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Quality by Design Enabled Development of Oral Self-Nanoemulsifying Drug Delivery System of a Novel Calcimimetic Cinacalcet HCl Using a Porous Carrier: In Vitro and In Vivo Characterisation

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Abstract

In this present research, work quality by design-enabled development of cinacalcet HCl (CH)-loaded solid self-nanoemulsifying drug delivery system (S-SNEDDS) was conducted using a porous carrier in order to achieve immediate drug release and better oral bioavailability. Capmul MCM (CAP), Tween 20 (TW 20) and Transcutol P (TRP) were selected as excipients. Cumulative % drug release at 30 min (Q30), emulsification times (ET), mean globule size (GS) and polydispersity index (PDI) were identified as critical quality attributes (CQAs). Factor mode effect analysis (FMEA) and Taguchi screening design were applied for screening of factors. The optimised single dose of S-SNEDDS obtained using Box-Behnken design (BBD) consisted of 30 mg of CH, 50 mg of CAP, 149.75 mg of TW 20, 55 mg of TRP and 260.75 mg of Neusilin US2. It showed an average Q30 of 97.6%, ET of 23.3 min, GS of 89.5 nm and PDI of 0.211. DSC, XRD and SEM predict the amorphous form of S-SNEDDS. In vivo pharmacokinetic study revealed better pharmacokinetic parameters of S-SNEDDS. The above study concluded that the optimised S-SNEDDS is effective to achieve the desired objective.

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References

  1. Sorbera IA, Castañera RM, Bayés M. Cinacalcet hydrochloride: treatment of hyperparathyroidism. Drugs Future. 2002;27(9):831–6.

    Article  CAS  Google Scholar 

  2. de Francisco AL. Cinacalcet HCl: a novel therapeutic for hyperparathyroidism. Expert Opin Pharmacother. 2005;6(3):441–52.

    Article  PubMed  Google Scholar 

  3. Messa P, Alfieri C, Brezzi B. Cinacalcet: pharmacological and clinical aspects. Expert Opin Drug Metab Toxicol. 2008;4(12):1551–60.

    Article  CAS  PubMed  Google Scholar 

  4. Franceschini N, Joy MS, Kshirsagar A. Cinacalcet HCl: a calcimimetic agent for the management of primary and secondary hyperparathyroidism. Expert Opin Investig Drugs. 2003;12(8):1413–21.

    Article  CAS  PubMed  Google Scholar 

  5. Yousaf F, Charytan C. Review of cinacalcet hydrochloride in the management of secondary hyperparathyroidism. Ren Fail. 2014;36(1):131–8.

    Article  CAS  PubMed  Google Scholar 

  6. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1–3):3–26.

    Article  CAS  PubMed  Google Scholar 

  7. Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2004;1(4):337–41.

    Article  CAS  PubMed  Google Scholar 

  8. 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(21–22):958–65.

    Article  CAS  PubMed  Google Scholar 

  9. Padhi D, Harris R. Clinical pharmacokinetic and pharmacodynamic profile of cnacalcet hydrochloride. Clin Pharmacokinet. 2009;48(5):303–11.

    Article  CAS  PubMed  Google Scholar 

  10. Bachynsky MO, Shah NH, Patel CI, Malick AW. Factors affecting the efficiency of a self-emulsifying oral delivery system. Drug Dev Ind Pharm. 1997;23(8):809–16.

    Article  CAS  Google Scholar 

  11. Singh B, Bandopadhyay S, Kapil R, Singh R, Katare OP. Self-emulsifying drug delivery systems (SEDDS): formulation development, characterization, and applications. Crit Rev Ther Drug Carrier Syst. 2009;26(5):427–521.

    Article  CAS  PubMed  Google Scholar 

  12. Dokania S, Joshi AK. Self-microemulsifying drug delivery system (SMEDDS)—challenges and road ahead. Drug Deliv. 2015;22(6):675–90.

    Article  CAS  PubMed  Google Scholar 

  13. Kazi M, Al-Qarni H, Alanazi FK. Development of oral solid self-emulsifying lipid formulations of risperidone with improved in vitro dissolution and digestion. Eur J Pharm Biopharm. 2017;114:239–49.

    Article  CAS  PubMed  Google Scholar 

  14. Pouton CW. Formulation of self-emulsifying drug delivery systems. Adv Drug Deliv Rev. 1997;25(1):47–58.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Mohd AB, Sanka K, Bandi S, Diwan PV, Shastri N. Solid self-nanoemulsifying drug delivery system (S-SNEDDS) for oral delivery of glimepiride: development and antidiabetic activity in albino rabbits. Drug Deliv. 2015;22(4):499–508.

    Article  CAS  PubMed  Google Scholar 

  17. Ramasahayam B, Eedara BB, Kandadi P, Jukanti R, Bandari S. Development of isradipine loaded self-nano emulsifying powders for improved oral delivery: in vitro and in vivo evaluation. Drug Dev Ind Pharm. 2015;41(5):753–63.

    Article  CAS  PubMed  Google Scholar 

  18. Patra CN, Swain S, Panigrahi KC, Rao MEB. Porous carriers in drug delivery systems. Pharmaceutical drug delivery systems and vehicles. New Delhi: Woodhead Publishing India; 2016. p. 197–215.

    Google Scholar 

  19. Balakrishnan P, Lee B-J, Oh DH, Kim JO, Lee Y-I, Kim D-D, et al. Enhanced oral bioavailability of coenzyme Q10 by self-emulsifying drug delivery systems. Int J Pharm. 2009;374(1–2):66–72.

    Article  CAS  PubMed  Google Scholar 

  20. Do TT, Van Speybroeck M, Mols R, Annaert P, Martens J, Van Humbeeck J, et al. The conflict between in vitro release studies in human biorelevant media and the in vivo exposure in rats of the lipophilic compound fenofibrate. Int J Pharm. 2011;414(1–2):118–24.

    Article  CAS  PubMed  Google Scholar 

  21. Van Buskirk GA, Asotra S, Balducci C, Basu P, DiDonato G, Dorantes A, et al. Best practices for the development, scale-up, and post-approval change control of IR and MR dosage forms in the current quality-by-design paradigm. AAPS PharmSciTech. 2014;15(3):665–93.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Csóka I, Pallagi E, Paál TL. Extension of quality-by-design concept to the early development phase of pharmaceutical R&D processes. Drug Discov Today. 2018;23(7):1340–3.

    Article  PubMed  Google Scholar 

  23. Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, et al. Understanding pharmaceutical quality by design. AAPS J. 2014;16(4):771–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yekpe K, Abatzoglou N, Bataille B, Gosselin R, Sharkawi T, Simard JS, et al. Developing a quality by design approach to model tablet dissolution testing: an industrial case study. Pharm Dev Technol. 2018;23(6):646–54.

    Article  CAS  PubMed  Google Scholar 

  25. Charoo NA, Ali AA. Quality risk management in pharmaceutical development. Drug Dev Ind Pharm. 2013;39(7):947–60.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang L, Mao S. Applications of quality by design (QbD) and its tools in drug delivery. Asian J Pharm Sci. 2016;11(1):144–5.

    Article  Google Scholar 

  27. Salem HF, Kharshoum RM, Halawa AKA, Naguib DM. Preparation and optimization of tablets containing a self-nano-emulsifying drug delivery system loaded with rosuvastatin. J Liposome Res. 2018;28(2):149–60.

    Article  CAS  PubMed  Google Scholar 

  28. Quan Q, Kim DW, Marasini N, Kim DH, Kim JK, Kim JO, et al. Physicochemical characterization and in vivo evaluation of solid self-nanoemulsifying drug delivery system for oral administration of docetaxel. J Microencapsul. 2013;30(4):307–14.

    Article  CAS  PubMed  Google Scholar 

  29. Kanuganti S, Jukanti R, Veerareddy PR, Bandari S. Paliperidone-loaded self-emulsifying drug delivery systems (SEDDS) for improved oral delivery. J Dispers Sci Technol. 2012;33(4):506–15.

    Article  CAS  Google Scholar 

  30. Kadu PJ, Kushare SS, Thacker DD, Gattani SG. Enhancement of oral bioavailability of atorvastatin calcium by self-emulsifying drug delivery systems (SEDDS). Pharm Dev Technol. 2011;16(1):65–74.

    Article  CAS  PubMed  Google Scholar 

  31. Johnson B, Nornoo AO, Zheng H, Lopes LB, Johnson-Restrepo B, Kannan K, et al. Oral microemulsions of paclitaxel: in situ and pharmacokinetic studies. Eur J Pharm Biopharm. 2008;71(2):310–7.

    Google Scholar 

  32. FDA. Quality by design for ANDAs: an example for immediate-release dosage forms. FDA 2012, pp. 1–107. Available from: https://www.fda.gov/media/83664/download. Accessed 02 Aug 2017

  33. Fahmy R, Kona R, Dandu R, Xie W, Claycamp G, Hoag SW. Quality by design I: application of failure mode effect analysis (FMEA) and Plackett–Burman design of experiments in the identification of “main factors” in the formulation and process design space for roller-compacted ciprofloxacin hydrochloride immediate-release tablets. AAPS PharmSciTech. 2012;13(4):1243–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Varzakas TH, Arvanitoyannis IS. Application of failure mode and effect analysis (FMEA), cause and effect analysis, and Pareto diagram in conjunction with HACCP to a corn curl manufacturing plant. Crit Rev Food Sci Nutr. 2007;47(4):363–87.

    Article  PubMed  Google Scholar 

  35. Panigrahi KC, Jena J, Jena GK, Patra CN, Rao MEB. QBD-based systematic development of Bosentan SNEDDS: formulation, characterization and pharmacokinetic assessment. J Drug Deliv Sci Technol. 2018;47:31–42.

    Article  CAS  Google Scholar 

  36. Beg S, Sandhu PS, Batra RS, Kaur R, Singh B, Beg S, et al. QbD-based systematic development of novel optimized solid self-nanoemulsifying drug delivery systems (SNEDDS) of lovastatin with enhanced biopharmaceutical performance. Drug Deliv. 2015;22(6):765–84.

    Article  CAS  PubMed  Google Scholar 

  37. 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 

  38. Li F, Song S, Guo Y, Zhao Q, Zhang X, Li F, et al. Preparation and pharmacokinetics evaluation of oral self-emulsifying system for poorly water-soluble drug Lornoxicam preparation and pharmacokinetics evaluation of oral self-emulsifying system for poorly water-soluble drug Lornoxicam. Drug Deliv. 2015;22(4):487–98.

    Article  PubMed  CAS  Google Scholar 

  39. Agarwal V, Alayoubi A, Siddiqui A, Nazzal S. Powdered self-emulsified lipid formulations of meloxicam as solid dosage forms for oral administration. Drug Dev Ind Pharm. 2013;39(11):1681–9.

    Article  CAS  PubMed  Google Scholar 

  40. Dharankar SD, Parakh DR, Patil MP, Kshirsagar SJ. Spray-dried solid self-emulsifying delivery system of Ketoprofen: development and its characterization. Dry Technol. 2015;33(15–16):2002–11.

    Article  CAS  Google Scholar 

  41. Mura P, Valleri M, Cirri M, Mennini N. New solid self-microemulsifying systems to enhance dissolution rate of poorly water soluble drugs. Pharm Dev Technol. 2012;17(3):277–84.

    Article  CAS  PubMed  Google Scholar 

  42. Čerpnjak K, Zvonar A, Vrečer F, Gašperlin M. Development of a solid self-microemulsifying drug delivery system (SMEDDS) for solubility enhancement of naproxen. Drug Dev Ind Pharm. 2015;41(9):1548–57.

    Article  PubMed  CAS  Google Scholar 

  43. Verma S, Singh SK, Verma PRP, Ahsan MN. Formulation by design of felodipine loaded liquid and solid self nanoemulsifying drug delivery systems using Box-Behnken design. Drug Dev Ind Pharm. 2014;40(10):1358–70.

    Article  CAS  PubMed  Google Scholar 

  44. Kaur P, Garg T, Rath G, Murthy RSR, Amit K, Kaur P, et al. Development, optimization and evaluation of surfactant-based pulmonary nanolipid carrier system of paclitaxel for the management of drug resistance lung cancer using Box-Behnken design. Drug Deliv. 2016;23(6):1912–25.

    CAS  PubMed  Google Scholar 

  45. Dudhipala N, Janga KY. Lipid nanoparticles of zaleplon for improved oral delivery by Box–Behnken design: optimization, in vitro and in vivo evaluation. Drug Dev Ind Pharm. 2017;43(7):1205–14.

    Article  CAS  PubMed  Google Scholar 

  46. 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(9):3209–23.

    Article  CAS  PubMed  Google Scholar 

  47. Zhang Y, He L, Yue S, Huang Q, Zhang Y. Characterization and evaluation of a self-microemulsifying drug delivery system containing tectorigenin, an isoflavone with low aqueous solubility and poor permeability. Drug Deliv. 2017;24(1):632–40.

    Article  PubMed  CAS  Google Scholar 

  48. Truong DH, Tran TH, Ramasamy T, Choi JY, Lee HH, Moon C, et al. Development of solid self-emulsifying formulation for improving the oral bioavailability of Erlotinib. AAPS PharmSciTech. 2016;17(2):466–73.

    Article  CAS  PubMed  Google Scholar 

  49. 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 

  50. Ali HH, Hussein AA. Oral solid self-nanoemulsifying drug delivery systems of candesartan citexetil: formulation, characterization and in vitro drug release studies. AAPS Open. 2017. https://doi.org/10.1186/s41120-017-0015-8.

  51. Kanaujia P, Ng WK, Tan RBH. Solid self-emulsifying drug delivery system (S-SEDDS) for improved dissolution rate of fenofibrate. J Microencapsul. 2014;31(3):293–8.

    Article  CAS  PubMed  Google Scholar 

  52. Kang MJ, Jung SY, Song WH, Park JS, Choi SU, Oh KT, et al. Immediate release of ibuprofen from Fujicalin®-based fast-dissolving self-emulsifying tablets. Drug Dev Ind Pharm. 2011;37(11):1298–305.

    Article  CAS  PubMed  Google Scholar 

  53. Gamal W, Fahmy RH, Mohamed MI. Development of novel amisulpride-loaded solid self-nanoemulsifying tablets: preparation and pharmacokinetic evaluation in rabbits. Drug Dev Ind Pharm. 2017;43(9):1539–47.

    Article  CAS  PubMed  Google Scholar 

  54. Negi JS, Chattopadhyay P, Sharma AK, Ram V. Development of solid lipid nanoparticles (SLNs) of lopinavir using hot self nano-emulsification (SNE) technique. Eur J Pharm Sci. 2013;48(1–2):231–9.

    Article  CAS  PubMed  Google Scholar 

  55. Cho H, Kang J, Ngo L, Tran P, Lee Y. Preparation and evaluation of solid-self-emulsifying drug delivery system containing paclitaxel for lymphatic delivery. J Nanomater. 2016;2016:1–14. https://doi.org/10.1155/2016/3642418.

    Article  CAS  Google Scholar 

  56. Zhao K, Yuan Y, Wang H, Li P, Bao Z, Li Y. Preparation and evaluation of valsartan by a novel semi-solid self-microemulsifying delivery system using Gelucire 44/14. Drug Dev Ind Pharm. 2016;42(10):1545–52.

    Article  CAS  PubMed  Google Scholar 

  57. ICH Quality Guideline: http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html.. Accessed 02 Aug 2017

  58. Khoo S-M, Humberstone AJ, Porter CJ, Edwards GA, Charman WN. Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine. Int J Pharm. 1998;167(1–2):155–64.

    Article  CAS  Google Scholar 

  59. Shafiq S, Shakeel F, Talegaonkar S, Ahmad FJ, Khar RK, Ali M. Development and bioavailability assessment of ramipril nanoemulsion formulation. Eur J Pharm Biopharm. 2007;66(2):227–43.

    Article  CAS  PubMed  Google Scholar 

  60. Danaei M, Dehghankhold M, Ataei S, Davarani FH, Javanmard R, Dokhani A, et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018. https://doi.org/10.3390/pharmaceutics10020057.

    Article  PubMed Central  CAS  Google Scholar 

  61. Kallakunta VR, Bandari S, Jukanti R, Veerareddy PR. Oral self emulsifying powder of lercanidipine hydrochloride: formulation and evaluation. Powder Technol. 2012;221:375–82.

    Article  CAS  Google Scholar 

  62. Humberstone AJ, Charman WN. Lipid-based vehicles for the oral delivery of poorly water soluble drugs. Adv Drug Deliv Rev. 1997;25(1):103–28.

    Article  CAS  Google Scholar 

  63. US EPA O. Predictive models and tools for assessing chemicals under the Toxic Substances Control Act (TSCA): https://www.epa.gov/tsca-screening-tools. Accessed 20 Aug 2017)

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Acknowledgements

The authors are thankful to Matrix Pharma India for providing the gift sample of Cinacalcet hydrochloride. M/s Gattefosse Pvt. Ltd. India, M/s BASF GmbH, Minden, Germany, Abitec Pvt. Ltd. USA and Gangwal Chemicals Pvt. Ltd. India are gratefully acknowledged for providing the essential excipients for the research work. The authors are grateful to Stat-Ease, Minneapolis, MN for the design expert ver. 11.1.01 software. The authors would also like to acknowledge BIT, Mesra, India for providing the facility of XRD and SEM. The authors are thankful to the Institute of Life Science, Bhubaneswar, India for the facility of Zetasizer.

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  1. Roland Institute of Pharmaceutical Sciences (Affiliated to Biju Patnaik University of Technology), Berhampur, Odisha, India

    Kahnu Charan Panigrahi, Ch. Niranjan Patra & M. E. Bhanoji Rao

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Panigrahi, K.C., Patra, C.N. & Rao, M.E.B. Quality by Design Enabled Development of Oral Self-Nanoemulsifying Drug Delivery System of a Novel Calcimimetic Cinacalcet HCl Using a Porous Carrier: In Vitro and In Vivo Characterisation. AAPS PharmSciTech 20, 216 (2019). https://doi.org/10.1208/s12249-019-1411-2

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