Saponin phytosome: A solution to enhance bioavailability of saponin

Saponin is a group of compounds occurring naturally in plants and animals. These compounds may own important biological effects. One of the factors reducing their pharmacological effect in vivo of these compounds is poor bioavailability.

JOURNAL OF MILITARY PHARMACO-MEDICINE N07-2016 SAPONIN PHYTOSOME: A SOLUTION TO ENHANCE BIOAVAILABILITY OF SAPONIN (A REVIEW) Nguyen Van Long*; Dang Truong Giang*; Vu Tuan Anh* Nguyen Thi Lan Huong*; Nguyen Thi Thu Hoai* SUMMARY Saponin is a group of compounds occurring naturally in plants and animals These compounds may own important biological effects However, one of the factors reducing their pharmacological effect in vivo of these compounds is poor bioavailability There are many factors affecting the bioavailability of saponins including solubility, stability and permeability Phytosomal technology is able to improve the bioavailability of saponins in vivo by increasing solubility, stability and permeability of these compounds This study aims to review the advances of this modern technology to enhance bioavailability of saponin * Key words: Saponin; Bioavailability; Phosphatidylcholine; Phytosomal technology INTRODUCTION Saponin is a class of glycosides found abundantly in various plant species In terms of chemical structure, saponin can be divided into two groups: triterpenoid saponins and steroidal saponins In general, saponins have many pharmacological effects as expectorant, anti-inflammatory, antihypertensive, immuno-modulatory, hypoglycemia, antifungal, antiparasitic effects, etc…) [1] However, the major challenge in developing saponins as clinically useful drugs is their poor bioavailability The poor bioavailability of saponins was caused by the physicochemical properties of its (e.g solubility, stability) and the ability of saponins to permeate a biological membrane [7] There were few reports about the pharmaceutical formulation study to enhance the oral bioavailability of saponins such as nanoparticles, liposome, phytosome… This report aims to review some factors affect the bioavailability of saponins and phytosomal technology bioavailability of saponins to enhance BIOAVAILABILITY OF SAPONINS Some recent studies showed that the bioavailability of some saponins is low Studies of oral bioavailability of ginsenoside Rh2, a secondary ginsenoside with anticancer effects, is lower than 1% in mice A/J after oral administration of mg/kg or 20 mg/kg Rh2 [8] An oral administration of glycyrrhizin (oleane type) in mice at a dose of 200 mg/kg body weight, the oral bioavailability was appoximately 4% In Beagle dogs, the bioavailability of orally glycyrrhizin was 3.24% [6] Astragaloside IV is another types of saponins which has bioactivities against cancer cell lines such as epithelial liver cells Pharmacokinetic studies have shown that the oral bioavailability of astragaloside IV in Sprague Dawley rats (at doses of 20 mg/kg) was 3.7% or 7.4% in Beagle dogs (at doses of 10 mg/kg) [5] * Military Medical University Corresponding author: Dang Truong Giang (dangtruonggiang.hvqy@gmail.com) 81 JOURNAL OF MILITARY PHARMACO-MEDICINE N07-2016 Bioavailability is therefore an important concern for saponins if they were to be developed as viable drug candidates Pharmaceutical companies usually not develop drugs whose oral bioavailability is lower than 30% Thus, enhancing bioavailability of saponins is necessary [7] SOME FACTORS AFFECT BIOAVAILABILITY OF SAPONINS Bioavailability of saponins is dramatically affected by some factors such as solubility, stability and permeability [7] Solubility The solubility of saponins depends on the number of sugar units in its chemical structure Aqueous solubility of aglycones is lower than their corresponding glycosides It was reported that the aqueous solubility of oleanolic acid and betulinic acid, two of the saponin triterpene aglycones were approximately 0.02 µg/mL [7] However, the increase in solubility of the drug does not necessarily lead to an increased absorption This is due to the fact that drug absorption is a complicated process that is affected by different factors Although the presence of sugar units can enhance solubility of saponin, other factors such as high molecular weight, hydrophilicity, and the large number of hydrogen bonds reduce the permeability of the saponin, which ultimately leads to poor absorption of saponins [7] Stability The complicated chemical structure of saponins can be changed during storage 82 or processing which leads to the transformation of their physicochemical properties and/or biological activities Glycosidic bonds (between sugar chains and aglycones), and inter-glycosidic bonds between sugar residues can be hydrolyzed in acid or base environment [7] The presence of the free carboxylic group of saponins can be the reason for releasing the corresponding ester as storing in alcohol Since free carboxylic groups from saponins are able to create enough acidity in alcohol, it catalyzes the formation of the corresponding ester which is the main reason of saponin instability [7] Permeability The ability of a drug to permeate a biological membrane was measured using permeability, which was a parameter widely used to describe the absorption of a drug Absorption of a molecular via intestinal epithelial cells was a complex process that may involve mutiple pathways (figure 1) [7] The stages of process greatly affected the absorption of drugs including passive diffusion, absorption, and excretion Poor membrane permeability was one of the significant factors decreasing the absorption of saponin in the digestive system Although the addition of sugar chains increases the solubility, it reduces the permeability of saponin due to considerable changes of hydrogen bonds, polarized surface area, and the flexibility of the molecular [7] JOURNAL OF MILITARY PHARMACO-MEDICINE N07-2016 Figure 1: The absorption and metabolisms of saponins in intestine and liver [7] ENHANCING BIOAVAIBILITY OF SAPONIN BY USING PHYTOSOMAL FORM Phytosome complex is a combination of the active compounds or standardized herbal extracts and phospholipids at molecular level phytosome form has many advantages such as rapid absorption of the active ingredients, enhancing bioavailability, increasing efficacy, reducing dose, improving the stability of the substance [4] The research has been conducted to improve the absorption of the Rg1 and Rb1 ginsenosides from Panax notoginseng (PNS) [2] Figures and 3, respectively show the mean plasma concentration versus time profiles of ginsenoside Rg1 and Rb1 obtained with PNS aqueous solution, PNS-phospholipid complex, and the complex dissolved in Labrafac cc/Capmul MCM (3:1) It was apparent that the markedly higher plasma levels of ginsenoside Rg1 and Rb1 were obtained when administered as dissolved complex in Labrafac cc/Capmul MCM (3:1), compared with those obtained as an aqueous solution [2] The peak plasma levels of ginsenoside Rg1 and Rb1 administered as PNS phospholipid complex were even lower than that given as aqueous solution Both the PNSphospholipid complex and the oil solution of the complex appeared to be absorbed at a slower rate and much longer residence time, so as to achieve higher extent of absorption [2] Figure 2: Concentration of Rg1 in plasma after oral PNS administration (at dose of 600 mg/kg body weight in rats): PNS , PNS-phospholipid complex , PNS-phospholipid complex in glyceride medium chain [2] 83 JOURNAL OF MILITARY PHARMACO-MEDICINE N07-2016 Figure 3: Concentration of Pb1 in plasma after oral PNS administration (at dose of 600 mg/kg body weight in rats): PNS ; PNS-phospholipid complex , PNSphospholipid complex in glyceride medium chain [2] The study prepared glycyrrhizic acidphospholipid complex (GL-PLC) as to improve the oral bioavailability of glycyrrhizic acid (GL), enhance the drug efficacy and reduce the side effects (GL is a aglycon of glycyrrhizin) The results of pharmacokinetic study displayed that the plasma concentration of glycyrrhetic acid, the metabolite of GL in vivo, increased after oral administration of GL-PLC The Cmax of GL-PLC was 2.14 times higher than that of free glycyrrhizic acid, while the AUC of GL-PLC was 1.74 times higher than that of free GL The results proved that GL-PLC improved the lipophilic property of GL, increased the bioavailability and anti-inflammatory activity [3] CONCLUSION Saponins have significant biological effects Poor bioavailability of saponins is affected by a number of factors including solubility, stability, and permeability Some studies have shown that phytosome 84 technology is a modern pharmaceutical technology to enhance the bioavailability of saponins in vivo Because of remarkable effects of phytosomal form, researchers at Vietnam Military Medical University have studied phytosome formulation from standardized saponin extract of Gynostemma pentaphyllum to prepare several products to serve soldiers and public healthcare REFERENCES Medicinal plants (part I) Publishing House 2006, pp.126-189 Hanoi Jing Xiong and Jianxin Guo The use of lipid-based formulations to increase the oral bioavailability of panax notoginseng saponins following a single oral gavage to rats Drug Development and Industrial Pharmacy 2008, 34, pp.65-72 Jingze Zhang et al Glycyrrhizic acidphospholipid complex: Preparation process optimization and therapeutic and pharmacokinetic evaluation in rats Lat Am J Pharm 2011, 30 (8), pp.1621-1630 JOURNAL OF MILITARY PHARMACO-MEDICINE N07-2016 Kidd PM Bioavailability and activity of phytosome complexes from botanical polyphenols: the silymarin, curcumin, green tea, and grape seed extracts Altern Med Rev 2009, 14 (3), pp.226-246 Qi H, Wei L, Han Y, Zhang Q, Lau AS, Rong J Proteomic characterization of the cellular response to chemopreventive triterpenoid astragaloside IV in human hepatocellular carcinoma cell line HepG2 Int J Oncol 2010, 36, pp.725-735 Ren W, Lu Y, Jing J et al Determination of glycyrrhizin in dog plasma by liquid chromatography-mass spectrometry and its application in pharmacokinetic studies Eur J Mass Spectrom (Chichester, Eng) 2010, 16, pp.673-678 Song Gao et al Bioavailability challenges asscoiated with development of saponin as therapeutic and chemopreventive agents Current Drug Targets 2012, 13, pp.1885-1899 Zhen Y, Song G, Wang J, Taijun Y, Ming Y, Ming H Enhancement of oral bioavailability of 20(S)-ginsenoside Rh2 through improved understanding of its absorption and efflux mechanisms Drug Metab Dispos 2011, 39, pp.1866-1872 85 ... oral bioavailability is lower than 30% Thus, enhancing bioavailability of saponins is necessary [7] SOME FACTORS AFFECT BIOAVAILABILITY OF SAPONINS Bioavailability of saponins is dramatically affected... property of GL, increased the bioavailability and anti-inflammatory activity [3] CONCLUSION Saponins have significant biological effects Poor bioavailability of saponins is affected by a number of factors... formulations to increase the oral bioavailability of panax notoginseng saponins following a single oral gavage to rats Drug Development and Industrial Pharmacy 2008, 34, pp.65-72 Jingze Zhang et al