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Assessment Of Spanlastic Vesicles Of Zolmitriptan For Treating Migraine In Rats
Authors El-Nabarawy NA , Teaima MH , Helal DA
Received 22 June 2019
Accepted for publication 21 October 2019
Published 21 November 2019 Volume 2019:13 Pages 3929—3937
DOI https://doi.org/10.2147/DDDT.S220473
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Professor Manfred Ogris
Nagla Ahmed El-Nabarawy,1 Mahmoud Hassan Teaima,2 Doaa Ahmed Helal3
1National Egyptian Center of Environmental & Toxicological Research (NECTR), Faculty of Medicine, Cairo University, Cairo, Egypt; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Fayoum University, Elfayoum, Egypt
Correspondence: Nagla Ahmed El-Nabarawy
National Egyptian Center of Environmental & Toxicological Research (NECTR), Faculty of Medicine, Cairo University, Kasr A Ainy Street, Cairo 11562, Egypt
Email [email protected]
Objective: To develop and evaluate zolmitriptan spanlastics (Zol SLs) as a brain-targeted antimigraine delivery system. Spanlastics (SLs) prepared using span 60: tween 80 (70:30%, respectively) gave the highest percentage of entrapment efficiency (EE%).
Materials and methods: A total of 60 adult male Wistar albino rats were divided into six groups (n=10 rats/group). Group 1 (Control) comprised rats serving as a negative control. Group 2 was treated with glyceryl trinitrate (NTG) and served as the positive control. Groups 3 (NTG+Zol com), Group 4 (NTG+Zol sol) and Group 5 (NTG+Zol SLs) received commercial zolmitriptan orally, zolmitriptan solution intranasally and Zol SLs F5 intranasally, respectively, 30 min before NTG. Group 6 (Zol SLs) comprised normal rats that received only Zol SLs intranasally.
Results: We found decreased Tmax, increased Cmax, AUC0–6, AUC0–∞ and ameliorated behaviour in rats (head scratching) treated with intranasal SLs compared to oral commercial zolmitriptan.
Conclusion: Our study substantiates the enhanced efficacy of Zol SLs in brain targeting for migraine treatment.
Keywords: zolmitriptan, Zol, intranasal delivery, brain targeting, spanlastics, SLs, pharmacokinetics, pharmacodynamics, migraine
Introduction
Migraine is a chronic relapsing and remitting brain disorder characterized by recurrent debilitating headache attacks that occur for at least 15 days/month. Apart from psychosis, dementia and quadriplegia, migraine is one of the highly disabling neurologic conditions.1–3 The high prevalence of migraine and the noticeably impaired quality of the sufferer’s life impose a heavy societal burden in terms of high medical costs, work productivity loss and unemployment.4
Pathogenesis of migraine involves an imbalance in activity between brain stem nuclei controlling the trigeminovascular nociceptive system and vascular control.5 Trigeminovascular system activation leads to the release of a number of vasoactive neuropeptides, mainly calcitonin gene-related peptide (CGRP) and substance P*,6,7 which further dilate cerebral blood vessels and elicit an inflammatory response causing pain.8 CGRP is firmly established as a key player in migraine9 and also stimulates the production and release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) from human lymphocytes.10
Nuclear factor-κB (NF-кB) is a redox-sensitive transcription factor that regulates the expression of a range of inflammatory genes and has been studied as a molecular target for migraine therapy.11 Nitric oxide (NO) also plays a vital role in migraine,12 and both inducible NOSand neuronal NOS have been essentially involved in the pathogenesis of migraine.13
Migraine patients striving for relief mostly regard the rapid onset of drug action a top priority. Therefore, pharmacokinetic parameters related to fast onset of action are of significant concern while developing antimigraine formulations.14,15
Zolmitriptan is a second-generation triptan derivative that is used principally for acute migraine and cluster headache treatment. It exerts a selective agonistic effect on 5HT1B/1D serotonin receptors, centrally and peripherally, thereby hampering the activation of the trigeminovascular system, reducing neurogenic inflammation, constricting dilated cerebral blood vessels and curbing vasoactive neuropeptide release. Zolmitriptan possesses an oral and nasal bioavailability of almost 40% and a plasma half-life of 3 hrs.14–16
Based on the importance of the central action of zolmitriptan, there is special concern for enhancing its availability and transport rate to the brain since one of the greatest challenges of targeting drugs to the CNS is the tight blood–brain barrier (BBB). The intranasal route is one of the different pathways for delivering the drug into the brain: the drug crosses the BBB, through the olfactory region and the trigeminal pathway where it is transported directly from nasal cavity to the central nervous system.17
Intranasal route provides an excellent site for rapid absorption of centrally acting drugs. In addition, nasal application circumvents first-pass elimination, degradation and irritation in GIT, and may be employed routinely without any pain. As it is noninvasive, it reduces the risk of infection compared to IV administration.18
Nanoparticles have lately been considered as suitable carriers for maximizing the brain targeting potential of many CNS active drugs19 as spanlastics (SLs) which are formed of a Span® and an edge activator (EA). SLs can be used to deliver both hydrophilic and hydrophobic drugs which are encapsulated in interior hydrophilic compartment and outer lipid layer, respectively.18 Therefore, zolmitriptan can be entrapped in SL where the transport across the BBB to reach the brain is based on the characteristics of SL dispersion and not on that of the therapeutic agent; also, they have the ability to squeeze themselves between membranes.
The objective of the present study was to develop and evaluate the efficacy of intranasally delivered Zol SLs, compared to the orally delivered drug, in a rat model of glyceryl trinitrate (NTG)-induced migraine.
Materials And Methods
Materials
Zolmitriptan was purchased from BMR Pharma and Chemical Company (India). Sorbitan monoesters (Span 60), polysorbates (Tween 60 and 80), ethanol and methanol were kindly supplied by the Egyptian International Pharmaceutical Industries Co. (EPICO, Egypt). Commercial zolmitriptan (Zomig®, 2.5 mg tablets) was obtained from Vichy Laboratories (France). NTG as Nitronal® aqueous solution (1 mg/mL) was obtained from POHL-BOSKAMP (Hohenlockstedt, Germany). Water for liquid chromatography, HPLC and spectrophotometry was manufactured by Honeywell Burdick & Jackson (Mexico City, Mexico). Dichloromethane (CHROMASOL®, for HPLC containing amylene as stabilizer) was obtained from Sigma-Aldrich Chemical Co. (St. Louis, MO, USA).
Methods
Preparation Of Zol SLs
Zol SLs systems composed of Span 60 and EAs (namely Tween 60 and Tween 80) were prepared using different weight ratios of Span 60: EA (80:20, 70:30 and 50:50 w:w) (Table 1), using ethanol injection method as described by Kakkar and Kaur (2011).20 Briefly, Span 60 and calculated amount of zolmitriptan were dissolved in 4 ml ethanol and then the dissolved solution was injected dropwise at a constant rate into a preheated aqueous phase (66°C) containing EA. It was continuously stirred using a magnetic stirrer (Model MSH-20D; Witeg Labortechnik GmbH Germany) at 1000 rpm for 45 min, and Zol SLs dispersions were obtained.
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Table 1 Composition, Mean Particle Size, Polydispersity Index (PDI), Zeta (ζ) Potential And Entrapment Efficiency Of Zolmitriptan Spanlastics Dispersions |
In Vitro Evaluation Of The Prepared SLs
The SL vesicles were disrupted by methanol and release the drug. Total drug content of the prepared formulae was determined by dissolving 1 mL of SL dispersion in 10 mL methanol and then zolmitriptan was quantified spectrophotometrically using UV/VIS spectrophotometer (model UV-1601PC, Shimadzu, Kyoto, Japan) at λmax 283 nm.21 Entrapment efficiency was determined as follows:18,22,23
(1)
Particle size (PS) analysis, zeta (ζ)-potential measurements, polydispersity index (PDI) were calculated by conducting morphological examination.
The vesicular size, ζ-potential, and PDI of diluted Zol SL dispersion were determined using dynamic light scattering with Malvern Zetasizer (Malvern Instrument Ltd., UK).24 The PDI was used to show the homogeneity of PS.25
A negatively stained Zol SL with 2% (w/v) phosphotungstic acid solution was visualized using a TEM (Jeol – JXA-840A – Electron Microscope – Japan).26
In Vitro Dissolution Of Zol SLs
The dissolution profile of zolmitriptan powder, Zol SLs and the commercial Zomig® tablets were determined using the membrane diffusion technique. An accurately weighed amount of the prepared Zol SL dispersion system equivalent to 2.5 mg zolmitriptan was transferred to a glass cylinder having the length 8 cm and diameter 2.5 cm with surface area 4.91 cm2 and fitted at its lower end with presoaked dialysis membrane on which the SL spread over (Spectra/Pore dialysis membrane, 12,000–14,000 Mwt cut-off (Spectrum Laboratories Inc., USA). The glass cylinder was attached to the shaft of the dissolution apparatus and then was placed in vessels of the U.S.P. Dissolution Tester. Dissolution was carried out in triplicate using 500 mL phosphate buffer at pH 6.8, the basket was rotated at 100 rpm, and the dissolution medium temperature was maintained at 37°C. Aliquots of 5 mL were withdrawn at 5, 10, 15, 30, 45, 60, 90, 120, 150, 180 and 240 min, and the media were replaced. Samples were filtered using 0.45 Millipore filters before measuring their absorbance at λmax 283 nm.
In Vivo Evaluation Of Zol SLs
A total of 60 adult male Wistar albino rats (8 weeks old, weight: 200–250 g), obtained from the breeding unit of Faculty of Pharmacy, Cairo University, were used in the in vivo study. NTG was used to induce migraine in rats at a dose of 10 mg/kg through intraperitoneal injection.27–30 Successful model establishment was confirmed by the presence of ear flushing, scratching the head frequently using forelimbs, increased activity to climb the cage, biting tails and reciprocating motion.30 Zolmitriptan was administered to treatment groups at a dose of 5 mg/kg, 30 min before the intraperitoneal injection of NTG. Six hours after NTG administration, rats were sacrificed.27,28
Ethics Approval
All the experimental procedures used in the present study were conducted according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996) and were approved by the research ethics committee for experimental and clinical studies at Faculty of Pharmacy, Cairo University (Approval date: 28/03/2016, Permit number: PI 1645).
Study Design
Rats were randomly allocated into six groups (n=10 rats/group). Group 1 (Control) comprised normal rats serving as a negative control. Group 2 (NTG) was treated with NTG and served as the positive control. Groups 3 (NTG+Zol com), 4 (NTG+Zol sol) and 5 (NTG+Zol SLs) received commercial zolmitriptan orally, zolmitriptan solution intranasally and Zol SLs F5 intranasally, respectively, 30 min before NTG. Group 6 (Zol SLs) comprised normal rats that received only Zol SLs intranasally.
Pharmacokinetic Study
The pharmacokinetic study was performed on 60 rats (10 rats/group).
Quantitative evaluation was done by analysis of plasma zolmitriptan concentration for NTG+Zol com, NTG+Zol sol and NTG+Zol SLs groups. Blood samples of 0.2 mL each were collected into heparinized microcentrifuge tubes, through the retro-orbital vein from alternative eye at each time interval. Time intervals of blood sampling were 0.5, 1, 1.5, 2, 2.5, 3, 4, 5 and 6 hrs after zolmitriptan administration. The blood samples were centrifuged at 4000 rpm for 20 min to separate the plasma that was stored at −20°C until drug analysis. Frozen plasma samples were thawed at room temperature.
One milliliter plasma was added to 4 mL methyl tertiary butyl ether, then vortexed for 1 min, centrifuged at 4000 rpm for 10 min, and the supernatant was evaporated at 45°C. A volume of 250 µL caffeine internal standard (10 µg/mL) was added to the residue. Finally, injection into the HPLC chromatograph was performed (HPLC Device: Shimadzu, Autosampler: SiL 20 A, System controller: SCL-10 A vp, Detector: SPD-10 A vp UV-Vis, Pump: LC-10 AD vp liquid chromatograph, Degasser: DGU-12 A, Column: Scharlau 250x4.6 mm P/N 066-B6Y803).
Mobile phase: buffer:acetonitrile:MeOH (55:20:25), wavelength: 225 nm, flow rate (mL/min): 1, column: C18 300×46, internal standard: caffeine.
Pharmacokinetic analysis of plasma zolmitriptan concentration was performed using pharmacokinetic add-in package for Microsoft excel 201631 applying non-compartmental analysis. The determined pharmacokinetic parameters include maximum concentration in plasma (Cmax), the time for maximum concentration in plasma (Tmax), the area under plasma concentration versus time curve from 0 to 6 hrs (AUC0–6), area under the plasma concentration versus time curve from zero to infinity (AUC0–∞), the area under momental plasma concentration versus time curve from 0 to 6 hrs (AUMC0–6), area under momental plasma concentration versus time curve from zero to infinity (AUMC0–∞), mean residence time (MRT) and half-life (t1/2).
Behavioral Study
The behavioral changes in the treated rats were monitored through counting the number of head scratchings during the 1st, 2nd, 3rd and 4th hrs after NTG administration.
Statistical Analysis
Data are presented as mean±SD and were analysed using one-way ANOVA with extended least significant difference post hoc tests (subsequent multiple comparisons using Tukey’s test), except for Tmax data which were analysed by non-parametric Kruskal–Wallis test. All statistical tests were performed using IBM SPSS Statistics version 23, 64-bit edition, NY, USA. A P value of less than 0.05 was considered statistically significant.
Results And Discussion
In Vitro Evaluation Of The Prepared Zol SLs
Table 1 shows the EE%, mean PS (nm), size distribution (PDI), and zeta (ζ)-potential distribution (ZP) of different vesicles. Zolmitriptan was successfully entrapped in all SL vesicles prepared with different ratios of EA with Span 60. The EE% varied between 51.00±5.03% and 89.58±6.03%.
SL vesicles (F5) prepared from span 60 and Tween 80 (70:30 respectively) gave the highest EE% of 89.58±6.03% that was statistically significant compared to the other formulae. The EE% showed the following trend: F5 > F4 > F2 > F1> F3> F6.
The PS of formed vesicles ranged from 143.06±95.09 nm to 305.02±190 nm. The homogeneity of Zol SL dispersion was evaluated by the PDI parameter which ranged from 0.24±0.09 to 0.61±0.24; values less than 0.4 indicated a homogeneous population, while values more than 0.4 indicated a broad distribution32. ZP values ranged from −31.2±4.18 to −32.92±3.77 mV which give stable SL vesicles due to the presence of electrical repulsion; the higher the value of ζ-potential, the more stable the SL vesicles.18,25,32
The previous results reveal that the SL vesicles prepared using S60:T80 (70:30 respectively) (F5) are superior to other prepared formulae.
The prepared SLs (F5) were spherical in shape using the transmission electron microscopy (TEM) images (Figure 1).
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Figure 1 (A) TEM image of zolmitriptan spanlastics prepared using F2. (B) TEM image of zolmitriptan spanlastics prepared using F5. |
In Vitro Dissolution Of Zol SLs
The dissolution profiles of zolmitriptan powder, Zol SLs and commercial zolmitriptan tablets in phosphate buffer (pH 6.8) are shown in Figure 2. The cumulative % of zolmitriptan dissolved after 1 hr (Q1hr) and 6 hrs (Q6hr) for different formulae can be ranked as follows: zolmitriptan powder > F5 Zol SL dispersion > commercial zolmitriptan tablets.
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Figure 2 Mean percentage of zolmitriptan dissolved from zolmitriptan powder, zolmitriptan spanlastic dispersion F5 and commercial zolmitriptan (2.5 mg tablets). |
The dissolution results indicated lower zolmitriptan release from an SL formula when compared with free zolmitriptan powder, which could be attributed to the reduced leakage and permeability of SL formulations. On the contrary, the release of zolmitriptan from F5 SL vesicles was faster than that from commercial zolmitriptan.
In all formulae, it was found that Q1hr and Q6hrs from SLs have non-significantly lower values (p > 0.05) compared to the pure zolmitriptan powder and non-significantly higher values compared to the commercial zolmitriptan tablets (p > 0.05).
In Vivo Evaluation Of Zol SLs
Pharmacokinetic Study
A sample of the HPLC chromatograms of zolmitriptan in plasma is presented in Figure 3. The mean zolmitriptan plasma levels in rats after administration of the different zolmitriptan treatments versus time are presented in Figure 4. The pharmacokinetic parameters of different zolmitriptan treatments, such as Cmax, Tmax, AUC0–6, AUC0–∞, AUMC0–6, AUMC0–∞, MRT and T1/2, are presented in Table 3.
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Table 2 Number Of Head Scratching In Different Groups |
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Figure 3 Representative HPLC chromatograms of zolmitriptan in rat plasma. |
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Figure 4 Mean plasma level of zolmitriptan following administration of intranasal zolmitriptan. |
After administration of oral commercial zolmitriptan, intranasal zolmitriptan solution and intranasal F5 Zol SL dispersion, the maximum plasma concentrations were observed at 0.5 hr, 1 hr, and 1.5 hrs, respectively. The mean maximum plasma drug concentration in the NTG+Zol SLs group was higher than those of NTG+Zol com and NTG+Zol sol groups. The mean time to reach the peak concentration (Tmax) was significantly lower in the NTG+Zol sol and NTG+Zol SLs groups compared to the NTG+Zol com group. These findings, along with the AUC0–6, AUC0–∞, AUMC0–6 and AUMC0–∞ results, suggest that the oral commercial zolmitriptan product showed the lowest rate and extent of drug absorption, whereas intranasal Zol SL dispersion showed the highest rate and extent of drug absorption.
The differences between the values of log Cmax, log AUC0–6, log AUC0–∞, log AUMC0–6, log AUMC0–∞ and Tmax calculated for NTG+Zol com, NTG+Zol sol and NTG+Zol SLs groups were statistically significant as shown in Table 3.
Behavioral Study
As shown in Table 2, the number of head scratchings in the NTG group was significantly greater compared to the negative control group. The number of head scratchings in NTG+Zol com, NTG+Zol sol and NTG+Zol SLs groups decreased significantly compared to the NTG group, with the NTG+Zol SLs group showing a significantly lower number compared to the NTG+Zol com and NTG+Zol sol groups.
Furthermore, our results revealed variation in head scratching frequency over different time intervals. During the first hour, the negative control group showed 10.83±2.48, whereas scratching reached a maximal level in the NTG group 67.50±14.89. During the second hour, the head scratching frequency was sustained at the peak level in the NTG group 52.50±11.72. In addition, a significant difference in head scratching frequency was observed between zolmitriptan-treated groups (NTG+Zol Com, NTG+Zol sol, NTG+Zol SLs) which were 37.33±0.81, 24.83±1.16 and 13.67±0.81 respectively compared to NTG group 52.50±11.72. On the other hand during the third hour, the head scratching frequency decreased in the NTG group to 32.83 ± 7.05 but was still significantly different from the control group 9.83±2.31 and zolmitriptan treated groups (NTG+Zol Com, NTG+Zol sol, NTG+Zol SLs) which were 29.17±1.16, 21.50±0.54 and 11.83±0.98 respectively. Also, during the fourth hour, the NTG group showed gradual decrease in head scratching frequency to 25.17±6.36. However, the number of scratching remains at its peak compared with the negative control group.
The behaviours of rats can reflect the influence of treatment. NTG (NTG also referred to as nitro-glycerine) is widely used as an exogenous NO donor which depends on the mitochondrion. Mitochondrial aldehyde dehydrogenase-2facilitates the formation of NTG and generates 1,2-glyceryl dinitrate and nitrite then metabolizes to NO. Two main pathways have been shown for NTG formation: one based on NTG producing NO which directly causes vasodilatation, and the other is based on detoxification that produces inorganic nitrite anions.33
Also, our results are compatible with those reported by Greco et al34 who found that NTG is a potent vasodilator and NO donor. In addition, NTG causes upregulation of pro-inflammatory mediators, macrophage activation, edema formation and mast cell degranulation by a direct action on meningeal tissues35 Moreover, Jim36 suggested that NF-kB is a mediator of pro-inflammatory cytokines and other neurochemical signals leading to migraine attacks in the presence of NTG induced increase NF-kB transcriptional activity. In addition, our results corroborate with Monteith and Goadsby37 who found that zolmitriptan was developed with the strategy to create a more lipophilic compound with faster absorption and better ability to cross the BBB than other triptans. It also acts through stimulating vascular 5-HT1B receptors, thus causing vasoconstriction of cerebral, meningeal, dural or pial vessels, and inhibition of dural neurogenic inflammation through stimulation of 5-HT1D and 5-HT1F receptors. In addition, stimulation of 5-HT1B, 5-HT1D and 5-HT1F receptors causes inhibition of trigeminal neurons in the brain stem and upper spinal cord.38 Moreover, our results coincided with Akbari et al39 who found that recent advances in non-ionic surfactant vesicles of zolmitriptan can be considered economically, chemically, physically stable and have potential advantages of phospholipid vesicles of being able to accommodate both water and lipid-soluble drug molecules, control their release, and serve as devices of numerous applications.
Nanoparticles and drug delivery increase the stability of the pharmaceutical agents and can be easily and inexpensively fabricated in large quantities. Nanoparticles have been investigated in biomedical and biotechnological areas and in drug delivery system for drug targeting. The advantages of targeted drug delivery to the specific site of the body paved the way for applying nanoparticles to achieve the type of drug delivery. The nasal route was adopted to exploit its avoidance of hepatic first-pass metabolism to increase the bioavailability. Therefore, the formulation of nose to brain Zol SL was selected to enhance permeability across BBB against nitroglycerine-induced migraine.40
The model of migraine induced by NTG has provided a growing body of information about pathophysiology of migraine headache and therapeutic targets.28,41
NTG triggers headache in normal subjects and induces migraine in patients.42 In rodents, NTG-evoked hyperalgesia has been developed as a model for sensory hypersensitivity associated with migraine.43,44
Only a limited number of animal studies have investigated aspects of headache disorders which remains unexplored of pathogenesis. So, the selection for NTG model systems has a great field for research of migraine headache.
Anti-migraine medications such as triptans were tested on this model and showed moderate efficiency. But SL vesicles of zolmitriptan will yield exciting advances in the treatment of migraine attacks in the future. It was developed with the strategy to create a more lipophilic compound with faster absorption and better ability to cross BBB.40 There is strong evidence to support the use of spanlastic vesicles of zolmitriptan who have had poor response to previous therapy. It is well effective across a wide range of migraine subtypes and well tolerated.
Finally, it was found that the intra-nasal administration of zolmitriptan as an SL dispersion enhanced the bioavailability of the drug by decreasing the time required to reach peak plasma concentration, increased the extent of absorption as well and its ability to cross the BBB and hence produced a superior ameliorative anti-migraine effect, behavior and pharmacokinetic profiles. The development of this new drug delivery system through the nasal route provides a faster and more efficient alternative to the commercially available oral tablet.
Conclusion
The present study substantiated that SL vesicles prepared using ethanol injection technique exhibited high zolmitriptan entrapment efficiency, a globule size in the nanometric range and faster in vitro dissolution compared to the commercial tablet. The in vivo findings demonstrated superior alleviation of migraine-related behavior by the SL formulation compared to the commercial product. In conclusion, intranasally delivered Zol SL vesicles represent a superior anti-migraine approach compared to the conventional tablet formulation.
Disclosure
The authors declare that they have no competing interests in this work.
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