AAPS PharmSciTech

, 20:216 | Cite as

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

  • Kahnu Charan PanigrahiEmail author
  • Ch. Niranjan Patra
  • M. E. Bhanoji Rao
Research Article


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.

Graphical Abstract


factor mode effect analysis Taguchi screening design Box-Behnken design pharmacokinetic study bioavailability enhancement 



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.

Compliance with Ethical Standards

Declaration of Interest

The authors declare that they have no conflict of interest.

Supplementary material

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  1. 1.
    Sorbera IA, Castañera RM, Bayés M. Cinacalcet hydrochloride: treatment of hyperparathyroidism. Drugs Future. 2002;27(9):831–6.CrossRefGoogle Scholar
  2. 2.
    de Francisco AL. Cinacalcet HCl: a novel therapeutic for hyperparathyroidism. Expert Opin Pharmacother. 2005;6(3):441–52.PubMedCrossRefGoogle Scholar
  3. 3.
    Messa P, Alfieri C, Brezzi B. Cinacalcet: pharmacological and clinical aspects. Expert Opin Drug Metab Toxicol. 2008;4(12):1551–60.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 5.
    Yousaf F, Charytan C. Review of cinacalcet hydrochloride in the management of secondary hyperparathyroidism. Ren Fail. 2014;36(1):131–8.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 7.
    Lipinski CA. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2004;1(4):337–41.CrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 9.
    Padhi D, Harris R. Clinical pharmacokinetic and pharmacodynamic profile of cnacalcet hydrochloride. Clin Pharmacokinet. 2009;48(5):303–11.PubMedCrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 12.
    Dokania S, Joshi AK. Self-microemulsifying drug delivery system (SMEDDS)—challenges and road ahead. Drug Deliv. 2015;22(6):675–90.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 14.
    Pouton CW. Formulation of self-emulsifying drug delivery systems. Adv Drug Deliv Rev. 1997;25(1):47–58.CrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 25.
    Charoo NA, Ali AA. Quality risk management in pharmaceutical development. Drug Dev Ind Pharm. 2013;39(7):947–60.PubMedCrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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. 32.
    FDA. Quality by design for ANDAs: an example for immediate-release dosage forms. FDA 2012, pp. 1–107. Available from: Accessed 02 Aug 2017Google Scholar
  33. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 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.CrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.
  51. 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.PubMedCrossRefGoogle Scholar
  52. 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.PubMedCrossRefGoogle Scholar
  53. 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.PubMedCrossRefGoogle Scholar
  54. 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.PubMedCrossRefGoogle Scholar
  55. 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. Scholar
  56. 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.PubMedCrossRefGoogle Scholar
  57. 57.
  58. 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.CrossRefGoogle Scholar
  59. 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.PubMedCrossRefGoogle Scholar
  60. 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. Scholar
  61. 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.CrossRefGoogle Scholar
  62. 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.CrossRefGoogle Scholar
  63. 63.
    US EPA O. Predictive models and tools for assessing chemicals under the Toxic Substances Control Act (TSCA): Accessed 20 Aug 2017)

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© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  1. 1.Roland Institute of Pharmaceutical Sciences (Affiliated to Biju Patnaik University of Technology)BerhampurIndia

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