Caprolactam-polyvinyl Acetate-polyethylene Glycol Research Articles

Fabrication of PLGA Nanoparticles Using Combination of PCL-PVA-PEG Copolymer as Surfactant: In-Vitro Characterization and Cytotoxicity Study

Objective: The present study aimed to fabricate Poly lactic acid co-glycolic acid (PLGA) nanoparticles loaded with resveratrol using a novel graft co-polymer surfactant named Soluplus®. Methods: The PLGA nanoparticles were prepared in the present study using polyvinyl caprolactam polyvinyl acetate polyethylene glycol amphiphilic graft copolymer named Soluplus® as surfactant through double emulsification and single emulsification-solvent evaporation method. The formulations were prepared successfully to encapsulate the drug resveratrol, and then evaluated for their particle size, polydispersity index, zeta potential, drug loading and the degree of entrapment of the drug. A scanning electron microscope was used to examine the morphology of the nanoparticles. In vitro drug release was assessed and, mathematical pharmacokinetic modelling was done to assess the release pattern. A comparative cytotoxicity study between free drug and prepared nanoparticles using MTT assay was carried out for cell viability evaluation. Uptake and internalization of nanoparticles were also studied using confocal fluorescence microscopy. Results: The results demonstrated successful fabrication of the PLGA nanoparticles using the Soluplus as polymer surfactant. The drug, polymer and the all the excipients were found to be compatible and did not indicate any interaction. The results also indicated the prepared nanoparticles (SF2) as suitable resveratrol delivery vehicle in terms of the compliant particle size (344.6 ±6.63 nm), polydispersity index (0.962), zeta potential (- 18.5±1.21), drug loading (18.94± 0.27%), the entrapment efficiency (39.62±0.17%) and drug release (75.13±0.17%). The shape and surface morphology of the formulated nanoparticles were found to be spherical and smooth. Cytotoxicity study also demonstrated significant reduction of cell viability by the nanoparticle compared to free resveratrol. The highest cytotoxicity of SF2 against MCF7 cell was found in 2000 nM concentration with 3.03±0.05 percent of cell viability. It was found that the percentage of growth inhibition was increasing with increasing concentration of SF2 and IC50 value of this assay was 108.94 μg/ml. Conclusion: It has been found that the Resveratrol loaded PLGA nanoparticles were successfully formulated and found to perform better in terms of efficacy and cytotoxicity.

Tableted hydrophilic electrospun nanofibers to promote meloxicam dissolution rate

This study investigated the ability of hydrophilic electrospun nanofibers to enhance the dissolution rate of poorly soluble drug Meloxicam (MLX). The drug was loaded into polyvinylpyrrolidone (PVP), polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol (Soluplus®), sodium lauryl sulfate (SLS) nanofibers using electrospinning as fibers fabrication technique. The drug-loaded nanofibers were characterized for their diameter, inter-fibers porosity and drug dissolution profiles, carried out in four different aqueous buffers. Nanofibers loaded with MLX were grinded and used to prepare a solid unit dosage form (Tablets: 7 mm × 4 mm) to facilitate their administration. Fibers nanostructure was characterized through SEM analysis showing a mean diameter in a nanometer size range. Moreover, SEM confirmed the maintenance of fibrous structure within tablets cross section.Dissolutions rate of MLX-loaded nanofibers is improved, compared to free drug, suggesting that nanofibers could be used as suitable carrier to enhance MLX dissolution rate. Moreover, the tablet formulation proposed showed faster release rate in comparison with commercial oral forms (Mobic®) particularly in the dissolution media characterized by lower pHs.

Plasmon-Coupled Directional Emission from Soluplus-Mediated AgAu Nanoparticles for Attomolar Sensing Using a Smartphone

Although there are numerous techniques for the synthesis of plasmonic (metallic Ag and Au) nanomaterials, eco-friendly and biocompatible methodologies that present diverse applications in nanophotonics and biomedical domains are seldom reported. Soluplus is a graft copolymer of polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol and is extensively used for improving the solubility and bioavailability of poorly water-soluble drugs. However, the utility of their amphiphilic chemical structure, strong UV-light absorbing, and bifunctional properties of the polymer matrix as well as its role as a solubilizer have not been explored for rapid synthesis of plasmonic bimetallic nanohybrids. Although a variety of nanoparticles (NPs) have been studied for surface plasmon-coupled emission (SPCE) spectroscopic applications, AgAu nanohybrids have not been examined in the subject platform hitherto. In this article, we demonstrate a synthesis route for obtaining AgNPs, AuNPs, and AgAu nanohybrids using soluplus as both the reducing and capping agent in a simple UV-light induced one-pot rapid technique. These hybrid nanomaterials were interfaced with propagating surface plasmon polaritons from a 50 nm Ag thin film to understand the plasmonic coupling phenomenon in spacer, cavity, and extended cavity nanoconfigurations. The obtained AgAu nanohybrids aided in addressing the three major long-standing challenges in SPCE technology development, namely, (i) unavoidable quenching in the presence of AuNPs, (ii) chemical instability in AgNPs, and (iii) intrinsic ohmic losses in plasmonic NPs. In addition to overcoming the above-mentioned caveats, unaccustomed >1200-fold sharply directional and polarized SPCE enhancements were achieved using AgAu nanohybrids. The multifold nanogaps generated in AgAu nanohybrid sustained multiple hotspots catering to attomolar sensitivity of the SPCE reporter molecule, rhodamine B (RhB). The proposed methodology to obtain dequenched as well as augmented SPCE enhancements is of utmost utility in biophysicochemical sensor development.

Hydrophilic nanofibers as a supersaturating delivery system for carvedilol

Polymer nanofibers represent a promising delivery system for poorly water-soluble drugs; however, their supersaturating potential has not been explored yet. Here, carvedilol-loaded nanofibers based on poly(ethyleneoxide) and on amphiphilic block copolymer poloxamer 407 were produced by electrospinning. These nanofibers provided high carvedilol loading and improved dissolution of carvedilol. Their dissolution resulted in a supersaturated system that was not stable, and thus to avoid carvedilol precipitation, hydroxypropyl methylcelluloses or polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus) were additionally incorporated into the nanofibers. The morphology of the electrospun product was not affected by incorporation of carvedilol and the polymer precipitation inhibitors, as shown by scanning electron microscopy. The hydroxypropyl methylcelluloses were not effective polymer precipitation inhibitors for carvedilol. Incorporation of Soluplus significantly extended the duration of carvedilol supersaturation (>24 h) compared to the dissolution of nanofibers without Soluplus. Moreover, after 1 h of dissolution, incorporation of Soluplus into the nanofibers provided significantly higher carvedilol concentration (94.4 ± 2.5 μg/mL) compared to the nanofibers without Soluplus (32.7 ± 5.8 μg/mL), the polymer film (24.0 ± 2.2 μg/mL), and the physical mixture (3.3 ± 0.4 μg/mL). Thus, this study shows the great potential for hydrophilic nanofibers as a delivery system for sustained carvedilol supersaturation.

Design and characterisation of an amorphous formulation of nifedipine for the treatment of autonomic dysreflexia.

Current treatment for autonomic dysreflexia (AD) involves rupturing a liquid-filled soft capsule of nifedipine to aid rapid drug release and absorption, however, this application is not covered under the manufacturer's license. The objective of the current work was to design a rapidly dissolving solid dosage formulation for the treatment of AD as an alternative to the off-license "bite and swallow" use of currently available commercial products. Amorphous solid dispersions (ASDs) of nifedipine were prepared by spray-drying using three different polymers: hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus), at a 15% w/w drug loading and were formulated and compressed into tablets. Dissolution testing was performed in the paddle dissolution apparatus using either a monophasic or biphasic medium. The PVP-nifedipine ASD tablets exhibited rapid dissolution, with 35% of the total nifedipine dose dissolving within 15 min in the monophasic dissolution medium. The HPMC-nifedipine ASD exhibited a very slow dissolution, while the Solupus-nifedipine system exhibited no nifedipine release over 120 min. When tested in the biphasic dissolution medium, the PVP-nifedipine ASD tablets exhibited a release profile comparable to that of the pre-split/ruptured nifedipine soft capsule product. This study demonstrates that a nifedipine-PVP ASD is a promising formulation strategy in the treatment of AD.

Improved anticancer activity of betulinic acid on breast cancer through a grafted copolymer-based micelles system

Betulinic acid (3β-Hydroxy-20(29)-lupaene-28-oic acid, BA) has excellent anti-cancer activity but poor solubility and low bioavailability. To improve the antitumor activity of BA, a polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol (PVCL–PVA–PEG) graft copolymer (Soluplus) encapsulated BA micelle (Soluplus-BA) was fabricated. The Soluplus-BA micelles presented a mean size of 54.77 ± 1.26 nm and a polydispersity index (PDI) of 0.083. The MTT assay results showed that Soluplus-BA micelles increased the inhibitory effect of BA on MDA-MB-231 cells, mainly due to the enhanced accumulation of reactive oxygen species (ROS) and the destruction of mitochondrial membrane potential (MMP). Soluplus-BA micelles induced the DNA double-strand breaks (DSBs) as the γH2AX foci increased. Moreover, Soluplus-BA also inhibited the tube formation and migration of human umbilical vein endothelial cells (HUVECs), and inhibited the neovascularization of the chicken chorioallantoic membrane (CAM). This angiogenesis inhibitory effect may be accomplished by regulating the HIF-1/VEGF-FAK signaling pathway. The in vivo study confirmed the improved anti-tumor effect of Soluplus-BA and its inhibitory effect on angiogenesis, demonstrating the possibility of Soluplus-BA as an effective anti-breast cancer drug delivery system.

Preparation of silver-decorated Soluplus® nanoparticles and antibacterial activity towards S. epidermidis biofilms as characterized by STEM-CL spectroscopy

Biofilm infections present a serious problem because antibacterial drugs are not effective against mature biofilms or biofilms formed by drug-resistant bacteria. To address this issue, we developed a drug delivery system based on metal-decorated polymeric particles. Polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®) is an amphiphilic polymer used in biomedical formulations, while silver nanoparticles are widely acknowledged to have high antibacterial activity. We prepared silver-decorated Soluplus® micelle nanoparticles with high antibacterial activity using the emulsion solvent diffusion method. Decoration of Soluplus® micelles with silver nanoparticles was found to increase their antibacterial activity. Scanning transmission electron microscopy-cathodoluminescence (STEM-CL) spectroscopy allows imaging of the spatial distribution of labeled targets and the chemical identification of materials. However, STEM-CL spectroscopy of fragile polymer materials is challenging. We optimized the STEM-CL spectroscopy technique to determine the distribution of silver nanoparticles in Soluplus® micelles. Additionally, the surface plasmon properties of the silver nanoparticles were successfully characterized without deactivation. The developed silver-decorated Soluplus® nanoparticles were effective against biofilm infections and have the potential to be applied for other biofilm-related diseases. Additionally, the optimized STEM-CL spectroscopy technique is expected to contribute to the analysis and imaging of fragile polymer materials, as well as other soft materials such as cells and tissues.

Design, fabrication, and characterization of graft co-polymer assisted ocular insert: a state of art in reducing post-operative pain

Purpose Targeted delivery of drugs at appropriate concentrations to ocular tissues is required to avoid wastage. Hence, advanced systems that maximize the release of poorly soluble drugs and deliver them at ocular sites must be designed. Methods In this study, Soluplus® (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol–graft copolymer) was selected as a solubilizer as well as film former for preparing ocular inserts and polyethylene glycol 400 (PEG-400) as a plasticizer. On the basis of an initial phase solubility study, the maximum concentration of Soluplus® possible was used for developing the inserts. An optimized formulation was obtained using a 32-factorial design. Two factors at three levels were used to design the ocular inserts. Soluplus® (X 1) and the plasticizer, PEG-400 (X 2), were set as the independent variables at various levels, and the Rel4h (drug release in 4 h, Y 1) and tensile strength (Y 2) were set as the dependent variables. A pre-formulation study was conducted to select suitable materials. Results Various physico-chemical parameters of the optimized formulation, including the tensile strength and folding endurance, were studied using FT-IR, DSC, XRD, and SEM. An in vitro dissolution study was conducted to determine the amount of drug released. There was no redness, swelling, or watering of the rabbit eye. Conclusion It was concluded that the ocular inserts of the poorly soluble nepafenac developed using a graft-co-polymer enhanced the solubility and utilization of the drug for a prolonged period.

Copolymeric Micelles Overcome the Oral Delivery Challenges of Amphotericin B.

Classified as a Biopharmaceutical Classification System (BCS) class IV drug, amphotericin B (AmB) has low aqueous solubility and low permeability leading to low oral bioavailability. To improve these limitations, this study investigated the potential of AmB-loaded polymeric micelles (AmB-PM) to increase intestinal absorption. AmB-PM were prepared with polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol copolymer (Soluplus®) as a polymeric carrier and used a modified solvent diffusion and microfluidics (NanoAssemblr®) method. AmB-PM have a mean particle size of ~80 nm and are mono-disperse with a polydispersity index <0.2. The entrapment efficiency of AmB was up to 95% and achieved with a high drug loading up to ~20% (w/w) with a total amount of incorporated drug of 1.08 ± 0.01 mg/mL. Importantly, compared to free drug, AmB-PM protected AmB from degradation in an acidic (simulated gastric) environment. Viability studies in Caco-2 cells confirmed the safety/low toxicity of AmB-PM. In vitro cellular absorption studies confirmed that AmB-PM increased AmB uptake in Caco-2 cells 6-fold more than free AmB (i.e., 25% compared with 4% within 30 min). Furthermore, the permeability of AmB across Caco-2 monolayers was significantly faster (2-fold) and more pronounced for AmB-PM in comparison to free drug (3.5-fold increase). Thus, the developed AmB-PM show promise as a novel oral delivery system for AmB and justifies further investigation.

Molecular modelling and simulation of fusion-based amorphous drug dispersions in polymer/plasticizer blends

A realistic molecular description of amorphous drug-polymer-plasticizer matrices, suitable for the preparation of amorphous solid dispersions (ASDs) with the aid of fusion-based techniques, was evaluated. Specifically, the incorporation of two model drugs (i.e. ibuprofen, IBU, and carbamazepine, CBZ) having substantially different thermal properties and glass forming ability, on the molecular representation of polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (SOL)/polyethylene glycol (PEG, working as a plasticizer) molecular and thermal properties were evaluated with the aid of classical molecular dynamics (MD) and docking simulations. Results showed good agreement between molecular modelling estimations and experimentally determined properties. Specifically, the computed Tg values that resulted from MD simulations for IBU-SOL/PEG and CBZ-SOL/PEG (53.8 and 54.2 °C, respectively) were in reasonable agreement with the corresponding values resulting from differential scanning calorimetry (DSC) measurements (49.8 and 50.1 °C), while both molecular modelling and experimental obtained results suggested miscibility among system components. Additionally, interactions between CBZ and SOL observed during MD simulations were verified by FTIR analysis, while MD simulations of the hydration process suggested strong molecular interactions between IBU-SOL and CBZ-SOL.

Effect of melt extrudability and melt binding efficiency of polyvinyl caprolactam polyvinyl acetate polyethylene glycol graft copolymer (Soluplus®) on release pattern of hydrophilic and high dose drugs

The present study explores the effect of melt binding of Soluplus® on in vitro release profiles of two hydrophilic drugs, metformin hydrochloride, and paracetamol. The melt viscosities of bulk polymer and physical mixtures with different concentrations of selected APIs were analyzed by using a rheometer. The rheological evaluation revealed both the suitable temperature range for melt extrusion process and drug-polymer extrudability. The effect of formulation and processing parameters (e.g. polymer/drug ratio, temperature, screw speed) on extrudability were evaluated in terms of torque and residence time analysis. The extrudates obtained via hot melt extrusion (HME) processing exhibited good flow and compressibility. Differential scanning calorimetry (DSC) and X-ray diffraction studies examined the change in glass transition temperature (Tg) and crystalline pattern of extruded formulations where all extruded formulations seemed to have retained their crystallinity. The thermogravimetric analysis determined the thermal stability (weight loss) as a function of operating temperature whereas scanning electron microscopy (SEM) showed agglomerated microstructure and rough surface with a porous network and void spaces. The tablets obtained after compression of milled extrudates showed excellent hardness with robust tablet characteristics. The in vitro release studies of individual batches performed in various USP recommended dissolution media (for paracetamol) showed the pH-independent release of the hydrophilic drugs from the polymer matrices.

New micelle myricetin formulation for ocular delivery: improved stability, solubility, and ocular anti-inflammatory treatment

Myricetin (Myr) is a naturally occurring flavonoid exhibiting diverse biological and pharmacological properties, but its characteristics such as water insolubility, poor aqueous stability, and poor bioavailability limit its clinical application, including in ophthalmology. To increase its clinical application in ophthalmology, Myr was designed to be encapsulated in a polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (PVCL-PVA-PEG) polymeric micelles to increases its aqueous solubility, stability, and corneal permeability to promote its efficacy in eye disease treatments. Thus, the Myr micelle ophthalmic solution was prepared and characterized encapsulation efficiency (EE), micelle size, and zeta potential. The chemical stability of Myr and the short-term storage stability of the Myr micelle ophthalmic solution were evaluated, followed by in vitro cytotoxicity and in vivo ocular irritation; in vitro cellular uptake and in vivo corneal permeation; and in vitro antioxidant activity and in vivo anti-inflammatory efficacy were also further evaluated. Myr could be incorporated into micelles with high EE. PVCL-PVA-PEG micelles significantly enhanced Myr’s aqueous solubility and chemical stability. The Myr micelle ophthalmic solution also showed high storage stability. In rabbits, the Myr micelle ophthalmic solution displayed good in vitro cellular tolerance. Remarkable improvements in in vitro cellular uptake and in vivo corneal permeation were also observed in the Myr micelle ophthalmic solution, and significant improvements in the in vitro antioxidant activity and in vivo anti-inflammatory efficacy were also obtained. Overall, these results supported that the Myr micelle ophthalmic solution could be a promising nanomedicine for ocular tissues.

Molecular simulations for amorphous drug formulation: Polymeric matrix properties relevant to hot-melt extrusion

In the present study molecular modelling was used to evaluate polymeric drug carrier matrix properties suitable for hot-melt extrusion (HME). Specifically, the effect of three commonly used plasticizers, namely, citric acid (CA), triethyl citrate (TEC) and polyethylene glycol (PEG), on Soluplus® (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer, SOL) properties were evaluated with the aid of classical molecular dynamics (MD) and docking simulations. Differential scanning calorimetry (DSC) and ATR-FTIR spectroscopy of polymer-plasticizer mixtures were used to experimentally verify the in silico predictions. Computed Tg value by MD simulations for SOL was in reasonable agreement with the experimentally determined Tg value (72.0 vs. 69.4 °C, for MD and DSC measurement, respectively). Solubility parameter calculations with the aid of MD simulations along with calculated molecular lipophilicity potential interaction (MLPI) scores based on molecular docking, suggested component miscibility only in the case of SOL and PEG. This was verified by a positive deviation of the Tg values determined by DSC, compared to the Gordon-Taylor theoretical predictions. Additionally, the calculated MLPI scores suggested strong interactions between SOL and PEG, verified also by ATR-FTIR. Finally, MD simulations of the hydration process suggested strong hydrogen bonding between SOL - CA, and CA - water molecules.

New nanomicelle curcumin formulation for ocular delivery: improved stability, solubility, and ocular anti-inflammatory treatment

Context: A stable topical ophthalmic curcumin formulation with high solubility, stability, and efficacy is needed for pharmaceutical use in clinics.Objectives: The objective of this article was to describe a novel curcumin containing a nanomicelle formulation using a polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol (PVCL–PVA–PEG) graft copolymer.Methods: Nanomicelle curcumin was formulated and optimized and then further evaluated for in vitro cytotoxicity/in vivo ocular irritation, in vitro cellular uptake/in vivo corneal permeation, and in vitro antioxidant activity/in vivo anti-inflammatory efficacy.Results: The solubility, chemical stability, and antioxidant activity were greatly improved after the encapsulation of the PVCL–PVA–PEG nanomicelles. The nanomicelle curcumin ophthalmic solution was simple to prepare and the nanomicelles are stable to the storage conditions, and it had good cellular tolerance. Nanomicelle curcumin also had excellent ocular tolerance in rabbits. The use of nanomicelles significantly improved in vitro cellular uptake and in vivo corneal permeation as well as improved anti-inflammatory efficacy when compared with a free curcumin solution.Conclusions: These findings indicate that nanomicelles could be promising topical delivery systems for the ocular administration of curcumin.

Novel self-assembled tacrolimus nanoparticles cross-linking thermosensitive hydrogels for local rheumatoid arthritis therapy

The aim was to explore the potential application of novel self-assembled nanoparticles cross-linking thermosensitive hydrogels composed of polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol (Soluplus) and tacrolimus (FK-506) for local therapy of rheumatoid arthritis (RA). The sol-gel transition temperature (Tsol-gel), gelation time, rheological behaviors, in vitro release, in vivo gelation and retention, and therapeutic efficacy against adjuvant-induced arthritis (AIA) rats were compared between the Soluplus hydrogels and widely studied poloxamer 407 (P407) delivery systems. In sol, the spherical and uniform FK506 loaded Soluplus nanoparticles (Soluplus-SNPs) were self-assembled with encapsulation efficiency of 99.5±1.5% and particle size of 73.9±2.9nm. The decreased Tsol-gel of Soluplus-SNPs hydrogels was associated with the addition of salts, elevation of pH and ionic strength. The optimal Tsol-gel of Soluplus-SNPs with concentrations of 10%–30% in phosphate buffer (50mM, pH 7.4) was from 37.4±0.1°C to 32.8±0.3°C and the gelation time was not greater than 2min. Soluplus-SNPs gelling systems showed lower viscosity and wider range concentrations in sol state at 25°C and stronger gel strength at 37°C than P407, which resulting in longer sustained release of FK506 but without burst-release in vitro, and longer retention time in the local injection site in vivo. The therapeutic efficacy to treat AIA rats was significantly enhanced from d10 to d17 after a single dose of FK506 loaded in 10% and 20% Soluplus-SNPs hydrogels. In conclusion, Soluplus-SNPs hydrogel is a potential sustainable delivery system for FK506 to treat RA locally.

Effect of polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer on bioadhesion and release rate property of eplerenone pellets

The present study involved the design and development of oral bioadhesive pellets of eplerenone. A solid dispersion of eplerenone was developed with a hydrophilic carrier, polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®). Bioadhesive pellets were prepared from this solid dispersion using a combination of HPMC K4M and Carbopol 934P. Both the solid dispersion and the pellets were evaluated for various physicochemical properties such as solubility, entrapment efficiency, drug content, surface morphology, mucoadhesion and swelling behavior. Analysis carried out using FT-IR, DSC and XRD found no interaction between the eplerenone and excipients. The solid dispersion had irregular-shaped smooth-surfaced particles of diameter 265 ± 105.5 μm. In TEM analysis, eplerenone particles of size 79–120 nm were found. The solubility and dissolution of eplerenone in the Soluplus®-based solid dispersion were 5.26 and 2.50 times greater, respectively. Investigation of the swelling behavior of the pellets showed that the thickness of the gel layer increased continuously over the duration of the study. Moreover, a correlation was observed between the thickness and strength of the gel layer and the percentage release. The mechanism of drug release was found to be non-Fickian (anomalous), with the release kinetics approaching first-order kinetics. The bioavailability of the eplerenone bioadhesive pellet formulation was studied using Wistar rats and was found to be improved. An in vivo mucoadhesion study showed that the pellets are retained for 24 h in rabbits. It was concluded that Soluplus® had a positive effect on the solubility and dissolution of pellets without affecting the bioadhesion.

Solubility and dissolution performances of spray-dried solid dispersion of Efavirenz in Soluplus

Efavirenz (EFV), a first-line anti-HIV drug largely used as part of antiretroviral therapies, is practically insoluble in water and belongs to BCS class II (low solubility/high permeability). The aim of this study was to improve the solubility and dissolution performances of EFV by formulating an amorphous solid dispersion of the drug in polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®) using spray-drying technique. To this purpose, spray-dried dispersions of EFV in Soluplus® at different mass ratios (1:1.25, 1:7, 1:10) were prepared and characterized using particle size measurements, SEM, XRD, DSC, FTIR and Raman microscopy mapping. Solubility and dissolution were determined in different media. Stability was studied at accelerated conditions (40 °C/75% RH) and ambient conditions for 12 months. DSC and XRD analyses confirmed the EFV amorphous state. FTIR spectroscopy analyses revealed possible drug–polymer molecular interaction. Solubility and dissolution rate of EFV was enhanced remarkably in the developed spray-dried solid dispersions, as a function of the polymer concentration. Spray-drying was concluded to be a proper technique to formulate a physically stable dispersion of amorphous EFV in Soluplus®, when protected from moisture.

Magnetic polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol micelles for docetaxel delivery in breast cancer: an in vitro study on two cell lines of breast cancer

The aim of the present study was to load docetaxel (DCT) and Fe3O4 magnetic nanoparticles (MNPs) in polymeric micelles to concentrate them by an external magnetic field in target tissues. Oleic acid (OA) coated MNPs were prepared by hydrothermal method. The micelles were characterized for their zeta potential, particle size, drug loading and release efficacy. Fe loading efficacy was determined by atomic absorption. The magnetic micelles were characterized by Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), transmission electron microscopy and vibrating sample magnetometer (VSM). The cytotoxicity of the micelles was studied by MTT assay on L929 fibroblast cells and also on two breast cancer cell lines of MCF-7 and MDA-MB-231. The optimum formulation showed 70% drug loading efficiency, zeta potential of −2.58 mV, particle size of 144.3 nm and drug release efficiency within 24 h of 68.9% at pH 5.5. Fe was loaded in these nanomicelles 290 μg/100 ml. TGA results confirmed the coating of MNPs with OA and polymeric micelles. The VSM analysis confirmed superparamagnetic property of the micelles. DCT loaded in micelles showed significantly more cytotoxicity compared to free drug on MCF-7 and MDA-MB-231 cells, but blank magnetic micelles had no significant cytotoxicity on normal fibroblast cells.

Novel Soluplus®—TPGS mixed micelles for encapsulation of paclitaxel with enhanced in vitro cytotoxicity on breast and ovarian cancer cell lines

The aim of this work was to develop mixed micelles based on two biocompatible copolymers of polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol (Soluplus®) and D-α-tocopheryl polyethylene-glycol 1000 succinate (TPGS), to improve the aqueous solubility and the in vitro anti-tumor activity of paclitaxel (PTX). Pure and mixed nanomicelles were prepared by solvent evaporation method and characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS). Solubility of PTX was increased 60,000 and 38,000 times, when it was formulated in pure Soluplus® micelles and in mixed micelles (Soluplus®:TPGS; 4:1 ratio), respectively. The in vitro PTX release profile from micellar systems was characterized employing the dialysis membrane method where all drug-loaded formulations showed a sustained and slow release of PTX. In vitro assays were conducted on human cancer cell lines including ovarian cancer cells SKOV-3, breast cancer cells MCF-7 and triple negative breast cancer cells MDA-MB-231. Cytotoxicity studies showed that mixed micelles exhibited better antitumor activity compared to PTX solution against the three cell lines. Furthermore mixed micelles showed a significant increase on PTX cellular uptake in comparison with pure Soluplus® micelles and free drug in all cell lines assayed. More important, blank mixed micelles have shown cytotoxic activity due to the ability of TPGS to induce apoptosis in cancer cells. This effect was associated with the expression levels of cleaved-PARP, an apoptosis-related protein. On the basis of these results, the mixed micelles developed in this study might be a potential nano-drug delivery system for cancer chemotherapy.

A (polyvinyl caprolactam-polyvinyl acetate–polyethylene glycol graft copolymer)-dispersed sustained-release tablet for imperialine to simultaneously prolong the drug release and improve the oral bioavailability

Imperialine, extracted from Bulbus Fritillariae Cirrhosae, is an efficient antitussive and expectorant medicine. However, its short half-life and stomach degradation limited imperialine from further clinical use. The current study was conducted to develop a sustained-release tablet for imperialine both to prolong absorption time and to improve the oral bioavailability of the drug. The tablets were prepared by a direct compression method formulated on optimized solid dispersion (SD) for imperialine based on polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®) with imperialine/Soluplus® ratio of 1:8 (w/w). In order to obtain the optimized formulation, factors that affected the drug release were investigated by in vitro dissolution studies in the media of pH1.2, 5.8, 7.0 and 7.4. Powder X-ray diffraction and scanning electron microscope confirmed that the imperialine in SD was amorphous instead of crystalline, and still stayed amorphous even after the direct compression. And besides, pharmacokinetic study in Beagle dogs was performed to inspect the in vivo sustained release. Plasma concentration-time curves and pharmacokinetic parameters were gained. As a result, the Cmax of imperialine was one-fold reduced and Tmax was two-fold prolonged, and the mean AUC0–24 was expressed as 89.581±21.243μgh/L, which showed that the oral bioavailability of imperialine was 2.46-fold improved. Moreover, the in vitro–in vivo correlation was recommended to carry out, demonstrating the percentages of drug release in vitro were well-correlated with the absorptive fraction in vivo with the correlation coefficients above 0.9900. By mathematically modeling and moment imaging of the drug release, Peppas equation was selected as the most fitted model for the sustained-release tablets with the diffusional coefficient in the range of 0.59–0.62, indicating the release of imperialine from the sustained-release tablets was an anomalous process involving polymer swelling, drug diffusion and matrix erosion.