A continuous flow method for estimation of drug release rates from emulsion formulations.

We present a continuous-flow method that allows the release of drugs from submicron colloidal carriers to be estimated on a millisecond timescale. The technique is applied to the study of release of a model drug (tetracaine) from lipid emulsions, and shows that the solute drug is released in this timescale, and thus is primarily controlled by the rapid diffusion of the drug within the oil droplet. This confirms our previous claims that existing methods, such as dialysis or centrifugation, are too slow to provide useful release data for drug-containing emulsions, and demonstrates that it is unlikely that a simple emulsion could be used as a circulating sustained-release formulation, as has been suggested by some workers.

Self-assembling peptides and their potential applications in biomedicine.

For many years, peptides have been known to self-assemble to form nano- and micro-scale structures. Their nature of assembly and assembled morphology has since been investigated as this area of research has important implications for the development of both drug delivery and tissue regeneration. In this article, we explore the process of peptide self-assembly in vivo, and experiments that exploit the structures formed. Particular focus is directed towards diphenylalanine, the simplest self-assembling peptide, which generally forms tube-like structures on assembly. In addition, different peptides that may assemble into a range of other morphologies are highlighted and potential applications in regenerative medicine and drug delivery discussed.

Solubilisation of model adjuvants by Pluronic block copolymers.

The effect of two model adjuvants (benzyl benzoate and benzyl alcohol) on the structure and dynamics of three Pluronic triblock copolymers (P85, P105 and F127) was studied using small-angle neutron scattering and pulsed-field gradient NMR. The two adjuvants studied have different aqueous solubilities. It was found that both adjuvants promoted the micellisation of the Pluronic block copolymers. In addition they lead to a swelling of the micelles, as shown by small-angle neutron scattering. From the pulsed-field gradient NMR results it was possible to determine the amount of adjuvant bound to the micelles.

Structural behaviour of 2-hydroxypropyl-beta-cyclodextrin in water: molecular dynamics simulation studies.

PURPOSE: To investigate the effect of 2-hydroxypropyl side group substitutions on the structure of beta-cyclodextrin (CD) in water. METHODS: Molecular dynamics simulations were carried out on four HPBCDs that broadly represent a range of degree of substitutions in order to investigate the effect of substitution of beta-cyclodextrin with 2-hydroxypropyl groups at various O2 and O6 positions of the glucose units. RESULTS: The 2-hydroxypropyl side groups located at the O2 positions widen the cavity entrance at the secondary OH position of the CD molecule. These groups are spatially more spread out but dynamically more restricted, due to the formation of a hydrogen bond network between the hydroxyl groups of the side chains and the glucose units. On the other hand, the 2-hydroxypropyl groups at the O6 positions are dynamically more flexible. CONCLUSIONS: The extent and the location of the substitution can affect the cavity structure of the CD molecule, and thus possibly the molecular encapsulation capabilities.

Design and evaluation of an emulsion vehicle for paclitaxel. II. Suppression of the crystallization of paclitaxel by freeze-drying technique.

Although paclitaxel is soluble in vitamin E up to 40 mg per g, crystallization was detected at loadings higher than 15 mg per g. Water appeared to be an important factor causing the observed crystallization, and therefore, a freeze-drying technique was investigated to produce reconstitutible vitamin E emulsions, to increase drug loading without crystal formation after reconstitution. The emulsion was freeze-dried using a laboratory freeze-drier and the droplet size was measured using dynamic light scattering. The freeze-dried emulsions using sucrose as a cryoprotectant could be easily reconstituted. The loading of paclitaxel in the freeze-dried emulsions could be increased to 25 mg per g of vitamin E without crystal formation, and the mean emulsion droplet size remained smaller than 0.2 mum over 430 days (4 +/- 2 degrees C). The previously observed surfactant-enhanced crystallization could also be suppressed using the freeze-drying technique.

Design and evaluation of an emulsion vehicle for paclitaxel. I. Physicochemical properties and plasma stability.

PURPOSE: The current formulation of paclitaxel contains ethanol and Cremophor EL and has been reported to cause serious adverse reactions. The purpose of the present work was to develop an improved emulsion vehicle for paclitaxel and to study the physicochemical properties of such a system. METHODS: Emulsions were prepared by either microfluidization or sonication method and the droplet size characterized by dynamic light scattering and light microscopy. RESULTS: Stable emulsions could be made using mixtures of lecithin/sodium deoxycholate as the emulsifiers. The formulation was further improved by using a combination of free acid and the sodium salt. Paclitaxel could be loaded into the emulsions at 2.5 mg/ml without the formation of drug crystals. While these emulsions were stable on storage, they flocculated when mixed with plasma. Steric stabilization of the emulsion droplets with poloxamer 188 increased the stability of the emulsions in plasma but promoted the crystallization of paclitaxel. The crystallization tendency could be reduced by using PEG5000PE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[poly (ethylene glycol) 5000]), a less water-soluble stabilizer. CONCLUSIONS: Emulsions with good stability characteristics containing 2.5 mg/ml paclitaxel could be made using bile salt/acid and lecithin, and the excellent stability of these emulsions in plasma was achieved by steric stabilization using PEG5000PE.

A concentric cylinder shear device for the study of stability in intravenous emulsions.

This paper introduces the use of a concentric cylinder shear device for studying the stability of intravenous emulsions under shear, and examines the relationship between shearing conditions and the emulsion droplet size and distribution, as characterised by laser diffraction and optical counting. Theoretically, the device generated flow in the Taylor region, but a linear relationship between the natural log mean droplet diameter and time, which was observed at all shear rates, suggested that coalescence kinetics could be treated in a manner analogous to laminar flow. An order of magnitude increase in coalescence rate was achieved within the shear rate range examined (2802-6164 s(-1)), yet irrespective of shear rate, the particle size distribution evolved a similar multi-peak pattern with common secondary peaks at 1.8 and 3.8 microm. This pattern was similar to that observed during shake testing of the emulsion. In emulsions destabilised with increasing concentrations of NaCl, a shear-dependent threshold was observed above which there was a marked increase in coalescence. This threshold behaviour also occurred on shake testing, and it appears to be analogous to the critical coagulation concentration observed when shear testing of suspension. The concentric cylinder device allows a variable shear rate to be applied in a precise and controlled way and therefore represents an advance over shake testing. Emulsions of differing stability may be examined, and the technique has application in the study of emulsion behaviour and stability under shear, and potentially in accelerated stability studies.