Abstract
Background: Silymarin is extracted from the seeds of milk thistle (Silybum marianum), exhibits antioxidant properties, and is considered to treat numerous hepatic ailments like chronic liver disease, cirrhosis, and chemical degradation of liver cells and prevent hepatotoxicity from various drugs.
Objective: The objective of the present study was to preclude the problem of poor dissolution of the relatively water-insoluble drug by formulating solid dispersions of the drug.
Methods: Solid dispersions of silymarin were prepared by solvent evaporation method by using different polymers, i.e., PEG 6000 and poloxamer 407, in various ratios such as 1:2, 1:4 and 1:6. The compatibility of ingredients with the drug was tested by using Differential scanning calorimetry (DSC), X-Ray Diffractometry, and Fourier Transform-Infrared Spectroscopy (FT-IR). The scavenging activity of DPPH (2,2 diphenyl-1-picrylhydrazyl) radical was used to study the antioxidant activity, and an in vitro release study was conducted using phosphate buffer pH 6.8 as dissolution medium followed by the kinetic assessment to study the drug release mechanism.
Results: Solid dispersions with different polymers were successfully prepared by the solvent evaporation method. FTIR spectroscopy and DSC showed no chemical interaction between the drug and polymers. Powder XRD analyses of optimized solid dispersions showed a relative decrease in crystallinity compared to the pure drug. The dissolution profile of solid dispersions successfully exhibited 90.78% drug released, and the optimized batch was found to follow Higuchi drug release kinetics with an R2 value of 0.990. Furthermore, the optimized formulation F6 showed higher antioxidant activity compared to pure silymarin and ascorbic acid.
Conclusion: The elevated bioavailability, as well as absorption, consistently regulates the specific therapeutic effect of the water-insoluble drug. The specific response of silymarin to various bodily functions upgrades various activities like anti-aging effects, anti-cancer, antihypertensive, etc. Solid dispersion of drugs with good aqueous solubility results in a decrease in dose frequency and enhanced specificity of the drug mechanism.
Graphical Abstract
[1]
Kshirsagar A, Ingawale D, Ashok P, Vyawahare N. Silymarin: A comprehensive review. Pharmacogn Rev 2009; 3(5): 126-34.
[2]
Das SK, Mukherjee S. Biochemical and immunological basis of silymarin effect, a milk thistle (Silybum marianum) against ethanol-induced oxidative damage. Toxicol Mech Methods 2012; 22(5): 409-13.
[http://dx.doi.org/10.3109/15376516.2012.673090] [PMID: 22409310]
[http://dx.doi.org/10.3109/15376516.2012.673090] [PMID: 22409310]
[3]
Dixit N, Baboota S, Kohli K, Ahmad S, Ali J. Silymarin: A review of pharmacological aspects and bioavailability enhancement approaches. Indian J Pharmacol 2007; 39(4): 172-9.
[http://dx.doi.org/10.4103/0253-7613.36534]
[http://dx.doi.org/10.4103/0253-7613.36534]
[4]
Xie Y, Zhang D, Zhang J, Yuan J. Metabolism, transport and drug-drug interactions of silymarin. Molecules 2019; 24(20): 3693.
[5]
Karimi G, Vahabzadeh M, Lari P, Rashedinia M, Moshiri M. “Silymarin”, a promising pharmacological agent for treatment of diseases. Iran J Basic Med Sci 2011; 14(4): 308-17.
[PMID: 23492971]
[PMID: 23492971]
[6]
Saller R, Melzer J, Reichling J, Brignoli R, Meier R. An updated systematic review of the pharmacology of silymarin. Forsch Komplement Med 2007; 14(2): 70-80.
[PMID: 17464157]
[PMID: 17464157]
[7]
Tyagi A, Agarwal C, Chan D, Agarwal R. Synergistic anti-cancer effects of silibinin with conventional cytotoxic agents doxorubicin, cisplatin and carboplatin against human breast carcinoma MCF-7 and MDA-MB468 cells. Oncol Rep 2004; 11(2): 493-9.
[http://dx.doi.org/10.3892/or.11.2.493] [PMID: 14719089]
[http://dx.doi.org/10.3892/or.11.2.493] [PMID: 14719089]
[8]
Katiyar S. Silymarin and skin cancer prevention: Anti-inflammatory, antioxidant and immunomodulatory effects. (Review). Int J Oncol 2005; 26(1): 169-76.
[http://dx.doi.org/10.3892/ijo.26.1.169] [PMID: 15586237]
[http://dx.doi.org/10.3892/ijo.26.1.169] [PMID: 15586237]
[9]
Sonali D, Tejal S, Vaishali T, Tejal G. Silymarin-solid dispersions: Characterization and influence of preparation methods on dissolution. Acta Pharm 2010; 60(4): 427-43.
[http://dx.doi.org/10.2478/v10007-010-0038-3] [PMID: 21169135]
[http://dx.doi.org/10.2478/v10007-010-0038-3] [PMID: 21169135]
[10]
Yang G, Zhao Y, Feng N, Zhang Y, Liu Y, Dang B. Improved dissolution and bioavailability of silymarin delivered by a solid dispersion prepared using supercritical fluids. As. J Pharm Sci 2015; 10(3): 194-202.
[http://dx.doi.org/10.1016/j.ajps.2014.12.001]
[http://dx.doi.org/10.1016/j.ajps.2014.12.001]
[11]
Peng Y, Deng Z, Wang C. Preparation and prodrug studies of quercetin pentabenzensulfonate. Yakugaku Zasshi 2008; 128(12): 1845-9.
[http://dx.doi.org/10.1248/yakushi.128.1845] [PMID: 19043305]
[http://dx.doi.org/10.1248/yakushi.128.1845] [PMID: 19043305]
[12]
Javed S, Kohli K, Ahsan W. Solubility and dissolution enhancement of Silymarin with fulvic acid carrier. Int J Drug Dev Res 2016; 8(1): 9-14.
[13]
Nakhat PD, Naidu RA, Babla IB, Khan S, Yeole PG. Design and evaluation of silymarin-HP-β-CD solid dispersion tablets. Indian J Pharm Sci 2007; 69(2): 287.
[http://dx.doi.org/10.4103/0250-474X.33160]
[http://dx.doi.org/10.4103/0250-474X.33160]
[14]
Li FQ, Hu JH, Wang H, Zhu QG, Sun HJ, Cai Z. Relativities between lattice changes and the function of dissolution improvement of poorly soluble drug silymarin based upon PEG 6,000 solid dispersion system. Yao Xue Xue Bao 2002; 37(4): 294-8.
[PMID: 12579827]
[PMID: 12579827]
[15]
Schick C. Differential Scanning Calorimetry (DSC) of semicrystalline polymers. Anal Bioanal Chem 2009; 395(6): 1589-611.
[http://dx.doi.org/10.1007/s00216-009-3169-y] [PMID: 19834693]
[http://dx.doi.org/10.1007/s00216-009-3169-y] [PMID: 19834693]
[16]
Vanden Poel G, Mathot VBF. High-speed/high performance differential scanning calorimetry (HPer DSC): Temperature calibration in the heating and cooling mode and minimization of thermal lag. Thermochim Acta 2006; 446(1-2): 41-54.
[http://dx.doi.org/10.1016/j.tca.2006.02.022]
[http://dx.doi.org/10.1016/j.tca.2006.02.022]
[17]
Merzlyakov M, Schick C. Step response analysis in DSC — a fast way to generate heat capacity spectra. Thermochim Acta 2001; 380(1): 5-12.
[http://dx.doi.org/10.1016/S0040-6031(01)00631-1]
[http://dx.doi.org/10.1016/S0040-6031(01)00631-1]
[18]
de Barros TMVR, Santos RC, Fernandes AC, da Piedade MEM. Accuracy and precision of heat capacity measurements using a heat flux differential scanning calorimeter. Thermochim Acta 1995; 269-270: 51-60.
[http://dx.doi.org/10.1016/0040-6031(95)02706-8]
[http://dx.doi.org/10.1016/0040-6031(95)02706-8]
[19]
Chauhan A, Chauhan P. Powder XRD technique and its applications in science and technology. J Anal Bioanal Tech 2014; 5(6): 1-5.
[http://dx.doi.org/10.4172/2155-9872.1000212]
[http://dx.doi.org/10.4172/2155-9872.1000212]
[20]
Li P, Chu Y, Wang L, et al. Structure determination of the theophylline–nicotinamide cocrystal: A combined powder XRD, 1D solid-state NMR, and theoretical calculation study. CrystEngComm 2014; 16(15): 3141-7.
[http://dx.doi.org/10.1039/C4CE00012A]
[http://dx.doi.org/10.1039/C4CE00012A]
[21]
Chauhan A, Kaith B. X-Ray Powder diffraction studies to evaluate the transition in graft copolymers procured from roselle fiber. J Nat Fibers 2012; 9(2): 87-97.
[http://dx.doi.org/10.1080/15440478.2012.682434]
[http://dx.doi.org/10.1080/15440478.2012.682434]
[22]
Kaith BS, Singha AS, Chauhan A, Misra BN. X-ray diffraction studies and thermogravimetric/differential thermal analysis of graft copolymers of methyl acrylate onto Hibiscus sabdariffa fiber. J Polym Mater 2006; 23: 349-56.
[23]
Zhu J, Zhao-GangYang XM, Sun JB, Awuti G, Zhang X, Zhang Q. Preparation and physicochemical characterization of solid dispersion of quercetin and polyvinylpyrrolidone. J Chin Pharm Sci 2007; 16: 51.
[24]
Indian Pharmacopeia, Government of India Ministry of Health & Family Welfare. Ghaziabad. Indian Pharmacopoeia Commission 2007; 477: pp. 177-183.
[25]
Gupta SP, Gupta HP. Regression Analysis Business Statistics 16 Edi. New Delhi: Sultan Chand and Sons 2011; pp. 238-71.
[26]
Sethia S, Squillante E. Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods. Int J Pharm 2004; 272(1-2): 1-10.
[http://dx.doi.org/10.1016/j.ijpharm.2003.11.025] [PMID: 15019063]
[http://dx.doi.org/10.1016/j.ijpharm.2003.11.025] [PMID: 15019063]
[27]
Özkan Y. Doğanay N, Dikmen N, Işımer A. Enhanced release of solid dispersions of etodolac in polyethylene glycol. Farmaco 2000; 55(6-7): 433-8.
[http://dx.doi.org/10.1016/S0014-827X(00)00062-8] [PMID: 11204743]
[http://dx.doi.org/10.1016/S0014-827X(00)00062-8] [PMID: 11204743]
[28]
Patel T, Patel LD, Patel T, Makwana S, Patel T. Enhancement of dissolution of fenofibrate by solid dispersion technique. Int J Res Pharm Sci 2010; 1: 127-32.
[29]
Ming-Thau S, Ching-Min Y, Sokoloski TD. Characterization and dissolution of fenofibrate solid dispersion systems. Int J Pharm 1994; 103(2): 137-46.
[http://dx.doi.org/10.1016/0378-5173(94)90094-9]
[http://dx.doi.org/10.1016/0378-5173(94)90094-9]
[30]
Sjökvist E, Nyström C. Physicochemical aspects of drug release. VI. Drug dissolution rate from solid particulate dispersions and the importance of carrier and drug particle properties. Int J Pharm 1988; 47(1-3): 51-66.
[http://dx.doi.org/10.1016/0378-5173(88)90215-3]
[http://dx.doi.org/10.1016/0378-5173(88)90215-3]
[31]
Abrol S, Trehan A, Katare O. Comparative study of different silymarin formulations: Formulation, characterisation and in vitro/in vivo evaluation. Curr Drug Deliv 2005; 2(1): 45-51.
[http://dx.doi.org/10.2174/1567201052772870] [PMID: 16305407]
[http://dx.doi.org/10.2174/1567201052772870] [PMID: 16305407]
[32]
Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci 2001; 13(2): 123-33.
[http://dx.doi.org/10.1016/S0928-0987(01)00095-1] [PMID: 11297896]
[http://dx.doi.org/10.1016/S0928-0987(01)00095-1] [PMID: 11297896]
[33]
Liu YM, Wu ZQ, Bao S, et al. The possibility of changing the wettability of material surface by adjusting gravity. Research 2020; 2020: 2640834.
[http://dx.doi.org/10.34133/2020/2640834] [PMID: 32043083]
[http://dx.doi.org/10.34133/2020/2640834] [PMID: 32043083]
[34]
Hohne G, McNaughton JL, Hemminger W, Flammersheim HJ, Flammersheim HJ. Differential scanning calorimetry. Springer 2003.
[35]
Von Stockar U, Marison IW. The use of calorimetry in biotechnology Bioprocesses and engineering advances in biochemical engineering/biotechnology. Berlin, Heidelberg: Springer 1989; Vol. 40.
[36]
Ivanisevic I, McClurg RB, Schields PJ. Uses of X‐ray powder diffraction in the pharmaceutical industry. Pharmaceutical sciences encyclopedia. Drug discovery, development, and manufacturing 2010; 1-42.
[37]
Permanadewi I, Kumoro AC, Wardhani DH, Aryanti N. Modelling of controlled drug release in gastrointestinal tract simulation. J Phys Conf Ser 2019; 1295(1): 012063.
[http://dx.doi.org/10.1088/1742-6596/1295/1/012063]
[http://dx.doi.org/10.1088/1742-6596/1295/1/012063]
[38]
Badarinath AV, Rao KM, Chetty CM, Ramkanth ST, Rajan TV, Gnanaprakash K. A review on in-vitro antioxidant methods: Comparisions, correlations and considerations. Int J Pharm Tech Res 2010; 2: 1276-85.
[39]
Li X, Yuan Q, Huang Y, Zhou Y, Liu Y. Development of silymarin self-microemulsifying drug delivery system with enhanced oral bioavailability. AAPS PharmSciTech 2010; 11(2): 672-8.
[http://dx.doi.org/10.1208/s12249-010-9432-x] [PMID: 20405254]
[http://dx.doi.org/10.1208/s12249-010-9432-x] [PMID: 20405254]
[40]
Wen Z, Dumas TE, Schrieber SJ, Hawke RL, Fried MW, Smith PC. Pharmacokinetics and metabolic profile of free, conjugated, and total silymarin flavonolignans in human plasma after oral administration of milk thistle extract. Drug Metab Dispos 2008; 36(1): 65-72.
[http://dx.doi.org/10.1124/dmd.107.017566] [PMID: 17913795]
[http://dx.doi.org/10.1124/dmd.107.017566] [PMID: 17913795]
[41]
Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007; 39(1): 44-84.
[http://dx.doi.org/10.1016/j.biocel.2006.07.001] [PMID: 16978905]
[http://dx.doi.org/10.1016/j.biocel.2006.07.001] [PMID: 16978905]
[43]
Korea United Pharm. Mosapride sustained-release formulation providing pharmacological and clinical effects with once-daily administration Patent US20160030436A1 2016.
[44]
Zhejiang University ZJU. Preparation and application of silymarin lipid nanoparticles Patent: CN105687159A 2016.
[46]
Chongqing medical & pharmaceutical college. Silymarin PLGA
nanoparticles and preparation method thereof. Patent:
CN105477039A, 2016.
[48]
Shanghai Institute of Pharmaceutical Industry. Silymarin nano granular preparation and process for preparing the same. Patent: CN1463700A,. 2002.
[49]
Howard J Smith & Associates Pt Ltd. Method of treatment of liver
disease. Patent: CN102573864A, 2010.
[50]
Utah Inha DDS & Advanced Therapeutics Res Center. Method for preparing microspheres for sustained release of drugs with low solubility. Available From: https://worldwide.espacenet.com/patent/search/family/073451650/publication/KR20200127964A?q=KR20200127964A (Assessed on December 1, 2021).
[51]
Chongqing Anshangyuan Agriculture Tech Dev Co. Veterinary
antimicrobial agent containing silymarin. Patent: CN106619813A, 2015.
[52]
Zhongxing Pharm Co. Preparation method for silymarin chitosan
polymer micelles. Patent: CN110934826A, 2019.
[53]
Chengdu Sibeijia Tech Co. Medicinal composition for injection,
used for improving stability of silymarin medicine injection preparation.
Patent: CN105935351A, 2016.
[54]
Nutramax Lab Inc. Compositions comprising sulforaphane and
silybum marianum extract or powder containing silymarin and/or
silibinin. Patent: JP2019014763A, 2019.
[55]
Jiangsu Jianjia Pharmaceutical Industry Co. Silymarinphospholipid
complex and preparation method thereof. Patent:
CN103751785A, 2014.
[56]
Chongqing Medical & Pharmaceutical College. Silymarin nanometer
anti-wrinkle eye cream and preparation method thereof.
Patent: CN110897908A, 2019.
[58]
Dr. Mithun B. A novel formulation of silymarin for treatment of hepatitis. Available From: https://worldwide.espacenet.com/patent/search/family/081259351/publication/au2021104541a4?Q= au2021104541a4 (Assessed on January 20,2023).
