There are no bibliometrics analyses on articles published in clinical pharmacology journals. We aimed to determine the countries in which authors of original investigations or meta-analyses were based and their international collaboration. This is a cross-sectional study conducted in six journals linked to learned clinical pharmacology societies/associations. For each journal, we started with the June-2025 issue and searched backward for articles meeting the selection criteria until 100 were identified or the January-2024 issue was reached. To calculate the credit by country, we used the complete fractionalized counting (CFC) method for assessing authors' contribution considering only the country of the authors included in the byline. CFC awards 1 credit among all authors and countries. A total of 503 articles were included in the analysis: 100 from four journals and 79 and 24 from the other two. Investigators from 66 countries from all continents contributed as authors; 46 countries provided lead authors. All but one were multi-authored articles; 9% were authored by international teams (range among the six journals: 16%-41%). Of the 503 credits, top countries were the United States (99.14), China (76.14), Japan (31.65), Denmark (28.69) and the Netherlands (27.29). The 17 EU countries obtained 151.86 credits (30.2% of the total). Among the top 25 countries, only five were not high-income countries. This exploratory analysis showed that with limited international collaboration, the authors of these studies worked mainly in wealthy countries, except for China.
Drug development researchShivani Tyagi, Jayendra Kumar
The goal of the work was to formulate, optimize, and evaluate liquid-Self-nanoemulsifying drug delivery system (L-SNEDDS) co-loaded with Selegiline (SEL), a monoamine oxidase type B (MAO-B) inhibitor, and Biochanin A (BCA), a potent adjunctive neuroprotective agent found in Trifolium pratense, to enhance oral delivery and accelerate anti-Parkinsonian efficacy for the management of Parkinson's disease (PD). Propylene glycol was chosen as co-surfactant, Tween 80 as surfactant, and peppermint oil as oil phase after excipients screening, as this combination exhibited the broadest emulsification region in pseudo-ternary phase diagram. A systematic Quality-by-Design (QbD) approach was adopted, and formulation variables were optimized using Design-Expert software to obtain an optimized L-SNEDDS formulation with desirable physicochemical attributes. Dilution of the optimized SNEDDS led to the spontaneous formation of a stable aqueous nanoemulsion exhibiting a droplet size of 110.9 nm, polydispersity index (PDI) 0.265, transmittance of 98.86 ± 0.37%, zeta potential of -16.3 mV, viscosity of 6.35 ± 2.51 cP, self-emulsification time of 27.35 s, and conductivity of 196.23 ± 0.324 μS cm-1. In vivo studies showed that SEL-BCA-loaded SNEDDS exhibited better oral bioavailability than pure SEL-BCA suspension. Notably, SNEDDS achieved higher brain Cmax values for SEL (5.6 ± 0.41 μg mL-1) and BCA (13.84 ± 1.14 μg mL-1), as well as elevated plasma concentrations of SEL (6.51 ± 0.43 μg mL-1) and BCA (762.65 ± 16.82 μg mL-1). Collectively, the results underscore the potential of the SEL-BCA SNEDDS as a combinational delivery platform that could improve the effectiveness of combination therapy for the management of PD.
Pharmacology research & perspectivesWerner Cordier, Princess Ijeoma
Pharmacology education, often reputed as complex, overtly didactic and decontextualised, may benefit from artificial intelligence-supported strategies. However, current guidance is fragmented across disciplines and contexts, thus weakening evidence-based curricular implementation. This scoping review mapped existing research to identify applications, strengths, limitations, and areas for future development. A double-blinded screening process facilitated by Covidence yielded 17 eligible studies from four databases. Studies mostly comprised cross-sectional studies from high-income countries in the medical context, with generative artificial intelligence being predominant (ChatGPT-3.5 and ChatGPT-4.0). Research comprised assessment (n = 12), paedagogy (n = 4), curriculum design (n = 1), and programme evaluation (n = 1). Most studies assessed tools' ability to answer examinations, with mixed success depending on the version, question type, and inclusion of context in prompt engineering. Few studies incorporated students, limiting insights into learning impact. Zero-shot prompting was mostly used, limited further by unclear design frameworks, which may bias outcomes considering downstream inefficiencies. Current research prioritises the performance of artificial intelligence, rather than its integration or impact in learning, which reduces its applicability for curriculum design and competency development. Although promising, the impact is limited, requiring clearer instructional design and rationalisation within the education ecosystem. Although there is considerable potential for pharmacology education, research requires greater structure, longitudinal design, and incorporation of students to inform clear impact. Purposeful, context-aligned implementation and continuous evaluation are needed to ensure ethical, valid, and meaningful use in pharmacology education. To support future research, recommendations are provided for practical reporting, scientific design, and impact measurement.
Pharmacology research & perspectivesJon Andsnes Berg, Trond Trætteberg Serkland, Monika Kvernenes, Johnson Liu, Waltraud Binder, Steve Gallagher, David Reith, Ullamari Pesonen, Dimitra Mitsa, Mar…
Medication errors, often arising from insufficient pharmacology knowledge, can have serious consequences, highlighting the importance of effective pharmacology education for health care students. This study hypothesized that virtual reality (VR) could improve student engagement, motivation and perceived learning of core concepts in pharmacology. A mixed-method approach was employed. Students who had completed a course in basic pharmacology were recruited from five international study sites to view a VR animation, explaining drug absorption and bioavailability. The students responded to an online questionnaire exploring their experience and understanding. In addition, 13 medical students from the University of Bergen participated in focus group interviews to further explore their perceptions of VR in pharmacology education. A total of 133 students participated in the VR session and completed the questionnaire, with approximately half reporting that the VR animation changed their understanding of drug absorption. Thematic analysis of the focus group interviews produced three themes descriptive of the students' learning experiences, each pivoting tensions between: (1) The role of VR in integrating pharmacology with other medical disciplines; (2) striking a balance between engaging and overwhelming learning experiences; (3) in-depth learning under the weight of assessment. The technical solution appears satisfactory, and students found the 360° VR animation engaging and useful for visualizing the complex concepts of absorption and bioavailability. VR animation shows potential to enhance integration of pharmacology to other medical disciplines. However, careful design is required to support self-paced learning and minimize cognitive overload.
Topics in antiviral medicineKimberly K Scarsi, Catia Marzolini, Fiona Marra, Alice L Tseng
Clinical pharmacology plays a crucial role in the successful treatment and prevention of HIV and other viral infections. Information from the field of clinical pharmacology leads to the development of novel antiviral treatments, supports the evaluation of efficacy and safety of antiviral therapies, informs the management of drug-drug interactions, and defines the optimal dosing and drug selection for special populations. The International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs recently held its 26th meeting. This review focuses on selected abstracts presented at the 2025 workshop and provides insights to assist clinicians in applying this new knowledge to clinical practice.
Drug deliveryGabriela Koutná, Jan Kotouček, Jan Macků, Kateřina Kubová, Martina Urbanová, Larisa Janisová, Ivana Šeděnková, Jan Muselík, Jakub Vysloužil, Josef Mašek, Elišk…
Self-microemulsifying drug delivery systems (SMEDDS) containing volatile phytotherapeutics such as thymol (T), carvacrol (C), and eugenol (E) present significant formulation challenges, even when solidified. Their instability and interactions with coatings often hinder intestinal delivery. To address these limitations, we developed solid SMEDDS consisting of pellets (microcrystalline cellulose/magnesium aluminometasilicate/chitosan) and enteric capsules (CEC) for enhanced intestinal delivery. Based on solubility and pseudo-ternary phase diagrams, SMEDDS formulations (SES1-3) differing in component ratios (glycerol monooleate/caprylocaproyl macrogol-8 glycerides/diethylene glycol monoethyl ether) with 5% w/w of each drug were identified, demonstrating nano-scale droplet sizes (PDI <0.4) and showing no phase separation over 6 months. Thermodynamic stability and liquid-state NMR revealed particle size variations with preserved structural integrity. The lead formulation SES1 exhibited superior ex-vivo intestinal permeation (T-SES1). CECs filled with T-, C-, and E-loaded SES1 pellets, respectively, prepared via extrusion/spheronization, exhibited in-vitro gastro-resistant release, and achieved > 85% drug release within 120 min after a pH change to 6.8 during a one-year stability study (25 °C; 60% RH). FTIR-ATR analysis of the CEC internal surface confirmed the temperature-dependent restructuring of hypromellose and E sorption, a phenomenon not observed with C or T, which is likely attributable to physicochemical distinctions. Oral administration of CEC with T-SES1-pellets (0.5 mg/kg) in piglets demonstrated a delayed peak plasma concentration (Cmax 11.67 ng/mL at 9 h) and sustained systemic exposure (AUC 119.8 ng·h/mL). These in-vivo findings substantiate the gastro-protective effect and enhanced intestinal absorption, positioning the pellet/CEC system as a promising strategy for the application of volatile phytotherapeutics in current pharmacotherapy.
ChemMedChemMaría Laura Lavaggi, María Fernanda García, Mauricio Cabrera, Marcos Couto, Hugo Cerecetto
This review summarizes the evolution of our research on anticancer agents, from early efforts on hypoxia-selective cytotoxins to more recent developments in chemoprevention, molecular targeting, and radiopharmacy. Initial studies focused on the design of N-oxide-containing heterocycles as bioreductive-prodrugs activated under tumor hypoxia. While early triazine N-oxides and furoxans showed limited selectivity, these studies underscored the importance of redox-properties in biological activities. This led to the identification of phenazine 5,10-dioxides as a more suitable pharmacophore, affording compounds with improved potency- and hypoxia-selectivity, supported by mechanistic-, physicochemical-, and in vivo studies. Parallel efforts explored metal-based complexes and formulation strategies enhancing bioavailability and therapeutic performance. Alongside these efforts, cancer chemopreventive-agents were investigated, particularly chalcone-derived scaffolds and related hybrids capable of modulating phase I/II enzymes through Nrf2 activation. Additionally, attention has shifted toward targeted- and diagnostic-approaches, including radiopharmaceuticals for hypoxia-imaging and the use of biomolecular recognition systems, such as aptamers, polypeptides, and antibodies, to selectively address tumor-associated biomarkers. These strategies include aptamer-based biotherapeutics for drug delivery and imaging, as well as approaches combining tyrosine kinase receptor targeting with BNCT. Furthermore, bioorthogonal-methodologies have been explored enabling selective in situ activation and targeting. Together, these studies illustrate a multidisciplinary approach integrating chemistry, biology, and pharmacology toward more selective anticancer strategies.
ChemMedChemMaria-Eleni Kouridaki, Mercè Pallàs, Carmen Escolano
The imidazoline receptor (IR) system, comprising the I1R, I2R, and I3R subtypes, consists of binding sites involved in cardiovascular, metabolic, and neurological disorders. This review updates the 2004 compilation by Dardonville and Rozas on IR ligands, emphasizing promising ligands, subtype selectivity, and pharmacological profiling. Representative ligands for each subtype are analyzed to highlight key pharmacological aspects, including affinity, selectivity, and functional activity, integrating findings from preclinical and clinical studies. Critical molecular targets such as Nischarin/IRAS for I1R and MAO-B-associated sites for I2R are discussed in the context of ligand design and CNS penetration. I1R-selective ligands, exemplified by rilmenidine, show improved selectivity over α2-adrenoceptors and exhibit antihypertensive, metabolic, and neuroprotective effects. I2R ligands display neuroprotective, anti-inflammatory, and analgesic activities, with CR4056 progressing to Phase II trials. PET imaging with [11C]BU99008 has validated I2R upregulation as a biomarker for neurodegeneration. Overall, the IR system presents therapeutic opportunities: I1R for cardiovascular and metabolic disorders, I2R for pain and neurodegeneration, and I3R for diabetes. Continued ligand optimization and receptor characterization are essential for clinical translation.
Human mutationIoanna Poulida, Kariofyllis Karamperis, Ioanna Konstantina Routsi, Ioannis Sarris, George Mantzouranis, Vassilis Kostopoulos, Christina Mitropoulou, George P P…
Traditional medicine is now moving from the "one-size-fits-all" model toward personalized medicine, where diagnostic and therapeutic decisions are guided by the patient's unique genetic profile. Recent advances in genomics and pharmacogenomics have facilitated the identification of genetic variants linked to disease susceptibility and progression, as well as variability in drug response. However, translating these findings into clinical practice remains challenging, primarily due to the high cost and sophisticated genetic analysis infrastructure, which is only available in centralized genetic laboratories. A newly developed Portable Genetic Analyzer (PortaGen) was designed for point-of-care molecular genetics and pharmacogenomics analysis and evaluated in this study. PortaGen integrates 3D-printed parts and laptop-based centralized software control, along with digital recording and storage of results to support decentralized genetic testing. The prototype portable device was validated in comparison with an established portable polymerase chain reaction (PCR) workstation that complies with current operational standards and a reference laboratory-based method. Genotyping analysis was performed using ARMS-PCR (Amplification Refractory Mutation System Polymerase Chain Reaction) to detect and analyze CYP2C19 genetic variants (CYP2C19 ∗ 2; rs4244285, and CYP2C19 ∗ 17; rs12248560), relevant to pharmacogenomics, as well as the HBB: c.93-21(G>A) genetic variant, the most common variant leading to β-thalassemia. Concordance in genotyping calls between the new device, the established portable workstation, and the reference method was assessed using percentage agreement and Cohen's kappa coefficient, demonstrating consistently high concordance with statistically significant results (p < 0.05). These findings demonstrate that the new portable genotyping analyzer has improved throughput, visualization, and workflow efficiency into a suitcase-sized, portable point-of-care molecular genetic analysis device, which holds promise to advance personalized medicine interventions in a scalable and affordable fashion.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VMuzaffaruddin Ahmed Madny, Khushwant S Yadav
Parkinson's disease is a distinctly age-associated neurodegenerative disorder in which oral levodopa remains the therapeutic foundation, particularly in older adults. Yet with advancing age, the reliability of oral therapy progressively declines not simply due to inadequate dosing, but because ageing reshapes the gastrointestinal environment on which drug absorption depends. This review integrates evidence spanning neuromuscular decline, epithelial barrier fragility, altered luminal chemistry, immune dysregulation, microbiome remodelling, and enteric neurodegeneration to explain how the ageing gut generates exposure instability. Delayed gastric emptying, inconsistent proximal intestinal delivery, microbial drug metabolism, and real-world administration constraints collectively amplify pharmacokinetic variability, producing erratic onset, fluctuating plasma profiles, and reduced therapeutic predictability. Using levodopa as a clinically established model system, we extend these insights to the broader challenge of ensuring reliable performance of oral therapies in ageing populations. We argue that therapeutic success in older adults depends less on maximizing mean bioavailability and more on stabilising exposure under heterogeneous physiological and practical conditions. Accordingly, the review integrates ageing-associated gastrointestinal decline, altered luminal and epithelial determinants of drug absorption, pharmacokinetic instability, and formulation design responses into a unified translational framework for ageing-aware oral therapy. By reframing levodopa failure as a consequence of ageing-driven gut-drug instability, this review proposes an ageing-aware formulation framework and identifies exposure-stability endpoints to guide the development and evaluation of physiologically resilient oral therapies for older adults.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VJuan Ma
The growing demand for subcutaneous (SC) self-administration of biotherapeutics, driven by the rising prevalence of chronic diseases and healthcare cost-containment pressures, has accelerated the development of high-concentration formulations (HCFs). However, protein concentrations exceeding 100 mg/mL introduce significant challenges, including solubility limitations, high viscosity, aggregation propensity, injectability constraints, and manufacturing complexities. This review systematically examines the primary obstacles in HCF development and highlights recent advances in formulation and process technologies. Key strategies include: (i) excipient-based viscosity reducers; (ii) hyaluronidase-enabled large-volume SC delivery; (iii) lyophilization for decoupling manufacturing from final concentration; (iv) spray drying platforms including SnapShot™ and XeriJect®; (v) electrostatic spray drying (Elektroject™ Hypercon™); (vi) Microglassification™ dehydration technology; and (vii) protein crystallization (Crystalomics®). Collectively, these innovations are reshaping the landscape of high-concentration biologic drug products, enabling the transition from intravenous to subcutaneous administration for a broader range of therapeutics. This review serves as a strategic guide for formulation scientists and drug developers engaged in next-generation subcutaneous biologics.
Medical science monitor : international medical journal of experimental and clinical researchDongde Xie, Mingming Deng, Xiaoming Yang, Jie Huang, Xucan Hong, Ning Xu
BACKGROUND Hypertension management is often suboptimal due to interindividual variability in drug response. Pharmacogenomics testing may guide personalized therapy by identifying genetic polymorphisms affecting drug efficacy and safety. This study aimed to evaluate whether pharmacogenomics-guided therapy improves blood pressure control and treatment compliance and reduces rehospitalization in patients with hypertension. MATERIAL AND METHODS In this prospective randomized controlled trial, 900 patients with hypertension were assigned to a control group (CG, n=450) receiving conventional care or a study group (SG, n=450) receiving pharmacogenomic-guided therapy. Six gene loci (CYP2D6, CYP2C9, AGTR1, ACE, NPPA, CYP3A5) related to 5 antihypertensive drug classes were tested. Outcomes included blood pressure control rate, compliance, adverse reactions, drug adjustments, and 6-month readmission rate. RESULTS The SG achieved significantly higher blood pressure control rates at 3 months (80.7% vs 70.2%, P<0.001) and 6 months (78.4% vs 65.1%, P<0.001) compared with the CG. Treatment compliance was also higher in the SG (98.0% vs 74.0%, P<0.001). angiotensin-converting enzyme inhibitor-related dry cough incidence was lower in the SG (1.6% vs 8.3%, P<0.001). The SG required fewer drug adjustments during hospitalization and had a lower 6-month readmission rate (2.4% vs 8.9%, P<0.001). CONCLUSIONS Pharmacogenomic-guided individualized therapy improves blood pressure control, enhances treatment adherence, reduces specific adverse reactions, and decreases rehospitalization. These findings support integrating pharmacogenomic testing into personalized hypertension management.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VYuta Shiga, Naoto Sakurai, Luca Chiari
Understanding long-term physical changes in lyophilized matrices is essential for rational formulation design and stability assessment. In this study, positron annihilation lifetime spectroscopy (PALS) was applied to monitor time-dependent structural evolution in simple lyophilized carbohydrate-polymer matrices stored for up to 21 months under low and elevated humidity conditions. Formulations containing saccharides, polyols and starch were selected as model amorphous systems to investigate molecular mobility and phase evolution in the absence of active pharmaceutical ingredients. The free volume and ortho-positronium (o-Ps) intensity were determined as complementary indicators of free volume within the amorphous phase and relative amorphous fraction, respectively. Over prolonged storage, composition- and humidity-dependent changes in these parameters were observed. Under elevated humidity, selected formulations exhibited reductions in o-Ps intensity consistent with partial recrystallization, while variations in free volume reflected concurrent structural relaxation within the remaining amorphous phase. Solid-state 1H NMR and X-ray diffraction provided complementary support for these evolution trends. The results demonstrate that PALS sensitively detects physical aging and structural changes in lyophilized matrices by probing free-volume evolution during storage. These findings support the utility of PALS as a non-destructive analytical tool for monitoring long-term physical stability of amorphous lyophilized matrices under defined environmental conditions.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VEun-Soo Jung, Hui-Yeon Jang, Su-Jin Jung, Byoung-Hag Kim, Yoo-Jung Kim, Jeong-Han Moon, Soo-Wan Chae, Seung-Ok Lee
BACKGROUND: Glutathione is a tripeptide involved in antioxidant defense; however, its systemic availability following oral administration remains controversial, and pharmacokinetic differences between formulations in humans are not well characterized. OBJECTIVE: This study compared the pharmacokinetics and short-term supplementation effects of an orally dissolving film (ODF) and a conventional tablet formulation of glutathione in healthy adults. METHODS: In Study I, a randomized open-label crossover trial evaluated single-dose (300 mg) pharmacokinetics following administration of ODF or tablets. In Study II, participants consumed ODF (100 mg/day) or tablets (100 mg/day) for 4 weeks. RESULTS: Plasma glutathione concentrations were higher in the ODF group, with significant differences at 4 and 6 h. The ODF formulation showed a longer Tmax and tended toward higher Cmax and systemic exposure (iAUC0-6h). During 4-week supplementation, both formulations increased circulating glutathione levels, with no significant changes in oxidative stress-related biomarkers. No adverse events were reported. CONCLUSIONS: The ODF formulation exhibited a distinct pharmacokinetic profile and showed a trend toward greater systemic glutathione exposure compared with the tablet formulation. These findings suggest that formulation characteristics may contribute to differences in the bioavailability and pharmacokinetic behavior of orally administered glutathione. CLINICAL TRIAL REGISTRATION: Clinical Research Information Service (CRIS), KCT0011710.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VMaria Antonia S de Albuquerque, Douglas F de Albuquerque
Mathematical models for drug release from polymeric nanocapsules have traditionally relied on Noyes-Whitney-based first-order kinetics, which implicitly predict faster release for drugs exhibiting higher solubility in the oily core. This prediction is inconsistent with numerous experimental observations in which more lipophilic compounds are released more slowly. To address this apparent paradox, a partition-controlled kinetic framework is derived in which the effective release rate scales inversely with oily-core solubility. The resulting model, [Formula: see text] introduces a dimensionless correction factor α and a reference solubility S0, yielding a dimensionally consistent formulation while preserving the mechanistic inverse-solubility dependence predicted by partition equilibrium arguments. A re-analysis of the previously published nanocapsule model reveals a dimensional inconsistency and a tabulation error affecting the reported kinetic parameters. After correction, the published adapalene data are found to be consistent with the proposed inverse-solubility scaling. The model is further evaluated using four release datasets (adapalene in two oily cores, capsaicin, and dihydrocapsaicin), yielding R2 values between 0.925 and 0.969 with Cmax fixed at the final experimental value. These results support partition-controlled release as a physically plausible and dimensionally consistent framework for describing drug release from polymeric nanocapsules.
Drug deliveryJoanna Sobocińska, Chun Yuen Jerry Wong, Emre Gezer, Hui Xin Ong, Youssef Daali, Véronique Serre-Beinier, Daniela Traini, Muriel Cuendet
Resveratrol is a polyphenolic compound with therapeutic potential for pulmonary diseases, yet its use is limited mostly due to low oral bioavailability. Inhalable powder formulations are a promising strategy to help overcome those challenges. Here, we report the development and physicochemical characterization of a spray-dried resveratrol formulation suitable for pulmonary delivery. The pharmacokinetic profile and in vivo toxicity were then assessed. Particle size, interparticle cohesion, morphology, uptake, and stability of the formulation were evaluated. Intratracheal administration was then performed in A/J mice and pulmonary distribution was compared to a micronized resveratrol formulation. Lung and plasma concentrations were quantified by LC-MS/MS at 5-70 min postadministration, followed by long-term toxicity evaluation. The spray-drying process produced resveratrol with improved lung exposure while preserving properties essential for pulmonary delivery. In vivo, the spray-dried formulation achieved improved pulmonary and lower systemic distribution compared to the micronized form, increasing the lung to plasma AUC ratio from 77 to 282. Moreover, a greater number of mice had detectable concentrations of resveratrol in the lungs following spray-dried administration (62.5% vs 37.5% for micronized). The long-term intratracheal administration of spray-dried resveratrol (1 mg, 3× per week for 12 weeks) was well tolerated, with no clinical, biochemical, or histopathological signs of toxicity. Altogether, the spray-dried formulation of resveratrol could be efficiently delivered to the lungs and displayed an excellent safety profile, supporting its future investigation in respiratory disease models.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VTiandian Wang, Anuj A Biswas, Feng Zhang, Rongjin Sun, Ming Hu
With annual overdose deaths in the United States over 1 million, medication-assisted treatment with buprenorphine (BUP) remains the first-line, gold-standard therapy for opioid use disorder (OUD). Because OUD is a chronic, relapsing condition that requires long-term pharmacotherapy, long acting injectables (LAI) and implantable formulations offer important advantages over daily formulations for maintenance treatment. By comparing transmucosal BUP and LAI formulations' systemic exposure profiles and μ-opioid receptor (MOR) occupancy, converging data demonstrate that higher and more sustained BUP exposure with low variability is required to fully suppress withdrawal, cravings, and illicit opioid use. These findings indicated that currently marketed formulations may not adequately address the clinical challenges associated in the fentanyl/polysubstance era. Accordingly, this rationale-based review proposes a mechanistic framework supporting the development of next-generation BUP-PLGA solid biodegradable implants to maintain a conservative therapeutic benchmark (e.g. Css ≥ 5 ng/mL) for extended durations (e.g. 3-6 months) with low variability (e.g. no large burst release, major lag phase or phase inversion). However, progress in implant development has been hindered by limited mechanistic understanding of drug release. In PLGA-BUP systems, poor IVIVC is largely driven by the low and pH-dependent solubility of BUP, which can make dissolution rate-limiting in vivo and interact with the evolving PLGA acidic microenvironment (acidification, porosity formation, and autocatalytic degradation). Future research should be prioritized to determine directly whether polymer erosion coincides with drug release in PLGA depots, or whether residual, poorly soluble BUP persists locally and releases under dissolution-limited kinetics. Clarifying these mechanisms is not only essential to fulfill the regulatory and translational expectations of the FDA and NIDA, but also to deepen mechanistic understanding and accelerate the rational development of LAI formulations for poorly soluble drug.
Journal of medicinal chemistryDominga Evangelista, Elliot Nelson, Ben Tehan, Greta Bagnolini, Marinella Roberti, Giovanni Bottegoni
Drug-induced liver injury (DILI) is a leading cause of drug failure and post-market withdrawals. Traditional preclinical methods fail to detect up to 40-45% of clinical hepatotoxicity cases. Computational approaches, particularly those based on machine learning and deep learning (DL), are emerging as promising tools to support medicinal chemistry and early drug discovery, though their predictive capabilities remain under active investigation. In this perspective, we review the development of DILI annotation data sets, tracing their growth from small collections to large, comprehensive resources. We also outline the evolution of computational methods, from simple descriptor-based models to advanced DL and ensemble approaches that incorporate interpretable features. Finally, we highlight recent efforts to integrate standardized causality frameworks, pharmacogenomics, and mechanistic models, aiming to connect computational advances with clinical relevance. This perspective provides valuable insight for researchers and promotes the development of more robust and consensual DILI prediction strategies.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VHai Van Ngo, Stijn Daems, Matthias Govaerts, Clara Aguilar-Pérez, Guy Van den Mooter
Fixed-dose combinations (FDCs) offer significant advantages in the treatment of multidrug-resistant tuberculosis (MDR-TB), including reduced pill burden, increased treatment adherence, minimization of resistance development, and decreased relapse rates. A critical prerequisite for developing FDCs in single-unit formulations is ensuring physicochemical compatibility between the combined drugs, particularly for ionizable compounds. Bedaquiline (BDQ) and clofazimine (CFZ) are weakly basic drugs and promising candidates for next-generation antituberculosis FDCs. BDQ fumarate (BDQF) is widely used in the commercial product due to its improved solubility and oral bioavailability. This study provides a comparative evaluation of binary systems containing BDQ or BDQF with CFZ at different molar ratios, including 1:1, 1:2, and 2:1. Through physicochemical characterization using Fourier transform - InfraRed (FTIR) spectroscopy, X-ray powder diffraction (XRPD), apparent solubility and dissolution studies, we demonstrate that BDQF undergoes counterion transfer with CFZ, leading to the formation of new salts of either CFZ or BDQ. These new salts significantly enhance the dissolution behavior of CFZ in the BDQF-CFZ binary systems, which cannot be seen in the BDQ-CFZ systems. On the other hand, the dissolution rate of BDQF was also decreased in specific drug ratios. More specifically, we found that the ratio of 2:1 can synergistically enhance the solubility of CFZ, maintain the equibilirum solubility and provide adequate dissolution of BDQF. The findings provide mechanistic insights of selecting suitable drug forms in optimizing FDC performance and designing optimal formulations for MDR-TB therapy.
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.VFabrício Costa Fanhani, Laiene Antunes Alves, Marcel Henrique Marcondes Sari, Antônio Eduardo Matoso Mendes, Roberto Pontarolo, Luana Mota Ferreira
BACKGROUND: Extemporaneous liquid antihypertensive formulations are widely used in pediatrics but frequently lack detailed reporting of excipient safety data, particularly regarding age-specific physiological vulnerability and cumulative exposure. METHODS: A scoping review was conducted in accordance with PRISMA-ScR guidelines to map excipients used in pediatric extemporaneous antihypertensive liquid formulations. A regulatory-oriented assessment was applied, emphasizing age-appropriate safety considerations and exposure-based risk principles, including theoretical daily intake expressed as mg/kg/day. RESULTS: Forty-two studies were included. Reporting of excipient concentrations, age targets, and safety justifications was heterogeneous and often incomplete. Vehicles, co-solvents, preservatives, buffers, antioxidants, surfactants, and flavoring agents were identified, with selection typically driven by a focus on physicochemical stability rather than patient-centered criteria, such as age-appropriate excipient safety, dose flexibility, and acceptable volumes. Exposure-based considerations were addressed by a limited number of studies (n = 5). Exposure calculations based on typical pediatric dosing showed that concentrations considered acceptable in adult formulations may translate into clinically relevant toxicity risks in neonates and infants. Based on observed patterns, a conceptual risk stratification framework was developed to categorize excipients according to age-dependent toxicity, cumulative dose burden, and functional tolerability. CONCLUSIONS: The available literature on compounding antihypertensive formulations mainly emphasizes physicochemical performance, with less attention given to exposure-related safety parameters in pediatric patients. Integrating total daily excipient exposure metrics and structured justification for excipient selection may improve alignment with regulatory expectations and support safer, patient-centered compounding practices in pediatric clinical care.