Alternatives to Conventional Topical Dosage Forms for Targeted Skin Penetration of Diclofenac Sodium.

Skin penetration of an active pharmaceutical ingredient is key to developing topical drugs. This penetration can be adjusted for greater efficacy and/or safety through the selection of dosage form. Two emerging dosage forms, cream-gel and gel-in-oil emulsion, were tested for their ability to deliver diclofenac into the skin, with the target of maximising skin retention while limiting systemic exposure. Prototypes with varying amounts of solvents and emollients were formulated and evaluated by in vitro penetration testing on human skin. Cream-gel formulas showed better skin penetration than the emulgel benchmark drug even without added solvent, while gel-in-oil emulsions resulted in reduced diffusion of the active into the receptor fluid. Adding propylene glycol and diethylene glycol monoethyl ether as penetration enhancers resulted in different diclofenac penetration profiles depending on the dosage form and whether they were added to the disperse or continuous phase. Rheological characterisation of the prototypes revealed similar profiles of cream-gel and emulgel benchmark, whereas gel-in-oil emulsion demonstrated flow characteristics suitable for massaging product into the skin. This study underlined the potential of cream-gel and gel-in-oil emulsions for adjusting active penetration into the skin, broadening the range of choices available to topical formulation scientists.

Proderm technology: a water- based lipid delivery system for dermatitis that penetrates viable epidermis and has antibacterial effects.

BACKGROUND: A defective skin barrier and bacterial colonization are two important factors in maintenance and progression of atopic dermatitis and chronic allergic/irritant hand dermatitis. A water-based lipid delivery system containing physiologic lipids was previously shown to be a useful adjunct in the treatment of hand dermatitis. We tested the ability of this formulation to penetrate into the viable epidermis and in addition assessed its antibacterial properties. METHODS: Epidermal penetration of the product was assessed by fluorescence microscopy. Recovery of Escherichia coli and Staphylococcus aureus MRSA from skin treated with Neosalus® foam was quantified. RESULTS: Components of Neosalus® penetrated the stratum corneum and were distributed throughout the viable epidermis. Neosalus® significantly decreased recovery of both Staphylococcus aureus and Escherichia coli from the skin surface. CONCLUSIONS: The ability of components of Neosalus® to be taken up into the viable epidermis and potentially made available for incorporation into the barrier lipids, combined with antibacterial properties, indicate that this formulation may be valuable not only in chronic hand dermatitis, but also in various other forms of dermatitis. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18191379 , 28/12/2018, retrospectively registered.

Analysis of absorption and spreading of moisturizer on the microscopic region of the skin surface with near-infrared imaging.

BACKGROUND/PURPOSE: Near-infrared (NIR) light with high water absorption enables us to visualize the water content distribution appeared in the superficial skin layer. The light penetration depth with the wavelength of 1920 nm is almost 100 µm from the skin surface. Thus, the water distribution in the stratum corneum can be effectively imaged by detecting the wavelength band around 1920 nm. The aim of this article was to measure the time-lapse behavior of the tiny droplet of the moisturizer spreading on the skin surface by imaging in 1920 nm wavelength band for investigating the correlation with the traditional index of the skin condition such as the water content and transepidermal water loss (TEWL). METHODS: Experiment is performed with three moisturizer products and seven volunteer subjects. The NIR image is acquired by an originally designed imaging scope equipped with the white light of the strong brightness [super continuum (SC) light], the bandpass filter with the center wavelength of 1920 nm, and the NIR image sensor. A tiny droplet of the moisturizer is put on the surface of the skin and the time-lapse images are saved. Each acquired image is analyzed from a view point of the droplet area and elapsed time for absorption into the skin. The water content and TEWL of all subjects are measured by the conventional electrical method for investigating the relationship with the measured droplet dynamics parameters. RESULTS: Elapsed time for moisturizer droplet to be absorbed into the skin, the droplet area just before absorption for three moisturizer products, skin water contents, and TEWL for seven subjects were measured and correlation coefficients for each parameters were calculated. It was found that the skin with higher water contents or lower TEWL absorbed the moisturizer faster and spreads moisturizer wider. Also absorption and spreading speed depend on moisturizer property (moisturizing or fresh) which is originated from the moisturizer constituents. CONCLUSION: The correlation values between the moisturizer dynamics on the skin surface and the traditional index of the skin property were clarified. It was found that the skin with the high water content or low TEWL absorbs the moisturizer droplet fast. The spreading area depends not only on the skin property but on the constituents of the moisturizers.

Safety Assessment of Panax spp Root-Derived Ingredients as Used in Cosmetics.

The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 13 Panax spp root-derived ingredients as used in cosmetics. Panax "spp" indicates that multiple species within the genus are used in cosmetics, but not all species within that genus. Four species are being considered in this safety assessment. These ingredients function mostly as skin-conditioning agents-miscellaneous, fragrance ingredients, skin-conditioning agents-humectant, skin-conditioning agents-emollient, and cosmetic astringents. The Panel reviewed available data related to these ingredients and addressed the issue of pulegone, a constituent of these ingredients and other ingredients, such as peppermint oil. The Panel concluded that these Panax spp root-derived ingredients are safe in the practices of use and concentration as given in this safety assessment.

Appearance benefits of skin moisturization.

BACKGROUND/PURPOSE: Skin hydration is essential for skin health. Moisturized skin is generally regarded as healthy and healthy looking. It is thus speculated that there may be appearance benefits of skin moisturization. This means that there are corresponding changes in the optical properties when skin is moisturized. METHODS: The appearance of the skin is the result of light reflection, scattering and absorption at various skin layers of the stratum corneum, epidermis, dermis and beyond. The appearance benefits of skin moisturization are likely primarily due to the changes in the optical properties of the stratum corneum. We hypothesize that the major optical effect of skin moisturization is the decrease of light scattering at the skin surface, i.e., the stratum corneum. This decrease of surface scattering corresponds to an increase of light penetration into the deeper layers of the skin. An experiment was conducted to measure the corresponding change in skin spectral reflectance, the skin scattering coefficient and skin translucency with a change in skin hydration. In the experiment, skin hydration was decreased with the topical application of acetone and alcohol and increased with the topical application of known moisturizers and occlusives such as PJ. RESULT AND CONCLUSION: It was found that both the skin spectral reflectance and the skin scattering coefficient increased when the skin was dehydrated and decreased when the skin was hydrated. Skin translucency increased as the skin became moisturized. The results agree with the hypothesis that there is less light scattering at the skin surface and more light penetration into the deeper skin layers when the skin is moisturized. As a result, the skin appears darker, more pinkish and more translucent.

Percutaneous penetration modifiers and formulation effects: thermal and spectral analyses.

The study investigated the formulation effects of laurocapram and iminosulfurane derived penetration modifiers on human stratum corneum using thermal and spectral analyses. Firstly, formulations of penetration modifiers were assessed as enhancers/retardants using the model permeant, diethyl-m-toluamide followed by investigation of their mechanisms of action using differential scanning calorimetry (DSC) and attenuated total reflectance Fourier-transform infra-red spectroscopy. The penetration modifiers investigated were laurocapram, 3-dodecanoyloxazolidin-2-one (N-0915), S,S-dimethyl-N-(4-bromobenzoyl) iminosulfurane (DMBIS), S,S-dimethyl-N-(2-methoxycarbonylbenzenesulfonyl) iminosulfurane (DMMCBI) and tert-butyl 1-dodecyl-2-oxoazepan-3-yl-carbamate (TBDOC) that were formulated in either water, propylene glycol (PG), ethanol or polyethylene glycol 400 (PEG 400). The results explain the mechanism for the first time why an enhancer can become a retardant or vice versa depending upon the vehicle in which it is applied to the skin. DSC indicated that penetration modifier formulations enhanced permeation of active mainly by disruption and fluidization of the stratum corneum lipid bilayers while IR data indicated characteristic blue shifts with decreases in peak intensity. On the other hand, DSC of penetration modifier formulations showing retardation depicted elevated T (m2) with a strengthening of lipid-protein complex while IR results indicated formation of multiple peaks around 1,738 cm(-1) transition in stratum corneum spectra suggesting retardation may be caused by organization of SC lipids by increased H-bonding.

Evaluating lotion transfer from products to skin using the behind-the-knee test.

BACKGROUND/PURPOSE: Adding lotions or emollients to the surface of a variety of paper products confers a number of benefits to the skin of consumers. A modification of the 'behind-the-knee (BTK)' test model was used as a means of measuring the effectiveness of lotion transfer to the skin. METHODS: Two series of feminine protection pads were prepared: (1) identically constructed pads differing only in the amount of lotion applied to the surface and (2) pads of various compositions to compare the influence of other product characteristics. For the first series, pads were applied for 3 h using the BTK protocol, and lotion transfer was evaluated. For the second series of products, two sample pads were applied consecutively for 3 h each, and lotion transfer was evaluated a both time points (e.g., 3 and 6 h). In addition, a clinical in-use study was used to evaluate lotion transfer for the second product series. RESULTS: In the BTK model using pads of identical composition, lotion transfer was a function of the amount of lotion placed on the pad. However, results from the second product series indicated that when pads were prepared using different absorbant materials (supreabsorbent gelling material, or AGM and cellulose), pads with the AGM core transferred lotion more effectively than pads with a cellulose core. Other product characteristics, i.e., pad thickness and lotion configuration, did not detectibly influence lotion transfer. The results of an in-use clinical study conducted on the second series of test products were directionally similar to those from the BTK, but statistical significance was not reached. CONCLUSIONS: An adaptation of the BTK test method provides an effective means of evaluating the transfer of lotion formulations from feminine protection pads at a fraction of the cost of clinical in-use studies.

Differential deposition of emollients from tripartite formulation systems.

To date, emollients are included in skin care formulations although not much is known about their adsorption/deposition properties and/or the interactions of the constituents within these multi-component systems. The modulation of the adsorption/deposition via the use of specific surfactant and/or emollient systems could therefore help to increase performance and sensorial benefits as well as to reduce adverse effects. In this study, the effects of various tripartite systems consisting of sodium laureth sulphate (SLES), a co-surfactant and an emollient were studied. The two different emollients tested adsorbed with varying amounts although the same surfactant/co-surfactant system was used. Interestingly, the deposition of both SLES and/or the emollient is also substantially influenced by the emollient component itself as well as by the co-surfactant used. Sensory assessments showed that although SLES has a negative effect on the skin feel, adsorbed emollients improve skin softness and smoothness. These results show that optimization of performance is possible when using a co-surfactant best suited for the emollient.

Final report on the safety assessment of PPG-2 methyl ether, PPG-3 methyl ether, and PPG-2 methyl ether acetate.

PPG-2 methyl ether, PPG-3 methyl ether, and PPG-2 methyl ether acetate are used in cosmetics as fragrance ingredients and/or solvents at concentrations of 0.4% to 2%. Propylene glycol ethers are rapidly absorbed and distributed throughout the body when introduced by inhalation or oral exposure, but the inhalation toxicity of PPG-2 methyl ether vapor, for example, is low. Aerosols, such as found with hair sprays, produce particle sizes that are not respirable. Because these ingredients are highly water-soluble, they are likely to be absorbed through the human skin only at slow rates, resulting in low blood concentrations and rapid removal by the kidney. These ingredients are not genotoxic and are not reproductive or developmental toxicants. Overall the data are sufficient to conclude that PPG-2 methyl ether, PPG-3 methyl ether, and PPG-2 methyl ether acetate are safe as used in cosmetics.

Impact of order of application of moisturizers on percutaneous absorption kinetics: evaluation of sequential application of moisturizer lotions and azelaic acid gel 15% using a human skin model.

The medical management of rosacea increasingly has involved not only the appropriate selection of topical medication but also patient education and specific recommendations regarding appropriate skin care. The recognition that epidermal barrier dysfunction and transepidermal water loss (TEWL) play a pathophysiologic role in rosacea and that skin moisturization may help to mitigate signs and symptoms of the disease has led to a deeper appreciation of the importance of proper skin care in the treatment of rosacea. Data from a percutaneous penetration study performed using human skin suggest that any of the tested moisturizer lotions may be applied either before or after azelaic acid gel 15% without a major change in the percutaneous absorption profile of azelaic acid.

Pilot study: absorption and efficacy of multiple hormones delivered in a single cream applied to the mucous membranes of the labia and vagina.

BACKGROUND/AIMS: There is a lack of evidence in the literature supporting vaginal application of a combination hormone-containing cream for local and systemic symptom relief. This pilot study examined the extent of absorption of a single cream containing estriol, estradiol, progesterone, DHEA, and testosterone. METHODS: A combination cream was administered to 12 postmenopausal women in two differing doses over two independent time periods. Following 28 days (arm 1) and an additional 14 days (arm 2), measurement of hormones in saliva and blood and measurements of symptom relief, patient tolerability, and health-related quality of life (HRQoL) were obtained. RESULTS: The dosage and time of evaluation for study arm 1 was not ideal for providing documented increases in hormone levels. HRQoL measurements supported measured improvement in this arm. The second arm did document absorption of the various hormones when given vaginally. CONCLUSION: This study is the first documenting systemic absorption of multiple hormones by both saliva and blood as well as improvement of HRQoL. This therapy was generally well-tolerated with only 2 patients experiencing minor irritation, not necessitating discontinuation. Additional studies in larger numbers of patients will provide better knowledge for clinicians wanting to provide similar therapy at the lowest effective dose.

Kinetics of moisturizing and firming effects of cosmetic formulations.

The assessment of cosmetic efficacy is rarely performed in studies comparing different concentrations of active compounds. The aim of the present study was to determine the skin hydrating and the skin firming dose-response effects of cosmetic formulations enriched in compounds derived from algae and fish collagen. A series of factors were studied including the type of formulation (cream or serum), the concentration in active ingredients, the effect of repetitive applications, as well as any residual effect of the formulations after stopping their applications. The serum enriched in marine compounds showed a better moisturizing effect in short term. The cream appeared more active later, particularly following repeat applications. A sustained tensor (firming) effect was observed during treatment with both the lotion and the cream. However, no remnant firming effect was perceived after stopping treatment.

Vaginal distribution of Replens and K-Y Jelly using three imaging techniques.

BACKGROUND: Determination of vaginal distribution is important to the development of potential vaginal microbicidal or spermicidal products. STUDY DESIGN: This was a descriptive study of three imaging techniques with a randomized crossover assignment of two gels and activity status within each technique. METHOD: Each of three sites utilized one technique. Three nulligravid women and three parous women were to be enrolled at each site. We studied the effects of time, ambulation, parity and body mass index on vaginal spreading of two commonly used gels, K-Y Jelly and Replens. Imaging by magnetic resonance imaging and gamma scintigraphy was performed at 5, 20, 35 and 50 min after insertion of 3.5 mL of gel. Imaging with a fiberoptic probe was performed at 5 and 20 min after insertion. RESULTS: Initial application of the gel resulted in approximately two thirds of maximum coverage possible, both in linear extent along the vaginal axis and in surface area covered. Over the next 45 min, spreading increased to about three quarters of the maximum possible. Ambulation generally increased linear spreading and the proportions of women with gel at the introitus and os. Effects of parity and body mass index (BMI) were similar on most measures of gel spreading, with nulligravid women tending toward greater spread than parous women and women of high BMI usually showing somewhat greater spread than women of normal weight. Differences between the two gels were not seen when all conditions of application were considered together. CONCLUSION: In vivo imaging of gel distribution demonstrated that ambulation, parity and BMI affect vaginal gel spreading. The three imaging techniques have advantages and disadvantages and provide complementary information for microbicide development.

Protection effect of cosmetics on human skin under simulated rigorous environment.

BACKGROUND/PURPOSE: The efficacy of cosmetics on human skin measured under normal mild laboratory environment might be discounted by exterior environment factors such as wind, UV exposure, etc. Few studies have focused on the 'genuine' efficacy of cosmetics on human skin during exposure to external rigorous environment. The aim of this study was to develop a model for the evaluation of the efficacy of cosmetics on human skin under simulated rigorous environment. METHODS: We measured skin water content and transepidermal water loss (TEWL) before and after products application under simulated windy and sub-erythema UV exposure treatment in a constant temperature and humidity laboratory. RESULTS: The results showed that the products had higher water content and lower TEWL at 2, 4 and 8 h of products application, and ameliorated the skin moisturization situation after a 3-week continuous use of the products. In addition, the products might protect the skin to maintain the normal water content and TEWL under the simulated windy or sub-erythema UV exposure treatment in our laboratory when compared with untreated area. CONCLUSION: Our data indicate that this model may provide a more accurate evaluation for the genuine moisturizing effect of cosmetics under external natural climate.

Placebo-controlled, double-blind, randomized, prospective study of a glycerol-based emollient on eczematous skin in atopic dermatitis: biophysical and clinical evaluation.

BACKGROUND/AIMS: Atopic dermatitis (AD) is a frequent, chronic inflammatory disease influenced by local, immunological, genetic and environmental factors. Important symptoms of AD are dry skin, intense pruritus and impaired epidermal barrier function. The therapeutic management of AD is difficult and needs individualized concepts. Moisturizing creams and emollients are useful and important treatment adjuncts for the daily skin care of patients with dry and inflamed skin, e.g. AD. Glycerol is known to increase stratum corneum (SC) hydration, improve epidermal barrier function and decrease clinical signs of inflammation. However, no controlled study on the efficacy of glycerol on barrier function and SC hydration in AD has been published. In the present study, a topical 20% glycerol preparation was compared with its vehicle in patients with AD. The aim of the present study was to evaluate the effect of a single emollient ingredient in AD within the full frame of a phase III drug study. METHODS: 24 patients with AD were treated for 4 weeks twice daily with a glycerol-based emollient in a randomized, double-blind study. Transepidermal water loss, skin capacitance, erythema and skin surface pH were assessed with biophysical, non-invasive instruments. The SCORAD and a local severity score were evaluated. After a wash-out period of 2 weeks, these parameters were assessed in order to quantify the sustained effect of this treatment. RESULTS: SC hydration was significantly improved, and epidermal barrier function was restored under treatment with glycerol-containing cream compared to the glycerol-free placebo. No significant differences were detectable for erythema values, SCORAD and local severity between the glycerol-containing cream and placebo. However, an improvement over time was detectable in the assessed parameters in both groups indicating the importance of emollient treatment in AD. CONCLUSIONS: Glycerol-based emollients have a positive influence on the skin of patients with AD. They enhance the SC hydration. Furthermore, it was possible to evaluate skin care products with a protocol design for efficacy studies of fully registered drugs in a placebo-controlled study.

New cosmetic emulsions for dry skin.

The aim of this study was to formulate stable water-in-oil (w/o) emulsions containing oils with a high percentage of fatty acids, sterols, vitamins, cholesterol, and ceramides in order to improve topical treatment of dry skin conditions. Two w/o emulsions were developed and physicochemical characterized. The biological effects of the formulations were assessed on the volar surface of the human foreharm over 28 days. The results obtained showed that areas treated by either cream were significantly different from the control area, as assessed by epidermal capacitance and sebometry over the 28 days. Treatment with cream containing ceramides presented higher values of sebometry and corneometry. According to the sensory evaluation performed, both creams were found to have good acceptability.

Skin-conditioning products in occupational dermatology.

Moisturizers are frequently used in the prevention of occupational contact dermatitis. This review discusses their chemistry and mode of action. Methods to prove their preventive efficacy are presented. In addition to pharmacological efficacy, subjective factors that influence application of the products and compliance come into play. In conclusion, moisturizers are only one element of skin-disease prevention at the workplace that should be viewed as a complex, inter-dependent system. The efficacy of the complete, integrated system of occupational skin care has to be proven.

In vitro evaluation of the efficacy of skin barrier creams and protective gloves on percutaneous absorption of industrial solvents.

OBJECTIVES: The aim of the experiments was to evaluate the efficacy of skin barrier creams (SBCs) and protective gloves and its potential for reduction of percutaneous absorption of industrial solvents. METHODS: We assessed percutaneous absorption of ethylene glycol (EG), isopropyl alcohol (IA) and 1,2,4-trimethylbenzene (TMB), using static diffusion cells. These solvents were applied neat (EG, TMB) as well as in 10% and 50% aqueous solution (EG, IA) or in 10% and 50% ethanol-diluted solution (TMB). Furthermore, we tested the percutaneous absorption of IA mixed in one cleaning agent (CA), used in newspaper printing shops to clean the rollers of printing machines. Additionally, the penetration behaviour of 10% and 50% solutions of EG, IA and TMB was tested. The experiments were carried out on untreated and on SBC-treated excised human skin from one donor, and on protective gloves. Saline was used as receptor fluid for EG and IA, and neat ethanol for TMB. RESULTS: The penetration of 50% EG, IA and TMB solutions through SBC-treated skin was higher than in untreated skin (factor 3.9 for EG, 0.32 for IA and 0.06 for TMB). The penetration of IA in the IA-CA mixture was five-times higher through untreated skin as for the single compound in 10% aqueous solution. In skin, treated with SBC, we found a 17-fold penetration enhancement of IA in the IA-CA mixture. No appreciable penetration of EG and IA was observed through nitrile rubber gloves. CONCLUSIONS: Our in vitro experiments could not demonstrate an efficacy of SBC to protect skin penetration for the tested solvents. The percutaneous absorption of all solvents in 50% solution was increased through skin treated with SBCs. Furthermore, SBCs enhance the penetration rates of solvents from complex mixtures compared with the single solvents. The tested gloves showed sufficient protection for the hydrophilic solvents, but not for TMB.

In vivo measurement of human skin absorption of topically applied substances by a photoacoustic technique.

A photoacoustic technique is used for studying topically applied substance absorption in human skin. The proposed method utilizes a double-chamber PA cell. The absorption determination was obtained through the measurement of the thermal effusivity of the binary system substance-skin. The theoretical model assumes that the effective thermal effusivity of the binary system corresponds to that of a two-phase system. Experimental applications of the method employed different substances of topical application in different parts of the body of a volunteer. The method is demonstrated to be an easily used non-invasive technique for dermatology research. The relative concentrations as a function of time of substances such as ketoconazol and sunscreen were determined by fitting a sigmoidal function to the data, while an exponential function corresponds to the best fit for the set of data for nitrofurazona, vaseline and vaporub. The time constants associated with the rates of absorption, were found to vary in the range between 10 and 58 min, depending on the substance and the part of the body.