Delivery of free amino acids into and through the stratum corneum of the skin using micro emulsions and microemulsion-based hydrogels: Formulation, characterization, and ex-vivo permeation studies.

Free amino acids constitute the largest portion (40%) of the natural moisturizing factor. Their level might decline and cause dry skin condition. The treatment strategy involves the replenishment of these components to the skin, and, to our knowledge, there are no reports that involve dermal delivery of free amino acids. The purpose of the current study was therefore to prepare and characterize different micro-emulsions, micro-emulsion-based hydrogels, and hydrophilic creams loaded with free amino acids for dermal delivery. Oil-in-water microemulsions were prepared using carefully selected formulation components. Poloxamer® 407 and carbopol® 934 were used to prepare the hydrogels. All the formulations were characterized for physico-chemical, permeation and cytotoxicity properties. The results showed that the prepared microemulsions had desired droplet size, size distribution, zeta potential, refractive index, and pH. In the gel preparations, the elastic properties prevailed over the viscous behavior. The hydrogels had non-Newtonian shear-thinning behavior with some thixotropic properties. The free amino acids permeated into the deeper layers of the stratum corneum from the microemulsions, and microemulsion-based hydrogels as compared to conventional hydrophilic cream. The hydrogels were more effective than the microemulsions to deliver the FAAs to the desired site of the skin in a sustained manner. Poloxamer-based hydrogel permeated into deeper skin layers than Carbopol-based hydrogel. Formulations prepared using standard free amino acids and those extracted and purified from oyster mushroom had similar characteristics. All the formulations were stable and safe to be applied topically. In conclusion, microemulsions and microemulsion-based hydrogels can be considered as safe carrier systems for dermal delivery of free amino acids.

[Development of an ivermectin-containing syrup as an extemporaneous preparation for treatment of scabies in children]. / Entwicklung eines Ivermectin-haltigen Saftes als Magistralrezeptur für Kinder zur Therapie der Skabies.

BACKGROUND: Oral ivermectin can be used to treat scabies. Evidence for safe and effective use in young children in individual treatment situations has been developed and published. In order to also ensure a body weight-adapted dosage for children, an ivermectin-containing syrup was developed as an extemporaneous preparation. MATERIALS AND METHODS: Since ivermectin is not available as a pure substance for the formulation, tablets containing active ingredient were used as a basic material for development. The formulation was designed according to pharmaceutical, regulatory and use-oriented criteria. An HPLC (high-pressure liquid chromatography) method was developed and validated to demonstrate chemical stability. In order to facilitate the practical implementation, information on suitable packaging material and application aids was also developed and the formulation was evaluated. RESULTS: It has been demonstrated that the final formulation produced in the pharmacy was stable and can be stored for 3 weeks. No concerns were raised regarding the tolerability of the syrup formulation. The physicochemical properties and the taste of the formulation allow the intended use as a well-dosed syrup for children. CONCLUSION: The developed formulation meets the requirements of the Apothekenbetriebsordnung (Pharmacy Work Rules; Section 7 ApBetrO) and enables an exact, body weight-adapted dosage of oral ivermectin in young children. Studies on human pharmacokinetics or clinical studies to demonstrate tolerability and/or efficacy are not available for the formulation.

Assessment of the applicability of HLB values for natural phospholipid emulsifiers for preparation of stable emulsions.

Natural phospholipid (PL) excipients are native, biocompatible and relatively inexpensive alternatives to synthetic emulsifiers. A well-known PL excipient is lecithin, which primarily contains phosphatidylcholine (PC) and (depending on the purity grade) also contains a well-defined mixture of other PLs with a fatty acid composition, which reflects their natural source. Since all of these lipid species are emulsifiers, natural PLs can be considered as a mixture of (co-) emulsifiers. Many different HLB values for lecithins are given in the literature, which is why this needs to be clarified. To assess this, HLB values of thirteen different plant derived PLs differing in PC content were determined using a centrifugation stress method to determine the relative stability of an emulsion with the respective emulsifier and different oil phases. It could be shown that the studied PLs can be characterized by a broad HLB range, which may be linked to the composition of the PLs and the oil used. In order to emphasize the results of the HLB determination, it could be demonstrated that stable emulsions could be prepared with a wide range of oils using the plant-based PLs and that the preparation method of the emulsions is important in order to obtain stable emulsions. Therefore, assigning a specific exact HLB value to natural PLs instead of a wider range is inappropriate. The broad HLB ranges indicate the suitability of the studied PL emulsifiers for the preparation of oil-in-water emulsions for a wide range of oils: It is recommended to experimentally evaluate the suitability of these natural emulsifiers for the preparation of stable emulsions and to benefit from the wide range of HLB values of these emulsifiers instead of relying on inaccurate and confusing HLB values in the literature.

Dermal peptide delivery using enhancer molecules and colloidal carrier systems - part V#: Influence of enhancers on the permeation of PKEK through snake skin.

In a previous study, it was shown, that shed snake skin is a good alternative model membrane for the human stratum corneum (SC). In this study, the influence of the enhancers dimethyl sulfoxide (DMSO), 1,2-propanediol, 1,3-butanediol, 1,2-pentanediol, 1,2-hexanediol and 1,2-octanediol in a concentration of 10 % on the permeation of l-prolyl- l-lysyl-l-α-glutamyl-l-lysin (PKEK) through shed snake skin was conducted. Pharmacokinetic parameters (diffusion coefficient, permeation coefficient, t-lag, Flux) were calculated. All examinations were performed on the skin of an individual and thus allowed a very good comparability of the data. All enhancers have overcome the shed snake skin and could be proven in the acceptor. DMSO does not affect the permeability of the membrane. Nevertheless, PKEK permeates faster in the presence of DMSO than PKEK being used alone. PKEK permeated the same, no matter if an auxiliary material was added or not. Without their addition, in all other enhancers no significant difference towards permeation could be determined.

Studies of the Corneocytary Pathway Across the Stratum Corneum. Part I: Diffusion of Amino Acids Into the Isolated Corneocytes.

Amino acids (AAs), important constituents of natural moisturizing factors (NMFs) of the skin are decreased in diseased conditions such as psoriasis and atopic dermatitis. No study so far investigated the uptake of AAs into isolated corneocytes (COR). The present study was performed using 19 AAs, including taurine (TAU), to measure their amount diffused into the COR and binding of these AAs to keratin. Incubation of alanine, aspartic acid, asparagine, glutamine, glutamic acid, histidine, proline, serine and TAU with the isolated COR showed uptake after 24 h of 51.6, 95.4, 98.6, 94.1, 95.6, 90.1, 94.6, 72.9 and 57.8 %, respectively, into the COR but no binding with keratin. Uptake of TAU was validated by time dependent in-vitro diffusion models 'without COR and 'with COR'. The time dependent curve fitting showed that in in-vitro diffusion model 'without COR' there was no change in the total concentration of TAU until 72 hours, while in diffusion model 'with COR' the total conc. decreased to 37.8 % after 72 hours. The Pearson's correlation coefficient 'r' between the conc. curves of both in-vitro diffusion models was -0.54 that was an evidence of significant amount of TAU uptake by the COR. AAs as part of the NMFs have a great potential to be diffused into the COR. This property of the AAs can be employed in further dermatological research on diseased or aged skin conditions with NMFs deficiency.

The effect of urea and taurine as hydrophilic penetration enhancers on stratum corneum lipid models.

To optimize transdermal application of drugs, the barrier function of the skin, especially the stratum corneum (SC), needs to be reduced reversibly. For this purpose, penetration enhancers like urea or taurine are applied. Until now, it is unclear if this penetration enhancement is caused by an interaction with the SC lipid matrix or related to effects within the corneocytes. Therefore, the effects of both hydrophilic enhancers on SC models with different dimensionality, ranging from monolayers to multilayers, have been investigated in this study. Many sophisticated methods were applied to ascertain the mode of action of both substances on a molecular scale. The experiments reveal that there is no specific interaction when 10% urea or 5% taurine solutions are added to the SC model systems. No additional water uptake in the head group region and no decrease of the lipid chain packing density have been observed. Consequently, we suppose that the penetration enhancing effect of both substances might be based on the introduction of large amounts of water into the corneocytes, caused by the enormous water binding capacity of urea and a resulting osmotic pressure in case of taurine.

[Clotrimazole and ciclopirox olamine respectively in combination with methylprednisolone aceponate as extemporaneous formulations]. / Clotrimazol und Ciclopiroxolamin jeweils in Kombination mit Methylprednisolonaceponat in magistralen Rezepturen.

The combination of topical fungicide and glucocorticoids has been proven as a successful therapy of cutaneous mycoses with accompanying inflammatory reactions, particularly when used at an early stage. Various national and international therapeutic guidelines recommend this practice. In this context, two individually manufactured formulations have been developed and tested for stability: the combination of methylprednisolone aceponate-a topical glucocorticoid with the therapeutic index of 2.0-with clotrimazole and with ciclopirox olamine, respectively. This has been conducted in compliance with the requirements for quality controlled extemporaneous formulations and the legal framework of the German Pharmacy Working Regulations (Apothekenbetriebsordnung). There are now two formulations for clinical use that are microbiologically, physically, and chemically stable, which combine methylprednisolone aceponate-a glucocorticoid with a good risk-benefit ratio-with the broad-spectrum fungicides clotrimazole and, for the first time, ciclopirox olamine.

Effect of hyaluronic acid initial concentration on cross-linking efficiency of hyaluronic acid - based hydrogels used in biomedical and cosmetic applications.

This work was aimed to explore the potential effect of hyaluronic acid (HA) initial concentration (7.0 - 14.0 % w/v) on cross-linking efficiency of HA hydrogels cross-linked with 1,4-butanediol diglycidyl ether (BDDE). The results revealed that the hydrogel prepared at 10.0 % HA concentration exhibited a slower degradation rate, a lower swelling ability and more regular porosity than those prepared at either lower or higher HA concentration. After four days incubating with hyaluronidase, the content of NAG (N-acetyl glucosamine) remaining in the 10.0 HA hydrogel was 25.1±1.9 % with respect to the total NAG content found in the original mass. In contrast, the hydrogels prepared at 7.0 % and 14.0 % HA concentration showed a less remaining content of NAG equaled to approximately 15.9±5.4 % and 19.5±2.6 % respectively. On the other hand, the swelling ability of tested hydrogels was steadily decreased with the increase of HA initial concentration until the 10.0 % HA hydrogel and then showed an opposite trend. Based on this finding, the 10.0 % HA hydrogel exhibited the lowest swelling ratio which was observed at 129±3.2 g/g in distilled water and at 116±2.4 g/g in phosphate buffer saline (PBS). The SEM images showed various morphologies within the entire range of tested hydrogels. However, the hydrogel prepared at 10.0 % HA concentration was more homogenous and appeared with narrower pore-size distribution ranged in diameter from less than 50 µm to approximately 300 µm. Finally, the effect of HA initial concentration was investigated by FTIR which confirmed that the 10.0 % HA hydrogel was subject to a greater loss of (- OH) at 3343 cm-1 than other hydrogels except the 11.0 % HA hydrogel. This phenomenon was probably attributed to the formation of pendants that allowed the 11.0 % HA hydrogel to appear with a lower peak intensity than the 10.0 % HA hydrogel in the FTIR spectra. In conclusion, the HA initial concentration plays a crucial role in determining the cross-linking efficiency of HA hydrogels cross-linked with BDDE.

Retarder action of isosorbide in a microemulsion for a targeted delivery of ceramide NP into the stratum corneum.

Ceramide [NP] is an integral component of the stratum corneum (SC) lipid matrix and is capable of forming tough and stable lamellar structures. It was proven, that in skin diseases as psoriasis or atopic dermatitis different ceramide (CER) classes, including [NP], are degraded. It is obvious that topically application of CER on impaired skin is useful for repairing the skin barrier but a tendency for low penetration due to its poor solubility in conventional dosage forms was observed. Therefore, a stable and physiologic compatible colloidal carrier system, a microemulsion (ME), was developed and characterized. The increasing knowledge of the new colloidal systems in this last decade shows their benefits in dermal application. Isosorbide (Polysorb P) was incorporated into the ME developed. It was expected that Polysorb P has a retarder potential in order to accumulate the CER in the SC, the outermost layer of the skin. Thereby the CER [NP] would be able to interact with the affected skin layers to strengthen the skin barrier. The release and penetration behavior of the CER [NP] from the ME was assessed ex vivo in a Franz diffusion cell. The results of the study showed that CER [NP] penetrate largely in the upper layers of the skin (from SC to stratum basale), which was the desired region. A recovery in the acceptor could not be detected that underlines an accumulation in upper layers. Furthermore, significantly increased values for the SC for the ME with retarder were not received. No differences in the concentrations of CER [NP] were observed. However, the toxicity of MEs was investigated using hens egg test chorioallantoic membrane (HET-CAM). For the isosorbide-containing ME no difference was obtained in comparison to the non-containing. The results showed that both MEs are safe to be used on the skin for the controlled penetration of CER [NP] into the skin. The isosorbide had no effect on the irritating effect as well as on the penetration of the used CER.

Investigation in W/O developed microemulsions with DMSO as a cosurfactant.

In this study the effect of dimethylsulfoxide (DMSO) radii on the droplets and on the required non-ionic surfactant volume for preparing water-in-oil microemulsions (MEs) was investigated. Five series of MEs were prepared either with the aid of isopropylpalmitate or medium chain triglycerides (MCTG) as continuous phases. The MEs were stabilized via either Tween80 or Span20 or a mixture of both. A mixture of water:DMSO (W:DMSO) with different ratios formed the colloidal phase of the first four MEs series. Only DMSO was used as colloidal phase of the fifth series. Dynamic light scattering (DLS) was used for measuring the radii of the droplets of MEs. The results showed that the consumed volumes of the surfactants were related to the W:DMSO ratio and the surfactant type. Moreover, the consumed surfactant volumes increased with decreasing radii of the droplets of the MEs. The MEs stabilized with Span20 had lower radii of the droplets (4-15 nm) than MEs stabilized by Tween80 (25-65 nm). It was evident that DMSO changed the interfacial tension which is reflected by changing the the volume of the surfactant consumed and by altering the droplets sizes. Consequently, DMSO acted as co-surfactant in stabilizing the MEs by reducing the required volumes of the surfactant which is important for reducing their toxicity.

Penetration studies of an extremely lipophilic active model substance from an oil-in-water emulsion: influence of the lipophilicity of the formulation in human skin - part 2.

The effect of the lipophilicity of a carrier on human skin penetration of an extremely lipophilic active model substance was evaluated by using Franz type diffusion cells. Oil-in-water model emulsions containing different amounts of the oily phase were prepared, and Myritol® PC (M-PC) was selected as lipophilic marker component of the oily phase. The penetrated amounts of the lipophilic model substance salicyloyl phytosphingosine (SP) were determined by high-performance liquid chromatography with ultraviolet detection, while M-PC was detected using gas chromatography coupled with mass spectrometry. It has been ascertained that the amount of the lipid phase within the emulsion influenced the penetration profile of the active ingredient SP. The emulsion containing the lowest proportion of the lipid phase provides the best conditions for SP penetration. Surprisingly, the penetration behavior of M-PC was influenced by the oily phase in the same way. Regarding the M-PC and the SP penetration profiles from each emulsion, a solvent drag mechanism can be assumed whereby M-PC acts as penetration enhancer. In conclusion, the penetration rate of the active ingredient SP and the marker component M-PC are in reverse proportion to the oil content of the formulations. The lipophilicity of SP and M-PC, their solubility and their thermodynamic activity within the vehicle could have an effect on their penetration behavior. Additionally, M-PC has the property to enhance the penetration rates of extremely lipophilic substances even at low concentrations.

Study of the influence of the penetration enhancer isopropyl myristate on the nanostructure of stratum corneum lipid model membranes using neutron diffraction and deuterium labelling.

In order to elucidate the mode of action of the lipophilic penetration enhancer isopropyl myristate (IPM) on a molecular scale, we investigated oriented quaternary stratum corneum (SC) lipid model membranes based on ceramide AP, cholesterol, palmitic acid and cholesterol sulfate containing 10 wt% IPM by means of neutron diffraction. Our results indicate that IPM affects the lamellar lipid assembly in terms of bilayer perturbation and disordering. Phase segregation occurred, indicating that IPM is not likely to mix properly with the other SC lipids due to its branched structure. We used selective deuterium labelling to localize the penetration enhancer, and could successfully prove the presence of IPM in the two coexisting lamellar phases. We conclude that IPM's mode of action as penetration promoter is presumably based on incorporation into the SC lipid matrix, extraction of certain SC lipids into a separate phase and perturbation of the multilamellar lipid assembly.

Dermal peptide delivery using enhancer molecules and colloidal carrier systems--part I: carnosine.

Due to the lipophilic properties of the uppermost skin layer of the stratum corneum (SC), it is highly challenging to attain therapeutic concentrations of active substances; hydrophilic drugs, in particular, penetrate poorly. The purpose of this study was the improvement of the topical bioavailability of the hydrophilic dipeptides L-carnosine and its related compound N-acetyl-L-carnosine. Different strategies were investigated. On the one hand, an enhancer molecule, 1,2-pentylene glycol (PG), was added to a standard preparation, and on the other hand, a microemulsion (ME-PG) system was developed. Both were compared to the standard formulation without an enhancer molecule. For all 3 preparations, the penetration of the peptides in ex vivo human skin was investigated. This allows statements to be made regarding dermal penetration, localization and distribution of the active substances in each skin layer as well as the influence of vehicle variations, in this case, the addition of PG or the incorporation of N-acetyl-L-carnosine in an ME-PG system. For L-carnosine and N-acetyl-L-carnosine, the use of the standard preparation with PG resulted in a significant increase of the substance within the SC. Approximately 6-fold and higher dipeptide concentrations in the SC and in the viable skin layers were detected at all experimental periods compared to the formulation without the enhancer molecule and the ME-PG. High concentrations of the compounds were found after a short period of time in the viable skin layers after applying the enhancer molecule, even in concentrations of 5%. The application of the colloidal carrier system did not lead to a higher penetration rate of N-acetyl-L-carnosine in comparison to both standard preparations, although it must be said that the microstructure of the investigated ME-PG might not have been optimal for the hydrophilic properties of the dipeptide.

Investigation of the molecular structure of the human stratum corneum ceramides [NP] and [EOS] by mass spectrometry.

The aim of this study was to characterize the two ceramide (CER) subclasses CER[NP] and CER[EOS] of human stratum corneum and to identify the chemical structures of their subspecies. High-performance thin-layer chromatography and normal-phase high-performance liquid chromatography were used for the separation of CER fractions, whereas nanoelectrospray ionization tandem mass spectrometry was applied to investigate the chemical structures in detail. Thus, CER[EOS] fragmentation revealed that in addition to linoleic acid other esterified fatty acids occur in the ω-position. Of particular interest is the identification of a 17:2 fatty acid located in this part of the molecule. Several subspecies of CER[NP], including subspecies with odd numbers of carbon atoms in both chains, the non-α-hydroxylated fatty acid moiety (part N) and the phytosphingosine (part P), were identified. Furthermore, it was found that 12% of CER[NP] subspecies have an odd number of carbon atoms in both chains of the molecule. Similar results were obtained for CER[EOS]. Both the esterified fatty acid (part E) and the sphingosine base (part S) were found to contain odd-numbered chain lengths. These results underline the heterogeneity of the CER composition in the stratum corneum lipid bilayer.

Hydrocortisone aceponate activity and benefit/risk ratio in relation to reference topical glucocorticoids.

The evaluation of the benefit/risk ratio (BRR) for topical glucocorticoids (TGC) allows the comparison of active ingredients and thereby includes aspects of dosage (blanching response, BR) as well as adverse effects (skin atrophy). In the present study, the BRR of hydrocortisone aceponate, prednicarbate and betamethasone valerate was investigated according to an adapted procedure for investigating the BR. The main difference is the longer application period of the investigational substance without occlusion. Thus, the pharmacokinetic characteristics of all of the systems are considered more intensely and the penetration conditions are designed in a realistic way, namely oriented towards the preparation in order to improve the significance and relevance of the BRR for practical use. The results demonstrate that the investigated substances also show differences in the extent of the BR, but on the other hand they show that the improved penetration characteristics of the double-esterified compounds are clearly less effective. In comparison to the BRR, this results to a large extent in a balanced picture without relevant advantages for single preparations. Nevertheless, the already mentioned positive characteristics of the investigated TGC and the positive practical clinical experiences have been approved. Further investigations have to show whether the method presented here for investigating the BR offers advantages in the comparative assessment of TGC.

Optimization of a metformin effervescent floating tablet containing hydroxypropylmethylcellulose and stearic acid.

This study optimizes the composition of an effervescent floating tablet (EFT) containing metformin hydrochloride (M) regarding tablet hardness (H), time to dissolve 60% of the embedded drug (t60%), and buoyancy, the floating lag time (FLT). A simplex lattice experimental design has been used comprising different levels of hydroxypropylmethylcellulose (HPMC), stearic acid (SA), sodium bicarbonate (SB) as tablet matrix components, and hardness (H), t60%, FLT as response variables. Two models have been applied to decide which composition will result in Fickian diffusion or in overlapping of two dissolution mechanisms, diffusion and matrix erosion. Three of EFT showed the two dissolution mechanisms but most of EFT showed Fickian diffusion only. Checking the experimental response by a linear, quadratic, special cubic and cubic model using multivariate regression analysis resulted in best fit for the cubic model. Overlaying the results for the cubic model under constraints defined shows the domain of accepted values of response variables. The optimized EFT shall have been included HPMC between 15.6% and 24.2%, SA between 12.8 and 15.6% and SB between 16.1% and 17.5%. The result of this study has been critically evaluated considering analogous EFT described in literature.

The effect of hydrophilic penetration/diffusion enhancer on stratum corneum lipid models: Part II*: DMSO.

To optimize dermal and transdermal administration of drugs, the barrier function of the skin, particularly the stratum corneum (SC), needs to be reduced reversibly. For this purpose, penetration/diffusion enhancers such as DMSO can be applied. However, there is the question whether DMSO is an aggressive penetration/diffusion enhancer in pharmaceutical and cosmetical relevant concentrations? Until now, it is unclear if this penetration/diffusion enhancement is caused by an interaction with the SC lipid matrix or related to effects within the corneocytes. Therefore, the effects of the hydrophilic enhancer DMSO on SC models with different dimensionality ranging from bilayers (liposomes) via oligo-layers to multilayers have been investigated in this study. The effects of DMSO should be compared to that of other relevant hydrophilic enhancers such as urea and taurine. An innovative spectrum of methods was applied to ascertain the mode of action of DMSO in relevant concentrations on a molecular scale. The experiments reveal that there is no specific interaction of 10% and 30% DMSO solutions with the SC model systems. Hence, if DMSO is applied in pharmaceutically and cosmetically relevant concentrations, it has no influence on the SC model systems used. Neither an additional water uptake in the head group region nor a decrease of the lipid chain packing density have been observed. The leakage studies on liposomes show that 10% DMSO is causing just a very slight leakage of 8%, lower than the leakage of 19.4% caused by 10% urea (Müller et al., 2016). Consequently, the interactions of DMSO with the SC model lipids used are very low in concentrations of 10% and 30%, respectively. Since the lipid composition in native SC lipid matrix is far more complex than this model mixture, the results can not be directly transferred to the native SC lipid matrix. However, the outcome of this study, together with various findings in the literature give rise to the assumption that the enhancing effect of DMSO concerning the diffusion of relevant hydrophilic drugs and actives appears to be realized via the corneocytes.

Hydrophilic silica aerogels as dermal drug delivery systems--dithranol as a model drug.

A special class of porous silica materials, silica aerogels, was recently shown to be a potential candidate for oral drug delivery systems. It was demonstrated, that stability of drugs and their dissolution rate can essentially be improved through the adsorption on to these materials. In this work, drug loaded silica aerogels are firstly applied as dermal drug delivery systems. Dithranol is used as a representative drug since there is a need to enhance its dermal availability. The unstable and nearly water-insoluble drug exhibits a poor penetration. Release of dithranol from aerogels into various semi-solid formulations and its dissolution as well as the release and penetration into artificial membranes were investigated by Fourier-transform infrared attenuated total reflection (FTIR-ATR) spectroscopy. Two model membranes (one hydrophilic and one lipophilic) were applied. Several formulations were tested and the most promising one was used in order to study the penetration of dithranol into human stratum corneum (SC). Dithranol adsorbed on hydrophilic silica aerogels exhibited superior penetration behaviour compared to that of the standard ointment (dithranol in white soft paraffin).

Optical methods for measurements of skin penetration.

Fourier transform infrared photoacoustic (PAS), photothermal deflection (PDS) and Raman spectroscopy belong to the modern innovative noninvasive analytical tools that are beginning to be recognized as highly potential techniques for the noninvasive study of biological tissues and human skin under in vivo conditions. They can be applied to obtain information regarding the molecular composition of the skin down to several hundred micrometers below the skin surface. All three methods allow depth-resolved investigations. While PAS and PDS use a frequency modulation of the excitation beam to reach deeper regions in the sample, the principle of confocal Raman microspectroscopy (CRM) is a movement of the specimen in the focal plane. In consideration of depth measurements PAS and PDS complete the applicable spectrum of CRM, since Raman microscopy requires particular transparent materials.

Properties of ceramides and their impact on the stratum corneum structure. Part 2: stratum corneum lipid model systems.

The stratum corneum (SC) represents the outermost layer of the mammalian skin, exhibits the main skin barrier and plays an important role in the water penetration pathway through the SC. Knowing the structure and properties of the SC at the molecular level is essential for studying drug penetration through the SC and for the development of new dermal drug delivery systems. Therefore, research interest is focused on the SC lipid matrix and on water diffusion through it. Thus, the ultimate aim is to design a lipid mixture that mimics the barrier properties of the human SC to a high extent and that can substitute the SC in drug delivery systems. This review summarizes various studies performed on either isolated animal or human ceramide based SC model systems, coming to the result that using synthetic lipids with a well-defined architecture allows good extrapolation to the in vivo situation. This review is the continuation of part 1 that is focused on a detailed description of the thermotropic and/or lyotropic phase behaviour of single ceramide types obtained by various experimental techniques. The objective of part 2 is to reflect the numerous studies on SC lipid model systems, namely binary, ternary and multicomponent systems, during the last decade. In this context, neutron diffraction as a prospective tool for analyzing the internal membrane structure is addressed in particular. Based on these new insights, current SC models are presented, whose validations are still under discussion. A profound knowledge about SC lipid organization at the molecular level is still missing.