State of the art of nanocrystals – Special features, production, nanotoxicology aspects and intracellular delivery

Abstract

Drug nanocrystals are the latest, broadly introduced nanoparticulate carrier to the pharmaceutical market from the year 2000 onwards. The special features of nanocrystals for the delivery of poorly soluble drugs are briefly reviewed (saturation solubility, dissolution velocity, adhesiveness). The industrially relevant bottom up (precipitation) and top down production technologies (pearl milling, high pressure homogenization, combination technologies) are presented. As nanotoxicological aspects, the effect of size, degradability versus biopersistency and intracellular uptake are discussed, classifying the nanocrystals in the low/non-risk group. Intracellular uptake plays a minor or no role for dermal and oral nanocrystals, but it plays a key role for intravenously injected nanocrystals (e.g. nevirapine, paclitaxel, itraconazole). Uptake by the macrophages of the mononuclear phagocytic system (MPS, liver spleen) can modify/optimize blood profiles via prolonged release from the MPS (itraconazole), but also target toxicity by too high organ concentrations and thus cause nanotoxicity. The balance in the competitive intracellular uptake by MPS and the target cells (e.g. blood-brain barrier) decides about therapeutic efficiency. The concept of "differential protein adsorption" to modulate this balance is shown for its applicability to nanocrystals for intracellular delivery to the cells of the blood-brain barrier (atovaquone).

Paracrine signalling of inflammatory cytokines from an in vitro blood brain barrier model upon exposure to polymeric nanoparticles

“…Müller et al suggested a nanotoxicological classification system considering both particle size and biodegradability as important factors for nanotoxicity. 41 Thus, loading of the lysosomes with the non-degrading PS-COOH NPs appears to lead to some stress for the cells and to the observed increase in signalling.…”

Development and characterization of lecithin stabilized glibenclamide nanocrystals for enhanced solubility and drug delivery

“…To achieve this objective, the particle size of coarse GLB was reduced by precipitation and the surface properties were improved by complexation. Complexation or coating could provide a higher circulation of NCs in blood, avoid clearance and facilitate higher cellular uptake of drug (Müller et al, 2011;Gao et al, 2012). This leads to the enhanced therapeutic effect and the drug can be targeted to the site.…”

“…This unusual result indicates that particle size and uniformity is crucial in NCs, because uneven NCs were not only invalid but also showed increased individual differences. Also, particles of size 155 nm are taken up by all cells by endocytosis and they are considered as high risk particles thereby decreasing the concentration of drug in site (Müller et al, 2011).…”

Xylan, a Promising Hemicellulose for Pharmaceutical Use

“…A large variety of drug delivery systems are described in the literature, such as liposomes (Torchilin, 2006), micro and nanoparticles (Kumar, 2000), polymeric micelles (Torchilin, 2006), nanocrystals (Muller et al, 2011), among others. Microparticles are usually classified as microcapsules or microspheres (Figure 8).…”