Gillian M. Eccleston

Validation of a static Franz diffusion cell system for in vitro permeation studies.

Over the years, in vitro Franz diffusion experiments have evolved into one of the most important methods for researching transdermal drug administration. Unfortunately, this type of testing often yields permeation data that suffer from poor reproducibility. Moreover, this feature frequently occurs when synthetic membranes are used as barriers, in which case biological tissue-associated variability has been removed as an artefact of total variation. The objective of the current study was to evaluate the influence of a full-validation protocol on the performance of a tailor-made array of Franz diffusion cells (GlaxoSmithKline, Harlow, UK) available in our laboratory. To this end, ibuprofen was used as a model hydrophobic drug while synthetic membranes were used as barriers. The parameters investigated included Franz cell dimensions, stirring conditions, membrane type, membrane treatment, temperature regulation and sampling frequency. It was determined that validation dramatically reduced derived data variability as the coefficient of variation for steady-state ibuprofen permeation from a gel formulation was reduced from 25.7% to 5.3% (n = 6). Thus, validation and refinement of the protocol combined with improved operator training can greatly enhance reproducibility in Franz cell experimentation.

Structure and rheology of semisolid O/W creams containing cetyl alcohol/Non-Ionic surfactant mixed emulsifier and different polymers

Oil‐in‐water (o/w) emulsions for cosmetic use, such as lotions and creams, are complex multiple‐phase systems, which may contain a number of interacting surfactants, fatty amphiphiles, polymers and other excipients. This study investigates the influence of two synthetic cationic polymers, Polyquaternium‐7 and Polyquaternium‐11, and the natural anionic polymer, gum of acacia, on the rheology and microstructure of creams prepared with a non‐ionic mixed emulsifier (cetyl stearyl alcohol‐12EO/cetyl alcohol) using rheology (continuous shear, and viscoelastic creep and oscillation), microscopy and differential scanning calorimetry (DSC). A control cream containing no polymer was also investigated. The semisolid control cream was structured by a swollen lamellar gel network phase formed from the interaction of cetyl alcohol and the POE surfactant, in excess of that required to stabilize oil droplets, with continuous phase water. Endothermic transitions between 25 and 100 °C were identified as components of this phase. Incorporation of cationic polymer into the formulation caused significant loss of structure to produce a mobile semisolid containing larger oil droplets. The microscopical and thermal data implied that the cationic polymer caused the swollen lamellar gel network phase to transform into non‐swollen crystals of cetyl alcohol. In contrast, incorporation of gum of acacia produced a thicker cream than the control, with smaller droplet sizes and little evidence of the gel network. Microscopical and thermal data implied that although there were also interactions between gum of acacia and both the surfactant and the swollen gel network phase, the semisolid properties were probably because of the ability of the gum of acacia to stabilize and thicken the emulsion in the absence of the swollen lamellar network.

Characterisation of freeze-dried wafers and solvent evaporated films as potential drug delivery systems to mucosal surfaces.

Freeze-dried (lyophilised) wafers and solvent cast films from sodium alginate (ALG) and sodium carboxymethylcellulose (CMC) have been developed as potential drug delivery systems for mucosal surfaces including wounds. The wafers (ALG, CMC) and films (CMC) were prepared by freeze-drying and drying in air (solvent evaporation) respectively, aqueous gels of the polymers containing paracetamol as a model drug. Microscopic architecture was examined using scanning electron microscopy, hydration characteristics with confocal laser scanning microscopy and dynamic vapour sorption. Texture analysis was employed to investigate mechanical characteristics of the wafers during compression. Differential scanning calorimetry was used to investigate polymorphic changes of paracetamol occurring during formulation of the wafers and films. The porous freeze-dried wafers exhibited higher drug loading and water absorption capacity than the corresponding solvent evaporated films. Moisture absorption, ease of hydration and mechanical behaviour were affected by the polymer and drug concentration. Two polymorphs of paracetamol were observed in the wafers and films, due to partial conversion of the original monoclinic to the orthorhombic polymorph during the formulation process. The results showed the potential of employing the freeze-dried wafers and solvent evaporated films in diverse mucosal applications due to their ease of hydration and based on different physical mechanical properties exhibited by both type of formulations.

Development and mechanical characterization of solvent-cast polymeric films as potential drug delivery systems to mucosal surfaces

Solvent-cast films from three polymers, carboxymethylcellulose (CMC), sodium alginate (SA), and xanthan gum, were prepared by drying the polymeric gels in air. Three methods, (a) passive hydration, (b) vortex hydration with heating, and (c) cold hydration, were investigated to determine the most effective means of preparing gels for each of the three polymers. Different drying conditions [relative humidity – RH (6–52%) and temperature (3–45°C)] were investigated to determine the effect of drying rate on the films prepared by drying the polymeric gels. The tensile properties of the CMC films were determined by stretching dumbbell-shaped films to breaking point, using a Texture Analyser. Glycerol was used as a plasticizer, and its effects on the drying rate, physical appearance, and tensile properties of the resulting films were investigated. Vortex hydration with heating was the method of choice for preparing gels of SA and CMC, and cold hydration for xanthan gels. Drying rates increased with low glycerol content, high temperature, and low relative humidity. The residual water content of the films increased with increasing glycerol content and high relative humidity and decreased at higher temperatures. Generally, temperature affected the drying rate to a greater extent than relative humidity. Glycerol significantly affected the toughness (increased) and rigidity (decreased) of CMC films. CMC films prepared at 45°C and 6% RH produced suitable films at the fastest rate while films containing equal quantities of glycerol and CMC possessed an ideal balance between flexibility and rigidity.

A Comparative Study of Transmembrane Diffusion and Permeation of Ibuprofen across Synthetic Membranes Using Franz Diffusion Cells

Synthetic membranes used in Franz diffusion cells for topical formulation quality assessment should provide least resistance to drug diffusion. In this study, the diffusion rates of ibuprofen across thirteen membranes were determined using Franz diffusion cells. Correlation of the membrane thickness, pore size and MWCO with drug fluxes was also made. The drug diffusion results showed that the porous membranes were categorized into high-flux (8–18 mg/cm2/h) and low-flux (0.1–3 mg/cm2/h) membranes. The drug fluxes did not show strong correlations (r2 < 0.99) with membrane parameters. Synthetic membranes can give variable drug fluxes, thus investigators should be careful in choosing membrane for formulation quality assessment.

In vitro drug release studies of polymeric freeze-dried wafers and solvent-cast films using paracetamol as a model soluble drug

Drug dissolution and release characteristics from freeze-dried wafers and solvent-cast films prepared from sodium carboxymethylcellulose (CMC) have been investigated to determine the mechanisms of drug release from the two systems. The formulations were prepared by freeze-drying (wafers) or drying in air (films), the hydrated gel of the polymer containing paracetamol as a model soluble drug. Scanning electron microscopy (SEM) was used to examine differences between the physical structure of the wafers and films. Dissolution studies were performed using an exchange cell and drug release was measured by UV spectroscopy at 242 nm. The effects of drug loading, polymer content and amount of glycerol (films) on the release characteristics of paracetamol were investigated. The release profiles of paracetamol from the wafers and films were also compared. A digital camera was used to observe the times to complete hydration and dissolution of the wafers containing different amounts of CMC and how that impacts on drug release rates. Both formulations showed sustained type drug release that was modelled by the Korsmeyer-Peppas equation. Changes in the concentration of drug and glycerol (films) did not significantly alter the rate of drug release while increasing polymer content significantly decreased the rate of drug release from both formulations. The results show that the rate of paracetamol release was faster from the wafers than the corresponding films due to differences in their physical structures. The wafers which formed a porous network, hydrated faster than the more dense and continuous, (non-porous) sheet-like structure of the films.

Synchrotron X-ray investigations into the lamellar gel phase formed in pharmaceutical creams prepared with cetrimide and fatty alcohols

Semisolid liquid paraffin-in-water emulsions (aqueous creams) prepared from cetrimide/fatty alcohol mixed emulsifiers, and ternary systems formed by dispersing the mixed emulsifier in controlled percentages of water were examined as they aged using a combination of low and high angle X-ray diffraction measurements (Daresbury Laboratory Synchrotron Radiation Source). The results were correlated with the rheological properties measured in earlier studies. The cationic emulsifying wax showed phenomenal swelling in water. The reflection that incorporates interlamellar water increased continuously from 74 A at 28% water to over 500 A at 93% water. The trend was not influenced by the method of incorporation of the components and swollen lamellar phase was also identified in the corresponding emulsion. The swelling, which was due to electrostatic repulsion, was suppressed by salt and was reduced when the surfactant counterion was changed from Br(-) to Cl(-). Changes in rheological properties on storage and in the presence of salt were correlated with changes in water layer thickness. High angle diffraction confirmed that the hydrocarbon bilayers were in the hexagonal alpha-crystalline mode of packing. Ternary systems and creams prepared from pure alcohols, although initially semisolid, were rheologically unstable and broke down. Low angle X-ray study into the kinetics of structure breakdown showed that the swollen lamellar gel phase formed initially swells even further on storage before separating.

Formulation, stability and thermal analysis of lyophilised wound healing wafers containing an insoluble MMP-3 inhibitor and a non-ionic surfactant

Lyophilised wafers are being developed as topical drug delivery systems for the treatment of chronic wounds. This study describes the formulation of xanthan wafers containing a selective, insoluble MMP-3 inhibitor (UK-370,106) and a non-ionic surfactant, designed to release accurate doses of UK-370,106 directly to a suppurating wound bed. Stability of UK-370,106 in the wafer compared to a non-lyophilised gel suspension was investigated using a combination of light scattering, thermal and microscopic techniques. Particle size distributions in UK-370,106-loaded wafers were constant throughout an accelerated stability study (12 weeks, 40 degrees C) while the mean particle size in a non-lyophilised suspension increased by 15 microm in the same period. Thermal analysis of UK-370,106-loaded wafers highlighted an unexpected interaction between the drug and the surfactant that was further investigated using simple mixtures of each component. It was concluded that an in situ solvate of UK-370,106 and the non-ionic surfactant can form and that this may have implications towards the stability of UK-370,106 during the formulation process. Further concerns regarding high water contents (14%) in the wafer and its effect on product stability were unfounded and it was concluded that these novel delivery systems provided a viable alternative to gel suspensions.

Microstructural Changes During the Storage of Systems Containing Cetostearyl Alcohol/Polyoxyethylene Alkyl Ether Surfactants

AbstractNon-ionic emulsifying wax/water ternary systems composed of water, cetostearyl alcohol and non-ionic polyoxyethylene alkyl ether surfactants (R-(OCH2CH2)AOH with polyoxyethylene (POE) chain lengths, A, varying from 10-30 and R = cetostearyl were examined as they aged for several weeks. The technigues employed included Theological (Ferranti-Shirley cone and plate viscometer), microscopical (brightfield and between crossed polars), thermal (thermogravimetry and D.S.C) and ultracentrifuqation.The rheological properties of the samples were complex. They confirmed, however, that all ternary systems increased in consistency on storage. For each ternary system apparent viscosities (Oapp) increased as the samples aged. In addition, ternary systems prepared with surfactants with long POE chains were generally of a higher consistency than similar ternary systems containing shorter POE chains.Each ternary system was considered to be composed of crystalline and gel (Lβ), phases dispersed in bulk (free) water....

Phase transitions in ternary systems and oil-in-water emulsions containing cetrimide and fatty alcohols

Abstract Differential scanning calorimetry (D.S.C.) was used to investigate phase transitions in stable and unstable emulsions prepared with cetrimide/fatty alcohols. Ternary systems, formed by interacting cetrimide and fatty alcohol in water and chosen to represent the continuous phases of the corresponding emulsions, were also investigated. Stability was followed using rheological techniques. The ternary systems prepared from each alcohol showed similar properties to the corresponding emulsions. All systems were semisolid immediately after preparation. Thus flow curves were in the form of anticlockwise hysteresis loops and apparent viscosities high. On storage, the cetostearyl alcohol systems remained semisolid and stable, whereas the pure alcohol systems became mobile and emulsions eventually separated. In unstable systems, flow curves changed and apparent viscosities reduced. The D.S.C. data for each ternary system gave similar transitions to those of the corresponding emulsion. In the stable cetostearyl alcohol ternary system and emulsion, two broad endotherms were present. These did not alter over the 30-day testing period. In contrast, the unstable pure alcohol ternary systems and emulsions, showed several endothermic transitions, which changed as systems aged and became mobile. The D.S.C. results correlated well with microscopic and rheological experiments from previous work. They imply that emulsion continuous phases, formed from the interaction of cetrimide and fatty alcohol in water can exist in several forms, each