Development of a bladder instillation of the indoloquinone anticancer agent EO-9 using tert-butyl alcohol as lyophilization vehicle

Abstract

The purpose of this research was to develop a stable bladder instillation of EO-9 for the treatment of superficial bladder cancer. First, stability and dissolution studies were performed. Subsequently, the freeze-drying process was optimized by determination of the freeze-drying characteristics of the selected cosolvent/water system and differential scanning calorimetry analysis of the formulation solution. Furthermore, the influence of the freeze-drying process on crystallinity and morphology of the freeze-dried product was determined with x-ray diffraction analysis and scanning electron microscopy, respectively. Subsequently, a reconstitution solution was developed. This study revealed that tert-butyl alcohol (TBA) can be used to both dramatically improve the solubility and stability of EO-9 and to shorten the freeze-drying cycle by increasing the sublimation rate. During freeze drying, 3 TBA crystals were found: TBA hydrate-ice crystals, crystals of TBA hydrate, and a third crystal, probably composed of TBA hydrate crystals containing~90% to 95% TBA. Furthermore, it was shown that crystallization of TBA hydrate was inhibited in the presence of both sodium bicarbonate (NaHCO 3 ) and mannitol. Addition of an annealing step resulted in a minor increase in the crystallinity of the freeze-dried product and formation of the δ-polymorph of mannitol. A stable bladder instillation was obtained after reconstitution of the freeze-dried product (containing 8 mg of EO-9, 20 mg of NaHCO 3 , and 50 mg of mannitol per vial) to 20 mL with a reconstitution solution composed of propylene glycol/water for injection (WfI)/NaHCO 3 /sodium edetate 60%/40%/2%/0.02% vol/ vol/wt/wt, followed by dilution with WfI to a final volume of 40 mL.

t-Butanol Enables Dual Functionality of Mannitol: A Cryoprotectant in Frozen Systems and Bulking Agent in Freeze-Dried Formulations

“…9 TBA is a popular organic cosolvent for freeze-drying poorly water-soluble pharmaceuticals. 10 In addition to enhancing solubility, the use of TBA reduced the drying times and enabled the freeze-drying of lipophilic drugs. Notable commercial examples are prostaglandin E-1 (Caverject, Pharmacia and Upjohn Inc., MI), 11 prepared by freeze-drying from a 20% w/w TBA solution and bendamustine hydrochloride (Treanda, Cephalon Inc., PA).…”

“…TBA is a popular organic cosolvent for freeze-drying poorly water-soluble pharmaceuticals . In addition to enhancing solubility, the use of TBA reduced the drying times and enabled the freeze-drying of lipophilic drugs.…”

Pharmaceutical development of an oral tablet formulation containing a spray dried amorphous solid dispersion of docetaxel or paclitaxel

“…Residual tert-butanol and ethanol were determined by gas chromatography (GC) as described earlier (Van der Schoot et al, 2007). Fifty mg per sample was dissolved in 5 mL DMSO in triplicate.…”

EO9 (Apaziquone): from the clinic to the laboratory and back again

“…Recurrence‐free rates were good in comparison with the results of other ablative studies (Hendricksen et al ., 2009; Jain et al ., 2009). EO9 was reformulated in 2007 (van der Schoot et al ., 2007a; 2008; van der Schoot et al ., 2007b), and it is currently undergoing phase III clinical evaluation in several centres across North America and Europe. Additionally, studies where EO9 was administered within 24 h of TUR, which is the standard recommended treatment for superficial TCC of the bladder (Sylvester et al ., 2004), demonstrated that EO9 was well tolerated and has a good safety profile (Hendricksen et al ., 2008).…”