Hydrophilic Model Research Articles

Liposome Crosslinked Polyacrylamide/DNA Hydrogel: a Smart Controlled-Release System for Small Molecular Payloads.

A novel stimuli-responsive hydrogel system with liposomes serving as both noncovalent crosslinkers and functional small molecules carriers for controlled-release is developed. Liposomes can crosslink polyacrylamide copolymers functionalized with cholesterol-modified DNA motifs to yield a DNA hydrogel system, due to the hydrophobic interaction between cholesteryl groups and the lipid bilayer of liposomes. Functional information encoded DNA motifs on the polymer backbones endow the hydrogel with programmable smart responsive properties. In a model system, the hydrogel exhibits stimuli-responsive gel-to-sol transformation triggered by the opening of DNA motifs upon the presence of a restriction endonuclease enzyme, EcoR I, or temperature change, realizing the controlled-release of liposomes which are highly efficient carriers of active small molecules payloads. Two active molecules, 1,1-dioctadecyl-3,3,3,3-tetramethylindodicarbocyanine perchlorate (DiIC18(5)) and calcein, are chosen as the hydrophobic and hydrophilic model payloads, respectively, to address the feasibility of the releasing strategy. Moreover, the hydrogel exhibits injectable property as well as self-recovery behaviors.

Nanomotor‐Based Strategy for Enhanced Penetration across Vasculature Model

AbstractHere the first nanomotor‐based strategy is reported to effectively cross tumor vasculature endothelium. The designed nanomotors are based on (poly(ethylene glycol)‐b‐polystyrene and poly(acrylic acid)‐b‐polystyrene) building blocks, which further self‐assemble into polymersomes of tunable sizes (100, 300 nm). The polymersomes are readily loaded with hydrophilic model drug into the aqueous compartment. A catalytic platinum cap is then partially deposited on the surface of the polymersome via electron beam evaporation, resulting in a polymersome Janus nanomotor. In a tumor vasculature model, these cargo‐loaded polymersome nanomotors demonstrate enhanced penetration across the endothelium.

Ocular Delivery System for Propranolol Hydrochloride Based on Nanostructured Lipid Carrier.

One drawback of traditional forms of medical ocular dosage is drug dilution by tear; moreover, drugs are rapidly drained away from pre-corneal cavity by tear flow and lacrimo-nasal drainage. Prolonging contact time with different strategies and mucoadhesive vehicles will help to continuously deliver drugs to the eyes. For this study, we prepared and evaluated the effects of a nanostructure lipid carrier (NLC) on propranolol hydrochloride as a hydrophilic drug model for rabbit corneal permeation. Propranolol hydrochloride NLC was prepared using cold homogenization. The lipid was melted, then the drug and surfactant were dispersed and stirred into the melted lipid. This fused lipid phase was scattered in aqueous solution containing the cosurfactant at 4 °C and then homogenized. We evaluated particle size, drug loading, drug release, and NLC permeability through rabbit cornea as well as the formula’s effect on the cornea. Our results show that drug loading efficiency depended on the surfactant/lipid ratio (S/L) and the percentages of liquid lipid and Transcutol (Gattefosse, Saint-Priest, France) (as solubilizer). Drug release data were evaluated with the Higuchi model and a significant correlation was shown between the S/L ratio and the amount of drug released after 4 and 48 h. NLC formulations improved propranolol hydrochloride permeation. We conclude that the effect of the NLC formulations was due to mucoadhesive and film forming properties.

Ultrahigh verapamil-loaded controlled release polymeric beads using superamphiphobic substrate: D-optimal statistical design, in vitro and in vivo performance

Controlled-release multiparticulate systems of hydrophilic drugs usually suffer from poor encapsulation and rapid-release rate. In the present study, ultra-high loaded controlled release polymeric beads containing verapamil hydrochloride (VP) as hydrophilic model drug were efficiently prepared using superamphiphobic substrates aiming to improve patient compliance by reducing dosing frequency. Superamphiphobic substrates were fabricated using clean aluminum sheets etched with ammonia solution and were treated with 1.5% (w/v) perfluorodecyltriethoxysilane (PFDTS) alcoholic solution. The effect of the main polymer type (lactide/glycolide (PLGA) 5004A, PLGA 5010, and polycaprolactone (PCL)), copolymer (Eudragit RS100) content together with the effect of drug load on encapsulation efficiency (EE%) and in vitro drug release was statistically studied and optimized via D-optimal statistical design. In vivo pharmacokinetic study was carried out to compare the optimized system relative to the market product (Isoptin®). Results revealed that superamphiphobic substrates were successfully prepared showing a rough micro-sized hierarchical structured surface upon observing with scanning electron microscope and were confirmed by high contact angles of 151.60 ± 2.42 and 142.80°±05.23° for water and olive oil, respectively. The fabricated VP-loaded beads showed extremely high encapsulation efficiency exceeding 92.31% w/w. All the prepared systems exhibited a controlled release behavior with Q12 h ranging between 5.46 and 95.90%w/w. The optimized VP-loaded system composed of 150 mg (1.5% w/v) PCL without Eudragit RS100 together with 160 mg VP showed 2.7-folds mean residence time compared to the market product allowing once daily administration instead of three times per day.

Hyperbranched polyglycerol coated on copper oxide nanoparticles as a novel core-shell nano-carrier hydrophilic drug delivery model

Core-shell novel nanocarriers were synthesized using copper oxide nanoparticle as a core and hyperbranched polyglycerol (HPG) as the shell. The shell with hydrophilic properties is solubilized and dispersed on copper oxide nanoparticles. The chemical precipitation and ring opening polymerization methods were used for the synthesis of nanoparticles. Transmission electron microscopy (TEM) and atomic force microscopy (AFM) showed the size of copper oxide NPs to be 8nm and hyperbranched polyglycerol coated copper oxide nanoparticle to be 70nm. X-ray diffraction (XRD) showed the purity and FT-IR determines the entire coating of copper oxide nanoparticles. Tetracycline as a soluble drug was loaded to this nano-metal polymer with the efficiency of 92% encapsulation and more than 35% of the drug released through dialysis during five days. This slow and gradual released of antibiotic can propose a promising alternative as an antibiotic carrier for chronic infection. The MTT assay showed that this nano metal branched polymer loaded with tetracycline was not cytotoxic to L929 and MCF7 cell lines.

Benign preparation of aqueous core poly lactic-co-glycolic acid (PLGA) microcapsules

Poly lactic-co-glycolic acid (PLGA) has attracted considerable attention as a polymer for drug delivery carriers. However, the hydrophobic property of PLGA often leads to the use of harmful organic solvents and poor encapsulation efficiency of hydrophilic materials. To our knowledge, a preparation method of aqueous core PLGA microcapsules without using harmful organic solvents has not been proposed. In this study, we attempted to establish an encapsulation technique of hydrophilic materials in aqueous core biodegradable and biocompatible PLGA microcapsules using vegetable oil as a continuous phase. As a result, the temperature of the oil/water mixture was required to be above the glass transition temperature. In this condition, two different types of morphology were prepared. When the water volume was below the solubility limit, PLGA microcapsules with a smooth shell were formed. In contrast, when the water volume was above the solubility limit, colloidosome-like microcapsules with PLGA nanoparticles assembled at the interface were formed. The obtained microcapsules were then heated at the glass transition temperature. The result is that aqueous core PLGA microcapsules with a smooth shell were prepared using plant oil as a continuous phase. Rhodamine B used as a hydrophilic model encapsulant, was successfully encapsulated in the PLGA microcapsules.

Preparation of Ethyl Cellulose Nanoparticles by Solvent-Displacement Using the Conventional Method and a Recirculation System

<p>Ethyl cellulose polymeric nanoparticles (NPs) were prepared using the solvent-displacement technique with ethanol as the solvent. Optimization of the method included evaluating stirring rate and stabilizer type. NPs of 142.1 to 226.5 nm were obtained in a reproducible and efficient way (95% process efficiency) and with good stability (at room temperature). Moreover, a recirculation device was used in order to obtain concentrated NPs dispersions by a continuous process with potential scale-up. This method was challenged to encapsulate a hydrophilic antiviral model molecule (glycyrrhizinic acid) resulting in low entrapment efficiencies (approximately 1%).</p><p> </p><p>The results indicate that NPs are obtained using this simple, economical process that offers the possibility to transport different agents for applications in food-processing, cosmetics production or pharmaceutical products.</p>

Iontophoretic transdermal delivery using chitosan-coated PLGA nanoparticles for positively charged drugs

Recently, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles prepared using a combination of an antisolvent diffusion method with preferential solvation was shown to be beneficial for the iontophoretic transdermal delivery of therapeutic agents. Also, this preparation method can contain a hydrophilic drug. However, since PLGA nanoparticles were negatively charged, it was difficult to apply iontophoresis for positively charged hydrophilic drugs. In this study, we prepared positively charged PLGA nanoparticles containing donepezil hydrochloride (DP). DP was used as a positively charged hydrophilic drug model. The PLGA nanoparticles were coated with chitosan hydroxypropyltrimonium chloride. The average particle diameter of the nanoparticles was 117.7±60.6nm and the surface charge number density changed from negative to positive. Ex vivo skin accumulation study was carried out using abdominal rat skin and a Franz-type diffusion cell with/without iontophoresis. When iontophoresis was applied, the DP concentration in the rat skin of chitosan-coated PLGA nanoparticles was 2.2 times higher than that of non-coated PLGA nanoparticles. This indicated that chitosan-coated PLGA nanoparticles were suitable for iontophoresis. To investigate the transdermal delivery route of the nanoparticles, we prepared chitosan-coated PLGA nanoparticles containing DP, coumarin-6, and rhodamine 6G. Coumarin-6 and rhodamine 6G were used as a trace marker of the PLGA nanoparticles and positively charged hydrophilic drug model, respectively. From the results of ex vivo accumulation test of this fluorescent nanoparticles, it was suggested that positively charged hydrophilic drugs reached the hair follicles as a nanoparticle, and then they were released from the nanoparticles.

Eyelid skin as a potential site for drug delivery to conjunctiva and ocular tissues

The feasibility of topical application onto the (lower) eyelid skin to deliver hydrophilic and lipophilic compounds into the conjunctiva and ocular tissues was evaluated by comparing with conventional eye drop application. Skin permeation and the concentration of several model compounds, and skin impedance were determined utilizing eyelid skin from hairless rats, as well as abdominal skin in the same animals for comparison. In vitro static diffusion cells were used to assess the skin permeation in order to provide key insights into the relationship between the skin sites and drugs. The obtained results revealed that drug permeation through the eyelid skin was much higher than that through abdominal skin regardless of the drug lipophilicity. Specifically, diclofenac sodium salt and tranilast exhibited approximately 6-fold and 11-fold higher permeability coefficients, respectively, through eyelid skin compared with abdominal skin. Histomorphological evaluation and in vivo distribution of model fluorescent dyes were also examined in the conjunctiva and skin after eyelid administration by conventional microscope and confocal laser scanning microscope analyses. The result revealed that eyelid skin has a thinner stratum corneum, thereby showing lower impedance, which could be the reason for the higher drug permeation through eyelid skin. Comparative evaluation of lipophilic and hydrophilic model compounds administered via the eyelid skin over 8h revealed stronger fluorescence intensity in the skin and surrounding tissues compared with eye drop administration. These results suggested that the (lower) eyelid skin is valuable as a prospective site for ophthalmic medicines.

Novel concentrated water-in-oil emulsions based on a non-ionic silicone surfactant: Appealing application properties and tuneable viscoelasticity

Silicone excipients are non-irritating ingredients that are extensively used in topical formulations. In the present study, innovative water-in-oil emulsions with a high water content stabilised by a non-ionic silicone surfactant were developed. Effects of formulation composition on its properties and stability were investigated. It was possible to prepare highly stable emulsions with a water volume fraction of up to 80%. The emulsions exhibited desirable application properties such as non-sticky and cooling qualities. A dependency of the viscosity on the water fraction was found; this offers the opportunity to create emulsions with fine-tuned rheological properties.Furthermore, it could be shown in skin studies that the in vitro release of a hydrophilic model drug is influenced by the configuration of the oil phase. The penetration of the silicone surfactant and the other deployed additives was monitored using combined tape stripping and ATR-FTIR experiments, revealing that the compounds remain in the superficial layers of the stratum corneum, thus minimising the risk for skin irritation.

Clinical outcomes after implantation of a toric intraocular lens with a transitional conic toric surface

PurposeTo evaluate the postoperative outcomes after implantation of a hydrophilic toric intraocular lens (tIOL) with a transitional conic toric surface in patients with astigmatism undergoing refractive lens exchange (RLE) or...

Microgels of silylated HPMC as a multimodal system for drug co-encapsulation

Combined therapy is a global strategy developed to prevent drug resistance in cancer and infectious diseases. In this field, there is a need of multifunctional drug delivery systems able to co-encapsulate small drug molecules, peptides, proteins, associated to targeting functions, nanoparticles. Silylated hydrogels are alkoxysilane hybrid polymers that can be engaged in a sol−gel process, providing chemical cross linking in physiological conditions, and functionalized biocompatible hybrid materials.In the present work, microgels were prepared with silylated (hydroxypropyl)methyl cellulose (Si-HPMC) that was chemically cross linked in soft conditions of pH and temperature. They were prepared by an emulsion templating process, water in oil (W/O), as microreactors where the condensation reaction took place.The ability to functionalize the microgels, so-called FMGs, in a one-pot process, was evaluated by grafting a silylated hydrophilic model drug, fluorescein (Si-Fluor), using the same reaction of condensation. Biphasic microgels (BPMGs) were prepared to evaluate their potential to encapsulate lipophilic model drug (Nile red). They were composed of two separate compartments, one oily phase (sesame oil) trapped in the cross linked Si-HPMC hydrophilic phase.The FMGs and BPMGs were characterized by different microscopic techniques (optic, epi-fluorescence, Confocal Laser Scanning Microscopy and scanning electronic microscopy), the mechanical properties were monitored using nano indentation by Atomic Force Microscopy (AFM), and different preliminary tests were performed to evaluate their chemical and physical stability.Finally, it was demonstrated that it is possible to co-encapsulate both hydrophilic and hydrophobic drugs, in silylated microgels, that were physically and chemically stable. They were obtained by chemical cross linking in soft conditions, and without surfactant addition during the emulsification process. The amount of drug loaded was in favor of further biological activity. Mechanical stimulations should be necessary to trigger drug release.

PDMS-b-PMOXA polymersomes for hepatocyte targeting and assessment of toxicity.

Nanoparticles, such as polymersomes, can be directed to the hepatic asialoglycoprotein receptor to achieve targeted drug delivery. In this study, we prepared asialofetuin conjugated polymersomes based on the amphiphilic di-block copolymer poly(dimethylsiloxane)-b-poly(2-methyloxazoline) (PDMS-b-PMOXA). They had an average diameter of 150nm and formed monodisperse vesicles. Drug encapsulation and sustained release was monitored using the hydrophilic model compound carboxyfluorescein. Asialoglycoprotein receptor specific uptake by HepG2 cells in vitro was energy dependent and could be competitively inhibited by the free targeting ligand. Mechanistic uptake studies revealed intracellular trafficking of asialofetuin conjugated polymersomes from early endosomes and to the lysosomal compartment. Polymersomes showed no toxicity in the MTT assay up to concentrations of 500μg/mL. In addition, acute toxicity and tolerability of our PDMS-b-PMOXA polymersome formulations was assessed in vivo using zebrafish embryos as a vertebrate screening model. In conclusion, a hepatocyte specific drug delivery system was designed, which is safe and biocompatible and which can be used to implement liver-specific targeting strategies.

Application of continuous twin screw granulation for the metformin hydrochloride extended release formulation

This study focuses on evaluating the potential of transferring from a batch process to continuous process for manufacturing of the extended release formulation. Metformin hydrochloride (HCl) was used in the model formulation which was intended to contain the high amount of hydrophilic drug. The effects of barrel temperature, binder type, powder feed rate, and screw speed on granule properties (size and strength) and torque value in twin screw granulation were investigated. Due to the high content of hydrophilic model drug, the granules prepared at a higher temperature with HPMC binding solution had the narrower size distribution and greater strength than the granules prepared with distilled water as a binding solution. After continuous drying and milling steps, the granules (continuous process) satisfied the fundamental purpose of granulation with size and flowability, despite different shape compared with the granules (batch process). Furthermore, there were no significant differences between two granulation processes in tablet properties, such as tablet hardness and in vitro release. The considerations and strategies used in this study to transfer from a batch to continuous process can be applied to other existing formulations based on high shear granulation to enable rapid process transfer in the pharmaceutical industry.

Polyarginine nanocapsules: A versatile nanocarrier with potential in transmucosal drug delivery

The objective of this work was to investigate the potential utility of nanocapsules composed of an oily core decorated with a single polyarginine (PARG), or double PARG/polyacrylic acid (PAA) layer as oral peptide delivery carrier. A step-by-step formulation optimization process was designed, which involved the study of the influence of the surfactants, oils and polymer shells (PARG of different molecular weight and PAA) on the nanocapsules physicochemical properties, peptide loading efficiency, stability in simulated intestinal fluids (SIF) and capacity to enhance the permeability of the intestinal epithelium. Despite the lipophilic nature of the nanocapsules, it was possible to achieve a moderate loading of the hydrophilic model peptide salmon calcitonin and control its release in SIF, by adjusting the formulation conditions. Finally, studies in the Caco-2 epithelial cell line showed the capacity of the nanocapsules to reduce the transepithelial electric resistance of the monolayer, without compromising their viability. Overall, these properties suggest the capacity of polyarginine nanocapsules for enhancing the transport of peptides across epithelia.

In vivo transdermal penetration enhancing activity of essential oil from Zanthoxyli Pericarpium by using microdialysis technique

The aim of this paper is to investigate the topical pharmacodynamics behavior of different lipophilic model drugs after treatment with essential oil from Zanthoxyli Pericarpium by using the cutaneous microdialysis technique, and then evaluate its in vivo transdermal penetration enhancing properties. Two traditional Chinese medicine active components, namely tetramethylpyrazine and puerarin, were chosen as lipophilic and hydrophilic model drugs, respectively. Firstly, the concentration difference method was employed to measure the in vitro recovery rate and loss of the microdialysis probe, and the in vivo recoveries of two model drugs were determined by using the retrodialysis method. Secondly, the skin pharmacodynamics behaviors of two model drugs were studied after treatment with different concentrations of the essential oil, and the well-established and standard penetration enhancer Azone was selected as a positive control. It was found that the recovery of microdialysis probe was equal to its loss for two model drugs, with no interaction between drugs in dialysis membranes. The retrodialysis studies revealed that the in vivo recovery of tetramethylpyrazine and puerarin were 59.17%, 19.85%, respectively. The skin pharmacodynamics studies showed that the essential oil could facilitate the transdermal absorption of tetramethylpyrazine in a concentration-dependent manner, and the enhancement ratio (ER) for 5% essential oil was 98.64, which was higher than that of the optimum concentration of Azone (3% Azone, ER=89.11). Meanwhile, the Zanthoxyli Pericarpium could effectively promote the transdermal permeation of the puerarin in a concentration-dependent manner. Hence, this study further confirmed that the Zanthoxyli Pericarpium had excellent penetration-enhancing activity as a natural transdermal penetration enhancer, providing data support for its application in traditional Chinese medicine external preparations.

In vitro release profiles of PLGA core-shell composite particles loaded with theophylline and budesonide

We investigated the effects of drug loading location, matrix material and shell thickness on the in vitro release of combinational drugs from core-shell PLGA (i.e., poly(lactic-co-glycolic acid)) particles. Budesonide and Theophylline were selected as highly hydrophobic and hydrophilic model drugs, respectively. The dual-capillary electrospray (ES) technique, operated at the cone-jet mode, was used to produce samples of drug-loaded core-shell composite particles with selected overall sizes, polymer materials, and shell thicknesses. Theophylline and Budesonide were loaded at different locations in a PLGA composite particle. This study illustrated how the aforementioned factors affect the release rates of Budesonide and Theophylline loaded in core-shell PLGA composites. We further identified that core-shell composite particles with both model drugs loaded in the core and with matrix PLGA polymers of low molecular weights and low LA/GA ratios are the best formulation for the sustained release of highly hydrophilic and hydrophobic active pharmaceutical ingredients from PLGA composite particles. The formulation strategy obtained in this study can be in principle generalized for biopharmaceutical applications in fixed-dose combination therapy.

Polylactide/poly(ethylene glycol)/polylactide triblock copolymer micelles as carrier for delivery of hydrophilic and hydrophobic drugs: a comparison study

Tri-block poly(lactide)–poly(ethylene glycol)–poly(lactide) (PLA–PEG–PLA) copolymers were synthesized and self-assembled into micelles in aqueous solution by double emulsion and nanoprecipitation methods. These micelles were loaded by atorvastatin and lisinopril as hydrophobic and hydrophilic model drugs, respectively. The resulting nanostructures were characterized by various techniques. Atomic force microscopy images disclosed that the micelles have spherical structure with the average size of 100 nm. The micelles exhibited high encapsulation efficiency of about 48 ± 0.13% and 84 ± 0.13 for atorvastatin and lisinopril, respectively. Fourier transform infrared spectroscopy and differential scanning calorimetry confirmed that strong interaction between atorvastatin and copolymer was the major driving force behind drug loading which subsequently lead to more sustained release behavior of corresponding micelles. Whereas, in case of lisinopril there was no evidence for strong interaction between drug and copolymer. The surface adsorption was the main parameter for drug loading which in turn caused the drug to be quick released. Overall, the results indicated that PLA–PEG–PLA micelles can be considered as a promising carrier for both hydrophilic and hydrophobic drugs with different release characteristics.

Dual-responsive supramolecular self-assembly of inclusion complex of an azobenzene-ended poly(ε-caprolactone) with a water-soluble pillar[6]arene and its application in controlled drug release

Dual photo- and pH-responsive polymeric vesicles are constructed from a host–guest complex between a water-soluble pillar[6]arene and an azobenzene ended functionalized poly(ε-caprolactone). Reversible morphological transitions between vesicles and solid aggregates are achieved upon repeated UV stimulus and pH stimulus. Moreover, the polymeric vesicles present excellent cytocompatibility toward HepG2 cells and can be further applied for controlled release of a hydrophilic model drug, DOX•HCl. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 2477–2482

Liposomal structure: A comparative study on light scattering and chromatography techniques

ABSTRACTLiposomes play an important role in medical and pharmaceutical science as, nanoscale drug carriers. One of the most important features is their size and size distribution, influencing both their bio-distribution and their targeting efficiency to tumors and also therapeutic activity of liposomal antitumor drugs. In this study, the effect of preparation method and molecular interaction on size and shape of liposome was studied. The size and shape characterization of liposomes was performed by asymmetrical flow field-flow fractionation coupled online with multi-angle light scattering (AF4-MALS). The size distributions obtained by AF4-MALS were compared to mean particle sizes and size distribution measured with other standard method such as Photon Correlation Spectroscopy (PCS). Furthermore, the effect of molecular interaction (hydrophilic and hydrophobic model drugs) on liposomal structure was assessed.