Generic placeholder image

Drug Delivery Letters


ISSN (Print): 2210-3031
ISSN (Online): 2210-304X

Research Article

D-Optimal Mixture Design Enabled Development of Lyophilized Nanoemulsifying Drug Delivery System of Paliperidone

Author(s): Prativa Das*, Jyanaranjan Panda, Kahnu Charan Panigrahi, Chinam Niranjan Patra and Goutam Kumar Jena

Volume 14, Issue 2, 2024

Published on: 24 January, 2024

Page: [165 - 178] Pages: 14

DOI: 10.2174/0122103031273803231221070539

Price: $65


Background: Schizophrenia is a chronic disease with acute psychotic symptoms, which is having frequent recurrence. Paliperidone palmitate (PP) is a second-generation antipsychotic drug to treat schizophrenia.

Aims: The aim of the study was to prepare lyophilized nanoemulsifying drug delivery system (NEDDS) of paliperidone (PD).

Objectives: The primary objective of the current research work was to develop a lyophilized nanoemulsifying drug delivery system (NEDDS) of paliperidone (PD) to improve its oral bioavailability and stability.

Methods: Optimization using D-Optimal Mixture Design DMD) was conducted, and optimized NEDDS was further lyophilized to improve stability. The lyophilized optimized NEDDS was further evaluated for biopharmaceutical evaluation.

Results: A saturation solubility study revealed Peceol, Tween 80, and Plurol Olique CC497 as suitable candidates for oil, surfactant, and co-surfactant, respectively. Optimized NEDDS of PD showed mean globule size (MGS) of 185 nm, PDI of 0.27 and cumulative % drug release within 15 min Q15 of 86.6%. Lyophilized optimized NEDDS was found to have no significant change in quality attributes within the stability study period. A pharmacokinetic study revealed more than two-fold increases in bioavailability for lyophilized optimized NEDDS.

Conclusion: Hence, lyophilized NEDDS of PD can be used as an effective approach for the improvement of oral bioavailability and stability.

Keywords: NEDDS, mean globule size, bioavailability, stability study, lyophilized, paliperidone.

« Previous
Graphical Abstract
Robinson, D.; Woerner, M.G. Jose, Alvir, MJ; Bilder, R; Goldman, R Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch. Gen. Psychiatry, 1999, 56(3), 241-247.
Jarema, M.; Bieńkowski, P.; Heitzman, J.; Parnowski, T.; Rybakowski, J. Paliperidone palmitate: Effectiveness, safety, and the use for treatment of schizophrenia. Psychiatr. Pol., 2017, 51(1), 7-21.
[] [PMID: 28455891]
Mauri, M.C.; Reggiori, A.; Paletta, S.; Di Pace, C.; Altamura, A.C. Paliperidone for the treatment of schizophrenia and schizoaffective disorders - a drug safety evaluation. Expert Opin. Drug Saf., 2017, 16(3), 365-379.
[] [PMID: 28140680]
Kanuganti, S.; Jukanti, R.; Veerareddy, P.R.; Bandari, S. Paliperidone-loaded self-emulsifying drug delivery systems (SEDDS) for improved oral delivery. J. Dispers. Sci. Technol., 2012, 33(4), 506-515.
Jaiswal, M; Dudhe, R; Sharma, PK Nanoemulsion: An advanced mode of drug delivery system. 3 Biotech, 2015, 5, 123-127.
Fofaria, N.M.; Qhattal, H.S.S.; Liu, X.; Srivastava, S.K. Nanoemulsion formulations for anti-cancer agent piplartine—Characterization, toxicological, pharmacokinetics and efficacy studies. Int. J. Pharm., 2016, 498(1-2), 12-22.
[] [PMID: 26642946]
Panigrahi, K.C.; Patra, C.N.; Rao, M.E.B.; Jena, G.K.; Sahoo, L. SEDDS basic design and recent formulation advancement: A concurrent review. Pharm. Nanotechnol., 2022, 10(4), 289-298.
[] [PMID: 35980062]
Tripathi, C.B.; Beg, S.; Kaur, R.; Shukla, G.; Bandopadhyay, S.; Singh, B. Systematic development of optimized SNEDDS of artemether with improved biopharmaceutical and antimalarial potential. Drug Deliv., 2016, 23(9), 3209-3223.
[] [PMID: 27022886]
Sindi, A.M.; Hosny, K.M.; Alharbi, W.S. Lyophilized composite loaded with meloxicam-peppermint oil nanoemulsion for periodontal pain. Polymers, 2021, 13(14), 2317.
[] [PMID: 34301073]
Van Buskirk, G.A.; Asotra, S.; Balducci, C.; Basu, P.; DiDonato, G.; Dorantes, A.; Eickhoff, W.M.; Ghosh, T.; González, M.A.; Henry, T.; Howard, M.; Kamm, J.; Laurenz, S.; MacKenzie, R.; Mannion, R.; Noonan, P.K.; Ocheltree, T.; Pai, U.; Poska, R.P.; Putnam, M.L.; Raghavan, R.R.; Ruegger, C.; Sánchez, E.; Shah, V.P.; Shao, Z.J.; Somma, R.; Tammara, V.; Thombre, A.G.; Thompson, B.; Timko, R.J.; Upadrashta, S.; Vaithiyalingam, S. Best practices for the development, scale-up, and post-approval change control of IR and MR dosage forms in the current quality-by-design paradigm. AAPS PharmSciTech, 2014, 15(3), 665-693.
[] [PMID: 24578237]
Schlindwein, WS; Gibson, M Pharmaceutical quality by design: A practical approach. Pharm. Med. Chem., 2017.
Ahmed, S.; Gull, A.; Alam, M.; Aqil, M.; Sultana, Y. Ultrasonically tailored, chemically engineered and “QbD” enabled fabrication of agomelatine nanoemulsion; Optimization, characterization, ex-vivo permeation and stability study. Ultrason. Sonochem., 2018, 41, 213-226.
[] [PMID: 29137746]
Herneisey, M.; Lambert, E.; Kachel, A.; Shychuck, E.; Drennen, J.K., III; Janjic, J.M. Quality by design approach using multiple linear and logistic regression modeling enables microemulsion scale up. Molecules, 2019, 24(11), 2066.
[] [PMID: 31151246]
Panigrahi, K.C.; Jena, J.; Jena, G.K.; Patra, C.N.; Rao, M.E.B. QBD-based systematic development of Bosentan SNEDDS: Formulation, characterization and pharmacokinetic assessment. J. Drug Deliv. Sci. Technol., 2018, 47, 31-42.
Ombredane, A.S.; Araujo, V.H.S.; Borges, C.O.; Costa, P.L.; Landim, M.G.; Pinheiro, A.C.; Szlachetka, Í.O.; Benedito, L.E.C.; Espindola, L.S.; Dias, D.J.S.; Oliveira, D.M.; Chaker, J.A.; da Silva, S.W.; de Azevedo, R.B.; Joanitti, G.A. Nanoemulsion-based systems as a promising approach for enhancing the antitumoral activity of pequi oil (Caryocar brasilense Cambess.) in breast cancer cells. J. Drug Deliv. Sci. Technol., 2020, 58, 101819.
Kassem, A.A.; Salama, A.; Mohsen, A.M. Formulation and optimization of cationic nanoemulsions for enhanced ocular delivery of dorzolamide hydrochloride using Box-Behnken design: In vitro and in vivo assessments. J. Drug Deliv. Sci. Technol., 2022, 68, 103047.
Jyotshna; Chand Gupta, A.; Bawankule, D.U.; Verma, A.K.; Shanker, K. Nanoemulsion preconcentrate of a pentacyclic triterpene for improved oral efficacy: Formulation design and in-vivo antimalarial activity. J. Drug Deliv. Sci. Technol., 2020, 57, 101734.
Chudasama, A.; Patel, V.; Nivsarkar, M.; Vasu, K.; Shishoo, C. Role of lipid-based excipients and their composition on the bioavailability of antiretroviral self-emulsifying formulations. Drug Deliv., 2015, 22(4), 531-540.
[] [PMID: 24601856]
Kassem, A.A.; Mohsen, A.M.; Ahmed, R.S.; Essam, T.M. Self-nanoemulsifying drug delivery system (SNEDDS) with enhanced solubilization of nystatin for treatment of oral candidiasis: Design, optimization, in vitro and in vivo evaluation. J. Mol. Liq., 2016, 218, 219-232.
Tarik Alhamdany, A.; Saeed, A.M.H.; Alaayedi, M. Nanoemulsion and solid nanoemulsion for improving oral delivery of a breast cancer drug: Formulation, evaluation, and a comparison study. Saudi Pharm. J., 2021, 29(11), 1278-1288.
[] [PMID: 34819790]
Groo, A.C.; Hedir, S.; Since, M.; Brotin, E.; Weiswald, L.B.; Paysant, H.; Nee, G.; Coolzaet, M.; Goux, D.; Delépée, R.; Freret, T.; Poulain, L.; Voisin-Chiret, A.S.; Malzert-Fréon, A. Pyridoclax-loaded nanoemulsion for enhanced anticancer effect on ovarian cancer. Int. J. Pharm., 2020, 587, 119655.
[] [PMID: 32712252]
Sharma, T.; Jain, A.; Kaur, R.; Saini, S.; Katare, OP.; Singh, B. Supersaturated LFCS type III self-emulsifying delivery systems of sorafenib tosylate with improved biopharmaceutical performance: QbD-enabled development and evaluation. Drug Deliv. Transl. Res., 2020, 10, 839-861.
Perez-Roman, I.; Kiekens, F.; Cordoba-Diaz, D.; Garcia-Rodriguez, J.J.; Cordoba-Diaz, M. Development of a solid formulation containing a microemulsion of a novel artemisia extract with nematocidal activity for oral administration. Pharmaceutics, 2020, 12(9), 873.
[] [PMID: 32937773]
Verma, R.; Kaushik, A.; Almeer, R.; Rahman, M.H.; Abdel-Daim, M.M.; Kaushik, D. Improved pharmacodynamic potential of rosuvastatin by self-nanoemulsifying drug delivery system: An in vitro and in vivo evaluation. Int. J. Nanomedicine, 2021, 16, 905-924.
[] [PMID: 33603359]
Xue, X.; Cao, M.; Ren, L.; Qian, Y.; Chen, G. Preparation and optimization of rivaroxaban by self-nanoemulsifying drug delivery system (SNEDDS) for enhanced oral bioavailability and no food effect. AAPS PharmSciTech, 2018, 19(4), 1847-1859.
[] [PMID: 29637496]
AboulFotouh. K.; Allam, A.A.; El-Badry, M.; El-Sayed, A.M. Development and in vitro/in vivo performance of self-nanoemulsifying drug delivery systems loaded with candesartan cilexetil. Eur. J. Pharm. Sci., 2017, 109, 503-513.
[] [PMID: 28889028]
Park, S.J.; Choo, G.H.; Hwang, S.J.; Kim, M.S. Quality by design: Screening of critical variables and formulation optimization of Eudragit E nanoparticles containing dutasteride. Arch. Pharm. Res., 2013, 36(5), 593-601.
[] [PMID: 23446651]
Yasir, M.; Sara, U.V.S.; Chauhan, I.; Gaur, P.K.; Singh, A.P.; Puri, D. Ameeduzzafar, Solid lipid nanoparticles for nose to brain delivery of donepezil: formulation, optimization by Box–Behnken design, in vitro and in vivo evaluation. Artif. Cells Nanomed. Biotechnol., 2017, 46, 1-14.
Gurumukhi, V.C.; Bari, S.B. Development of ritonavir-loaded nanostructured lipid carriers employing quality by design (QbD) as a tool: characterizations, permeability, and bioavailability studies. Drug Deliv. Transl. Res., 2021, 2021, 1-21.
[] [PMID: 34671949]
Arsiccio, A.; Pisano, R. Application of the quality by design approach to the freezing step of freeze-drying: Building the design space. J. Pharm. Sci., 2018, 107(6), 1586-1596.
[] [PMID: 29432761]
Routray, S.B.; Patra, C.N.; Raju, R.; Panigrahi, K.C.; Jena, G.K. Lyophilized SLN of cinnacalcet HCl: BBD enabled optimization, characterization and pharmacokinetic study. Drug Dev. Ind. Pharm., 2020, 46(7), 1080-1091.
[] [PMID: 32486863]
Jena, G.K.; Patra, C.N.; Panigrahi, K.C.; Sruti, J.; Patra, P.; Parhi, R. QbD enabled optimization of solvent shifting method for fabrication of PLGA-based nanoparticles for promising delivery of Capecitabine for antitumor activity. Drug Deliv. Transl. Res., 2021.
[] [PMID: 34505271]
Bonde, G.V.; Ajmal, G.; Yadav, S.K.; Mittal, P.; Singh, J.; Bakde, B.V.; Mishra, B. Assessing the viability of Soluplus® self-assembled nanocolloids for sustained delivery of highly hydrophobic lapatinib (anticancer agent): Optimisation and in-vitro characterisation. Colloids Surf. B Biointerfaces, 2020, 185, 110611.
[] [PMID: 31704609]
Quality Guidelines ICH n.d., Available from: (accessed December 26, 2018).
Buya, A.B.; Ucakar, B.; Beloqui, A.; Memvanga, P.B.; Préat, V. Design and evaluation of self-nanoemulsifying drug delivery systems (SNEDDSs) for senicapoc. Int. J. Pharm., 2020, 580, 119180.
[] [PMID: 32135227]
Tung, N.T.; Tran, C.S.; Nguyen, H.A.; Nguyen, T.D.; Chi, S.C.; Pham, D.V.; Bui, Q.D.; Ho, X.H. Formulation and biopharmaceutical evaluation of supersaturatable self-nanoemulsifying drug delivery systems containing silymarin. Int. J. Pharm., 2019, 555, 63-76.
[] [PMID: 30448315]
Zhang, N.; Zhang, F.; Xu, S.; Yun, K.; Wu, W.; Pan, W. Formulation and evaluation of luteolin supersaturatable self-nanoemulsifying drug delivery system (S-SNEDDS) for enhanced oral bioavailability. J. Drug Deliv. Sci. Technol., 2020, 58, 101783.
Panigrahi, K.C.; Patra, C.N.; Rao, M.E.B. Quality by design enabled development of oral self-nanoemulsifying drug delivery system of a novel calcimimetic cinacalcet HCl using a porous carrier: In vitro and in vivo characterisation. In: AAPS PharmSciTech; , 2019; p. 20.
Tartaro, G.; Mateos, H.; Schirone, D.; Angelico, R.; Palazzo, G. Microemulsion microstructure(s): A tutorial review. Nanomaterials, 2020, 10(9), 1657.
[] [PMID: 32846957]
Azeem, A.; Rizwan, M.; Ahmad, F.J.; Iqbal, Z.; Khar, R.K.; Aqil, M.; Talegaonkar, S. Nanoemulsion components screening and selection: A technical note. AAPS PharmSciTech, 2009, 10(1), 69-76.
[] [PMID: 19148761]
Qin, X.; Zhou, Y.; Wang, Y.; Wang, Z.; Wang, Y.; Chen, J.; Zhu, L.; Quan, X.; Liu, Z.; Zhang, H.; Jiang, L.; Dong, H.; Zhang, Z. Preparation and characterization of protein-loaded PFC nanoemulsions for the treatment of heart diseases by pulmonary administration. Eur. J. Pharm. Sci., 2021, 158, 105690.
[] [PMID: 33359617]
Mirković, D.; Ibrić, S.; Balanč, B.; Knez, Ž.; Bugarski, B. Evaluation of the impact of critical quality attributes and critical process parameters on quality and stability of parenteral nutrition nanoemulsions. J. Drug Deliv. Sci. Technol., 2017, 39, 341-347.
Patra, C.N.; Mishra, A.; Jena, G.K.; Panigrahi, K.C.; Sruti, J.; Ghose, D.; Sahoo, L. QbD enabled formulation development of nanoemulsion of nimodipine for improved biopharmaceutical performance. J. Pharm. Innov., 2023.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy