Preparation, characterization and evaluation of kaempferol phospholipid complex: Improvement of its solubility and biological effect

Abstract

Kaempferol (KA), as one of the flavonoids, has extensive pharmacological properties. However, the poor solubility of KA severely limits its clinical application. In our study, the kaempferol phospholipid complex (KA-PC) has been prepared by solvent evaporation for the enhancement of the bioavailability of KA. KA-PC was verified by scanning electron microscope characterization methods. Drug loading, solubility and long-term stability were measured. The characterization results showed that KA-PC was formed through the intermolecular interaction between KA and phospholipids. The solubility of KA-PC in water was 189 times higher than that of KA, and the solubility in n-octanol was also significantly improved. Besides, pharmacodynamic studies showed that KA-PC can significantly reduce the level of serum uric acid in mice without causing renal injury. This study expanded the clinical application of KA by preparing KA-PC.

Keywords

kaempferol / phospholipid complex / solubility / uric acid-lowering effect

Acknowledgements

This research was funded by Young and Middle Aged Teachers’ Career Development Support Project of Shenyang Pharmaceutical University (ZQN2019005).

References

[1] Valls J, Millán S, Martí MP, et al. Advanced separation methods of food anthocyanins, isoflavones and flavanols[J]. J Chromatogr A, 2009, 1216 (43): 7143-7172.

[2] Felice MR, Maugeri A, Sarro GD, et al. Molecular pathways involved in the anti-cancer activity of flavonols: A focus on myricetin and kaempferol[J]. Int J Mol Sci, 2022, 23 (8): 4411.

[3] Liu Z Y, Yao XQ, Sun BH, et al. Pretreatment with kaempferol attenuates microglia-mediate neuroinflammation by inhibiting MAPKs-NF-κB signaling pathway and pyroptosis after secondary spinal cord injury[J]. Free Radic Biol Med, 2021, 168: 142-154.

[4] Qiu YX, He D, Yang JX, et al. Kaempferol separated from Camellia oleifera meal by high-speed countercurrent chromatography for antibacterial application[J]. Eur Food Res Technol, 2020, 246 (12): 2383-2397.

[5] Alam W, Khan H, Shah MA, et al. Kaempferol as a dietary anti-inflammatory agent: Current therapeutic standing[J]. Molecules, 2020, 25 (18): 4073.

[6] Alshehri AS. Kaempferol attenuates diabetic nephropathy in streptozotocin-induced diabetic rats by a hypoglycaemic effect and concomitant activation of the Nrf-2/Ho-1/ antioxidants axis[J]. Arch Physiol Biochem, 2023, 129 (4): 984-997.

[7] Deng SP, Yang YL, Cheng XX, et al. Synthesis, spectroscopic study and radical scavenging activity of kaempferol derivatives: Enhanced water solubility and antioxidant activity[J]. Int J Mol Sci, 2019, 20 (4): 975.

[8] Zhang KX, Gu LQ, Chen JP, et al. Preparation and evaluation of kaempferol-phospholipid complex for pharmacokinetics and bioavailability in SD rats[J]. J Pharm Biomed Anal, 2015, 114: 168-175.

[9] Kazmi I, Alabbasi FA, Afzal M, et al. Formulation and evaluation of kaempferol loaded nanoparticles against experimentally induced hepatocellular carcinoma: In vitro and in vivo studies[J]. Pharmaceutics, 2021, 13 (12): 2086.

[10] Huang MG, Su EZ, Zheng FP, et al. Encapsulation of flavonoids in liposomal delivery systems: The case of quercetin, kaempferol and luteolin[J]. Food Funct, 2017, 8 (9): 3198-3208.

[11] Qian YS, Ramamurthy S, Candasamy M, et al. Production, characterization and evaluation of kaempferol nanosuspension for improving oral bioavailability[J]. Curr Pharm Biotechnol, 2016, 17 (6): 549-555.

[12] Li JQ, Di LY, Cheng X, et al. The characteristics and mechanism of co-administration of lovastatin solid dispersion with kaempferol to increase oral bioavailability[J]. Xenobiotica, 2020, 50 (5): 593-601.

[13] Ding L, Cui XX, Jiang R, et al. Design, synthesis and characterization of a novel type of thermo-responsible phospholipid microcapsule-alginate composite hydrogel for drug delivery[J]. Molecules, 2020, 25 (3): 694.

[14] Me A, Hsa B, Sy A, et al. Lysophosphatidylethanolamine acyltransferase 2 (LPEAT2) incorporates DHA into phospholipids and has possible functions for fatty acid- induced cell death - ScienceDirect[J]. Biochem Biophys Res Commun, 2020, 526 (1): 246-252.

[15] Garner LE, Park J, Dyar SM, et al. Modification of the optoelectronic properties of membranes via insertion of amphiphilic phenylenevinylene oligoelectrolytes[J]. J Am Chem Soc, 2010, 132 (29): 10042-10052.

[16] Gnananath K, Nataraj KS, and Rao BG. Phospholipid complex technique for superior bioavailability of phytoconstituents[J]. Adv Pharm Bull, 2017, 7 (1): 35-42.

[17] Chi C, Zhang CS, L iu Y, e t al. Phytosome- nanosuspensions for silybin-phospholipid complex with increased bioavailability and hepatoprotection efficacy[J]. Eur J Pharm Sci, 2020, 144 (1): 105212.

[18] Gangarde Y, Sajeev TK, Panigrahi N, et al. Amphiphilic small molecule assemblies to enhance the solubility and stability of hydrophobic drugs[J]. ACS Omega, 2020, 5 (4): 28375-28381.

[19] Ita KB, Du-Preez J, Lane ME, et al. Dermal delivery of selected hydrophilic drugs from elastic liposomes: effect of phospholipid formulation and surfactants[J]. J Pharm Pharmacol, 2007, 59 (9): 1215-1222.

[20] Kai S, Cui F, Yu Y, et al. Preparation and characterization of a novel insulin-phospholipid complex[J]. J Control Release, 2006, 114 (2): 242-250.

[21] Chen S, Xie Q, Yang M, et al. Scutellaria baicalensis extract-phospholipid complex: Preparation and initial pharmacodynamics research in rats[J]. Curr Pharm Biotechnol, 2021, 23 (6): 847-860.

[22] Qian Y, Chen G, Wang J, et al. Preparation and evaluation of probucol-phospholipid complex with enhanced bioavailability and no food effect[J]. AAPS PharmSciTech, 2018, 19 (8): 3599-3608.

[23] Zou F, Zhao H, Ma A, et al. Preparation of an isorhamnetin phospholipid complex for improving solubility and anti- hyperuricemia activity[J]. Pharm Dev Technol, 2022, 27 (7): 842-852.

[24] Kuche K, Bhargavi N, Dora CP, et al. Drug-phospholipid complex-a go through strategy for enhanced oral bioavailability[J]. AAPS PharmSciTech, 2019, 20 (2): 43.

[25] Zhang W, Chen Y, Wang W, et al. Soy lecithin increases the stability and lipolysis of encapsulated algal oil and probiotics complex coacervates[J]. J Sci Food Agric, 2023, 103 (8): 4164-4173.

[26] Biswas S, Mukherjee PK, Harwansh RK, et al. Enhanced bioavailability and hepatoprotectivity of optimized ursolic acid-phospholipid complex[J]. Drug Dev Ind Pharm, 2019, 45 (6): 946-958.

[27] Wang L, Urriola PE, Luo ZH, et al. Metabolomics revealed diurnal heat stress and zinc supplementation- induced changes in amino acid, lipid, and microbial metabolism[J]. Physiol Rep, 2016, 4 (1): e12676.

[28] Villalba JM, López-Domínguez JA, Chen Y, et al. The influence of dietary fat source on liver and skeletal muscle mitochondrial modifications and lifespan changes in calorie-restricted mice[J]. Biogerontology, 2015, 16 (5): 655-670.

[29] Yuluğ E, Türedi S, Yıldırım Ö, et al. Biochemical and morphological evaluation of the effects of propolis on cisplatin induced kidney damage in rats[J]. Biotech Histochem, 2019, 94 (3): 204-213.

[30] Chen S, Xie Q, Yang M, et al. Scutellaria baicalensis extract-phospholipid complex: Preparation and initial pharmacodynamics research in rats[J]. Curr Pharm Biotechnol, 2022, 23 (6): 847-860.

[31] Xie DW, Shen YL, Su EZ, et al. Anti-hyperuricemic, nephroprotective, and gut microbiota regulative effects of separated hydrolysate of α-lactalbumin on potassium oxonate- and hypoxanthine-induced hyperuricemic mice[J]. Mol Nutr Food Res, 2023, 67 (1): e2200162.

[32] Bangar SP, Chaudhary V, Sharma N, et al. Kaempferol: A flavonoid with wider biological activities and its applications[J]. Crit Rev Food Sci Nutr, 2023, 63 (28): 9580-9604.

[33] Xiao J, Zhu S, Guan H, et al. AMPK alleviates high uric acid-induced Na(+)-K(+)-ATPase signaling impairment and cell injury in renal tubules[J]. Exp Mol Med, 2019, 51 (5): 1-14.

[34] Wang MX, Wang MM, Liu C, et al. A geniposide- phospholipid complex ameliorates posthyperuricemia chronic kidney disease induced by inflammatory reactions and oxidative stress[J]. Eur J Pharmacol, 2022, 930: 175157.