Injectable In-Situ Forming Depot Based on PLGA and PLGA-PEG-PLGA for Sustained-Release of Risperidone: In Vitro Evaluation and Pharmacokinetics in Rabbits

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2023 Apr 28

PMID 37111714

Authors

Seyedeh Nesa Rezaeian Shiadeh

Farzin Hadizadeh

Elham Khodaverdi

Mahmoud Gorji Valokola

Saleh Rakhshani

Hossein Kamali

Ali Nokhodchi

Affiliations

Soon will be listed here.

Abstract

In the current research, novel drug delivery systems based on in situ forming gel (ISFG) (PLGA-PEG-PLGA) and in situ forming implant (ISFI) (PLGA) were developed for one-month risperidone delivery. In vitro release evaluation, pharmacokinetics, and histopathology studies of ISFI, ISFG, and Risperdal CONSTA were compared in rabbits. Formulation containing 50% (/ %) of PLGA-PEG-PLGA triblock revealed sustained release for about one month. Scanning electron microscopy (SEM) showed a porous structure for ISFI, while a structure with fewer pores was observed in the triblock. Cell viability in ISFG formulation in the first days was more than ISFI due to the gradual release of NMP to the release medium. Pharmacokinetic data displayed that optimal PLGA-PEG-PLGA creates a consistent serum level in vitro and in vivo through 30 days, and histopathology results revealed nearly slight to moderate pathological signs in the rabbit's organs. The shelf life of the accelerated stability test didn't affect the results of the release rate test and demonstrated stability in 24 months. This research confirms the better potential of the ISFG system compared with ISFI and Risperdal CONSTA, which would increase patients' compliance and avoid problems of further oral therapy.

Citing Articles

Forming, Enzyme-Responsive Peptoid-Peptide Hydrogels: An Advanced Long-Acting Injectable Drug Delivery System.

Coulter S, Pentlavalli S, An Y, Vora L, Cross E, Moore J J Am Chem Soc. 2024; 146(31):21401-21416.

PMID: 38922296 PMC: 11311241. DOI: 10.1021/jacs.4c03751.

Sustained Inhibition of VEGF and TNF-α Achieves Multi-Ocular Protection and Prevents Formation of Blood Vessels after Severe Ocular Trauma.

Zhou C, Lei F, Sharma J, Hui P, Wolkow N, Dohlman C Pharmaceutics. 2023; 15(8).

PMID: 37631272 PMC: 10458495. DOI: 10.3390/pharmaceutics15082059.

References

Nuntamool N, Ngamsamut N, Vanwong N, Puangpetch A, Chamnanphon M, Hongkaew Y . Pharmacogenomics and Efficacy of Risperidone Long-Term Treatment in Thai Autistic Children and Adolescents. Basic Clin Pharmacol Toxicol. 2017; 121(4):316-324. DOI: 10.1111/bcpt.12803. View

Wang L, Wang A, Zhao X, Liu X, Wang D, Sun F . Design of a long-term antipsychotic in situ forming implant and its release control method and mechanism. Int J Pharm. 2012; 427(2):284-92. DOI: 10.1016/j.ijpharm.2012.02.015. View

Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C . DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J. 2010; 12(3):263-71. PMC: 2895453. DOI: 10.1208/s12248-010-9185-1. View

Huang M, ShenTu J, Chen J, Liu J, Zhou H . Determination of risperidone in human plasma by HPLC-MS/MS and its application to a pharmacokinetic study in Chinese volunteers. J Zhejiang Univ Sci B. 2008; 9(2):114-20. PMC: 2225493. DOI: 10.1631/jzus.B0710439. View

Eroglu I, Gultekinoglu M, Bayram C, Erikci A, Yabanoglu Ciftci S, Aksoy E . Gel network comprising UV crosslinked PLGA-b-PEG-MA nanoparticles for ibuprofen topical delivery. Pharm Dev Technol. 2019; 24(9):1144-1154. DOI: 10.1080/10837450.2019.1643880. View

Hulse G, Stalenberg V, McCallum D, Smit W, ONeil G, Morris N . Histological changes over time around the site of sustained release naltrexone-poly(DL-lactide) implants in humans. J Control Release. 2005; 108(1):43-55. DOI: 10.1016/j.jconrel.2005.08.001. View

Rezaeian Shiadeh S, Khodaverdi E, Faal Maleki M, Eisvand F, Boujaran H, Zarei H . Lipid-liquid crystals for 2 months controlled risperidone release: In-vitro evaluation and pharmacokinetics in rabbits. Int J Pharm. 2022; 618:121649. DOI: 10.1016/j.ijpharm.2022.121649. View

Vesna Milacic V, Schwendeman S . Lysozyme release and polymer erosion behavior of injectable implants prepared from PLGA-PEG block copolymers and PLGA/PLGA-PEG blends. Pharm Res. 2013; 31(2):436-48. PMC: 3930621. DOI: 10.1007/s11095-013-1173-6. View

Qiao M, Chen D, Ma X, Liu Y . Injectable biodegradable temperature-responsive PLGA-PEG-PLGA copolymers: synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels. Int J Pharm. 2005; 294(1-2):103-12. DOI: 10.1016/j.ijpharm.2005.01.017. View

10.

Fischer D, Li Y, Ahlemeyer B, Krieglstein J, Kissel T . In vitro cytotoxicity testing of polycations: influence of polymer structure on cell viability and hemolysis. Biomaterials. 2003; 24(7):1121-31. DOI: 10.1016/s0142-9612(02)00445-3. View

11.

Ruel-Gariepy E, Leroux J . In situ-forming hydrogels--review of temperature-sensitive systems. Eur J Pharm Biopharm. 2004; 58(2):409-26. DOI: 10.1016/j.ejpb.2004.03.019. View

12.

Liu Q, Zhang H, Zhou G, Xie S, Zou H, Yu Y . In vitro and in vivo study of thymosin alpha1 biodegradable in situ forming poly(lactide-co-glycolide) implants. Int J Pharm. 2010; 397(1-2):122-9. DOI: 10.1016/j.ijpharm.2010.07.015. View

13.

Mohamadnia Z, Zohuriaan-Mehr M, Kabiri K, Jamshidi A, Mobedi H . Ionically cross-linked carrageenan-alginate hydrogel beads. J Biomater Sci Polym Ed. 2008; 19(1):47-59. DOI: 10.1163/156856208783227640. View

14.

Ma H, He C, Cheng Y, Li D, Gong Y, Liu J . PLK1shRNA and doxorubicin co-loaded thermosensitive PLGA-PEG-PLGA hydrogels for osteosarcoma treatment. Biomaterials. 2014; 35(30):8723-34. DOI: 10.1016/j.biomaterials.2014.06.045. View

15.

Kloosterboer S, de Winter B, Reichart C, Kouijzer M, de Kroon M, van Daalen E . Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder. Br J Clin Pharmacol. 2020; 87(3):1069-1081. PMC: 9328651. DOI: 10.1111/bcp.14465. View

16.

Qiao M, Chen D, Ma X, Hu H . Sustained release of bee venom peptide from biodegradable thermosensitive PLGA-PEG-PLGA triblock copolymer-based hydrogels in vitro. Pharmazie. 2006; 61(3):199-202. View

17.

Zhang Y, Huo M, Zhou J, Xie S . PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed. 2010; 99(3):306-14. DOI: 10.1016/j.cmpb.2010.01.007. View

18.

Veta M, van Diest P, Kornegoor R, Huisman A, Viergever M, Pluim J . Automatic nuclei segmentation in H&E stained breast cancer histopathology images. PLoS One. 2013; 8(7):e70221. PMC: 3726421. DOI: 10.1371/journal.pone.0070221. View

19.

Chan P, Li Q, Zhang B, To K, Leung S . In vivo biocompatibility and efficacy of dexamethasone-loaded PLGA-PEG-PLGA thermogel in an alkali-burn induced corneal neovascularization disease model. Eur J Pharm Biopharm. 2020; 155:190-198. DOI: 10.1016/j.ejpb.2020.08.022. View

20.

Cao D, Zhang X, Akabar M, Luo Y, Wu H, Ke X . Liposomal doxorubicin loaded PLGA-PEG-PLGA based thermogel for sustained local drug delivery for the treatment of breast cancer. Artif Cells Nanomed Biotechnol. 2019; 47(1):181-191. DOI: 10.1080/21691401.2018.1548470. View