Oral bioavailability enhancement of flubendazole by developing nanofibrous solid dosage forms.

The bioavailability of the anthelminthic flubendazole was remarkably enhanced in comparison with the pure crystalline drug by developing completely amorphous electrospun nanofibres with a matrix consisting of hydroxypropyl-ß-cyclodextrin and polyvinylpyrrolidone. The thus produced formulations can potentially be active against macrofilariae parasites causing tropical diseases, for example, river blindness and elephantiasis, which affect altogether more than a hundred million people worldwide. The bioavailability enhancement was based on the considerably improved dissolution. The release of a dose of 40 mg could be achieved within 15 min. Accordingly, administration of the nanofibrous system ensured an increased plasma concentration profile in rats in contrast to the practically non-absorbable crystalline flubendazole. Furthermore, easy-to-grind fibers could be developed, which enabled compression of easily administrable immediate release tablets.

Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole.

This study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance.

Agglomeration of mesoporous silica by melt and steam granulation. part II: screening of steam granulation process variables using a factorial design.

The objectives of this study were to identify the key process parameters during steam granulation of disordered mesoporous silica material Syloid® 244 FP (244) and to compare two different binders: polyvinylpyrrolidone (PVP) K25 and hydroxypropylmethyl cellulose (HPMC). Itraconazole (ITZ) was selected as the model compound for the development of an oral dosage form for enhanced release. Six factors: binder content, steam amount, mixing time, impeller speed, spray pause time, and filler content were investigated using a two-level quarter-fraction factorial design of experiment (DOE) for each binder type. As experimental responses, characteristics correlating to both granules and tablets were selected. Granules prepared from PVP resulted in an overall higher bulk density, granule size, increased flow properties, and better compression and compaction behavior. Although granulation with PVP resulted in the most ITZ to extract from the pores during processing, the premature drug release was less than 5%. The results of the DOE indicate that the risk of extracting the drug from the pores during processing is governed both by the process parameters and the binder properties. Centerpoint replicates of granules prepared with HPMC were highly variable.

Agglomeration of mesoporous silica by melt and steam granulation. Part I: a comparison between disordered and ordered mesoporous silica.

The objective of this study was to compare agglomerations by melt and steam granulation of ordered, COK-12, and disordered, Syloid(®) 244 FP (244), mesoporous silica material. Poloxamer 188 (P188) and polyvinylpyrrolidone K25 (PVP) were chosen as binders for melt and steam granulation, respectively. The poorly water-soluble compound, itraconazole (ITZ), was selected for the development of an immediate-release oral dosage form. Steam granulation resulted in the largest granules, however, the slowest release. Compression behavior and tablet properties of steam-granulated material prepared with COK-12 and 244 were similar. As determined by X-ray powder diffraction, melt granulation resulted in the most ITZ to extract from the pores during processing. However, the enhanced release rate was still maintained when compared with the crystalline form. Moreover, no additional drug extraction was observed following the 6 month storage in 25°C/60% relative humidity (RH) and 40°C/75%RH. P188 diffraction peaks were present in the 244 melt-granulated material, but disappeared because of the degradation following 1 week in 40°C/75%RH conditions. The differential scanning calorimetry analysis indicated that the degradation of P188 already occurred during the granulation process itself. Based on these results, steam granulation with PVP is the preferred method over melt granulation with P188.

Risk assessment of premature drug release during wet granulation of ordered mesoporous silica loaded with poorly soluble compounds itraconazole, fenofibrate, naproxen, and ibuprofen.

In this study, the potential of wet granulation of ordered mesoporous silica (OMS) material was evaluated to assess the risk of premature drug release during processing and to improve the bulk powder flow properties and compactibility for the development of an immediate release oral dosage form. The poorly water soluble model compounds, itraconazole, fenofibrate, naproxen, and ibuprofen were loaded into the model OMS, COK-12, and granulated using a polyvinylpyrrolidone (PVP) binder solution. Preliminary assessments were made with itraconazole loaded COK-12 to study the effects of the initial drug load, binder concentration, binder addition rate, and granulation temperature on premature drug release. Comparison to pure COK-12 revealed particle size enlargement and enhanced powder flow based on Carr Index and Hausner Ratio results. Following compression to 120 MPa, the compactibility of the granulated material also improved when compared to the untreated COK-12. In vitro release of itraconazole from the compressed granulated material was assessed with and without the disintegrant, croscarmellose sodium. Incorporation of 2.4 wt. croscarmellose sodium prior to compression successfully recovered the slight release loss following compression. To assess premature drug release, developments made with itraconazole loaded COK-12 were applied to loaded fenofibrate, naproxen, and ibuprofen. Results from modulated differential scanning calorimetry (MDSC) indicated that the risk of premature drug release during wet granulation was primarily compound dependent. These findings highlight challenges in preparation for a successful manufacturing process of OMS based formulations.

Evaluation of ordered mesoporous silica as a carrier for poorly soluble drugs: influence of pressure on the structure and drug release.

Ordered mesoporous silica (OMS) materials are considered a promising drug delivery system for the dissolution enhancement of poorly soluble compounds. The purpose of the present work was to determine structural and behavioral changes of compressed OMS material necessary for the development of an immediate-release oral-dosage formulation. Two types of OMS materials (SBA-15 and COK-12) were subjected to pressures both in and beyond the tabletting region and characterized by nitrogen physisorption, scanning and transmission electron microscopy, small-angle X-ray scattering, and differential scanning calorimetry. Itraconazole was used as the poorly soluble model drug and the release process with respect to pressure was determined in vitro. The resulting decreased drug release due to increased pressure was recovered by incorporating a plastically deforming material such as microcrystalline cellulose in combination with croscarmellose sodium. These findings further elucidate the understanding of their structural behavior for the advancement as a drug delivery carrier.

Potential of ordered mesoporous silica for oral delivery of poorly soluble drugs.

The use of ordered mesoporous silica is one of the more recent and rapidly developing formulation techniques for enhancing the solubility of poorly water-soluble drugs. Their large surface area and pore volume make ordered mesoporous silica materials excellent candidates for efficient drug loading and rapid release. While this new approach offers many promising advantages, further research is still necessary to elucidate the molecular mechanisms and to improve our scientific insight into the behavior of this system. In this review, the significant developments to date are presented and research challenges highlighted. Aspects of downstream processability are discussed in view of their special bulk powder properties and unique pore architecture. Lastly, perspectives for successful oral dosage form development are presented.