Nanocrystals based pulmonary inhalation delivery system: advance and challenge

Figures & data

Figure 1. The structure of lung and pulmonary mucus barrier.

Figure 2. Preparation methods of nanocrystals based pulmonary inhalation delivery system.

Table 1. Examples of nanocrystal preparation.

Drug	Disease	Method of preparation	Stabilizer (concentration)	Average particle size (nm)	Performance
Curcumin (Pelikh et al., 2021)	Atopic dermatitis, psoriasis, and androgenetic alopecia	Bead milling	TPGS (d-α-tocopherol polyethylene glycol 1000 succinate) (1.0% (w/w)	290	Nanocrystals were efficiently taken up by the hair follicles and more permeable.
Andrographolide (Basu et al., 2020)	Hepatoprotective	Solvent-diffusion followed by homogenization	Tween 80 (1%)	630 ± 12	Aqueous solubility increased nearly fivefold. More significant liver protection effect.
Quercetin (Manca et al., 2020)	Skin disorders	Wet media milling	P188, Tween 80	326–474	In vitro studies showed the high biocompatibility of nanosuspensions and their ability to counteract the oxidative effect of hydrogen peroxide on cells.
Ginkgolide B (Liu et al., 2020)	Parkinson’s disease	Antisolvent precipitation	Hydroxypropyl methylcellulose (HPMC) E5 (0.5 mg/mL)	83.48 ± 1.77	Cmax of the GB-NCs up to 13-fold higher than unformulated GB, AUC0–t increased fivefold.
Resveratrol (Xiong et al., 2020)	Parkinson's disease	Antisolvent precipitation	HPMC (1.8 mg/mL)	222.54 ± 1.66	No significant toxic effects on zebrafish embryos and larvae, exhibited more favorable pharmacokinetics than pure RES.
Lutein (Chang et al., 2018)	Prophylaxis of cardiovascular	Anti-solvent precipitation –ultrasonication	Soy phosphatidylcholine (0.08%)	110.7	The Cmax and AUC0–24 h of lutein nanocrystals after oral administration in rats was 3.24 and 2.28 times higher than those of lutein suspension.
Glycyrrhetinic acid (Lei et al., 2016)	Chronic hepatitis	Anti-solvent precipitation –ultrasonication	TPGS (0.5%)	220	The bioavailability of GA nanocrystals in rats was 4.3-fold higher than that of the coarse GA after oral administration.
Pramipexole (Li et al., 2018)	Parkinson's disease	Wet media milling	PVP K30 (2.4%)	352.07 ± 21.29	In vitro permeation studies through rabbit ear skin indicated that the cumulative permeation amount of pramipexole from nanocrystals in 24 h was 2.75 times more than that from coarse suspension.
Meloxicam (Yu et al., 2018)	Rheumatoid arthritis and osteoarthritis	Nanoprecipitation technique	Poloxamer 407/Tween 80 (80/20, w/w) (0.1%)	175 ± 4	2.58- and 4.4-fold increase in AUC0 → 24 h was achieved by nanocrystals comparing with solution and suspension.
Baicalin (Wei et al., 2018)	Anti-oxidant; anti-inflammatory	High-pressure homogenization	TPGS 10% (w/w)	189.21 ± 0.36	The transdermal flux of BCA-NC-gel with 1% HLA were 20.65-fold higher (p<.01) than that of coarse BCA-gel.

Table 2. Examples of nanocrystals pulmonary inhalation system.

Nanocrystals lung inhalation delivery system	Drug	Preparation methods	Effect of drug administration
Inhalable nanocrystals based aerosol	Budesonide (Kraft et al., 2004)	Nanometer precipitation method	Fast adsorption, less systemic exposure
	Itraconazole (Rundfeldt et al., 2013)	Wet ball mill method
	Betamethasone dipropionate (Song et al., 2013)	High pressure homogenization method
	Fluticasone (Chiang et al., 2009)	Wet ball mill method
	Coenzyme Q10 (Rossi et al., 2018)	High pressure homogenization method
	Beclomethasone (Ostrander et al., 1999)	Dielectric grinding method
Inhalable nanocrystals based composite microparticle	Meloxicam (Pomázi et al., 2013)	High pressure uniform method, spray drying method	Deep lung deposition rate and fast dissolution rate
	Salbutamol sulfate (Bhavna et al., 2009)	Antisolvent precipitation method, spray drying method
	Tranilast (Onoue et al., 2011)	Wet ball grinding, freeze drying
	Carvedilol (Abdelbary et al., 2015)	Antisolvent precipitation ultrasonic method, freeze drying
	Niclosamide (Costabile et al., 2015)	High pressure homogenization method, spray drying method
	Budesonide + salbutamol sulphate (Raula et al., 2013)	Wet ball milling, aerosol flow reactor
	Breviscapine (Chen et al., 2021)	homogenization method, spray drying
	Indometacin (Laaksonen et al., 2011)	Wet ball milling, aerosol flow reactor
	A ring spore element (Yamasaki et al., 2011)	Antisolvent precipitation method, spray drying method
	Ciprofloxacin (Cipolla et al., 2016)	Freeze–thaw method
	Rifampicin (Mehanna et al., 2019)	Antisolvent precipitation ultrasonic method, spray drying method
Inhalable nanocrystals based adhesive microparticles	Budesonide (Liu et al., 2018)	Wet ball grinding, spray drying	Prolonged lung retention and slow drug release
	Resveratrol (Liu et al., 2019)	High pressure homogenization method, spray drying method
	Cinaciguat (Ni et al., 2017)	High pressure homogenization, spray drying
Inhalable mucus-penetrating nanocrystals	C109 (Costabile et al., 2020)	Nano precipitation, freeze drying	Easily penetrate mucus and reduce drug clearance

Figure 3. (A) Schematic diagram of BUD-INAM in vitro and in vivo release of BUD, (B) in vitro release profile, (C) retention on the porcine tracheal mucosa surface as a function of time, and (D) plasma concentration–time profiles. Adapted with permission from Liu et al. (2018).

Figure 4. (A) Schematic diagram of PEGylated mucus-penetrating nanocrystals and lung treatment in vivo, (B) in vitro release profile, (C) inhibition ability B. cenocepacia J2315 biofilm, cytotoxicity of C109 formulations to wild type 16HBE (D) and CF (CFBE41o−) bronchial epithelial cells (E). Adapted with permission from Costabile et al. (2020).

Figure 5. (A) Schematic illustration of curcumin nanocrystals on dissolution, airway mucosa penetration, lung tissue distribution, and absorption by pulmonary delivery. (B) Confocal microscopy images of calu-3 cells after incubation with CUR-NCs for 2 h (the scale bar is 50 μm); (C) calu-3 cell viability upon exposure to NC formulations at different drug concentrations; (D) mean fluorescence intensity of cells determined by flow cytometry (n = 3); (E) z-stack confocal images of the calu-3 cell layer with the polyester membrane after transport of NCs formulations for 1 h (the scale bar in xy plane was 50 μm). Adapted with permission from He et al. (2020).

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