PHARMACOKINETIC STUDY IN HUMANS AND IN-VITRO EVALUATION OF BIOENHANCED BILAYER SUBLINGUAL FILMS FOR THE MANAGEMENT OF ACUTE MIGRAINE
Objective: Long-lasting migraine pain is one of the most disabling neurological disorders and requires a quick onset of action from the administered dosage form. This study aimed to provide sublingual administration of the frequently used combination of NSAID and triptan in order to trigger their action immediately by escaping the first pass metabolism, simultaneously improving patient compliance.
Methods: In the present research, bilayer sublingual films were developed by joining the two loaded layers with zolmitriptan and piroxicam, respectively. Each layer was prepared and loaded separately using the traditional solvent casting method. Mechanical support was provided by the 1:1 combination of HPMC E-15 and pullulan, which were used as water-soluble film-forming polymers with polyethylene glycol 400 as a plasticizer. Films were evaluated for various physicochemical and mechanical properties. Finally, a pharmacokinetic study was performed on six healthy human volunteers to compare the PK parameters of the best formulation, BSTF-3, with those of a commercially available formulation. Sepitrap 80 and Sepitrap 4000 were used as bioenhancers to achieve faster systemic delivery.
Results: The thin flexible bilayer films were observed to provide quick action alone with increase patient compliance by preventing the first pass metabolism and dysphagia. Sepitrap 80 successfully increased the permeation of both the drugs. Approximately 92 percent of zolmitriptan was released from the formed bilayer sublingual thin films within 3 minutes, whereas 92 percent of piroxicam was released within 4.5 minutes from the best formulation. Within 30 minutes of the commencement of the pharmacokinetic investigation, plasma concentrations of the active component began to rise rapidly.
Conclusion: When compared to commercial formulations, the developed films had a greater AUC and Cmax with a shorter Tmax, indicating a faster trigger of action and higher bioavailability.
Feigin VL, Murray C JL, Vos T. Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol 2019;18 (5):459–480. https://doi.org/10.1016/S1474-4422(18)30499-X.
Stovner, L. J.; Hagen, K.; Linde, M. The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain. 2022, 23 (34) 2-17. https://doi.org/10.1186/s10194-022-01402.
Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev 2017; 97 (2): 553–622. https://doi.org/10.1152/physrev.00034.2015.
Munakata J, Hazard E, Serrano D, Klingman D, Rupnow MF, Tierce J, Reed M, Lipton, RB. Economic burden of transformed migraine: results from the american migraine prevalence and prevention (ampp) study. Headache 2009;49(4):498–508. https://doi.org/10.1111/j.1526-4610.2009.01369.x.
Olesen J. Headache classification committee of the international headache society (IHS) The international classification of headache disorders, 3rd Edition. Cephalalgia 2018;38 (1):1–211. https://doi.org/10.1177/0333102417738202.
Raval AD, Shah A. National trends in direct health care expenditures among us adults with migraine: 2004 to 2013. J Pain 2017;18(1):96–107. https://doi.org/10.1016/j.jpain.2016.10.005.
Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the united states: figures and trends from government health studies. Headache 2018, 58 (4), 496–505. https://doi.org/10.1111/head.13281.
Leonardi M, Raggi A. A narrative review on the burden of migraine: when the burden is the impact on people’s life. J Headache Pain 2019;20(1);92-99. https://doi.org/10.1186/s10194-019-0993-0.
Jayakumari S, Gokul Krishna A. Prescription pattern analysis of anti-inflammatory drugs in general medicine and surgery department at a tertiary care hospital. Int J Pharm Pharm Sci 2016; 08:114-118.
Schytz HW, Bendtsen L, Sumatriptan plus naproxen for acute migraine attacks in adults. Ugeskr.Laeger 2014;176 (32):47-55. https://doi.org/10.1002/14651858.CD008541.pub3.www.cochranelibrary.com.
Gilmore B, Michael M. Treatment of acute migraine headache. Am Fam Physician 2011; 83 (3):271–280.
Ong JJ, De Felice M. Migraine treatment: current acute medications and their potential mechanisms of action. Neurotherapeutics 2018;15(2):274–290. https://doi.org/10.1007/s13311-017-0592-1.
Tfelt-Hansen PC. Delayed absorption of many (paracetamol, aspirin, other nsaids and zolmitriptan) but not all (sumatriptan, rizatriptan) drugs during migraine attacks and most likely normal gastric emptying outside attacks. a review. Cephalalgia 2017;37 (9):892–901. https://doi.org/10.1177/0333102416644745.
Jenkins B. Migraine management. Aust Prescr 2020;43(5):148–151. https://doi.org/10.18773/austprescr.2020.047.
Nappi G, Manzoni GC, Oliani C. Piroxicam-β-cyclodextrin in the treatment of headache. Drug Investig. 1990;2 (4):79–85. https://doi.org/10.1007/BF03258232.
Nawal AR, Mohammad SJ. Formulation and in vitro evaluation of piroxicam microsponge as a tablet. Int J Pharm Pharm Sci 2016:08;104-114.
Hoffmann EM, Breitenbach A, Breitkreutz J. Advances in orodispersible films for drug delivery. Expert Opin Drug Deliv 2011;8(3):299–316. https://doi.org/10.1517/17425247.2011.553217.
Karki S, Kim H, Na SJ, Shin D, Jo K, Lee J. Thin films as an emerging platform for drug delivery. Asian J Pharm Sci 2016;11(5);559–574. https://doi.org/10.1016/j.ajps.2016.05.004.
Bala R, Khanna S, Pawar P, Arora S. orally dissolving strips: a new approach to oral drug delivery system. Int J Pharm Investig. 2013;3 (2):67. https://doi.org/10.4103/2230-973x.114897.
İnce O, Güncel F, Bakış B, Özakar RS. Current overview of oral thin films. 2021, 18 (1), 111–121. https://doi.org/10.4274/tjps.galenos.2020.76390.
Irfan M, Rabel S, Bukhtar Q, Qadir MI, Jabeen F, Khan A. Orally disintegrating films: a modern expansion in drug delivery system. Saudi Pharm J 2016;24(5):537–546. https://doi.org/10.1016/j.jsps.2015.02.024.
Rajesh J, Rajendra D, Shrinivas M. Enhancement of solubility & dissolution rate of nifedipine by using novel solubilizer sepitrap 80 & sepitrap 4000. J Drug Deliv Ther 2018; 8:293–300.
Jagtap S, Magdum C, Jagtap R. Ameliorated solubility and dissolution of flurbiprofen using solubilizer sepitrap 80 and sepitrap 4000. Res J Pharm Technol. 2021;14 (1):21–27. https://doi.org/10.5958/0974-360x.2021.00005.6.
Juliano, C.; Cossu, M.; Pigozzi, P.; Rassu, G.; Giunchedi, P. Preparation, in Vitro Characterization and Preliminary in Vivo Evaluation of Buccal Polymeric Films Containing Chlorhexidine. AAPS PharmSciTech 2008, 9 (4), 1153–1158. https://doi.org/10.1208/s12249-008-9153-6.
Chaudhary H, Gauri S, Rathee P, Kumar V. Development and optimization of fast dissolving oro-dispersible films of granisetron hcl using box–behnken statistical design. Bull Fac Pharmacy Cairo Univ 2013;51(2):193–201. https://doi.org/10.1016/j.bfopcu.2013.05.002.
Adrover A, Varani G, Paolicelli P, Petralito S, Di Muzio L, Casadei MA, Tho I. Experimental and modeling study of drug release from hpmc-based erodible oral thin films. Pharmaceutics 2018;10 (4):1–24. https://doi.org/10.3390/pharmaceutics10040222.
Dinge, A.; Nagarsenker, M. Formulation and Evaluation of Fast Dissolving Films for Delivery of Triclosan to the Oral Cavity. AAPS PharmSciTech 2008, 9 (2), 349–356. https://doi.org/10.1208/s12249-008-9047-7.
Mali K, Dias R, Ghorpade V, Havaldar V, Rupnoor B, Dhane N. Taste masked oral fast dissolving sublingual strips of rizatriptan benzoate for migraine therapy. Marmara Pharm J 2017;21 (2):235–235. https://doi.org/10.12991/marupj.300316.
Bhyan B, Jangra S, Kaur M, Singh H. orally fast dissolving films: innovations in formulation and technology. Int J Pharm Sci Rev Res 2011; 9 (2):50–57.
Bhupinder B, Sarita J. Formulation and evaluation of fast dissolving sublingual films of rizatriptan benzoate. Int J Drug Del Res 2012;4 (1):133–143.
Esim O, Ozkan CK, Kurbanoglu S, Arslan A, Tas C. Development and in vitro/in vivo evaluation of dihydroergotamine mesylate loaded maltodextrin-pullulan sublingual films. Drug Dev Ind Pharm 2019; 45 (6): 914–921. https://doi.org/10.1080/03639045.2019.1578788.
Rimkiene L, Baranauskaite J, Marksa M, Jarukas L, Ivanauskas L. Development and Evaluation of Ginkgo Biloba L. extract loaded into carboxymethyl cellulose sublingual films. Appl Sci 2021; 11 (1): 1–13. https://doi.org/10.3390/app11010270.
Chana-Thaworn J, Chanthachum S, Wittaya T. Properties and antimicrobial activity of edible films incorporated with kiam wood (cotyleobium lanceotatum) extract. LWT - Food Sci. Technol. 2011; 44 (1):284–292. https://doi.org/10.1016/j.lwt.2010.06.020.
Bala R, Sharma S. Formulation optimization and evaluation of fast dissolving film of aprepitant by using design of experiment. Bull Fac Pharmacy Cairo Univ. 2018; 56 (2): 159–168. https://doi.org/10.1016/j.bfopcu.2018.04.002.
Senthilkumar K, Vijaya C. Formulation development of mouth dissolving film of etoricoxib for pain management. 2015;4:85-91.
Singh H, Singla YP, Narang RS, Pandita D, Singh S, Narang JK. Frovatriptan loaded hydroxy propyl methyl cellulose/treated chitosan based composite fast dissolving sublingual films for management of migraine. J Drug Deliv Sci Technol 2018; 47: 230–239. https://doi.org/10.1016/j.jddst.2018.06.018.
Mashru RC, Sutariya VB, Sankalia MG, Parikh PP. Development and evaluation of fast-dissolving film of salbutamol sulphate. Drug Dev Ind Pharm 2005: 31 (1); 25–34. https://doi.org/10.1081/ddc-200043947.
Huanbutta K, Sriamornsak P, Singh I, Sangnim T. Manufacture of 2D-printed precision drug-loaded orodispersible film prepared from tamarind seed gum substrate. Appl Sci 2021; 11: 5852. https://doi.org/10.3390/app11135852
Bala R, Khanna S, Pawar, P. Design optimization and in vitro - in vivo evaluation of orally dissolving strips of clobazam 2014. J Drug Del 2014: doi: 10.1155/2014/392783
Singh H, Narang JK, Singla YP, Narang RS, Mishra V. TPGS stabilized sublingual films of frovatriptan for the management of menstrual migraine: formulation, design and antioxidant activity. J Drug Deliv Sci Technol 2017;41:144–156. https://doi.org/10.1016/j.jddst.2017.07.008.
El-Samaligy MS, Yahia SA, Basalious EB. Formulation and evaluation of diclofenac sodium buccoadhesive discs. Int J Pharm 2004;286(1–2):27–39. https://doi.org/10.1016/j.ijpharm.2004.07.033.
Fouad SA, Basalious EB, El-Nabarawi MA, Tayel SA. Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot: in vitro/in vivo evaluation. Int. J. Pharm. 2013; 453 (2):569–578. https://doi.org/10.1016/j.ijpharm.2013.06.009.
El-Setouhy D A, Basalious EB, Abdelmalak NS. Bioenhanced sublingual tablet of drug with limited permeability using novel surfactant binder and microencapsulated polysorbate: in vitro/in vivo evaluation. Eur J Pharm Biopharm 2015; 94:386–392. https://doi.org/10.1016/j.ejpb.2015.06.006.
Shin SC, Kim JY. Enhanced permeation of triamcinolone acetonide through the buccal mucosa. Eur J Pharm Biopharm 2000; 50 (2): 217–220. https://doi.org/10.1016/S0939-6411(00)00101-6.
Shimoda H, Taniguchi K, Nishimura M, Matsuura K, Tsukioka T, Yamashita H, Inagaki, N, Hirano K, Yamamoto M, Kinosada Y, Itoh Y. Preparation of a fast dissolving oral thin film containing dexamethasone: a possible application to antiemesis during cancer chemotherapy. Eur J Pharm Biopharm 2009; 73 (3): 361–365. https://doi.org/10.1016/j.ejpb.2009.08.010.
Nishimura M, Matsuura K, Tsukioka T, Yamashita H, Inagaki N, Sugiyama T, Itoh Y In vitro and in vivo characteristics of prochlorperazine oral disintegrating film. Int J Pharm 2009; 368 (1–2): 98–102. https://doi.org/10.1016/j.ijpharm.2008.10.002.
Abdelbary A, Bendas ER, Ramadan AA, Mostafa DA. Pharmaceutical and pharmacokinetic evaluation of a novel fast dissolving film formulation of flupentixol dihydrochloride. Ageing Int 2014; 15 (6): 1603–1610. https://doi.org/10.1208/s12249-014-0186-8.
Choudhary DR, Patel VA, Chhalotiya UK, Patel HV, Kundawala AJ. Development and characterization of pharmacokinetic parameters of fast-dissolving films containing levocetirizine. Sci Pharm. 2012;80 (3): 779–787. https://doi.org/10.3797/scipharm.1205-15.
Mettu SR, Veerareddy PR. Formulation and pharmacokinetics of ketorolac tromethamine fast dissolving tablets. Drug Res (Stuttg) 2013;63(11):586–590. https://doi.org/10.1055/s-0033-1348258.
Holstila E, Vallittu A, Ranto S, Lahti T, Manninen A. Helsinki. Cities as Engines Sustain. Compet Eur Urban Policy Pract 2016; 175–189. https://doi.org/10.4324/9781315572093-15.
Zhang Y, Huo M, Zhou J, Xie S PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in microsoft excel. Comput Methods Programs Biomed. 2010;99 (3): 306–314. https://doi.org/10.1016/j.cmpb.2010.01.007.
Zaman M, Hanif M, Shaheryar Z. Development of tizanidine HCl-meloxicam loaded mucoadhesive buccal films: in-vitro and in-vivo evaluation. PLoS One 2018; 13 (3): 1–14. https://doi.org/10.1371/journal.pone.0194410.
Mashru RC, Sutariya V, Sankalia MG, Parikh P. Development and evaluation of fast-dissolving film of salbutamol sulphate. Drug Dev. Ind. Pharm. 2005; 31: 25-34.
Vinay R, Patel Gerard G, Dumancas Lakshmi C, Bryan John J. Castor oil: properties, uses, and optimization of processing parameters in commercial production. Lipid Insights. 2016;9: 119-125, https://doi.org/10.4137/LPI.S40233
Fu Q, Tan J, Wang F, Zhu X. Study on the Synthesis of Castor Oil-Based Plasticizer and the Properties of Plasticized Nitrile Rubber. Polymers (Basel). 2020; 12(11):2584. doi: 10.3390/polym12112584. PMID: 33153151;
Renata P, Herrera B, Fabio Y. The effect of surfactant Tween 80 on the hydrophilicity, water vapor permeation, and the mechanical properties of cassava starch and poly(butylene adipate-co-terephthalate) (PBAT) blend films, Carbohydrate Polymers. 2010; 82:4: 1102-1109.
Shah A, Gao B, Kamal R, Razzaq A, Huang L, Cremin G, Iqbal H. Development and characterizations of pullulan and maltodextrin-based oral fast-dissolving films employing a box–behnken experimental design. Materials. 2022; 15: 3591. https:// doi.org/10.3390/ma15103591
Bhagawati T, Chonkar D, Dengale J, Reddy S, Bhat K. Bioavailability enhancement of rizatriptan benzoate by oral disintegrating strip: In vitro and In vivo evaluation. Curr. Drug Deliv. 2016; 13: 462–470.
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