Development of rasagiline mesylate loaded solid lipid nanoparticles in a thermosensitive mucoadhesive gel: Formulation design using DoE, in-vitro and ex-vivo characterization

Mahmut Ozan Toksoy; Fahriye Figen Tirnaksiz

Development of rasagiline mesylate loaded solid lipid nanoparticles in a thermosensitive mucoadhesive gel: Formulation design using DoE, in-vitro and ex-vivo characterization

Abstract

Rasagiline mesylate (RM) is a selective irreversible MAO-B inhibitor used in the treatment of Parkinson’s disease. This study was designed to prepare and optimize RM loaded solid lipid nanoparticles (RM-SLNs) in a thermosensitive mucoadhesive gel (RM-SLNs-GEL). RM-SLNs were prepared combining Gelucire 50/13 (10%), Labrasol (0.3%) Cremophor RH40 (12%) with a mixing rate and time of 500 rpm, 45 min. Mucoadhesive gels were prepared combining Poloxamer 407 and HPMC E5 (15.5% + 0.25%). Optimized formulation (RM-SLNs-GEL) was evaluated for sol-gel transition temperature, viscosity, mucoadhesive force, particle size and distribution, SEM imaging, in-vitro drug release and ex-vivo drug permeation. It was found that optimal formulation had a suitable gelation temperature at 31°C ± 0.2°C. It was observed that the system was fluid during nasal application at 25°C and viscous at nasal temperature at 32°C. RM-SLNs-GEL has shown particle size, polydispersity index (PDI), % encapsulation efficiency (EE%); 253 nm, 0.282, 37.8% respectively. Ex-vivo permeation study exposed significant enhancement of permeability of RM-SLNs-GEL across mucosa than RM loaded thermosensitive gel (RM-GEL). Our results show that RM-SLNs-GEL formulation could be a potential drug delivery system for the treatment of Parkinson’s disease.

Keywords

References

[1] De Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol. 2006; 5(6):525-535.
[2] Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry. 2008; 79(4):368-376.
[3] Purvin S, Vuddanda PR, Singh SK, Jain A, Singh S. Pharmacokinetic and tissue distribution study of solid lipid nanoparticles of zidovudine in rats. J Nanotechnol. 2014, 854018.
[4] Chahine LM, Stern MB. Rasagiline in Parkinson's disease. Int Rev Neurobiol. 2011; 100: 151-168. . [5] Oldfield V, Keating GM, Perry CM. Rasagiline: a review of its use in the management of Parkinson's disease. Drugs. 2007; 67(12):1725-1747.
[6] Ravi PR, Aditya N, Patil S, Cherian L. Nasal in-situ gels for delivery of rasagiline mesylate: improvement in bioavailability and brain localization. Drug Deliv. 2015; 22(7): 903-910.
[7] Jiang Y, Zhang X, Mu H, Hua H, Duan D, Yan X, et al. Preparation and evaluation of injectable Rasagiline mesylate dual-controlled drug delivery system for the treatment of Parkinson’s disease. Drug Deliv. 2018; 25(1):143-152.
[8] Pardridge WM. Drug and gene delivery to the brain: the vascular route. Neuron. 2002; 36(4):555-558.
[9] Rao M, Agrawal DK, Shirsath C. Thermoreversible mucoadhesive in situ nasal gel for treatment of Parkinson’s disease. Drug Dev Ind Pharm. 2017; 43(1):142-150.

[10] Wen MM. Olfactory targeting through intranasal delivery of biopharmaceutical drugs to the brain: current development. Discov Med. 2011; 11(61): 497-503
[11] Erdo F, Bors LA, Farkas D, Bajza A, Gizurarson S. Evaluation of intranasal delivery route of drug administration for brain targeting. Brain Res Bull. 2018; 143: 155-170.
[12] Schipper NG, Verhoef JC, Merkus FW. The nasal mucociliary clearance: relevance to nasal drug delivery. Pharm Res. 1991; 8(7):807-814.
[13] Marttin E, Schipper NGM, Verhoef JC, Merkus FW. Nasal mucociliary clearance as a factor in nasal drug delivery. Adv Drug Deliv Rev. 1998; 29(1-2): 13-38.
[14] Tirnaksiz F, Robinson JR. Rheological, mucoadhesive and release properties of pluronic F-127 gel and pluronic F- 127/polycarbophil mixed gel systems. Pharmazie. 2005; 60(7):518-523. [15] Lindemann J, Leiacker R, Rettinger G, Keck T. Nasal mucosal temperature during respiration. Clin Otolaryngol Allied Sci. 2002; 27(3):135-139.
[16] Majithiya RJ, Ghosh PK, Umrethia ML, Murthy RS. Thermoreversible-mucoadhesive gel for nasal delivery of sumatriptan. AAPS PharmSciTech. 2006; 7(3): 67.
[17] John MS, Nair SC, Anoop KR. Thermoreversible mucoadhesive gel for nasal delivery of anti-hypertensive drug. IJSR. 2013; 21: 57-63
[18] Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery–a review of the state of the art. Eur J Pharm Biopharm. 2000; 50(1): 161-177.
[19] Martins S, Tho I, Reimold I, Fricker G, Souto E, Ferreira D, et al. Brain delivery of camptothecin by means of solid lipid nanoparticles: formulation design, in vitro and in vivo studies. Int J Pharm. 2012; 439(1-2): 49-62.
[20] Singh AP, Saraf SK, Saraf SA. SLN approach for nose-to-brain delivery of alprazolam. Drug Deliv Transl Res. 2012; 2(6): 498-507.
[21] Wissing SA, Kayser O, Muller RH. Solid lipid nanoparticles for parenteral drug delivery. Adv Drug Deliv Rev. 2004; 56(9): 1257-1272.
[22] Mohammadi-Samani S, Zojaji S, Entezar-Almahdi E. Piroxicam loaded solid lipid nanoparticles for topical delivery: Preparation, characterization and in vitro permeation assessment. J Drug Deliv Sci Technol. 2018; 47: 427-433.
[23] Ahmad I, Pandit J, Sultana Y, Mishra AK, Hazari PP, Aqil M. Optimization by design of etoposide loaded solid lipid nanoparticles for ocular delivery: Characterization, pharmacokinetic and deposition study. Mater Sci Eng C Mater Biol Appl. 2019; 100: 959-970.
[24] Ban C, Jo M, Park YH, Kim JH, Han JY, Lee KW, et al. Enhancing the oral bioavailability of curcumin using solid lipid nanoparticles. Food Chem. 2020; 302:125328.
[25] Ghadiri M, Fatemi S, Vatanara A, Doroud D, Najafabadi AR, Darabi M, et al. Loading hydrophilic drug in solid lipid media as nanoparticles: Statistical modeling of entrapment efficiency and particle size. Int J Pharm. 2012; 424(1-2): 128-137.
[26] Shah RM, Malherbe F, Eldridge D, Palombo EA, Harding IH. Physicochemical characterization of solid lipid nanoparticles (SLNs) prepared by a novel microemulsion technique. J Colloid Interface Sci. 2014; 428: 286-294.
[27] Schwarz C, Mehnert W. Freeze-drying of drug-free and drug-loaded solid lipid nanoparticles (SLN). Int J Pharm. 1997; 157(2):171-179.
[28] Varshosaz J, Eskandari S, Tabbakhian M. Freeze-drying of nanostructure lipid carriers by different carbohydrate polymers used as cryoprotectants. Carbohydr Polym. 2012; 88(4): 1157-1163.
[29] Pereira GG, Dimer FA, Guterres SS, Kechinski CP, Granada JE, Cardozo NSM. Formulation and characterization of poloxamer 407®: thermoreversible gel containing polymeric microparticles and hyaluronic acid. Quim Nova. 2013; 36(8): 1121-1125.
[30] Deshmukh T, Deshmukh V, Jadhav P, Kasat K, Patil R. Formulation and evaluation of mucoadhesive microspheres of ziprasidone hydrochloride for oral controlled release. Curr Pharm Res. 2012; 2(2): 497-502.
[31] Dorraj G, Moghimi HR. Preparation of SLN-containing Thermoresponsive In-situ Forming Gel as a Controlled Nanoparticle Delivery System and Investigating its Rheological, Thermal and Erosion Behavior. Iran J Pharm Res. 2015; 14(2): 347-358.
[32] Din FU, Choi JY, Kim DW, Mustapha O, Kim DS, Thapa RK, et al. Irinotecan-encapsulated double-reverse thermosensitive nanocarrier system for rectal administration. Drug Deliv. 2017; 24(1): 502-510.
[33] Bali NR, Shinde MP, Rathod SB, Salve PS. Enhanced transdermal permeation of Rasagiline mesylate nanoparticles: design, optimization and effect of binary combinations of solvent systems across biological membrane. Int J Polym Mater. 2020; 70(3): 158-173.
[34] Kanwar N, Bhandari R, Kuhad A, Sinha VR. Polycaprolactone-based neurotherapeutic delivery of Rasagiline targeting behavioral and biochemical deficits in Parkinson’s disease. Drug Deliv. 2019; 9(5):891-905.
[35] Kunasekaran V, Krishnamoorthy K. Experimental design fort he optimization of nanoscale solid lipid nanoparticles containing Rasagiline mesylate. J Young Pharm. 2015; 7(4): 285-295.
[36] Zimmermann E, Souto EB, Müller RH, Müller RH. Physicochemical investigations on the structure of drug-free and drug-loaded solid lipid nanoparticles (SLNTM) by means of DSC and 1H NMR. Pharmazie. 2005; 60(7): 508-513. [37] Guo X, Cui F, Xing Y, Mei Q, Zhang Z. Investigation of a new injectable thermosensitive hydrogel loading solid lipid nanoparticles. Pharmazie. 2011; 66(12): 948-952.
[38] Silva AC, Amaral MH, Gonzalez-Mira E, Santos D, Ferreira D. Solid lipid nanoparticles (SLN)--based hydrogels as potential carriers for oral transmucosal delivery of risperidone: preparation and characterization studies. Colloid Surface B. 2012; 93:241-248.
[39] Souto EB, Muller RH. Rheological and in vitro release behaviour of clotrimazole-containing aqueous SLN dispersions and commercial creams. Pharmazie. 2007; 62(7): 505-509.
[40] Kesharwani R, Sachan A, Singh S, Patel D. Formulation and evaluation of solid lipid nanoparticle (SLN) based topical gel of etoricoxib. J Appl Pharm Sci. 2016; 6(10):124-131.
[41] Anjum R, Lakshmi PK. Dolutegravir sodium loaded solid lipid nanoparticles: A vaginal drug delivery system for pre-exposure prophylaxis of HIV. J Res Pharm. 2020; 24(4): 552-561.
[42] Abdel-Mottaleb MM, Neumann D, Lamprecht A. In vitro drug release mechanism from lipid nanocapsules (LNC). Int J Pharm. 2010; 390(2): 208-213.
[43] Yang R, Gao R, Li F, He H, Tang X. The influence of lipid characteristics on the formation, in vitro release, and in vivo absorption of protein-loaded SLN prepared by the double emulsion process. Drug Dev Ind Pharm. 2011; 37(2): 139-148.
[44] Ahmed TA, Badr-Eldin SM, Ahmed OAA, Aldawsari H. Intranasal optimized solid lipid nanoparticles loaded in situ gel for enhancing trans-mucosal delivery of simvastatin. J Drug Deliv Sci Technol. 2018; 48: 499-508.
[45] Van De Waterbeemd H, Smith DA, Beaumont K, Walker DK. Property-based design: optimization of drug absorption and pharmacokinetics. J Med Chem. 2001; 44(9): 1313-1333.
[46] Liu Z, Zhang X, Wu H, Li J, Shu L, Liu R, et al. Preparation and evaluation of solid lipid nanoparticles of baicalin for ocular drug delivery system in vitro and in vivo. Drug Dev Ind Pharm. 2011; 37(4):475-481.
[47] Chirio D, Gallarate M, Peira E, Battaglia L, Muntoni E, Riganti C, et al. Positive-charged solid lipid nanoparticles as paclitaxel drug delivery system in glioblastoma treatment. Eur J Pharm Biopharm. 2014; 88(3):746-758.
[48] Chavan SS, Ingle SG, Vavia PR. Preparation and characterization of solid lipid nanoparticle-based nasal spray of budesonide. Drug Deliv Transl Res. 2013; 3(5):402-408.
[49] Gasco MR. Method for producing solid lipid microspheres having a narrow size distribution. 1993. U.S. Patent No: 5250236. https://patents.google.com/patent/US5250236A/en (accessed July 21, 2021). [50] Viveksarathi K, Kannan K. Effect of the moist-heat sterilization on fabricated nanoscale solid lipid particles containing rasagiline mesylate. Int J Pharm Investig. 2015; 5(2): 87-91.
[51] Fakhari A, Corcoran M, Schwarz A. Thermogelling properties of purified Poloxamer 407. Heliyon. 2017; e00390.
[52] Choi HG, Jung JH, Ryu JM, Yoon SJ, Oh YK, Kim CK. Development of in situ gelling and mucoadhesive acetaminophen liquid suppository. Int J Pharm. 1998; 165(1): 33-44.
[53] Ryu JM, Chung SJ, Lee MH, Kim CK, Shim Ck. Increased bioavailability of propranolol in rats by retaining thermally gelling liquid suppositories in the rectum. J Control Release. 1999; 59(2): 163-172.
[54] Castile J, Cheng Y-H, Simmons B, Perelman M, Smith A, Watts P. Development of in vitro models to demonstrate the ability of PecSys®, an in situ nasal gelling technology, to reduce nasal run-off and drip. Drug Dev Ind Pharm. 2013; 39(5): 816-824. . [55] Pardeshi CV, Belgamwar VS. Improved brain pharmacokinetics following intranasal administration of N,N,N- trimethyl chitosan tailored mucoadhesive NLCs. Mater Technol. 2020; 35(5): 249-266.

Details

Primary Language

English

Subjects

Pharmaceutical Delivery Technologies

Journal Section

Research Article

Authors

Mahmut Ozan Toksoy ^*
Türkiye

Fahriye Figen Tirnaksiz This is me
Türkiye

Publication Date

June 28, 2025

Submission Date

June 2, 2021

Acceptance Date

July 22, 2021

Published in Issue

Year 2021 Volume: 25 Number: 5

IZ

https://izlik.org/JA86WC93AG

Cite

RIS / Bibtex

APA

Toksoy, M. O., & Tirnaksiz, F. F. (2025). Development of rasagiline mesylate loaded solid lipid nanoparticles in a thermosensitive mucoadhesive gel: Formulation design using DoE, in-vitro and ex-vivo characterization. Journal of Research in Pharmacy, 25(5), 702-714. https://izlik.org/JA86WC93AG

AMA

1.Toksoy MO, Tirnaksiz FF. Development of rasagiline mesylate loaded solid lipid nanoparticles in a thermosensitive mucoadhesive gel: Formulation design using DoE, in-vitro and ex-vivo characterization. J. Res. Pharm. 2025;25(5):702-714. https://izlik.org/JA86WC93AG

Chicago

Toksoy, Mahmut Ozan, and Fahriye Figen Tirnaksiz. 2025. “Development of Rasagiline Mesylate Loaded Solid Lipid Nanoparticles in a Thermosensitive Mucoadhesive Gel: Formulation Design Using DoE, In-Vitro and Ex-Vivo Characterization”. Journal of Research in Pharmacy 25 (5): 702-14. https://izlik.org/JA86WC93AG.

EndNote

Toksoy MO, Tirnaksiz FF (July 1, 2025) Development of rasagiline mesylate loaded solid lipid nanoparticles in a thermosensitive mucoadhesive gel: Formulation design using DoE, in-vitro and ex-vivo characterization. Journal of Research in Pharmacy 25 5 702–714.

IEEE

[1]M. O. Toksoy and F. F. Tirnaksiz, “Development of rasagiline mesylate loaded solid lipid nanoparticles in a thermosensitive mucoadhesive gel: Formulation design using DoE, in-vitro and ex-vivo characterization”, J. Res. Pharm., vol. 25, no. 5, pp. 702–714, July 2025, [Online]. Available: https://izlik.org/JA86WC93AG

ISNAD

Toksoy, Mahmut Ozan - Tirnaksiz, Fahriye Figen. “Development of Rasagiline Mesylate Loaded Solid Lipid Nanoparticles in a Thermosensitive Mucoadhesive Gel: Formulation Design Using DoE, In-Vitro and Ex-Vivo Characterization”. Journal of Research in Pharmacy 25/5 (July 1, 2025): 702-714. https://izlik.org/JA86WC93AG.

JAMA

1.Toksoy MO, Tirnaksiz FF. Development of rasagiline mesylate loaded solid lipid nanoparticles in a thermosensitive mucoadhesive gel: Formulation design using DoE, in-vitro and ex-vivo characterization. J. Res. Pharm. 2025;25:702–714.

MLA

Toksoy, Mahmut Ozan, and Fahriye Figen Tirnaksiz. “Development of Rasagiline Mesylate Loaded Solid Lipid Nanoparticles in a Thermosensitive Mucoadhesive Gel: Formulation Design Using DoE, In-Vitro and Ex-Vivo Characterization”. Journal of Research in Pharmacy, vol. 25, no. 5, July 2025, pp. 702-14, https://izlik.org/JA86WC93AG.

Vancouver

1.Mahmut Ozan Toksoy, Fahriye Figen Tirnaksiz. Development of rasagiline mesylate loaded solid lipid nanoparticles in a thermosensitive mucoadhesive gel: Formulation design using DoE, in-vitro and ex-vivo characterization. J. Res. Pharm. [Internet]. 2025 Jul. 1;25(5):702-14. Available from: https://izlik.org/JA86WC93AG