Desonide Nanoemulsion Gel for Transdermal Absorption Drug Delivery: Pharmacodynamic and Safety Evaluation.

BACKGROUND: When administered transdermally, desonide is ineffective due to its poor solubility. As a new transdermal delivery system, nanoemulsion gel has demonstrated significant advantages for drug delivery over conventional formulations. We have established desonide nanoemulsion gel (DES NE gel) for better transdermal absorption, but its efficacy and safety still need to be evaluated. This study aims to provide additional evidence demonstrating the improved pharmacodynamics and safety of transdermal delivery of Desonide via nanoemulsion gel. METHODS: Pharmacodynamics and safety of Desonide nanoemulsion gel were evaluated using Desonate ® as the reference formulation. To assess the difference in curative effect between DES NE gel and Desonate® and to ensure safety, atopic dermatitis (AD) models in KM mice were developed using 2,4-dinitrofluorobenzene (DNFB). The degree of ear swelling, ear mass difference, thymus, spleen index, and HE conventional pathology of mice were used as pharmacodynamic evaluation indexes, and the irritation was predicted by the New Zealand rabbit epidermal stimulation assay. RESULTS: Nanoemulsion gels may facilitate transdermal penetration of drugs by influencing the skin condition. Medium and high doses of DES NE gel significantly ameliorated the inflammation and swelling of the ear caused by dermatitis/eczema in mice. In addition, compared with DES gel, skin irritation extent did not increase. CONCLUSION: Nanoemulsion gel can be applied to improve the efficacy of drugs with low potency or poor solubility. DES NE gel provides a higher transdermal potential than other delivery systems. In this study, it was found that nanoemulsion gel is a promising percutaneous carrier of DES. DES NE-GEL has a significant curative effect on dermatitis/eczema in a mouse model and is expected to provide a new, efficient, and low toxic preparation for clinical treatment of dermatitis/eczema through the percutaneous system.

Development of a nanotechnological hydrogel containing desonide nanocapsules in association with acai oil: design and in vivo evaluation.

Nanotechnological products have been used as strategies to optimize the therapy and minimize the side effects of topical corticoids. The objective of this study was to develop hydrogels by the addition of sclerotium gum to the suspensions of desonide-loaded açai oil-based nanocapsules and to study their biological effect using an animal model of acute skin inflammation. The hydrogels presented a pH compatible with topical application (4.4 to 5.0), nanometric mean diameter (131 to 165 nm), pseudoplastic behavior, and stability under room conditions during 30 days. The in vitro skin permeation/penetration study demonstrated that a higher amount of desonide (p < 0.05) was retained in the epidermis from the nanotechnological-hydrogels (0.33 to 0.36 µg.cm2) in comparison to the commercial gel cream (0.16 µg.cm2). In the dermis, the nanostructured hydrogels promoted a lower DES retention compared to the non-nanostructured formulations (p < 0.05). This result may indicate a smaller amount of drug reaching the bloodstream and, thus, fewer side effects can be expected. Concerning the anti-inflammatory effect, the developed hydrogels reduced both ear edema and inflammatory cell infiltration, showing an effect comparable to the commercially available formulation, which presents twice the drug concentration. The hydrogels developed may be considered a promising approach to treat dermatological disorders.

Suppression of toxicity of the mutant huntingtin protein by its interacting compound, desonide.

Identifying inhibitors of pathogenic proteins is the major strategy of targeted drug discoveries. This strategy meets challenges in targeting neurodegenerative disorders such as Huntington's disease (HD), which is mainly caused by the mutant huntingtin protein (mHTT), an "undruggable" pathogenic protein with unknown functions. We hypothesized that some of the chemical binders of mHTT may change its conformation and/or stability to suppress its downstream toxicity, functioning similarly to an "inhibitor" under a broader definition. We identified 21 potential mHTT selective binders through a small-molecule microarray­based screening. We further tested these compounds using secondary phenotypic screens for their effects on mHTT-induced toxicity and revealed four potential mHTT-binding compounds that may rescue HD-relevant phenotypes. Among them, a Food and Drug Administration­approved drug, desonide, was capable of suppressing mHTT toxicity in HD cellular and animal models by destabilizing mHTT through enhancing its polyubiquitination at the K6 site. Our study reveals the therapeutic potential of desonide for HD treatment and provides the proof of principle for a drug discovery pipeline: target-binder screens followed by phenotypic validation and mechanistic studies.

Desonide nanoencapsulation with açai oil as oil core: Physicochemical characterization, photostability study and in vitro phototoxicity evaluation.

This study aimed to develop Eudragit® RL 100 nanocapsules loaded with desonide (DES) using açai oil (AO) or medium chain triglycerides (MCT) as oil core. Pre-formulation study showed that AO and MCT are suitable for nanocapsules preparation. The nanocapsules prepared with AO and MCT presented mean particle size around 165 and 131 nm, respectively; polydispersity index values <0.20, positive zeta potential values, drug content close to the theoretical value (0.25 mg mL-1), and DES encapsulation efficiency around 81%, regardless of the oil core (AO or MCT). Considering the photoinstability reported to DES, photodegradation studies were performed. The UV-A (365 nm) and UV-C (254 nm) photodegradation studies revealed less DES degradation when associated to the nanocapsules containing AO in comparison to those with MCT. The in vitro release study showed a biphasic release profile for both nanocapsule suspensions: an initial burst effect followed by a prolonged DES release. In addition, the formulations were considered non-phototoxic at 0.5 mg mL-1 when tested on 3 T3 murine fibroblasts and HaCaT human keratinocytes using the MTT and NRU viability assays. The irritant potential of the prepared nanocapsules and DES in free form were evaluated by HET-CAM method. All formulations were classified as slightly irritant, including the non-associate DES. In conclusion, the nanocapsule formulations developed in this study may be promising for therapeutic applications.

In vitro and in vivo evaluation of a desonide gel-cream photostabilized with benzophenone-3.

CONTEXT: Our group previously reported the photoinstability of some desonide topical commercial formulations under direct exposure to UVA radiation. OBJECTIVE: This study aimed to prepare and characterize a gel-cream containing desonide, with greater photostability than the commercial gel-cream (C-GC). Benzophenone-3 (BP-3) was used as a photostabilizing agent. METHODS: The gel-cream developed (D-GC) containing BP-3 at 0.1% was prepared and characterized regarding its pH, drug content, spreadability, viscosity, in vitro drug release and in vitro permeation. The in vivo anti-inflammatory effect was assessed by ear edema measurement, croton oil-induced acute skin inflammation and myeloperoxidase assay. RESULTS AND DISCUSSION: D-GC presented characteristics compatible with topical application, appropriate drug content and good spreadability, and non-Newtonian behavior with pseudoplastic flow. D-GC showed a good photostability profile, presenting a desonide content of 95.70% after 48 h of exposure to UVA radiation, and stability under room conditions during 60 days. The amount of desonide released from D-GC and C-GC was 57.8 and 51.7 µg/cm2, respectively, measured using the vertical Franz cell. The in vitro skin permeation showed that desonide reached the site of action of the topical corticosteroids, from both formulations; however, the desonide amount retained in the dermis was lower with D-GC. The in vivo evaluation of topical anti-inflammatory activity indicated that D-GC presented the same biological effect as C-GC. CONCLUSION: D-GC represents a promising approach to treat dermatological disorders, since it presented satisfactory physicochemical characteristics, the same biological activity as C-GC and superior photostability, conferred by the addition of BP-3 at 0.1%.

Desonide foam: a review.

Desonide foam is a newly approved topical corticosteroid preparation of 0.05% desonide. It has been shown effective compared with vehicle placebo in the treatment of mild-to-moderate atopic dermatitis in both pediatric and adult populations. Given the favorable safety profile of all other desonide preparations and their utility as a low potency corticosteroid, desonide foam promises to be a useful addition to the armamentarium, when other desonide vehicles might be less acceptable.

Effect of desonide hydrogel 0.05% on the hypothalamic-pituitary-adrenal axis in pediatric subjects with moderate to severe atopic dermatitis.

Desonide, a low potency corticosteroid, has been used widely as a topical treatment for inflammatory dermatoses for over 30 years. A recent formulation advance has enabled the development of desonide 0.05% into a novel moisturizing aqueous gel (hydrogel) that is free of alcohol and surfactants. This multicenter, open-label study evaluated the hypothalamic-pituitary-adrenal axis suppression potential, tolerability, and efficacy of this new Class VI topical steroid formulation in pediatric subjects with moderate-to-severe atopic dermatitis (mean body surface area = 51%). Forty children, aged 6 months to 6 years were enrolled and treated twice daily for 4 weeks. Desonide hydrogel 0.05% was well tolerated and no treatment-related adverse events were reported. No suppression of adrenal function was observed in subjects who completed the study without protocol violations related to cosyntropin administration or cortisol testing (n=34). Of the subjects who completed the study with complications in cortisol testing (n=3), there was one subject (1/37=3%) who had a low poststimulation cortisol level at week 4. Efficacy was demonstrated by marked improvement in overall disease state and in the signs and symptoms of atopic dermatitis. This study validates the systemic safety of a novel desonide hydrogel formulation in young pediatric patients and confirms the longstanding tolerability and efficacy profile of desonide.

Photochemistry of desonide, a non-fluorinated steroidal anti-inflammatory drug.

The photochemistry of anti-inflammatory drug desonide (De, 1) was studied in aerobic as well as in anaerobic condition with different irradiation wavelengths (254, 310 nm) in acetonitrile and 2-propanol. All photoproducts obtained were isolated and characterized on the basis of IR, (1)H-, (13)C-NMR spectroscopy and elemental analysis study. The products were: 11beta,21-dihydroxy-16alpha,17alpha-(1-methylethylidenedioxy)-1,5-cyclopregn-3-ene-2,20-dione 2 (254 nm), 11beta-hydroxy-16alpha,17alpha-(1-methylethylidenedioxy)androsta-1,4-diene-3-one 3 (310 nm/2-propanol), 17beta-hydroperoxy-11beta-hydroxy-16alpha,17alpha-(1-methylethylidenedioxy)androsta-1,4-diene-3-one 4 (310 nm/O(2)/2-propanol). Cyclohexadienone moiety in ring A and keto group at C(17) were found to be deeply modified by UV light therefore, loss of biological activity both during storage and in vivo can not be ruled out.

Quantification of skin-colour changes induced by topical corticosteroid preparations using the Minolta Chroma Meter.

The Minolta tri-stimulus colorimeter CR-200 was used to quantify the blanching effect of topical corticosteroids in a non-occluded vasoconstriction test. To investigate the influence of time on variations in colorimetric parameters, an initial series of measurements was performed on Day 1 on six predetermined sites on the ventral surface of the forearm of six healthy volunteers every 2 h over a 12-h period. The colorimetric values were shown to be site related but hourly variations occurred with similar profiles for all the sites. On Day 2, four topical corticosteroid creams, representative of their potency groups, as well as a base were applied in a randomized double-blind manner on five of the predetermined sites. Visual gradings and colorimetric measurements were carried out every 2 h over the following 12-h diurnal period and were continued on Day 3. The colorimetric parameters L* (luminance) and a* (colour hue ranging from green(-) to red(+] gave a rank order correlated to corticosteroid potency that showed superior discrimination compared to simple visual grading. In this study, L* was more discriminative parameter than a*. The Minolta Chroma Meter CR-200 appears to be a simple and accurate device for objectively measuring the blanching effects of topical corticosteroids.

Potency ranking of two new topical corticosteroid creams containing 0.1% desonide or 0.05% halometasone utilising the human skin blanching assay.

The human blanching assay was used to assess the potency of two new proprietary corticosteroid creams. The blanching abilities of 0.1% desonide cream and 0.05% halometasone cream were evaluated relative to the blanching elicited by 0.05% clobetasol 17-propionate cream, 0.1% betamethasone 17-valerate cream and 0.05% clobetasone 17-butyrate cream. The results of the trial indicated that the 0.1% desonide cream falls into the potent group of topical corticosteroid preparations and the 0.05% halometasone cream falls into the moderately potent group.

Comparison of the cutaneous/systemic antiinflammatory activity ratios for desonide and hydrocortisone in various experimental models.

The ratios of antiinflammatory activity after oral administration (oral ED50/cutaneous ED50) for desonide (Locapred) and hydrocortisone (hydrocortisone acetate) were compared in various nonimmunological and immunological experimental models on mouse ears: edema induced by croton oil; primary irritation due to picryl chloride; the acute phase (6 h) and the beginning of the chronic phase (24 h) of inflammation due to cantharidin; delayed contact hypersensitivity to picryl chloride; and the semi-delayed (6 h) and delayed (24 h) phases of contact hypersensitivity to oxazolone. These investigations showed that, besides having a better antiinflammatory effect, desonide had a better ratio of local activity to systemic effect in all the models. In addition, by contrast with orally active doses, locally active doses did not induce any thymolytic effect. Such results were confirmed in rats in which desonide reduced 24 h carrageenin abscess after cutaneous application without any significant thymolytic effect. Hydrocortisone was inactive.

[Comparative antiallergic and anti-inflammatory action of F1865, mepyramine maleate, desonide and disodium cromoglycate after cutaneous administration]. / Action antiallergique et anti-inflammatoire comparative du F1865, du maléate de mépyramine, du désonide et du cromoglycate disodique après application cutanée.

The actions of F 1865 (ethyl 4' methoxy 4 phenyl thiazolyl 2 oxamate), an inhibitor of the release of histamine from mast cell, desonide, a corticosteroid, mepyramine maleate, an anti-H1 antihistaminic, and disodium cromoglycate were compared after cutaneous application in various experimental models of allergy and inflammation. F 1865 decreased IgE- and IgG-dependent passive cutaneous anaphylaxis in rats at doses having no effect on histamine- and serotonin-induced capillary permeability. Disodium cromoglycate showed the same activity spectrum, but its action was only found after intradermal application. The reduction of cutaneous anaphylaxis by desonide was found parallel to its inhibition of histamine effects, and to a lesser extent of serotonin effects. In the case of mepyramine, the antiallergic effect may be explained by its antihistaminic action. Desonide was highly active on cantharidin-induced non-immune inflammation and on non-immune and delayed hypersensitivity reactions induced by picryl chloride in mouse ear. Although far less active than the corticosteroid, F 1865, mepyramine and disodium cromoglycate did reduce the three types of reactions in mice. This evidenced a part played by histamine in such inflammations. Then it is likely that the inhibition of histamine release by F 1865 plays an important part in the effect of the compound observed in the various inflammations studied. However we cannot exclude actions against other mediators involved in these reactions.

Comparison of the effects of a non-steroidal anti-inflammatory agent, an immunosuppressive, a corticosteroid and an immunomodulator on various immunological and non-immunological inflammatory experimental models.

The effects of a non-steroidal anti-inflammatory agent, phenylbutazone, a corticosteroid, desonide, an immunosuppressive, cyclophosphamide and an immunomodulator, levamisole on a number of experimental inflammatory models were compared. Compounds were first tested in carrageenin-induced pleurisy as a non-immune acute inflammation, then in passive skin anaphylaxis and reversed passive Arthus oedema in the rat as models of humoral immunity. Finally the compounds were investigated in various delayed hypersensitivity tests: reaction to sheep red cells and to oxazolone in the mouse, skin reaction to purified protein derivative (P.P.D.) in the rat and guinea-pig, P.P.D. induced pleurisy in the guinea-pig.

Action of various drugs with anti-inflammatory or anti-rheumatic properties on pleurisy due to Bordetella pertussis hypersensitivity in the rat.

The authors studied various drugs with anti-inflammatory or antirheumatic properties on pleurisy due to Bordetella pertussis hypersensitivity in the rat. The following compounds were studies according to various methods of treatment: indomethacin, phenylbutazone, cyclophosphamide, desonide, chloroquine, levamisole, D-penicillamine and sodium aurothiopropanol sulphonate. The action on the volume of pleural exudate and on cell events depended on the compounds and the conditions of treatment. Only gold salt produced no reduction in the pleural volume under all methods of treatment. All the compounds studied produced various degrees of significant modifications at the level of the cell events.

Growth rate of cultured human fibroblasts increased by glucocorticoids.

Selected glucocorticoids have been demonstrated to increase the growth rate of human skin fibroblasts in culture, over a physiologically significant concentration range. At the same concentrations and identical conditions, the glucocorticoid compounds tested inhibited the growth rate of mouse L-929 cells. We have discussed currently acceptable theories of glucocorticoid mechanism of action that permit this dichotomous effect, the main point being that inhibition can no longer be regarded as the only response of fibroblasts to glucocorticoids. Conclusions drawn from observations of cell cultures affected by addition of glucocorticoids must have considered the source of the cells, as response may vary with source and biologic state of the cells in culture.

Corticosteroid-induced dermal atrophy in the rat.

Corticosteroid-induced dermal atrophy has been studied in the rat using daily application of ethanolic solutions to small areas of flank skin. After 12 days of treatment, the degree of atrophy was determined by comparing the weights of skin plugs (16 mm diameter) taken from the treated areas with contralaterally paired control areas. Doses can be adjusted so that systemic effects are minimized and only local effects are observed. Hydrocortisone, hydrocortisone butyrate, dexamethasone, betamethasone, desonide and triamcinolone acetonide all produce atrophy in the rat, and the degree of thinning is dose dependent. Potencies in the dermal atrophy assay compare directly with topical anti-inflammatory potencies in the rat, and the presence of fluorine in the steroid molecule is not a determining factor in the production of atrophy.