Hot-Melt Coating Technology. I. Influence of Compritol® 888 Ato and Granule Size on Theophylline Release

The aim of this work was to study the influence of theophylline granule size and the percentage of Compritol® 888 Ato on in vitro drug release from granules and tablets. The granules were coated in a fluidized bed apparatus. The dissolution profiles of these granules differed from those of granules coated with classical agents, and there were also differences between the various sieve fractions studied. Drug release was characterized by a rapid-release phase, followed by a slow-release phase. Results indicate that theophylline release can be controlled by controlling granule size. Inspection of the appearance of the tablets at the end of the dissolution test revealed that all tablets containing Compritol 888 Ato remained intact. This indicated that the Compritol 888 Ato used in the tablet formulation created an inert matrix through which the drug diffused. It was found that the Higuchi relationship of linear square root of time was the best model to describe the release kinetics of the drug from tablets. This also confirmed that a matrix diffusion-controlled mechanism was operative. Given the difference between the dissolution profiles of the granules and the tablets, it was concluded that this matrix is formed during compression.     

Development and evaluation of orally disintegrating tablets of cilostazol-β-cyclodextrin inclusion complexes

Context: The clinical applications of cilostazol (CLZ) are limited by its low aqueous solubility (<5?µg/ml) and high biovariability.

Objective: The aim of this study was to enhance the solubility of CLZ by forming inclusion complexes (ICs) with beta cyclodextrin (β-CD) and formulating them into oral disintegrating tablets.

Methods: Phase solubility study of CLZ with β-CD was performed in water. Job’s plot was constructed to determine the stoichiometry of ICs. ICs, prepared by spray-drying technique, were characterized using Fourier transform infrared spectroscopy, differential scanning calorimetry, hot stage microscopy, powder X-ray diffraction and nuclear magnetic resonance. Molecular modeling studies were performed to understand the mode of interaction of CLZ with β-CD. The formulation process was undertaken using a reproducible design of experiment generated model, attained by variation of diluents and disintegrants at three levels. Tablets were evaluated for drug content, hardness, friability, disintegration time (DT), wetting time (WT) and dissolution profiles.

Results and discussion: Phase solubility studies suggested an A_L type curve with stability constant (K_s) of 922.52?M^?1. Job’s plot revealed 1:2 stoichiometry. All analytical techniques confirmed inclusion complexation. Molecular modeling revealed dispersive van der Waals interaction energy as a major contributor for stabilization of complex. The spray-dried complexes showed higher solubility and faster dissolution compared to plain CLZ. The optimized formulation showed DT of 11.1?±?0.8?s, WT of 8.7?±?0.9?s and almost complete dissolution of CLZ in 15?min.

Conclusion: The prepared tablets with low DT and fast dissolution will prove to be a promising drug delivery system with improved bioavailability and better patient compliance.     

Preparation and evaluation of self-assembly Soluplus®-sodium cholate-phospholipid ternary mixed micelles of docetaxel

Abstract

Ternary mixed micelles constituted of Soluplus^®, sodium cholate, and phospholipid were prepared as nano-delivery system of the anticancer drug, docetaxel. The formulation of docetaxel-loaded ternary mixed micelles (DTX-TMMs) with an optimized composition (Soluplus^®/sodium cholate/phospholipid= 3:2:1 by weight) were obtained. The main particle size of DTX-TMMs was 76.36?±?2.45?nm, polydispersity index (PDI) was 0.138?±?0.039, and the zeta potential was ?8.46?±?0.55?mv. The encapsulation efficiency was 94.24?±?4.30% and the drug loading was 1.25%. The critical micelle concentration value was used to assess the ability of carrier materials to form micelles. The results indicated that the addition of Soluplus^® to sodium cholate-phospholipid mixed micelles could reduce the critical micelle concentration and improve the stability. In vitro release studies demonstrated that compared with DTX-Injection group, the DTX-TMMs presented a controlled release property of drugs. In vivo pharmacodynamics results suggested that DTX-TMMs had the most effective inhibitory effect on tumor proliferation and had good biosafety. In addition, the relative bioavailability of mixed micelles was increased by 1.36 times compared with the DTX-Injection in vivo pharmacokinetic study indicated that a better therapeutic effect could be achieved. In summary, the ternary mixed micelles prepared in this study are considered to be promising anticancer drug delivery systems.     

Quantitative evaluation of sulfur–polymer matrix composite quality

In order to predict service life of the sulfur–polymer composite, the samples were subjected to the induced destruction using 10% hydrochloric acid solution. Control specimens were prepared using Portland cement binder. Sulfur–polymer composite showed limited mechanical strength and mass loss, while physico-mechanical properties of Portland cement composite regressed rapidly. The Image Pro Plus software was used for surface destruction monitoring. The simulations for composites were applied to the previously reported model for predicting the mechanical strength degradation during durability testing, based on the image analysis results. The results proved that the time gradient of structural change was useful for quantification of service life, therefore it can be accepted as a parameter that represents service life.     

In vitro and in vivo evaluation of the safety and stability of the TAXUS® Paclitaxel-Eluting Coronary Stent

Functional aspects of the styrene-b-isobutylene-b-styrene triblock copolymer (SIBS) which is incorporated into a drug-eluting stent (DES) coating are described. The SIBS copolymer is employed on the TAXUS^® Paclitaxel-Eluting Coronary Stent as a carrier for paclitaxel (PTx). Optical and scanning electron microscopic analysis of stents explanted from rabbit and porcine models after 2 years and 6 months, respectively, showed that the SIBS coating maintained physical integrity. Gel permeation chromatography (GPC) of the copolymer extracted from the coating verified that no polymer degradation occurred over the same period of time. The coating on TAXUS^® Stents was shown to maintain physical integrity after 400 million cycles of pulsatile or mechanical (tensile) fatigue, simulating 10 years real time use. Inspection of the samples compared to untested controls showed no change in the coating under these cyclic simulated conditions. Films prepared with the same formulation found on TAXUS^® Stents maintained mechanical strength and resistance throughout the time of testing. Intentional defects introduced into the stent coating were shown to have only a minimal impact on PTx release. These data support the suitability of the SIBS copolymer as a drug carrier for DES applications.     

Development and mechanical properties of metal–particulate glass matrix composites from recycled glasses

The great number of glasses available from recycling activity and vitrification treatment of industrial wastes leads to the need for new applications, with the development of new materials, such as low-cost composite materials from a powder technology route. In the present work a variety of recycled glasses is investigated, in order to obtain aluminium reinforced glass matrix composites via cold-pressing and viscous flow sintering. A good compatibility between lead silicate glasses from cathode ray tubes dismantling and aluminium reinforcement is found to be effective. Composites exhibiting good mechanical properties were developed from these materials. A particular attention was due to fracture toughness (K_IC) determination. The absolute K_IC of glass matrix composites value remains low, but a notable increment in relation to unreinforced matrix is observed.     

Preparation and evaluation of a timolol maleate drug–resin ophthalmic suspension as a sustained-release formulation in vitro and in vivo

Abstract

The aim of this work was to assess the performance of resin as an ocular delivery system. Timolol maleate (TM) was chosen as the model drug and an ion exchange resin (IER) as the carrier. The drug–resin complex was prepared using an oscillation method and then characterized regarding particle size, zeta potential, morphology, and drug content. After in vitro drug release study and corneal permeation study were performed, in vivo studies were performed in New Zealand albino rabbits using a suspension with particles sized 4.8?±?1.2?μm and drug loading at 43.00?±?0.09 %. The results indicate that drug released from the drug–resin ophthalmic suspension permeated the cornea and displayed a sustained-release behavior. Drug levels in the ocular tissues after administration of the drug–resin ophthalmic suspension were significantly higher than after treatment with an eye drop formulation but were lower in body tissues and in the plasma. In conclusion, resins have great potential as effective ocular drug delivery carriers to increase ocular bioavailability of timolol while simultaneously reducing systemic drug absorption.     

Development and performance evaluation of a dead weight force machine in 2–50N range

Results of the performance evaluation of a newly designed, developed and fabricated dead weight machines to realize forces in the range of (2–50) N are reported in this paper. Precision load cells of 20N, 50N and 100N having an expanded uncertainty of ± 0.03% are used for this evaluation. The calibration of these load cells against the dead weight force machine shows that the repeatability (Rep) and reproducibility (Repr) are better than 0.003% and 0.005% respectively, over the entire range. The calibration data observed is found to closely agree with the calibration results obtained directly against the Physikalsich-Technische Bundesanstalt (PTB), Germany force standard machine having the relative measurement uncertainty of the force scale in the measuring range ≤ 0.002%.     

Influence of reinforcement morphology and matrix strength of metal–matrix composites on the cyclic deformation and fatigue behaviour

The cyclic deformation behaviour of three metal–matrix composites, namely AA6061-T6 reinforced with 20 vol.% alumina particles and short-fibres, respectively, and pure aluminium reinforced with 20 vol.% short-fibres, has been investigated at temperatures between T=−100°C and T=300°C in total strain controlled symmetrical push–pull fatigue tests. The cyclic stress response exhibits initial cyclic hardening, subsequent saturation and cyclic softening, depending on the test parameters for temperatures lower than T=150°C. Initial cyclic hardening is less pronounced with increasing temperature and decreasing applied strain amplitude. Short-fibre reinforced composites — both with alloyed and unalloyed aluminium matrix — harden cyclically more than the particulate-reinforced composite. The comparison of the cyclic with monotonic stress–strain curves indicates that, depending on the testing conditions, both cyclic hardening and cyclic softening can occur.     

Development and in vitro–in vivo evaluation of a water-in-oil microemulsion formulation for the oral delivery of troxerutin

Objective: The main objective of this study was to develop and evaluate a W/O microemulsion formulation of troxerutin to improve its oral bioavailability.

Methods: The W/O microemulsion was optimized using a pseudo-ternary phase diagram and evaluated for physical properties. In vitro MDCK cell permeability studies were carried out to evaluate the permeability enhancement effect of microemulsion, and in vivo absorption of troxerutin microemulsion in the intestine was compared with that of solution after single-dose administration (56.7?mg/kg) in male Wistar rats.

Results: The optimal formulation consisted of lecithin, ethanol, isopropyl myristate and water (23.30/11.67/52.45/12.59 w/w) was physicochemical stable and the mean droplet size was about 50.20?nm. In vitro study, the troxerutin-loaded microemulsion showed higher intestinal membrane permeability across MDCK monolayer when compared with the control solution. The W/O microemulsion can significantly promote the intestinal absorption of troxerutin in rats in vivo, and the relative bioavailability of the microemulsion was about 205.55% compared to control solution.

Conclusion: These results suggest that novel W/O microemulsion could be used as an effective formulation for improving the oral bioavailability of troxerutin.     

In vitro and in vivo evaluation of the effects of demineralized bone matrix or calcium sulfate addition to polycaprolactone–bioglass composites

The objective of this study was to improve the efficacy of polycaprolactone/bioglass (PCL/BG) bone substitute using demineralized bone matrix (DBM) or calcium sulfate (CS) as a third component. Composite discs involving either DBM or CS were prepared by compression moulding. Bioactivity of discs was evaluated by energy dispersive X-ray spectroscopy (ESCA) and scanning electron microscopy (SEM) following simulated body fluid incubation. The closest Calcium/Phosphate ratio to that of hydroxyl carbonate apatite crystals was observed for PCL/BG/DBM group (1.53) after 15 day incubation. Addition of fillers increased microhardness and compressive modulus of discs. However, after 4 and 6-week PBS incubations, PCL/BG/DBM discs showed significant decrease in modulus (from 266.23 to 54.04 and 33.45 MPa, respectively) in parallel with its highest water uptakes (36.3 and 34.7%). Discs preserved their integrity with only considerable weight loss (7.5–14.5%) in PCL/BG/DBM group. In vitro cytotoxicity tests showed that all discs were biocompatible. Composites were implanted to defects on rabbit humeri. After 7 weeks, new tissue formation and mineralization at bone-implant interface were observed for all implants. Bone mineral densities at interface were higher than that of implant site and negative controls (defects left empty) but lower than healthy bone level. However, microhardness of implant sites was higher than in vitro results indicating in vivo mineralization of implants. Addition of DBM or CS resulted with higher microhardness values at interface region (ca. 650 μm from implant) compared to PCL/BG and negative control. Histological studies revealed that addition of DBM enhanced bone formation around and into implant while CS provided cartilage tissue formation around the implant. From these results, addition of DBM or CS could be suggested to improve bone healing efficacy of PCL/BG composites.     

Evaluation of hydrophilic matrix tablets based on Carbopol® 971P and low-viscosity sodium alginate for pH-independent controlled drug release

Background: The aim of this study was to evaluate matrix tablets containing different ratios of Carbopol^® 971P (CP) to low-viscosity sodium alginate (SA) and assess their suitability for pH-independent controlled drug release. Methods: Two processing methods (physical mixing, PM and spray-drying, SD) were applied before compaction and the release from corresponding matrices was compared. The release from CP-SA PM matrices was also investigated using three model drugs (paracetamol, salicylic acid, and verapamil HCl) and two dissolution media (0.1 N HCl or phosphate buffer, pH?=?6.8), and the release rate, mechanism, and pH-dependence were characterized by fitting of Higuchi and Peppas models, and evaluation of similarity factor. Furthermore, swelling behavior of CP-SA matrix tablets was studied for evaluating its impact on drug release. Results: The processing method (SD or PM) markedly affected the drug release from CP-SA matrices. ANOVA tests showed significant effects of the CP:SA ratio and drug type on the release rate (expressed by the constant, K_H, from Higuchi model) and of the dissolution medium on the release mechanism (expressed by the exponent, n, from Peppas model). Similarity factor (f₂) indicated that the CP:SA ratios ≥?25:75 and ≥?50:50 were suitable for pH-independent release of paracetamol and salicylic acid, respectively, although for verapamil HCl, the matrix with low CP:SA ratio (0:100) showed remarkably reduced pH-dependence of release. Swelling parameters (water uptake and mass loss) were significantly changed with experimental variables (CP:SA ratio, medium, and time) and were in good correlation with drug release. Conclusion: Matrix tablets based on CP and SA form a potentially useful versatile system for pH-independent controlled drug release.     

Development and Background of Shells Theories-A Review Study

Thin shells are one of the structural elements that have versatile contributions in different engineering sectors,specifically in architectural,civil,mechanical,aeronautical,and marine engineering industries.Liquid-retaining structures,wide-span roofs,water tanks,arch dooms,and shells used in building nuclear power plants are recognized application examples of shell structures in architectural and civil engineering.This variety in using shells in different engineering sectors is due to the productivity of load-carrying behavior,excellent reservation in strength and structural integrity,shell structures are preferable in comparison to structural systems having the same span and dimensions;high stiffness,and covering a large areas.Besides the above distinguishing mechanical pros,it is widely accepted that structures and building containing shells are usually preferred by architectures and designers for aesthetic purposes.The analysis of shells has gone through many stages until the arrival of modern theories.In this study the different theories of shells were discussed,the background and development of shell theories were illustrated in this investigation.     

Development and evaluation of a novel drug delivery: Soluplus®/TPGS mixed micelles loaded with piperine in vitro and in vivo

Background: Although piperine can inhibit cells of tumors, the poor water solubility restricted its clinical application. This paper aimed to develop mixed micelles based on Soluplus^® and D-α-tocopherol polyethylene glycol succinate (TPGS) to improve the aqueous solubility and anti-cancer effect.

Methods: Piperine-loaded mixed micelles were prepared using a thin-film hydration method, and their physicochemical properties were characterized. The cellular uptake of the micelles was confirmed by confocal laser scanning microscopy in A549 lung cancer cells and HepG₂ liver cancer cells. In addition, cytotoxicity of the piperine mixed micelles was studied in A549 lung cancer cells and HepG₂ liver cancer cells. Free piperine or piperine-loaded Soluplus^®/TPGS mixed micelles were administered at an equivalent dose of piperine at 3.2?mg/kg via a single intravenous injection in the tail vain for the pharmacokinetic study in vivo.

Results: The diameter of piperine-loaded Soluplus^®/TPGS (4:1) mixed micelles was about 61.9?nm and the zeta potential –1.16?±?1.06?mV with 90.9% of drug encapsulation efficiency and 4.67% of drug-loading efficiency. Differential scanning calorimetry (DSC) studies confirmed that piperine is encapsulated by the Soluplus^®/TPGS. The release results in vitro showed that the piperine-loaded Soluplus^®/TPGS mixed micelles presented sustained release behavior compared to the free piperine. The mixed micelles exhibited better antitumor efficacy compared to free piperine and physical mixture against in A549 and HepG₂ cells by MTT assay. The pharmacokinetic study revealed that the AUC of piperine-loaded mixed micelles was 2.56 times higher than that of piperine and the MRT for piperine-loaded mixed micelles was 1.2-fold higher than piperine (p?Conclusion: The results of the study suggested that the piperine-loaded mixed micelles developed might be a potential nano-drug delivery system for cancer chemotherapy. These results demonstrated that piperine-loaded Soluplus^®/TPGS mixed micelles are an effective strategy to deliver piperine for cancer therapy.     

Development of zolmitriptan transfersomes by Box–Behnken design for nasal delivery: in vitro and in vivo evaluation

The aim was to prepare an optimized zolmitriptan (ZT)-loaded transfersome formulation using Box–Behnken design for improving the bioavailability by nasal route for quick relief of migraine and further to compare with a marketed nasal spray. Here, three factors were evaluated at three levels. Independent variables include: amount of soya lecithin (X₁), amount of drug (X₂) and amount of tween 80 (X₃). The dependent responses were vesicle size (Y₁), flexibility index (Y₂) and regression coefficient of drug release kinetics (Y₃). Prepared formulations were evaluated for physical characters and an optimal system was identified. Further, in vivo pharmacokinetic study was performed in male wistar rats to compare the amount of drug in systemic circulation after intranasal administration. Optimized ZT-transfersome formulation containing 82.74?mg of lecithin (X₁), 98.37?mg of zolmitriptan (X₂) and 32.2?mg of Tween 80 (X₃) and had vesicle size of 93.3?nm, flexibility index of 20.25 and drug release regression coefficient of 0.992. SEM picture analysis revealed that the vesicles were spherical in morphology and had a size more than 1?µm. The formulations were found to be physically stable upon storage at room temperature up to 2?months period, as there were no significant changes noticed in size and ZP. The nasal bioavailability of optimized transfersome formulation was found to be increased by 1.72 times than that of marketed nasal spray (Zolmist^®). The design and development of zolmitriptan as transfersome provided improved nasal delivery over a conventional nasal spray for a better therapeutic effect.     

Modelling of strain rate effects on matrix dominated elastic and failure properties of unidirectional fibre-reinforced polymer–matrix composites

A phenomenological-based, strain rate dependent failure theory, which is suitable for the numerical modelling of unidirectional (UD) carbon fibre reinforced polymer composites (CFRPs), is presented. A phenomenological-based approach is also proposed for the three-dimensional (3D) modelling of strain rate induced material hardening in UD polymer composites. The proposed theory and approach are implemented in the Finite element (FE) code ABAQUS/Explicit for one integration point solid elements. Validation is presented against experimental data from dynamic compressive tests using results available in the published literature.     

Clotrimazole-loaded Eudragit® RS100 nanocapsules: Preparation,characterization and in vitro evaluation of antifungal activity against Candida species

Clotrimazole is a common choice for the treatment of vulvovaginal infections, but its low solubility and some side effects pose a challenge to its application. This work evaluated the feasibility to formulate clotrimazole-loaded cationic nanocapsules using Eudragit® RS100 and medium chain triglycerides as polymer and oily core, respectively, by the method of interfacial deposition of a preformed polymer. The physicochemical characteristics of nanocapsule formulations were evaluated at 0 day and 60 days after preparation. Particle size, zeta potential, polydispersity index, pH and drug content were stable during this period. In addition, nanocapsules were able to protect clotrimazole from photodegradation under UV radiation. By the dialysis bag diffusion technique, the nanosized formulations showed prolonged release of clotrimazole by anomalous transport and first order kinetics. A microbiological study was carried out by the microdilution method and showed that nanocapsules (mean size: 144 nm; zeta potential: + 12 mV) maintained the antifungal activity of clotrimazole against Candida albicans and Candida glabrata strains susceptible and resistant to fluconazole.     

Operator matrix and non-uniqueness of Beltrami–Schaefer stress functions

Beltrami–Schaefer stress functions are general solutions of the equilibrium equations of an elastic body without body force. In this paper, the representation of the non-uniqueness of these solutions is deduced by converting the equations into operator matrix form—including an operator matrix and its generalized inverse—and then deriving the representation using linear algebra. The completeness of the representation is proved in the process. In addition, the non-uniqueness of Helmholtz’s decomposition of a vector is proved.