A new concept of drug delivery for acne.

Adapalene is a stable naphthoic acid derivative that displays a strong retinoid agonist pharmacology. This drug controls cell proliferation and differentiation, and possesses significant anti-inflammatory action. The retinoid action of adapalene are mediated by the ligand-activated gene transcription factors retinoic acid receptors RAR beta and RAR gamma. We describe here how an aqueous gel containing adapalene was selected for the topical treatment of acne.

Skin distribution and pharmaceutical aspects of adapalene gel.

BACKGROUND: The formulation of topical dermatologic products must take into account efficacy, safety, and patient compliance. OBJECTIVE: We describe how an aqueous gel containing adapalene, a novel naphthoic acid derivative was selected for the topical treatment of acne. METHODS AND RESULTS: Dose selection was made using established in vivo models. In the Rhino mouse the comedolytic effect of adapalene 0.1% gel was similar or superior to that of a reference formulation containing 0.025% tretinoin. Qualitative distribution of adapalene after topical application was assessed on cryosections of human skin. They showed rapid penetration of adapalene into the pilosebaceous unit. A liberation/penetration study demonstrated that significant quantities of adapalene were present in epidermis and dermis, but only 0.01% of the applied dose penetrated through the skin. CONCLUSION: This formulation should result in effective and well-tolerated treatment of acne vulgaris with good patient compliance.

Site-specific drug delivery to pilosebaceous structures using polymeric microspheres.

In order to improve the therapeutic index of adapalene, a new drug under development for the treatment of acne, site-specific delivery to the hair follicles using 50:50 poly(DL-lactic-co-glycolic acid) microspheres as particulate carriers was investigated in vitro and in vivo. The percutaneous penetration pathway of the microspheres was shown to be dependent on their mean diameter. Thus, after topical application onto hairless rat or human skin, adapalene-loaded microspheres (5-microns diameter) were specifically targeted to the follicular ducts and did not penetrate via the stratum corneum. The in vitro release of adapalene from the microspheres into artificial sebum at 37 degrees C was controlled and faster than the in vivo sebum excretion in humans. Aiming to reduce either the applied dose of drug or the frequency of administration, different formulations of adapalene-loaded microspheres were evaluated in vivo in the rhino mouse model. A dose-related comedolytic activity of topical formulations of adapalene-loaded microspheres was observed in this model. Furthermore, by applying a site-specific drug delivery system (0.1% adapalene) every other day or by administering a 10-fold less concentrated targeted formulation (0.01%) every day, a pharmacological activity equivalent to a daily application of an aqueous gel containing drug crystals (0.1% adapalene) was observed. Since an aqueous gel containing 10% adapalene-loaded microspheres was not irritating in a rabbit skin irritancy test, this formulation was applied onto forearms of human volunteers. Site-specific drug delivery was further evidenced by follicular biopsy. Since an aqueous gel containing 10% adapalene-loaded microspheres was not irritating in a rabbit skin irritancy test, this formulation was applied onto forearms of human volunteers. Site-specific drug delivery was further evidenced by follicular biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)

The rhino mouse model: the effects of topically applied all-trans retinoic acid and CD271 on the fine structure of the epidermis and utricle wall of pseudocomedones.

The histological and ultrastructural effects following 3 weeks' topical treatment with two agents (all-trans retinoic acid and a new synthetic retinoid-like substance, CD271) were evaluated on the epidermis and the epithelial wall of the pseudocomedones in rhino mouse skin. The comedolytic effects of these drugs were similar, and consisted of a reduction of the utricular diameter, with normalization of follicular units. Morphological examinations revealed a hyperplastic response with an increase in the number of cell layers of both epidermis and follicular epithelium, and modifications in keratinocyte differentiation. Ultrastructural changes in the epidermis and epithelial wall were observed mainly in the granular and horny layers, with increased desquamation, and a decrease in the cohesiveness of corneocytes. During the first week of treatment, some cutaneous toxic effects were noticed, but they normalized within two weeks. On the other hand, a fine granular material persisted in the intercellular spaces. It is confirmed that the skin of the rhino mouse is a good model for the evaluation of the comedolytic effects of drugs. Moreover, it reveals the specific effects of retinoids on epidermal differentiation. We have demonstrated that topically applied CD271 induces modifications similar to those obtained with all-trans retinoic acid. It is thus concluded that CD271 is a potentially effective anti-acne agent.

Quantification of epidermal histological changes induced by topical retinoids and CD271 in the rhino mouse model using a standardized image analysis technique.

The rhino mouse has been used as an experimental model to screen topically active comedolytic agents. Adult rhino mice were treated on the back once daily for 5 consecutive days per week during 3 weeks. Skin histological preparations were analyzed by image analysis techniques to quantify the number of epidermal comedones, comedo profile and epidermal thickness. Using both a negative (treated with acetone) and a positive (treated with Aberel gel 0.025%) control group of animals in all experiments conducted over a period of about 3 years, we defined the upper and lower limit of acceptability of the results. Topical treatment with an acetone solution of all-trans retinoic acid (0.01, 0.03, 0.1%) and 13-cis-retinoic acid (0.1%) induced comedolysis and a marked increase in epidermal thickness. Commercial preparations of all-trans retinoic acid (Aberel lotion, gel and cream, Retin A cream, Retacnyl cream) presented a similar comedolytic activity. However, the epidermal thickening was higher with Retin A and weaker with Retacnyl. CD271, a new modulator of cell differentiation, applied either in acetone solution (0.01, 0.1%) or in lotion, gel or cream formulations (0.1%) also demonstrated a marked activity (i.e. comedolysis and epidermal thickening). These data confirm that the rhino mouse model can be used to assay drugs applied either in solvent or in topical formulations. Activity in this model compares favorably with published clinical observations in the treatment of acne.

Hexadecane-induced skin hyperplasia in the hairless rat: time course of histological and biochemical events related to the synthesis of polyamines and DNA.

Several biochemical parameters including ornithine decarboxylase activity (ODC) and tissue polyamine levels were measured during the hexadecane-induced epidermal hyperplasia of hairless rat skin. Animals received three applications of 200 microliters pure n-hexadecane on day 1. ODC activity and polyamine levels (putrescine, spermidine and spermine) in the epidermis were significantly increased and reached maximum elevations at 12 h after the start of n-hexadecane treatment with DNA synthesis peaking at 24 h. Histological studies confirmed a significant cellular edema at 24 h after the beginning of the treatment followed at 48 h by an epidermal hyperplasia which was maximum at 72 h. These data support the view that ODC activation, increased biosynthesis of polyamines and DNA are early events in epidermal cell hyperproliferation.