Int J Pharm [JOURNAL]
Sun
200 papers
Dual drug-loaded nanofibrous scaffolds for targeting dormant breast cancer cells: design, mechanisms, and translational perspectives.
Malarvannan M, Yadav D, Methri SM … +2 more , Natesan S, Paul D
Int J Pharm · 2026 Jun · PMID 42203084 · Publisher ↗
Breast cancer is the most commonly diagnosed malignancy among women worldwide. Recurrence associated with maintenance therapy may promote the development of multidrug resistance, while dormant breast cancer cells (DBCCs)...
Breast cancer is the most commonly diagnosed malignancy among women worldwide. Recurrence associated with maintenance therapy may promote the development of multidrug resistance, while dormant breast cancer cells (DBCCs) within the tumor microenvironment (TME) are inherently resistant to conventional therapies. These factors collectively contribute to late-stage relapse and metastasis. Nanofibers (NFs) have recently emerged as valuable platforms for formulating biomedical and healthcare applications, including tissue engineering, wound healing, and post-surgical cancer management. In particular, polymeric NFs fabricated via electrospinning and loaded with dual drugs have shown great promise for sustained and targeted delivery. This review discusses the development of dual-drug-releasing nanofibrous scaffolds designed for prolonged and localised delivery of cytotoxic agents directly to the tumor bed. Emphasis is placed on polymer selection, drug-loading strategies, and preclinical outcomes in the prevention of cancer recurrence. Furthermore, the review highlights the advantages of these therapies over conventional therapies, as well as relevant in vitro and in vivo evaluation models, regulatory considerations, Pathways, clinical translation prospects, and future directions. By bridging materials and pharmaceutical sciences, this article provides a comprehensive overview of how dual-drug-loaded NF scaffolds can redefine localised cytotoxic drug delivery and offer novel therapeutic strategies against DBCCs.
L-aspartic acid as a formulation-enabled platform: translational opportunities in programmable drug delivery systems.
Zhang Y, Liao Z
Int J Pharm · 2026 Jun · PMID 42203083 · Publisher ↗
L-Aspartic acid (L-Asp) is an endogenous amino acid with physicochemical properties relevant to pharmaceutical formulation design. Its ionization behavior, coordination capacity, and chemical derivatization support sever...
L-Aspartic acid (L-Asp) is an endogenous amino acid with physicochemical properties relevant to pharmaceutical formulation design. Its ionization behavior, coordination capacity, and chemical derivatization support several formulation functions. However, free L-Asp is an endogenous and readily metabolized molecule, which limits exposure control, tissue residence, and sustained performance when administered without a formulation. Its pharmaceutical value emerges from molecular derivatization and formulation engineering rather than from the biological activity of the free molecule itself. In this review, we evaluate L-Asp-derived and poly(aspartic acid) (PAsp)-based systems from a formulation-centered perspective and differentiate the biological characteristics of free L-Asp from the emergent properties of L-Asp-derived and PAsp-derived materials. Moreover, we discuss the pharmaceutical outcomes enabled by formulation design and representative platforms, including salt and co-amorphous systems, PAsp-based carriers and hydrogels, targeted and stimuli-responsive systems, and biomaterial- or mineral-interactive systems. In this review, we benchmark L-Asp-derived and PAsp-derived systems against established delivery materials and assess formulation functions, potential advantages, common limitations, and evidence requirements for translational positioning. Development-related considerations, including stability, manufacturability, quality attributes, safety, and route-specific performance, are further discussed. Overall, free L-Asp, L-Asp-derived materials, and PAsp-based platforms should be regarded as related but distinct formulation entities. Their pharmaceutical value depends on rational molecular modifications, appropriate system architecture, and application-specific formulation design.
A novel liposomal formulation of irinotecan comprising a combination of copper complexation and a transmembrane pH gradient to significantly improve irinotecan encapsulation and retention.
Sun X, Sharifiaghdam M, Sarrami N … +8 more , Popescu I, Wretham N, Santos ND, Sutherland B, Leung AWY, Redelmeier T, Abram M, Bally M
Int J Pharm · 2026 Jul · PMID 42191000 · Publisher ↗
A liposomal CPT-11 formulation was previously developed and approved for pancreatic cancer (Onivyde), but it carries a FDA black-box warning because it exacerbated CPT-11 associated gastrointestinal (GI) toxicities. An a...
A liposomal CPT-11 formulation was previously developed and approved for pancreatic cancer (Onivyde), but it carries a FDA black-box warning because it exacerbated CPT-11 associated gastrointestinal (GI) toxicities. An alternative liposomal irinotecan formulation, Irinophore C, reduced GI toxicity as judged by a validated animal model of irinotecan mediated early and late onset diarrhea. Irinophore C did not progress to clinical trials, partly because its development coincided with the approval of Onivyde. Nevertheless, an Irinophore C-like formulation remains of interest because of its potential to reduce GI toxicity and its potential to be developed as a combination product. Irinophore C was prepared using liposomes containing entrapped copper (Cu). The divalent metal ionophore A23187 was used to exchange entrapped Cu for protons, creating a transmembrane pH gradient. Following addition of CPT-11 to the liposomes, it crossed into the liposome interior to achieve efficient (>95%) liposome association. The results were consistent with previous findings that CPT-11 can be loaded into liposomes with a transmembrane pH gradient (inside acid). The presence of copper, however, imparted unique properties. The resulting formulation retained CPT-11 better than liposomes loaded using a simple transmembrane pH gradient or a pH gradient generated with A23187 added to liposomes containing other divalent metal ions (e.g., Mg, Mn, Zn). The data suggested improved drug retention arose due to Cu binding with CPT-11 and/or with lipids in the inner membrane of the liposomes. It was further suggested that Cu may mitigate GI toxicity. In this study it is argued that if Cu ions confer unique advantages to the liposomal CPT-11 formulation, then the original method used to prepare Irinophore C was not optimal. This is because A23187 significantly reduced the amount of copper retained in the liposomes. Here, we characterize an alternative method for CPT-11 encapsulation; a method that retains Cu within liposomes. In this formulation, A23187 is not required and the low internal pH is maintained with ammonium sulfate. The results showed that CPT-11 can be efficiently loaded into these liposomes, achieving CPT-11 to liposomal-lipid ratios exceeding 0.6 (mol:mol). The resulting formulation exhibits significantly improved drug retention and cryo-transmission electron microscopy analysis suggests the morphology of the new formulation differs from Irinophore C. Efficacy studies in a syngeneic BALB/c CT26 colorectal cancer model demonstrated the therapeutic potential of the new formulation, but highlight a challenge when developing high CPT-11 to liposomal-lipid ratio formulations. Specifically, high drug to liposomal-lipid formulations utilize significantly lower lipid doses that are eliminated rapidly after administration. It is suggested that this new formulation is suitable for development in combination with other therapies, however the rapid elimination of the liposomes administered at low liposomal lipid dosed must be addressed.
Electrospun nanofibers for antibiotic and probiotic co-delivery to target bacterial vaginosis.
Verhoeven D, Kyser AJ, Greiner A … +3 more , Lewis WG, Lewis AL, Frieboes HB
Int J Pharm · 2026 Jun · PMID 42190999 · Full text
Despite initial success, antibiotic therapy for bacterial vaginosis (BV) often fails within a year to prevent recurrence. Probiotic therapy has shown promise, but inconvenient and frequent administration may affect user...
Despite initial success, antibiotic therapy for bacterial vaginosis (BV) often fails within a year to prevent recurrence. Probiotic therapy has shown promise, but inconvenient and frequent administration may affect user adherence. Recently, probiotic (lactobacilli) therapy alone was shown insufficient to dislodge fastidious anaerobic bacteria such as Gardnerella. Nanofiber devices offer a means for controlled delivery of active agents for vaginal application. This study developed a novel nanofiber vehicle for antibiotic and probiotic co-delivery with the goal of targeting anaerobes while simultaneously promoting lactobacilli. Nanofibers were designed with 3:1 v/v PEO:PLGA ratio in a meshed architecture. Fibers were loaded with 7.5 mg metronidazole and 8.33x10 CFU L. crispatus per mg of material and characterized via SEM imaging and thermal analysis. Metronidazole burst release into simulated vaginal fluid and sustained L. crispatus recovery over 6 days in MRS broth were measured. Nanofiber inhibition of Gardnerella in coculture was assessed via serial dilutions. Metronidazole was released up to 93.95% of the theoretical load within 20 min. Cumulative recovery of metabolically active L. crispatus of 1.33x10 CFU/mL corresponded with lactic acid reaching 7.50 mg/mg of fiber for 6 days. Gardnerella exposed to fibers in coculture were cleared by 24 hr while L. crispatus recovery reached 8.71x10 CFU/mL. VK2/E6E7 cells exposed to fibers in coculture showed minimal LDH release comparable to untreated. Overall, the results support the feasibility of antibiotic and probiotic co-delivery via electrospun nanofibers designed for staged release, with the longer term goal to target BV while promoting user adherence.
Stage-adaptive nanotherapeutic design for blood-brain barrier navigation in ischemic stroke.
Li T, Zhou Y, Chen Y … +1 more , Zou L
Int J Pharm · 2026 Jun · PMID 42190998 · Publisher ↗
Ischemic stroke remains one of the leading causes of mortality and long-term disability worldwide, yet effective pharmacological intervention is profoundly limited by the blood-brain barrier (BBB). As a highly selective...
Ischemic stroke remains one of the leading causes of mortality and long-term disability worldwide, yet effective pharmacological intervention is profoundly limited by the blood-brain barrier (BBB). As a highly selective and dynamically regulated interface, the BBB preserves neural homeostasis but simultaneously restricts the delivery of most neuroprotective agents. Nanomedicine has emerged as a promising approach to overcome this obstacle. However, many existing strategies remain largely decoupled from the evolving pathological landscape of the ischemic brain. This review presents a mechanism-driven framework for BBB navigation that explicitly integrates nanocarrier design with the spatiotemporal progression of ischemic pathology. The dynamic remodeling of the BBB is first outlined across distinct stages, from the hyperacute phase with largely intact barrier function, through acute disruption, to the subsequent repair phase. Building on this foundation, we analyze advanced delivery strategies that enable brain entry under these varying conditions, including receptor-mediated transcytosis (RMT), biomimetic transport via immune cell-inspired systems, and pharmacological or physical BBB modulation. Particular attention is given to stimuli-responsive nanocarriers that leverage pathological cues within the ischemic microenvironment-such as oxidative stress, acidosis, and enzyme activation-to achieve localized and on-demand drug release. Therapeutic effects are further discussed from a neurovascular unit (NVU) perspective, highlighting coordinated modulation of oxidative damage, inflammatory responses, neuronal survival, and vascular remodeling. Translational barriers remain substantial. Biological heterogeneity, limitations of current animal models, and the growing complexity of nanocarrier design continue to impede clinical progress. By linking BBB dynamics with engineering strategies and therapeutic mechanisms, this review provides a conceptual framework for the development of stage-adaptive and clinically translatable nanomedicine for ischemic stroke.
Evaluation of powder discharge-based KinetiSol (pKSD) as a fast and solvent-free particle engineering process for pulmonary drug delivery.
Behrend-Keim B, Jara MO, Davis DA … +2 more , Miller DA, Williams RO
Int J Pharm · 2026 Jul · PMID 42190997 · Publisher ↗
This research evaluated the viability of powder discharge-based KinetiSol (pKSD) as a rapid, solvent-free particle engineering technology for producing inhalable dry powders. This study focused on how the physicochemical...
This research evaluated the viability of powder discharge-based KinetiSol (pKSD) as a rapid, solvent-free particle engineering technology for producing inhalable dry powders. This study focused on how the physicochemical characteristics of amorphous and crystalline excipients influence resulting powder morphology and aerosol performance. Results from laser diffraction and SEM analysis confirmed that excipient properties, specifically morphology and solid-state, directly influence particle breakage during pKSD processing Hydroxypropyl β-cyclodextrin (HPBCD) and L-leucine blends exhibited a significant reduction in particle size (up to 3-fold), which enhanced aerosolization efficiency, yielding fine particle fractions (FPF) of 48 % and 51 %, respectively. Conversely, various grades of lactose and sulfobutylether β- cyclodextrin (SBECD) largely maintained their initial morphology and particle size, resulting in lower FPF values ranging from 21 % to 36 %. Additionally, WAXS analysis confirmed that pKSD processing maintained the crystalline traces of the model drug, fenbendazole. These findings establish pKSD as a viable alternative for the engineering of inhalable particles.
Computational fluid dynamics and machine learning modeling of drug delivery by hydroxypropyl methylcellulose.
Chen J, He Z, Lin Y … +3 more , Peng S, Liu J, Yu G
Int J Pharm · 2026 Jun · PMID 42184876 · Publisher ↗
This study integrates computational fluid dynamics (CFD) simulations with machine learning (ML) models to develop a framework for predicting drug release from hydroxypropyl methylcellulose (HPMC) matrices. Transient, thr...
This study integrates computational fluid dynamics (CFD) simulations with machine learning (ML) models to develop a framework for predicting drug release from hydroxypropyl methylcellulose (HPMC) matrices. Transient, three-dimensional CFD models were constructed to solve the conservation equations for fluid flow and mass transfer, explicitly simulating the swelling front propagation, polymer dissolution, and diffusive drug release from a cylindrical HPMC carrier into a dissolution medium. The key results from parametric CFD studies quantified the nonlinear relationship between initial drug loading and the resultant concentration gradients and release rates over time, providing a high-resolution dataset on the underlying transport phenomena. These CFD simulations were validated against experimental release data, achieving excellent agreement (mean absolute error of 1.54% and R-squared of 0.9997). The CFD-generated data, combined with experimental measurements from the literature for eight model drugs (ribavirin, ranitidine hydrochloride, isoniazid, diltiazem hydrochloride, theophylline, tinidazole, sulfamethoxazole, and propylthiouracil), were used to train the machine learning techniques. A systematic topology search identified an optimized least-squares support vector regression (LS-SVR) as the most accurate predictor. This LS-SVR model, configured with the Gaussian kernel function, successfully predicts the overall dataset with an R-squared of 0.99850, an average absolute relative deviation of 1.27%, and a root mean squared error of 0.833. This hybrid CFD-ML approach provides a powerful tool for the rational design of HPMC-based drug formulations with targeted release profiles.
Erythromycin-encapsulated tri-arm PCL/APTMS-Functionalized magnetic nanocomposite for targeted therapy of deep skin infections.
Paul S, Ray Gupta SB, Rahman M … +2 more , Ali R, Hasan T
Int J Pharm · 2026 Jun · PMID 42184875 · Publisher ↗
Antibiotic-resistant deep skin infections are a global challenge. To address this, new drug-delivery methods using advanced nanocomposites for precise, efficient, and site-specific therapy are required. In this study, Er...
Antibiotic-resistant deep skin infections are a global challenge. To address this, new drug-delivery methods using advanced nanocomposites for precise, efficient, and site-specific therapy are required. In this study, Erythromycin (Ery), a macrolide-class antibiotic, has been encapsulated by a nanocomposite composed of 3-arm polycaprolactone (PCL) and 3-aminopropyltrimethoxysilane (APTMS)-functionalized magnetic iron oxide nanoparticles (MIONPs), producing Ery-PCL-APTMS/MIONPs. This nanocomposite demonstrated significant antibiofilm activity against Escherichia coli, Enterobacter sp., Pseudomonas sp., and Staphylococcus aureus, with dose- and time-dependent effectiveness and enhanced antibacterial activity at various concentrations compared with the standard drug. The sustained, time-dependent drug release exhibited an increasing release rate over time, achieving 48.35% at 56 h. In vivo assessment using an S. aureus-induced skin infection model demonstrated therapeutic efficacy, as reflected by a notable decrease in skin infection and improvements in physiological parameters, including increased body weight and normalization of hematological profiles (RBC, WBC, platelets). Histological investigation further confirmed the protective effects on the kidney and skin tissues. The physicochemical characterization using GPC and NMR (for PCl), along with FTIR, SEM, EDX, XRD, TGA, and VSM, confirmed the successful production of the Ery-PCL-APTMS/MIONPs nanocomposite, with a particle size of 14.91 nm, thermal stability, and nonmagnetic behavior. These results suggest that the Ery-encapsulated Ery-PCL-APTMS/MIONPs is a promising new nanocomposite system for localized antibiotic delivery, particularly for the treatment of deep skin infections and biomedical applications.
Repurposing copper diethyldithiocarbamate (CuET) in a polymeric nanofibrous patch for topical therapy of psoriasis.
Guo X, Meng Q, Liu W … +7 more , Rui H, Ruan X, Guan T, Dai A, Liu Y, Su J, Duan C
Int J Pharm · 2026 Jun · PMID 42177924 · Publisher ↗
The management of psoriasis remains challenging due to the limitations of current therapies. This study explores the repurposing of copper diethyldithiocarbamate (CuET)-a metabolite of the anti-alcoholism drug disulfiram...
The management of psoriasis remains challenging due to the limitations of current therapies. This study explores the repurposing of copper diethyldithiocarbamate (CuET)-a metabolite of the anti-alcoholism drug disulfiram-as a novel topical agent for psoriasis. To this end, we developed an advanced delivery platform by fabricating a CuET-loaded nanofiber patch via electrospinning of a polyvinylpyrrolidone/polyethylene glycol/citric acid (PVP/PEG/CA) blend. This rationally designed matrix provided optimal mechanical strength, moisture-activated adhesion, and precise local drug delivery performance, thereby addressing the application challenges associated with xerotic psoriatic skin. In an imiquimod-induced psoriasis mouse model, the nanofiber patch exhibited efficacy comparable to the that of clinical standard clobetasol propionate ointment, significantly alleviating clinical scores and epidermal hyperplasia. Mechanistically, the patch mediated a multimodal therapeutic action: it potently suppressed pathological angiogenesis (reducing CD31 + vessel density by 73.97%) and macrophage infiltration. Crucially, it normalized the dysregulated immune microenvironment by concurrently inhibiting key pro-inflammatory cytokines (IL-17A, IL-22, and IL-1β) and restoring the anti-inflammatory cytokine IL-10 to physiological levels, indicating a reset of the Th17/Treg balance. Comprehensive safety evaluation revealed no systemic toxicity. This work not only validates psoriasis as a new therapeutic indication for CuET but also presents a pioneering combined strategy of drug repurposing and material engineering, offering a safe and effective topical therapy that targets the core immune-vascular pathology of the disease.
Single-dose intrapalatal injection of erythromycin-loaded microparticles mitigates periodontitis-induced alveolar bone loss and enhances bone regeneration.
Surboyo MDC, El Fadhlallah PM, Sirisereephap K … +12 more , Sato-Yamada Y, Fang M, Yamauchi M, Yoshiba N, Tabeta K, Terao Y, Rosenkranz AL, Maeda T, Takabatake R, Miyaji H, Takemoto H, Maekawa T
Int J Pharm · 2026 Jun · PMID 42177923 · Publisher ↗
OBJECTIVE: Erythromycin (ERM) has demonstrated therapeutic potential in promoting alveolar bone regeneration by enhancing developmental endothelial locus 1 (DEL-1) activity in periodontitis. Because this regenerative eff...
OBJECTIVE: Erythromycin (ERM) has demonstrated therapeutic potential in promoting alveolar bone regeneration by enhancing developmental endothelial locus 1 (DEL-1) activity in periodontitis. Because this regenerative effect requires sustained local exposure at low, controlled doses, formulating ERM into microparticles can help deliver the drug directly to periodontal tissues while maintaining its therapeutic concentration over time. This study introduces a novel intrapalatal injection strategy for ERM-loaded microparticle delivery, to enhance bone regeneration and maintain periodontal health by activating endogenous DEL-1 signaling, supporting the potential of these formulations as pocket-injectable, bone-regenerative agents. METHODS: ERM-loaded nano- and microparticles were prepared using biodegradable polymers-poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA)-with varying lactic/glycolic ratios and molecular weights. Four formulations (SP0073-1 to SP0073-4) were produced by an oil-in-water emulsion solvent evaporation method, with ERM concentrations (12-16%). Ligature-induced periodontitis was created in 8-week-old male C57BL/6J mice, followed by a single intrapalatal injection of ERM formulations or blank particles. Mice were sacrificed after 9 or 21 days for histological evaluation using alkaline phosphatase and tartrate-resistant acid phosphatase staining. DEL-1 expression was assessed by immunofluorescence, and RNA-seq analysis of gingival tissue identified bone regeneration-related gene expression. The effects of ERM, blank particles, and ERM-loaded nano- and microparticles on osteogenic activity were assessed in MC3T3-E1, human periodontal ligament, and mouse bone marrow cells. RESULTS: Among ERM-loaded microparticles, SP0073-4 significantly upregulatedEdil3, Bglap2, Sp7, and Col5a1 expression, increased DEL-1 and osteocalcin expression in periodontal tissue, and preserved alveolar bone in young mice while promoting bone growth in aged mice. SP0073-4 enhanced osteoblast activity, reduced osteoclastogenesis, and increased mineralization compared with ERM alone. CONCLUSION: ERM-based microparticles (SP0073-4) promote bone regeneration and maintain periodontal integrity by activating DEL-1 signaling and modulating bone remodeling dynamics.
In situ forming hydrogel incorporating celastrol-loaded copper-doped Prussian blue nanoparticles for oxidative stress amplified multimodal breast cancer therapy.
Yang Z, Liu L, Wang X … +5 more , Qi Z, Hu B, Li W, Sun X, Yuan Y
Int J Pharm · 2026 Jun · PMID 42177922 · Publisher ↗
Breast cancer therapy is often hindered by limited tumor-specific accumulation of therapeutic agents, strong antioxidant defenses within the tumor microenvironment (TME), and the limitations of single-modal therapeutic s...
Breast cancer therapy is often hindered by limited tumor-specific accumulation of therapeutic agents, strong antioxidant defenses within the tumor microenvironment (TME), and the limitations of single-modal therapeutic strategies, which collectively reduce efficacy and increase systemic toxicity. In this study, we developed an injectable, thermosensitive hydrogel (CuPB@Cel-CG), composed of a chitosan (CS)/β-glycerophosphate disodium salt (β-GP) matrix incorporating celastrol-loaded, copper-doped Prussian blue nanoparticles (CuPB). After intratumoral injection, the hydrogel forms in situ, enabling sustained local retention and controlled drug release. Under near-infrared (NIR) irradiation, the system produces a mild photothermal therapy (PTT) that promotes Cu-mediated glutathione (GSH) depletion and triggers chemodynamic therapy (CDT), while the released celastrol disrupts tumor antioxidant defenses, amplifying oxidative stress and enhancing tumor cell apoptosis. In 4T1 tumor-bearing mice, CuPB@Cel-CG combined with NIR irradiation significantly inhibited tumor growth (∼84.9% inhibition) and caused extensive tumor necrosis without noticeable damage to major organs, demonstrating good biosafety. Overall, this work presents an innovative injectable hydrogel that integrates celastrol-loaded CuPB nanoparticles to realize localized tumor therapy through combined photothermal-chemodynamic effects and celastrol-induced oxidative stress amplification, providing a safe and effective strategy for multimodal breast cancer treatment.
Predicting the compressibility and compactibility profiles of pharmaceutical active ingredients for design of multi-component tablets.
Cheng C, Wang K, Schlindwein W … +5 more , Crean C, Wu CY, He Z, Liu X, Li M
Int J Pharm · 2026 Jun · PMID 42177921 · Publisher ↗
Digital design of multi-component pharmaceutical tablets based on the properties of individual constituents plays a critical role in the rational design and optimisation of pharmaceutical formulations. Most active pharma...
Digital design of multi-component pharmaceutical tablets based on the properties of individual constituents plays a critical role in the rational design and optimisation of pharmaceutical formulations. Most active pharmaceutical ingredients (APIs) used in tablet formulations are crystalline materials with diverse mechanical properties, including elastic, plastic, brittle, or combined deformation characteristics. These properties can lead to manufacturing challenges such as capping and sticking during the tableting process, or the formation of fragile tablets, making the direct compaction and testing of pure API tablets difficult or even impossible. In this study, we present an approach to predict the compressibility and compactibility profiles of APIs that cannot be directly compacted into tablets without the support of excipients. The method is based on the assumptions of additive volume fractions and the geometric mean mixing rule applied to the compactibility models of the individual components. API compressibility and compactibility models were derived from the analysis of "out-of-die" compaction data obtained from binary powder mixtures containing 50% API and 50% microcrystalline cellulose, compressed at different compaction pressures. Five APIs with diverse mechanical properties, i.e., aspirin, carbamazepine, metronidazole, paracetamol, and theophylline, were investigated. The proposed approach successfully predicted tablet solid fractions and tensile strengths for both binary (API and filler) and ternary (API, filler and disintegrant) mixtures of the APIs. The predicted tablet solid fractions were within ± 5% of the measured values, while tensile strength predictions showed errors typically ranging from ± 20% to ± 50%, depending on the API, formulation, and compaction pressure. Overall, the approach provides a practical digital design tool for the formulation of multi-component pharmaceutical tablets based on constituent material properties.
3D polyurethane vaginal rings for the delivery of steroid hormones using material extrusion additive manufacturing.
Junqueira LA, Tabriz AG, Koltsakidis S … +5 more , Tzetzis D, Raposo FJ, Douroumis D, Fernandes Brandão MA, Barbosa Raposo NR
Int J Pharm · 2026 Jun · PMID 42176762 · Publisher ↗
Three-dimensional printing has emerged as a novel technology to produce vaginal rings (VRs). However, the inherent high flexibility demanded by VRs poses a challenge when using filaments during the printing process. Here...
Three-dimensional printing has emerged as a novel technology to produce vaginal rings (VRs). However, the inherent high flexibility demanded by VRs poses a challenge when using filaments during the printing process. Here, we introduce a new approach for continuous 3D printing that eradicates the dependence on filaments and their printability for the fabrication of highly flexible VRs. Herein, Hot Melt Extrusion (HME) was used to create progesterone (PGR)-loaded thermoplastic polyurethane (TPU) pellets that were used as feedstock for 3D printing material extrusion of VRs. The TPU-based VRs presented excellent printability performance. Further physicochemical characterization indicated the presence of high amorphous PGR content while mechanical tests revealed that the VRs were consistently manufactured without significant deformation under prolonged compression and their performance was comparable to that of commercial VRs. The printed rings presented sustained release of clinically relevant quantities of progesterone over 28 days. Ex vivo studies showed that PGR permeated the porcine mucosa in a sustained manner for at least seven days. Finally, no cytotoxicity was observed in murine fibroblasts for the plain and progesterone-loaded pellets. This study demonstrates the potential of coupling HME and direct extrusion to produce 3D-printed VRs, aligning with the characteristics of traditional devices.
Cyclodextrins as multifunctional supramolecular carriers in ocular drug delivery.
Menkudale AR, Lewis SA
Int J Pharm · 2026 Jun · PMID 42176761 · Publisher ↗
Topical and non-invasive ocular drug delivery remains challenged by the rapid precorneal clearance, ocular epithelial and blood-retinal barriers, and poor aqueous solubility resulting in less than 5% bioavailability. Oft...
Topical and non-invasive ocular drug delivery remains challenged by the rapid precorneal clearance, ocular epithelial and blood-retinal barriers, and poor aqueous solubility resulting in less than 5% bioavailability. Often, there is requirement for irritant cosolvents or invasive intravitreal routes of administration. Cyclodextrins (CDs) have been known to improve solubility, but the supramolecular aspects of CDs have not been fully incorporated into the treatment of various diseases. In this review, the supramolecular aspects of CDs as drug delivery systems are discussed, with the emphasis being the relationship between the structure and host-guest thermodynamics and the efficacy, safety, and translational potential of CDs in the treatment of various ocular diseases. Recent developments in native and modified CDs, most specifically hydroxypropyl-β-CD (HPβCD), sulfobutyl ether-β-CD (SBEβCD), and γ-CD, are reviewed in the context of inclusion complexes, nanoaggregates, nanosponges, pseudopolyrotaxane hydrogels, nanofibers, and in situ gelling systems. The mechanistic influences on solubility, stability, corneal and scleral permeability, residence time, and controlled release are correlated with therapeutic outcomes in dry eye disease, uveitis, ocular infections, glaucoma, and non-invasive posterior segment delivery. In contrast to previous reviews that focused on CDs as solubilizers, this review highlights CDs as multifunctional supramolecular carriers that modulate solubility, permeability, and release kinetics while improving ocular tolerability. The review provides a disease-driven, mechanism-based framework for CD selection and integrates computational and regulatory perspectives to facilitate rational and clinical-ready design.
Self-nanonizing gelatin oleyl conjugate solid dispersions for enhanced solubility and permeability of tetrabenazine.
Nguyen SN, Yang BG, Dinh NH … +1 more , Lee BJ
Int J Pharm · 2026 Jun · PMID 42176760 · Publisher ↗
The oral delivery of tetrabenazine (TBZ), a weakly basic drug, is markedly affected by its poor permeability and solubility, particularly under neutral pH conditions. This study aimed to design self-nanonizing solid disp...
The oral delivery of tetrabenazine (TBZ), a weakly basic drug, is markedly affected by its poor permeability and solubility, particularly under neutral pH conditions. This study aimed to design self-nanonizing solid dispersions (SDs) using a fattigated gelatin-oleic acid conjugate (GOC) to achieve a synergistic enhancement of the solubility and permeability of TBZ. Successful conjugation of amphiphilic GOC through N-acylation was confirmed using Fourier transform-infrared and proton nuclear magnetic resonance spectroscopies. Binary GOC-based SDs prepared by spray drying could encapsulate the drug into self-assembled nanoparticles, forming approximately 130 nm above critical micellar concentration (0.887 mg/mL) and enabling enhanced drug release of 62.38 ± 1.14% for 120 min with minimized drug precipitation in aqueous media. Furthermore, ternary SDs incorporating fumaric acid (Fu) as a microenvironmental pH (pHm) modifier showed the highest improvement of dissolution rate and permeability, achieving a 9-fold increased release of 85.32 ± 2.76% within 120 min and a 2.4-fold increase in transmembrane permeability compared to pure TBZ. Reduced crystallinity and increased affinity through hydrogen-bonded molecular dispersion of TBZ into the hydrophobic oleyl cores of GOC and the formation of an amorphous drug-Fu electrostatic complex are also crucial, boosting encapsulation efficiency and dissolution rates by producing approximately 170 nm-sized nanoparticles. Collectively, the current self-nanonizing SD system resolved the solubility and permeability issues associated with TBZ to improve oral drug treatment.
Simple formulations with only excipients for stable lyophilization and ambient-temperature storage of adeno-associated viral vectors.
Okuda T, Sugiura M, Hirose H … +1 more , Okamoto H
Int J Pharm · 2026 Jun · PMID 42176759 · Publisher ↗
In the present study, we newly attempted the stable lyophilization of adeno-associated viral (AAV) vectors under simple formulations with only excipients containing no buffer, salt, or surfactant. An in vitro transfectio...
In the present study, we newly attempted the stable lyophilization of adeno-associated viral (AAV) vectors under simple formulations with only excipients containing no buffer, salt, or surfactant. An in vitro transfection study demonstrated that the intrinsic gene expression activity of AAV vectors was completely lost after lyophilization with no excipient, whereas it was partly maintained after lyophilization with some excipients, the efficacy of which was in the following order: cellulose derivatives and dileucine (diLeu) ≥ trehalose > other carbohydrates and dipeptides > amino acids. Methyl cellulose (MC), a cellulose derivative, almost completely maintained the intrinsic gene expression activity of AAV vectors with various serotypes after lyophilization up to a vector content of 8 × 10 genome copies/mg excipient. In an in vivo transfection study through intratracheal or intranasal administration to mice, AAV vectors lyophilized with MC exhibited a similar gene expression pattern in the nose or lungs to the original AAV vectors with MC, causing no body weight loss. Furthermore, diLeu alone or its combination with MC prolonged the gene expression activity of lyophilized AAV vectors for at least 4 weeks after their storage at room temperature.
An eye on metformin: Applications and drug delivery strategies for ocular conditions.
Regu VR, Subudhi BB
Int J Pharm · 2026 Jun · PMID 42176758 · Publisher ↗
Metformin, a widely recognized anti-hyperglycaemic agent, shows pleiotropic effects across various disease states. Recent research has highlighted its potential therapeutic applications in ocular conditions, including in...
Metformin, a widely recognized anti-hyperglycaemic agent, shows pleiotropic effects across various disease states. Recent research has highlighted its potential therapeutic applications in ocular conditions, including inflammation, oxidative stress, burns, conjunctivitis, and neovascularization. Although the high-water solubility of metformin is considered advantageous, it may pose challenges for conventional eye drops due to the potential for rapid solubilization in aqueous-based lacrimal fluid and removal via tear turnover. To address this limitation, innovative ocular delivery systems, such as in situ gels, polymeric films, and nanoparticles, have been developed and shown efficacy in treating ocular diseases. However, further exploration and optimization of these delivery strategies are essential to enhance clinical outcomes. Moreover, the role of organic cation transporters in facilitating metformin's trans-barrier movement within ocular tissues offers a promising avenue for non-invasive drug delivery. This review outlines current ocular applications of metformin, evaluates emerging delivery technologies, and discusses future perspectives to overcome existing therapeutic barriers.
Smart-responsive lentinan-DMXAA conjugate for synergistic STING-mediated pancreatic cancer immunotherapy.
Zhang Z, Zhu X, Cui J … +5 more , Han J, Wang J, Zhou H, Wu X, Zeng H
Int J Pharm · 2026 Jun · PMID 42173385 · Publisher ↗
Pancreatic cancer is a highly aggressive malignancy with a poor prognosis, primarily due to its immunosuppressive tumor microenvironment (TME) and suboptimal efficacy of current immunotherapies. Herein, we developed a no...
Pancreatic cancer is a highly aggressive malignancy with a poor prognosis, primarily due to its immunosuppressive tumor microenvironment (TME) and suboptimal efficacy of current immunotherapies. Herein, we developed a novel conjugate (LNT-DMXAA) by covalently grafting the STING agonist DMXAA onto the immunomodulatory polysaccharide (lentinan, LNT) via esterification and Schiff-base reactions, showing high drug loading (DMXAA, 9.91%; LNT, 90.09%) and enzyme/pH-responsive drug release. In vitro experiments revealed that LNT-DMXAA effectively elicited STING-dependent BMDC maturation via the TBK1-IRF3 axis, upregulating IFN-β and CXCL10, and exhibiting negligible cytotoxicity. Additionally, DMXAA synergized with LNT to enhance BMDC activation and OVA antigen presentation, with LNT-DMXAA demonstrating greater effectiveness. In Pan02 mice, LNT-DMXAA significantly inhibited tumor growth by activating dendritic cells for antigen presentation, promoting intratumoral CD8/CD4 T-cell infiltration, and performed better than DMXAA, LNT and physical mixtures. In addition, the conjugate exhibited excellent biocompatibility without notable organ toxicity or hemolysis, while enhancing DMXAA solubility. Collectively, LNT-DMXAA demonstrates potential as a pancreatic cancer immunotherapy agent by integrating LNT and DMXAA to synergistically address tumor immune evasion.
Ultrafast-dissolving voriconazole-cyclodextrin complex-based ocular microneedle patch: a novel approach for the treatment of fungal keratitis.
Gowda BHJ, Pandya AK, Gade S … +6 more , Duncan RM, Ahmed MG, Tian Y, Donnelly RF, Thakur RRS, Vora LK
Int J Pharm · 2026 Jun · PMID 42167466 · Publisher ↗
Fungal keratitis (FK) is a leading cause of corneal blindness worldwide. Although voriconazole (VOR) is effective, its poor corneal permeability limits its topical use, whereas intrastromal injections are invasive and ri...
Fungal keratitis (FK) is a leading cause of corneal blindness worldwide. Although voriconazole (VOR) is effective, its poor corneal permeability limits its topical use, whereas intrastromal injections are invasive and risky. Over the past 9 years, dissolving microneedle array patches (dMAPs) has emerged as a promising approach for ocular drug delivery; however, these methods face challenges in delivering poorly soluble drugs that can form depots within the cornea, delay drug release into surrounding tissues, and require longer application times than conventional methods, such as intrastromal injections and eye drops. This study presents an ultrafast-dMAP incorporating a VOR/sulfobutylether-β-cyclodextrin (SBE-β-CD) inclusion complex as a novel ocular delivery system for localized FK treatment. The VOR/SBE-β-CD inclusion complex, prepared via freeze-drying, showed a marked increase in VOR solubility. Using an optimized concentration of inclusion complex, dMAPs were fabricated through a micromoulding technique, resulting in strong mechanical integrity and efficient insertion capability. Ex vivo studies on porcine eyes demonstrated complete dMAP tip dissolution within 15 s, which was significantly faster than that of conventional polymer-based dMAPs. Compared with the solution formulation, the dMAP resulted in a 3.06-fold increase in corneal drug permeation and a 2.2-fold increase in drug deposition. Additionally, these compounds displayed potent in vitro antifungal activity against Candida albicans and Aspergillus fumigatus, which was attributed to improved drug solubility. Cytocompatibility and HET-CAM assays confirmed the nonirritant and biocompatible nature of the formulation. Overall, the present study, for the first time, reports a VOR/SBE-β-CD-based ultrafast-dMAP for ocular drug delivery, providing a minimally invasive and highly efficient alternative to conventional topical and intrastromal antifungal therapies. These findings demonstrate its strong potential for clinical translation, but further validation through in vivo studies is needed.
Development of a pH-modulating vaginal film through direct powder extrusion 3D printing for on-demand, hormone-free contraception: a quality by design approach.
Lakkala P, Munnangi SR, Narala N … +4 more , Baisa S, Alluri R, Vemula SK, Repka MA
Int J Pharm · 2026 Jun · PMID 42162810 · Publisher ↗
This study reports the development and optimization of a pH-modulating vaginal film fabricated via solvent-free direct powder extrusion 3D printing for localized sperm immobilization. The formulation incorporates lactic...
This study reports the development and optimization of a pH-modulating vaginal film fabricated via solvent-free direct powder extrusion 3D printing for localized sperm immobilization. The formulation incorporates lactic acid (90 mg), citric acid (50 mg), and potassium bitartrate (20 mg), the same clinically validated actives present in the Food and Drug Administration (FDA) - approved contraceptive gel Phexxi®. These actives were reformulated within a flexible polyethylene oxide matrix to enable a convenient, applicator-free solid dosage form. A Quality by Design (QbD) framework employing a four-factor, three-level Box-Behnken design was implemented to optimize independent variables like plasticizer concentration, printing temperature, extrusion pressure, and printing speed against dependent variables like disintegration time, film elasticity, and printability. The optimized film disintegrated within 84 s in simulated vaginal fluid and maintained vaginal pH within 3.5-4.0 over two hours under a six-fold excess of seminal fluid simulant, consistent with the acidic threshold required for sperm immobilization. FTIR and H NMR confirmed chemical stability post-processing, and three months of accelerated stability testing verified preservation of mechanical and functional performance. These findings establish a QbD-guided, on-demand vaginal film as a promising hormone-free contraceptive platform that combines a clinically validated pH-modulating composition with a convenient applicator-free solid dosage form.
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