The present work describes the development and optimization of a poly (lactide-co- glycolide) based sustained release injectable microsphere formulation of exenatide using a coacervation and in oil drying process. The internal phase composition, containing exenatide and stabilizer, were evaluated to identify critical parameters affecting stability, drug loading, particle morphology, and burst release of exenatide. Incorporation of chondroitin sulfate(0.5-2% w/w), formed stable uniform coacervates providing consistent particle size distribution, drug loading up to 4.7% w/w, initial burst (<1%) and impurities, with "shrunken" microsphere morphology. The secondary emulsification temperature of 2-8 °C produced smaller and more uniform particles. A gradient quenching process for hardening of microspheres using n heptane: diethyl ether (1:9) to (10:0) provided low porosity and burst release relative to n-Heptane alone. The drying and lyophilization conditions reduced residual solvent levels (<5000 ppm or below quantitation) and improved its wetting characteristics. The formulation remained stable for 24 months at 2-8 °C, with minimal loss of assay content. In vitro release showed controlled release for over one month. This translated into approximately 28 days of drug exposure in rat pharmacokinetic studies and sustained glycemic control for 28 days in a db/db mice, thus, correlating microsphere erosion, in‑vitro release, and in‑vivo outcomes. This study provides insight into the manufacturing process dynamics.
Soft gelatin capsules (softgels) are among the most commercially significant oral dosage forms, offering hermetic liquid and semi-solid encapsulation with superior bioavailability. Central to their manufacture is the rotary die encapsulation process, in which precision die rolls simultaneously form, fill, and seal capsules from two gelatin ribbons. Despite its critical role in determining seam integrity, leakage resistance, and efficiency, a comprehensive peer-reviewed analysis of die roll design classifications has not been published previously. This review analyses seven principal designs: single-step (uni-lip), double-step (bi-lip), D-Step Outer (DS-O), D-Step Inner (DS-I), triple-step (tri-lip), Max Offset Seal (MOS), and blasted surface. For each design, the mechanistic basis, application domain, advantages, limitations, and quality implications are examined. Special attention is given to the MOS architecture for trailing-edge seam asymmetry in suspension fills, the DS-I configuration for moisture-sensitive active pharmaceutical ingredients, and the glass bead-blasted surface for universal pinhole leakage mitigation. A global survey of encapsulation machine and die roll manufacturers - including Changsung, Technophar, Schaefer Technologies, United Pharmatek, Joysun, SEC Softgel, Hedagel, SKY Softgel, CapPlus Technologies, and AIPAK/SaintyCo - is presented (Table 2). Five comparative tables and six annotated figure placeholders cover die roll specifications, process parameters, service life, troubleshooting, and advantages versus limitations. Regulatory considerations under ICH Q8/Q9/Q10, FDA 21 CFR 314.70, and GCC/SFDA frameworks are discussed. Future directions include digital twin simulation, AI-assisted die design, and additive manufacturing tooling. This review serves as an authoritative reference for die roll selection, optimisation, troubleshooting, and regulatory lifecycle management.
Although therapeutic proteins are susceptible to visible light-induced photooxidation, the underlying mechanisms remain unclear because amino acid residues do not directly absorb light above 400 nm. To evaluate the role of light source characteristics, three monoclonal antibodies formulated in water were exposed to spectrally distinct fluorescent and light-emitting diode (LED) sources, eliminating excipient-related effects. Following exposure to visible light (400-800 nm), degradation was assessed by size-exclusion, Protein A, and ion-exchange chromatography, together with mass spectrometry. The LED spectrum displayed a pronounced emission at 451 nm and a broad band between 480 and 800 nm, whereas the fluorescent lamp exhibited prominent emissions at 436, 545, and 612 nm, with additional blue-light contributions overlapping antibody absorption. Both light sources induced dose- and antibody-dependent photodegradation, characterized by increased high molecular weight species, Fc-oxidation, acidic and basic charge variants, and methionine and tryptophan oxidation, without detectable fragmentation. Monomer content decreased by 1-4 %, Fc-oxidized variants increased by 5-20 %, and the ion-exchange main peak decreased by 2-8 %. LED-induced degradation was less pronounced than that induced by fluorescent light, reflecting reduced short-wavelength emission. These findings support photosensitizer-mediated oxidation at 400-450 nm and highlight the importance of controlling light exposure during bioprocessing.
The study aimed to develop and optimize chitosan-based mucoadhesive nanomicelles for intranasal delivery of lamotrigine (LTG), to enhance epilepsy treatment, bypass the blood-brain barrier, and potentially improve brain targeting. LTG-loaded nanomicelles were prepared using thin-film hydration and optimized using a central composite design, response surface methodology, and artificial neural networks. The formulation included D-ɑ-tocopheryl polyethylene glycol succinate, Poloxamer 407, chitosan, and glycerol. Critical quality attributes assessed were micelle size (MS), polydispersity index (PDI), Zeta potential (ZP), pH, LTG content, transmittance, in vitro mucoadhesion, LTG release, and 28-day stability. The MS, PDI, ZP, pH, and LTG content of the optimized mucoadhesive nanomicelles was 31.28 ± 0.34 nm, 0.487 ± 0.00, +31.37 ± 1.97 mV, 4.61 ± 0.01, and 2.89 ± 0.01 mg/mL, respectively. The transmittance was 98.50 ± 0.10%, and significant in vitro mucoadhesion, with reduced migration, was observed for mucin-containing gels. LTG release (96.94% at 6 h) followed the Higuchi diffusion model, with sufficient LTG released at 40 min to potentially reach the minimum effective concentration, based on in vitro release data alone. The formulation remained stable for 28 days at 4 °C and 25 °C. Chitosan-based mucoadhesive nanomicelles are a promising intranasal delivery system for LTG, with the potential for brain targeting, controlled LTG release, and improved epilepsy management.
Atopic dermatitis (AD) features impaired skin barrier, elevated cutaneous pH, and Staphylococcus aureus overcolonization. Restoring acidic skin pH while suppressing microbial overgrowth represents a promising non-steroidal strategy. To develop a copper-based acidic hydrogel and evaluate its properties, antimicrobial activity, efficacy, and safety. A hydrogel with 0.115% copper ions was prepared from basic copper carbonate, acetic acid (6% w/w), and xanthan gum, formulated at a final pH of ∼3.2, and characterized by rheology and stability testing. Antimicrobial activity was evaluated by a quantitative carrier test against S. aureus, E. coli, and C. albicans. Efficacy was assessed in DNFB-induced AD-like BALB/c mice. Dermal safety was examined in a 14-day study in rabbits. The hydrogel showed gel-like behavior (G' > G″) with 94.6% structural recovery and remained stable over 23 months. It achieved >98% killing of all pathogens within 5 min and >99.6% within 10 min. In mice, treatment dose-dependently reduced ear swelling and dermatitis scores, attenuated epidermal hyperplasia, and decreased mast cell infiltration. In rabbits, only mild, reversible local irritation occurred, without systemic toxicity. This copper-based acidic hydrogel exhibits potent broad-spectrum antimicrobial activity, ameliorates AD-like lesions, and shows a favorable short-term dermal safety profile, supporting further development as a non-steroidal topical option for AD.
Cotinus coggygria Scop. is a polyphenol-rich medicinal plant traditionally used in topical preparations, and the formulation-dependent effects of its extracts on fibroblast behavior remain insufficiently characterized. In this study, a 60% ethanol extract of C. coggygria was prepared and chemically profiled by LC-HRMS, identifying 6-OH-luteolin-7-O-glucoside as a major constituent. In silico bioactivity prediction of this compound indicated the highest mean probability of activity within the membrane/barrier-associated category (mean Pa = 0.895). An optimized Pluronic F127-HPMC gel formulation incorporating the extract was developed and evaluated using human fibroblasts as an in vitro screening model. Intracellular ATP levels were measured to examine potential effects on cellular bioenergetics, and cell migration was assessed by scratch assay. Within the tested concentration range (5-15 µg/mL), treatment with the extract-loaded gel resulted in reduced intracellular ATP levels by 25% and decreased migration modestly, whereas the extract alone did not significantly alter these parameters, indicating a formulation-dependent modulation of cellular response. In an exploratory Caenorhabditis elegans assay, the extract exhibited a biphasic concentration-dependent response, with the lowest concentration tested (3 µg/mL) producing the greatest lifespan extension, whereas higher concentrations (3000-50 000 µg/mL) progressively reduced survival. Collectively, these findings demonstrate that incorporation of C. coggygria extract into a gel matrix alters cellular bioenergetics and motility.
Ufasomes-vesicular systems formed from long-chain unsaturated fatty acids such as oleic acid-have re-emerged as cost-effective, biocompatible alternatives to phospholipid liposomes. These bilayered assemblies self-organize at specific pH conditions and efficiently encapsulate both hydrophilic and lipophilic drugs. Their highly fluid membranes, attributed to cis-double-bond-induced structural disorder, enhance interaction with biological barriers, particularly the stratum corneum, making them valuable for topical and transdermal delivery. This review outlines the chemistry and self-assembly of ufasomes, followed by a critical appraisal of preparation techniques-including thin-film hydration and reverse-phase evaporation-and their influence on vesicle size, stability and encapsulation efficiency. Advantages such as biocompatibility, biodegradability and pH-responsive release are highlighted alongside limitations including pH-dependent instability and oxidative susceptibility. Key characterization approaches are summarized, and the therapeutic scope of ufasomes is examined, encompassing enhanced dermal delivery of antifungals and antidepressants, targeted cancer therapy, and improved oral bioavailability of nutraceuticals like oleuropein. The review concludes with emerging strategies to overcome current constraints and perspectives on advancing ufasomes toward clinical translation as versatile drug-delivery systems.
Chrysin, a natural flavonoid compound found in honey, propolis, and various plant sources, was reported to promote adipocyte thermogenesis and improve metabolism in obese mice. However, its clinical application is hindered by poor water solubility and low bioavailability. In this study, water-soluble chrysin solid dispersions were prepared using polyvinylpyrrolidone (K10, K40, K90), polyethylene glycol (1000, 2000, 6000), and maltitol. Among these, polyvinylpyrrolidone K40 (PVPK40) was identified as the optimal carrier for preparing PVPK40-chrysin solid dispersion (PVPK40-Chy SD), achieving a 1200-fold higher aqueous solubility than crystalline chrysin. The PVPK40-Chy SD exhibited a more soluble amorphous structure compared to crystalline chrysin. Hydrogen bonding interactions were observed between chrysin and the carrier. Additionally, an in vitro digestion model confirmed the improved dissolution behavior of chrysin. Finally, in vivo and in vitro experiments have demonstrated that the water-soluble chrysin solution, which was formed by dissolving PVPK40-Chy SD in water, can effectively promote adipocyte thermogenesis in C3H10T1/2 cells and mice. The mean UCP1 protein level in the water-soluble chrysin-treated group reached 2.02-fold that of the control group, thereby stimulating adipocyte thermogenesis. Following 2 h of cold exposure, mice in the water-soluble chrysin-treated group exhibited a mean rectal temperature 3.2 °C higher than animals in the PVPK40 carrier group, indicating remarkably enhanced cold tolerance.
The purpose of this feasibility study was to develop a co-delivery inclusion complex of Simvastatin (SIM) and Piperine (PIP) using different cyclodextrins to enhance solubility and evaluate its antiproliferative activity in hepatocellular carcinoma (HCC) cells. SIM has recently been repurposed as a potential anticancer agent; however, its low bioactivity is mainly driven by its poor aqueous solubility. SIM and PIP inclusion complexes were prepared using Beta-cyclodextrin (βCD), Methyl β-cyclodextrin (M βCD), and Hydroxypropyl β-cyclodextrin (HP βCD) via solvent evaporation (SE) and microwave irradiation (MI). Phase solubility studies revealed AL-type profiles, with a higher stability constant for M βCD. The optimized ternary complex PIP-SIM-M βCD (F6-SE) increased the solubility of PIP and SIM to 708.58 ± 19.1 and 127.1 ± 4.9 µg/mL, respectively. In vitro cytotoxicity studies demonstrated that the PIP-SIM-M βCD complex significantly inhibited HepG2 cell viability. Apoptosis data indicated a higher proportion of late apoptotic cells and suggested G1 phase arrest. Overall, these findings support the use of M βCD-based inclusion complexes as a promising formulation strategy for co-delivering SIM and PIP and enhancing their in vitro antiproliferative activity in liver cancer cells.
Aiming to provide rapid and extended drug release and increase patient adherence, bepotastine salicylate (BEP-S), a selective antihistamine, was formulated into a once-daily bilayer tablet (BLT). The BLT, consisting of immediate-release (IR) and extended-release (ER) layers, was prepared via direct compression and optimized based on mechanical strength, content uniformity, and dissolution performance. The optimized BLT first rapidly released 50% of the BEP-S within 1 h and then provided extended BEP-S release for more than 12 h. In a pharmacokinetic study in beagle dogs, the maximum drug concentration and extent of drug absorption of the once-daily BLT system were comparable to those of the twice-daily IR tablet. The half-life of the once-daily BLT under fasted and fed conditions was longer than that of the twice-daily tablet, with no significant differences in maximum plasma concentration or area under the plasma concentration-time curve between the tablet types. The optimized BLT was stable for 6 months under accelerated conditions (40 °C/75% relative humidity); the appearance, drug content, impurities, and dissolution of the BLT did not notably change during this period. In conclusion, the developed BEP-S BLT is a promising once-daily oral formulation with appropriate IR/ER release characteristics and a bioequivalent pharmacokinetic profile.
A series of semaglutide-loaded sustained-release formulations is developed using thermosensitive hydrogel as the release system. Micro-needle jet injection (MNJI) devices are used to deliver the highly viscous material and achieve a desired dispersion at delivery. Physicochemical properties, in vitro drug release behavior, and biocompatibility are systematically characterized. Therapeutic efficacy is evaluated in DIO rats, with non-sustained formulation as control to assess efficacy and sustainability. P407-based hydrogel has temperature-dependent sol-gel transition: at low temperature it is injectable, while at body temperature it becomes a solid gel to restrict semaglutide release. Drug incorporation did not interfere with this property. MNJI devices effectively delivered the formulation with consistency and showed favorable safety without severe inflammation. The system prolonged half-life to 15 h, extended Tmax from 8 to 24 h, and maintained effective levels to day 6. In DIO rats, GT10 50 achieved continuous weight loss over 20 days, overcoming the plateau of non-sustained formulations. Serum assays revealed significant reductions in TC (p < 0.01), ALT (p < 0.05), and AST (p < 0.01), indicating improved dyslipidemia and liver injury. Glucose tolerance tests confirmed alleviation of hyperglycemia without hypoglycemia. This study provides a strategy for obesity management with good efficacy and improved compliance via reduced dosing.
Lipid-based nanoparticulate systems provide a versatile and multifaceted platform that directly addresses critical drug delivery challenges. By encapsulating a diverse spectrum of therapeutic agents, these systems significantly enhance biocompatibility, improve bioavailability, and ensure superior stability, thereby maximizing therapeutic potential. These systems can act as non-viral vectors for successful delivery of gene-based molecules to required sites and provide the desired therapeutic effects. Conversely, the implementation of a co-delivery strategy for both oncological and non-oncological conditions holds significant promise for substantially improving clinical outcomes, and one of the main platforms for achieving synergistic effects is employing lipid-based systems. This article aims to review the recent progress in co-delivery approaches by employing lipid-based delivery systems containing gene-based cargoes.
In this work, the potential anti-cancer activity of silver nanoparticles (AgNPs-CS) prepared using Camellia sinensis, C. sinensis (CS) aqueous extract and its pro-apoptotic effects on human lung adenocarcinoma alveolar (A549) cells were investigated. AgNPs-CS were prepared by reduction of AgNO3 using C. sinensis aqueous extract, CSaq. Furthermore, they were characterized for their size, polydispersity index (PDI), ζ-potentials, morphology, and antioxidant activity. of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), acridine orange/ethidium bromide (AO/EB) staining, and Western blotting techniques were used to measure cell proliferation, apoptosis, and poly (ADP-ribose) polymerase, PARP cleavage. AgNPs-CS had a size, PDI and ζ-potential of 101 nm, 0.12, and -21 ± 1.2 mV, respectively. Furthermore, they are spherical with a core size of ∼20-40 nm and have significant antioxidant activity compared with quercetin. A sigmoidal dose-response curve exhibiting significant concentration-dependent reductions in cell viability was obtained. AgNPs-CS had an IC50 of 6.5 µg/ml and a significant level of apoptosis (∼57%) compared to CSaq and doxorubicin (Dox). Western blot analysis showed a higher level of cleaved PARP, with cPARP/β-actin ratios of 1.8 and 2.9 for CSaq and AgNPs-CS, respectively, confirmed the caspase-dependent apoptosis. AgNPs-CS is a promising green-based nanotherapeutic for treating lung cancer with an enhanced ability to kill cells and cause apoptosis in A549 cells.
In this study, PEGylated liposomes (PEG-Lip) were combined with polysaccharides to sustain their oral absorption-enhancing effect. PEG-Lip was prepared by the thin-film hydration method and mixed with carrageenan (CGN), xanthan gum (XG), or locust bean gum (LBG). The prepared PEG-Lip had a particle size of ∼100 nm and a zeta potential of approximately -50 mV. The polysaccharide concentrations that did not inhibit PEG-Lip behavior were 0.5% for CGN and 0.25% for XG and LBG. At 25 °C, the release of PEG-Lip from each polysaccharide was generally consistent with its diffusion within the polysaccharide. In the rheological evaluation, only XG3-LBG7, a 3:7 mixture of XG and LBG, exhibited gel-like behavior, whereas the other formulations functioned as viscosity modifiers. Oral administration in rats showed improved gastrointestinal retention compared with PEG-Lip alone. Furthermore, XG3-LBG7 provided the greatest improvement in the oral absorption of FITC-dextran (FD4). These findings suggest that optimizing both PEG-Lip release and the rheological properties of polysaccharides is important for improving oral absorption.
The present study focuses on the development of zanubrutinib nanocrystals (ZBR-NCs) to enhance its solubility, dissolution rate and oral bioavailability. The ZBR-NCs were successfully prepared by antisolvent precipitation method and subjected to physicochemical and pharmacokinetic evaluations. The resulting nanocrystals exhibited a particle size of 258.8 ± 12.56 nm, a polydispersity index value of 0.24 ± 0.02, a zeta potential of -18.4 ± 1.40 mV, and drug content of 93.56 ± 2.5%. The solubility studies revealed a 57-fold increase in ZBR solubility as compared to the pure drug. The solid-state characterization studies confirmed reduced crystallinity of the ZBR within the nanocrystals and its compatibility with Poloxamer 188® as a stabilizing agent. The spherical shape of ZBR-NCs was demonstrated by high-resolution transmission electron microscopy study. The ZBR-NCs exhibited 98.67 ± 3.49% release at 10 h, showing an increased ZBR release as compared to free ZBR. Pharmacokinetic evaluation of ZBR-NCs after oral administration displayed a 4.41-fold increase (p < 0.001) in bioavailability. The stability study of ZBR-NCs showed good stability over a 2-month period at refrigerated (2-8 °C) condition, with retention of their physicochemical properties. Collectively, these findings emphasize the potential of ZBR-NCs as a promising strategy to improve solubility and oral absorption of ZBR. HIGHLIGHTSThe ZBR-NCs were prepared using PVPK-30, Poloxamer 407® and Poloxamer 188®.The solubility of ZBR was improved 57-fold with NCs.The ZBR-NCs showed higher drug release than free ZBR.The ZBR-NCs achieved a 4.41-fold increase in bioavailability.
Lidocaine hydrochloride (LiH) is a widely used local anesthetic administered topically or parenterally. However, passive delivery of LiH through the skin is hindered by its hydrophilicity and discomfort associated with injections. Dissolving microneedles (DMNs) offer a minimally invasive alternative for intradermal delivery. This study developed LiH-loaded DMNs (LiH-DMNs) using a combination of poly(vinylpyrrolidone) K-29/32 (PVP) and hyaluronic acid (HA). LiH-DMNs were evaluated in terms of their mechanical properties, insertion ability, dissolution, drug content, in vitro dermatokinetic tests, and in vivo local anesthetic tests on rats. Nine formulations were prepared, among which DMN-7 (PVP 30%; HA 1.25%) and DMN-8 (PVP 30%; HA 2.5%) showed needle height reduction of <10% and drug content of 97-100%. Both formulations penetrated skin to a depth of approximately 500 μm and fully dissolved within 1 h In vitro dermatokinetic studies demonstrated higher drug accumulation for DMN-7 (Cmax of 6.75 ± 1.36 μg/mL in the dermis and 7.47 ± 0.97 μg/mL in the epidermis) compared to DMN-8. Consequently, DMN-7 was selected for in vivo evaluation. DMN-7 caused no erythema or edema in irritation studies and produced significant local anesthetic effects in rats. Overall, PVP-HA-based DMNs represent a promising, safe, and effective approach for intradermal delivery of LiH.
Olaparib (OLA), a poorly water-soluble anticancer drug (0.0601 mg/mL) with limited oral bioavailability (>50%), belongs to Biopharmaceutics Classification System (BCS) class IV and requires advanced formulation strategies to improve its biopharmaceutical performance. This study developed and optimised OLA-loaded silica-enabled lipid hybrid nanoparticles (SLHNs) using a quality by design (QbD) approach. The lipid hybrid nanosystem was prepared by the melt emulsification method and converted into free-flowing SLHN powder by impregnation onto mesoporous silica carrier Parteck® SLC. Screening studies, supported by molecular docking and solubility assessment, selected Capmul® MCM, Cremophor® RH40, and Transcutol® HP as the oil, surfactant, and co-surfactant, respectively. Pseudo-ternary phase diagram analysis showed a broad nanoemulsion region at a Smix ratio of 3:1. Plackett-Burman screening identified oil concentration, Smix concentration, and stirring time as critical factors influencing globule size (41.67 ± 0.73 to 154 ± 2.35 nm), polydispersity index (0.183 ± 0.017 to 0.621 ± 0.018), optical transmittance (91.10 ± 0.889% to 99.83 ± 0.404%), and zeta potential (-17.2 ± 0.34 to -37.7 ± 0.37 mV). The optimised SLHNs showed rapid self-emulsification, nanosized globules, high clarity, and improved dissolution with 30% burst release followed by sustained release up to 2.5 h.
Polymer coating of nanocarriers has emerged as a powerful strategy to improve the performance of advanced drug delivery systems by enhancing stability, bioavailability, targeting capability, and therapeutic efficiency. Surface functionalization with biocompatible polymers can significantly modify the physicochemical and biological behavior of nanoparticles, enabling improved interaction with biological barriers and controlled drug release profiles. This review provides a comprehensive overview of the most widely used polymers for nanocarrier surface modification, including chitosan, alginate, hyaluronic acid, polyethylene glycol (PEG), methacrylate copolymers, pectin, dextran, and poly-L-lysine. The mechanisms by which these polymers enhance nanocarrier functionality are discussed in detail. In addition, the review summarizes commonly employed coating techniques such as adsorption, covalent conjugation, layer-by-layer assembly, and polymer grafting, highlighting their influence on nanoparticle characteristics and therapeutic performance. Particular emphasis is placed on the pharmaceutical outcomes associated with polymer-coated nanocarriers, including improved drug stability, enhanced bioavailability, site-specific targeting, and prolonged circulation time. Finally, the major scientific, manufacturing, safety, and regulatory challenges that limit the clinical translation of polymer-coated nanocarrier systems are critically discussed. Overall, polymer surface engineering represents a promising approach for the development of next-generation nanomedicines, although further advances in large-scale manufacturing, standardized characterization, and regulatory frameworks are required to facilitate their successful clinical and commercial implementation.
Powder compaction remains the key step in pharmaceutical tablet manufacturing, but its multiscale and path-dependent nature makes accurate prediction of tablet properties difficult. Compression equations have long been used to relate applied pressure to densification, porosity, and mechanical strength, providing descriptors for material comparison and formulation design. Classical models such as Heckel, Kawakita-Lüdde, and Cooper-Eaton remain widely used, although they are limited by pressure-range dependence, sensitivity to in-die versus out-of-die measurements, and restricted mechanistic interpretation. Recent developments have expanded compression modeling to include extended in-die formulations incorporating solid compressibility, continuum constitutive laws for finite-element simulations, particle-scale discrete-element approaches, and data-driven process analytical technology (PAT) frameworks. These approaches are critically evaluated alongside classical equations with respect to constitutive validity, calibration transferability, contact-law realism, computational cost, data governance, model drift, and regulatory acceptability. Together, they form a hierarchical modeling framework spanning empirical screening, mechanistic prediction, and real-time process control. This review integrates classical and emerging compaction models and discusses their relevance to critical quality attributes, scale-up, and digital-twin-enabled pharmaceutical manufacturing.
Intranasal nose-to-brain delivery remains difficult to translate because regional deposition, mucociliary clearance, epithelial transport, local instability, tolerability feedback, and systemic absorption jointly determine central nervous system (CNS) exposure. This evidence-mapping review evaluates mucoadhesive biomaterial platforms as formulation-development tools for improving residence, release control, deposition reproducibility, and exposure interpretability in neuroactive intranasal delivery, using insomnia-relevant timing requirements as a stringent case for controlled onset and offset. PubMed/MEDLINE, Embase, Web of Science Core Collection, and Scopus were searched from 1 January 2008 to 30 April 2026. Seventeen primary intranasal platform studies were included; route-attribution credibility was high in five studies, moderate in five, low in six, and not assessable in one. Platform classes included in situ gelling depots, pre-formed gels, polymeric nanoparticles, lipid or vesicular carriers, hybrid nanoparticle-in-gel systems, and device-coupled dry powders. Key formulation variables were translated into development endpoints, including rheology, gelation, mucoadhesion, release kinetics, deposition, permeability, systemic leakage, and nasal tolerability. The proposed model-informed strategies are conceptual; no new physiologically based pharmacokinetic simulations were performed. Successful platforms should be judged by reproducible onset, controlled offset, bounded systemic exposure, and recovery-phase safety rather than by peak brain concentrations or targeting ratios alone.
