Development of Silymarin Self-Microemulsifying Drug Delivery System with Enhanced Oral Bioavailability

Li, Xinru; Yuan, Quan; Huang, Yanqing; Zhou, Yanxia; Liu, Yan

doi:10.1208/s12249-010-9432-x

Cited by 67 publications

(32 citation statements)

References 26 publications

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“…We previously demonstrated that silymarin flavonolignans do not reach peak plasma concentrations above 0.2 mM with use of this dose regimen (Hawke et al, 2010); these concentrations are significantly lower than those associated with drug interaction risk identified in the present study. However, higher oral doses and improved formulations of silymarin (e.g., nanoemulsions) are being evaluated to increase systemic/tissue concentrations to achieve desired clinical outcomes (Flaig et al, 2010;Li et al, 2010;Wang et al, 2012). On the basis of the present study, these higher doses and/or improved formulations may increase the risk of OATP-mediated interactions.…”

Section: Discussionmentioning

confidence: 97%

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

et al. 2013

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Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/ day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1-and OATP1B3-mediated estradiol-17b-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC 50 values of 1.3, 2.2 and 0.3 mM, respectively), silybin A (IC 50 values of 9.7, 2.7 and 4.5 mM, respectively), silybin B (IC 50 values of 8.5, 5.0 and 0.8 mM, respectively), and silychristin (IC 50 values of 9.0, 36.4, and 3.6 mM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 mM) significantly inhibited OATP-mediated estradiol-17b-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC 50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients.

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Section: Discussionmentioning

confidence: 97%

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

et al. 2013

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“…[3][4][5][6] However, its clinical efficacy is compromised by its poor oral bioavailability due to poor water solubility and low permeability. 7,8 In order to improve the oral bioavailability of SM, several delivery systems have been explored such as self-microemulsifying drug delivery systems, [9][10][11] porous silica nanoparticles, 12 solid dispersions, 13 glyceryl monooleate/poloxamer 407 liquid crystalline matrices, 14 proliposomes, 15 silybinphospholipid complexes, 16 and solid lipid nanoparticles. 17 It seems that lipid-based drug delivery systems are more promising in improving the oral absorption of SM owing to their specific absorption-enhancing mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Binary lipids-based nanostructured lipid carriers for improved oral bioavailability of silymarin

Shangguan

Lü

et al. 2013

J Biomater Appl

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The main purpose of this study was to prepare binary lipids-based nanostructured lipid carriers to improve the oral bioavailability of silymarin, a poorly water-soluble liver protectant. Silymarin-loaded nanostructured lipid carriers were prepared by the method of high-pressure homogenization with glycerol distearates (Precirol ATO-5) and oleic acid as the solid and liquid lipids, respectively, and lecithin (Lipoid E 100) and Tween-80 as the emulsifiers. The silymarin-nanostructured lipid carrier prepared under optimum conditions was spherical in shape with mean particle size of ∼78.87 nm, entrapment efficiency of 87.55%, loading capacity of 8.32%, and zeta potential of -65.3 mV, respectively. In vitro release of silymarin-nanostructured lipid carriers was very limited even after 12 h, while in vitro lipolysis showed fast digestion of nanostructured lipid carriers within 1 h. Relative oral bioavailability of silymarin-nanostructured lipid carriers in Beagle dogs was 2.54- and 3.10-fold that of marketed Legalon® and silymarin solid dispersion pellets, respectively. It was concluded that nanostructured lipid carriers were potential drug delivery systems to improve the bioavailability of silymarin. Other than improved dissolution, alternative mechanisms such as facilitated absorption as well as lymphatic transport may contribute to bioavailability enhancement.

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“…34) UV absorption spectra of ATR and EZT in each excipient and blank SMEDDS were also measured to find the molecular location of solubilized drugs in a micellar environment. 35,36) The molecular locations of solutes (drugs) in the specific micelle structure can be regarded the same as another micelle structure if the wavelength of maximum absorbance (λ max ) of the two spectra are similar because the location of λ max reflects solvent polarity surrounding solutes in micelles. If the drug is solubilized in a specific excipient, its λ max will be similar to the λ max of the drug in the microemulsion.…”

Section: )mentioning

confidence: 99%

Formulation and <i>in Vitro</i> Evaluation of Self-microemulsifying Drug Delivery System Containing Fixed-Dose Combination of Atorvastatin and Ezetimibe

Hwang

Park

Kim

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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This paper focuses on the development and physicochemical characterization of a self-microemulsifying drug delivery system (SMEDDS) containing a fixed-dose combination of atorvastatin (ATR) and ezetimibe (EZT). The solubility of both drugs was determined in excipient screening studies. Ternary-phase diagrams were drawn for 27 systems composed of different surfactants, cosurfactants, and oils at different surfactantto-cosurfactant (S/CoS) ratios, and the system exhibiting the largest percentage area of the self-microemulsifying region was selected. The optimum oil ratio in the SMEDDS was selected by evaluating the mean droplet size of the resultant microemulsions. The underlying mechanism of the lower ATR loading capacity compared with EZT was elucidated by measurement of the zeta potential and UV absorption analysis. The results implied that ATR was located exclusively in the surfactant-cosurfactant layer, whereas EZT was located both in the microemulsion core and the surfactant-cosurfactant layer. In vitro dissolution studies showed that the SMEDDS had higher initial dissolution rates for both drugs when compared with marketed products. More importantly, EZT had a significantly increased dissolution profile in distilled water and pH 4.0 acetate buffer, implying enhanced bioavailability.Key words self-microemulsifying drug delivery system; fixed-dose combination; ezetimibe; atorvastatin calcium; solubilization Atorvastatin (ATR) is a fully synthetic drug that lowers cholesterol level by competitively blocking 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase. However, it has an absolute bioavailability of only 14% due to rapid clearance by CYP3A4 in gastrointestinal mucosa and liver. 1) Ezetimibe (EZT) is a lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. However, EZT has a very low solubility and dissolution rate resulting in highly variable bioavailability, which is also in part due to extensive efflux by p-glycoprotein (P-gp). 2,3)When co-administered with statins, EZT provides significant incremental reductions in low density lipoprotein (LDL)-cholesterol and triglycerides and increases in high density lipoprotein (HDL)-cholesterol when compared with statin monotherapy.4) Co-administration of EZT and ATR is well tolerated with no serious adverse effects. 5) Therefore, the addition of 10 mg EZT to low-dose ATR therapy may significantly reduce the risk of severe side effects, such as myopathy, while increasing its efficacy.Despite the clear synergism of the two drugs, incorporating both drugs in one drug delivery system poses some challenges due to different physicochemical properties. ATR is a weak acid with a solubility of 0.8 mg/mL and pK a of 4.46. 6) On the contrary, EZT is a practically insoluble and weakly basic compound with solubility of 0.012 mg/mL, and pK a of 9.75. 7)Therefore, it may be difficult for both drugs to be solubilized using a single solubilizing agent or strategy (e.g., pH-modifying...

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Development of Silymarin Self-Microemulsifying Drug Delivery System with Enhanced Oral Bioavailability

Cited by 67 publications

References 26 publications

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

Binary lipids-based nanostructured lipid carriers for improved oral bioavailability of silymarin

Formulation and <i>in Vitro</i> Evaluation of Self-microemulsifying Drug Delivery System Containing Fixed-Dose Combination of Atorvastatin and Ezetimibe

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