The influence of surface modification on the cytotoxicity of PAMAM dendrimers.

The influence of surface modification on the cytotoxicity of PAMAM dendrimers was examined using Caco-2 cells. Dendrimers were modified by conjugating either lauroyl chains or polyethylene glycol (PEG) 2000 onto the surface of cationic PAMAM dendrimers (G2, G3, G4). The cytotoxicity of unmodified dendrimers towards Caco-2 cells was appreciably higher for cationic (whole generation) compared with anionic (half generation) dendrimers and for both types increased with increasing size (generation) and concentration. A marked decrease in the cytotoxicity of cationic PAMAM dendrimers was noted when the surface was modified, with the addition of six lauroyl or four PEG chains being particularly effective in decreasing cytotoxicity. This decrease in cytotoxicity is thought to be due to a reduction/shielding of the positive charge on the dendrimer surface by the attached chains. The cytotoxicity of dendrimer-based delivery systems is likely to be very different from the parent dendrimer.

On-off transport through a thermoresponsive hydrogel composite membrane.

A novel thermoresponsive composite membrane is described through which the permeation of molecules is dependent on the temperature of the milieu. The thermoresponsive composite membranes utilise a thermosensitive crosslinked polymeric hydrogel, which possesses a volume phase transition temperature (VPTT). The hydrogel was polymerised in situ within the pores of a sintered glass filter, through which significant permeation of molecules only occurred at temperatures above the VPTT of the hydrogel. It was found that the permeation of molecules through the thermoresponsive composite membranes could be modulated by changing the environmental temperature.

Polyamidoamine Starburst dendrimers as solubility enhancers.

The solubility of the hydrophobic drug ibuprofen has been compared in an aqueous solution of polyamidoamine (PAMAM) G4 dendrimer and sodium dodecyl sulphate (SDS). The PAMAM G4 dendrimer solution significantly enhanced the solubility of ibuprofen compared to 2% SDS solution. It was found that the solubility of ibuprofen in dendrimer solution was directly proportional to dendrimer concentration and inversely proportional to temperature. The influence of dendrimer solution pH on the solubility enhancement of ibuprofen suggests that it involves an electrostatic interaction between the carboxyl group of the ibuprofen molecule and the amine groups of the dendrimer molecule.

Effect of fabrication technique on the erosion characteristics of polyanhydride matrices.

The aim of this study was to investigate the effect of device fabrication technique on the erosion characteristics of poly[1,3-bis(p-carboxyphenoxy) propane:sebacic acid] [p(CPP:SA)] 20:80 copolymer. Devices were prepared using melt-molding, solvent-casting, and compression-molding techniques and their erosion was followed by determining changes in device morphology, molecular weight, water uptake, mass loss, and release of monomers, with time of immersion in phosphate buffer pH 7.4 at 37 degrees C. Melt-molded devices had a very dense and uniform structure and displayed characteristics typical of surface eroding systems. Devices produced using a solvent-casting technique had a very porous structure with no detectable erosion zone and the erosion profiles were indicative of bulk rather than pure surface erosion. Compression-molded devices had a dense structure and revealed a faster rate of erosion than melt-molded devices. A comparison of the extent of changes of polymer molecular weight, water uptake, mass loss, and monomer release showed a marked dependence on the method of fabrication.

The use of sonication for the efficient delivery of plasmid DNA into cells.

PURPOSE: Ultrasonic methods have considerable potential for the introduction of macromolecules into cells. In this paper we demonstrate that, under controlled conditions, application of 20 kHz ultrasound to a suspension of yeast cells facilitates the delivery of plasmid DNA into these cells. METHODS: Aliquots of growing yeast cells (Saccharomyces cerevisae, strain AH22) were suspended in buffer and exposed to 20 kHz ultrasound from a laboratory (probe-type) sonicator in the presence of microgram quantities of plasmid DNA. Efficiency of DNA delivery was scored as the number of cells transformed. RESULTS: Cell transformation was optimal at 30 seconds sonication using an output of 2.0 watts and resulted in a 20 fold enhancement over control values. At extended sonication times, fewer cells showed evidence of transformation because of reduced cell viability. The increased DNA uptake and the decreased cell viability were both attributable to acoustic cavitation events during sonication. The extent of acoustic cavitation was measured and it was found that there was an increase in cavitation events with increased sonication time. Cell viability was shown to be directly related to the number of cavitation events. The effects of sonication on plasmid DNA were investigated and indicated that the structural integrity of plasmid DNA was unaffected by the sonication conditions employed. CONCLUSIONS: Under controlled conditions, ultrasound is an effective means of delivering plasmid DNA into cells. The subsequent expression of DNA molecules in cells depends upon a balance between transient cell damage and cell death.

Applications of the environmental scanning electron microscope to the analysis of pharmaceutical formulations.

Electron microscopy has been used for several years as a routine tool for the study of pharmaceutical formulations. However, it is usually desirable to obtain information on these systems in the wet state, and there are concerns regarding the interpretation of information provided by conventional electron microscopy where samples are subjected to preparation techniques which may include freezing, drying, fracturing, and coating. The environmental scanning electron microscope (ESEM) has been used to analyse a number of pharmaceutical samples in their natural state. Results obtained from these samples, including biodegradable matrices, microparticulate systems (both degradable and non-biodegradable), and bioadhesive matrices, will be discussed and the merits and limitations of the ESEM will be highlighted.

Responsive polymeric drug delivery systems. Meeting the patient's needs.

Current approaches to the development of drug delivery systems are based typically on the premise that the relationship between the plasma concentration and therapeutic effect of a drug is invariant with time. Release kinetics from these systems are, therefore, usually engineered to be either zero-order or a simple function of time. It has been recognised for some time, however, that this approach may not be appropriate for certain drugs and it has been suggested that therapeutic efficacy may be improved by the utilisation of triggered, pulsed and programmed delivery systems. This article considers an approach to the development of responsive drug delivery system based on the utilisation of functional polymers, which aim to improve therapeutic efficacy by varying drug release in accordance with a patients's varying requirements.

The effect of ultrasound on Escherichia coli viability.

The effect of continuous-wave ultrasound on the viability of Escherichia coli HB101 was assessed using a 20 kHz ultrasonic processor. A standardised cell suspension of fixed concentration was used to investigate the influence of different physical and environmental conditions on ultrasound susceptibility. Cell viability decreased exponentially with time at different intensities of ultrasound. Increasing intensity caused a decrease in decimal reduction times. Loss of cell viability occurred primarily from the mechanical effects of ultrasound rather than free radical damage. E. coli susceptibility was also shown to vary with growth conditions, whereby cells cultivated either on agar or harvested from the stationary phase of liquid culture were significantly more susceptible to ultrasound than an equivalent population obtained from the exponential phase of liquid growth. The implication of these results is discussed in relation to the use of ultrasound as a novel means of bacterial transformation.

A survey of drug treatment and outcomes in diabetic patients with acute myocardial infarcts.

Sixty-four diabetic patients suffering an acute myocardial infarct were retrospectively matched, by age, gender and smoking habit, to non-diabetic controls. The two groups were compared for cardiovascular risk factors, pre-admission and discharge drug treatment, in-hospital drug treatment, and complication and mortality rates. Hypertension was more prevalent in the diabetic (63%) than in the control (42%) group. When comparing drugs on admission to those at discharge, there was a significant increase in antiplatelet and nitrate usage in both groups (P < 0.001), in beta-blocker usage in the control group (P < 0.001) and in loop diuretic usage in the diabetic group (P < 0.001). The usage of angiotensin converting enzyme inhibitors was low: 16% of diabetic patients and 5% of controls at discharge. Thrombolytic therapy was used in 29 diabetics and 37 controls. There was a significantly higher complication rate in the diabetic group than in the control group (P < 0.006), the most common being congestive cardiac failure (59% vs 30%, P < 0.001). Four controls and 13 diabetic patients died; three of the latter had their diabetes diagnosed during the admission. This study did not clearly demonstrate any underlying risk factors or treatment variables to account for the increased morbidity or mortality in diabetic patients with acute myocardial infarct, when compared to a matched non-diabetic population. However, modest associations not detected by this relatively small study are still possible.

Molecular weight changes in polymer erosion.

We report a study of the effects of polymer molecular weight on the erosion of polyanhydride copolymer matrices composed of 1,3-bis(p-carboxyphenoxy)-propane (CPP) and sebacic acid (SA) in aqueous solution. The erosion profile characteristically displays an induction period during which the erosion rate is relatively slow. The length of this period depends on the initial molecular weight of the polymer. The induction period may be characterized as a time during which a rapid decrease in polymer molecular weight occurs, the end of this period correlating with the time required for the polymer molecular weight to decrease to below a value of approximately 5000 (MW).

An electrically modulated drug delivery device. III. Factors affecting drug stability during electrophoresis.

A number of factors affecting the stability of propranolol HCl during electrophoretic control were investigated. It was found that significant degradation of propranolol HCl and hydrolysis of water occurred when a current of 15 mA was used with platinized electrodes. This degradation was thought to be due to decomposition of propranolol HCl at the electrodes. Degradation could be significantly reduced by using uncoated platinum electrodes and currents in the range of 0 to 2.5 mA, while still allowing control of drug delivery rates. Electrode reaction processes were found at high ionic strengths and high drug concentrations but were not thought to be associated with drug decomposition.

An electrically modulated drug delivery device. II. Effect of ionic strength, drug concentration, and temperature.

The effects of various physicochemical parameters on the changes in drug delivery rate produced by an electrophoretic current are examined using a model system. It was shown that ionic strength has an inverse relationship with the change in delivery rate produced by a given current. Small changes in pH were measured during electrophoresis experiments which were considered to be insignificant. Drug reservoir concentration selection is critical in the design of an electrophoretic device and is based on achieving a balance between providing a suitable reservoir and allowing adequate electrophoretic control. Electrophoretic control is affected by temperature in a manner which can be predicted using the Arrhenius relationship. The low power requirements of the model system demonstrate the feasibility of using the principle of electrophoresis to control drug delivery rates in a therapeutic system.

An electrically modulated drug delivery device: I.

A controlled drug delivery device based on the principle of electrophoresis is described. A model system using propranolol HCl and PHEMA films was used to demonstrate how control over the release of a model drug may be achieved using low constant electric currents. It was found that a linear relationship existed between electric current and drug delivery rate. Additionally, two main effects of applying an electric current during the lag period of delivery from the system were identified. First, the drug delivery rate was less when a current was applied before the lag period had expired, and second, the voltage-time profiles were found to be significantly different. The model shows the feasibility of using an electrophoretically controlled drug delivery device to provide truly controllable and predictable release rates.