dynamics (MD) simulation. In general, the former method was more complicated than the latter was. The dynamic behavior of TMP release from the hydrogel was revealed by analysis of the mean square displacement of the trajectory in the MD simulation. The coefficient of TMP diffusion from the hydrogel was calculated at different temperatures (277, 298, and 310 K) by using MD software. The results showed that the coefficient of diffusion increased with an increase in temperature. This trend was observed both experimentally and in the MD simulation. Therefore, the MD simulation was a complementary method to verify the experimental data.

Hongmei Xia

Yinxiang Xu

Zhiqing Cheng

Yongfeng Cheng

Tetramethylpyrazine-Loaded Hydrogels: Preparation, Penetration Through a Subcutaneous-Mucous-Membrane Model, and a Molecular Dynamics Simulation

载四甲基吡嗪水凝胶：制备、透过皮下黏膜模型渗透及分子动力学模拟

The oral drug bioavailability (BA) problems have remained inevitable over the years, impairing drug efficacy and indirectly leading to eventual human morbidity and mortality. However, some conventional lab-based methods improve drug absorption leading to enhanced BA, and the recent experimental techniques are up-and-coming. Nevertheless, some have inherent drawbacks in improving the efficacy of poorly insoluble and low impermeable drugs. Drug BA and strategies to overcome these challenges were briefly highlighted. This review has significantly unravelled the different computational models for studying and predicting drug bioavailability. Several computational approaches provide mechanistic insights into the oral drug delivery system simulation of descriptors like solubility, permeability, transport protein-ligand interactions, and molecular structures. The in silico techniques have long been known still are just being applied to unravel drug bioavailability issues. Many publications have reported novel applications of the computational models towards achieving improved drug BA, including predicting gastrointestinal tract (GIT) drug absorption properties and passive intestinal membrane permeability, thus maximizing time and resources. Also, the classical molecular simulation models for free solvation energies of soluble-related processes such as solubilization, dissolutions, supersaturation, and precipitation have been used in virtual screening studies. A few of the tools are GastroPlusTM that supports biowaiver for drugs, mainly BCS class III and predicts drug compounds’ absorption and pharmacokinetic process; SimCyp® simulator for mechanistic modelling and simulation of drug formulation processes; pharmacodynamics analysis on non-linear mixed-effects modelling; and mathematical models, predicting absorption potential/maximum absorption dose. This review provides in silico-experiment annexation in the drug bioavailability enhancement, possible insights that lead to critical opinion on the applications and reliability of the various in silico models as a growing tool for drug development and discovery, thus accelerating drug development processes.

Mahmoud E. Soliman

Adeniyi T. Adewumi

Oluwole B. Akawa

Temitayo I. Subair

Felix O. Okunlola

Oluwayimika E. Akinsuku

Shahzeb Khan

Simulation Models for Prediction of Bioavailability of Medicinal Drugs—the Interface Between Experiment and Computation

药物生物利用度预测的模拟模型——实验与计算的接口

The current study aimed to develop a prolonged-release pramipexole (PPX) transdermal patch for the treatment of Parkinson's disease. Permeation parameters of PPX were investigated using human cadaver skin. Pramipexole patches were prepared using DURO-TAK® pressure-sensitive-adhesive (PSA) and evaluated for drug stability, drug loading, in vitro drug release, and in vitro permeation through mouse skin. The results indicated that blends of DURO-TAK® 87-2852 and DURO-TAK® 87-2510 were suitable for creating a prolonged-release PPX patch due to their advantages in drug release, drug loading, and stability. The final formulation consisted of 87-2852/87-2510 (70:30), 10% PG, and 15% PPX and showed a cumulative permeation amount of 1497.19 ± 102.90 μg/cm2 with a continuous flux over 6.0 μg/(cm2·h) across human cadaver skin for 7 days. In vivo studies in rats indicated that PPX patch produced a significantly longer (p < 0.001) half-life (t 1/2, 75.16 ± 17.37 h) and mean residence time (MRT, 135.89 ± 24.12 h) relative to oral tablets (Sifrol®) and had a relative bioavailability of 51.64 ± 21.32%. Therefore, this study demonstrated the feasibility of developing a prolonged-release PPX patch, which proposed the potential to serve as an alternate to conventional oral tablets and may therefore improve patient compliance.

Tingting Pu

Xiaohui Li

Yuming Sun

Xue Ding

Yaqing Pan

Qing Wang

Development of a Prolonged-Release Pramipexole Transdermal Patch: In Vitro and In Vivo Evaluation

普拉克索缓释透皮贴剂的开发：体外和体内评价

Glycyrrhetinic acid (GA) possesses various pharmacological effects, including anti-inflammatory, anti-tumor, and anti-viral properties. However, its clinical application is limited by poor solubility and low oral bioavailability. Polymers play a crucial role in pharmaceutical formulations, particularly as matrices in excipients to enhance the solubility, bioavailability, and stability of active pharmaceutical ingredients. The amorphous solid dispersions (ASDs) of GA were prepared with three different polymers (i.e., GA-S-ASD, GA-VA64-ASD, and GA-K30-ASD). The ASDs were characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR spectroscopy), molecular docking, and contact angle measurement. Pharmacokinetics were evaluated in Beagle dogs, and long-term stability was examined. The solubility of GA increased with the rising weight of the polymer, and the optimal drug-to-carrier ratio was 1:5. In all ASDs, GA was amorphous, thus suggesting that a hydrogen bonding must have formed between GA and the polymers. The molecular docking showed that the binding energy was the highest and the hydrogen bonding was the strongest between GA and Soluplus. The dissolution of the ASDs was primarily driven by carrier-controlled dissolution, and there was minor influence from diffusion-limited release in the case of GA-S-ASD. The three ASDs significantly improved the bioavailability of GA. However, only GA-S-ASD passed the accelerated stability test. In the case of GA-VA64-ASD and GA-K30-ASD, due to serious moisture absorption, the originally fluffy ASDs became gels, and recrystallization occurred. Overall, GA-S-ASD presents promising potential for pharmaceutical applications due to its superior solubility, bioavailability, and stability.

Meng-yu Zhao

Xian-bao Shi

Jin-hua Chang

Ru-xing Wang

Jian-yu Zhou

Pei Liu

Amorphous Solid Dispersions of Glycyrrhetinic Acid: Using Soluplus, PVP, and PVPVA as the Polymer Matrix to Enhance Solubility, Bioavailability, and Stability

甘草次酸的无定形固体分散体：利用Soluplus、PVP和PVPVa作为聚合物基质提高溶解度、生物利用度和稳定性

Over the past years, many significant advances have been made in the field of gene therapy and shown promising results in clinical trials conducted. Gene therapy aims at modifying or replacing a defective, inefficient, or nonfunctional gene with a healthy, functional gene by administration of genome material into the cell to cure genetic diseases. Various methods have been devised to do this by using several viral and non-viral vectors which are either administered by in vivo or ex vivo technique. Viral vectors are best suitable for this therapy due to their potential to invade cells and deliver their genetic material whereas non-viral vectors are less efficient than viral vectors but possess some advantages such as less immunogenic response and large gene carrying capacity. Recent advances in biotechnology such as CRISPR-Cas9 mediated genome engineering and Cancer treatment with Chimeric antigen receptor (CAR) T-cell therapy are addressed in this review. This review article also delves into some recent research studies, gene therapy trials, and its applications, laying out future hopes for gene therapy in the treatment of various diseases namely haemophilia, Muscular dystrophy, SCID, Sickle cell disease, Familial Hypercholesterolemia, Cystic Fibrosis. Additionally, it also includes various nanoformulations and clinical trial data related to gene therapy.

Mokshit Bhagat

Raj Kamal

Jyoti Sharma

Kirandeep Kaur

Amit Sharma

Gurjeet Singh Thakur

Rohit Bhatia

Ankit Awasthi

Gene Therapy: Towards a New Era of Medicine

基因治疗：迈向医学新时代

This review paper discusses the key aspects of ocular biopharmaceutics, with emphasis on the crucial role played by ocular compartmental modelling and simulation in deciphering physiological conditions related to various eye diseases. It describes eye's intricate structure and function and the need for precise and targeted drug delivery systems to address prevalent eye conditions. The review categorizes and discusses various formulations employed in ocular drug delivery, delineating their respective advantages and limitations. Additionally, it probes the challenges inherent in diverse routes of drug administration for ocular therapies and provides insights into the complexities of achieving optimal drug concentrations at the target site within the eye. The central theme of this work is the ocular compartmental modelling and simulations. Hence, this works discusses on the nuanced understanding of physiological conditions within the eye, drug distribution, drug release kinetics, and key considerations for ocular compartmental modelling and simulations. By combining information from various sources, this review aims to serve as a comprehensive reference for researchers, clinicians, and pharmaceutical developers. It covers the multifaceted landscape of ocular biopharmaceutics and the transformative impact of modelling and simulation in optimizing ocular drug delivery strategies.

Mohammed Shareef Khan

Aditya Murthy

Tausif Ahmed

Advancements in Ocular Modelling and Simulations: Key Considerations and Case Studies

眼模型与模拟的进展：关键考虑因素与案例研究

A slight variation in in vivo exposure for tacrolimus extended-release (ER) capsules, which have a narrow therapeutic index (NTI), significantly affects the pharmacodynamics of the drug. Generic drug bioequivalence (BE) standards are stricter, necessitating accurate assessment of the rate and extent of drug release. Therefore, an in vitro dissolution method with high in vivo predictive power is crucial for developing generic drugs. In this study, physiologically based biopharmaceutics modeling (PBBM) for 5 mg tacrolimus ER capsules was developed and validated. The reference and non-BE test formulations were assessed using the Flow-Through Cell apparatus (USP IV) with biorelevant media to establish a biopredictive dissolution method. Using PBBM, virtual bioequivalence trials with virtual batches were conducted to propose a BE safe space. These criteria can identify formulations that pass the internal quality control test but are likely non-BE. This study highlights the benefits of developing biopredictive dissolution methods that are based on biorelevant dissolution. The PBBM, constructed by integrating various drug parameters, combined with the developed biopredictive dissolution methods, is a convenient approach for BE evaluation of NTI drugs and a practical tool for developing new drugs.

Fulin Bi

Tong Yuan

Baohong Zhang

Jixia Li

Yan Lin

Jin Yang

Establishment of Biopredictive Dissolution and Bioequivalence Safe Space Using the Physiologically Based Biopharmaceutics Modeling for Tacrolimus Extended-Release Capsules

基于生理生物药剂学模型的他克莫司缓释胶囊生物预测性溶出和生物等效性安全空间的建立

Abstract The hot-melt extrusion process is currently considered a prominent manufacturing technique in the pharmaceutical industry. The present study is intended to develop amlodipine besylate (AMB)-loaded subcutaneous implants to reduce the frequency of administration, thus improving patient compliance during hypertension management. AMB subcutaneous implants were prepared using continuous hot-melt extrusion technology using poly(caprolactone) and poly(lactic-co-glycolic acid) with dimensions of 3.70 cm (length) by 2.00 mm (diameter). The implants were characterized for thermal characteristics, drug-excipient incompatibilities, surface morphology, fracturability, in vitro drug release, and stability studies. Differential scanning calorimetry study confirmed the drug's crystalline state within the fabricated implants, while textural analysis demonstrated good fracturability in the lead formulation. Scanning electron microscopy revealed the smooth surface morphology of the lead subcutaneous implant. The lead formulation showed an extended drug release profile over 30 days (~ 2.25 mg per day) and followed zero-order release kinetics (R 2 value to 0.9999) with a mean dissolution time of 14.96 days. The lead formulation remained stable for 30 days at accelerated stability conditions of 40°C and 75% relative humidity. In conclusion, developing hot-melt extruded implants could be an alternative to the conventional amlodipine besylate (AMB) formulation. Graphical Abstract

Kshitij Chitnis

Nagarjuna Narala

Sateesh Kumar Vemula

Sagar Narala

Sivaram Munnangi

Michael A. Repka

Formulation, Development, and Characterization of AMB-Based Subcutaneous Implants using PCL and PLGA via Hot-Melt Extrusion

基于AMB的热熔挤出法制备PCL和PLGA皮下植入剂的配方、开发与表征

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Journal Impact	3.50
mbqgSu	PHARMACOLOGY & PHARMACY(Q2)
xGGr6y	SCI Q3中科院 4 区

ISSN	1530-9932
h-index	116
hQoIdU	医学(4区)医学药学(4区)

u9zg3I	化学生物有机化学工程类材料科学医学物理化学工程色谱法生物化学药理学复合材料物理化学遗传学量子力学纳米技术内科学生物信息学心理学热力学精神科地质学核磁共振药品聚合物古生物学生物利用度药物输送溶解度光学
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JrpmBe	网友分享经验：平均2.0个月
jdemjX	网友分享经验：容易

AAPS PharmSciTech

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Understanding the Oral Absorption of Irbesartan Using Biorelevant Dissolution Testing and PBPK Modeling

In silico Tools at Early Stage of Pharmaceutical Development: Data Needs and Software Capabilities

Tetramethylpyrazine-Loaded Hydrogels: Preparation, Penetration Through a Subcutaneous-Mucous-Membrane Model, and a Molecular Dynamics Simulation

Simulation Models for Prediction of Bioavailability of Medicinal Drugs—the Interface Between Experiment and Computation

Development of a Prolonged-Release Pramipexole Transdermal Patch: In Vitro and In Vivo Evaluation

Amorphous Solid Dispersions of Glycyrrhetinic Acid: Using Soluplus, PVP, and PVPVA as the Polymer Matrix to Enhance Solubility, Bioavailability, and Stability

Gene Therapy: Towards a New Era of Medicine

Advancements in Ocular Modelling and Simulations: Key Considerations and Case Studies

Establishment of Biopredictive Dissolution and Bioequivalence Safe Space Using the Physiologically Based Biopharmaceutics Modeling for Tacrolimus Extended-Release Capsules

Formulation, Development, and Characterization of AMB-Based Subcutaneous Implants using PCL and PLGA via Hot-Melt Extrusion