Formulation development and evaluation, in silico PBPK modeling and in vivo pharmacodynamic studies of clozapine matrix type transdermal patches
Abstract Clozapine is a potent serotonin receptor antagonist and commonly used for the treatment of Schizophrenia. The study aimed to develop and optimize the transdermal matrix patch of clozapine. A 3-level, 3-factor Central Composite Design was applied to examine and validate the impact of various...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-024-81918-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841544635411857408 |
|---|---|
| author | Abdul Qadir Syed Umer Jan Muhammad Harris Shoaib Muhammad Sikandar Rabia Ismail Yousuf Fatima Ramzan Ali Fahad Siddiqui Abdul Jabbar Magsi Ghulam Mustafa Muhammad Talha Saleem Shafi Mohammad Mohammad Younis Muhammad Arsalan |
| author_facet | Abdul Qadir Syed Umer Jan Muhammad Harris Shoaib Muhammad Sikandar Rabia Ismail Yousuf Fatima Ramzan Ali Fahad Siddiqui Abdul Jabbar Magsi Ghulam Mustafa Muhammad Talha Saleem Shafi Mohammad Mohammad Younis Muhammad Arsalan |
| author_sort | Abdul Qadir |
| collection | DOAJ |
| description | Abstract Clozapine is a potent serotonin receptor antagonist and commonly used for the treatment of Schizophrenia. The study aimed to develop and optimize the transdermal matrix patch of clozapine. A 3-level, 3-factor Central Composite Design was applied to examine and validate the impact of various formulation variables, Eudragit, PEG, and oleic acid on in vitro drug release, flux, and tensile strength (TS). Different formulation characteristics were studied in terms of physico-chemical characterization, Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), drug release performance, and in vitro permeability. The numerical and graphical optimization was based on the desirability function and the optimized formulation obtained from the polynomial equation was further validated and evaluated for the targeted critical attributes. The optimized patch was further evaluated for skin irritation, in vivo pharmacodynamics, in silico prediction, and simulation using the GastroPlus TCAT® model and stability. The experimental results of the optimized formulation, such as tensile strength 1.220 kg/cm2, flux 147.376 μg/cm2/h and Q24 94.874%, showed similarity with the values predicted by numerical and graphical optimization. In vivo Neuro-pharmacological studies showed that the results were comparable to the standard. The C max , T max , AUC t, and AUC inf were predicted as 38.396 ng/mL, 28.960 h, 1625.500 ng-h/mL, and 1175.700 ng-h/mL for a 50 mg patch. No skin irritation was found for the optimized transdermal patch as per the Draize score method. The shelf life of the optimized formulation was 30.41 months under accelerated conditions. The study showed that the matrix-type transdermal patch of clozapine can be used for the management of schizophrenia in terms of improved patient compliance. |
| format | Article |
| id | doaj-art-fe937bf8667a4554b0afd35be858d02e |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-fe937bf8667a4554b0afd35be858d02e2025-01-12T12:23:34ZengNature PortfolioScientific Reports2045-23222025-01-0115112110.1038/s41598-024-81918-6Formulation development and evaluation, in silico PBPK modeling and in vivo pharmacodynamic studies of clozapine matrix type transdermal patchesAbdul Qadir0Syed Umer Jan1Muhammad Harris Shoaib2Muhammad Sikandar3Rabia Ismail Yousuf4Fatima Ramzan Ali5Fahad Siddiqui6Abdul Jabbar Magsi7Ghulam Mustafa8Muhammad Talha Saleem9Shafi Mohammad10Mohammad Younis11Muhammad Arsalan12Department of Pharmaceutics, Faculty of Pharmacy and Health Sciences, University of BalochistanDepartment of Pharmaceutics, Faculty of Pharmacy and Health Sciences, University of BalochistanDepartment of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, University of KarachiDepartment of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, University of KarachiDepartment of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, University of KarachiDepartment of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, University of KarachiDepartment of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, University of KarachiDepartment of Pharmacognosy, Faculty of Pharmacy and Health Sciences, University of BalochistanDepartment of Pharmaceutics, Faculty of Pharmacy and Health Sciences, University of BalochistanDepartment of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, University of KarachiDepartment of Pharmacognosy, Faculty of Pharmacy and Health Sciences, University of BalochistanDepartment of Pharmacology, Faculty of Pharmacy and Health Sciences, University of BalochistanDepartment of Pharmacognosy, Faculty of Pharmacy and Health Sciences, University of BalochistanAbstract Clozapine is a potent serotonin receptor antagonist and commonly used for the treatment of Schizophrenia. The study aimed to develop and optimize the transdermal matrix patch of clozapine. A 3-level, 3-factor Central Composite Design was applied to examine and validate the impact of various formulation variables, Eudragit, PEG, and oleic acid on in vitro drug release, flux, and tensile strength (TS). Different formulation characteristics were studied in terms of physico-chemical characterization, Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), drug release performance, and in vitro permeability. The numerical and graphical optimization was based on the desirability function and the optimized formulation obtained from the polynomial equation was further validated and evaluated for the targeted critical attributes. The optimized patch was further evaluated for skin irritation, in vivo pharmacodynamics, in silico prediction, and simulation using the GastroPlus TCAT® model and stability. The experimental results of the optimized formulation, such as tensile strength 1.220 kg/cm2, flux 147.376 μg/cm2/h and Q24 94.874%, showed similarity with the values predicted by numerical and graphical optimization. In vivo Neuro-pharmacological studies showed that the results were comparable to the standard. The C max , T max , AUC t, and AUC inf were predicted as 38.396 ng/mL, 28.960 h, 1625.500 ng-h/mL, and 1175.700 ng-h/mL for a 50 mg patch. No skin irritation was found for the optimized transdermal patch as per the Draize score method. The shelf life of the optimized formulation was 30.41 months under accelerated conditions. The study showed that the matrix-type transdermal patch of clozapine can be used for the management of schizophrenia in terms of improved patient compliance.https://doi.org/10.1038/s41598-024-81918-6Central composite designPBPKTransdermal drug deliveryPermeation enhancers, in silicoIn vitroIn vivo |
| spellingShingle | Abdul Qadir Syed Umer Jan Muhammad Harris Shoaib Muhammad Sikandar Rabia Ismail Yousuf Fatima Ramzan Ali Fahad Siddiqui Abdul Jabbar Magsi Ghulam Mustafa Muhammad Talha Saleem Shafi Mohammad Mohammad Younis Muhammad Arsalan Formulation development and evaluation, in silico PBPK modeling and in vivo pharmacodynamic studies of clozapine matrix type transdermal patches Scientific Reports Central composite design PBPK Transdermal drug delivery Permeation enhancers, in silico In vitro In vivo |
| title | Formulation development and evaluation, in silico PBPK modeling and in vivo pharmacodynamic studies of clozapine matrix type transdermal patches |
| title_full | Formulation development and evaluation, in silico PBPK modeling and in vivo pharmacodynamic studies of clozapine matrix type transdermal patches |
| title_fullStr | Formulation development and evaluation, in silico PBPK modeling and in vivo pharmacodynamic studies of clozapine matrix type transdermal patches |
| title_full_unstemmed | Formulation development and evaluation, in silico PBPK modeling and in vivo pharmacodynamic studies of clozapine matrix type transdermal patches |
| title_short | Formulation development and evaluation, in silico PBPK modeling and in vivo pharmacodynamic studies of clozapine matrix type transdermal patches |
| title_sort | formulation development and evaluation in silico pbpk modeling and in vivo pharmacodynamic studies of clozapine matrix type transdermal patches |
| topic | Central composite design PBPK Transdermal drug delivery Permeation enhancers, in silico In vitro In vivo |
| url | https://doi.org/10.1038/s41598-024-81918-6 |
| work_keys_str_mv | AT abdulqadir formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches AT syedumerjan formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches AT muhammadharrisshoaib formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches AT muhammadsikandar formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches AT rabiaismailyousuf formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches AT fatimaramzanali formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches AT fahadsiddiqui formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches AT abduljabbarmagsi formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches AT ghulammustafa formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches AT muhammadtalhasaleem formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches AT shafimohammad formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches AT mohammadyounis formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches AT muhammadarsalan formulationdevelopmentandevaluationinsilicopbpkmodelingandinvivopharmacodynamicstudiesofclozapinematrixtypetransdermalpatches |