Optimizing the Formula of Polymeric-Based Aripiprazole Nanosuspension Using Response Surface Methodology for Intranasal Drug Delivery
Keywords:
Aripiprazole, Nanosuspension, High Shear Homogenization, Ultrasonication
Abstract
This study aimed to optimize the formula of aripiprazole nanosuspension for intranasal drug delivery. Response Surface Methodology (RSM) was employed to determine the influence of independent variables, including drug concentration, polymer concentration, and the ratio of polymer combination, on the nanosuspension characteristics. The parameters under investigation were particle size (d mean), polydispersity index, and drug content. Fifteen formulas were prepared using the high-shear homogenization–ultrasonication method, and the Design Expert software was applied for optimum formula determination. The result showed significant effects of the independent variables on the nanosuspension characteristics, with particle sizes ranging from 143.6 – 334.6 nm, PDI values of 0.302 – 0.649, and drug content was 98.7 – 102.1 %. The predicted optimum formula had a drug concentration of 28 mg/mL in the organic solvent, polymer concentration of 1.5% (w/v), and HPMC to PVP ratio of 1.4 with desirability of 0.94. Additionally, it exhibited desirable characteristics, such as a particle size of 171.2 11.4 nm, a PDI value of 0.317 0.02, and a high drug content of 100.04 0.65%. In conclusion, the presented methodology appeared to be perfect for the optimization of the aripiprazole nanosuspension formula to ensure suitability for nose-to-brain drug delivery.
References
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Dalvi, S. v., & Dave, R. N. (2009). Controlling particle size of a poorly water-soluble drug using ultrasound and stabilizers in antisolvent precipitation. Industrial and Engineering Chemistry Research, 48(16), 7581–7593. https://doi.org/10.1021/ie900248f
Eerdenbrugh, B., Stuyven, B., Froyen, L., van Humbeeck, J., Martens, J. A., Augustijns, P., & van der Mooter, G. (2009). Downscaling drug nanosuspension production: Processing aspects and physicochemical characterization. AAPS PharmSciTech, 10(1), 44–53. https://doi.org/10.1208/s12249-008-9170-5
Elmowafy, M., Shalaby, K., Al-Sanea, M. M., Hendawy, O. M., Salama, A., Ibrahim, M. F., & Ghoneim, M. M. (2021). Influence of stabilizer on the development of luteolin nanosuspension for cutaneous delivery: An in vitro and in vivo evaluation. Pharmaceutics, 13(11). https://doi.org/10.3390/pharmaceutics13111812
Gajera, B. Y., Shah, D. A., & Dave, R. H. (2019). Development of an amorphous nanosuspension by sonoprecipitation-formulation and process optimization using design of experiment methodology. International Journal of Pharmaceutics, 559, 348–359. https://doi.org/10.1016/j.ijpharm.2019.01.054
Gänger, S., & Schindowski, K. (2018). Tailoring formulations for intranasal nose-to-brain delivery: A review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa. Pharmaceutics, 10(3). https://doi.org/10.3390/pharmaceutics10030116
Hao, J., Gao, Y., Zhao, J., Zhang, J., Li, Q., Zhao, Z., & Liu, J. (2014). Preparation and Optimization of Resveratrol Nanosuspensions by Antisolvent Precipitation Using Box-Behnken Design. AAPS PharmSciTech, 16(1), 118–128. https://doi.org/10.1208/s12249-014-0211-y
Kakran, M., Sahoo, N. G., Tan, I. L., & Li, L. (2012). Preparation of nanoparticles of poorly water-soluble antioxidant curcumin by antisolvent precipitation methods. Journal of Nanoparticle Research, 14(3). https://doi.org/10.1007/s11051-012-0757-0
Kassem, M., ElMeshad, A., & Fares, A. (2017). Enhanced Solubility and Dissolution Rate of Lacidipine Nanosuspension: Formulation Via Antisolvent Sonoprecipitation Technique and Optimization Using Box–Behnken Design. AAPS PharmSciTech, 18(4), 983–996. https://doi.org/10.1208/s12249-016-0604-1
Kirschbaum, K. M., Uhr, M., Holthoewer, D., Namendorf, C., Pietrzik, C., Hiemke, C., & Schmitt, U. (2010). Pharmacokinetics of acute and sub-chronic aripiprazole in P-glycoprotein deficient mice. Neuropharmacology, 59(6), 474–479. https://doi.org/10.1016/j.neuropharm.2010.06.010
Kocbek, P., Baumgartner, S., & Kristl, J. (2006). Preparation and evaluation of nanosuspensions for enhancing the dissolution of poorly soluble drugs. International Journal of Pharmaceutics, 312(1–2), 179–186. https://doi.org/10.1016/j.ijpharm.2006.01.008
Koczkur, K. M., Mourdikoudis, S., Polavarapu, L., & Skrabalak, S. E. (2015). Polyvinylpyrrolidone (PVP) in nanoparticle synthesis. Dalton Transactions, 44(41), 17883–17905. https://doi.org/10.1039/c5dt02964c
Kumbhar, S., Kokare, C., Shrivastava, B., & Choudhury, H. (2020). Specific and Sensitive RP-HPLC Method Development and Validation for the Determination of Aripiprazole: Application in Preformulation Screening of Nanoemulsion. Current Nanomedicine, 10(1), 76–86. https://doi.org/10.2174/2468187309666190823155215
Lindfors, L., Forssén, S., Skantze, P., Skantze, U., Zackrisson, A., & Olsson, U. (2006). Amorphous drug nanosuspensions. 2. Experimental determination of bulk monomer concentrations. Langmuir, 22(3), 911–916. https://doi.org/10.1021/la052367t
Mallick, A., Gupta, A., Hussain, A., Aparajay, P., Singh, S., Singh, S. K., & Dev, A. (2020). Intranasal delivery of gabapentin loaded optimized nanoemulsion for augmented permeation. Journal of Drug Delivery Science and Technology, 56(February), 101606. https://doi.org/10.1016/j.jddst.2020.101606
Morrison, E. E., & Costanzo, R. M. (1992). Morphology of olfactory epithelium in humans and other vertebrates. Microscopy Research and Technique, 23(1), 49–61. https://doi.org/10.1002/jemt.1070230105
Patel, H. P., Chaudhari, P. S., Gandhi, P. A., Desai, B. V., Desai, D. T., Dedhiya, P. P., Vyas, B. A., & Maulvi, F. A. (2021). Nose to brain delivery of tailored clozapine nanosuspension stabilized using (+)-alpha-tocopherol polyethylene glycol 1000 succinate: Optimization and in vivo pharmacokinetic studies. International Journal of Pharmaceutics, 600(March), 120474. https://doi.org/10.1016/j.ijpharm.2021.120474
Sawant, K., Pandey, A., & Patel, S. (2016). Aripiprazole loaded poly(caprolactone) nanoparticles: Optimization and in vivo pharmacokinetics. Materials Science and Engineering C, 66, 230–243. https://doi.org/10.1016/j.msec.2016.04.089
Sinha, B., Müller, R. H., & Möschwitzer, J. P. (2013). Bottom-up approaches for preparing drug nanocrystals: Formulations and factors affecting particle size. International Journal of Pharmaceutics, 453(1), 126–141. https://doi.org/10.1016/j.ijpharm.2013.01.019
Sole, I. (2013). Encyclopedia of Colloid and Interface Science. In Encyclopedia of Colloid and Interface Science. https://doi.org/10.1007/978-3-642-20665-8
Ubgade, S., Bapat, A., & Kilor, V. (2021). Effect of various stabilizers on the stability of lansoprazole nanosuspension prepared using high shear homogenization: Preliminary investigation. Journal of Applied Pharmaceutical Science, 11(9), 085–092. https://doi.org/10.7324/JAPS.2021.110910
Wang, J. S., Zhu, H. J., Donovan, J. L., Yuan, H. J., Markowitz, J. S., Geesey, M. E., & DeVane, C. L. (2009). Aripiprazole brain concentration is altered in P-glycoprotein deficient mice. Schizophrenia Research, 110(1–3), 90–94. https://doi.org/10.1016/j.schres.2009.01.011
Xia, D., Quan, P., Piao, H., Piao, H., Sun, S., Yin, Y., & Cui, F. (2010). Preparation of stable nitrendipine nanosuspensions using the precipitation-ultrasonication method for enhancement of dissolution and oral bioavailability. European Journal of Pharmaceutical Sciences, 40(4), 325–334. https://doi.org/10.1016/j.ejps.2010.04.006
Zhang, H. X., Wang, J. X., Zhang, Z. B., Le, Y., Shen, Z. G., & Chen, J. F. (2009). Micronization of atorvastatin calcium by antisolvent precipitation process. International Journal of Pharmaceutics, 374(1–2), 106–113. https://doi.org/10.1016/j.ijpharm.2009.02.015
Ahmed, S., Govender, T., Khan, I., ur Rehman, N., Ali, W., Shah, S. M. H., Khan, S., Hussain, Z., Ullah, R., & Alsaid, M. S. (2018). Experimental and molecular modeling approach to optimize suitable polymers for fabrication of stable fluticasone nanoparticles with enhanced dissolution and antimicrobial activity. Drug Design, Development and Therapy, 12, 255–269. https://doi.org/10.2147/DDDT.S148912
Anggraini, R., Surini, S., & Saputri, F. C. (2021). Formulation and characterization of bitter melon (Momordica charantia Linn.) fruit fraction loaded solid lipid nanoparticles. Pharmacognosy Journal, 13(6), 1347–1354. https://doi.org/10.5530/PJ.2021.13.170
Aydar, A. Y. (2018). Utilization of Response Surface Methodology in Optimization of Extraction of Plant Materials. In Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes (Vol. 32, pp. 137–144). InTech. https://doi.org/10.5772/intechopen.73690
Brittain, H. G. (2013). Profiles of Drug Substances, Excipients, and Related Methodology Vol 38 (A. A. Al-Badr, Y. Goldberg, G. Indrayanto, & K. Florey, Eds.; First Edit). Elsevier Academic Press.
Costa, C. P., Moreira, J. N., Sousa Lobo, J. M., & Silva, A. C. (2021). Intranasal delivery of nanostructured lipid carriers, solid lipid nanoparticles and nanoemulsions: A current overview of in vivo studies. Acta Pharmaceutica Sinica B, 11(4), 925–940. https://doi.org/10.1016/j.apsb.2021.02.012
Dalvi, S. v., & Dave, R. N. (2009). Controlling particle size of a poorly water-soluble drug using ultrasound and stabilizers in antisolvent precipitation. Industrial and Engineering Chemistry Research, 48(16), 7581–7593. https://doi.org/10.1021/ie900248f
Eerdenbrugh, B., Stuyven, B., Froyen, L., van Humbeeck, J., Martens, J. A., Augustijns, P., & van der Mooter, G. (2009). Downscaling drug nanosuspension production: Processing aspects and physicochemical characterization. AAPS PharmSciTech, 10(1), 44–53. https://doi.org/10.1208/s12249-008-9170-5
Elmowafy, M., Shalaby, K., Al-Sanea, M. M., Hendawy, O. M., Salama, A., Ibrahim, M. F., & Ghoneim, M. M. (2021). Influence of stabilizer on the development of luteolin nanosuspension for cutaneous delivery: An in vitro and in vivo evaluation. Pharmaceutics, 13(11). https://doi.org/10.3390/pharmaceutics13111812
Gajera, B. Y., Shah, D. A., & Dave, R. H. (2019). Development of an amorphous nanosuspension by sonoprecipitation-formulation and process optimization using design of experiment methodology. International Journal of Pharmaceutics, 559, 348–359. https://doi.org/10.1016/j.ijpharm.2019.01.054
Gänger, S., & Schindowski, K. (2018). Tailoring formulations for intranasal nose-to-brain delivery: A review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa. Pharmaceutics, 10(3). https://doi.org/10.3390/pharmaceutics10030116
Hao, J., Gao, Y., Zhao, J., Zhang, J., Li, Q., Zhao, Z., & Liu, J. (2014). Preparation and Optimization of Resveratrol Nanosuspensions by Antisolvent Precipitation Using Box-Behnken Design. AAPS PharmSciTech, 16(1), 118–128. https://doi.org/10.1208/s12249-014-0211-y
Kakran, M., Sahoo, N. G., Tan, I. L., & Li, L. (2012). Preparation of nanoparticles of poorly water-soluble antioxidant curcumin by antisolvent precipitation methods. Journal of Nanoparticle Research, 14(3). https://doi.org/10.1007/s11051-012-0757-0
Kassem, M., ElMeshad, A., & Fares, A. (2017). Enhanced Solubility and Dissolution Rate of Lacidipine Nanosuspension: Formulation Via Antisolvent Sonoprecipitation Technique and Optimization Using Box–Behnken Design. AAPS PharmSciTech, 18(4), 983–996. https://doi.org/10.1208/s12249-016-0604-1
Kirschbaum, K. M., Uhr, M., Holthoewer, D., Namendorf, C., Pietrzik, C., Hiemke, C., & Schmitt, U. (2010). Pharmacokinetics of acute and sub-chronic aripiprazole in P-glycoprotein deficient mice. Neuropharmacology, 59(6), 474–479. https://doi.org/10.1016/j.neuropharm.2010.06.010
Kocbek, P., Baumgartner, S., & Kristl, J. (2006). Preparation and evaluation of nanosuspensions for enhancing the dissolution of poorly soluble drugs. International Journal of Pharmaceutics, 312(1–2), 179–186. https://doi.org/10.1016/j.ijpharm.2006.01.008
Koczkur, K. M., Mourdikoudis, S., Polavarapu, L., & Skrabalak, S. E. (2015). Polyvinylpyrrolidone (PVP) in nanoparticle synthesis. Dalton Transactions, 44(41), 17883–17905. https://doi.org/10.1039/c5dt02964c
Kumbhar, S., Kokare, C., Shrivastava, B., & Choudhury, H. (2020). Specific and Sensitive RP-HPLC Method Development and Validation for the Determination of Aripiprazole: Application in Preformulation Screening of Nanoemulsion. Current Nanomedicine, 10(1), 76–86. https://doi.org/10.2174/2468187309666190823155215
Lindfors, L., Forssén, S., Skantze, P., Skantze, U., Zackrisson, A., & Olsson, U. (2006). Amorphous drug nanosuspensions. 2. Experimental determination of bulk monomer concentrations. Langmuir, 22(3), 911–916. https://doi.org/10.1021/la052367t
Mallick, A., Gupta, A., Hussain, A., Aparajay, P., Singh, S., Singh, S. K., & Dev, A. (2020). Intranasal delivery of gabapentin loaded optimized nanoemulsion for augmented permeation. Journal of Drug Delivery Science and Technology, 56(February), 101606. https://doi.org/10.1016/j.jddst.2020.101606
Morrison, E. E., & Costanzo, R. M. (1992). Morphology of olfactory epithelium in humans and other vertebrates. Microscopy Research and Technique, 23(1), 49–61. https://doi.org/10.1002/jemt.1070230105
Patel, H. P., Chaudhari, P. S., Gandhi, P. A., Desai, B. V., Desai, D. T., Dedhiya, P. P., Vyas, B. A., & Maulvi, F. A. (2021). Nose to brain delivery of tailored clozapine nanosuspension stabilized using (+)-alpha-tocopherol polyethylene glycol 1000 succinate: Optimization and in vivo pharmacokinetic studies. International Journal of Pharmaceutics, 600(March), 120474. https://doi.org/10.1016/j.ijpharm.2021.120474
Sawant, K., Pandey, A., & Patel, S. (2016). Aripiprazole loaded poly(caprolactone) nanoparticles: Optimization and in vivo pharmacokinetics. Materials Science and Engineering C, 66, 230–243. https://doi.org/10.1016/j.msec.2016.04.089
Sinha, B., Müller, R. H., & Möschwitzer, J. P. (2013). Bottom-up approaches for preparing drug nanocrystals: Formulations and factors affecting particle size. International Journal of Pharmaceutics, 453(1), 126–141. https://doi.org/10.1016/j.ijpharm.2013.01.019
Sole, I. (2013). Encyclopedia of Colloid and Interface Science. In Encyclopedia of Colloid and Interface Science. https://doi.org/10.1007/978-3-642-20665-8
Ubgade, S., Bapat, A., & Kilor, V. (2021). Effect of various stabilizers on the stability of lansoprazole nanosuspension prepared using high shear homogenization: Preliminary investigation. Journal of Applied Pharmaceutical Science, 11(9), 085–092. https://doi.org/10.7324/JAPS.2021.110910
Wang, J. S., Zhu, H. J., Donovan, J. L., Yuan, H. J., Markowitz, J. S., Geesey, M. E., & DeVane, C. L. (2009). Aripiprazole brain concentration is altered in P-glycoprotein deficient mice. Schizophrenia Research, 110(1–3), 90–94. https://doi.org/10.1016/j.schres.2009.01.011
Xia, D., Quan, P., Piao, H., Piao, H., Sun, S., Yin, Y., & Cui, F. (2010). Preparation of stable nitrendipine nanosuspensions using the precipitation-ultrasonication method for enhancement of dissolution and oral bioavailability. European Journal of Pharmaceutical Sciences, 40(4), 325–334. https://doi.org/10.1016/j.ejps.2010.04.006
Zhang, H. X., Wang, J. X., Zhang, Z. B., Le, Y., Shen, Z. G., & Chen, J. F. (2009). Micronization of atorvastatin calcium by antisolvent precipitation process. International Journal of Pharmaceutics, 374(1–2), 106–113. https://doi.org/10.1016/j.ijpharm.2009.02.015
Published
2024-09-25
How to Cite
Aisiah, N. F., & Surini, S. (2024). Optimizing the Formula of Polymeric-Based Aripiprazole Nanosuspension Using Response Surface Methodology for Intranasal Drug Delivery. Indonesian Journal of Pharmacy, 35(3), 501–511. https://doi.org/10.22146/ijp.9104
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Research Article
