Int J Pharm [JOURNAL]
Sun
200 papers
Hydroxyethyl starch-based enzyme/pH dual-responsive polymer prodrug micelles for improved stability and antitumor efficacy of 10-hydroxycamptothecin.
Liu J, Gou J, Wang Y … +2 more , He H, Tang X
Int J Pharm · 2026 Jun · PMID 42361999 · Publisher ↗
Cancer remains a major global public health challenge, posing a substantial threat to human health and socioeconomic development. 10-hydroxycamptothecin (10-HCPT), a potent topoisomerase I inhibitor, exhibits broad antit...
Cancer remains a major global public health challenge, posing a substantial threat to human health and socioeconomic development. 10-hydroxycamptothecin (10-HCPT), a potent topoisomerase I inhibitor, exhibits broad antitumor activity; however, its clinical application is limited by poor aqueous solubility, rapid lactone-ring opening under physiological pH, and low bioavailability. To address these limitations, we developed an enzyme- and pH-dual-responsive polymer prodrug nanocarrier based on hydroxyethyl starch (HES). 10-HCPT was conjugated to the HES backbone through a hydrolysable succinate ester linkage, yielding an amphiphilic HES-10-HCPT prodrug capable of self-assembling into micelles. The resulting polymer prodrug micelles exhibited favorable storage and plasma stability. Importantly, drug release was accelerated under acidic and enzymatic conditions, suggesting tumor microenvironment-responsive release behavior. In vitro cytotoxicity assays against 4T1 breast cancer cells showed that the high-drug-loading micelles, HH-2, displayed markedly enhanced potency, with an IC50 value of 0.651 μg/mL, compared with free 10-HCPT, which showed an IC50 value of 27.7 μg/mL. In vivo studies in 4T1 tumor-bearing mice demonstrated that, at an equivalent 10-HCPT dose, HH-2 achieved a tumor inhibition rate of 46.31%, compared with 19.70% for free 10-HCPT. Histological analysis further suggested a favorable preliminary safety profile. Overall, this HES-based polymer prodrug micelle system provides a promising strategy for improving the stability, therapeutic efficacy, and safety of 10-HCPT and may serve as a potential platform for cancer chemotherapy.
Rational nanoengineering and personalized strategies for overcoming cancer stem cell-driven tumor heterogeneity.
Chen C, Chen Z, Cheng T … +2 more , Liu J, Li F
Int J Pharm · 2026 Jun · PMID 42361998 · Publisher ↗
Tumor heterogeneity, particularly the spatiotemporal heterogeneity driven by cancer stem cells (CSCs), is a key obstacle leading to therapy resistance, recurrence, and metastasis in malignant tumors. Although targeting C...
Tumor heterogeneity, particularly the spatiotemporal heterogeneity driven by cancer stem cells (CSCs), is a key obstacle leading to therapy resistance, recurrence, and metastasis in malignant tumors. Although targeting CSCs holds the potential for eradicating tumors at their root, current therapies are limited by poor delivery efficiency and systemic toxicity. Nano drug delivery systems (NDDSs), with their designable physicochemical properties and intelligent responsive mechanisms, offer a revolutionary strategy to overcome these limitations. Moving beyond a conventional summary of NDDS applications, this review for the first time systematically integrates two cutting-edge perspectives: "rational carrier engineering" and a "personalized therapeutic framework." It elaborates on how design principles-such as surface engineering, biomimetic modification, and barrier-penetrating strategies-enable efficient targeting and drug delivery to CSCs via NDDSs. The review also critically evaluates the synergistic potential of combining NDDSs with multimodal therapies (e.g., photodynamic, sonodynamic, and magnetothermal therapy) as well as advanced modalities like gene editing and immunotherapy to comprehensively eradicate CSCs. More importantly, we propose a personalized NDDS framework tailored to tumor heterogeneity subtypes. This framework links deep molecular subtyping with adaptive carrier engineering and therapeutic feedback loops, providing a methodological blueprint for developing next-generation precision nanotherapies. Finally, the review discusses challenges in clinical translation, aiming to provide a new theoretical and strategic foundation for overcoming CSC-driven tumor heterogeneity and therapy resistance.
Valence-activated arsenic nanozyme enables cascade-amplified chemodynamic therapy for hepatocellular carcinoma.
Chen D, Chen S, Zhang Y … +7 more , Ma Y, Zheng S, Li J, Tao T, Jiang L, Zhuang R, Li F
Int J Pharm · 2026 Jun · PMID 42349733 · Publisher ↗
Hepatocellular carcinoma (HCC) exhibits intratumoral heterogeneity and poor responsiveness to conventional therapies, necessitating strategies that combine high therapeutic potency with minimal systemic toxicity. Arsenic...
Hepatocellular carcinoma (HCC) exhibits intratumoral heterogeneity and poor responsiveness to conventional therapies, necessitating strategies that combine high therapeutic potency with minimal systemic toxicity. Arsenic trioxide (As) is a potent chemotherapeutic agent for HCC; nevertheless, its application in solid tumors is limited by off-target toxicity and dose-limiting adverse effects. Herein, we report a valence-activated nanozyme platform that enables tumor-confined generation of therapeutically active As from low-toxicity arsenate (As) for safe and effective HCC treatment. A manganese dioxide-coated arsenate-zinc sulfide core-shell-shell nanozyme (As-ZnS@MnO NPs) was engineered to undergo pH-responsive disassembly in the mildly acidic tumor microenvironment, resulting in the release of HS, As, and Mn. The generated HS drives the in situ reduction of As to As, thereby activating arsenic chemotherapy. Simultaneously, Mn catalyzes Fenton-like reactions with endogenous HO to generate hydroxyl radicals (·OH), while the produced As further amplifies oxidative stress, leading to enhanced chemodynamic therapy. In addition, Mn serves as a T-weighted magnetic resonance imaging contrast agent for noninvasive therapeutic monitoring. Through this tightly coupled cascade of arsenic activation, oxidative amplification, and imaging guidance, the nanozyme achieves potent antitumor efficacy with reduced systemic toxicity. This reaction-programmed strategy provides a promising approach for arsenic-based nanomedicine in hepatocellular carcinoma therapy.
A light-controlled hydrogel for regulating oxidative stress in the treatment of psoriasis.
Shi J, Li X, Mao Y … +2 more , Ling G, Zhang P
Int J Pharm · 2026 Jun · PMID 42349732 · Publisher ↗
Psoriasis is a common chronic autoinflammatory skin disease characterized by excessive proliferation of keratinocytes and marked thickening of the stratum corneum. The condition is often recurrent and difficult to cure,...
Psoriasis is a common chronic autoinflammatory skin disease characterized by excessive proliferation of keratinocytes and marked thickening of the stratum corneum. The condition is often recurrent and difficult to cure, and its development is closely associated with redox imbalance. Excessive accumulation of reactive oxygen species (ROS) at the lesional sites drives inflammatory responses. Additionally, the impaired epidermal barrier in psoriatic lesions renders the skin susceptible to secondary bacterial infections, which further exacerbates the disease. However, elevated ROS also possesses potential therapeutic effects by inducing keratinocyte apoptosis and inhibiting epidermal hyperplasia. Achieving controllable synergy between ROS generation and elimination remains a challenge. Here, we develop a light-controlled hydrogel for staged psoriasis treatment. The hydrogel integrates Chlorella for ROS scavenging and silver‑zinc oxide heterojunction nanoparticles (Ag@ZnO) for photocatalytic ROS generation, forming a composite system denoted as Chl-Ag@ZnO/C-P (Chlorella and Ag@ZnO‑loaded carboxymethyl chitosan/polyvinyl alcohol hydrogel). In the initial dark phase, Chlorella scavenges pathological ROS to alleviate inflammation. Upon light irradiation, Ag@ZnO generates therapeutic ROS to induce keratinocyte apoptosis, while Chlorella simultaneously produces oxygen to enhance the photodynamic effect. This light-controlled bidirectional ROS regulation enables sequential anti-inflammatory and pro-apoptotic actions. In an IMQ-induced psoriasis mouse model, the hydrogel reduced epidermal thickness, decreased inflammatory cytokines (IL-17A, TNF-α), and restored ROS levels. The results demonstrate that this hydrogel system regulates oxidative stress in a staged manner for psoriasis treatment.
Chitosan-based nanocomposites for targeted colorectal cancer therapy: design strategies, functionalization, and therapeutic advances.
Dudhwala YD, Shah DP, Haswani NG … +4 more , Kapoor DU, Prajapati BG, Alsaidan OA, Alzarea SI
Int J Pharm · 2026 Jun · PMID 42349731 · Publisher ↗
Colorectal cancer is a major global health concern, accounting for nearly 10% of all cancer deaths and causing over 900,000 deaths annually. Despite therapeutic advances, issues like poor drug bioavailability, systemic t...
Colorectal cancer is a major global health concern, accounting for nearly 10% of all cancer deaths and causing over 900,000 deaths annually. Despite therapeutic advances, issues like poor drug bioavailability, systemic toxicity, and drug resistance persist. Chitosan, a naturally derived polysaccharide, has gained attention as a versatile nanocarrier for colorectal cancer therapy due to its pH responsiveness, mucoadhesiveness, and enzymatic biodegradability, which enable site-specific and controlled drug release. This review highlights recent progress in the design and functionalization of chitosan-based nanocomposites for targeted colon delivery. Approaches such as ligand-mediated targeting (e.g., folate, hyaluronic acid), enzyme-triggered systems, and smart hydrogels enhance tumor selectivity and therapeutic efficacy. Moreover, co-delivery systems integrating chemotherapeutics with gene modulators or immunotherapeutics offer solutions to tumor heterogeneity and drug resistance. Preclinical findings indicate improved bioavailability, tumor accumulation, and reduced systemic toxicity, while early clinical studies report favorable safety and pharmacokinetic profiles. Challenges including pH solubility and rapid clearance are being addressed through PEGylation, chemical grafting, and hybrid nanocomposites. Overall, chitosan's multifunctional nature positions it as a promising platform for next-generation, colon-targeted nanomedicine in colorectal cancer treatment.
New delivery carrier from Tenebrio molitor polar lipids larvae: from the green enzymatic extraction process to the INFOGEST in vitro digestion evaluation.
Pruvost L, Gerlei M, Amara S … +3 more , Paris C, Linder M, Jasniewski J
Int J Pharm · 2026 Jun · PMID 42341964 · Publisher ↗
Given the current challenges related to the need for more environmentally friendly and cost-effective complete nutritional sources, the insect Tenebrio molitor is increasingly studied for its interesting composition in p...
Given the current challenges related to the need for more environmentally friendly and cost-effective complete nutritional sources, the insect Tenebrio molitor is increasingly studied for its interesting composition in proteins and lipids. This study highlights the presence of polar lipids (phospholipids) in the larvae and the valorization of phospholipid and peptide fractions to produce nanoliposomes encapsulating peptides obtained from the same source via green enzymatic hydrolysis. The phospholipid profile revealed a predominance of phosphatidylethanolamine and phosphatidylcholine, rich in unsaturated fatty acids (60.47%). Liposomes predominantly have a size around 150 nm, with low polydispersity (0.2) and a strongly negative zeta potential around - 40 mV. These liposomes are capable of encapsulating peptides from Tenebrio molitor larvaes with molecular weights of 10 kDa and 10 to 30 kDa. The addition of peptides enhances the stability of the liposomes by reducing their size. Moreover, a static in vitro digestion study shows that these liposomes are resistant to gastric enzymes and undergo limited hydrolysis in the intestinal phase, with an extent of hydrolysis of approximately 10%, highlighting their potential to improve the bioavailability of encapsulated biomolecules. These findings demonstrate that, beyond being a promising future nutritional source, Tenebrio molitor can also be exploited for the formulation of functional pet foods (aquaculture or domestical), pharmaceutical and nutraceutical delivery systems.
On-demand radiofrequency-controlled drug release from microcapsule depot in ex vivo tissue model.
Slonková K, Navrátil O, Huňa R … +3 more , Dolenský B, Lizoňová D, Štěpánek F
Int J Pharm · 2026 Jun · PMID 42341963 · Publisher ↗
Passive antibiotic release from implanted depot systems often leads to sub-therapeutic dosing, which in some cases may increase the risk of bacterial resistance. Addressing this limitation requires precise, controllable...
Passive antibiotic release from implanted depot systems often leads to sub-therapeutic dosing, which in some cases may increase the risk of bacterial resistance. Addressing this limitation requires precise, controllable dosing strategies that do not rely on additional surgical interventions. To this end, this work presents a core-shell depot microcapsule system that enables externally controlled, on-demand antibiotic release using radiofrequency (RF) heating. The microcapsules (d ≈ 500 µm) consist of a norfloxacin-loaded wax solid core and a dually crosslinked methacrylated alginate shell containing superparamagnetic iron oxide nanoparticles (SPIONs). RF-induced heating of the SPIONs triggers the melting of the wax core, initiating drug release only when required, enabling precise repeated delivery up to 10 times. The dual-crosslinked shell ensures structural integrity, maintaining prolonged stability under physiological conditions. Mathematical and experimental models confirm the thermal safety of the process. Furthermore, antibacterial efficacy was validated on Escherichia coli-coated agar plates and in ex vivo animal tissue model, showing significant bactericidal effects in vitro. The findings highlight a promising approach for targeted, responsive antibacterial treatment while minimizing the risks of resistance development.
Machine learning algorithms to predict spray dried protein/peptide formulations.
Wei L, Deng J, Sun Y … +10 more , Yang Y, Wang X, Gao Q, Hou Y, Sun S, Foderà V, van de Weert M, Cun D, Ouyang D, Yang M
Int J Pharm · 2026 Jun · PMID 42341962 · Publisher ↗
Proteins and peptides hold immense promises for treating fatal and rare diseases. However, their complex structures and intrinsic instability pose significant challenges in drug development. The spray drying process offe...
Proteins and peptides hold immense promises for treating fatal and rare diseases. However, their complex structures and intrinsic instability pose significant challenges in drug development. The spray drying process offers a continuous and rapid method to stabilize these biomacromolecules, converting them from liquid to solid formulations. However, the spray drying process remains trial-and-error based, requiring extensive resources. This study employs machine learning (ML) algorithms to predict key properties of spray-dried protein and peptide powders, including yield, particle size, residual solvent content, solid states properties, and aggregation, with the aim to help accelerate formulation development and optimize process parameters. In total, 321 yield data points, 288 particle size data points, 357 residual solvent content data points, 205 solid states of the dry powder data points, and 305 aggregation data points were collected and described using various molecular descriptors for model building. Seven ML algorithms were tested to identify the best model to predict the key properties. Light Gradient Boosting Machine (LightGBM) exhibited the best performance for regression tasks, particularly for residual solvent content (mean absolute error = 0.841), and logistic regression excelling in predicting solid state characteristics and aggregation. Feature importance analysis identified protein, excipient, processing parameters, and environmental conditions as critical factors influencing various properties of spray-dried proteins/peptides formulation. The generalizability of the models was experimentally validated using alpha-lactalbumin formulations, the mean absolute error (MAE) in the models of yield, particle size, and residual solvent content were 0.755, 1.591, and 14.492 respectively, and the accuracies in predicting solid states of the dry powder and aggregation were 78.0% and 100.0% respectively. This study demonstrates the potential of machine learning to streamline the development of spray-dried protein formulations, providing a material- and time-saving solution as a reference.
Corrigendum to "Self-assembled multifunctional polymeric micelles for tumor-specific bioimaging and synergistic chemo-phototherapy of cancer" [Int. J. Pharm. 602 (2021) 120651].
Yang Y, Yun K, Li Y … +6 more , Zhang L, Zhao W, Zhu Z, Tian B, Chen F, Pan W
Int J Pharm · 2026 Jun · PMID 42341458 · Publisher ↗
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Corrigendum to "Variable pore size of mesoporous silica in improving physical stability and oral bioavailability of insoluble drugs" [Int. J. Pharm. 674 (2025) 125394].
Qi W, Chen J, Rui S … +7 more , Li S, Ding Y, Feng S, Liu Z, Liu Q, Wang S, Zhao Q
Int J Pharm · 2026 Jun · PMID 42341457 · Publisher ↗
Abstract loading — click title to view on PubMed.
Membrane mechanics as critical quality attributes in liposomal drug delivery: linking bilayer structure, mechanics, and performance.
Maheshwari N, Ghode P, Maheshwari R
Int J Pharm · 2026 Jun · PMID 42336333 · Publisher ↗
Mechanical properties of liposomes, particularly bending rigidity (k), membrane area compressibility modulus (k), and effective Young's modulus (E), are increasingly recognized as potentially important factors influencin...
Mechanical properties of liposomes, particularly bending rigidity (k), membrane area compressibility modulus (k), and effective Young's modulus (E), are increasingly recognized as potentially important factors influencing clinical translation and regulatory assessment. This review establishes liposome mechanics as an underexplored determinant in predictive performance, moving beyond conventional descriptors such as size and surface charge. We provide an in-depth and systematic analysis of how bilayer mechanics governs key biological processes, including circulation stability, deformability, trans-barrier transport, and cellular uptake. Special emphasis is placed on elastic liposomes, where reduction in k (often to <10 kBT) and modulation of k enable extreme deformability, facilitating pore-squeezing and enhanced tissue penetration. We integrate fundamental frameworks such as Helfrich elasticity with experimental and computational approaches (atomic force microscopy, micropipette aspiration, scattering, and molecular dynamics) to establish quantitative structure-mechanics-function relationships. The review further examines how lipid composition, sterols, and edge activators tune mechanical constants and how these parameters translate into drug-delivery performance. Emerging concepts such as mechanomorphic liposomes and mechanically triggered drug release are also critically discussed. Importantly, we discuss the potential for parameters such as k and k to be considered as future CQAs, pending further standardization and validation of measurement methodologies. This review, therefore, provides a roadmap for engineering mechanics-driven liposomal systems.
Dapagliflozin embedded polymeric nanomicelles for enhanced ocular drug delivery: A promising strategy for glaucoma therapy.
Chitre A, Dhapte-Pawar V, Sathiyanarayanan A … +1 more , Kanse A
Int J Pharm · 2026 Jun · PMID 42331119 · Publisher ↗
Glaucoma, a progressive neurodegenerative disorder, accentuates the need for a neuroprotective therapy to overcome the risk of blindness. Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain co...
Glaucoma, a progressive neurodegenerative disorder, accentuates the need for a neuroprotective therapy to overcome the risk of blindness. Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing protein 3 (NLRP3) inhibitors like dapagliflozin (DAPA) may exert neuroprotective effects in the glaucoma therapy. As DAPA suffers from poor permeability and solubility challenges, it cannot be administered in the eyes. Also, invasive methods as well as retinal drug delivery suffers from compliance and safety issues. Thus, the aim was to develop and assess DAPA loaded mixed polymeric, nanomicellar (DAPA MPN) formulation using non-ionic polymers, Poloxamer 188 and Soluplus. In-silico studies involving DAPA and brinzolamide (BRZ) revealed the key targets of glaucoma for comparative analysis. Ensuing CMC determination and drug-polymer ratio optimization, stable, DAPA MPN batch was formulated with particle size of 144.57 nm, spherical morphology with 90.18 % entrapment efficiency. Topical DAPA MPN formulation showed effective encapsulation, drug-excipient compatibility and sustained drug release with 1.45 folds enhancement. As per the OECD TG 405 studies, DAPA MPN was found to be safe for ocular application. During in-vivo screening in ɑ-chymotrypsin induced glaucoma model of New Zealand white rabbits, DAPA MPN demonstrated significant anti-inflammatory, anti-oxidative and anti-apoptotic benefits on the retina. Also, DAPA MPN showed IOP lowering effects as confirmed from the TGF-β1 levels in the aqueous humor. In conclusion, polymeric nanomicelles proved to be promising platform for successful retinal delivery of DAPA, thereby exerting neuroprotective benefits during glaucoma therapy.
Dual DNAzyme-loaded Treg-derived extracellular vesicles for targeted ocular delivery in diabetic retinopathy.
Zhang Y, Wang T, Cao J … +6 more , Xing Z, Li J, Wu Z, Xiao K, Liu K, You Z
Int J Pharm · 2026 Jun · PMID 42331118 · Publisher ↗
Diabetic retinopathy (DR) is one of the leading causes of preventable blindness worldwide. Current treatments, primarily based on anti-VEGF therapy, often require frequent intravitreal injections and have limited long-te...
Diabetic retinopathy (DR) is one of the leading causes of preventable blindness worldwide. Current treatments, primarily based on anti-VEGF therapy, often require frequent intravitreal injections and have limited long-term efficacy. Ocular drug delivery with sustained release and stability remains a significant challenge. In this study, we developed a Treg-derived extracellular vesicle (EV) system loaded with dual DNAzymes for targeted ocular delivery in the treatment of DR. We evaluated the efficacy, safety, and stability of this delivery system both in vitro and in vivo. Our results demonstrated that the Treg-EV-loaded dual DNAzyme system effectively targeted the ocular vasculature, achieved sustained inhibition of VEGF and VEGFR2 expression, and significantly reduced retinal inflammation. Additionally, the system showed prolonged retinal retention and favorable safety profiles. This study presents a novel approach for DR treatment, providing a promising therapeutic strategy that could reduce the frequency of intravitreal injections and improve treatment outcomes. The Treg-EV-based delivery system holds great potential for clinical application in managing DR and improving patient outcomes.
From simplicity to complexity: how excipients shape stability and disintegration of immediate-release tablets.
Ibrahim I, Mann J, Winge F … +6 more , Davis A, Hens B, Khadra I, Virrankoski M, DeAngelis A, Markl D
Int J Pharm · 2026 Jun · PMID 42331117 · Publisher ↗
Physical stability is a critical aspect of tablet formulation, with excipients significantly influencing long-term tablet performance, especially under humid conditions. This study investigated storage-induced changes in...
Physical stability is a critical aspect of tablet formulation, with excipients significantly influencing long-term tablet performance, especially under humid conditions. This study investigated storage-induced changes in increasingly complex tablet formulations by sequentially incorporating croscarmellose sodium (CCS), magnesium stearate (MgSt), and lactose into microcrystalline cellulose (MCC)-based tablets prepared at different porosities and stored at 50°C/75% RH for up to 42 days. Storage induced changes occurred through two distinct stages. The first stage was governed by moisture uptake, with most sorption occurring within the first day of storage, resulting in tablet swelling and tensile strength reductions of 16-51% depending on formulation and porosity. The rate of these structural changes was strongly correlated with sorption kinetics. The second stage occurred after moisture uptake had largely stabilised and was characterised by continued changes in liquid penetration and swelling behaviour (quantified by sessile drop analysis), and disintegration performance. These later changes were highly formulation dependent, with MgSt containing formulations showing the greatest deterioration, where disintegration times increased from approximately 40 s to 500 s after storage. DVS measurements successfully predicted moisture uptake and tensile strength evolution across formulations and porosity levels. The results demonstrate that tablet stability is governed by a sequence of moisture driven structural changes followed by slower performance related changes, providing a practical framework for predicting stability assessment and formulation development from short-term measurements.
Preparation of orodispersible minitablets containing a poorly compactable drug substance by aqueous fluid bed layering onto coprocessed excipients.
Badawi S, Fischer B, Lillotte T … +3 more , Esser E, Nueboldt C, Breitkreutz J
Int J Pharm · 2026 Jun · PMID 42331116 · Publisher ↗
This study investigates the application of fluid bed processing (FBP) to improve the tabletability of a poorly compactable drug substance through the aqueous suspension layering onto coprocessed excipient for direct comp...
This study investigates the application of fluid bed processing (FBP) to improve the tabletability of a poorly compactable drug substance through the aqueous suspension layering onto coprocessed excipient for direct compression to produce orodispersible minitablets (ODMTs). For for this purpose, the aqueous drug suspension was sprayed-layered onto two coprocessed excipients using the FBP technology. The produced batches were compressed into ODMTs and systematically compared to the direct compression (DC) batches with equivalent composition. The tableting of the DC batches progressively deteriorated with increasing drug loading and was halted at higher drug loads due to reaching the machine safety limits. Moreover, the produced tablets exhibited several tablet defects (capping and sticking) and poor content uniformity. On the other hand, the tableting performance was evaluated through the ejection forces recorded, tablet defects observed and content uniformity assessment. The FBP batches successfully enabled tableting, achieving drug loading of the investigated active pharmaceutical ingredient up to ∼ 66 % (w/w) per ODMT with no tableting defects and acceptance values compliant with the Level 1 of the European Pharmacopoeia. Confocal raman microscopy and micro computed tomography imaging demonstrated that FBP improved blend uniformity thereby facilitating uniform drug distribution throughout the tablet matrix which was not the case for the DC blend. These findings demonstrate the benefit of the FBP step to enable the tableting of this poorly compactable drug substance even at higher drug loads while maintaining content uniformity and tablet integrity.
Subdermal implants for HIV prevention with increased dapivirine release rates.
Wang S, Murtadha RZ, Malcolm RK
Int J Pharm · 2026 Jun · PMID 42324049 · Publisher ↗
Dapivirine (DPV) is an antiretroviral drug used for prevention of sexually acquired HIV infection in the form of a monthly matrix-type silicone elastomer vaginal ring. As part of efforts to develop longer acting antiretr...
Dapivirine (DPV) is an antiretroviral drug used for prevention of sexually acquired HIV infection in the form of a monthly matrix-type silicone elastomer vaginal ring. As part of efforts to develop longer acting antiretroviral products for HIV pre-exposure prophylaxis (PrEP), we previously reported reservoir-type DPV-releasing silicone elastomer subdermal implants. These early prototypes were constrained by relatively low DPV daily release rates (7-14 µg/day), which are likely too low to prevent sexual transmission of HIV. Here, we report in vitro formulation development of next-generation implant formulations as part of efforts to increase DPV release rates. Three strategies were evaluated-(i) reservoir-type implants fabricated from medical-grade silicone tubing comprising a core containing DPV solubilised in a liquid polyethoxylated castor oil (Kolliphor® EL), (ii) dip-coated reservoir rods, comprising a matrix-type silicone core and a relatively thin (∼0.33-0.66 mm) drug-free, silicone elastomer, rate-controlling membrane applied by dip coating, and (iii) simple matrix-type silicone elastomer rods. Replacing the conventional silicone elastomer core of the implants with Kolliphor® EL increased DPV solubility and enhanced steady-state flux ∼1.5-fold. Dip-coated implants provided mean daily release rates of 19-41 µg/day. Matrix-type implants lacking a rate-controlling membrane delivered up to 185 µg/day. While these release rates represent a substantial improvement over first-generation devices, it remains uncertain whether they would produce systemic concentrations sufficient for HIV prevention, given dapivirine's relatively low potency and the absence of a local delivery advantage with subdermal administration. Nonetheless, the findings are useful in demonstrating the feasibility of designing silicone-based implants, illustrating how core composition, membrane geometry, and release conditions influence DPV release from silicone subdermal implants, and providing a basis for future in vivo pharmacokinetic and preclinical evaluation.
Heated nebulization of ambroxol hydrochloride: engineering submicron aerosols for pulmonary drug delivery.
Tao Y, Chu M, Deng J … +8 more , Zhao J, Zhang W, Jin L, Xu T, Wu Z, Liu Z, Liu Z, Lu J
Int J Pharm · 2026 Jun · PMID 42323034 · Publisher ↗
Chronic respiratory diseases (CRDs) remain challenging to treat, largely due to the difficulty in delivering therapeutic agents to the deep lung. Ambroxol hydrochloride (AH), a widely used mucolytic agent that promotes m...
Chronic respiratory diseases (CRDs) remain challenging to treat, largely due to the difficulty in delivering therapeutic agents to the deep lung. Ambroxol hydrochloride (AH), a widely used mucolytic agent that promotes mucus clearance, is indicated for conditions such as asthma, emphysema, and chronic bronchitis. This study reports the in vitro characterization of a heated medical nebulizer (MD6-HA20-2) for the generation of AH inhalable aerosols. The device vaporizes a liquid AH formulation via a battery-operated heating element; upon inhalation, the vapor condenses into aerosols exhibiting a mass median aerodynamic diameter of 0.53 ± 0.06 µm (GSD = 1.26). Across 200 consecutive inhalation actuations, the nebulizer delivered 25.21 ± 0.06 µg of AH per actuation with an atomization efficiency of 99.66 ± 0.47%, confirming highly reproducible dosing. High-performance liquid chromatography verified the thermal stability of AH throughout the nebulization process, and analysis of carbonyl compounds and trace toxic metals in the aerosol indicated that exposures to potentially harmful by-products remained below established health-based benchmarks. Collectively, these in vitro findings demonstrate that the heated nebulization platform can reliably generate submicron AH aerosols with a favorable preliminary chemical safety profile, supporting its continued development for pulmonary drug delivery.
Effect of composition dependence in Flory-Huggins parameters on solid dispersion stability prediction.
Meere M, Pontrelli G, McGinty S
Int J Pharm · 2026 Jun · PMID 42323033 · Publisher ↗
Flory-Huggins models underpin phase diagram construction and stability analysis in a wide range of polymer-solute systems, including pharmaceutical solid dispersions, where phase diagrams are routinely used to guide form...
Flory-Huggins models underpin phase diagram construction and stability analysis in a wide range of polymer-solute systems, including pharmaceutical solid dispersions, where phase diagrams are routinely used to guide formulation design and stability risk assessment during product development. In practice, the interaction parameter is commonly represented as a temperature-dependent function, χ=χ(T), fitted to experimental data. However, multiple studies and experimental observations suggest that χ may depend on both temperature and composition (ϕ), that is, χ=χ(ϕ,T). Focusing on solid dispersions, here we develop and interrogate a novel composition-dependent Flory-Huggins mathematical framework and quantify the consequences of using χ(ϕ,T) in place of χ(T) when predicting and interpreting phase behaviour. We derive the appropriate chemical potentials and stability conditions required for binodal and spinodal calculations when χ depends on both composition and temperature, and we present generalized criteria for the existence of both upper critical solution temperature (UCST) and lower critical solution temperature (LCST) behaviour. We construct phase diagrams for three solid dispersion systems based on independent experimental data taken from the literature and directly compare predictions obtained using χ=χ(T) and χ=χ(ϕ,T) for each system. We demonstrate that allowing χ to depend on composition can lead not only to substantial quantitative differences, but also to qualitatively different phase behaviour. Finally, we illustrate the implications of these differing phase diagrams by developing a partial differential equation model that enables simulation of microstructural spatiotemporal evolution. The resulting simulations validate the predicted stability landscapes and reveal rich demixing morphologies, including bicontinuous networks and droplet formation.
Role of oligopeptides as co-formers in stabilizing amorphous dipyridamole: mechanistic insights using molecular docking simulations.
Kamruzzaman M, McLoughlin P, Cathcart H … +1 more , O'Reilly NJ
Int J Pharm · 2026 Jun · PMID 42323032 · Publisher ↗
The amorphous form of poorly water-soluble drugs can be stabilized using low- molecular weight co-formers in co-amorphous systems. However, the limited choice of suitable co-formers and the need to understand the underly...
The amorphous form of poorly water-soluble drugs can be stabilized using low- molecular weight co-formers in co-amorphous systems. However, the limited choice of suitable co-formers and the need to understand the underlying stabilization mechanism remain challenging for the widespread adoption of this formulation approach. In this study, a number of commercially available and custom-designed oligo- (di/tri)-peptides were used as co-formers to prepare stable co-amorphous systems of the BCS class II drug dipyridamole (DPM), using spray drying. Feed solutions were prepared by dissolving drug and co-former in a 1:1 molar ratio in methanol-water mixtures. The spray drying process was evaluated and solid-state properties of the resulting formulations were compared to assess the effectiveness of different co-formers in preparing stable co-amorphous systems. Stability was investigated at 25 °C/60% RH and 40 °C/75% RH using non-ambient X-ray powder diffraction (XRPD), with performance quantified by the point of failure (POF), a time when co-amorphous systems exhibit crystalline peaks in the XRPD diffractograms.Spectroscopic techniques, together with molecular docking, were employed to investigate the underlying stabilization mechanisms. A direct correlation between the increasing number of amino acids in the peptide chain with the co-amorphous properties could not established within the range of co-formers investigated. It was found however that co- formers with more complex molecular structures and lower hygroscopicity were generally associated with improved stability. In addition, a correlation between higher binding affinity and increased POF time was observed, suggesting that computational screening may support the selection of suitable drug-co-former combinations prior to experimental development.
Functionalized extracellular vesicles for enhanced brain targeted delivery of luteolin as a novel anti-neuroinflammatory therapy.
Zhou W, Deng Z, Jiang J … +6 more , Kuang X, Wu Z, Wang Z, Chen H, Du Z, Yuan Z
Int J Pharm · 2026 Jun · PMID 42323031 · Publisher ↗
BACKGROUND: The blood-brain barrier (BBB) remains the most formidable obstacle in CNS drug development, severely hindering the delivery of therapeutic agents to the brain. While many natural compounds, such as the flavon...
BACKGROUND: The blood-brain barrier (BBB) remains the most formidable obstacle in CNS drug development, severely hindering the delivery of therapeutic agents to the brain. While many natural compounds, such as the flavonoid luteolin (Lut), possess potent anti-neuroinflammatory properties, their clinical potential is restricted by poor pharmacokinetic profiles and minimal BBB permeability. METHODS: To address this systemic challenge, we developed a versatile, brain-targeting nanoplatform utilizing mesenchymal stem cell-derived extracellular vesicles (MSC-EVs). For active CNS targeting, these EVs were functionalized with a chimeric RVG-CP05 peptide via modular, non-covalent anchoring and subsequently loaded with Lut. This RVG@EV-Lut nanocomposite was characterized for its physicochemical properties and evaluated using a Transwell-based in vitro BBB model. Therapeutic efficacy and biodistribution were assessed in a C57BL/6J mouse model of LPS-induced neuroinflammation. RESULTS: RVG functionalized EVs exhibited dynamic stability in vitro, significantly increased cellular uptake by both endothelial cells and microglia and and enhanced the active transport of Lut across the BBB in vitro. Compared to free Lut and non-targeted vesicles, the RVG@EV-Lut platform demonstrated superior brain accumulation and prolonged retention during in vivo imaging. This targeted delivery resulted in a robust suppression of cerebral pro-inflammatory cytokines, reduced neuronal apoptosis, and preservation of hippocampal cytoarchitecture. Critically, these effects were translated into a marked restoration of spatial memory and cognitive performance in the treated mice. CONCLUSION: Our findings demonstrate that the RVG@EV-Lut platform effectively overcomes the BBB to deliver therapeutic payloads directly to the CNS. This modular engineering strategy provides a scalable and broadly applicable solution for enhancing the brain delivery of compounds with poor pharmacokinetics.
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