TY  - JOUR
AU  - Shi, Changzhi
AU  - Guo, Kewei
AU  - Zhang, Li
AU  - Guo, Yi
AU  - Feng, Yu
AU  - Cvijić, Sandra
AU  - Cun, Dongmei
AU  - Yang, Mingshi
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5080
AB  - Respiratory antibiotics delivery has been appreciated for its high local concentration at the infection sites. Certain formulation strategies are required to improve pulmonary drug exposure and to achieve effective antimicrobial activity, especially for highly permeable antibiotics. This study aimed to investigate lung exposure to various inhalable ciprofloxacin (CIP) formulations with different drug release rates in a rat model. Four formulations were prepared, i.e., CIP-loaded PLGA micro-particles (CHPM), CIP microcrystalline dry powder (CMDP), CIP nanocrystalline dry powder (CNDP), and CIP spray-dried powder (CHDP), which served as a reference. The physicochemical properties, drug dissolution rate, and aerosolization performance of these powders were characterized in vitro. Pharmacokinetic profiles were evaluated in rats. All formulations were suitable for inhalation (mass median aerodynamic diameter < 5 µm). CIP in CHPM and CHDP was amorphous, whereas the drug in CMDP and CNDP remained predominantly crystalline. CHDP exhibited the fastest drug release rate, while CMDP and CNDP exhibited much slower drug release. In addition, CMDP and CNDP exhibited significantly higher in vivo lung exposure to CIP compared with CHDP and CHPM. This study suggests that lung exposure to inhaled drugs with high permeability is governed by drug release rate, implying that lung exposure of inhaled antibiotics could be improved by a sustained-release formulation strategy.
PB  - MDPI
T2  - Pharmaceutics
T1  - In Vitro and In Vivo Evaluation of Inhalable Ciprofloxacin Sustained Release Formulations
VL  - 15
IS  - 9
DO  - 10.3390/pharmaceutics15092287
ER  - 

@article{
author = "Shi, Changzhi and Guo, Kewei and Zhang, Li and Guo, Yi and Feng, Yu and Cvijić, Sandra and Cun, Dongmei and Yang, Mingshi",
year = "2023",
abstract = "Respiratory antibiotics delivery has been appreciated for its high local concentration at the infection sites. Certain formulation strategies are required to improve pulmonary drug exposure and to achieve effective antimicrobial activity, especially for highly permeable antibiotics. This study aimed to investigate lung exposure to various inhalable ciprofloxacin (CIP) formulations with different drug release rates in a rat model. Four formulations were prepared, i.e., CIP-loaded PLGA micro-particles (CHPM), CIP microcrystalline dry powder (CMDP), CIP nanocrystalline dry powder (CNDP), and CIP spray-dried powder (CHDP), which served as a reference. The physicochemical properties, drug dissolution rate, and aerosolization performance of these powders were characterized in vitro. Pharmacokinetic profiles were evaluated in rats. All formulations were suitable for inhalation (mass median aerodynamic diameter < 5 µm). CIP in CHPM and CHDP was amorphous, whereas the drug in CMDP and CNDP remained predominantly crystalline. CHDP exhibited the fastest drug release rate, while CMDP and CNDP exhibited much slower drug release. In addition, CMDP and CNDP exhibited significantly higher in vivo lung exposure to CIP compared with CHDP and CHPM. This study suggests that lung exposure to inhaled drugs with high permeability is governed by drug release rate, implying that lung exposure of inhaled antibiotics could be improved by a sustained-release formulation strategy.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "In Vitro and In Vivo Evaluation of Inhalable Ciprofloxacin Sustained Release Formulations",
volume = "15",
number = "9",
doi = "10.3390/pharmaceutics15092287"
}

Shi, C., Guo, K., Zhang, L., Guo, Y., Feng, Y., Cvijić, S., Cun, D.,& Yang, M.. (2023). In Vitro and In Vivo Evaluation of Inhalable Ciprofloxacin Sustained Release Formulations. in Pharmaceutics
MDPI., 15(9).
https://doi.org/10.3390/pharmaceutics15092287

Shi C, Guo K, Zhang L, Guo Y, Feng Y, Cvijić S, Cun D, Yang M. In Vitro and In Vivo Evaluation of Inhalable Ciprofloxacin Sustained Release Formulations. in Pharmaceutics. 2023;15(9).
doi:10.3390/pharmaceutics15092287 .

Shi, Changzhi, Guo, Kewei, Zhang, Li, Guo, Yi, Feng, Yu, Cvijić, Sandra, Cun, Dongmei, Yang, Mingshi, "In Vitro and In Vivo Evaluation of Inhalable Ciprofloxacin Sustained Release Formulations" in Pharmaceutics, 15, no. 9 (2023),
https://doi.org/10.3390/pharmaceutics15092287 . .

TY  - JOUR
AU  - Shi, Changzhi
AU  - Ignjatović, Jelisaveta
AU  - Wang, Junwei
AU  - Guo, Yi
AU  - Zhang, Li
AU  - Cvijić, Sandra
AU  - Cun, Dongmei
AU  - Yang, Mingshi
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4291
AB  - Respiratory antibiotics have been proven clinically beneficial for the treatment of severe lung infections such as Pseudomonas aeruginosa. Maintaining a high local concentration of inhaled antibiotics for an extended time in the lung is crucial to ensure an adequate antimicrobial efficiency. In this study, we aim to investigate whether an extended exposure of ciprofloxacin (CIP), a model fluoroquinolone drug, in the lung epithelial lining fluid (ELF) could be achieved via a controlled-release formulation strategy. CIP solutions were intratracheally instilled to the rat lungs at 3 different rates, i.e., T0h (fast), T2h (medium), and T4h (slow), to mimic different release profiles of inhaled CIP formulations in the lung. Subsequently, the concentration-time profiles of CIP in the plasma and the lung ELF were obtained, respectively, to determine topical exposure index (ELF-Plasma AUC Ratio, EPR). The in silico PBPK model, validated based on the in vivo data, was used to identify the key factors that influence the disposition of CIP in the plasma and lungs. The medium and slow rates groups exhibited much higher EPR than that fast instillation group. The ELF AUC of the medium and slow instillation groups were about 200 times higher than their plasma AUC. In contrast, the ELF AUC of the fast instillation group was only about 20 times higher than the plasma AUC. The generated whole-body PBPK rat model, validated by comparison with the in vivo data, revealed that drug pulmonary absorption rate was the key factor that determined pulmonary absorption of CIP. This study suggests that controlled CIP release from inhaled formulations may extend the exposure of CIP in the ELF post pulmonary administration. It also demonstrates that combining the proposed intratracheal installation model and in silico PBPK model is a useful approach to identify the key factors that influence the absorption and disposition of inhaled medicine.
PB  - Elsevier B.V.
T2  - Chinese Chemical Letters
T1  - Evaluating the pharmacokinetics of intrapulmonary administered ciprofloxacin solution for respiratory infections using in vivo and in silico PBPK rat model studies
VL  - 34
IS  - 1
DO  - 10.1016/j.cclet.2022.04.061
ER  - 

@article{
author = "Shi, Changzhi and Ignjatović, Jelisaveta and Wang, Junwei and Guo, Yi and Zhang, Li and Cvijić, Sandra and Cun, Dongmei and Yang, Mingshi",
year = "2023",
abstract = "Respiratory antibiotics have been proven clinically beneficial for the treatment of severe lung infections such as Pseudomonas aeruginosa. Maintaining a high local concentration of inhaled antibiotics for an extended time in the lung is crucial to ensure an adequate antimicrobial efficiency. In this study, we aim to investigate whether an extended exposure of ciprofloxacin (CIP), a model fluoroquinolone drug, in the lung epithelial lining fluid (ELF) could be achieved via a controlled-release formulation strategy. CIP solutions were intratracheally instilled to the rat lungs at 3 different rates, i.e., T0h (fast), T2h (medium), and T4h (slow), to mimic different release profiles of inhaled CIP formulations in the lung. Subsequently, the concentration-time profiles of CIP in the plasma and the lung ELF were obtained, respectively, to determine topical exposure index (ELF-Plasma AUC Ratio, EPR). The in silico PBPK model, validated based on the in vivo data, was used to identify the key factors that influence the disposition of CIP in the plasma and lungs. The medium and slow rates groups exhibited much higher EPR than that fast instillation group. The ELF AUC of the medium and slow instillation groups were about 200 times higher than their plasma AUC. In contrast, the ELF AUC of the fast instillation group was only about 20 times higher than the plasma AUC. The generated whole-body PBPK rat model, validated by comparison with the in vivo data, revealed that drug pulmonary absorption rate was the key factor that determined pulmonary absorption of CIP. This study suggests that controlled CIP release from inhaled formulations may extend the exposure of CIP in the ELF post pulmonary administration. It also demonstrates that combining the proposed intratracheal installation model and in silico PBPK model is a useful approach to identify the key factors that influence the absorption and disposition of inhaled medicine.",
publisher = "Elsevier B.V.",
journal = "Chinese Chemical Letters",
title = "Evaluating the pharmacokinetics of intrapulmonary administered ciprofloxacin solution for respiratory infections using in vivo and in silico PBPK rat model studies",
volume = "34",
number = "1",
doi = "10.1016/j.cclet.2022.04.061"
}

Shi, C., Ignjatović, J., Wang, J., Guo, Y., Zhang, L., Cvijić, S., Cun, D.,& Yang, M.. (2023). Evaluating the pharmacokinetics of intrapulmonary administered ciprofloxacin solution for respiratory infections using in vivo and in silico PBPK rat model studies. in Chinese Chemical Letters
Elsevier B.V.., 34(1).
https://doi.org/10.1016/j.cclet.2022.04.061

Shi C, Ignjatović J, Wang J, Guo Y, Zhang L, Cvijić S, Cun D, Yang M. Evaluating the pharmacokinetics of intrapulmonary administered ciprofloxacin solution for respiratory infections using in vivo and in silico PBPK rat model studies. in Chinese Chemical Letters. 2023;34(1).
doi:10.1016/j.cclet.2022.04.061 .

Shi, Changzhi, Ignjatović, Jelisaveta, Wang, Junwei, Guo, Yi, Zhang, Li, Cvijić, Sandra, Cun, Dongmei, Yang, Mingshi, "Evaluating the pharmacokinetics of intrapulmonary administered ciprofloxacin solution for respiratory infections using in vivo and in silico PBPK rat model studies" in Chinese Chemical Letters, 34, no. 1 (2023),
https://doi.org/10.1016/j.cclet.2022.04.061 . .

TY  - JOUR
AU  - Shi, Changzhi
AU  - Ignjatović, Jelisaveta
AU  - Liu, Tingting
AU  - Han, Meihua
AU  - Cun, Dongmei
AU  - Đuriš, Jelena
AU  - Yang, Mingshi
AU  - Cvijić, Sandra
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3902
AB  - This study aims to understand the absorption patterns of three different kinds of inhaled formulations via in silico modeling using budesonide (BUD) as a model drug. The formulations investigated in this study are: (i) commercially available micronized BUD mixed with lactose (BUD-PT), (ii) BUD nanocrystal suspension (BUD-NC), (iii) BUD nanocrystals embedded hyaluronic acid microparticles (BUD-NEM). The deposition patterns of the three inhaled formulations in the rats’ lungs were determined in vivo and in silico predicted, which were used as inputs in GastroPlus™ software to predict drug absorption following aerosolization of the tested formulations. BUD pharmacokinetics, estimated based on intravenous data in rats, was used to establish a drug-specific in silico absorption model. The BUD-specific in silico model revealed that drug pulmonary solubility and absorption rate constant were the key factors affecting pulmonary absorption of BUD-NC and BUD-NEM, respectively. In the case of BUD-PT, the in silico model revealed significant gastrointestinal absorption of BUD, which could be overlooked by traditional in vivo experimental observation. This study demonstrated that in vitro-in vivo-in silico approach was able to identify the key factors that influence the absorption of different inhaled formulations, which may facilitate the development of orally inhaled formulations with different drug release/absorption rates.
PB  - Elsevier B.V.
T2  - Asian Journal of Pharmaceutical Sciences
T1  - In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug
VL  - 16
IS  - 3
SP  - 350
EP  - 362
DO  - 10.1016/j.ajps.2020.12.001
ER  - 

@article{
author = "Shi, Changzhi and Ignjatović, Jelisaveta and Liu, Tingting and Han, Meihua and Cun, Dongmei and Đuriš, Jelena and Yang, Mingshi and Cvijić, Sandra",
year = "2021",
abstract = "This study aims to understand the absorption patterns of three different kinds of inhaled formulations via in silico modeling using budesonide (BUD) as a model drug. The formulations investigated in this study are: (i) commercially available micronized BUD mixed with lactose (BUD-PT), (ii) BUD nanocrystal suspension (BUD-NC), (iii) BUD nanocrystals embedded hyaluronic acid microparticles (BUD-NEM). The deposition patterns of the three inhaled formulations in the rats’ lungs were determined in vivo and in silico predicted, which were used as inputs in GastroPlus™ software to predict drug absorption following aerosolization of the tested formulations. BUD pharmacokinetics, estimated based on intravenous data in rats, was used to establish a drug-specific in silico absorption model. The BUD-specific in silico model revealed that drug pulmonary solubility and absorption rate constant were the key factors affecting pulmonary absorption of BUD-NC and BUD-NEM, respectively. In the case of BUD-PT, the in silico model revealed significant gastrointestinal absorption of BUD, which could be overlooked by traditional in vivo experimental observation. This study demonstrated that in vitro-in vivo-in silico approach was able to identify the key factors that influence the absorption of different inhaled formulations, which may facilitate the development of orally inhaled formulations with different drug release/absorption rates.",
publisher = "Elsevier B.V.",
journal = "Asian Journal of Pharmaceutical Sciences",
title = "In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug",
volume = "16",
number = "3",
pages = "350-362",
doi = "10.1016/j.ajps.2020.12.001"
}

Shi, C., Ignjatović, J., Liu, T., Han, M., Cun, D., Đuriš, J., Yang, M.,& Cvijić, S.. (2021). In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug. in Asian Journal of Pharmaceutical Sciences
Elsevier B.V.., 16(3), 350-362.
https://doi.org/10.1016/j.ajps.2020.12.001

Shi C, Ignjatović J, Liu T, Han M, Cun D, Đuriš J, Yang M, Cvijić S. In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug. in Asian Journal of Pharmaceutical Sciences. 2021;16(3):350-362.
doi:10.1016/j.ajps.2020.12.001 .

Shi, Changzhi, Ignjatović, Jelisaveta, Liu, Tingting, Han, Meihua, Cun, Dongmei, Đuriš, Jelena, Yang, Mingshi, Cvijić, Sandra, "In vitro - in vivo - in silico approach in the development of inhaled drug products: Nanocrystal-based formulations with budesonide as a model drug" in Asian Journal of Pharmaceutical Sciences, 16, no. 3 (2021):350-362,
https://doi.org/10.1016/j.ajps.2020.12.001 . .