Development and Fabrication of Zavegepant Loaded Mucoadhesive Microemulsion for Intranasal Delivery

Akshay Vikhe; Rahul K. Godge; Ganesh S. Shinde; Dattaprasad N. Vikhe; Shubham B. Mhaske

doi:10.24017/

Authors

Akshay Vikhe Department of Pharmaceutical Quality Assurance, Pravara Rural College of Pharmacy, Maharashtra, India. https://orcid.org/0009-0002-9420-6183
Rahul K. Godge Department of Pharmaceutical Quality Assurance, Pravara Rural College of Pharmacy, Maharashtra, India. https://orcid.org/0000-0002-1275-9853
Ganesh S. Shinde Department of Pharmaceutics, Institute of Pharmacy, Maharashtra, India. https://orcid.org/0000-0003-3461-6236
Dattaprasad N. Vikhe Department of Pharmacognosy, Pravara Rural College of Pharmacy, Maharashtra, India. https://orcid.org/0000-0002-2421-3727
Shubham B. Mhaske Department of Pharmaceutical Quality Assurance, Pravara Rural College of Pharmacy, Maharashtra, India. https://orcid.org/0009-0007-5951-1760

Abstract

To develop and optimize zavegepant-loaded mucoadhesive microemulsions for intranasal delivery, utilizing quality-by-design principles for enhanced bioavailability and rapid onset in acute migraine management. Zavegepant-loaded microemulsions were formulated using Labrafil M 1944 CS (oil), Brij 35 (surfactant), polyethylene glycol (PEG) 400 (co-surfactant), gellan gum (mucoadhesive polymer), and double distilled water. A central composite design with 4 factors (oil, surfactant, co-surfactant, and water concentrations) was employed to optimize critical quality attributes including globule size, zeta potential, and polydispersity index. Comprehensive characterization included particle size analysis, surface charge determination, drug content, permeation studies, and accelerated stability testing. Twenty-seven formulations were evaluated, with statistical analysis identifying concentration as the primary determinant of microemulsion properties (F-values: 144.64-375.27). Optimization yielded formulation (10% Labrafil M 1944 CS, 52% Brij 35, 18% PEG 400, 20% water) with ideal characteristics: globule size 58.7 nm, Polydispersity index 0.142, zeta potential -12.7± mV, and drug content 99.6. It demonstrated superior ex-vivo drug permeation (91.7% at 12h) and remained stable for 6 months under accelerated conditions. The optimized mucoadhesive microemulsion showed good in vitro results with fast drug release, strong permeation, and stable performance. This suggests it could be a useful intranasal system for zavegepant in treating migraines, but in vivo studies are still needed to confirm its clinical use.

Keywords:

Intranasal delivery, Zavegepant, Response surface methodology, Mucoadhesive, Migraine therapy, Quality-by-design, Optimization

References

J. Gupta, and S. S. Gaurkar, "Migraine: an underestimated neurological condition affecting billions," Cureus, vol. 14, no. 8, p. e28347, 2022, doi: 10.7759/cureus.28347.

L. Dong, W. Dong, Y. Jin, Y. jiang, Z. Li, and D. Yu, "The global burden of migraine: A 30-year trend review and future projections by age, sex, country, and region," Pain and Therapy, vol. 14, p. 297–315, 2025, doi: 10.1007/s40122-024-00690-7.

J. Khan, et al., "Genetics, pathophysiology, diagnosis, treatment, management, and prevention of migraine," Biomedi-cine and Pharmacotherapy, vol. 139, p.111557, 2021, doi: 10.1016/j.biopha.2021.111557.

P. Gawde, et al., "Revisiting migraine: The evolving pathophysiology and the expanding management armamentari-um," Cureus, vol. 15, no. 2, p. e34553, 2023, doi: 10.7759/cureus.34553.

K. Mitrović, I. Petrušić, A. Radojičić, M. Dakovic, and A, Savić, "Migraine with aura detection and subtype classifica-tion using machine learning algorithms and morphometric magnetic resonance imaging data," Frontiers in Neurolo-gy, vol. 14, p. 1106612, 2023, doi: 10.3389/fneur.2023.1106612.

M. Waqas, et al., "Zavegepant nasal spray for the acute treatment of migraine: A meta analysis," Medicine (Baltimore), vol. 102, no. 43, p. e35632, 2023, doi: 10.1097/MD.0000000000035632.

S. Dhillon, "ZaveFgepant: first approval," Drugs, vol. 83, p. 825–31, 2023, doi: 10.1007/s40265-023-01885-6.

Z. Zhu, et al., "The efficacy and safety of zavegepant nasal inhalation versus oral calcitonin-gene related peptide recep-tor antagonists in the acute treatment of migraine: a systematic review and network meta-analysis of the literature," The Journal of Headache and Pain, vol. 26, p. 48, 2025, doi: 10.1186/s10194-025-01984-7.

U. Ahmed, M. M. Saleem, M. A. Osman and S. F. Shamat, "Novel FDA-approved zavegepant drug for treating mi-graine," Annals of Medicine and Surgery, vol. 86, p. 923, 2024, doi: 10.1097/MS9.0000000000001620.

M. O. Larik, M. A. Iftekhar, B. U. Syed, O. Ansari, and M. Ansari, "Nasal spray (Zavegepant) for migraines: a mini-review," Annals of Medicine and Surgery, vol. 85, p. 2787, 2023, doi: 10.1097/MS9.0000000000000843.

B. Francis, and B. Joshua, "Transmucosal drug delivery: prospects, challenges, advances, and future directions," Expert opinion on drug delivery, vol. 22, no. 4, p. 525-553, 2025, doi: 10.1080/17425247.2025.2470224.

N. N. Porfiryeva, I. I Semina, I. A. Salakhov, R. I. Moustafine, and V. V. Khutoryanskiy, "Mucoadhesive and mucus-penetrating inter polyelectrolyte complexes for nose-to-brain drug delivery," Nanomedicine: Nanotechnology, Biology and Medicine, vol. 37, p. 102432, 2021, doi: 10.1016/j.nano.2021.102432.

X. Shan, S. Aspinall, D. B. Kaldybekov, F. Buang, A. C. Williams, and V. V. Khutoryanskiy, "Synthesis and evaluation of methacrylated poly(2-ethyl-2-oxazoline) as a mucoadhesive polymer for nasal drug delivery," ACS Applied Polymer Materials Journal, vol. 3, p. 5882–92, 2021, doi: 10.1021/acsapm.1c01097.

D. J. Patil, R. K. Godge, S. N. Jahagirdar, and S. B. Mandhare, "Validated stability indicating Rp-hplc method for the quantification of process related impurities of solifenacin and mirabegron in pharmaceutical formulations," Interna-tional Journal of Drug Delivery Technology, vol. 14, no. 1, p. 55–60, 2024, doi: 10.25258/ijddt.14.1.10.

R. K. Godge, G. S Shinde, and M. S Bhosale, "RP-HPLC method for estimation of alogliptin and glibenclamide in syn-thetic mixture," Research Journal of Pharmacy and Technology, 2020, vol. 13, no. 2, p. 555–559, 2020. https://rjptonline.org/HTMLPaper.aspx?Journal=Research+Journal+of+Pharmacy+and+Technology%3bPID%3d2020-13-2-8.

S. R. Pattan et al., "Synthesis and biological evaluation of some heterocycles containing oxadiazole and pyrazole ring for anti-bacterial, anti-fungal and anti-tubercular activities," Indian Drugs, vol. 49, no. 3, pp. 18–24, 2012.doi: 10.53879/id.49.03.p0018.

R. C. Silva, M. G. Trevisan, and J. S Garcia, "Characterization and drug-excipient compatibility study of bromopride by DSC, FTIR and HPLC," Journal of Thermal Analysis and Calorimetry, vol. 149, p.9333–42, 2024, doi: 10.1007/s10973-024-13392-1.

R. Denolf, et al., "Constructing and validating ternary phase diagrams as basis for polymer dissolution recycling," Journal of Molecular Liquids, vol. 387, p. 122630, 2023, doi: 10.1016/j.molliq.2023.122630.

D. Yadav, A. Mazumder, and R. K. Khar, "Preparation and characterization of mucoadhesive nanoemulsion contain-ing piperine for nasal drug delivery system," Research Journal of Pharmacy and Technology, vol. 14, no. 5, p. 2381–6, 2021, doi: 10.52711/0974-360X.2021.00420.

P. N. Kendre , S. N. Lateef , R. K. Godge , P. D. Chaudhari , S. L. Fernandes, and S. K.Vibhute, "Oral sustained delivery of theophylline floating matrix tablets- formulation and in-vitro evaluation," International Journal of PharmTech Research, vol. 2, no.1, pp 130-139, Jan-Mar 2010, https://sphinxsai.com/sphinxsaiVol_2No.1/PharmTech_Vol_2No.1/PharmTech_Vol_2No.1PDF/PT=22%20(130-139).pdf.

A. Rajora, K. Kohli, and K. Nagpal, "Formulation of itraconazole loaded clove oil based nanoemulsion using pseudoternary phase diagram for improved thermodynamic stability," Indian Journal of Pure and Applied Physics, vol. 62, no. 2, p. 124-132, 2024, doi: 10.56042/ijpap.v62i2.7698.

S. Talole, R. Godge, N. Tambe, and N. Mhase, "Formulation and optimization of upadacitinib-loaded transdermal patches for rheumatoid arthritis with zeroorder release kinetics," Journal of Applied Pharmaceutical Research, vol. 13, no. 2, p. 181, 2025, doi: 10.69857/joapr.v13i2.1037.

M. Cordova-Gonzalez, and S. H. Hejazi, "Integrating phase change materials and spontaneous emulsification: In-situ particle formation at oil–water interfaces," Colloids and Surfaces A: Physicochemical and Engineering Aspects, vol. 698, p. 134439, 2024, doi: 10.1016/j.colsurfa.2024.134439.

Y. Zheng, C. R. Davis, J. A. Howarter, K. A. Erk, and C J Martinez, "Spontaneous emulsions: adjusting spontaneity and phase behaviour by hydrophilic–lipophilic difference-guided surfactant, salt, and oil selection," Langmuir, vol. 38, p. 4276–86, 2022, doi:10.1021/acs.langmuir.1c03444.

A. M. Al-Mahallawi, D. Ahmed, M. Hassan, D. A. El-Setouhy, "Enhanced ocular delivery of clotrimazole via loading into mucoadhesive microemulsion system: in vitro characterization and in vivo assessment," Journal of Drug Delivery Science and Technology, vol. 64, p.102561, 2021, doi: 10.1016/j.jddst.2021.102561.

M. T. Talianu, C. E. Dinu-Pîrvu, M. V. Ghica, V. Anuţa, R. M. Prisada, and L. Popa, "Development and characterization of new miconazole-based microemulsions for buccal delivery by implementing a full factorial design model-ing," Pharmaceutics, vol. 16, p. 271, 2024, doi: 10.3390/pharmaceutics16020271.

M. U. Patil, A. P. Rajput, V. S. Belgamwar, and S. S. Chalikwar, "Development and characterization of amphotericin B nanoemulsion-loaded mucoadhesive gel for treatment of vulvovaginal candidia-sis," Heliyon, vol. 8, no. 11, p. e11489, 2022, doi: 10.1016/j.heliyon.2022.e11489.

B. Sipos, et al., "Mucoadhesive meloxicam-loaded nanoemulsions: Development, characterization and nasal applica-bility studies," European Journal of Pharmaceutical Sciences,

vol. 175, p. 106229, 2022, doi: 10.1016/j.ejps.2022.106229.

R. Phongpradist, et al, "KLVFF conjugated curcumin microemulsion-based hydrogel for transnasal route: formulation development, optimization, physicochemical characterization, and ex vivo evaluation," Gels, vol. 9, p. 610, 2023, doi: 10.3390/gels9080610.

M. Imran, et al., "Intranasal delivery of a silymarin loaded microemulsion for the effective treatment of parkinson’s disease in rats: formulation, optimization, characterization, and in vivo evaluation," Pharmaceutics, vol. 15, p. 618, 2023, doi: 10.3390/pharmaceutics15020618.

A. P Tartari, J. Jacumazo, A. K. P. Lorenzett, R. A. de Freitas, and R M. Mainardes, "Development and characterization of silibinin-loaded nanoemulsions: a promising mucoadhesive platform for enhanced mucosal drug deliv-ery," Pharmaceutics, vol. 17, p. 192, 2025, doi: 10.3390/pharmaceutics17020192.

O. M. Alwan, and I. S. Jaafar, "Development of synergistic antifungal in situ gel of miconazole nitrate loaded micro-emulsion as a novel approach to treat vaginal candidiasis," Scientific Reports,

vol. 14, p. 23168, 2024, doi: 10.1038/s41598-024-74021-3.

A. Haasbroek-Pheiffer, S. Van Niekerk, F. Van der Kooy, T. C. Cloete, J. Steenekamp, and J. Hamman, "In vitro and ex vivo experimental models for evaluation of intranasal systemic drug delivery as well as direct nose-to-brain drug de-livery," Biopharmaceutics and Drug Disposition, vol. 44, p. 94–112, 2023. doi: 10.1002/bdd.2348.

C. Bartos, P. Szabó-Révész, T. Horváth, P. Varga, and R. Ambrus, "Comparison of modern in vitro permeability meth-ods with the aim of investigation nasal dosage forms," Pharmaceutics, vol. 13, no. 6, p. 846, 2021, doi: 10.3390/pharmaceutics13060846.

O. González-González, et al., "Drug stability: ICH versus accelerated predictive stability studies," Pharmaceutics, vol. 14, p. 2324, 2022, doi: 10.3390/pharmaceutics14112324.

S. Haq, et al,, "Antibacterial, antioxidant and physicochemical investigations of tin dioxide nanoparticles synthesized via microemulsion method," Materials Research Express, vol. 8, p. 035013, 2021, doi: 10.1088/2053-1591/abed8a.

H. Y. Aati, A. Ismail, M. E. Rateb, A. M. AboulMaged, H. M. Hassan, and M. H. Hetta, "Garcinia cambogia phenolics as potent anti-COVID-19 agents: phytochemical profiling, biological activities, and molecular docking," Plants, vol. 11, p. 2521, 2022, doi: 10.3390/plants11192521.

N. Kothawade, and V. V. Pande, "Formulation and evaluation of amisulpride loaded intranasal microemulsion," Indi-an Drugs, vol. 60, no. 9, p. 49-56, 2023, doi: 10.53879/id.60.09.13783.

Y. Ding, et al., "Microemulsion-thermosensitive gel composites as in situ-forming drug reservoir for periodontitis tis-sue repair through alveolar bone and collagen regeneration strategy," Pharmaceutical Development and Technology Jour-nal, vol. 28, p. 30–9. doi: 10.1080/10837450.2022.2161574.

P. C. Pires, A. C. Paiva-Santos, and F. Veiga, "Nano and microemulsions for the treatment of depressive and anxiety disorders: an efficient approach to improve solubility, brain bioavailability and therapeutic efficacy," Pharmaceutics, vol. 14, p. 2825.2022, doi: 10.3390/pharmaceutics14122825.

P. Mohan, J. Rajeswari, and K. Kesavan "Cationic microemulsion of voriconazole for the treatment of fungal keratitis: in vitro and in vivo evaluation," Therapeutic Delivery, vol. 15, p. 23–39, 2024, doi: 10.4155/tde-2023-0069.

S. Rençber, and E. Gündoğdu, Ç. K. Karayıldırım, and Y. Başpınar "Preparation and characterization of mucoad-hesive gels containing pentoxifylline loaded nanoparticles for vaginal delivery of genital ulcer," Iranian Polymer Jour-nal, vol. 30, p. 569–82,2021, doi: 10.1007/s13726-021-00913-0.

A. Rahdar, et al., "Biochemical, ameliorative and cytotoxic effects of newly synthesized curcumin microemulsions: evidence from in vitro and in vivo studies," Nanomaterials, vol. 11, p. 817, 2021, doi: 10.3390/nano11030817

S. Vashist, and M. M. Gadewar, Preparation and characterization of mucoadhesive proniosomal gel of curcumin with thiolate chitosan for the treatment of oral mucositis. International Journal of Pharmaceutical Investigation, vol.13, p. 666–72, 2023, doi: 10.5530/ijpi.13.3.083.

O. M. Alwan, and I. S. Jafar, "Formulation and characterization of poloxamer-based mucoadhesive vaginal in situ gelling system of miconazole nitrate," Hilla University College Journal for Medical Science, vol. 2, p. 32–9, 2024, doi: 10.62445/2958-4515.1029.

S. Golshani, A. Vatanara, S. Balalaie, Z. Kadkhoda, M. Abdollahi, and M. Amin, "Development of a novel histatin-5 mucoadhesive gel for the treatment of oral mucositis: in vitro characterization and in vivo evaluation," AAPS PharmSciTech, vol. 24, p.177, 2023, doi: 10.1208/s12249-023-02632-6.