Preparation and Evaluation of Paliperidone Thermal Muco-Adhesive in Situ Gel as a Nasal to Brain Delivery System

Muna Yehia Ismail; Fatima Jalal Al-Gawahri

doi:10.54133/ajms.v8i2.1830

Authors

Muna Yehia Ismail Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq https://orcid.org/0009-0002-2857-4949
Fatima Jalal Al-Gawahri Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq. https://orcid.org/0000-0002-4906-6241

DOI:

https://doi.org/10.54133/ajms.v8i2.1830

Keywords:

In situ gels, Paliperidone, Poloxamer 407, Thermo-sensitive polymers

Abstract

Background: Paliperidone PAL is a second-generation (atypical) antipsychotic medication widely used in the treatment of schizophrenia disorders. It is practically insoluble in water (class II) and has a first-pass metabolism, with oral bioavailability of about 28%. Objective: To optimize and evaluate PAL in a nanothermal residence gel as an intranasal in situ gel formula near or at the site of the nasal-brain delivery system. Methods: The previously prepared nanosuspension formula of PAL was introduced into the creation of in-situ gel formulas using Poloxamer 407 (18–20%w/v), hydroxypropyl methylcellulose HPMC K4 (0.5–1%w/v), and hyaluronic acid (0.5–1%w/v). The selected prepared formula was subjected to different in vitro evaluation studies. Results: The previously prepared nanosuspension formula of PAL, which enhanced its dissolution rate using Soluplus® as a stabilizer, was incorporated into mucoadhesive thermal sensitive gel formulas, using poloxamer 407 as a thermal gelling agent and different concentrations of mucoadhesive polymers. The formula NIG, which contains 20% w/w poloxamer 407 and 1%w/w HPMC K4, exhibited favorable and accepted characteristics, including the ideal gelation temperature of 33°C and drug content of 99.96%, gel strength of 55.0 seconds, spreadability of 5.2cm, and 98.0% in vitro cumulative drug release extended for 6 hours in simulated nasal fluid (SNF) at pH 6.5 maintained at 34°C. Conclusions: The current mucoadhesive in situ gel PAL formula is a promising nasal-to-brain formula that can be used for the management of psychotic disorders drug therapy in the future.

Downloads

Download data is not yet available.

References

Cunha S, Forbes B, Sousa Lobo JM, Silva AC. Improving drug delivery for Alzheimer's disease through nose-to-brain delivery using nanoemulsions, nanostructured lipid carriers (NLC) and in situ hydrogels. Int J Nanomedicine. 2021;16:4373-4390. doi: 10.2147/IJN.S305851. DOI: https://doi.org/10.2147/IJN.S305851

Cassano R, Servidio C, Trombino S. Biomaterials for drugs nose–brain transport: a new therapeutic approach for neurological diseases. Materials. 2021;14(7):1802. doi: 10.3390/ma14071802. DOI: https://doi.org/10.3390/ma14071802

Nguyen TT, Maeng HJ. Pharmacokinetics and pharmacodynamics of intranasal solid lipid nanoparticles and nanostructured lipid carriers for nose-to-brain delivery. Pharmaceutics. 2022;14(3):572. doi: 10.3390/pharmaceutics14030572. DOI: https://doi.org/10.3390/pharmaceutics14030572

Gulsun T, Borna SE, Vural I, Sahin S. Preparation and characterization of furosemide nanosuspensions. J Drug Del Sci Technol. 2018;45:93-100. doi: 10.1016/j.jddst.2018.03.005. DOI: https://doi.org/10.1016/j.jddst.2018.03.005

Wei S, Ma Y, Luo J, He X, Yue P, Guan Z, et al. Hydroxypropylcellulose as matrix carrier for novel cage-like microparticles prepared by spray-freeze-drying technology. Carbohydr Polym. 2017;157:953-961. doi: 10.1016/j.carbpol.2016.10.043. DOI: https://doi.org/10.1016/j.carbpol.2016.10.043

Hao J, Zhao J, Zhang S, Tong T, Zhuang Q, Jin K, et al. Fabrication of an ionic-sensitive in situ gel loaded with resveratrol nanosuspensions intended for direct nose-to-brain delivery. Colloids Surf B Biointerfaces. 2016;147:376-386. doi: 10.1016/j.colsurfb.2016.08.011. DOI: https://doi.org/10.1016/j.colsurfb.2016.08.011

Karavasili C, Fatouros DG. Smart materials: in situ gel-forming systems for nasal delivery. Drug Discov Today. 2016;21(1):157–166. doi: 10.1016/j.drudis.2015.10.016. DOI: https://doi.org/10.1016/j.drudis.2015.10.016

Li X, Du L, Chen X, Ge P, Wang Y, Fu Y, et al. Nasal delivery of analgesic ketorolac tromethamine thermo- and ion-sensitive in situ hydrogels. Int J Pharm. 2015;489(1-2):252-60. doi: 10.1016/j.ijpharm.2015.05.009. DOI: https://doi.org/10.1016/j.ijpharm.2015.05.009

Corena-McLeod M. Comparative pharmacology of risperidone and paliperidone. Drugs Res Dev. 2015;15(2):163-174. doi: 10.1007/s40268-015-0092-x. DOI: https://doi.org/10.1007/s40268-015-0092-x

Dolder C, Nelson M, Deyo Z. Paliperidone for schizophrenia. Am J Health-Syst Pharm. 2008;65(5):403-413. doi: 10.2146/ajhp070261. DOI: https://doi.org/10.2146/ajhp070261

Ghazwani M, Vasudevan R, Kandasamy G, Manusri N, Devanandan P, Puvvada RC, et al. Formulation of intranasal mucoadhesive thermos triggered in situ gel containing mirtazapine as an antidepressant drug. Gels. 2023;9(6):457. doi: 10.3390/gels9060457. DOI: https://doi.org/10.3390/gels9060457

Aldosari BN, Ibrahim MA, Alqahtani Y, Amal El Sayeh F. Formulation and evaluation of Fluconazole Nanosuspensions: In vitro characterization and transcorneal permeability studies. Saudi Pharm J. 2024;32(7):102104. doi: 10.1016/j.jsps.2024.102104. DOI: https://doi.org/10.1016/j.jsps.2024.102104

Hussien RM, Ghareeb MM. Formulation and characterization of isradipine nano particle for dissolution enhancement. Iraqi J Pharm Sci. 2021;30(1):218-225. doi: 10.31351/vol30iss1pp218-225. DOI: https://doi.org/10.31351/vol30iss1pp218-225

Corazza E, Di Cagno MP, Bauer-Brandl A, Abruzzo A, Cerchiara T, Bigucci F, et al. Drug delivery to the brain: In situ gelling enhances carbamazepine diffusion through nasal mucosa models with mucin. Eur J Pharm Sci. 2022;179:106294. doi: 10.1016/j.ejps.2022.106294. DOI: https://doi.org/10.1016/j.ejps.2022.106294

Obayes KK, Thomas LM. Development and characterization of hyaluronic acid-incorporated thermosensitive nasal in situ gel of meclizine hydrochloride. Al-Rafidain J Med Sci. 2024;6(1):97-104. doi: 10.54133/ajms.v6i1.499. DOI: https://doi.org/10.54133/ajms.v6i1.499

Thakkar H, Vaghela D, Patel BP. Brain targeted intranasal in-situ gelling spray of paroxetine: Formulation, characterization and in-vivo evaluation. J Drug Deliv Sci Technol. 2021;62:102317. doi: 10.1016/j.jddst.2020.102317. DOI: https://doi.org/10.1016/j.jddst.2020.102317

Vemula SK, Vangala M. Formulation development and characterization of meclizine hydrochloride sublimated fast dissolving tablets. Int Sch Res Notices. 2014;2014:281376. doi: 10.1155/2014/281376. DOI: https://doi.org/10.1155/2014/281376

Hamzah ML, Kassab HJ. Formulation and characterization of intranasal drug delivery of frovatriptan-loaded binary ethosomes gel for brain targeting. Nanotechnol Sci Appl. 2024:1-9. doi: 10.2147/NSA.S442951. DOI: https://doi.org/10.2147/NSA.S442951

El-Shenawy AA, Mahmoud RA, Mahmoud EA, Mohamed MS. Intranasal in situ gel of apixaban-loaded nano ethosomes: Preparation, optimization, and in vivo evaluation. AAPS PharmSciTech. 2021;22(4):147. doi: 10.1208/s12249-021-02020-y. DOI: https://doi.org/10.1208/s12249-021-02020-y

Jaber S, Rajab NA. Lasmiditan nano emulsion based in situ gel intra nasal dosage form formulation, characterization and in vivo study. Farmacia. 2023;71(6). doi: 10.31925/farmacia.2023.6.15. DOI: https://doi.org/10.31925/farmacia.2023.6.15

Dalvi A, Ravi PR, Uppuluri CT. Design and evaluation of rufinamide nanocrystals loaded thermos responsive nasal in situ gelling system for improved drug distribution to brain. Front Pharmacol. 2022;13:943772. doi: 10.3389/fphar.2022.943772. DOI: https://doi.org/10.3389/fphar.2022.943772

Pires PC, Rodrigues M, Alves G, Santos AO. Strategies to improve drug strength in nasal preparations for brain delivery of low aqueous solubility drugs. Pharmaceutics. 2022;14(3). doi: 10.3390/pharmaceutics_14030588 DOI: https://doi.org/10.3390/pharmaceutics14030588

Lee H, Choj J, Yoon J, Joe N, Kim CH, Kim JY. The study of pH in nasal secretion in normal and chronic rhinosinusitis. J Rhinol. 2009;16(2):105-109. doi: 10.1109/5.771073. DOI: https://doi.org/10.1109/5.771073

Paul A, Fathima KM, Nair SC. Intra nasal in situ gelling system of lamotrigine using ion activated mucoadhesive polymer. Open Med Chem J. 2017;11:222-244. doi: 10.2174/1874104501711010222. DOI: https://doi.org/10.2174/1874104501711010222

Xia Y, Li L, Huang X, Wang Z, Zhang H, Gao J, et al. Performance and toxicity of different absorption enhancers used in the preparation of Poloxamer thermosensitive in situ gels for ketamine nasal administration. Drug Dev Ind Pharm. 2020;46(5):697–705. doi: 10.1080/03639045.2020.1750625. DOI: https://doi.org/10.1080/03639045.2020.1750625

Brambilla E, Locarno S, Gallo S, Orsini F, Pini C, Farronato M, et al. Poloxamer-based hydrogel as drug delivery system: How polymeric excipients influence the chemical-physical properties. Polymers. 2022;14(17):3624. doi: 10.3390/polym14173624. DOI: https://doi.org/10.3390/polym14173624

Shastri DH, Prajapati ST, Patel Ld. Design and development of thermoreversible ophthalmic in situ hydrogel of moxifloxacin HCl. Curr Drug Deliv. 2010;7(3):238–243. doi: 10.2174/156720110791560928. DOI: https://doi.org/10.2174/156720110791560928

Tamer MA, Kassab HJ. the Development of a brain targeted muco adhesive amisulpride loaded nanostructured lipid carrier. Farmacia. 2023;71(5):1032–1044. doi: 10.31925/farmacia.2023.5.18. DOI: https://doi.org/10.31925/farmacia.2023.5.18

Hussein AA. Preparation and evaluation of liquid and solid self micro emulsifying drug delivery system of mebendazole. Iraqi J Pharm Sci. 2014;23(1):89–100. doi: 10.31351/vol23iss1pp89-100. DOI: https://doi.org/10.31351/vol23iss1pp89-100

Pathan IB, More B. Formulation and characterization of intra nasal delivery of nortriptyline hydrochloride thermos reversible gelling system in treatment of depression. Acta Pharm Sci. 2017;55(2):35–44. doi: 10.23893/1307-2080.APS.05510. DOI: https://doi.org/10.23893/1307-2080.APS.05510

Alkufi HK, Kassab HJ. Formulation and evaluation of sustained release sumatriptan mucoadhesive intranasal in-situ gel. Iraqi J Pharm Sci. 2019;28(2):95–104. doi: 10.31351/vol28iss2pp95-104. DOI: https://doi.org/10.31351/vol28iss2pp95-104

Mahajan HS, Tyagi V, Lohiya G, Nerkar P. Thermally reversible xyloglucan gels as vehicles for nasal drug delivery. Drug Deliv. 2012;19(5):270–276. doi: 10.3109/10717544.2012.704095. DOI: https://doi.org/10.3109/10717544.2012.704095

De PK, Ghatak S. Formulation optimization, permeation kinetic and release mechanism study of in-situ nasal gel containing ondansetron. Saudi J Med Pharm Sci. 2020;06(01):91–101. doi: 10.36348/sjmps.2020.v06i01.014. DOI: https://doi.org/10.36348/sjmps.2020.v06i01.014