Wechselbeziehungen zwischen Haut,Vehikel und Arzneimittel bei der Penetration in die menschliche Haut I: Mechanismus der Penetration

Interrelationships between Skin, Vehicle and Drug in the Penetration through Human Skin I: Mechanisms of Penetration The terms adsorption, absorption, penetration and permeation are defined and methods for the determination of penetration are described. The barrier function, the reservoir function of the corneous layer, dimensions of penetration, the penetration of pure substances, metabolism, directed transport, as well as the kinetics of penetration (corneous layer, epidermis, cutis) are discussed.     

Modellversuche an isolierter Epidermis zur Prüfung der Permeabilität der menschlichen Haut und der Kinetik des Penetrationsvorganges

Model Experiments on Isolated Epidermis for Examining Permeability of Human Skin and Kinetics of the Process of Penetration Investigation on isolated epidermis using solutions of salicylic acid and resorcinol in water and organic solvents have shown that extent of penetration of a substance depends on its effective concentration in the horn layer; this concentration is dependent on partition coefficients. At high concentrations, organic solvents exhibit a different behaviour. Whereas in the case of ethanol, penetration from aqueous solution continuously increases, penetration of propanol attains a maximum at a concentration of 50% and decreases thereafter strongly. Salicylic acid promotes the penetration of organic solvents whereas resorcinol inhibits penetration.     

Untersuchungen an excidierter Haut mit einer beidseitig durchströmten Diffusionskammer zur Prüfung der permeabilitätssteigerden Wirkung von Dimethylsulfoxyd und anderen Lösungsmitteln

Investigations on Excised Skin with a Diffusion Chamber, Permitting Flow on both the Directions, for Testing the Permeability Increasing Effect of Dimethylsulfoxide and other Solvents A diffusion chamber is described, which allows experiments to be carried out serially with the same piece of skin for evaluation of the penetration properties of the test substance as well as the changes in the permeability of the skin. The investigated solvents, dimethylsulfoxide, dimethylformamid and dimethylacetamid, have one thing in common that they considerably increase the permeability of the skin. Inspite of the property to increase the permeability, the penetrating ability of salicylic acid dissolved in the solvents mentioned above is negligible in comparison to its penetrability in aqueous solution. The conception that the solvents named take the role of a vehicle in the process of penetration in rejected.     

Gas-chromatographische Untersuchungen zur Frage der “Vehikel”-Funktion des Dimethylsulfoxids

Gas Chromatographic Investigations on the “Vehicle” Function of Dimethyl Sulfoxide In order to answer the question, whether during penetration process DMSO functions as a vehicle, investigations were carried out on isolated epidermis employing solutions of salicylic acid and phenol in DMSO. The experiments showed that during the diffusion process the dissolved substances and the solvent did not behave in a similar fashion; instead they counteracted each other. With increasing DMSO concentration of the starting solution the extent of diffusion of salicylic acid and phenol became lesser whereas the amount of diffused DMSO rose. The vehicle theory has been completely rejected.     

Externa-Trägerstoffe und Wirkstoffverfügbarkeit in der Haut

External Carriers and Availability of Active Principles in the Skin Under the assumption of adequate liberation of the active principle from the vehicle in vitro, an attempt is made to use the term ?Bioavailability”? in the local therapy. Although the indirect way via the transport organ, blood, is not necessary, as for all other drugs, distinct differences in action are found for the different carriers. In addition essential functions of the externally applied medicaments are attributed to the vehicle. Thus, each stage of a particular disease of the skin requires a different vehicle. In this context, the possibility of the concept of a palette of different galenic preparations is discussed. Since the cornea has the principal barrier function towards penetration of foreign agents into the skin, its structure is the main criterium in the availability of active principles in the skin. The differences in the penetration of active principles from various vehicles and a possible improvement of biological availability through cornea are discussed. An optimum vehicle would enable the least concentration of the active principle in the externally applied medicament and improve the safety of the medicament. Theoretical prognosis concerning a high availability of the active principle from an externally applied medicament can hardly be made. At the best, such prognosis is possible, if one excludes the interaction between the active principle, cornea and vehicle.     

Penetration der Steroide

Penetration of Steroids Chemical structure, vehicle, mode of application and texture of skin determine the degree of penetration, permeation and absorption of a steroid. In the synthesis of so-called “Dermato-Corticoids”, the aim is to attain a maximum topical effect and minimum absorption. These properties dominate when hydrocortisone, and especially prednisolone, are hydroxylated, methylated or fluorinated; only fluocortolone and clocortolone are derived from corticosterone. Various clinical testing procedures, such as estimation of the kinetics of penetration using isotopes, are available for the difficult task of comparing the action of numerous valuable steroid-containing externa. By observing certain precautions, percutaneous absorption of steroids and especially those of the topicum can be minimized; hence, even long-time application is without any consequent side effect. Occasional skin changes, which are said to be local side effects due to corticoids, are relatively seldom compared to the number of patients who permanently receive external application of corticoids. Compared to cortico (stero)ids, sexual hormones, that are resorbed to a much greater extent, show considerably lower external indications.     

Neue Befunde zum natürlichen und künstlichen Lichtschutz der Haut

New Observations on the Natural and Artificial Light Protection of Skin The hitherto known properties and mechanism of action of artificial light protection agents on human skin have been compared with author's own investigations pertaining to the base on which the preparations are formulated, significance of the UV B-absorption and the interrelationships between erythema and pigment reaction. Following results could be established: 1. Solutions of light filters in volatile solvents can act strongly light protecting; 2. the light protecting action is not only dependent on the protective film formed on the skin; 3. substances without appreciable UV B-absorption (purines and pyrimidines) have light protecting action; 4. intensity of browning of the skin is dependent on the preceding erythema reaction.     

Mikrozirkulation der Haut und wissenschaftliche Kosmetik

Micro-Circulation of Skin and Cosmetic Science For fundamental cosmetic research, more exact informations regarding the relationships of blood- and lymph-vessels to ageing of the skin are needed. The currently available methods for the investigation of micro-circulation are inadequate. The skin is provided with a very extensive blood circulation so that only major disturbances in circulation and those occurring for prolonged periods result in alterations of the skin. The connecting tissues of the true skin are significant in the ageing of the skin. Complicated physico-chemical alterations of the cells and fibres, which are promoted by the chronic action of light, lead to atrophy and senile elastose, the two main factors involved in the ageing of skin. A long lasting protection of the skin against light is therefore significant in preserving a “young” skin. As against this the micro-circulation with its possible disorders are less important, although the damages to the true skin caused by light may extend to the walls of the small blood vessels as well.     

Der Gehalt der Haut an basischen niedermolekularen Aminen

Basic Low Molecular Weight Amines Content of the Skin Mediators of the nervous system, intermediate and decomposition products of high molecular weight, nitrogenous components and structural intermediated in protein, carbohydrate and phosphatide metabolism belong to the group of biogenic amines. This class of substances was detected in human skin by the thin-layer chromatographic procedure according to Seiler and Wiechman. The alkyl amines, namely colamine, piperidine, histamine, spermine, spermidine and catechol amines were detected. The above substances were separately detected in different skin layers like horn layer, stratum malpighi and corium. Varying levels of these substances indicate metabolic characteristics and different types of binding.     

Application of Single Molecule Fluorescence Microscopy to Characterize the Penetration of a Large Amphiphilic Molecule in the Stratum Corneum of Human Skin

We report here on the application of laser-based single molecule total internal reflection fluorescence microscopy (TIRFM) to study the penetration of molecules through the skin. Penetration of topically applied drug molecules is often observed to be limited by the size of the respective drug. However, the molecular mechanisms which govern the penetration of molecules through the outermost layer of the skin are still largely unknown. As a model compound we have chosen a larger amphiphilic molecule (fluorescent dye ATTO-Oxa12) with a molecular weight >700 Da that was applied to excised human skin. ATTO-Oxa12 penetrated through the stratum corneum (SC) into the viable epidermis as revealed by TIRFM of cryosections. Single particle tracking of ATTO-Oxa12 within SC sheets obtained by tape stripping allowed us to gain information on the localization as well as the lateral diffusion dynamics of these molecules. ATTO-Oxa12 appeared to be highly confined in the SC lipid region between (intercellular space) or close to the envelope of the corneocytes. Three main distinct confinement sizes of 52 ± 6, 118 ± 4, and 205 ± 5 nm were determined. We conclude that for this amphiphilic model compound several pathways through the skin exist.     

纳能托[注]超微载体系统的透皮性能研究

研究了质量分数为 2 %维生素E醋酸酯分别在纳能托[注 ] 超微载体系统、超小脂质体系统以及辛酸 /癸酸甘油三酯溶液中的体外活皮肤渗透性能。精确测定了皮肤不同深度层面区间中总维生素E以及纯维生素E的含量。研究发现 :含有维生素E醋酸酯的纳能托[注 ] 超微载体—天来达[注 ] E能够以其超小的体积 (d平均 <3 0nm )和紧密的结构有效通过人体皮肤的角质层屏障到达表皮层、真皮层、皮下组织以及深达 12 5 0 μm的皮肤脂肪层 ,并能够在皮肤中活性酶的作用下大量转化成为具有活性的纯维生素E (即维生素E醇 ) ,从而有效营养皮肤 ,防止皮肤细胞质的氧化及紫外线引起的自由基老化等     

Über Meßergebnisse und Meßmöglichkeiten an der Haut

Possibilities and Results of Measurement on the Skin Taking the example of examination of light-protecting agents, different possibilities of measurements on the skin are discussed. The investigations involving actions and side actions in the shaving procedure as well as those associated with washing agents are described. Thereby, the methods for the measurement of inflammatory changes, estimation of water liberation from the skin as well as assay of pH-values and determinations of alkali neutralisation are dealt with. It is worth-while to combine as many methods as possible in order to evaluate a definite function and to determine different functions in a testing program.     

Der Einfluß enzymhaltiger Waschmittel auf den Eiweiß- und Lipidmantel der Haut

Influence of Enzyme-Containing Washing Agents on Protein- and Lipid-Layer of the Skin Bioactive enzyme-containing washing agents differ very little from washing agents free of enzymes with regard to their skin tolerance. Whereas dry (sebostatic) skin is attacked more strongly by all the washing agents, water and lipid-rich seborrhoic skin exhibits excellent tolerance towards such washing agents. Primary state of the skin is dependent on the skin-type and age. None of the 609 subjects tested have shown any ekzematisation or rhino-conjunctivitis. These studies reveal the significance of lipid layer of the skin in the tolerance towards washing agents, including those containing enzymes.     

Zur unterschiedlichen Wirksamkeit sauer und alkalisch eingestellter Tenside an der menschlichen Haut

Difference in the Action of Surfactants Adjusted to Acidic and Alkaline Conditions on Human Skin Sequel to previous investigations, the results of the examination of synthetic washing agents, which exhibit optimum washing action at pH 6–8, are reported. It was found that the side-effects, such as those involved in the alkali neutralisation test, are directly proportional to pH-value. The side-effects which are associated with the determination of wetting and water removal of skin are directly proportional to values between pH 6 and 8, depending on whether alkali soaps or surfactants of the type Na-laurylsulfate are employed. Unexpectedly, the roughness of the skin increased with increased alkalinity of the solutions. As observed in one particular case, the adjustment of a surfactant to a definite pH-value may result in totally unexpected changes in its action.     

Staphylokokken der Haut als Symbionten,Epiphyten und Parasiten

Staphylococci of the Skin as Symbionts, Epiphytes and Parasites Not only the sick, but also the healthy carriers of germs are infectional sources of parasital staphylococci. As practically all eruptions of the skin are caused by pathogenic staphylococci, the interests of hygiene and cosmetics are focussed towards the germ carriers. During the study of resistance mechanisms of the skin against parasitic staphylococci, the author observed strong antibiotic actions of non-pathogenic staphylococci. The clinical and epidemiological observations confirm the peculiarities in the antibiotic action of these germs.     

Skin Penetration of Fatty Acids from Soap Surfactants in Cleansers Dependent on Foam Bubble Size

Skin cleansers exhibiting less irritation are required. Although most skin cleansers are applied to the skin in a foam state, the amount of surfactant penetrating into the skin is measured in the solution state. Due to the fact that surfactant penetration causes skin irritation, liquid chromatography/mass spectrometry was used in this study to investigate, from the viewpoint of surfactant penetration, the correlation between foam characteristics and the condition of skin treated with foam. Results demonstrated that as the concentration of surfactant in water drainage from the foam decreased, the composition of surfactants in water drainage shifted to contain smaller amounts of longer-chain surfactants, whereas the bubble size of the foam became smaller, notwithstanding any change in compounds. When several bubble sizes of foam were added to the skin, it was confirmed that the amount of surfactant penetrating into the skin depends on the levels in the water drainage. The amount of surfactant penetrating into the skin increased with foam bubble size. It was thought that the surfactant at the gas–liquid interface cannot act freely, and thus surfactants in the water drainage tended to penetrate the skin. These results suggest that along with the type of surfactant, both foam morphology and the actual way in which the foam is produced are also important factors that need to be considered when designing milder cleansers.     

Synthesis and Characterization of Fluorescent Surfactants for Studying the Penetration of Cosmetic Surfactants on the Skin

Surfactants are one of the important ingredients of cosmetics. However, their penetration and penetration-promoting behavior in the skin has not been well understood. Aiming to explore the surfactant penetration in skin, a novel fluorescent surfactant F-C16, based on sodium fluorescein, was synthesized in this paper. F-C16 has a fluorescence maxima (λ_em) of around 530 nm, and its fluorescence increased with the polarity of solvent. It possesses good emulsifying properties and low cytotoxicity. Hence, it can be used as a quickly detected indicator for surfactants in cosmetics. As demonstrated by this fluorescent surfactant, it was found that the surfactants can penetrate well into skin and cells. It seems that surfactants in cosmetics can enter the cells and reach the dermal layer of skin.     

Das Lymphgefäßsystem der Haut

The Lymph Vessels of Skin The lymph vessels of skin serve, as those in other organs, for the transport of liquids, substances and particles from the extracellular space. The lymph capillaries channel these tissue fluids in the lymph tract and the transport vessels lead the resulting lymph over the lymphatic ganglions back to blood. For keeping the optimum composition of the tissue fluid constant, the unhindered continuence of both the part-functions is of great importance. Whichever substances penetrate through the epidermis must be transported by the blood or lymph paths. The path of the bigger molecules and particles goes over the lymph tract to the filter of lymphatic ganglions and with that to a very active controll station of reticuloendothelial system.     

Partikelgröße und Permeation

Particle Size and Permeation Using the Tesafilm (adhesive tape)-tear off method and by microscopie evaluation of the resulting films in polarized light the penetration of crystalline particles in the horny skin can be followed. As seen with examples, such as Tolnaftat, Na₂CO₃ · 10 H₂O and KF 224, crystalline particles can permeate upto remarkable depths in the horny skin. These studies indicate that the particle size of the crystals are only of minor significance. Possibly the depth of penetration depends more upon the crystalline form and on the solubility of substances in the components of the horny layer. Such processes can be determining factors for the intensity and duration of action of dermatological agents.     

Die Bedeutung der Vitamine für die gesunde und kranke Haut

Significance of Vitamins for the Healthy and Diseased Skin A review is given of the relationship between vitamin supply and the normal functional processes in the organism. The importance of the vitamins A, B₂, nicotinamide, pantothenic acid and vitamin E for the skin is discussed with some examples considering the morphological and biochemical changes caused by deficiencies. Finally, the therapeutic use of vitamins in skin diseases is summarized. The application of vitamins in cosmetics is mentioned.