Young Bin Choy

Controlled release of donepezil intercalated in smectite clays.

The inorganic-organic hybrid for a drug delivery system was successfully realized by intercalating donepezil molecules into smectite clays (laponite XLG, saponite, and montmorillonite). According to the powder XRD patterns, TG profiles, and FT-IR spectra, it was confirmed that donepezil molecules were well stabilized in the interlayer space of clay via mono or double layer stacking. The adsorption amount and molecular structure of donepezil appeared to depend on the cation exchange capacity of the clay, which in turn, tailored the drug release patterns. Especially in the presence of a bulky cationic polymer (Eudragit E-100) in the release media, the release rate was found to be improved due to its effective replacement with intercalated donepezil molecules. Therefore, to formulate a complete drug delivery system, the hybrids were coated with Eudragit E-100 using a spray dryer, which also showed great enhancement in the release rate during a short period of time (180min).

A microneedle roller for transdermal drug delivery

Microneedle rollers have been used to treat large areas of skin for cosmetic purposes and to increase skin permeability for drug delivery. In this study, we introduce a polymer microneedle roller fabricated by inclined rotational UV lithography, replicated by micromolding hydrophobic polylactic acid and hydrophilic carboxy-methyl-cellulose. These microneedles created micron-scale holes in human and porcine cadaver skin that permitted entry of acetylsalicylic acid, Trypan blue and nanoparticles measuring 50nm and 200nm in diameter. The amount of acetylsalicylic acid delivered increased with the number of holes made in the skin and was 1-2 orders of magnitude greater than in untreated skin. Lateral diffusion in the skin between holes made by microneedles followed expected diffusional kinetics, with effective diffusivity values that were 23-160 times smaller than in water. Compared to inserting microneedles on a flat patch, the sequential insertion of microneedles row by row on a roller required less insertion force in full-thickness porcine skin. Overall, polymer microneedle rollers, prepared from replicated polymer films, offer a simple way to increase skin permeability for drug delivery.

The Rule of Five for Non-Oral Routes of Drug Delivery: Ophthalmic, Inhalation and Transdermal

ABSTRACTThe Rule of Five predicts suitability of drug candidates, but was developed primarily using orally administered drugs. Here, we test whether the Rule of Five predicts drugs for delivery via non-oral routes, specifically ophthalmic, inhalation and transdermal. We assessed 111 drugs approved by FDA for those routes of administration and found that >98% of current non-oral drugs have physicochemical properties within the limits of the Rule of Five. However, given the inherent bias in the dataset, this analysis was not able to assess whether drugs with properties outside those limits are poor candidates. Indeed, further analysis indicates that drugs well outside the Rule of Five limits, including hydrophilic macromolecules, can be delivered by inhalation. In contrast, drugs currently administered across skin fall within more stringent limits than predicted by the Rule of Five, but new transdermal delivery technologies may make these constraints obsolete by dramatically increasing skin permeability. The Rule of Five does appear to apply well to ophthalmic delivery. We conclude that although current non-oral drugs mostly have physicochemical properties within the Rule of Five thresholds, the Rule of Five should not be used to predict non-oral drug candidates, especially for inhalation and transdermal routes.

In-vivo measurement of swine myocardial resistivity

We used a four-terminal plunge probe to measure myocardial resistivity in two directions at three sites from the epicardial surface of eight open-chest pigs in-vivo at eight frequencies ranging from 1 Hz to 1 MHz. We calibrated the plunge probe to minimize the error due to stray capacitance between the measured subject and ground. We calibrated the probe in saline solutions contained in a metal cup situated near the heart that had an electrical connection to the pigs heart. The mean of the measured myocardial resistivity was 319 /spl Omega//spl middot/cm at 1 Hz down to 166 /spl Omega//spl middot/cm at 1 MHz. Statistical analysis showed the measured myocardial resistivity of two out of eight pigs was significantly different from that of other pigs. The myocardial resistivity measured with the resistivity probe oriented along and across the epicardial fiber direction was significantly different at only one out of the eight frequencies. There was no significant difference in the myocardial resistivity measured at different sites.

Using electrical impedance to predict catheter-endocardial contact during RF cardiac ablation

During radio-frequency (RF) cardiac catheter ablation, there is little information to estimate the contact between the catheter tip electrode and endocardium because only the metal electrode shows up under fluoroscopy. We present a method that utilizes the electrical impedance between the catheter electrode and the dispersive electrode to predict the catheter tip electrode insertion depth into the endocardium. Since the resistivity of blood differs from the resistivity of the endocardium, the impedance increases as the catheter tip lodges deeper in the endocardium. In vitro measurements yielded the impedance-depth relations at 1, 10, 100, and 500 kHz. We predict the depth by spline curve interpolation using the obtained calibration curve. This impedance method gives reasonably accurate predicted depth. We also evaluated alternative methods, such as impedance difference and impedance ratio.

Mucoadhesive Microdiscs Engineered for Ophthalmic Drug Delivery: Effect of Particle Geometry and Formulation on Preocular Residence Time

PURPOSEnTo test the hypothesis that mucoadhesive microdiscs formulated in a rapidly dissolving tablet can increase preocular residence time.nnnMETHODSnMicroparticles smaller than 10 mum in diameter were fabricated by emulsification with poly(lactic-co-glycolic acid) as a core material and, in some cases, poly(ethylene glycol) as a mucoadhesion promoter. To examine the effect of particle geometry, microparticles were also cut to have flat surfaces (i.e., microdiscs) and were compared with spherical particles (i.e., microspheres). In vitro mucoadhesion of microparticles was tested on a mucous layer under shear stress, mimicking the human blink. The resultant microparticles were also formulated in two dosage forms, an aqueous suspension and a dry tablet, to test the effect of formulation on the retention capacity of microparticles on the preocular space of rabbits in vivo.nnnRESULTSnMucoadhesive microdiscs adhered better to the simulated ocular surface than did other types of microparticles. When a dry tablet embedded with mucoadhesive microdiscs was administered in the cul-de-sac of the rabbit eye in vivo, these microdiscs exhibited longer retention than the other formulations tested in this study. More than 40% and 17% of mucoadhesive microdiscs remained on the preocular surface at 10 minutes and 30 minutes after administration, respectively. Fluorescence images from the eye surface showed that mucoadhesive microdiscs remain for at least 1 hour in the lower fornix.nnnCONCLUSIONSnThis study demonstrated that mucoadhesive microdiscs formulated in a dry tablet can achieve a prolonged residence time on the preocular surface and thus are a promising drug delivery system for ophthalmic applications.

Monodisperse Gelatin Microspheres as a Drug Delivery Vehicle: Release Profile and Effect of Crosslinking Density

Uniform gelatin microspheres (GMS) of a wet size of 100 microm in diameter were fabricated by the electric field assisted precision particle fabrication (E-PPF) method and crosslinked with different glutaraldehyde (GA) concentrations to study the effect of the crosslinking density on drug release. The drug release profiles of the crosslinked GMS were studied along with the intraparticle drug distribution and the particle degradation characteristics. Due to the concentration gradient of GA along the diffusion path into the GMS, the crosslinking density is higher on the GMS surface, making it less susceptible to degradation. As a result, the GMS with higher GA concentrations (0.375-0.875%) exhibited a highly resistant surface toward enzymatic degradation. On the other hand, the amount of drug complexation at the surface decreases as the GA concentration increases, which can be attributed to the lowered basicity of gelatin caused by the increased crosslinking density. These factors collectively affect the drug release kinetics and give rise to similar release profiles for GMS above a GA concentration of 0.375%.

Flow effect on lesion formation in RF cardiac catheter ablation

This study investigated the flow effect on the lesion formation during radio-frequency cardiac catheter ablation in temperature-controlled mode. The blood flow in heart chambers carries heat away from the endocardium by convection. This cooling effect requires more power from the ablation generator and causes a larger lesion. The authors set up a flow system to simulate the flow inside the heart chamber. They performed in vitro ablation on bovine myocardium with three different flow rates (0 L/min, 1 L/min and 3 L/min) and two target temperatures (60/spl deg/C and 80/spl deg/C). During ablation, the authors also recorded the temperatures inside the myocardium with a three-thermocouple temperature probe. The results show that lesion dimensions (maximum depth, maximum width and lesion volume) are larger in high flow rates (p<0.01). Also, the temperature recordings show that the tissue temperature rises faster and reaches a higher temperature under higher flow rate.

A nanofibrous sheet-based system for linear delivery of nifedipine

We developed a nanofibrous sheet-based system to achieve linear release of nifedipine for oral delivery. The nanofibrous sheets of micro-porosity were fabricated by the electrospinning method, using a biocompatible polymer, poly (lactic-co-glycolic acid). The sheets were then used as a drug diffusion barrier by capping and sealing a compressed tablet, composed of nifedipine and a solubility enhancer, polyvinylpyrrolidone. The nanofibrous sheets of different thicknesses were prepared to vary the rate of drug diffusion in this work. In vitro drug release study revealed that as the sheet thickness increased, drug release was more retarded, where a lag phase of drug release became more evident. We were to realize linear drug release by combining two distinctly capped tablets, each showing a different drug release, which exhibited an almost linear release of nifedipine during 24h (R(2)>0.986). The drug release profile was not influenced by the pH of the release media as the morphological structure of nanofibrous sheets was seen to be not very different at both pHs 1.2 and 6.8. Therefore, we conclude that a combination of two tablets, each capped with nanofibrous sheets of different thickness, is a promising system for linear delivery of oral drug.

Lesion size estimator of cardiac radiofrequency ablation at different common locations with different tip temperatures

Finite element method (FEM) analysis has become a common method to analyze the lesion formation during temperature-controlled radiofrequency (RF) cardiac ablation. We present a process of FEM modeling a system including blood, myocardium, and an ablation catheter with a thermistor embedded at the tip. The simulation used a simple proportional-integral (PI) controller to control the entire process operated in temperature-controlled mode. Several factors affect the lesion size such as target temperature, blood flow rate, and application time. We simulated the time response of RF ablation at different locations by using different target temperatures. The applied sites were divided into two groups each with a different convective heat transfer coefficient. The first group was high-flow such as the atrioventricular (AV) node and the atrial aspect of the AV annulus, and the other was low-flow such as beneath the valve or inside the coronary sinus. Results showed the change of lesion depth and lesion width with time, under different conditions. We collected data for all conditions and used it to create a database. We implemented a user-interface, the lesion size estimator, where the user enters set temperature and location. Based on the database, the software estimated lesion dimensions during different applied durations. This software could be used as a first-step predictor to help the electrophysiologist choose treatment parameters.