Carrier particle design for stabilization and isolation of drug nanoparticles

Abstract

Nanoparticles of poorly water-soluble drugs were prepared in suspension via antisolvent precipitation in order to improve their dissolution behaviour. Insoluble, surface-functionalized, micron-range, clay carrier particles were employed for the dual purpose of stabilizing the nanoparticles in suspended state, and facilitating their unhindered isolation to solid state; often a 15 challenging step in nanoparticle production. The carrier particles, which were functionalized with an optimal level of cationic polymer (protamine), attracted negatively-charged nanoparticles to their surface as a uniform and segregated nanoparticle layer, at drug loadings up to 9% w/w. By using carrier particles to stabilise the nanoparticles on their surface, the traditionally used solubilised nanosuspension stabilisers could be eliminated, thus avoiding time-consuming stabiliser screening 20 tests. The carrier particle system facilitated stabilisation of nanoparticles in suspension, isolation of nanoparticles to the solid state via filtration, and preservation of fast nanoparticle-induced dissolution rates of the dried nanoparticle-carrier composites, indicating preservation of their high surface area during drying. The process was validated with two poorly water-soluble BCS Class II drugs, fenofibrate and mefenamic acid, both of which demonstrated negative surface charge in 25 aqueous suspension.

Drug Loading and Dissolution Properties of Dalcetrapib–Montmorillonite Nanocomposite Microparticles

“…The presence of PA or PVP at an amount of 2.2 mg/g MMT, which did not interfere with the high level of nanoparticle attachment, did not show any improvement on the dissolution profile of the freshly prepared suspension at a 20.9% drug loading of the nanocomposite microparticles (Figure 4). In addition, in the case of the positively charged surface modifier PA, required for the isolation of negatively charged fenofibrate and mefenamic acid nanoparticles, 33 no significant improvement was found even at a decreased DCP nanoparticle loading of 4.2% or an increased amount of PA up to 22 mg/g MMT (Figure S3a,b in the Supporting Information, respectively). Dissolution of DCP nanoparticles from a freshly prepared suspension (not isolated) in the presence of MMT was faster with DOSS or with the combination of DOSS and PVP compared to the dissolution profile in the presence of MMT only (Figure 4).…”

“…Methanol (HPLC grade) and sodium chloride (NaCl) were obtained from Fisher. Montmorillonite K10 (MMT, D 50 = 28.0 ± 1.3 μm, determined by laser diffraction method 33 ), protamine sulfate salt (PA), poly(vinylpyrrolidone) (PVP, 40 kDa) hydroxypropylmethylcellulose (HPMC, 15 cP), Pluronic F127 (PF127), Tween 20, sodium docusate (dioctyl sulfosuccinate sodium salt, DOSS), hydrochloric acid (HCl), and sodium dodecyl sulfate (SDS) were purchased from Sigma-Aldrich. Deionized water was used for aqueous solutions (18 MΩ.…”

“…24 As an alternative, several isolation strategies have been suggested, including spray granulation with carrier particles, 25 fluid bed coating and drying, 26−28 wet film casting, 29 nanoparticle embedment in polymer gels, 30 nanoextrusion, 31 and carrier particle-mediated filtration of nanoparticles. 32,33 Depending on the drug properties, product requirements, technology cost, and availability, one can select the most suitable method for isolation.…”

“…Although the improved dissolution properties of the nanoparticles were retained in the dried form, the method was limited by the low drug loading of the composite particles, being only 0.35 w/w %. As a development of this approach, we previously reported a one-step method for carrier particlemediated stabilization and isolation of fenofibrate, mefenamic acid, 33 and valsartan 34 nanoparticles using surface-functionalized montmorillonite (MMT) as carrier microparticles in an antisolvent precipitation process. In this process, the use of soluble additives was not required as the fast attachment of nanoparticles onto the montmorillonite surface stabilized the particles, eliminating the need for a time-consuming additive selection process.…”

Formulation and Characterization of Fenofibrate Loaded Solid Dispersion with Enhanced Dissolution Profile

“…To overcome this limitation, large number of investigations had been conducted. Some reported approaches are development of self-microemulsifying drug delivery system [11] [12], impregnation of drug into various silica [13] [14] [15], impact of fillers [16], oral push-pull osmotic pump [17], electrosprayed nanospherules [18], nanosuspension [19], solid dispersion [10] [20] [21], nanoparticles formations [22], anti-solvent precipitation technique [23], a pair of side by side diffusion cells [24], holt-melt extrusion [25], core shell dual mesoporous silica nanoparticles [28], nanocomposites [26] [27], dry suspension and dry emulsion [28], controlled release matrix [29], lipidic dispersion [30] and co-crystals formation [31]. Among these physi- Although many SD approaches using various carriers have been examined, but there is no report regarding the use of blend of silica and PEG on dissolution property of FF.…”