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Year 2025, Volume: 29 Issue: 3, 947 - 958, 04.06.2025

Avinash Tekade Mukesh Ratnaparkhi Ashutosh Shewale , Rushikesh Shinde , Gajanan Kulkarni Parth Pawar

https://doi.org/10.12991/jrespharm.1693796

Abstract

References

  • [1] Schizophrenia. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/schizophrenia (accessed: October 17, 2023).
  • [2] Rajendran R, Menon KN, Nair SC. Nanotechnology approaches for enhanced CNS drug delivery in the management of schizophrenia. Adv Pharm Bull. 2022;12(3):490–508. http://dx.doi.org/10.34172/apb.2022.052.
  • [3] Pires PC, Paiva-Santos AC, Veiga F. Antipsychotics-loaded nanometric emulsions for brain delivery. Pharmaceutics. 2022;14(10):2174. http://dx.doi.org/10.3390/pharmaceutics14102174.
  • [4] El-Setouhy DA, Ibrahim AB, Amin MM, Khowessah OM, Elzanfaly ES. Intranasal haloperidol-loaded miniemulsions for brain targeting: Evaluation of locomotor suppression and in-vivo biodistribution. Eur J Pharm Sci. 2016;92:244–254. http://dx.doi.org/10.1016/j.ejps.2016.05.002.
  • [5] Olivier J-C. Drug transport to the brain with targeted nanoparticles. NeuroRx. 2005;2(1):108-119. http://dx.doi.org/10.1602/neurorx.2.1.108.
  • [6] Mistry A, Stolnik S, Illum L. Nanoparticles for direct nose-to-brain delivery of drugs. Int J Pharm. 2009;379(1):146–157. http://dx.doi.org/10.1016/j.ijpharm.2009.06.019.
  • [7] Abdelrahman FE, Elsayed I, Gad MK, Badr A, Mohamed MI. Investigating the cubosomal ability for transnasal brain targeting: In vitro optimization, ex vivo permeation and in vivo biodistribution. Int J Pharm. 2015;490(1–2):281–291. http://dx.doi.org/10.1016/j.ijpharm.2015.05.064.
  • [8] Eissa EM, Elkomy MH, Eid HM, Ali AA, Abourehab MAS, Alsubaiyel AM, Naguib IA, Alsalahat I, Hassan AH. Intranasal delivery of granisetron to the brain via nanostructured cubosomes-based ın situ gel for ımproved management of chemotherapy-ınduced emesis. Pharmaceutics. 2022;14(7):1374. http://dx.doi.org/10.3390/pharmaceutics14071374.
  • [9] Illum L. Intranasal delivery to the central nervous system. Blood‐Brain Barrier in Drug Discovery. Wiley; 2015. p. 535–65. http://dx.doi.org/10.1002/9781118788523.ch25
  • [10] Elsenosy FM, Abdelbary GA, Elshafeey AH, Elsayed I, Fares AR. Brain targeting of duloxetine hcl via ıntranasal delivery of loaded cubosomal gel: In vitro characterization, ex vivo permeation, and in vivo biodistribution studies. Int J Nanomedicine. 2020;15:9517–9537. http://dx.doi.org/10.2147/ijn.s277352.
  • [11] Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, Khorasani S, Mozafari MR. Impact of particle size and polydispersity ındex on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):57. http://dx.doi.org/10.3390/pharmaceutics10020057.
  • [12] Clogston JD, Patri AK. Zeta Potential Measurement. In: Methods in Molecular Biology. Totowa, NJ: Humana Press; 2011. p. 63–70.
  • [13] Tan MSA, Parekh HS, Pandey P, Siskind DJ, Falconer JR. Nose-to-brain delivery of antipsychotics using nanotechnology: a review. Expert Opin Drug Deliv. 2020;17(6):839–853. http://dx.doi.org/10.1080/17425247.2020.1762563
  • [14] Yoo BK, Baskaran R, Madheswaran T, Sundaramoorthy P, Kim HM. Entrapment of curcumin into monoolein-based liquid crystalline nanoparticle dispersion for enhancement of stability and anticancer activity. Int J Nanomedicine. 2014;3119. http://dx.doi.org/10.2147/ijn.s61823.
  • [15] Yasir M, Sara UVS. Solid lipid nanoparticles for nose to brain delivery of haloperidol: in vitro drug release and pharmacokinetics evaluation. Acta Pharm Sin B. 2014;4(6):454–463. http://dx.doi.org/10.1016/j.apsb.2014.10.005. [16] Nasr M, Ghorab MK, Abdelazem A. In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting. Acta Pharm Sin B. 2015;5(1):79–88. http://dx.doi.org/10.1016/j.apsb.2014.12.001.
  • [17] Hosny KM. Nanosized cubosomal thermogelling dispersion loaded with saquinavir mesylate to improve its bioavailability: Preparation, optimization, in vitro and in vivo evaluation. Int J Nanomedicine. 2020;15:5113–5129. http://dx.doi.org/10.2147/ijn.s261855.
  • [18] Ahirrao M, Shrotriya S. In vitro and in vivo evaluation of cubosomal in situ nasal gel containing resveratrol for brain targeting. Drug Dev Ind Pharm. 2017;43(10):1686–1693. http://dx.doi.org/10.1080/03639045.2017.1338721.
  • [19] Sabale V, Paranjape A, Patel V. Isolation and characterization of jackfruit mucilage and its comparative evaluation as a mucoadhesive and controlled release component in buccal tablets. Int J Pharm Investig. 2012;2(2):61. http://dx.doi.org/10.4103/2230-973x.100039.
  • [20] Ranasinghe RASN, Maduwanthi SDT, Marapana RAUJ. Nutritional and health benefits of jackfruit (Artocarpus heterophylluslam.): A review. Int J Food Sci. 2019;2019:4327183. http://dx.doi.org/10.1155/2019/4327183.
  • [21] Rarokar NR, Saoji SD, Raut NA, Taksande JB, Khedekar PB, Dave VS. Nanostructured cubosomes in a thermoresponsive depot system: An alternative approach for the controlled delivery of docetaxel. AAPS PharmSciTech. 2016;17(2):436–445. http://dx.doi.org/10.1208/s12249-015-0369-y.
  • [22] Tekade A, Ghodke P, Patange A, Patil P. Nanostructured cubosomal in situ nasal gel for the treatment of migraine. J Drug Deliv Sci Technol. 2023;87(104797):104797. http://dx.doi.org/10.1016/j.jddst.2023.104797.
  • [23] Patil RP, Pawara DD, Gudewar CS, Tekade AR. Nanostructured cubosomes in an in situ nasal gel system: an alternative approach for the controlled delivery of donepezil HCl to brain. J Liposome Res. 2019;29(3):264–273. http://dx.doi.org/10.1080/08982104.2018.1552703.
  • [24] Galgatte UC, Kumbhar AB, Chaudhari PD. Development ofin situgel for nasal delivery: design, optimization,in vitro and in vivo evaluation. Drug Deliv. 2014;21(1):62–73. http://dx.doi.org/10.3109/10717544.2013.849778.
  • [25] Saudagar RB, Khandbahale SV. Formulation development and evaluation of nasal in-situ gel of fluticasone propionate. Int J Curr Pharm Res. 2017;45–54. http://dx.doi.org/10.22159/ijcpr.2017v9i5.22135.
  • [26] Mahajan H, Shaikh H, Gattani S, Nerkar P. In-situ gelling system based on thiolated gellan gum as new carrier for nasal administration of dimenhydrinate. Int J Pharm Sci Nanotechnol. 2009;2(2):544–550. http://dx.doi.org/10.37285/ijpsn.2009.2.2.8.
  • [27] Basu S, Bandyopadhyay AK. Development and characterization of mucoadhesive in situ nasal gel of midazolam prepared with Ficus carica mucilage. AAPS PharmSciTech. 2010;11(3):1223–1231. http://dx.doi.org/10.1208/s12249-010-9477-x.
  • [28] Majithiya RJ, Ghosh PK, Umrethia ML, Murthy RSR. Thermoreversible-mucoadhesive gel for nasal delivery of sumatriptan. AAPS PharmSciTech. 2006;7(3):E80–86. http://dx.doi.org/10.1208/pt070367.
  • [29] Shah BM, Misra M, Shishoo CJ, Padh H. Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization. Drug Deliv. 2015;22(7):918–930. http://dx.doi.org/10.3109/10717544.2013.878857.
  • [30] Washington N, Steele RJ, Jackson SJ, Bush D, Mason J, Gill DA, Pitt K, Rawlins DA. Determination of baseline human nasal pH and the effect of intranasally administered buffers. Int J Pharm. 2000;198(2):139-146. http://dx.doi.org/10.1016/s0378-5173(99)00442-1.
  • [31] Kakad S, Kshirsagar S. Nose to brain delivery of efavirenz nanosuspension for effective neuro AIDS therapy: In-vitro, in-vivo and pharmacokinetic assessment. Heliyon. 2021;7(11):e08368. http://dx.doi.org/10.1016/j.heliyon.2021.e08368.
  • [32] Mahajan HS, Gattani S. In situ gels of metoclopramide hydrochloride for intranasal delivery: In vitro evaluation and in vivo pharmacokinetic study in rabbits. Drug Deliv. 2010;17(1):19–27. http://dx.doi.org/10.3109/10717540903447194.

Design and assessment of in-situ nasal gel incorporated with nanostructured cubosomes for the targeted therapy of schizophrenia

Year 2025, Volume: 29 Issue: 3, 947 - 958, 04.06.2025

Avinash Tekade Mukesh Ratnaparkhi Ashutosh Shewale , Rushikesh Shinde , Gajanan Kulkarni Parth Pawar

https://doi.org/10.12991/jrespharm.1693796

Abstract

This study aimed to pioneer an innovative treatment tactic for schizophrenia by harnessing the potential of haloperidol (HPD) loaded nanostructured cubosomes infused into an in-situ nasal gel. An Artocarpus heterophyllus L. (Jackfruit) mucilage (AH mucilage) was used as a novel mucoadhesive substance in intranasal formulation. The formulation strategy included high-pressure homogenization (HPH) employing poloxamer 407 functions as a surface-active agent, serving the role of a surfactant, while polyvinyl alcohol is employed as a stabilizing agent in the formulation. The resulting HPD cubosomal structure exhibited particle size ranging from 64 to 198 nm, facilitating efficient brain delivery through the nasal route. Among the prepared batches, H7 stood out notably with a particle size (PS) of 156 ± 7.46 nm, the polydispersity index (PDI) was determined to be 0.2667, indicating the degree of heterogeneity in the particle size distribution. Simultaneously, the zeta potential (ZP) was measured at -21.71 mV, signifying the electrostatic charge on the particles in the solution. Entrapment efficiency of 78.80 ± 0.76% and drug content of 84 ± 1.00% were achieved. Transmission electron micrographs vividly illustrated the cubosomal morphology. In ex-vivo investigations conducted on sheep nasal mucosa, the cubogel formulated with AH mucilage displayed superior nasal mucoadhesion and enhanced drug permeation in comparison to Carbopol P934, a synthetic mucoadhesive agent. In conclusion, the developed HPD cubogel, incorporating mucoadhesive mucilage from Artocarphus heterophyllus L., presents a hopeful and inventive strategy for the effective management of schizophrenia.

Keywords

Schizophrenia cubosomal in-situ gel Haloperidol Artocarpus heterophyllus L. mucilage nose to brain delivery.

References

  • [1] Schizophrenia. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/schizophrenia (accessed: October 17, 2023).
  • [2] Rajendran R, Menon KN, Nair SC. Nanotechnology approaches for enhanced CNS drug delivery in the management of schizophrenia. Adv Pharm Bull. 2022;12(3):490–508. http://dx.doi.org/10.34172/apb.2022.052.
  • [3] Pires PC, Paiva-Santos AC, Veiga F. Antipsychotics-loaded nanometric emulsions for brain delivery. Pharmaceutics. 2022;14(10):2174. http://dx.doi.org/10.3390/pharmaceutics14102174.
  • [4] El-Setouhy DA, Ibrahim AB, Amin MM, Khowessah OM, Elzanfaly ES. Intranasal haloperidol-loaded miniemulsions for brain targeting: Evaluation of locomotor suppression and in-vivo biodistribution. Eur J Pharm Sci. 2016;92:244–254. http://dx.doi.org/10.1016/j.ejps.2016.05.002.
  • [5] Olivier J-C. Drug transport to the brain with targeted nanoparticles. NeuroRx. 2005;2(1):108-119. http://dx.doi.org/10.1602/neurorx.2.1.108.
  • [6] Mistry A, Stolnik S, Illum L. Nanoparticles for direct nose-to-brain delivery of drugs. Int J Pharm. 2009;379(1):146–157. http://dx.doi.org/10.1016/j.ijpharm.2009.06.019.
  • [7] Abdelrahman FE, Elsayed I, Gad MK, Badr A, Mohamed MI. Investigating the cubosomal ability for transnasal brain targeting: In vitro optimization, ex vivo permeation and in vivo biodistribution. Int J Pharm. 2015;490(1–2):281–291. http://dx.doi.org/10.1016/j.ijpharm.2015.05.064.
  • [8] Eissa EM, Elkomy MH, Eid HM, Ali AA, Abourehab MAS, Alsubaiyel AM, Naguib IA, Alsalahat I, Hassan AH. Intranasal delivery of granisetron to the brain via nanostructured cubosomes-based ın situ gel for ımproved management of chemotherapy-ınduced emesis. Pharmaceutics. 2022;14(7):1374. http://dx.doi.org/10.3390/pharmaceutics14071374.
  • [9] Illum L. Intranasal delivery to the central nervous system. Blood‐Brain Barrier in Drug Discovery. Wiley; 2015. p. 535–65. http://dx.doi.org/10.1002/9781118788523.ch25
  • [10] Elsenosy FM, Abdelbary GA, Elshafeey AH, Elsayed I, Fares AR. Brain targeting of duloxetine hcl via ıntranasal delivery of loaded cubosomal gel: In vitro characterization, ex vivo permeation, and in vivo biodistribution studies. Int J Nanomedicine. 2020;15:9517–9537. http://dx.doi.org/10.2147/ijn.s277352.
  • [11] Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, Khorasani S, Mozafari MR. Impact of particle size and polydispersity ındex on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):57. http://dx.doi.org/10.3390/pharmaceutics10020057.
  • [12] Clogston JD, Patri AK. Zeta Potential Measurement. In: Methods in Molecular Biology. Totowa, NJ: Humana Press; 2011. p. 63–70.
  • [13] Tan MSA, Parekh HS, Pandey P, Siskind DJ, Falconer JR. Nose-to-brain delivery of antipsychotics using nanotechnology: a review. Expert Opin Drug Deliv. 2020;17(6):839–853. http://dx.doi.org/10.1080/17425247.2020.1762563
  • [14] Yoo BK, Baskaran R, Madheswaran T, Sundaramoorthy P, Kim HM. Entrapment of curcumin into monoolein-based liquid crystalline nanoparticle dispersion for enhancement of stability and anticancer activity. Int J Nanomedicine. 2014;3119. http://dx.doi.org/10.2147/ijn.s61823.
  • [15] Yasir M, Sara UVS. Solid lipid nanoparticles for nose to brain delivery of haloperidol: in vitro drug release and pharmacokinetics evaluation. Acta Pharm Sin B. 2014;4(6):454–463. http://dx.doi.org/10.1016/j.apsb.2014.10.005. [16] Nasr M, Ghorab MK, Abdelazem A. In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting. Acta Pharm Sin B. 2015;5(1):79–88. http://dx.doi.org/10.1016/j.apsb.2014.12.001.
  • [17] Hosny KM. Nanosized cubosomal thermogelling dispersion loaded with saquinavir mesylate to improve its bioavailability: Preparation, optimization, in vitro and in vivo evaluation. Int J Nanomedicine. 2020;15:5113–5129. http://dx.doi.org/10.2147/ijn.s261855.
  • [18] Ahirrao M, Shrotriya S. In vitro and in vivo evaluation of cubosomal in situ nasal gel containing resveratrol for brain targeting. Drug Dev Ind Pharm. 2017;43(10):1686–1693. http://dx.doi.org/10.1080/03639045.2017.1338721.
  • [19] Sabale V, Paranjape A, Patel V. Isolation and characterization of jackfruit mucilage and its comparative evaluation as a mucoadhesive and controlled release component in buccal tablets. Int J Pharm Investig. 2012;2(2):61. http://dx.doi.org/10.4103/2230-973x.100039.
  • [20] Ranasinghe RASN, Maduwanthi SDT, Marapana RAUJ. Nutritional and health benefits of jackfruit (Artocarpus heterophylluslam.): A review. Int J Food Sci. 2019;2019:4327183. http://dx.doi.org/10.1155/2019/4327183.
  • [21] Rarokar NR, Saoji SD, Raut NA, Taksande JB, Khedekar PB, Dave VS. Nanostructured cubosomes in a thermoresponsive depot system: An alternative approach for the controlled delivery of docetaxel. AAPS PharmSciTech. 2016;17(2):436–445. http://dx.doi.org/10.1208/s12249-015-0369-y.
  • [22] Tekade A, Ghodke P, Patange A, Patil P. Nanostructured cubosomal in situ nasal gel for the treatment of migraine. J Drug Deliv Sci Technol. 2023;87(104797):104797. http://dx.doi.org/10.1016/j.jddst.2023.104797.
  • [23] Patil RP, Pawara DD, Gudewar CS, Tekade AR. Nanostructured cubosomes in an in situ nasal gel system: an alternative approach for the controlled delivery of donepezil HCl to brain. J Liposome Res. 2019;29(3):264–273. http://dx.doi.org/10.1080/08982104.2018.1552703.
  • [24] Galgatte UC, Kumbhar AB, Chaudhari PD. Development ofin situgel for nasal delivery: design, optimization,in vitro and in vivo evaluation. Drug Deliv. 2014;21(1):62–73. http://dx.doi.org/10.3109/10717544.2013.849778.
  • [25] Saudagar RB, Khandbahale SV. Formulation development and evaluation of nasal in-situ gel of fluticasone propionate. Int J Curr Pharm Res. 2017;45–54. http://dx.doi.org/10.22159/ijcpr.2017v9i5.22135.
  • [26] Mahajan H, Shaikh H, Gattani S, Nerkar P. In-situ gelling system based on thiolated gellan gum as new carrier for nasal administration of dimenhydrinate. Int J Pharm Sci Nanotechnol. 2009;2(2):544–550. http://dx.doi.org/10.37285/ijpsn.2009.2.2.8.
  • [27] Basu S, Bandyopadhyay AK. Development and characterization of mucoadhesive in situ nasal gel of midazolam prepared with Ficus carica mucilage. AAPS PharmSciTech. 2010;11(3):1223–1231. http://dx.doi.org/10.1208/s12249-010-9477-x.
  • [28] Majithiya RJ, Ghosh PK, Umrethia ML, Murthy RSR. Thermoreversible-mucoadhesive gel for nasal delivery of sumatriptan. AAPS PharmSciTech. 2006;7(3):E80–86. http://dx.doi.org/10.1208/pt070367.
  • [29] Shah BM, Misra M, Shishoo CJ, Padh H. Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization. Drug Deliv. 2015;22(7):918–930. http://dx.doi.org/10.3109/10717544.2013.878857.
  • [30] Washington N, Steele RJ, Jackson SJ, Bush D, Mason J, Gill DA, Pitt K, Rawlins DA. Determination of baseline human nasal pH and the effect of intranasally administered buffers. Int J Pharm. 2000;198(2):139-146. http://dx.doi.org/10.1016/s0378-5173(99)00442-1.
  • [31] Kakad S, Kshirsagar S. Nose to brain delivery of efavirenz nanosuspension for effective neuro AIDS therapy: In-vitro, in-vivo and pharmacokinetic assessment. Heliyon. 2021;7(11):e08368. http://dx.doi.org/10.1016/j.heliyon.2021.e08368.
  • [32] Mahajan HS, Gattani S. In situ gels of metoclopramide hydrochloride for intranasal delivery: In vitro evaluation and in vivo pharmacokinetic study in rabbits. Drug Deliv. 2010;17(1):19–27. http://dx.doi.org/10.3109/10717540903447194.
There are 31 citations in total.

Details

Primary Language English
Subjects Pharmacology and Pharmaceutical Sciences (Other)
Journal Section Articles
Authors

Avinash Tekade

Mukesh Ratnaparkhi

Ashutosh Shewale

Rushikesh Shinde

Gajanan Kulkarni

Parth Pawar

Publication Date June 4, 2025
Submission Date February 6, 2024
Acceptance Date June 19, 2024
Published in Issue Year 2025 Volume: 29 Issue: 3

Cite

APA Tekade, A., Ratnaparkhi, M., Shewale, A., Shinde, R., et al. (2025). Design and assessment of in-situ nasal gel incorporated with nanostructured cubosomes for the targeted therapy of schizophrenia. Journal of Research in Pharmacy, 29(3), 947-958. https://doi.org/10.12991/jrespharm.1693796
AMA Tekade A, Ratnaparkhi M, Shewale A, Shinde R, Kulkarni G, Pawar P. Design and assessment of in-situ nasal gel incorporated with nanostructured cubosomes for the targeted therapy of schizophrenia. J. Res. Pharm. June 2025;29(3):947-958. doi:10.12991/jrespharm.1693796
Chicago Tekade, Avinash, Mukesh Ratnaparkhi, Ashutosh Shewale, Rushikesh Shinde, Gajanan Kulkarni, and Parth Pawar. “Design and Assessment of in-Situ Nasal Gel Incorporated With Nanostructured Cubosomes for the Targeted Therapy of Schizophrenia”. Journal of Research in Pharmacy 29, no. 3 (June 2025): 947-58. https://doi.org/10.12991/jrespharm.1693796.
EndNote Tekade A, Ratnaparkhi M, Shewale A, Shinde R, Kulkarni G, Pawar P (June 1, 2025) Design and assessment of in-situ nasal gel incorporated with nanostructured cubosomes for the targeted therapy of schizophrenia. Journal of Research in Pharmacy 29 3 947–958.
IEEE A. Tekade, M. Ratnaparkhi, A. Shewale, R. Shinde, G. Kulkarni, and P. Pawar, “Design and assessment of in-situ nasal gel incorporated with nanostructured cubosomes for the targeted therapy of schizophrenia”, J. Res. Pharm., vol. 29, no. 3, pp. 947–958, 2025, doi: 10.12991/jrespharm.1693796.
ISNAD Tekade, Avinash et al. “Design and Assessment of in-Situ Nasal Gel Incorporated With Nanostructured Cubosomes for the Targeted Therapy of Schizophrenia”. Journal of Research in Pharmacy 29/3 (June 2025), 947-958. https://doi.org/10.12991/jrespharm.1693796.
JAMA Tekade A, Ratnaparkhi M, Shewale A, Shinde R, Kulkarni G, Pawar P. Design and assessment of in-situ nasal gel incorporated with nanostructured cubosomes for the targeted therapy of schizophrenia. J. Res. Pharm. 2025;29:947–958.
MLA Tekade, Avinash et al. “Design and Assessment of in-Situ Nasal Gel Incorporated With Nanostructured Cubosomes for the Targeted Therapy of Schizophrenia”. Journal of Research in Pharmacy, vol. 29, no. 3, 2025, pp. 947-58, doi:10.12991/jrespharm.1693796.
Vancouver Tekade A, Ratnaparkhi M, Shewale A, Shinde R, Kulkarni G, Pawar P. Design and assessment of in-situ nasal gel incorporated with nanostructured cubosomes for the targeted therapy of schizophrenia. J. Res. Pharm. 2025;29(3):947-58.