Improved Supersaturation and Oral Absorption of Dutasteride by Amorphous Solid Dispersions

Abstract

In this study, amorphous solid dispersions containing dutasteride and various excipients, manufactured by spray-drying processes, were characterized to determine the effects on their ability to form supersaturated solutions and to identify the effects of supersaturation on increasing the bioavailability of dutasteride. The excipients included Eudragit E, hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), and polyvinylpyrrolidone (PVP K30). A solid dispersion with Eudragit E displayed a high maximum supersaturation with extended supersaturation, compared with a water-soluble polymer. The maximum concentration and the degree of supersaturation increased in the following order: PVP K30<HP-β-CD HPC<HPMC<Eudragit E. Oral drug absorption of solid dispersions was obviously higher when compared with micronized raw material and physical mixtures, in the following order: HPC<HPMC<Eudragit E. In fact, the AUC 0 24 h and C max of dutasteride increased with supersaturation concentration. These results suggest that amorphous solid dispersions containing Eudragit E, formed by a spray-drying process, offer enhanced supersaturation characteristics, leading to increased oral absorption of dutasteride.Key words dutasteride; supersaturation; amorphous; poorly water-soluble drug; solid dispersion Dutasteride (17b-N-(2,5-bis-(trifluoromethyl) phenyl carbamoyl)-4-aza-5-and-rost-1-en-3-one) is a synthetic 4-azasteroid compound that inhibits steroid 5-α reductase (5-AR).1) It is used for the treatment of benign prostatic hyperplasia (BPH) and hair loss, by inhibiting 5-AR.2) Although dutasteride has many advantages, it is presently marketed only as a soft gelatin capsule that contains 0.5 mg dutasteride in a mixture of oils, such as mono-diglycerides of caprylic/capric acid and butylated hydroxytoluene, because it is insoluble in water (solubility below the quantitation limit of the assay, 0.038 ng/mL). 3)A capsule filled with a solution usually has limited stability and a relatively short shelf-life period. Soft gelatin capsules also have problems with cross-linking of gelatin, resulting in decreased solubility of gelatin and a reduced release rate of the drug. 4)To deliver dutasteride orally in a solid dosage form, the major problems of the dissolution and absorption of dutasteride must be overcome. Many technological methods have been reported with regard to enhancing the dissolution and absorption properties of drugs with low water solubility, such as self-emulsifying formulations, solid dispersions, ionic inclusion complexation, lipid-based complexation, formation of salts, polymorphs, cocrystals, and prodrugs, and particle size reduction techniques, such as micronization or nanomilling. 5)Among these, solid dispersions with hydrophilic carriers are particularly promising methods for improving the solubility and dissolution rate of poorly water-soluble drugs.6,7) Solid dispersion formulations currently on the market include griseofulvin in polyethylene glycol (PEG) (Gris-PEG...

Influence of hydrophilic additives on the supersaturation and bioavailability of dutasteride-loaded hydroxypropyl- &beta;-cyclodextrin nanostructures

“…Dutasteride was extracted from the plasma matrix by protein precipitation, and drug concentrations in the plasma samples were analyzed using liquid chromatography with tandem mass spectrometry as previously reported. 6 The pharmacokinetic parameters, ie, AUC 0→24h (area under the concentration-time curve), C max (peak concentration), and T max (time to peak concentration), were calculated using noncompartmental analysis. Relative bioavailability was calculated using the following equation, with the commercial product used as a reference: relative bioavailability (%) = AUC test / AUC reference × 100.…”

“…[6][7][8][9] Among these formulations studied, the Eudragit E nanoparticle suspension afforded a dutasteride bioavailability 5.5-fold higher than that afforded by a 0.3% w/v Soluplus suspension (mean particle size 1.92 µm). However, use of the Eudragit E nanoparticle suspension was limited by its stability and difficulty in scaleup.…”

Preparation and Evaluation of Solid Dispersion of Atorvastatin Calcium with Soluplus® by Spray Drying Technique

“…2,3) Consequently, amorphous solid dispersion has become an increasingly utilized approach for improving the bioavailability of poorly water-soluble compounds. [4][5][6][7] In many cases, a supersaturated drug solution generated by amorphous solid dispersion is thermodynamically unstable and energetically tends to return to equilibrium via precipitation. 8) To maintain supersaturation, precipitation must be inhibited, in many cases by a polymeric precipitation inhibitor.…”

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

“…[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).…”