Skip to main content
SpringerLink
Log in

Anticonvulsant and acute toxicity evaluation of phenytoin sodium–loaded polymeric nanomicelle in MES rat model

  • Research paper
  • Published:
Journal of Nanoparticle Research Aims and scope Submit manuscript

Abstract

An acute seizure is a medical condition which, if untreated, can lead to brain damage and even death. Phenytoin sodium is a second-line drug of choice for seizure emergencies. Due to the administration issues as well as pharmacokinetic issues of the drug, it is now being replaced with newer anticonvulsant drugs despite short half life and sedative effects. This study aims to develop a polymeric nanomicelle of phenytoin sodium that decreases administration difficulties, enhances drug availability in the brain, and lowers the dose, all of which could be advantageous in the treatment of seizure emergencies. Phenytoin sodium–loaded polymeric nanomicelle was prepared by thin-film hydration method. A novel polymeric nanomicelle of size less than 20 nm loaded with phenytoin sodium was prepared with pluronic F127. Drug-loaded polymeric nanomicelle showed an immediate release profile with reduced PPB and improved lipid permeation when compared with the marketed iv injection of Phenytoin sodium. The in vivo acute toxicity study results revealed that the optimized formulation is safe for administration. The pharmacodynamic study by the MES model proved the enhanced brain availability as well as the reduced dose, thereby reducing peripheral toxicity. Results from the above studies confirm that the phenytoin sodium–loaded polymeric nanomicelle could potentially to be a better candidate for seizure emergencies, as it could reduce the administration issues, improve the brain availability of phenytoin, and lower the dose requirements.

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
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  • Aboud HM, Mahmoud MO, Mohammed MA, Awad MS, Sabry D (2019) Preparation and appraisal of self assembled valsartan-loaded amalgamated Pluronic F127/Tween 80 polymeric micelles: Boosted cardioprotection via regulation of Mhrt/Nrf2 and Trx1 pathways in cisplatin-induced cardiotoxicity. J Drug Target 28:1–45

    Google Scholar 

  • Ai X, Zhong L, Niu H, He Z (2014) Thin-film hydration preparation method and stability test of DOX-loaded disulfide-linked polyethylene glycol 5000-lysine-di-tocopherol succinate nanomicelles. Asian J Pharm Sci 9:244–250

    Article  Google Scholar 

  • Bodmeier R, McGinity JW (1988) Solvent selection in the preparation of poly(dl-lactide) microspheres prepared by the solvent evaporation method. Int J Pharm 43:179–186

    Article  CAS  Google Scholar 

  • Dehghan Kelishady P, Saadat E, Ravar F, Akbari H, Dorkoosh F (2014) Pluronic F127 polymeric micelles for co-delivery of paclitaxel and lapatinib against metastatic breast cancer: preparation, optimization and in vitro evaluation. Pharm Dev Technol 20:1009–1017

    Article  Google Scholar 

  • Deng Z J, Liang M, Toth I, Monteiro M, Minchin R F (2013) PPB of positively and negatively charged polymer-coated gold nanoparticles elicits different biological responses. Nanotoxicology 314–22.

  • Divya G, Rajitha P, Swati G, Jayakumar R, Sabitha M (2016) Acitretin and aloe-emodin loaded chitin nanogel for the treatment of psoriasis. Eur J Pharm Biopharm 107:97–109

    Article  CAS  Google Scholar 

  • Fang Z, Chen S, Qin J, Chen B, Ni G, Chen Z et al (2016) Pluronic P85-coated poly(butylcyanoacrylate) nanoparticles overcome phenytoin resistance in P-glycoprotein overexpressing rats with lithium-pilocarpine-induced chronic temporal lobe epilepsy. Biomaterials 97:110–121

    Article  CAS  Google Scholar 

  • Folch J, Lees M, Slone Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497–509

    Article  CAS  Google Scholar 

  • Garbovsky LA, Drumheller BC, Perrone J (2015) Purple glove syndrome after phenytoin or fosphenytoin administration: review of reported cases and recommendations for prevention. J Med Toxicol 11:445–459

    Article  CAS  Google Scholar 

  • Ghezzi M, Pescina S, Padula C, Santi P, Del Favero E, Cantù L, Nicoli S (2021) Polymeric micelles in drug delivery: an insight of the techniques for their characterization and assessment in biorelevant conditions. J Control Release 332:312–336

    Article  CAS  Google Scholar 

  • Howell M, Mallela J, Wang C, Ravi S, Dixit S, Garapati U, Mohapatra S (2013) Manganese-loaded lipid-micellar theranostics for simultaneous drug and gene delivery to lungs. J Control Release 167:210–218

    Article  CAS  Google Scholar 

  • Jesse F, Sheril A, Mariana B (2018) A novel HPLC method for determination of phenytoin in human plasma. J Pharm Res Int 22:1–7

    Google Scholar 

  • Joana B, Gilberto A, Ana F, Patrício SS, Amílcar F (2016) A new PAMPA model using an in-house brain lipid extract for screening the blood-brain barrier permeability of drug candidates. Int J Pharm 501:102–111

    Article  Google Scholar 

  • Kabanov AV, Batrakova EV, Alakhov VY (2002) Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. J Control Release 2:189–212

    Article  Google Scholar 

  • Kabanov AV, Batrakova EV, Alakhov VY (2002) Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. J Control Release 82:189–212

    Article  CAS  Google Scholar 

  • Kim S, Shi YZ, Kim JY, Park K, Cheng JX (2010) Overcoming the barriers in micellar drug delivery: Loading efficiency, in vivo stability, and micelle-cell interaction, Expert Opin. Drug Deliv 7:49–62

    CAS  Google Scholar 

  • Lemaire V, Bélair J, Hildgen P (2003) Structural modeling of drug release from biodegradable porous matrices based on a combined diffusion/erosion process. Int J Pharm 258:95–107

    Article  CAS  Google Scholar 

  • Liu JS, Wang JH, Zhou J (2014) Enhanced brain delivery of lamotrigine with Pluronic(®) P123-based nanocarrier. Int J Nanomedicine 9:3923–3935

    CAS  Google Scholar 

  • Lu Y, Zhang E, Yang J, Cao Z (2018) Strategies to improve micelle stability for drug delivery. Nano Res 11:4985–4998

    Article  Google Scholar 

  • Marchi N, Betto G, Fazio V (2009) Blood-brain barrier damage and brain penetration of antiepileptic drugs: role of serum proteins and brain edema. Epilepsia 50:664–677

    Article  CAS  Google Scholar 

  • Mohammed AS, Osama AA, Gehan FB, Almalki WH (2018) Self-assembled biodegradable polymeric micelles to improve dapoxetine delivery across the blood–brain barrier. Int J Nanomedicine 13:3679–3687

    Article  Google Scholar 

  • Nadeem MN, Maqdoom M (2020) Potentiation of anticonvulsant effect of phenytoin by celecoxib against maximum electroshock induced convulsions in albino rats. Int J Basic Clin Pharmacol 9:1491–1496

    Article  Google Scholar 

  • Nagarwal RC, Ridhurkar DN, Pandit JK (2010) In vitro release kinetics and bioavailability of gastroretentive cinnarizine hydrochloride tablet. AAPS Pharm Sci Tech 11:294–303

    Article  CAS  Google Scholar 

  • OECD (2001) Guideline for the testing of chemicals. No. 423: acute oral toxicity — acute toxic class method, OECD 14.

  • Ogutu BR, Newton CR, Muchohi SN (2003) Pharmacokinetics and clinical effects of phenytoin and fosphenytoin in children with severe malaria and status epilepticus. Br J Clin Pharmacol 56:112–119

    Article  CAS  Google Scholar 

  • Paliwal R, Babu RJ, Palakurthi S (2014) Nanomedicine scale-up technologies: feasibilities and challenges. AAPS Pharm Sci Tech 15:1527–1534

  • Panonnummal R, Sabitha M (2018) Anti-psoriatic and toxicity evaluation of methotrexate chitin nanogel in imiquimod induced mice model. Int J Biol Macromol 10:245–258

    Article  Google Scholar 

  • Panonnummal R, Jayakumar R, Sabitha M (2017) Comparative anti-psoriatic efficacy studies of clobetasol loaded chitin nanogel and marketed cream. Eur J Pharm Sci 96:193–206

    Article  CAS  Google Scholar 

  • Patocka J, Wu Q, Nepovimova E, Kuca K (2020) Phenytoin–an anti-seizure drug: overview of its chemistry, pharmacology and toxicology. Food Chem Toxicol 142:111393

    Article  CAS  Google Scholar 

  • Shafer WG (1961) Effect of dilantin sodium on various cell lines in tissue culture. Proc Soc Exp Biol Med 108:694–696

    Article  CAS  Google Scholar 

  • Shubhra QTH, Toth J, Gyenis J, Feczko T (2014) Surface modification of HSA containing magnetic PLGA nanoparticles by poloxamer to decrease plasma protein adsorption. Colloids Surf B 122:529–536

    Article  CAS  Google Scholar 

  • Sreedhar R, Kumar VS, Bhaskaran Pillai AK, Mangalathillam S (2019) Omega-3 fatty acid based nanolipid formulation of atorvastatin for treating hyperlipidemia. Adv Pharm Bull 9:271–280

    Article  CAS  Google Scholar 

  • Stafstrom CE, Carmant L (2015) Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harb Perspect Med 5:a022426

    Article  Google Scholar 

  • Stolnik S, Daudali B, Arien A, Whetstone J, Heald C, Garnett M, Illum L (2001) The effect of surface coverage and conformation of poly(ethylene oxide) (PEO) chains of poloxamer 407 on the biological fate of model colloidal drug carriers. Biochim Biophys Acta Biomembr 1514:261–279

    Article  CAS  Google Scholar 

  • Vert M, Domurado D (2000) Poly(ethylene glycol): Protein-repulsive or albumin-compatible? J Biomater Sci Polym 11:1307–1317

    Article  CAS  Google Scholar 

  • Wei Z, Hao J, Yuan S (2009) Paclitaxel-loaded pluronic P123/F127 mixed polymeric micelles: formulation, optimization and in vitro characterization. Int J Pharm 376:176–185

    Article  CAS  Google Scholar 

  • White GC (2003) The partial thromboplastin time: defining an era in coagulation. J Thromb Haemost 1:2267–2270

    Article  CAS  Google Scholar 

  • Xu W, Ling P, Zhang T (2013) Polymeric micelles, a promising drug delivery system to enhance bioavailability of poorly water-soluble drugs. J Drug Deliv 2013:1–15

    Article  CAS  Google Scholar 

  • Yousefpour Marzbali M, Yari Khosroushahi A (2017) Polymeric micelles as mighty nanocarriers for cancer gene therapy: a review, Cancer Chemother. Pharmacol 79:637–649

    CAS  Google Scholar 

  • Zasada K, Lukasiewicz-Atanasov M, Kłysik K, Lewandowska-Lancucka J, Gzyl-Malcher B et al (2015) ‘One-component’ ultrathin multilayer films based on poly(vinyl alcohol) as stabilizing coating for phenytoin-loaded liposomes. Colloids Surf B 135:133–142

    Article  CAS  Google Scholar 

  • Zhao YZ, Lv HF, Lu CT (2013) Evaluation of a novel thermosensitive heparin-poloxamer hydrogel for improving vascular anastomosis quality and safety in a rabbit model. PLoS ONE 8:e73178

    Article  CAS  Google Scholar 

  • Zhou Q, Zhang Z, Chen T, Guo X, Zhou S (2011) Preparation and characterization of thermosensitive pluronic F127-b-poly(ε-caprolactone) mixed micelles. Colloids Surf B 86:45–57

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are thankful to the staffs in the Central Lab Animal Facility, Amrita Institute of Medical Science, Kochi, for their valuable guidance and support during the in vivo animal studies. The authors are also grateful to Department of Science and Technology (DST)-Nanomission for funding this project (SR/NM/NS-1118/2015).

Author information

Authors and Affiliations

  1. Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi, 682041, Kerala, India

    Vrinda S Kumar & Sabitha M

  2. Division of Paediatric Neurology, Department of Neurology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, 682041, Kerala, India

    Vinayan KP

Authors
  1. Vrinda S Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vinayan KP
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sabitha M
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sabitha M.

Ethics declarations

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumar, V.S., KP, V. & M, S. Anticonvulsant and acute toxicity evaluation of phenytoin sodium–loaded polymeric nanomicelle in MES rat model. J Nanopart Res 24, 154 (2022). https://doi.org/10.1007/s11051-022-05502-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11051-022-05502-7

Keywords

Search

Navigation