Skip to main content
SpringerLink
Log in

A Novel Multi-Unit Tablet for Treating Circadian Rhythm Diseases

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

This study aimed to develop and evaluate a novel multi-unit tablet that combined a pellet with a sustained-release coating and a tablet with a pulsatile coating for the treatment of circadian rhythm diseases. The model drug, isosorbide-5-mononitrate, was sprayed on microcrystalline cellulose (MCC)-based pellets and coated with Eudragit® NE30D, which served as a sustained-release layer. The coated pellets were compressed with cushion agents (a mixture of MCC PH-200/ MCC KG-802/PC-10 at a ratio of 40:40:20) at a ratio of 4:6 using a single-punch tablet machine. An isolation layer of OpadryII, swellable layer of HPMC E5, and rupturable layer of Surelease® were applied using a conventional pan-coating process. Central-composite design-response surface methodology was used to investigate the influence of these coatings on the square of the difference between release times over a 4 h time period. Drug release studies were carried out on formulated pellets and tablets to investigate the release behaviors, and scanning electron microscopy (SEM) was used to monitor the pellets and tablets and their cross-sectional morphology. The experimental results indicated that this system had a pulsatile dissolution profile that included a lag period of 4 h and a sustained-release time of 4 h. Compared to currently marketed preparations, this tablet may provide better treatment options for circadian rhythm diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

5-ISMN:

Isosorbide-5-mononitrate

MCC:

Microcrystalline cellulose

PC:

Pregelatinized starch

HPMC:

Hydroxypropyl methyl cellulose

h:

Hours

min:

Minutes

rpm:

Rotations per minute

ANOVA:

Analysis of variance

GMS:

Glyceryl monostearate

REFERENCES

  1. Mandal AS, Biswas N, Karim KM, et al. Drug delivery system based on chronobiology—a review. J Control Release. 2010;147(3):314–25.

    Article  CAS  PubMed  Google Scholar 

  2. Youan BB. Chronopharmaceutics: gimmick or clinically relevant approach to drug delivery? J Control Release. 2004;98(3):337–53.

    Article  CAS  PubMed  Google Scholar 

  3. Lemmer B. Chronobiology, drug-delivery, and chronotherapeutics. Adv Drug Deliv Rev. 2007;59(9–10):825–7.

    Article  CAS  PubMed  Google Scholar 

  4. Verma RK, Kaushal AM, Garg S. Development and evaluation of extended release formulations of isosorbide mononitrate based on osmotic technology. Int J Pharm. 2003;263(1–2):9–24.

    Article  CAS  PubMed  Google Scholar 

  5. Bonn R. Sustained-release isosorbide mononitrate (50 mg): optimization of a once-daily dosage form for long-term treatment of angina pectoris. Am J Cardiol. 1988;61(9):12–4.

    Article  Google Scholar 

  6. Bussemer T, Dashevsky A, Bodmeier R. A pulsatile drug delivery system based on rupturable coated hard gelatin capsules. J Control Release. 2003;93(3):331–9.

    Article  CAS  PubMed  Google Scholar 

  7. Sungthongjeen S, Puttipipatkhachorn S, Paeratakul O, Dashevsky A, Bodmeier R. Development of pulsatile release tablets with swelling and rupturable layers. J Control Release. 2004;95(2):147–59.

    Article  CAS  PubMed  Google Scholar 

  8. Mohamad A, Dashevsky A. Development of pulsatile multiparticulate drug delivery system coated with aqueous dispersion Aquacoat ECD. Int J Pharm. 2006;318(1–2):124–31.

    PubMed  Google Scholar 

  9. Clarke GM, Newton JM, Short MB. Comparative gastrointestinal transit of pellet systems of varying density. Int J Pharm. 1995;114(1):1–11.

    Article  CAS  Google Scholar 

  10. Bodmeier R. Tableting of coated pellets. Eur J Pharm Biopharm. 1997;43(1):1–8.

    Article  CAS  Google Scholar 

  11. Yadav D, Survase S, Kumar N. Dual coating of swellable and rupturable polymers on glipizide loaded MCC pellets for pulsatile delivery: formulation design and in vitro evaluation. Int J Pharm. 2011;419(1–2):121–30.

    Article  CAS  PubMed  Google Scholar 

  12. Cassano GB, Maggini C, Guazzelli M. Nocturnal angina and sleep. Prog Neuro-Psychopharmacol. 1981;5(1):99–104.

    Article  CAS  Google Scholar 

  13. Phelps CE, Buysman EK, Gomez Rey G. Costs and clinical outcomes associated with use of ranolazine for treatment of angina. Clin Ther. 2012;34(6):1395.e4–407.e4.

    Article  Google Scholar 

  14. Abshagen U, Sporl-Radun S. First data on effects and pharmacokinetics of isosorbide-5-mononitrate in normal man. Eur J Clin Pharmacol. 1981;19(6):423–9.

    Article  CAS  PubMed  Google Scholar 

  15. Schaumann W. Pharmacokinetics of isosorbide dinitrate and isosorbide-5-mononitrate. Int J Clin Pharmacol Ther Toxicol. 1989;27(9):445–53.

    CAS  PubMed  Google Scholar 

  16. Jonathan A, Uri E, Udho T, et al. Tolerance: an historical overview. Am J Cardiol. 1998;81(1):3A–14A.

    Article  Google Scholar 

  17. Bodmeier R, Paeratakul O. Mechanical properties of dry and wet cellulosic and acrylic films prepared from aqueous colloidal polymer dispersions used in the coating of solid dosage forms. Pharm Res. 1994;11(6):882–8.

    Article  CAS  PubMed  Google Scholar 

  18. Cui Y, Zhang Y, Tang X. In vitro and in vivo evaluation of ofloxacin sustained release pellets. Int J Pharm. 2008;360(1–2):47–52.

    CAS  PubMed  Google Scholar 

  19. Torrado JJ, Augsburger LL. Effect of different excipients on the tableting of coated particles. Int J Pharm. 1994;106(2):149–55.

    Article  CAS  Google Scholar 

  20. Asahi Chemical Corp, Yaginuma Y, Yoshida N (2010) Process for production of tablets containing both crystalline cellulose and granules: WO, WO 2009/028487 A1[P]. 2009-03-05.

  21. Huang YH, Zhang YL, Wang F. Determination of isosorbide-5-mononitratesustained release capsule by HPLC. HeiLongJiang Med J. 2004;17(4):243–4.

    Google Scholar 

  22. Shajahan A, Anil VC, Sunil BJ. A flexible technology for modified-release drug: multiple-unit pellet system (MUPS). J Control Release. 2010;147(1):2–16.

    Article  Google Scholar 

  23. Paulo C, José MS. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13(2):123–33.

    Article  Google Scholar 

Download references

ACKNOWLEDGMENTS

This study was financially supported by a program supporting scientific research conducted by college graduates in Jangsu Province (No. CXLX12_0313). We would like to thank the Asahi Kasei, ISP, Evonik and Colorcon Corporations for providing the blank MCC pellets, excipients, and coating materials.

Author information

Authors and Affiliations

  1. Pharmaceutical Research Institute, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing, 210009, China

    Qi Liu, Yinhua Gong, Yun Shi, Liqun Jiang, Chunli Zheng, Liang Ge, Jianping Liu & Jiabi Zhu

Authors
  1. Qi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yinhua Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yun Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liqun Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chunli Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Liang Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jianping Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jiabi Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jianping Liu or Jiabi Zhu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, Q., Gong, Y., Shi, Y. et al. A Novel Multi-Unit Tablet for Treating Circadian Rhythm Diseases. AAPS PharmSciTech 14, 861–869 (2013). https://doi.org/10.1208/s12249-013-9975-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-013-9975-8

KEY WORDS

Search

Navigation