Ciclesonide

Absorption

Ciclesonide and des-ciclesonide have negligible oral bioavailability (both less than 1%) due to low gastrointestinal absorption and high first-pass metabolism. The intranasal administration of ciclesonide at recommended doses results in negligible serum concentrations of ciclesonide.

Description

Ciclesonide, a new inhaled corticosteroid (ICS), is indicated for the prophylactic treatment of persistent asthma. ICS treatment is a widely accepted standard of care for maintenance therapy of chronic asthma, and the currently available agents include fluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, and beclomethasone dipropionate. These agents exert their potent anti-inflammatory effects via modulation of the glucocorticoid receptor (GR). Although ICS drugs are generally safe and well tolerated compared with oral corticosteroids, many have measurable systemic exposures, and concerns over potential side effects resulting from it severely limit the dose at which they can be administered for long-term therapy. Systemic adverse effects associated with corticosteroids include HPA axis suppression, osteoporosis, abnormal glucose metabolism, cataracts, and glaucoma, some of which could potentially occur with the long-term use of high dose ICS. The key differentiators for ciclesonide relative to other ICS drugs are its longer duration of action and lower systemic exposure. Ciclesonide is an isobutyryl ester prodrug. It is cleaved by the endogenous esterases in the lung to des-isobutyryl ciclesonide (des- CIC), which is a potent GR agonist. The binding affinity of des-CIC for human GR (K_i=0.31 nM) is similar to other ICS such as budesonide (K_i=0.44nM) and fluticasone propionate (K_i=0.24nM), while ciclesonide itself has about 100-fold lower affinity (K_i=37nM). In lung tissue, des-CIC undergoes reversible lipid conjugation to form oleate and palmitate ester conjugates, which act as a slow-release pool for the drug and increase the pulmonary residence time. This, in turn, contributes to the enhanced local effects and the long duration of action.
Inhaled ciclesonide was generally well tolerated in these clinical studies. Ciclesonide did not suppress biochemical markers of adrenal function in 52-week studies; however, the long-term (＞52 weeks) systemic effects remain unknown. Ciclesonide is chemically produced via a semi-synthesis starting from 16-α-hydroxyprednisolone by first converting to a triisobutyryl ester intermediate with isobutyric anhydride, and subsequent reaction of the triester with cyclohexane carboxaldehyde and hydrochloric acid in dioxane. The latter step produces the cyclic ketal as a mixture of diastereomers, which is subjected to HPLC and fractional crystallization to produce ciclesonide.

Chemical properties

White Solid

Originator

Recordati Espana (Spain)

The Uses of Ciclesonide

A glucocorticoid microemulsion nasal preparation allergy inhibitor rhinitis.

Indications

For the treatment of nasal symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents 12 years of age and older.

Background

Ciclesonide is a glucocorticoid used to treat obstructive airway diseases. It is marketed under the brand name Alvesco.

Definition

ChEBI: Ciclesonide is an organic molecular entity.

brand name

Alvesco (Dynamit Nobel GmbH).

General Description

Ciclesonide (Omnaris) is a prodrug that requireshydrolysis of the isobutyrate ester at C21 to form theactive corticosteroid (des-ciclesonide). It has minimal oralbioavailability due to extensive metabolism, mainly byCYP3A4. The metabolites of ciclesonide have not beenfully characterized.

Pharmacokinetics

Ciclesonide is a pro-drug that is enzymatically hydrolyzed to a pharmacologically active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1) following intranasal application. Des-ciclesonide has anti-inflammatory activity with affinity for the glucocorticoid receptor that is 120 times higher than the parent compound. The precise mechanism through which ciclesonide affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic inflammation.

Synthesis

Two separate approaches to the syntheses of the chiral ciclesonide have been described in the patent literature. The first route involves a chiral resolution step and the second approach highlights a stereoselective trans acetalization approach. The first synthesis of ciclesonide started by reacting (11|?,16|á)-11, 16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione (1) with isobutyric anhydride to make the tri-isobutyl ester in 87% yield. Reaction of the tri-ester with cyclohexane carboxaldehyde in the presence of HCl and 70% perchloric acid gave the cyclohexane acetal 3, which was then separated into the desired isomer ciclesonide (I) by HPLC or recrystallization.

Metabolism

Des-ciclesonide undergoes metabolism in the liver to additional metabolites mainly by the cytochrome P450 (CYP) 3A4 isozyme and to a lesser extent by CYP 2D6.

storage

Store at +4°C