Clocortolone

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Clocortolone pivalate
Clocortolone pivalate.svg
Clinical data
Trade names Cloderm
AHFS/Drugs.com Consumer Drug Information
Routes of
administration
Topical
ATC code
Legal status
Legal status
Identifiers
  • [2-(9-Chloro-6-fluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-7,8,11,12,14,15,16,17-octahydro-6H-cyclopenta[a]phenanthren-17-yl)-2-oxo-ethyl] 2,2-dimethylpropanoate
CAS Number
PubChem CID
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UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.023.096 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H36ClFO5
Molar mass 495.03 g·mol−1
3D model (JSmol)
  • O=C(OCC(=O)[C@@H]3[C@]2(C[C@H](O)[C@]4(Cl)[C@@]/1(\C(=C/C(=O)\C=C\1)[C@@H](F)C[C@H]4[C@@H]2C[C@H]3C)C)C)C(C)(C)C
  • InChI=1S/C27H36ClFO5/c1-14-9-16-17-11-19(29)18-10-15(30)7-8-26(18,6)27(17,28)21(32)12-25(16,5)22(14)20(31)13-34-23(33)24(2,3)4/h7-8,10,14,16-17,19,21-22,32H,9,11-13H2,1-6H3/t14-,16+,17+,19+,21+,22-,25+,26+,27+/m1/s1 Yes check.svgY
  • Key:SXYZQZLHAIHKKY-GSTUPEFVSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Clocortolone (Cloderm) is a topical steroid. [1] It is used in the form of an ester, clocortolone pivalate, and applied as a cream. [2] It is used for the treatment of dermatitis and is considered a medium-strength corticosteroid. It is unusual among steroids in that it contains a chlorine atom and a fluorine atom.

Contents

Pharmacology

Clocortolone is an upper-mid potency topical corticosteroid formulation. It is rated at a class 4 potency on a scale of 1 (highest potency) to 7 (lowest potency). [3] Most patients are treated with mid-potency topical corticosteroids, for they are an effective medium between safety and efficacy for short and long-term conditions.

Vital to the pharmacological action of clocortolone is the presence and location of its functional groups. There were several molecular modifications done to create clocortolone pivalate, including beta-hydroxylation at C-11, methylation at C-16, double bonds at C-12, esterification at C-21, and halogenation at C-6 and C-9. It is common in the medical community to associate halogenation of topical corticosteroids with adverse effects. This notion is, in fact, incorrect—it is both the presence and location of halogenation in steroids that matter. In comparison to all other topical corticosteroids, the combination of the chlorine at C-9 and the fluorine at C-6 is unique to clocortolone. Clocortolone pivalate, due to its unique nature, has both upper-mid potency and the safety profile associated with a lower potency topical corticosteroid. This versatility allows for Cloderm cream to be a treatment option for a variety of patients. [3]

Cream vehicle

Clocortolone pivalate 0.1% is formulated in a cream that contains three ingredients which assist in stratum corneum permeability barrier integrity: white petrolatum (occlusive), mineral oil (humectant), and stearyl alcohol (long-chain fatty alcohol emollient). This cream does not contain lanolin, fragrance, nor propylene glycol, all of which have been known to be problematic for some patients. [4]

Clinical studies

In Phase III trials, Cloderm was found to be especially useful in treating eczema, atopic dermatitis, and psoriasis. [3] Phase III trials also showed rapid action and relief for the majority of the patients involved. There is no age restriction on the use of clocortolone pivalate 0.1% cream. [5] Clinical trials comparing clocortolone pivalate 0.1% topical cream with vehicle in atopic dermatitis/eczematous dermatitis, psoriasis, and contact dermatitis included pediatric patients (N=44). The mean age of pediatric subjects was 10 years (range 3–14 years). Clocortolone pivalate 0.1% cream was efficacious for the majority (75%) of the pediatric patients in these trials, with no serious adverse effects occurring in either group. [4]

In six parallel, double-blind, placebo-controlled trials, patients with atopic dermatitis/eczematous dermatitis were randomized to treatment with clocortolone pivalate 0.1% topical cream (total n=109) or vehicle (total n=100), applied three times daily over a duration of 14 days. According to evaluations completed by the physician investigators, a significantly higher proportion of patients in the clocortolone pivalate group than patients in the vehicle group demonstrated a good or excellent response at Days 4, 7, and 14. [4]

Due to the chronic and lengthy nature of some steroid responsive dermatoses such as atopic dermatitis and psoriasis, a study of 27 patients was conducted, wherein these patients were treated with Cloderm from 30 days up to 7 months. The results of these treatments showed a low rate of adverse reactions and no signs of striae, atrophy, or hypopigmentation. Adverse reactions that were experienced included burning, itching, irritation, dryness, and/or folliculitis. [5]

Additionally, a clinical study investigated the potential of hypothalamic–pituitary–adrenal (HPA) axis suppression. Ten men with no major health issues applied 30g of clocortolone pivalate 0.1% cream twice a day for 21 days while wearing a plastic sweat suit for twelve hours per day. Through the measurements of plasma cortisol and urinary 17-ketosteroid levels, the investigators monitored effects on the HPA axis, and no signs of adrenal suppression were evident. [5]

In total to date, 559 patients have participated in clinical trials involving Cloderm, and there was little evidence of local and/or systemic adverse effects. [5] Specifically, only 4.4 percent experienced adverse events, most of which were local application-site reactions, such as dryness, stinging, burning, or itching. [4]

Regulation history

Cloderm, the brand formulation of clocortolone pivalate 0.1% cream, was approved by the Food and Drug Administration in 1977 for the treatment of corticoid responsive dermatoses. [6]

Commercialization

Manufacturing process

Clocortolone is synthesized by the reaction of 6α-fluoro-16α-methyl-21-hydroxy-1,4,9(11)-pregnatriene-3,20-dione with tert-butyl hypochlorite. [7]

Commercialization history

The synthesis of clocortolone was invented and patented by Emanuel Kaspar and Rainer Philippson in 1973 with United States Patent 3,729,495. The original assignee of the patent was Schering AG, a research-centered German pharmaceutical company. [8] The rights to Clocortolone were then sold to Germapharm, and then to Coria Laboratories, Ltd. of DFB Pharmaceuticals, Inc., [7] a Fort Worth-based pharmaceutical company. [9] Coria Laboratories, Ltd., the dermatology division of DFB Pharmaceuticals, Inc., was then sold to Valeant Pharmaceuticals in 2008. [9] In 2011, Promius Pharma, LLC, an affiliate of Dr. Reddy's Laboratories, and Valeant Pharmaceuticals International, Inc. announced that they had signed a joint agreement for Cloderm. Per this collaborative agreement, Promius Pharma made an upfront payment will continue to pay royalties as the consideration for the right to manufacture, distribute and market Cloderm in the United States. [10]

Price listing

In August 2016 Cloderm Cream 0.1% clocortolone pivalate was priced at $3.64 per gram and $140.98 per 45 gm tube. [11]

See also

Related Research Articles

<span class="mw-page-title-main">Dermatitis</span> Inflammatory disease of the skin

Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can vary from small to covering the entire body. Dermatitis is often called eczema, and the difference between those terms is not standardized.

<span class="mw-page-title-main">Corticosteroid</span> Class of steroid hormones

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.

<span class="mw-page-title-main">Tacrolimus</span> Immunosuppressive drug

Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After allogenic organ transplant, the risk of organ rejection is moderate. To lower the risk of organ rejection, tacrolimus is given. The drug can also be sold as a topical medication in the treatment of T-cell-mediated diseases such as eczema and psoriasis. For example, it is prescribed for severe refractory uveitis after a bone marrow transplant, exacerbations of minimal change disease, Kimura's disease, and vitiligo. It can be used to treat dry eye syndrome in cats and dogs.

<span class="mw-page-title-main">Pimecrolimus</span> Immunosuppressive drug

Pimecrolimus is an immunosuppressant drug of the calcineurin inhibitor class used in the treatment of atopic dermatitis (eczema).

Antipruritics, abirritants, or anti-itch drugs, are medications that inhibit the itching often associated with sunburns, allergic reactions, eczema, psoriasis, chickenpox, fungal infections, insect bites and stings like those from mosquitoes, fleas, and mites, and contact dermatitis and urticaria caused by plants such as poison ivy or stinging nettle. It can also be caused by chronic kidney disease and related conditions.

<span class="mw-page-title-main">Desonide</span> Chemical compound

Desonide (INN) is a low-potency topical corticosteroid anti-inflammatory that has been available since the 1970s. It is primarily used to treat atopic dermatitis (eczema), seborrheic dermatitis, contact dermatitis and psoriasis in both adults and children. It has a fairly good safety profile and is available as a cream, ointment, lotion, and as a foam under the tradename Verdeso Foam. Other trade names for creams, lotions, and ointments include Tridesilon, DesOwen, Desonate. It is a group VI corticosteroid under US classification, the second least potent group.

<span class="mw-page-title-main">Betamethasone dipropionate</span> Glucocorticoid steroid (chemical compound)

Betamethasone dipropionate is a glucocorticoid steroid with anti-inflammatory and immunosuppressive properties. It is applied as a topical cream, ointment, lotion or gel (Diprolene) to treat itching and other skin conditions such as eczema. Minor side effects include dry skin and mild, temporary stinging when applied. Betamethasone dipropionate is a "super high potency" corticosteroid used to treat inflammatory skin conditions such as dermatitis, eczema and psoriasis. It is a synthetic analog of the adrenal corticosteroids. Although its exact mechanism of action is not known, it is effective when applied topically to cortico-responsive inflammatory dermatoses. It is available as a generic medication.

<span class="mw-page-title-main">Calcipotriol</span> Chemical compound

Calcipotriol, also known as calcipotriene, is a synthetic derivative of calcitriol, a form of vitamin D. It is used in the treatment of psoriasis. It is safe for long-term application in psoriatic skin conditions.

<span class="mw-page-title-main">Perioral dermatitis</span> Medical condition

Perioral dermatitis, also known as periorificial dermatitis, is a common type of skin rash. Symptoms include multiple small (1–2 mm) bumps and blisters sometimes with background redness and scale, localized to the skin around the mouth and nostrils. Less commonly the eyes and genitalia may be involved. It can be persistent or recurring and resembles particularly rosacea and to some extent acne and allergic dermatitis. The term "dermatitis" is a misnomer because this is not an eczematous process.

<span class="mw-page-title-main">Alclometasone</span> Chemical compound

Alclometasone is a synthetic corticosteroid for topical dermatologic use, possessing anti-inflammatory, antipruritic, and vasoconstrictive properties.

<span class="mw-page-title-main">Diflorasone diacetate</span> Chemical compound and topical steroid

Diflorasone diacetate is a topical steroid that comes in the form of a cream. It is manufactured by E. Fougera & Co. and is used as an anti-inflammatory and anti-itching agent, like other topical corticosteroids. It is prescribed for psoriasis and atopic dermatitis, among other conditions. With respect to potency, it is regarded as a Class I corticosteroid [of classes I – VII] in the United States.

<span class="mw-page-title-main">Amcinonide</span> Chemical compound

Amcinonide is a topical glucocorticoid used to treat itching, redness and swelling associated with several dermatologic conditions such as atopic dermatitis and allergic contact dermatitis. Amcinonide can also be classified as a multi-functional small molecule corticosteroid, which has been approved by the FDA and is currently marketed as an ointment, lotion, or cream. It acts as both a transcription factor for responses to glucocorticoids and modulator for other transcription factors while also regulating phospholipase A2 activity.

<span class="mw-page-title-main">Halometasone</span> Chemical compound

Halometasone is a potent synthetic tri-halogenated corticosteroid for topical application possessing pronounced anti-inflammatory, antiexudative, antiepidermoplastic, antiallergic, and antipruritic properties. It has been approved in many European countries including Spain, Germany, Switzerland, Austria, Netherlands, Belgium, and Portugal and other regions such as China, Hong Kong, Turkey, Israel, South Africa and India.

In medicine, a finger tip unit (FTU) is defined as the amount of ointment, cream or other semi-solid dosage form expressed from a tube with a 5 mm diameter nozzle, applied from the distal skin-crease to the tip of the index finger of an adult. The "distal skin-crease" is the skin crease over the joint nearest the end of the finger. One FTU is enough to treat an area of skin twice the size of the flat of an adult's hand with the fingers together, i.e. a "handprint". Two FTUs are approximately equivalent to 1 g of topical steroid.

<span class="mw-page-title-main">Spongiosis</span> Intercellular epidermal edema characteristic of dermatitis

Spongiosis is mainly intercellular edema in the epidermis, and is characteristic of eczematous dermatitis, manifested clinically by intraepidermal vesicles, "juicy" papules, and/or lichenification. It is a severe case of eczema that affects the epidermis, dermis or subcutaneous skin tissues. The three types of spongiotic dermatitis are acute, subacute and chronic. A dermatologist can diagnose acute spongiotic dermatitis by examining the skin during an office visit, but a biopsy is needed for an accurate diagnosis of the type.

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<span class="mw-page-title-main">Calcipotriol/betamethasone dipropionate</span> Combination drug

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<span class="mw-page-title-main">Topical steroid withdrawal</span> Medical condition

Topical steroid withdrawal, also known as red burning skin and steroid dermatitis, has been reported in people who apply topical steroids for 2 weeks or longer and then discontinue use. Symptoms affect the skin and include redness, a burning sensation, and itchiness, which may then be followed by peeling.

<span class="mw-page-title-main">Topical glucocorticoids</span>

Topical glucocorticoids are the topical forms of glucocorticoids. Topical glucocorticoids are used in the treatment of many skin conditions. They provide anti-inflammatory, antimitotic, and immune-system suppressing actions through various mechanisms.

<span class="mw-page-title-main">Topical hydrocortisone</span> Pharmaceutical drug

Topical hydrocortisone is a drug under the class of corticosteroids, which is used for the treatment of skin inflammation, itchiness and allergies. Some examples include insect bites, dermatitis and rash.

References

  1. Nierman MM (June 1981). "Safety and efficacy of clocortolone pivalate 0.1 percent cream in the treatment of atopic dermatitis, contact dermatitis, and seborrheic dermatitis". Cutis. 27 (6): 670–1. PMID   6453703.
  2. Drugs.com: Clocortolone topical
  3. 1 2 3 Kircik L (September 2011). "Get Reacquainted with Clocortolone Pivalate" (PDF). The Dermatologist. The Dermatologist. Archived from the original (PDF) on 4 March 2016.
  4. 1 2 3 4 Del Rosso JQ, Kircik L (July 2012). "A Comprehensive Review of Clocortolone Pivalate 0.1% Cream: Structural Development, Formulation Characteristics, and Studies Supporting Treatment of Corticosteroid-responsive Dermatoses". The Journal of Clinical and Aesthetic Dermatology. 5 (7): 20–4. PMC   3396454 . PMID   22798972.
  5. 1 2 3 4 Hougeir FG (July 2013). "Spotlight on Clocortolone Pivalate: Discussion and Case Reports". JDD: Current Clinical Solutions.
  6. Del Rosso JQ, Kircik LH (July 2014). "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". Journal of Drugs in Dermatology. 13 (7): s77-83. PMID   25007376.
  7. 1 2 Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. William Andrew Publishing.
  8. Process for the preparation of 9alpha-chloro-11beta-hydroxy steroids , retrieved 2015-12-07
  9. 1 2 Savage S (2008-09-17). "DFB Sells Coria Labs to Valeant Pharmaceuticals". Red Orbit. Red Orbit.
  10. "Promius Pharma and Valeant Form Collaboration to Market Cloderm(R) Cream in the United States". Valeant Pharmaceuticals International, Inc. April 1, 2011. Archived from the original on December 10, 2015.
  11. Clocortolone, August 17, 2016, retrieved January 1, 2017