Controlled release formulation of ranitidine-containing montmorillonite and Eudragit® E-100

Aim: The objective of this work was to illustrate the suitability of montmorillonite (MMT) as a drug delivery carrier, by developing a new clay–drug composite of ranitidine hydrochloride (RT) intercalated in MMT. Methods: The MMT–RT composite was prepared by ion-exchange process. X-ray diffraction and Fourier transform infrared spectra were employed to confirm the intercalation of RT in the MMT interlayers. The prepared MMT–RT hybrid was coated with cationic polymer Eudragit® E-100 by oil-in-water solvent evaporation method. The release processes of RT from MMT–RT and MMT–RT/Eudragit® E-100 were monitored under in vitro condition in the gastric fluid. Results: X-ray diffraction and Fourier transform infrared spectra analysis indicated the intercalation of RT molecules within the clay lattice. The in vitro release studies showed that MMT–RT released RT in a controlled manner. In the case of MMT–RT/Eudragit® E-100, both the release rate and the release percentages noticeably increased in the presence of Eudragit® E-100, because of its effective exchange with intercalated RT molecules. The release kinetics followed parabolic diffusion mechanism. Conclusion: MMT has great potential as a drug delivery carrier with various scenarios. The dosage of the MMT–RT/Eudragit® E-100 can be in the tablet form. The hybrid material and polymer-coated hybrids are microparticles.     

Mechanical Properties of LaRCTM-IA and ULTEM® Melt-Extruded Fibers and Melt-Pressed Films

LaRCTM-IA, the polyimide prepared with 3,4-oxydianiline (3,4-ODA) and oxydiphthalic anhydride (ODPA), is useful as a film, coating, adhesive, and composite matrix. The high temperature capability and fire-resistance of polyimides also makes them attractive candidates for textile fibers for a variety of uses in the automotive, chemical, and aerospace industries. This research describes for the first time the melt-spinning of phthalic anhydride endcapped LaRCTM-IA and the effects of processing conditions on the mechanical properties of slightly-drawn fibers. Average draw ratios varied from 1 to 3.9. Tensile strengths ranged from 103 to 159 MPa; moduli ranged from 2.80 to 3.21 GPa; elongations at break ranged from 14 to 103%. For comparison, tensile properties of compression-molded films prepared at the same temperatures are also reported. Melt-extruded fibers and melt-pressed films of another thermoplastic, ULTEM®, were also fabricated. ULTEM® fibers exhibited tensile strengths ranging from 138 to 207 MPa for average draw ratios of 4.5 to 10.3. Moduli ranged from 2.70 to 3.22 GPa. Elongations at break ranged from 47 to 111%.     

Thermal stability and nonisothermal kinetics of Folnak® degradation process

Aim: The purpose of this article is to investigate the thermal stability and nonisothermal kinetics of Folnak® drug degradation process using different thermoanalytical techniques. Methods: The nonisothermal degradation of Folnak® powder samples was investigated by simultaneous thermogravimetry–differential thermal analysis, in the temperature range from ambient to 810°C. Results: It was found that the degradation proceeds through five reaction stages, which include the dehydration, the melting process of excipients, the decomposition of folic acid, corn starch, and saccharose. The presence of compounds such as excipients increases the thermal stability of the drug and some kind of solid–solid and/or solid–gas interaction occurs. Conclusion: It was concluded that the main degradation stage of Folnak® sample represents the decomposition of folic acid. It was established that the folic acid decomposition cannot be explained by simple reaction order model (n = 1) but with the complex reaction mechanism that includes higher reaction orders (n > 1). The isothermal predictions of the folic acid decomposition at four different temperatures (T_iso = 180°C, 200°C, 220°C, and 260°C) were established. It was concluded that the shapes of conversion curves at lower temperatures (180–200°C) were similar, whereas they became more complex with further temperature increase because of the complexity of the decomposition reaction.     

Hydration of Nafion® studied by AFM and X-ray scattering

Nafion® is a commercially available perfluorosulphonate cation exchange membrane commonly used as a perm-selective separator in chlor-alkali electrolysers and as the electrolyte in solid polymer fuel cells. This usage arises because of its high mechanical, thermal and chemical stability coupled with its high conductivity and ionic selectivity, which depend strongly on the water content. The membrane was therefore studied in different states of hydration with two complementary techniques: atomic force microscopy (AFM) and small angle X-ray scattering (SAXS) combined with a maximum entropy (MaxEnt) reconstruction. Tapping mode phase imaging was successfully used to identify the hydrophobic and hydrophilic regions of Nafion. The images support the MaxEnt interpretation of a cluster model of ionic aggregation, with spacings between individual clusters ranging from 3 to 5 nm, aggregating to form cluster agglomerates with sizes from 5 to 30 nm. Both techniques indicate that the number density of ionic clusters changes as a function of water content, and this explains why the bulk volumetric swelling in water is observed to be significantly less than the swelling inferred from scattering measurements.     

Ramizol® encapsulation into extended release PLGA micro- and nanoparticle systems for subcutaneous and intramuscular administration: in vitro and in vivo evaluation

Objective: Novel antibiotic Ramizol^® is advancing to clinical trials for the treatment of gastrointestinal Clostridium difficile associated disease. Despite this, previous studies have shown a rapid plasma clearance upon intravenous administration and low oral bioavailability indicating pure drug is unsuitable for systemic infection treatment following oral dosing. The current study aims to investigate the development of poly-lactic-(co-glycolic) acid (PLGA) particles to overcome this limitation and increase the systemic half-life following subcutaneous and intramuscular dosing.

Significance: The development of new antibiotic treatments will help in combatting the rising incidence of antimicrobial resistance.

Methods: Ramizol^® was encapsulated into PLGA nano and microparticles using nanoprecipitation and emulsification solvent evaporation techniques. Formulations were analyzed for particle size, loading level and encapsulation efficiency as well as in vitro drug release profiles. Final formulation was advanced to in vivo pharmacokinetic studies in Sprague–Dawley rats.

Results: Formulation technique showed major influence on particle size and loading levels with optimal loading of 9.4% and encapsulation efficiency of 92.06%, observed using emulsification solvent evaporation. Differences in formulation technique were also linked with subsequent differences in release profiles. Pharmacokinetic studies in Sprague–Dawley rats confirmed extended absorption and enhanced bioavailability following subcutaneous and intramuscular dosing with up to an 8-fold increase in T_max and T_1/2 when compared to the oral and IV routes.

Conclusions: Subcutaneous and intramuscular dosing of PLGA particles successfully increased systemic half-life and bioavailability of Ramizol^®. This formulation will allow further development of Ramizol^® for systemic infection eradication.     

Evaluation of emcocel® 50 and emcocel® 90, a new excipient in direct compression

Abstract

The tabletting properties of a new microcrystalline cellulose product, Emcocel® 50 and Emcocel® 90 were evaluated and compared with the tabletting properties of Avicel® PH 101. The evaluation of placebo tablets, of the dilution potential, of formulations with active compounds as Aspirin, Phenobarbital and a spraydried extract in high concentrations showed that Emcocel® has comparative tabletting properties in regard of Avicel® PH 101.     

Evaluation of in vitro bioactivity and biocompatibility of Bioglass®-reinforced polyethylene composite

The bioactivity and biocompatibility of Bioglass®-reinforced high-density polyethylene composite (Bioglass®/HDPE) have been evaluated in simulated body fluid (SBF) and by in vitro cell culture, respectively. The formation of a biologically active hydroxy-carbonate apatite (HCA) layer on the composite surface after immersion in SBF was demonstrated by thin-film X-ray diffraction, infrared spectroscopy and scanning electron microscopy, indicating the in vitro bioactivity of Bioglass®/HDPE composites. The HCA layer was formed on the 40 vol% composite surface within 3 days immersion in SBF at a formation rate comparable to those on bioactive glass-ceramics, showing that in vitro bioactivity could be obtained in a composite. Furthermore, the composite was biocompatible to primary human osteoblast-like cells. In comparison with unfilled HDPE and tissue culture plastic control, a significant increase in cellular metabolic activity was found on the composite. Therefore, Bioglass®/HDPE composites have a promising biological response as a potential implant material.     

Free volume and mechanical properties of Palacos® R bone cement

The free volume and the mechanical properties of Palacos® R bone cement were determined from positron annihilation lifetime spectroscopy (PALS) and from dynamic mechanical thermal analysis (DMA) in the temperature ranges 24–220 °C and 30–120 °C, respectively. The heating of bone cement caused an appreciable reduction of the free volume, measured as a decrease in the ortho-positronium lifetime ₃ from 2.04 to 1.91 ns, as well as a clear increase in the storage modulus from 2.3 to 3.0 GPa. The changes in free volume and storage modulus after the heat treatment were interpreted as an effect of elimination of residual monomer from the bone cement. The free volume of the bulk-polymerized phase of bone cement was estimated from a simple difference method, suggesting that the residual monomer was eliminated from the bone cement between 60 and 90 °C, thus implying a glass transition temperature of only 60 °C for the bulk-polymerized phase. The spherical free volume cavity size estimated from the ortho-positronium lifetime V(₃), and the storage modulus E_storage from DMA measurements were found to correlate by a linear relationship throughout the studied temperature range, and the correlation appeared to be independent of the presence of residual monomer.     

Biodegradation of hydrophilic–hydrophobic hydrogels and its effect on albumin release

The objective of this study was to examine the effects of composition ratio of a new class of bicomponent biodegradable hydrogels and the molecular weights of the constituents on the hydrolytic degradability of the hydrogels and their release of bovine serum albumin (BSA). Biodegradable hydrogels were prepared from dextran derivative of allyl isocyanate (dex-AI) and poly (D,L) lactide diacrylate macromer (PDLLAM) over a wide range of dex-AI to PDLLAM composition ratio. The results obtained indicated that the hydrolytic degradation of these biodegradable hydrogels could be controlled by adjusting the composition ratio of dex-AI to PDLLAM or by changing their molecular weights. Along with the hydrogel degradation, water content of the hydrogels changed, and 3D porous network structure was observed. Generally, as the PDLLAM composition in the hydrogels increased, the rate of weight loss increased due to the hydrolytic degradation of the PDLLAM. The increase in molecular weights of either dex-AI or PDLLAM would decrease the degradation rate of the dex-AI/PDLLAM hydrogels. BSA release data correlated well with the hydrogel degradation profiles, suggesting that the extent and rate of BSA release would be mainly controled by hydrogel degradation. As the PDLLAM composition in the hydrogel increased, the extent and rate of BSA release also increased. An increase in the molecular weights of the hydrogel constituents, however, led to a decrease in BSA release.     

Nonlinear viscoelasticity of Hydrothane®

The nonlinear viscoelastic behaviour of Hydrothane^®, a hydrophilic polyurethane used for biomedical applications, has been studied. The material has been tested in stress-relaxation experiments in a range of deformation up to 25%. Isochrone curves have been predicted by using the rubber elasticity theory and separating strain and time effect. Stress-strain curves obtained at different strain rates have been interpreted introducing strain rate dependent scaling factors.This paper was accepted for publication after the 1995 conference of the European Society of Biomaterials, Oporto, Portugal, 10–13 September.     

The story of Bioglass®

Historically the function of biomaterials has been to replace diseased or damaged tissues. First generation biomaterials were selected to be as bio-inert as possible and thereby minimize formation of scar tissue at the interface with host tissues. Bioactive glasses were discovered in 1969 and provided for the first time an alternative; second generation, interfacial bonding of an implant with host tissues. Tissue regeneration and repair using the gene activation properties of Bioglass provide a third generation of biomaterials. This article reviews the 40 year history of the development of bioactive glasses, with emphasis on the first composition, 45S5 Bioglass, that has been in clinical use since 1985. The steps of discovery, characterization, in vivo and in vitro evaluation, clinical studies and product development are summarized along with the technology transfer processes.     

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.     

Processing and bioactivity of 45S5 Bioglass®-graphene nanoplatelets composites

Well dispersed 45S5 Bioglass^® (BG)-graphene nanoplatelets (GNP) composites were prepared after optimising the processing conditions. Fully dense BG nanocomposites with GNP loading of 1, 3 and 5 vol% were consolidated using Spark plasma sintering (SPS). SPS avoided any structural damage of GNP as confirmed using Raman spectroscopy. GNP increased the viscosity of BG-GNP composites resulting in an increase in the sintering temperature by ~50 °C compared to pure BG. Electrical conductivity of BG-GNP composites increased with increasing concentration of GNP. The highest conductivity of 13 S/m was observed for BG-GNP (5 vol%) composite which is ~9 orders of magnitude higher compared to pure BG. For both BG and BG-GNP composites, in vitro bioactivity testing was done using simulated body fluid for 1 and 3 days. XRD confirmed the formation of hydroxyapatite for BG and BG-GNP composites with cauliflower structures forming on top of the nano-composites surface. GNP increased the electrical conductivity of BG-GNP composites without affecting the bioactivity thus opening the possibility to fabricate bioactive and electrically conductive scaffolds for bone tissue engineering.     

Influence of the preparation procedure and chitosan type on physicochemical properties and release behavior of alginate–chitosan microparticles

Background: The potential for use of chitosan-treated alginate microparticles as a vehicle for oral phenytoin delivery has not been thoroughly exploited. Aim: We studied the influence of preparation procedure and chitosan type on physicochemical properties and release behavior of alginate-chitosan microparticles. Method: The total number of 24 microparticles formulations prepared by varying contents of calcium gelling ions and varying contents and type of chitosan was examined. As an additional variable, two different hardening times (1 and 24 hours) were employed. Possible interactions of components, surface morphology of microparticles as well as release profile of phenytoin were studied. Results: Both series of formulations with regard to hardening times, irrespective of the chitosan type and/or concentration employed appeared to be highly loaded with the model drug (above 90%). The drug release studies showed that the kinetics of phenytoin cannot be straightforwardly predicted based on the molecular weight of chitosan alone. On the other hand, prolonging the hardening time from 1 to 24 hours had significantly improved phenytoin kinetics, and gave rise to a formulation with the liberation half-time of about 2.5 hours. Conclusion: This study showed that the latter formulation is eligible for further modifications aimed at improving the regularity of phenytoin absorption.     

Permeation and skin retention of quercetin from microemulsions containing Transcutol® P

A microemulsion for the cutaneous release of quercetin was prepared. An aqueous phase, containing 40% Transcutol(?) P as solubilizing agent and permeation enhancer, was emulsified with Labrafil(?) as oil phase and Labrasol(?)/Capryol(?) 90 as Solvent/Co-solvent. Quercetin was dissolved in the microemulsion at the concentration of 1%. Ternary phase diagrams were generated to determine the optimal concentration of each excipient composing the microemulsion. The physicochemical properties of the microemulsion, such as pH, viscosity, refractive index, and particle size distribution were determined. The microemulsion was stable for 12 months at the storing conditions of 25.0 ± 1.0°C. The in vitro quercetin permeability into and through the abdominal hairless pig skin was determined by vertical Franz's cells. Quercetin showed hardly any permeability through the skin when dissolved in water- and Transcutol(?) P-free media, whereas a remarkable increase in cutaneous permeability was observed when quercetin was formulated in the microemulsion or when simply dissolved in Transcutol(?) P. These two last formulations are those showing the lower skin retention.     

The Use of Precirol® to Prepare Sustained Release Tablets of Theophylline and Quinidine Gluconate

Abstract

Tablets were made using theophylline, lactose and Precirol by a granulation technique, resulting in more than 12 hours release. Granulation and hot fusion methods were used to prepare admixtures of quinidine gluconate and Precirol at different ratios of Precirol: drug, 1:9, 3:7 and 1:1. Dissolution studies in 0.1N HCl showed drastic differences in the release of quinidine gluconate from tablets made by the two different methods; granulation method gave a faster release while the hot fusion method gave slower and incomplete release at higher Precirol content. The release rate decreases with higher Precirol content.     

Modeling Temperature in Coupled Electrical and Thermal Simulations of the Electroconsolidation® Process

Electroconsolidation® is a process for densifying complex-shaped parts by using electrically conductive particulate solids as a pressure-transmitting medium. The part is immersed in a bed of the particulate medium contained in a die chamber. Sintering temperature is achieved by resistive heating of the medium while applying compaction pressure. The process is capable of ultrahigh temperatures and short cycle times and offers the potential for low processing costs. Control of the process and selection of process conditions require knowledge of the temperatures within the die. Temperature gradients exist because of the high heating rate and because of variations of density and electrical resistivity of the medium due to the presence of the part. Direct measurement of temperature with thermocouples or other conventional means is impractical because of the high temperatures, high currents, and high pressures that are involved. Therefore, a computer model was developed to predict temperature as a function of time and applied voltage for any location in the die. The computer model is composed of three parts: a geometrical model to approximate the density and resistivity variations in the medium, a finite-element model to calculate the rate of resistive heating within each element, and a finite-difference model to calculate the temperature distribution based on solution of the heat-transfer equations. Predicted temperatures have been shown to be in excellent agreement with measurements, and numerical simulation provided encouraging consistency and reasonably accurate predictions of temperature profiles within the die. The model demonstrated the feasibility of a new process to achieve simultaneous application of pressure and heat to powder densification in Electroconsolidation.     

Fabrication of a PLGA-collagen peripheral nerve scaffold and investigation of its sustained release property in vitro

This study deals with the fabrication of a peripheral nerve scaffold prepared with poly (lactic acid -co- glycolic acid) [PLGA] and acellularized pigskin collagen micro particles and the investigation of its sustained release property in vitro. We took bovine serum albumin [BSA] as model drug to investigate the sustained-release property of the scaffold in vitro. The results showed the scaffold could release BSA steadily with a rate of 6.6 ng/d (r = 0.994) or so. In a 1-month test period, the accumulative release ratio of BSA from the scaffold was up to 43%, and the shape of the scaffold was still originally well kept. In addition, the scaffold outcome non-immunogenicity, good cell adhesion and biodegradability. The results indicated a scaffold constructed by this technique would be a potential implanting support with prolonged sustained release function, such as for the use of nerve scaffold.