Table 1.

Collected attempts to increase the bioavailability of hesperidin and hesperetin.

Hesperidin
Technique	Observations	Reference
Hesperidin–chitosan complexes	The enhancement of solubility by 1.6-, 2.7-, and 3.8-fold and visible correlation between improved solubility and antioxidant activity. The greater the solubility improvement was, the better antioxidant activity reported	[16]
Inclusion complex of hesperidin with HP-β-CD	Obtaining the complex translated into increased solubility by 95-fold with respect to unmodified compound	[17]
Solid lipid nanoparticles loaded with Hesperidin	The increase of solubility by 20-fold. Impact on apparent permeability, leading to enhancement nearly by 5-fold. After oral administration, the overall bioavailability increased by 4.5-times in the study performed in a rat model. The obtained system affected biological activity as well, providing attenuation of Doxorubicin-induced cardiotoxicity and oxidative stress	[34]
Amorphous systems of Hesperidin with mesoporous material	Significant improvement in solubility by 51-fold for the best system and an impact on dissolution rate, better dissolution behavior in terms of apparent solubility	[35]
Nanoparticles of Hesperidin loaded by PLGA-Poloxamer 407	In in vitro release profiles, sustained and slow release, and higher apparent solubility were observed. This modification provided stronger inhibitory activity on the breast cancer cells	[36]
Hesperidin-β-CD inclusion complexes	The systems showed better behavior in dissolution studies and also demonstrated an enhancement of antibacterial and antioxidant activity compared with unmodified hesperidin	[37]
Inclusion complexes of Hesperidin with HP-β-CD	The obtained complexes showed an improvement in dissolution rate, and antioxidant as well as antimicrobial activity	[38]
A Solid self-microemulsifying system with Hesperidin composing of Maisine CC, Tween 80 and PEG 400	Significantly better dissolution rate profiles than that of free hesperidin, which enabled the release of almost all polyphenol from the system (>98%) after 60 min. Moreover, formulation showed better therapeutic activity for the management of diabetes mellitus in vivo	[39]
Solid nanocrystals	In the solubility studies, the system provided enhancement in solubility by 4.8-fold with respect to pure compound, faster dissolution, and higher apparent solubility	[40]
Inclusion system of Hesperidin with octenyl succinic anhydride modified sweet potato starch	The increase in solubility by 6.52-fold in the optimal conditions	[41]
Nanocrystals by combining Hesperidin with HPMC E5 and Poloxamer 188	The systems enhanced the solubility by 5-times as well as the drug dissolution rate. The systems were characterized by comparable antioxidant activity with regard to pure compound.	[42]
Hesperidin-PEG 6000 complex	Enhancement of solubility by 21-fold.	[43]
Hesperetin
Cocrystals with different excipients such as caffeine, nicotinamide and picolinic acid	It translated into about 5-times better solubility as compared with pure substance. The parachute effect was observed in dissolution rate studies. Moreover, significant improvements in biological activity and pharmacokinetic profile were noticed.	[44]
Eutectic mixtures	In dissolution studies, the increase of apparent solubility was evident and reached about 3-times higher than the pure compound. The biological models revealed a direct impact of solubility on antioxidant and antihemolytic activity	[45]
Complexes of Hesperetin with β-CD and HP-β-CD	Higher solubility by 25-fold for β-CD and 467-fold for HP-β-CD complexes.	[46]
Nanocrystals	Significant enhancement in dissolution rate and apparent solubility was reported. In dissolution rate studies, authors reported the spring effect, leading to a dramatic increase in solubility in a short time from the beginning. However, the amount of dissolved substance decreased over time, and thus the parachute effect was not observed.	[47]
The systems of Hesperetin with Mg- or Ag-modified SBA-16 carriers	In dissolution studies, higher apparent solubility and dissolution velocity were reported. However, the total drug release was unnoticed.	[48]
Nanoemulsion	The authors reported 5.67-fold higher oral bioavailability	[49]
Nanoparticles composed of Hesperetin and Eudragit E 100	Systems were characterized by sustained release with a pattern of initial rapid release of about 30% of the drug in the first 8 h, followed by a slow and continuous release of approximately 82% drug release in the next 24 h.	[50]
Self-assembling rebaudioside A nanomicelles with hesperetin	A drug release study revealed that prepared systems considerably increased apparent solubility and provided sustained release of the compound, reaching almost 81% at 24 h time point. This approach had a positive impact on the biological activity of hesperidin with respect to anticancer efficacy.	[51]
Formulations of hesperetin-D-alpha-tocopheryl polyethylene glycol 1000 succinate micelles and hesperetin-phosphatidylcholine complexes	The micelles formation was connected to an increase of solubility of 21.5-fold, whereas phosphatidylcholine complexes by 20.7-fold. Moreover, the solubility enhancement translated into a 4.2-fold boost in antioxidant activity for micelles and 3.9-fold for complexes. A significant improvement in bioavailability was also reported. The AUC increased by 16.2-fold for micelles formulation, whereas for complexes it was 18.0-fold.	[52]
Hesperetin complexes with β-CD and methylated-β-CD	The complexation caused an increase in apparent solubility and improved the dissolution profile. It also helped to increase the anti-inflammatory activity by reducing IL-6 secretion from LPS-stimulated macrophages.	[53]
Hesperetin-PLGA nanoparticles	Sustained release from formulation, which enabled a constant, slow-release within 7 days. Enhancement in the cytotoxic activity of prepared delivery system as compared with free compound.	[54]
Biocompatible gold nanoparticles of hesperetin	Sustained release of hesperetin from nanoparticles and increased cytotoxicity on cancer cells.	[55]
Chitosan-based nanoparticles	Sustained release of hesperetin and enhanced anticancer activity by an increase of inhibitory effect on colon cancer cell growth by 6-fold.	[56]