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Improved Oral Pharmacokinetics of Pentoxifylline with Palm Oil and Capmul® MCM Containing Self-Nano-Emulsifying Drug Delivery System

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Abstract

Pentoxifylline (PTX), an anti-hemorrhage drug used in the treatment of intermittent claudication, is extensively metabolized by the liver resulting in a reduction of the therapeutic levels within a short duration of time. Self-nano-emulsifying drug delivery system (SNEDDS) is well reported to enhance the bio-absorption of drugs by forming nano-sized globules upon contact with the biological fluids after oral administration. The present study aimed to formulate, characterize, and improve the oral bioavailability of PTX using SNEDDS. The formulated SNEDDS consisted of palm oil, Capmul® MCM, and Tween® 80 as oil, surfactant, and co-surfactant, respectively. The mixture design module under the umbrella of the design of experiments was used for the optimization of SNEDDS. The dynamic light-scattering technique was used to confirm the formation of nanoemulsion based on the globule size, in addition to the turbidity measurements. In vivo bioavailability studies were carried out on male Wistar rats. The pharmacokinetic parameters upon oral administration were calculated using the GastroPlus software. The optimized SNEDDS had a mean globule size of 165 nm with minimal turbidity in an aqueous medium. Bioavailability of PTX increased 1.5-folds (AUC = 1013.30 ng h/mL) as SNEDDS than the pure drug with an AUC of 673.10 ng h/mL. In conclusion, SNEDDS was seen to enhance the bioavailability of PTX and can be explored to effectively control the incidents of intermittent claudication.

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References

  1. Salhiyyah K, Forster R, Senanayake E, Abdel-Hadi M, Booth A, Michaels JA. Pentoxifylline for intermittent claudication. Cochrane Database Syst Rev. 2015;9(9):CD005262.

    PubMed  Google Scholar 

  2. Patel SK, Surowiec SM. Intermittent claudication [internet]. StatPearls. Treasure Island: StatPearls Publishing; 2019.

    Google Scholar 

  3. Cassar K. Intermittent claudication. BMJ. 2006;333(7576):1002–5.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yentes JM, Huisinga JM, Myers SA, Pipinos II, Johanning JM, Stergiou N. Pharmacological treatment of intermittent claudication does not have a significant effect on gait impairments during claudication pain. J Appl Biomech. 2012;28(2):184–91.

    Article  PubMed  PubMed Central  Google Scholar 

  5. McCarty MF, O’Keefe JH, DiNicolantonio JJ. Pentoxifylline for vascular health: a brief review of the literature. Open Heart. 2016;3(1):e000365.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Chen Y-M, Chiang W-C, Lin S-L, Tsai T-J. Therapeutic efficacy of pentoxifylline on proteinuria and renal progression: an update. J Biomed Sci. 2017;24(1):84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Dorner GT, Zawinka C, Resch H, Wolzt M, Schmetterer L, Garhofer G. Effects of pentoxifylline and alprostadil on ocular hemodynamics in healthy humans. Investig Opthalmol Vis Sci. 2007;48(2):815.

    Article  Google Scholar 

  8. Incandela L, Cesarone MR, Belcaro G, De Sanctis MT, Nicolaides AN, Griffin M, et al. Treatment of vascular inner ear disease with pentoxifylline: a 4-week, controlled, randomized trial. Angiology. 53(Suppl 1):S19–22.

  9. Magnusson M, Gunnarsson M, Berntorp E, Björkman S, Höglund P. Effects of pentoxifylline and its metabolites on platelet aggregation in whole blood from healthy humans. Eur J Pharmacol. 2008;581(3):290–5.

    Article  CAS  PubMed  Google Scholar 

  10. Zhang M, Xu Y-J, Mengi SA, Arneja AS, Dhalla NS. Therapeutic potentials of pentoxifylline for treatment of cardiovascular diseases. Exp Clin Cardiol. 2004;9(2):103–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Best BM, Burns JC, DeVincenzo J, Phelps SJ, Blumer JL, Wilson JT, et al. Pharmacokinetic and tolerability assessment of a pediatric oral formulation of pentoxifylline in Kawasaki disease. Curr Ther Res Clin Exp. 2003;64(2):96–115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mauro VF, Mauro LS, Hageman JH. Comparison of Pentoxifylline pharmacokinetics between smokers and nonsmokers. J Clin Pharmacol. 1992;32(11):1054–8.

    Article  CAS  PubMed  Google Scholar 

  13. Ghate VM, Kodoth AK, Shah A, Vishalakshi B, Lewis SA. Colloidal nanostructured lipid carriers of pentoxifylline produced by microwave irradiation ameliorates imiquimod-induced psoriasis in mice. Colloids Surf B: Biointerfaces. 2019;181:389–99.

    Article  CAS  PubMed  Google Scholar 

  14. AL Shuwaili AH, Rasool BKA, Abdulrasool AA. Optimization of elastic transfersomes formulations for transdermal delivery of pentoxifylline. Eur J Pharm Biopharm. 2016;102:101–14.

    Article  CAS  PubMed  Google Scholar 

  15. Sant VP, Nagarsenker MS, Rao SGA, Gude RP. Enhancement of anti-metastatic activity of pentoxifylline by encapsulation in conventional liposomes and sterically stabilized liposomes in murine experimental B16F10 melanoma model. J Pharm Pharmacol. 2000;52(12):1461–6.

    Article  CAS  PubMed  Google Scholar 

  16. Yan KS, Yan TX, Guo H, Li JZ, Wei LL, Wang C, et al. Evaluation of transdermal permeability of pentoxifylline gel: In vitro skin permeation and in vivo microdialysis using Wistar rats. Drug Discov Ther. 2007;1(1):78–83.

    CAS  PubMed  Google Scholar 

  17. Baloch J, Sohail MF, Sarwar HS, Kiani MH, Khan GM, Jahan S, et al. Self-nanoemulsifying drug delivery system (SNEDDS) for improved oral bioavailability of chlorpromazine: in vitro and in vivo evaluation. Medicina (Kaunas). 2019;55(5).

    Article  PubMed Central  Google Scholar 

  18. Singh B, Khurana L, Bandyopadhyay S, Kapil R, Katare OOP. Development of optimized self-nano-emulsifying drug delivery systems (SNEDDS) of carvedilol with enhanced bioavailability potential. Drug Deliv. 2011;18(8):599–612.

    Article  CAS  PubMed  Google Scholar 

  19. Mancinelli A, Pace S, Marzo A, Arrigoni Martelli E, Passetti G. Determination of pentoxifylline and its metabolites in human plasma by high-performance liquid chromatography with solid-phase extraction. J Chromatogr B Biomed Sci Appl. 1992;575(1):101–7.

    Article  CAS  Google Scholar 

  20. Yen C-C, Chang C-W, Hsu M-C, Wu Y-T. Self-nanoemulsifying drug delivery system for resveratrol: enhanced oral bioavailability and reduced physical fatigue in rats. Int J Mol Sci. 2017;18(9).

    Article  PubMed Central  CAS  Google Scholar 

  21. Avachat AM, Patel VG. Self nanoemulsifying drug delivery system of stabilized ellagic acid–phospholipid complex with improved dissolution and permeability. Saudi Pharm J. 2015;23(3):276–89.

    Article  PubMed  Google Scholar 

  22. Tran T, Rades T, Müllertz A. Formulation of self-nanoemulsifying drug delivery systems containing monoacyl phosphatidylcholine and Kolliphor® RH40 using experimental design. Asian J Pharm Sci. 2018;13(6):536–45.

    Article  PubMed  Google Scholar 

  23. Kodoth AK, Ghate VM, Lewis SA, Badalamoole V. Application of pectin-zinc oxide hybrid nanocomposite in the delivery of a hydrophilic drug and a study of its isotherm, kinetics and release mechanism. Int J Biol Macromol. 2018;115:418–30.

    Article  CAS  PubMed  Google Scholar 

  24. Patel J, Patel A, Raval M, Sheth N. Formulation and development of a self-nanoemulsifying drug delivery system of irbesartan. J Adv Pharm Technol Res. 2011;2(1):9–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Eid AM, El-Enshasy HA, Aziz R, Elmarzugi NA. The preparation and evaluation of self-nanoemulsifying systems containing Swietenia oil and an examination of its anti-inflammatory effects. Int J Nanomedicine. 2014;9:4685–95.

    PubMed  PubMed Central  Google Scholar 

  26. Ghate VM, Kodoth AK, Vishalakshi B, Lewis SA. Development of MART for the rapid production of nanostructured lipid carriers loaded with all-trans retinoic acid for dermal delivery. AAPS PharmSciTech. 2019; (in press).

  27. Shahba AA-W, Mohsin K, Alanazi FK. Novel self-nanoemulsifying drug delivery systems (SNEDDS) for oral delivery of cinnarizine: design, optimization, and in-vitro assessment. AAPS PharmSciTech. 2012;13(3):967–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kumar A, Jaiswal M. Effect of self nanoemulsifying drug delivery system (snedds) on intestinal permeation and anti-diabetic activity of;Berberis aristata extract: in-vitro and ex-vivo studies. J Nanopharmaceutics Drug Deliv. 2016;3(1):51–62.

    Article  Google Scholar 

  29. Ke Z, Hou X, Jia X-B. Design and optimization of self-nanoemulsifying drug delivery systems for improved bioavailability of cyclovirobuxine D. Drug Des Devel Ther. 2016;10:2049–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kazi M, Al-Swairi M, Ahmad A, Raish M, Alanazi FK, Badran MM, et al. Evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for poorly water-soluble Talinolo: preparation, in vitro and in vivo assessment. Front Pharmacol. 2019;10:459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Daga PR, Bolger MB, Haworth IS, Clark RD, Martin EJ. Physiologically based pharmacokinetic modeling in lead optimization. 1. Evaluation and adaptation of GastroPlus to predict bioavailability of Medchem series. Mol Pharm. 2018;15(3):821–30.

    Article  CAS  PubMed  Google Scholar 

  32. Hosea NA, Jones HM. Predicting pharmacokinetic profiles using in silico derived parameters. Mol Pharm. 2013;10(4):1207–15.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang X, Lionberger RA, Davit BM, Yu LX. Utility of physiologically based absorption modeling in implementing quality by design in drug development. AAPS J. 2011;13(1):59–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Ali H, Prasad Verma PR, Dubey SK, Venkatesan J, Seo Y, Kim S-K, et al. In vitro–in vivo and pharmacokinetic evaluation of solid lipid nanoparticles of furosemide using Gastroplus™. RSC Adv. 2017;7(53):33314–26.

    Article  CAS  Google Scholar 

  35. Sharma A, Benbrook DM, Woo S. Pharmacokinetics and interspecies scaling of a novel, orally-bioavailable anti-cancer drug, SHetA2. Kim J, editor. PLoS One. 2018;13(4):e0194046.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Patel G, Shelat P, Lalwani A. Statistical modeling, optimization and characterization of solid self-nanoemulsifying drug delivery system of lopinavir using design of experiment. Drug Deliv. 2016;23(8):3027–42.

    Article  CAS  PubMed  Google Scholar 

  37. Taha EL, Al-Saidan S, Samy AM, Khan MA. Preparation and in vitro characterization of self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate. Int J Pharm. 2004;285(1–2):109–19.

    Article  CAS  PubMed  Google Scholar 

  38. Caliph SM, Charman WN, Porter CJ. Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balanace in lymph-cannulated and non-cannulated rats. J Pharm Sci. 2000;89:1073–84.

    Article  CAS  PubMed  Google Scholar 

  39. Porter CJ, CHarman WN. In vitro assessment of oral lipid based formulations. Adv Drug Deliv Rev. 2001;50(Suppl 1):S127–47.

    Article  CAS  PubMed  Google Scholar 

  40. Chudasama A, Patel V, Nivsarkar M, Vasu K, Shishoo C. Role of lipid-based excipients and their compostition on the bioavailability of antiretroviral self-emulsifying formulations. Drug Deliv. 2015;22(4):531–40.

    Article  CAS  PubMed  Google Scholar 

  41. Carriere F. Impact of gastrointestinal lipolysis on oral lipid-based formulations and bioavailability of lipophilic drugs. Biochimie. 2016;125:297–305.

    Article  CAS  PubMed  Google Scholar 

  42. Singh B, Garg B, Kaur R, Jain A, Kumar R, Katare O. Self-nanoemulsifying systems for oral bioavailability enhancement: Recent paradigms. In: Fabrication and Self-Assembly of Nanobiomaterial. Amsterdam: Elsevier; 2016. p. 91–115.

    Chapter  Google Scholar 

  43. Qi X, Wang L, Zhu J, Hu Z, Zhang J. Self-double-emulsifying drug delivery systems (SDEDDS): a new way for oral delivery of drugs with high solubility and low permeability. Int J Pharm. 2011;409(1–2):245–51.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India

    Ashay Manisha Shailendrakumar, Vivek M. Ghate & Shaila A. Lewis

  2. Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India

    Manas Kinra

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Shailendrakumar, A.M., Ghate, V., Kinra, M. et al. Improved Oral Pharmacokinetics of Pentoxifylline with Palm Oil and Capmul® MCM Containing Self-Nano-Emulsifying Drug Delivery System. AAPS PharmSciTech 21, 118 (2020). https://doi.org/10.1208/s12249-020-01644-w

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