Pharmaceutics最新文献

Background/Objectives: The high volatility of volatile drugs significantly restricts their clinical applicability. Although excipients capable of strong interactions can reduce volatilization, conventional screening methods rely on empirical trial-and-error, resulting in low efficiency and high resource consumption. To address this limitation, this study introduces an artificial intelligence (AI)-driven strategy for screening drug-excipient interactions. Using d-borneol as a model drug, this approach aims to efficiently identify strongly interacting excipients and develop stable nano-formulations. Methods: High-throughput simulations were performed using the Protenix structure prediction model to evaluate interactions between d-borneol and 472 FDA-approved excipients. The top 50 candidate excipients were selected based on these simu-lations. Molecular docking and stability experiments were conducted to validate the predictions. Results: Molecular docking and stability experiments confirmed the consistency between predicted and experimental results, validating the model's reliability. Among the candidates, soybean phospholipid (PC) was identified as the optimal excipient. A lyophilized liposomal formulation prepared with PC significantly suppressed the volatilization of d-borneol and improved both thermal and storage stability. Mechanistic investigations indicated that d-borneol stably incorporates into the hydro-phobic region of phospholipids, enhancing membrane ordering via hydrophobic interactions without disturbing the polar headgroups. Conclusions: This study represents the first application of a structure prediction model to excipient screening for volatile drugs. It successfully addresses the stability challenges associated with d-borneol and offers a new paradigm for developing nano-formulations for volatile pharmaceuticals.

Epigenetics involves heritable changes in gene expression-such as DNA methylation (5-methylcytosine; 5mC), histone modifications, and regulation by non-coding RNAs at the mRNA translation level-without altering the underlying DNA sequence. As targeting these mechanisms enables intervention at the root cause of disease rather than the symptoms alone, epigenetics has become a rapidly advancing field in pharmaceutical sciences. Various epigenetic modulators, including histone deacetylase (HDAC) inhibitors, histone acetyltransferase (HAT) inhibitors, DNA methyltransferase (DNMT) inhibitors, and microRNAs (miRNAs), have been developed, and some have already been approved for cancer therapy. However, these agents often face significant challenges such as poor membrane permeability, enzymatic instability, and suboptimal biodistribution. Incorporating functionalized accessory units-serving as vectors (e.g., transporter recognition units, cell-penetrating peptides, tumor-homing peptides, monoclonal antibodies) or as carriers (e.g., monoclonal antibodies, nanoparticles)-into epigenetic modulators may help overcome these delivery barriers. In this narrative review, I discuss the potential and advantages of effective non-invasive delivery of epigenetic drugs using such functionalized accessory unit conjugates.

Background/Objectives: Digoxin is a cardiotonic agent with a narrow therapeutic window and a high risk of toxicity. The current clinical use is based on an empirically FDA-recommended regimen which has wide dosing ranges, introducing the risk of inappropriate dosing and related adverse events. This study aims to develop a physiologically based pharmacokinetic (PBPK) model to characterize digoxin pharmacokinetics in adult and pediatric patients with heart failure, and then to evaluate the FDA-recommended regimen. Methods: The PBPK model was initially developed in healthy adults using PK-Sim^®. Then, it was translated to adults with heart failure by incorporating disease factors. Next, it was further translated to pediatrics by scaling age-related parameters. Finally, through two-step translations, the model was used to evaluate current dosing regimens to inform safety and effectiveness based on observing predicted trough concentrations at a steady state. Results: This PBPK model has strong predicting ability, where observed concentrations and key PK metrics (C_max, AUC_0-t) were within 0.5-2.0-fold of predictions in healthy adults, adults with heart failure, neonates, and infants. The model prediction work on the evaluation of recommended dosing regimens from the FDA shows that the current regimen may not achieve the lowest boundary of the therapeutic window (0.5-2 ng/mL) in neonates (0-30 days), whereas infants (1-2 months) and children (<18 years) are generally good within it. Conclusions: This PBPK model explained major physiological and pathological contributors to differences in digoxin pharmacokinetics across populations and showed good performance in pediatric extrapolation. It also pointed out the shortage of empirical dosing regimens for such a drug with a narrow therapeutic window. The model may assist in optimizing the pediatric dosing strategies of digoxin, and suggests that current neonatal dosing regimens need refinement.

Background: Nanotechnology provides innovative strategies to enhance drug delivery and therapeutic efficacy through advanced nanocarrier systems. Objectives: This study aimed to develop and optimize a nanostructured lipid carrier (NLC) co-encapsulating curcumin (CUR) and resveratrol (RESV) using a fractional factorial design to develop a topical formulation with antioxidant and anti-inflammatory properties. Methods: NLCs were produced via hot emulsification followed by high-pressure homogenization, and their physicochemical characteristics, drug content, stability, release profile, antioxidant activity, skin delivery, and cellular compatibility were evaluated. Results: The optimized formulation exhibited an average particle size of approximately 300 nm, a polydispersity index below 0.3, and high drug loading for both compounds. Stability studies over 90 days revealed no significant changes in physicochemical parameters, confirming the formulation's robustness. In vitro release assays demonstrated sustained release of both actives, with 58.6 ± 2.9% of CUR and 97 ± 3% of RESV released after 72 h. Antioxidant activity, assessed by the DPPH and ABTS assays, showed concentration-dependent radical-scavenging effects, indicating antioxidant potential. Skin permeation/retention experiments using porcine skin showed enhanced retention of CUR and RESV within the tissue, with no detectable permeation, indicating suitability for topical delivery. In addition, in vitro cell assays using human keratinocytes showed concentration-dependent responses and acceptable cellular compatibility. Conclusions: Overall, this study demonstrates the successful application of nanotechnology and experimental design to develop stable and efficient lipid-based nanocarriers containing natural polyphenol for topical therapy targeting oxidative and inflammatory skin disorders.

In this article, a systematic review and analysis of the present literature is conducted, regarding the excipients present in dry powder inhaler formulations. Until now, there has been no list of excipients recorded, specifically for DPIs, with the number of approved excipients for pulmonary delivery being restricted, despite their choice as a pivotal step for the formulating process. Understanding the DPI formulations, physicochemical characteristics, efficiency, and release profiles, demonstrated in detail here, could contribute to their application in future studies and be a useful research tool in the choice of excipients in the field of inhalation technology and specifically DPIs.

Background: Drug delivery against ciprofloxacin-resistant microbial strains is one of the most challenging areas of research in the pharmaceutical industry. The broad-spectrum antibiotic ciprofloxacin often faces challenges due to its poor bioavailability; thus, the activity of this drug is generally compromised against resistant strains. Traditional drug delivery systems, such as liposomes, are utilized to address this issue; however, niosomes have surfaced as a promising successor to their liposomal counterparts due to their superior attributes, such as enhanced stability and reduced toxicity. However, owing to environmental and toxicological concerns over commonly used chemical surfactants in niosomes, there is a pressing need to explore greener and safer alternatives. This study is focused on the application of sophorolipids (SLs), a biosurfactant that is synthesized by the yeast Starmerella bombicola, as a vesicular assembly for ciprofloxacin encapsulation. Methods: The SL-based niosomal formulation was characterized for particle size, zeta potential, and polydispersity index (PDI), while transmission electron microscopy (TEM) was employed to determine the morphology of niosomes. Agar well diffusion, broth dilution, and biofilm inhibition assays were performed to assess efficacy. Results: The niosomal formulations were successfully prepared; among them, the (+)vely charged formulation exhibited a more organized morphology, and their size and zeta potential values were found to be around ~371 nm and 63 mV for the blank niosomes (without the loaded drug) and ~269 nm and 51 mV for the ciprofloxacin-loaded niosomes. The minimum inhibitory concentration and biofilm inhibitory concentration against the MRSA strain were 5 µg/mL and 25 µg/mL, respectively, for the ciprofloxacin-loaded, (+)vely charged SL niosomes-for free ciprofloxacin these values were 40 µg/mL and 100 µg/mL-presenting remarkable potential for biofilm inhibition. Conclusion: This study highlights the promising therapeutic potential of SL-based ciprofloxacin-loaded niosomes against the emerging health threat of the MRSA strain.

The emergence of multidrug-resistant (MDR) bacterial pathogens has heightened the urgency for novel antibacterial agents. The bacterial cell wall usually comprises peptidoglycan, which presents a prime target for antibacterial drug development due to its indispensable role in maintaining cellular integrity. Conventional antibiotics such as β-lactams and glycopeptides hinder peptidoglycan synthesis through competitive binding of penicillin-binding proteins (PBPs) and sequestration of lipid-linked precursor molecules. Nevertheless, prevalent resistance mechanisms including target modification, β-lactamase hydrolysis, and multi-drug efflux pumps have limited their clinical utility. This comprehensive analysis explicates the molecular machinery underlying bacterial cell wall assembly, evaluates both explored and unexplored enzymatic nodes within this pathway, and highlights the transformative impact of high-resolution structural elucidation in accelerating structure-guided drug discovery. Novel targets such as GlmS, GlmM, GlmU, Mur ligases, D,L-transpeptidases are assessed for their inclusiveness for the discovery of next-generation antibiotics. Additionally, cell wall inhibitors are also examined for their mechanisms of action and evolutionary constraints on MDR development. High-resolution crystallographic data provide valuable insights into molecular blueprints for structure-guided optimization of pharmacophores, enhancing binding affinity and circumventing resistance determinants. This review proposes a roadmap for future innovation, advocating for the convergence of computational biology platforms, machine learning-driven compound screening, and nanoscale delivery systems to improve therapeutic efficacy and pharmacokinetics. The synergy of structural insights and cutting-edge technologies offers a multidisciplinary framework for revitalizing the antibacterial arsenal and combating MDR infections efficiently.

Background/Objectives: Levofloxacin (LVX) is a fluoroquinolone approved for the treatment of bacterial pneumonia, sinusitis, and prostatitis. Emerging in vitro and preclinical evidence suggests that efflux transporters are involved in LVX's target tissue site distribution. Methods: The objective of this research was to characterize tissue exposure using a physiologically based pharmacokinetic (PBPK) model to be able to make more educated choices for optimal doses using target site pharmacokinetics data. Results: The final PBPK model in humans was applied to simulate free target site concentrations of LVX in lung and prostate, linking to minimum inhibitory concentrations (MIC) to assess appropriateness of currently approved dosing regimens for infections in both tissues. The clinical PBPK model was able to reproduce total plasma as well as free lung and prostate exposure of LVX in humans. Efflux transporters participate in LVX distribution to prostatic but not pulmonary tissue. Our results show a good penetration of LVX in both tissues with unbound partition coefficient (Kp,uu) equal to 0.79 and 0.72 for lung and prostate, respectively. Since LVX penetration in lung and prostate is similar, different sensitivities of the pathogens to LVX will dictate the effectiveness of the approved therapeutic regimen in the treatment of bacterial pneumonia, sinusitis, and prostatitis. Conclusions: Our research provides relevant insight into LVX's target site exposure in lung and prostate. When integrated with pathogen-specific susceptibility data, these findings can be applied to refine current dosing regimens and help optimize the pharmacological treatment outcomes.

Background: Liposomes are attractive topical carriers, yet translating laboratory fabrication to scalable, well-controlled processes remains challenging. Objectives: We compared three manufacturing methods for diclofenac-loaded liposomes: probe sonication, microfluidic mixing, and a high-turbulence microreactor, under a Quality-by-Design framework. Methods: Differential scanning calorimetry (DSC) was used to define a processing-relevant liquid-crystalline temperature window for the lipid excipients. For sonication scale-up, a Plackett-Burman screening design identified key process factors and supported an energy-density (W·s·L^-1) control approach. For microfluidics, the effects of flow-rate ratio (FRR) and total flow rate (TFR) were mapped and optimized using a desirability function. Microreactor trials were performed at elevated throughput. Residual ethanol during post-processing was monitored at-line by Raman spectroscopy calibrated against gas chromatography (GC). Particle size and dispersity were measured by DLS and morphology assessed by cryo-TEM. Results: DSC supported a 70-85 °C processing window. Sonication scale-up using an energy-density target (~11,000 W·s·L^-1) reproduced lab-scale quality at 8 L (Z-average ~87-92 nm; PDI 0.16-0.23; %EE 86-94%). Microfluidics optimization selected FRR 3:1/TFR 4 mL·min^-1, yielding ~64 nm liposomes with PDI ~0.13 and %EE ~93%. The microreactor achieved ~50 nm liposomes with %EE ~95% at 50 mL·min^-1. Cryo-TEM corroborated size trends and showed no evident aggregates. Conclusions: All three routes met topical CQAs (~50-100 nm; PDI ≤ 0.30; high %EE). Method selection should be guided by target size/dispersity and operational constraints: sonication enables energy-based scale-up, microfluidics offers precise size control, and microreactors provide higher throughput.

Background/objectives: Mathematical modelling provides a quantitative way to describe the fate and action of drugs in the oral cavity, where transport processes are shaped by salivary flow, pellicle formation, biofilm structure and the wash-out effect of gingival crevicular fluid (GCF). Local pharmacokinetics in the mouth differ substantially from systemic models, and therefore a dedicated framework is required. The aim of this work was to present a structured, physiologically based concept that links in vitro release testing with local pharmacokinetics and pharmacodynamics.

Methods: A narrative review with elements of systematic search was conducted in PubMed, Scopus and Web of Science (1980-2025) for publications describing drug release, local PBPK, and PK/PD modelling in the oral cavity. Mathematical formulations were grouped into release kinetics, mini-PBPK transport and local PK/PD relations. Classical models (Higuchi, Korsmeyer-Peppas, Peppas-Sahlin) were integrated with a mini-PBPK structure describing saliva-mucosa-biofilm-pocket interactions.

Results: The combined model captures adsorption to pellicle, diffusion within biofilm and wash-out by GCF. It allows simulation of variable clinical conditions, such as inflammation-related changes in Q_GCF, and links local exposure to pharmacodynamic outcomes. Case studies with PerioChip^®, Arestin^®, and Atridox^® demonstrate how mechanistic models explain observed therapeutic duration and low-systemic exposure.

Conclusions: The proposed mini-PBPK framework bridges empirical release data and physiological transport in the oral cavity. It supports rational formulation design, optimisation of local dosage, and personalised prediction of drug retention in gingival pockets. This modelling approach can become a practical tool for the development of dental biomaterials and subgingival therapies.