Abstract
Epilepsy, characterized by abnormalities in neuronal activity, remains a challenge for a significant proportion of patients despite the increasing armamentarium of antiseizure medications available. Despite various treatment options available for patients including monotherapy and polytherapy, drug resistance is a challenging issue. Researchers are still actively looking into not only the discovery of novel antiseizure medications and combination therapies but also refinement of the pharmaceutical formulations of existing antiseizure medications. Advancements in technology have vastly improved the research which led to several developments and approval of antiseizure medications formulation including diazepam rectal gel, intranasal midazolam, and intranasal diazepam. These present opportunities for physicians and researchers to further optimize the efficacy, tolerability, and accessibility of these medications. This chapter explores various pharmaceutical formulations of antiseizure medications, such as buccal, injectables, rectal, intranasal, and transdermal formulations, highlighting their potential advantages, disadvantages, and application in treating different types of seizures. The discussion aims to contribute to a broader understanding of the therapeutic landscape for epilepsy and encourage personalized approaches to treatment selection and administration where the end goal is always for the overall well-being of the people living with epilepsy.
References
Anderson GD, Saneto RP (2012) Current oral and non-oral routes of antiepileptic drug delivery. Adv Drug Deliv Rev 64(10):911–918. https://doi.org/10.1016/j.addr.2012.01.017
Asadi-Pooya A, Sperling M (2015) Antiepileptic drugs: a clinician’s manual. Oxford University Press. https://doi.org/10.1093/med/9780190214968.001.0001
Asadi-Pooya AA et al (2022) Recommendations for treatment strategies in people with epilepsy during times of shortage of antiseizure medications. Epileptic Disord 24(5):751–764. https://doi.org/10.1684/epd.2022.1468
Aykaç K, Başaran E (2022) Formulation and characterization of lacosamide-loaded polymeric microneedles. J Explor Res Pharmacol 7(2):61–75. https://doi.org/10.14218/jerp.2021.00051
Baumgartner R et al (2016) Rational design and characterization of a nanosuspension for intraoral administration considering physiological conditions. J Pharm Sci 105(1):257–267. https://doi.org/10.1016/j.xphs.2015.10.021
Bialer M (2007) Extended-release formulations for the treatment of epilepsy. CNS Drugs 21(9):765–774. https://doi.org/10.2165/00023210-200721090-00005
Boddu SHS, Kumari S (2020) A short review on the intranasal delivery of diazepam for treating acute repetitive seizures. Pharmaceutics 12(12):1–17. https://doi.org/10.3390/pharmaceutics12121167
Bouw MR et al (2021) Clinical pharmacokinetic and pharmacodynamic profile of midazolam nasal spray. Epilepsy Res 171:106567. https://doi.org/10.1016/j.eplepsyres.2021.106567
Brouard A et al (1990) Rectal administration of carbamazepine gel. Clin Pharm 9(1):13–14
de Boer AG et al (1982) Rectal drug administration: clinical pharmacokinetic considerations. Clin Pharmacokinet 7(4):285–311. https://doi.org/10.2165/00003088-198207040-00002
Dreifuss FE et al (1998) A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med 338(26):1869–1875. https://doi.org/10.1056/NEJM199806253382602
Dulac O, Alvarez J-C (2005) Bioequivalence of a new sustained-release formulation of sodium valproate, valproate modified-release granules, compared with existing sustained-release formulations after once- or twice-daily administration. Pharmacotherapy 25(1):35–41. https://doi.org/10.1592/phco.25.1.35.55626
Eeg-Olofsson O et al (1990) Diurnal variation of carbamazepine and carbamazepine-10,11-epoxide in plasma and saliva in children with epilepsy: a comparison between conventional and slow-release formulations. J Child Neurol 5(2):159–165. https://doi.org/10.1177/088307389000500219
Elger C et al (2007) Eslicarbazepine acetate: a double-blind, add-on, placebo-controlled exploratory trial in adult patients with partial-onset seizures. Epilepsia 48(3):497–504. https://doi.org/10.1111/j.1528-1167.2007.00984.x
Eriksson K, Kälviäinen R (2005) Pharmacologic management of convulsive status epilepticus in childhood. Expert Rev Neurother 5(6):777–783. https://doi.org/10.1586/14737175.5.6.777
Fedak Romanowski EM et al (2021) Seizure rescue medications for out-of-hospital use in children. J Pediatr 229:19–25. https://doi.org/10.1016/j.jpeds.2020.10.041
Fisher RS et al (2017) Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58(4):522–530. https://doi.org/10.1111/epi.13670
Gidal B, Klein P, Hirsch LJ (2020) Seizure clusters, rescue treatments, seizure action plans: unmet needs and emerging formulations. Epilepsy Behav 112:107391. https://doi.org/10.1016/j.yebeh.2020.107391
Gidal BE et al (2021) Use of extended-release and immediate-release anti-seizure medications with a long half-life to improve adherence in epilepsy: a guide for clinicians. Epilepsy Behav 120:107993. https://doi.org/10.1016/j.yebeh.2021.107993
Graves NM et al (1989) Relative bioavailability of rectally administered phenobarbital sodium parenteral solution. DICP: Ann Pharmacother 23(7–8):565–568. https://doi.org/10.1177/1060028089023007-806
Grossmann R, Maytal J, Fernando J (1994) Rectal administration of felbamate in a child with Lennox-Gastaut syndrome. Neurology 44(10):1979. https://doi.org/10.1212/wnl.44.10.1978-a
Hanada S et al (2014) Cell-based in vitro blood-brain barrier model can rapidly evaluate nanoparticles’ brain permeability in association with particle size and surface modification. Int J Mol Sci 15(2):1812–1825. https://doi.org/10.3390/ijms15021812
He W et al (2009) Study on the mechanisms of chitosan and its derivatives used as transdermal penetration enhancers. Int J Pharm 382:234–243. https://doi.org/10.1016/j.ijpharm.2009.07.038
Holliday SM, Benfield P, Plosker GL (1998) Fosphenytoin. Pharmacoeconomic implications of therapy. PharmacoEconomics 14(6):685–690. https://doi.org/10.2165/00019053-199814060-00008
Hua S (2019) Advances in nanoparticulate drug delivery approaches for sublingual and buccal administration. Front Pharmacol 10(November):1–9. https://doi.org/10.3389/fphar.2019.01328
Irving G et al (2009) Efficacy and tolerability of gastric-retentive gabapentin for the treatment of postherpetic neuralgia: results of a double-blind, randomized, placebo-controlled clinical trial. Clin J Pain 25(3):185–192. https://doi.org/10.1097/AJP.0b013e3181934276
Jensen PK et al (1990) Pharmacokinetic comparison of two carbamazepine slow-release formulations. Acta Neurol Scand 82(2):135–137. https://doi.org/10.1111/j.1600-0404.1990.tb01603.x
Kalia YN, Guy RH (2001) Modeling transdermal drug release. Adv Drug Deliv Rev 48(2–3):159–172. https://doi.org/10.1016/s0169-409x(01)00113-2
Keppel Hesselink JM, Kopsky DJ (2017) Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action. J Neurol 264(8):1617–1621. https://doi.org/10.1007/s00415-017-8391-5
Kriel RL et al (1991) Home use of rectal diazepam for cluster and prolonged seizures: efficacy, adverse reactions, quality of life, and cost analysis. Pediatr Neurol 7(1):13–17. https://doi.org/10.1016/0887-8994(91)90099-7
Kriel RL et al (1997) Failure of absorption of gabapentin after rectal administration. Epilepsia 38(11):1242–1244. https://doi.org/10.1111/j.1528-1157.1997.tb01223.x
Kwan P et al (2010) Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51(6):1069–1077. https://doi.org/10.1111/j.1528-1167.2009.02397.x
Lahat E et al (2000) Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study. BMJ (Clin Res) 321(7253):83–86. https://doi.org/10.1136/bmj.321.7253.83
Lockman PR et al (2004) Nanoparticle surface charges alter blood-brain barrier integrity and permeability. J Drug Target 12(9–10):635–641. https://doi.org/10.1080/10611860400015936
Logroscino G et al (2001) Time trends in incidence, mortality, and case-fatality after first episode of status epilepticus. Epilepsia 42(8):1031–1035. https://doi.org/10.1046/j.1528-1157.2001.0420081031.x
Lombroso CT (1989) Intermittent home treatment of status and clusters of seizures. Epilepsia 30(Suppl 2):S11–S14. https://doi.org/10.1111/j.1528-1157.1989.tb05819.x
Löscher W (2017) Animal models of seizures and epilepsy: past, present, and future role for the discovery of antiseizure drugs. Neurochem Res 42(7):1873–1888. https://doi.org/10.1007/s11064-017-2222-z
Lowenstein DH (2006) The management of refractory status epilepticus: an update. Epilepsia 47(Suppl 1):35–40. https://doi.org/10.1111/J.1528-1167.2006.00658.X
Lu R et al (2015) Nanoemulsions as novel oral carriers of stiripentol: insights into the protective effect and absorption enhancement. Int J Nanomedicine 10:4937–4946. https://doi.org/10.22147/IJN.S87471
Maaz A, Blagbrough IS, De Bank PA (2021) In vitro evaluation of nasal aerosol depositions: an insight for direct nose to brain drug delivery. Pharmaceutics 13(7). https://doi.org/10.3390/pharmaceutics13071079
Maia J et al (2005) Effect of food on the pharmacokinetic profile of eslicarbazepine acetate (BIA 2-093). Drugs R&D 6(4):201–206. https://doi.org/10.2165/00126839-200506040-00002
Markovic M, Ben-Shabat S, Dahan A (2020) Prodrugs for improved drug delivery: lessons learned from recently developed and marketed products. Pharmaceutics 12(11):1–12. https://doi.org/10.3390/pharmaceutics12111031
McMullan J et al (2010) Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis. Acad Emerg Med 17(6):575–582. https://doi.org/10.1111/j.1553-2712.2010.00751.x
Merritt HH, Putnam TJ (1984) Landmark article Sept 17, 1938: sodium diphenyl hydantoinate in the treatment of convulsive disorders. By H. Houston Merritt and Tracy J. Putnam. JAMA 251(8):1062–1067. https://doi.org/10.1001/jama.251.8.1062
Miller AD, Krauss GL, Hamzeh FM (2004) Improved CNS tolerability following conversion from immediate- to extended-release carbamazepine. Acta Neurol Scand 109(6):374–377. https://doi.org/10.1111/j.1600-0404.2004.00291.x
Millikan D, Rice B, Silbergleit R (2009) Emergency treatment of status epilepticus: current thinking. Emerg Med Clin North Am 27(1):101–13, ix. https://doi.org/10.1016/j.emc.2008.12.001
Mittal P, Manohar R, Rawat AK (2006) Comparative study of intranasal midazolam and intravenous diazepam sedation for procedures and seizures. Indian J Pediatr 73(11):975–978. https://doi.org/10.1007/BF02758299
Mpimbaza A et al (2008) Comparison of buccal midazolam with rectal diazepam in the treatment of prolonged seizures in Ugandan children: a randomized clinical trial. Pediatrics 121(1):e58–e64. https://doi.org/10.1542/peds.2007-0930
Naritoku DK et al (2007) Lamotrigine extended-release as adjunctive therapy for partial seizures. Neurology 69(16):1610–1618. https://doi.org/10.1212/01.wnl.0000277698.33743.8b
Neurelis I (2023) VALTOCO® (diazepam nasal spray) full prescribing information, approved by the U.S. Food and Drug Administration. Accessed on July 2023
Nguyen J et al (2016) The influence of solid microneedles on the transdermal delivery of selected antiepileptic drugs. Pharmaceutics 8(4). https://doi.org/10.3390/pharmaceutics8040033
O’Regan ME, Brown JK, Clarke M (1996) Nasal rather than rectal benzodiazepines in the management of acute childhood seizures? Dev Med Child Neurol 38(11):1037–1045. https://doi.org/10.1111/j.1469-8749.1996.tb15064.x
Patel SI et al (2015) Intravenous and intramuscular formulations of antiseizure drugs in the treatment of epilepsy. CNS Drugs 29(12):1009–1022. https://doi.org/10.1007/s40263-015-0289-0
Pellock JM et al (2004) Extended-release formulations: simplifying strategies in the management of antiepileptic drug therapy. Epilepsy Behav 5(3):301–307. https://doi.org/10.1016/j.yebeh.2004.01.009
Peltola J et al (2009) Once-daily extended-release levetiracetam as adjunctive treatment of partial-onset seizures in patients with epilepsy: a double-blind, randomized, placebo-controlled trial. Epilepsia 50(3):406–414. https://doi.org/10.1111/j.1528-1167.2008.01817.x
Perucca E (2009) Extended-release formulations of antiepileptic drugs: rationale and comparative value. Epilepsy Curr 9(6):153–157. https://doi.org/10.1111/j.1535-7511.2009.01326.x
Perucca E (2021) The pharmacological treatment of epilepsy: recent advances and future perspectives. Acta Epileptol 3(1):22. https://doi.org/10.1186/s42494-021-00055-z
Pinheiro RGR et al (2021) Nanoparticles for targeted brain drug delivery: what do we know? Int J Mol Sci 22(21). https://doi.org/10.3390/ijms222111654
Qiu Y, Zhou D (2011) Understanding design and development of modified release solid oral dosage forms. J Valid Technol 17(2):23–32
Rahman M, Nguyen H (2022) Valproic Acid. In StatPearls. StatPearls Publishing
Ramsay RE, DeToledo J (1996) Intravenous administration of fosphenytoin. Neurology 46(6 Suppl 1):S17–S19. https://doi.org/10.1212/WNL.46.6_Suppl_1.17S
Randinitis EJ, Buchanan RA, Kinkel AW (1990) Pharmacokinetic profile of a 300-mg extended phenytoin sodium capsule (Dilantin) formulation. Epilepsia 31(4):458–464. https://doi.org/10.1111/j.1528-1157.1990.tb05503.x
Rémi C et al (2023) Rectal use of levetiracetam: best practice report for a stepwise approach for sustainable off-label decision making and treatment. Int J Clin Pharm 45:774–780. https://doi.org/10.1007/s11096-023-01539-3
Scheffer IE et al (2021) Safety and tolerability of transdermal cannabidiol gel in children with developmental and epileptic encephalopathies: a nonrandomized controlled trial. JAMA Netw Open 4(9):1–11. https://doi.org/10.1001/jamanetworkopen.2021.23930
Shefrin S et al (2019) Anti-epileptic drug loaded niosomal transdermal patch for enhanced skin permeation. Int J Appl Pharm 11(2):31–43. https://doi.org/10.22159/ijap.2019v11i2.27034
Soroushnia A et al (2021) Preparation, optimization, and evaluation of midazolamnanosuspension: enhanced bioavailability for buccaladministration. Prog Biomater 10(1):19–28
Steinhoff BJ, Wendling AS (2009) Short-term impact of the switch from immediate-release to extended-release oxcarbazepine in epilepsy patients on high dosages. Epilepsy Res 87(2–3):256–259. https://doi.org/10.1016/j.eplepsyres.2009.09.013
Stella VJ (2004) Prodrugs as therapeutics. Expert Opin Ther Pat 14(3):277–280. https://doi.org/10.1517/13543776.14.3.277
Sun X, Vilar S, Tatonetti NP (2013) High-throughput methods for combinatorial drug discovery. Sci Transl Med 5(205):205rv1. https://doi.org/10.1126/scitranslmed.3006667
UCB I (1998) NAYZILAM® (midazolam) nasal spray. Interactions. http://pi.lilly.com/us/zyprexa-pi.pdf
van de Donk HJ et al (1982) The effects of nasal drops and their additives on human nasal mucociliary clearance. Rhinology 20(3):127–137
Virani A et al (2023) Effect of penetration enhancers on transdermal delivery of oxcarbazepine, an antiepileptic drug using microemulsions. Pharmaceutics 15(1). https://doi.org/10.3390/pharmaceutics15010183
Wahab A (2010) Difficulties in treatment and management of epilepsy and challenges in new drug development. Pharmaceuticals 3(7):2090–2110. https://doi.org/10.3390/ph3072090
Wermeling DP (2009) Intranasal delivery of antiepileptic medications for treatment of seizures. Neurotherapeutics 6(2):352–358. https://doi.org/10.1016/j.nurt.2009.01.002
Wohlfart S, Gelperina S, Kreuter J (2012) Transport of drugs across the blood-brain barrier by nanoparticles. J Control Release 161(2):264–273. https://doi.org/10.1016/j.jconrel.2011.08.017
Yasiry Z, Shorvon SD (2012) How phenobarbital revolutionized epilepsy therapy: the story of phenobarbital therapy in epilepsy in the last 100 years. Epilepsia 53(Suppl 8):26–39. https://doi.org/10.1111/epi.12026
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Ahmad, N., Arulsamy, A., Shaikh, M.F. (2023). Epilepsy and ASM Formulations. In: Mohamed, E. (eds) Handbook of Neurodegenerative Disorders . Springer, Singapore. https://doi.org/10.1007/978-981-19-3949-5_28-1
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