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.
Highlights
The number of newly developed drug molecules with greater lipophilicity, higher molecular weight, and poor water solubility has increased over the last few decades due to the emerging trends in combinatorial chemistry and drug design [1,2,3]
Poor redispersion and significantly slower GF release were observed at drug loadings above 50 wt.%. These results suggest that the greatest barriers to producing pharmaceutical films with high loadings of poorly water-soluble drug nanoparticles are overcoming poor film mechanical properties, and ensuring the recovery of the embedded drug nanoparticles, both of which can be conceivably overcome by further formulation development
Various quiescent or agitated redispersion methods can be used, because those formulations that do not redisperse in water or other biorelevant fluids will most likely lead to inferior dissolution enhancement
Summary
The number of newly developed drug molecules with greater lipophilicity, higher molecular weight, and poor water solubility has increased over the last few decades due to the emerging trends in combinatorial chemistry and drug design [1,2,3]. The majority of failures in new drug development have been attributed to poor water solubility of the drug. It is well-known that poor solubility and slow dissolution can lead to low bioavailability, resulting in suboptimal drug delivery [5,6]. Ultrafine particles, especially those with sizes less than ~100 nm, tend to show higher saturation solubility, which can be explained via the Ostwald–Freundlich equation [24]. Overall, all these features exhibited by nanoparticles improve the dissolution rates according to the Noyes–Whiney equation [25]; this in turn enhances bioavailability [26,27]. Besides enhanced solubility and dissolution rates leading to improved bioavailability, other advantages of drug nanoparticles include the elimination of food effects, safe dose escalation, and enhanced efficacy and tolerability profiles [28,29,30]
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