SpringerLink
Log in

Tailored Transdermal Drug Delivery System for Pain Management: Development and Evaluation of Clonidine Hydrochloride/Sodium Montmorillonite Composite Patch

  • Research
  • Published:
BioNanoScience Aims and scope Submit manuscript

Abstract

Researchers are always coming up with new techniques and methods to ensure that drug delivery systems are secure, therapeutically efficient, and patient-compliant. Clay minerals are nanolayered silicates considered potential nanomaterials in medical research. They have been widely used as both active agents and excipients since ancient times for the treatment of various illnesses. Owing to their remarkable characteristics of high biocompatibility, loading capacity, retention capacity, rheological and swelling properties, and affordable price, they can be used as advanced carriers for the effective delivery of drugs by varying their release rate, boosting their stability, and improving their dissolution profile. Nowadays, drug delivery through the skin has received attention as an alternative to the oral route because the skin is a potential route to deliver local and systemic drugs as nanoparticles. In this research work, clonidine hydrochloride (CH) was chosen as a model drug that plays a major role in preventing post-operative pain (both acute and chronic). The epidural solution of clonidine is already available for cancer pain. The transdermal patches of clonidine are also available in different dosages, which are intended to be administered for 7 days to treat neuropathic pain. However, there is no availability of extended-release transdermal patches of clonidine to date for the treatment of several pains mentioned earlier. Therefore, an attempt was made to prepare such transdermal patches. The intercalation of CH into the interlayers of sodium montmorillonite (Na-MMT) nanoclay via three different methods was demonstrated. Freshly prepared CH/Na-MMT composites were utilized to fabricate the transdermal patches to examine the analgesic activity of the drug for an extended period in a single dose or not after entering systemic circulation via skin barriers. The composites and patches were characterized by Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray diffraction (XRD). Sustained release of CH from CH/Na-MMT composites was observed for nearly 1 month during the in vitro release experiment. The results obtained from the ex vivo skin permeation study, as well as in vivo analgesic activity using those patches, corroborated the outcomes of the in vitro release study. Different kinetic models were applied to the ex vivo dissolution data to determine the best-fit kinetic model accompanied by drug release in both burst and sustained release periods.

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
Fig. 6

Similar content being viewed by others

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

References

  1. Kumar, A., Maitra, S., Khanna, P., & Baidya, D. K. (2014). Clonidine for management of chronic pain: A brief review of the current evidences. Saudi Journal of Anaesthesia, 8(1), 92–96. https://doi.org/10.4103/1658-354X.125955

  2. Hughes, P. L., & Morse, R. M. (1985). Use of clonidine in a mixed-drug detoxification regimen: Possibility of masking of clinical signs of sedative withdrawal. Mayo Clinic Proceedings, 60(1), 47–49. https://doi.org/10.1016/S0025-6196(12)65281-1

    Article  Google Scholar 

  3. Wrzosek, A., Woron, J., Dobrogowski, J., Jakowicka-Wordliczek, J., & Wordliczek, J. (2015). Topical clonidine for neuropathic pain. Cochrane Database of Systematic Reviews. John Wiley and Sons Ltd. https://doi.org/10.1002/14651858.CD010967.pub2

  4. Wang, J. G., Belley-Coté, E., Burry, L., Duffett, M., Karachi, T., Perri, D., Alhazzani, W., D’Aragon, F., Wunsch, H., & Rochwerg, B. (2017). Clonidine for sedation in the critically ill: A systematic review and meta-analysis. Critical Care, 21(1), 1–11. https://doi.org/10.1186/s13054-017-1610-8

  5. Singh, R., Chopra, N., Choubey, S., Tripathi, R., Prabhakar, & Mishra, A. (2014). Role of clonidine as adjuvant to intrathecal bupivacaine in patients undergoing lower abdominal surgery: A randomized control study. Anesthesia: Essays and Researches, 8(3), 307. https://doi.org/10.4103/0259-1162.143119

  6. Glynn, C., Dawson, D., & Sanders, R. (1988). A double-blind comparison between epidural morphine and epidural clonidine in patients with chronic non-cancer pain. Pain Vol. 34.

  7. Roh, D. H., Kim, H. W., Yoon, S. Y., Seo, H. S., Kwon, Y. B., Han, H. J., … Lee, J. H. (2008). Intrathecal clonidine suppresses phosphorylation of the n-methyl-D-aspartate receptor NR1 subunit in spinal dorsal horn neurons of rats with neuropathic pain. Anesthesia and Analgesia, 107(2), 693–700. https://doi.org/10.1213/ane.0b013e31817e7319

  8. Vasseur, B., Dufour, A., Houdas, L., Goodwin, H., Harries, K., Emul, N. Y., & Hutchings, S. (2017). Comparison of the systemic and local pharmacokinetics of clonidine mucoadhesive buccal tablets with reference clonidine oral tablets in healthy volunteers: An open-label randomised cross-over trial. Advances in Therapy, 34(8), 2022–2032. https://doi.org/10.1007/s12325-017-0585-9

    Article  Google Scholar 

  9. Jain, R., Segal, S., Kollins, S. H., & Khayrallah, M. (2011). Clonidine extended-release tablets for pediatric patients with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 50(2), 171–179. https://doi.org/10.1016/j.jaac.2010.11.005

    Article  Google Scholar 

  10. Weber, M. A., Drayer, J. I. M., McMahon, F. G., Hamburger, R., Shah, A. R., & Kirk, L. N. (1984). Transdermal administration of clonidine for treatment of high BP. Archives of Internal Medicine, 144(6), 1211–1213. https://doi.org/10.1001/archinte.1984.00350180139020

    Article  Google Scholar 

  11. Roelants, F., Lavand’homme, P. M., & Mercier-Fuzier, V. (2005). Epidural administration of neostigmine and clonidine to induce labor analgesia evaluation of efficacy and local anesthetic-sparing effect. Anesthesiology (Vol. 102). Retrieved from www.anesthesiology.org

  12. Ackerman, L. L., Follett, K. A., & Rosenquist, R. W. (2003). Long-term outcomes during treatment of chronic pain with intrathecal clonidine or clonidine/opioid combinations. Journal of Pain and Symptom Management, 26(1), 668–677. https://doi.org/10.1016/S0885-3924(03)00144-1

    Article  Google Scholar 

  13. Behrman, A., & Goertemoeller, S. (2007). A sticky situation: Toxicity of clonidine and fentanyl transdermal patches in pediatrics. Journal of Emergency Nursing, 33(3), 290–293. https://doi.org/10.1016/j.jen.2007.02.004

    Article  Google Scholar 

  14. Bloch, R., Bousquet, P., Feldman, J., & Schwartz, J. (1973). The mechanism of action of clonidine. Frontiers in Catecholamine Research, 853–857. https://doi.org/10.1016/B978-0-08-017922-3.50162-3

  15. Anderson, C., & Stone, T. W. (1974). On the mechanism of action of clonidine: Effects on single central neurones. British Journal of Pharmacology, 51(3), 359. https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.1974.tb10670.x

  16. Neil, M. J. (2011). Clonidine: Clinical pharmacology and therapeutic use in pain management. Current Clinical Pharmacology, 6(4), 280–287. https://doi.org/10.2174/157488411798375886

  17. Alam, M. I., Alam, N., Singh, V., Alam, M. S., Ali, M. S., Anwer, T., & Safhi, M. M. (2013). Type, preparation and evaluation of transdermal patch: A review. World Journal of Pharmacy and Pharmaceutical Sciences, 2(4), 2199–2233.

  18. Purushotham, K., & Anie Vijetha, K. (2023). A review on transdermal drug delivery system. GSC Biological and Pharmaceutical Sciences, 22(2), 245–255. https://doi.org/10.30574/gscbps.2023.22.2.0053

  19. Lohmann, V., Korner, F., Koch, J. O., Herian, U., Theilmann, L., & Bartenschlager, R. (1999). Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science, 285(5424), 110–113. https://doi.org/10.1126/science.285.5424.110

  20. Gaignaux, A., Réeff, J., Siepmann, F., Siepmann, J., De Vriese, C., Goole, J., & Amighi, K. (2012). Development and evaluation of sustained-release clonidine-loaded PLGA microparticles. International Journal of Pharmaceutics, 437(1–2), 20–28. https://doi.org/10.1016/j.ijpharm.2012.08.006

    Article  Google Scholar 

  21. Dubey, R., Dubey, B. K., Pandey, G. K., & Yadav, S. K. (2019). s):271-275 and characterization of alginate microbeads of clonidine hydrochloride by ionotropic gelation technique. Journal of Drug Delivery and Therapeutics, 9(2), 271–275. https://doi.org/10.22270/jddt.v9i2-s.2510

  22. Dangre, P. V., Phad, R. D., Surana, S. J., & Chalikwar, S. S. (2019). Quality by design (QbD) assisted fabrication of fast dissolving buccal film for clonidine hydrochloride: Exploring the quality Attributes. Advances in Polymer Technology, 2019, 1–88. https://doi.org/10.1155/2019/3682402

  23. Lanes, R., Recker, B., Fort, P., & Lifshitz, F. (1985). Low-dose oral clonidine: A simple and reliable growth hormone screening test for children. American Journal of Diseases of Children, 139(1), 87–88. https://doi.org/10.1001/archpedi.1985.02140030093040

    Article  Google Scholar 

  24. Viseras, C., Carazo, E., Borrego-Sánchez, A., García-Villén, F., Sánchez-Espejo, R., Cerezo, P., & Aguzzi, C. (2019). Clay minerals in skin drug delivery. Clays and Clay Minerals, 67(1), 59–71. https://doi.org/10.1007/s42860-018-0003-7

    Article  Google Scholar 

  25. Jayrajsinh, S., Shankar, G., Agrawal, Y. K., & Bakre, L. (2017). Montmorillonite nanoclay as a multifaceted drug-delivery carrier: A review. Journal of Drug Delivery Science and Technology, 39, 200–209. https://doi.org/10.1016/j.jddst.2017.03.023

  26. Dong, J., Cheng, Z., Tan, S., & Zhu, Q. (2021). Clay nanoparticles as pharmaceutical carriers in drug delivery systems. Taylor and Francis Ltd. https://doi.org/10.1080/17425247.2021.1862792

    Book  Google Scholar 

  27. Damato, A., Vianello, F., Novelli, E., Balzan, S., Gianesella, M., Giaretta, E., & Gabai, G. (2022). Comprehensive review on the interactions of clay minerals with animal physiology and production. Frontiers in Veterinary Science, 9, 889612. https://doi.org/10.3389/fvets.2022.889612

  28. Zhang, Y., Long, M., Huang, P., Yang, H., Chang, S., Hu, Y., ... & Mao, L. (2016). Emerging integrated nanoclay-facilitated drug delivery system for papillary thyroid cancer therapy. Scientific Reports, 6(1), 33335. https://doi.org/10.1038/srep33335

  29. Park, J. H., Shin, H. J., Kim, M. H., Kim, J. S., Kang, N., Lee, J. Y., Kim, K. T., Lee, J. I., & Kim, D. D. (2016). Application of montmorillonite in bentonite as a pharmaceutical excipient in drug delivery systems. Journal of Pharmaceutical Investigation, 46, 363–375. https://doi.org/10.1007/s40005-016-0258-8

  30. Salvé, J., Grégoire, B., Imbert, L., Hubert, F., Leitner, N. K. V., & Leloup, M. (2021). Design of hybrid chitosan-montmorillonite materials for water treatment: Study of the performance and stability. Chemical Engineering Journal Advances, 6, 100087. https://doi.org/10.1016/j.ceja.2021.100087

  31. Madurai, S. L., Joseph, S. W., Mandal, A. B., Tsibouklis, J., & Reddy, B. S. R. (2011). Intestine-specific, oral delivery of captopril/montmorillonite: Formulation and release kinetics. Nanoscale Research Letters, 6(1), 1–8. https://doi.org/10.1007/s11671-010-9749-0

    Article  Google Scholar 

  32. Adhikary, S., Al Hoque, A., Ray, M., Paul, S., Hossain, A., Goswami, S., & Dey, R. (2023). Investigation of paracetamol entrapped nanoporous silica nanoparticles in transdermal drug delivery system. Applied Biochemistry and Biotechnology. https://doi.org/10.1007/s12010-023-04576-w

    Article  Google Scholar 

  33. Banerjee, S., Chattopadhyay, P., Ghosh, A., Pathak, M. P., Singh, S., & Veer, V. (2013). Acute dermal irritation, sensitization, and acute toxicity studies of a transdermal patch for prophylaxis against ({+/-}) anatoxin-a poisoning. International journal of toxicology, 32(4), 308–313. https://doi.org/10.1177/1091581813489996

    Article  Google Scholar 

  34. de Kumar, P., Mallick, S., Mukherjee, B., Sengupta, S., Pattnaik, S., & Chakraborty, S. (2011). Optimization of in-vitro permeation pattern of ketorolac tromethamine transdermal patches. Iranian Journal of Pharmaceutical Research, 10(2), 193–201. https://doi.org/10.22037/ijpr.2011.927

  35. Ge, M., Li, Y., Zhu, C., Liang, G., Jahangir Alam, S. M., Hu, G., … Junaebur Rashid, M. (2021). Preparation of organic-modified magadiite–magnetic nanocomposite particles as an effective nanohybrid drug carrier material for cancer treatment and its properties of sustained release mechanism by Korsmeyer–Peppas kinetic model. Journal of Materials Science, 56(25), 14270–14286. https://doi.org/10.1007/s10853-021-06181-w

  36. Daher Pereira, E., Thomas, S., Gomes de Souza Junior, F., da Silva Cardoso, J., Thode Filho, S., Corrêa da Costa, V., … Galal Aboelkheir, M. (2021). Study of controlled release of ibuprofen magnetic nanocomposites. Journal of Molecular Structure, 1232, 130067. https://doi.org/10.1016/J.MOLSTRUC.2021.130067

  37. Fan, S.-H., Ali, N. A., & Basri, D. F. (2014). Evaluation of analgesic activity of the methanol extract from the galls of Quercus infectoria (Olivier) in rats. Evidence-Based Complementary and Alternative Medicine, 2014, 976764. https://doi.org/10.1155/2014/976764

    Article  Google Scholar 

  38. Li, C., Fang, K., He, W., Li, K., Jiang, Y., & Li, J. (2021). Evaluation of chitosan-ferulic acid microcapsules for sustained drug delivery: Synthesis, characterizations, and release kinetics in vitro. Journal of Molecular Structure, 1227, 129353. https://doi.org/10.1016/J.MOLSTRUC.2020.129353

    Article  Google Scholar 

  39. Uddin, F. (2018). Montmorillonite: An introduction to properties and utilization. In Current topics in the utilization of clay in industrial and medical applications. IntechOpen. https://doi.org/10.5772/intechopen.77987

  40. Romano, E., Davies, L., & Brandán, S. A. (2017). Structural properties and FTIR-Raman spectra of the anti-hypertensive clonidine hydrochloride agent and their dimeric species. Journal of Molecular Structure, 1133, 226–235. https://doi.org/10.1016/j.molstruc.2016.12.008

    Article  Google Scholar 

  41. Selvasudha, N., Dhanalekshmi, U.-M., Krishnaraj, S., Sundar, Y. H., Devi, N. S. D., & Sarathchandiran, I. (2020). Multifunctional clay in pharmaceuticals. In Clay science and technology. IntechOpen. https://doi.org/10.5772/intechopen.92408

  42. Van Gheluwe, L., Chourpa, I., Gaigne, C., & Munnier, E. (2021). Polymer-based smart drug delivery systems for skin application and demonstration of stimuli-responsiveness. Polymers, 13(8), 1285. https://doi.org/10.3390/polym13081285

  43. Aoi, W., Zou, X., **ao, J. B., & Marunaka, Y. (2020). Body fluid pH balance in metabolic health and possible benefits of dietary alkaline foods. Efood, 1(1), 12–23. https://doi.org/10.2991/efood.k.190924.001

  44. Mohamed, W. S., Mostafa, A. B., & Nasr, H. E. (2014). Characterization and application of intercalated montmorillonite with verapamil and its polymethyl methacrylate nanocomposite in drug delivery. Polymer - Plastics Technology and Engineering, 53(14), 1425–1433. https://doi.org/10.1080/03602559.2014.909462

    Article  Google Scholar 

  45. Akram, M. W., Jamshaid, H., Rehman, F. U., Zaeem, M., Khan, J. Z., & Zeb, A. (2022). Transfersomes: A revolutionary nanosystem for efficient transdermal drug delivery. AAPS PharmSciTech, 23, 1–18. https://doi.org/10.1208/s12249-021-02166-9

  46. Lademann, J., Patzelt, A., Richter, H., Antoniou, C., Sterry, W., & Knorr, F. (2009). Determination of the cuticula thickness of human and porcine hairs and their potential influence on the penetration of nanoparticles into the hair follicles. Journal of Biomedical Optics, 14(2), 021014. https://doi.org/10.1117/1.3078813

    Article  Google Scholar 

  47. Siepmann, J., & Peppas, N. A. (2011). Higuchi equation: Derivation, applications, use and misuse. International Journal of Pharmaceutics, 418(1), 6–12. https://doi.org/10.1016/j.ijpharm.2011.03.051

  48. Elmas, A., Akyüz, G., Bergal, A., Andaç, M., & Andaç, Ö. (2020). Mathematical modelling of drug release. Research on Engineering Structures and Materials, 6(4), 327–350. https://doi.org/10.17515/resm2020.178na0122

  49. Fu, Y., & Kao, W. J. (2010). Drug release kinetics and transport mechanisms of non-degradable and degradable polymeric delivery systems. Expert Opinion on Drug Delivery, 7(4), 429–444. https://doi.org/10.1517/17425241003602259

  50. Rehage, G., Ernst, O., & Fuhrmann, J. (1970). Fickian and non-Fickian diffusion in high polymer systems. Discussions of the Faraday Society, 49, 208–221. https://doi.org/10.1039/DF9704900208

    Article  Google Scholar 

  51. Bayer, I. S. (2023). Controlled drug release from nanoengineered polysaccharides. Pharmaceutics, 15(5), 1364. https://doi.org/10.3390/pharmaceutics15051364

Download references

Acknowledgements

We are thankful to the late Dr. Subrata Goswami, Department of Labour, ESI Institute of Pain Management, Kolkata, India, and Prof. (Dr.) Biswajit Mukherjee, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India, for their immense contribution to our research work.

Funding

Funding was provided by the Department of Higher Education, Science and Technology and Biotechnology, Government of West Bengal (File no: ST/P/S&T/6G-32/2017).

Author information

Authors and Affiliations

  1. School of Materials Science and Nanotechnology, Jadavpur University, 700032, Kolkata, India

    Sourav Adhikary, Manisheeta Ray, Pritha Pal & Mahua Ghosh Chaudhuri

  2. Department of Pharmaceutical Technology, Jadavpur University, 700032, Kolkata, India

    Ashique Al Hoque & Manisheeta Ray

  3. Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND, 58108, USA

    Ashique Al Hoque

  4. Metallurgical and Material Engineering Department, Jadavpur University, 700032, Kolkata, India

    Rajib Dey

Authors
  1. Sourav Adhikary
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ashique Al Hoque
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manisheeta Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pritha Pal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mahua Ghosh Chaudhuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rajib Dey
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Sourav Adhikary: conceptualization, data curation, formal analysis, investigation, methodology, and writing (original draft). Ashique Al Hoque: methodology and writing (review and editing). Manisheeta Ray: formal analysis and validation. Pritha Pal: investigation and validation. Mahua Ghosh Chaudhuri: resources and supervision. Rajib Dey: project administration, resources, and supervision.

Corresponding authors

Correspondence to Sourav Adhikary, Mahua Ghosh Chaudhuri or Rajib Dey.

Ethics declarations

Research Involving Humans and Animals Statement

Permission from the Institutional Animal Ethics Committee (IAEC) of Jadavpur University was received before commencing any animal experiments (JU-IAEC, Project proposal no.: JU-IAEC-22/11), under the norms of CPCSEA, Govt. of India (Jadavpur University Registration Number in CPCSEA: 1805/G.O./Re/S/15/CPCSEA). All experiments have been conducted following the guidelines of the Animal Ethics Committee of Jadavpur University.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Adhikary, S., Al Hoque, A., Ray, M. et al. Tailored Transdermal Drug Delivery System for Pain Management: Development and Evaluation of Clonidine Hydrochloride/Sodium Montmorillonite Composite Patch. BioNanoSci. (2024). https://doi.org/10.1007/s12668-024-01402-3

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12668-024-01402-3

Keywords

Search

Navigation