Skip to main content

Advertisement

SpringerLink
Log in

Optimization of Unidirectional Mucoadhesive Buccal Patches Based on Chitosan and Pluronic® F-127 for Metoprolol Controlled Release: In Vitro and Ex Vivo Evaluations

  • Original Article
  • Published:
Journal of Pharmaceutical Innovation Aims and scope Submit manuscript

Abstract

Purpose

The aim of this work was to optimize unidirectional buccal patches loaded with metoprolol (MT-MBPs) to provide adequate mucoadhesive and water uptake properties as well as controlled drug release for the effective treatment of different cardiovascular diseases.

Methods

The patches were prepared layer-by-layer using the solvent casting method. A central composite design was employed to statistically optimize the formulation variables. Chitosan and Pluronic® F-127 (poloxamer 407) concentrations were chosen as the independent variables, while ex vivo mucoadhesive force, ex vivo residence time, in vitro water uptake (%), and in vitro drug release (%) were to be considered the dependent variables. The optimized formulation was also characterized and evaluated in terms of morphology, thermal behavior, tensile strength, elongation at break, and ex vivo drug permeation.

Results

The optimized MT-MBPs were successful in terms of mucoadhesive force (3.58 ± 0.62 N), residence time (342.67 ± 17.21 min), and water uptake at 1 h (24.53 ± 3.62%). A controlled drug release was obtained for 8 h. Thermal and morphologic analyses demonstrated that metoprolol was homogeneously distributed throughout the microporous chitosan-based polymer matrix. Furthermore, the MT-MBPs exhibited a tensile strength of 3.76 ± 0.55 N/mm2 and an elongation at break of 36.52 ± 13.88%. The results of ex vivo permeation through pig buccal mucosa indicated that therapeutic metoprolol concentrations can be reached by using a patch of 5.62 cm2.

Conclusions

Optimal composition of the MT-MBPs included 2.9% (w/v) and 2.6% (w/v) of chitosan and Pluronic® F-127, respectively, which constitutes the most suitable makeup for metoprolol buccal delivery.

Graphical Abstract

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

Similar content being viewed by others

Abbreviations

MT:

metoprolol tartrate

MBPs

mucoadhesive buccal patches

MT-MBPs

mucoadhesive buccal patches loaded with metoprolol

CS

chitosan

PF-127

Pluronic® F-127

EC

ethyl cellulose

Eu-E100

Eudragit® E-100

RSM

response surface methodology

CCD

central composite design

SEM

scanning electron microscopy

DSC

differential scanning calorimetry

SSF

simulated salivary fluid

ANOVA

analysis of variance

References

  1. Patel VF, Liu F, Brown MB. Advances in oral transmucosal drug delivery. J Control Release. 2011;153:106–16.

    Article  CAS  Google Scholar 

  2. Hearnden V, Sankar V, Hull K, Juras DV, Greenberg M, Kerr AR, et al. New developments and opportunities in oral mucosal drug delivery for local and systemic disease. Adv Drug Deliv Rev. 2012;64:16–28.

    Article  CAS  Google Scholar 

  3. Smart JD. Buccal drug delivery. Expert Opin Drug Deliv. 2005;2:507–17.

    Article  CAS  Google Scholar 

  4. Ikeuchi-Takahashi Y, Ishihara C, Onishi H. Evaluation of polyvinyl alcohols as mucoadhesive polymers for mucoadhesive buccal tablets prepared by direct compression. Drug Dev Ind Pharm. 2017;43:1489–500.

    Article  CAS  Google Scholar 

  5. Cevher E, Taha MA, Orlu M, et al. Evaluation of mechanical and mucoadhesive properties of clomiphene citrate gels formulations containing carbomers and their thiolated derivatives. Drug Deliv. 2008;15:57–67.

    Article  CAS  Google Scholar 

  6. Kumria R, Al-Dhubiab BE, Shah J, et al. Formulation and evaluation of chitosan-based buccal bioadhesive films of zolmitriptan. J Pharm Innov. 2018;13:133–43.

    Article  Google Scholar 

  7. Morales JO, McConville JT. Manufacture and characterization of mucoadhesive buccal films. Eur J Pharm Biopharm. 2011;77:187–99.

    Article  CAS  Google Scholar 

  8. Kumria R, Nair AB, Goomber G, Gupta S. Buccal films of prednisolone with enhanced bioavailability. Drug Deliv. 2016;23:471–8.

    Article  CAS  Google Scholar 

  9. Mati-Baouche N, Pierre-Henri E, Baynast H, et al. Chitosan as an adhesive. Eur Polym J. 2014;60:198–212.

    Article  CAS  Google Scholar 

  10. Pitto-Barry A, Barry NPE. Pluronic® block-copolymers in medicine: from chemical and biological versatility to rationalization and clinical advances. Polym Chem. 2014;10:2381–496.

    Google Scholar 

  11. Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res. 2006;23:2709–28.

    Article  CAS  Google Scholar 

  12. Abou el ela ael S, Allam AA, Ibrahim EH. Pharmacokinetics and anti-hypertensive effect of metoprolol tartrate rectal delivery system. Drug Deliv. 2016;23:69–78.

    Article  Google Scholar 

  13. Ripley TL, Saseen JJ. β-Blockers: a review of their pharmacological and physiological diversity in hypertension. Ann Pharmacother. 2014;48:723–33.

    Article  CAS  Google Scholar 

  14. Grassi G. Metoprolol in the treatment of cardiovascular disease: a critical reappraisal. Curr Med Res Opin. 2018;34:1635–43.

    Article  CAS  Google Scholar 

  15. Fernandes GJ, Rathnanand M. J Pharm Innov. Formulation optimization for gastroretentive drug

  16. Abul Kalam M, Khan AA, Khan S, Almalik A, Alshamsan A. Optimizing indomethacin-loaded chitosan nanoparticle size, encapsulation, and release using Box–Behnken experimental design. Int J Biol Macromol. 2016;87:329–40.

    Article  CAS  Google Scholar 

  17. Parhi R, Panchamukhy T. RSM-based design and optimization of transdermal film of ondasteron HCl. J Pharm Innov. 2019. https://doi.org/10.1007/s12247-019-09373-9.

  18. Box GPE, Wilson KB. On the experimental attainment of optimum conditions. J Roy Stat Soc Ser B. 1951;13:1–45.

    Google Scholar 

  19. Escobar-Chávez JJ, Merino V, Diez-Sales O, et al. Transdermal nortriptyline hydrochloride patch formulated within a chitosan matrix intended to be used for smoking cessation. Pharm Dev Technol. 2011;16:162–9.

    Article  Google Scholar 

  20. Patel VF, Liu F, Brown MB. Modeling the oral cavity: in vitro and in vivo evaluations of buccal drug delivery systems. J Control Release. 2012;161:746–56.

    Article  CAS  Google Scholar 

  21. Perioli L, Ambrogi V, Angelici F, Ricci M, Giovagnoli S, Capuccella M, et al. Development of mucoadhesive patches for buccal administration of ibuprofen. J Control Release. 2004;99:73–82.

    Article  CAS  Google Scholar 

  22. El-Fek GS, Farouk Abdulmaguid R, Zayed GM, et al. Mucosal co-delivery of ketorolac and lidocaine using polymeric wafers for dental application. Drug Deliv. 2018;25:35–42.

    Article  Google Scholar 

  23. Shiledar RR, Tagalpallewar AA, Kokare CR. Formulation and in vitro evaluation of xanthan gum-based bilayered mucoadhesive buccal patches of zolmitriptan. Carbohydr Polym. 2014;101:1234–42.

    Article  CAS  Google Scholar 

  24. Nair AB, Kumria R, Harsha S, Attimarad M, al-Dhubiab BE, Alhaider IA. In vitro techniques to evaluate buccal films. J Control Release. 2013;166:10–21.

    Article  CAS  Google Scholar 

  25. Adhikari SN, Nayak BS, Nayak AK, et al. Formulation and evaluation of buccal patches for delivery of atenolol. AAPS PharmSciTech. 2010;11:1038–44.

    Article  CAS  Google Scholar 

  26. Yildiz Pekoz A, Sedef Erdal M, Okyar A, Ocak M, Tekeli F, Kaptan E, et al. Preparation and in-vivo evaluation of dimenhydrinate buccal mucoadhesive films with enhanced bioavailability. Drug Dev Ind Pharm. 2016;42:916–25.

    Article  CAS  Google Scholar 

  27. Samson G, de la García Calera A, Dupuis-Girod S, et al. Ex vivo study of bevacizumab transport through porcine nasal mucosa. Eur J Pharm Biopharm. 2012;80:465–9.

    Article  CAS  Google Scholar 

  28. Huang Y, Leobandung W, Fross A, et al. Molecular aspects of muco- and bioadhesion: tethered structures and site-specific surfaces. J Control Rellease. 2000;65:63–71.

    Article  CAS  Google Scholar 

  29. Khutoryanskiy VV. Advances in mucoadhesion and mucoadhesive polymers. Macromol Biosci. 2011;11:748–64.

    Article  CAS  Google Scholar 

  30. Shidhaye SS, Saindane NS, Sutar S, Kadam V. Mucoadhesive bilayered patches for administration of sumatriptan succinate. AAPS PharmSciTech. 2008;9:909–16.

    Article  CAS  Google Scholar 

  31. Escobar-Chávez JJ, López-Cervantes M, Naïk A, et al. Applications of thermo-reversible pluronic F-127 gels in pharmaceutical formulations. J Pharm Pharm Sci. 2006;9:339–58.

    PubMed  Google Scholar 

  32. Siepmman J, Peppas NA. Higuchi equation: derivation, applications, use and misuse. Int J Pharm. 2011;418:6–12.

    Article  Google Scholar 

  33. Gurny R, Doelker E, Peppas NA. Modelling of sustained release of water-soluble drugs from porous, hydrophobic polymers. Biomaterials. 1982;3:27–32.

    Article  CAS  Google Scholar 

  34. Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983;15:25–35.

    Article  CAS  Google Scholar 

  35. Varshosaz J, Faghihian H, Rastgoo K. Preparation and characterization of metoprolol controlled-release solid dispersions. Drug Deliv. 2006;13:295–302.

    Article  CAS  Google Scholar 

  36. Helmy AM, Elsabahy M, Soliman GM, et al. Development and in vivo evaluation of chitosan beads for the colonic delivery of azathioprine for treatment of inflammatory bowel disease. Eur J Pharm Sci. 2017;109:269–79.

    Article  CAS  Google Scholar 

  37. Mendosa NS, Murthy SN, Hashemnejad SM, et al. Development of poloxamer gel formulations via hot-melt extrusion technology. Int J Pharm. 2018;537:122–31.

    Article  Google Scholar 

  38. Palem CR, Gannu R, Doodipala N, Yamsani VV, Yamsani MR. Transmucosal delivery of domperidone from bilayered buccal patches: in vitro, ex vivo and in vivo characterization. Arch Pharm Res. 2011;34:1701–10.

    Article  CAS  Google Scholar 

  39. Lim H, Hoag SW. Plasticizer effects on physical-mechanicals properties of solvent cast Soluplus® films. AAPS PharmSciTech. 2013;14:903–10.

    Article  CAS  Google Scholar 

  40. Senel S, Kremer MJ, Kaş S, et al. Enhancing effect of chitosan on peptide drug delivery across buccal mucosa. Biomaterials. 2000;21:2067–71.

    Article  CAS  Google Scholar 

  41. Bernkop-Schnürch A, Dünnhaupt S. Chitosan-based drug delivery systems. Eur J Pharm Biopharm. 2012;81:463–79.

    Article  Google Scholar 

  42. Seelig A, Gerebtzoff G. Enhancement of drug absorption by noncharged detergents through membrane and P-glycoprotein binding. Expert Opin Drug Metab Toxicol. 2006;2:733–52.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Dr. Escobar Chávez wants to acknowledge PAPIIT IT/UNAM [200218]; Cátedra PIAPI [1817]; and PIAPIME [2.12.27.19].

Availability of Data and Materials

All data generated or analyzed in this study are included in this manuscript.

Author information

Authors and Affiliations

  1. Unidad de Investigación Multidisciplinaria, Laboratorio 12: Sistemas transdérmicos y formas farmacéuticas no convencionales, Carretera Cuautitlán-Teoloyucan, Facultad de Estudios Superiores Cuautitlán Universidad Nacional Autónoma de México, km 2.5 San Sebastián Xhala, C.P. 54714, Cuautitlán Izcalli, Mexico

    Cristian Fernando Escalona-Rayo, Pablo Serrano-Castañeda, Miriam López-Cervantes & José Juan Escobar-Chávez

Authors
  1. Cristian Fernando Escalona-Rayo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pablo Serrano-Castañeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miriam López-Cervantes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. José Juan Escobar-Chávez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José Juan Escobar-Chávez.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Escalona-Rayo, C.F., Serrano-Castañeda, P., López-Cervantes, M. et al. Optimization of Unidirectional Mucoadhesive Buccal Patches Based on Chitosan and Pluronic® F-127 for Metoprolol Controlled Release: In Vitro and Ex Vivo Evaluations. J Pharm Innov 15, 556–568 (2020). https://doi.org/10.1007/s12247-019-09401-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12247-019-09401-8

Keywords

Search

Navigation