Preparation and characterization of silk fibroin hydrogel as injectable implants for sustained release of Risperidone

The principal objective of the present study is to achieve a depot formulation of Risperidone by gelation of silk fibroin (SF). For this purpose, hydrochloric acid (HCl)/acetone-based and methanol-based hydrogels were prepared with different drug/polymer ratios (1:3, 1:6, and 1:15). For all the drug-loaded methanol-based hydrogels, gel transition of SF solutions occurred immediately and the gelation time was 1?min, while the gelation time of HCL/acetone-based hydrogels was around 360?min. According to the results obtined from Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) spectra, solvent systems and Risperidone could induce β-sheet structure, but HCL/acetone system had the lowest effect on induction of β-sheets. The crystallinity was increased by increasing the amount of Risperidone, and drug to polymer ratio of 1:3 possessed the highest crystallinity. Thermogravimetric analysis (TGA) indicated that increasing the amount of drug in formulation increased the stability of hydrogels, and methanol-based hydrogel with a ratio of 1:3 had the most stable structure. The release rate of Risperidone from methanol-based hydrogel at ratio of 1:3 was lower than that for HCl/acetone-based one, and it decreased by increasing the amount of Risperidone. The release of Risperidone from methanol hydrogel at ratios 1:3 and 1:6 continued up to 25?d which is acceptable for depot form of Risperidone and shows that the extended release of Risperidone was achieved successfully. In conclusion, SF hydrogel with the ability to respond to the environmental stimuli is an excellent candidate for injectable implants for extended release of Risperidone.     

Design of a 3D aligned myocardial tissue construct from biodegradable polyesters

The heart does not regenerate new functional tissue when myocardium dies following coronary artery occlusion, or if it is defective. Ventricular restoration involves excising the infarct and replacing it with a cardiac patch to restore the heart to a more healthy condition. The goal of this study was to design and develop a clinically applicable myocardial patch to replace myocardial infarcts and improve long-term heart function. A basic design composed of 3D microfibrous mats that house mesenchymal stem cells (MSCs) was developed from human umbilical cord matrix (Wharton’s Jelly) cells aligned in parallel to each other mimicking the native myocardium. Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(L-D,L-lactic acid) (P(L-D,L)LA) and poly(glycerol sebacate) (PGS) were blended and electrospun into aligned fiber mats with fiber diameter ranging between 1.10 and 1.25 μm. The micron-sized parallel fibers of the polymer blend were effective in cell alignment and cells have penetrated deep within the mat through the fiber interstices, occupying the whole structure; 8–9 cell layers were obtained. Biodegradable macroporous tubings were introduced to serve as nutrient delivery route. It was possible to create a thick myocardial patch with structure similar to the native tissue and with a capability to grow.     

Development of modified in situ gelling oral liquid sustained release formulation of dextromethorphan

Context: Alternative strategies are being employed to develop liquid oral sustained release formulation. These included ion exchange resin, sustained release suspensions and in situ gelling systems. The later mainly utilizes alginate solutions that form gels upon contact with calcium which may be administered separately or included in the alginate solution as citrate complex. This complex liberates calcium in the stomach with subsequent gellation. The formed gel can break after gastric emptying leading to dose dumping.

Objective: Development of modified in situ gelling system which sustain dextromethorphan release in the stomach and intestine.

Methods: Solutions containing alginate with calcium chloride and sodium citrate were initially prepared to select the formulation sustaining the release in the stomach. The best formulation was combined with chitosan. All formulations were characterized with respect to flow, gelling capacity, gelling strength and drug release.

Results: Increasing the concentration of alginate increased the gelling capacity and strength and reduced the rate of drug release in gastric conditions with 2% w/v alginate being the best formulation. However, these formulations failed to sustain the release in the intestinal conditions. Incorporation of chitosan with alginate increased the gelling capacity and strength and reduced the rate of drug release compared to alginate only system. The effect was optimum in formulation containing 1.5% w/v chitosan. The sustained release pattern was maintained both in the gastric and intestinal conditions and was comparable to that obtained from the marketed product.

Conclusion: Alginate-chitosan based in situ gelling system is promising for developing liquid oral sustained release.     

Controlled release of heparin from blended polyurethane and silk fibroin film

Polyurethane was blended with silk fibroin and heparin to prepare a heparin-releasing system. The release rate and the percentage of the cumulative amount of the released heparin can be controlled by the loading amount of heparin in the film, the composition ratio of silk fibroin to polyurethane, and the thickness of the film. The slower and more sustained release of heparin can be obtained by increasing the film thickness, the loading amount of heparin and the content of silk fibroin in the film. Thus the high bioactivity and long lasting antithrombogenicity of the raw heparin can be maintained for the blended film. The coagulation time tests showed that the composite film had good blood compatibility.     

壳聚糖-明胶体系的温敏凝胶及其药物缓释性能

用试管倒置法研究在甘油磷酸钠存在下,壳聚糖-明胶体系的温敏凝胶化性能。体系3组分的体积比V(壳聚糖)∶V(G)∶V(甘油磷酸钠)从10∶0.5∶1～10∶0.5∶2.5(体系pH值6.8),37℃下凝胶化时间由(1200±60)s降至150s;V(壳聚糖)∶V(G)∶V(甘油磷酸钠)体积比从10∶0.25∶2～10∶1.25∶2(体系pH值6.8),37℃下凝胶化时间从(300±10)s增至(690±30)s。固定三者体积配比,明胶浓度增大,37℃下凝胶化时间延长。pH值在6.8～7.2范围适合于体系凝胶化。调节体积配比及合适的pH值,可实现壳聚糖/明胶/甘油磷酸钠体系在37℃下快速凝胶化。以布洛芬为模型药物,24h载药温敏凝胶累积释放度为(79.28±2.0)%,而24h布洛芬原药累积释放度为(97.04±2.5)%,表明载药凝胶对药物具有缓释作用。     

Investigation of hypromellose particle size effects on drug release from sustained release hydrophilic matrix tablets

Selected combinations of six model drugs and four hypromellose (USP 2208) viscosity grades were studied utilizing direct compression and in vitro dissolution testing. Experimental HPMC samples with differing particle size distributions (coarse, fine, narrow, bimodal) were generated by sieving. For some formulations, the impact of HPMC particle size changes was characterized by faster drug release and an apparent shift in drug release mechanism when less than 50% of the HPMC passed through a 230 mesh (63 μm) screen. Within the ranges studied, drug release from other formulations appeared to be unaffected by HPMC particle size changes.     

Release of furosemide from sustained release microcapsules prepared by phase separation technique

Furosemide Eudragit RL-100 sustained release microcapsules were prepared using phase separation technique. The results of the release studies, in sorensen phosphate buffer at PH 7.4, indicated good sustained release of the prepared microcapsules. Increasing drug to polymer ratio resulted in a decrease in the release, while increased release obtained by increasing the PH of the dissolution medium. Dosing of healthy human volunteers with sustained release microcapsules resulted in a reduced and sustained urine volume compared to the profuse diuresis obtained with the conventional furosemide capsules.     

3D brain tumor segmentation in MRI images based on a modified PSO technique

Three-dimensional (3D) brain tumor segmentation is a clinical requirement for brain tumor diagnosis and radiotherapy planning. This is a challenging task due to variation in type, size, location, and shape of tumors. Several methods such as particle swarm optimization (PSO) algorithm formed a topological relationship for the slices that converts 2D images into 3D magnetic resonance imaging (MRI) images which does not provide accurate results and they depend on the number of input sections, positions, and the shape of the MRI images. In this article, we propose an efficient 3D brain tumor segmentation technique called modified particle swarm optimization. Also, segmentation results are compared with Darwinian particle swarm optimization (DPSO) and fractional-order Darwinian particle swarm optimization (FODPSO) approaches. The experimental results show that our method succeeded 3D segmentation with 97.6% of accuracy rate more efficient if compared with the DPSO and FODPSO methods with 78.1% and 70.21% for the case of T1-C modality.     

Preparation and dissolution characteristics of indomethacin sustained release beads

Indomethacin is a nonsteroidal anti-inflammatory agent and has a short half life, and causes gastric irritation. Sustained release beads of indomethacin were prepared and dissolution profiles were investigated. Beads were prepared by allowing drops of a suspension of the drug and excipients in a solution of cellulose acetate phthalate to drop into an acetic acid solution by means of a peristaltic pump. In a previous study¹, sulfadiazine was used as a model drug to prepare beads by a similar method and the effects of various viscosity agents on the properties of these beads were assessed. Glycerin, polymers (Methocel and Avicel), and surfactants (Tween 80 and Span 80) were used as excipients. The incorporation of various viscosity agents and polymers into the suspension yielded beads with different disintegration and dissolution values. A high performance liquid chromatography method showed no indication of drug degradation during the preparation. The dissolution studies of the indomethacin preparations demonstrated differences in drug release properties depending on composition and method of preparation. The preparation with equal quantities of the two surfactants (Tween 80 and Span 80) released the drug at the slowest rate.     

Preparation and dissolution characteristics of indomethacin sustained release beads

Abstract

Indomethacin is a nonsteroidal anti-inflammatory agent and has a short half life, and causes gastric irritation. Sustained release beads of indomethacin were prepared and dissolution profiles were investigated. Beads were prepared by allowing drops of a suspension of the drug and excipients in a solution of cellulose acetate phthalate to drop into an acetic acid solution by means of a peristaltic pump. In a previous study¹, sulfadiazine was used as a model drug to prepare beads by a similar method and the effects of various viscosity agents on the properties of these beads were assessed. Glycerin, polymers (Methocel and Avicel), and surfactants (Tween 80 and Span 80) were used as excipients. The incorporation of various viscosity agents and polymers into the suspension yielded beads with different disintegration and dissolution values. A high performance liquid chromatography method showed no indication of drug degradation during the preparation. The dissolution studies of the indomethacin preparations demonstrated differences in drug release properties depending on composition and method of preparation. The preparation with equal quantities of the two surfactants (Tween 80 and Span 80) released the drug at the slowest rate.     

Synthesis of surfactant‐modified ZIF‐8 with controllable microstructures and their drug loading and sustained release behaviour

Metal‐organic frameworks (MOFs) as drug carriers have many advantages than traditional drug carriers and have received extensive attention from researchers. However, how to regulate the microstructure of MOFs to improve the efficiency of drug delivery and sustained release behaviour is still a big problem for the clinical application. Herein, the authors synthesise surfactant‐modified ZIF‐8 nanoparticles with different microstructures by using different types of surfactants to modify ZIF‐8. The surfactant‐modified ZIF‐8 nanoparticles have the larger specific surface area and total micropore volumes than the original ZIF‐8, which enables doxorubicin (DOX) to be more effectively loaded on the drug carriers and achieve controlled drug sustained release. Excellent degradation performance of ZIF‐8 nanoparticles facilitates the metabolism of drug carriers. The formulation was evaluated for cytotoxicity, cellular uptake and intracellular location in the A549 human non‐small‐cell lung cancer cell line. ZIF‐8/DOX nano drugs exhibit higher cytotoxicity towards cells in comparison with free DOX, suggesting the potential application in nano drugs to cancer chemotherapy.Inspec keywords: nanomedicine, lung, nanofabrication, drug delivery systems, cellular biophysics, nanoparticles, cancer, toxicology, biomedical materials, drugs, organometallic compounds, surfactants, porosity, biodegradable materialsOther keywords: controlled drug sustained release, nanodrugs, controllable microstructures, drug loading, metal‐organic frameworks, traditional drug carriers, drug delivery, surfactant‐modified ZIF‐8 nanoparticles, specific surface area, micropore volumes, doxorubicin, degradation performance, metabolism, cytotoxicity, cellular uptake, intracellular location, A549 human nonsmall‐cell lung cancer cell line, cancer chemotherapy     

Phytantriol based liquid crystal provide sustained release of anticancer drug as a novel embolic agent

Phytantriol has received increasing amount of attention in drug delivery system, however, the ability of the phytantriol based liquid crystal as a novel embolic agent to provide a sustained release delivery system is yet to be comprehensively demonstrated. The purpose of this study was to prepare a phytantriol-based cubic phase precursor solution loaded with anticancer drug hydroxycamptothecine (HCPT) and evaluate its embolization properties, in vitro drug release and cytotoxicity. Phase behavior of the phytantriol–solvent–water system was investigated by visual inspection and polarized light microscopy, and no phase transition was observed in the presence of HCPT within the studied dose range. Water uptake by the phytantriol matrices was determined gravimetrically, suggesting that the swelling complied with the second order kinetics. In vitro evaluation of embolic efficacy indicated that the isotropic solution displayed a satisfactory embolization effect. In vitro drug release results showed a sustained-release up to 30 days and the release behavior was affected by the initial composition and drug loading. Moreover, the in vitro cytotoxicity and anticancer activity were evaluated by MTT assay. No appreciable mortality was observed for NIH 3T3 cells after 48?h exposure to blank formulations, and the anticancer activity of HCPT-loaded formulations to HepG2 and SMMC7721 cells was strongly dependent on the drug loading and treatment time. Taken together, these results indicate that phytantriol-based cubic phase embolic gelling solution is a promising potential carrier for HCPT delivery to achieve a sustained drug release by vascular embolization, and this technology may be potential for clinical applications.     

Cytotoxicity of modified glass ionomer cement on odontoblast cells

Recently a modified glass ionomer cement (GIC) with enhanced bioactivity due to the incorporation of wollastonite or mineral trioxide aggregate (MTA) has been reported. The aim of this study was to evaluate the cytotoxic effect of the modified GIC on odontoblast-like cells. The cytotoxicity of a conventional GIC, wollastonite modified GIC (W-mGIC), MTA modified GIC (M-mGIC) and MTA cement has been evaluated using cement extracts, a culture media modified by the cement. Ion concentration and pH of each material in the culture media were measured and correlated to the results of the cytotoxicity study. Among the four groups, conventional GIC showed the most cytotoxicity effect, followed by W-mGIC and M-mGIC. MTA showed the least toxic effect. GIC showed the lowest pH (6.36) while MTA showed the highest (8.62). In terms of ion concentration, MTA showed the largest Ca²⁺ concentration (467.3 mg/L) while GIC showed the highest concentration of Si⁴⁺ (19.9 mg/L), Al³⁺ (7.2 mg/L) and Sr²⁺ (100.3 mg/L). Concentration of F^? was under the detection limit (0.02 mg/L) for all samples. However the concentrations of these ions are considered too low to be toxic. Our study showed that the cytotoxicity of conventional GIC can be moderated by incorporating calcium silicate based ceramics. The modified GIC might be promising as novel dental restorative cements.     

Formulation and development of orodispersible sustained release tablet of domperidone

Abstract

Commercially available domperidone orodispersible tablets (ODT) are intended for immediate release of the drug, but none of them have been formulated for sustained action. The aim of the present research work was to develop and evaluate orodispersible sustained release tablet (ODT-SR) of domperidone, which has the convenience of ODT and benefits of controlled release product combined in one. The technology comprised of developing sustained release microspheres (MS) of domperidone, followed by direct compression of MS along with suitable excipients to yield ODT-SR which rapidly disperses within 30?seconds and yet the dispersed MS maintain their integrity to have a sustained drug release. The particle size of the MS was optimized to be less than 200?μm to avoid the grittiness in the mouth. The DSC thermograms of MS showed the absence of drug-polymer interaction within the microparticles, while SEM confirmed their spherical shape and porous nature. Angle of repose, compressibility and Hausner’s ratio of the blend for compression showed good flowability and high percent compressibility. The optimized ODT-SR showed disintegration time of 21?seconds and matrix controlled drug release for 9?h. In-vivo pharmacokinetic studies in Wistar rats showed that the ODT-SR had a prolonged MRT of 11.16?h as compared 3.86?h of conventional tablet. The developed technology is easily scalable and holds potential for commercial exploitation.     

A sustained release formulation of chitosan modified PLCL:poloxamer blend nanoparticles loaded with optical agent for animal imaging

The objective of this study was to develop optical imaging agent loaded biodegradable nanoparticles with indocynanine green (ICG) using chitosan modified poly(L-lactide-co-epsilon-caprolactone) (PLCL):poloxamer (Pluronic F68) blended polymer. Nanoparticles were formulated with an emulsification solvent diffusion technique using PLCL and poloxamer as blend-polymers. Polyvinyl alcohol (PVA) and chitosan were used as stabilizers. The particle size, shape and zeta potential of the formulated nanoparticles and the release kinetics of ICG from these nanoparticles were determined. Further, biodistribution of these nanoparticles was studied in mice at various time points until 24 h following intravenous administration, using a non-invasive imaging system. The average particle size of the nanoparticles was found to be 146 ± 3.7 to 260 ± 4.5 nm. The zeta potential progressively increased from - 41.6 to + 25.3 mV with increasing amounts of chitosan. Particle size and shape of the nanoparticles were studied using transmission electron microscopy (TEM) which revealed the particles to be smooth and spherical in shape. These nanoparticles were efficiently delivered to the cytoplasm of the cells, as observed in prostate and breast cancer cells using confocal laser scanning microscopy. In vitro release studies indicated sustained release of ICG from the nanoparticles over a period of seven days. Nanoparticle distribution results in mice showing improved uptake and accumulation with chitosan modified nanoparticles in various organs and slower clearance at different time points over a 24 h period as compared to unmodified nanoparticles. The successful formulation of such cationically modified nanoparticles for encapsulating optical agents may lead to a potential deep tissue imaging technique for tumor detection, diagnosis and therapy.     

Maximum energy release rate distribution from a generalized 3D virtual crack extension method

This paper presents a generalized 3D virtual crack extension (VCE) technique for determining the distribution of the maximum energy release rate along a general 3D crack front. The method allows for VCEs at any inclination to the local crack plane. By taking the component of the extension in the crack front's local normal plane it evaluates the local energy release rate, G, in that component's direction. Repeated VCEs applied to the crack front at different inclinations enable the maximum G and its associated direction in the normal plane to be determined. This technique has been applied to a quarter-circular crack in a square cross-section bar under axial and torsional loading. The evaluated maximum energy release rates show the expected antisymmetric direction and symmetric magnitude distributions. The test case also demonstrates a sinusoidal G distribution within the normal plane which would imply that the maximum G and its direction could be evaluated from only two local G values.