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Milk thistle (Silybum marianum) is the most well-researched plant in the treatment of liver diseases. Fruits of milk thistle contain flavonoids known for silymarin including silybin, silydianin and silychristin.
JOURNAL OF MILITARY PHARMACO-MEDICINE N07-2016 A REVIEW OF MANUFACTURE, BIOAVAILABILITY, SAFETY AND CLINICAL EFFICACY OF MILK THISTLE PHYTOSOME Dang Truong Giang*; Nguyen Van Long*; Dang Van Diep* Nguyen Thi Lan Huong*; Nguyen Thi Thu Hoai SUMMARY Milk thistle (Silybum marianum) is the most well-researched plant in the treatment of liver diseases Fruits of milk thistle contain flavonoids known for silymarin including silybin, silydianin and silychristin Although Silymarin has the most potent flavonoids in milk thistle, similar to other flavonoids, it is not well-absorbed In recent studies, the phytosome technology has increased absorption of conventional herbal extract This paper aims to review the researches about milk thistle phytosome including: manufacturing, bioavailability, safety and clinical efficacy * Key words: Phytosome; Silybin; Bioavailability; Phosphatidylcholine INTRODUCTION Milk thistle (Silybum marianum Asteraceae) is the most well-researched plant in the treatment of liver diseases Fruits of milk thistle contain flavonoids known for silymarin including silybin, silydianin and silychristin [4] Although clinical trials have shown silymarin is safe at high doses (> 1,500 mg/day) in humans over the past three decades, the pharmacokinetic studies related to absorption, distribution, metabolism and excretion of silymarin have revealed poor absorption, rapid metabolism and ultimately poor oral bioavailability For optimum silymarin bioavailability, issues of solubility, permeability, metabolism, and excretion must be addressed [2] An array of methods have been described in recent years that can improve bioavailability of silymarin, including complexes with β-cyclodextrins, solid dispersion method, formation of microparticles and nanoparticles, self-microemulsifying drug delivery systems, micelles, liposomes and phytosomes [2] The phytosome technology is a novel approach developed by Indena in an attempt to combat the issue of poor bioavailability The term “phyto” means plant and “some” means cell like This novel preparation comprises of incorporating a standardized plant extracted into phospholipids to produce lipid compatible molecular complexes with enhanced absorption and bioavailability [3] This paper aims to review the researches about milk thistle phytosome including: manufacturing, bioavailability, safety and clinical efficacy * Military Medical University Corresponding author: Dang Truong Giang (dangtruonggiang.hvqy@gmail.com) 86 JOURNAL OF MILITARY PHARMACO-MEDICINE N07-2016 MANUFACTURING MILK THISTLE PHYTOSOME Phytosome is prepared by reaction of - moles or mole of phospholipid preferably phosphatidylcholine or phosphatidylserine with the phytoconstituents like terpenoids or flavonoids in an aprotic solvent such as dioxane, ethyl acetate or acetone Lyophilization, freeze drying, precipitation with aliphatic hydrocarbons or evaporation of solvent under vacuum can be carried out for the isolation of the complex [3] YanYu X et al manufactured silybin phytosome by evaporating anhydrous ethanol [6] The required amounts of silybin and phospholipids were placed in a 100 mL round-bottom flask and dissolved in anhydrous ethanol After ethanol was evaporated off under vacuum at 40°C, the dried residues were collected and placed in desiccators overnight, then crushed in the mortar and sieved with a 100 mesh The resultant silybin-phospholipid complex was transferred into a glass bottle, flushed with nitrogen and stored at room temperature The content of silybin in the phospholipid complex was 49.73% (w/w) The silybin-phospholipid complex is stability The solubility of the silybin-phospholipid in water, n-octanol, chlohydric acid (pH 1.2) and phosphate buffer saline (pH 6.8) is increasing more than the conventional silybin [6] Wina Maryana et al developed a formulation of phytosome containing silymarin for the oral route as well as the characterization and stability studies [5] Whereby, silymarin and SPC with 1:5 molar ratio was dissolved in 20 mL of absolute ethanol The mixture was stirred at a temperature without an excess of 25°C for hours The mixture was then evaporated under vacuum The dried residues were collected and placed in desiccators overnight The content of silybin in the phospholipids complex was 95.63% (w/w) The preparation is stable with good physical properties [5] THE BIOAVAILABILITY OF MILK THISTLE PHYTOSOME The intermolecular bonding of silybin with PC proved to be specific and stable and the resulting molecular complex is more soluble in lipophilic, organic solvents This property predicts the enhanced ability of phytosomes to cross cell membranes and enter cells [4] Animal studies The superior bioavailability of complexed silybin with PC over non-complexed one has been documented through pharmacokinetic studies conducted in rats Figure 1: Relative plasma levels of total silybin in rats after dosing with silybin-PC or non-phytosome silybin [1] Figure showed that when rats were taken silymarin orally at a large dose of silybin, the concentration of silybin in the plasma for the six hour experiment was 87 JOURNAL OF MILITARY PHARMACO-MEDICINE N07-2016 virtually undetectable [1] In contrast, it was easily detected in plasma within minute when the same number of silybin-PC was given (200 mg per kg body weight) and its level peaked by one hour Its plasma levels significantly maintained at the sixhour mark [1] Human studies The studies conducted on 1,900 people showed that a group of eight healthy volunteers of 16 - 26 years old took orally single silybin at a dose of 360 mg, either as phytosomes or non-complexed silymarin The silybin rose slightly in the plasma beginning one hour after dosing and declined to minimal levels by eight hours (figure 3) By measuring the total area under the curve (AUC) for each line, it was determined that phytosomal silybin was absorbed 4.6 times better than the non-phytosome silybin [4] Figure 2: Plasma silybin uptake in healthy humans [4] SAFETY OF MILK THISTLE PHYTOSOME This phytosomal form of silybin has been studied for safety According to researchers Marena and Lampertico, healthy volunteers (total number not disclosed) received 360 mg silybin-phytosome complex three times 88 daily for three weeks without adverse effect [4] Another study on 232 patients with “liver disorders” for up to four months with either 240 or 360 mg of silybin-phytosome complex daily, concluding that the tolerability of the silybin-PC preparation was excellent Minor adverse effects (nausea, heartburn, dyspepsia, transient headache) were reported in 12 patients (5.2% of the total studied), compared with 8.2% of patients who received noncomplexed silybin and 5.1% of patients on placebo [4] Phytosomal silybin has also proven to be safe in traditional toxicological tests After 13-week subacute toxicity studies, the preparation was found safe for rats and monkeys at oral doses up to 2,000 mg per kg per day In 26-week sub-chronic toxicity studies, oral doses up to 1,000 mg per kg per day were well tolerated in rats and dogs In another 26-week oral toxicity study, rats were fed a daily 2,000 mg per kg dose of silybin-PC, equivalent to 160 g daily for an 80 kg human As published by Indena, body weight, liver weight and enzyme indicators of liver damage (AST, ALT) remained within normal, healthy range of the untreated control rats [1] Pharmacological studies in mice, rats and dogs indicate phytosomal silybin does not adversely affect central nervous system, cardiovascular or respiratory functions and does not influence stomach emptying or intestinal motility at oral doses as high as 1,000 mg per kg The silybin-PC complex had no obvious adverse effects on reproduction of rats and showed no mutagenic effects in several testing models [1] JOURNAL OF MILITARY PHARMACO-MEDICINE N07-2016 CLINICAL EFFICACY OF MILK THISTLE PHYTOSOME In 1992, researchers at the Universities of Milan and Bari reported in a controlled study of chronic persistent hepatitis The study recruited only the patients with biopsy-confirmed hepatitis These patients were randomized to receive either 240 mg silybin phytosome (n = 31) or placebo (n = 34), one capsule orally, twice daily for three months The phytosome group experienced significant loss of both serum ALT and AST while in the placebo group both enzyme indicators got worse [4] Data particularly useful in establishing dosing recommendations came from a larger 1993 hepatitis trial at the University of Pavia involving 54 patients Patients with chronic hepatitis of either viral or alcoholic origin were randomly assigned to one of three groups One group (n = 19) received phytosomal silybin at 160 mg daily; another group (n = 17) received 240 mg daily; and the third group (n = 18) received 360 mg daily The trial lasted two weeks, with enzyme indicator testing done after and weeks Despite short duration of the trial, AST was significantly lowered by all dosages At the two higher doses of 240 and 360 mg daily (but not at 160 mg daily), ALT and GGT were also significantly reduced [4] CONCLUSION Silymarin has the most potent flavonoids in milk thistle, similar to other flavonoids, it is not well-absorbed Silybin-PC complex was successfully prepared by a simple, novel method It had no obvious adverse effects on reproduction of rats and showed no mutagenic effects in several testing models The silybin-PC complex provides significant liver protection and enhances bioavailability when it was taken orally Because of remarkable effects of the milk thistle and advanced bioavailability of phytosome, reseachers in Vietnam Military Medical University have studied phytosome formulation from standardized extract of milk thistle fruit From these raw phytosome of milk thistle, we can prepare several products to servepublic and soldiers REFERENCES Indena Silybin-PC (TM) From silybum marianum (L.) Gaertn a new natural preventive targeted at the liver Seattle, WA: Indena USA Inc.; www indenausa.com 2004 Javed S, Kohli, Ali M Reassessing bioavailability Altern Med Rev 2011, pp.239249 Joseph A Kareparamban et al Phytosome: A novel revolution in herbal drugs International Journal of Research in Pharmacy and Chemistry 2012, pp.299-310 Parris Kidd, Kathleen A review of bioavailability and clinical efficacy of milk thistle phytosome: A silybin-phosphatidylcholine complex (Siliphos®) Alternative Medicine Review 2005, Vol 10, No 3, pp.193-203 Wina Maryana, Heni Rachmawati, Dicky Mudhakir Formation of phytosome containing silymarin using thin layer-hydration technique aimed for oral delivery Materials Today: Proceedings 2016, pp.855-866 Yanyu X, Yunmei S, Zhipeng C, Quineng P The preparation of silybin-phospholipid complex and the study on its pharmacokinetics in rats Int J Pharm 2006, p.307, pp.77-82 89 ... significant liver protection and enhances bioavailability when it was taken orally Because of remarkable effects of the milk thistle and advanced bioavailability of phytosome, reseachers in Vietnam... Kohli, Ali M Reassessing bioavailability Altern Med Rev 2011, pp.239249 Joseph A Kareparamban et al Phytosome: A novel revolution in herbal drugs International Journal of Research in Pharmacy and. .. is increasing more than the conventional silybin [6] Wina Maryana et al developed a formulation of phytosome containing silymarin for the oral route as well as the characterization and stability