Skip to main content
SpringerLink
Log in

Chronotherapeutic Drug Delivery of Ketoprofen and Ibuprofen for Improved Treatment of Early Morning Stiffness in Arthritis Using Hot-Melt Extrusion Technology

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

Abstract

This work developed a chronotherapeutic drug delivery system (CTDDS) utilizing a potential continuous hot-melt extrusion (HME) technique. Ketoprofen (KTP) and ibuprofen (IBU) were used as two separate model drugs. Eudragit S100 (ES100) was the matrix-forming agent, and ethyl cellulose (EC) (2.5 and 5%) was the release-retarding agent. A 16-mm extruder was used to develop the CTDDS to pilot scale. The obtained extrudate strands were transparent, indicating that the drugs were homogeneously dispersed in the matrix in an amorphous form, confirmed by both differential scanning calorimetry and powder X-ray diffraction. The strands were pelletized into 1, 2, and 3 mm size pellets. A 100% drug release from 1, 2, and 3 mm pellets with 2.5% EC was observed at 12, 14, and 16 h, whereas the drug release was sustained for 14, 16, and 22 h from 5% EC pellets, respectively, for KTP. The release characteristics of IBU were similar to those of KTP with modest variations in release at lag time. The in vitro drug release study conducted in three-stage dissolution media showed a desired lag time of 6 h. The percent drug release from 1, 2, and 3 mm pellets with 40% drug load showed < 20% release from all formulations at 6 h. The amount of ethyl cellulose and pellet size significantly affected drug release. Formulations of both KTP and IBU were stable for 4 months at accelerated stability conditions of 40°C/75% RH. In summary, HME is a novel technique for developing CTDDS.

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
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Khan Z, Pillay V, Choonara YE, Du Toit LC. Drug delivery technologies for chronotherapeutic applications. Pharm Dev Technol. 2009;14(6):602–12.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Saitoh T, Watanabe Y, Kubo Y, et al. Intragastric acidity and circadian rhythm. Biomed Pharmacother. 2001;55:138–41.

    Article  Google Scholar 

  4. Roy P, Shahiwala A. Statistical optimization of ranitidine HCl floating pulsatile delivery system for chronotherapy of nocturnal acid breakthrough. Eur J Pharm Sci. 2009;37(3–4):363–9.

    Article  PubMed  CAS  Google Scholar 

  5. Nayak UY, Shavi GV, Nayak Y, Averinen RK, Mutalik S, Reddy SM, et al. Chronotherapeutic drug delivery for early morning surge in blood pressure: a programmable delivery system. J Control Release. 2009;136(2):125–31.

    Article  PubMed  CAS  Google Scholar 

  6. Jose S, Prema MT, Chacko AJ, Thomas AC, Souto EB. Colon specific chitosan microspheres for chronotherapy of chronic stable angina. Colloids Surf B Biointerfaces. 2011;83(2):277–83.

    Article  PubMed  CAS  Google Scholar 

  7. Shiohira H, Fujii M, Koizumi N, Kondoh M, Watanabe Y. Novel chronotherapeutic rectal aminophylline delivery system for therapy of asthma. Int J Pharm. 2009;379(1):119–24.

    Article  PubMed  CAS  Google Scholar 

  8. Wang H, Cheng L, Wen H, Li C, Li Y, Zhang X, et al. A time-adjustable pulsatile release system for ketoprofen: in vitro and in vivo investigation in a pharmacokinetic study and an IVIVC evaluation. Eur J Pharm Biopharm. 2017;119:192–200.

    Article  PubMed  CAS  Google Scholar 

  9. Patil H, Tiwari RV, Repka MA. Hot-melt extrusion: from theory to application in pharmaceutical formulation. AAPS PharmSciTech. 2016;17(1):20–42.

    Article  PubMed  CAS  Google Scholar 

  10. Repka MA, Bandari S, Kallakunta VR, Vo AQ, McFall H, Pimparade MB, et al. Melt extrusion with poorly soluble drugs—an integrated review. Int J Pharm. 2018;535(1–2):68–85.

    Article  PubMed  CAS  Google Scholar 

  11. Tiwari RV, Patil H, Repka MA. Contribution of hot-melt extrusion technology to advance drug delivery in the 21st century. Expert Opin Drug Deliv. 2016;13(3):451–64.

    Article  PubMed  CAS  Google Scholar 

  12. De Jaeghere W, De Beer T, Van Bocxlaer J, Remon JP, Vervaet C. Hot-melt extrusion of polyvinyl alcohol for oral immediate release applications. Int J Pharm. 2015;492(1–2):1–9.

    Article  PubMed  CAS  Google Scholar 

  13. Mohammed NN, Majumdar S, Singh A, Deng W, Murthy NS, Pinto E, et al. Klucel™ EF and ELF polymers for immediate-release oral dosage forms prepared by melt extrusion technology. AAPS PharmSciTech. 2012;13(4):1158–69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Puri V, Brancazio D, Desai PM, Jensen KD, Chun JH, Myerson AS, et al. Development of maltodextrin-based immediate-release tablets using an integrated twin-screw hot-melt extrusion and injection-molding continuous manufacturing process. J Pharm Sci. 2017;106(11):3328–36.

    Article  PubMed  CAS  Google Scholar 

  15. Patil H, Tiwari RV, Upadhye SB, Vladyka RS, Repka MA. Formulation and development of pH-independent/dependent sustained release matrix tablets of ondansetron HCl by a continuous twin-screw melt granulation process. Int J Pharm. 2015;496(1):33–41.

    Article  PubMed  CAS  Google Scholar 

  16. Verstraete G, Van RJ, Van Bockstal PJ, et al. Hydrophilic thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding. Int J Pharm. 2016;506(1–2):214–21.

    Article  PubMed  CAS  Google Scholar 

  17. Bhagurkar AM, Angamuthu M, Patil H, Tiwari RV, Maurya A, Hashemnejad SM, et al. Development of an ointment formulation using hot-melt extrusion technology. AAPS PharmSciTech. 2016;17(1):158–66.

    Article  PubMed  CAS  Google Scholar 

  18. Repka MA, McGinity JW. Influence of vitamin E TPGS on the properties of hydrophilic films produced by hot-melt extrusion. Int J Pharm. 2000;202(1–2):63–70.

    Article  PubMed  CAS  Google Scholar 

  19. Palem CR, Kumar Battu S, Maddineni S, Gannu R, Repka MA, Yamsani MR. Oral transmucosal delivery of domperidone from immediate release films produced via hot-melt extrusion technology. Pharm Dev Technol. 2013;18(1):186–95.

    Article  PubMed  CAS  Google Scholar 

  20. Mendonsa NS, Thipsay P, Kim DW, Martin ST, Repka MA. Bioadhesive drug delivery system for enhancing the permeability of a BCS class III drug via hot-melt extrusion technology. AAPS PharmSciTech. 2017;18(7):2639–47.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Patil H, Kulkarni V, Majumdar S, Repka MA. Continuous manufacturing of solid lipid nanoparticles by hot melt extrusion. Int J Pharm. 2014;471(1–2):153–6.

    Article  PubMed  CAS  Google Scholar 

  22. Ye X, Patil H, Feng X, Tiwari RV, Lu J, Gryczke A, et al. Conjugation of hot-melt extrusion with high-pressure homogenization: a novel method of continuously preparing nanocrystal solid dispersions. AAPS PharmSciTech. 2016;17(1):78–88.

    Article  PubMed  CAS  Google Scholar 

  23. Bruce LD, Shah NH, Malick AW, Infeld MH, McGinity JW. Properties of hot-melt extruded tablet formulations for the colonic delivery of 5-aminosalicylic acid. Eur J Pharm Biopharm. 2005;59(1):85–97.

    Article  PubMed  CAS  Google Scholar 

  24. Mehuys E, Remon JP, Vervaet C. Production of enteric capsules by means of hot-melt extrusion. Eur J Pharm Sci. 2005;24(2–3):207–12.

    Article  PubMed  CAS  Google Scholar 

  25. Castellsague J, Riera-Guardia N, Calingaert B, et al. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies. Drug Saf. 2012;35(12):1127–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Henness S, Yang LP. Modified-release prednisone: in patients with rheumatoid arthritis. Drugs. 2013;73(18):2067–76.

    Article  PubMed  CAS  Google Scholar 

  27. Pozzi P, Furlani A, Gazzanig, Davis SS, Wilding IR. The time clock system: a new oral dosage form for fast and complete release of drug after a predetermined lag time. J Control Release. 1994;31(1):99–108.

    Article  CAS  Google Scholar 

  28. Yang R, Wang Y, Zheng X, Meng J, Tang X, Zhang X. Preparation and evaluation of ketoprofen hot-melt extruded enteric and sustained-release tablets. Drug Dev Ind Pharm. 2008;34(1):83–9.

    Article  PubMed  CAS  Google Scholar 

  29. Schilling SU, Shah NH, Waseem Malick A, McGinity JW. Properties of melt extruded enteric matrix pellets. Eur J Pharm Biopharm. 2010;74(2):352–61.

    Article  PubMed  CAS  Google Scholar 

  30. Andrews GP, Jones DS, Diak OA, McCoy CP, Watts AB, McGinity JW. The manufacture and characterisation of hot-melt extruded enteric tablets. Eur J Pharm Biopharm. 2008;69(1):264–73.

    Article  PubMed  CAS  Google Scholar 

  31. Dokoumetzidis A, Macheras P. A century of dissolution research: from Noyes and Whitney to the biopharmaceutics classification system. Int J Pharm. 2006;321(1–2):1–11.

    Article  PubMed  CAS  Google Scholar 

  32. Kalivoda A, Fischbach M, Kleinebudde P. Application of mixtures of polymeric carriers for dissolution enhancement of fenofibrate using hot-melt extrusion. Int J Pharm. 2012;429(1–2):58–68.

    Article  PubMed  CAS  Google Scholar 

  33. Zhang F. Melt-extruded Eudragit® FS-based granules for colonic drug delivery. AAPS PharmSciTech. 2016;17(1):56–67.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors also thank the Pii Center for Pharmaceutical Technology for contributions in this project.

Funding

This study was partially supported by Grant Number P20GM104932 from the National Institute of General Medical Sciences (NIGMS), a component of the National Institute of Health (NIH).

Author information

Authors and Affiliations

  1. Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, Oxford, Mississippi, 38677, USA

    Nagi Reddy Dumpa, Sandeep Sarabu, Suresh Bandari & Michael A. Repka

  2. College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78712, USA

    Feng Zhang

  3. Pii Center for Pharmaceutical Technology, The University of Mississippi, University, Oxford, Mississippi, 38677, USA

    Michael A. Repka

Authors
  1. Nagi Reddy Dumpa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandeep Sarabu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suresh Bandari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Feng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael A. Repka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael A. Repka.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dumpa, N.R., Sarabu, S., Bandari, S. et al. Chronotherapeutic Drug Delivery of Ketoprofen and Ibuprofen for Improved Treatment of Early Morning Stiffness in Arthritis Using Hot-Melt Extrusion Technology. AAPS PharmSciTech 19, 2700–2709 (2018). https://doi.org/10.1208/s12249-018-1095-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-018-1095-z

KEY WORDS

Search

Navigation