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-
calin were significantly improved 2.98- and 2.14-fold, respectively,
after oral administration of a baicalin-phospholipid complex to rats
compared with baicalin (p < 0.01).
Although the solubility and oral absorption of these bioactive fla-
vonoids in the flavonoid-carrier complexes have been greatly promoted,
some shortcomings in the processes of preparation and storage have
restrained their widespread utility in the pharmaceutical area. In par-
ticular, the limited aqueous solubility of natural CDs and the potential
formation or even precipitation of crystalline complexes in the kidney
would result in low drug loading and encapsulation efficiency, in-
complete degradation of the carrier and nephrotoxicity. To overcome
these obstacles, discovering and employing CD derivatives as novel
carriers of flavonoids is imperative. Additionally, the physical in-
stability of solid dispersions and phospholipid complexes due to the
conversion from the amorphous state to the crystalline state upon sto-
rage severely impeded the enhancement in the dissolution rates of the
flavonoids in these two formulations. Introduction of a surfactant to the
solid dispersion is a viable choice because the combination of the
polymer and surfactant can reduce the molecular mobility and inhibit
recrystallization. Furthermore, the use of high-purity grades of phos-
pholipids is another measure to obtain a stable phospholipid complex of
flavonoids with longer shelf lives, as they could increase the hygro-
scopicity and compatibility of these formulations.
4.2. Nanotechnology
Nanotechnology is defined as the design, production, and applica-
tion of structures, devices, and systems through control of the size and
shape of the material on a nanometer scale (Samir et al., 2015). Na-
notechnology-based drug delivery systems have been widely used for a
long time to diagnose and treat different cancer types by visualizing
tumors and/or delivering therapeutic agents directly to the tumor sites
(Jabir et al., 2012). Owing to the special property of reduced particle
size, these nanosystems have also been applied to tackle the poor
bioavailability issue of various water-insoluble flavonoids by many
pharmaceutical scholars. To provide insight into the application of
these nanoformulations to deliver the active compounds, we summar-
ized the recent progress from the following aspects (shown in Table 3):
(1) the reduction of pure drug particle size, e.g., nanosuspensions, na-
nocrystals; (2) nanometer-scale emulsion droplet encapsulated systems,
e.g., nanoemulsions, self-nanoemulsifying drug delivery systems; and
(3) carrier-based nanoparticle delivery systems, e.g., lipid nano-
particles, polymer micelles, nanogels (Fig. 4).
A nanosuspension, also called a nanocrystal, is defined as a carrier-
free drug delivery system that commonly consists of pure drug particles
and stabilizers with a mean particle size in the nanometer range, ty-
pically between 10 and 1000 nm (Geng et al., 2017). At present, it has
been considered a promising strategy to enhance the oral bioavail-
ability of insoluble active flavonoid components because it can increase
the saturation solubility and dissolution velocity by directly reducing
the particle size of the drugs to the nanometer range and thus enlarging
their surface area. To date, there have been numerous studies on the
enhanced pharmacokinetic properties of many common flavonoid
candidates through the use of nanosuspension technology. As reported
by Singh et al. (2018), the AUC0-12h of naringenin, a bioactive com-
ponent of Citrus aurantium L., in rats after oral administration of its
nanosuspension with a mean particle size of 118 nm was approximately
3.76-fold greater than that of its raw drug suspension. Our research
group also found that the saturation solubility of myricetin in four
different myricetin nanosuspensions (300–500 nm) stabilized with D-α-
tocopheryl polyethylene glycol 1000 succinate (TPGS), soya lecithin,
soya lecithin + TPGS, or HP-β-CD + TPGS, increased from 6.23 mg/mL
for pure myricetin to 399.63, 367.15, 466.28, and 267.90 mg/mL,
which resulted in an increase in the oral relative bioavailability of
myricetin-nanosuspensions in rats of 244%, 357%, 161%, and 296%,
13
respectively (Hong et al., 2014).
Nanoemulsions (NEs), with fine droplet sizes between 1 and
100 nm, are thermodynamically and thermokinetically stable trans-
parent nanodispersions of oil and water stabilized by an interfacial film
of surfactant that are usually used in combination with cosurfactant
molecules (Date et al., 2010). It is noteworthy that by enhancing their
solubility in gastrointestinal fluid, enhancing their permeability
through the intestinal wall, and protecting them from enzymatic de-
gradation in the gastrointestinal tract, these formulations can success-
fully improve the undesirable oral absorption of the poorly water-so-
luble flavonoid compounds. For example, the oral bioavailability of
myricetin in the NE formulation in rats was approximately 14.43 times
higher than that of the native myricetin suspension, probably resulting
from the increased saturation solubility (1225-fold) of myricetin in its
NE (Guo et al., 2016). Nevertheless, a potential drawback of NEs is that
some encapsulated bioactive flavonoid drugs can easily diffuse into the
surrounding water phase because of the relatively low viscosity of the
oil phase, which would lead to the degradation or loss of these com-
ponents (Jafari and McClements, 2017). To overcome this obstacle, a
self-nanoemulsifying drug delivery system (SNEDDS), which is an an-
hydrous homogeneous liquid mixture of oil, surfactant, and cosurfac-
tant, has been proposed to deliver the active ingredients because of
their increased solubilization capacity and stabilizing effect. Based on
this consideration, Qian et al. (2017) prepared four optimized myr-
icetin-SNEDDS formulations, and the AUC0-24h of myricetin in these
SNEDDS formulations improved 5.13-, 6.33-, 4.69- and 2.53-fold after
oral administration to rats compared with crude myricetin. In another
study, the cell permeability of QU in a SNEDDS form increased 23.75-
fold compared to that in its pure form, which caused the oral bioa-
vailability of QU-SNEDDS in rats to be approximately 5-fold greater
than that of QU (Jain et al., 2013).
Lipid-based nanoparticles composed of physiologically acceptable
lipid vehicles have emerged as another feasible drug delivery system
because they can encapsulate large amounts of hydrophobic flavonoid
compounds, thereby enhancing drug solubility, protecting the drug
from degradation in the gastrointestinal tract, and increasing the total
systemic bioavailability via the enhanced permeability and lymphatic
absorption (Ahn and Park, 2016; Teixeira et al., 2017). According to the
physical state (solid and/or liquid) of the lipid materials, the lipid-based
nanoparticles are generally divided into two groups: solid lipid nano-
particles (SLNs) and nanostructured lipid carriers (NLCs). More speci-
fically, by use of SLNs, the submicron particulate drug delivery system
composed of natural or artificial synthetic solid lipids, the dissolution
rate (48 h) of the total flavonoid extract from Dracocephalum moldavica
L. (TFDM) improved from 86.51% for the crude TFDM to 96.23% for its
TFDM-SLNs. (Tan et al., 2017a). In another study, the AUC0-∞ of hy-
droxysafflor yellow A (HSYA) was improved approximately 3.99-fold
after oral administration of a HSYA SLNs to rats compared with HSYA,
which was likely attributable to the reduced hepatic first pass meta-
bolism caused by the lymphatic transport in intestine. Moreover, be-
cause of the presence of liquid lipids in the matrix, NLCs exhibit rela-
tively high intrinsic defects (grain area) in the core compared to those
found in SLNs, which can accommodate more flavonoid molecules and
thus further increase their oral absorption. With regard to this, Aditya
et al. (2014) prepared a novel QU-NLC formulation, which increases the
loading efficiency of QU from 0.6% in the SLN system to 0.9%. Con-
sequently, the oral bioavailability of QU in the NLC form in rats was
approximately 1.71 times higher than that in SLN form.
In recent years, with the ability of targeted and/or controlled/sus-
tained drug release, many biocompatible and biodegradable macro-
molecular materials have been used to encapsulate different types of
poorly soluble flavonoids to form nanoparticles, resulting in their en-
hanced solubility, prolonged retention time, and improved oral ab-
sorption. To date, numerous natural and synthetic macromolecular
substances have been successfully applied in the preparation of flavo-
noid nanoparticles. For example, bovine serum albumin (BSA), a
 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.
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
and developed into a macromolecular material nanoparticle system
with hydrophobic QU, thereby significantly increasing the antioxidant
activity of QU. After 96 h, the half maximal inhibitory concentration
(IC50) of the QU nanoparticles in sodium phosphate buffer was 7.5-fold
less than that of free QU (p < 0.05) (Antônio et al., 2016). Similarly,
Jeong et al. (2013) found that the cytotoxicity of fisetin (a potent
polyphenolic flavonoid from various vegetables and fruits such as cu-
cumber, onion, and apple) against human cervical cancer HeLa cells in
its nanoparticle formulation with the macromolecular material cationic
cyclosophoraose dimer (Cys dimer) was approximately 1.25 times
higher than that of its pure form, probably resulting from the increased
saturation solubility (6.5-fold) of fisetin in its nanoparticles. Further-
more, polymeric micelles, which are self-assembled core–shell nanos-
tructures formed in an aqueous solution consisting of amphiphilic block
copolymers, have also been utilized to strength the potency of poorly
water-soluble flavonoids because their inner hydrophobic core can load
the active compounds, thus improve their stability and bioavailability
(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-
cessed Epimedium koreanum)-loaded micelle by using TPGS, an amphi-
philic derivative of natural vitamin E, as the polymeric carrier, and
reported that the AUC0-∞ and Cmax of baohuoside I were significantly
improved by 5.63- and 2.67-fold, respectively, after oral administration
of the baohuoside I-polymeric micelle to rats compared with baohuo-
side I (p < 0.01).
Overall, although these nanotechnology-based drug delivery sys-
tems offer promising solutions for the formulation of poorly water-so-
luble flavonoids, they are far from optimal due to the serious side ef-
fects, toxicity to healthy tissues and organs caused by off-target
biodistribution and accumulation, and the absorption of the surfactants,
cosurfactants, and emulsifiers, etc. To address these obstacles, the
binding of surface ligands to some specific biological target associated
with pathological tissue is probably an alternative measure to acquire
nanoformulations for hydrophobic flavonoids. Moreover, the in-
troduction of nontoxic and nonmutagenic natural materials, which can
be fully excreted from the body once bioabsorbed, as the excipients is
also highly necessary. In this field, our research group has successfully
16
International Journal of Pharmaceutics 570 (2019) 118642
designed novel myricetin-loaded nanogels/gels with biocompatible
chitosan, which showed an in increase in oral bioavailability (2.20-fold
increase relative to myricetin) and low cytotoxicity (the cell viability
ranged from 90% to 110% after 24 h and 48 h of incubation with
myricetin-loaded nanogels/gels at myricetin concentrations of
41.82 μM and 83.64 μM, respectively) (Yao et al., 2016). Furthermore,
the low encapsulation efficacy and loading capacity of the existing
nanosystems is another severe problem that remains to be solved,
which limits flavonoids from exerting their therapeutic effects ade-
quately. To overcome this major hurdle, the following aspects should be
considered when designing a nanoformulation of these active flavonoid
compounds: (1) choose high surface areas or large pore volumes for the
pharmaceutical excipients as the nanocarriers; (2) reduce the reaction
steps to as few as possible and/or optimize the processing parameters;
and (3) develop carrier-free nanomedicines on the premise of guaran-
teeing a therapeutic effect and function.
4.3. Cocrystals
Pharmaceutical cocrystals are defined as a multicomponent systems
that contain an active pharmaceutical ingredient (API) and cocrystal
coformer (CCF) in a definite stoichiometric ratio held together via
noncovalent interactions such as hydrogen bonds, π-π stacking, and van
der Waals forces (Emami et al., 2018; Karashima et al., 2016). Owing to
the competitive hydrogen bonding sites within a molecular framework,
i.e., donors and acceptors, the poorly water-soluble flavonoid com-
pounds can easily form cocrystals with CCFs, which also contain hy-
drogen bond acceptors and donors, thus improving their physico-
chemical properties without altering their inherent chemical structures.
Currently, a series of flavonoid cocrystals with proper coformers, such
as caffeine, isoniazid, nicotinamide, isonicotinamide, acetamide, 4,4′-
bipyridine, proline, betaine, and theophylline, have been successfully
generated, and some exhibited good solubility, dissolution rate, and
oral bioavailability properties (Cui et al., 2019; Hong et al., 2015; Li
et al., 2018b; Liu et al., 2016b; Luo et al., 2018; Luo et al., 2019;
Mureşan-Pop et al., 2016; Ren et al., 2019; Smith et al., 2011; Zhang
et al., 2017a, b). For instance, the solubility of luteolin in luteolin-iso-
niazid cocrystals improved from 35.1 µg/mL for crude luteolin to
J. Zhao, et al.
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
AUC0-∞ of luteolin in the luteolin-isoniazid cocrystals compared with
crude luteolin (Luo et al., 2019). In addition, our research group pre-
sented the novel strategy of pharmaceutical cocrystal generation by
solution crystallization based on the ternary phase diagram (TPD)
principle (Hong et al., 2015), by which myricetin-proline cocrystals
with a 1:1 stoichiometric ratio were obtained, and the oral bioavail-
ability in rats of myricetin in the myricetin-proline cocrystals was ap-
proximately 3.03 times higher than that of the native myricetin sus-
pension (Liu et al., 2016b). Furthermore, based on the nanotechnology
principle that decreasing the particle size can commonly increase the
dissolution of flavonoids, some pharmaceutical cocrystals have been
prepared as nano-cocrystals to further enhance their solubility. In our
previous research, myricetin-nicotinamide nano-cocrystals (with a
stoichiometric ratio of 1:2) were prepared using a modified solution
method in conjunction with sonochemistry (Fig. 5), in which the
maximum dissolution amount of myricetin was further increased from
33 µg/mL in its cocrystals to 42 µg/mL (Liu et al., 2016a).
Nevertheless, a potential risk of pharmaceutical cocrystals is their
propensity to undergo unintended dissociation because of their weak
intermolecular interactions, which could negate the solubility, dis-
solution, and oral bioavailability advantages conferred by these for-
mations. To avoid this problem, choosing the correct coformer based on
the chemical structure of each flavonoid component is of utmost im-
portance since the physicochemical properties of the cocrystals gen-
erally depend upon those of the coformer that is used. In addition, in-
corporation of hydrophilic silica as the film coating is probably another
strategy to obtain a stable flavonoid cocrystal, as they could reduce the
likelihood of water-mediated cocrystal dissociation during storage.
Furthermore, cocrystals have commonly been prepared through em-
pirical understanding or experimental attempts, which consumes much
time and energy; a much simpler and easier scaled-up synthetic ap-
proach to generate pharmaceutical cocrystals would be helpful to
widen their application in the drug delivery field.
5. Conclusion and prospects
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-
vantages, possible limitations, and oral delivery efficiency. To date,
many formulation approaches, including absorption enhancers, struc-
tural transformation (e.g., prodrugs, glycosylation), and pharmaceu-
tical technologies (e.g., carrier complexes, nanotechnology, cocrystals),
17
International Journal of Pharmaceutics 570 (2019) 118642
have been developed to circumvent the issue of low bioavailability of
active flavonoids by enhancing their solubility and dissolution rate,
increasing their mucosal permeation, preventing their degradation or
metabolism in the gastrointestinal tract and delivering them directly to
the physiological tract. As expected, by using these strategies, the
pharmacokinetic behavior of various flavonoids have been greatly im-
proved, which is beneficial for their pharmaceutical development and
further clinical application.
However, the applications of some formulations to deliver insoluble
flavonoid compounds still suffer from the following challenges: (1) the
physical instability and low drug loading is probably caused by the
required abundance of pharmaceutical adjuvants and/or reaction steps
and the tedious preparation methods, and (2) the undesirable side ef-
fects arise from the nonselective distribution of oral formulations, the
generation of the byproducts, and the incomplete degradation of the
carriers. With regard to this, the following several aspects should be
considered in future studies to break through the barriers and conse-
quently expedite their development.
First, more efforts should be focused on modifying the existing drug
delivery systems for flavonoids by exploring some convenient and safe
techniques and procedures and by using some biocompatible natural ma-
terials or carriers. In addition, more attention should also be paid to sys-
tematically evaluate the potential toxicity of these oral formulations and
determine the relationship between their efficacy and safety to reasonably
guide their effective application. Second, the design of some new drug
delivery systems can be triggered remotely to obtain flexible control of dose
magnitude and timing by combining interdisciplinary knowledge, in-
cluding polymer chemistry, materials science, biology, and pharmacy
might provide feasible to further improve the oral absorption of flavonoid
compounds. Third, many related studies are still kept at the lab level; in this
case, translating laboratory achievements into products and then propelling
the related clinical trial is highly desired. This can be achieved by enhan-
cing the drug payload within the oral formulations, using inexpensive ex-
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-
dies, a bright future can be foreseen for these insoluble active flavonoids for
the effective treatment of various human diseases.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
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.
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