Migraine is a debilitating neuromuscular disorder marked by severe, one-sided headaches. Triptans, such as Zolmitriptan (ZMP), act as serotonin receptor agonists and are commonly used in migraine treatment. However, ZMP, classified under Bio-pharmaceutics Classification System Class III, suffers from low oral bioavailability (<4%), limiting its therapeutic efficacy. To address this, intranasal delivery using nanostructured lipid carriers (NLCs) has emerged as a promising strategy to enhance bioavailability and enable targeted brain delivery. The study aimed to improve the bioavailability of ZMP by developing intranasal NLCs and evaluating their potential for targeted brain delivery in migraine treatment. ZMP-loaded NLCs (ZMP-NLCs) were formulated using the hot melt emulsification method with high-speed stirring. The NLCs were optimized based on particle size, zeta potential, entrapment efficiency (EE), and drug release over 8 h. The optimized formulation consisted of 1% Glycerol Monostearate (solid lipid), 1% Capmul MCM (liquid lipid), and 1.5% Tween 80 (surfactant). The NLCs were characterized using Fourier transmission infrared (FTIR) spectroscopy, powder X-ray diffraction (XRD), and scanning electron microscopy (SEM) to confirm drug incorporation and particle morphology. Pharmacodynamic studies were conducted to assess brain delivery and antimigraine efficacy. The optimized NLC formulation exhibited a particle size of 233 ± 9.07 nm, a polydispersity index of 0.257 ± 0.03, a zeta potential of −42.8 ± 0.5 mV, an EE of 89.35 ± 0.9%, and a drug release of 87.1 ± 1.03% after 8 h. FTIR and XRD analyses confirmed the successful incorporation of ZMP into the NLCs without significant chemical interactions. SEM revealed uniform, spherical particles. Pharmacodynamic studies demonstrated effective brain delivery of ZMP, bypassing the blood–brain barrier, and significantly enhancing its antimigraine potential. This study highlights the potential of ZMP-NLCs for intranasal delivery. NLCs offer improved bioavailability and targeted brain therapy for effective migraine management. The findings suggest that NLCs are a promising approach for enhancing the therapeutic efficacy of ZMP.
Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia: An International Journal of Headache, 2018; 38(1):1–211; doi: 10.1177/0333102417738202
4.
BonafedeM, SapraS, ShahN, et al.Direct and indirect healthcare resource utilization and costs among migraine patients in the United States. Headache, 2018; 58(5):700–714; doi: 10.1111/head.13275
5.
EdmeadsJ, MackellJA. The economic impact of migraine: An analysis of direct and indirect costs. Headache, 2002; 42(6):501–509; doi: 10.1046/j.1526-4610.2002.04262
6.
SteinerTJ, StovnerLJ, JensenR, UluduzD, KatsaravaZ, Lifting The Burden: the Global Campaign against Headache. Migraine remains second among the world’s causes of disability, and first among young women: Findings from GBD2019. J Headache Pain, 2020; 21(1):137; doi: 10.1186/s10194-020-01208-0
7.
EdvinssonL, HaanesKA, WarfvingeK, et al.CGRP as the target of new migraine therapies—successful translation from bench to clinic. Nat Rev Neurol, 2018; 14(6):338–350.
8.
GendollaA, RauerN, KraemerS, et al.Epidemiology, demographics, triptan contraindications, and prescription patterns of patients with migraine: A German claims database study. Neurol Ther, 2022; 11(1):167–183.
9.
AntonaciF, GhiottoN, WuS, et al.Recent advances in migraine therapy. Springerplus, 2016; 5:637; doi: 10.1186/s40064-016-2211-8
10.
AwadeenRH, BoughdadyMF, MeshaliMM. Quality by design approach for preparation of Zolmitriptan/Chitosan nanostructured lipid carrier particles formulation and pharmacodynamic assessment. Int J Nanomedicine, 2020; 15:8553–8568.
11.
MoffatAC, OsseltonMD, WiddopB, et al.Analysis of Drugs and Poisons, 4th ed. The Pharmaceutical Press: London, UK, 2011.
12.
SeaberE, OnN, DixonRM, et al.The absolute bioavailability and metabolic disposition of the novel antimigraine compound zolmitriptan (311C90). Br J Clin Pharmacol, 1997; 43(6):579–587; doi: 10.1046/j.1365-2125.1997.00614
13.
González-HernándezA, Marichal-CancinoBA, MaassenVanDenBrinkA, et al.Side effects associated with current and prospective antimigraine pharmacotherapies. Expert Opin Drug Metab Toxicol, 2018; 14(1):25–41.
14.
NadhTHH, KumarPS, RamanaMV, et al.Formulation and optimization of Zolmitriptan orodispersible tablets. J. Drug Deliv. Ther, 2021; 11:50–57.
15.
KumriaR, Al-DhubiabBE, ShahJ, et al.Formulation and evaluation of chitosan-based buccal bioadhesive films of Zolmitriptan. J Pharm Innov, 2018; 13(2):133–143.
16.
KovacicK, LiBUK. Cyclic vomiting syndrome: A narrative review and guide to management. Headache, 2021; 61(2):231–243.
17.
MostafaDAE, KhalifaMKA, GadSS. Zolmitriptan brain targeting via intranasal route using solid lipid nanoparticles for migraine therapy: Formulation, characterization, in-vitro and in-vivo assessment. Int. J. Appl. Pharm, 2020; 12:86–93.
18.
UemuraN, OnishiT, MitaniyamaA, et al.Bioequivalence and rapid absorption of zolmitriptan nasal spray compared with oral tablets in healthy Japanese subjects. Clin Drug Investig, 2005; 25(3):199–208; doi: 10.2165/00044011-200525030-00006
19.
Geszke-MoritzM, MoritzM. Solid lipid nanoparticles as attractive drug vehicles: Composition, properties and therapeutic strategies. Mater Sci Eng C Mater Biol Appl, 2016; 68:982–994.
20.
IzzaN, SugaK, OkamotoY, et al.Systematic characterization of nanostructured lipid carriers from Cetyl Palmitate/Caprylic Triglyceride/Tween 80 mixtures in an aqueous environment. Langmuir, 2021; 37(14):4284–4293.
21.
HaiderM, AbdinSM, KamalL, et al.Nanostructured lipid carriers for delivery of chemotherapeutics: A review. Pharmaceutics, 2020; 12(3):288.
22.
CostaCP, MoreiraJN, Sousa LoboJM, et al.Intranasal delivery of nanostructured lipid carriers, solid lipid nanoparticles and nanoemulsions: A current overview of in vivo studies. Acta Pharmaceutica Sinica. B, 2021; 11(4):925–940; doi: 10.1016/j.apsb.2021.02.012
23.
PatharapankalEJ, AjiboyeAL, MatternC, et al.Nose-to-brain (N2B) delivery: An alternative route for the delivery of biologics in the management and treatment of central nervous system disorders. Pharmaceutics, 2023; 16(1):66; doi: 10.3390/pharmaceutics16010066
24.
ElmowafyM, Al-SaneaMM. Nanostructured lipid carriers (NLCs) as drug delivery platform: Advances in formulation and delivery strategies. Saudi Pharm J, 2021; 29(9):999–1012; doi: 10.1016/j.jsps.2021.07.015
25.
DhandeH, BodheR, LadeS, et al.An overview of the usage of nanostructured lipid carriers in the treatment of migraines. Int J Med Healthcare Rep, 2024; 3(1):1–10.
26.
LiX, WangD, ZhangJ, et al.Preparation and pharmacokinetics of docetaxel based on nanostructured lipid carriers. J Pharm Pharmacol, 2009; 61(11):1485–1492; doi: 10.1211/jpp/61.11.0007
27.
ShelkeS, ShahiS, JalalpureS, et al.Poloxamer 407-based intranasal thermoreversible gel of zolmitriptan-loaded nanoethosomes: Formulation, optimization, evaluation and permeation studies. J Liposome Res, 2016; 26(4):313–323.
28.
PandaN, ReddyAV, ReddyGS, et al.Formulation design and in vitro evaluation of zolmitriptan immediate-release tablets using Primojel and AC-Di-Sol. J Pharm Sci Res, 2015; 7:545.
29.
ClogstonJD, PatriAK. Zeta potential measurement. In Characterization of Nanoparticles Intended for Drug Delivery. Springer Berlin/Heidelberg; 2011: 63–70.
30.
PatelR, PatelG, PatelH, et al.Formulation and evaluation of transdermal patch of Aceclofenac. Research Journal of Pharmaceutical Dosage Form and Technology, 2009; 1(2):108–115; doi: 10.5138/ijdd.2009.0975.0215.01005
31.
SultanaA, LuoH, RamakrishnaS, et al.Antimicrobial peptides and their applications in biomedical sector. Antibiotics (Basel), 2021; 10(9):1094; doi: 10.3390/antibiotics10091094
32.
El-GazayerlyON, HikalAH. Preparation and evaluation of acetazolamide liposomes as an ocular delivery system. Int. J. Pharm, 1997; 158(2):121–127.
33.
LuoY, ChenD, RenL, ZhaoX, QinJ. Solid lipid nanoparticles for enhancing vinpocetine’s oral bioavailability. J Control Release, 2006; 114(1):53–59.
34.
GirotraPH, SinghSK, KumarP. Sumatriptan succinate loaded chitosan solid lipid nanoparticles for enhanced anti-migraine potential. Int. J. Biol. Macromol, 2015; 81:467–476.
35.
OkamotoK, Kondo-OkamotoN, OhsumiY, et al.Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Dev Cell, 2009; 17(1):87–97; doi: 10.1016/j.devcel.2009.06.013
36.
BadwaikHR, SakureK, AlexanderA, et al.Synthesis and characterisation of poly(acryalamide) grafted carboxymethyl xanthan gum copolymer. Int J Biol Macromol, 2016; 85:361–369.
37.
AgrawalM, SarafS, SarafS, et al.Recent strategies and advances in the fabrication of nano lipid carriers and their application towards brain targeting. J Control Release, 2020; 321:372–415.
38.
PradhanAA, SmithML, McGuireB, et al.Characterization of a novel model of chronic migraine. Pain R, 2014; 155(2):269–274; doi: 10.1016/j.pain.2013.10.004
39.
TiptonAF, TarashI, McGuireB, et al.The effects of acute and preventive migraine therapies in a mouse model of chronic migraine. Cephalalgia, 2016; 36(11):1048–1056; doi: 10.1177/0333102415623070
40.
MoyeLS, PradhanAAA. Animal model of chronic migraine-associated pain. Curr Protoc Neurosci, 2017; 80:9.60.1–9.60.9; doi: 10.1002/cpns.33
41.
Sureda-GibertP, Romero-ReyesM, AkermanS. Nitroglycerin as a model of migraine: Clinical and preclinical review. Neurobiol Pain, 2022; 12:100105; doi: 10.1016/j.ynpai.2022.100105
42.
ChaplanSR, BachFW, PogrelJW, et al.Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods, 1994; 53(1):55–63; doi: 10.1016/0165-0270(94)90144-9
43.
NaguibMJ, HassanYR, Abd-ElsalamW H. 3D printed Ocusert laden with ultra-fluidic glycerosomes of ganciclovir for the management of ocular cytomegalovirus retinitis. Int J Pharm, 2021;;607:121010; doi: 10.1016/j.ijpharm.2021.121010
44.
BawazeerS, El-TelbanyDFA, Al-SawahliMM, et al.Effect of nanostructured lipid carriers on transdermal delivery of tenoxicam in irradiated rats. Drug Deliv., 2020; 27(1):1218–1230.
45.
MahdiWA, BukhariSI, ImamSS, et al.Formulation and optimization of butenafine-loaded topical nano lipid carrier-based gel: Characterization, irritation study, and anti-fungal activity. Pharmaceutics, 2021; 13(7):1087.
46.
DanaeiM, DehghankholdM, AtaeiS, et al.Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics., 2018; 10(2):57.
47.
PezeshkiA, GhanbarzadehB, MohammadiM, et al.Encapsulation of vitamin A palmitate in nanostructured lipid carrier (NLC)-effect of surfactant concentration on the formulation properties. Adv Pharm Bull, 2014; 4(Suppl 2):563–568.
48.
SinghS, DobhalAK, JainA, et al.Formulation and evaluation of solid lipid nanoparticles of a water-soluble drug. Chem Pharm Bull (Tokyo), 2010; 58(5):650–655.
49.
RaeisiS, OjaghSM, QuekSY, et al.Nano-Encapsulation of fish oil and garlic essential oil by a novel composition of wall material: Persian Gum-Chitosan. LWT, 2019; 116:108494.
50.
VerheyenS, BlatonN, KingetR, et al.Mechanism of increased dissolution of diazepam and temazepam from polyethylene glycol 6000 solid dispersions. Int J Pharm, 2002; 249(1–2):45–58.
51.
KhanN, ShahFA, RanaI, et al.Nanostructured lipid carriers-mediated brain delivery of carbamazepine for improved in vivo anticonvulsant and anxiolytic activity. Int J Pharm, 2020; 577:119033.
52.
KhanAA, MudassirJ, AkhtarS, et al.Freeze-dried lopinavir-loaded nanostructured lipid carriers for enhanced cellular uptake and bioavailability: Statistical optimization in vitro and in vivo evaluations. Pharmaceutics, 2019; 11(2):97.
53.
KhezriFANZ, LakshmiCSR, BukkaR, et al.Pharmacokinetic study and brain tissue analysis of Zolmitriptan loaded chitosan nanoparticles in rats by LC-MS method. Int J Biol Macromol, 2020; 142:52–62; doi: 10.1016/j.ijbiomac.2019.08.236
54.
JainSK, ChourasiaMK, MasurihaR, et al.Solid lipid nanoparticles bearing flurbiprofen for transdermal delivery. Drug Deliv, 2005; 12(4):207–215.
55.
MuntimaduguE, DhommatiR, JainA, et al.Intranasal delivery of nanoparticle encapsulated tarenflurbil: A potential brain targeting strategy for Alzheimer’s disease. Eur J Pharm Sci, 2016; 92:224–234.
56.
BaigMS, AhadA, AslamM, et al.Application of box–Behnken design for preparation of levofloxacin-loaded stearic acid solid lipid nanoparticles for ocular delivery: Optimization, in vitro release, ocular tolerance, and antibacterial activity. Int J Biol Macromol, 2016; 85:258–270.
57.
SwatiL, NirmalS, SushilB. Nanostructured lipid carriers: A vital drug carrier for migraine treatment. Res J Pharm Technol, 2022; 15(07):3309–3316.
58.
SwatiL, ShahN, BurleS. Estimation of Naratriptan hydrochloride by using RP-HPLC method. Neuroquantology, 2022; 20(10):5127–5144.
