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Novel cationic supersaturable nanomicellar systems of raloxifene hydrochloride with enhanced biopharmaceutical attributes

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Abstract

The work describes systematic development of nanomicellar cationic supersaturable self-nanoemulsifying drug delivery systems (CS-SNEDDS) for augmenting oral biopharmaceutical performance of raloxifene hydrochloride. Plain SNEDDS formulation containing Capryol 90, Cremophor RH 40, and Transcutol HP was optimized using D-optimal mixture design. SNEDDS were characterized for emulsification time, globule size, in vitro drug release, and ex vivo permeation. The CS-SNEDDS formulation was prepared from the optimized SNEDDS by adding oleylamine as the cationic charge inducer and HPMC as the polymeric precipitation inhibitor. Evaluation of CS-SNEDDS was carried out through in vitro cell line studies on Caco-2 and MCF-7 cells, in situ perfusion, and in vivo pharmacokinetic studies, which indicated significant improvement in biopharmaceutical attributes of the drug from CS-SNEDDS over plain drug.

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References

  1. Singh B, Garg B, Chaturvedi SC, Arora S, Mandsaurwale R, Kapil R, et al. Formulation development of gastroretentive tablets of lamivudine using the floating-bioadhesive potential of optimized polymer blends. J Pharm Pharmacol. 2012;64:654–69.

    Article  CAS  PubMed  Google Scholar 

  2. Gupta H, Bhandari D, Sharma A. Recent trends in oral drug delivery: a review. Recent Pat Drug Deliv Formul. 2009;3:162–73.

    Article  CAS  PubMed  Google Scholar 

  3. Thanki K, Gangwal RP, Sangamwar AT, Jain S. Oral delivery of anticancer drugs: challenges and opportunities. J Control Release. 2013;170:15–40.

    Article  CAS  PubMed  Google Scholar 

  4. Mazzaferro S, Bouchemal K, Ponchel G. Oral delivery of anticancer drugs I: general considerations. Drug Discov Today. 2012;18:25–34.

    Article  PubMed  Google Scholar 

  5. Stuurman FE, Nuijen B, Beijnen JH, Schellens JHM. Oral anticancer drugs: mechanisms of low bioavailability and strategies for improvement. Clin Pharmacokinet. 2013;52:399–414.

    Article  CAS  PubMed  Google Scholar 

  6. Lee WL, Chao HT, Cheng MH, Wang PH. Rationale for using raloxifene to prevent both osteoporosis and breast cancer in postmenopausal women. Maturitas. 2008;60:92–107.

    Article  CAS  PubMed  Google Scholar 

  7. Snyder KR, Sparano N, Malinowski JM. Raloxifene hydrochloride. Am J Health Syst Pharm. 2000;57:1669–75. quiz 1676-8

    CAS  PubMed  Google Scholar 

  8. Heringa M. Review on raloxifene: profile of a selective estrogen receptor modulator. Int J Clin Pharmacol Ther. 2003;41:331–45.

    Article  CAS  PubMed  Google Scholar 

  9. Chen Y, Jia X, Chen J, Wang J, Hu M. The pharmacokinetics of raloxifene and its interaction with apigenin in rat. Molecules. 2010;15:8478–87.

    Article  CAS  PubMed  Google Scholar 

  10. Tran TH, Poudel BK, Marasini N, Chi SC, Choi HG, Yong CS, et al. Preparation and evaluation of raloxifene-loaded solid dispersion nanoparticle by spray-drying technique without an organic solvent. Int J Pharm. 2013;443:50–7.

    Article  CAS  PubMed  Google Scholar 

  11. Tran TH, Poudel BK, Marasini N, Woo JS, Choi HG, Yong CS, et al. Development of raloxifene-solid dispersion with improved oral bioavailability via spray-drying technique. Arch Pharm Res. 2013;36:86–93.

    Article  CAS  PubMed  Google Scholar 

  12. Wempe MF, Wacher VJ, Ruble KM, Ramsey MG, Edgar KJ, Buchanan NL, et al. Pharmacokinetics of raloxifene in male Wistar-Hannover rats: influence of complexation with hydroxybutenyl-beta-cyclodextrin. Int J Pharm. 2008;346:25–37.

    Article  CAS  PubMed  Google Scholar 

  13. Jha RK, Tiwari S, Mishra B. Bioadhesive microspheres for bioavailability enhancement of raloxifene hydrochloride: formulation and pharmacokinetic evaluation. AAPS Pharm SciTech. 2011;12:650–7.

    Article  CAS  Google Scholar 

  14. Jagadish B, Yelchuri R, K B, et al. Enhanced dissolution and bioavailability of raloxifene hydrochloride by co-grinding with different superdisintegrants. Chem Pharm Bull. 2010;58:293–300.

    Article  CAS  PubMed  Google Scholar 

  15. Fontana MC, Beckenkamp A, Buffon A, Beck RC. Controlled release of raloxifene by nanoencapsulation: effect on in vitro antiproliferative activity of human breast cancer cells. Int J Nanomedicine. 2014;9:2979–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kushwaha AK, Vuddanda PR, Karunanidhi P, et al. Development and evaluation of solid lipid nanoparticles of raloxifene hydrochloride for enhanced bioavailability. Biomed Res Int. 2013;2013:584549.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Tran TH, Ramasamy T, Cho HJ, Kim YII, Poudel BK, Choi HG, et al. Formulation and optimization of raloxifene-loaded solid lipid nanoparticles to enhance oral bioavailability. J Nanosci Nanotechnol. 2014;14:4820–31.

    Article  CAS  PubMed  Google Scholar 

  18. Singh B, Bandopadhyay S, Kapil R, Singh R, Katare O. Self-emulsifying drug delivery systems (SEDDS): formulation development, characterization, and applications. Crit Rev Ther Drug Carrier Syst. 2009;26:427–521.

    Article  CAS  PubMed  Google Scholar 

  19. Porter CJ, Trevaskis NL, Charman WN. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat Rev Drug Discov. 2007;6:231–48.

    Article  CAS  PubMed  Google Scholar 

  20. Kohli K, Chopra S, Dhar D, Arora S, Khar RK. Self-emulsifying drug delivery systems: an approach to enhance oral bioavailability. Drug Discov Today. 2010;15:958–65.

    Article  CAS  PubMed  Google Scholar 

  21. Singh B, Beg S, Khurana RK, Sandhu PS, Kaur R, Katare OP. Recent advances in self-emulsifying drug delivery systems (SEDDS). Crit Rev Ther Drug Carrier Syst. 2014;31:121–85.

    Article  CAS  PubMed  Google Scholar 

  22. Gao P, Morozowich W. Development of supersaturatable self-emulsifying drug delivery system formulations for improving the oral absorption of poorly soluble drugs. Expert Opin Drug Deliv. 2006;3:97–110.

    Article  CAS  PubMed  Google Scholar 

  23. Mathews CDC, Sugano K. Supersaturable formulations. Drug Deliv Systems. 2010;25:371–4.

    Article  Google Scholar 

  24. Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009;98:2549–72.

    Article  CAS  PubMed  Google Scholar 

  25. Elsheikh MA, Elnaggar YS, Gohar EY, Abdallah OY. Nanoemulsion liquid preconcentrates for raloxifene hydrochloride: optimization and in vivo appraisal. Int J Nanomedicine. 2012;7:3787–802.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Singh B, Singh R, Bandyopadhyay S, Kapil R, Garg B. Optimized nanoemulsifying systems with enhanced bioavailability of carvedilol. Colloids Surf B Biointerfaces. 2013;101:465–74.

    Article  CAS  PubMed  Google Scholar 

  27. Beg S, Jena SS, Patra Ch N, et al. Development of solid self-nanoemulsifying granules (SSNEGs) of ondansetron hydrochloride with enhanced bioavailability potential. Colloids Surf B Biointerfaces. 2013;101:414–23.

    Article  CAS  PubMed  Google Scholar 

  28. Singh B, Kaur T, Singh S. Correction of raw dissolution data for loss of drug during sampling. Ind J Pharm Sci. 1997;59:196–9.

    CAS  Google Scholar 

  29. Gao P, Rush BD, Pfund WP, Huang T, Bauer JM, Morozowich W, et al. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J Pharm Sci. 2003;92:2386–98.

    Article  CAS  PubMed  Google Scholar 

  30. Klein S. The use of biorelevant dissolution media to forecast the in vivo performance of a drug. AAPS J. 2010;12:397–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jain AK, Thanki K, Jain S. Solidified self-nanoemulsifying formulation for oral delivery of combinatorial therapeutic regimen: part I. Formulation development, statistical optimization, and in vitro characterization. Pharm Res. 2013;31:923–45.

    Article  PubMed  Google Scholar 

  32. Beg S, Sharma G, Thanki K, Jain S, Katare OP, Singh B. Positively charged self-nanoemulsifying oily formulations of olmesartan medoxomil: systematic development, in vitro, ex vivo and in vivo evaluation. Int J Pharm. 2015;493:466–82.

    Article  CAS  PubMed  Google Scholar 

  33. 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;18:599–612.

    Article  CAS  PubMed  Google Scholar 

  34. Yang ZY, Zhang ZF, He XB, et al. Validation of a novel HPLC method for the determination of raloxifene and its pharmacokinetics in rat plasma. Chromatographia. 2006;65:197.

    Article  Google Scholar 

  35. Chen ZQ, Liu Y, Zhao JH, Wang L, Feng NP. Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system. Int J Nanomedicine. 2012;7:1115–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Beg S, Sandhu PS, Batra RS, et al. QbD-based systematic development of novel optimized solid self-nanoemulsifying drug delivery systems (SNEDDS) of lovastatin with enhanced biopharmaceutical performance. Drug deliv 2014; 1–20.

  37. Tripathi CB, Beg S, Kaur R, Shukla G, Bandopadhyay S, Singh B. Systematic development of optimized SNEDDS of artemether with improved biopharmaceutical and antimalarial potential. Drug Deliv. 2016;23:3209–23.

    Article  CAS  PubMed  Google Scholar 

  38. Gao P, Akrami A, Alvarez F, Hu J, Li L, Ma C, et al. Characterization and optimization of AMG 517 supersaturatable self-emulsifying drug delivery system (S-SEDDS) for improved oral absorption. J Pharm Sci. 2009;98:516–28.

    Article  CAS  PubMed  Google Scholar 

  39. Xu S, Dai WG. Drug precipitation inhibitors in supersaturable formulations. Int J Pharm. 2013;453:36–43.

    Article  CAS  PubMed  Google Scholar 

  40. Singh G, Pai RS. In vitro and in vivo performance of supersaturable self-nanoemulsifying system of trans-resveratrol. Artif Cells Nanomed Biotechnol. 2016;44:510–6.

    Article  CAS  PubMed  Google Scholar 

  41. Gao P, Guyton ME, Huang T, Bauer JM, Stefanski KJ, Lu Q. Enhanced oral bioavailability of a poorly water soluble drug PNU-91325 by supersaturatable formulations. Drug Dev Ind Pharm. 2004;30:221–9.

    Article  CAS  PubMed  Google Scholar 

  42. Khanfar M, Sheikh Salem M, Hawari R. Formulation factors affecting the release of ezetimibe from different liquisolid compacts. Pharm Dev Technol 2012

  43. Gulsun T, Gursoy RN, Oner L. Design and characterization of nanocrystal formulations containing ezetimibe. Chem Pharm Bull (Tokyo). 2011;59:41–5.

    Article  CAS  Google Scholar 

  44. Chen Y, Chen C, Zheng J, Chen Z, Shi Q, Liu H. Development of a solid supersaturatable self-emulsifying drug delivery system of docetaxel with improved dissolution and bioavailability. Biol Pharm Bull. 2011;34:278–86.

    Article  CAS  PubMed  Google Scholar 

  45. Thomas N, Holm R, Garmer M, et al. Supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) enhance the bioavailability of the poorly water-soluble drug simvastatin in dogs. AAPS J. 2012;15:219–27.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Warren DB, Benameur H, Porter CJ, et al. Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: a mechanistic basis for utility. J Drug Target. 2010;18:704–31.

    Article  CAS  PubMed  Google Scholar 

  47. Raghavan SL, Trividic A, Davis AF, Hadgraft J. Effect of cellulose polymers on supersaturation and in vitro membrane transport of hydrocortisone acetate. Int J Pharm. 2000;193:231–7.

    Article  CAS  PubMed  Google Scholar 

  48. Thomas N, Holm R, Mullertz A, et al. In vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS). J Control Release. 2012;160:25–32.

    Article  CAS  PubMed  Google Scholar 

  49. Marques RC, Cole E, Kruep D, et al. Liquid-filled gelatin capsules. USP Pharmacopeial. Forum. 2009;35:1029–41.

    Google Scholar 

  50. Madan J, Chawla G, Arora V, Malik R, Bansal AK. Unbiased membrane permeability parameters for gabapentin using boundary layer approach. AAPS J. 2005;7:E224–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Oh DM, Curl RL, Amidon GL. Estimating the fraction dose absorbed from suspensions of poorly soluble compounds in humans: a mathematical model. Pharm Res. 1993;10:264–70.

    Article  CAS  PubMed  Google Scholar 

  52. Takekuma Y, Takenaka T, Kiyokawa M, Yamazaki K, Okamoto H, Kitabatake A, et al. Evaluation of effects of polymorphism for metabolic enzymes on pharmacokinetics of carvedilol by population pharmacokinetic analysis. Biol Pharm Bull. 2007;30:537–42.

    Article  CAS  PubMed  Google Scholar 

  53. Polli JE, Rekhi GS, Augsburger LL, Shah VP. Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets. J Pharm Sci. 1997;86:690–700.

    Article  CAS  PubMed  Google Scholar 

  54. Rao MRP, Aghav S, Sukre G, et al. Determination of required HLB of Capryol 90. J Dispers Sci Technol. 2012;35:161–7.

    Article  Google Scholar 

  55. Rao Z, Si L, Guan Y, Pan H, Qiu J, Li G. Inhibitive effect of cremophor RH40 or tween 80-based self-microemulsiflying drug delivery system on cytochrome P450 3A enzymes in murine hepatocytes. J Huazhong Univ Sci Technol. 2010;30:562–8.

    Article  CAS  Google Scholar 

  56. Bandyopadhyay S, Katare OP, Singh B. Development of optimized supersaturable self-nanoemulsifying systems of ezetimibe: effect of polymers and efflux transporters. Expert Opin Drug Deliv. 2014;11:479–92.

    Article  CAS  PubMed  Google Scholar 

  57. Sharma G, Beg S, Thanki K, Katare OP, Jain S, Kohli K, et al. Systematic development of novel cationic self-nanoemulsifying drug delivery systems of candesartan cilexetil with enhanced biopharmaceutical performance. RSC Adv. 2015;5:71500–13.

    Article  CAS  Google Scholar 

  58. Farahmandjou M. Effect of oleic acid and oleylamine surfactants on the size of FePt nanoparticles. J Supercond Novel Magn. 2012;25:2075–9.

    Article  CAS  Google Scholar 

  59. Mourdikoudis S, Liz-Marz án LM. Oleylamine in nanoparticle synthesis. Chem Mater. 2013;25:1465–76.

    Article  CAS  Google Scholar 

  60. Chokprasombata K, Sirisathitkula C, Hardinga P, et al. Monodisperse magnetic nanoparticles: effects of surfactants on the reaction between iron acetylacetonate and platinum acetylacetonate. Revista Mexicana de Fısica. 2013;59:224–8.

    Google Scholar 

  61. Harris RA, Shumbula PM, van der Walt H. Analysis of the interaction of surfactants oleic acid and oleylamine with iron oxide nanoparticles through molecular mechanics modeling. Langmuir. 2015;31:3934–43.

    Article  CAS  PubMed  Google Scholar 

  62. Mourdikoudis S, Liz-Marzán LM. Oleylamine in nanoparticle synthesis. Chem Mater. 2013;25:1465–76.

    Article  CAS  Google Scholar 

  63. Nan Z, Lijun G, Tao W, Dongqin Q. Evaluation of carbamazepine (CBZ) supersaturatable self-microemulsifying (S-SMEDDS) formulation in-vitro and in-vivo. Iran J Pharm Res. 2012;11:257–64.

    PubMed  PubMed Central  Google Scholar 

  64. Song WH, Yeom DW, Lee DH, et al. In situ intestinal permeability and in vivo oral bioavailability of celecoxib in supersaturating self-emulsifying drug delivery system. Arch Pharm Res. 2013;37:626–35.

    Article  PubMed  Google Scholar 

  65. Brewster ME, Vandecruys R, Verreck G, Peeters J. Supersaturating drug delivery systems: effect of hydrophilic cyclodextrins and other excipients on the formation and stabilization of supersaturated drug solutions. Pharmazie. 2008;63:217–20.

    CAS  PubMed  Google Scholar 

  66. Feeney OM, Crum MF, McEvoy CL, et al. 50 years of oral lipid-based formulations: provenance, progress and future perspectives. Adv Drug Deliv Rev. 2016;101:167–94.

    Article  CAS  PubMed  Google Scholar 

  67. Chen Y, Li G, Wu X, Chen Z, Hang J, Qin B, et al. Self-microemulsifying drug delivery system (SMEDDS) of vinpocetine: formulation development and in vivo assessment. Biol Pharm Bull. 2008;31:118–25.

    Article  CAS  PubMed  Google Scholar 

  68. Sun M, Zhai X, Xue K, Hu L, Yang X, Li G, et al. Intestinal absorption and intestinal lymphatic transport of sirolimus from self-microemulsifying drug delivery systems assessed using the single-pass intestinal perfusion (SPIP) technique and a chylomicron flow blocking approach: linear correlation with oral bioavailabilities in rats. Eur J Pharm Sci. 2011;43:132–40.

    Article  CAS  PubMed  Google Scholar 

  69. Beg S, Swain S, Singh HP, Patra CN, Rao MEB. Development, optimization, and characterization of solid self-nanoemulsifying drug delivery systems of valsartan using porous carriers. AAPS PharmSciTech. 2012;13:1416–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Garg B, Katare OP, Beg S, Lohan S, Singh B. Systematic development of solid self-nanoemulsifying oily formulations (S-SNEOFs) for enhancing the oral bioavailability and intestinal lymphatic uptake of lopinavir. Colloids Surf B Biointerfaces. 2016;141:611–22.

    Article  CAS  PubMed  Google Scholar 

  71. Sandhu PS, Beg S, Mehta F, Singh B, Trivedi P. Novel dietary lipid-based self-nanoemulsifying drug delivery systems of paclitaxel with p-gp inhibitor: implications on cytotoxicity and biopharmaceutical performance. Expert Opin Drug Deliv. 2015;12:1809–22.

    Article  PubMed  Google Scholar 

  72. Bandyopadhyay S, Beg S, Katare OP, Sharma G, Singh B. QbD-oriented development of self-nanoemulsifying drug delivery systems (SNEDDS) of valsartan with improved biopharmaceutical performance. Curr Drug Deliv. 2015;12:544–63.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors deeply acknowledge the support provided by M/s Zydus Cadila (Ahmedabad, India), M/s Gattefosse (Saint Priest, France), M/s BASF (Mumbai, India), M/s Colorcon Asia Pvt. Ltd. (Verna, India), M/s ACG Capsules (Mumbai, India), and M/s Stat-Ease (Minneapolis, USA) in conducting the present research work.

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Authors and Affiliations

  1. University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh, 160 014, India

    Atul Jain, Rajpreet Kaur & Bhupinder Singh

  2. UGC-Centre of Excellence in Applications of Nanomaterials, Nanoparticles and Nanocomposites (Biomedical Sciences), Panjab University, Chandigarh, 160 014, India

    Atul Jain, Sarwar Beg & Bhupinder Singh

  3. Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Punjab, 160 062, India

    Varun Kushwah & Sanyog Jain

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  1. Atul Jain
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Jain, A., Kaur, R., Beg, S. et al. Novel cationic supersaturable nanomicellar systems of raloxifene hydrochloride with enhanced biopharmaceutical attributes. Drug Deliv. and Transl. Res. 8, 670–692 (2018). https://doi.org/10.1007/s13346-018-0514-8

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