AAPS PharmSciTech最新文献

{"title":"Tea Saponins: a Novel Stabilizer for Enhancing the Oral Bioavailability of Albendazole Nanocrystals","authors":"Sumin Lan,&nbsp;Kexi Chen,&nbsp;Liqiang Feng,&nbsp;Panle Sima,&nbsp;Xiaoyao Ji,&nbsp;Feihua Wu,&nbsp;Yining Lin","doi":"10.1208/s12249-024-03015-1","DOIUrl":"10.1208/s12249-024-03015-1","url":null,"abstract":"<div><p>Albendazole serves as a broad-spectrum anthelmintic medication for treating hydatid cysts and neurocysticercosis. However, its therapeutic effectiveness is limited by poor solubility. Nanocrystals offer a promising technology to address this limitation by enhancing drug solubility. The objective of this study is to evaluate an effective stabilizer for creating an albendazole nanocrystal formulation to improve oral absorption. Among different surfactants and polymers examined, tea saponins were used as the stabilizer to develop a nanosuspension with the particle size of 180 nm through a wet grinding approach. The physical characteristics of the nanocrystals were assessed using SEM, DSC, and XRPD. The nanocrystals significantly enhanced solubility by 2.9–2602 fold in different media and showed significant enhancement in dissolution rate compared to albendazole crystals in both pH 1.0 and pH 6.8 medium. Everted gut sacs experiments demonstrated that the nanocrystals increased <i>P</i>_app by 3.60-fold in duodenum, 3.76-fold in jejunum, 3.71-fold in ileum, and 5.26-fold in colon, respectively. Furthermore, pharmacokinetic studies revealed that the nanocrystals significantly enhanced oral bioavailability, resulting in a 4.65-fold increase in plasma AUC_0−t value of albendazole sulfoxide (the primary active metabolite of albendazole) compared to the albendazole group. The present data indicates that tea saponins are potential natural stabilizers for preparing nanocrystals with enhanced oral bioavailability for insoluble drugs.</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":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939106","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}

{"title":"New Ionic Liquid Forms of Antituberculosis Drug Combinations for Optimized Stability and Dissolution","authors":"Hanan E. Rasmy,&nbsp;Sara A. Abouelmagd,&nbsp;Elsayed A. Ibrahim","doi":"10.1208/s12249-024-03023-1","DOIUrl":"10.1208/s12249-024-03023-1","url":null,"abstract":"<div><p>Isoniazid (INH) and rifampicin (RIF) are the two main drugs used for the management of tuberculosis. They are often used as a fixed drug combination, but their delivery is challenged by suboptimal solubility and physical instability. This study explores the potential of active pharmaceutical ingredient-ionic liquids (API-ILs) to improve the physicochemical and pharmaceutical properties of INH and RIF. Antitubercular drugs, INH, or RIF, were paired with different counter ions (ascorbic acid (AsA), citric acid (CA), tartaric acid (TA), benzoic acid (BA), salicylic acid (SA), and p-amino salicylic acid (PAS)) using the solvent evaporation method. INH and RIF API-ILs were formed successfully using AsA and CA counter ions. IL formation was examined and analyzed using Fourier transform infrared (FTIR) spectroscopy, x-ray powder diffraction (XRPD), and polarized optical microscopy (POM). XRPD and POM confirmed their amorphous nature, while FTIR analysis demonstrated the contribution of hydrogen bonding to IL formation. IL formation enhanced the storage stability of the INH + RIF mixture in the presence of CA. Moreover, RIF-CA IL significantly increased the rate and extent of RIF dissolution. An effect that is unattainable with the RIF/CA physical mixture. Thus, API-IL formation not only enhances RIF dissolution but also facilitates the preparation of stable, compatible INH-RIF combinations.</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":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-024-03023-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939197","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}

{"title":"Investigation of the Thermal Stability and Hydrolytic Degradation Kinetics of Poly(Lactide-co-Glycolide) Melts","authors":"Beibei Chen,&nbsp;Mark A. Costello,&nbsp;Louise Kuehster,&nbsp;Nathaniel A. Lynd,&nbsp;Bin Qin,&nbsp;Yan Wang,&nbsp;Feng Zhang","doi":"10.1208/s12249-024-03018-y","DOIUrl":"10.1208/s12249-024-03018-y","url":null,"abstract":"<div><p>Poly(lactide-co-glycolide) (PLGA) is widely used in a variety of long-acting injectables. However, its biodegradable nature creates potential chemical stability challenges during melt extrusion, where PLGA is exposed to elevated temperature (100–140 °C) for several minutes. This study evaluated the thermal stability of three PLGA grades (Resomer® 502, 502H, and 505) with varying molecular weights and chain-ends using a differential scanning calorimeter and twin-screw extruder. DSC results revealed that both residual water content and chain-end groups significantly accelerate PLGA degradation. At 0.2% water content, all samples maintained good stability (less than 15% reduction in molecular weight). However, at 0.4% water content, Resomer 502H, which has acid end groups, experienced significant degradation (45% reduction in molecular weight) after 30 min at 140 °C due to catalyzed hydrolysis. The extruded samples remained stable across tested barrel temperatures (100 °C and 140 °C) and screw speeds (125 and 250 rpm). Further investigations of PLGA with 0.2% water content demonstrates that the hydrolysis rates of Resomer® 502 and 505 were comparable, indicating that molecular weight does not influence hydrolysis rate. In contrast, Resomer® 502H exhibited a higher hydrolysis rate and a slightly higher activation energy, suggesting a greater temperature dependency. Additionally, when subjected to 200 °C for one hour with less than 0.03% water content, Resomer® 505 showed a less than 7% reduction in molecular weight, indicating minimal thermal degradation. Conversely, Resomer® 502 and 502H experienced an increase in molecular weight, which was likely attributed to recombination reactions, particularly in Resomer® 502H, which has higher tin content (170 ppm).</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":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939201","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}

{"title":"In Silico and Experimental Evidence for the Stabilization of rhEPO by Glycine, Glutamic Acid and Lysine","authors":"Yoshio Aldo Alarcón-López,&nbsp;Pablo Aguirre-Vidal,&nbsp;Hugo Víctor Vásquez-Valadez,&nbsp;Alejandro Manuel Hernández-Serda,&nbsp;Alfonso Luis Cárdenas-Granados,&nbsp;Carlos E. Espinosa de la Garza,&nbsp;Néstor O. Pérez,&nbsp;Enrique Angeles,&nbsp;Víctor Pérez Medina Martínez","doi":"10.1208/s12249-024-03008-0","DOIUrl":"10.1208/s12249-024-03008-0","url":null,"abstract":"<div><p>The available literature indicates that amino acids can stabilize proteins. Our experimental data demonstrated that lysine and glutamic acid can stabilize recombinant human erythropoietin (rhEPO) at 40°C for at least 1 month, as measured by RP-UPLC. Studies with different excipient concentrations demonstrated optimal concentrations of these amino acids within 10–12 mM. The results suggest that a lower concentration of amino acids may not be sufficient to stabilize formulations, while a higher concentration of amino acids can lead lower stability. In silico studies highlighted the importance of the FA4G4S4 model in experimental glycosylation determination, particularly in glycoprotein analysis. We obtained insights into the interactions between the glycosylated ligands of rhEPO and amino acids, as well as their impact on protein behavior and stability. We observed different interactions between the amino acids glycine, glutamic acid, and lysine and the rhEPO protein using this model in docking experiments. They also made it easier to find specific interaction areas by analyzing ligand‒protein interaction fingerprints (PLIFs). This demonstrated how the ligands bind to the proteins or remain outside their vicinity. Furthermore, this study revealed specific places where ligands and rhEPO residues can interact, which helps us learn more about how they stabilize rhEPO.</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":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939108","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}

{"title":"Therapeutic Potential of Microneedle Assisted Drug Delivery for Wound Healing: Current State of the Art, Challenges, and Future Perspective","authors":"Devesh Kumar,&nbsp;Shubham Pandey,&nbsp;Jailani Shiekmydeen,&nbsp;Mohit Kumar,&nbsp;Shruti Chopra,&nbsp;Amit Bhatia","doi":"10.1208/s12249-024-03017-z","DOIUrl":"10.1208/s12249-024-03017-z","url":null,"abstract":"<div><p>Microneedles (MNs) appear as a transformative and minimally invasive platform for transdermal drug delivery, representing a highly promising strategy in wound healing therapeutics. This technology, entailing the fabrication of micron-scale needle arrays, enables the targeted and efficient delivery of bioactive agents into the epidermal and dermal layers without inducing significant pain or discomfort. The precise penetration of MNs facilitates localized and sustained drug release, which significantly enhances tissue regeneration and accelerates wound closure. Furthermore, MNs can be engineered to encapsulate essential bioactive compounds, including antimicrobial agents, growth factors, and stem cells, which are critical for modulating the wound healing cascade and mitigating infection risk. The biodegradable nature of these MNs obviates the need for device removal, rendering them particularly advantageous in the management of chronic wounds such as diabetic ulcers and pressure sores. The integration of nanotechnology within MNs further augments their drug-loading capacity, stability, and controlled-release kinetics, offering a sophisticated therapeutic modality. This cutting-edge approach has the potential to redefine wound care by optimizing therapeutic efficacy, reducing adverse effects, and enhancing patient adherence. As MN technology advances, its application in wound healing exemplifies a dynamic frontier within biomedical engineering and regenerative medicine.</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":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939200","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}

{"title":"Multi-Layered Microneedles Loaded with Microspheres","authors":"Andrew R. Tadros,&nbsp;Xin Dong Guo,&nbsp;Mark R. Prausnitz","doi":"10.1208/s12249-024-03016-0","DOIUrl":"10.1208/s12249-024-03016-0","url":null,"abstract":"<div><p>Delivery of therapies into skin is attractive for medical indications including vaccination and treatment of dermatoses but is highly constrained by the stratum corneum barrier. Microneedle (MN) patches have emerged as a promising technology to enable non-invasive, intuitive, and low-cost skin delivery. When combined with biodegradable polymer formulations, MN patches can further enable controlled-release drug delivery without injection. Herein, we sought to expand on the capability of MN patches to deliver therapies into skin by providing improved spatiotemporal control. Polylactic-co-glycolic acid (PLGA) microspheres were used to encapsulate model dye and then loaded into MN patches through a layer-by-layer fabrication method that created multiple layers of different composition within each MN. MN patches were loaded with up to 5 μg/MN of PLGA microspheres. Mechanical testing demonstrated that mechanical strength of MNs decreased with increasing number of microsphere layers. Microsphere-loaded MN patches inserted into porcine skin <i>ex vivo</i> and murine skin <i>in vivo</i> fully dissolved within 15 min, administering drug-loaded microspheres for controlled release lasting over 45 days. These data support the feasibility of multi-layered, microsphere-loaded MN patches designed for spatially targeted and sustained delivery of therapies into skin.</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":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925578","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}

{"title":"Use of Remote Regulatory Assessment (RRA) for Site Evaluations during the COVID-19 Pandemic: The USFDA’s Office of Study Integrity and Surveillance (OSIS) Perspective","authors":"Tahseen Mirza,&nbsp;Nicola Fenty-Stewart,&nbsp;Clint Mitchell,&nbsp;Brian Folian,&nbsp;Sean Kassim","doi":"10.1208/s12249-024-03024-0","DOIUrl":"10.1208/s12249-024-03024-0","url":null,"abstract":"<div><p>Travel restrictions during the novel coronavirus, SARS-CoV-2 (COVID-19) public health emergency affected the U.S. Food and Drug Administration’s (FDA) ability to conduct on-site bioavailability/bioequivalence (BA/BE) and Good Laboratory Practice (GLP) nonclinical inspections. FDA’s Office of Study Integrity and Surveillance (OSIS) developed a remote regulatory assessment (RRA) as an alternate tool to evaluate the reliability and integrity of data from such studies submitted in marketing applications for drug approval. This manuscript provides a retrospective comparative evaluation of metrics from three pre-pandemic years (2017–2019) <i>versus</i> those of RRAs performed during the COVID-19 pandemic (2020–2022). More clinical inspections than analytical inspections were conducted during the pre-pandemic years, while this trend was reversed during the pandemic years. A normalized comparison of inspections and RRAs revealed that RRAs were able to identify potential concerns in study conduct and data reliability comparable to on-site BA/BE and GLP nonclinical study inspections. The number of studies, types of studies, and final classification of site evaluations were reviewed. During the pandemic years, fewer RRAs were performed by OSIS as compared with the number of on-site inspections performed by OSIS during the pre-pandemic years. This can be attributed in part to the dedication of resources for the development of the RRA approach, the need to focus all efforts on the highest priority sites, the limited availability of staff, or the lack of adequate data sharing software or audio-visual hardware at the sites.</p></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925542","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}

{"title":"Amorphous Solid Dispersions of Glycyrrhetinic Acid: Using Soluplus, PVP, and PVPVA as the Polymer Matrix to Enhance Solubility, Bioavailability, and Stability","authors":"Meng-yu Zhao,&nbsp;Xian-bao Shi,&nbsp;Jin-hua Chang,&nbsp;Ru-xing Wang,&nbsp;Jian-yu Zhou,&nbsp;Pei Liu","doi":"10.1208/s12249-024-03007-1","DOIUrl":"10.1208/s12249-024-03007-1","url":null,"abstract":"<div><p>Glycyrrhetinic acid (GA) possesses various pharmacological effects, including anti-inflammatory, anti-tumor, and anti-viral properties. However, its clinical application is limited by poor solubility and low oral bioavailability. Polymers play a crucial role in pharmaceutical formulations, particularly as matrices in excipients to enhance the solubility, bioavailability, and stability of active pharmaceutical ingredients. The amorphous solid dispersions (ASDs) of GA were prepared with three different polymers (i.e., GA-S-ASD, GA-VA64-ASD, and GA-K30-ASD). The ASDs were characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR spectroscopy), molecular docking, and contact angle measurement. Pharmacokinetics were evaluated in Beagle dogs, and long-term stability was examined. The solubility of GA increased with the rising weight of the polymer, and the optimal drug-to-carrier ratio was 1:5. In all ASDs, GA was amorphous, thus suggesting that a hydrogen bonding must have formed between GA and the polymers. The molecular docking showed that the binding energy was the highest and the hydrogen bonding was the strongest between GA and Soluplus. The dissolution of the ASDs was primarily driven by carrier-controlled dissolution, and there was minor influence from diffusion-limited release in the case of GA-S-ASD. The three ASDs significantly improved the bioavailability of GA. However, only GA-S-ASD passed the accelerated stability test. In the case of GA-VA64-ASD and GA-K30-ASD, due to serious moisture absorption, the originally fluffy ASDs became gels, and recrystallization occurred. Overall, GA-S-ASD presents promising potential for pharmaceutical applications due to its superior solubility, bioavailability, and stability.</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":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142859797","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}

{"title":"Gene Therapy: Towards a New Era of Medicine","authors":"Mokshit Bhagat,&nbsp;Raj Kamal,&nbsp;Jyoti Sharma,&nbsp;Kirandeep Kaur,&nbsp;Amit Sharma,&nbsp;Gurjeet Singh Thakur,&nbsp;Rohit Bhatia,&nbsp;Ankit Awasthi","doi":"10.1208/s12249-024-03010-6","DOIUrl":"10.1208/s12249-024-03010-6","url":null,"abstract":"<div><p>Over the past years, many significant advances have been made in the field of gene therapy and shown promising results in clinical trials conducted. Gene therapy aims at modifying or replacing a defective, inefficient, or nonfunctional gene with a healthy, functional gene by administration of genome material into the cell to cure genetic diseases. Various methods have been devised to do this by using several viral and non-viral vectors which are either administered by <i>in vivo</i> or <i>ex vivo</i> technique. Viral vectors are best suitable for this therapy due to their potential to invade cells and deliver their genetic material whereas non-viral vectors are less efficient than viral vectors but possess some advantages such as less immunogenic response and large gene carrying capacity. Recent advances in biotechnology such as CRISPR-Cas9 mediated genome engineering and Cancer treatment with Chimeric antigen receptor (CAR) T-cell therapy are addressed in this review. This review article also delves into some recent research studies, gene therapy trials, and its applications, laying out future hopes for gene therapy in the treatment of various diseases namely haemophilia, Muscular dystrophy, SCID, Sickle cell disease, Familial Hypercholesterolemia, Cystic Fibrosis. Additionally, it also includes various nanoformulations and clinical trial data related to gene therapy.</p><h3>Graphical Abstract</h3><p>Gene therapy is a technique that aims at altering or replacing a defective gene with a healthy functional gene by administration of genetic material into the cell. The Ex-vivo technique involves transfer of genetic material by modifying the cell outside the body and transplanting it back into a patient. In the In-vivo technique genetic material is directly transferred into the patient’s body by using a liposome or viral vector.</p>\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":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142859582","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}

{"title":"Establishment of Biopredictive Dissolution and Bioequivalence Safe Space Using the Physiologically Based Biopharmaceutics Modeling for Tacrolimus Extended-Release Capsules","authors":"Fulin Bi,&nbsp;Tong Yuan,&nbsp;Baohong Zhang,&nbsp;Jixia Li,&nbsp;Yan Lin,&nbsp;Jin Yang","doi":"10.1208/s12249-024-03006-2","DOIUrl":"10.1208/s12249-024-03006-2","url":null,"abstract":"<div><p>A slight variation in <i>in vivo</i> exposure for tacrolimus extended-release (ER) capsules, which have a narrow therapeutic index (NTI), significantly affects the pharmacodynamics of the drug. Generic drug bioequivalence (BE) standards are stricter, necessitating accurate assessment of the rate and extent of drug release. Therefore, an <i>in vitro</i> dissolution method with high <i>in vivo</i> predictive power is crucial for developing generic drugs. In this study, physiologically based biopharmaceutics modeling (PBBM) for 5 mg tacrolimus ER capsules was developed and validated. The reference and non-BE test formulations were assessed using the Flow-Through Cell apparatus (USP IV) with biorelevant media to establish a biopredictive dissolution method. Using PBBM, virtual bioequivalence trials with virtual batches were conducted to propose a BE safe space. These criteria can identify formulations that pass the internal quality control test but are likely non-BE. This study highlights the benefits of developing biopredictive dissolution methods that are based on biorelevant dissolution. The PBBM, constructed by integrating various drug parameters, combined with the developed biopredictive dissolution methods, is a convenient approach for BE evaluation of NTI drugs and a practical tool for developing new drugs.</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":"142844821","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}