دسترسی یکساله به بیش از ۵۰۰ ژورنال روز جهان موجود در سامانه
-
http://medilib.ir
- ﻣﺪﺕ ﺯﻣﺎﻥ : 365 ﺭﻭﺯ
قیمت : 3,800,000 تومان- قیمت ویژه : 1,900,000تومان
A Novel Self-Assembled Paclitaxel Nanodispersion Facilitates Rapid In-Vitro/In-Vivo Dissociation and Protein Binding
Ajay J. Khopade, Malay D. Shah & Bhushan Borole
doi : 10.1208/s12249-024-02996-3
Volume 26, article number 9, (2025)
The study aims to prepare and characterize a novel paclitaxel (PtX) preconcentrate formulation using polymer and lipid excipients that forms nanodispersion upon dilution. The goal was to understand the mechanism of nanodispersion formation and its properties. The water-insoluble PtX was dissolved in organic solvents containing ethanol, polyethylene glycol (PEG400), povidone (PVP), caprylic acid (CA), and sodium cholesterol sulfate (CS). This formulation was diluted in 5% w/v dextrose medium to form PtX nanodispersion, which was assessed for particle size, stability, in-vitro/in-vivo dissociation and protein binding. Transmission electron microscopy (TEM), Small Angle Neutron Scattering (SANS), and Molecular Dynamics (MD) simulations were used to analyse the structure of the nanoparticles. The formulation was a clear, slightly yellow solution. The PtX nanodispersion displays particle size of ~ 100 nm with a zeta potential of -25, and the pH of 4.0. It displayed nearly spherical coacervate nanoparticles with a sponge-like structure, lacking internal structure order as revealed by TEM and SANS. MD simulations confirmed self-assembly of PtX and excipients forming nanoparticles. In vitro dissociation studies in simulated plasma demonstrated rapid dissociation of nanodispersion, releasing free PtX that immediately binds to plasma proteins. In vivo studies in rabbits corroborated these findings, showing rapid dissolution. The results present a novel formulation design that forms sponge-like coacervate nanoparticle due to complimentary interactions of the excipients that otherwise are unable to self-assemble under similar conditions of dilution. This alternative formulation solves the limitations of currently marketed PtX products and can provide its effective delivery in clinical settings.
Pharmacokinetic Prediction of Immediate- and Extended-Release Tablets for Patients with Liver Disease Using Whole Body Physiologically-Based Pharmacokinetic Modeling for the Antipsychotic Drug Quetiapine
Ji-Hun Jang & Seung-Hyun Jeong
doi : 10.1208/s12249-024-02995-4
Volume 26, article number 8, (2025)
Although quetiapine metabolism occurs extensively in the liver and careful dosing is recommended in patients with liver disease, there has been a paucity of pharmacometric studies to adjust the clinical dose of quetiapine according to liver-disease severity. This study aimed to establish a whole-body, physiologically-based pharmacokinetic (WB-PBPK) model to explain interindividual variability in quetiapine PK and quantitatively predict PK in patients with liver disease. The developed WB-PBPK model well described the PK characteristics of different quetiapine regimens in healthy populations. The PK predictions could also be applied to patients with schizophrenia (without significant differences from healthy subjects). For the same total dose of quetiapine, both immediate-release (IR) and extended-release (ER) tablets showed significantly increased exposure and decreased clearance in patients with liver disease compared to healthy subjects. The model showed that steady-state plasma quetiapine concentrations exceeded the usual therapeutic range after multiple doses of IR tablets 250 mg three times daily or ER tablets 800 mg once daily in patients with liver disease. Therefore, the doses of quetiapine IR or ER tablets could be reduced by 0.10–0.50 times depending on liver-disease severity, so that mean steady-state plasma concentrations could be positioned near the therapeutic range. WB-PBPK modeling for quetiapine enabled quantitative prediction of PK according to IR or ER formulation and liver-disease severity. The results of this study provide useful data for improving the therapeutic use of quetiapine by enabling dose selection based on formulation and liver-disease severity.
Impact of Storage on In Vitro Permeation and Mucoadhesion Setup Experiments Using Swine Nasal Mucosa
Jaiza Samara Macena de Araújo, Gabriela Gama Xavier Augusto, Aylla Mesquita Pestana, Francisco Carlos Groppo, Flávia Sammartino Mariano Rodrigues, Pedro Duarte Novaes & Michelle Franz-Montan
doi : 10.1208/s12249-024-03002-6
Volume 26, article number 7, (2025)
Intranasal topical administration offers a promising route for local and systemic drug delivery, with in vitro permeation and mucoadhesion studies often using porcine models. However, the impact of storage on mucosal integrity after the procedure remains unaddressed. This study aimed to standardize the preparation process and evaluated whether storage of porcine nasal mucosa impairs its integrity and permeability for experimental comparisons. Additionally, an optimized in vitro mucoadhesion experiment using texture analyzer equipment was investigated. Porcine nasal mucosa was subjected to different storage conditions ("fresh"; refrigerated at 4°C for 24 h and 48 h, and frozen at -20°C for two or three weeks) and assessed using optical and transmission electron microscopy. In vitro permeation assays were performed in a Franz-type vertical diffusion system with lidocaine hydrochloride (LDC). In vitro mucoadhesion assays were conducted using fresh nasal mucosa and a commercial nasal topical formulation using TA.XT. Plus texture analyzer. The variables involved (probe speed, contact time, and application force) in assessing mucoadhesive capacity (maximum mucoadhesive force Fmax and work of mucoadhesion Wmuc) were optimized using a Central Composite Design. Fresh tissues showed no alterations in histological arrangement or in the ultrastructure of adherence junctions. Stored tissues exhibited histological disorganization, reduced thickness, and loss of epithelial integrity. LDC permeability increased in storage tissues (p < 0.05). Contact force had a positive effect on Fmax and Wmuc (p < 0.0001), with a minimum required value of 0.48 N. Variations in contact time and probe speed did not affect the responses (p > 0.05). In conclusion, the preparation technique was adequate to maintain mucosa integrity for permeability studies. However, storing the mucosa at 4 or -20°C overestimated LDC permeation, which could mislead critical data for formulation development. Therefore, the use of fresh mucosa is recommended to ensure more reliable results. For in vitro mucoadhesion assays, a minimum contact force of 0.48N is required for optimal responses.
Mesogenic Architectures for Advanced Drug Delivery: Interrogating Lyotropic and Thermotropic Liquid Crystals
Induja Govindan, Angeeta Paul, Annamalai Rama, Anjana A. Kailas, K. A. Abutwaibe, Thamizharasan Annadurai & Anup Naha
doi : 10.1208/s12249-024-02985-6
Volume 26, article number 6, (2025)
The possibility of precisely regulating and targeting drug release with mesophase or Liquid crystal drug delivery systems has drawn much attention recently. This review offers a thorough investigation of liquid crystal drug delivery systems with an emphasis on their mesogenic architecture. It describes the various liquid crystal forms such as thermotropic and lyotropic liquid crystals and their applicability in advanced drug delivery. Liquid crystals are used as excellent carriers due to their distinctive characteristics, such as stimuli-responsive drug delivery and sustained release patterns. Comprehending the materials that form mesophase provides insight into their distinct physiochemical characteristics and their use in drug delivery. This review highlights the important role lyotropic and thermotropic liquid crystals play in drug delivery, underscoring their considerable potential. The transition of thermotropic liquid crystals from their conventional technological applications to drug delivery has been studied. Nonetheless, a few challenges still need to be addressed, including formulation strategy refinement, regulating release rates, maximising the loading of hydrophilic drugs, and storage stability. In the pharmaceutical field, addressing these issues will open the door to a revolutionary paradigm that will revolutionise therapeutic outcomes and improve patient care.
Isoquercitrin Loaded PEGylated Long Circulating Liposomes Improve Bone Mass and Reduce Oxidative Stress After Osteoporosis
Liangju Sheng, Fuping Gao, Zhe Lan, Bin Zong & Qilong Wang
doi : 10.1208/s12249-024-02993-6
Volume 26, article number 5, (2025)
Osteoporosis has increasingly become a major public health concern because of its associated heightened risk of bone fragility and fractures. In order to avoid the adverse risk of hormone therapy, scientists have considered isoquercitrin (IQ) as a natural phytoestrogen to potentially prevent osteoporosis. However, IQ has poor solubility and bioavailability which culminates in rapid elimination of phytoestrogen. Herein, this study sought to solve limited applications of IQ by preparing IQ-loaded PEGylated long circulating liposomes (IQ-Lips) via thin-film hydration method. After appropriate characterization using zeta-potential, polydispersed index (PDI), particle size and entrapment efficiency (EE), IQ-Lips were applied to ovariectomized rat models to evaluate their effect on osteoporosis. The results showed that the prepared IQ-Lips exhibited smaller sized nanoparticles (125.35 ± 4.50 nm), excellent PDI (0.244 ± 0.001) and zeta-potential (-28.64 ± 0.71 mV) with stable property and higher EE (92.10 ± 0.32%). Importantly, administration of IQ-Lips through oral route increased aqueous solvability, bioavailability and circulation time of IQ. Moreover, the IQ-Lips could increase bone microstructural densities and bone mass, as well as reduce oxidative stress in ovariectomized rat models. Altogether, the IQ-Lips may serve as a novel avenue to potentially prolong the circulation of IQ in the body and improve the bioavailability of IQ for treatment of osteoporosis.
Investigation of Minipigs as the Optimal Non-rodent Pre-clinical Species: Exploring Plasma Protein Binding of Marketed Cardiovascular Drugs Across Species
Subodh Mondal, Ritika Uppal & Satish CS
doi : 10.1208/s12249-024-03005-3
Volume 26, article number 4, (2025)
Pre-clinical studies in animals are an essential part of drug development for new chemical entities. Before clinical trials in humans, submission of safety data from one rodent and one non-rodent species is compulsory as per regulatory guidelines. Even though minipigs and monkeys are physiologically closer to humans, dogs are usually employed as the non-rodent pre-clinical species. In this study, the in vitro plasma protein binding of eleven marketed cardiovascular drugs was studied in dog, minipig, monkey and human to determine the preferred species. To conduct plasma protein binding studies, the most reliable equilibrium dialysis method was adopted. Ten out of eleven tested cardiovascular drugs showed statistically similar plasma protein binding in minipig and human plasma which was different from dog and monkey plasma. The results from the studies showed greater similarity between minipigs and humans suggesting that the minipig species maybe a better pre-clinical non-rodent model during drug development of cardiovascular drugs instead of the conventional dog species. Additionally, use of the more accessible minipig species may help in saving time, and resources during pre-clinical studies and may also be more predictive during the safety studies in humans during later stage clinical trials.
Cyclodextrin Drugs in Liposomes: Preparation and Application of Anticancer Drug Carriers
Lanni Feng, Ruting Wei, Jiali Wu, Xinmei Chen, Yan Wen & Jianming Chen
doi : 10.1208/s12249-024-02999-0
Volume 26, article number 3, (2025)
Cyclodextrin complexes have been widely used in pharmaceutical applications, but disadvantages such as the rapid clearance of cyclodextrins from the blood stream after in vivo administration or their replacement by other molecules in the biological medium with higher luminal affinity for cyclodextrins limit the application of cyclodextrins as drug carriers. Liposome-encapsulated hydrophobic drugs have low and unstable drug loading rates. Drug-in-CD-in-liposome (DCL), which encapsulate cyclodextrin inclusion complexes into liposomes, combine the advantages of both delivery systems, can effectively avoid the leakage and rapid release of lipophilic drugs in the lipid bilayer, and help to maintain the integrity of liposomes. This paper focuses on the preparation method, characterization and application of DCL, with a view to providing methods and references for the research and application of DCL technology.
Bifunctional Oxaliplatin (IV) Prodrug Based pH-Sensitive PEGylated Liposomes for Synergistic Anticancer Action Against Triple Negative Breast cancer
Lavkesh Bhute, Sayali Dighe, Oly Katari, Vivek Yadav & Sanyog Jain
doi : 10.1208/s12249-024-02988-3
Volume 26, article number 2, (2025)
Triple negative breast cancer (TNBC) exhibits higher susceptibility towards oxaliplatin (OXA) due to a faulty DNA damage repair system. However, the unfavorable physicochemical properties and risk of toxicities limit the clinical utility of OXA. Therefore, to impart kinetic inertness, site-specific delivery, and multidrug action, an octahedral Pt(IV) prodrug was developed by using chlorambucil (CBL) as a choice of ligand. The combination of OXA and CBL exhibited synergistic anti-cancer action in TNBC cell lines. Further, to maximize tumor-specific delivery, intracellular accumulation, and in-vivo performance, the developed prodrug (OXA-CBL) was encapsulated in pH-sensitive PEGylated liposomes into (OXA-CBL/PEG-Liposomes). The fabricated liposomes had smaller particle size < 200 nm and higher drug loading (~ 4.26 ± 0.18%). In-vitro release displayed pH-dependent sustained release for up to 48 h. Cellular internalization revealed maximal uptake via clathrin-mediated endocytosis. The cytotoxicity assay showed reduced IC50 in the 4T1 (~ 1.559-fold) and MDA-MB-231 (~ 1.539-fold) cell lines than free OXA-CBL. In-vivo efficacy in 4T1-induced TNBC model revealed a marked increase in % tumor inhibition rate, while diminished % tumor burden in OXA-CBL/BSA-NPs treated animals. Toxicity assessment displayed no signs of systemic and hemolytic toxicity. Overall, delivery of Pt (IV) prodrug as a pH-sensitive PEGylated liposomes offers a safer and efficient system to manage TNBC.
Physiologically Based Biopharmaceutics Modeling Coupled with Biopredictive Dissolution in Development of Bioequivalent Formulation for Mesalamine Enteric Coated Tablet: A Tough Nut to Crack
Sivacharan Kollipara, Pankaj Kumar Prabhat, Paramita Saha, Saurabh Gupta, Venkat Ramana Naidu & Tausif Ahmed
doi : 10.1208/s12249-024-02990-9
Volume 26, article number 1, (2025)
Mesalamine is a locally acting anti-inflammatory drug used to treat mild to moderate ulcerative colitis. Because of complex formulation principle and high in vivo variability, development of bioequivalent formulation for mesalamine is challenging. Further, fed state possess significant challenges for bioequivalence (BE) due to interplay of multiple factors. In the work, we have developed a novel biopredictive media for mesalamine enteric coated tablets and integrated into physiologically based biopharmaceutics model (PBBM) to predict in vivo fed behavior. USP III based gradient media was developed to mimic in vivo fed condition. The developed PBBM was initially validated with literature data and subsequently re-optimized with pilot BE study data. Further, virtual bioequivalence (VBE) was performed to evaluate model predictability for pilot BE data. Later, the model was applied for prospective BE predictions with increased subjects and parametric sensitivity analysis was performed to identify physiological factors that can impact in vivo performance. Further, the model was used to predict luminal and enterocyte concentrations in colon to demonstrate equivalent efficacy. Additionally, a novel dissolution/permeation tool (Dissoflux) was employed to compare permeability behavior of formulations. Overall, this work enabled BE prediction for complex mesalamine enteric coated tablets and helped to understand parameters that can impact in vivo performance.
