Tolerability comparison of adapalene gel, 0.3% versus tazarotene cream, 0.05% in subjects with healthy skin

BACKGROUND: Topical retinoids, including adapalene and tazarotene, are a primary treatment choice for patients with acne. Adapalene is currently marketed in a 0.1% concentration in gel and cream formulation. A new gel containing a higher concentration (0.3%) of adapalene has been developed. In clinical studies, adapalene 0.1% concentration has proven to be better tolerated than other retinoids in skin treatment. However, the tolerability of adapalene gel 0.3% has yet to be compared to other topical retinoids. PURPOSE: The purpose of this study was to compare the local cutaneous tolerability of adapalene gel 0.3% once daily versus tazarotene cream 0.05% once daily. METHODS: Subjects reported to the investigative site each day Monday through Friday, cleansed the faced and then applied adapalene 0.3% gel to one side of the face and tazarotene 0.05% cream to the other in the presence of study personnel. For the weekends, subjects were instructed to apply the treatment at home according to the same procedure. Tolerability was assessed during each weekday visit. The study lasted for 3 weeks. RESULTS: Tolerability results for adapalene 0.3% gel and tazarotene 0.05% cream were statistically similar throughout the study. Investigator-assessed overall tolerability was in favor of adapalene at days 19 and 22 (P=.043). A cosmetic acceptability survey also showed results were better for adapalene 0.3% gel. CONCLUSION: Adapalene gel 0.3% is very well-tolerated with good cosmetic acceptability.     

Adapalene: a review of its use in the treatment of acne vulgaris

Adapalene (Differin) is a retinoid agent indicated for the topical treatment of acne vulgaris. In clinical trials, 0.1% adapalene gel has proved to be effective in this indication and was as effective as 0.025% tretinoin gel, 0.1% tretinoin microsphere gel, 0.05% tretinoin cream and 0.1% tazarotene gel once every two days; however, the drug was less effective than once-daily 0.1% tazarotene gel. It can be used alone in mild acne or in combination with antimicrobials in inflammatory acne and has proved efficacious as maintenance treatment. Adapalene has a rapid onset of action and a particularly favourable tolerability profile compared with other retinoids. These attributes can potentially promote patient compliance, an important factor in treatment success. Adapalene is, therefore, assured of a role in the first-line treatment of acne vulgaris.     

Assessing the bioequivalence of topical retinoid products by pharmacodynamic assay

Purpose: To develop a simple pharmacodynamic (PD) assay for the evaluation of the bioequivalence of topically applied retinoid products. Methods: Daily applications of products containing tretinoin or adapalene were made to the forearms of human subjects for up to 21 days. Percutaneous absorption was enhanced through the use of polyethylene film occlusion (5 h). Pharmacologic activity was assessed through the daily measurement of three cutaneous responses intimately linked to retinoid-induced changes in epidermal differentiation: (1) erythema; (2) exfoliation (scaling/peeling), and (3) increased transepidermal water loss. Results: The PD model exhibited the sensitivity and specificity required to function as a bioequivalence surrogate. It was possible to differentiate between: (1) three concentrations of tretinoin in a commercial cream product line; (2) two concentrations of tretinoin in a commercial gel product line; (3) different vehicles (gel vs. cream) containing the same concentration of tretinoin, and (4) tretinoin and adapalene at the same concentration. The applicability of this model for bioequivalence testing was established by showing that it had sufficient power to determine that three test tretinoin cream products and two approved generic tretinoin gel products were equivalent to their corresponding reference products. Conclusions: A surrogate PD model to assess retinoid bioequivalence has been developed.     

Tazarotene cream versus adapalene cream in the treatment of facial acne vulgaris: a multicenter, double-blind, randomized, parallel-group study

A multicenter, double-blind, randomized, parallel-group trial compared tazarotene 0.1% cream with adapalene 0.1% cream, once daily for 12 weeks, in 173 patients with facial acne vulgaris. Tazarotene was associated with a significantly greater incidence of patients achieving 50% or greater global improvement (77% vs. 55%, P < or = .01), and a significantly greater reduction in comedo count (median of 68% vs. 36%, P < or =.001, compared with adapalene. A significant between-group difference in baseline inflammatory lesion count precluded a comparison of efficacy against inflammatory acne. The most common adverse events were dryness, peeling/flaking, itching, redness/erythema, burning, and facial irritation with comparable incidences of each between groups. Mean peeling and burning levels were milder with adapalene, though were trace or less in both groups throughout. There were no significant between-group differences in the incidence of patients discontinuing due to lack of efficacy or adverse events. Tazarotene cream offers significantly greater efficacy and comparable tolerability to adapalene cream.     

Tazarotene versus tazarotene plus clindamycin/benzoyl peroxide in the treatment of acne vulgaris: a multicenter, double-blind, randomized parallel-group trial

Topical retinoids offer highly effective treatment for both inflammatory and non-inflammatory acne, with tazarotene demonstrating greater efficacy than other topical retinoids. A multicenter, double-blind, randomized, parallel-group trial has been performed to evaluate whether the adjunctive use of clindamycin/benzoyl peroxide could enhance the efficacy of tazarotene still further. Patients with moderate to severe inflammatory acne applied tazarotene 0.1% cream each evening and were randomly assigned to morning applications of vehicle gel or a ready-to-dispense formulation of clindamycin 1%/benzoyl peroxide 5 % gel containing 2 emollients. Tazarotene/clindamycin/benzoyl peroxide achieved a significantly greater reduction in comedo count than tazarotene monotherapy and, among patients with a baseline papule plus pustule count of > or =25 (the median value), a significantly greater reduction in inflammatory lesion count. The combination therapy was also at least as well-tolerated as tazarotene monotherapy. The adjunctive use of clindamycin/benzoyl peroxide gel with tazarotene cream promotes greater efficacy and may also enhance tolerability. Any improvements in tolerability could be due to the emollients in the clindamycin/benzoyl peroxide gel formulation.     

他扎罗汀乳膏与阿达帕林凝胶随机对照治疗寻常型痤疮多中心临床试验

目的 评价国产0．1％他扎罗汀乳膏治疗面部轻中度寻常型痤疮的疗效及安全性。方法 用多中心、随机单盲对照试验方法，0．1％他扎罗汀乳膏或0．1％阿达帕林凝胶局部外用每日1次，疗程8周。在治疗前、治疗2，4和8周进行观察。入选病例142例，其中0．1％他扎罗汀乳膏组71例，完成8周观察64例。0．1％阿达帕林凝胶组71例，完成8周观察67例。结果他扎罗汀乳膏组有效率72．3％，阿达帕林凝胶组有效率62．7％。两组之间无显著统计学差异。两组的不良反应均表现为轻度到中度的局部刺激，发生率分别为28．70％和23．50％。结论 他扎罗汀乳膏治疗寻常型痤疮安全有效。     

Novel Beads Made of Alpha-cyclodextrin and Oil for Topical Delivery of a Lipophilic Drug

Purpose To investigate the potential of a novel lipid carrier, comprising beads of alpha-cyclodextrin and soybean oil, for topical drug delivery. Adapalene was chosen as a model drug to explore the ability of the beads to encapsulate and release a highly lipophilic compound. Materials and Methods Adapalene-loaded beads were prepared and characterised. Skin tolerance to unloaded beads was tested on human volunteers, while drug release and delivery into stratum corneum, was evaluated in pig skin ex vivo. Results The preparation and physical characteristics of the beads were not dependent on whether adapalene had been previously dissolved or dispersed in soybean oil. Drug encapsulation efficiency was high (>96%) and drug loading on the order of a therapeutic level could be achieved in freeze-dried beads prepared from an oily dispersion of adapalene. After application to human skin, unloaded beads induced no adverse reaction and were better tolerated than an alcoholic gel. Tape-stripping the stratum corneum from treated pig skin showed that adapalene release and penetration from the beads was comparable to that from gel and cream formulations available on the market. Conclusion These novel beads may offer a well-tolerated and efficient system for the encapsulation and topical delivery of lipophilic drugs.     

Novel microemulsion-based gel formulation of tazarotene for therapy of acne

The objective of this study was to develop and evaluate a novel microemulsion based gel formulation containing tazarotene for targeted topical therapy of acne. Psudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant, and co-surfactant for microemulsion formation. The optimized microemulsion formulation containing 0.05% tazarotene was formulated by spontaneous microemulsification method consisting of 10% Labrafac CC, mixed emulsifiers 15% Labrasol–Cremophor–RH 40 (1:1), 15% Capmul MCM, and 60% distilled water (w/w) as an external phase. All plain and tazarotene-loaded microemulsions were clear and showed physicochemical parameters for desired topical delivery and stability. The permeation profiles of tazarotene through rat skin from optimized microemulsion formulation followed the Higuchi model for controlled permeation. Microemulsion-based gel was prepared by incorporating Carbopol®971P NF in optimized microemulsion formulation having suitable skin permeation rate and skin uptake. Microemulsion-based gel showed desired physicochemical parameters and demonstrated advantage over marketed formulation in improving the skin tolerability of tazarotene indicating its potential in improving its topical delivery. The developed microemulsion-based gel may be a potential drug delivery vehicle for targeted topical delivery of tazarotene in the treatment of acne.     

Mechanism-based treatment of acne vulgaris: the value of combination therapy

Acne vulgaris has multiple pathogenic mechanisms that act in concert to produce disease. Effective therapy addresses more than one pathogenic factor to speed resolution of disease. Typically, retinoids are used to inhibit comedo formation and an antibacterial is used to suppress Propionibacterium acnes (P. acnes). Using combinations of agents can enhance efficacy, but increase side effects. Therefore, the tolerability of a topical retinoid is important. Strategies to enhance retinoid tolerability include the use of new retinoids such as adapalene, new delivery systems such as the tretinoin microsphere delivery system, or alternative dosing schedules such as short contact or every other day (QOD).     

他扎罗汀倍他米松乳膏对小型猪经皮给药后的系统吸收及其相互作用研究

目的：通过与已上市单方他扎罗汀凝胶（tazarotene gel）和二丙酸倍他米松乳膏（betamethasone dipropionate cream）比较，研究新的复方制剂他扎罗汀倍他米松乳膏（tazarotene and betamethasone dipropionate cream，简称"复方"）对小型猪经皮给药后的药物吸收以及药物组分间吸收的相互影响。方法：将18只小型猪随机分入复方组、他扎罗汀凝胶组和二丙酸倍他米松乳膏组，每组6只。小型猪按20%的体表面积2 mg·cm^-2给予相应组别的药物，并在给药后24 h清除药物。分别于给药前和给药后不同时间点采集血样。高效液相色谱-串联质谱（liquid chromatography-tandem mass spectrometry，LC-MS/MS）法测定血浆中他扎罗汀及其代谢物他扎罗汀酸和/或二丙酸倍他米松及其代谢物倍他米松的浓度。DAS 2.1.1软件进行药代动力学（pharmacokinetic，PK）参数计算并统计分析。结果：复方他扎罗汀倍他米松乳膏与单方他扎罗汀凝胶中的他扎罗汀均不易透过小型猪皮肤到达血液，系统吸收非常低，而复方组血浆中的他扎罗汀及其活性代谢产物他扎罗汀酸较单方组更低；复方他扎罗汀倍他米松乳膏和二丙酸倍他米松乳膏中的二丙酸倍他米松几乎不透过小型猪皮肤到达血液，系统吸收非常低，其中复方组与单方组中二丙酸倍他米松及其代谢产物倍他米松到达血液的量未见明显的差异。结论：复方制剂中他扎罗汀对二丙酸倍他米松的系统吸收未产生相互作用，而二丙酸倍他米松对他扎罗汀的系统吸收产生了有益的相互作用，有利于用药安全。     

Evidence-based review: fixed-combination therapy and topical retinoids in the treatment of acne

Topical fixed-combination products and topical retinoid monotherapy are established first-line treatments for mild-to-moderate acne vulgaris, yet adequate comparative data are lacking. The following evidence-based review addresses the question: "In patients with mild-to-moderate acne, are topical fixed-combination products or topical retinoids a more efficacious choice in reducing noninflammatory, inflammatory and total lesions after 12 weeks of treatment?" To identify relevant studies, a PubMed search was performed using "acne" and search terms for adapalene, tretinoin, tazarotene, benzoyl peroxide, clindamycin, or erythromycin. Forty-two studies from January 1991 to November 2009 were included. The studies were evaluated using the Strength of Recommendation Taxonomy, and all but seven received the highest level of evidence grade. To evaluate efficacy, a side-by-side comparison was made using reduction in acne lesion counts at week 12 for study groups treated with fixed-combination therapy or retinoid monotherapy. Twenty-nine studies containing relevant efficacy data for fixed-combination therapy and retinoid monotherapy are summarized here. Nine studies compared fixed-combination therapy with retinoid monotherapy; in eight of these studies, fixed-combination therapy was significantly more efficacious in reducing acne lesion counts. This evidence-based review analyzes clinical evidence to date for these therapies to provide guidance in determining appropriate treatment for patients with mild-to-moderate acne.     

Epidermal effects of tretinoin and isotretinoin: influence of isomerism

The efficacy of tretinoin is well established in the treatment of acne and photoaged skin, however as a typical side effect of tretinoin treatment most patients develop a low-grade irritant dermatitis. Since isotretinoin topical treatment usually shows much lower incidence and intensity of adverse effects than tretinoin topical treatment, histological studies are needed to scientifically evaluate the effects of isotretinoin application on epidermis and also to assess if it can be used in anti-aging products as an alternative to tretinoin. Thus, the aim of this study was to compare the effects of topical use of tretinoin or isotretinoin on hairless mice epidermis, using appropriate histopathological and histometric techniques, in order to evaluate the influence of isomerism on skin effects. For this, gel cream formulations containing or not 0.05% tretinoin or 0.05% isotretinoin were applied in the dorsum of hairless mice, once a day for seven days. Histopathological evaluation, viable epidermal and horny layer thicknesses as well as the number of epidermal cell layers were determined. Our results showed that tretinoin and isotretinoin were effective in the enhancement of viable epidermis thickness and number of epidermal cell layers, suggesting that they could be used for stimulation of cellular renewal. However isomerism influenced skin effects since isotretinoin had more pronounced effects than tretinoin in viable epidermis. In addition only isotretinoin treatment enhanced horny layer thickness when compared to the gel cream treatment.     

阿达帕林凝胶治疗寻常痤疮临床观察

目的 :观察 0 1%阿达帕林凝胶治疗寻常痤疮的临床疗效和安全性。方法 :16 0例寻常痤疮患者 ,分别给予外涂 0 1%阿达帕林凝胶 (80例 )及 0 0 2 5 %全反维A酸凝胶 (80例 )。根据治疗前后炎性损害和非炎性损害总数减少的百分率评价疗效。结果 :两组痊愈率、显效率、有效率均无统计学差异 ,阿达帕林组不良反应率明显低于全反维A酸组。结论 :0 1%阿达帕林是一种局部治疗寻常痤疮的有效的安全的药物     

润燥止痒胶囊联合培氟沙星乳膏、阿达帕林凝胶治疗寻常型痤疮疗效观察

目的：观察润燥止痒胶囊联合培氟沙星乳膏、阿达帕林凝胶治疗寻常型痤疮的临床疗效。方法将86例痤疮患者随机分为两组,对照组43例应用培氟沙星乳膏及阿达帕林凝胶外用治疗;治疗组加用润燥止痒胶囊口服。疗程均为4周。结果治疗组有效率为81.39%,对照组有效率为58.13%,治疗组疗效优于对照组,两组疗效比较差异有统计学意义（P〈0.05）。结论润燥止痒胶囊联合培氟沙星乳膏及阿达帕林凝胶治疗寻常型痤疮疗效肯定,无不良反应。     

The pharmacology of a novel topical retinoid, BMY 30123: comparison with tretinoin.

Preclinical studies pertaining to the pharmacology and toxicology of BMY 30123 (4-acetamidophenyl retinoate) are reported. BMY 30123 is a novel compound which has topical retinoid activity. This compound exhibits lower toxicity, both local and systemic, than other clinically used topical retinoids such as tretinoin (all-trans retinoic acid) in animal models. BMY 30123 is effective in a number of retinoid sensitive skin models including the rhino mouse utriculi reduction assay, the mouse epidermal hyperplasia model and in the suppression of DNA synthesis in mouse skin stimulated with phorbol ester. BMY 30123 was equipotent with tretinoin in these topical models. In the rhino mouse model the ED30 values for BMY 30123 and tretinoin were 0.037 and 0.015 mM, respectively. In addition, BMY 30123 was active in the UVB-induced photodamaged mouse model, another retinoid sensitive model. One of the problems associated with topically applied tretinoin is local irritation. Therefore, for topical therapy to be optimal, it is important to reduce or minimize local irritation. Repeated applications of BMY 30123 to rabbit skin resulted in low skin irritation. The first perceptible signs of skin irritation produced by BMY 30123 occurred at a dose 10 times higher than that observed for tretinoin. BMY 30123 also exhibits low retinoid activity after oral or i.p. administration in mice and produced no signs of hypervitaminosis A-related toxicity at twenty times the no effect dose of tretinoin. Because retinoids are effective modulators of epidermal growth and differentiation, this compound should be useful for the treatment of cutaneous disorders that exhibit altered epidermal differentiation such as acne, psoriasis, ichthyosis and epithelial tumours.(ABSTRACT TRUNCATED AT 250 WORDS)     

Safety and efficacy of micronized tretinoin gel (0.05%) in treating adolescent acne

Tretinoin is widely used in the treatment of acne. Despite significant advances in formulation development, irritation and dryness can be particularly bothersome, especially during the first 3-4 weeks, impacting adherence. Dose titration and adjunct use of moisturizers have been commonly employed. Co-prescribing with benzoyl peroxide (BPO) or a BPO/antibiotic combination is also common practice. The tretinoin molecule is unstable and can be degraded by BPO, further complicating treatment regimens. Lately, formulation technology has focused on providing more efficient penetration of the tretinoin into the skin layers so that lower concentrations of tretinoin might afford better tolerability, but maintain good efficacy; incorporating moisturizing excipients to minimize irritation; and providing greater stability to the tretinoin molecule. This approach would be particularly relevant in a pediatric acne population where efficacy/tolerability balance is important and treatment regimens must take into account lifestyles, but little data exist on the use of tretinoin in this patient population. A micronized formulation of tretinoin (0.05%) gel has been developed that provides a more efficient delivery of tretinoin, because of its optimal particle size, no degradation by BPO and better cutaneous tolerability than tretinoin microsphere (0.1%) gel without compromising efficacy in a pediatric population.     

Solid lipid nanoparticles (SLN) of tretinoin: potential in topical delivery

The objective of this investigation was to develop solid lipid nanoparticles (SLN) of tretinoin (TRE) with the help of facile and simple emulsification-solvent diffusion (ESD) technique and to evaluate the viability of an SLN based gel in improving topical delivery of TRE. The feasibility of fabricating SLN of TRE by the ESD method was successfully demonstrated in this investigation. The developed SLN were characterized for particle size, polydispersity index, entrapment efficiency of TRE and morphology. Studies were carried out to evaluate the ability of SLN in improving the photostability of TRE as compared to TRE in methanol. Encapsulation of TRE in SLN resulted in a significant improvement in its photostability in comparison to methanolic TRE solution and also prevented its isomerization. Furthermore, the skin irritation studies carried out on rabbits showed that SLN based TRE gel is significantly less irritating to skin as compared to marketed TRE cream and clearly indicated its potential in improving the skin tolerability of TRE. In vitro permeation studies through rat skin indicated that an SLN based TRE gel has permeation profile comparable to that of the marketed TRE cream.     

Clinical pharmacokinetics and drug metabolism of tazarotene: a novel topical treatment for acne and psoriasis.

Tazarotene (AGN 190168) is a new acetylenic retinoid which is effective for the topical treatment of patients with stable plaque psoriasis and mild to moderate acne vulgaris. Topical gel application provides direct delivery of tazarotene into the skin. At 10 hours after a topical application of 0.1% tazarotene gel to the skin of healthy individuals and patients with psoriasis, approximately 4 to 6% of the dose resided in the stratum corneum and 2% of the dose distributed to the viable epidermis and dermis. Tazarotene is rapidly hydrolysed by esterases to its active metabolite, tazarotenic acid. Tazarotenic acid does not accumulate in adipose tissue, but undergoes further metabolism to its sulfoxide and to other polar metabolites and is rapidly eliminated via both urinary and faecal pathways with a terminal half-life of about 18 hours. Percutaneous absorption is similar between healthy individuals and patients with facial acne, leading to plasma concentrations below 1 microg/L. The systemic bioavailability of tazarotene (measured as tazarotenic acid) is low, approximately 1% after single and multiple topical applications to healthy skin. In patients with psoriasis under typical conditions of use, systemic bioavailability increased during the initial 2 weeks of treatment from 1% (single dose) to 5% or less (steady state). The increased bioavailability is probably related to decreases in plaque elevation and scaling due to successful treatment, resulting in a less effective skin penetration barrier to tazarotene. Steady-state concentrations of tazarotenic acid are achieved within 2 weeks of topical treatment in both healthy and psoriatic skin types. The large variability in plasma concentrations observed in patients with psoriasis is probably because of the large differences in lesional skin condition, the amount of drug applied and the surface area of application. There was no significant drug accumulation in the body with long term treatment of patients with psoriasis. Topical administration of tazarotene requires dosages much smaller than those usually required for oral retinoids, such as isotretinoin, acitretin and etretinate, and it delivers the drug directly into the target skin tissues. The low systemic absorption and rapid systemic elimination of tazarotene and tazarotenic acid results in limited systemic exposure. Thus, topical tazarotene has a low potential for systemic adverse effects and is effective in the treatment of patients with acne and psoriasis.