Difluprednate

Absorption

Difluprednate penetrates the corneal epithelium rapidly and effectively. Low systemic absorption.

Toxicity

Preclinical pharmacokinetic and toxicity studies have established that difluprednate ophthalmic emulsion 0.05% given 4 times a day is not toxic to the eye.

Description

Difluprednate is a synthetic glucocorticoid that potently activates the glucocorticoid receptor (K_i = 78 pM). In vivo, ocular administration of difluprednate (0.05% w/v) increases intraocular pressure in sheep. Formulations containing difluprednate have been used to treat diabetic macular edema and inflammation following cataract surgery.

Chemical properties

White Solid

Originator

Epitopic,Clin Midy,France,1978

The Uses of Difluprednate

Difluprednate-d3 is the isotope labeled form of Difluprednate (D445925), a corticosteroid (derivative of prednisolone), approved for the treatment of post-operative ocular inflammation.

Indications

For the treatment of inflammation and pain associated with ocular surgery.

Background

Difluprednate is a topical corticosteroid indicated for the treatment of infammation and pain associated with ocular surgery. It is a butyrate ester of 6(α), 9(α)-difluoro prednisolone acetate. Difluprednate is abbreviated DFBA, or difluoroprednisolone butyrate acetate. It is indicated for treatment of endogenous anterior uveiti.

Definition

ChEBI: Difluprednate is a corticosteroid hormone and a butyrate ester.

Manufacturing Process

Orthoesterification: A mixture of 1 g of 6α,9α-difluoroprednisolone, 10 mg of p-toluenesulfonic acid, 5 cc of dimethylformamide and 3 cc of methyl orthobutyrate is heated for 15 hours on an oil bath at 105°C while a slow stream of nitrogen is passed through the mixture so that the methanol produced as a by-product of the reaction, is distilled off. After addition of several drops of pyridine to neutralize the acid catalyst, the reaction mixture is evaporated under vacuum and there is obtained a solid residue which is taken up with methanol, and filtered. The product is recrystallized from a methylene chloride-methanol mixture to yield 682 mg of 6α,9αdifluoroprednisolone 17α,21-methylorthobutyrate, also identified as 17α,21- (1'-methoxy)-n-butylidenedioxy-6α,9α-difluoro-δ1,4-pregnadiene-11β-ol-3,20- dione, MP 194°C-198°C.
Upon chromatography of the mother liquor on a column of alumina another 338 mg of a crystalline mixture of the epimeric orthobutyrates are isolated.
Hydrolysis: A suspension of 1 g of the 6α,9α-difluoroprednisolone 17α,21- methylorthobutyrate in 10 cc of methanol is treated with 2 cc of a 2 N aqueous solution of oxalic acid and heated on a water bath at 40°-50°C for about 5-10 minutes and, afterwards, the mixture is concentrated under vacuum. The residue is then shaken with water, the insoluble product is filtered off and then dried. The solid material is recrystallized from acetoneether and 6α,9α-difluoroprednisolone 17-butyrate is obtained, MP 193°-196°C
Esterification: A solution of 500 mg of 6α,9α-difluoroprednisolone-17-butyrate in 2.5 cc of pyridine is treated with 1.25 cc of acetic anhydride and the reaction mixture permitted to stand overnight at 0°C. The reaction mixture is then poured into ice water and the crystalline precipitate formed is filtered off and recrystallized from a methylene chloride-ether-petroleum ether mixture to yield 494 mg of 6α,9α-difluoroprednisolone 17-butyrate, 21-acetate; MP 191°- 194°C.

Therapeutic Function

Antiinflammatory

General Description

Difluprednate, 21-(acetyloxy)-6α,9-difluoro-11β-hydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione is being developed (phase III) as a topical ophthalmicemulsion to treat inflammatory eye diseases.

Pharmacokinetics

Difluprednate is a corticosteroid used as an anti-inflammatory steroidal drug used primarily in ocular surgery.

Metabolism

Difluprednate is rapidly deacetylated in the aqueous humor to difluoroprednisolone butyrate (DFB), the drug’s active metabolite. Endogenous tissue esterases then metabolize DFB to the inert metabolite hydroxyfluoroprednisolone butyrate (HFB), which limits systemic exposure to the active compound.