Formulation of a Danazol Cocrystal with Controlled Supersaturation Plays an Essential Role in Improving Bioavailability

Cocrystals
have become an established and adopted approach for
creating crystalline solids with improved physical properties, but
incorporating cocrystals into enabling pre-clinical formulations suitable
for animal dosing has received limited attention. The dominant approach
to in vivo evaluation of cocrystals has focused on
deliberately excluding additional formulation in favor of “neat”
aqueous suspensions of cocrystals or loading neat cocrystal material
into capsules. However, this study demonstrates that, in order to
take advantage of the improved solubility of a 1:1 danazol:vanillin
cocrystal, a suitable formulation was required. The neat aqueous suspension
of the danazol:vanillin cocrystal had a modest in vivo improvement of 1.7 times higher area under the curve compared to
the poorly soluble crystal form of danazol dosed under identical conditions,
but the formulated aqueous suspension containing 1% vitamin E-TPGS
(TPGS) and 2% Klucel LF Pharm hydroxypropylcellulose improved the
bioavailability of the cocrystal by over 10 times compared to the
poorly soluble danazol polymorph. In vitro powder
dissolution data obtained under non-sink biorelevant conditions correlate
with in vivo data in rats following 20 mg/kg doses
of danazol. In the case of the danazol:vanillin cocrystal, using a
combination of cocrystal, solubilizer, and precipitation inhibitor
in a designed supersaturating drug delivery system resulted in a dramatic
improvement in the bioavailability. When suspensions of neat cocrystal
material fail to return the anticipated bioavailability increase,
a supersaturating formulation may be able to create the conditions
required for the increased cocrystal solubility to be translated into
improved in vivo absorption at levels competitive
with existing formulation approaches used to overcome solubility limited
bioavailability.