Pub Date : 2024-12-17DOI: 10.1208/s12249-024-03001-7
Mohammed Shareef Khan, Aditya Murthy, Tausif Ahmed
This review paper discusses the key aspects of ocular biopharmaceutics, with emphasis on the crucial role played by ocular compartmental modelling and simulation in deciphering physiological conditions related to various eye diseases. It describes eye’s intricate structure and function and the need for precise and targeted drug delivery systems to address prevalent eye conditions. The review categorizes and discusses various formulations employed in ocular drug delivery, delineating their respective advantages and limitations. Additionally, it probes the challenges inherent in diverse routes of drug administration for ocular therapies and provides insights into the complexities of achieving optimal drug concentrations at the target site within the eye. The central theme of this work is the ocular compartmental modelling and simulations. Hence, this works discusses on the nuanced understanding of physiological conditions within the eye, drug distribution, drug release kinetics, and key considerations for ocular compartmental modelling and simulations. By combining information from various sources, this review aims to serve as a comprehensive reference for researchers, clinicians, and pharmaceutical developers. It covers the multifaceted landscape of ocular biopharmaceutics and the transformative impact of modelling and simulation in optimizing ocular drug delivery strategies.
Graphical Abstract
{"title":"Advancements in Ocular Modelling and Simulations: Key Considerations and Case Studies","authors":"Mohammed Shareef Khan, Aditya Murthy, Tausif Ahmed","doi":"10.1208/s12249-024-03001-7","DOIUrl":"10.1208/s12249-024-03001-7","url":null,"abstract":"<div><p>This review paper discusses the key aspects of ocular biopharmaceutics, with emphasis on the crucial role played by ocular compartmental modelling and simulation in deciphering physiological conditions related to various eye diseases. It describes eye’s intricate structure and function and the need for precise and targeted drug delivery systems to address prevalent eye conditions. The review categorizes and discusses various formulations employed in ocular drug delivery, delineating their respective advantages and limitations. Additionally, it probes the challenges inherent in diverse routes of drug administration for ocular therapies and provides insights into the complexities of achieving optimal drug concentrations at the target site within the eye. The central theme of this work is the ocular compartmental modelling and simulations. Hence, this works discusses on the nuanced understanding of physiological conditions within the eye, drug distribution, drug release kinetics, and key considerations for ocular compartmental modelling and simulations. By combining information from various sources, this review aims to serve as a comprehensive reference for researchers, clinicians, and pharmaceutical developers. It covers the multifaceted landscape of ocular biopharmaceutics and the transformative impact of modelling and simulation in optimizing ocular drug delivery strategies.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142844822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tyrosine kinase inhibitors like tofacitinib (TCB), are excellent examples of small molecular compounds that have demonstrated success in treating psoriasis. The current study aims to improve the efficacy of TCB and reduce its systemic adverse effects by developing a topical w/o emulgel formulation that will ameliorate the anti-psoriatic activity in a model of Imiquimod-induced BALB/c mice. In order to create w/o emulgel, the TCB was incorporated into the w/o emulsion using Peppermint oil, Transcutol P®, and PEG-200 followed by converted into a gel by adding Carbopol 940. The final formulation was optimized by applying a 3-level, 3-factor Box-Behnken Design (BBD). The optimized formulation showed a viscosity of 560606.6 ± 80.8 cps (560 Pa.S), and firmness of 356 ± 48 g, and that was within the acceptable range with respect to the marketed emulgel preparation available for topical application. The developed TCB-emulgel also exhibited a controlled release profile, with 68.26 ± 8.33% release of TCB over 24 h and a 5-fold greater skin permeation as compared to normal TCB-gel. Apart from that, the application of TCB-emulgel on the diseased model results in a 3.3-times reduction in the PASI (Psoriasis Area Severity Index) scoring. Lastly, the epidermal reduction in histopathological evaluation, along with the reduction in TNF-α and Ki-67 levels observed in immunostaining, ensures the enhanced anti-psoriatic effect of the developed TCB-emulgel in comparison to the marketed product. To put it briefly, the findings of the study and the therapeutic effectiveness of the developed TCB-emulgel provide a strong basis for the clinical management of psoriasis in the future.
Graphical abstract
{"title":"Contemplating Novel W/O Emulsion Based Gel for Anti-Psoriatic Activity of Tofacitinib in Imiquimod-Induced Balb/C Mice Model","authors":"Ashwini Aratwar, Indrani Maji, Shrilekha Chilvery, Srushti Mahajan, Mayur Aalhate, Ujala Gupta, Chandraiah Godugu, Pankaj Kumar Singh","doi":"10.1208/s12249-024-03003-5","DOIUrl":"10.1208/s12249-024-03003-5","url":null,"abstract":"<div><p>Tyrosine kinase inhibitors like tofacitinib (TCB), are excellent examples of small molecular compounds that have demonstrated success in treating psoriasis. The current study aims to improve the efficacy of TCB and reduce its systemic adverse effects by developing a topical w/o emulgel formulation that will ameliorate the anti-psoriatic activity in a model of Imiquimod-induced BALB/c mice. In order to create w/o emulgel, the TCB was incorporated into the w/o emulsion using Peppermint oil, Transcutol P<sup>®</sup>, and PEG-200 followed by converted into a gel by adding Carbopol 940. The final formulation was optimized by applying a 3-level, 3-factor Box-Behnken Design (BBD). The optimized formulation showed a viscosity of 560606.6 ± 80.8 cps (560 Pa.S), and firmness of 356 ± 48 g, and that was within the acceptable range with respect to the marketed emulgel preparation available for topical application. The developed TCB-emulgel also exhibited a controlled release profile, with 68.26 ± 8.33% release of TCB over 24 h and a 5-fold greater skin permeation as compared to normal TCB-gel. Apart from that, the application of TCB-emulgel on the diseased model results in a 3.3-times reduction in the PASI (Psoriasis Area Severity Index) scoring. Lastly, the epidermal reduction in histopathological evaluation, along with the reduction in TNF-α and Ki-67 levels observed in immunostaining, ensures the enhanced anti-psoriatic effect of the developed TCB-emulgel in comparison to the marketed product. To put it briefly, the findings of the study and the therapeutic effectiveness of the developed TCB-emulgel provide a strong basis for the clinical management of psoriasis in the future. </p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142810841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Reactive oxygen species (ROS) play a dual role in cancer, acting as both signaling molecules that promote tumour growth and as agents that can inhibit tumour progression through cytotoxic effects. In cancer therapy, ROS-responsive drug delivery systems take advantage of the elevated ROS levels found in tumors compared to healthy tissues. These systems are engineered to release drugs precisely in response to increased ROS levels in tumour cells, allowing targeted and controlled treatment, minimizing side effects, and enhancing therapeutic outcomes. ROS generation in cancer cells is linked to metabolic changes, mitochondrial dysfunction, and oncogenic signaling, leading to increased oxidative stress. Tumour cells manage this by upregulating antioxidant defenses to prevent ROS from reaching harmful levels. This balance between ROS production and neutralization is critical for cancer cell survival, making ROS both a challenge and an opportunity for targeted therapies. ROS also connect inflammation and cancer. Chronic inflammation leads to elevated ROS, which can damage DNA and proteins, promoting mutations and cancer development. Additionally, ROS contribute to protein degradation, affecting essential cellular functions. Therapeutic strategies targeting ROS aim to either increase ROS beyond tolerable levels for cancer cells or inhibit their antioxidant defenses. Nanocarriers responsive to ROS show great potential in improving the precision of cancer treatments by releasing drugs specifically in high ROS environments, like tumors. This review discusses the mechanisms of ROS in cancer, its role in inflammation and protein degradation, and the advances in ROS-targeted nanocarrier therapies across different cancer types.
Graphical Abstract
{"title":"From Bench to Bedside: ROS-Responsive Nanocarriers in Cancer Therapy","authors":"Abhishek Chauhan, Raj Kamal, Rohit Bhaita, Gurjeet Singh Thakur, Ankit Awasthi","doi":"10.1208/s12249-024-03011-5","DOIUrl":"10.1208/s12249-024-03011-5","url":null,"abstract":"<div><p>Reactive oxygen species (ROS) play a dual role in cancer, acting as both signaling molecules that promote tumour growth and as agents that can inhibit tumour progression through cytotoxic effects. In cancer therapy, ROS-responsive drug delivery systems take advantage of the elevated ROS levels found in tumors compared to healthy tissues. These systems are engineered to release drugs precisely in response to increased ROS levels in tumour cells, allowing targeted and controlled treatment, minimizing side effects, and enhancing therapeutic outcomes. ROS generation in cancer cells is linked to metabolic changes, mitochondrial dysfunction, and oncogenic signaling, leading to increased oxidative stress. Tumour cells manage this by upregulating antioxidant defenses to prevent ROS from reaching harmful levels. This balance between ROS production and neutralization is critical for cancer cell survival, making ROS both a challenge and an opportunity for targeted therapies. ROS also connect inflammation and cancer. Chronic inflammation leads to elevated ROS, which can damage DNA and proteins, promoting mutations and cancer development. Additionally, ROS contribute to protein degradation, affecting essential cellular functions. Therapeutic strategies targeting ROS aim to either increase ROS beyond tolerable levels for cancer cells or inhibit their antioxidant defenses. Nanocarriers responsive to ROS show great potential in improving the precision of cancer treatments by releasing drugs specifically in high ROS environments, like tumors. This review discusses the mechanisms of ROS in cancer, its role in inflammation and protein degradation, and the advances in ROS-targeted nanocarrier therapies across different cancer types.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-13DOI: 10.1208/s12249-024-03013-3
Nivedita Pant, Sarika Wairkar
This research aimed to develop a mupirocin-doped α-cellulose nanopaper (MDAC-NP) as a wound dressing to accelerate wound healing while limiting localized bacterial growth. The α-cellulose nanofibrils suspension was prepared by ultrasonication followed by microfluidization and subsequently doped with 0.05% w/v mupirocin to prepare nanopaper (MDAC-NP-A). The optimized batch of MDAC-NP had a porosity of 47.46 ± 0.60%, a thickness of 30 μm and a tensile strength of 0.113 MPa. The transmission electron microscopy images revealed long, slender, intertwined nanofibrillar structures and the scanning electron microscopy confirmed stable lamellar structures with tight nanofibrillar networks, giving them translucency. MDAC-NP-A had an excellent water vapor transmission rate of 2963 ± 10.26 g/m2/day, providing an optimal moist environment locally to promote wound healing. The mupirocin inclusion in the nanopapers was corroborated by the Fourier transform infrared spectroscopy and its crystallinity by X-ray diffraction, and differential scanning calorimetry results. The 100% drug release, was observed at 12 h from optimized MDAC-NP-A with a controlled release pattern. The MDAC-NP showed better antimicrobial activity, against S. aureus (41 mm) than E. coli (25 mm) and P. aeruginosa (17 mm) and was found to be better than marketed ointment. Thus, mupirocin-doped α-cellulose nanopapers emerge as a potential wound dressing for treating primary and secondary skin infections caused by external wounds.
Graphical Abstract
{"title":"Mupirocin-Doped α-Cellulose Nanopaper for Wound Dressing: Development, In Vitro Characterization and Antimicrobial Studies","authors":"Nivedita Pant, Sarika Wairkar","doi":"10.1208/s12249-024-03013-3","DOIUrl":"10.1208/s12249-024-03013-3","url":null,"abstract":"<div><p>This research aimed to develop a mupirocin-doped α-cellulose nanopaper (MDAC-NP) as a wound dressing to accelerate wound healing while limiting localized bacterial growth. The α-cellulose nanofibrils suspension was prepared by ultrasonication followed by microfluidization and subsequently doped with 0.05% w/v mupirocin to prepare nanopaper (MDAC-NP-A). The optimized batch of MDAC-NP had a porosity of 47.46 ± 0.60%, a thickness of 30 μm and a tensile strength of 0.113 MPa. The transmission electron microscopy images revealed long, slender, intertwined nanofibrillar structures and the scanning electron microscopy confirmed stable lamellar structures with tight nanofibrillar networks, giving them translucency. MDAC-NP-A had an excellent water vapor transmission rate of 2963 ± 10.26 g/m<sup>2</sup>/day, providing an optimal moist environment locally to promote wound healing. The mupirocin inclusion in the nanopapers was corroborated by the Fourier transform infrared spectroscopy and its crystallinity by X-ray diffraction, and differential scanning calorimetry results. The 100% drug release, was observed at 12 h from optimized MDAC-NP-A with a controlled release pattern. The MDAC-NP showed better antimicrobial activity, against <i>S. aureus</i> (41 mm) than <i>E. coli</i> (25 mm) and <i>P. aeruginosa</i> (17 mm) and was found to be better than marketed ointment. Thus, mupirocin-doped α-cellulose nanopapers emerge as a potential wound dressing for treating primary and secondary skin infections caused by external wounds.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-05DOI: 10.1208/s12249-024-02985-6
Induja Govindan, Angeeta Paul, Annamalai Rama, Anjana A. Kailas, K. A. Abutwaibe, Thamizharasan Annadurai, Anup Naha
The possibility of precisely regulating and targeting drug release with mesophase or Liquid crystal drug delivery systems has drawn much attention recently. This review offers a thorough investigation of liquid crystal drug delivery systems with an emphasis on their mesogenic architecture. It describes the various liquid crystal forms such as thermotropic and lyotropic liquid crystals and their applicability in advanced drug delivery. Liquid crystals are used as excellent carriers due to their distinctive characteristics, such as stimuli-responsive drug delivery and sustained release patterns. Comprehending the materials that form mesophase provides insight into their distinct physiochemical characteristics and their use in drug delivery. This review highlights the important role lyotropic and thermotropic liquid crystals play in drug delivery, underscoring their considerable potential. The transition of thermotropic liquid crystals from their conventional technological applications to drug delivery has been studied. Nonetheless, a few challenges still need to be addressed, including formulation strategy refinement, regulating release rates, maximising the loading of hydrophilic drugs, and storage stability. In the pharmaceutical field, addressing these issues will open the door to a revolutionary paradigm that will revolutionise therapeutic outcomes and improve patient care.
Graphical Abstract
{"title":"Mesogenic Architectures for Advanced Drug Delivery: Interrogating Lyotropic and Thermotropic Liquid Crystals","authors":"Induja Govindan, Angeeta Paul, Annamalai Rama, Anjana A. Kailas, K. A. Abutwaibe, Thamizharasan Annadurai, Anup Naha","doi":"10.1208/s12249-024-02985-6","DOIUrl":"10.1208/s12249-024-02985-6","url":null,"abstract":"<div><p>The possibility of precisely regulating and targeting drug release with mesophase or Liquid crystal drug delivery systems has drawn much attention recently. This review offers a thorough investigation of liquid crystal drug delivery systems with an emphasis on their mesogenic architecture. It describes the various liquid crystal forms such as thermotropic and lyotropic liquid crystals and their applicability in advanced drug delivery. Liquid crystals are used as excellent carriers due to their distinctive characteristics, such as stimuli-responsive drug delivery and sustained release patterns. Comprehending the materials that form mesophase provides insight into their distinct physiochemical characteristics and their use in drug delivery. This review highlights the important role lyotropic and thermotropic liquid crystals play in drug delivery, underscoring their considerable potential. The transition of thermotropic liquid crystals from their conventional technological applications to drug delivery has been studied. Nonetheless, a few challenges still need to be addressed, including formulation strategy refinement, regulating release rates, maximising the loading of hydrophilic drugs, and storage stability. In the pharmaceutical field, addressing these issues will open the door to a revolutionary paradigm that will revolutionise therapeutic outcomes and improve patient care.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-024-02985-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-05DOI: 10.1208/s12249-024-03002-6
Jaiza Samara Macena de Araújo, Gabriela Gama Xavier Augusto, Aylla Mesquita Pestana, Francisco Carlos Groppo, Flávia Sammartino Mariano Rodrigues, Pedro Duarte Novaes, Michelle Franz-Montan
Intranasal topical administration offers a promising route for local and systemic drug delivery, with in vitro permeation and mucoadhesion studies often using porcine models. However, the impact of storage on mucosal integrity after the procedure remains unaddressed. This study aimed to standardize the preparation process and evaluated whether storage of porcine nasal mucosa impairs its integrity and permeability for experimental comparisons. Additionally, an optimized in vitro mucoadhesion experiment using texture analyzer equipment was investigated. Porcine nasal mucosa was subjected to different storage conditions ("fresh"; refrigerated at 4°C for 24 h and 48 h, and frozen at -20°C for two or three weeks) and assessed using optical and transmission electron microscopy. In vitro permeation assays were performed in a Franz-type vertical diffusion system with lidocaine hydrochloride (LDC). In vitro mucoadhesion assays were conducted using fresh nasal mucosa and a commercial nasal topical formulation using TA.XT. Plus texture analyzer. The variables involved (probe speed, contact time, and application force) in assessing mucoadhesive capacity (maximum mucoadhesive force Fmax and work of mucoadhesion Wmuc) were optimized using a Central Composite Design. Fresh tissues showed no alterations in histological arrangement or in the ultrastructure of adherence junctions. Stored tissues exhibited histological disorganization, reduced thickness, and loss of epithelial integrity. LDC permeability increased in storage tissues (p < 0.05). Contact force had a positive effect on Fmax and Wmuc (p < 0.0001), with a minimum required value of 0.48 N. Variations in contact time and probe speed did not affect the responses (p > 0.05). In conclusion, the preparation technique was adequate to maintain mucosa integrity for permeability studies. However, storing the mucosa at 4 or -20°C overestimated LDC permeation, which could mislead critical data for formulation development. Therefore, the use of fresh mucosa is recommended to ensure more reliable results. For in vitro mucoadhesion assays, a minimum contact force of 0.48N is required for optimal responses.
Graphical Abstract
{"title":"Impact of Storage on In Vitro Permeation and Mucoadhesion Setup Experiments Using Swine Nasal Mucosa","authors":"Jaiza Samara Macena de Araújo, Gabriela Gama Xavier Augusto, Aylla Mesquita Pestana, Francisco Carlos Groppo, Flávia Sammartino Mariano Rodrigues, Pedro Duarte Novaes, Michelle Franz-Montan","doi":"10.1208/s12249-024-03002-6","DOIUrl":"10.1208/s12249-024-03002-6","url":null,"abstract":"<div><p>Intranasal topical administration offers a promising route for local and systemic drug delivery, with <i>in vitro</i> permeation and mucoadhesion studies often using porcine models. However, the impact of storage on mucosal integrity after the procedure remains unaddressed. This study aimed to standardize the preparation process and evaluated whether storage of porcine nasal mucosa impairs its integrity and permeability for experimental comparisons. Additionally, an optimized <i>in vitro</i> mucoadhesion experiment using texture analyzer equipment was investigated. Porcine nasal mucosa was subjected to different storage conditions (\"fresh\"; refrigerated at 4°C for 24 h and 48 h, and frozen at -20°C for two or three weeks) and assessed using optical and transmission electron microscopy. <i>In vitro</i> permeation assays were performed in a Franz-type vertical diffusion system with lidocaine hydrochloride (LDC). <i>In vitro</i> mucoadhesion assays were conducted using fresh nasal mucosa and a commercial nasal topical formulation using TA.XT. Plus texture analyzer. The variables involved (probe speed, contact time, and application force) in assessing mucoadhesive capacity (maximum mucoadhesive force F<sub>max</sub> and work of mucoadhesion W<sub>muc</sub>) were optimized using a Central Composite Design. Fresh tissues showed no alterations in histological arrangement or in the ultrastructure of adherence junctions. Stored tissues exhibited histological disorganization, reduced thickness, and loss of epithelial integrity. LDC permeability increased in storage tissues (<i>p</i> < 0.05). Contact force had a positive effect on F<sub>max</sub> and W<sub>muc</sub> (<i>p</i> < 0.0001), with a minimum required value of 0.48 N. Variations in contact time and probe speed did not affect the responses (<i>p</i> > 0.05). In conclusion, the preparation technique was adequate to maintain mucosa integrity for permeability studies. However, storing the mucosa at 4 or -20°C overestimated LDC permeation, which could mislead critical data for formulation development. Therefore, the use of fresh mucosa is recommended to ensure more reliable results. For <i>in vitro</i> mucoadhesion assays, a minimum contact force of 0.48N is required for optimal responses.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-05DOI: 10.1208/s12249-024-02995-4
Ji-Hun Jang, Seung-Hyun Jeong
Although quetiapine metabolism occurs extensively in the liver and careful dosing is recommended in patients with liver disease, there has been a paucity of pharmacometric studies to adjust the clinical dose of quetiapine according to liver-disease severity. This study aimed to establish a whole-body, physiologically-based pharmacokinetic (WB-PBPK) model to explain interindividual variability in quetiapine PK and quantitatively predict PK in patients with liver disease. The developed WB-PBPK model well described the PK characteristics of different quetiapine regimens in healthy populations. The PK predictions could also be applied to patients with schizophrenia (without significant differences from healthy subjects). For the same total dose of quetiapine, both immediate-release (IR) and extended-release (ER) tablets showed significantly increased exposure and decreased clearance in patients with liver disease compared to healthy subjects. The model showed that steady-state plasma quetiapine concentrations exceeded the usual therapeutic range after multiple doses of IR tablets 250 mg three times daily or ER tablets 800 mg once daily in patients with liver disease. Therefore, the doses of quetiapine IR or ER tablets could be reduced by 0.10–0.50 times depending on liver-disease severity, so that mean steady-state plasma concentrations could be positioned near the therapeutic range. WB-PBPK modeling for quetiapine enabled quantitative prediction of PK according to IR or ER formulation and liver-disease severity. The results of this study provide useful data for improving the therapeutic use of quetiapine by enabling dose selection based on formulation and liver-disease severity.
Graphical Abstract
{"title":"Pharmacokinetic Prediction of Immediate- and Extended-Release Tablets for Patients with Liver Disease Using Whole Body Physiologically-Based Pharmacokinetic Modeling for the Antipsychotic Drug Quetiapine","authors":"Ji-Hun Jang, Seung-Hyun Jeong","doi":"10.1208/s12249-024-02995-4","DOIUrl":"10.1208/s12249-024-02995-4","url":null,"abstract":"<div><p>Although quetiapine metabolism occurs extensively in the liver and careful dosing is recommended in patients with liver disease, there has been a paucity of pharmacometric studies to adjust the clinical dose of quetiapine according to liver-disease severity. This study aimed to establish a whole-body, physiologically-based pharmacokinetic (WB-PBPK) model to explain interindividual variability in quetiapine <i>PK</i> and quantitatively predict <i>PK</i> in patients with liver disease. The developed WB-PBPK model well described the PK characteristics of different quetiapine regimens in healthy populations. The PK predictions could also be applied to patients with schizophrenia (without significant differences from healthy subjects). For the same total dose of quetiapine, both immediate-release (IR) and extended-release (ER) tablets showed significantly increased exposure and decreased clearance in patients with liver disease compared to healthy subjects. The model showed that steady-state plasma quetiapine concentrations exceeded the usual therapeutic range after multiple doses of IR tablets 250 mg three times daily or ER tablets 800 mg once daily in patients with liver disease. Therefore, the doses of quetiapine IR or ER tablets could be reduced by 0.10–0.50 times depending on liver-disease severity, so that mean steady-state plasma concentrations could be positioned near the therapeutic range. WB-PBPK modeling for quetiapine enabled quantitative prediction of <i>PK</i> according to IR or ER formulation and liver-disease severity. The results of this study provide useful data for improving the therapeutic use of quetiapine by enabling dose selection based on formulation and liver-disease severity.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-05DOI: 10.1208/s12249-024-02993-6
Liangju Sheng, Fuping Gao, Zhe Lan, Bin Zong, Qilong Wang
Osteoporosis has increasingly become a major public health concern because of its associated heightened risk of bone fragility and fractures. In order to avoid the adverse risk of hormone therapy, scientists have considered isoquercitrin (IQ) as a natural phytoestrogen to potentially prevent osteoporosis. However, IQ has poor solubility and bioavailability which culminates in rapid elimination of phytoestrogen. Herein, this study sought to solve limited applications of IQ by preparing IQ-loaded PEGylated long circulating liposomes (IQ-Lips) via thin-film hydration method. After appropriate characterization using zeta-potential, polydispersed index (PDI), particle size and entrapment efficiency (EE), IQ-Lips were applied to ovariectomized rat models to evaluate their effect on osteoporosis. The results showed that the prepared IQ-Lips exhibited smaller sized nanoparticles (125.35 ± 4.50 nm), excellent PDI (0.244 ± 0.001) and zeta-potential (-28.64 ± 0.71 mV) with stable property and higher EE (92.10 ± 0.32%). Importantly, administration of IQ-Lips through oral route increased aqueous solvability, bioavailability and circulation time of IQ. Moreover, the IQ-Lips could increase bone microstructural densities and bone mass, as well as reduce oxidative stress in ovariectomized rat models. Altogether, the IQ-Lips may serve as a novel avenue to potentially prolong the circulation of IQ in the body and improve the bioavailability of IQ for treatment of osteoporosis.
Graphical Abstract
{"title":"Isoquercitrin Loaded PEGylated Long Circulating Liposomes Improve Bone Mass and Reduce Oxidative Stress After Osteoporosis","authors":"Liangju Sheng, Fuping Gao, Zhe Lan, Bin Zong, Qilong Wang","doi":"10.1208/s12249-024-02993-6","DOIUrl":"10.1208/s12249-024-02993-6","url":null,"abstract":"<div><p>Osteoporosis has increasingly become a major public health concern because of its associated heightened risk of bone fragility and fractures. In order to avoid the adverse risk of hormone therapy, scientists have considered isoquercitrin (IQ) as a natural phytoestrogen to potentially prevent osteoporosis. However, IQ has poor solubility and bioavailability which culminates in rapid elimination of phytoestrogen. Herein, this study sought to solve limited applications of IQ by preparing IQ-loaded PEGylated long circulating liposomes (IQ-Lips) via thin-film hydration method. After appropriate characterization using zeta-potential, polydispersed index (PDI), particle size and entrapment efficiency (EE), IQ-Lips were applied to ovariectomized rat models to evaluate their effect on osteoporosis. The results showed that the prepared IQ-Lips exhibited smaller sized nanoparticles (125.35 ± 4.50 nm), excellent PDI (0.244 ± 0.001) and zeta-potential (-28.64 ± 0.71 mV) with stable property and higher EE (92.10 ± 0.32%). Importantly, administration of IQ-Lips through oral route increased aqueous solvability, bioavailability and circulation time of IQ. Moreover, the IQ-Lips could increase bone microstructural densities and bone mass, as well as reduce oxidative stress in ovariectomized rat models. Altogether, the IQ-Lips may serve as a novel avenue to potentially prolong the circulation of IQ in the body and improve the bioavailability of IQ for treatment of osteoporosis.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-05DOI: 10.1208/s12249-024-03005-3
Subodh Mondal, Ritika Uppal, Satish CS
Pre-clinical studies in animals are an essential part of drug development for new chemical entities. Before clinical trials in humans, submission of safety data from one rodent and one non-rodent species is compulsory as per regulatory guidelines. Even though minipigs and monkeys are physiologically closer to humans, dogs are usually employed as the non-rodent pre-clinical species. In this study, the in vitro plasma protein binding of eleven marketed cardiovascular drugs was studied in dog, minipig, monkey and human to determine the preferred species. To conduct plasma protein binding studies, the most reliable equilibrium dialysis method was adopted. Ten out of eleven tested cardiovascular drugs showed statistically similar plasma protein binding in minipig and human plasma which was different from dog and monkey plasma. The results from the studies showed greater similarity between minipigs and humans suggesting that the minipig species maybe a better pre-clinical non-rodent model during drug development of cardiovascular drugs instead of the conventional dog species. Additionally, use of the more accessible minipig species may help in saving time, and resources during pre-clinical studies and may also be more predictive during the safety studies in humans during later stage clinical trials.
Graphical Abstract
{"title":"Investigation of Minipigs as the Optimal Non-rodent Pre-clinical Species: Exploring Plasma Protein Binding of Marketed Cardiovascular Drugs Across Species","authors":"Subodh Mondal, Ritika Uppal, Satish CS","doi":"10.1208/s12249-024-03005-3","DOIUrl":"10.1208/s12249-024-03005-3","url":null,"abstract":"<div><p>Pre-clinical studies in animals are an essential part of drug development for new chemical entities. Before clinical trials in humans, submission of safety data from one rodent and one non-rodent species is compulsory as per regulatory guidelines. Even though minipigs and monkeys are physiologically closer to humans, dogs are usually employed as the non-rodent pre-clinical species. In this study, the <i>in vitro</i> plasma protein binding of eleven marketed cardiovascular drugs was studied in dog, minipig, monkey and human to determine the preferred species. To conduct plasma protein binding studies, the most reliable equilibrium dialysis method was adopted. Ten out of eleven tested cardiovascular drugs showed statistically similar plasma protein binding in minipig and human plasma which was different from dog and monkey plasma. The results from the studies showed greater similarity between minipigs and humans suggesting that the minipig species maybe a better pre-clinical non-rodent model during drug development of cardiovascular drugs instead of the conventional dog species. Additionally, use of the more accessible minipig species may help in saving time, and resources during pre-clinical studies and may also be more predictive during the safety studies in humans during later stage clinical trials.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-024-03005-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cyclodextrin complexes have been widely used in pharmaceutical applications, but disadvantages such as the rapid clearance of cyclodextrins from the blood stream after in vivo administration or their replacement by other molecules in the biological medium with higher luminal affinity for cyclodextrins limit the application of cyclodextrins as drug carriers. Liposome-encapsulated hydrophobic drugs have low and unstable drug loading rates. Drug-in-CD-in-liposome (DCL), which encapsulate cyclodextrin inclusion complexes into liposomes, combine the advantages of both delivery systems, can effectively avoid the leakage and rapid release of lipophilic drugs in the lipid bilayer, and help to maintain the integrity of liposomes. This paper focuses on the preparation method, characterization and application of DCL, with a view to providing methods and references for the research and application of DCL technology.
Graphical Abstract
{"title":"Cyclodextrin Drugs in Liposomes: Preparation and Application of Anticancer Drug Carriers","authors":"Lanni Feng, Ruting Wei, Jiali Wu, Xinmei Chen, Yan Wen, Jianming Chen","doi":"10.1208/s12249-024-02999-0","DOIUrl":"10.1208/s12249-024-02999-0","url":null,"abstract":"<div><p>Cyclodextrin complexes have been widely used in pharmaceutical applications, but disadvantages such as the rapid clearance of cyclodextrins from the blood stream after <i>in vivo</i> administration or their replacement by other molecules in the biological medium with higher luminal affinity for cyclodextrins limit the application of cyclodextrins as drug carriers. Liposome-encapsulated hydrophobic drugs have low and unstable drug loading rates. Drug-in-CD-in-liposome (DCL), which encapsulate cyclodextrin inclusion complexes into liposomes, combine the advantages of both delivery systems, can effectively avoid the leakage and rapid release of lipophilic drugs in the lipid bilayer, and help to maintain the integrity of liposomes. This paper focuses on the preparation method, characterization and application of DCL, with a view to providing methods and references for the research and application of DCL technology.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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