Production of nabumetone nanoparticles: Effect of molecular weight, concentration and nature of cellulose ether stabiliser.

The ability of a range of hydrophilic nonionic cellulose ethers (CEs) (namely methylhydroxethylcellulose, hydroxypropylmethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose and hydroxypropylcellulose) to prepare stable nabumetone nanoparticles (<1000nm, as measured by laser diffraction) using wet-bead milling has been investigated. Due to the limited range of CE molecular weights commercially available, the CEs were degraded using ultrasonication for varying lengths of time to yield CEs of lower molecular weight. Of the CEs tested, only hydroxyethylcellulose was found not to stabilise the production of nabumetone nanoparticles at any of the molecular weights tested, namely viscosity average molecular weights (Mv) in the range of 236-33kg/mol. All other CEs successfully stabilised nabumetone nanoparticles, with the lower molecular weight/viscosity polymers within a series being more likely to result in nanoparticle production than their higher molecular weight counterparts. Unfortunately due to the nature of the ultrasonication process, it was not possible to compare the size of nabumetone particles produced using polymers of identical Mv. There was, however, enough similarity in the Mv of the various polymers to draw the general conclusion that there was no strong correlation between the Mv of the various polymers and their ability to produce nanoparticles. For example hydroxypropylcellulose of 112.2kg/mol or less successfully produced nanoparticles while only ethylhydroxyethylcellulose and hydroxypropylmethyl polymers of 52 and 38.8kg/mol or less produced nanoparticles. These results suggest that polymer molecular weight is not the only determinant of nanoparticle production and that structure of the polymer is at least as important as its molecular weight. In particular the hydrophobic nature of the CE was thought to be an important factor in the production of nabumetone nanoparticles: the more hydrophobic the polymer, the stronger its interaction with nabumetone and the greater its ability to produce nanoparticles. In this context HPC was the most hydrophobic polymer and HEC the least hydrophobic.

Manufacturing high quality urinary catheters.

Forty-four percent of hospital patients with indwelling catheters can develop significant bacteriuria within 72 hours of catheterisation. It is, therefore, critical that catheters are manufactured with perfectly smooth surfaces and apertures to reduce the potential for infection. An ultrasonic cutting technology is described here that produces smooth apertures and eliminates problems associated with debris.

Using ultrasonic technology to manufacture products.

The use of ultrasonics in medical device manufacturing is gaining momentum as designers and engineers take advantage of the benefits it offers. A number of example medical applications are described that demonstrate the utility of ultrasonic processing in their manufacturer.

Effects of plasma irradiation on the wettability and dissolution of compacts of griseofulvin.

In this study, the use of plasma irradiation was investigated as a possible technique for increasing the dissolution rate of the poorly soluble drug griseofulvin. Plasma is a partially ionised gas consisting of ions, electrons and neutral species. Oxygen plasma was used to treat griseofulvin compacts as this would lead to the formation of oxygen containing functional groups on the surface of the compact thus increasing the wettability. Compacts containing 300 mg of the drug were prepared using a stainless steel punch and die assembly and plasma treated. The effect of the length and power of the plasma treatment upon the dissolution rate of griseofulvin was investigated. Dissolution experiments of griseofulvin were carried out using the paddle method using 0.1 M HCl and 0.1 M HCl with 2% sodium dodecyl sulphate (SDS) as the dissolution media. The wettability was assessed by contact angle measurements using the sessile drop technique with the contact angle being measured every second for a period of ten seconds using pure water (to European Pharmacopoeia standards). Plasma treated and untreated samples were also analysed by scanning electron microscopy. Although plasma treatment was found to increase the wettability of griseofulvin it was not found to increase the dissolution rate as the treatment caused surface fusion of the material.

Effects of oxygen plasma treatment on the surface wettability and dissolution of furosemide compacts.

The plasma irradiation of furosemide (frusemide) was investigated as a possible technique for increasing the dissolution rate of this drug. Oxygen plasma was used to generate oxygen-containing functional groups on the surface of the compact to increase the wettability of the surface and the dissolution rate of the drug. Compacts of furosemide (300 mg) were produced using a stainless steel die and punch assembly, which was placed into a KBr press. The time of the plasma treatment was varied to assess the effect if any upon the dissolution rate and the wettability of the drug. Dissolution experiments of the plasma-treated and untreated compacts were carried out using the paddle apparatus method. Dissolution was carried out at 37 degrees C using 1 L of 0.1 M HCl and phosphate buffer (pH 6). The wettability was assessed by contact angle measurements using the sessile drop technique. Untreated and plasma-treated samples were analysed by scanning electron microscopy at x 5000 magnification. Plasma treatment was found to lower the equilibrium contact angle from approximately 50 to 35 degrees but the dissolution rate was not significantly affected. This was attributed to fusion of the surface by the plasma treatment.

Enhancing oral absorption in animals.

Optimizing absorption can present unique demands in many animal studies because where dose-response linearity and high tissue exposure levels are required, doses may be greater than when administered for therapeutic effect. At the same time, investigative molecular constructs designed to enhance potency and specificity can have features that militate against efficient absorption. Pre-treatment or formulation to optimize absorption may be warranted. This article reviews various physicochemical approaches employed for absorption enhancement. Strategies based on capitalizing or neutralizing physiological processes are also discussed, as there is much current interest in exploiting novel non-invasive routes to deliver medicinal agents.

The release of 5-fluorouracil from microspheres of poly(epsilon-caprolactone-co-ethylene oxide).

The purpose of this study was to evaluate the in vitro release of 5-fluorouracil from microspheres prepared using a novel triblock copolymer of epsilon-caprolactone and ethylene oxide as the encapsulating material. Microspheres of poly(epsilon-caprolactone-co-ethylene oxide) were prepared by employing the "hot-melt" method of microencapsulation. Microspheres were sized using sieve analysis and scanning electron microscopy (SEM). Release studies were performed using a custom-made rotating paddle dissolution apparatus. Copolymer microspheres, fabricated by the hot melt method were shown by electron microscopy to have smooth, nonporous surfaces. Drug-loaded microspheres were found to have a broad distribution of sizes, which was thought to be a consequence of the wide range of crystal sizes of the encapsulated unmilled drug. Nonlinear release kinetics were observed from microspheres in the size fraction 75-250 microns, with a pronounced "burst release" associated with the presence of drug at the surface of the microspheres. A specific delineation of the drug release mechanism was not possible due to rapid gelation, swelling, and subsequent dissolution of the microspheres that occurred on hydration. This work describes the preparation of microspheres that swell rapidly and coalesce together on hydration, accompanied by rapid drug release and copolymer dissolution over a 2-hr period.

The use of a hydrophobic matrix for the sustained release of a highly water soluble drug.

An experimental investigation into the use of a hydrophobic matrix to control the release of a highly water soluble drug was undertaken. Matrices consisting of hydrogenated vegetable oil and calcium sulfate with a 4% drug loading showed a sustained-release profile of up to 24 hr. The release mechanism from such matrices seemed to obey both root time kinetics and first-order behavior. Investigations showed that the effect of geometry had a significant effect on the drug release rate.

Solubility parameter and oral absorption.

The solubility parameter (delta) for a series of structurally diverse compounds was determined using a group contribution method devised by Fedors, and then related to the degree of oral absorption. Solubility parameter values around 22.5 MPa1/2 were shown to be associated with compounds that were well absorbed, whereas, compounds with a high delta (30-40 MPa1/2) showed poor absorption. A correlation was also evident between the number of H-bonding acceptor groups in a compound and the extent of oral absorption. Surprisingly, when C Log P values were used in comparison, no obvious correlation existed. The conclusion from this work is that the solubility parameter may be a more reasonable predictor of absorption than using C Log P values.

The release of 5-fluorouracil from a swellable matrix of a triblock copolymer of epsilon-caprolactone and ethylene oxide.

PURPOSE: The purpose of this study was to investigate the influence of hydration characteristics on the in vitro release of 5-fluorouracil from a swellable matrix prepared using a novel triblock copolymer of poly(epsilon-caprolactone) and poly(oxyethylene). METHODS: Matrices were prepared by dry compression of mixtures of the drug and copolymer using low compressional forces. Release studies were performed using a custom made rotating basket dissolution apparatus. The positions of the eroding and swelling fronts within the matrices during hydration were monitored using freeze fracture scanning electron microscopy. RESULTS: Analysis of the release data revealed a predominantly diffusion controlled mechanism. Observations of the swelling characteristics of the copolymer matrices on immersion in Sørensen's buffer at pH 7.4 revealed gel formation and preferential swelling in the radial direction with visible erosion of the matrix after 4h. During hydration, a gradual increase in gel layer thickness was noted prior to the erosion and eventual dissolution of the matrix. CONCLUSIONS: This study demonstrates a means of differentiating the relative importance of the swelling characteristics in determining the release mechanism and subsequent release rate from swellable matrices.