Parenteral nanosuspensions: a brief review from solubility enhancement to more novel and specific applications

Abstract

Advancements in in silico techniques of lead molecule selection have resulted in the failure of around 70% of new chemical entities (NCEs). Some of these molecules are getting rejected at final developmental stage resulting in wastage of money and resources. Unfavourable physicochemical properties affect ADME profile of any efficacious and potent molecule, which may ultimately lead to killing of NCE at final stage. Numerous techniques are being explored including nanocrystals for solubility enhancement purposes. Nanocrystals are the most successful and the ones which had a shorter gap between invention and subsequent commercialization of the first marketed product. Several nanocrystal-based products are commercially available and there is a paradigm shift in using approach from simply being solubility enhancement technique to more novel and specific applications. Some other aspects in relation to parenteral nanosuspensions are concentrations of surfactant to be used, scalability and in vivo fate. At present, there exists a wide gap due to poor understanding of these critical factors, which we have tried to address in this review. This review will focus on parenteral nanosuspensions, covering varied aspects especially stabilizers used, GRAS (Generally Recognized as Safe) status of stabilizers, scalability challenges, issues of physical and chemical stability, solidification techniques to combat stability problems and in vivo fate.

Keywords: ADME, absorption distribution metabolism elimination; ASEs, aerosols solvent extractions; AUC, area under curve; BBB, blood–brain barrier; BCS, Biopharmaceutical Classification System; BDP, beclomethasone dipropionate; CFC, critical flocculation concentration; CLSM, confocal laser scanning microscopy; CMC, critical micelle concentration; DMSO, dimethyl sulfoxide; EDI, estimated daily intake; EHDA, electrohydrodynamic atomization; EPAS, evaporative precipitation in aqueous solution; EPR, enhanced permeability and retention; FITC, fluorescein isothiocyanate; GRAS, Generally Recognized as Safe; HEC, hydroxyethylcellulose; HFBII, class II hydrophobin; HP-PTX/NC, hyaluronic acid-paclitaxel/nanocrystal; HPC, hydroxypropyl cellulose; HPH, high-pressure homogenization; HPMC, hydroxypropyl methylcellulose; IM, intramuscular; IP, intraperitoneal; IV, intravenous; IVIVC, in vivo–in vitro correlation; In vivo fate; LD50, median lethal dose (50%); MDR, multidrug resistance effect; NCE, new chemical entities; Nanosuspension; P-gp, permeation glycoprotein; PEG, polyethylene glycol; PTX, paclitaxel; PVA, polyvinyl alcohol; Parenteral; QbD, quality by design; SC, subcutaneous; SEDS, solution enhanced dispersion by supercritical fluids; SEM, scanning electron microscopy; SFL, spray freezing into liquids; Scalability; Solidification; Stabilizer; TBA, tert-butanol; TEM, transmission electron microscopy; US FDA, United States Food and Drug Administration; Vitamin E TPGS, d-α-tocopheryl polyethylene glycol 1000 succinate.

Graphical abstract

Figure 1

Parameters to be critically monitored during initial screening of lead optimization. Reprinted (adapted) with permission from Ref. . Copyright © 2004 Nature Publishing Group.

Figure 2

Advances in bottom-up techniques for preparation of nanocrystals.

Figure 3

SEM pictures of the freeze-dried powders: (B) unmodified API; (C) dimethyl sulfoxide:tert-butanol (DMSO:TBA), 90:10 (low TBA); (D) 75:25, (E) 50:50 (medium); (F) 25:75; and (G) 10:90 (high TBA). Left: 200 µm scale bar/right: 10 µm scale bar (3000× magnification). Reprinted (adapted) with permission from Ref. . Copyright © 2012 Elsevier.

Figure 4

Cell viability after being treated with different formulations for 48 h. A, Effects of paclitaxel/TPGS nanocrystals, paclitaxel/F127 nanocrystals, Taxol and paclitaxel at the same 5 μmol/L paclitaxel concentration on NCI/ADR-RES, KB and H460 cells. B, Effects of paclitaxel/TPGS nanocrystals (10 μmol/L) with different amount of TPGS and paclitaxel/TPGS mixture (10 μmol/L) with different amount of TPGS. Reprinted (adapted) with permission from Ref. . Copyright © 2010 American chemical society.

Figure 5

TEM images showing beclomethasone dipropionate (BDP) precipitation in deionized water (A) without class II hydrophobin (HFBII), (B) with 0.005% HFBII, (C) with 0.05% HFBII, and (D) with 0.1% HFBII (Scale bar: 0.5 µm). Reprinted (adapted) with permission from Ref. . Copyright © 2010 American chemical society.

Figure 6

EPR effect shown by smaller size nanocrystals.

Figure 7

Fluorescein isothiocyanate (FITC) tagged nanocrystals uptake by (A) Confocal laser scanning microscopy (CLSM), (B) Flow cytometry (blue: hyaluronic acid-paclitaxel/nanocrystal (HP-PTX/NC); orange: HP-PTX/NC); (C) Cytotoxicity of paclitaxel formulation on MDA-MB 231 cells after 48 h, M, mol/L; (D) Microscopic images of MDA-MB-231 spheroids on 2–8 days after incubation of different formulations at alternate days (paclitaxel equivalent dose 0.5 µmol/L). Scale bar 500 µm. (E) and (F), Antitumor efficacy of control, Taxol™ and HA-PTX/NCs against LA-7 mammary gland rat cancer model at a dose equivalent to 10 mg/kg paclitaxel. (E) Morphology of the harvested tumors at the end of the study; (F) Lungs isolated from animals of different groups at the end of tumor regression study to demonstrate metastasis of tumor cells to lungs. Reprinted (adapted) with permission from Ref. . Copyright © 2016 Royal Society of Chemistry.

Figure 8

The in vivo fate of drug nanocrystals following intravenous administration.