(724c) Fast-Dissolving, High Drug Loaded, Surfactant-Free Nanocomposites Prepared Via Spray Drying

Mohammad Azad, Rajesh Davé, Ecevit Bilgili^*

Otto H. York Department of Chemical, Biological and Pharmaceutical Engineering,

New Jersey Institute of Technology, Newark, New Jersey, USA

^*Address correspondence to Ecevit Bilgili. Phone: +1-973-596-2998. Email: bilgece@njit.edu

A large percentage of newly discovered drug compounds suffer from inadequate oral bioavailability due to poor aqueous solubility. Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspension and subsequently drying it into nanocomposite microparticles (NCMPs). NCMPs can be incorporated into the final solid dosage forms using standard pharmaceutical unit operations, thus offering a promising platform for production of solid dosage forms of poorly water-soluble drugs.

Unfortunately, drug nanoparticles aggregate during milling and drying, causing incomplete drug recovery during aqueous redispersion and slow in vitro and in vivo dissolution¹. To prevent aggregation during wet media milling and maintain good physical stability during storage, polymers and/or surfactants are generally added to drug suspensions prior to milling. Besides these dispersants, sugars (e.g., sucrose, lactose), sugar alcohols (e.g., mannitol, sorbitol), and additional water-soluble polymers (e.g., HPC, HPMC, PVP, PVA, long chained PEG) are commonly added to milled precursor suspensions in high concentrations of 50–1000% w/w w.r.t. They help minimize aggregation during drying and enhance drug nanoparticle recovery from NCMPs. However, such high dispersant concentrations render drug concentration in the composite particles relatively low, minimizing the drug carrying capacity of the NCMPs. This issue has been addressed by the use of a combination of a sterically stabilizing polymer and an anionic surfactant in the NCMPs,which allows for fast drug nanoparticle recovery and enhanced drug dissolution¹. Despite their effectiveness as dispersants, anionic surfactants pose several challenges such as toxicity, physical stability, GIT irritation, incompatibilities with other ionic molecules, and sensitivity to pH, salt or temperature changes. Hence, development of surfactant-free formulations or formulations with minimal amount of surfactants using novel dispersants is highly desired.

Recent studies^2,3 have explored the use of wet-milled superdisintegrants, which are swellable crosslinked polymers, as a novel class of dispersants that could improve the recovery/dissolution of drug nanoparticles from drug-carrying NCMPs in the absence of surfactants. The core–shell type NCMPs obtained had a relatively low drug loading: <13% w/w. A higher drug loading in NCMPs has several advantages in the development of final solid dosage forms: smaller dosages for a desired dose (more desirable by patients) or higher drug dosing for a fixed dosage size allowing higher therapeutic levels of the drug. While higher drug loading could be achieved by prolonging the spray time during fluidized bed coating¹, an alternative for preparation of high drug loaded NCMPs is spray drying. To the best knowledge of the authors, spray drying has not been used before for the production of drug NCMPs with swellable crosslinked polymers like superdisintegrants.

In this study, we investigate the impact of various classes of dispersants on the enhancement of drug dissolution from NCMPs prepared via spray drying of wet-milled drug suspensions, with the ultimate goal of formulating high drug loaded, surfactant-free NCMPs. To this end, precursor griseofulvin (GF, model drug) suspensions prepared via wet media milling in the presence of various dispersants were spray dried. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as a base-line stabilizer/dispersant during milling. Two swellable crosslinked polymers, croscarmellose sodium (CCS) and sodium starch glycolate (SSG), and conventional soluble matrix former, Mannitol, were used in addition to HPC. Besides being used as-received, CCS was also wet co-milled with GF for two different durations to examine the impact of CCS particle size. The Mannitol and crosslinked polymer concentrations in the suspension were 100% and 10% wrt drug. Laser diffraction, SEM, X-ray diffraction, and UV spectroscopy were used to characterize the suspensions and NCMPs. Dissolution and redispersion test results show that incorporation of CCS/SSG, preferably wet-milled to a wide particle size distribution, into the NCMPs resulted in fast release and dispersion of drug nanoparticle clusters. The swellable dispersants were superior to Mannitol in dissolution enhancement, and could achieve fast release comparable to SDS. This study demonstrates the feasibility of preparing high drug-loaded, surfactant-free nanocomposites incorporating swellable crosslinked polymers via spray drying.

References:

1. A. Bhakay, M. Azad, E. Bilgili, R. Dave, Redispersible Fast Dissolving Nanocomposite Microparticles of Poorly Water-Soluble Drugs, Int. J. Pharm. Sci. 461(2014) 367–379.
2. A. Bhakay, M. Azad, E. Vizotti, R. Dave, E. Bilgili, Enhanced Recovery and Dissolution of Griseofulvin Nanoparticles from Surfactant-Free Nanocomposite Microparticles Incorporating Wet-Milled Swellable Dispersants, Drug Dev. Ind. Pharm. (2013), doi: 10.3109/03639045.2013.831442.
3. E. Bilgili, R. Dave, A. Bhakay, M. Azad, Systems and Methods for Superdisintegrant-Based Composite Particles for Dispersion and Dissolution of Agents, U.S. Patent Application, Pub. No. US2013/0295190 A1, Pub. Date: Nov. 07, 2013.