Influence of hydrophilic additives on the supersaturation and bioavailability of dutasteride-loaded hydroxypropyl- β-cyclodextrin nanostructures

Abstract

Abstract:The objectives of this study were to develop a novel solid dutasteride formulation with improved physicochemical properties and oral bioavailability, and to examine the correlation between its in vitro dissolution and in vivo pharmacokinetic parameters. Hydroxypropyl-β-cyclodextrin (HP-β-CD) nanostructures with or without hydrophilic additives were manufactured using the supercritical antisolvent process. The dutasteride-loaded HP-β-CD nanoparticles formed aggregates with a mean particle size of less than 160 nm and a specific surface area greater than 100 m 2 /g. Increases in the supersaturation and dissolution rate for dutasteride were dependent on the type of additive; increases in maximum solubility and extended supersaturation were observed in dutasteride-loaded HP-β-CD nanostructures with hydroxypropylmethyl cellulose, whereas the dissolution rate was the highest for nanostructures containing d-α-tocopheryl polyethylene glycol 1000 succinate. In rats, the oral bioavailability of dutasteride increased with the supersaturation induced by the HP-β-CD nanostructures. In addition, compared with the in vitro drug release rate, the in vivo pharmacokinetic parameters were more closely correlated with in vitro parameters related to supersaturation (solubility). Further, the bioavailability of the dutasteride-loaded HP-β-CD nanostructures with hydroxypropylmethyl cellulose was similar to that of the commercially available soft gelatin capsule (Avodart ® ). In conclusion, preparation of dutasteride-loaded HP-β-CD nanostructures using the supercritical antisolvent process affords a viable alternative solid dosage form for dutasteride.

Preparation and in Vivo Evaluation of a Dutasteride-Loaded Solid-Supersaturatable Self-Microemulsifying Drug Delivery System

“…To improve the oral bioavailability of dutasteride, it is important that a high concentration of dutasteride is maintained for a long period of time in vitro. These results were similar to our previous IVIVC study using dutasteride-loaded HP-β-CD nanostructures prepared using the SAS process [ 7 ]. IVIVC studies using DE are recommended for poorly water-soluble APIs as previously reported [ 28 , 29 , 30 ].…”

“…In GlaxoSmithKline’s commercial formulation, Avodart ® , dutasteride’s poor aqueous solubility (<0.038 ng/mL) is overcome by using mono-di-glycerides of caprylic/capric acid and butylated hydroxytoluene to form soft gelatin capsules containing 0.5 mg dutasteride. To develop a solid dutasteride dosage form with high oral bioavailability, we evaluated various formulations, such as Eudragit E nanosuspension, hydroxypropyl-β-cyclodextrin (HP-β-CD) nanostructures, silica nanomatrices, self-microemulsifying drug delivery systems (SMEDDS), and solid dispersions [ 2 , 3 , 4 , 5 , 6 , 7 ]. Among the solid formulations tested, the bioavailability of dutasteride-loaded HP-β-CD nanostructures with hydroxypropylmethyl cellulose (HPMC) prepared using a supercritical antisolvent (SAS) process was similar to that of the commercial product [ 7 ].…”

Design of a gelatin microparticle-containing self-microemulsifying formulation for enhanced oral bioavailability of dutasteride

“…In fact, gelatin, as a precipitation inhibitor, provided prolonged supersaturation of dutasteride, which suggested that mechanisms including inhibition of nucleation and/or crystal growth from a highly supersaturated state were responsible for the stabilization effects. 19 , 20 Therefore, gelatin can be used as a solid carrier and recrystallization inhibitor for a SMF of poorly water-soluble dutasteride.…”

Fabrication and evaluation of valsartan&ndash;polymer&ndash;surfactant composite nanoparticles by using the supercritical antisolvent process

“…Based on our previous study, the supercritical conditions within the particle formation vessel were set to 40°C and 15 MPa. 13 After spraying the drug solution, fresh supercritical carbon dioxide was delivered into the particle formation vessel to remove residual organic solvents, followed by depressurization of the system to atmospheric pressure. The fabricated valsartan-loaded composite nanoparticles were collected from the particle formation vessel basket.…”

“…[10][11][12] Recently, it was reported that composite nanoparticles could be fabricated by using supercritical fluid technology. 13 Carbon dioxide has been widely used as a supercritical fluid because it is nontoxic, nonflammable, and it has relatively low critical parameters (P c [critical pressure] =7.38 MPa, T c [critical temperature] =31.1°C). During the last 20 years, supercritical carbon dioxide has been used successfully as a solvent or an antisolvent in the pharmaceutical industry for various purposes such as particle formation and extraction of the active ingredient, and as an alternative green solvent to conventional organic solvents.…”