Increased Drug Loading Research Articles

Hot-melt extruded-FDM 3D-printed polyethylene oxide tablets: Dissolution imaging analysis of swelling and drug release.

Recent developments in pharmacogenetics have emphasised the importance of customised medication, driving interest in technologies like FDM 3D-printing for tailored drug delivery. FDM 3D-printing is a promising technique for the on-demand manufacturing of customised oral dosage forms, providing flexibility in terms of shape and size, dose and drug release profiles. This study investigates the fabrication and characterisation of 3D-printed oral dosage forms using PEO as the primary polymer and PEG 6 K as a plasticiser. Firstly, the printability of the PEO filaments with different propranolol hydrochloride concentrations was explored using the hot-melt extrusion technology. The influence of the propranolol hydrochloride concentrations on the mechanical properties of the filaments was examined was then examined after which surface characteristics, including roughness and wettability, were evaluated. Dissolution imaging was used to visualise the effects of drug content on the swelling and dissolution characteristics of the PEO-based 3D-printed tablets. Results showed a reduction in the flexural stress of the filaments with increasing drug load. It was also observed that increasing the drug load led to higher surface roughness and lower contact angles of the 3D-printed PEO tablets, implying increased surface hydrophilicity. The swelling behaviour of the tablets increased with higher drug concentrations, resulting in a larger gel layer formation. When comparing the drug release percentages, the release rate was higher in the 10 mg propranolol tablets, suggesting that a lower drug content led to a faster release. The greater gel layer of the 40 mg PPN tablets hindered the drug release by acting as a diffusion barrier, while the 10 mg PPN tablets, with less swelling and gel formation, experienced a faster drug release. These findings show the importance of drug content in modifying the surface properties, swelling behaviour, and drug release profiles of 3D-printed PEO tablets. The study also demonstrates the novel use of dissolution imaging for 3D-printed dosage forms, providing valuable quantitative and qualitative insights into swelling dynamics and channel formation to optimise 3D-printed tablets for drug delivery systems.

Delivery of Islatravir via High Drug-Load, Long-acting Microarray Patches for the Prevention or Treatment of Human Immunodeficiency Virus.

This research focuses on developing and characterizing islatravir-loaded dissolving microarray patches (MAPs) to provide an effective, minimally invasive treatment option for human immunodeficiency virus (HIV-1) prevention and treatment. The research involves manufacturing these MAPs using a double-casting approach, and conducting in vitro and in vivo evaluations. Results show that the MAPs have excellent needle fidelity, structural integrity, and mechanical strength. in vitro studies demonstrate that the MAPs can penetrate skin up to 580µm and dissolve within 2 hours. Permeation studies reveal that the delivery efficiency of islatravir across the skin is around 40%. In rodent models, these dissolving MAPs sustain islatravir delivery for up to 3 months. Scaling up the MAPs and increasing drug loading produced detectable levels in minipig. Projections from animal data suggest that these dissolving MAPs can achieve effective islatravir levels for a month after a single application in humans. These findings indicate dissolving MAPs as a minimally invasive approach to sustained release of islatravir.

Liposomal Formulations: A Recent Update.

Liposome-based drug delivery technologies have showed potential in enhancing medication safety and efficacy. Innovative drug loading and release mechanisms highlighted in this review of next-generation liposomal formulations. Due to poor drug release kinetics and loading capacity, conventional liposomes have limited clinical use. Scientists have developed new liposomal carrier medication release control and encapsulation methods to address these limits. Drug encapsulation can be optimized by creating lipid compositions that match a drug's charge and hydrophobicity. By selecting lipids and adding co-solvents or surfactants, scientists have increased drug loading in liposomal formulations while maintaining stability. Nanotechnology has also created multifunctional liposomes with triggered release and personalized drug delivery. Surface modification methods like PEGylation and ligand conjugation can direct liposomes to disease regions, improving therapeutic efficacy and reducing off-target effects. In addition to drug loading, researchers have focused on spatiotemporal modulation of liposomal carrier medication release. Stimuli-responsive liposomes release drugs in response to bodily signals. Liposomes can be pH- or temperature-sensitive. To improve therapeutic efficacy and reduce systemic toxicity, researchers added stimuli-responsive components to liposomal membranes to precisely control drug release kinetics. Advanced drug delivery technologies like magnetic targeting and ultrasound. Pro Drug, RNA Liposomes approach may improve liposomal medication administration. Magnetic targeting helps liposomes aggregate at illness sites and improves drug delivery, whereas ultrasound-mediated drug release facilitates on-demand release of encapsulated medicines. This review also covers recent preclinical and clinical research showing the therapeutic promise of next-generation liposomal formulations for cancer, infectious diseases, neurological disorders and inflammatory disorders. The transfer of these innovative liposomal formulations from lab to clinical practice involves key difficulties such scalability, manufacturing difficulty, and regulatory limits.

Nanocrystals in Dermal Drug Delivery: A Breakthrough for Enhanced Skin Penetration and Targeted Skin Disorder Treatments.

One of the major challenges in dermal drug delivery is the adequate penetration of the active compound into the skin without causing any skin irritation and inflammation. Nanocrystals (NCs) are nanoscale particles, and their sizes are below 1000 nm. NCs are made up of drug particles only, which are used to improve the aqueous solubility and bioavailability of poorly water-soluble drugs. NCs are typically prepared either by bottom-up or top-down techniques. The advantages of using NC-based formulations in enhancing dermal drug delivery include increased drug loading capacity, easier and deeper penetration into the skin tissue, and increased passive diffusion. NC-based formulations with the capacity of enhanced dermal drug delivery can be effectively used to treat a wide range of skin disorders, including melanoma, inflammation, psoriasis, acne vulgaris, bacterial infections, fungal infections, eczema, skin aging, herpes simplex virus infections, skin manifestations of tick bites, frostbite-related infections, hyperpigmentation, and diabetic foot ulcer. In this review, major challenges in dermal drug delivery across the skin barrier, mechanism of action of dermal NCs, advantages of using NCs in enhancing dermal drug delivery, NC preparation methods, and applications of NCs in the treatment of various skin disorders have been discussed.

Quantitative Analysis of Physical Stability Mechanisms of Amorphous Solid Dispersions by Molecular Dynamic Simulation.

Amorphous solid dispersions (ASDs) represent a promising strategy for enhancing the solubility of poorly soluble drugs. However, the mechanisms underlying the physical stability of ASDs remain insufficiently understood. This study aims to investigate these mechanisms and propose quantitative thresholds to predict the maximum stable drug loading using molecular dynamics simulations. Poly(vinylpyrrolidone) (PVP) and poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA64) are selected as polymeric carriers, while naproxen and acetaminophen serve as model drugs, resulting in the formulation of 18 distinct ASDs across four types for comparison with experimental results. Our findings indicate that the molecular mobility of active pharmaceutical ingredients (APIs) is the primary determinant of solid dispersion stability. High polymer concentrations limit drug molecular mobility through spatial structural constraints and ASD viscosity. As drug loading increases, the polymer concentration reaches a critical threshold (C*), beyond which drug-rich regions form, leading to potential aggregation, rearrangement, and recrystallization of drug molecules into more energetically stable forms. Notably, both the interaction energy and diffusion coefficient show sharp fluctuations at the maximum stable drug loading, which can serve as predictive indicators for ASD stability. Additionally, a search strategy is used to identify potential pre-crystalline sites. By integrating kinetic, thermodynamic, and pre-crystalline analyses through molecular dynamics simulations, this study provides a foundation for more accurate predictions of ASD stability, significantly aiding future formulation development.

Ultrasound-triggered drug release and cytotoxicity of microbubbles with diverse drug attributes

Ultrasound (US)-triggered cavitation of drug-loaded microbubbles (MBs) represents a promising approach for targeted drug delivery, with substantial benefits attainable through precise control over drug release dosage and form. This study investigates Camptothecin-loaded MBs (CPT-MBs) and Doxorubicin-loaded MBs (DOX-MBs), focusing on how properties such as hydrophilicity, hydrophobicity, and charged functional groups affect their interaction with the lipid surfaces of MBs, thereby influencing the fundamental characteristics and acoustic properties of the drug-loaded MBs. In comparison to DOX-MBs, CPT-MBs showed larger MB size (2.2 ± 0.3 and 1.4 ± 0.1 μm, respectively), a 2-fold increase in drug loading, and an 18 % reduction in leakage after 2 h at 37℃. Under 1 MHz US with a 100 ms pulse repetition interval (PRI), 1000 cycles, 5-minute duration, and 550 kPa acoustic pressure, CPT-MBs undergo inertial cavitation, while DOX-MBs undergo stable cavitation. Drug particles released from these MBs under US-induced cavitation were analyzed using dynamic light scattering, NanoSight, cryo-electron microscopy, and density gradient ultracentrifugation. Results showed that CPT-MBs mainly release free CPT, while DOX-MBs release multilayered DOX-lipid aggregates. The cytotoxicity to C6 cells induced by US-triggered cavitation of these two types of MBs also differed. DOX-lipid aggregates delayed initial uptake, leading to less pronounced short-term (2 h) effects compared to the rapid release of free CPT from CPT-MBs. These findings underscore the need to optimize drug delivery strategies by fine-tuning MB composition and US parameters to control drug release kinetics and achieve the best tumoricidal outcomes.

Development of Minodronic Acid-Loaded Dissolving Microneedles for Enhanced Osteoporosis Therapy: Influence of Drug Loading on the Bioavailability of Minodronic Acid.

Osteoporosis is a metabolic bone disorder with impaired bone microstructure and increased bone fractures, seriously affecting the quality of life of patients. Among various bisphosphonates prescribed for managing osteoporosis, minodronic acid (MA) is the most potent inhibitor of bone context resorption. However, oral MA tablet is the only commercialized dosage form that has extremely low bioavailability, severe adverse reactions, and poor patient compliance. To tackle these issues, we developed MA-loaded dissolving microneedles (MA-MNs) with significantly improved bioavailability for osteoporosis therapy. We investigated the influence of drug loading on the physicochemical properties, transdermal permeation behavior, and pharmacokinetics of MA-MNs. The drug loading of MA-MNs exerted almost no effect on their morphology, mechanical property, and skin insertion ability, but it compromised the transdermal permeability and bioavailability of MA-MNs. Compared with oral MA, MA-MNs with the lowest drug loading (224.9μg/patch) showed a 9-fold and 25.8-fold increase in peak concentration and bioavailability, respectively. This may be ascribed to the reason that the increased drug loading can generate higher burst release, higher drug residual rate, and drug supersaturation effect in skin tissues, eventually limiting drug absorption into the systemic circulation. Moreover, MA-MNs prolonged the half-life of MA and provided more steady plasma drug concentrations than intravenously injected MA, which helps to reduce dosing frequency and side effects. Therefore, dissolving MNs with optimized drug loading provides a promising alternative for bisphosphonate drug delivery.

Impact of dissolution medium pH and ionization state of the drug on the release performance of amorphous solid dispersions

Amorphous solid dispersions (ASDs) are widely employed as a strategy to improve oral bioavailability of poorly water soluble compounds. Typically, optimal dissolution performance from a polyvinylpyrrolidone vinyl acetate (PVPVA) based ASD is observed at relatively low drug loading limit. Above a certain drug load, termed limit of congruency (LoC), the release from ASDs significantly decreases. So far, the majority of the dissolution behavior has been tested in conditions where the drug primarily exists in unionized form. In this work, the impact of pH of the dissolution environment on the release performance of ASDs of an ionizable drug was studied. Atazanavir (ATZ), a weakly basic drug with a pKa of 4.5 was used as a model compound and PVPVA was used as a non-ionizable matrix polymer. Dissolution rate was measured using Wood's apparatus which normalizes the surface area of the dissolving tablet. The pH of the dissolution media was varied between 1 and 6.8, to cover a range where ATZ exists as >99 % ionized or unionized species. At pH 6.8, near complete release was observed only when the drug load was ≤ 6 %. Unlike typically observed drastic decline in release behavior for PVPVA based ASDs above LoC, ATZ ASDs underwent gradual decline in dissolution behavior when the DL was increased to 8 %. This was attributed to potential formation of an ATZ-PVPVA associated phase with dissolution rate slower than neat PVPVA. However, the 10 % DL ASD showed negligible ATZ release. On another extreme (pH 1) where ATZ is ∼100 % ionized, the dissolution rate of ATZ was faster than that of PVPVA. ASD dissolution rate was found to be slower than that of the neat drug but faster than PVPVA and interestingly, did not change with DL. This can be attributed to formation of an ionized ATZ-PVPVA phase which controls the dissolution rate of the ASD. At pH 3, where the drug is ∼97 % ionized, near complete release was observed for drug loads ≤ 8 %. To observe significant increase in drug loading with near complete release, >98 % ionization of ATZ was required. At pH 2 where ATZ is ∼99.7 % ionized, near complete release was observed for drug loads up to 30 %. Furthermore, the deterioration in dissolution performance with an increase in drug load continued to be gradual at pH 2. The enhancement in dissolution performance did not correlate with solubility enhancement of ATZ due to ionization. We theorize that the enhancement in the dissolution performance due to ionization is the result of formation of an ionized ATZ-PVPVA phase which increases the hydrophilicity and the miscibility of the ASD. This can help resist water induced phase separation during ASD dissolution and therefore, result in continuous, and congruent dissolution of the drug and polymer.

Amorphous Solid Dispersion Formation for Enhanced Release Performance of Racemic and Enantiopure Praziquantel.

Praziquantel (PZQ) is the treatment of choice for schistosomiasis, which affects more than 250 million people globally. Commercial tablets contain the crystalline racemic compound (RS-PZQ) which limits drug dissolution and oral bioavailability and can lead to unwanted side effects and poor patient compliance due to the presence of the S-enantiomer. While many approaches have been explored for improving PZQ's dissolution and oral bioavailability, studies focusing on investigating its release from amorphous solid dispersions (ASDs) have been limited. In this work, nucleation induction time experiments were performed to identify suitable polymers for preparing ASDs using RS-PZQ and R-PZQ, the therapeutically active enantiomer. Cellulose-based polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS, MF grade) and hydroxypropyl methylcellulose (HPMC, E5 LV grade), were the best crystallization inhibitors for RS-PZQ in aqueous media and were selected for ASD preparation using solvent evaporation (SE) and hot-melt extrusion (HME). ASDs prepared experimentally were subjected to X-ray powder diffraction to verify their amorphous nature and a selected number of ASDs were monitored and found to remain physically stable following several months of storage under accelerated-stability testing conditions. SE HPMCAS-MF ASDs of RS-PZQ and R-PZQ showed faster release than HPMC E5 LV ASDs and maintained good performance with an increase in drug loading (DL). HME ASDs of RS-PZQ formulated using HPMCAS-MF exhibited slightly enhanced release compared to that of SE ASDs. SE HPMCAS-MF ASDs showed a maximum release increase of the order of 6 times compared to generic and branded (Biltricide) PZQ tablets. More importantly, SE R-PZQ ASDs with HPMCAS-MF released the drug as effectively as RS-PZQ or better, depending on the DL used. These findings have significant implications for the development of commercial PZQ formulations comprised solely of the R-enantiomer, which can result in mitigation of the biopharmaceutical and compliance issues associated with current commercial tablets.

Magnetically targeted lidocaine sustained-release microspheres: optimization, pharmacokinetics, and pharmacodynamic radius of effect

ObjectiveThis study aimed to optimize the formulation of magnetically targeted lidocaine microspheres, reduce the microsphere particle size, and increase the drug loading and encapsulation rate of lidocaine. The optimized microspheres...

Prolonged release from lipid nanoemulsions by modification of drug lipophilicity

In addition to the solubilization of poorly water-soluble, highly lipophilic drugs, lipid nanoemulsions bear potential for drug targeting approaches. This requires that the drug remains within the emulsion droplets until they reach the site of action. Since drug release is rather controlled by the lipophilicity of the drug than by the formulation, this study systematically investigated the influence of drug lipophilicity on the course of drug transfer in (physiological) acceptor media. An increase in drug lipophilicity, according to ClogD/P values, was achieved by the formation of lipophilic prodrugs of 5-phenylanthranilic acid – a potential pathoblocker. The range of substances was supplemented by orlistat, lumefantrine and cholesteryl acetate as model drugs. Drug transfer from supercooled trimyristin nanodroplets was determined via differential scanning calorimetry by monitoring their onset crystallization temperature, which decreases linearly with increasing drug content. Release of the model (pro)drugs ranged from burst to hardly any release in the order of the ClogD/P values. Except for cholesteryl acetate, the results were in line with the lipophilicity of the model (pro)drugs estimated by their retention times on a reversed-phase HPLC column under isocratic conditions. An approximate prediction of drug release kinetics was, thus, possible by logP calculations and, to a limited extent, also by reversed-phase HPLC. A further finding was the increased drug loading capacity of the lipid nanoemulsion for lipophilic prodrugs, if the structural changes of the parent compound were accompanied by a lower melting point.

New theory to explain the effect of lactose fines on the performance of adhesive mixtures for inhalation

A new theory for the dispersibility enhancing effect of excipient fines for adhesive mixtures for inhalation is presented in this paper, while at the same time the shortcomings of current hypotheses are discussed. The proposed mechanism, denoted the ‘viscoelastic damping effect’, states that the presence of fines particles acts to dampen the collisions between carrier particles during mixing. As a consequence, fewer fine particles are ‘irreversibly’ pressed into the carriers, which in turn entails a higher fine particle fraction. The mechanism was demonstrated experimentally at different levels of added lactose fines by studying the influence of processing on fine particle fraction. This approach furthermore enabled quantification of the effect. All fine particles present in the blend (APIs and excipient fines) act together to exert the damping effect. The proposed mechanism is able to explain the main body of published data, including the effect of added excipient fines, the effect of an increased drug load, and the effect of removal of carrier fines. The viscoelastic damping mechanism is general in nature and conveys a broader and more general understanding of the behavior of adhesive mixtures for inhalation.

Exploring novel type of lipid-bases drug delivery systems that contain one lipid and one water-soluble surfactant only

None of transitional lipid-based drug delivery systems (LBDDS) includes compositions containing one lipid and one water-soluble surfactant that form stable microemulsions. The conversion of liquid LBDDS to solid LBDDS has been limited by low drug loading. Previously, we have developed drug solid microemulsions containing one lipid and TPGS (a water-soluble surfactant) that achieved high drug loading and remarkably increased oral bioavailability. This study aimed to test if binary lipid systems (BLS), composed of one lipid and one water-soluble surfactant that form stable self-emulsifying microemulsions, is not an exclusive but widely applicable type of LBDDS for other lipids and surfactants and evaluate the influences of chemical structures of lipids and surfactants on microemulsions and solid microemulsions. We systemically identified new BLS by using a library of lipids and surfactants. Propylene glycol diesters and glycerol triesters were favorable for forming stable microemulsions with Tween 80, Cremophor EL, or TPGS. To the best of our knowledge, this is the first report exploring and confirming that the BLS is a new addition to traditional LBDDS, provides a promising option for researchers, and has the potential to increase drug loading to facilitate the development of solid microemulsions.

In silico-guided discovery and in vitro validation of novel sugar-tethered lysinated carbon nanotubes for targeted drug delivery of doxorubicin

ContextMultiwalled carbon nanotubes (MWCNTs) functionalized with lysine via 1,3-dipolar cycloaddition and conjugated to galactose or mannose are potential nanocarriers that can effectively bind to the lectin receptor in MDA-MB-231 or MCF-7 breast cancer cells. In this work, a method based on molecular dynamics (MD) simulation was used to predict the interaction of these functionalized MWCNTs with doxorubicin and obtain structural evidence that allows a better understanding of the drug loading and release process. The MD simulations showed that while doxorubicin only interacted with pristine MWCNTs through π-π stacking interactions, functionalized MWCNTs were also able to establish hydrogen bonds, suggesting that the functionalized groups improve doxorubicin loading. Moreover, the elevated adsorption levels observed for functionalized nanotubes further support this enhancement in loading efficiency. MD simulations also shed light on the intratumoral pH-specific release of doxorubicin from functionalized MWCNTs, which is induced by protonation of the daunosamine moiety. The simulations show that this change in protonation leads to a lower absorption of doxorubicin to the MWCNTs. The MD studies were then experimentally validated, where functionalized MWCNTs showed improved dispersion in aqueous medium compared to pristine MWCNTs and, in agreement with the computational predictions, increased drug loading capacity. Doxorubicin-loaded functionalized MWCNTs demonstrated specific release of doxorubicin in tumor microenvironment (pH = 5.0) with negligible release in the physiological pH (pH = 7.4). Furthermore, doxorubicin-free MWNCT nanoformulations exhibited insignificant cytotoxicity. The experimental studies yielded nearly identical results to the MD studies, underlining the usefulness of the method. Our functionalized MWCNTs represent promising non-toxic nanoplatforms with enhanced aqueous dispersibility and the potential for conjugation with ligands for targeted delivery of anti-cancer drugs to breast cancer cells.MethodsThe computational model of a pristine carbon nanotube was created with the buildCstruct 1.2 Python script. The lysinated functionalized groups were added with PyMOL and VMD. The carbon nanotubes and doxorubicin molecules were parameterized using the general AMBER force field, and RESP charges were determined using Gaussian 09. Molecular dynamics simulations were carried out with the AMBER 20 software package. Adsorption levels were calculated using the water-shell function of cpptraj. Cytotoxicity was evaluated via a MTT assay using MDA-MB-231 and MCF-7 breast cancer cells. Drug uptake of doxorubicin and doxorubicin-loaded MWCNTs was measured by fluorescence microscopy.

Understanding adsorption ability of CNT (6, 6-6) and BNNT (6, 6-7) nanotubes for a novel hybrid pyrazole-indole drug, InPy-7a

The quest for enhanced drug delivery efficacy across diverse physiological conditions has spurred the exploration of various nanomaterials, including carbon-based materials like carbon nanotubes (CNTs) and boron nitride nanotubes (BNNTs). These materials offer high surface areas conducive to increased drug loading, with considerations such as surface charge, size, shape, and biocompatibility being paramount. The hybrid drug, synthesized by combining indole derivatives with a pyrazole moiety, has shown promising cytotoxicity against various cancer cell lines. In this context, we have explored the adsorption ability of CNT (6, 6-6) and BNNT (6, 6-7) nanotubes for a novel hybrid drug, InPy-7a, using density functional theory (DFT) calculations. Our study has aimed to elucidate the adsorption mechanisms and electronic properties of InPy-7a on the surfaces of CNT (6, 6-6) and BNNT (6, 6-7). Through computational tools, we have analyzed the geometry optimization of InPy-7a onto the nanotube surfaces, evaluating molecular interactions, quantum descriptors, frontier molecular orbitals (FMO), natural bond orbitals (NBO), nuclear magnetic resonance (NMR), and molecular electrostatic potential (MEP). Our results have illuminated the underlying mechanisms by revealing unique interactions and electronic changes during complexation. Based on predicted electronic aspects and molecular interactions, the CNT@InPy-7a-S5 complex system showed greater chemical reactivity, adsorption, and stability than BNNT@InPy-7a-S6. These findings open up opportunities for additional experimental validations and offer insightful information about the possible uses of drug delivery systems based on nanotubes.

Recent Advances in Targeted Therapies for Infantile Hemangiomas.

Targeted therapy for infantile hemangiomas (IHs) has been extensively studied as they can concentrate drugs, increase therapeutic efficacy and reduce drug dosage. Meanwhile, they can extend drug release times, enhance drug stability, decrease dosing frequency, and improve patient compliance. Moreover, carriers made from biocompatible materials reduced drug immunogenicity, minimizing adverse reactions. However, current targeted formulations still face numerous challenges such as the non-absolute safety of carrier materials; the need to further increase drug loading capacity; the limitation of animal hemangioma models in fully replicating the biological properties of human infantile hemangiomas; the establishment of models for deep-seated hemangiomas with high incidence rates; and the development of more specific targets or markers. In this review, we provided a brief overview of the characteristics of IHs and summarized the past decade's advances, advantages, and targeting strategies of targeted drug delivery systems for IHs and discussed their applications in the treatment of IHs. Furthermore, the goal is to provide a reference for further research and application in this field.

Microfluidic-based preparation of PLGA microspheres facilitating peptide sustained-release

It is challenging for the manufacturing of microspheres loaded with peptide due to the complicated preparation process and the issue of burst release. In this construct, a microfluidic flow-focusing device is developed to prepare and optimize poly (lactic-co-glycolic acid) (PLGA) Exenatide −loaded microspheres. Surfactants was added to greatly improve the stability of the emulsion, leading to increase drug loading capacity. By increasing the particle size of the drug-loaded microspheres to 30 μm, the burst release was significantly reduced. Additionally, multi-channel droplet microfluidic devices are prepared with the capability to achieve a 100-fold increase in throughput, which could achieve a production rate of 2 g per hour.

A strong, silk protein-inspired tissue adhesive with an enhanced drug release mechanism for transdermal drug delivery

In transdermal drug delivery system (TDDS) patches, achieving prolonged adhesion, high drug loading, and rapid drug release simultaneously presented a significant challenge. In this study, a PHT-SP-Cu2+ adhesive was synthesized using polyethylene glycol (PEG), hexamethylene diisocyanate (HDI), trimethylolpropane (TMP), and silk protein (SP) as functional monomers which were combined with Cu2+ to improve the adhesion, drug loading, and drug release of the patch. The structure of the adhesion chains and the formation of Cu2+-p-π conjugated network in PHT-SP-Cu2+ were characterized and elucidated using different characterization methods including FT-IR, 13C NMR, XPS, SEM imaging and thermodynamic evaluation. The formulation of pressure-sensitive adhesive (PSA) was optimized through comprehensive research on adhesion, mechanics, rheology, and surface energy. The formulation of 3 wt.% SP and 3 wt.% Cu2+ provided superior adhesion properties compared to commercial standards. Subsequently, the peel strength of PHT-SP-Cu2+ was 7.6 times higher than that of the commercially available adhesive DURO-TAK® 87–4098 in the porcine skin peel test. The adhesion test on human skin confirmed that PHT-SP-Cu2+ could adhere to the human body for more than six days. Moreover, the drug loading, in vitro release test and skin permeation test were investigated using ketoprofen as a model drug, and the results showed that PHT-SP-Cu2+ had the efficacy of improving drug compatibility, promoting drug release and enhancing skin permeation as a TDDS. Among them, the drug loading of PHT-SP-Cu2+ was increased by 6.25-fold compared with PHT, and in the in vivo pharmacokinetic analysis, the AUC was similarly increased by 19.22-fold. The mechanism of α-helix facilitated drug release was demonstrated by Flori-Hawkins interaction parameters, molecular dynamics simulations and FT-IR. Biosafety evaluations highlighted the superior skin cytocompatibility and safety of PHT-SP-Cu2+ for transdermal applications. These results would contribute to the development of TDDS patch adhesives with outstanding adhesion, drug loading and release efficiency. Statement of significanceA new adhesive, PHT-SP-Cu2+, was created for transdermal drug delivery patches. Polyethylene glycol, hexamethylene diisocyanate, trimethylolpropane, silk protein, and Cu2+ were used in synthesis. Characterization techniques confirmed the structure and Cu2+-p-π conjugated networks. Optimal formulation included 3 wt.% SP and 3 wt.% Cu2+, exhibiting superior adhesion. PHT-SP-Cu2+ showed 7.6 times higher peel strength than DURO-TAK® 87–4098 on porcine skin and adhered to human skin for over six days. It demonstrated a 6.25-fold increase in drug loading compared to PHT, with 19.22-fold higher AUC in vivo studies. α-helix facilitated drug release, proven by various analyses. PHT-SP-Cu2+ showed excellent cytocompatibility and safety for transdermal applications. This study contributes to developing efficient TDDS patches.

Enabling superior drug loading in lipid-based formulations with lipophilic salts for a brick dust molecule: Exploration of lipophilic counterions and in vitro-in vivo evaluation

Lipid-based formulations (LbFs) are an extensively used approach for oral delivery of poorly soluble drug compounds in the form of lipid suspension and lipid solution. However, the high target dose and inadequate lipid solubility limit the potential of brick dust molecules to be formulated as LbFs. Thus, the complexation of such molecules with a lipophilic counterion can be a plausible approach to improve the solubility in lipid-based solutions via reducing drug crystallinity and polar surface area. The study aimed to enhance drug loading in lipid solution for Nilotinib (Nil) through complexation or salt formation with different lipophilic counterions. We synthesized different lipophilic salts/ complexes via metathesis reactions and confirmed their formation by 1H NMR and FTIR. Docusate-based lipophilic salt showed improved solubility in medium-chain triglycerides (∼7 to 7.5-fold) and long-chain triglycerides (∼30 to 35-fold) based lipids compared to unformulated crystalline Nil. The increased lipid solubility could be attributed to the reduction in drug crystallinity which was further confirmed by the PXRD and DSC. Prototype LbFs were prepared to evaluate drug loading and their physicochemical characteristics. The findings suggested that structural features of counterion including chain length and lipophilicity affect the drug loading in LbF. In addition, physical stability testing of formulations was performed, inferring that aliphatic sulfate-based LbFs were stable with no sign of drug precipitation or salt disproportionation. An in vitro lipolysis-permeation study revealed that the primary driver of absorptive flux is the solubilization of the drug and reduced amount of lipid. Further, the in vivo characterization was conducted to measure the influence of increased drug load on oral bioavailability. Overall, the results revealed enhanced absorption of lipophilic salt-based LbF over unformulated crystalline Nil and conventional LbF (drug load equivalent to equilibrium solubility) which supports the idea that lipophilic salt-based LbF enhances drug loading, and supersaturation-mediated drug solubilization, unlocking the full potential of LbF.

Innovative chitosan-polyacrylic acid-MoS2 nanocomposite for enhanced and pH-responsive quercetin delivery

Cancer remains a global health challenge, with current treatments often leading to adverse side effects. Herein, a pH-sensitive, biocompatible nanocomposite composed of chitosan (CS), polyacrylic acid (PAA), and MoS2 nanosheets, loaded with quercetin (QCT) as a model anticancer drug has been synthesized via the water-oil-water (W/O/W) emulsification method, with the aim to be used for targeted breast cancer treatment. Characterization via Fourier-transform infrared spectroscopy (FT-IR) revealed strong interaction between the polymers via hydrogen bonding, and X-ray diffraction (XRD) showed a reduction in the level of crystallinity upon drug loading. Dynamic light scattering (DLS), zeta potential, and field-emission scanning electron microscopy (FE-SEM) tests revealed that the synthesized nanocarriers were spherical in shape and had a hollow structure, with a mean size of 484 nm and a high zeta potential of +44.3 mV, which confirms their high colloidal stability. The addition of MoS2 nanosheets to the polymeric mixture increased drug loading and encapsulation efficiency to 47% and 89%, respectively. The nanocomposite showed high potential as a pH-responsive drug delivery system, releasing 97% and 68% of QCT in acidic and neutral environments, respectively, over 96 hours. The biological performance was investigated using MTT and flow cytometry assays, which confirmed the efficiency of the nanocomposite for tumor cell removal.