Model Hydrophobic Compound Research Articles

Tethered gold-liposome nanoparticles for iontophoresis-enhanced topical delivery for anti-inflammation

Topical delivery is a widely utilized drug administration route globally due to its convenience, non-invasiveness, and minimal drug metabolism. However, the skin barrier, particularly the stratum corneum (SC), poses a challenge by hindering drug absorption and permeation. To address this issue, green-synthesized gold nanoparticles (AuG) were loaded into liposomes to increase electron density and facilitate cathodal iontophoresis for topical drug delivery enhancement. Ginger rhizome extract served as a model hydrophobic compound encapsulated within the gold-liposomes to evaluate its anti-inflammatory effect. Our study demonstrated that the ginger-gold loaded liposomes (AuGL) enhanced cellular uptake of the hydrophobic payload and improved drug penetration through skin layers compared to conventional liposomes following iontophoresis. We investigated different ratios of gold nanoparticles to liposomes and characterized the nanoparticles using DLS, TEM, and FT-IR. Additionally, AuGL significantly inhibited nitric oxide release and TNF-α in RAW 264.7 cells. Furthermore, we formulated AuGL-loaded topical emulgel, which exhibited good stability under accelerated conditions. Our findings suggest that the AuGL combined with iontophoresis offers superior benefits for topical drug delivery, potentially enabling the treatment of skin inflammations and inflammation-related skin cancers.

A glance into factors affecting the possible combined entrapment of curcumin and methylene blue into niosomal formulations as a potential anticancer therapy

Niosomes are non-ionic surfactant vesicles that has successfully attracted a great deal of attention over the last few decades. The best ratio between main components is the key to creating the optimum formulations with substantial loading capacity. Therefore, this study investigated formulation factors that could affect the entrapment of two compounds with different solubilities, namely Methylene blue (MB) and curcumin (CUR) as model hydrophilic and hydrophobic compounds, respectively. The aim was to propose an optimum formula to encapsulate both compounds as a potential hybrid anticancer therapy. The factors with potential influence on the entrapment efficiency (EE) included the type of the non-ionic surfactants (Span 60 versus Span 65), cholesterol to surfactant ratio, and the concentrations of the co-surfactant (Cremophor RH40). Niosomes were prepared by thin film hydration technique and downsized using probe sonicator. The morphology, vesicle size and polydispersity index (PDI) of the prepared vesicles were inspected. The data showed the superiority of Span 65 over Span 60 in terms of higher encapsulation efficiency for MB and CUR. The results reflected positive impact of cholesterol and Cremophor RH40 concentration on EE of the two compounds. The optimum composition of Span 65:cholesterol:Ccremophor RH40 was at the mol% ratio of 45:45:10, respectively, with EE of 91.19 % for CUR alone, 51.70 % for MB alone, and 45.32 %/84.40 % for combined MB/CUR loaded formulations. The vesicle size of the formulations after probe sonication, fall into the range of 100–200 nm, ideal for parenteral delivery to the target sites.

Simultaneous vehiculation of curcumin and riboflavin in bigels produced through WPI cold-set gelation

The influence of curcumin (model hydrophobic compound) and riboflavin (model hydrophilic compound) on the structure and physicochemical properties of bigels produced with cold-set whey protein isolates (WPI) was assessed. The hydrogel phase was produced with WPI (11% w/v) while for the oleogel phase, sunflower oil and glycerol monostearate (GM) (10% w/v) were used. Curcumin (0.03 mg/mL) was added to the oil phase and riboflavin (0.5 mg/mL) to the water phase. Bigels were produced by hot emulsification (18.000 min−1, 2 min, 55 °C) of different hydrogel:oleogel ratios (90:10, 50:50 and 10:90). NaCl (200 mM) was added to the aqueous phase prior the emulsification. Bigels were evaluated through microscopy, XRD, FTIR, viscoelastic, texture, release kinetics and in vitro digestion analyses. XRD and FTIR showed that the addition of compounds led to some possible structural differences. Microscopy images showed an increase of the oil droplets size proportionally to the amount of oil present, and a conversion of the structure from oil in water (O/W) to water in oil (W/O). The structural differences led to different mechanical behavior. For the bigels with the isolated compounds an improvement in the gel network was observed, making it more structured, according to the phase that is being added. Regarding controlled release, higher values for the 90:10 formulation were observed for both compounds due to the matrix erosion. For bioaccessibility, curcumin presented similar values for 90:10 and 10:90 bigels, and riboflavin showed a growing bioaccessibility, with lower values for bigel 90:10.

Solubilization of Phospholipid by Surfactin Leading to Lipid Nanodisc and Fibrous Architecture Formation.

Nanodiscs belong to a category of water-soluble lipid bilayer nanoparticles. In vivo nanodisc platforms are useful for studying isolated membrane proteins in their native lipid environment. Thus, the development of a practical method for nanodisc reconstruction has garnered consider-able research interest. This paper reports the self-assembly of a mixture of bio-derived cyclic peptide, surfactin (SF), and l-α-dimyristoylphosphatidylcholine (DMPC). We found that SF induced the solubilization of DMPC multilamellar vesicles to form their nanodiscs, which was confirmed by size-exclusion chromatography, dynamic light scattering, and transmission electron microscopy analyses. Owing to its amphiphilic nature, the self-assembled structure prevents the exposure of the hydrophobic lipid core to aqueous media, thus embedding ubiquinol (CoQ10) as a hydrophobic model compound within the inner region of the nanodiscs. These results highlight the feasibility of preparing nanodiscs without the need for laborious procedures, thereby showcasing their potential to serve as promising carriers for membrane proteins and various organic compounds. Additionally, the regulated self-assembly of the DMPC/SF mixture led to the formation of fibrous architectures. These results show the potential of this mixture to function as a nanoscale membrane surface for investigating molecular recognition events.

Flash NanoPrecipitation as an Agrochemical Nanocarrier Formulation Platform: Phloem Uptake and Translocation after Foliar Administration.

The increasing severity of pathogenic and environmental stressors that negatively affect plant health has led to interest in developing next-generation agrochemical delivery systems capable of precisely transporting active agents to specific sites within plants. In this work, we adapt Flash NanoPrecipitation (FNP), a scalable nanocarrier (NC) formulation technology used in the pharmaceutical industry, to prepare organic core-shell NCs and study their efficacy as foliar or root delivery vehicles. NCs ranging in diameter from 55 to 200 nm, with surface zeta potentials from -40 to +40 mV, and with seven different shell material properties were prepared and studied. Shell materials included synthetic polymers poly(acrylic acid), poly(ethylene glycol), and poly(2-(dimethylamino)ethyl methacrylate), naturally occurring compounds fish gelatin and soybean lecithin, and semisynthetic hydroxypropyl methylcellulose acetate succinate (HPMCAS). NC cores contained a gadolinium tracer for tracking by mass spectrometry, a fluorescent dye for tracking by confocal microscopy, and model hydrophobic compounds (alpha tocopherol acetate and polystyrene) that could be replaced by agrochemical payloads in subsequent applications. After foliar application onto tomato plants with Silwet L-77 surfactant, internalization efficiencies of up to 85% and NC translocation efficiencies of up to 32% were observed. Significant NC trafficking to the stem and roots suggests a high degree of phloem loading for some of these formulations. Results were corroborated by confocal microscopy and synchrotron X-ray fluorescence mapping. NCs stabilized by cellulosic HPMCAS exhibited the highest degree of translocation, followed by formulations with a significant surface charge. The results from this work indicate that biocompatible materials like HPMCAS are promising agrochemical delivery vehicles in an industrially viable pharmaceutical nanoformulation process (FNP) and shed light on the optimal properties of organic NCs for efficient foliar uptake, translocation, and delivery.

Ultrasonic-antisolvent two-step assembly of carboxymethylated corn fiber gum-coated zein particles for enhanced curcumin delivery

Zein particles (ZPs) have garnered considerable interest in delivery system construction for its capacity to encapsulate hydrophobic substances. Nonetheless, the instability of ZPs is an obstacle to application. Coating carboxymethylated corn fiber gum (CMCFG) which is a modified polysaccharide molecule enriched with anionic groups on the surface of ZPs is expected to overcome this limitation. Here, we evaluated the cell viability of CMCFG to Caco-2, proving the safety of CMCFG with different substitution degree (0.42, 0.52 and 0.70) below 20 mg/mL. Furthermore, curcumin, a hydrophobic model compound, was loaded onto ZPs coated with CMCFG using ultrasonic-antisolvent method, achieving a remarkable encapsulation efficiency (91.19%) and enhanced stability and bioaccessibility. Multiple characteristic approaches, such as zeta potential, FTIR, XRD, ultraviolet absorption spectra revealed that the assembly process mainly relied on hydrophobic interactions and electrostatic interactions. This study provides novel insights into encapsulation methods for hydrophobic nutrients.

Standard Water Generating Vials for Lipophilic Compounds

The study of non-polar compounds in aqueous environments has always been challenging due to their poor solubility in aqueous media. The low affinity of non-polar compounds toward polar solutions facilitates their attachment to glassware, which results in unstable sample concentrations. To address this challenge, and to enable the preparation of a stable mixture of hydrophobic compounds in an aquatic environment, we introduce an in-vial standard water generating system consisting of a vial containing appropriate aqueous solution and a polydimethylsiloxane thin film spiked with target compounds. In this system, a solution with a stable analyte concentration is attained once equilibrium between the thin-film and aqueous solution has been achieved. The developed standard water system was studied using endocannabinoids and phospholipids as model hydrophobic compounds of biological importance, with results indicating that the concentration of hydrophobic compounds in water can remain stable over multiple days. The results also showed that analytes released from the thin film can compensate for analyte loss due to extractions with solid-phase microextraction fibers, thereby re-establishing equilibrium. Thus, the vial is suitable for the repeatable generation of non-polar standards for routine analysis and quality control. The results of this work show that the developed system is stable and reproducible and therefore appropriate for studies requiring the measurement of free concentrations and accurate quantification.

Development of 3D-printed subcutaneous implants using concentrated polymer/drug solutions

Implantable drug-eluting devices that provide therapeutic cover over an extended period of time following a single administration have potential to improve the treatment of chronic conditions. These devices eliminate the requirement for regular and frequent drug administration, thus reducing the pill burden experienced by patients. Furthermore, the use of modern technologies, such as 3D printing, during implant development and manufacture renders this approach well-suited for the production of highly tuneable devices that can deliver treatment regimens which are personalised for the individual. The objective of this work was to formulate subcutaneous implants loaded with a model hydrophobic compound, olanzapine (OLZ) using robocasting - a 3D-printing technique. The formulated cylindrical implants were prepared from blends composed of OLZ mixed with either poly(caprolactone) (PCL) or a combination of PCL and poly(ethylene)glycol (PEG). Implants were characterised using scanning electron microscopy (SEM), thermal analysis, infrared spectroscopy, and X-ray diffraction and the crystallinity of OLZ in the formulated devices was confirmed. In vitro release studies demonstrated that all the formulations were capable of maintaining sustained drug release over a period of 200 days, with the maximum percentage drug release observed to be c.a. 60 % in the same period.

Ultrasensitive Surface‐Enhanced Raman Spectroscopy Detection by Porous Silver Supraparticles from Self–Lubricating Drop Evaporation

AbstractThis work demonstrates an original and ultrasensitive approach for surface‐enhanced Raman spectroscopy (SERS) detection based on evaporation of self‐lubricating drops containing silver supraparticles. The developed method detects an extremely low concentration of analyte that is enriched and concentrated on sensitive SERS sites of the compact supraparticles formed from drop evaporation. A low limit of detection of 10−16 m is achieved for a model hydrophobic compound rhodamine 6G (R6G). The quantitative analysis of R6G concentration is obtained from 10−5 to 10−11 m. In addition, for a model micro‐pollutant in water triclosan, the detection limit of 10−6 m is achieved by using microliter sample solutions. The intensity of SERS detection in this approach is robust to the dispersity of the nanoparticles in the drop but became stronger after a longer drying time. The ultrasensitive detection mechanism is the sequential process of concentration, extraction, and absorption of the analyte during evaporation of self‐lubrication drop and hot spot generation for intensification of SERS signals. This novel approach for sample preparation in ultrasensitive SERS detection can be applied to the detection of chemical and biological signatures in areas such as environment monitoring, food safety, and biomedical diagnostics.

Molecular Mechanism of Hydrotropic Properties of GTP and ATP.

Hydrotropes are small amphiphilic compounds that increase the aqueous solubility of hydrophobic molecules. Recent evidence suggests that adenosine triphosphate (ATP), which is the primary energy carrier in cells, also assumes hydrotropic properties to prevent the aggregation of hydrophobic proteins, but the mechanism of hydrotropy is unknown. Here, we compare the hydrotropic behavior of all four biological nucleoside triphosphates (NTPs) using molecular dynamics (MD) simulations. We launch all atom MD simulations of aqueous solutions of NTPs [ATP, guanosine triphosphate (GTP), cytidine triphosphate (CTP), and uridine triphosphate (UTP)] with pyrene, which acts both as a model hydrophobic compound and as a spectroscopic reporter for aggregation. GTP prevents pyrene aggregation effectively. Dissolution is not achieved in the presence of CTP and UTP. The higher stability of the base stacking in guanine is responsible for the higher hydrotropic efficiency of GTP. Consistent with the simulations, spectroscopic measurements also suggest that the hydrotropic activity of GTP is higher than ATP. Stacking of aromatic pyrene with the aromatic base of NTPs is a characteristic feature of this hydrotropic property. Both ATP and GTP also dissolve clusters of di- and tripeptides containing tryptophan but with equal potency. Importantly, the presence of aromatic amino acids is a necessary condition for the hydrotropic potency of ATP and GTP. Our results can have broad implications for hydrotrope design in the pharmaceutical industry, as well as the possibility of cells employing GTP as a hydrotrope to regulate the hydrophobic protein aggregation in membrane-less biological condensates.

Poly(2‐(dimethylamino) ethyl methacrylate)‐b‐poly(lauryl methacrylate)‐b‐poly(oligo ethylene glycol methacrylate) triblock terpolymer micelles as drug delivery carriers for curcumin

AbstractThis work aims to investigate the ability of poly[2‐(dimethylamino)ethyl methacrylate‐b‐lauryl methacrylate‐b‐(oligo ethylene glycol)methacrylate], PDMAEMA‐b‐PLMA‐b‐POEGMA amphiphilic triblock terpolymers, to encapsulate the model hydrophobic compound curcumin. The terpolymers were synthesized by RAFT polymerization methodologies at variable molecular weights and compositions and self‐assemble into spherical micelles with mixed PDMAEMA/POEGMA coronas and PLMA cores, when inserted in aqueous solutions. Fourier transform infrared and UV–Vis spectroscopy measurements were utilized in order to confirm and quantify the encapsulation of curcumin within the polymeric micelles respectively. Dynamic light scattering was used for the investigation of the size of the nanostructures formed and transmission electron microscopy proved that their morphology is spherical. Moreover, the colloidal stability of the systems in physiological conditions was assessed and two independent in vitro cytotoxicity assays revealed that curcumin‐loaded PDMAEMA‐b‐PLMA‐b‐POEGMA micelles were not cytotoxic.

Encapsulation of Hydrophobic Porphyrins into Biocompatible Nanoparticles: An Easy Way to Benefit of Their Two-Photon Phototherapeutic Effect without Hydrophilic Functionalization.

Simple SummaryEfficient photosensitizers for photodyanmic therapy (PDT) need to be soluble in physiologic media. This requirement often complicates significantly the chemical access to such compounds, resulting in lower availability and higher production costs for the best representatives. Given that their screening and selection is often initially conducted in organic media from series of hydrophobic model compounds, the possibility to use directly such hydrophobic photosensitizers in real PDT studies was highly desirable to speed up their definitive identification but also to alleviate their cost. In this respect, PMLABe polymeric nanoparticles (NPs) were presently probed as nanocarriers to water-solubilize hydophobic star-shaped porphyrin-based which turned out to be promising oxygen photosensitizers for theranostic approaches. We show here that PDT conducted using such NPs loaded with these compounds is as efficient than when functional hydrosoluble analogues of these photosensitiers are tested alone and that tracking of the photosensitizer by fluorescence imaging is even easier.Star-shaped hydrophobic porphyrins, acting as powerful fluorescent two-photon photosensitizers for oxygen in organic solvents, can easily be loaded into PMLABe polymeric nanoparticles at various concentrations. In this contribution, the performance of these porphyrin-containing nanoparticles in terms of photodynamic therapy (PDT) is compared to those of the corresponding water-soluble porphyrin analogues when irradiated in MCF-7 cancer cells. While quite promising results are obtained for performing PDT with these nanoparticles, validating this approach as a mean for using more easily accessible and less expensive photosensitizers, from a synthetic perspective, we also show that their luminescence can still be used for bioimaging purposes in spite of their confinement in the nanoparticles, validating also the use of these nano-objects for theranostic purposes.

Enhanced aqueous dissolution of hydrophobic apixaban via direct incorporation of hydrophilic nanographene oxide

In this study, we have directly incorporated nanographene oxide (nGO) into a hydrophobic drug for enhanced dissolution performance through an antisolvent technique. Apixaban (APX) drug composites were synthesized with nGO incorporation ranging from 0.8% to 2.0% concentration. It was observed that the nGO was successfully embedded without any changes to the original drug crystal structure or physical properties. Dissolution of the drug composites was evaluated using US Pharmacopeia Paddle Method (USP 42). The time needed to reach a 50% release (T50) reduced from 106 min to 24 min with the integration of 1.96% nGO in APX and the T80 also dropped accordingly. Alternatively, dissolution rate showed promising performance with increase in nGO concentration. Initial dissolution rate increased dramatically from 74 µg/min to 540 µg/min. Further, work done in intestinal media revealed T50 went from not dissolving to 79.0 min. Decreased lipophilicity or logP value and increased aqueous solubility are both accredited to hydrophilic nGO water dispersion, producing a hydrophilic channel into the drug crystal surfaces through intermolecular interaction. Additionally, physical, and chemical characterizations confirm that hydrophobic apixaban was successfully transformed into a hydrophilic composite, showing potential for this technology to improve dissolution rate of a model hydrophobic compound.

Modulation of Paracellular-like Drug Transport across an Artificial Biomimetic Barrier by Osmotic Stress-Induced Liposome Shrinking.

Various types of artificial biomimetic barriers are widely utilized as in vitro tools to predict the passive “transcellular” transport of drug compounds. The current study investigated if the sandwich barrier PermeaPad®, which is composed of tightly packed phospholipid vesicles enclosed between two support sheets, contributes to a transport mechanism that is paracellular-like, representing one of the alternative pathways of passive transport in vivo, primarily of relevance for hydrophilic drug compounds. To this end, we pretreated the commercial PermeaPad® barrier with NaCl solutions of either high or low osmolality prior to permeation experiments on reversed Franz cell setups with hydrophilic model compounds calcein and acyclovir and hydrophobic model compounds hydrocortisone and celecoxib. Our starting hypothesis was that the liposomes formed in the barrier during the hydration step should either shrink or swell upon contact with test media (drug solutions) due to osmotic pressure difference as compared to the pretreatment solutions. Apparent permeabilities for calcein and acyclovir across the PermeaPad® barrier were found to increase approximately 2.0 and 1.7 fold, respectively, upon hypo-osmotic pretreatment (soaking in hypotonic medium, while the permeation of hydrocortisone and celecoxib remained unchanged. A control experiment with lipid-free barriers (support sheets) indicated that the permeation of all the compounds was virtually unchanged upon hypo-osmotic pretreatment. In conclusion, soaking PermeaPad® in a medium of lower osmotic pressure than that used during the permeation study appears to induce the osmotic shrinking of the lipid vesicles in the barrier, leaving wider water channels between the vesicles and, thus, allowing hydrophilic compounds to pass the barrier in a paracellular-like manner.

Universal Microcarriers Based on Natural and Synthetic Polymers for Co-Delivery of Hydrophilic and Hydrophobic Compounds.

Several variants of hybrid polyelectrolyte microcapsules (hPEMC) were designed and produced by modifying in situ gelation methods and layer-by-layer (LbL) techniques. All of the hPEMC designs tested in the study demonstrated high efficiency of the model hydrophilic compound loading into the carrier cavity. In addition, the microcarriers were characterized by high efficiency of incorporating the model hydrophobic compound rhodamine B isothiocyanate (RBITC) into the hydrophobic layer consisting of poly-(d,l)-lactide-co-glycolide (PLGA), oligo-(l)-lactide (OLL), oligo-(d)-lactide (OLD) and chitosan/gelatin/poly-l-lactide copolymer (CGP). The obtained microcapsules exhibited high storage stability regardless of the composition and thickness of the polyelectrolyte shell. Study of the impact of hybrid polyelectrolyte microcapsules on viability of the adhesive L929 and suspension HL-60 cell lines revealed no apparent toxic effects of hPEMC of different architecture on live cells. Interaction of hPEMC with peritoneal macrophages for the course of 48 h resulted in partial deformation and degradation of microcapsules accompanied by release of the content of their hydrophilic (BSA–fluorescein isothiocyanate conjugate (BSA-FITC)) and hydrophobic (RBITC) layer. Our results demonstrate the functional efficiency of novel hybrid microcarriers and their potential for joint delivery of drugs with different physico-chemical properties in complex therapy.

Self-Assembled Nanostructures from Amphiphilic Sucrose-Soyates for Solubilizing Hydrophobic Guest Molecules.

We studied self-assembly and colloidal properties of poly(ethylene glycol) (pEG) conjugated sucrose soyate polyols (PSSP). These molecular platforms were synthesized by covalently connecting PEGs of different molecular weights (Mn) (12 and 16 ethylene oxide units) to epoxidized sucrose soyate (ESS). The synthesized PSSP products showed amphiphilicity, reduced water surface tension, and exhibited critical Aggregation Concentration (CAC) within the range of 0.3-0.4 mg/mL. We observed that PSSP self-assembles in water in the form of nanoparticles without the need of any cosolvents. These nanoparticles exhibited number-average hydrodynamic diameter of 120 ± 8 nm with a polydispersity index (PDI) of <0.3, and negatively charged surfaces. We also found out that PSSP nanoparticles can encapsulate and homogeneously distribute a hydrophobic model compound, such as a phthalocyanine dye, Solvent Blue-70 (BL-70), on a metal surface. Collectively, our studies explored and demonstrated the possibility of molecular diversification of biobased starting materials to form amphiphilic nanoparticles with industrially relevant colloidal and surface properties.

The Effect of Modifying TiO2 with Lanthanides on the Photocatalytic Degradation of Ciprofloxacin, A Hydrophobic Compound

Background: Recent years have seen the increased use of antibiotics and hormones in domestic, agricultural and healthcare applications. As a result, waste streams contain more and more of these compounds, which eventually end up in the environment, where they might cause serious damage to flora and fauna, even in miniscule amounts. This issue is currently not resolved by conventional waste treatment plants, as their adequacy for handling these compounds, many of which are non-polar, is quite limited. Objective: This work studies the effect of modifying the hydrophilic photocatalyst TiO2 with various rare earth oxides (REOs), of the lanthanide family (Er, La, Gd, Ce), on the photocatalytic activity toward degrading non-polar compounds. Ciprofloxacin, a widely used antibiotic, was chosen as a model hydrophobic compound. Its degradation rate was compared with that of caffeine, used as a model hydrophilic compound. Methods: Fused silica plates were coated with REO-containing films comprising TiO2 and silica. The latter was used as a binder to assure high integrity and strong adherence of the films to their substrates. The plates were characterized by SEM, EDS, XPS, and scratch-resistance measurements. The photocatalytic kinetics were determined with UV-Vis spectroscopy (caffeine) or fluorescence spectroscopy (ciprofloxacin). Further information was obtained by measuring the kinetics in the presence of charge scavengers and by SEM-EDS mapping of the surface following photodeposition of platinum. Results: Most REOs-modified TiO2 coatings showed increased activity and selectivity towards ciprofloxacin compared to coatings that did not contain REOs. A study on the silica binder's role suggests that the binder's hydrophobicity plays an important role in promoting ciprofloxacin degradation. With respect to REOs contribution, SEM-EDS mapping of REOs-containing films indicated that the REOs act as electron sinks, despite the position of their conduction bands. This charge accumulation is likely responsible for the contribution of the REOs to the enhanced degradation of ciprofloxacin. The hydrophobicity of lanthanide oxides, while affecting the adsorption of the non-polar ciprofloxacin, cannot explain the observed effects. Conclusion: Oxides of erbium, gadolinium and lanthanum may be used to increase photocatalytic rates via electron accumulation, despite the location of their conduction bands. This is in parallel to their effect as adsorption promotors of hydrophobic compounds

Considerations for Defining the Intravenous Administration Procedure for Nano-dose Sterile Drug Product in Clinical Studies

The loss of active substance, both small and large molecules, from sterile liquid drug products after contact with an administration kit has been extensively reported in the literature. This loss has been reported to be caused by incompatibility of the active substances with the contact surfaces of the administration kit and adsorption or sticking of the active substance to the surfaces of the administration kit. This paper investigates the mechanism for loss of a highly potent active substance based on the type and design of the administration kit. Two administration kits (syringe/Insyte Catheter and syringe/Nexiva Catheter) of different designs were used to administer a solution formulation of an ultra-low dose (nanograms) of a model hydrophobic active substance Compound X. The Nexiva Catheter was longer with tubing and Y connectors while the Insyte Catheter was shorter with no split septum tubing. Dose recovery from both administration kits was determined using high pressure liquid chromatography. The results indicated that the full dose was recovered from the syringes and Insyte Catheter. However, there was a significant loss of active substance from the Nexiva Catheter configuration even after post administration flush, which was due to holdup volume of the formulation within dead spaces of the Nexiva Catheter. It was also demonstrated that the dose recovery from the Nexiva Catheter can be significantly increased with increase in the post administration flush volume, which further confirms that the observed loss of active substance was not due to incompatibility or surface adsorption. The significance of this work is to provide awareness to formulation scientists that closed system Catheter design with Y connectors can be the main contributor for the loss in active substance, especially at ultra-low doses, and therefore dose recovery experiments should be expanded to include proper flushing of the Y connectors to expel any holdup volume from the Catheter.

Synthesis, Self-Assembly and In Vitro Cellular Uptake Kinetics of Nanosized Drug Carriers Based on Aggregates of Amphiphilic Oligomers of N-Vinyl-2-pyrrolidone.

Development of nanocarrier-based drug delivery systems is a major breakthrough in pharmacology, promising targeted delivery and reduction in drug toxicity. On the cellular level, encapsulation of a drug substantially affects the endocytic processes due to nanocarrier–membrane interaction. In this study we synthesized and characterized nanocarriers assembled from amphiphilic oligomers of N-vinyl-2-pyrrolidone with a terminal thiooctadecyl group (PVP-OD). It was found that the dissolution free energy of PVP-OD depends linearly on the molecular mass of its hydrophilic part up to = 2 × 104, leading to an exponential dependence of critical aggregation concentration (CAC) on the molar mass. A model hydrophobic compound (DiI dye) was loaded into the nanocarriers and exhibited slow release into the aqueous phase on a scale of 18 h. Cellular uptake of the loaded nanocarriers and that of free DiI were compared in vitro using glioblastoma (U87) and fibroblast (CRL2429) cells. While the uptake of both DiI/PVP-OD nanocarriers and free DiI was inhibited by dynasore, indicating a dynamin-dependent endocytic pathway as a major mechanism, a decrease in the uptake rate of free DiI was observed in the presence of wortmannin. This suggests that while macropinocytosis plays a role in the uptake of low-molecular components, this pathway might be circumvented by incorporation of DiI into nanocarriers.

Tannic Acid-Stabilized Self-Degrading Temperature-Sensitive Poly(2-n-propyl-2-oxazoline)/Gellan Gum Capsules for Lipase Delivery.

In recent years, stable hydrogen-bonded stimuli-responsive polymer capsules have been receiving great interest for the encapsulation and release of sensitive molecules such as lipase enzymes. Compartmental capsules having a liquid gel core stabilized with temperature-responsive hydrogen-bonded multilayers are advantageous over other conventional systems because of their ability to maintain hydrophilic lipase and other hydrophobic compounds in compatible protected molecular vehicle environments and prolong their native properties, e.g., in the body. In this work, we report a methodology to stabilize an aqueous liquid gellan gum (GG) core in a capsule using neutral and nontoxic building blocks, namely, poly(2-n-propyl-2-oxazoline) (PnPrOx) and tannic acid (TA), to fabricate temperature-responsive capsules, comprising both lipase and hydrophobic oil droplets. The capsules were fabricated by adding GG droplets to a PnPrOx suspension at a temperature (T) higher than its cloud point temperature (TCP). Notably, the formed capsules were not stable in water without TA stabilization via hydrogen bonding. Scanning electron microscopy (SEM) investigations of the GG/building block interphase revealed that the collapsed PnPrOx globules that are present above the TCP stabilized the GG interphase as a Pickering emulsion, while undergoing a configurational transformation into its linear form by interacting with TA in the next step of capsule formation resulting in a smooth PnPrOx/TA capsule wall. The encapsulation efficiencies of the capsules for model fluorescent molecules were found to be 52, 54, and 24% for FITC-dextran, rhodamine, and Nile red, respectively. The stability experiments exhibited swelling and shell thinning at certain locations followed by complete rupture of the capsules at 37 °C, while the capsules were stable for several weeks at temperatures below the TCP of PnPrOx. The capsules were found to be stable in stimulated gastric fluid (SGF) for several hours at 37 °C while successfully releasing the encapsulated lipase and Nile red (model hydrophobic compound) in stimulated intestinal fluid (SIF). The released lipase was found to retain almost 100% of its activity. The reported capsules have high potential for use as carriers for encapsulation and release of a variety of payloads ranging from proteins and vitamin supplements to enzymes and probiotics through the oral route of administration.