Background/Objectives: Fixed-dose combinations (FDCs) hold significant clinical value for the management of hypertension, diabetes and other chronic diseases. However, since the complexity of formulations, generic compounds require both in vitro pharmaceutical equivalence and in vivo bioequivalence (BE) for each active pharmaceutical ingredient (API). Physiologically based biopharmaceutics modeling (PBBM) not only bridges in vitro drug properties to in vivo pharmacokinetics but effectively assesses the impact of formulations on systemic exposure. This study was aimed at developing a PBBM for metformin–glyburide FDC and investigating its clinically relevant quality specifications. Methods: PK-Sim® software (Version 11.3) was used to establish a PBBM for a metformin–glyburide FDC. Sensitivity analysis identified critical parameters and guided design of virtual populations. Subsequently, virtual bioequivalence (VBE) was assessed between both reference and test formulations, and BE-ensuring dissolution space was explored by the change in dissolution characteristics. Results: The in vivo behavior of products was successfully captured by the developed model. Sensitivity analysis indicated that systemic exposure was primarily sensitive to gastrointestinal (GI) pH and transit times. VBE analysis confirmed BE between the reference and test formulations. The dissolution safe space for the FDC was defined as the concurrent achievement of ≥ 50% dissolution within 25 min for metformin and between 35 and 170 min for glyburide, which constituted equivalent specification. Conclusions: The PBBM developed in this study systematically evaluated the VBE of metformin–glyburide FDC, optimized the acceptance criteria for traditional in vitro dissolution testing, and thereby explored its clinically relevant quality specification.

Background/Objectives: Despite the advantages of polycaprolactone (PCL) for drug delivery, it still lacks effective approaches to enhance its encapsulation of drugs. Blending PCL with less hydrophobic polymers can tailor physicochemical properties to overcome these limitations. This study, for the first time, integrates two beneficial approaches—polymer blending and Box–Behnken design (BBD) optimisation—to develop PCL-based blend nanoparticles (NPs) with enhanced encapsulation efficiency (EE), controlled particle size, and improved stability through surface charge modulation. Methods: Drug-loaded blend NPs were developed using a double emulsion method, with different polymer ratios. A BBD model was employed to investigate the influential factors that control the size, charge, and EE. Results: Blending PCL with a less hydrophobic polymer significantly improved EE, achieving 60.96% under optimal conditions. The BBD model successfully predicted conditions for obtaining NPs with optimum size, negative charge, and enhanced drug encapsulation. The drug amount was identified as the most influential factor for EE, while polymer amounts significantly impacted size and charge. Conclusions: Careful control of polymer ratios, drug amount, and surfactant levels was shown to significantly influence particle size, surface charge, and EE, with the balanced 50:50 PCL:PLGA blend achieving optimal physicochemical performance. Using the BBD, the study identified the predicted optimal formulation consisting of 162 mg polymer blend, 8.37 mg drug, and 8% surfactant, which is expected to yield NPs with a size of 283.06 nm, zeta potential of −31.54 mV, and EE of 70%. The application of BBD allowed systematic evaluation of the factors and their interactions, providing robust predictive models.

As one of the primary fatal diseases globally, cancer represents a severe threat to human health because of its high incidence and fatality rates. While traditional treatments including surgery, radiation, and conventional pharmacotherapy demonstrate therapeutic effects, they commonly suffer from issues like severe side effects, high rates of relapse, and immunosuppression. The advent of immune checkpoint inhibitors and targeted drugs has undoubtedly revolutionized cancer management and improved survival; however, a significant proportion of patients still encounter obstacles such as acquired resistance, an immunosuppressive tumor microenvironment, and poor drug delivery to avascular tumor regions. Recent integration of engineered bacteria with nanomaterials has offered novel strategies for cancer immunotherapy. Engineered bacteria feature natural tumor tropism, immune-stimulating properties, and programmability, while nanomaterials are characterized by high drug payload, tunable release profiles, and versatile functionality. This article reviews the application of hybrid systems integrating engineered bacteria and nanomaterials in cancer immunotherapy, exploring their potential for drug delivery, immunomodulation, targeted treatment, and smart responsiveness. The construction of an “intelligent drug factory” through the merger of bacterial biological traits and sophisticated nanomaterial functions enables precise manipulation of the tumor microenvironment and potent immune activation, thereby establishing a novel paradigm for the precise treatment of solid tumors. However, its clinical translation faces challenges such as long-term biosafety, genetic stability, and precise spatiotemporal control. Synergistic integration with therapies such as radiotherapy, chemotherapy, and immunotherapy represents a promising direction worthy of exploration.

Background/Objectives: Glioblastoma (GBM) is a fatal tumor in the central nervous system (CNS) with a poor prognosis. Preventing tumors from post-surgical recurrence is a significant clinical challenge, since current methods deliver chemotherapeutic agents in a rapid manner and are not effective against the residual tumor cells. To address these limitations, we develop a blue light-crosslinking hydrogel which can be rapidly gelled in situ and tightly adhere on the tissues for controlled chemotherapy, radiotherapy, and enhanced laser interstitial thermal therapy (LITT) to inhibit residual tumor cells from post-surgical recurrence. Methods: We utilize gelatin-MA based hydrogel with crosslinker VA-086 as hydrogel scaffold to encapsulate small-molecule drugs (Epirubicin and Cisplatin) and LITT agent polypyrrole-coated graphine oxide (PPy@GO). The mixture can form into hydrogel in situ by blue light irradiation and performed chemo-LITT and radio therapy simultaneously. Then we determine the prevailing factors that affect efficient encapsulation of therapeutic agents within hydrogels, efficiency of gelation, LITT enhancement, and drug release. Then evaluate efficiency in human cancer cells and an in vivo tumor model. Results: Our results demonstrate that 18 wt% Gelatin MA formulation achieved >95% gelation within 2 min, with drug-loaded gels forming within 5 min. The gelation can perform both in vitro and in vivo without affect the drug efficiency. This multi-treatment system can effectively prevent tumor recurrence and significantly prolong the medium survival of glioma-bearing (MBR-614 or U87-MGFL) mice to above 65 days compared with the control group (36 days). Conclusions: The results demonstrated promising effect of this system as a multi-therapeutic platform which combined chemo-LITT and RT. This synergistic strategy presents a new approach to the development of a local drug delivery system for the prevention of brain tumor recurrence.

Poly(lactic-co-glycolic acid) (PLGA) sustained-release systems for intra-articular (IA) delivery aim to extend joint residence time and reduce the reinjection frequency of conventional IA therapies. This review synthesizes current understanding of PLGA degradation, the acidic microenvironment inside degrading microspheres, and release behavior in joints, and surveys clinical experience with extended-release corticosteroid depots alongside emerging platforms for nonsteroidal and biologic agents. To situate PLGA within the broader IA field, we briefly summarize selected non-PLGA sustained-release approaches—such as multivesicular liposomes, hyaluronic acid conjugates, and hybrid matrices—to contextualize comparative performance and safety. For proteins and peptides, central barriers include acidification inside degrading microspheres, aggregation during fabrication and storage, and incomplete or delayed release, as illustrated by glucagon-like peptide-1 analog formulations. Mitigation strategies span pH buffering, excipient-based stabilization, and gentler manufacturing that improve encapsulation efficiency and preserve bioactivity. Translation hinges on manufacturing scale-up and quality systems that maintain critical particle attributes and enable informative in vitro–in vivo interpretation. Clinically, prolonged symptom relief after single dosing has been demonstrated for corticosteroid depots (e.g., ~50% pain reduction over 12 weeks with a single PLGA–triamcinolone injection), whereas repeat-dose safety and indication expansion beyond the knee remain active needs best addressed through multicenter trials incorporating imaging and patient-reported outcomes. Consistent real-world performance will depend on controlling batch-to-batch variability and implementing pharmacovigilance approaches suited to long dosing intervals, enabling broader clinical adoption.

Background/Objectives: Lidocaine hydrochloride (LD-HCl) is the most commonly used local anesthetic in dentistry, often administered with epinephrine to extend its duration and reduce systemic absorption. However, its relatively short duration of action, the need for repeated injections, and the unpleasant taste may limit patient compliance and procedural efficiency. This study aimed to develop and evaluate a novel injectable nanoemulsion-based in situ gel depot system of LD to provide prolonged anesthetic activity. Methods: LD-loaded nanoemulsions were formulated by high-shear homogenization followed by probe sonication, employing Miglyol 812 N (oil phase), a combination of Tween 80 and soy lecithin (surfactant–co-surfactant), glycerin, and deionized water (aqueous phase). The selected nanoemulsion (S1) was dispersed in a thermoreversible poloxamer solution to form a nanoemulgel. The preparation was evaluated for globule diameter and uniformity, zeta potential, surface morphology, pH, drug content, stability, rheological behavior, injectability, and in vitro drug release. Analgesic efficacy was assessed via tail-flick and thermal paw withdrawal latency tests in Wistar rats. Cardiovascular safety was monitored using non-invasive electrocardiography and blood pressure measurements. Results: The developed nanoemulsions demonstrated a spherical shape, nanometer size (206 nm), high zeta-potential (−66.67 mV) and uniform size distribution, with a polydispersity index of approximately 0.40, while the nanoemulgel demonstrated appropriate thixotropic properties for parenteral administration. In vitro release profiles showed steady LD release (5 h), following the Higuchi model. In vivo studies showed significantly prolonged analgesic effects lasting up to 150 min (2.5 h) compared to standard LD-HCl injection (p < 0.001), with no adverse cardiovascular effects observed. Conclusions: The developed injectable LD in situ nanoemulgel offers a promising, patient-friendly alternative for prolonged anesthetic delivery in dental and operative procedures, potentially reducing the need for repeated injections and enhancing procedural comfort.

Biodegradable polymers such as Polycaprolactone (PCL), Polylactic acid (PLA), and Poly(lactic-co-glycolic acid) (PLGA) are attracting attention as key platforms for anticancer drug delivery systems due to their excellent biocompatibility and controllable degradation rates. These polymers can overcome limitations of existing chemotherapeutics, such as low bioavailability, systemic toxicity, and nonspecific cell damage, and contribute to the development of precision medicine approaches and long-acting therapeutics. This paper discusses the chemical and physicochemical properties of these three polymers, their synthetic strategies, and the controlled drug release technology through surface functionalization and stimuli-responsive design. Furthermore, we highlight their potential for use in various formulations, including micelles, nanoparticles, hydrogels, and microspheres, enabling enhanced drug solubility, sustained release, and tumor targeting. Preclinical and clinical applications demonstrate that these polymer-based DDSs represent a promising approach for implementing next-generation precision anticancer treatment strategies, with further potential for clinical translation and widespread adoption.

Carcinogenesis is driven by aberrant activation of molecular signaling pathways governing cell proliferation, apoptosis, and differentiation. Among these, the RAS/RAF/MEK/ERK (RAS/MAPK) cascade is one of the most frequently dysregulated oncogenic pathways, driving tumor initiation and progression across diverse cancer types. Although inhibitors of BRAF and MEK have achieved clinical success in selected malignancies, adaptive resistance often undermines therapeutic durability. This has spurred interest in alternative nodes within the pathway. The kinase suppressor of Ras (KSR) is a scaffold protein that organizes RAF, MEK, and ERK into functional complexes, ensuring efficient and sustained signal transmission. Once regarded as a passive structural component, KSR1 is now recognized as an active regulator of pathway dynamics. Emerging evidence indicates that KSR1 overexpression promotes cancer cell proliferation and survival, while genetic or pharmacologic inhibition of KSR1 attenuates RAS/MAPK signaling and suppresses tumor growth in preclinical models. In this review, we provide a comprehensive overview of accessory and scaffold proteins modulating the RAS/MAPK pathway, with a particular focus on KSR1. We highlight its structural and functional properties, summarize preclinical evidence for KSR1-targeted interventions, and discuss its therapeutic potential in cancer, with emphasis on hepatocellular carcinoma (HCC).

Background/Objectives: Compaction of sustained release coated pellets into tablets is associated with damage to the functional coat and loss in sustained release. The influences of precompression, trilayering, and tableting rate on the compaction of sustained release coated pellets into tablets are not well defined and were herein investigated to enhance the current limited understanding of these factors. Methods: Pellets coated with acrylic polymer (AC) or ethylcellulose (EC) were combined with filler material and compacted into multi-unit pellet system (MUPS) tablets prepared using different levels of precompression, as a trilayered MUPS tablet and at different tableting rates. The physical properties of the resulting MUPS tablets were evaluated. Trilayering was achieved by adding cushioning layers at the top and bottom of the MUPS tablet to avoid direct contact of pellets with punch surfaces. Results: With precompression, slightly stronger MUPS tablets were made compared to the tablets without precompression for EC pellets but not AC pellets. However, precompression led to a slight reduction in pellet coat damage for AC pellets but not EC pellets. Trilayering led to significant reductions in pellet coat damage and significant increases in tablet tensile strength. When EC pellets were lubricated with sodium stearyl fumarate, pellet coat damage was significantly lower. Increasing the tableting rate from 20 to 100 rpm did not result in increased pellet coat damage but in significantly weaker tablets due to the shorter dwell time. Conclusions: This study provides key insights on how compaction parameters and techniques could be altered to produce better MUPS tablets.

Background/Objectives: Nanocrystals (NCs) are a relatively underexplored yet adaptable platform with broad potential for various applications. Currently, the surface modification of NCs leads to the development of versatile platforms capable of enhancing targeted delivery potential and supporting the advancement of precision medicine. With this in mind, this study focused on the design and surface functionalization of a resveratrol (RSV) NC selected for its antioxidant and neuroprotective effects. Methods: The design of the RSV NC was assessed by the Quality by Design approach. With the aim of intranasal administration, we assessed the RSV NC functionalization with a cationic poly (amino acid) belonging to the class of cell-penetrating peptides. Both naked and surface-modified RSV nanosuspensions were characterized in terms of mucoadhesion, behavior in artificial cerebrospinal fluid, crystallinity, solubility, and storage stability. The scavenging activity (%) of neat RSV and its nanosized forms was measured using the DPPH assay. Results: RSV NCs were successfully designed, producing truncated cubic crystals (~240 nm) with an ~80% drug content. Functionalization was efficiently achieved with poly-l-arginine hydrochloride as revealed by DSC and FTIR and resulted in a positively charged nanosuspension. Nanonization technology improved drug solubility in water and did not affect RSV scavenging activity. Technological characterization demonstrated that both nanosuspensions present suitable properties for intranasal administration in terms of particle size, mucoadhesive tendency, and stability in artificial cerebrospinal fluid. An MTT assay revealed the safety of all treatments in human microglia (HMC3) cells. Conclusions: RSV NCs’ functionalization enhanced their brain delivery potential, establishing a promising platform to improve therapeutic outcomes in neurodegenerative diseases.