(489g) Enhanced Dissolution of Itraconazole from Surfactant-Free Nanocomposite Microparticles

Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspension and subsequently drying it into nanocomposite microparticles^1,2. Unfortunately, drug nanoparticles aggregate during milling and drying, causing incomplete recovery and relatively slow dissolution^3,4. Various dispersants can be used to mitigate the extent of nanoparticle aggregation. The aim of this study is to investigate the impact of various classes of dispersants on the dissolution of drug nanoparticles, with the ultimate goal of enhancing the bioavailability of poorly water-soluble drugs via high drug nanoparticle loaded, surfactant-free nanocomposites. Precursor suspensions of itraconazole (ITZ, a model poorly water-soluble BCS Class II drug) nanoparticles in the presence of various dispersants were prepared via wet stirred media milling and spray dried to form the nanocomposites. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as base-line stabilizers/dispersants during milling. Three swellable crosslinked polymers known as superdisintegrants, croscarmellose sodium (CCS), sodium starch glycolate (SSG), and crospovidone (CP) as well as two conventional soluble matrix formers, sucrose and mannitol, were used in addition to HPC. Laser diffraction, scanning electron microscopy, powder X-ray diffraction, ultraviolet spectroscopy, and dissolution tests were used for the characterization. The results indicate that the enhanced wettability imparted by SDS was critical to the full recovery of drug nanoparticles and their dissolution, whereas HPC had relatively small positive effect. Use of co-milled superdisintegrants led to significant enhancement of the drug dissolution with SSG performing close to SDS, thus demonstrating the feasibility of spray drying to prepare high drug-loaded, surfactant-free nanocomposites. The positive impact of the superdisintegrants positively correlated with their swelling capacity (SSG > CCS >CP), signifying a swelling-induced erosion/disintegration mechanism for fast drug release from the nanocomposite particles.

References Cited

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3. Bhakay A, Azad M, Vizzotti E, Dave RN, Bilgili E. Enhanced recovery and dissolution of griseofulvin nanoparticles from surfactant-free nanocomposite microparticles incorporating wet-milled swellable dispersants. Drug Development and Industrial Pharmacy. 2013(0):1-14.

4. Bhakay A, Davé R, Bilgili E. Recovery of BCS Class II drugs during aqueous redispersion of core–shell type nanocomposite particles produced via fluidized bed coating. Powder Technology. 2013;236(0):221-234.