Fast Release Profile Research Articles

Investigating the effect of drug release on in-stent restenosis: A hybrid continuum – agent-based modelling approach

Background and objectiveIn-stent restenosis (ISR) following percutaneous coronary intervention with drug-eluting stent (DES) implantation remains an unresolved issue, with ISR rates up to 10%. The use of antiproliferative drugs on DESs has significantly reduced ISR. However, a complete knowledge of the mechanobiological processes underlying ISR is still lacking. Multiscale agent-based modelling frameworks, integrating continuum- and agent-based approaches, have recently emerged as promising tools to decipher the mechanobiological events driving ISR at different spatiotemporal scales. However, the integration of sophisticated drug models with an agent-based model (ABM) of ISR has been under-investigated. The aim of the present study was to develop a novel multiscale agent-based modelling framework of ISR following DES implantation. MethodsThe framework consisted of two bi-directionally coupled modules, namely (i) a drug transport module, simulating drug transport through a continuum-based approach, and (ii) a tissue remodelling module, simulating cellular dynamics through an ABM. Receptor saturation (RS), defined as the fraction of target receptors saturated with drug, is used to mediate cellular activities in the ABM, since RS is widely regarded as a measure of drug efficacy. Three studies were performed to investigate different scenarios in terms of drug mass (DM), drug release profiles (RP), coupling schemes and idealized vs. patient-specific artery geometries. ResultsThe studies demonstrated the versatility of the framework and enabled exploration of the sensitivity to different settings, coupling modalities and geometries. As expected, changes in the DM, RP and coupling schemes illustrated a variation in RS over time, in turn affecting the ABM response. For example, combined small DM – fast RP led to similar ISR degrees as high DM – moderate RP (lumen area reduction of ∼13/17% vs. ∼30% without drug). The use of a patient-specific geometry with non-equally distributed struts resulted in a heterogeneous RS map, but did not remarkably impact the ABM response. ConclusionThe application to a patient-specific geometry highlights the potential of the framework to address complex realistic scenarios and lays the foundations for future research, including calibration and validation on patient datasets and the investigation of the effects of different plaque composition on the arterial response to DES.

Comparative Study of Selected Excipients' Influence on Carvedilol Release from Hypromellose Matrix Tablets.

Solid dosage forms based on hypromellose (HPMC) with prolonged/extended drug release are very important from the research and industrial viewpoint. In the present research, the influence of selected excipients on carvedilol release performance from HPMC-based matrix tablets was studied. A comprehensive group of selected excipients was used within the same experimental setup, including different grades of excipients. Compression mixtures were directly compressed using constant compression speed and main compression force. LOESS modelling was used for a detailed comparison of carvedilol release profiles via estimating burst release, lag time, and times at which a certain % of carvedilol was released from the tablets. The overall similarity between obtained carvedilol release profiles was estimated using the bootstrapped similarity factor (f2). In the group of water-soluble carvedilol release modifying excipients, which produced relatively fast carvedilol release profiles, POLYOXᵀᴹ WSR N-80 and Polyglykol® 8000 P demonstrated the best carvedilol release control, and in the group of water-insoluble carvedilol release modifying excipients, which produced relatively slow carvedilol release profiles, AVICEL® PH-102 and AVICEL® PH-200 performed best.

Fast-Disintegrating Nanofibrous Web of Pullulan/Griseofulvin-Cyclodextrin Inclusion Complexes.

Griseofulvin (GSF) is one of the most widely used antifungal suffering from low water solubility and limited bioavailability. Here, cyclodextrin (CD) derivatives of hydroxypropyl-beta-CD (HPβCD) known for its high-water solubility were used to form inclusion complexes (ICs) with GSF. Here, the molecular modeling study revealed the more efficient complex formation with 1:2 (guest:CD) stoichiometry, so ICs of GSF-HPβCD were prepared using a 1:2 molar ratio (GSF:HPβCD) and then mixed with pullulan (PULL) to generate nanofibers (NFs) using the electrospinning technique. PULL is a nontoxic water-soluble biopolymer and the ultimate PULL/GSF-HPβCD-IC NF was obtained with a defect-free fiber morphology having 805 ± 180 nm average diameter. The self-standing and flexible PULL/GSF-HPβCD-IC NF was achieved to be produced with a loading efficiency of ∼98% corresponding to ∼6.4% (w/w) of drug content. In comparison, the control sample of PULL/GSF NF was formed with a lower loading efficiency value of ∼72% which equals to ∼4.7% (w/w) of GSF content. Additionally, PULL/GSF-HPβCD-IC NF provided an enhanced aqueous solubility for GSF compared to PULL/GSF NF so a faster release profile with ∼2.5 times higher released amount was obtained due to inclusion complexation between GSF and HPβCD within the nanofibrous web. On the other hand, both nanofibrous webs rapidly disintegrated (∼2 s) in the artificial saliva medium that mimics the oral cavity environment. Briefly, PULL/GSF-HPβCD-IC NF can be a promising dosage formulation as a fast-disintegrating delivery system for antifungal oral administration owing to the improved physicochemical properties of GSF.

Microscopic Cascading Devices for Boosting Mucus Penetration in Oral Drug Delivery-Micromotors Nesting Inside Microcontainers.

In the case of macromolecules and poorly permeable drugs, oral drug delivery features low bioavailability and low absorption across the intestinal wall. Intestinal absorption can be improved if the drug formulation could be transported close to the epithelium. To achieve this, a cascade delivery device comprising Magnesium-based Janus micromotors (MMs) nesting inside a microscale containers (MCs) has been conceptualized. The device aims at facilitating targeted drug delivery mediated by MMs that can lodge inside the intestinal mucosa. Loading MMs into MCs can potentially enhance drug absorption through increased proximity and unidirectional release. The MMs will be provided with optimal conditions for ejection into any residual mucus layer that the MCs have not penetrated. MMS confined inside MCs propel faster in the mucus environment as compared to non-confined MMs. Upon contact with a suitable fuel, the MM-loaded MC itself can also move. An in vitro study shows fast release profiles and linear motion properties in porcine intestinal mucus compared to more complex motion in aqueous media. The concept of dual-acting cascade devices holds great potential in applications where proximity to epithelium and deep mucus penetration are needed.

Effect of Tartrazine as Photoabsorber for Improved Printing Resolution of 3D Printed “Ghost Tablets”: Non-Erodible Inert Matrices

Stereolithography (SLA) 3D printing of pharmaceuticals suffers from the problem of light scattering, which leads to over-curing, resulting in the printing of objects that are non-compliant with design dimensions and the overloading of drugs. To minimize this problem, photoabsorbers such as tartrazine (food grade) can be used to absorb the stray light produced by scattering, leading to unintended photopolymerization. Ghost tablets (i.e., non-erodible inert matrices) were additively manufactured using SLA with varying ratios of polyethylene glycol diacrylate (PEGDA): polyethylene glycol (PEG) 300, along with tartrazine concentrations. The 3D printed ghost tablets containing maximum (0.03%) tartrazine were extremely precise in size and adhered to the nominal value of the metformin hydrochloride content. Resolution analysis reinstated the influence of tartrazine in achieving highly precise objects of even 0.07 mm2 area. Furthermore, 3D printed ghost tablets were characterized using analytical means, and swelling studies. Additionally, ghost tablets were tested for their mechanical robustness using dynamic mechanical and texture analysis, and were able to withstand strains of up to 5.0% without structural failure. The printed ghost tablets displayed a fast metformin hydrochloride release profile, with 93.14% release after 12 h when the PEG 300 ratio was at its maximum. Ghost tablets were also subjected to in vivo X-ray imaging, and the tablets remained intact even after four hours of administration and were eventually excreted in an intact form through fecal excretion.

Combining rapid and sustained insulin release from conducting hydrogels for glycemic control

Innovative insulin delivery systems contemplate combining multi-pharmacokinetic profiles for glycemic control. Two device configurations have been designed for the controlled release of insulin using the same chemical compounds. The first insulin delivery system, which displays a rapid release response that, in addition, is enhanced on a short time scale by electrical stimulation, consists on an insulin layer sandwiched between a conducting poly(3,4-ethylenedioxythiophene) (PEDOT) film and a poly-γ-glutamic acid (γ-PGA) hydrogel. The second system is constituted by γ-PGA hydrogel loaded with insulin and PEDOT nanoparticles by in situ gelation. In this case, the insulin release, which only starts after the degradation of the hydrogel over time (i.e. on a long time scale), is slow and sustained. The combination of an on-demand and fast release profile with a sustained and slow profile, which act on different time scales, would result in a very efficient regulation of diabetes therapy in comparison to current systems, allowing to control both fast and sustained glycemic events. Considering that the two systems developed in this work are based on the same chemical components, future work will be focused on the combination of the two kinetic profiles by re-engineering a unique insulin release device using γ-PGA, PEDOT and insulin.

Development and In vitro characterization of pullulan fast dissolving films loaded with Panax ginseng extract, antioxidant properties and cytotoxic efficiency on lung and breast cancer cell lines

The objectives of the current research were to produce fast dissolving oral films (FDOFs) containing standardised freeze-dried ginseng root extract (FDG) and to exploit and evaluate the effect of pullulan on the fast-dissolving oral films to impart desirable features to the drug formulation, such as rapid drug release, high release rates and improve the active ingredients' stability. Pullulan was used as a film-forming polymer and propylene glycol as a plasticizer, and films were produced by a solvent-casting method. The FDOFs were evaluated for the physicomechanical properties such as disintegration, Young's modulus, tensile strength and elongation at the break. The interaction between the polymer and freeze-dried ginseng extract in the film formulation was determined by ATR-FTIR method. Morphological characteristics were identified by scanning electron microscopy. Along with the formulation study, its antioxidant capacity and anti-cancer effect on lung and breast cancer cell lines were also observed. In different antioxidant experiments (FRAP, CUPRAC, DPPH and ABTS), the total antioxidant content of FDG was observed to be between 3.379 and 11,216 mg/g extract. In the present study, we also tested FDG extract on human breast cancer model MCF-7 and human lung cancer model A549 cell lines in vitro. Based on MCF-7 and A549 cell viability results, FDG extract exerted cytotoxicity on both cancer lines in a dose-dependent manner. The results manifested that the FDOFs containing FDG had good physicomechanical properties and fast release profiles. The incorporation of the FDG into the films promoted reduction of the tensile strength and Young's modulus, and an increase in elongation compared to F1. The film exhibited maximal release in 10 min of the active compounds (Rb1 and RG2), and it was more than 97 ± 0.35%. The results may lay the groundwork for future studies, regarding the development of FDOFs as P. ginseng extract-based dosage forms, which might increase the pharmacological activity and multifunctional properties closer to the desired level and may be a useful and effective anticancer-containing product with future in vivo studies.

An Insight into the Impact of Thermal Process on Dissolution Profile and Physical Characteristics of Theophylline Tablets Made through 3D Printing Compared to Conventional Methods.

The dissolution profile is of great importance in drug delivery and is affected by the manufacturing method. Thus, it is important to study the influence of the thermal process on drug release in emerging technologies such as 3D printing-fused deposition modeling (FDM). For this purpose, the characteristics of 3D printed tablets were compared to those of tablets prepared by other thermal methods such as hot-melt extrusion (HME) and non-thermal methods such as physical mixture (PM). Theophylline was used as a drug model and blends of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) were used as a matrix former. The solid state of the drug in all formulations was investigated by differential scanning calorimetry, X-ray powder diffraction, and Fourier-transformed infrared spectroscopy. All studied tablets had the same weight and surface area/volume (SA/V). Dissolution data showed that, for some formulations, printed tablets interestingly had a faster release profile despite having the highest hardness values (>550 N) compared to HME and PM tablets. Porosity investigations showed that 100% infill printed tablets had the highest porosity (~20%) compared to HME (<10%) and PM tablets (≤11%). True density records were the lowest in printed tablets (~1.22 g/m3) compared to tablets made from both HME and PM methods (~1.26 g/m3), reflecting the possible increase in polymer specific volume while printing. This increase in the volume of polymer network may accelerate water and drug diffusion from/within the matrix. Thus, it is a misconception that the 3D printing process will always retard drug release based on increased tablet hardness. Hardness, porosity, density, solid-state of the drug, SA/V, weight, and formulation components are all factors contributing to the release profile where the total balance can either slow down or accelerate the release profile.

Nanoconfinement of a Pharmaceutical Cocrystal with Praziquantel in Mesoporous Silica: The Influence of the Solid Form on Dissolution Enhancement.

Nanoconfinement is a recent strategy to enhance solubility and dissolution of active pharmaceutical ingredients (APIs) with poor biopharmaceutical properties. In this work, we combine the advantage of cocrystals of racemic praziquantel (PZQ) containing a water-soluble coformer (i.e., increased solubility and supersaturation) and its confinement in a mesoporous silica material (i.e., increased dissolution rate). Among various potential cocrystalline phases of PZQ with dicarboxylic acid coformers, the cocrystal with glutaric acid (PZQ-GLU) was selected and successfully loaded by the melting method into nanopores of SBA-15 (experimental pore size of 5.6 nm) as suggested by physical and spectroscopic characterization using various complementary techniques like N2 adsorption, powder X-ray diffraction (PXRD), infrared spectroscopy (IR), solid-state NMR (ss-NMR), differential scanning calorimetry (DSC), and field emission-scanning electron microscopy (FE-SEM) analysis. The PZQ-GLU phase confined in SBA-15 presents more mobility according to ss-NMR studies but still retains its cocrystal-like features in the IR spectra, and it also shows depression of the melting transition temperature in DSC. On the contrary, pristine PZQ loaded into SBA-15 was found only in the amorphous state, according to the aforementioned studies. This dissimilar behavior of the composites was attributed to the larger crystal lattice of PZQ over the PZQ-GLU cocrystal (3320.1 vs 1167.9 Å3) and to stronger intermolecular interactions between PZQ and GLU, facilitating the confinement of a more mobile solid-like phase in the constrained channels. Powder dissolution studies under extremely nonsink conditions (SI = 0.014) of the confined PZQ-GLU and amorphous PZQ phases embedded in mesoporous silica showed transient supersaturation behavior when dissolving in simulated gastric fluid (HCl pH 1.2 at 37 ± 0.5 °C) in a similar fashion to the bare cocrystal PZQ-GLU. A comparison of the area under the curve (AUC0-90min) of the dissolution profiles afforded a dissolution advantage of 2-fold (p < 0.05) of the new solid phases over pristine racemic PZQ after 90 min; under these conditions, the solubilized API reprecipitated as the recently discovered PZQ hemihydrate (PZQ-HH). In the presence of a cellulosic polymer, sustained solubilization of PZQ from composites SBA-15/PZQ or SBA-15/PZQ-GLU was observed, increasing AUC0-90min up to 5.1-fold in comparison to pristine PZQ. The combination of a confined solid phase in mesoporous silica and a methylcellulose polymer in the dissolution medium effectively maintained the drug solubilized during times significant to promote absorption. Finally, powder dissolution studies under intermediate nonsink conditions (SI = 1.99) showed a fast release profile from the nanoconfined PZQ-GLU phase in SBA-15, which reached rapid saturation (95% drug dissolved at 30 min); the amorphous PZQ composite and bare PZQ-GLU also displayed an immediate release of the API but at a lower rate (69% drug dissolved at 30 min). In all of these cases, a large dissolution advantage was observed from any of the novel solid phases over PZQ.

Antibacterial nanofibers of pullulan/tetracycline-cyclodextrin inclusion complexes for Fast-Disintegrating oral drug delivery

Tetracycline is a widely used antibiotic suffering from poor water solubility and low bioavailability. Here, hydroxypropyl-beta-cyclodextrin (HPβCD) was used to form inclusion complexes (IC) of tetracycline with 2:1 M ratio (CD:drug). Then, tetracycline-HPβCD-IC was mixed with pullulan- a non-toxic, water-soluble biopolymer - to form nanofibrous webs via electrospinning. The electrospinning of pullulan/tetracycline-HPβCD-IC was yielded into defect-free nanofibers collected in the form of a self-standing and flexible material with the loading capacity of ∼ 7.7 % (w/w). Pullulan/tetracycline nanofibers was also generated as control sample having the same drug loading. Tetracycline was found in the amorphous state in case of pullulan/tetracycline-HPβCD nanofibers due to inclusion complexation. Through inclusion complexation with HPβCD, enhanced aqueous solubility and faster release profile were provided for pullulan/tetracycline-HPβCD-IC nanofibers compared to pullulan/tetracycline one. Additionally, pullulan/tetracycline-HPβCD-IC nanofibers readily disintegrated when wetted with artificial saliva while pullulan/tetracycline nanofibers were not completely absorbed by the same simulate environment. Electrospun nanofibers showed promising antibacterial activity against both gram-positive and gram-negative bacteria. Briefly, our findings indicated that pullulan/tetracycline-HPβCD-IC nanofibers could be an attractive material as orally fast disintegrating drug delivery system for the desired antibiotic treatment thanks to its promising physicochemical and antibacterial properties.

Fabrication of Multiresponsive Magnetic Nanocomposite Double-Network Hydrogels for Controlled Release Applications.

Nanocomposite double-network hydrogels (ncDN hydrogels) have been demonstrated as promising biomaterials to present several desired properties (e.g., high mechanical strength, stimuli-responsiveness, and local therapy) for biomedicine. Here, a new type of ncDN hydrogels featuring definable microstructures and properties as well as multistimuli responsiveness for controlled release applications is developed. Amine-functionalized iron oxide nanoparticles (IOPs_NH2 ) are used as nanoparticle cross-linkers to simultaneously connect the dual networks of gelatin (Gel) and polydextran aldehyde (PDA) through hydrogen bonding, electrostatic interactions, and dynamic imine bonds. The pH- and temperature-responsive Gel/PDA/IOP_NH2 ncDN hydrogels present a fast release profile of proteins at acidic pH and high temperature. Besides, IOP_NH2 also contributes the magnetic-responsiveness to the ncDN hydrogels, allowing the use of magnetic field to generate heat to facilitate the structural change of hydrogels and the subsequent applications. Taken together, a versatile ncDN hydrogel platform capable of multistimuli responsiveness and local heating for controlled release is developed for advanced biomedical applications.

Long-Term Sustained Drug Delivery via 3D Printed Masks for the Development of a Heparin-Loaded Interlayer in Vascular Tissue Engineering Applications.

Current approaches in small-diameter vascular grafts for coronary artery bypass surgeries fail to address physiological variations along the graft that contribute to thrombus formation and ultimately graft failure. We present an innovative interlayer drug delivery system that can be utilized for the sustained delivery of heparin through a graft with a high degree of temporal and spatial control. A heparin-loaded gelatin methacrylate (gelMA) interlayer sits within a biohybrid composed of decellularized bovine pericardium (dECM) and poly(propylene fumarate) (PPF), and its UV crosslinking is controlled via three-dimensional (3D) printed shadow masks. The masks can be readily designed to modulate the incident light intensity on the graft, enabling us to control the resultant gelMA crosslinking and properties. A high heparin loading efficiency was obtained in gelMA and was independent of crosslinking. We achieved sustained heparin release over the course of 2 weeks within the biohybrid material using the 3D printed mask patterns. High doses of heparin were observed to have detrimental effects on endothelial cell function. However, when exposed to heparin in a slower, more sustained manner consistent with the masks, endothelial cells behave similarly to untreated cells. Further, slower release profiles cause significantly more release of tissue factor pathway inhibitor, an anticoagulant, than a faster release profile. The heparin-loaded gelMA interlayer we have developed is a useful tool for the temporal and spatial control of heparin release that supports endothelial function and promotes an antithrombotic environment.

Preparation of Fine-Drugs Layered Spherical Particles with Good Micromeritic and Dissolution Properties through Ultra Cryo-Milling and Mechanical Powder Processing.

The particles of phenytoin (Phe), a poorly water-soluble model drug, were bead-milled alone or co-milled with a hydrophilic waxy additive using an ultra cryo-milling technique in liquid nitrogen (LN2) to improve its dissolution properties. However, the micronized drug particles adhered and aggregated, resulting in poor handling in manufacturing processes such as blending or tableting. To improve the dissolution profile and powder properties of the drug simultaneously, the milled products were secondarily processed together with larger spherical particles by mechanical powder processing. These secondary products were composite particles with a core-shell structure, with fine drug particles adhered and deposited on the core, based on order mixing theory. As a core, three types/sizes of spherical pharmaceutical excipient particles were applied. The resultant composite particles produced much faster release profiles than just milled or co-milled mixtures. In addition, the composite particles showed good micromeritic properties depending on the size of the core particles. These results indicate that the ultra cryo-milling and subsequent dry composite mixing is a potential approach for developing drug particles with improved dissolution.

STUDY OF KINETICS MODEL OF FLAVONOID TOTAL RELEASE IN PATCH OF ANTIHYPERTENSIVE HERBS

The liquid extract of antihypertensive herbs could reduce blood pressure equivalent to Hydrochlorothiazide 25 mg based on research conducted in “Hortus Medicus” clinic, Tawangmangu, Central Java, but parameters of herbal medicine taste, design, and packaging had the lowest scores. Transdermal patch was chosen as an alternative to resolve those problems. Polymers determined the effectiveness of the active substance release from the formula. Patch was formulated from combination of hydrophilic hydroxy methylcellulose (HPMC) and carboxymethylcellulose natrium (CMC-Na) polymer which would produce a fast release profile. The objective of this research was to study the kinetics models of total flavonoid release and to study the total number of flavonoids released from the antihypertensive herbs patch for 5 hours, as well as to determine the optimum formula for observing the weight, pH and loss on drying. Herbs were infused with distilled water at 90 ° C for 15 minutes, filtered then evaporated. Release kinetics model used a modified type-5 dissolution apparatus equipment with a cellophane membrane. The optimum proportion of HPMC and CMC-Na was 220:180 mg. Patch was dark brown, circle shaped, moist and flexible. It had pH value of 7.29 ± 0.09, folding endurance of &gt;350, and thickness of 0.64 ± 0.05 mm. The average percentage of total flavonoids released from the matrix patch was 37.23% for 5 hours. The release kinetics followed the Higuchi kinetics model with a diffusion mechanism.

Microencapsulation of Acidithiobacillus thiooxidans by spray drying using biopolymers as wall materials: A potential alternative for its application in the mining industry

Acidithiobacillus thiooxidans is a microorganism of great interest in bio-hydrometallurgical processes, as it is potentially capable of treating complex, low-grade (purity) sulfur minerals. However, there are concerns in the metallurgical industry regarding the microbial manipulation due to problems arising related to cellular integrity, metabolic activities, genetic stability and maintainability of a continuous generation of microbial cultures. In this work, a spray drying (SD) process (inlet temperature: 150 °C, feed flow: 1.2 L/h, and atomization rate: 27,500 rpm) was adopted to encapsulate Acidithiobacillus thiooxidans using different biopolymers as wall materials. The physicochemical properties of the powders obtained by SD reveal water activity (aw) below 0.55 with less than 10% moisture, which ensures better stability of the powders during storage with a trapping efficiency above 80%. Morphology studies by scanning electron microscopy (SEM) of the microparticles showed defined surfaces with no collapsing structures, quasi-modal size particles, low viscosity of the reconstituted powders and fast release profiles. Calorimetric analysis confirmed the viability of A. thiooxidans to withstand the SD process. By infrared analysis, the same peaks of the functional groups corresponding to the biopolymers after spray drying were observed, which evidences the microorganism encapsulation (whose signal disappeared after SD). The presence of A. thiooxidans in the microcapsules was confirmed by Transmission Electron Microscopy (TEM). Finally, viability was verified by respiratory assessment of the bacterium rendering high survival rate (1.4 × 109 Cells/mL) after the spray drying process.

Coaxial electrospun PVA/PCL nanofibers with dual release of tea polyphenols and ε-poly (L-lysine) as antioxidant and antibacterial wound dressing materials

Preparing wound dressing with dual-delivery of antioxidant and antibacterial agents is highly desirable in clinical wound treatment. Herein, a series of coaxial nanofiber membranes loaded with antioxidant tea polyphenols (TP) in the core and antibacterial ε-poly (L-lysine) (ε-PL) in the shell layer were successfully fabricated by coaxial electrospinning. The physicochemical characterizations by transmission electron microscopy, inverted fluorescence microscopy and fourier transform infrared spectroscopy confirmed the formation of core-shell structure. The results of in vitro drug release indicated that ε-PL exhibited a fast release profile while TP released in a sustained manner, which is favorable to the achievement of quick bacteria inhibition in the initial phase as well as long-term antioxidant activity during wound healing. The antioxidant activity of coaxial nanofibers was found to be increased with the increment of TP content and incubation time. The antibacterial assays against Escherichia coli and Staphylococcus aureus demonstrated that the incorporation of ε-PL in the coaxial nanofibers led to strong antibacterial activity. Additionally, all the coaxial nanofibers possessed good cytocompatibility. Therefore, the prepared coaxial nanofibers simultaneously incorporated with ε-PL and TP are promising as potential wound dressing materials.

Development of pH-sensitive vaginal films based on methacrylate copolymers for topical HIV-1 pre-exposure prophylaxis

Interest is growing in “smart” vaginal microbicides as a strategy to protect women from sexual transmission of human immunodeficiency virus (HIV). The concept is based on the development of products featuring low drug release in acidic media such as vaginal fluid but switch to a fast release profile when the medium becomes neutral or slightly alkaline. This mimics the surge in pH occurring in the vagina after sexual intercourse due to the seminal fluid. Semen is the main vehicle for HIV-1, and increasing antiretroviral drug levels in the vagina upon ejaculation may contribute to enhanced protection against viral sexual transmission. This work explores the use of different pharmaceutical-grade methacrylic acid-based polymers (EudragitⓇ RL, RS, L and S) for developing vaginal films allowing the pH-dependant release of the antiretroviral drug tenofovir (TFV). EudragitⓇ L 100 and EudragitⓇ S 100, containing triethyl citrate as plasticiser, proved to be suitable for manufacturing films with optimal dual in vitro drug-release behaviour. TFV-release can be sustained for several days after film administration and all the drug is released in a few hours in conditions simulating ejaculation. The films’ mechanical properties were also deemed suitable for comfortable vaginal administration. Two optimized films were further assessed using HEC-1-A and Ca Ski cell monolayer models and were found to possess favourable drug permeability profiles and drug levels associated to cell monolayer as compared to free TFV. Overall, pH-dependant films containing tenofovir may constitute promising candidates for “smart” vaginal microbicides to protect women from sexual HIV transmission.

Intranasal fosphenytoin: The promise of phosphate esters in nose-to-brain delivery of poorly soluble drugs.

Intranasal administration could increase both safety and efficacy of drugs acting on the central nervous system, but low solubility severely limits administration through this route. Phenytoin's prodrug, fosphenytoin, is hydrophilic and freely soluble in water, but less permeable since it is dianionic. We aimed to assess whether this phosphoester prodrug could be a suitable alternative to phenytoin in intranasal delivery. Secondly, we aimed to compare simple formulation strategies in fosphenytoin delivery. Fosphenytoin formulations containing thermosensitive and/or mucoadhesive (hydroxypropyl methylcellulose, HPMC) polymers were developed, guided by viscosity, gelling temperatures, osmolality, and in vitro drug release tests. Then, a pharmacokinetic study was performed, comparing an intravenous fosphenytoin solution, an intranasal fosphenytoin solution, and intranasal fosphenytoin mucoadhesive formulations with or without albumin. Formulations containing HPMC allowed high drug strengths, and had a relatively fast release profile, which was not changed by albumin. Intranasal administration of a formulation with HPMC and albumin prolonged drug concentration over time and led to complete or even increased absolute bioavailability. Moreover, phenytoin's blood levels did not reach the high peak obtained with intravenous administration. In conclusion, the use of phosphate ester prodrugs could be an efficient and safe strategy to increase the intranasal bioavailability of poorly soluble drugs.

Encapsulated doxorubicin crystals influence lysolipid temperature-sensitive liposomes release and therapeutic efficacy in vitro and in vivo

Doxorubicin (DOX)-loaded lysolipid temperature-sensitive liposomes (LTSLs) are a promising stimuli-responsive drug delivery system that rapidly releases DOX in response to mild hyperthermia (HT). This study investigates the influence of loaded DOX crystals on the thermosensitivity of LTSLs and their therapeutic efficacy in vitro and in vivo. The properties of DOX crystals were manipulated using different remote loading methods (namely (NH4)2SO4, NH4-EDTA and MnSO4) and varying the lipid:DOX weight ratio during the loading step. Our results demonstrated that (NH4)2SO4 or NH4-EDTA remote loading methods had a comparable encapsulation efficiency (EE%) into LTSLs in contrast to the low DOX EE% obtained using the metal complexation method. Cryogenic transmission electron microscopy (cryo-TEM) revealed key differences in the nature of DOX crystals formed inside LTSLs based on the loading buffer or/and the lipid:DOX ratio used, resulting in different DOX release profiles in response to mild HT. The in vitro assessment of DOX release/uptake in CT26 and PC-3 cells revealed that the use of a high lipid:DOX ratio exhibited a fast and controlled release profile in combination with mild HT, which correlated well with their cytotoxicity studies. Similarly, in vivo DOX release, tumour growth inhibition and mice survival rates were influenced by the physicochemical properties of LTSLs payload. This study demonstrates, for the first time, that the characteristics of DOX crystals loaded into LTSLs, and their conformational rearrangement during HT, are important factors that impact the TSLs performance in vivo.

Tracking the Footprints of Paclitaxel Delivery and Mechanistic Action via SERS Trajectory in Glioblastoma Cells.

The design and development of an efficacious tumor-specific drug-delivery system is a challenging task. In this study, we have synthesized target-specific small peptide substrates on an octaguanidine sorbitol scaffold, named small molecular targeted drug-delivery conjugate (SMTDDC). The SMTDDC fabrication, with dual targeting cRGD and Cathepsin B (Cath B)-specific tripeptide (Glu-Lys-Phe), altered the microtubule network of glioblastoma cells by the orchestrated release of the cytotoxic paclitaxel (PTX). Cath B assisted PTX delivery was monitored by high-performance liquid chromatography and Surface-Enhanced Raman Scattering (SERS) modalities. The time-dependent SERS fingerprinting and imaging revealed a fast and accurate PTX release profile and subsequent in vitro cytotoxicity as well as the apoptotic events and microtubule network alteration in U-87 MG glioblastoma cells. Furthermore, SMTDDC displayed adequate stability under physiological conditions and demonstrated biocompatibility toward red blood cells and lymphocytes. This study indicated a new insight on SERS-guided peptidomimetic sorbitol molecular transporter, enabling a greater promise with high potential for the further development of PTX delivery in glioblastoma treatment.