Globex Lotion - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Clobex Lotion - Scientific Information

Manufacture: Galderma Laboratories
Country: Canada
Condition: Psoriasis vulgaris (Plaque Psoriasis), Psoriasis, Skin Conditions (Dermatological Disorders)
Class: Dermatological agents
Ingredients: clobetasol propionate lotion 0.05%, hydroxypropylmethyl cellulose, propylene glycol, mineral oil, polyoxyethylene glycol 300 isostearate, carbomer 1342, sodium hydroxide, purified water

Pharmaceutical Iinformation

Drug Substance: clobetasol propionate
Proper name: clobetasol propionate
Chemical name: 21–chloro–9–fluoro–11β, 17–dihydroxy–16β–methylpregna–1,4–diene–3, 20–dione 17–propionate

Structural Formula:

Molecular Formula: C25H32CIFO5
Molecular Weight: 466.98
Physical Form: White to practically white crystalline powder.
Solubility: Insoluble in water. Soluble in acetone, chloroform and dioxane.Sparingly soluble in methanol.

Composition

Active ingredients

Each g of lotion contains 0.5 mg of clobetasol propionate, USP.

Inactive ingredients:

Hydroxypropylmethyl cellulose

Propylene glycol

Mineral oil

Polyoxyethylene glycol 300 isostearate

Carbomer 1342

Sodium hydroxide

Purified water

Stability and Storage Recommendations

Store at controlled room temperature (15 – 30°C). Do not freeze.

Availability of Dosage Forms

Clobex Lotion (clobetasol propionate lotion, 0.05%) is supplied in 120 mL HDPE bottles.

Pharmacology

Pharmacodynamics

Clobetasol propionate demonstrated marked anti–inflammatory, antiproliferative and vasoconstrictive activity in various animal models including in croton oil–induced ear edema in rats and in mice, and inhibition of UV–induced dermatitis, picryl chloride – induced hypersensitization and epidermal DNA synthesis in hairless mice, as well as inhibition of growth of granulomatous tissue in impregnated cotton pellet test. Clobetasol propionate induced epidermal thinning in mouse tail and mouse ear models, followed by recovery.

Clobetasol propionate was slightly less potent than halobetasol propionate and clearly more potent than hydrocortisone. Clobetasol propionate and halobetasol propionate had a very strong antiproliferative action on hexadecane-induced hyperplasia of the epidermis and showed marked anti-mitotic effect.

Results of two studies in healthy volunteers have shown the vasoconstriction capacity of Clobex Lotion (clobetasol propionate lotion, 0.05%) to be comparable to that of other cream formulations of clobetasol propionate and superior to that of DIPROLENE7 (0.05% betamethasone dipropionate) cream, Clobex Lotion vehicle, and untreated controls.

Pharmacokinetics

An in–vitro study was comparing the liberation-penetration of clobetasol propionate from Clobex Lotion showed that the amount of clobetasol propionate recovered in the skin was higher with Clobex Lotion than with the other two formulations of clobetasol propionate cream. Once absorbed through the skin, topical clobetasol propionate is metabolised by the liver and excreted primarily via bile into the feces.

Therapeutic Clinical Trials

The efficacy of Clobex Lotion in psoriasis and atopic dermatitis has been demonstrated in two well-controlled clinical trials. The first study was conducted in patients with moderate to severe plaque-type psoriasis. Patients were treated twice daily for four weeks with either Clobex or vehicle lotion. After 4 weeks of treatment, results demonstrated that the efficacy of Clobex Lotion in treating moderate to severe plaque-type psoriasis was superior to that of the vehicle.

Patients with no clinical signs of psoriasis after 4 weeks of treatment [N(%)]
Clinical signs of psoriasis Clobex Lotion
N=82
Vehicle
N=29
Scaling 48 (58.5) 2 (6.9)
Erythema 45 (54.9) 0 (0.0)
Plaque Elevation 13 (15.9) 0 (0.0)
Treatment Success* 60 (73.2) 1 (3.4)

*Success rate is the proportion of patients who achieved success at the week 4 endpoint. Success is defined as a score of none, very mild, or mild on the Global Severity scale of psoriasis signs.

The second study was conducted in patients with moderate to severe atopic dermatitis. Patients were treated twice daily for 2 weeks with either Clobex or vehicle lotion. After 2 weeks of treatment, Clobex Lotion was shown to be superior to the vehicle in treating moderate to severe atopic dermatitis.

Patients with no clinical signs of atopic dermatitis after 2 weeks of treatment [N(%)]
Clinical signs and symptoms of atopic dermatitis< Clobetasol Lotion
N=96
Vehicle
N=33
Pruritus 56 (58.3) 5 (15.2)
Excoriation 67 (69.8) 13 (39.4)
Erythema 34 (35.4) 2 (6.1)
Induration⁄Papulation 50 (52.1) 5 (15.2)
Lichenification 47 (49.0) 5 (15.2)
Treatment Success* 70 (72.9) 12 (36.4)

*Success rate is the proportion of patients who achieved success at the week 2 endpoint. Success is defined as a score of none, verymild, or mild on the Global Severity scale of atopic dermatitis signs and symptoms.

Toxicology

Acute Toxicity

Acute toxicity studies showed an oral LD50 over 3000 mg⁄kg in mice and rats.

Long–Term Toxicity

The effects obtained in the subchronic and chronic studies by the subcutaneous or the percutaneous route in the rat did not indicate any intrinsic toxic effects by clobetasol propionate. They are comparable in nature and extent to those of other highly active corticosteroids. Hence, they are considered as extensions of the pharmacological activity of clobetasol proprionate. The subcutaneous No Adverse Effects Level (NOAEL) is 20 Fg⁄kg. Adverse effects observed in percutaneous studies included thinning of the skin and retardation of hair growth at the application site. Decreased body weight gain, decreased serum corticosterone levels, lymphopenia, involution of the thymus, adrenal gland atrophy and localised hepatic necrosis were also observed in animals treated.

Results of local tolerance studies showed that clobetasol propionate lotion did not produce any signs of dermal or eye irritation or delayed-type hypersensitivity in rabbits. These results are consistent with the results obtained in a human study, in which there was no evidence of sensitisation to clobetasol propionate lotion vehicle.

Carcinogenicity

No animal carcinogenicity studies were conducted.

Results of a 13–week preliminary topical study with clobetasol propionate lotion in hairless mice, with or without simulated sunlight confirmed the strong pharmacological effects of clobetasol propionate (skin atrophy, significant body weight loss, mortality). The severity of the toxic effects observed after 13 weeks of treatment even in the lowest dose group (dose volume of 25 FL administered three times per week) show that similar experimental conditions are not feasible for a photocarcinogenicity study with treatment duration of 40 weeks.

Mutagenicity

Clobetasol propionate was shown to be not mutagenic in Ames test, gene conversion tests and E. coli B WP2 fluctuation test. The long history of clinical practice of clobetasol propionate gives no rise to suspicion for an impact on genetic material.

Reproduction & Teratology

In a fertility study in the rat by the subcutaneous route, no effects on the reproductive organs or on the mating performance were observed in either sex at doses up to 50 Fg⁄kg⁄day. The only effect observed in the females at this dosage was an increased number of absorbed embryos and a decreased number of living fetuses.

Clobetasol propionate, like other corticosteroids, induced teratogenicity in laboratory animals when administered systemically but also after dermal application. Topical teratogenicity occurred at relatively low dose levels but at relatively high plasma concentrations. These were due to the occlusion applied to minimize oral uptake.

Clobetasol propionate is absorbed percutaneously, and when administered subcutaneously, it was a significant teratogen in both the rabbit and the mouse. Clobetasol propionate has greater teratogenic potential than steroids that are less potent.

Teratogenicity studies in mice using the subcutaneous route resulted in fetotoxicity at the highest dose tested (1 mg⁄kg) and teratogenicity at all dose levels tested down to 0.03 mg⁄kg. Abnormalities seen included cleft palate and skeletal abnormalities.

In rabbits, clobetasol propionate was teratogenic at doses approximately 0.02 and 0.05 times the human topical dose of clobetasol propionate lotion, 0.05%. Abnormalities were observed including cleft palate, cranioschisis, and other skeletal abnormalities.

A teratogenicity study in rats using the dermal route resulted in dose related maternal and fetal effects from 0.05 to 0.5 mg⁄kg⁄day of clobetasol propionate. Abnormalities seen included fetal immaturity and several malformations, in combination with maternal toxicity.