Geoffrey Lee

Use of a model lipid matrix to demonstrate the dependence of the stratum corneum's barrier properties on its internal geometry

Abstract An attempt was made to confirm the relative importance of the stratum corneums internal geometry and extracellular lipid permeability for its barrier properties. Drug diffusivity, D lip , was first measured in a structured matrix composed of model stratum corneum lipids by using a simple release model. Although the values obtained depended on the lipid composition, they all lie within the range 10 −9 –10 −8 cm 2 /s and must be considered as spatially-averaged values over all existing bilayer orientations. The effective drug diffusivity, D eff , within excised human stratum corneum was then determined from permeation data using the applicable solution to the diffusion equation for an isotropic membrane. From these two results it was possible to calculate an experimental ratio of D lip to D eff of 6.6 × 10 3 . This value is considered to be greater than unity by reason of the internal geometry of the stratum corneum, where an extended diffusional pathlcngth and reduced diffusional area exist when compared with an isotropic membrane. A model was then developed to simulate the influence of the internal geometry of the stratum corneum on D / D eff , where D is now diffusivity within the extracellular lipid pathway. The model is tailored specifically to allow variation of those dimensions thought to be of importance for drug permeation, i.e. stratum corneum thickness and lipid content, as well as corneocyte diameter and thickness. The theoretical values for D / D eff obtained with this model lie in the range 10 2 –10 4 and, hence, can account for the experimentally determined value of D lip / D eff . The simple model and methods adopted in this study thus provide a useful insight into the stratum corneums barrier properties. Clearly, many questions are left unanswered, for example, the importance of anisotropic diffusional relaxation within the extracellular lamellar lipid structure.

Relating the concentration-dependent action of Azone and dodecyl-L-pyroglutamate on the structure of excised human stratum corneum to changes in drug diffusivity, partition coefficient and flux☆

Abstract The concentration-dependent effects of the two lipophilic permeation enhancers Azone and dodecyl- L -pyroglutamate (dlp) on excised human stratum corneum have been examined. Stratum corneum (SC) memranes were prepared having enhancer loadings within the range 0–30% w/w, and transport and structural experiments conducted with them. The permeation of the model drug diazepam through the enhancer-loaded SC membranes was measured, and drug diffusitives, partition coefficients and fluxes determined. For this calculation, a non-steady state model for permeation through an isotropic membrane valid for non-sink boundary conditions was used. With enhancer loadings up to approx. 12% w/w, the diffusitive increased whilst the partition coefficient remained constant. The diffusivity apparebtly decreased at higher loadings. Careful consideration of the results indicated that the application of the model at high enhancer loadings was questionable. By using differential scanning calorimetry, it was found that the skin lipid ‘melting’ peak progressively disappeared with increasing loading with enhancer. This occurred with approx. 12% Azone; for dlp, more than 25% was required. At high enhancer loadings, crystallized dodecyl- L -pyroglutamate was detected within the stratum corneum preparation. The concentration dependence of these changes in stratum corneum structure and barrier properties could be compared to those found previously with insoluble monolayers of skin lipids.

Diffusivity and structural polymorphism in some model stratum corneum lipid systems

Mixtures of model stratum corneum lipids were prepared in water from cholesterol, six fatty acids and ceramides. The influence of composition on the polymorphism of these mixtures and also on the diffusivity of a model drug within them, Dlip, was determined. The former was obtained from X-ray diffraction and Fourier transform infrared spectrometry, and the latter from a diffusional release model. An L beta structure was formed for the composition approximating that of the extracellular lipids in intact human abdominal stratum corneum. Dlip was independent of water content in the range 20-40% w/w, with the bilayers showing one dimensional swelling without lateral expansion. Although removal of the ceramides did not result in a significant alteration in Dlip, crystalline cholesterol now appeared. The ceramides were, therefore, necessary for solubilization within the fatty acid bilayers of the large proportion of cholesterol present in the lipid fraction of intact SC. They were also responsible for a thermal L alpha-HII transition observed at approx. 68 degrees. At the concentration in which it exists in intact SC, cholesterol also had only a minimal effect on Dlip, but was necessary to suppress HII phase formation within the fatty acids and ensure an L beta structure. All lipid mixtures that had an L beta structure presented a diffusional barrier approx. 1 order of magnitude greater than that of an unstructured, isotropic lipid mixture. HII structures formed at cholesterol/fatty acid proportions less than approx 8:92 mol% and appeared more permeable than L beta ones. All the results indicate that the diffusional barrier within the model lipid mixtures is guaranteed essentially by the presence of an L beta phase. Although the ceramides and cholesterol exert no intrinsic influence on the magnitude of Dlip, their presence in necessary for the existence of an L beta phase at 33 degrees that is free of both crystalline cholesterol and HII character.

Levitated single-droplet drying: case study with itraconazole dried in binary organic solvent mixtures.

The objective of this case study of the single-droplet drying of two itraconazole/polymer formulations was to determine how the solvent system influences drying rate and dried particle morphology. A clear dual functionality of the two solutes could be identified. The polymeric component (PVP or HPMC) determined drying rate, whereas the drug determined end particle morphology. This could be related to solubilities of the two components in the binary solvent mixtures used. The formulation of a surface skin early on in drying only occurred with HPMC and strongly influenced drying rate but not dried particle morphology.

An X-ray diffraction study of some model stratum corneum lipids containing Azone and dodecyl-L-pyroglutamate

Abstract The effects of the lipophilic permeation enhancers Azone and dodecyl- l -pyroglutamate (dlp) on some model stratum comeum lipids have been examined using small angle X-ray diffraction and differential scanning calorimetry. A matrix composed only of six fatty acids showed an endothermic transition at 43°C, below which a diffraction pattern characteristic of a mixed hexagonal and lamellar structure was seen. Combining the fatty acids with cholesterol and ceramides shifted the endothermic transition up to 54°C. The diffraction pattern now indicated a lamellar structure below this temperature, with a primary reflection at 6.5 nm. The addition of up to 30% w/w Azone or dip strongly attenuated the mainly hexagonal periodicity of the fatty acid matrix, although the d-spacing was only altered (decreased) with dlp. The lamellar periodicity of the fatty acid/cholesterol/ceramide matrix was attenuated much less by the enhancers. In this case, an initial small decrease in d-spacing with Azone could also be detected. The temperature and enthalpy of the fatty acid matrixs endothermic transition were continually reduced with increasing enhancer concentrations, whereas those for the fatty acid/ cholesterol/ceramide system were hardly altered. Higher concentrations of enhancer dispersed completely the hexagonal diffraction pattern of the fatty acid matrix, leaving only lamellar periodicity. It was evident that both Azone and dlp were intercolated into the lipid structures and induced lateral swelling. These findings could be explained on the basis of the shapes of the enhancer molecules, which have large interfacial areas and head groups compared with their alkyl chain volumes.

Measurement of drug diffusivity in stratum corneum membranes and a polyacrylate matrix

Abstract Diffusivities have been determined for the drug clenbuterol for three non-sink, diffusional problems: diffusion out of a polymer matrix, diffusion through excised, human stratum corneum, and the combined case of diffusion out of a polymer matrix through contiguous, excised stratum corneum. Numerical solution of the diffusion equation for these problems yields theoretical values of drug mass in the acceptor phase, m a ( t ) th , vs time. Diffusion was then measured experimentally and the best value for diffusivity obtained by comparing the values of drug mass in the acceptor phase, m a ( t ) exp , with the corresponding m a ( t ) th data. In this fashion it was possible to obtain diffusivities for diffusion out of the polymer matrix for various values of drug loading and matrix thickness. For the problem of diffusion through stratum corneum a value for the partition coefficient of clenbuterol as well as for its diffusivity could be determined. The two diffusivities obtained for the combined model (i.e., D m within the matrix and D s within the stratum corneum) agree quite well with those obtained for the two separate problems, but are more scattered. Partition coefficients could not be accurately determined for diffusion out of the matrix or the combined problem.

An improved diffusion/compartmental model for transdermal drug delivery from a matrix-type device

Abstract A mathematical model is presented for the description of transdermal drug delivery from a matrix-type delivery device. The model is partly diffusional and partly compartmental in nature. The matrix and stratum corneum are both considered to be diffusion layers, connected to a three-compartment model representing the viable epidermis/dermis, plasma, and peripheral tissues. The diffusion equation was solved numerically for the two diffusion layers under non-sink conditions. The ordinary differential equations for the comparamental model were also solved numerically. Combination of the two numerical solutions yielded a model which directly relates the properties of the matrix to the profile of drug mass in the plasma and the urinary excretion profile. The model was first used to analyse data obtained from an in vivo trial of a matrix-type transdermal delivery device for the drug clenbuterol. Fitting of the model to the profile of drug concentration in the plasma, the urinary excretion profile, and the mass of drug remaining in the matrix with a modified simplex method yielded values for the model constants. These compared very favourably with independent values taken from the literature. Simulations of the influences of drug diffusivity within the stratum corneum, drug loading in the matrix, matrix thickness and drug diffusivity within the matrix on the profile of drug concentration in the plasma were then made. The model is not restricted to a steady state nor does it specify particular drug release kinetics from the matrix. It does assume isotropic diffusion layers and spontaneous partitioning at boundaries.

The influence of endogenous surfactant on the structure and drug-release properties of Eudragit NE30D-matrices

The influence of an endogenous surfactant present in Eudragit NE30D on the structure and drug release (clenbuterol) properties of thin matrices has been examined. Both drug-free and drug-loaded matrices were found to be non-isotropic in structure, the former having a marbled appearance under the polarising light microscope, and the latter showing numerous needle-shaped crystals. At loading above approx. 10% w/w clenbuterol it was also possible to observe aggregates of the drug. Differential scanning calorimetry enabled the identification of melting peaks at approx. 50°C for the needle-shaped crystals and approx. 80°C for the larger drug aggregates. The former are composed of a surfactant used by the manufacturer for the synthesis of Eudragit NE30D by emulsion polymerization. This surfactant undergoes a phase separation from the polymer on storage at room temperature. It could, however, be extracted from the polymer by refluxing in water to yield an isotropic system. The extract showed a melting peak at 50°C and also UV, IR, NMR, and mass spectra in accordance with an o-substituted nonyl phenol surfactant. Matrices prepared from the purified Eudragit NE30D showed drug release rates of only one third the magnitude of those found with matrices prepared from the raw polymer. Substantially reduced scatter in the release data was also found with the purified polymer.

The influence of Azone on monomolecular films of some stratum corneum lipids

Abstract The effects of the lipophilic permeation enhancer Azone on the compressional behaviour of monomolecular films of cholesterol, ceramide, and a mixture of six fatty acids have been investigated using a Langmuir trough. These lipids are those which build the backbone of the lamellar, bilayer structure postulated to exist within the lipid fraction of stratum corneum. Azone changed the solid film of cholesterol and the liquid condensed film of ceramide in a concentration-dependent manner to liquid expanded films of high compressibility. A mixture of the three lipids in proportions corresponding to that which exists in human stratum corneum produced a highly condensed liquid condensed film, which was also changed to liquid expanded in the presence of Azone. These results indicate that Azone reduces the state of condensation of monomolecular films of these lipids, corresponding to increased fluidity within the monolayers. It was also found that Azone alters the rate of loss of water through the monomolecular lipid films, although this effect was very slight. Its effects on the passage of acetone through the monolayers were negligible.

Determining the solubility and crystal form of clenbuterol in thin films of eudragit NE30D

The solubility of the drug clenbuterol in thin films of surfactant-free Eudragit NE30D has been measured. Light microscopy and differential scanning calorimetry were supplemented by a technique based on measurement of the rate of drug release from the films. The clenbuterol crystals had the form of a fractal, as could be shown by a computer simulation of diffusion-controlled aggregation.