Skin acidification with a water-in-oil emulsion (pH 4) restores disrupted epidermal barrier and improves structure of lipid lamellae in the elderly.

The pH of the skin surface increases with age and thus reduces epidermal barrier function. Aged skin needs appropriate skin care to counterbalance age-related pH increase and improve barrier function. This confirmatory randomized study investigated the efficacy of water-in-oil (w/o) emulsions with either pH 4 or pH 5.8 in 20 elderly subjects after 4 weeks of treatment. After the treatment, the skin was challenged with a sodium dodecyl sulphate (SDS) solution in order to analyze barrier protection properties of both formulations. The pH 4 w/o emulsion resulted in a significantly lower skin pH compared with the pH 5.8 w/o emulsion and an improved skin hydration after 4-week treatment. Further, the pH 4 emulsion led to more pronounced improvements in length of intercellular lipid lamellae, lamellar organization as well as lipid levels than the pH 5.8 emulsion. Following SDS-induced barrier damage to the skin, the pH of all test areas increased, but the area treated with the pH 4 emulsion showed the lowest increase compared with baseline. In addition, even after the SDS challenge the skin area treated with the pH 4 emulsion still maintained a significantly increased length of intercellular lipid lamellae compared with the beginning of the study. This study provides evidence that topical application of a w/o emulsion with pH 4 reacidifies the skin in elderly and has beneficial effects on skin moisturization, regeneration of lipid lamellae and lipid content. Application of a pH 4 emulsion can improve the epidermal barrier as well as the stratum corneum organization in aged skin.

Efficacy of hydrophilic or lipophilic emulsions containing Echinacea purpurea extract in treatment of different types of pruritus.

BACKGROUND: Pruritus reduces quality of life and may occur at different sites of the body. To alleviate pruritus, lipid replenishing and rehydration of the skin is often unsatisfactory. Thus, products with additional antipruritic effects are needed. OBJECTIVES: Antipruritic effects and cosmetic properties of two different emulsions, water-in-oil (w/o) or oil-in-water (o/w), and a shampoo containing a lipophilic Echinacea purpurea root extract (Ec.-extract) were assessed in adults suffering from pruritus. METHODS: Adults (n = 55) with pruritus of the body applied a w/o emulsion for 2 weeks. In a separate study, adults (n = 33) with a pruritic scalp applied an o/w-emulsion for 4 weeks. In a third study, shampoo (n = 34) was applied for 4 weeks. Objective (erythema, dryness, and papules) and subjective (intensity, duration, and burden of pruritus) parameters were assessed. RESULTS: Treatment with the w/o emulsion significantly reduced erythema and dryness (P < 0.0001) as well as pruritus (in 93% of participants) on the body. Treatment with the o/w-emulsion on the scalp significantly (P < 0.0001) reduced objective (erythema in 61% and dryness in 85% of participants) and subjective (85% of participants had reduced pruritus) parameters. Similar results in reduction of dryness (76% of participants) and pruritus (70 % of participants) were seen after 4 weeks of shampoo use. CONCLUSION: Independent from the type of emulsion (w/o or o/w), cosmetic products containing a proprietary Ec.-extract significantly reduced objective and subjective parameters in adults suffering from acute or chronic pruritus exhibiting excellent tolerability.

Metamorphosis of Vehicles: Mechanisms and Opportunities.

The visibility of a skin condition or dermatosis led to the reasonable assumption that the direct application of a therapeutic remedy to the target tissue holds many advantages. Through centuries, the nomenclature of topical preparations has proliferated and finally been moulded into the compulsory nomenclature of official compendia. In everyday life, many terms have been added and have complicated understanding and communication among and between healthcare professionals and laypersons. A large proportion of marketed topical preparations contain significant amounts of volatile vehicle ingredients that evaporate once they are applied onto the skin, that is, the vehicle format as well as the sum of vehicle ingredients in the primary container are different from the vehicle format and the sum of vehicle ingredients on the skin. This phenomenon and the potential consequences have so far been often ignored by many healthcare professionals and laypersons. To gain a better understanding, this phenomenon has been coined as the metamorphosis of the vehicle. The metamorphosis of the vehicle describes the vehicle (a) in the primary container (primary formulation), (b) during and immediately after application onto the skin (secondary formulation) and (c) after all volatile vehicle ingredients have evaporated from the vehicle on top of the skin (tertiary or residual formulation). The secondary and tertiary formulations may offer increased delivery of cosmetic or pharmaceutical actives. This is achieved by (a) an intended post-application creation of supersaturation of actives in the secondary and tertiary formulations or by (b) physico-chemical triggers such as pH.

Echinacea purpurea-derived alkylamides exhibit potent anti-inflammatory effects and alleviate clinical symptoms of atopic eczema.

BACKGROUND: Atopic eczema (AE) is a chronic inflammatory and pruritic skin disease. There is still an unmet need for topical anti-inflammatory and anti-pruritic substances exhibiting an excellent safety profile. The endocannabinoid system is known to regulate various aspects of cutaneous barrier and immune functions, thus targeting it may be a valid approach for alleviating the symptoms of AE. OBJECTIVE: To assess the putative efficacy of Echinacea purpurea-derived alkylamides (Ec. extract) activating cannabinoid (CB)-2 receptors in exerting anti-inflammatory effects and alleviating symptoms of AE. METHODS: In vitro anti-inflammatory efficiency was investigated by monitoring the effects of Ec. extract on poly-(I:C)-induced pro-inflammatory cytokine expression (Q-PCR) and release (ELISA) of HaCaT keratinocytes. Irritancy and sensitization potential (assessed by Human Repeat Insult Patch Test; Clinical trial 1); clinical efficiency in alleviating symptoms of AE (Clinical trial 2) as well as effects on human skin structure and lipid content (Clinical trial 3 followed by transmission electron microscopy and HPTLC) were investigated in randomized double blind clinical trials. RESULTS: Ec. extract significantly reduced mRNA expression as well as release of poly-(I:C)-induced pro-inflammatory cytokines (IL-6 and IL-8) in keratinocytes. Thus, not surprisingly, the well-tolerated (Clinical trial 1) Ec. extract-based cream reduced local SCORAD statistically significantly, not only compared to baseline, but also compared to the comparator (Clinical trial 2). Of great importance, besides the in vitro anti-inflammatory effects, administration of the Ec. extract-based cream also resulted in significantly higher levels of overall epidermal lipids, ceramide EOS (ω-esterified fatty acid+sphingosine sphingoid base), and cholesterol at Day 15 compared to baseline as well as significantly greater numbers of intercellular lipid lamellae in the intercellular space (Clinical trial 3). CONCLUSION: The investigated Ec. extract shows great potential in alleviating cutaneous symptoms of AE, and by exerting remarkable anti-inflammatory actions and restoring the epidermal lipid barrier, it will be very likely a well-tolerated, powerful novel ingredient for the adjuvant therapy of AE.

Design and Synthesis of Enantiomerically Pure Decahydroquinoxalines as Potent and Selective κ-Opioid Receptor Agonists with Anti-Inflammatory Activity in Vivo.

In order to develop novel κ agonists restricted to the periphery, a diastereo- and enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5-8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5-8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full κ agonistic activity in the [35S]GTPγS assay, and high selectivity over µ, δ, σ1, and σ2 receptors as well as the PCP binding site of the NMDA receptor. Several analogues were selective for the periphery. The anti-inflammatory activity of 5-8 after topical application was investigated in two mouse models of dermatitis. The methanesulfonamide 8a containing the (S)-configured hydroxypyrrolidine ring was identified as a potent (Ki = 0.63 nM) and highly selective κ agonist (EC50 = 1.8 nM) selective for the periphery with dose-dependent anti-inflammatory activity in acute and chronic skin inflammation.

Significant improvement in mild acne following a twice daily application for 6 weeks of an acidic cleansing product (pH 4).

BACKGROUND: Cleansing products for acne should remove excessive sebum, reduce acne-related bacteria and improve inflammation. AIMS: The aim of the study was to investigate a topical cleansing product containing glycolic acid with pH 4 in mild acne vulgaris. METHODS: Sixty patients were recruited for this open uncontrolled clinical trial. The tested product was exclusively applied twice a day for 6 weeks. The efficacy was judged by a dermatologist according to the Leeds score after 3 and 6 weeks. In addition, efficacy and tolerability were judged subjectively by physician and patients. RESULTS: Mild acne improved significantly after 6 weeks (baseline: 0.699 vs. day 42: 0.602; P < 0.001). Efficacy and tolerability were judged better by physician as compared with patients' assessment. CONCLUSION: In this clinical trial, a topical cleansing product containing glycolic acid with pH 4 improved mild acne significantly following twice-daily application for 6 weeks as monotherapy.

Cosmetic and dermatologic use of alpha hydroxy acids.

Alpha hydroxy acids (AHAs), in particular glycolic acid, are a class of chemical compounds frequently used in cosmetics and dermatology. This review summarizes the current knowledge regarding chemistry, mechanism of action as well as the different indications ranging from cosmetic skin hydration to acne proven by clinical trials. Overall AHAs depending on the concentration used present an ingredient for cosmetic products or medical devices with proven efficacy.

A 10% glycolic acid containing oil-in-water emulsion improves mild acne: a randomized double-blind placebo-controlled trial.

BACKGROUND: Acne is characterized by hyperseborrhea, follicular hyperkeratosis, and growth of propionibacteria. Alpha hydroxy acids depending on the pH of the finished product exhibit comedolytic as well as antimicrobial properties. OBJECTIVES: The aim of this study was to investigate an oil-in-water emulsion-containing 10% glycolic acid (pH 4; Dr. August Wolff GmbH & Co. KG Arzneimittel, Bielefeld, Germany) as monotherapy in mild acne regarding clinical efficacy and tolerability for 90 days. PATIENTS AND METHODS: Patients (n = 120; 73 f, 47 m) suffering from mild acne (Leeds score 0.25-1) aged ≥12 (mean 21 ± 5.8) were included in this double-blind, placebo-controlled, randomized, monocentric trial. The cream was applied once daily in the evening. No additional products were used. Cleansing was standardized by supplying the same product to all patients. RESULTS: The number of patients (n = 115) in the per-protocol and intention-to-treat analysis was the same. Acne improved significantly in the verum group up to day 90. Already at day 45, there was a statistical significant (5% level) difference against placebo. The subjective evaluation of the verum by physicians and patients regarding clinical efficacy and tolerability was favorable. Regarding reported adverse effects, there was no statistically significant difference (5% level) between verum and placebo. CONCLUSIONS: The 10% glycolic acid containing oil-in-water emulsion improved mild acne applied as monotherapy in this study significantly, already after 45 days of treatment. Regarding tolerability, there was no objective or subjective difference between the 10% glycolic acid containing oil-in-water emulsion and the corresponding placebo.

Dermal targeting using colloidal carrier systems with linoleic acid.

In the basic therapy of chronic skin diseases characterized by xerosis, the local treatment is an essential strategy to reach ideal therapeutic effects. Suitable active ingredients for this aim are fatty acids, in particular linoleic acid, which is an essential component for the organization and perpetuation of the skin barrier. In the present work, the development of a well-tolerated colloidal carrier system (microemulsion) containing linoleic acid as active ingredient is described. A comprehensive physiochemical characterization of the novel microemulsion system was performed using different techniques. The potential of the developed microemulsion system compared to a cream as suitable carrier for the dermal delivery of linoleic acid was determined. Penetration studies showed higher linoleic acids concentrations after administration of the colloidal carrier system in all skin layers independent of the time of incubation. Up to 23% of applied dose reached the skin from the colloidal carrier system whereas at most 8% of the active ingredient could be detected after applying the cream. Particularly, the percentage of the linoleic acids penetrated through the microemulsion in the stratum corneum and the viable epidermis differed significantly (p<0.01) when compared to that through a standard cream. Furthermore, linoleic acids accumulated in the epidermis at longer incubation times. Using the microemulsion, the penetration of linoleic acids was enhanced significantly (p<0.01). Hence, the microemulsion might be an innovative vehicle for the delivery of linoleic acids to the epidermis improving its use as their barrier regeneration and providing possible anti-inflammatory effects.

Galenics of dermal products--vehicles, properties and drug release.

The efficiency, tolerability, and applicability of topical agents are directly related to employed vehicles. Thus to achieve optimum topical therapy, a solid knowledge of the vehicles, their composition, and their physical and dermato-pharmacological actions are important. Common vehicles are complex mixtures consisting of diverse ingredients belonging to six major groups, i. e. hydrophilic and lipophilic bases, emulsifiers, gel-forming agents, preservatives, and antioxidants. This makes it possible to optimize both the cosmetic features and to adjust a vehicle to the properties of an incorporated drug and site of application. On the other hand it makes it difficult to make a proper choice between several alternatives or to use it in individual prescriptions. In order to simplify the selection of a formulation, it is useful to categorize them systemically into several groups, such as ointments, creams, gels, emulsions, and suspensions. Within these groups some general rules can be derived for the selection of a vehicle with respect to skin conditions and the application site. When active substances are incorporated into a base the dermato-biopharmaceutical properties of the whole system (drug + vehicle) also have to be considered. If for a given vehicle drug transport into the skin does not suffice, several methods are described to facilitate its penetration, such as by hydrating the skin or by adding chemical penetration enhancers.