Steven L. Krill

Solvent-mediated alterations of the stratum corneum

Abstract The intercellular lipid multilayers of stratum corneum, the outermost layer of mammalian skin, are generally accepted as the rate-determining pathway of transmembrane diffusion for lipophilic solutes. The effects of a series of saturated and unsaturated octadecanoic acids (saturated stearic acid, cis- and trans-octadecenoic acid) and a series of short-chain alcohols (ethanol, n-propanol, isopropanol and n-butanol) on the thermotropic phase behavior of stratum corneum have been investigated. In conjunction with the thermotropic phase behavior, fatty-acid-induced effects on the permeation of a lipophilic compound have also been studied. The alcohol-induced effects were determined at concentrations that haue given penetration enhancement for the respective alcohols in order to relate the findings to available skin transport data from literature. Permeation enhancement of lipophilic solutes does not necessarily occur with a concomitant decrease in the gel to liquid-crystalline phase transition. The unsaturated fatty acids in the presence of aqueous ethanol solutions have been associated with conformational alterations of the gel phase lipid domain. However, the effect of fatty acids is complicated by the presence of the cosolvent. Therefore, the thermotropic phase behavior of the stratum corneum was also investigated in the presence of a series of short-chain alcohols. Short-chain alcohol enhanced permeation may result from a reduction of lipid polar head interactions, an inter facial transport pathway between limited populations of interdigitated and noninterdigitated gel phases within the membrane or further disordering of possible liquid-crystalline phases within the membrane.

Physicochemical aspects of transdermal permeation

Abstract The nature and state of lipids are often important regulators in many membrane functions and properties. Current studies probe the physicochemical aspects of the enhanced permeabilities of lipophilic solutes through hairless mouse stratum corneum. The barrier properties of the stratum corneum to lipophilic solutes haue been related to the order and mobility of the hydrocarbon portion of the lipoidal pathway. Temperature enhanced permeabilities of the solutes were associated with the gel to liquid crystalline transition of the lipid hydrocarbon chains. Minor enhancement also resulted from decreased order within pathway. Thermal pretreatments in the presence or absence of hydration also affected the pretransitional order of the lipids, although the gel to liquid crystalline transition remained within the same temperature region during thermal perturbation. Therefore, the physicochemical nature of the lipoidal pathway affects the barrier properties of the stratum corneum.

Ethanol effects on the stratum corneum lipid phase behavior

The stratum corneum is considered to be the diffusional barrier of mammalian skin for water and most solutes. The intercellular lipid multilayer domains of the stratum corneum are believed to be the diffusional pathway for most lipophilic solutes. Fluidization of the lipid multilayers in the presence of ethanol is frequently conceived to result in enhanced permeation. Current investigations address the effect of ethanol on the phase behavior in terms of stratum corneum lipid alkyl chain packing, mobility and conformational order as measured by Fourier transform infrared (FTIR) spectroscopy. Phospholipid multilamellar vesicles were also studied as model systems. There appeared to be no effect of ethanol on either the solid-solid phase transition or the gel phase interchain coupling of the stratum corneum lipids. However, there was a reduction in the mobility of the alkyl chains in the presence of ethanol. Possible mechanistic relationships between the current FTIR spectroscopic results with available literature data of ethanol induced lipophilic solute penetration enhancement through the skin are discussed.

The stratum corneum lipid thermotropic phase behavior

The stratum corneum, the outermost layer of mammalian skin, is considered the least permeable skin layer to the diffusion of water and other solutes. It is generally accepted that the intercellular lipid multilayer domain is the diffusional pathway for most lipophilic solutes. Fluidization of the lipid multilayers is believed to result in the loss of barrier properties of the stratum corneum. Current investigations address the lipid thermotropic phase behavior in terms of lipid alkyl chain packing, mobility and conformational order as measured by Fourier transform infrared (FTIR) spectroscopy. A solid-solid phase transition is observed with increased alkyl chain mobility followed by a gel to liquid-crystalline phase transition near 65 degrees C. These results further elucidate the role of lipid fluidity that may contribute to the transport properties of the stratum corneum.

Dose-dependent enhancement effects of azone on skin permeability

In vitro permeability experiments have been combined with differential scanning calorimetry (DSC) studies in an attempt to address the dose-dependent influence of Azone on the permeability coefficients of solutes for hairless mouse stratum corneum. A spray technique was developed to deliver uniformly and quantitatively small amounts of Azone to the stratum corneum. Permeability data obtained for several model solutes of varying lipophilicity suggest lipid fluidization and polar route enhancement as the mechanisms of action for Azone. Alkanols and steroids, both of which are enhanced primarily by lipid fluidization, had different degrees of relative enhancement. This provides evidence that the stratum corneum barrier is heterogeneous, rather than a homogeneous slab barrier. Two effects of Azone on the stratum corneum were detected by DSC. A decrease in the area and a shift to lower temperatures were noted for the lipid endotherms with increasing doses of Azone. A lipid fluidizing effect would qualitatively account for the increases in the permeability coefficients noted for more lipophilic solutes. The stratum corneum keratin endotherm also appears to be altered in the presence of Azone. It is possible that alteration of the keratin structure could lead to the development of polar routes in the stratum corneum.

Design of sustained-release matrix systems for a highly water-soluble compound, ABT-089

Abstract ABT-089 is a potent cholinergic channel modulator under investigation for treatment of cognitive disorders. It is a highly water soluble compound with a short elimination half-life of 1.7 h in dogs. Hydrophilic and hydrophobic matrix systems were designed to investigate the feasibility of prolonged oral delivery of ABT-089 and to explore the preliminary in vitro and in vivo correlations. The sustained-release single and layered matrix tablets were prepared by compression. In vitro release testing using a USP apparatus II was performed for formulation screening. The release rates were modulated by varying concentrations of different types of rate controlling materials and by restricting surface area available for drug release. The transport mechanism of the compound from different types of systems typically followed Fickian diffusion. Based on the in vitro release characteristics, two types of prototype matrix systems were evaluated in beagle dogs. Both formulations provided prolonged plasma levels of ABT-089 above the minimum effective concentration for over 22 h with reduced fluctuation of plasma levels. In vivo drug release from the tablet matrix estimated by deconvolution correlated well with drug release in vitro. In conclusion, prolonged oral delivery of highly soluble ABT-089 was achieved using diffusion controlled matrix systems. The hydrophobic matrix was found to be more effective than hydrophilic matrix in extending the release of the compound. Linear relationships between in vitro and in vivo drug release indicated by the initial results for both types of systems can provide useful information for further formulation development.

Pulmonary lung surfactant synthetic peptide concentration-dependent modulation of DPPC and POPG acyl chain order in a DPPC:POPG:palmitic acid lipid mixture

Lung surfactant-associated protein interaction with lipid matrices and the effects on lipid thermotropic phase behavior are areas of active research. Many studies limit the lipids to a single or two-component system. The current investigation utilizes a three-lipid component matrix (DPPC:POPG:palmitic acid) to investigate the impact of a synthetic surfactant protein B fragment (SP-B 53-78 DiACM) on the dynamic surface activity of the lipid admixture as measured by a Wilhelmy surface balance. Also, the modulation of the individual lipid acyl chain order by the peptide within the lipid matrix is studied through the use of thermal perturbation FTIR spectroscopy. The data clearly demonstrate a concentration-dependent effect of the peptide on the surface activity with an improvement in the dynamic surface tension diagram characteristics (decreased surface tension and increased collapse plateau) especially at low, 0.36 M%, peptide concentrations. These effects are diminished upon further addition of the peptide. FTIR spectral data demonstrate that the peptide addition results in a significant increase in the acyl chain order of the DPPC and POPG components as measured by the position of the methylene stretching vibrational bands. DPPC is most sensitive to the peptide presence, while the palmitic acid is least affected. The transition temperatures of the individual lipids are also increased with the addition of the peptide. The presence of POPG in the matrix achieves the surface activity similarly seen with natural lung surfactant relative to a DPPC/palmitic acid lipid matrix alone. Its presence increases the sensitivity of the DPPC acyl chains to the presence of the peptide. These effects on the chain order are most probably related to the increased acyl chain fluidity which POPG imparts to the lipid matrix because of the presence of the cis double bond. The phosphatidylglycerol headgroup also adds a negative charge to the lipid matrix which enhances the peptide-lipid interaction. Although the palmitic acid is minimally affected by the peptide, its presence, as suggested by surface balance measurements, results in the establishment of a stable lipid film with DPPC, capable of achieving low surface tension values.

The influence of iso-propanol, n-propanol and n-butanol on stratum corneum lipid phase behavior

Abstract The intercellular lipid multilayers of stratum corneum, the outermost layer of mammalian skin, is generally accepted as the rate determining pathway of transmembrane diffusion for lipophilic solutes. The short chain alcohols, iso-propanol, n -propanol and n -butanol, are known to enhance permeation through the stratum corneum at low concentrations. The effects of these alcohols, at concentrations giving equivalent penetration enhancement, on the stratum corneum lipid alkyl chain packing, mobil- ity and conformational order as measured by Fourier transform infrared (FTIR) spectroscopy have been investigated. Reference is made to studies of model DSPC/DSPA phospholipid multilamellar vesicles in the presence of the alcohols. Iso-propanol and n -butanol do not alter the stratum corneum lipid interchain interactions and gel-gel phase transition. n -Butanol is shown to increase the lipid chain freedom of motion above 45 ° C. However, only n -propanol appears to alter the stratum corneum lipid gel to liquid-crystalline phase transition. In the densely packed gel state (below 45°C), n -butanol was demonstrated to decrease the alkyl chain freedom of motion.

Activity loss on room temperature storage of Survanta®, a bovine lung extract based surfactant

Abstract The rapid loss in Survanta®, a bovine lung extract based surfactant, activity upon storage at 30°C is investigated. During 3 months, the minimum surface tension as measured by both Wilhelmy plate and pulsating bubble methods rose by 8–9 mN/m. Additionally, a decrease in the in situ rat lung bioactivity of approximately 40% was observed. Disaturated phosphatidylcholine levels decreased while free fatty acid levels increased under the same storage conditions. Thus, the presence of both lysolecithins and additional free fatty acids is believed to result in the loss in activity.