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Locoid Lipocream (Hydrocortisone Butyrate Topical) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Locoid Lipocream contains hydrocortisone butyrate, a non-fluorinated hydrocortisone ester [Pregn-4-ene-3, 20-dione, 11, 21-dihydroxy-17- [(1-oxobutyl) oxy (11β)-] for topical dermatologic use.

Chemically, hydrocortisone butyrate is C25H36O6. It has the following structural formula:

Hydrocortisone butyrate is a white to practically white powder with a molecular weight of 432.56. It is practically insoluble in water, slightly soluble in ether, soluble in methanol, in alcohol, and in acetone, and freely soluble in chloroform.

Each gram of Locoid Lipocream contains 1 mg hydrocortisone butyrate in a hydrophilic base consisting of cetostearyl alcohol, ceteth-20, mineral oil, white petrolatum, citric acid, sodium citrate, propylparaben and butylparaben (preservatives) and water.

CLINICAL PHARMACOLOGY

Mechanism of Action

Topical corticosteroids share anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical corticosteroids is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.

Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings.

Topical corticosteroids can be absorbed through normal intact skin. Inflammation and/or other disease processes in the skin, occlusive dressings, or widespread application may increase percutaneous absorption and increase the risk of HPA Axis suppression.

The vasoconstrictor assay showed that Locoid Lipocream had a more pronounced skin blanching effect than Locoid Cream, suggesting greater percutaneous absorption from the former.

Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids.

Corticosteroids are bound to plasma proteins in varying degrees.

Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys.

Some of the topical corticosteroids and their metabolites are also excreted into the bile.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies were conducted to determine the photoco-carcinogenic or dermal carcinogenic potential of Locoid Lipocream.

Hydrocortisone butyrate revealed no evidence of mutagenic or clastogenic potential based on the results of two in vitro genotoxicity tests (Ames test and L5178Y/TK+ mouse lymphoma assay) and one in vivo genotoxicity test (mouse micronucleus assay).

No evidence of impairment of fertility or effect on mating performance was observed in a fertility and general reproductive performance study conducted in male and female rats at subcutaneous doses up to and including 1.8 mg/kg/day (0.7X MTHD). Mild effects on maternal animals, such as reduced food consumption and a subsequent reduction in body weight gain, were seen at doses ≥0.6 mg/kg/day (0.2X MTHD).

CLINICAL STUDIES

Pediatric Atopic Dermatitis

In a multicenter, randomized, vehicle-controlled trial of 264 pediatric subjects 3 months to 18 years of age with mild to moderate atopic dermatitis, Locoid Lipocream or vehicle was applied twice daily for up to four weeks. Treatment success was assessed at day 29 (after 28 days of treatment) and was defined as the proportion of patients who achieved both "clear" or "almost clear" and at least a two grade improvement from baseline on a 5-point Physician's Global Assessment (PGA) scale.

Study results are shown in Table 3.

TABLE 3. Efficacy Results at Day 29 in Pediatric Subjects
Locoid Lipocream
(n=131)
Vehicle
(n=133)
Number (%) successes 82 (63%) 37 (28%)

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