Enhanced physical stabilization of fenofibrate nanosuspensions via wet co-milling with a superdisintegrant and an adsorbing polymer

Azad, Mohammad; Afolabi, Afolawemi; Bhakay, Anagha; Leonardi, Jonathan; Davé, Rajesh N.; Bilgili, Ecevit

doi:10.1016/j.ejpb.2015.05.028

Cited by 54 publications

(34 citation statements)

References 49 publications

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“…This finding is not surprising because comprehensive characterization of the milled GF particles via DSC, XRD, and Raman spectroscopy demonstrated that even apparently more aggressive wet stirred media milling process did not cause notable change to the crystallinity (27,44). Moreover, similar observations were made for the crystallinity of other wet media milled, poorly water-soluble drugs such as fenofibrate (49)(50)(51) and indomethacin (44). Figure 6c illustrates the remarkably fast dissolution, i.e., complete dissolution within 2 min, in water for the vibratory milled GF (Run 13) in comparison to the slow dissolution of the as-received GF and GF in the physical mixture.…”

Section: Further Characterization Of the Gf Particlessupporting

confidence: 64%

An Intensified Vibratory Milling Process for Enhancing the Breakage Kinetics during the Preparation of Drug Nanosuspensions

Zhang

Davé

et al. 2015

AAPS PharmSciTech

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Abstract. As a drug-sparing approach in early development, vibratory milling has been used for the preparation of nanosuspensions of poorly water-soluble drugs. The aim of this study was to intensify this process through a systematic increase in vibration intensity and bead loading with the optimal bead size for faster production. Griseofulvin, a poorly water-soluble drug, was wet-milled using yttrium-stabilized zirconia beads with sizes ranging from 50 to 1500 μm at low power density (0.87 W/g). Then, this process was intensified with the optimal bead size by sequentially increasing vibration intensity and bead loading. Additional experiments with several bead sizes were performed at high power density (16 W/g), and the results were compared to those from wet stirred media milling. Laser diffraction, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and dissolution tests were used for characterization. Results for the low power density indicated 800 μm as the optimal bead size which led to a median size of 545 nm with more than 10% of the drug particles greater than 1.8 μm albeit the fastest breakage. An increase in either vibration intensity or bead loading resulted in faster breakage. The most intensified process led to 90% of the particles being smaller than 300 nm. At the high power intensity, 400 μm beads were optimal, which enhanced griseofulvin dissolution significantly and signified the importance of bead size in view of the power density. Only the optimally intensified vibratory milling led to a comparable nanosuspension to that prepared by the stirred media milling.

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Section: Further Characterization Of the Gf Particlessupporting

confidence: 64%

An Intensified Vibratory Milling Process for Enhancing the Breakage Kinetics during the Preparation of Drug Nanosuspensions

Zhang

Davé

et al. 2015

AAPS PharmSciTech

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“…For HPC SSL at the highest concentration (7.5%), the dissolution of drug particles only reached 50.2% at 60 min. Applying f 1 and f 2 tests and t-test [41,42], we found that the dissolution profiles of the composite formulations with 1-7.5% HPC SSL presented in Fig. 9 were not statistically different.…”

Section: Drug Dissolution From the Compositesmentioning

confidence: 90%

A study of the impact of polymer–surfactant in drug nanoparticle coated pharmatose composites on dissolution performance

Lopez

Bilgili

2016

Advanced Powder Technology

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Without a proper stabilizer formulation, drug nanoparticles can aggregate during the formation of nanosuspensions and their drying into composite powders, which in turn can cause inadequate bioavailability enhancement from nanoparticles and ensuing lack of therapeutic efficacy. In this study, formulations with various polymer concentrations-molecular weights in the presence/absence of a surfactant were explored to assess their impact on redispersibility and drug dissolution from the composites. Suspensions of griseofulvin (GF), a poorly water-soluble drug, were prepared by wet stirred media milling and subsequently dried via fluidized bed dryingcoating onto Pharmatose ® carrier particles. Hydroxypropyl cellulose (HPC), with various molecular weights, sodium dodecyl sulfate (SDS), and their combinations were used as stabilizers during the milling. The dried composites were redispersed in water and SDS solution to recover the GF nanoparticles. Particle sizing via laser diffraction, SEM imaging, and dissolution testing were performed to investigate the redispersion and dissolution performance. Results show that good physical stability of the milled suspension is necessary, but not sufficient to guarantee fast redispersion-drug dissolution. For best performance, presence of SDS is critical; a minimum concentration of the polymer, as a film former, is also required to prevent the formation of hard aggregates during drying.

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“…Amorphous drug nanosuspensions usually show poor stability, and the particles tend to aggregate through Ostwald ripening [4] and attractive interparticle forces [32] during storage. In this study, to investigate the physical stability of the optimized formulation, the particle size and morphology were monitored for 2 months during storage at 4 C. As can be seen in Table 4, the bufadienolide suspension, without stabilizer or with CCS/SLS alone, all of them exhibited a strong sedimentation or size increase trend, which suggested that CCS/SLS alone cannot ensure physical stability.…”

Section: Physical Stability Of Bufadienolide Nanosuspension During Stmentioning

confidence: 99%

Fabrication of multicomponent amorphous bufadienolides nanosuspension with wet milling improves dissolution and stability

Zuo

et al. 2017

Artificial Cells, Nanomedicine, and Biotechnology

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Multicomponent formulations have attracted increasing attention because of their favourable patient compliance and greater therapeutic effect. The aim of this study was to develop a multicomponent nanosuspension formulation of bufadienolides, the antitumor components of a traditional Chinese medicine, toad venom, using a wet-milling technique to improve its dissolution behaviour. Croscarmellose sodium (CCS) and sodium lauryl sulfate (SLS) were chosen as the combined stabilizers of the nanosuspension. A Taguchi orthogonal array design was used for this study to optimize the formulation and process parameters. The optimized nanosuspension was characterized by its particle size distribution, zeta potential, morphology, crystallinity, molecular interactions, stability and dissolution. The results showed that the nanosuspension was a homogeneous amorphous system with average particle sizes of <100 nm and significantly improved dissolution behaviour. It was also physically stable for at least 2 months; steric and kinetic stabilization were its main stability mechanisms. These findings suggested that the use of wet milling to fabricate nanosuspensions is a promising method for achieving the fast and synchronized dissolution of multicomponent formulations, presumably increasing the bioavailability of poorly water-soluble drugs.

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Enhanced physical stabilization of fenofibrate nanosuspensions via wet co-milling with a superdisintegrant and an adsorbing polymer

Cited by 54 publications

References 49 publications

An Intensified Vibratory Milling Process for Enhancing the Breakage Kinetics during the Preparation of Drug Nanosuspensions

An Intensified Vibratory Milling Process for Enhancing the Breakage Kinetics during the Preparation of Drug Nanosuspensions

A study of the impact of polymer–surfactant in drug nanoparticle coated pharmatose composites on dissolution performance

Fabrication of multicomponent amorphous bufadienolides nanosuspension with wet milling improves dissolution and stability

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