Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                

4.2. Nanotechnology: J. Zhao, Et Al. International Journal of Pharmaceutics 570 (2019) 118642

Download as pdf or txt
Download as pdf or txt
You are on page 1of 9

J. Zhao, et al.

International Journal of Pharmaceutics 570 (2019) 118642

2015a). Wu et al. (1999) reported that the AUC0-24h and Cmax of bai- respectively (Hong et al., 2014).
calin were significantly improved 2.98- and 2.14-fold, respectively, Nanoemulsions (NEs), with fine droplet sizes between 1 and
after oral administration of a baicalin-phospholipid complex to rats 100 nm, are thermodynamically and thermokinetically stable trans-
compared with baicalin (p < 0.01). parent nanodispersions of oil and water stabilized by an interfacial film
Although the solubility and oral absorption of these bioactive fla- of surfactant that are usually used in combination with cosurfactant
vonoids in the flavonoid-carrier complexes have been greatly promoted, molecules (Date et al., 2010). It is noteworthy that by enhancing their
some shortcomings in the processes of preparation and storage have solubility in gastrointestinal fluid, enhancing their permeability
restrained their widespread utility in the pharmaceutical area. In par- through the intestinal wall, and protecting them from enzymatic de-
ticular, the limited aqueous solubility of natural CDs and the potential gradation in the gastrointestinal tract, these formulations can success-
formation or even precipitation of crystalline complexes in the kidney fully improve the undesirable oral absorption of the poorly water-so-
would result in low drug loading and encapsulation efficiency, in- luble flavonoid compounds. For example, the oral bioavailability of
complete degradation of the carrier and nephrotoxicity. To overcome myricetin in the NE formulation in rats was approximately 14.43 times
these obstacles, discovering and employing CD derivatives as novel higher than that of the native myricetin suspension, probably resulting
carriers of flavonoids is imperative. Additionally, the physical in- from the increased saturation solubility (1225-fold) of myricetin in its
stability of solid dispersions and phospholipid complexes due to the NE (Guo et al., 2016). Nevertheless, a potential drawback of NEs is that
conversion from the amorphous state to the crystalline state upon sto- some encapsulated bioactive flavonoid drugs can easily diffuse into the
rage severely impeded the enhancement in the dissolution rates of the surrounding water phase because of the relatively low viscosity of the
flavonoids in these two formulations. Introduction of a surfactant to the oil phase, which would lead to the degradation or loss of these com-
solid dispersion is a viable choice because the combination of the ponents (Jafari and McClements, 2017). To overcome this obstacle, a
polymer and surfactant can reduce the molecular mobility and inhibit self-nanoemulsifying drug delivery system (SNEDDS), which is an an-
recrystallization. Furthermore, the use of high-purity grades of phos- hydrous homogeneous liquid mixture of oil, surfactant, and cosurfac-
pholipids is another measure to obtain a stable phospholipid complex of tant, has been proposed to deliver the active ingredients because of
flavonoids with longer shelf lives, as they could increase the hygro- their increased solubilization capacity and stabilizing effect. Based on
scopicity and compatibility of these formulations. this consideration, Qian et al. (2017) prepared four optimized myr-
icetin-SNEDDS formulations, and the AUC0-24h of myricetin in these
4.2. Nanotechnology SNEDDS formulations improved 5.13-, 6.33-, 4.69- and 2.53-fold after
oral administration to rats compared with crude myricetin. In another
Nanotechnology is defined as the design, production, and applica- study, the cell permeability of QU in a SNEDDS form increased 23.75-
tion of structures, devices, and systems through control of the size and fold compared to that in its pure form, which caused the oral bioa-
shape of the material on a nanometer scale (Samir et al., 2015). Na- vailability of QU-SNEDDS in rats to be approximately 5-fold greater
notechnology-based drug delivery systems have been widely used for a than that of QU (Jain et al., 2013).
long time to diagnose and treat different cancer types by visualizing Lipid-based nanoparticles composed of physiologically acceptable
tumors and/or delivering therapeutic agents directly to the tumor sites lipid vehicles have emerged as another feasible drug delivery system
(Jabir et al., 2012). Owing to the special property of reduced particle because they can encapsulate large amounts of hydrophobic flavonoid
size, these nanosystems have also been applied to tackle the poor compounds, thereby enhancing drug solubility, protecting the drug
bioavailability issue of various water-insoluble flavonoids by many from degradation in the gastrointestinal tract, and increasing the total
pharmaceutical scholars. To provide insight into the application of systemic bioavailability via the enhanced permeability and lymphatic
these nanoformulations to deliver the active compounds, we summar- absorption (Ahn and Park, 2016; Teixeira et al., 2017). According to the
ized the recent progress from the following aspects (shown in Table 3): physical state (solid and/or liquid) of the lipid materials, the lipid-based
(1) the reduction of pure drug particle size, e.g., nanosuspensions, na- nanoparticles are generally divided into two groups: solid lipid nano-
nocrystals; (2) nanometer-scale emulsion droplet encapsulated systems, particles (SLNs) and nanostructured lipid carriers (NLCs). More speci-
e.g., nanoemulsions, self-nanoemulsifying drug delivery systems; and fically, by use of SLNs, the submicron particulate drug delivery system
(3) carrier-based nanoparticle delivery systems, e.g., lipid nano- composed of natural or artificial synthetic solid lipids, the dissolution
particles, polymer micelles, nanogels (Fig. 4). rate (48 h) of the total flavonoid extract from Dracocephalum moldavica
A nanosuspension, also called a nanocrystal, is defined as a carrier- L. (TFDM) improved from 86.51% for the crude TFDM to 96.23% for its
free drug delivery system that commonly consists of pure drug particles TFDM-SLNs. (Tan et al., 2017a). In another study, the AUC0-∞ of hy-
and stabilizers with a mean particle size in the nanometer range, ty- droxysafflor yellow A (HSYA) was improved approximately 3.99-fold
pically between 10 and 1000 nm (Geng et al., 2017). At present, it has after oral administration of a HSYA SLNs to rats compared with HSYA,
been considered a promising strategy to enhance the oral bioavail- which was likely attributable to the reduced hepatic first pass meta-
ability of insoluble active flavonoid components because it can increase bolism caused by the lymphatic transport in intestine. Moreover, be-
the saturation solubility and dissolution velocity by directly reducing cause of the presence of liquid lipids in the matrix, NLCs exhibit rela-
the particle size of the drugs to the nanometer range and thus enlarging tively high intrinsic defects (grain area) in the core compared to those
their surface area. To date, there have been numerous studies on the found in SLNs, which can accommodate more flavonoid molecules and
enhanced pharmacokinetic properties of many common flavonoid thus further increase their oral absorption. With regard to this, Aditya
candidates through the use of nanosuspension technology. As reported et al. (2014) prepared a novel QU-NLC formulation, which increases the
by Singh et al. (2018), the AUC0-12h of naringenin, a bioactive com- loading efficiency of QU from 0.6% in the SLN system to 0.9%. Con-
ponent of Citrus aurantium L., in rats after oral administration of its sequently, the oral bioavailability of QU in the NLC form in rats was
nanosuspension with a mean particle size of 118 nm was approximately approximately 1.71 times higher than that in SLN form.
3.76-fold greater than that of its raw drug suspension. Our research In recent years, with the ability of targeted and/or controlled/sus-
group also found that the saturation solubility of myricetin in four tained drug release, many biocompatible and biodegradable macro-
different myricetin nanosuspensions (300–500 nm) stabilized with D-α- molecular materials have been used to encapsulate different types of
tocopheryl polyethylene glycol 1000 succinate (TPGS), soya lecithin, poorly soluble flavonoids to form nanoparticles, resulting in their en-
soya lecithin + TPGS, or HP-β-CD + TPGS, increased from 6.23 mg/mL hanced solubility, prolonged retention time, and improved oral ab-
for pure myricetin to 399.63, 367.15, 466.28, and 267.90 mg/mL, sorption. To date, numerous natural and synthetic macromolecular
which resulted in an increase in the oral relative bioavailability of substances have been successfully applied in the preparation of flavo-
myricetin-nanosuspensions in rats of 244%, 357%, 161%, and 296%, noid nanoparticles. For example, bovine serum albumin (BSA), a

13
Table 3
Improvement of the solubility and oral absorption of flavonoids applying nanotechnologies.
Nanoformulation Flavonoid Nanoformulation component Preparation method Drug Solubility/Dissolution/Bioavailability Ref.
J. Zhao, et al.

loading (%) enhancement

Nanosuspension Naringenin Stabilizer: D-α-tocopherol polyethylene glycol 1000 Precipitation-ultrasonication 0.75 Cmax: 2.14-fold; AUC0-12h: 3.76-fold Singh et al. (2018)
succinate (TPGS)
Myricetin TPGS; Soya-lecithin; Soya-lecithin, TPGS; (2- Precipitation-high pressure – Solubility: 64.15-; 58.93-; 74.84-; 43.00- Hong et al. (2014)
hydroxypropyl)-β-cyclodextrin (HP-β-CD), TPGS homogenization fold; Cmax: 1.54-; 2.25-; 1.29-; 1.59-fold;
AUC0-48h: 2.64-; 3.89-; 1.64-; 2.68-fold
Scutellarin Poloxamer 188 (PXM 188) Antisolvent precipitation 0.02 Cmax: 12.00-fold Yang et al. (2014)
Kaempferol PXM High pressure homogenization – Cmax: 2.44-fold; AUC0-12h: 2.93-fold Qian et al. (2016)
Quercetin – Evaporative precipitation – Solubility: 41.09-fold; Dissolution: 1.09- Gao et al. (2011)
fold (10 min)

Nanocrystal Quercetin Stabilizer: Hydrophobically modified starch (HMS) Media milling and spray, 48.70 Solubility: 11.00-fold Lu et al. (2017)
freeze drying process
Icaritin Hydroxypropyl methylcellulose (HPMC) Antisolvent precipitation – Cmax: 4.67-fold; AUC0-36h: 2.02-fold Li et al. (2013)
Baicalin Sodium dodecyl sulfate (SDS), PXM 188 Ultrasonic-homogenization- – Solubility: 9.30-fold; Cmax: 2.47-fold; Jin et al. (2014)
fluid bed drying AUC0-36h: 2.08-fold
Taxifolin Ethanol, Deionized water, PXM 188 Liquid antisolvent 8.00 Solubility: 1.72-fold; Bioavailability: Zu et al. (2014a)
precipitation 7.00-fold
Artocarpin Polyvinylpyrrolidone (PVP) Nanoprecipitation – Solubility: 1401.77-fold Tzeng et al. (2016)

Nanoemulsion Silymarin Oil: Propylene glycol-monocaprylic ester (Sefsol 218); – – Cmax: 4.00-fold; AUC0-72h: 6.00-fold Parveen et al. (2011)
Surfactant: Polyoxyethylene sorbitan monooleate (Tween
80); Cosurfactant: Ethyl alcohol
Tangeretin Medium chain triglyceride (MCT), Lecithin – 2.3–2.5 Bioavailability: 2.3-fold Ting et al. (2015)
Baicalin Isopropyl myristate (IPM); Polyoxyethylene castor oil – 0.98 AUC0-48h: 14.56-fold Wu et al. (2018)
(Cremophor EL 35); Polyethylene glycol 400 (PEG 400)

14
IPM; Soy-lecithin, Tween 80; PEG 400 – – Cmax: 2.76-; 4.05-fold; AUC0-∞: 7.20-; Zhao et al. (2013)
4.05-fold
Myricetin Labrafac lipophile WL 1349 (WL 1349); polyoxyl 40 – 1.78 Solubility: 1225.00-fold; Bioavailability: Guo et al. (2016)
hydrogenated castor oil (Cremophor RH 40), Tween 80; 14.43-fold
Highly purified diethylene glycol monoethylether
(Transcutol HP)

Self-nanoemulsifying drug Myricetin Propylene glycol (Capryol 90)/Cremophor RH 40/PEG –- 2.00; 2.00; AUC0-24h: 5.13-; 6.33-; 4.69-; 2.53-fold Qian et al. (2017)
delivery system 400; Capryol 90/Cremophor RH 40/1,2-propanediol; 3.00; 1.00
Capryol 90/Cremophor EL/Transcutol HP; Capryol 90/
Cremephor RH 40/Transcutol HP
Quercetin Propylene glycol monocaprylate (Capryol 90), Oleoyl – – Papp: 188.00-fold (Artificial intestinal Pangeni et al. (2017)
polyoxylglycerides (Labrafil M 1944 CS);Caprylocaproyl membran); 3.37-fold (Caco-2 cell);
macrogol-8-glycerides (Labrasol), Tween 80; Cremophor Bioavailability: 33.51-fold
EL
Castor oil; Tween 80, Cremophor RH 40; PEG 400 – 3.00 Cmax: 3.00-fold; AUC0-24h: 2.00-fold Tran et al. (2014)
Glycerol monocaprylate (MCM); Tween 20; Ethanol – 2.10 Papp: 23.75-fold (Caco-2 cells); Jain et al. (2013)
Bioavailability: 5.00-fold

(continued on next page)


International Journal of Pharmaceutics 570 (2019) 118642
Table 3 (continued)

Nanoformulation Flavonoid Nanoformulation component Preparation method Drug Solubility/Dissolution/Bioavailability Ref.


J. Zhao, et al.

loading (%) enhancement

Lipid nanoparticles (Solid Hydroxysafflor yellow A Lipid: Glyceryl monostearate (GMS) Warm microemulsion – Cmax: 7.76-fold; AUC0-∞: 3.99-fold Zhao et al. (2018)
lipid) (HSYA)
Total flavonoid of Glyceryl behenate (Compritol 888 ATO) High-shear homogenization 8.61 Dissolution: 1.11-fold (48 h) Tan et al. (2017a)
Dracocephalum moldavica
L. (TFDM)
Ginkgo biloba extract Cholesterol Film dispersion- – Release time: increased by 48 h (pH 6.8) Jin et al. (2013b)
(GBE) homogenization
Baicalin Stearic acid alkaline salt Coacervation – Cmax: 1.60-fold; AUC0-∞: 2.60-fold Hao et al. (2012)
Hydrogenated soya phosphatidylcholine (HSPC) Effervescent dispersion – Cmax: 2.82-fold; AUC0-24h: 3.04-fold Wei et al. (2014)
Quercetin GMS Low-temperature 13.20 Cmax: 2.07-fold; AUC0-48h: 5.71-fold Li et al. (2009)
solidification
Emulsion solvent evaporation- 8.36 Cmax: 1.67-fold; AUC0-24h: 3.56-fold Ahmad et al. (2016)
high pressure homogenization
Imwitor 900 K High pressure homogenization 0.60 Bioavailability: 5.00-fold Aditya et al. (2014)

Lipid nanoparticles (Mixed Baicalin Liquid: GMS, Polyethylene glycol monostearate, Oleic acid Emulsion-evaporation and 6.50; 6.00 AUC0-∞: 3.03-; 7.56-fold Zhang et al. (2016c)
lipids) low temperature-solidification
Quercetin Triglyceride, Phosphatidylcholine, vitamin E acetate, Phase inversion-based process 11.00 Solubility: 100.00-fold Sun et al. (2014)
Polyoxyl 15 Hydroxystearate
Imwitor 900 K, Medium chain triglyceride (MCT) High pressure homogenization 0.90 Bioavailability: 8.57-fold Aditya et al. (2014)

Macromolecular material Naringin Carrier: Amylose, α-linoleic acid, β-lactoglobulin (β-Lg) – 14.51 Release rate: increased by 55.00% (2 h); Feng et al. (2017)
nanoparticles 89.00% (6 h)
Naringenin β-Lg – – Solubility: 3.00-fold Shpigelman et al.
(2014)
Baicalin Folic acid, Poly(amidoamine) dendrimers – 22 Increased anti-tumor efficacy (Lv et al. (2017)

15
Chrysin (D, L-lactic-coglycolic acid) poly (ethylene glycol) (PLGA- Double emulsion-probe type 16.19 IC50: decreased from 68.24 μM to 58.24 Mohammadian et al.
PEG) sonication-solvent μM (24 h) (2016)
evaporation
Quercetin Bovine serum albumin (BSA) Desolvation 17.00 Increased antioxidant activity Antônio et al. (2016)
Fisetin Cationic cyclosophoraose dimer (Cys dimer) Double emulsion-physically – Solubility: 6.50-fold; Jeong et al. (2013)
encapsulated
Silibinin PLGA-PEG-Fe3O4 Double emulsion-physically 76.00 Inhibit cancer cell gene expression (up to Ebrahimnezhad et al.
encapsulated 98%) (2013)

Polymer micelles Myricetin Carrier: SDS, Pluronic F68 (F68), Labrasol Solvent evaporation 16.27 Cmax: 1.82-fold; AUC0-∞: 1.40-fold Wang et al. (2016a)
Baicalin Sodium taurocholate (ST), Pluronic P123 block copolymer Thin-film dispersion 16.94 Solubility: increased by 10.20 mg/mL; Zhang et al. (2014b)
(P123)
Baohuoside I Phospholipid, TPGS Solvent evaporation – Solubility: 88.00-fold; Relative Jin et al. (2013a)
bioavailabilities: 533%
Icariside II Polyoxyl 15, Hydroxystearate, F127 Ethanol thin-film hydration 9.70 Solubility: 900.00-fold; Relative Hou et al. (2016)
bioavailabilities: 317%
Quercetin Polyvinyl caprolactam-polyvinyl acetate-polyethylene Film dispersion 6.70 Relative bioavailabilities: 286% Dian et al. (2014)
glycol, F127
P12, P407; P123, P407, TPGS Thin film hydration 8.75; 9.01 Solubility: 3481.65-; 3075.23-fold; Patra et al. (2018)

Nanogels Myricetin Carrier: Chitosan – – Cmax: 1.73-fold; AUC0-24h: 2.20-fold Yao et al. (2016)
International Journal of Pharmaceutics 570 (2019) 118642
J. Zhao, et al. International Journal of Pharmaceutics 570 (2019) 118642

Fig. 4. Schematic illustration of the existing nanoformulation used to orally deliver flavonoids and their classification.

physiological protein containing 583 amino acids, has been designed designed novel myricetin-loaded nanogels/gels with biocompatible
and developed into a macromolecular material nanoparticle system chitosan, which showed an in increase in oral bioavailability (2.20-fold
with hydrophobic QU, thereby significantly increasing the antioxidant increase relative to myricetin) and low cytotoxicity (the cell viability
activity of QU. After 96 h, the half maximal inhibitory concentration ranged from 90% to 110% after 24 h and 48 h of incubation with
(IC50) of the QU nanoparticles in sodium phosphate buffer was 7.5-fold myricetin-loaded nanogels/gels at myricetin concentrations of
less than that of free QU (p < 0.05) (Antônio et al., 2016). Similarly, 41.82 μM and 83.64 μM, respectively) (Yao et al., 2016). Furthermore,
Jeong et al. (2013) found that the cytotoxicity of fisetin (a potent the low encapsulation efficacy and loading capacity of the existing
polyphenolic flavonoid from various vegetables and fruits such as cu- nanosystems is another severe problem that remains to be solved,
cumber, onion, and apple) against human cervical cancer HeLa cells in which limits flavonoids from exerting their therapeutic effects ade-
its nanoparticle formulation with the macromolecular material cationic quately. To overcome this major hurdle, the following aspects should be
cyclosophoraose dimer (Cys dimer) was approximately 1.25 times considered when designing a nanoformulation of these active flavonoid
higher than that of its pure form, probably resulting from the increased compounds: (1) choose high surface areas or large pore volumes for the
saturation solubility (6.5-fold) of fisetin in its nanoparticles. Further- pharmaceutical excipients as the nanocarriers; (2) reduce the reaction
more, polymeric micelles, which are self-assembled core–shell nanos- steps to as few as possible and/or optimize the processing parameters;
tructures formed in an aqueous solution consisting of amphiphilic block and (3) develop carrier-free nanomedicines on the premise of guaran-
copolymers, have also been utilized to strength the potency of poorly teeing a therapeutic effect and function.
water-soluble flavonoids because their inner hydrophobic core can load
the active compounds, thus improve their stability and bioavailability 4.3. Cocrystals
(Xu et al., 2013). In this context, Jin et al (2013a) designed and syn-
thesized a baohuoside I (the main effective component of heat-pro- Pharmaceutical cocrystals are defined as a multicomponent systems
cessed Epimedium koreanum)-loaded micelle by using TPGS, an amphi- that contain an active pharmaceutical ingredient (API) and cocrystal
philic derivative of natural vitamin E, as the polymeric carrier, and coformer (CCF) in a definite stoichiometric ratio held together via
reported that the AUC0-∞ and Cmax of baohuoside I were significantly noncovalent interactions such as hydrogen bonds, π-π stacking, and van
improved by 5.63- and 2.67-fold, respectively, after oral administration der Waals forces (Emami et al., 2018; Karashima et al., 2016). Owing to
of the baohuoside I-polymeric micelle to rats compared with baohuo- the competitive hydrogen bonding sites within a molecular framework,
side I (p < 0.01). i.e., donors and acceptors, the poorly water-soluble flavonoid com-
Overall, although these nanotechnology-based drug delivery sys- pounds can easily form cocrystals with CCFs, which also contain hy-
tems offer promising solutions for the formulation of poorly water-so- drogen bond acceptors and donors, thus improving their physico-
luble flavonoids, they are far from optimal due to the serious side ef- chemical properties without altering their inherent chemical structures.
fects, toxicity to healthy tissues and organs caused by off-target Currently, a series of flavonoid cocrystals with proper coformers, such
biodistribution and accumulation, and the absorption of the surfactants, as caffeine, isoniazid, nicotinamide, isonicotinamide, acetamide, 4,4′-
cosurfactants, and emulsifiers, etc. To address these obstacles, the bipyridine, proline, betaine, and theophylline, have been successfully
binding of surface ligands to some specific biological target associated generated, and some exhibited good solubility, dissolution rate, and
with pathological tissue is probably an alternative measure to acquire oral bioavailability properties (Cui et al., 2019; Hong et al., 2015; Li
nanoformulations for hydrophobic flavonoids. Moreover, the in- et al., 2018b; Liu et al., 2016b; Luo et al., 2018; Luo et al., 2019;
troduction of nontoxic and nonmutagenic natural materials, which can Mureşan-Pop et al., 2016; Ren et al., 2019; Smith et al., 2011; Zhang
be fully excreted from the body once bioabsorbed, as the excipients is et al., 2017a, b). For instance, the solubility of luteolin in luteolin-iso-
also highly necessary. In this field, our research group has successfully niazid cocrystals improved from 35.1 µg/mL for crude luteolin to

16
J. Zhao, et al. International Journal of Pharmaceutics 570 (2019) 118642

Fig. 5. Schematic illustration of the solution method with sonochemistry used to prepare the myricetin-nicotinamide nano-cocrystals. The amounts of myricetin/
nicotinamide/solvent used in the reaction is based on the principle of TPD. After the reaction, each component was dissolved separately in methanol and injected
together under ultrasonic conditions. This figure is based on one published previously (Liu et al., 2016a).

112.3 µg/mL, which caused an approximately 2.7-fold increase in the have been developed to circumvent the issue of low bioavailability of
AUC0-∞ of luteolin in the luteolin-isoniazid cocrystals compared with active flavonoids by enhancing their solubility and dissolution rate,
crude luteolin (Luo et al., 2019). In addition, our research group pre- increasing their mucosal permeation, preventing their degradation or
sented the novel strategy of pharmaceutical cocrystal generation by metabolism in the gastrointestinal tract and delivering them directly to
solution crystallization based on the ternary phase diagram (TPD) the physiological tract. As expected, by using these strategies, the
principle (Hong et al., 2015), by which myricetin-proline cocrystals pharmacokinetic behavior of various flavonoids have been greatly im-
with a 1:1 stoichiometric ratio were obtained, and the oral bioavail- proved, which is beneficial for their pharmaceutical development and
ability in rats of myricetin in the myricetin-proline cocrystals was ap- further clinical application.
proximately 3.03 times higher than that of the native myricetin sus- However, the applications of some formulations to deliver insoluble
pension (Liu et al., 2016b). Furthermore, based on the nanotechnology flavonoid compounds still suffer from the following challenges: (1) the
principle that decreasing the particle size can commonly increase the physical instability and low drug loading is probably caused by the
dissolution of flavonoids, some pharmaceutical cocrystals have been required abundance of pharmaceutical adjuvants and/or reaction steps
prepared as nano-cocrystals to further enhance their solubility. In our and the tedious preparation methods, and (2) the undesirable side ef-
previous research, myricetin-nicotinamide nano-cocrystals (with a fects arise from the nonselective distribution of oral formulations, the
stoichiometric ratio of 1:2) were prepared using a modified solution generation of the byproducts, and the incomplete degradation of the
method in conjunction with sonochemistry (Fig. 5), in which the carriers. With regard to this, the following several aspects should be
maximum dissolution amount of myricetin was further increased from considered in future studies to break through the barriers and conse-
33 µg/mL in its cocrystals to 42 µg/mL (Liu et al., 2016a). quently expedite their development.
Nevertheless, a potential risk of pharmaceutical cocrystals is their First, more efforts should be focused on modifying the existing drug
propensity to undergo unintended dissociation because of their weak delivery systems for flavonoids by exploring some convenient and safe
intermolecular interactions, which could negate the solubility, dis- techniques and procedures and by using some biocompatible natural ma-
solution, and oral bioavailability advantages conferred by these for- terials or carriers. In addition, more attention should also be paid to sys-
mations. To avoid this problem, choosing the correct coformer based on tematically evaluate the potential toxicity of these oral formulations and
the chemical structure of each flavonoid component is of utmost im- determine the relationship between their efficacy and safety to reasonably
portance since the physicochemical properties of the cocrystals gen- guide their effective application. Second, the design of some new drug
erally depend upon those of the coformer that is used. In addition, in- delivery systems can be triggered remotely to obtain flexible control of dose
corporation of hydrophilic silica as the film coating is probably another magnitude and timing by combining interdisciplinary knowledge, in-
strategy to obtain a stable flavonoid cocrystal, as they could reduce the cluding polymer chemistry, materials science, biology, and pharmacy
likelihood of water-mediated cocrystal dissociation during storage. might provide feasible to further improve the oral absorption of flavonoid
Furthermore, cocrystals have commonly been prepared through em- compounds. Third, many related studies are still kept at the lab level; in this
pirical understanding or experimental attempts, which consumes much case, translating laboratory achievements into products and then propelling
time and energy; a much simpler and easier scaled-up synthetic ap- the related clinical trial is highly desired. This can be achieved by enhan-
proach to generate pharmaceutical cocrystals would be helpful to cing the drug payload within the oral formulations, using inexpensive ex-
widen their application in the drug delivery field. cipients, simplifying scale-up manufacturing steps, and systematically in-
vestigating the in vivo stability, biodistribution, and disease treatment
efficacy. We are convinced that with rational design and continuing stu-
5. Conclusion and prospects dies, a bright future can be foreseen for these insoluble active flavonoids for
the effective treatment of various human diseases.
This review summarized some valuable studies to improve the oral
bioavailability of poorly water-soluble flavonoids using alternative oral
delivery systems and discussed their design principles, potential ad- Declaration of Competing Interest
vantages, possible limitations, and oral delivery efficiency. To date,
many formulation approaches, including absorption enhancers, struc- The authors declare that they have no known competing financial
tural transformation (e.g., prodrugs, glycosylation), and pharmaceu- interests or personal relationships that could have appeared to influ-
tical technologies (e.g., carrier complexes, nanotechnology, cocrystals), ence the work reported in this paper.

17
J. Zhao, et al. International Journal of Pharmaceutics 570 (2019) 118642

Acknowledgments collaborators, fruit and vegetable intake and mortality from ischaemic heart disease:
results from the european prospective investigation into cancer and nutrition (EPIC)-
heart study. Eur. Heart J. 32, 1235–1243.
This work was funded by the National Science Foundation of China Cui, L., Zhang, Z.H., Sun, E., Jia, X.B., 2012. Effect of β-cyclodextrin complexation on
(81873198), the “Shu Guang” project supported by the Shanghai solubility and enzymatic conversion of naringin. Int. J. Mol. Sci. 13, 14251–14261.
Education Development Foundation and the Shanghai Municipal Cui, W., He, Z., Zhang, Y., Fan, Q., Feng, N., 2019. Naringenin cocrystals prepared by
solution crystallization method for improving bioavailability and anti-hyperlipidemia
Education Commission (15SG39), the Program of Shanghai Academic/ effects. AAPS PharmSciTech. 20, 115.
Technology Research Leader (19XD1423700), and the Shanghai Damian, F., Blaton, N., Naesens, L., Balzarini, J., Kinget, R., Augustijns, P., Van den
Natural Science Foundation (18ZR1436400, 19ZR1444200). Mooter, G., 2000. Physicochemical characterization of solid dispersions of the anti-
viral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14. Eur. J. Pharm.
Sci. 10, 311–322.
References Dang, Y., Lin, G., Xie, Y., Duan, J., Ma, P., Li, G., Ji, G., 2014. Quantitative determination
of myricetin in rat plasma by ultra performance liquid chromatography tandem mass
spectrometry and its absolute bioavailability. Drug Res. (Stuttg) 64, 516–522.
Abet, V., Filace, F., Recio, J., Alvarez-Builla, J., Burgos, C., 2017. Prodrug approach: an
Daruházi, Á.E., Szente, L., Balogh, B., Mátyus, P., Béni, S., Takács, M., Gergely, A.,
overview of recent cases. Eur. J. Med. Chem. 127, 810–827.
Horváth, P., Szoke, É., Lemberkovics, É., 2008. Utility of cyclodextrins in the for-
Aditya, N.P., Macedo, A.S., Doktorovova, S., Souto, E.B., Kim, S., Chang, P.S., Ko, S.,
mulation of genistein part 1. Preparation and physicochemical properties of genistein
2014. Development and evaluation of lipid nanocarriers for quercetin delivery: a
complexes with native cyclodextrins. J. Pharm. Biomed. Anal. 48, 636–640.
comparative study of solid lipid nanoparticles (SLN), nanostructured lipid carriers
Das, S., Chaudhury, A., 2011. Recent advances in lipid nanoparticle formulations with
(NLC), and lipid nanoemulsions (LNE). LWT-Food Sci. Technol. 59, 115–121.
solid matrix for oral drug delivery. AAPS PharmSciTech 12, 62–76.
Ahmad, N., Banala, V.T., Kushwaha, P., Karvande, A., Sharma, S., Tripathi, A.K., Verma,
Date, A.A., Desai, N., Dixit, R., Nagarsenker, M., 2010. Self-nanoemulsifying drug de-
A., Trivedi, R., Mishra, P.R., 2016. Quercetin-loaded solid lipid nanoparticles im-
livery systems: formulation insights, applications and advances. Nanomedicine
prove osteoprotective activity in an ovariectomized rat model: a preventive strategy
(Lond) 5, 1595–1616.
for post-menopausal osteoporosis. RSC Adv. 6, 97613–97628.
Deng, Y.H., Su, L.N., Pang, Y.H., Guo, Y.F., Wang, F., Liao, X.L., Yang, B., 2017.
Ahn, H., Park, J.H., 2016. Liposomal delivery systems for intestinal lymphatic drug
Preparation, characterization and water solubility of inclusion complexes of daidzein
transport. Biomater. Res. 20, 36.
with amino-modified β-cyclodextrins. Chinese J. Anal. Chem. 45, 648–653.
Alama, T., Katayama, H., Hirai, S., Ono, S., Kajiyama, A., Kusamori, K., Katsumi, H.,
Dian, L., Yu, E., Chen, X., Wen, X., Zhang, Z., Qin, L., Wang, Q., Li, G., Wu, C., 2014.
Sakane, T., Yamamoto, A., 2016. Enhanced oral delivery of alendronate by sucrose
Enhancing oral bioavailability of quercetin using novel soluplus polymeric micelles.
fatty acids esters in rats and their absorption-enhancing mechanisms. Int. J. Pharm.
Nanoscale Res. Lett. 9, 684.
515, 476–489.
Ebrahimnezhad, Z., Zarghami, N., Keyhani, M., Amirsaadat, S., Akbarzadeh, A., Rahmati,
Antônio, E., Khalil, N.M., Mainardes, R.M., 2016. Bovine serum albumin nanoparticles
M., Mohammad Taheri, Z., Nejati-Koshki, K., 2013. Inhibition of hTERT gene ex-
containing quercetin: characterization and antioxidant activity. J. Nanosci.
pression by silibinin-loaded PLGA-PEG-Fe3O4 in T47D breast cancer cell line.
Nanotechnol. 16, 1346–1353.
Bioimpacts 3, 67–74.
Athmouni, K., Mkadmini Hammi, K., El Feki, A., Ayadi, H., 2018. Development of ca-
Emami, S., Siahi-Shadbad, M., Adibkia, K., Barzegar-Jalali, M., 2018. Recent advances in
techin-phospholipid complex to enhance the bioavailability and modulatory potential
improving oral drug bioavailability by cocrystals. Bioimpacts 8, 305–320.
against cadmium-induced oxidative stress in rats liver. Physiol. Biochem Arch.
Ezzat, H.M., Elnaggar, Y.S.R., Abdallah, O.Y., 2019. Improved oral bioavailability of the
https://doi.org/10.1080/13813455.2018.1493608.
anticancer drug catechin using chitosomes: design, in-vitro appraisal and in-vivo
Aungst, B.J., 2000. Intestinal permeation enhancers. J. Pharm. Sci. 89, 429–442.
studies. Int. J. Pharm. 565, 488–498.
Aungst, B.J., 2012. Absorption enhancers: applications and advances. AAPS J. 14, 10–18.
Fang, Y., Cao, W., Xia, M., Pan, S., Xu, X., 2017. Study of structure and permeability
Aungst, B.J., Saitoh, H., Burcham, D.L., Huang, S.M., Mousa, S.A., Hussain, M.A., 1996.
relationship of flavonoids in Caco-2 cells. Nutrients 9, 1301.
Enhancement of the intestinal absorption of peptides and nonpeptides. J. Control.
Feng, T., Wang, K., Liu, F., Ye, R., Zhu, X., Zhuang, H., Xu, Z., 2017. Structural char-
Release 41, 19–31.
acterization and bioavailability of ternary nanoparticles consisting of amylose, alpha-
Cai, X., Fang, Z., Dou, J., Yu, A., Zhai, G., 2013. Bioavailability of quercetin: problems and
linoleic acid and β-lactoglobulin complexed with naringin. Int. J. Biol. Macromol. 99,
promises. Curr. Med. Chem. 20, 2572–2582.
365–374.
Cao, F., Guo, J.X., Ping, Q.N., Liao, Z.G., 2006. Prodrugs of scutellarin: ethyl, benzyl and
Fenyvesi, É., Vikmon, M., Szente, L., 2016. Cyclodextrins in food technology and human
N, N-diethylglycolamide ester synthesis, physicochemical properties, intestinal me-
nutrition: benefits and limitations. Crit. Rev. Food Sci. Nutr. 56, 1981–2004.
tabolism and oral bioavailability in the rats. Eur. J. Pharm. Sci. 29, 385–393.
Fu, Q., Wang, H., Xia, M., Deng, B., Shen, H., Ji, G., Li, G., Xie, Y., 2015. The effect of
Chen, C., Wang, Z., Zhang, Z., Liu, X., Kang, S.S., Zhang, Y., Ye, K., 2018a. The prodrug of
phytic acid on tight junctions in the human intestinal Caco-2 cell line and its me-
7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s
chanism. Eur. J. Pharm. Sci. 80, 1–8.
disease. Proc. Natl. Acad. Sci. U.S.A 115, 578–583.
Fukuhara, K., Nakanishi, I., Kansui, H., Sugiyama, E., Kimura, M., Shimada, T., Urano, S.,
Chen, R., Wu, P., Cai, Z., Tang, L., Ye, L., Hou, C., Yang, N., Zhao, J., 2018b. The com-
Yamaguchi, K., Miyata, N., 2002. Enhanced radical-scavenging activity of a planar
bination of Puerariae Lobatae Radix and Chuanxiong Rhizoma enhanced the ab-
catechin analogue. J. Am. Chem. Soc. 124, 5952–5953.
sorption and pharmacokinetics of puerarin by modulating the intestinal barrier and
Gao, L., Liu, G., Wang, X., Liu, F., Xu, Y., Ma, J., 2011. Preparation of a chemically stable
influenced gut microbiota. J. Funct. Foods 47, 72–82.
quercetin formulation using nanosuspension technology. Int. J. Pharm. 404,
Chen, Z.P., Sun, J., Chen, H.X., Xiao, Y.Y., Liu, D., Chen, J., Cai, H., Cai, B.C., 2010.
231–237.
Comparative pharmacokinetics and bioavailability studies of quercetin, kaempferol
Geng, T., Banerjee, P., Lu, Z., Zoghbi, A., Li, T., Wang, B., 2017. Comparative study on
and isorhamnetin after oral administration of Ginkgo biloba extracts, Ginkgo biloba
stabilizing ability of food protein, non-ionic surfactant and anionic surfactant on BCS
extract phospholipid complexes and Ginkgo biloba extract solid dispersions in rats.
type II drug carvedilol loaded nanosuspension: physicochemical and pharmacokinetic
Fitoterapia 81, 1045–1052.
investigation. Eur. J. Pharm. Sci. 109, 200–208.
Chiou, W.L., Riegelman, S., 1971. Pharmaceutical applications of solid dispersion sys-
Ghadiri, M., Canney, F., Pacciana, C., Colombo, G., Young, P.M., Traini, D., 2018. The use
tems. J. Pharm. Sci. 60, 1281–1302.
of fatty acids as absorption enhancer for pulmonary drug delivery. Int. J. Pharm. 541,
Choonara, B.F., Choonara, Y.E., Kumar, P., Bijukumar, D., du Toit, L.C., Pillay, V., 2014. A
93–100.
review of advanced oral drug delivery technologies facilitating the protection and
Guo, R.X., Fu, X., Chen, J., Zhou, L., Chen, G., 2016. Preparation and characterization of
absorption of protein and peptide molecules. Biotechnol. Adv. 32, 1269–1282.
microemulsions of myricetin for improving its antiproliferative and antioxidative
Chuang, S.Y., Lin, Y.K., Lin, C.F., Wang, P.W., Chen, E.L., Fang, J.Y., 2017. Elucidating the
activities and oral bioavailability. J. Agric. Food Chem. 64, 6286–6294.
skin delivery of aglycone and glycoside flavonoids: how the structures affect cuta-
Hao, J., Wang, F., Wang, X., Zhang, D., Bi, Y., Gao, Y., Zhao, X., Zhang, Q., 2012.
neous absorption. Nutrients 9, 1304.
Development and optimization of baicalin-loaded solid lipid nanoparticles prepared
Chung, M.J., Kang, A.Y., Lee, K.M., Oh, E., Jun, H.J., Kim, S.Y., Auh, J.H., Moon, T.W.,
by coacervation method using central composite design. Eur. J. Pharm. Sci. 47,
Lee, S.J., Park, K.H., 2006. Water-soluble genistin glycoside isoflavones up-regulate
497–505.
antioxidant metallothionein expressionand scavenge free radicals. J. Agric. Food
Havsteen, B.H., 2002. The biochemistry and medical significance of the flavonoids.
Chem. 54, 3819–3826.
Pharmacol. Ther. 96, 67–202.
Cong, W., Shen, L., Xu, D., Zhao, L., Ruan, K., Feng, Y., 2014. Solid dispersion tablets of
Hofer, B., 2016. Recent developments in the enzymatic O-glycosylation of flavonoids.
breviscapine with polyvinylpyrrolidone K30 for improved dissolution and bioavail-
Appl. Microbiol. Biotechnol. 100, 4269–4281.
ability to commercial breviscapine tablets in beagle dogs. Eur. J. Drug Metab.
Hong, C., Dang, Y., Lin, G., Yao, Y., Li, G., Ji, G., Shen, H., Xie, Y., 2014. Effects of
Pharmacokinet. 39, 203–210.
stabilizing agents on the development of myricetin nanosuspension and its char-
Cook, N.C., Samman, S., 1996. Flavonoids-Chemistry, metabolism, cardioprotective ef-
acterization: an in vitro and in vivo evaluation. Int. J. Pharm. 477, 251–260.
fects, and dietary sources. J. Nutr. Biochem. 7, 66–76.
Hong, C., Xie, Y., Yao, Y., Li, G., Yuan, X., Shen, H., 2015. A novel strategy for phar-
Crowe, F.L., Roddam, A.W., Key, T.J., Appleby, P.N., Overvad, K., Jakobsen, M.U.,
maceutical cocrystal generation without knowledge of stoichiometric ratio: myricetin
Tjonneland, A., Hansen, L., Boeing, H., Weikert, C., Linseisen, J., Kaaks, R.,
cocrystals and a ternary phase diagram. Pharm. Res. 32, 47–60.
Trichopoulou, A., Misirli, G., Lagiou, P., Sacerdote, C., Pala, V., Palli, D., Tumino, R.,
Hou, J., Wang, J., Sun, E., Yang, L., Yan, H.M., Jia, X.B., Zhang, Z.H., 2016. Preparation
Panico, S., Bueno-de-Mesquita, H.B., Boer, J., van Gils, C.H., Beulens, J.W.,
and evaluation of icariside II-loaded binary mixed micelles using Solutol HS15 and
Barricarte, A., Rodriguez, L., Larranaga, N., Sanchez, M.J., Tormo, M.J., Buckland, G.,
Pluronic F127 as carriers. Drug Deliv. 23, 3248–3256.
Lund, E., Hedblad, B., Melander, O., Jansson, J.H., Wennberg, P., Wareham, N.J.,
Jabir, N.R., Tabrez, S., Ashraf, G.M., Shakil, S., Damanhouri, G.A., Kamal, M.A., 2012.
Slimani, N., Romieu, I., Jenab, M., Danesh, J., Gallo, V., Norat, T., Riboli, E., 2011.
Nanotechnology-based approaches in anticancer research. Int. J. Nanomed. 7,
European prospective investigation into cancer and nutrition (EPIC)-heart study
4391–4408.

18
J. Zhao, et al. International Journal of Pharmaceutics 570 (2019) 118642

Jafari, S.M., McClements, D.J., 2017. Nanotechnology approaches for increasing nutrient Li, W., Pi, J., Zhang, Y., Ma, X., Zhang, B., Wang, S., Qi, D., Li, N., Guo, P., Liu, Z., 2018b.
bioavailability. Adv. Food Nutr. Res. 81, 1–30. A strategy to improve the oral availability of baicalein: the baicalein-theophylline
Jain, S., Jain, A.K., Pohekar, M., Thanki, K., 2013. Novel self-emulsifying formulation of cocrystal. Fitoterapia 129, 85–93.
quercetin for improved in vivo antioxidant potential: implications for drug-induced Li, Y., Sun, S., Chang, Q., Zhang, L., Wang, G., Chen, W., Miao, X., Zheng, Y., 2013. A
cardiotoxicity and nephrotoxicity. Free Radic. Biol. Med. 65, 117–130. strategy for the improvement of the bioavailability and antiosteoporosis activity of
Jeong, D., Choi, J.M., Choi, Y., Jeong, K., Cho, E., Jung, S., 2013. Complexation of fisetin BCS IV flavonoid glycosides through the formulation of their lipophilic aglycone into
with novel cyclosophoroase dimer to improve solubility and bioavailability. nanocrystals. Mol. Pharm. 10, 2534–2542.
Carbohydr. Polym. 97, 196–202. Liao, D., Liu, X., Dai, W., Tang, T., Ou, G., Zhang, K., Han, M., Kang, R., Yang, S., Xiang,
Jiang, J.R., Yuan, S., Ding, J.F., Zhu, S.C., Xu, H.D., Chen, T., Cong, X.D., Xu, W.P., Ye, H., D., 2015. N-trimethyl chitosan (TMC)-modified microemulsions for improved oral
Dai, Y.J., 2008. Conversion of puerarin into its 7-O-glycoside derivatives by bioavailability of puerarin: preparation and evaluation. Drug Deliv. 22, 516–521.
Microbacterium oxydans (CGMCC 1788) to improve its water solubility and phar- Liu, M., Hong, C., Li, G., Ma, P., Xie, Y., 2016a. The generation of myricetin-nicotinamide
macokinetic properties. Appl. Microbiol. Biotechnol. 81, 647–657. nanococrystals by top down and bottom up technologies. Nanotechnology 27,
Jin, X., Zhang, Z.H., Sun, E., Qian, Q., Tan, X.B., Jia, X.B., 2012a. Preparation of a na- 395601.
noscale baohuoside I-phospholipid complex and determination of its absorption: in Liu, M., Hong, C., Yao, Y., Shen, H., Ji, G., Li, G., Xie, Y., 2016b. Development of a
vivo and in vitro evaluations. Int. J. Nanomed. 7, 4907–4916. pharmaceutical cocrystal with solution crystallization technology: preparation,
Jin, X., Zhang, Z.H., Sun, E., Tan, X.B., Zhu, F.X., Jia, X.B., 2013a. A novel drug-phos- characterization, and evaluation of myricetin-proline cocrystals. Eur. J. Pharm.
pholipid complex loaded micelle for baohuoside I enhanced oral absorption: in vivo Biopharm. 107, 151–159.
and in vivo evaluations. Drug Dev. Ind. Pharm. 39, 1421–1430. Liu, P., Yang, B., Kallio, H., 2010. Characterization of phenolic compounds in Chinese
Jin, X., Zhang, Z.H., Sun, E., Tan, X.B., Zhu, F.X., Li, S.L., Jia, X.B., 2012b. Preparation of hawthorn (Crataegus pinnatifida Bge. var. major) fruit by high performance liquid
icariside II-phospholipid complex and its absorption across Caco-2 cell monolayers. chromatography-electrospray ionization mass spectrometry. Food Chem. 121,
Pharmazie 67, 293–298. 1188–1197.
Jin, Y., Wen, J., Garg, S., Liu, D., Zhou, Y., Teng, L., Zhang, W., 2013b. Development of a Lu, M., Ho, C.T., Huang, Q., 2017. Improving quercetin dissolution and bioaccessibility
novel niosomal system for oral delivery of Ginkgo biloba extract. Int. J. Nanomed. 8, with reduced crystallite sizes through media milling technique. J. Funct. Foods 37,
421–430. 138–146.
Karashima, M., Kimoto, K., Yamamoto, K., Kojima, T., Ikeda, Y., 2016. A novel solubili- Luo, C., Liang, W., Chen, X., Wang, J., Deng, Z., Zhang, H., 2018. Pharmaceutical co-
zation technique for poorly soluble drugs through the integration of nanocrystal and crystals of naringenin with improved dissolution performance. CrystEngComm 20,
cocrystal technologies. Eur. J. Pharm. Biopharm. 107, 142–150. 3025–3033.
Kawabata, Y., Wada, K., Nakatani, M., Yamada, S., Onoue, S., 2011. Formulation design Luo, Y., Chen, S., Zhou, J., Chen, J., Tian, L., Gao, W., Zhang, Y., Ma, A., Li, L., Zhou, Z.,
for poorly water-soluble drugs based on biopharmaceutics classification system: basic 2019. Luteolin cocrystals: characterization, evaluation of solubility, oral bioavail-
approaches and practical applications. Int. J. Pharm. 420, 1–10. ability and theoretical calculation. J. Drug Deliv. Sci. Technol. 50, 248–254.
Ken, V., Kubisch, J., Sedmera, P., Halada, P., Pikrylová, V., Jegorov, A., Cvak, L., Lv, T., Yu, T., Fang, Y., Zhang, S., Jiang, M., Zhang, H., Zhang, Y., Li, Z., Chen, H., Gao, Y.,
Gebhardt, R., Ulrichová, J., Šimánek, V., 1997. Glycosylation of silybin. J. Chem. Soc. 2017. Role of generation on folic acid-modified poly(amidoamine) dendrimers for
Perkin Trans. 1, 2467–2474. targeted delivery of baicalin to cancer cells. Mat. Sci. Eng. C Biol. Appl. 75, 182–190.
Khan, A.W., Kotta, S., Ansari, S.H., Sharma, R.K., Ali, J., 2015. Enhanced dissolution and Ma, T., Dai, Y.Q., Li, N., Huo, Q., Li, H.M., Zhang, Y.X., Piao, Z.H., Wu, C.Z., 2017.
bioavailability of grapefruit flavonoid naringenin by solid dispersion utilizing fourth Enzymatic biosynthesis of novel neobavaisoflavone glucosides via Bacillus UDP-gly-
generation carrier. Drug Dev. Ind. Pharm. 41, 772–779. cosyltransferase. Chin. J. Nat. Med. 15, 281–287.
Khan, J., Alexander, A., Ajazuddin, Saraf, S., Saraf, S., 2013. Recent advances and future Mahadevan, S., Park, Y., 2008. Multifaceted therapeutic benefits of Ginkgo biloba L.:
prospects of phyto-phospholipid complexation technique for improving pharmaco- chemistry, efficacy, safety, and uses. J. Food Sci. 73, R14–R19.
kinetic profile of plant actives. J. Control. Release 168, 50–60. Mekjaruskul, C., Yang, Y.T., Leed, M.G., Sadgrove, M.P., Jay, M., Sripanidkulchai, B.,
Khan, J., Alexander, A., Ajazuddin, Saraf, S., Saraf, S., 2014. Luteolin-phospholipid 2013. Novel formulation strategies for enhancing oral delivery of methoxyflavones in
complex: preparation, characterization and biological evaluation. J. Pharm. Kaempferia parviflora by SMEDDS or complexation with 2-hydroxypropyl-β-cyclo-
Pharmacol. 66, 1451–1462. dextrin. Int. J. Pharm. 445, 1–11.
Khan, J., Saraf, S., Saraf, S., 2016. Preparation and evaluation of luteolin-phospholipid Middleton, E.J., Kandaswami, C., Theoharides, T.C., 2000. The effects of plant flavonoids
complex as an effective drug delivery tool against GalN/LPS induced liver damage. on mammalian cells: implications for inflammation, heart disease, and cancer.
Pharm. Dev. Technol. 21, 475–486. Pharmacol. Rev. 52, 673–751.
Kim, M.K., Oh, Y.M., Park, K., Chong, Y., 2009a. A novel prodrug of quercetin, 3-N, N- Mohammadian, F., Pilehvar-Soltanahmadi, Y., Mofarrah, M., Dastani-Habashi, M.,
dimethyl carbamoyl quercetin (DCQ), with improved stability against hydrolysis in Zarghami, N., 2016. Down regulation of miR-18a, miR-21 and miR-221 genes in
cell culture medium. Bull. Korean Chem. Soc. 30, 2114–2116. gastric cancer cell line by chrysin-loaded PLGA-PEG nanoparticles. Artif. Cells
Kim, M.K., Park, K.S., Yeo, W.S., Choo, H., Chong, Y., 2009b. In vitro solubility, stability Nanomed. Biotechnol. 44, 1972–1978.
and permeability of novel quercetin-amino acid conjugates. Bioorg. Med. Chem. 17, Morand, C., Manach, C., Crespy, V., Remesy, C., 2000. Respective bioavailability of
1164–1171. quercetin aglycone and its glycosides in a rat model. BioFactors 12, 169–174.
Kometani, T., Nishimura, T., Nakae, T., Takii, H., Okada, S., 1996. Synthesis of neohe- Mukund, V., Mukund, D., Sharma, V., Mannarapu, M., Alam, A., 2017. Genistein: its role
speridin glycosides and naringin glycosides by cyclodextrin glucanotransferase from in metabolic diseases and cancer. Crit. Rev. Oncol. Hematol. 119, 13–22.
an Alkalophilic Bacillus Species. Biosci. Biotechnol. Biochem. 60, 645–649. Mureşan-Pop, M., Chiriac, L.B., Martin, F., Simon, S., 2016. Novel nutraceutical Myricetin
Kosina, P., Křen, V., Gebhardt, R., Grambal, F., Ulrichová, J., Walterová, D., 2002. composite of enhanced dissolution obtained by co-crystallization with acetamide.
Antioxidant properties of silybin glycosides. Phytother. Res. 16 (Suppl. 1), S33–S39. Compos. B Eng. 89, 60–66.
Kumar, S., Pandey, A.K., 2013. Chemistry and biological activities of flavonoids: an Ng, C.L., Lee, S.E., Lee, J.K., Kim, T.H., Jang, W.S., Choi, J.S., Kim, Y.H., Kim, J.K., Park,
overview. Sci. World J. 2013, 162750. J.S., 2016. Solubilization and formulation of chrysosplenol C in solid dispersion with
LeCluyse, E.L., Sutton, S.C., 1997. In vitro models for selection of development candi- hydrophilic carriers. Int. J. Pharm. 512, 314–321.
dates. Permeability studies to define mechanisms of absorption enhancement. Adv. Ninomiya, M., Tanaka, K., Tsuchida, Y., Muto, Y., Koketsu, M., Watanabe, K., 2011.
Drug Deliv. Rev. 23, 163–183. Increased bioavailability of tricin-amino acid derivatives via a prodrug approach. J.
Leuner, C., Dressman, J., 2000. Improving drug solubility for oral delivery using solid Med. Chem. 54, 1529–1536.
dispersions. Eur. J. Pharm. Biopharm. 50, 47–60. Nishijima, T., Iwai, K., Saito, Y., Takida, Y., Matsue, H., 2009. Chronic ingestion of apple
Li, D., Park, J.H., Park, J.T., Park, C.S., Park, K.H., 2004a. Biotechnological production of pectin can enhance the absorption of quercetin. J. Agric. Food Chem. 57, 2583–2587.
highly soluble daidzein glycosides using Thermotoga maritima maltosyltransferase. J. Otake, Y., Hsieh, F., Walle, T., 2002. Glucuronidation versus oxidation of the flavonoid
Agric. Food Chem. 52, 2561–2567. galangin by human liver microsomes and hepatocytes. Drug Metab. Dispos. 30,
Li, D., Park, S.H., Shim, J.H., Lee, H.S., Tang, S.Y., Park, C.S., Park, K.H., 2004b. In vitro 576–581.
enzymatic modification of puerarin to puerarin glycosides by maltogenic amylase. Pan, C., Cao, X., Tang, L., Zhang, Y., He, H., Yin, T., Piao, H., Tang, X., 2018. Phospholipid
Carbohydr. Res. 339, 2789–2797. complex of ICA and ICA II prepared by wet media milling for improving bioavail-
Li, D., Roh, S.A., Shim, J.H., Mikami, B., Baik, M.Y., Park, C.S., Park, K.H., 2005. ability. Eur. J. Lipid Sci. Technol. 120, 1700317.
Glycosylation of genistin into soluble inclusion complex form of cyclic glucans by Pangeni, R., Kang, S.W., Oak, M., Park, E.Y., Park, J.W., 2017. Oral delivery of quercetin
enzymatic modification. J. Agric. Food Chem. 53, 6516–6524. in oil-in-water nanoemulsion: in vitro characterization and in vivo anti-obesity effi-
Li, F.Q., Hu, J.H., 2004. Improvement of the dissolution rate of silymarin by means of cacy in mice. J. Funct. Foods 38, 571–581.
solid dispersions. Chem. Pharm. Bull. (Tokyo) 52, 972–973. Park, J.H., Ku, H.J., Kim, J.K., Park, J.W., Lee, J.H., 2018. Amelioration of high fructose-
Li, H., Zhao, X., Ma, Y., Zhai, G., Li, L., Lou, H., 2009. Enhancement of gastrointestinal induced cardiac hypertrophy by naringin. Sci. Rep. 8, 9464.
absorption of quercetin by solid lipid nanoparticles. J. Control. Release 133, Parveen, R., Baboota, S., Ali, J., Ahuja, A., Vasudev, S.S., Ahmad, S., 2011. Oil based
238–244. nanocarrier for improved oral delivery of silymarin: in vitro and in vivo studies. Int.
Li, H.B., Jiang, Y., Chen, F., 2004c. Separation methods used for Scutellaria baicalensis J. Pharm. 413, 245–253.
active components. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 812, Patra, A., Satpathy, S., Shenoy, A.K., Bush, J.A., Kazi, M., Hussain, M.D., 2018.
277–290. Formulation and evaluation of mixed polymeric micelles of quercetin for treatment of
Li, L., Fu, Q., Xia, M., Xin, L., Shen, H., Li, G., Ji, G., Meng, Q., Xie, Y., 2018a. Inhibition of breast, ovarian, and multidrug resistant cancers. Int. J. Nanomed. 13, 2869–2881.
P-glycoprotein mediated efflux in Caco-2 cells by phytic acid. J. Agric. Food Chem. Pavanato, A., Tuñón, M.J., Sánchez-Campos, S., Marroni, C.A., Llesuy, S., González-
66, 988–998. Gallego, J., Marroni, N., 2003. Effects of quercetin on liver damage in rats with
Li, N., Miao, J., Li, J., Zhao, Y.R., Li, H.M., Dai, Y.Q., Huo, Q., Wu, C.Z., Ma, T., 2017. carbon tetrachloride-induced cirrhosis. Dig. Dis. Sci. 48, 824–829.
Enzymatic synthesis of novel corylifol A glucosides via a UDP-glycosyltransferase. Peng, Y., Deng, Z., Wang, C., 2008. Preparation and prodrug studies of quercetin pen-
Carbohydr. Res. 446–447, 61–67. tabenzensulfonate. Yakugaku Zasshi 128, 1845–1849.

19
J. Zhao, et al. International Journal of Pharmaceutics 570 (2019) 118642

Pinho, E., Grootveld, M., Soares, G., Henriques, M., 2014. Cyclodextrins as encapsulation silymarin flavonolignans: drug formulations and biotransformation. Phytochem. Rev.
agents for plant bioactive compounds. Carbohydr. Polym. 101, 121–135. 13, 1–18.
Pleguezuelos-Villa, M., Mir-Palomo, S., Diez-Sales, O., Buso, M., Sauri, A.R., Nacher, A., Thilakarathna, S.H., Rupasinghe, H.P., 2013. Flavonoid bioavailability and attempts for
2018. A novel ultradeformable liposomes of naringin for anti-inflammatory therapy. bioavailability enhancement. Nutrients 5, 3367–3387.
Colloids. Surf. B Biointerfaces 162, 265–270. Tian, X.J., Yang, X.W., Yang, X., Wang, K., 2009. Studies of intestinal permeability of 36
Qian, J., Meng, H., Xin, L., Xia, M., Shen, H., Li, G., Xie, Y., 2017. Self-nanoemulsifying flavonoids using Caco-2 cell monolayer model. Int. J. Pharm. 367, 58–64.
drug delivery systems of myricetin: formulation development, characterization, and Ting, Y., Jiang, Y., Lan, Y., Xia, C., Lin, Z., Rogers, M.A., Huang, Q., 2015. Viscoelastic
in vitro and in vivo evaluation. Colloids Surf. B Biointerfaces 160, 101–109. emulsion improved the bioaccessibility and oral bioavailability of crystalline com-
Qian, Y.S., Ramamurthy, S., Candasamy, M., Shadab, M., Kumar, R.H., Meka, V.S., 2016. pound: a mechanistic study using in vitro and in vivo models. Mol. Pharm. 12,
Production, characterization and evaluation of kaempferol nanosuspension for im- 2229–2236.
proving oral bioavailability. Curr. Pharm. Biotechnol. 17, 549–555. Tran, T.H., Guo, Y., Song, D., Bruno, R.S., Lu, X., 2014. Quercetin-containing self-na-
Qiao, L., Sun, Y., Chen, R., Fu, Y., Zhang, W., Li, X., Chen, J., Shen, Y., Ye, X., 2014. noemulsifying drug delivery system for improving oral bioavailability. J. Pharm. Sci.
Sonochemical effects on 14 flavonoids common in citrus: relation to stability. PLoS 103, 840–852.
One 9, e87766. Tzeng, C.W., Tzeng, W.S., Lin, L.T., Lee, C.W., Yen, F.L., Lin, C.C., 2016. Enhanced au-
Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Jarvinen, T., Savolainen, J., tophagic activity of artocarpin in human hepatocellular carcinoma cells through
2008. Prodrugs: design and clinical applications. Nat. Rev. Drug Discov. 7, 255–270. improving its solubility by a nanoparticle system. Phytomedicine 23, 528–540.
Rawat, D.S., Thakur, B.K., Semalty, M., Semalty, A., Badoni, P., Rawat, M.S.M., 2013. Virtanen, J.A., Cheng, K.H., Somerharju, P., 1998. Phospholipid composition of the
Baicalein phospholipid complex: a novel drug delivery technology for phytother- mammalian red cell membrane can be rationalized by a superlattice model. Proc.
apeutics. Curr. Drug Discov. Technol. 10, 224–232. Natl. Acad. Sci. U.S.A 95, 4964–4969.
Ren, S., Liu, M., Hong, C., Li, G., Sun, J., Wang, J., Zhang, L., Xie, Y., 2019. The effects of Wang, G., Wang, J.J., Li, F., To, S.S., 2016a. Development and evaluation of a novel drug
pH, surfactant, ion concentration, coformer, and molecular arrangement on the so- delivery: pluronics/SDS mixed micelle loaded with myricetin in vitro and in vivo. J.
lubility behavior of myricetin cocrystals. Acta. Pharm. Sin. B 9, 59–73. Pharm. Sci. 105, 1535–1543.
Rüfer, C.E., Bub, A., Möseneder, J., Winterhalter, P., Stürtz, M., Kulling, S.E., 2008. Wang, H., Cui, Y., Fu, Q., Deng, B., Li, G., Yang, J., Wu, T., Xie, Y., 2015a. A phospholipid
Pharmacokinetics of the soybean isoflavone daidzein in its aglycone and glucoside complex to improve the oral bioavailability of flavonoids. Drug Dev. Ind. Pharm. 41,
form: a randomized, double-blind, crossover study. Am. J. Clin. Nutr. 87, 1314–1323. 1693–1703.
Samir, A., Elgamal, B.M., Gabr, H., Sabaawy, H.E., 2015. Nanotechnology applications in Wang, W., Kang, Q., Liu, N., Zhang, Q., Zhang, Y., Li, H., Zhao, B., Chen, Y., Lan, Y., Ma,
hematological malignancies (Review). Oncol. Rep. 34, 1097–1105. Q., Wu, Q., 2015b. Enhanced dissolution rate and oral bioavailability of Ginkgo bi-
Savic, I.M., Nikolic, V.D., Savic-Gajic, I., Nikolic, L.B., Radovanovic, B.C., Mladenovic, loba extract by preparing solid dispersion via hot-melt extrusion. Fitoterapia 102,
J.D., 2015. Investigation of properties and structural characterization of the quercetin 189–197.
inclusion complex with (2-hydroxypropyl)-β-cyclodextrin. J. Incl. Phenom. Macro. Wang, W., Sun, C., Mao, L., Ma, P., Liu, F., Yang, J., Gao, Y., 2016b. The biological
82, 383–394. activities, chemical stability, metabolism and delivery systems of quercetin: a review.
Semalty, A., Tanwar, Y.S., Semalty, M., 2013. Preparation and characterization of cy- Trends Food Sci. Technol. 56, 21–38.
clodextrin inclusion complex of naringenin and critical comparison with phospho- Wang, Y., Yan, Y., Cui, J., Hosta-Rigau, L., Heath, J.K., Nice, E.C., Caruso, F., 2010.
lipid complexation for improving solubility and dissolution. J. Therm. Aanl. Calorim. Encapsulation of water-insoluble drugs in polymer capsules prepared using meso-
115, 2471–2478. porous silica templates for intracellular drug delivery. Adv. Mater. 22, 4293–4297.
Jin, S.Y., Han, J., Jin, S.X., Lv, Q.Y., Bat, J.X., Chen, H.G., Li, R.S., Wu, W., Yuan, H.L., Wedick, N.M., Pan, A., Cassidy, A., Rimm, E.B., Sampson, L., Rosner, B., Willett, W., Hu,
2014. Characterization and evaluation in vivo of baicalin-nanocrystals prepared by F.B., Sun, Q., van Dam, R.M., 2012. Dietary flavonoid intakes and risk of type 2
an ultrasonic-homogenization-fluid bed drying method. Chin. J. Nat. Med. 12, 71–80. diabetes in US men and women. Am. J. Clin. Nutr. 95, 925–933.
Shimizu, R., Shimabayashi, H., Moriwaki, M., 2014. Enzymatic production of highly so- Wei, Y., Guo, J., Zheng, X., Wu, J., Zhou, Y., Yu, Y., Ye, Y., Zhang, L., Zhao, L., 2014.
luble myricitrin glycosides using β-Galactosidase. Biosci. Biotechnol. Biochem. 70, Preparation, pharmacokinetics and biodistribution of baicalin-loaded liposomes. Int.
940–948. J. Nanomed. 9, 3623–3630.
Shpigelman, A., Shoham, Y., Israeli-Lev, G., Livney, Y.D., 2014. β-lactoglobulin-nar- Wei, Y., Zhang, J., Memon, A.H., Liang, H., 2017. Molecular model and in vitro anti-
ingenin complexes: nano-vehicles for the delivery of a hydrophobic nutraceutical. oxidant activity of a water-soluble and stable phloretin/hydroxypropyl-β-cyclodex-
Food Hydrocolloid. 40, 214–224. trin inclusion complex. J. Mol. Liq. 236, 68–75.
Singh, D., Rawat, M.S., Semalty, A., Semalty, M., 2012a. Quercetin-phospholipid com- Wen, J., Liu, B., Yuan, E., Ma, Y., Zhu, Y., 2010. Preparation and physicochemical
plex: an amorphous pharmaceutical system in herbal drug delivery. Curr. Drug properties of the complex of naringenin with hydroxypropyl-β-cyclodextrin.
Discov. Technol. 9, 17–24. Molecules 15, 4401–4407.
Singh, D., Rawat, M.S., Semalty, A., Semalty, M., 2012b. Rutin-phospholipid complex: an Williams, H.D., Trevaskis, N.L., Charman, S.A., Shanker, R.M., Charman, W.N., Pouton,
innovative technique in novel drug delivery system-NDDS. Curr. Drug Deliv. 9, C.W., Porter, C.J.H., 2013. Strategies to address low drug solubility in discovery and
305–314. development. Pharmacol. Rev. 65, 315–499.
Singh, H., Singh, S., Srivastava, A., Tandon, P., Bharti, P., Kumar, S., Maurya, R., 2014. Wu, J., Chen, D., Zhang, R., 1999. Study on the bioavailability of baicalin-phospholipid
Conformational analysis and vibrational study of daidzein by using FT-IR and FT- complex by using HPLC. Biomed. Chromatogr. 13, 493–495.
Raman spectroscopies and DFT calculations. Spectrochim. Acta A Mol. Biomol. Wu, L., Bi, Y., Wu, H., 2018. Formulation optimization and the absorption mechanisms of
Spectrosc. 120, 405–415. nanoemulsion in improving baicalin oral exposure. Drug Dev. Ind. Pharm. 44,
Singh, M.K., Pooja, D., Ravuri, H.G., Gunukula, A., Kulhari, H., Sistla, R., 2018. 266–275.
Fabrication of surfactant-stabilized nanosuspension of naringenin to surpass its poor Xiang, D., Wang, C.G., Wang, W.Q., Shi, C.Y., Xiong, W., Wang, M.D., Fang, J.G., 2017.
physiochemical properties and low oral bioavailability. Phytomedicine 40, 48–54. Gastrointestinal stability of dihydromyricetin, myricetin, and myricitrin: an in vitro
Slámová, K., Kapešová, J., Valentová, K., 2018. “Sweet Flavonoids”: glycosidase-cata- investigation. Int. J. Food Sci. Nutr. 68, 704–711.
lyzed modifications. Int. J. Mol. Sci. 19, 2126. Xiao, J., Cao, H., Wang, Y., Zhao, J., Wei, X., 2009. Glycosylation of dietary flavonoids
Smith, A.J., Kavuru, P., Wojtas, L., Zaworotko, M.J., Shytle, R.D., 2011. Cocrystals of decreases the affinities for plasma protein. J. Agric. Food Chem. 57, 6642–6648.
quercetin with improved solubility and oral bioavailability. Mol. Pharm. 8, Xiao, J., Muzashvili, T.S., Georgiev, M.I., 2014. Advances in the biotechnological glyco-
1867–1876. sylation of valuable flavonoids. Biotechnol. Adv. 32, 1145–1156.
So, F.V., Guthrie, N., Chambers, A.F., Moussa, M., Carroll, K.K., 1996. Inhibition of Xiao, L., Yi, T., Chen, M., Lam, C.W., Zhou, H., 2016. A new mechanism for increasing the
human breast cancer cell proliferation and delay of mammary tumorigenesis by oral bioavailability of scutellarin with Cremophor EL: activation of MRP3 with con-
flavonoids and citrus juices. Nutr. Cancer 26, 167–181. current inhibition of MRP2 and BCRP. Eur. J. Pharm. Sci. 93, 456–467.
Stella, V.J., Nti-Addae, K.W., 2007. Prodrug strategies to overcome poor water solubility. Xie, Y., Li, G., Yuan, X., Cai, Z., Rong, R., 2009. Preparation and in vitro evaluation of
Adv. Drug Deliv. Rev. 59, 677–694. solid dispersions of total flavones of Hippophae rhamnoides L. AAPS PharmSciTech
Sun, M., Nie, S., Pan, X., Zhang, R., Fan, Z., Wang, S., 2014. Quercetin-nanostructured 10, 631–640.
lipid carriers: characteristics and anti-breast cancer activities in vitro. Colloids Surf. B Xie, Y., Luo, H., Duan, J., Hong, C., Ma, P., Li, G., Zhang, T., Wu, T., Ji, G., 2014. Phytic
Biointerfaces 113, 15–24. acid enhances the oral absorption of isorhamnetin, quercetin, and kaempferol in total
Suvarna, V., Gujar, P., Murahari, M., 2017. Complexation of phytochemicals with cy- flavones of Hippophae rhamnoides L. Fitoterapia 93, 216–225.
clodextrin derivatives-an insight. Biomed. Pharmacother. 88, 1122–1144. Xie, Y., Zeng, X., Li, G., Cai, Z., Ding, N., Ji, G., 2010. Assessment of intestinal absorption
Tan, M.E., He, C.H., Jiang, W., Zeng, C., Yu, N., Huang, W., Gao, Z.G., Xing, J.G., 2017a. of total flavones of Hippophae rhamnoides L. in rat using in situ absorption models.
Development of solid lipid nanoparticles containing total flavonoid extract from Drug Dev. Ind. Pharm. 36, 787–794.
Dracocephalum moldavica L. and their therapeutic effect against myocardial Xu, W., Ling, P., Zhang, T., 2013. Polymeric micelles, a promising drug delivery system to
ischemia-reperfusion injury in rats. Int. J. Nanomed. 12, 3253–3265. enhance bioavailability of poorly water-soluble drugs. J. Drug Deliv. 2013, 1–15.
Tan, Z., Cheng, J., Liu, Q., Zhou, L., Kenny, J., Wang, T., Lin, X., Yuan, J., Quinn, J.M.W., Yang, L.J., Xia, S., Ma, S.X., Zhou, S.Y., Zhao, X.Q., Wang, S.H., Li, M.Y., Yang, X.D., 2016.
Tickner, J., Hong, G., Qin, A., Zhao, J., Xu, J., 2017b. Neohesperidin suppresses os- Host-guest system of hesperetin and β-cyclodextrin or its derivatives: preparation,
teoclast differentiation, bone resorption and ovariectomised-induced osteoporosis in characterization, inclusion mode, solubilization and stability. Mat. Sci. Eng. C Biol.
mice. Mol. Cell. Endocrinol. 439, 369–378. Appl. 59, 1016–1024.
Teixeira, M.C., Carbone, C., Souto, E.B., 2017. Beyond liposomes: recent advances on Yang, X., Miao, X., Cao, F., Li, S., Ai, N., Chang, Q., Lee, S.M.Y., Zheng, Y., 2014.
lipid based nanostructures for poorly soluble/poorly permeable drug delivery. Prog. Nanosuspension development of scutellarein as an active and rapid orally absorbed
Lipid Res. 68, 1–11. precursor of its BCS class IV glycoside scutellarin. J. Pharm. Sci. 103, 3576–3584.
Thanou, M., Verhoef, J.C., Junginger, H.E., 2001. Chitosan and its derivatives as in- Yao, Y., Lin, G., Xie, Y., Ma, P., Li, G., Meng, Q., Wu, T., 2014a. Preformulation studies of
testinal absorption enhancers. Adv. Drug Deliv. Rev. 50, S91–S101. myricetin: a natural antioxidant flavonoid. Pharmazie 69, 19–26.
Theodosiou, E., Purchartová, K., Stamatis, H., Kolisis, F., Křen, V., 2014. Bioavailability of Yao, Y., Xia, M., Wang, H., Li, G., Shen, H., Ji, G., Meng, Q., Xie, Y., 2016. Preparation and

20
J. Zhao, et al. International Journal of Pharmaceutics 570 (2019) 118642

evaluation of chitosan-based nanogels/gels for oral delivery of myricetin. Eur. J. phospholipid complexes of total flavonoids from Persimmon (Diospyros kaki L.)
Pharm. Sci. 91, 144–153. leaves on experimental atherosclerosis rats. J. Ethnopharmacol. 191, 245–253.
Yao, Y., Xie, Y., Hong, C., Li, G., Shen, H., Ji, G., 2014b. Development of a myricetin/ Zhang, Q.F., Nie, H.C., Shangguang, X.C., Yin, Z.P., Zheng, G.D., Chen, J.G., 2013.
hydroxypropyl-β-cyclodextrin inclusion complex: preparation, characterization, and Aqueous solubility and stability enhancement of astilbin through complexation with
evaluation. Carbohydr. Polym. 110, 329–337. cyclodextrins. J. Agric. Food Chem. 61, 151–156.
Youdim, K.A., Joseph, J.A., 2001. A possible emerging role of phytochemicals in im- Zhang, S., Wang, J., Pan, J., 2016c. Baicalin-loaded PEGylated lipid nanoparticles:
proving age-related neurological dysfunction: a multiplicity of effects. Free Radic. characterization, pharmacokinetics, and protective effects on acute myocardial
Biol. Med. 30, 583–594. ischemia in rats. Drug Deliv. 23, 3696–3703.
Yu, H., Chang, J.S., Kim, S.Y., Kim, Y.G., Choi, H.K., 2017. Enhancement of solubility and Zhang, X.P., Zhang, J., Song, Q.L., Chen, H.Q., 2007. Mechanism of acute pancreatitis
dissolution rate of baicalein, wogonin and oroxylin A extracted from Radix scu- complicated with injury of intestinal mucosa barrier. J. Zhejiang Univ. Sci. B 8,
tellariae. Int. J. Pharm. 528, 602–610. 888–895.
Yue, P.F., Yuan, H.L., Xie, H., Xiao, X.H., Yang, M., Liao, M.X., Zhu, W.F., Cai, P.L., 2008. Zhang, Y.N., Yin, H.M., Zhang, Y., Zhang, D.J., Su, X., Kuang, H.X., 2017a. Cocrystals of
Preparation, characterization, and bioavailability of ursodeoxycholic acid-phospho- kaempferol, quercetin and myricetin with 4,4′-bipyridine: crystal structures, analyses
lipid complex in vivo. Drug Dev. Ind. Pharm. 34, 708–718. of intermolecular interactions and antibacterial properties. J. Mol. Struct. 1130,
Zhang, H., Mi, J., Huo, Y., Huang, X., Xing, J., Yamamoto, A., Gao, Y., 2014a. Absorption 199–207.
enhancing effects of chitosan oligomers on the intestinal absorption of low molecular Zhang, Y.N., Yin, H.M., Zhang, Y., Zhang, D.J., Su, X., Kuang, H.X., 2017b. Preparation of
weight heparin in rats. Int. J. Pharm. 466, 156–162. a 1:1 cocrystal of genistein with 4,4′-bipyridine. J. Cryst. Growth 458, 103–109.
Zhang, H., Zhao, L., Chu, L., Han, X., Zhai, G., 2014b. Preparation, optimization, char- Zhao, B., Gu, S., Du, Y., Shen, M., Liu, X., Shen, Y., 2018. Solid lipid nanoparticles as
acterization and cytotoxicity in vitro of baicalin-loaded mixed micelles. J. Colloid carriers for oral delivery of hydroxysafflor yellow A. Int. J. Pharm. 535, 164–171.
Interface Sci. 434, 40–47. Zhao, L., Wei, Y., Huang, Y., He, B., Zhou, Y., Fu, J., 2013. Nanoemulsion improves the
Zhang, J.Q., Jiang, K.M., An, K., Ren, S.H., Xie, X.G., Jin, Y., Lin, J., 2015a. Novel water- oral bioavailability of baicalin in rats: in vitro and in vivo evaluation. Int. J.
soluble fisetin/cyclodextrins inclusion complexes: preparation, characterization, Nanomed. 8, 3769–3779.
molecular docking and bioavailability. Carbohydr. Res. 418, 20–28. Zhou, M., Zhang, R.H., Wang, M., Xu, G.B., Liao, S.G., 2017. Prodrugs of triterpenoids and
Zhang, K., Gu, L., Chen, J., Zhang, Y., Jiang, Y., Zhao, L., Bi, K., Chen, X., 2015b. their derivatives. Eur. J. Med. Chem. 131, 222–236.
Preparation and evaluation of kaempferol-phospholipid complex for pharmacoki- Zu, Y., Wu, W., Zhao, X., Li, Y., Wang, W., Zhong, C., Zhang, Y., Zhao, X., 2014a.
netics and bioavailability in SD rats. J. Pharm. Biomed. Anal. 114, 168–175. Enhancement of solubility, antioxidant ability and bioavailability of taxifolin nano-
Zhang, K., Zhang, M., Liu, Z., Zhang, Y., Gu, L., Hu, G., Chen, X., Jia, J., 2016a. particles by liquid antisolvent precipitation technique. Int. J. Pharm. 471, 366–376.
Development of quercetin-phospholipid complex to improve the bioavailability and Zu, Y., Wu, W., Zhao, X., Li, Y., Zhong, C., Zhang, Y., 2014b. The high water solubility of
protection effects against carbon tetrachloride-induced hepatotoxicity in SD rats. inclusion complex of taxifolin-γ-CD prepared and characterized by the emulsion
Fitoterapia 113, 102–109. solvent evaporation and the freeze drying combination method. Int. J. Pharm. 477,
Zhang, K., Zhang, Y., Zhang, M., Gu, L., Liu, Z., Jia, J., Chen, X., 2016b. Effects of 148–158.

21

You might also like