The use of biodegradable microneedle patches to increase penetration of topical steroid for prurigo nodularis.

BACKGROUND: The stratum corneum is an almost impermeable barrier. Recently, microneedles have been used to increase drug delivery passing the stratum corneum by incorporating the drug within the microneedle or by coating the surface of the microneedle with the drug. OBJECTIVE: This study was performed to investigate whether applying a biodegradable microneedle patch after topical steroid application increases penetration of the steroid in vitro, as well as treatment efficacy in patients with prurigo nodularis. MATERIALS & METHODS: In vitro penetration of topical steroids after biodegradable microneedle patch application was measured using a 3D skin model. To evaluate the treatment efficacy of the combination of biodegradable microneedle and topical steroids, a split-body clinical study was performed. RESULTS: Penetration of topical steroid in the in vitro skin model was significantly greater in the microneedle-applied skin. In a split-body clinical study with prurigo nodularis patients, the area and height of skin lesions decreased after four weeks of treatment on both sides, however, the microneedle patch side exhibited a significantly greater decrease in both area and height, compared to the control side. The pruritus visual analogue scale was also significantly lower on the microneedle side. CONCLUSION: We suggest that simply applying a microneedle patch after topical steroid application could be a useful strategy for treating refractory skin diseases such as prurigo nodularis.

Preclinical Assessment of Steroidal Nanostructured Lipid Carriers Based Gels for Atopic Dermatitis: Optimization and Product Development.

BACKGROUND: Betamethasone Valerate (BV) is a potent topical corticosteroid. Preparation of nanostructured lipid carriers (NLC) involves process parameters optimization and formulations were developed. It is available in several conventional formulations like creams and ointments which have well-known problems of frequent dosing and consequently additional side effects. The aim is to ascertain the probability of NLC as an exclusive carrier for betamethasone valerate topical application with regard to release modulation and improved therapeutic effect. METHOD: Preparation of BVNLC formulations involves rigorous broad range optimization of process parameters viz. selection of lipids, surfactants, formulation technique, stirring time, stirring speed and homogenization cycles. Accordingly, optimized parameters were selected and formulation table was developed. Characterizations of developed NLC comprise particle shape, size, zeta potential, percent drug entrapment, in vitro drug release studies. The optimized NLC formulation was gelled and evaluated for ex vivo permeation studies and preclinical anti-inflammatory testing. RESULTS: The permeation studies revealed that enhancement ratio of BVNLC based gel was 2.59 folds higher as compared to plain BV gel. Release models indicated anomalous (non-fickian) diffusion viz. drug release is controlled by more than one process i.e. superposition of both phenomenon, the diffusion controlled as well as swelling controlled release. Preclinical studies indicated a significant (P < 0.05) extended anti-inflammatory effect and 16.5% inhibition compared to plain gel. CONCLUSION: The outcome of entire characterization advocates that the developed formulation is efficient as once a day dosing in therapy of atopic dermatitis.

Bioequivalence Methodologies for Topical Drug Products: In Vitro and Ex Vivo Studies with a Corticosteroid and an Anti-Fungal Drug.

OBJECTIVE: To examine whether in vitro and ex vivo measurements of topical drug product performance correlate with in vivo outcomes, such that more efficient experimental approaches can be reliably and reproducibly used to establish (in)equivalence between formulations for skin application. MATERIALS AND METHODS: In vitro drug release through artificial membranes, and drug penetration into porcine skin ex vivo, were compared with published human in vivo studies. Two betamethasone valerate (BMV) formulations, and three marketed econazole nitrate (EN) creams were assessed. RESULTS: For BMV, the stratum corneum (SC) uptake of drug in 6 h closely matched data observed in vivo in humans, and distinguished between inequivalent formulations. SC uptake of EN from the 3 creams mirrored the in vivo equivalence in man (both clinically and via similar tape-stripping experiments). However, EN clearance from SC ex vivo did not parallel that in vivo, presumably due to the absence of a functioning microcirculation. In vitro release of BMV from the different formulations did not overlap with either ex vivo or in vivo tape-stripping data whereas, for EN, a good correlation was observed. No measurable permeation of either BMV or EN was detected in a 6-h in vitro skin penetration experiment. CONCLUSIONS: In vitro and ex vivo methods for topical bioequivalence determination can show correlation with in vivo outcomes. However, these surrogates have understandable limitations. A "one-size-fits-all" approach for topical bioequivalence evaluation may not always be successful, therefore, and the judicious use of complementary methods may prove a more effective and reliable strategy.

Biophysical elucidation of the mechanism of enhanced drug release and topical delivery from polymeric film-forming systems.

The effect of incorporating the lipidic medium-chain triglyceride (MCT) into polymeric film-forming systems (FFS) for topical drug delivery has been evaluated. First, the in vitro release of betamethasone-17-valerate (BMV), a representative dermatological drug, was determined from FFS comprising either hydrophobic polyacrylate co-polymers, or hydrophilic hydroxypropyl cellulose, with and without MCT. Release was enhanced from both polymers in the presence of MCT. Atomic force microscopy imaging and nanoindentation of FFS with MCT revealed two-phase structured films with softer inclusions (0.5 to 4µm in diameter) surrounded by a more rigid structure. Chemical mapping with Raman micro-spectroscopy showed that MCT was primarily confined to the inclusions within the polymer, which predominated in the surrounding film. BMV was distributed throughout the film but was more concentrated outside the inclusions. Furthermore, while BMV dissolved better into the hydrophobic films, it was more soluble in the MCT inclusions in hydrophilic films, suggesting its increased availability for diffusion from these softer regions of the polymer and explaining the release enhancement observed. Second, ex vivo skin penetration studies clearly revealed that uptake of BMV was higher from hydrophobic FFS than that from the more hydrophilic polymer due, at least in part, to the superior anti-nucleation efficiency of the former. Drug was quickly taken up into the SC from which it then diffused continuously over a sustained period into the lower, viable skin layers. In the presence of MCT, the overall uptake of BMV was increased and provides the basis for further optimisation of FFS as simple, convenient and sustained formulations for topical therapy.

Comparison of PLGA and lecithin/chitosan nanoparticles for dermal targeting of betamethasone valerate.

Poly(lactide-co-glycolide) (PLGA) and lecithin/chitosan (LC) nanoparticles were prepared to evaluate the difference in the behavior upon administration on skin, for steroidal treatment. For this purpose, betamethasone-17-valerate (BMV)-loaded nanoparticles with a narrow size distribution and high entrapment efficiency were prepared. Permeation studies showed that both polymeric nanoparticles enhanced the amount of BMV in epidermis, which is the target site of topical steroidal treatment, when compared with commercial formulation. 1.58-Fold increase was determined in the epidermis concentration of BMV by LC nanoparticles with respect to PLGA nanoparticles. Nanoparticles were diluted in chitosan gel (10%, w/w) to prepare suitable formulation for topical application. Accumulation from both gel formulations were found significantly higher than commercial formulation in skin layers (p < 0.05). In addition, pharmacodynamic responses were also investigated as anti-inflammatory and skin-blanching parameters. Both formulations significantly improved these parameters although they contained 10 times less amount of BMV than commercial cream. Moreover, TEWL measurement exhibited no barrier function changes upon the application of nanoparticles on skin. Overall, both nanoparticles improved the localization of BMV within skin layers; but when compared with PLGA nanoparticles, the LC nanoparticles could be classified as a better candidate for topical delivery vehicle in the treatment of various dermatological inflammatory diseases.

Drug release and skin penetration from solid lipid nanoparticles and a base cream: a systematic approach from a comparison of three glucocorticoids.

Solid lipid nanoparticles (SLNs) can enhance drug penetration into the skin, yet the mechanism of the improved transport is not known in full. To unravel the influence of the drug-particle interaction on penetration enhancement, 3 glucocorticoids (GCs), prednisolone (PD), the diester prednicarbate (PC) and the monoester betamethasone 17-valerate (BMV), varying in structure and lipophilicity, were loaded onto SLNs. Theoretical permeability coefficients (cm/s) of the agents rank BMV (-6.38) ≥ PC (-6.57) > PD (-7.30). GC-particle interaction, drug release and skin penetration were investigated including a conventional oil-in-water cream for reference. Both with SLN and cream, PD release was clearly superior to PC release which exceeded BMV release. With the cream, the rank order did not change when studying skin penetration, and skin penetration is thus predominantly influenced by drug release. Yet, the penetration profile for the GCs loaded onto SLNs completely changed, and differences between the steroids were almost lost. Thus, SLNs influence skin penetration by an intrinsic mechanism linked to a specific interaction of the drug-carrier complex and the skin surface, which becomes possible by the lipid nature and nanosize of the carrier and appears not to be derived by testing drug release. Interestingly, PC and PD uptake from SLN even resulted in epidermal targeting. Thus, SLNs are not only able to improve skin penetration of topically applied drugs, but may also be of particular interest when specifically aiming to influence epidermal dysfunction.

Percutaneous permeation of betamethasone 17-valerate incorporated in lipid nanoparticles.

Corticosteroids are therapeutic agents widely used in the pharmacological treatment of skin diseases such as eczema or psoriasis. Unfortunately, their use is restricted by the side effects that frequently occur at the systemic level. The goal of the research described here was to develop and characterize a solid lipid nanoparticle (SLN) system containing corticosteroids for prolonged and localized delivery of the active drugs into the skin. In vitro measurements of Betamethasone 17-valerate (BMV) permeation through human epidermis were conducted using static Franz diffusion cells. The reservoir formation of the drug in the epidermal and dermal layers of the skin was also investigated. Monostearin SLN showed remarkable controlled release properties and a significant epidermis drug reservoir. On the other hand, beeswax SLN could not reduce the drug permeation through the skin, nor increase the drug content in the upper layers of the skin. The diffusion of corticosteroids into the skin appeared to be dependent on the lipid composition of the monostearin SLN. Topical SLN products show great potential for treating dermatological conditions by targeting corticosteroids to epidermal/upper dermal disease sites while minimizing systemic drug absorption.

Deoxycholate hydrogels of betamethasone-17-valerate intended for topical use: In vitro and in vivo evaluation.

The aim of this study was to evaluate the suitability of sodium-deoxycholate (Na-DOC) gels containing betamethasone-17-valerate (BMV) for topical application. The gels were characterized for rheological and textural properties. The in vitro flux of BMV from Na-DOC gels across rat skin was 2.5 (0.05% gel) and 8.5 times (0.1% gel) higher compared to the commercial cream (0.1%), respectively. The pharmacodynamic responses after in vivo topical application in rats were also determined. A significant correlation between anti-inflammatory activity and in vitro permeation of BMV was observed. Na-DOC gels produced significantly higher edema inhibition compared to commercial cream at all time intervals. Finally, according to the results of histology studies, Na-DOC gel has no irritant effect on the skin. In conclusion, Na-DOC gel formulation could be suggested as a promising alternative system for the topical application of BMV.

Corticosteroid solubility and lipid polarity control release from solid lipid nanoparticles.

Solid lipid nanoparticles (SLN) show promise as a drug delivery system for skin administration. The solid state of the lipid particle enables efficient drug encapsulation and controlled drug release. The present study addresses the influence of lipid composition and drug substance lipid solubility on the in vitro release profile of corticosteroids from SLN for topical administration. Firstly, the effect of lipid composition on the lipid solubility and in vitro release of betamethasone-17-valerate (BMV) was determined by varying the lipid monoglyceride content and the chain length of the fatty acid moiety. Secondly, the effect of drug substance physicochemical properties was determined by studying five different corticosteroid derivatives with different lipophilicity. A high concentration of monoglyceride in SLN increased the amount of BMV released. The corticosteroid release rate depended on the drug substance lipophilicity and it was clear that the release profiles depended on drug partitioning to the aqueous phase as indicated by zero order kinetics. The results emphasize that the corticosteroid solubility in the lipid phase greatly influence drug distribution in the lipid particles and release properties. Thus knowledge of drug substance solubility and lipid polarity contributes to optimize SLN release properties.

Comparative permeation studies of nondiluted and diluted betamethasone-17-valerate semisolid formulations through isolated human stratum corneum and artificial skin construct.

PURPOSE OF THE STUDY: This article deals with a comparative study of the permeation of the halogenated corticosteroid betamethasone-17-valerate (BM-17-V) through isolated human stratum corneum (SC) and artificial skin constructs (ASC) from different semisolid formulations described in the German Pharmacopoeia, i.e. wool fat alcohol ointment (WO), basis cream DAC (German Drug Code) and commercial products containing BM-17-V 0.1% weight such as Celestan-V cream, Celestan-V ointment, and Soderm ointment. In this study, pharmacopoeial ointment and cream were loaded in each case with BM-17-V. METHODS: In vitropermeation experiments of BM-17-V were carried out in Franz diffusion cells using isolated human SC and ASC. Permeation data from both systems were compared statistically and those data were linearly correlated to each other. The saturation concentrations of BM-17-V within the formulations were calculated based on microscopical examination. The BM-17-V was metabolized via BM-21-V into betamethasone (BM) as its hydrolization product during the permeation experiments across SC. Since ASC has a higher enzymatic activity and less barrier qualities than SC, furthering the course of the permeation experiment, not only BM permeates besides the noncatabolized drug BM-17-V, but also 9alpha-fluoro-prednisolone as another decomposition product. The detection of BM-17-V and its degradation product was performed by high-performance liquid chromatography. RESULTS: It was observed that the permeation of BM across ASC from all the formulations tested was higher by factors 9.7-27.7 than that from the same formulations permeating through SC, while the permeation sequence of the tested formulations was almost the same for SC and ASC. Afterwards the effect of the dilution of the semisolid formulations containing BM-17-V 0.1% weight on their permeation through SC was examined by mixing them with different ointments and a cream base. The permeation rate of BM from the dilution of Soderm ointment with WO and from WO diluted with different formulations from the German Pharmacopoeia were very similar.

Dermatopharmacokinetics of betamethasone 17-valerate: influence of formulation viscosity and skin surface cleaning procedure.

The objective was to compare the in vivo distribution profiles of betamethasone 17-valerate (BMV) across the stratum corneum (SC) following (a) delivery from gelled and un-gelled formulations, and (b) two different skin cleaning procedures at the end of the application period. BMV was dissolved in gelled and un-gelled vehicles comprising either medium chain triglycerides (MCT) or a brand microemulsion (ME). The BMV concentration was adjusted to 80% of saturation and applied to the forearms of healthy volunteers. After 2 h, the treated skin site was cleaned either with a dry paper towel or with an isopropyl alcohol swab, and the SC was then progressively removed by repeated adhesive tape-stripping. BMV distribution profiles across the SC showed reasonable reproducibility, and that delivery from the ME was significantly superior to that from MCT. Gelled vehicles were less efficiently removed from the skin surface by dry wiping than un-gelled formulations. Removing excess formulation more aggressively with isopropyl alcohol resulted in a lower apparent uptake of drug into the SC. Excess gelled formulation may be trapped in the skin 'furrows', and requires an efficient skin cleaning procedure to ensure its complete removal.

Pharmacodynamics and dermatopharmacokinetics of betamethasone 17-valerate: assessment of topical bioavailability.

BACKGROUND: The bioavailability of most topically delivered drugs is difficult to quantify, but is generally believed to be very low. With the exception of the vasoconstrictor assay for corticosteroids, no methodology to quantify the rate and extent of drug delivery to the skin has been validated. Recent research has examined the dermatopharmacokinetic (DPK) technique, which is based on stratum corneum (SC) tape-stripping. OBJECTIVE: To compare the in vivo bioavailability of different topical formulations of betamethasone 17-valerate (BMV) using the vasoconstrictor assay and the DPK method. METHODS: BMV was formulated in different vehicles and the drug concentration was adjusted to either (i) equal thermodynamic activity, or (ii) a range of values up to that corresponding to 80% of maximum thermodynamic activity. Vasoconstriction, an accepted and widely used method to determine bioavailability and bioequivalence of topical steroids, was quantified with a chromameter over 24 h post-removal of the formulation. Drug uptake into the SC was assessed by tape-stripping. RESULTS: BMV at the same thermodynamic activity in different vehicles provoked similar skin blanching responses, while DPK profiles distinguished between the formulations. Further, skin blanching responses and drug uptake into the SC clearly depended upon the absolute BMV concentration applied. However, while the saturable nature of the pharmacodynamic response was clear, the tape-stripping method distinguished unequivocally between the different formulations and different concentrations. CONCLUSIONS: The DPK approach offers a reliable metric with which to quantify transfer of drug from the vehicle to the SC, and may be useful for topical bioavailability and bioequivalence determinations.

Multilayer PVA adsorption onto hydrophobic drug substrates to engineer drug-rich microparticles.

Despite the availability of numerous crystal engineering techniques, generating drug-rich microparticles with a predetermined size, morphology and crystallinity still represents a significant challenge. A microparticle manufacturing method has recently been developed that attempts to 'shield' the physicochemical properties of micronised drugs by the application of a microfine polymer coating. The aims of this study were to investigate the nature of the drug-polymer interactions and determine the effects of this manufacturing strategy upon release of the drug from the microparticles. The adsorption of poly(vinyl alcohol) (PVA) on the micronised hydrophobic drug surface was found to reach equilibrium between 23 and 27 h. The Freundlich isotherm model was shown to give the most accurate fit to the experimental data and thus multilayer adsorption was assumed. The adsorptive capacity (1/n) was specific to the substrate and PVA grade. An increase in the PVA (%) hydrolysis value caused 1/n to increase from 0.76 to 1.05 using budesonide and from 0.31 to 0.79 when betamethasone valerate (BMV) was used. Increasing the molecular weight of the adsorbing polymer caused a reduction in the strength of PVA-adsorbate interaction when budesonide was used as the substrate (from 0.76 to 0.59), whereas a three-fold increase (from 0.31 to 0.86) was achieved when the BMV substrate was employed. A proportion of the adsorbed polymer was shown to remain associated with the substrate during the spray-drying process and the polymer coating resulted in a significantly higher (p<0.05, ANOVA) amount of drug release in 60 min (ca. 100%) compared to budesonide alone.

Development of an in vitro skin permeation model simulating atopic dermatitis skin for the evaluation of dermatological products.

Atopic dermatitis (AD) skin has a defective barrier function as indicated by increased transepidermal water loss (TEWL). In order to test potential new formulations for AD, it was our aim to develop a skin permeation model simulating AD skin by inducing barrier impairment to otherwise healthy skin simulating the barrier properties of AD skin as evaluated by TEWL measurements. Pig ear skin was mounted to Franz-type diffusion cells. Skin barrier impairment was induced by tape strippings. As the number of strips increased, higher TEWL values were obtained. By performing 25 tape strippings, the TEWL value within the range reported for involved skin of AD patients was reached. The in vitro skin permeation of fusidic acid and betamethasone-17-valerate was found to correlate with the number of tape strippings used to remove stratum corneum cell layers. A comparison of the permeability of fusidic acid and betamethasone-17-valerate from Fucicort cream to a new Fucicort Lipid formulation was studied with intact (0 strippings) and barrier-impaired skin simulating involved AD skin (25 strippings). As opposed to intact skin, no statistically significant difference through barrier-impaired skin was found for fusidic acid and betamethasone-17-valerate for the two formulations. This is in accordance with the clinical results of an international multicentre study and thus confirms the predictability of the model.

Topical corticosteroid in foam vehicle offers comparable coverage compared with traditional vehicles.

BACKGROUND: A new preparation of betamethasone valerate in a novel foam vehicle is available for treatment of scalp dermatoses. The vehicle spreads between hair until it reaches the scalp, where it melts and delivers the active drug. Solids make up only a tiny fraction of the foam vehicle, leaving no apparent residue on the skin or hair. The uniqueness of this vehicle raises the question of how to compare it with other topical corticosteroid preparations. OBJECTIVE: The purpose of this study was to determine the equivalency of a given quantity of the foam product to quantities of drugs in conventional vehicles. METHODS: The number of fingertip units (FTUs) per gram and the area of coverage of an FTU of betamethasone valerate foam vehicle were determined and compared with those of cream, lotion, gel, and solution psoriasis treatments. RESULTS: The weight of an FTU of foam vehicle was 52.5 +/- 5.7 microg. There were 9 to 12 times as many FTUs in 100 g of vehicle foam as in 100 g of cream or gel and 2.3 to 2.8 times as many as in 100 g of lotion or solution. The area covered by an FTU of foam vehicle was less than the area covered by an FTU of cream or gel. CONCLUSION: The characteristics of foam vehicle are different from those of other vehicles. The greater number of FTUs in 100 g of foam vehicle made up for the lower coverage per FTU, such that total coverage area for 100 g of foam vehicle was comparable to the coverage area for 100 g of the drugs in traditional vehicles.

Betamethasone valerate foam 0.12%: a novel vehicle with enhanced delivery and efficacy.

BACKGROUND: A new topical formulation of betamethasone valerate (BMV) with enhanced dermal penetration has been developed. OBJECTIVE: These studies were designed to evaluate: (1) the relative bioavailability of BMV foam, and (2) the safety and efficacy of BMV foam in the treatment of scalp psoriasis as compared to a lotion formulation of BMV and placebo. METHODS: Safety and efficacy were evaluated in a randomized, multicenter, double-blind, active-and placebo-controlled trial in adult patients with moderate to severe scalp psoriasis. A separate study in 18 patients was conducted to evaluate the potential for suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Relative bioavailability was measured using the human cadaver skin model. RESULTS: 72% of patients using BMV foam were clear or almost clear of disease at the end of 28-days of treatment as judged by the investigator's global assessment of response. Only 47% of BMV lotion patients and 21% of placebo showed a similar level of response. There was no evidence of increased toxicity or HPA-axis suppression for BMV foam, but assessment of relative bioavailability showed BMV penetration into the skin to be more than two-fold greater than from BMV lotion. CONCLUSIONS: A novel foam formulation with enhanced BMV bioavailability has been shown to be of increased efficacy in the treatment of scalp psoriasis without an associated increase in toxicity.

Skin penetration and metabolism of topical glucocorticoids in reconstructed epidermis and in excised human skin.

PURPOSE: To investigate pharmacokinetic differences between the nonhalogenated double ester prednicarbate (PC) and the fluorinated monoester betamethasone 17-valerate (BM17V) their metabolism in human keratinocytes and fibroblasts as well as their permeation and biotransformation in reconstructed epidermis and excised human skin was compared. Special attention was given to the 17-monoesters because of their high receptor affinity and antiproliferative effects. METHODS: Glucocorticoid penetration was determined using Franz diffusion cells, quantifying metabolite concentrations by HPLC. Chemical stability and reactivity of the monoesters was determined by molecular modeling analysis. RESULTS: PC accumulated in the stratum corneum. A considerable amount of penetrating PC was hydrolyzed by viable keratinocytes to prednisolone 17-ethylcarbonate (PI7EC), P17EC permeated the skin very rapidly when compared to BM17V. Overall P17EC concentrations in viable tissue were low. Inside of the acceptor fluid, but not within the tissue, P17EC was converted to the more stable prednisolone 21-ethylcarbonate (P21EC). CONCLUSIONS: The inactivation of highly potent, but also cell toxic, 17-monoesters to almost inactive 21-congeners seen with isolated cell monolayers appears less important in the skin. In vitro determination of the dermal 17-monoesters concentrations may allow the prediction of the atrophogenic risk in man. BM17V levels exceeding P17EC concentration about 6-fold may contribute to its lower tolerance when compared to PC.

In vitro percutaneous absorption of fusidic acid and betamethasone 17-valerate across canine skin.

The penetration of betamethasone 17-valerate and fusidic acid through dog skin was measured in vitro. In order to detect the small amounts of diffused compounds, a liquid chromatography-mass spectrometric method was developed with sensitivity limits for both compounds of 5 ng/ml. After application to the skin surface of a topical gel preparation containing these compounds at the anticipated therapeutic dose rate, about 10 per cent of the betamethasone 17-valerate penetrated the skin over a 24-hour period, with no significant metabolism of the ester. About 1.3 per cent of the applied dose of fusidic acid was similarly recovered. The results demonstrated rapid penetration of both compounds through the epidermis.