Preparation and in vivo evaluation of a dutasteride-loaded solid-supersaturatable self-microemulsifying drug delivery system.

The purpose of this study was to prepare a dutasteride-loaded solid-supersaturatable self-microemulsifying drug delivery system (SMEDDS) using hydrophilic additives with high oral bioavailability, and to determine if there was a correlation between the in vitro dissolution data and the in vivo pharmacokinetic parameters of this delivery system in rats. A dutasteride-loaded solid-supersaturatable SMEDDS was generated by adsorption of liquid SMEDDS onto Aerosil 200 colloidal silica using a spray drying process. The dissolution and oral absorption of dutasteride from solid SMEDDS significantly increased after the addition of hydroxypropylmethyl cellulose (HPMC) or Soluplus. Solid SMEDDS/Aerosil 200/Soluplus microparticles had higher oral bioavailability with 6.8- and 5.0-fold higher peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) values, respectively, than that of the equivalent physical mixture. A linear correlation between in vitro dissolution efficiency and in vivo pharmacokinetic parameters was demonstrated for both AUC and Cmax values. Therefore, the preparation of a solid-supersaturatable SMEDDS with HPMC or Soluplus could be a promising formulation strategy to develop novel solid dosage forms of dutasteride.

Fabrication and evaluation of celecoxib microparticle surface modified by hydrophilic cellulose and surfactant.

This study was undertaken to improve the solubility and dissolution of a poorly water-soluble drug, celecoxib, by surface modification with a hydrophilic polymer and a surfactant by using a spray-drying technique. Based on the preliminary solubility tests, hydroxypropylmethyl cellulose (HPMC) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were selected as the polymer and the surfactant, respectively. A novel surface-modified celecoxib microparticle was successfully fabricated using a spray-drying process with water, HPMC, and TPGS, and without the use of an organic solvent. The physicochemical properties of the surface-modified celecoxib microparticle were characterized using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), a particle size analyzer, and contact angle determination. The formulation with drug/HPMC/TPGS at the weight ratio of 1:0.5:1.5 was determined to be the most effective composition in the preparation of the surface-modified celecoxib microparticle, based on the results of wettability, solubility, and dissolution studies. We found that the surface modification of microparticles with HPMC and TPGS can be an effective formulation strategy for new dosage forms of poorly water-soluble active pharmaceutical ingredients (APIs) to provide higher solubility and dissolution.

Dissolution and bioavailability of lercanidipine-hydroxypropylmethyl cellulose nanoparticles with surfactant.

The objective of this study was to develop lercanidipine-hydroxypropylmethyl cellulose (HPMC) nanoparticles with high oral bioavailability. The lercanidipine-HPMC nanoparticles with/without surfactants were manufactured using a supercritical antisolvent (SAS) process. Gelucire 44/14, poloxamer 407, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were evaluated as surfactants. Spherical lercanidipine-HPMC nanoparticles with a mean particle size less than 400 nm were successfully prepared using a SAS process. The dissolution and oral bioavailability of lercanidipine was significantly increased by addition of surfactants. Especially lercanidipine-HPMC nanoparticles with TPGS showed a 2.47-fold higher oral bioavailability than raw material. Furthermore, the dissolution efficiency was strongly correlated to the in vivo Cmax and AUC0 → 24h. Therefore, the preparation of HPMC nanoparticles with TPGS using a SAS process is a highly effective formulation strategy for enhanced oral bioavailability of lercanidipine.

Formulation, characterization, and in vivo evaluation of celecoxib-PVP solid dispersion nanoparticles using supercritical antisolvent process.

The aim of this study was to develop celecoxib-polyvinylpyrrolidone (PVP) solid dispersion nanoparticles with and without surfactant using the supercritical antisolvent (SAS) process. The effect of different surfactants such as gelucire 44/14, poloxamer 188, poloxamer 407, Ryoto sugar ester L1695, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) on nanoparticle formation and dissolution as well as oral absorption of celecoxib-PVP K30 solid dispersion nanoparticles was investigated. Spherical celecoxib solid dispersion nanoparticles less than 300 nm in size were successfully developed using the SAS process. Analysis by differential scanning calorimetry and powder X-ray diffraction showed that celecoxib existed in the amorphous form within the solid dispersion nanoparticles fabricated using the SAS process. The celecoxib-PVP-TPGS solid dispersion nanoparticles significantly enhanced in vitro dissolution and oral absorption of celecoxib relative to that of the unprocessed form. The area under the concentration-time curve (AUC0→24 h) and peak plasma concentration (Cmax) increased 4.6 and 5.7 times, respectively, with the celecoxib-PVP-TPGS formulation. In addition, in vitro dissolution efficiency was well correlated with in vivo pharmacokinetic parameters. The present study demonstrated that formulation of celecoxib-PVP-TPGS solid dispersion nanoparticles using the SAS process is a highly effective strategy for enhancing the bioavailability of poorly water-soluble celecoxib.

Oral absorption of a valsartan-loaded spray-dried emulsion based on hydroxypropylmethyl cellulose.

The aim of this study was to develop a novel valsartan-loaded spray-dried emulsion based on hydroxypropylmethyl cellulose (HPMC) with enhanced oral absorption. The valsartan-loaded redispersible dry emulsion was prepared by using a high-pressure homogenization and spray-drying process with water, Capryol 90, HPMC, and different surfactants, based on the results of the solubility study. The spray-dried emulsions formed small and homogeneous emulsions with a mean droplet emulsion size ranging from 133.5 to 152.5nm at the dispersion state in water. The valsartan-loaded redispersible dry emulsion with HPMC/poloxamer 407 showed enhanced pH-independent valsartan release, resulting in a dramatically enhanced oral bioavailability of valsartan compared to the raw material and commercial product. Therefore, a formulation strategy using the redispersible dry emulsion with HPMC/poloxamer 407 is very effective for the development of a new dosage form containing valsartan.

Dissolution and oral absorption of pranlukast nanosuspensions stabilized by hydroxypropylmethyl cellulose.

The objective of this study was to investigate the effect of particle size on the dissolution and oral absorption of pranlukast microsuspensions and nanosuspensions stabilized by hydroxypropylmethyl cellulose. Four pranlukast suspensions with different mean particle sizes (0.16, 0.89, 3.13, and 18.21µm) were prepared by various top-down processes such as jet milling, high pressure homogenization, and bead milling. The dissolution rate and oral absorption of pranlukast suspensions were significantly affected by the particle size. The in vivo pharmacokinetic parameters of pranlukast suspensions were increased with decreasing mean particle size of suspensions. Especially, the AUC0→24h and Cmax values of pranlukast nanosuspension with a particle size of 0.16µm were approximately 3.5- and 6.3-fold greater, respectively, than that of pranlukast microsuspension with a particle size of 18.21µm. Therefore, the preliminary results from our study suggest that a pranlukast nanosuspension with a mean particle size of about 0.16µm may have significant potential for clinical application.

Quality by design: screening of critical variables and formulation optimization of Eudragit E nanoparticles containing dutasteride.

The study was aimed at screening, understanding, and optimizing product variability of dutasteride-loaded Eudragit E nanoparticles prepared by solvent displacement using Plackett-Burman screening and a central composite design. The independent process and formulation factors selected included: drug loading (%), solute concentration (mg/mL), Soluplus concentration (mg/mL), injection rate (mL/min), organic solvent type (methanol or ethanol), stirring rate (rpm), and organic-to-aqueous phase volume ratio. Among these factors, solute concentration was associated with increased particle size, broad particle size distribution, and enhanced entrapment efficiency. On the other hand, Soluplus concentration played a role in decreasing particle size, narrowing particle size distribution, and reducing entrapment efficiency. Other formulation and process factors did not have a significant impact on nanoparticle properties, assuming they were within the limits used in this study. The optimized formulation was achieved with 20 mg/mL solute and 3.22 mg/mL Soluplus, and the observed responses were very close to the values predicted using the response surface methodology. The results clearly showed that quality by design concept could be effectively applied to optimize dutasteride-loaded Eudragit E nanoparticles.