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A taster of science research advances

A selection of some of the research work presented by pharmaceutical scientists at the science podium presentations is reported here.

Dendrimers to enhance drug absorption for poorly soluble drugs

Mohammed Najlah, of the University of Manchester, reports on the evaluation of polyamidoamine dendrimers as drug carriers to enhance the permeability, hence oral absorption, of drugs that are substrates for P-glycoprotein efflux transporters.

The influence of the dendrimer prodrugs on the integrity and viability of human Caucasian colon adenocarcinoma cells (Caco-2) was determined by measuring the transepithelial electrical resistance and leakage of lactate dehydrogenase. The permeability coefficient of terfenadine and conjugates through Caco-2 cell monolayers was measured.

The dendrimers had no impact on the viability of Caco-2 cells up to a concentration of 1 mM, but an increase in the apparent permeability coefficient of terfenadine was demonstrated. The results suggest that these dendrimers have potential as nanocarriers for the enhancement of oral bioavailability of poorly soluble drugs such as terfenadine.

Dynamic molecular modelling of cysteamine prodrugs and beta-cyclodextrin

Research by Don Cairns, of the Robert Gordon University, has focused on more reliable and acceptable dosage forms for cysteamine prodrugs in the treatment of nephropathic cystinosis.

Dynamic molecular modelling was used extensively to speed up the evaluation process for putative drug products using commercially available software. In particular the effect of beta-cyclodextrin on the aqueous solubility of five prodrugs with different drug:cyclodextrin ratios was evaluated. Optimised molecular models were constructed for prodrug and beta-cyclodextrin and for the corresponding complexes.

The results suggest that beta-cyclodextrin may be a good enhancer of aqueous solubility for this series of prodrugs, and that increasing the number of cyclodextrin molecules in the model yields a more favourable binding enthalpy. The most hydrophobic of the compounds studied (according to its calculated partition coefficient) displayed the most favourable binding enthalpy.

Microneedles for pain-free injection

One of the purported advantages of the use of microneedles for the transdermal delivery of medicines is that the stimulation of underlying pain receptors or blood vessels is avoided.

M. I. Haq, of the Welsh School of Pharmacy, describes studies specifically designed to test this point. Twelve participants were randomised to receive on their buttocks two types of microneedle array (36 pyramidal microneedles of either 180µm or 280µm height) and a 25-gauge subcutaneous hypodermic needle.

A visual analogue scale measured the pain experienced (from “no pain” to “worst pain imaginable”) following application of each device. The hypodermic caused significantly more pain than the 180µm and 280µm needle arrays, but there was no significant difference between the two microneedles.

The study demonstrated that microneedles indeed represent a less painful method for disrupting skin barrier properties than the conventional hypodermic.

Terahertz spectroscopy for quality control of film-coated tablets

The quality of tablet film coating is a crucial factor for complex dosage forms and a non-destructive means of assessing the coat thickness is desirable, particularly where process analytical technology is embraced.

Louise Ho, of the University of Otago, New Zealand, reports on the first application of terahertz pulsed imaging to the analysis of coating quality. Terahertz pulsed imaging operates and obtains information in the 2 to 120cm-1 range. In this range, most pharmaceutical excipients are semi-transparent, thus allowing the non-destructive investigation and accurate determination of the thickness of the coating-layer.

It was concluded that terahertz pulsed imaging affords non-destructive, detailed coating analysis on a range of aspects of coating quality.

Aerosol delivery of amphotericin B

Satyanarayana Somavarapu, of the University of London School of Pharmacy, reports on an investigation of the antifungal activity of chitosan-enriched liposomes produced from amphotericin B proliposomes.

The surface charge of liposomes produced in the presence of chitosan showed positive values indicating the existence of chitosan on the surface of liposomes. Inclusion of chitosan had a minor effect on the mean liposome size while chitosan coating markedly enhanced amphotericin B loading following hydration.

Chitosan-free liposomes loaded with amphotericin B had activities against Candida albicans similar to a comparator preparation, amphotericin B desoxycholate. The antifungal activity of amphotericin B was enhanced four-fold with chitosan-enriched liposomes.

The study demonstrated that amphotericin B can be efficiently incorporated into lipsomes produced by hydrating proliposomes with chitosan solutions. Chitosan coating of liposomes enhanced in vitro antifungal activity of amphotericin B, and the resultant formulations were efficiently delivered from a medical nebuliser.

A new method for rapid, reliable and effective polymorph screening

Polymorphism can be a major issue in the development of new drugs, and yet current state-of-the-art methods are not underpinned by any rigorous theory.

Jonathan Burley, of De Montfort University, reports a constrained crystallisation method which allows an enforcement of Ostwald’s Rule of Stages. This well-established rule states that a crystallising system moves towards equilibrium (the most stable crystal polymorph) in stages corresponding to metastable polymorphs.

By reducing the number of degrees of freedom available to the crystallising system, it is possible to force the system to move to equilibrium in well-defined stages and thereby fully characterise its polymorphic behaviour.

Implementation of this new theory resulted in the ready isolation of all three polymorphs of paracetamol, not previously achieved using state-of-the-art high-throughput methods.

Typical experiment times for the new experimental protocol were of the order of minutes, with sample sizes of a milligram or less. This small sample size is important for early-stage screens, when only a small amount of the development drug is usually available.

Local delivery of AZT nanoparticles

Oral AZT therapy is effective in managing HIV infection. However the poor bioavailability of AZT in the brain requires large doses to be administered. The need for localised drug delivery is evident, as this will lower the dose administered, eliminating systemic side effects. Particle size determination and surface morphology of the nanoparticles enables optimisation of the nanoparticles formulated.

S. Harilall, of the University of Witwatersrand, Johannesburg, reports on the preparation of AZT-loaded and drug-free nanoparticles using controlled gelification of alginate. Fourier-transform infrared spectroscopy indicated a change in the molecular assemblage of both the nanoparticles and the scaffold due to surface interactions occurring during the preparation process.

However, the basic polymeric structure of the parent compounds was maintained. Drug release studies indicated first-order kinetics from the nanoparticles with 100 per cent being released within four hours. Incorporation of nanoparticles into the polymeric scaffold significantly retarded drug release to less than 4 per cent after four hours, while inducing a mixture of upcurving and zero-order kinetics.

Thus, nanoparticle incorporation into a multipolymeric scaffold restricts AZT release, allowing for the development of a controlled release drug delivery system for site-specific administration of AZT to manage AIDS dementia complex.

Citation: The Pharmaceutical Journal URI: 10004906

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