Application Research of Betamethasone 17,21-dipropionate

Introduction

Betamethasone 17,21-dipropionate is a synthetic glucocorticoid that appears as white solid crystalline powder.(Figure 1) The crystals exist in orthorhombic shape. Chemically, it is an ester of betamethasone with IUPAC nomenclature which is (11β,16β)-9-Fluoro-11--hydroxy-16-methyl-17,21-bis(1-oxopropoxy)-pregna-1,4-diene-3,20-dione with molecular formula C₂₈H₃₇FO₇ and molecular weight of 504.595 g/mol. The octanol/water partition coefficient of betamethasone 17,21-dipropionate is 4.07 suggesting hydrophobic nature of the drug. Betamethasone 17,21-dipropionate is highly potent corticosteroid acting as receptor agonist with immunosuppressive, anti-infammatory, and anti-proliferative activity. It obstructs the synthesis of arachidonic acid and controls the biosynthesis of prostaglandins and leukotrienes by controlling the inhibition of phospholipase A2. There are different types of dosage forms available for topical applications—cream, lotion, ointment,and foams. Moreover, the poor permeability forms the clinical limitation of betamethasone 17,21-dipropionate, which reduces its therapeutic efficacy at the site of action. Also, the possibility to poor adherence to the therapy is of great concern. Thus, for the topical formulations, drug penetration into the skin without signifcantly effecting barrier function of the skin and its retention is a major challenge for the formulation scientists. [1]

Characteristic of Betamethasone 17,21-dipropionate Nanocrystals 

Corticosteroids, such as betamethasone 17,21-dipropionate (BMD), have been the mainstay in topical therapy as potent glucocorticoid receptor agonist with immune suppression, anti-proliferative, and anti-inflammatory effects. Moreover, they have poor skin penetration, which is a hurdle against its potential therapeutic benefits. In present investigation, nanocrystals as carrier for effective topical delivery of betamethasone 17,21-dipropionate were explored using wet milling as technique and polysorbate 80 as a non-ionic stabilizer. Upon optimizing different process parameters, promising results were observed at stabilizer concentration of 0.9% w/v having particle size analysis (PSA) and PDI as 284 nm and 0.299, respectively. These results were supported by the FTIR and PXRD spectra of BMD-API and BMD nanocrystals, suggesting strong crystal lattice structure of BMD being reduced due to milling. The reduction in particle morphology was evident from the FESEM images. The optimized batch of betamethasone 17,21-dipropionate nanocrystals was incorporated into Carbopol gel base, showing pH 6.2±0.2 and viscosity 87.00±5.2 Pa s at 25°C. A drug diffusion study using Franz diffusion cell proclaimed around ~86% BMD release from nanogel across the membrane. Also, it was observed that the BMD permeation across the skin was 2.39-fold higher with marketed formulation in contrast to betamethasone 17,21-dipropionate nanogel, suggesting prolonged drug release. The skin permeation flux with nanogel was at a much lower rate along with ~50.27% drug retention in different strata of skin, resulting in retention of drug nanocrystals. Thus, in nutshell the prolonged drug release from nanogel would fulfill the aim of once a day application and would aid in reducing the adverse events associated with repeated drug applications.[1]

Calcipotriol/betamethasone 17,21-dipropionate for the treatment of psoriasis

The two-compound product calcipotriol/betamethasone 17,21-dipropionate is arising as a first-line treatment for mild-to-moderate plaque psoriasis. Its beneficial action is attributed to the synergistic effect of its components on keratinocyte proliferation and differentiation, and on inflammation. The good tolerability of the two-compound product is thought to be due to the anti-inflammatory effect of betamethasone. Evidence from short-term (4-12 weeks) and long-term use (> 1 year) has shown a good safety profile. Areas such as the face or skin folds, which are sensitive to the components of the combination, should be avoided. Finally, it is unsuitable for use in unstable psoriasis, in which potent steroids may lead to an increased inflammatory response.[2]

Characteristic of Calcipotriol/betamethasone 17,21-dipropionate

Calcipotriol/betamethasone 17,21-dipropionate (calcipotriol 50 μg/g and betamethasone 0.5 mg/g;CBD) is a fixed-dose combination of a vitamin D3 analogue and a corticosteroid indicated for the once-daily, topical treatment of psoriasis vulgaris of the trunk, limbs and scalp in adults. Both the ointment (Daivobet®; Dovobet®) and gel (Xamiol®; Daivobet® Gel; Dovobet® Gel) formulations of calcipotriol/betamethasone 17,21-dipropionate can be used to treat psoriasis vulgaris of the trunk and/or limbs, although the gel formulation was specifically developed for the treatment of scalp psoriasis.  Calcipotriol/betamethasone 17,21-dipropionate has low systemic absorption and displays local anti-inflammatory and immunoregulatory properties. It reduces the hyperproliferation of keratinocytes and helps normalize keratinocyte differentiation. In large, well designed clinical trials, CBD, either as the ointment or the gel formulation, applied once daily for 4-8 weeks, was more effective than placebo, calcipotriol and tacalcitol, as well as betamethasone 17,21-dipropionate in most instances, for the topical, symptomatic treatment of psoriasis vulgaris of the trunk/limbs. Likewise, CBD gel applied once daily for 8 weeks was more effective than placebo or either component alone in the topical, symptomatic treatment of psoriasis vulgaris of the scalp. Long-term, once-daily, when required therapy with calcipotriol/betamethasone 17,21-dipropionate for 52 weeks was more effective than calcipotriol alone for the treatment of scalp psoriasis, and was at least as effective as switching to calcipotriol for 48 weeks after 4 weeks of CBD or alternating between CBD and calcipotriol every 4 weeks for 52 weeks in the treatment of psoriasis vulgaris of the trunk/limbs. CBD also improved health-related quality of life. Calcipotriol/betamethasone 17,21-dipropionate was generally well tolerated, with most adverse drug reactions being lesional or perilesional effects of mild or moderate severity. It was often associated with fewer lesional/perilesional adverse reactions than calcipotriol or tacalcitol and did not appear to be associated with a higher incidence of corticosteroid-related adverse events during long-term therapy. Pharmacoeconomic analyses predicted calcipotriol/betamethasone 17,21-dipropionate to be more cost effective than other topical therapies. Thus, CBD is an important, effective, once-daily, topical therapy for the symptomatic treatment of psoriasis vulgaris of the trunk, limbs and scalp.[3]

References

[1] Patel V, Mehta TA. Betamethasone Dipropionate Nanocrystals: Investigation, Feasibility and In Vitro Evaluation. AAPS PharmSciTech. 2022;23(6):197. Published 2022 Jul 14. doi:10.1208/s12249-022-02346-1

[2] Charakida A, Dadzie O, Teixeira F, Charakida M, Evangelou G, Chu AC. Calcipotriol/betamethasone dipropionate for the treatment of psoriasis. Expert Opin Pharmacother. 2006;7(5):597-606. doi:10.1517/14656566.7.5.597

[3] McCormack PL. Calcipotriol/betamethasone dipropionate: a review of its use in the treatment of psoriasis vulgaris of the trunk, limbs and scalp. Drugs. 2011;71(6):709-730. doi:10.2165/11207300-000000000-00000

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