Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation⁻Processing Aspects and Challenges

Abstract

Drug nanoparticles embedded in a dispersant matrix as a secondary phase, i.e., drug-laden nanocomposites, offer a versatile delivery platform for enhancing the dissolution rate and bioavailability of poorly water-soluble drugs. Drug nanoparticles are prepared by top-down, bottom-up, or combinative approaches in the form of nanosuspensions, which are subsequently dried to prepare drug-laden nanocomposites. In this comprehensive review paper, the term “nanocomposites” is used in a broad context to cover drug nanoparticle-laden intermediate products in the form of powders, cakes, and extrudates, which can be incorporated into final oral solid dosages via standard pharmaceutical unit operations, as well as drug nanoparticle-laden strip films. The objective of this paper is to review studies from 2012⁻2017 in the field of drug-laden nanocomposites. After a brief overview of the various approaches used for preparing drug nanoparticles, the review covers drying processes and dispersant formulations used for the production of drug-laden nanocomposites, as well as various characterization methods including quiescent and agitated redispersion tests. Traditional dispersants such as soluble polymers, surfactants, other water-soluble dispersants, and water-insoluble dispersants, as well as novel dispersants such as wet-milled superdisintegrants, are covered. They exhibit various functionalities such as drug nanoparticle stabilization, mitigation of aggregation, formation of nanocomposite matrix⁻film, wettability enhancement, and matrix erosion/disintegration. Major challenges such as nanoparticle aggregation and poor redispersibility that cause inferior dissolution performance of the drug-laden nanocomposites are highlighted. Literature data are analyzed in terms of usage frequency of various drying processes and dispersant classes. We provide some engineering considerations in comparing drying processes, which could account for some of the diverging trends in academia vs. industrial practice. Overall, this review provides rationale and guidance for drying process selection and robust nanocomposite formulation development, with insights into the roles of various classes of dispersants.

Keywords: BCS Class II drugs; aggregates; dissolution enhancement; drug nanosuspensions; formulation; nanocomposites; redispersion.

Figure 1

Schematic illustrating the steps involved in the preparation of drug-laden nanocomposites including their characterization. Nanocomposites in the form of powders, cakes, or extrudates are intermediate products that are incorporated into final solid oral dosage forms such as tablets, capsules, and sachets via standard pharmaceutical unit operations upon use of additional excipients. Polymeric strip films prepared by wet film casting–drying are the final product.

Figure 2

Classification of various types of aggregates that may be present in nanocomposite particles based on their redispersion behavior.

Figure 3

The number of published journal articles from 2010–2017 which reported the preparation of drug nanoparticles and drug nanocomposites. Source: Scopus database, key words used: “drug nanoparticles” or “drug nanocomposites” or “drug + drying + nanocrystals” or “drug + drying + nanosuspensions”.

Figure 4

The usage frequency of various drug nanosuspension preparation methods in the studies reported in Table 2. The sample size for the analysis here is 94, even though the number of publications in Table 2 is 92, because two studies compared two different preparation methods.

Figure 5

The usage frequency of various drying methods in the studies reported in Table 2. The sample size for the analysis here is 103, even though the number of publications in Table 2 is 92, because some studies compared two drying methods.

Figure 6

Comparison of drug release from the nanocomposite particles: (a) ITZ coated on PrismaLac 40 vs. GranuLac 200, (b) FNB coated on PrismaLac 40 vs. GranuLac 200, during the USP II dissolution test. Dissolution was performed using 7.2 mg/mL SDS solution for (a) and 2.88 mg/mL SDS solution for (b). (Figure adapted from Azad et al. [91] with permission from Elsevier, www.elsevier.com).

Figure 7

Images of redispersion dynamics of griseofulvin (GF) nanocomposite particles, which were prepared by fluidized bed coating of GF nanosuspension on Pharmatose carrier particles with various dispersants, in quiescent water (no external agitation/shear) (left panel), and after addition of a drop of water on a single nanocomposite particle, visualized under optical microscope (right panel). Nanocomposite formulations in the figure from top to bottom contain GF nanoparticles without stabilizers, GF nanoparticles with HPC, GF nanoparticles with HPC–SDS, and GF with HPC–croscarmellose sodium (CCS) milled for 60 min. (Adapted from Bhakay et al. [92] with permission from Springer Nature, www.springernature.com).

Figure 8

The usage frequency of (a) various classes of dispersants and (b) classes of dispersants in the formulations that led to formation of redispersible nanocomposites in the studies reported in Table 2. The sample size for the analysis here is 120, even though the number of publications in Table 2 is 92, because some studies investigated more than one drug. WSD: other water-soluble dispersant (besides soluble polymer–surfactant), WID: water-insoluble dispersant, CLP: crosslinked polymers.

Figure 9

Drug (GF) release profiles of the nanocomposites prepared using wet-milled GF suspensions containing 0.05% SDS and HPC with different molecular weights of HPC: (a) HPC SSL (40 kDa); (b) HPC SL (100 kDa); and (c) HPC L (140 kDa) (Adapted from Li et al. [86] with permission from Elsevier, www.elsevier.com).

Figure 10

Impact of drug loading in the nanocomposite and drying method on redispersion of griseofulvin (GF)–HPC–SDS nanocomposite microparticles (NCMP) in water after 2 min paddle stirring at 200 rpm. FBD refers to fluid bed coating/drying of the GF nanosuspension onto Pharmatose; SD stands for spray drying. “Before redisp” particle sizes refer to the particle sizes in the wet media milled drug nanosuspension with HPC–SDS. (Adapted from Bhakay et al. [85] with permission from Elsevier, www.elsevier.com).

Figure 11

A correlation between percentage of GF dissolved in 2 min in the USP II dissolution test and percentage of GF nanoparticles recovered in 2 min during the agitated redispersion test with a paddle stirrer. Markers correspond to various dispersant formulations in the GF nanocomposites prepared by fluidized bed coating of wet media milled GF suspensions on Pharmatose. The redispersion–dissolution medium is water. (Adapted from Bhakay et al. [8] with permission from Taylor & Francis Ltd., www.tandfonline.com.