Pharmaceutics最新文献

Background: Physiologically based pharmacokinetic (PBPK) modeling is a mathematical approach that integrates human physiological parameters with drug-specific characteristics (including both active pharmaceutical ingredients and excipients), and it has emerged as one of the core technologies for optimizing the efficiency and reliability of drug development. Methods: This study synthesizes applications of PBPK models in FDA-approved drugs (2020-2024), systematically analyzing model utilization frequency, indication distribution, application domains and choice of modeling platforms, to reveal their substantive contributions to regulatory submissions. Additionally, we conducted an in-depth analysis of the PBPK models for 2024, classifying models into three tiers based on critical assessment of FDA reviewer comments. Results: Among 245 FDA-approved new drugs during this period, 65 NDAs/BLAs (26.5%) submitted PBPK models as pivotal evidence. Oncology drugs accounted for the highest proportion (42%). In application scenarios, drug-drug interaction (DDI) was predominant (81.9%), followed by dose recommendations for patients with organ impairment (7.0%), pediatric population dosing prediction (2.6%), and food-effect evaluation. Regarding modeling platforms, Simcyp^® emerged as the industry-preferred modeling platform, with an 80% usage rate. In terms of regulatory evaluation, a core concern for reviewers is whether the model establishes a complete and credible chain of evidence from in vitro parameters to clinical predictions. Conclusions: Detailed regulatory reviews demonstrate that although some PBPK models exhibit certain limitations and shortcomings, this does not preclude them from demonstrating notable strengths and practical value in critical applications. Benefiting from the strong support these successful implementations provide for regulatory decision-making, the technology is gaining increasing recognition across the industry. Looking forward, the integration of PBPK modeling with artificial intelligence (AI) and multi-omics data will unprecedentedly enhance predictive accuracy, thereby providing critical and actionable insights for decision-making in precision medicine and global regulatory strategies.

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous spectrum of disorders that lead to progressive and irreversible vision loss. Gene therapy is the most promising emerging treatment for IRDs. While gene augmentation strategies have demonstrated clinical benefit and results within the first approved ocular gene therapy, their application is restricted by adeno-associated virus (AAV) packaging capacity and limited efficacy for dominant mutations. Recent breakthroughs in precision genome editing, particularly base editing (BE) and prime editing (PE), have provided alternatives capable of directly correcting pathogenic variants. BE enables targeted single-nucleotide conversions, whereas PE further allows for precise insertions and deletions, both circumventing the double-strand DNA cleavage or repair processes typically induced by conventional CRISPR-Cas editing systems, thereby offering advantages in post-mitotic retinal cells. Preclinical investigations across murine and non-human primate models have demonstrated the feasibility, molecular accuracy, and preliminary safety profiles of these platforms in targeting IRD-associated mutations. However, critical challenges remain before clinical application can be realized, including limited editing efficiency in photoreceptors, interspecies variability in therapeutic response, potential risks of off-target effects, and barriers in large-scale vector manufacturing. Moreover, the delivery of genome editors to the outer retina remains suboptimal, prompting intensive efforts in capsid engineering and the development of non-viral delivery systems. This review synthesizes the current progress in BE and PE optimization, highlights innovations in delivery platforms that encompass viral and emerging non-viral systems and summarizes the major barriers to clinical translation. We further discuss AI-driven strategies for the rational design of BE/PE systems, thereby outlining their future potential and perspectives in the treatment of IRDs.

Background: Current disease-modifying therapies (DMTs) for multiple sclerosis (MS) attenuate pathogenic immune responses but are limited by safety and tolerability concerns. Antigen-specific tolerance approaches provide targeted immunomodulation yet remain constrained by their dependence on known autoantigens. LPX-TI641, an orally bioavailable, clinical-stage small-molecule agonist of Tim-3/4, represents an antigen-independent strategy to restore immune tolerance by expanding regulatory T cells (Tregs). Methods: LPX-TI641 was evaluated in vitro for its ability to induce Treg populations in murine splenocytes. Therapeutic efficacy was assessed in vivo using MOG_35-55- and PLP_139-151-induced experimental autoimmune encephalomyelitis (EAE) mouse models. Ex vivo, peripheral blood mononuclear cells (PBMCs) from people with MS (PwMS) were analyzed for Treg phenotype and function in response to LPX-TI641. Results: LPX-TI641 induced dose-dependent expansion of CD4⁺Foxp3⁺ and CD4⁺Foxp3⁺Tim-3⁺ Tregs in vitro. In EAE models, treatment significantly reduced disease severity, prevented relapses, and maintained clinical benefit after discontinuation. In PBMCs from patients with MS, LPX-TI641 restored diminished Tim-3⁺ Treg populations and reversed Treg dysfunction in recall assays. Efficacy in animal models was comparable to or exceeded that of high-efficacy DMTs, including natalizumab. Conclusions: LPX-TI641 promotes antigen-independent immune tolerance through Tim receptor agonism and Treg expansion. These findings support its potential as a novel therapeutic candidate for MS, addressing the limitations of current DMTs.

Background/Objectives: Paediatric patients continue to lack access to age-appropriate oral medicines for their treatment and have to depend on the off-label use of medicines approved for adults, which compromises dosing accuracy and exposes children to unpleasant bitterness. Building on previous proof-of-concept work with flucloxacillin sodium, this study investigated the effects of fatty-acid chain length on the formation, stability, dissolution, and sensory acceptability of diclofenac sodium (DS)-Eudragit® EPO (EE)-fatty acid (FA) polyelectrolyte complexes (PECs). Four saturated fatty acids, lauric (C12), myristic (C14), palmitic (C16), and stearic acid (C18), were evaluated at stoichiometric equimolar DS:EE:FA ratio (1:1:1). Methods: PEC microparticles were prepared by solvent evaporation. A stability-indicating RP-HPLC assay was developed and validated according to ICH guidelines to quantify DS content. Drug content and stability were monitored over 3 months at ambient storage. In vitro dissolution was performed in pH 5.5 medium at 37 °C. Taste acceptability and willingness to take again was assessed with 25 healthy adult volunteers using 11-point scale. Results: All PECs retained >90% of expected drug content after 3 months. Compared with neat DS, PECs markedly suppressed early drug release (32-39% vs. 94% at 2 min) but achieved >87% cumulative drug release in 60 min. Sensory evaluation showed significant differences across samples (p < 0.001): neat DS was least acceptable (20.8% willing to take again), while DS-EE-PA was most acceptable (92%), followed by DS-EE-SA and DS-EE-MA. DS-EE-LA was least favoured among PECs. Conclusions: Fatty-acid chain length influenced PEC formation and taste acceptability, but not the PEC stability and drug dissolution profile. Palmitic acid (DS-EE-PA) offered the best overall profile and represents a promising candidate for further development of paediatric-appropriate diclofenac formulations.

Background/Objectives: Palmitoylethanolamide (PEA) is an endogenous lipid mediator with endocannabinoid-like activity. Despite its therapeutic potential in muscle-related inflammatory disorders, including sarcopenia, its clinical use is limited by poor solubility and bioavailability. To overcome these issues, we developed hybrid nanoparticles combining poly(lactic-co-glycolic acid) (PLGA) and lipids to enhance PEA encapsulation and ok delivery. Methods: PEA-loaded hybrid nanoparticles (PEA-Hyb-np) were produced via a modified single-emulsion solvent evaporation method using stearic acid and Gelucire^® 50/13 as lipid components. Characterization included particle size, morphology, PDI, and zeta potential, as well as DSC, FT-IR, and XRD analyses. For the biological evaluation in a C2C12 myoblasts cell culture, coumarin-6-labeled nanoparticles were employed. Results: PEA-Hyb-np showed mean particle sizes of ~150 nm, with internal lipid-polymer phase separation. This structure enabled high encapsulation efficiency (79%) and drug loading (44.2 mg/g). Drug release in physiological and non-physiological media was enhanced due to drug amorphization, confirmed by DSC, FT-IR, and XRD analyses. Cytocompatibility studies showed no toxicity and improved cell viability compared to unloaded nanoparticles. Cellular uptake studies by confocal microscopy and flow cytometry demonstrated efficient and time-dependent internalization. Conclusions: PEA-Hyb-np represent a promising delivery platform to improve the solubility, bioavailability, and therapeutic efficacy of PEA for muscle-targeted applications.

Objective: The aim of this work is to improve the understanding of the mechanisms underlying the polymorphic transformations of pharmaceutical materials during milling. Elucidating these mechanisms is essential for controlling the polymorphism of active pharmaceutical ingredients and thereby improving their performance. Method: The structural evolution of various pharmaceutical compounds (sulfamerazine, glycine, mannitol, and famotidine) upon milling was followed using ex situ laboratory X-ray diffraction and in situ synchrotron measurements, complemented by DSC analyses. Results: For each compound, the kinetics of the polymorphic transformation was found to be sigmoidal and the presence of an intermediate amorphous phase during the transition from the initial to the final polymorphic form was also identified. Conclusions: The kinetic data obtained for sulfamerazine and glycine, together with the detection of an amorphous intermediate during the transformations of mannitol and famotidine, support the conclusion that milling-induced polymorphic transformations in pharmaceutical materials generally proceed via an amorphization-recrystallization mechanism.

Background/Objectives: Direct compression offers a cost-effective route for tablet manufacturing but is often limited by poor powder flow and compressibility. This study reported the development of a co-processed excipient comprising 98% mannitol and 2% pregelatinized rice starch (PRS) using spray drying with ammonium bicarbonate as a pore-forming agent. Methods: This optimized excipient demonstrated balanced powder flow and enhanced compressibility suitable for direct compression applications. The SeDeM expert system guided the optimization process by evaluating raw and spray-dried components. PRS exhibited excellent flowability that decreased after spray drying but displayed significantly enhanced compressibility, whereas mannitol maintained superior flow but continued to show limited compressibility post-drying. Scanning electron microscopy, differential scanning calorimetry, Fourier-transform infrared spectroscopy, and X-ray powder diffraction confirmed the absence of chemical interactions and unchanged wettability during co-processing. Results: The resulting excipient combined the favorable flow characteristics of mannitol with the improved compressibility of PRS, rendering it suitable for direct compression. Cetirizine dihydrochloride (CET) tablets were formulated via exponential curve fitting within the SeDeM framework, yielding an optimal CET-to-excipient ratio of 13:87. The tablets met all pharmacopeial physicochemical requirements, including uniform mass, adequate tensile strength, rapid disintegration, and dissolution profiles comparable to a reference product, with dissimilarity (f₁ = 4.28) and similarity (f₂ = 64.03) factors within regulatory acceptance limits. Conclusions: These findings represented the first application of SeDeM methodology to a co-processed mannitol-pregelatinized rice starch system, enabling predictive optimization of powder flow and compressibility in direct compression formulations.

The treatment of central nervous system (CNS) diseases faces huge challenges, mainly due to the blood-brain barrier (BBB) restricting drug delivery, which leads to many potential treatment methods being unable to effectively reach the target area. In recent years, nasal administration has received extensive attention as a non-invasive drug delivery route because of its anatomical connection with the brain, enabling direct delivery to brain tissue. In particular, the siRNA delivery system based on nanocarriers has shown great promise in the treatment of CNS diseases due to its unique advantages in targeting gene silencing. This article reviews the latest research progress on nasal administration of siRNA nanocarriers, with a focus on the design strategies, administration mechanisms, in vivo and in vitro effects, and safety evaluations of different nanocarriers. The aim is to provide a systematic theoretical basis and future research directions for the application of siRNA nasal administration in the treatment of CNS diseases (see the abstract of the picture).

Background/Objectives: Currently, infections caused by fungi of the Candida genus remain a significant global health concern. The rising incidence of mycoses, coupled with the rapid emergence of fungal resistance, highlights the urgent need to search for new antifungal agents. Here, we obtained the recombinant hevein-like peptide from Amaranthus caudatus with two amino acid substitutions (F18W in the chitin-binding motif and M13A preventing the peptide from cleavage with cyanogen bromide during its biotechnological production). Methods: Antifungal potential of the modified hevein-like peptide, designated as mAc-AMP2, against susceptible and resistant strains of Candida albicans and non-albicans Candida species was studied. Results: We showed that mAc-AMP2 possessed anticandidal activities against all strains tested at nanomolar peptide concentrations. The presence of salts or serum affected the action of the peptide but its antifungal activity remained quite high. mAc-AMP2 exhibited anti-adherent properties and inhibited the formation of fungal biofilms. Using RP-HPLC, we demonstrated that degradation of the peptide in the presence of serum occurred rather slowly. mAc-AMP2 did not exhibit hemolytic and cytotoxic activities against the Caco-2 cell monolayer and peripheral blood mononuclear cells. Using flow cytometry, we demonstrated that the peptide at its high concentrations increased fungal membrane permeability. In resistance induction experiments, sensitivity of C. albicans toward mAc-AMP2 decreased over time, but restored after the peptide elimination. Conclusions: Taking into account all the data obtained, we suggest that the modified hevein-like peptide is a promising candidate for development of novel therapeutic agents to combat fungal infections caused by C. albicans and other Candida species.

Background/Objectives: Lipid nanoparticles (LNPs) have demonstrated notable clinical success as advanced drug delivery systems. However, the development of novel covalently bonded ionizable lipids faces substantial technical challenges, as their modification is difficult and they have a high molecular weight. To address this issue, we report the use of host-guest complexes in supramolecular chemistry as functional lipid motifs for constructing LNPs. Methods: Ionizable amine β-cyclodextrin (amine β-CD)-derived host-guest amphiphilic lipid molecules (HGLs) were designed for the construction of multi-stage assembly supramolecular LNPs (MSLNPs). The structure-function relationships and stability of MSLNPs were explored by screening eight types of amine β-CDs and varying the ratio of HGL to yolk phosphatidylcholine. Stability screening and molecular dynamics simulations were performed to clarify the self-assembly mechanisms and optimal formulations, followed by a systematic evaluation of delivery performance. Results: MSLNPs showed a high drug-loading efficiency (> 30%), a rapid-response release in acidic environments, and multi-pathway cellular uptake. In vivo delivery experiments using ethylenediamine β-CD-based MSLNPs in mice revealed no significant immunogenicity, no significant abnormalities in organs/tissues or their functions, a unique biodistribution pattern, and pronounced renal targeting. The successful development of MSLNPs with acidic pH-responsive control, a high delivery efficiency, and renal-targeting properties simplifies LNP preparation. Conclusions: This study offers novel insights into the design of simplified LNPs and the optimization of targeted delivery, with potential applications in renal disease therapy.