Nano-sized Droplets of Self-Emulsifying System for Enhancing Oral Bioavailability of Chemotherapeutic Agent VP-16 in Rats: A Nano Lipid Carrier for BCS Class IV Drugs

  • Nayab Khalid Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Punjab, Pakistan.
  • Muhammad Sarfraz Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. College of Pharmacy, Al Ain University of Science and Technology, Al Ain, Abu Dhabi, UAE.
  • Mosab Arafat College of Pharmacy, Al Ain University of Science and Technology, Al Ain, Abu Dhabi, UAE.
  • Muhammad Akhtar Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Punjab, Pakistan. Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King’s College London, London, UK.
  • Raimar Löbenberg Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canad
  • Nisar Ur Rehman Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Punjab, Pakistan. Faculty of Pharmacy, Margalla Institute of Health Sciences, Rawalpindi, Pakistan.

Abstract

PURPOSE: The purpose of this study was to investigate the ability of a self-nano-emulsifying drug delivery system (SNEDDS) to enhance the oral bioavailability of a BCS class IV drug, etoposide (VP-16). METHOD: A series of SNEDDS formulations with VP-16 were prepared consisting of medium chain triglycerides, polysorbate 80, diethylene glycol monoethyl ether and propylene glycol monolaurate type-1.  Based on an obtained ternary phase diagram, an optimum formulation was selected and characterized in terms of size, zeta potential, loading, morphology and in vitro drug release. The pharmacokinetic parameters and oral bioavailability of VP-16 suspension and VP-16 in SNEDDS was assessed using 30 Male Sprague–Dawley rats and compared with the commercial product (VePesid®). RESULTS: Pharmacokinetic data showed that the mean values for AUC0-t of VP-16 in SNEDDS was 6.4 fold higher compared to a drug suspension and 2.4-folds higher than VePesid®. Similarly, the mean value for Cmax of VP-16 in SNEDDS (1.13± 0.07 µg/ml µg.h/mL) was higher than VePesid® (0.62± 0.09 µg/mL) and drug suspension (0.13± 0.07 µg/mL). CONCLUSION: The SNEDDS formulation was able to enhance the oral bioavailability of the BCS Class IV chemotherapeutic agent VP-16 by increasing the dissolution and absorption of the drug. A good in vitro in vivo correlation was found between the in vitro dissolution and in vivo absorption data of VP-16 SNEDDS preparation. Therefore, SNEDDS formulations might be a very promising approach for BCS Class IV drugs.

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References

Mazzaferro S, Bouchemal K, Ponchel G. Oral delivery of anticancer drugs I: general considerations. Drug Discov Today. 2013;18: 25-34.

Liu G, Franssen E, Fitch M, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol.1997;15:110-115.

O’Neill VJ, Twelves CJ. Oral cancer treatment: developments in chemotherapy and beyond. Br J Cancer. 2002;87:933-937.

Arafat M. The effect of intestinal bile on the stability of lipid-based vesicular system used as oral drug carriers. Glob Drugs Therapy.2016; 2:1-2.

R. Löbenberg and G. L. Amidon. Modern bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards. Eur. J. Pharm. Biopharm.2000;50:3–12.

Shirazi FH, Bahrami G, Stewart DJ, Tomiak E, Delorme F, Noel D, Goel R. A rapid reversed phase high performance liquid chromatographic method for determination of etoposide (VP-16) in human plasma. J Pharm Biomed Anal. 2001; 25:353-356.

Burden DA, Kingma PS, Froelich-Ammon SJ, Bjornsti MA, Patchan MW, Thompson RB, Osheroff N. Topoisomerase II. Etoposide interactions direct the formation of drug-induced enzyme-DNA cleavage complexes. J Biol Chem.1996;271:29238-44.

Cavalli R, Caputo O, Gasco MR. Preparation and characterization of solid lipid nano-spheres containing paclitaxel. Eur J Pharm Sci.2000;10:305–309.

Chen DB, Yang TZ, Lu WL, Zhang Q. In vitro and in vivo study of two types of long-circulating solid lipid nanoparticles containing paclitaxel. Chem Pharm Bull. 2001;49:1444-1447.

Shaha JC, Chen JR, Chowa D. Oral bioavailability and in situ absorption of etoposide in rat. Int J Pharm.1992; 84;20:223-232.

Wu Z, Guo D, Deng L, Zhang Y, Yang Q, Chen J. Preparation and evaluation of a self-emulsifying drug delivery system of etoposide–phospholipid complex. Drug Dev Ind Pharm. 2011;37:103–112.

Jain J, Fernandes C, Patravale V. Formulation Development of Parenteral Phospholipid-based Microemulsion of Etoposide. AAPS Pharm Sci Tech.2010;11:826–831.

Sandeep-Kalepu, Manthina M, Padavala V. Oral lipid-based drug delivery systems – an overview. Acta Pharm Sin B. 2013; 3: 361-372.

Sambaraj S, Ammula D, Nagabandi V. Furosemide Loaded Silica-Lipid Hybrid Microparticles: Formulation Development, in vitro and ex vivo Evaluation. Adv Pharm Bull. 2015; 5: 403–409.

Bhoyar PK, Morani DO, Biyani DM, Umekar MJ, Mahure JG, Amgaonkar YM. Encapsulation of Naproxen in Lipid-Based Matrix Microspheres: Characterization and Release Kinetics. J Young Pharm.2011; 3: 105–111.

Barbosa SF, Takatsuka T, Tavares GD, Araújo GLB, Wang H, Vehring R, Löbenberg R,Bou-Chacra N.A. Physical-chemical properties of furosemide nanocrystals developed using rotation-revolution mixer. Pharm. Dev. Technol. 2016; 21: 812-822.

Zhang P, Liu Y, Feng N, Xu H. Preparation and evaluation of self-emulsifying drug delivery system of oridonin. Int J Pharm 2008; 355:269–76.

Jabir NR, Tabrez S, Ashraf GM, Shakil S, Damanhouri GA, Kamal MA. Nanotechnology-based approaches in anticancer research. Int J Nanomedicine. 2012; 7: 4391-4408.

Singh AK, Chaurasiya A., Awasthi A, Mishra G, Asati D, Khar RK., Mukherjee R. Oral bioavailability enhancement of exemestane from self-microemulsifying drug delivery system (SMEDDS). AAPS Pharm Sci Tech. 2009; 10: 906–916.

Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci.2006;29:278–87.

Pouton CW. Lipid formulations for oral administration of drugs: nonemulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery systems. Eur J Pharm Sci.2000;11 (Suppl. 2) S93–8.

Hauss DJ, Fogal SE, Ficorilli JV, Price CA, Roy T, Jayaraj AA, et al. Lipid-based delivery systems for improving the bioavailability and lymphatic transport of a poorly water-soluble LTB4 inhibitor. J Pharm Sci.1998;87:164–9.

Hong EP, Kim JY, Kim SH, Hwang KM, Park CW, Lee HJ, Kim DW, Weon KY, Jeong SY, Park ES. Formulation and Evaluation of a Self-microemulsifying Drug Delivery System Containing Bortezomib. Chem Pharm Bull. 2016; 64:1108-1117.

Yang S., Gursoy RN, Lambert G, Benita S. Enhanced oral absorption of paclitaxel in a novel self-microemulsifying drug delivery system with or without concomitant use of P-glycoprotein inhibitors. Pharm Res. 2004; 21:261-270.

Kamal T, Sarfraz M, Arafat M, Mikov M, Rahman N. Cross-linked guar gum and sodium borate based microspheres as colon-targeted anticancer drug delivery systems for 5-fluorouracil. Pak J Pharm Sci.2017; 30(Suppl.6): 2329-2336.

Ujhelyi Z, Kalantari A, Vecsernyés M, Róka E, Fenyvesi F, Póka R, Kozma B, Bácskay I. The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells. Molecules.2015; 20:13226-13239.

Wu Z, Guo D, Deng L, Zhang Y, Yang Q, Chen J. Preparation and evaluation of a self-emulsifying drug delivery system of etoposide-phospholipid complex. Drug Dev Ind Pharm. 2011;37:103-12.

Khalid N, Rahman N, Löbenberg R, Akhtar M, Sarfaraz M, Hajjar M. Design and Evaluation of SMEDDS to Enhance Solubility and Dissolution of Anticancer Drug Using Modified Cylinder Method. Lat Am J Pharm. 2017; 36: 647-57.

Arafat M, Kirchhoefer C, Mikov M, Sarfraz M, Löbenberg R. Nanosized liposomes containing bile salt: A vesicular nanocarrier for enhancing oral bioavailability of BCS class III drug. J Pharm Pharm Sci 2017; 20: 305-318.

Zuo J, Gao Y, Bou-Chacra N, Löbenberg R. Evaluation of the DDSolver software applications. Biomed Res Int. 2014;2014:204925. doi: 10.1155/2014/204925.

Gershanik T, Haltne E, Lehr CM, Benita S. Chargedependent interaction of self-emulsifying oil formulations with Caco-2 cell monolayers: Binding, effects on barrier function and cytotoxicity. Int J Pharm.2000; 211:29–36.

Aungst BJ, Saitoh H, Burchman DL, Huang S-M, Mousa SA, Hussain MA. Enhancement of the intestinal absorption of peptides and nonpeptides. J Control Release 1996; 41:19-31.

Hanbali OA, Hamed R, Arafat M, Bakkour Y, Matubsi H, Mansour R, Bataineh Y, Aldhoun M, Sarfraz M, Dardas Y, Formulation and evaluation of diclofenac controlled release matrix tablets made of HPMC and Poloxamer 188 polymer: An assessment on mechanism of drug release. Pak J Pharm Sci.2018;31(Suppl.1):345-351.

Y. Gao, J. Zuo, N. Bou-Chacra et al., “In vitro release kinetics of anti-tuberculosis drugs from nanoparticles assessed using a modified dissolution apparatus,” BioMed Research International,2013; Article ID 136590, 9 pages.

Gao, Yuan; Sarfraz, Muhammad Khan; Clas, Sophie-Dorothee; Roa, Wilson; Löbenberg, Raimar.Hyaluronic acid-tocopherol succinate-based self-assembling micelles for targeted delivery of rifampicin to alveolar macrophages Journal of Biomedical Nanotechnology, 2015;11:1312-1329.

Arafat M, Kirchhoefer C, Mikov M. Mixed micelles loaded with bile salt: an approach to enhance intestinal transport of the BCS class III drug cefotaxime in rats. Eur J Drug Metab Pharmacokinet.2017; 42:635-645.

Venkatesh G, Majid MIA, Mansor SM, Nair NK, Croft SL, Navaratnam V. In vitro and in vivo evaluation of selfmicroemulsifying drug delivery system of buparvaquone. Drug Dev Ind Pharm. 2010; 36:735–745.

Sachs-Barrable K, Lee SD, Wasan EK, Thorntona SJ, Wasana KM. Enhancing drug absorption using lipids: A case study presenting the development and pharmacological evaluation of a novel lipid-based oral amphotericin B formulation for the treatment of systemic fungal infections. Adv Drug Deliv Rev. 2008; 60:692–701

Li Y, Pan WS, Chen SL, Xu HX, Yang DJ, Chan ASC. (Pharmacokinetic, tissue distribution, and excretion of puerarin and puerarin-phospholipid complex in rats. Drug Dev Ind Pharm. 2006, 32:413–22.

Tazawa Y, Usukubo I, Takada K, Takekuma Y, Shibayama Y, Sugawara M. Schedule-dependent cytotoxicity of Etoposide and cyclophosphamide in P-glycoprotein-expressing human leukemic K-562 cells. Biol Pharm Bull. 2014; 37: 1323-1329.

Samaa Alrushaid, Casey L. Sayre, Jaime A. Yáñez, M. Laird Forrest, Sanjeewa N. Senadheera, Frank J. Burczynski, Raimar Löbenberg and Neal M. Davies. Pharmacokinetic and Toxicodynamic Characterization of a Novel Doxorubicin Derivative. Pharmaceutics. 2017,9,35.

Lim, S.J., Lee, M.K., Kim, C.K. Altered chemical and biological activities of alltrans retinoic acid incorporated in solid lipid nanoparticle powders. J Control. Release. 2004; 100:53-61.

Published
2018-10-26
How to Cite
Khalid, N., Sarfraz, M., Arafat, M., Akhtar, M., Löbenberg, R., & Ur Rehman, N. (2018). Nano-sized Droplets of Self-Emulsifying System for Enhancing Oral Bioavailability of Chemotherapeutic Agent VP-16 in Rats: A Nano Lipid Carrier for BCS Class IV Drugs. Journal of Pharmacy & Pharmaceutical Sciences, 21(1), 398-408. https://doi.org/10.18433/jpps30097
Section
Pharmaceutical Sciences; Original Research Articles