Zhao 2019

International Journal of Pharmaceutics 570 (2019) 118642
Contents lists available at ScienceDirect
International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm
Review
Improvement strategies for the oral bioavailability of poorly water-soluble T

flavonoids: An overview
Juanjuan Zhaoa,b, Jun Yangb, , Yan Xiea,
⁎ ⁎
a
Research Center for Health and Nutrition, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
b
Pharmacy Department, Xiangshan Hospital of Traditional Chinese Medicine, Shanghai 200020, China
ARTICLE INFO ABSTRACT
Chemical compounds studied in this article: Although flavonoid compounds have various pharmacological applications, they generally exhibit low oral
Chitosan (PubChem CID16213812) bioavailability due to their poor aqueous solubility. To address this problem, numerous promising strategies,
Quercetin (PubChem CID5280343) such as the use of an absorption enhancer, structural transformation (e.g., prodrugs, glycosylation), and phar-
Daidzein (PubChem CID5281708) maceutical technologies (e.g., carrier complexes, nanotechnology, cocrystals), have been developed and applied
Isorhamnetin (PubChem CID5281654)
to deliver poorly water-soluble flavonoids. These formulation approaches can effectively improve the oral
Kaempferol (PubChem CID5280863)
bioavailability of flavonoids by enhancing their solubility, dissolution rate and permeability; preventing their
Myricetin (PubChem CID5281672)
β-Cyclodextrin (PubChem CID444041) degradation or metabolism in the gastrointestinal tract; and/or delivering them directly to their physiological
Phytic acid (PubChem CID890) targets. This review comprehensively summarizes the viable oral delivery systems for insoluble flavonoids to
Isoniazid (PubChem CID3767) date and discusses their design principles, potential advantages, possible limitations, and oral delivery efficiency,
Nicotinamide (PubChem CID936) which will provide some useful clues and references to overcome the absorption barrier of these insoluble
flavonoids.
Keywords:
Flavonoids
Oral bioavailability
Absorption enhancers
Structural transformation
Pharmaceutical technologies
1. Introduction naringenin), isoflavones (e.g., daidzein, puerarin), flavonols (e.g.,

myricetin, quercetin (QU), and rutin), anthocyanins (e.g., delphinidin,
Flavonoids represent a group of natural phenolic compounds that cyaniding), and others (Middleton et al., 2000; Thilakarathna and
are characterized by a phenyl benzo (γ) pyrone-derived structure con- Rupasinghe, 2013). These flavonoids are widespread in many herbal
sisting of two benzene rings (A and B) linked via pyrane rings (C) plants and have been proven to be the main active compounds, such as
(Fig. 1) (Cook and Samman, 1996). According to the presence (or ab- in Ginkgo biloba L., Scutellaria baicalensis Georgi, Puerariae lobatae
sence) of a carbonyl at position 4, a double bond between positions 2 Radix, Sea buckthorn, and Crataegus pinnatifida Bge (Chen et al., 2018b;
and 3, or a hydroxyl group at position 3, they are usually subdivided Li et al., 2004c; Liu et al., 2010; Mahadevan and Park, 2008; Xie et al.,
into flavones (e.g., apigenin, chrysin), flavanones (e.g., hesperitin, 2010). As flavonoid compounds possess a wide range of biological
Abbreviations: AUC, Area under the concentration-time curve; AP, Apple pectin; IS, Isorhamnetin; KA, Kaempferol; QU, Quercetin; BCS, Biopharmaceutics
Classification System; IP6, Phytic acid; TFH, Total flavones of Hippophae rhamnoides L.; TJs, Tight junctions; P-gp, P-glycoprotein; TMC, Trimethyl chitosan chloride;
TMC-MEs, Trimethyl chitosan chloride-modified microemulsions; MRT, Mean residence time; Cmax, Maximum plasma concentration; DG, Daidzein-7-O-β-D-gluco-
side; LogP, The apparent lipid/water partition coefficient; QPBS, Pentabenzensulfonate; DCQ, Dimethyl carbamoyl quercetin; 7,8-DHF, 7,8-dihydroxyflavone; CDs,
Cyclodextrins; HP-β-CD, Hydroxyalkylated-β-cyclodextrin; SD, Solid dispersion; PXM, Poloxamer 188; PVP K25, Polyvinylpyrrolidone K25; PEG 6000, Polyethylene
glycol 6000; PCs, Phospholipid complexes; TPGS, D-α-tocopheryl polyethylene glycol 1000 succinate; NEs, Nanoemulsions; SNEDDS, Self-nanoemulsifying drug
delivery system; SLNs, Solid lipid nanoparticles; NLCs, Nanostructured lipid carriers; TFDM, Total flavonoid extract from Dracocephalum moldavica L.; HSYA,
Hydroxysafflor yellow A; BSA, Bovine serum albumin; IC50, Half maximal inhibitory concentration; Cys dimer, Cyclosophoraose dimer; API, Active pharmaceutical
ingredient; CCF, Cocrystal conformer; TPD, Ternary phase diagram
⁎
Corresponding authors at: Pharmacy Department, Xiangshan Hospital of Traditional Chinese Medicine, 528 Fuxing Zhong Road, Shanghai 200020, China (J.
Yang). Research Center for Health and Nutrition, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China (Y. Xie).
E-mail addresses: [email protected] (J. Yang), [email protected] (Y. Xie).
https://doi.org/10.1016/j.ijpharm.2019.118642
Received 30 June 2019; Received in revised form 20 August 2019; Accepted 21 August 2019
Available online 22 August 2019
0378-5173/ © 2019 Elsevier B.V. All rights reserved.
J. Zhao, et al. International Journal of Pharmaceutics 570 (2019) 118642
Over the past several decades, various approaches have been ex-
plored to develop highly efficient drug formulations to enhance the
solubility and/or dissolution rate of poorly soluble drugs and improve
their oral bioavailability, which are more promising means in phar-
macotherapy than the development of new drug entities. In the pre-
formulation research phase, approaches to improve the dissolution
behavior of drug candidates include salt formation, cocrystal formation,
and the utilization of metastable crystalline forms (Kawabata et al.,
2011). Additionally, prodrug approaches might also enhance the aqu-
eous solubility of drug candidates by introducing a polar functional
group into the structure of a molecule (Stella and Nti-Addae, 2007). In
the phase of formulation design, particle size reduction (e.g., micro-
nization, nanosuspension formation, and solid lipid nanoparticle for-
Fig. 1. General chemical structure of flavonoids. mation), complexation/solubilization (e.g., use of surfactants and cy-
clodextrins), drug dispersion in carriers (e.g., solid dispersions and
phospholipid complexes), and mesoporous silica templates are viable
activities, including antioxidant, anti-inflammatory, antitumor, hepa- formulation options to improve the dissolution behavior of poorly
toprotective, antithrombotic, and antiviral properties (Kumar and water-soluble drugs (Leuner and Dressman, 2000; Wang et al., 2010). In
Pandey, 2013), they have gained increasing attention for their ther- addition, for an ionizable drug, enhancing its solubility or dissolution
apeutic effects on cardiovascular disease, diabetes mellitus, Alzheimer's rate through pH adjustment is regarded as a primary strategy (Williams
disease, hepatic cirrhosis, breast cancer, and others (Crowe et al., 2011; et al., 2013). Therefore, these strategies can be used alone or in com-
Havsteen, 2002; Pavanato et al., 2003; So et al., 1996; Wedick et al., bination to revitalize poorly soluble drugs, and many of these strategies
2012; Youdim and Joseph, 2001). Thus, flavonoids are promising have been successfully adopted by pharmaceutical companies.
candidates for new natural drugs and are worthy of further exploration It is noteworthy that the above-mentioned strategies have also been
for their potential role in disease prevention and/or therapy. used to improve the solubility and oral bioavailability of poorly water-
Oral administration is the most popular drug delivery route due to soluble flavonoids and consequently increase their delivery efficiency.
its greater convenience, lower pain, higher patient compliance, reduced Although some flavonoid oral delivery approaches have been discussed
risk of cross-infection, etc. compared to other delivery routes (Das and in previous studies (Cai et al., 2013; Thilakarathna and Rupasinghe,
Chaudhury, 2011). For flavonoids, which generally originate from 2013; Wang et al., 2016b), the present review is intended to provide
many traditional Chinese decoctions, oral administration is also ac- readers with an updated comprehensive catalog of these ongoing ap-
cepted as the main clinical administration method. However, most proaches, with the goal of harnessing the true potential of these agents
flavonoids commonly exhibit the limited oral bioavailability probably in the clinical area. To comprehensively understand the application of
resulting from their poor solubility, low permeability, and inferior these novel strategies in delivering flavonoid compounds, we searched
stability, which severely reduces their effectiveness as the therapeutic and collected related previous reports to date and generalized them
agents. For instance, the double bond between positions 2 and 3 of from the following aspects: absorption enhancers, structural transfor-
flavones and flavonols are amenable to form the planar structures, mations (e.g., prodrugs, glycosylation), and pharmaceutical technolo-
leading to the tight molecular arrangement, and consequently the sol- gies (e.g., carrier complexes, nanotechnology, cocrystals). In addition,
vent molecule is difficult to penetrate their molecule structures (Chuang the design principles, oral delivery efficiency, potential advantages and
et al., 2017; Fukuhara et al., 2002). This caused their low aqueous possible limitations of each technology are discussed as well as the
solubility and poor oral bioavailability, i.e., myricetin, a typical fla- pertinent future challenges and opportunities to deliver poorly water-
vonol with planar structure, has an oral bioavailability in rats of only soluble flavonoids. This work will provide some beneficial references
9.62%, likely owing to its low aqueous solubility of 16.60 μg/mL (Dang for efficiently resolving the low bioavailability issue of these insoluble
et al., 2014; Yao et al., 2014a). flavonoids.
Furthermore, as the excess free hydroxyl groups are easily glucur-
onidated and sulfated in intestine cells and then effluxed by some efflux 2. Absorption enhancers
transporters, the gastrointestinal permeability increased adversely with
the number of hydroxyl groups in a sub class of flavonoids, which ty- Absorption enhancers represent a group of components that can
pically results in their poor and erratic oral absorption (Fang et al., increase the intestinal absorption of pharmacologically active drugs and
2017; Otake et al., 2002; Tian et al., 2009). For instance, the oral therefore improve their oral bioavailability (Ghadiri et al., 2018).
bioavailability of catechin, a main type of flavonoids that can be pre- Currently, adding absorption enhancers has been considered a practical
dominantly found in green tea, chocolate, and grapes, in rats was only and effective method to promote the systemic availability of these
5%, which was ascribed to its poor permeability components since they can afford quick and efficacious plasma drug
(Papp = 6.0 × 10−7 cm/s) because of the 5 phenolic hydroxyl groups in levels in a manner that is rapidly reversible and easy to formulate with
its structure (Ezzat et al., 2019). Hence, to improve the oral bioavail- active pharmaceutical ingredients, which leads to a decreased cost of
ability of these biopharmaceutics classification system (BCS) class II or the final products (Alama et al., 2016; Aungst, 2012). Up until now,
BCS class IV flavonoids, enhancing their saturation solubility and/or fatty acids, bile salts, surfactants, chelating agents, cyclodextrin, and
membrane permeability is necessary. Additionally, due to the hydroxyl chitosan and its derivatives have been used as absorption enhancers to
and ketone groups and unsaturated double bonds, flavonoids are also improve the intestinal absorption of peptides, proteins, or other polar,
sensitive to the diverse physical (e.g., heat, light) and physiological high molecular weight drugs, such as heparin (Aungst, 2000; Aungst
(e.g., digestive enzymes, pH) environment stresses, which probably et al., 1996; Choonara et al., 2014; Zhang et al., 2014a).
leads to degradation or biotransformation during storage and systemic Recently, some absorption enhancers have been successfully de-
circulation, and thus seriously limits their efficacy via oral absorption veloped and employed to increase the oral bioavailability and efficacy
(Qiao et al., 2014; Xiang et al., 2017). With regard to these, it is urgent of poorly absorbable flavonoids by increasing their solubility or gas-
to introduce some effective strategies for the oral delivery of flavonoids trointestinal permeability and preventing their degradation and/or
to overcome the above mentioned problems to fully exert their ther- metabolism. By inhibiting the apical side transporters (MRP2 and
apeutic effects. BCRP) and activating the basolateral side transporter (MRP3), 1 and
2
5 mg/kg Cremophor EL (a nonionic surfactant) can significantly in- As mentioned above, absorption enhancement is a classical and
crease the area under the concentration–time curve (AUC0–12 h) of straightforward approach to overcome the absorption barrier of hy-
scutellarin in rats from 365.71 ± 28.34 ng·h/mL to drophobic flavonoids, while retaining their original chemical compo-
473.26 ± 64.08 ng·h/mL and 587.83 ± 42.45 ng·h/mL (p < 0.05), sition, conformation, and biological activity. An ideal absorption en-
respectively (Xiao et al., 2016). In addition, some natural components hancer should be highly efficient, biocompatible, and biodegradable
that are widely distributed in food (fruits, edible vegetables, cereal, because it needs to arrive at the absorption site together with the drug
nuts, etc.) and crustacean shells exhibit overwhelming advantages in to then work in our body. Nevertheless, when absorption enhancers
enhancing the entry of poorly water-soluble flavonoids from en- transiently disrupt tight junctions, they also help potentially toxic
terocytes into the blood circulation. Nishijima et al (2009) reported that molecules enter the systemic circulation, which likely causes im-
apple pectin (AP, a major type of dietary fiber) significantly enhanced munological issues, systemic endotoxemia, systemic inflammatory re-
the plasma concentration of QU, a typical plant flavonoid that is mainly sponse syndrome, and multiple-organ dysfunction, etc. (LeCluyse and
extracted and isolated from Sophora japonica L., in rats two hours after Sutton, 1997; Zhang et al., 2007). To reduce the possible side effects of
administration, from 3.45 ± 0.67 µM to 5.84 ± 1.60 µM (p < 0.05). absorption enhancers and efficiently enhance the oral bioavailability of
Furthermore, our research group found that the absorption enhance- flavonoid components by this technology, the following measures
ment ratios of isorhamnetin (IS), kaempferol (KA), and QU in rats were should be taken: (1) discover effective and nontoxic components from
3.21, 2.98, and 1.64, respectively, by coadministration of 200 mg/kg natural products as absorption enhancers; (2) systematically evaluate
phytic acid (myo-inositol hexaphosphate, IP6) with the total flavones of the potential toxicity of the absorption enhancer in a preclinical study;
Hippophae rhamnoides L. (TFH) (Xie et al., 2014). The reason for this and (3) determine the mechanism of the absorption enhancer ade-
enhancement is related to the fact that IP6 can increase the solubility of quately to control their concentration and exposure time at the in-
flavonoid components and their permeability through the intestinal testinal epithelial cells.
epithelium by reversibly opening the tight junctions (TJs) between
epithelial cells through downregulation of the distribution of TJ pro-
teins such as occludin, ZO-1, and claudin-1, as well as noncompetitively 3. Structural transformation
inhibit P-glycoprotein (P-gp) by decreasing P-gp ATPase activity and
changing the P-gp molecular conformation (Fig. 2) (Fu et al., 2015; Li It has been reported that some novel derivatives of bioactive natural
et al., 2018a). It was reported that chitosan, a type of nontoxic and compounds created through structural modification have displayed
biocompatible polymer, and its partially quaternized derivative N-tri- many advantages over their parent molecule, such as enhanced bioa-
methyl chitosan chloride (TMC) could facilitate the absorption of vailability and powerful pharmacological activity, which are caused by
macromolecules through the mucosal epithelium by reversibly opening the improved dissolution and stability (Theodosiou et al., 2014). Hy-
TJs (Thanou et al., 2001; Zhang et al., 2014a). On this basis, Liao et al. droxy groups on flavonoids are mainly responsible for their basic an-
(2015) designed TMC-modified microemulsions (TMC-MEs) to further tioxidant biological activity, and these hydroxy groups are also easily
increase the extent of oral absorption of puerarin and prolong its re- transformed into their O-methylated, O-glycosylated, O-sulfated, or O-
sidence time in the blood circulation. The AUC0-12h value and mean acylated forms. So far, some effective prodrugs and glycosylated forms
residence time (MRT0-12h) in the puerarin microemulsions were in- of flavonoid compounds have been obtained to improve the oral bioa-
creased from 0.908 ± 0.169 mg·h/L to 4.184 ± 1.727 mg·h/L and vailability or biological activity of their parent flavonoids.
from 1.953 ± 0.599 h to 2.473 ± 0.730 h, respectively.
Fig. 2. Potential mechanisms of IP6 to enhance the oral absorption of IS, KA, and QU in TFH.
3
Fig. 3. Various strategies for flavonoid glycosylation. This figure is based on one published previously (Xiao et al., 2014).
3.1. Glycosylation of flavonoids of these derivatives is proportional to the degree of glycosylation.

Although an attached sugar moiety on flavonoid molecules can in-
Glycosylation is an important tailoring reaction for the synthesis or crease their solubility and bioavailability, the antioxidant and other
modification of biologically active compounds, which can greatly alter biological activities of the flavonoid are usually suppressed (Slámová
the physicochemical characteristics of hydrophobic compounds such as et al., 2018), possibly resulting from the loss of stereochemical control
flavonoids (Hofer, 2016). Thus far, a range of biochemical and mole- from the glycosyl donor and the generation of the related byproducts.
cular biology tools have been used to glycosylate flavonoid aglycones in To avoid the above issues, the following two aspects should be con-
the laboratory, including chemical synthesis, enzyme pathway manip- sidered for glycosylation modifications of flavonoids: (1) building steric
ulation, and microbial biotransformation (Fig. 3) (Xiao et al., 2014). As hindrance into the glycosyl donor when only one diastereoisomer (α or
expected, by using these approaches, many novel flavonoid glycosides β) for the modified flavonoid is needed and (2) choosing the appro-
have been produced to improve the solubility and oral bioavailability of priate glycosylation approach based on the chemical structure of each
the parent flavonoid and widen their clinical application. As revealed flavonoid component and reducing the reaction steps as much as pos-
by Rüfer et al. (2008), the AUCinf, maximum plasma concentration sible. Moreover, some glycosylated flavonoids also exhibit new bioac-
(Cmax), and cumulative recovery of daidzein in urine after oral ad- tivities, such as anti-HIV, antistress, and antiobesity activities, which
ministration of daidzein-7-O-β-D-glucoside (DG) were 3–6 times greater could be beneficial for the prevention and/or therapy of the related
than the corresponding parameters after the ingestion of daidzein, in- diseases. Thus, further exploration of the biological activity of the novel
dicating that DG exhibited a greater bioavailability than its aglycone. In glycosylated flavonoid and its pharmacokinetic properties is probably
addition, although some flavonoids in nature are commonly found in helpful to screen out some useful flavonoid derivatives and find their
their glycosidic form in which one or more hydroxy group has been new application in human diseases.
replaced by sugar moieties, their pharmacological exploitation is still
limited due to their low bioavailability and poor water solubility (Xiao 3.2. Effective prodrugs of flavonoids
et al., 2009). Therefore, some structural modifications have also been
made to them to solve the above problem. A summary of flavonoid A prodrug is a biologically inactive derivative of a pharmacologi-
glycosylation improving the solubility based on the type of sugar, the cally active agent that elicits its desired pharmacological effect in the
position of the O-linked glycosides, and the glycosylation method are body via an enzymatic and/or chemical transformation into the active
given in Table 1, as well as the solubility change from the flavonoid to parent drug (Rautio et al., 2008). In drug research and development,
the corresponding glycosylated product. It can be easily seen from the prodrug approach has been widely used to enhance the stability,
Table 1 that the solubility of the flavonoid derivatives is probably re- solubility, or lipophilicity of drug candidates by introducing polar
lated to the reacted substrates, the type of sugar moiety, and the functional groups (e.g., sulfuric acids, amino acids, polymers) into the
method and position of O-glycosylation. Moreover, the water solubility structure of a molecule or masking polar ionizable groups, thereby
4
Table 1
Summary of the glycosylation strategy to enhance the solubility of flavonoids based on the type of flavonoid, sugar donors, glycosylation methods, etc.
Types of flavonoids Model flavonoid Source Sugar donor Glycosylated form Glycosylated method Water solubility (μM) Ref.
J. Zhao, et al.
Model flavonoid Glycosylated form
Flavonoid Sophora japonica L Glucose – 3.31 204.57 Morand

aglycones et al.
(2000),
Wang
et al.
(2016b)
Silybum marianum β-glucoside Helferich 891.30 2.69 × 104 Ken et al.

glycosylation; Lewis (1997),
acid catalysis Kosina
et al.
(2002)
5
β-galactoside 3.52 × 103
β-lactosyl 7.88 × 104
β-maltosyl 1.16 × 104

(continued on next page)
Table 1 (continued)
J. Zhao, et al.
Psoraleae corylifolia Glucopyranoside Enzymatic 4.5 787.9 Ma et al.

glycosylation (2017)
18143.5
6
Psoralea corylifolia Glucopyranoside Enzymatic 8.49 128.56 Li et al.
glycosylation (2017)
229.49
Table 1 (continued)
J. Zhao, et al.
Puerariae lobatae Radix Glucoside Microbial 1.25 × 104 2.1 × 105 Jiang
biotransformation et al.
(2008)
Isomaltoside 1.21 × 106
7
Flavonoid Myrica rubra Sieb. et Lactose Enzymatic 2.6 × 102 1 × 106 Shimizu
glycosides Zucc., Vitis vinifera transglycosylate et al.
Linn., and Dioscorea reaction (2014)
bulbifera L.
Citrus extracts Soluble starch Enzymatic 1500 times higher than Kometani
transglycosylate neohesperidin et al.
reaction (1996),
Table 1 (continued)
J. Zhao, et al.
Tan et al.
(2017b)
Grapefruit and related Soluble starch Enzymatic 1000 times higher than naringin Park et al.
citrus species transglycosylate (2018,
reaction Pleguezu-
elos-Villa
et al.
(2018)
Kudzu, Pueraria lobata, Maltosyl Enzymatic 24.71 1.86 × 106 Deng

and Butea monosperma transglycosylate et al.
reaction (2017), Li
et al.
(2004a,
Singh
et al.
(2014)
8
Genista tinctoria, Glucosyl Enzymatic 23 8.4 × 104 Chung
Soybean; Glycine max transglycosylate et al.
reaction (2006), Li
et al.
(2005),
Mukund
et al.
(2017)
1.012 × 106
Puerariae lobatae Radix Soluble starch Enzymatic 1.25 × 104 1.8 × 105 Li et al.
transglycosylate (2004b)
reaction

Table 1 (continued)
J. Zhao, et al.
2.09 × 106
9
increasing oral absorption (Zhou et al., 2017). Additionally, an effective slightly hydrophobic inner surface and a favorable cavity size, cyclo-
prodrug also shows the potential to deliver drugs to their site of action dextrins and their derivatives are easily used to form inclusion com-
by targeting specific enzymes or membrane transporters, which finally plexes with insoluble flavonoids through noncovalent bonds (Fenyvesi
improves the therapeutic index of the parent drug (Abet et al., 2017). et al., 2016). As reported, in addition to the improvement in solubility,
Given the increased water solubility, enhanced absorption, en- CDs protect the bioactive flavonoids from irritants or toxicological ef-
hanced membrane permeability, and stabilizing effects, prodrug stra- fects and hence enhance their shelf-life and reduce the concentration of
tegies have been applied for the improvement of the undesirable the agent required to achieve a biological effect (Pinho et al., 2014).
properties of flavonoid compounds. As reported, the diverse array of Examples of cyclodextrin inclusion complexes that have been used in
prodrugs, such as pentabenzensulfonate (QPBS) and QU-amino acid the oral delivery of poorly water-soluble flavonoids are provided in
conjugates, have been prepared to enhance the solubility, the apparent Table 2, including the types of CDs, the drug/CD ratio, the preparation
lipid/water partition coeffcient (LogP), and half-life of QU, thus im- methods and the solubility and pharmacokinetic parameter improve-
proving its bioavailability and biological efficacy (Kim et al., 2009b; ments of these promising candidates. According to the information
Peng et al., 2008). In another study, 3-N,N-dimethyl carbamoyl QU shown in Table 2, it can be inferred that the pharmaceutical properties
(DCQ) was designed and synthesized by introducing a dimethyl car- of these flavonoid-CD inclusion complexes might be related to the types
bamoyl promoiety at the 3-O position of QU, which showed a re- of carriers, the molar ratio, and the preparation methods of CD com-
markable increase in water solubility (14-fold increase relative to QU) plexation. In this regard, efforts have also been devoted by our research
and cell permeability (1.6-fold higher than that of QU) (Kim et al., group to develop a stable and valid cyclodextrin inclusion complex of
2009a). In addition, the prodrug strategies have also effectively en- flavonoids that exhibits high solubility, effective absorption, and sa-
hanced the oral delivery of other flavonoids with poor solubility and tisfactory therapeutic potential. Specifically, a myricetin/HP-β-CD (a
permeability. A series of tricin-amino acid conjugates, the potential hydroxyalkylated β-cyclodextrin derivative) inclusion complex with a
prodrugs of the flavone tricin, showed an increased plasma con- 1:1 stoichiometric ratio was prepared by the suspension method, which
centration (approximately 45 times higher than for the administration showed an increased oral bioavailability in rats (9.4-fold relative to free
of tricin alone), longer half-life, and higher stability after oral admin- myricetin) due to the increased solubility and dissolution rate of myr-
istration in rats (Ninomiya et al., 2011). Chen et al. (2018a) synthesized icetin in its cyclodextrin formulation (Yao et al., 2014b).
prodrug R13 via a carbamate group modification on the catechol ring of A solid dispersion (SD) is “the dispersion of one or more active in-
7,8-dihydroxyflavone (7,8-DHF), which can be readily hydrolyzed into gredients in an inert carrier or matrix at the solid-state prepared by
7,8-DHF in liver microsomes, that exhibited good absorption in 5XFAD melting (fusion), solvent or the melting-solvent method” (Chiou and
mice (the oral bioavailability of 7,8-DHF increased from 4.6% for the Riegelman, 1971; Damian et al., 2000). This system provides the pos-
parent compound to 10.5% with R13). sibility to reduce the particle size of drugs to nearly a molecular level,
Although the prodrug strategy has been proven to be an effective to transform drugs from the crystalline to the less crystalline or amor-
method for improving the bioavailability of insoluble active flavonoid phous state, as well as to locally increase the saturation solubility and
compounds, intestinal metabolism arising from the enzymatic attack dissolution rate (Damian et al., 2000). Therefore, preparing solid dis-
and chemical degradation before absorption still seriously limits its persion formulations of poorly soluble flavonoids with water-soluble
effectiveness at the site of action. To overcome this shortcoming, Cao polymers is a promising method for increasing their dissolution char-
et al. (2006) prepared an o/w emulsion of the scutellarin prodrug to acteristics and consequently, improving their oral bioavailability. Xie
decrease its degradation rate in the intestinal lumen; the remaining et al. (2009) found that the dissolution rate of TFH in its solid disper-
percent of the scutellarin prodrug after incubation with intestinal sion with the polymeric carrier poloxamer 188 (PXM) was approxi-
contents for 90 min increased from 61.44 ± 6.5% to 79.35 ± 1.2%. mately 3.06 times higher (20 min) than that of the native TFH, probably
However, protection of the metabolically labile but pharmacologically due to the conversion of TFH into a less crystalline and/or amorphous
essential functional groups could also decrease the presystemic meta- form. Similarly, the solubility of chrysosplenol C, a bioactive compo-
bolism of prodrugs and thus enhance their accumulation inside the nent of Miliusa balansae (Annonaceae) and Pterocaulon sphacelatum
target tissues. Moreover, owing to a possible toxic metabolite from the (Asteraceae), was improved from 2.76 ± 0.01 µg/mL in crude chry-
promoiety, the undesirable side effects caused by prodrugs, such as sosplenol C to 31.50 ± 0.16 µg/mL in its solid dispersion with the
gastrointestinal toxicity or liver function damage, should attract sig- binary hydrophilic polymers polyvinylpyrrolidone K25 (PVP K25) and
nificant research attention. Thus, the introduction of an apparently polyethylene glycol 6000 (PEG 6000) (Ng et al., 2016). In addition,
innocuous and nontoxic carrier transport moiety into the parent mo- other powerful examples of the potential utility of solid dispersions for
lecule is necessary when designing a prodrug of flavonoids. improving the water solubility, dissolution, and bioavailability of fla-
vonoid components are presented in Table 2.
4. Pharmaceutical technologies Additionally, more attention has been paid to phospholipid com-
plexation due to its positive impact on the limitations of drugs that are
4.1. Carrier complexation associated with poor water solubility and oral absorption. By forming
drug/phospholipid complexes (PCs) though intermolecular hydrogen
In recent years, the technique of complexing herbal drug molecules bonding and electrostatic attraction, both the solubility and the per-
with different carriers has arisen as a potential drug delivery system for meability of these poorly water-soluble compounds may be increased
improving the bioavailability and therapeutic efficacy of plant extracts/ and the bioavailability thereby improved (Yue et al., 2008). The unique
active compounds with poor absorption, as this technique can deliver structural components of the phospholipid molecules are similar to the
the drug molecules to the physiological target without losing integrity lipid content of the mammalian cell membrane, which makes phos-
or bioactivity (Khan et al., 2013; Pinho et al., 2014). Of these carrier pholipids highly compatible with the human physiological system
complexes, cyclodextrin inclusion complexes, solid dispersions, and (Virtanen et al., 1998). Notably, it has been reported that the aqueous
phospholipid complexes have been successfully employed to increase solubility and oral bioavailability of some natural flavonoid compo-
the aqueous solubility and stability of various hydrophobic flavonoid nents have also been improved through phospholipid complex for-
components (e.g., flavones, flavonols, and flavanones), resulting in mulation (shown in Table 2). The saturation solubility of IS, KA, and
improved oral bioavailability. QU in the TFH-phospholipid complex (TFH-PC) increased from 1.07,
Cyclodextrins (CDs) are cyclic oligosaccharides derived from starch 1.00, and 3.07 µg/mL for the pure TFH to 23.52, 24.21, and 82.28 µg/
degradation containing six (α-CD), seven (β-CD), eight (γ-CD), or more mL, which resulted in an increase in relative oral bioavailability for
(α-1,4)-linked α-D-glucopyranose units (Suvarna et al., 2017). With a TFH-PC in rats of 223%, 172%, and 242%, respectively (Wang et al.,
10
Table 2
Formulation design of carrier complexes on various hydrophobic flavonoids intended to enhance their oral delivery.
Types of carrier Types of flavonoids Model flavonoid Carrier Molar ratio Preparation method Solubility/Dissolution/Bioavailability Ref.
J. Zhao, et al.
complexes (drugs/ enhancement

carriers)
Cyclodextrin Flavone Kaempferia parviflora (KP) (5,7- (2-hydroxypropyl)-β-cyclodextrin 1:1 Solvent evaporation Bioavailability: 22.90-, 34.20-, 21.63-fold Mekjaruskul et al.
inclusion dimethoxyflavone, 5,7,4′ (HP-β-CD) (2013)
complex -trimethoxyflavone, 3,5,7,3′,4′-
pentamethoxyflavone)
Flavonol Myricetin HP-β-CD 1:1 Suspension Bioavailability: 9.40-fold Yao et al. (2014b)
Quercetin HP-β-CD 1:5 Co-precipitation Solubility: 129.00-fold Savic et al. (2015)
Fisetin β-CD; γ-CD 1:1 Suspension Solubility: 1.61-; 2.76-fold Zhang et al.
(2015a)
Flavanone Hesperetin β-CD; (2,6-di-O-methyl)-β-CD (DM-β- 1:4 Solvent evaporation Solubility: 213.24-; 162.76-; 125.00-; 412.76- Yang et al. (2016)
CD); (2,3,6-tri-O-methyl)-β-CD (TM- fold
β-CD); HP-β-CD
Taxifolin γ-CD 4:9 Emulsion solvent Solubility:18.50-fold (25℃); 19.80-fold (37℃); Zu et al. (2014b)
evaporation Dissolution: 2.84-fold (6 h); Bioavailability:
3.72-fold
Naringenin HP-β-CD 1:20 Solvent Solubility: 290.00-fold Wen et al. (2010)
β-CD 1:1; 1:2; 1:3 Solvent evaporation Solubility: 1.78-; 1.75-; 1.83-fold; Dissolution: Semalty et al.
2.03-; 1.99-; 2.05-fold (1 h) (2013)
Naringin β-CD 1:1 Dropping Solubility: 15.00-fold Cui et al. (2012)
Isoflavone Genistein β-CD 1:2 Wet kneading Solubility: 9.00-fold Daruhazi et al.
(2008)
Dihydroflavonol Astilbin β-CD; γ-CD 1:1 Solvent Solubility: 7.58-; 6.71-fold Zhang et al.
(2013)
Dihydrochalcone Phloretin HP-β-CD 1:1 Co-evaporation Solubility: 5808.00-fold Wei et al. (2017)
11
Solid dispersion Flavone Hippophae rhamnoides L. (THF) Poloxamer 188 (PXM 188) 1:4 Solvent evaporation Dissolution: 3.06-fold (20 min) Xie et al. (2009)
Chrysosplenol C Polyvinylpyrrolidone K25 (PVP K25), 2:1.8:0.2 Melting Solubility: 11.40-fold Ng et al. (2016)
Polyethylene glycol 6000 (PEG 6000)
Radix- scutellariae (Baicalein, Wogonin, PVP K30 1:5 Solvent Solubility: 35.10-, 6.40-, 12.90-fold Yu et al. (2017)
Oroxylin A)
Breviscapine PVP K30, Microcrystalline cellulose, 2:14:8:1 Solvent evaporation Dissolution: 2.00-fold (30 min); Bioavailability: Cong et al. (2014)
Crospovidone 3.45-fold
Ginkgo biloba extract (GBE) (Quercetin, Vinylpyrrolidone-vinyl acetate – Hot-melt extrusion Dissolution: 2.73-fold (2 h); Cmax: 149.20-, Wang et al.
Kaempferol, and Isorhamnetin) copolymers, Polyoxyl 40 423.20-, 45.32-fold; AUC0-48h: 5918.05-, (2015b)
hydrogenated castor oil (85:15) 13303.03-, 1390.83-fold
PXM 188 1:1 Solvent evaporation Cmax: 2.34-, 1.56-, 1.49-fold; AUC0-12h: 2.07-, Chen et al. (2010)
1.43-, 1.51-fold
Flavanone Naringenin Polyvinyl caprolactam-polyvinyl 1:4 Solvent evaporation Dissolution: 20.00-fold (2 h) Khan et al. (2015)
acetate-polyethylene glycol
Flavanonol Silymarin PEG 6000 1:12 Fusion Dissolution: 6.25-fold (30 min) Li and Hu (2004)

Table 2 (continued)
Types of carrier Types of flavonoids Model flavonoid Carrier Molar ratio Preparation method Solubility/Dissolution/Bioavailability Ref.
J. Zhao, et al.
complexes (drugs/ enhancement

carriers)
Phospholipid Flavone Baicalein Soya phosphatidylcholine (SPC) 1:1 Solvent Solubility: 32.10-fold; Dissolution: 1.71-fold Rawat et al.
complex (24 h) (2013)
Baicalin Soya phospholipid (SP) 1:1.7 Solvent evaporation Cmax: 2.14-fold; AUC0-24h: 2.98-fold Wu et al. (1999)
Luteolin Hydrogenated soya 1:2.33 Solvent evaporation Solubility: 2.50-fold Khan et al. (2014)
phosphatidylcholine (HSPC)
SPC 1:2.3 Solvent evaporation Relative bioavailability: 535.31% Khan et al. (2016)
TFH (Quercetin, Kaempferol, SP 1:1 Solvent evaporation Solubility: 22.00–26.80-fold; Wang et al.
Isorhamnetin) Dissolution:100.00%, 90.77%, and 84.32% (10 (2015a)
min); Relative bioavailabilities: 242.00%;
172.00% and 223.00%
GBE (Quercetin, Kaempferol, SP 1:1 Solvent evaporation Cmax: 4.04-, 1.79-, 3.44-fold; AUC0-12h: 2.42-, Wang et al.
Isorhamnetin) 1.95-, 2.35-fold (2015b)
Flavonol Kaempferol SPC 1:1 Solvent evaporation Solubility: 216.00-fold; Cmax: 2.76-fold; AUC0- Zhang et al.
48h: 4.24-fold (2015b)
Icariside II Phospholipid 1:1 Reduction Relative bioavailabilities: 165.00%- 342.00% Jin et al. (2012a)
vaporization
Phospholipid 1:1 Anhydrous co- PappA-B: increased by 91.00%; PappB-A: Jin et al. (2012b)
solvent reduction increased by 46.00%
vaporization
Total flavonoids of epimedium (TFE) SP 1:2 Wet media milling Relative bioavailabilities: 401.63%; 684.70% Pan et al. (2018)
(Icariin, Icariside II)
Rutin SPC 1:1 Refluxing Solubility: 15.88-fold Singh et al.
(2012b)
Quercetin SPC 1:1 Solvent evaporation Solubility:13.00-fold; Cmax: 2.36-fold; AUC0-∞: Zhang et al.
12
3.57-fold; T1/2: 1.61-fold (2016a)
SPC 1:1 Refluxing Solubility: 12.00-fold Singh et al.
(2012a)
Total flavonoids of Persimmon leaves SPC 1:2 Solvent evaporation Relative bioavailabilities: 242.00%; 337.00% Zhang et al.
(PLF) (Quercetin, Kaempferol) (2016b)
Flavan-3-ols Catechin (CT) Phospholipid 1:1 Solvent evaporation The absorbed CT levels: increased by 41.42% Athmouni et al.
(2018)
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

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)
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
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
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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International Journal of Pharmaceutics 570 (2019) 118642

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

Improvement strategies for the oral bioavailability of poorly water-soluble T

ARTICLE INFO ABSTRACT

1. Introduction naringenin), isoflavones (e.g., daidzein, puerarin), flavonols (e.g.,

3.1. Glycosylation of flavonoids of these derivatives is proportional to the degree of glycosylation.

Model flavonoid Glycosylated form

Flavonoid Sophora japonica L Glucose – 3.31 204.57 Morand

Silybum marianum β-glucoside Helferich 891.30 2.69 × 104 Ken et al.

β-lactosyl 7.88 × 104

β-maltosyl 1.16 × 104

Model flavonoid Glycosylated form

Psoraleae corylifolia Glucopyranoside Enzymatic 4.5 787.9 Ma et al.

Model flavonoid Glycosylated form

Isomaltoside 1.21 × 106

Model flavonoid Glycosylated form

Kudzu, Pueraria lobata, Maltosyl Enzymatic 24.71 1.86 × 106 Deng

(continued on next page)

Model flavonoid Glycosylated form

complexes (drugs/ enhancement

(continued on next page)

complexes (drugs/ enhancement

loading (%) enhancement

(continued on next page)

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

loading (%) enhancement

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