Enhanced Solubility and Permeability of Salicis cortex Extract by Formulating as a Microemulsion^[*]

Abstract

A microemulsion system was developed and investigated as a novel oral formulation to increase the solubility and absorption of Salicis cortex extract. This extract possesses many pharmacological activities, in particular, it is beneficial for back pain and osteoarthritic and rheumatic complaints. In this work, after qualitative and quantitative characterization of the extract and the validation of an HPLC/diode array detector analytical method, solubility studies were performed to choose the best components for microemulsion formulation. The optimized microemulsion consisted of 2.5 g of triacetin, as the oil phase, 2.5 g of Tween 20 as the surfactant, 2.5 g of labrasol as the cosurfactant, and 5 g of water. The microemulsion was visually checked, characterized by light scattering techniques and morphological observations. The developed formulation appeared transparent, the droplet size was around 40 nm, and the ζ-potential result was negative. The maximum loading content of Salicis cortex extract resulted in 40 mg/mL. Furthermore, storage stability studies and an in vitro digestion assay were performed. The advantages offered by microemulsion were evaluated in vitro using artificial membranes and cells, i.e., parallel artificial membrane permeability assay and a Caco-2 model. Both studies proved that the microemulsion was successful in enhancing the permeation of extract compounds, so it could be useful to ameliorate the bioefficacy of Salicis cortex.

Key words

icroemulsion - Salix species - Salicaceae - oral delivery - PAMPA - Caco-2 cells

^* Dedicated to Professor Dr. Robert Verpoorte in recognition of his outstanding contribution to natural products research.

• References

• 1 Meier B, Lehmann D, Sticher O, Bettschart A. Identifkation und Bestimmung von je acht Phenolglykosiden in Salix purpurea und Salix daphnoides mit moderner HPLC. Pharm Acta Helv 1985; 60: 269-275
• 2 ESCOP. Monograph: Salicis cortex (willow bark). Fascicule 4. Exeter, UK: European Scientific Cooperative on Phytotherapy; 1997
• 3 Blumenthal M, Busse WR. American Botanical Council, Integrative Medicine Communications, Germany Bundesgesundheitsamt. Commission E. The complete German Commission E monographs: therapeutic Guide to herbal Medicines. Boston, Ma.: American Botanical Council; 1998
• 4 Chrubasik S, Eisenberg E, Balan E, Weinberger T, Luzzati R, Conradt C. Treatment of low back pain exacerbations with willow bark extract: a randomized double-blind study. Am J Med 2000; 109: 9-14
• 5 Chrubasik S, Künzel O, Black A, Conradt C, Kerschbaumer F. Potential economic impact of using a proprietary willow bark extract in outpatient treatment of low back pain: an open non-randomized study. Phytomedicine 2001; 8: 241-251
• 6 Mills SY, Jacoby RK, Chacksfield M, Willoughby M. Effect of a proprietary herbal medicine on the relief of chronic arthritic pain: a double-blind study. Rheumatology 1996; 35: 874-878
• 7 Long L, Soeken K, Ernst E. Herbal medicines for the treatment of osteoarthritis: a systematic review. Rheumatology 2001; 40: 779-793
• 8 Pentz R, Busse HG, König R, Siegers CP. Bioverfügbarkeit von Salicylsäure und Coffein aus einem phytoanalgetischen Kombinationspräparat. Z Phytother 1989; 10: 92-96
• 9 Thilakarathna SH, Rupasinghe HP. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 2013; 5: 3367-3387
• 10 Bilia AR, Piazzini V, Guccione C, Risaliti L, Asprea M, Capecchi G, Bergonzi MC. Improving on nature: The role of nanomedicine in the development of clinical natural drugs. Planta Med 2017; 83: 366-381
• 11 Callender SP, Mathews JA, Kobernyk K, Wettig SD. Microemulsion utility in pharmaceuticals: Implications for multi-drug delivery. Int J Pharm 2017; 526: 425-442
• 12 McClements DJ. Nanoemulsions versus microemulsions: terminology, differences, and similarities. Soft Matter 2012; 8: 1719-1729
• 13 Rosen MJ, Kunjappu JT. Surfactants and interfacial Phenomena. 4th ed. New York: John Wiley & Sons; 2012
• 14 Shen Q, Li X, Li W, Zhao X. Enhanced intestinal absorption of daidzein by borneol/menthol eutectic mixture and microemulsion. AAPS PharmSciTech 2011; 12: 1044-1049
• 15 Kee JL, Hayes ER, McCuistion LE. Pharmacology: a patient-centered nursing Process Approach. 8th ed. St. Louis, Missouri: Elsevier Health Sciences; 2014
• 16 Liu W, Zhai Y, Heng X, Che FY, Chen W, Sun D, Zhai G. Oral bioavailability of curcumin: problems and advancements. J Drug Target 2016; 24: 694-702
• 17 Gupta S, Kesarla R, Omri A. Formulation strategies to improve the bioavailability of poorly absorbed drugs with special emphasis on self-emulsifying systems. ISRN Pharm 2013; 2013: 1-13
• 18 Bilia AR, Isacchi B, Righeschi C, Guccione C, Bergonzi MC. Flavonoids loaded in nanocarriers: an opportunity to increase oral bioavailability and bioefficacy. Food Nutr Sci 2014; 5: 1212-1227
• 19 Bergonzi MC, Hamdouch R, Mazzacuva F, Isacchi B, Bilia AR. Optimization, characterization and in vitro evaluation of curcumin microemulsions. LWT-Food Sci Technol 2014; 59: 148-155
• 20 Piazzini V, Monteforte E, Luceri C, Bigagli E, Bilia AR, Bergonzi MC. Nanoemulsion for improving solubility and permeability of Vitex agnus-castus extract: formulation and in vitro evaluation using PAMPA and Caco-2 approaches. Drug Deliv 2017; 24: 380-390
• 21 Piazzini V, Rosseti C, Bigagli E, Luceri C, Bilia AR, Bergonzi MC. Prediction of permeation and cellular transport of Silybum marianum extract formulated in a nanoemulsion by using PAMPA and Caco-2 cell models. Planta Med 2017; 56: 222-248
• 22 Schonrock U, Steckel F, Kux U, Inoue K. Use of salicin as an anti-irritative active compound in cosmetic and topical dermatological preparations. U.S. Patent 5, 876, 737; 1999. Available at: https://patents.google.com/patent/US5876737A/e Accessed April 20, 2018
• 23 Mitrea E, Lacatusu I, Badea N, Ott C, Oprea O, Meghea A. New approach to prepare willow bark extract – lipid based nanosystems with enhanced antioxidant activity. J Nanosci Nanotechnol 2015; 15: 4080-4089
• 24 Kammerer B, Kahlich R, Biegert C, Gleiter CH, Heide L. HPLC-MS/MS analysis of willow bark extracts contained in pharmaceutical preparations. Phytochem Anal 2005; 16: 470-478
• 25 Guideline ICH Harmonized Tripartite. Validation of analytical procedures: methodology. Text and Methodology Q2 (R1) (2005). Available at: http://www.ich.org/cache/compo/363-272-1.html Accessed 2010
• 26 European Medicines Agency. European Medicines Agency (EMA): Note for Guidance on Validation of Analytical Procedures: Text and Methodology (CPMP/ ICH/381/95). EMA Guidelines 2012; 44: 1-23 Available at http://www.ema.europa.eu Accessed April 20, 2018
• 27 Sharma G, Wilson K, Van der Walle CF, Sattar N, Petrie JR, Kumar MR. Microemulsions for oral delivery of insulin: design, development and evaluation in streptozotocin induced diabetic rats. Eur J Pharm Biopharm 2010; 76: 159-169
• 28 Fiume MZ. Final report on the safety assessment of triacetin. Int J Toxicol 2003; 22: 1-10
• 29 Shinde UA, Modani SH, Singh KH. Design and development of repaglinide microemulsion gel for transdermal delivery. AAPS PharmSciTech 2018; 19: 315-325
• 30 Nielsen CU, Abdulhussein AA, Colak D, Holm R. Polysorbate 20 increases oral absorption of digoxin in wild-type Sprague Dawley rats, but not in mdr1a (−/−) Sprague Dawley rats. Int J Pharm 2016; 513: 78-87
• 31 Woodcock DM, Linsenmeyer ME, Chojnowski G, Kriegler AB, Nink V, Webster LK, Sawyer WH. Reversal of multidrug resistance by surfactants. Br J Cancer 1992; 66: 62-68
• 32 Sha X, Yan G, Wu Y, Li J, Fang X. Effect of self-microemulsifying drug delivery systems containing Labrasol on tight junctions in Caco-2 cells. Eur J Pharm Sci 2005; 24: 477-486
• 33 Zhang P, Liu Y, Feng N, Xu J. Preparation and evaluation of self-microemulsifying drug delivery system of oridonin. Int J Pharm 2008; 355: 269-276
• 34 Kansy M, Senner F, Gubernator K. Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. J Med Chem 1998; 41: 1007-1010
• 35 Alvarez-Figueroa MJ, Pessoa-Mahana CD, Palavecino-González ME, Mella-Raipán J, Espinosa-Bustos C, Lagos-Muñoz ME. Evaluation of the membrane permeability (PAMPA and skin) of benzimidazoles with potential cannabinoid activity and their relation with the Biopharmaceutics Classification System (BCS). AAPS PharmSciTech 2011; 12: 573-578
• 36 Nekkanti V, Wang Z, Betageri GV. Pharmacokinetic evaluation of improved oral bioavailability of valsartan: proliposomes versus self-nanoemulsifying drug delivery system. AAPS PharmSciTech 2016; 17: 851-862
• 37 Petit C, Bujard A, Skalicka-Wozniak K, Cretton S, Houriet J, Christen P, Carrupt PA, Wolfender JL. Prediction of the passive intestinal absorption of medicinal plant extract constituents with the parallel artificial membrane permeability assay (PAMPA). Planta Med 2016; 82: 424-431
• 38 Graverini G, Piazzini V, Landucci E, Pantano D, Nardiello P, Casamenti F, Pellegrini-Giampietro DE, Bilia AR, Bergonzi MC. Solid lipid nanoparticles for delivery of andrographolide across the blood-brain barrier: in vitro and in vivo evaluation. Colloid Surf B Biointerfaces 2018; 161: 302-313
• 39 Hubatsch I, Ragnarsson EG, Artursson P. Determination of drug permeability and prediction of drug absorption in Caco-2 monolayers. Nat Protoc 2007; 2: 2111-2119
• 40 Palmgrén JJ, Mönkkönen J, Korjamo T, Hassinen A, Auriola S. Drug adsorption to plastic containers and retention of drugs in cultured cells under in vitro conditions. Eur J Pharm Biopharm 2006; 64: 369-378
• 41 Heikkinen AT, Mönkkönen J, Korjamo T. Kinetics of cellular retention during Caco-2 permeation experiments: role of lysosomal sequestration and impact on permeability estimates. J Pharmacol Exp Ther 2009; 328: 882-892
• 42 Aditya NP, Shim M, Lee I, Lee Y, Im MH, Ko S. Curcumin and genistein coloaded nanostructured lipid carriers: in vitro digestion and antiprostate cancer activity. J Agric Food Chem 2013; 61: 1878-1883
• 43 Wohnsland F, Faller B. High-throughput permeability pH profile and high-throughput alkane/water log P with artificial membranes. J Med Chem 2001; 44: 923-930
• 44 Sugano K, Hamada H, Machida M, Ushio H. High throughput prediction of oral absorption: improvement of the composition of the lipid solution used in parallel artificial membrane permeation assay. J Biomol Screen 2001; 6: 189-196
• 45 Iacomino G, Fierro O, DʼAuria S, Picariello G, Ferranti P, Liguori C, Addeo F, Mamone G. Structural analysis and Caco-2 cell permeability of the celiac-toxic A-gliadin peptide 31–55. J Agric Food Chem 2013; 61: 1088-1096