Transitioning from brand to generic with topical products and the importance of maintaining the formulation and therapeutic profiles of the original product: focus on clocortolone pivalate 0.1% cream.

Topical corticosteroids (TCSs) are a major part of the foundation of treatment for a wide variety of eczematous and inflammatory skin disorders in both adults and children. Mid-potency TCSs represent an important category as they are often used to treat eczematous dermatoses, such as atopic dermatitis. The TCS product must effectively release the active ingredient and promote cutaneous penetration so that therapeutic activity can occur. As many topical products eventually become available as generic formulations, it is important to recognize that although the active ingredient and its concentration are the same, the vehicle excipients may differ significantly, occasionally leading to potential differences in irritancy, in allergenicity, in effects on epidermal permeability barrier function, and, possibly, in efficacy. Clocortolone pivalate 0.1% cream is a mid-potency TCS formulated in an emollient formulation that has been shown to be effective and well-tolerated in the management of several corticosteroid-responsive dermatoses. This article outlines the pharmacologic and clinical data achieved with the original brand formulation of clocortolone pivalate 0.1% cream, and discusses the establishment of an authorized generic formulation that is identical in formulation to the original brand.

A study to assess the occlusivity and moisturization potential of three topical corticosteroid products using the skin trauma after razor shaving (STARS) bioassay.

Dysfunction of the epidermal barrier is generally considered a precursor of cutaneous inflammation that can directly contribute to the pathogenesis of skin diseases, notably atopic dermatitis (AD). We also know that topical corticosteroids may actually impair the epidermal barrier by interfering with epidermal lipid synthesis. Therefore, it is important to utilize topical corticosteroids in vehicles that will help at least to enhance the already disrupted epidermal barrier in atopic dermatitis patients. Two studies of identical design were conducted to determine and compare the occlusivity and moisturizing potential of three topical corticosteroid products when applied to skin whose barrier integrity has been disrupted by dry shaving. Findings in both studies showed the clocortolone pivalate cream decreased TEWL better than non-treatment or treatment with hydrocortisone butyrate lotion. Skin surface hydration increased significantly (P<0.001) in all three treated sites, compared to the non-treated damaged control and non-treated normal skin. Clocortolone pivalate cream increased skin surface hydration significantly (P<0.001) better than hydrocortisone butyrate lipocream or hydrocortisone butyrate lotion. These studies showed that clocortolone pivalate cream enhances barrier function by providing occlusion. While understanding of the structure and function of the stratum corneum (SC) and epidermal barrier function has evolved tremendously over the last several decades, and especially over the last 15 years,1 confusion and misinformation still persist. Dysfunction of the epidermal barrier is generally considered a precursor of cutaneous inflammation that can directly contribute to the pathogenesis of skin diseases, notably atopic dermatitis (AD).2,3 Topical steroids are standard of care in treatment of atopic dermatitis. However, we also know that topical corticosteroids may actually impair epidermal barrier by interfering with epidermal lipid synthesis.4,5 In addition to that, various penetration enhancers in the topical steroid formulations also contribute to the impairment of the epidermal barrier.4 Therefore, it is important to utilize topical corticosteroids in vehicles that will help at least to enhance the already disrupted epidermal barrier in atopic dermatitis patients. In this regard, these studies were designed to determine the hydrating effects of clocortolone pivalate cream 0.1% (Cloderm Cream, Promius Pharma).

Clocortolone pivalate: a topical corticosteroid with a unique structure.

As the accumulated clinical evidence and experience to be presented in the next several pages demonstrate, the unique engineering of the clocortolone pivalate molecule balances potency with documented efficacy and a favorable safety profile. Clocortolone pivalate 0.1% cream is a well-formulated and versatile therapeutic option to consider for many of our patients with steroid-responsive dermatoses.

The role of a midpotency topical corticosteroid and the clinical relevance of formulation characteristics in the management of commonly encountered eczematous and inflammatory dermatoses in adults and children: focus on the pharmacologic properties of clocortolone pivalate 0.1% cream.

Midpotency topical corticosteroids (TCSs) are frequently used for the treatment of common eczematous and inflammatory skin disorders in both adults and children. There are several commercially available products in this category, and many vehicles and formulations for the clinician to choose from. Clocortolone pivalate 0.1% cream is a midpotency TCS formulated in an emollient formulation that has been shown to be effective and well tolerated when used appropriately in the management of several corticosteroid-responsive dermatoses. This article discusses the physiochemical properties of the compound; the characteristics of its emollient cream formulation; the functions of individual excipients; and the efficacy, tolerability, and safety data supporting its use in adults and children, including for facial involvement.

The treatment of inflammatory facial dermatoses with topical corticosteroids: focus on clocortolone pivalate 0.1% cream.

OBJECTIVE: Study results evaluating the efficacy and safety of clocortolone pivalate 0.1% cream in the treatment of adults, young children, and infants with inflammatory facial dermatoses are reported in this article. Clocortolone pivalate 0.1% cream, indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses, is a mid-potency topical corticosteroid (Class 4) that has been studied and used extensively to treat a variety of corticosteroid-responsive inflammatory dermatoses, many of which often involve facial skin in both adults and children. METHODS: Clocortolone pivalate 0.01% cream was applied to affected facial skin in subjects presenting with seborrheic dermatitis, contact dermatitis, atopic dermatitis, or psoriasis. Application was completed three times daily for 21 days. Assessments of erythema, edema, transudation, lichenification, scaling, pruritus and/or pain were completed at baseline and Days 4, 7, 14, and 21. Overall therapeutic response was assessed at all follow-up visits. Forty-nine subjects were entered, ranging in age from 1 month to 88 years of age. Thirty-eight subjects completed the studies, with 11 subjects lost to follow-up after the first visit. Individuals between the ages of 13 and 19 years were pre-emptively excluded to avoid potential application of a corticosteroid to acne-affected or acne-prone skin. RESULTS: Treatment with clocortolone pivalate 0.1% cream resulted in decreases in erythema, edema, transudation, lichenification, scaling, and pruritus/pain in 76% of treated study subjects. The overall therapeutic response in approximately two-thirds of the subjects (68%) was rated as good to excellent. There were 7 adverse events noted over the course of the study that were judged to be related to treatment, all of which were cutaneous and localized to the site of application (acneiform eruptions, burning, and folliculitis). CONCLUSION: Clocortolone pivalate 0.1% cream was effective in relieving the signs and symptoms of corticosteroid-responsive inflammatory dermatoses involving facial skin, including seborrheic dermatitis, contact dermatitis, atopic dermatitis, and psoriasis. Overall, the safety profile was favorable and devoid of any treatment-related serious adverse events.

Identification and characterization of three impurities in clocortolone pivalate.

Clocortolone pivalate is a synthetic corticosteroid that can be used to cure corticosteroid-responsive dermatoses. Three previously unknown impurities detected by HPLC were isolated by semi-preparative LC. Based on the NMR and MS spectral data, these were identified as (6R,9R,16R)-9-chloro-6ß-fluoro-11ß,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-21-pivalate (Impurity I), (9R,16R)-9-chloro-4-fluoro-11ß,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-21-pivalate (Impurity II) and (9R,16R)-9-chloro-6α-fluoro-11ß,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-11,21-dipivalate (Impurity III). The possible mechanism of the formation of the impurities is discussed.

Adherence to clocortolone pivalate cream 0.1% in a pediatric population with atopic dermatitis.

Topical corticosteroids are first-line treatments for atopic dermatitis (AD) and their efficacy is well-established in randomized controlled clinical trials. When corticosteroids fail in clinical practice, it often is attributed to nonresponse. However, poor adherence also should be considered. With the advent of electronic monitoring systems, objective data on adherence can be obtained. The purpose of this study was to determine both self-reported and actual adherence to clocortolone pivalate cream 0.1% in the treatment of AD in a pediatric population. Six participants completed the 4-week study. Self-reported adherence was significantly higher than objectively measured adherence (P = .01). In general, adherence was best during the first week of treatment and tapered off thereafter. Clocortolone pivalate cream 0.1% was generally effective, with rapid improvement over the first week of treatment, even when adherence was limited. This study was limited by the small sample size and the failure of 2 participants to complete the study. Patients overestimate their adherence behavior. While some patients are adherent to treatment, others rapidly discontinue their use of medication over time. Midpotency topical corticosteroids such as clocortolone pivalate cream 0.1% are highly effective treatments for AD. Poor adherence should be considered when AD is not responding to topical corticosteroid treatment.

Clocortolone pivalate cream 0.1% used concomitantly with tacrolimus ointment 0.1% in atopic dermatitis.

This study was designed to evaluate the safety and efficacy of concomitant therapy with the corticosteroid clocortolone pivalate cream 0.1% (Cloderm Cream 0.1%) and the topical immunosuppressive agent tacrolimus ointment 0.1% (Protopic Ointment 0.1%) and to compare each drug alone for the treatment of atopic dermatitis in adolescents and adults. Concomitant therapy may minimize the potential adverse effects of both treatments taken alone and may potentially improve overall response. In this 21-day study with 57 patients with atopic dermatitis, groups of 19 patients were randomized to 1 of 3 treatments: concomitant treatment with clocortolone pivalate cream 0.1% and tacrolimus ointment 0.1% (CPC+ TO), monotherapy with clocortolone pivalate cream 0.1% (CPC), or monotherapy with tacrolimus ointment 0.1% (TO). CPC+ TO was statistically superior to TO alone in the percentage change for dermatologic sum score at days 14 (P = .024) and 21 (P = .033), excoriation at day 21 (P = .028), induration at day 21 (P = .033), and erythema at day 14 (P = .048). The dual therapy was also superior to CPC alone in excoriation at days 7 (P = .045) and 14 (P = .037), oozing or crusting at days 3 (P = .034) and 7 (P = .012), and lichenification at day 3 (P = .031). In addition, unlike the 2 single-therapy treatment groups, percentage reductions from baseline in scores for the sensation of transient pruritus and burning or stinging were statistically significant for the concomitant treatment at days 14 (P = .016) and 21 (P = .016).

An integrative approach to eczema (atopic dermatitis).

This article provides an integrative treatment protocol for eczema (atopic dermatitis) using natural therapies. The protocol addresses several primary causative factors such as essential fatty acid deficiency and food allergies. In addition, it identifies a patented chamomile preparation proven in clinical studies to be as effective as hydrocortisone in relieving associated symptoms of itching and inflammation while enhancing granulation and epithelialization without deleterious side effects associated with long-term use of corticosteroid therapy.

Glucocorticosteroids rapidly inhibit allergen-induced expression of E-selectin in vitro in a mucosal model of allergic rhinitis.

BACKGROUND: Transendothelial migration of cells to sites of inflammation is a hallmark of the allergic reaction. The adhesion cascade involves the initial expression of the adhesion molecule E-selectin on endothelial cells. The aim of the study was to determine the efficacy of a 30-min preincubation of the glucocorticosteroids (GCS) fluticasone, prednisolone, and fluocortin butyl on allergen- and interleukin (IL)-1beta-induced E-selectin expression in allergic rhinitis. METHODS: Freshly taken nasal inferior turbinate mucosa of 19 subjects with allergic rhinitis was cut into small cubes and preincubated for 30 min with prednisolone (n = 6), fluticasone (n = 5), and fluocortin butyl (n = 3) in different concentrations, followed by allergen exposure at a concentration of 1000 BU/ml for 1 and 2 h. Additionally, fluticasone-preincubated tissues were exposed to recombinant human rhIL-1beta (n = 5) at a concentration of 2 pg/ml. The expression of E-selectin was assessed by immunohistochemistry (APAAP technique) and computerized image evaluation. RESULTS: In this model, E-selectin expression was significantly upregulated by allergen and rhIL- 1beta within 1 and 2 h. After 30-min preincubation with prednisolone and fluocortin butyl at drug concentrations of 10-8 mol/1, we found a significant (> or = 50%) reduction of the E-selectin expression after 1 and 2 h. Allergen-induced E-selectin expression was nearly abolished at concentrations of 10-5 (prednisolone) and 10-4 mol/l (fluocortin butyl). Fluticasone significantly inhibited E-selectin expression by > or = 50% at concentrations of 10-14 and 10-12 mol/l after 1 and 2 h, and abolished E-selectin induction at concentrations of 10-12 and 10-10 mol/l, respectively. Exposure of mucosal cubes to rhIL-lbeta (n = 5) also induced rapid upregulation of E-selectin expression, an effect which could be only partially suppressed by fluticasone preincubation at concentrations of 10-l0 mol/l. CONCLUSIONS: Allergen-induced E-selectin expression is significantly and rapidly inhibited by GCS preincubation, fluticasone being more potent than prednisolone and fluocortin butyl. We suggest that this rapid effect is mainly indirect, possibly by inhibition of allergen-induced cytokine release.

Intranasal fluocortin butyl in patients with perennial rhinitis: a 12-month efficacy and safety study including nasal biopsy.

Fluocortin butyl (FCB) is a recently developed topical intranasal corticosteroid that is inhaled as a powder and has been demonstrated to be well tolerated and to improve symptoms and signs of perennial rhinitis in previous short-term studies. This multicenter, open-label study evaluated the efficacy and safety of FCB during a 12-month treatment period in patients with perennial rhinitis. Treatment was initiated with one inhalation of FCB in each nostril three times a day (total dosage, 3 mg/day). In subsequent months, one third of the patients was maintained at the dosage of 3 mg/day, one third at a lower dosage of 2 mg/day, and the remaining one third of the patients at a larger dosage of 4 to 8 mg/day. Of 109 patients enrolled in the study, 90 patients (82.6%) completed all 12 months of treatment. Symptom and sign scores decreased significantly (p less than 0.001) at the 2-month evaluation compared to scores at baseline, and the improvement was maintained throughout the 12-month study period. After 12 months, greater than 80% of the patients had substantial control of symptoms. Specimens of nasal biopsies, performed at the beginning and end of treatment, revealed a decrease in eosinophils and other cellular infiltrates, a slight tendency of an increase in mast cell counts, and a trend toward normalization of the nasal mucosa. There were few adverse effects. Mean plasma cortisol levels were normal before and after corticotropin stimulation at baseline and after 12 months of FCB therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

[Diflucortolone-21-valerate Reference Standard (Control 871) of National Institute of Hygienic Sciences].

Diflucortolone-21-valerate was tested for the preparation of "Diflucortolone-21-valerate Reference Standard (Control 871)". Analytical data obtained were as follows: loss on drying, 0.05%; infrared spectrum, 1745, 1727, 1667, 1625, 1611, 1169 cm-1; ultraviolet spectrum, lambda max = 239 nm; absorbance, E1%1cm (239 nm) = 348.8; optical rotation, [alpha]20D: + 100.8 degrees; melting point, 203.2 degrees C; thin-layer chromatography, three contaminants were detected; high-performance liquid chromatography, two contaminants were detected; fluorine, 8.06%. On the basis of those results, this material was authorized as the National Institute of Hygienic Sciences Reference Standard (Control 871).

[Croton oil-induced hemorrhoid model in rat: comparison of anti-inflammatory activity of diflucortolone valerate with other glucocorticoids].

A hemorrhoid model was prepared by means of application of croton oil onto the recto-anus of rats. Cotton swab soaked with the inducer, which consisted of water, pyridine, diethylether and 6% croton oil in diethylether, was inserted into the anus. The following conditions were found to be optimal for preparing the model: cotton swab containing 0.16 ml of the inducer solution was applied to the anus of a 6 week-old rat (body wt. about 140 g) for 10 sec. The edema developed linearly until 7-8 hr after application, and the severity of the edema was sustained almost constantly for more than 24 hr. Macroscopic observations at 6 hr p. a. revealed homogeneous and consistent inflammation in the recto-anus applied region. Histological observation showed appearance of edema, infiltration of fibrin, inflammatory cells, vasodilation, blood congestion and medium to high degrees of necrosis in the mucosal epithelium. Thus this model was useful for evaluating the effect of anti-hemorrhoidal drugs on intumescence and vasodilatation. The efficacy of diflucortolone valerate, hydrocortisone caproate and hydrocortisone was evaluated in this model. Wet weight and vasopermeability increased by the inducer was suppressed strongly by simultaneous application of the corticoids, and the degree of suppression was parallel with the potency of the glucocorticoid activity. Compared to Scheriproct, Posterisan forte, Posterisan and Borraginol N, Neriproct showed the strongest effects in the protection against and treatment of the experimental hemorrhoid. Scheriproct, which was less active than Neriproct, was also found to have higher efficacy than the others.

[Neriproct: its anti-inflammatory effect on an experimentally induced hemorrhoid model in the rat].

Several glucocorticoids as a cream formulation were applied to the recto-anus of the croton-oil-induced hemorrhoid rat. Among the steroids tested, i.e. diflucortolone valerate (DFV), prednisolone (PS), hydrocortisone caproate (HC), and hydrocortisone (H), DFV was found to suppress inflammation most effectively. The effect of DFV was not affected by combination with lidocaine. In this model, the analgesic effect of lidocaine was apparently prolonged by an increase of the threshold for pain by the anti-inflammatory effect of DFV. This additive effect is regarded as a merit of the combination in Neriproct. Therapeutic effects of Neriproct and several anti-hemorrhoid drugs were also examined by using a hemorrhoid model with abrasive irritation compared to those obtained by the croton-oil model. In both models, efficacy of Neriproct was superior to that of the other drugs such as Scheriproct, Proctosedyl, Posterisan forte, Borraginol N, Posterisan and Borraza G. Microscopic observation showed that destruction of the mucus epithelium, necrosis of the mucus layer, infiltration of inflammatory cells and vasodilatation in the croton-oil model were also suppressed markedly by Neriproct application. No difference was observed in the efficacy between the cream and suppository formulation of Neriproct. Suppression of wound healing was found with a dosage of DFV lower than those of PS, HC and H. However, the efficacy ratio of the wound-healing suppression and anti-inflammation of DFV was the largest among the steroids tested.

[Effect of topical glucocorticoids on endogenous cortisol production]. / Einfluss topischer Glukokortikoide auf die körpereigene Cortisolproduktion.

In a randomized double blind study, we investigated the systemic effects of 3 different ointments containing corticoids. Every 7 patients out of a total of 21 patients suffering from various skin diseases were daily treated with 40 g of one of the 3 corticoid preparations over 8 days (group A: 0.05% clobetasol-17-propionate; group B: 0.25% fluocortolone trimethyl acetate; group C: 0.25% fluocortolone trimethyl acetate + 0.25% fluocortolone capronate). The plasma cortisol levels were determined by radioimmune assay. In group B and C, we did not observe any effect on the pituitary-adrenal axis, whereas in group A the plasma cortisol levels were extremely low already after 1 day of corticoid application. This adrenal suppression did not return to normal within 4 days after discontinuation of the corticoid. Our results suggest that highly potent topical corticoids are capable of adrenal suppression even without occlusive dressing and even in healthy persons.