New amphiphilic and pH-sensitive hydrogel for controlled release of a model poorly water-soluble drug

This paper presents the development of new pH-sensitive, amphiphilic and biocompatible hydrogels based on alginate-g-PCL, cross-linked with calcium ions to form beads, prepared for controlled delivery of poorly water-soluble drug. We have focused our study on the effect of the length of PCL chains (530 and 1250 g mol⁻¹). Swelling profiles obtained clearly indicated that these hydrogels swell slightly (10-14%) in a simulated gastric fluid (pH 1.2), and strongly (700-1300% before disintegration) in a simulated intestinal fluid (pH 6.8). In both media, rates of swelling were lower for beads based on amphiphilic derivatives than for alginate/Ca²⁺ ones due to the hydrophobic PCL grafts, and decreased when hydrophobic character increased. A model drug, theophylline, was entrapped into these hydrogels and release studies were carried out. The drug was protected in acidic fluid (only 14-20% of release for alginate-g-PCL hydrogel against 35% of release for alginate hydrogel during 350 min). The drug is released completely in neutral fluid due to ion exchanges and disintegration of the hydrogel. PCL leads to decrease in the release kinetics in SIF (2 h for alginate-g-PCL/Ca²⁺ beads against 1 h for alginate/Ca²⁺ beads). It was demonstrated that the establishment of clusters inside beads by intramolecular interactions between PCL grafts of 530 g mol⁻¹ in salt media allowed to retain the drug and to slow down its release considerably.     

Cellular automata model for swelling-controlled drug release

A cellular automata approach for modeling swelling-controlled drug release is presented. In the model, a drug release device is divided into a square grid space. Each cell in the grid contains information about the material, drug, polymer or solvent in that domain. Cells are allowed to change their state according to statistical rules designed to mimic physical phenomena. Diffusion and swelling are modeled by a random walk of mobile cells, and kinetics of chemical or physical processes by probabilities of conversion from one state to another. The model is applied to drug release from a swelling binary polymer/drug device. The effect of simulation parameters on the drug release profiles and the locations of erosion and diffusion fronts are considered. The model was able to produce realistic simulations and is proposed as a new tool for the design of controlled release devices.     

Biodegradable poly(ɛ-caprolactone)–poly(ethylene glycol) copolymers as drug delivery system

Poly(?-caprolactone)–poly(ethylene glycol) (PCL–PEG) copolymers are important synthetic biomedical materials with amphiphilicity, controlled biodegradability, and great biocompatibility. They have great potential application in the fields of nanotechnology, tissue engineering, pharmaceutics, and medicinal chemistry. This review introduced several aspects of PCL–PEG copolymers, including synthetic chemistry, PCL–PEG micro/nanoparticles, PCL–PEG hydrogels, and physicochemical and toxicological properties.     

Synthesis and functionalization of chitosan built hydrogel with induced hydrophilicity for extended release of sparingly soluble drugs

Addressing the functional biomaterials as next-generation therapeutics, chitosan and alginic acid were copolymerized in the form of chemically crosslinked interpenetrating networks (IPNs). The native hydrogel was functionalized via carbodiimide (EDC), catalyzed coupling of soft ligand (1,2-Ethylenediamine) and hard ligand (4-aminophenol) to replace –OH groups in alginic acid units for extended hydrogel- interfaces with the aqueous and sparingly soluble drug solutions. The chemical structure, Lower solution critical temperature (LCST ≈ 37.88 °C), particle size (Z_h,app ≈ 150–200 nm), grain size (160–360 nm), surface roughness (85–250 nm), conductivity (37–74 mv) and zeta potential (16–32 mv) of native and functionalized hydrogel were investigated by using FT-IR, solid state-¹³C-NMR, TGA, DSC, FESEM, AFM and dynamic light scattering (DLS) measurements. The effective swelling, drug loading (47–78%) and drug release (53–86%) profiles were adjusted based on selective functionalization of hydrophobic IPNs due to electrostatic complexation and extended interactions of hydrophilic ligands with the aqueous and drug solutions. Drug release from the hydrogel matrices with diffusion coefficient n ≈ 0.7 was established by Non- Fickian diffusion mechanism. In vitro degradation trials of the hydrogel with a 20% loss of wet mass in simulated gastric fluid (SGF) and 38% loss of wet mass in simulated intestinal fluid (SIF), were investigated for 400 h through bulk erosion. Consequently, a slower rate of drug loading and release was observed for native hydrogel, due to stronger H-bonding, interlocking and entanglement within the IPNs, which was finely tuned and extended by the induced hydrophilic and functional ligands. In the light of induced hydrophilicity, such functional hydrogel could be highly attractive for extended release of sparingly soluble drugs.     

Emulating native periosteum cell population and subsequent paracrine factor production to promote tissue engineered periosteum-mediated allograft healing

Emulating autograft healing within the context of decellularized bone allografts has immediate clinical applications in the treatment of critical-sized bone defects. The periosteum, a thin, osteogenic tissue that surrounds bone, houses a heterogenous population of stem cells and osteoprogenitors. There is evidence that periosteum-cell derived paracrine factors, specifically vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2), orchestrate autograft healing through host cell recruitment and subsequent tissue elaboration. In previous work, we demonstrated that the use of poly(ethylene glycol) (PEG) hydrogels as a tissue engineered (T.E.) periosteum to localize mesenchymal stem cells (MSCs) to the surface of decellularized bone enhances allograft healing and integration. Herein, we utilize a mixed population of 50:50 MSCs and osteoprogenitor cells to better mimic native periosteum cell population and paracrine factor production to further promote allograft healing. This mixed cell population was localized to the surface of decellularized allografts within degradable hydrogels and shown to expedite allograft healing. Specifically, bone callus formation and biomechanical graft–host integration are increased as compared to unmodified allografts. These results demonstrate the dual importance of periosteum-mediated paracrine factors orchestrating host cell recruitment as well as new bone formation while developing clinically translatable strategies for allograft healing and integration.     

Hydrogel blends with adjustable properties as patches for transdermal delivery

The effect of different preparation parameters were analyzed with respect to the rheological and pharmaceutical characteristics of hydrogel blend patches, as transdermal delivery formulation. Mixtures of pectin and gelatin were employed for the production of patches, with adjustable properties, following a two-step gelation procedure. The first gelation, a thermal one, is trigged by the presence of gelatin, whereas, the second gelation, an ionic one, is due to the formation of the typical egg box structure of pectin. In particular, the patch structural properties were assessed by oscillation stress sweep measurements which provided information concerning their viscolelastic properties. In addition, different modalities for drug loading were analyzed with respect to drug homogeneous distribution; testosterone was employed as model drug for transdermal administration. Finally, the performances of the produced transdermal patches were studied, in term of reproducibility and reliability, by determination of in vitro drug release profiles.     

Acyclovir Liposomes for Intranasal Systemic Delivery: Development and Pharmacokinetics Evaluation

Intranasal route is one of the most attractive routes for distributing drugs to systemic circulation. Liposomes are used as biocompatible carriers to improve delivery properties across nasal mucosa. The objective of the present study was to formulate acyclovir liposomes and partition into poly-N-vinyl-2-pyrrolidone. Entrapment efficiency showed that multilamellar and unilamellar liposomes were 43.2% ± 0.83 and 21% ± 1.01, respectively. The bioavailability of acyclovir from nasal mucoadhesive gel was 60.72% compared with intravenous route. The use of liposomes acyclovir and mucoadhesive gel not only promoted the prolonged contact between the drug and the absorptive sites in the nasal cavity, but also facilitated direct absorption through the nasal mucosa.     

Photocrosslinkable methacrylated gelatin hydrogel as a cell-friendly injectable delivery system for chlorhexidine in regenerative endodontics

ObjectivesThis work sought to formulate photocrosslinkable chlorhexidine (CHX)-laden methacrylated gelatin (CHX/GelMA) hydrogels with broad spectrum of action against endodontic pathogens as a clinically viable cell-friendly disinfection therapy prior to regenerative endodontics procedures.MethodsCHX/GelMA hydrogel formulations were successfully synthesized using CHX concentrations between 0.12 % and 5 % w/v. Hydrogel microstructure was evaluated by scanning electron microscopy (SEM). Swelling and enzymatic degradation were assessed to determine microenvironmental effects. Compression test was performed to investigate the influence of CHX incorporation on the hydrogels’ biomechanics. The antimicrobial and anti-biofilm potential of the formulated hydrogels were assessed using agar diffusion assays and a microcosms biofilm model, respectively. The cytocompatibility was evaluated by exposing stem cells from human exfoliated deciduous teeth (SHEDs) to hydrogel extracts (i.e., leachable byproducts obtained from overtime hydrogel incubation in phosphate buffer saline). The data were analyzed using One- and Two-way ANOVA and Tukey’s test (α = 0.05).ResultsCHX/GelMA hydrogels were effectively prepared. NMR spectroscopy confirmed the incorporation of CHX into GelMA. The addition of CHX did not change the micromorphology (pore size) nor the swelling profile (p > 0.05). CHX incorporation reduced the degradation rate of the hydrogels (p < 0.001); whereas, it contributed to increased compressive modulus (p < 0.05). Regarding the antimicrobial properties, the incorporation of CHX showed a statistically significant decrease in the number of bacteria colonies at 0.12 % and 0.5 % concentration (p < 0.001) and completely inhibited the growth of biofilm at concentration levels 1 %, 2 %, and 5 %. Meanwhile, the addition of CHX, regardless of the concentration, did not lead to cell toxicity, as cell viability values were above 70 %.SignificanceThe addition of CHX into GelMA showed significant antimicrobial action against the pathogens tested, even at low concentrations, with the potential to be used as a cell-friendly injectable drug delivery system for root canal disinfection prior to regenerative endodontics.     

Dynamic and equilibrium swelling behaviour of pH-sensitive hydrogels containing 2-hydroxyethyl methacrylate

The equilibrium and dynamic swelling behaviour of hydrogels containing methacrylic acid or various acrylamides was studied as a function of copolymer composition. In all cases, the comonomer was 2-hydroxyethyl methacrylate, methyl methacrylate or N-vinyl-2-pyrrolidone. It is shown that pH-sensitive behaviour with a wide range of swelling ratios could be obtained using a range of compositional changes. The dynamic swelling behaviour was a function of the acidity of the buffered solution.     

Casein-based formulations as promising controlled release drug delivery systems

Casein, the major milk protein, forms an integral part of the daily diet in many parts of the world. Casein possesses a number of interesting properties that make it a good candidate for conventional and novel drug delivery systems. This article reviews approaches aimed to associate bioactive molecules to casein and analyze the evidence of their efficacy in modifying the release and/or improving the bioavailability of the associated molecules. The ability of casein to modify drug dissolution from compacts was reported. The high tensile strength of casein films, favors its use as an acceptable film-coating for tablets. Naturally occurring genipin and a natural tissue enzyme, transglutaminase, were used as crosslinkers to prepare novel casein-based hydrogels for the controlled release of bioactives. Casein floating beads were developed to increase the residence time of drugs in the stomach based on its emulsifying and bubble-forming properties. Casein-based microparticles entrapping bioactive molecules were prepared via emulsification-chemical crosslinking with glutaraldehyde, enzymatic crosslinking by transglutaminase, simple coacervation and electrostatic complexation. Casein nano-formulations were also prepared to deliver nutraceuticals and synthetic drugs via enzymatic crosslinking, graft copolymerization, heat-gelation and polyelectrolyte ionic complexation. It can be concluded that casein-based formulations are promising materials for controlled drug delivery.