ENHANCING NOSE- TO- BRAIN DELIVERY OF PIRIBEDIL: DEVELOPMENT OF A NANOSUSPENSION DISPERSED IN NASAL IN-SITU GELLING SYSTEM

CHEKKILLA BHARGAVI; PATHURI RAGHUVEER

doi:10.22159/ijap.2024v16i3.50242

Authors

CHEKKILLA BHARGAVI Department of Pharmaceutics, GITAM School of Pharmacy (Deemed to be University), Hyderabad, Telangana, India. Department of Pharmaceutics, Sarojini Naidu Vanita Pharmacy Maha Vidyalaya, Hyderabad, Telangana-502329, India https://orcid.org/0000-0002-8622-750X
PATHURI RAGHUVEER Department of Pharmaceutics, GITAM School of Pharmacy (Deemed to be University), Hyderabad, Telangana, India https://orcid.org/0000-0001-5918-1393

DOI:

https://doi.org/10.22159/ijap.2024v16i3.50242

Keywords:

Design of experiments, Process variables, Formulation variables, Intranasal delivery, Nanocrystals

Abstract

Objective: This study focuses on improving the delivery of Piribedil, a poorly soluble drug, to the brain through the nasal route using a nanosuspension in a nasal in-situ gel.

Methods: The nanosuspension was prepared using the sonoprecipitation method. Quality-by-Design (QbD) principles were used to optimize both the formulation and process parameters. The optimal process parameters were determined as sonication time (7.09 min), sonication amplitude (83.44%), and infusion rate (2.41 mL/min) with a desirability value of 0.970.

Results: The nanosuspension exhibited an average particle size ranging from 46.7 nm to 50.1 nm, and polydispersity index values between 0.393 and 0.425. Zeta potential values ranged from -33.78 ± 1.86 mV to -35.06 ± 2.12 mV, indicating favorable stability. FTIR studies revealed molecular interactions between Piribedil and stabilizers. XRPD and DSC analyses showed the transition from a crystalline to an amorphous state in the nanosuspension. Dissolution studies demonstrated significantly accelerated dissolution for the Piribedil nanosuspension, attributed to its nanosize and improved wettability. Stability assessments confirmed the robustness of the nanosuspension.

Conclusion: This innovative approach offers potential solutions for drug solubility challenges and blood-brain barrier penetration, holding promise for effective brain-targeted treatments.

Downloads

Download data is not yet available.

References

Achar A, Myers R, Ghosh C. Drug delivery challenges in brain disorders across the blood–brain barrier: novel methods and future considerations for improved therapy. Biomedicines. 2021 Dec;9(12):1834. doi: 10.3390/biomedicines9121834, PMID 34944650.

Vidyadhari J, Gayatriramya M, Durga SPVN, Pavani P, Rajesh K. Nanosuspensions: a strategy to increase the solubility and bioavailability of poorly water-soluble drugs. Asian J Pharm Clin Res. 2023 May;16(5):33-40.

Sowmya C, Suriyaprakaash KK, Abrar AH. Solid lipid nanoparticles: modern progress in nose-to-brain transduction. Int J Appl Pharm. 2023 Apr;15(4):20-6.

Partridge B, Eardley A, Morales BE, Campelo SN, Lorenzo MF, Mehta JN. Advancements in drug delivery methods for the treatment of brain disease. Front Vet Sci. 2022 Sep;9:1039745. doi: 10.3389/fvets.2022.1039745, PMID 36330152.

Lee D, Minko T. Nanotherapeutics for Nose-to-brain drug delivery: an approach to bypass the blood-brain barrier. Pharmaceutics. 2021 Dec;13(12):2049. doi: 10.3390/pharmaceutics13122049, PMID 34959331.

Bahadur S, Pardhi DM, Rautio J, Rosenholm JM, Pathak K. Intranasal nanoemulsions for direct nose-to-brain delivery of actives for CNS disorders. Pharmaceutics. 2020 Dec;12(12):1230. doi: 10.3390/pharmaceutics12121230, PMID 33352959.

Khalifa NE, Nur AO, Osman ZA. Artemether loaded ethylcellulose nanosuspensions: effects of formulation variables, physical stability and drug release profile. Int J Pharm Pharm Sci. 2017 Jun;9(6):90-6. doi: 10.22159/ijpps.2017v9i6.18321.

Grassin Delyle S, Buenestado A, Naline E, Faisy C, Blouquit Laye S, Couderc LJ. Intranasal drug delivery: an efficient and non-invasive route for systemic administration: focus on opioids. Pharmacol Ther. 2012 Mar;134(3):366-79. doi: 10.1016/j.pharmthera.2012.03.003, PMID 22465159.

Formica ML, Real DA, Picchio ML, Catlin E, Donnelly RF, Paredes AJ. On a highway to the brain: a review on nose-to-brain drug delivery using nanoparticles. Appl Mater Today. 2022 Jul;29:101631. doi: 10.1016/j.apmt.2022.101631.

Saindane NS, Pagar KP, Vavia PR. Nanosuspension based in situ gelling nasal spray of carvedilol: development, in vitro and in vivo characterization. AAPS PharmSciTech. 2013 Jun;14(1):189-99. doi: 10.1208/s12249-012-9896-y, PMID 23255198.

Hao J, Zhao J, Zhang S, Tong T, Zhuang Q, Jin K. Fabrication of an ionic-sensitive in situ gel loaded with resveratrol nanosuspensions intended for direct nose-to-brain delivery. Colloids Surf B Biointerfaces. 2016 Jan;147:376-86. doi: 10.1016/j.colsurfb.2016.08.011, PMID 27566226.

Kürti L, Gaspar R, Marki A, Kapolna E, Bocsik A, Veszelka S. In vitro and in vivo characterization of meloxicam nanoparticles designed for nasal administration. Eur J Pharm Sci. 2013 Jan;50(1):86-92. doi: 10.1016/j.ejps.2013.03.012, PMID 23542493.

Bartos C, Ambrus R, Sipos P, Budai Szucs M, Csanyi E, Gaspar R. Study of sodium hyaluronate-based intranasal formulations containing micro- or nanosized meloxicam particles. Int J Pharm. 2015 Jan;491(1-2):198-207. doi: 10.1016/j.ijpharm.2015.06.046, PMID 26142244.

Mittur A. Piribedil: antiparkinsonian properties and potential clinical utility in dopaminergic disorders. Curr Drug Ther. 2011 Jan;6(1):17-34. doi: 10.2174/157488511794079004.

Isaacson SH, Hauser RA, Pahwa R, Gray D, Duvvuri S. Dopamine agonists in Parkinson’s disease: impact of D1-like or D2-like dopamine receptor subtype selectivity and avenues for future treatment. Clin Park Relat Disord. 2023 Jul;9:100212. doi: 10.1016/j.prdoa.2023.100212, PMID 37497384.

Uppuluri CT, Ravi PR, Dalvi AV. Design, optimization and pharmacokinetic evaluation of piribedil-loaded solid lipid nanoparticles dispersed in nasal in situ gelling system for effective management of Parkinson’s disease. Int J Pharm. 2021 Jun;606:120881. doi: 10.1016/j.ijpharm.2021.120881, PMID 34273426.

Uppuluri CT, Ravi PR, Dalvi AV, Shaikh SS, Kale SR. Piribedil loaded thermo-responsive nasal in situ gelling system for enhanced delivery to the brain: formulation optimization, physical characterization, and in vitro and in vivo evaluation. Drug Deliv Transl Res. 2021 Nov;11(3):909-26. doi: 10.1007/s13346-020-00800-w, PMID 32514705.

Tsai RS, El Tayar N, Carrupt PA, Testa B. Physicochemical properties and transport behaviour of piribedil: considerations on its membrane-crossing potential. International Journal of Pharmaceutics. 1992 Mar;80(1-3):39-49. doi: 10.1016/0378-5173(92)90260-9.

Perez Lloret S, Rascol O. Piribedil for the treatment of motor and non-motor symptoms of parkinson disease. CNS Drugs. 2016 Jun;30(8):703-17. doi: 10.1007/s40263-016-0360-5, PMID 27344665.

Yardımcı C, Suslu I, Ozaltın N. Determination of piribedil in pharmaceutical formulations by micellar electrokinetic capillary chromatography. Anal Bioanal Chem. 2004 Jul;379(2):308-11. doi: 10.1007/s00216-004-2539-8, PMID 14985904.

Demirel M, Yazan Y, Muller RH, Kilic FA, Bozan B. Formulation and in vitro-in vivo evaluation of piribedil solid lipid micro and nanoparticles. J Microencapsul. 2001 Mar;18(3):359-71. doi: 10.1080/02652040010018119, PMID 11308226.

Uppuluri CT, Ravi PR, Dalvi AV. Design and evaluation of thermo-responsive nasal in situ gelling system dispersed with piribedil-loaded lecithin-chitosan hybrid nanoparticles for improved brain availability. Neuropharmacology. 2021 Dec;201:108832. doi: 10.1016/j.neuropharm.2021.108832.

Shete G, Bansal AK. NanoCrySP technology for generation of drug nanocrystals: translational aspects and business potential. Drug Deliv Transl Res. 2016 Aug;6(4):392-8. doi: 10.1007/s13346-016-0286-y, PMID 26912190.

Junyaprasert VB, Morakul B. Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian J Pharm Sci. 2015 Jan;10(1):13-23. doi: 10.1016/j.ajps.2014.08.005.

Jacobs C, Kayser O, Muller RH. Production and characterisation of mucoadhesive nanosuspensions for the formulation of bupravaquone. Int J Pharm. 2001 Jan;214(1-2):3-7. doi: 10.1016/s0378-5173(00)00622-0, PMID 11282227.

Aher SS, Malsane ST, Saudagar RB. Nanosuspension: an overview. Int J Curr Pharm Sci 2017;9(3):19-23. doi: 10.22159/ijcpr.2017.v9i3.19584.

Patel VR, Agrawal YK. Nanosuspension: an approach to enhance solubility of drugs. J Adv Pharm Technol Res. 2011 Feb;2(2):81-7. doi: 10.4103/2231-4040.82950, PMID 22171298.

Ranjita S. Nanosuspensions: a new approach for organ and cellular targeting in infectious diseases. J Pharm Investig. 2013 Jan;43(1):1-26. doi: 10.1007/s40005-013-0051-x.

Gigliobianco MR, Casadidio C, Censi R, Di Martino P. Nanocrystals of poorly soluble drugs: drug bioavailability and physicochemical stability. Pharmaceutics. 2018 Mar;10(3):134. doi: 10.3390/pharmaceutics10030134, PMID 30134537.

Ahire E, Thakkar S, Darshanwad M, Misra M. Parenteral nanosuspensions: a brief review from solubility enhancement to more novel and specific applications. Acta Pharm Sin B. 2018 May;8(5):733-55. doi: 10.1016/j.apsb.2018.07.011, PMID 30245962.

Ahmadi Tehrani A, Omranpoor MM, Vatanara A, Seyedabadi M, Ramezani V. Formation of nanosuspensions in a bottom-up approach: theories and optimization. Daru. 2019 Jun;27(1):451-73. doi: 10.1007/s40199-018-00235-2, PMID 30661188.

Peltonen L, Hirvonen J. Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods. J Pharm Pharmacol. 2010 Nov;62(11):1569-79. doi: 10.1111/j.2042-7158.2010.01022.x, PMID 21039542.

Pirincci Tok Y, Mesut B, Gungor S, Sarıkaya AO, Aldeniz EE, Dude U. Systematic screening study for the selection of proper stabilizers to produce physically stable canagliflozin nanosuspension by wet milling method. Bioengineering (Basel). 2023 Aug;10(8):927. doi: 10.3390/bioengineering10080927, PMID 37627812.

Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK. Understanding pharmaceutical quality by design. AAPS J. 2014;16(4):771-83. doi: 10.1208/s12248-014-9598-3, PMID 24854893.

Simao J, Chaudhary SA, Ribeiro AJ. Implementation of quality by design (QbD) for development of bilayer tablets. Eur J Pharm Sci. 2023 May;184:106412. doi: 10.1016/j.ejps.2023.106412, PMID 36828037.

Mothilal M, Chaitanya KM, Surya Teja SP, Manimaran V, Damodharan N. Formulation and evaluation of naproxen-eudragit RS 100 nanosuspension using 32 factorial design. Int J Pharm Pharm Sci. 2014 Jul;6(7):449-55.

Pielenhofer J, Meiser SL, Gogoll K, Ciciliani AM, Denny M, Klak M. Quality by design (QbD) approach for a nanoparticulate imiquimod formulation as an investigational medicinal product. Pharmaceutics. 2023 Feb;15(2):514. doi: 10.3390/pharmaceutics15020514, PMID 36839835.

Pailla SR, Talluri S, Rangaraj N, Ramavath R, Challa VS, Doijad N. Intranasal zotepine nanosuspension: intended for improved brain distribution in rats. Daru. 2019 Dec;27(2):541-56. doi: 10.1007/s40199-019-00281-4, PMID 31256410.

Nagaraj K, Narendar D, Kishan V. Development of olmesartan medoxomil optimized nanosuspension using the box-behnken design to improve oral bioavailability. Drug Dev Ind Pharm. 2017 Jul;43(7):1186-96. doi: 10.1080/03639045.2017.1304955, PMID 28271908.

Rahman SNR, Katari O, Pawde DM, Boddeda GSB, Goswami A, Mutheneni SR. Application of design of experiments® approach-driven artificial intelligence and machine learning for systematic optimization of reverse-phase high-performance liquid chromatography method to analyze simultaneously two drugs (cyclosporin a and etodolac) in solution, human plasma, nanocapsules, and emulsions. AAPS PharmSciTech. 2021 Apr;22(4):155. doi: 10.1208/s12249-021-02026-6, PMID 33987739.