Pub Date : 2024-08-20DOI: 10.1208/s12249-024-02913-8
Yanqiu Long, Fang Lei, Jie Hu, Zhiyun Zheng, Shuangying Gui, Ning He
The compound Salvia Recipe has been shown to have a relatively significant curative effect in management of cardiovascular and cerebrovascular diseases. This work aimed to prepare a thermosensitive in situ gel (ISG) delivery system that utilizes Poloxamer 407, Poloxamer 188, and hydroxypropyl methylcellulose for ocular administration of the compound Salvia recipe to treat cardiovascular and cerebrovascular diseases. The central composite design-response surface method was utilized to improve the prescription of the gel. The formulated gel was characterized and assessed in terms of stability, retention time, in vitro release, rheology, ocular irritation, pharmacokinetics studies, and tissue distribution. The gel was a liquid solution at room temperature and became semisolid at physiological temperature, prolonging its stay time in the eye. Pharmacokinetics and tissue distribution experiments indicated that thermosensitive ISG had enhanced targeting of heart and brain tissues. Additionally, it could lower drug toxicity and side effects in the lungs and kidneys. The compound Salvia ophthalmic thermosensitive ISG is a promising drug delivery system for the management of cardiovascular and cerebrovascular illnesses.
{"title":"Design and Evaluation of Ophthalmic Thermosensitive In Situ Gel of Compound Salvia.","authors":"Yanqiu Long, Fang Lei, Jie Hu, Zhiyun Zheng, Shuangying Gui, Ning He","doi":"10.1208/s12249-024-02913-8","DOIUrl":"https://doi.org/10.1208/s12249-024-02913-8","url":null,"abstract":"<p><p>The compound Salvia Recipe has been shown to have a relatively significant curative effect in management of cardiovascular and cerebrovascular diseases. This work aimed to prepare a thermosensitive in situ gel (ISG) delivery system that utilizes Poloxamer 407, Poloxamer 188, and hydroxypropyl methylcellulose for ocular administration of the compound Salvia recipe to treat cardiovascular and cerebrovascular diseases. The central composite design-response surface method was utilized to improve the prescription of the gel. The formulated gel was characterized and assessed in terms of stability, retention time, in vitro release, rheology, ocular irritation, pharmacokinetics studies, and tissue distribution. The gel was a liquid solution at room temperature and became semisolid at physiological temperature, prolonging its stay time in the eye. Pharmacokinetics and tissue distribution experiments indicated that thermosensitive ISG had enhanced targeting of heart and brain tissues. Additionally, it could lower drug toxicity and side effects in the lungs and kidneys. The compound Salvia ophthalmic thermosensitive ISG is a promising drug delivery system for the management of cardiovascular and cerebrovascular illnesses.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008052","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}
The intricate process of protein binding orchestrates crucial drug interactions within the bloodstream, facilitating the formation of soluble complexes. This research endeavours to improve the dissolution and oral bioavailability of Rifampicin (RMP) by strategically manipulating drug-protein binding dynamics and the hydrophobic characteristics of human serum albumin (HSA). Various precipitation techniques leveraging methanol, ammonium sulfate, and heat treatment were meticulously employed to tailor the properties of colloidal albumin (HSA NPs). The resultant complexes underwent comprehensive characterization encompassing evaluations of hydrophobicity, size distribution, surface charge, and structural analyses through FTIR, TG-DSC, XRD, and morphological examinations. The findings revealed a significant binding affinity of 78.07 ± 6.6% with native albumin, aligning with prior research. Notably, the complex RMP-HSA NPs-M13, synthesized via the methanolic precipitation method, exhibited the most substantial complexation, achieving a remarkable 3.5-fold increase, followed by the ammonium sulfate (twofold) and heat treatment (1.07-fold) methods in comparison to native albumin binding. The gastric simulated media exhibited accelerated drug release kinetics, with maximal dissolution achieved within two hours, contrasting with the prolonged release observed under intestinal pH conditions. These findings translated into significant improvements in drug permeation, as evidenced by pharmacokinetic profiles demonstrating elevated Cmax, AUC, t1/2, and MRT values for RMP-HSA NPs-M13 compared to free RMP. In summary, this innovative approach underscores the potential of precipitation methods in engineering stable colloidal carrier systems tailored to enhance the oral bioavailability of poorly soluble drugs, offering a pragmatic and scalable alternative to conventional surfactants, polymers, or high-energy methods for complex formation and production.
{"title":"Physicochemical Stimuli-Mediated Precipitation Approach for the Modulation of Rifampicin's Dissolution and Oral Bioavailability.","authors":"Vineet Kumar Rai, Deepak Pradhan, Jitu Halder, Tushar Kanti Rajwar, Ritu Mahanty, Ivy Saha, Priyanka Dash, Chandan Dash, Saroj Kumar Rout, Jameel Al-Tamimi, Hossan Ebaid, Salim Manoharadas, Biswakanth Kar, Goutam Ghosh, Goutam Rath","doi":"10.1208/s12249-024-02915-6","DOIUrl":"https://doi.org/10.1208/s12249-024-02915-6","url":null,"abstract":"<p><p>The intricate process of protein binding orchestrates crucial drug interactions within the bloodstream, facilitating the formation of soluble complexes. This research endeavours to improve the dissolution and oral bioavailability of Rifampicin (RMP) by strategically manipulating drug-protein binding dynamics and the hydrophobic characteristics of human serum albumin (HSA). Various precipitation techniques leveraging methanol, ammonium sulfate, and heat treatment were meticulously employed to tailor the properties of colloidal albumin (HSA NPs). The resultant complexes underwent comprehensive characterization encompassing evaluations of hydrophobicity, size distribution, surface charge, and structural analyses through FTIR, TG-DSC, XRD, and morphological examinations. The findings revealed a significant binding affinity of 78.07 ± 6.6% with native albumin, aligning with prior research. Notably, the complex RMP-HSA NPs-M13, synthesized via the methanolic precipitation method, exhibited the most substantial complexation, achieving a remarkable 3.5-fold increase, followed by the ammonium sulfate (twofold) and heat treatment (1.07-fold) methods in comparison to native albumin binding. The gastric simulated media exhibited accelerated drug release kinetics, with maximal dissolution achieved within two hours, contrasting with the prolonged release observed under intestinal pH conditions. These findings translated into significant improvements in drug permeation, as evidenced by pharmacokinetic profiles demonstrating elevated Cmax, AUC, t1/2, and MRT values for RMP-HSA NPs-M13 compared to free RMP. In summary, this innovative approach underscores the potential of precipitation methods in engineering stable colloidal carrier systems tailored to enhance the oral bioavailability of poorly soluble drugs, offering a pragmatic and scalable alternative to conventional surfactants, polymers, or high-energy methods for complex formation and production.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003359","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}
Currently, artificial intelligence (AI), machine learning (ML), and deep learning (DL) are gaining increased interest in many fields, particularly in pharmaceutical research and development, where they assist in decision-making in complex situations. Numerous research studies and advancements have demonstrated how these computational technologies are used in various pharmaceutical research and development aspects, including drug discovery, personalized medicine, drug formulation, optimization, predictions, drug interactions, pharmacokinetics/ pharmacodynamics, quality control/quality assurance, and manufacturing processes. Using advanced modeling techniques, these computational technologies can enhance efficiency and accuracy, handle complex data, and facilitate novel discoveries within minutes. Furthermore, these technologies offer several advantages over conventional statistics. They allow for pattern recognition from complex datasets, and the models, typically developed from data-driven algorithms, can predict a given outcome (model output) from a set of features (model inputs). Additionally, this review discusses emerging trends and provides perspectives on the application of AI with quality by design (QbD) and the future role of AI in this field. Ethical and regulatory considerations associated with integrating AI into pharmaceutical technology were also examined. This review aims to offer insights to researchers, professionals, and others on the current state of AI applications in pharmaceutical research and development and their potential role in the future of research and the era of pharmaceutical Industry 4.0 and 5.0.
{"title":"The Artificial Intelligence-Powered New Era in Pharmaceutical Research and Development: A Review.","authors":"Phuvamin Suriyaamporn, Boonnada Pamornpathomkul, Prasopchai Patrojanasophon, Tanasait Ngawhirunpat, Theerasak Rojanarata, Praneet Opanasopit","doi":"10.1208/s12249-024-02901-y","DOIUrl":"10.1208/s12249-024-02901-y","url":null,"abstract":"<p><p>Currently, artificial intelligence (AI), machine learning (ML), and deep learning (DL) are gaining increased interest in many fields, particularly in pharmaceutical research and development, where they assist in decision-making in complex situations. Numerous research studies and advancements have demonstrated how these computational technologies are used in various pharmaceutical research and development aspects, including drug discovery, personalized medicine, drug formulation, optimization, predictions, drug interactions, pharmacokinetics/ pharmacodynamics, quality control/quality assurance, and manufacturing processes. Using advanced modeling techniques, these computational technologies can enhance efficiency and accuracy, handle complex data, and facilitate novel discoveries within minutes. Furthermore, these technologies offer several advantages over conventional statistics. They allow for pattern recognition from complex datasets, and the models, typically developed from data-driven algorithms, can predict a given outcome (model output) from a set of features (model inputs). Additionally, this review discusses emerging trends and provides perspectives on the application of AI with quality by design (QbD) and the future role of AI in this field. Ethical and regulatory considerations associated with integrating AI into pharmaceutical technology were also examined. This review aims to offer insights to researchers, professionals, and others on the current state of AI applications in pharmaceutical research and development and their potential role in the future of research and the era of pharmaceutical Industry 4.0 and 5.0.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987140","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 : 2024-08-14DOI: 10.1208/s12249-024-02866-y
Malaz Yousef, Chulhun Park, Nadia Bou Chacra, Neal M Davies, Raimar Löbenberg
Conventional dissolution tests only assess the aqueous release of drugs to ensure quality and performance, without indicating whether absorption occurs through the portal or the lymphatic circulation. To address this issue, this study aimed to develop novel first-generation dissolution models that could investigate the release and uptake of oral lymphotropic drugs and examine relevant formulation issues. Dissolution of three commercial lymphotropic drug products (Terbinafina, Apo-terbinafine, and Lamisil) was done using modified versions of USP Apparatus II and IV. The developed models contained a lymphatic compartment filled with artificial chylomicrons to account for absorption through intestinal lymphatic pathway. The various products exhibited different release profiles into the aqueous media and the lymphatic media across the two tested models. The modified USP IV apparatus demonstrated greater distinction in aqueous release patterns. However, the release pattern into the lymphatic media remained similar in both models. This work represents a progress in meeting the challenges posed by the increasing complexity of pharmaceutical products containing lipophilic drugs or formulations, and has the potential to contribute towards the development of in-vitro bioequivalence standards for formulations targeting intestinal lymphatics.
传统的溶出试验只能评估药物的水释放情况,以确保药物的质量和性能,而不能说明药物是通过门静脉还是淋巴循环吸收的。针对这一问题,本研究旨在开发新型的第一代溶出度模型,以研究口服促淋巴药物的释放和吸收,并探讨相关的制剂问题。使用 USP Apparatus II 和 IV 的改良版,对三种商业淋巴药物产品(特比萘芬、Apo-terbinafine 和拉米西尔)进行了溶出试验。所开发的模型包含一个淋巴室,内装人造乳糜微粒,以考虑通过肠道淋巴途径的吸收。在两种测试模型中,各种产品在水介质和淋巴介质中的释放曲线各不相同。改良的 USP IV 仪器在水介质释放模式方面表现出更大的差异。不过,两种模型在淋巴介质中的释放模式仍然相似。这项工作标志着我们在应对含有亲脂性药物或制剂的药品日益复杂所带来的挑战方面取得了进展,并有可能为针对肠道淋巴管的制剂制定体外生物等效性标准做出贡献。
{"title":"Novel First-Generation Dissolution Models to Investigate the Release and Uptake of Oral Lymphotropic Drug Products.","authors":"Malaz Yousef, Chulhun Park, Nadia Bou Chacra, Neal M Davies, Raimar Löbenberg","doi":"10.1208/s12249-024-02866-y","DOIUrl":"10.1208/s12249-024-02866-y","url":null,"abstract":"<p><p>Conventional dissolution tests only assess the aqueous release of drugs to ensure quality and performance, without indicating whether absorption occurs through the portal or the lymphatic circulation. To address this issue, this study aimed to develop novel first-generation dissolution models that could investigate the release and uptake of oral lymphotropic drugs and examine relevant formulation issues. Dissolution of three commercial lymphotropic drug products (Terbinafina, Apo-terbinafine, and Lamisil) was done using modified versions of USP Apparatus II and IV. The developed models contained a lymphatic compartment filled with artificial chylomicrons to account for absorption through intestinal lymphatic pathway. The various products exhibited different release profiles into the aqueous media and the lymphatic media across the two tested models. The modified USP IV apparatus demonstrated greater distinction in aqueous release patterns. However, the release pattern into the lymphatic media remained similar in both models. This work represents a progress in meeting the challenges posed by the increasing complexity of pharmaceutical products containing lipophilic drugs or formulations, and has the potential to contribute towards the development of in-vitro bioequivalence standards for formulations targeting intestinal lymphatics.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981462","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 : 2024-08-13DOI: 10.1208/s12249-024-02907-6
Nadina Zulbeari, René Holm
Aqueous suspensions containing crystalline drug in the sub-micron range is a favorable platform for long-acting injectables where particle size can be used to obtain a desired plasma-concentration profile. Stabilizers are added to the suspensions and screened extensively to define the optimal formulation composition. In the initial formulation screening the amount of drug compound can be limited, necessitating milling methods for small-volume screening predictable for scale-up. Hence, adaptive focused ultrasound was investigated as a potential milling method for rapid small-volume suspensions by identifying the critical process parameters during preparation. Suspensions containing drug compounds with different mechanical properties and thereby grindability, i.e., cinnarizine, haloperidol, and indomethacin with brittle, elastic, and plastic properties, respectively, were investigated to gain an understanding of the manufacturing with adaptive focused acoustics as well as comparison to already established milling techniques. Using a DoE-design, peak incident power was identified as the most crucial process parameter impacting the milling process for all three compounds. It was possible to decrease the sizes of drug particles to micron range after one minute of focused ultrasound exposure which was superior compared to other milling techniques (e.g., non-focused ultrasound exposure). The addition of milling beads decreased the drug particle sizes even further, thus to a lower degree than other already established milling techniques such as milling by dual centrifugation. This study thereby demonstrated that adaptive focused ultrasonication was a promising method for rapid homogenization and particle size reduction to micron range for different compounds varying in grindability without altering the crystalline structure.
含有亚微米级结晶药物的水悬浮液是长效注射剂的一个有利平台,可利用其粒度获得理想的血浆浓度曲线。在悬浮液中加入稳定剂,并进行广泛筛选,以确定最佳配方成分。在最初的制剂筛选中,药物化合物的用量可能有限,因此必须采用可预测放大的研磨方法进行小剂量筛选。因此,研究人员通过确定制备过程中的关键工艺参数,将自适应聚焦超声作为一种潜在的研磨方法,用于快速制备小容量悬浮液。为了了解自适应聚焦超声技术的制造工艺,并与已有的研磨技术进行比较,研究人员对含有不同机械性能从而具有不同研磨性的药物化合物(即分别具有脆性、弹性和塑性的西那利嗪、氟哌啶醇和吲哚美辛)的悬浮液进行了调查。通过 DoE 设计,峰值入射功率被确定为影响所有三种化合物研磨过程的最关键工艺参数。聚焦超声波照射一分钟后,药物颗粒的尺寸就能减小到微米范围,这比其他研磨技术(如非聚焦超声波照射)更优越。研磨珠的加入进一步减小了药物颗粒的尺寸,因此其减小程度低于其他已经成熟的研磨技术,如双离心研磨技术。这项研究由此证明,自适应聚焦超声是一种很有前途的方法,可以在不改变晶体结构的情况下,将不同研磨性的化合物快速均质并将粒径减小到微米范围。
{"title":"A Systematic Investigation of Process Parameters for Small-Volume Aqueous Suspension Production by the Use of Focused Ultrasonication.","authors":"Nadina Zulbeari, René Holm","doi":"10.1208/s12249-024-02907-6","DOIUrl":"10.1208/s12249-024-02907-6","url":null,"abstract":"<p><p>Aqueous suspensions containing crystalline drug in the sub-micron range is a favorable platform for long-acting injectables where particle size can be used to obtain a desired plasma-concentration profile. Stabilizers are added to the suspensions and screened extensively to define the optimal formulation composition. In the initial formulation screening the amount of drug compound can be limited, necessitating milling methods for small-volume screening predictable for scale-up. Hence, adaptive focused ultrasound was investigated as a potential milling method for rapid small-volume suspensions by identifying the critical process parameters during preparation. Suspensions containing drug compounds with different mechanical properties and thereby grindability, i.e., cinnarizine, haloperidol, and indomethacin with brittle, elastic, and plastic properties, respectively, were investigated to gain an understanding of the manufacturing with adaptive focused acoustics as well as comparison to already established milling techniques. Using a DoE-design, peak incident power was identified as the most crucial process parameter impacting the milling process for all three compounds. It was possible to decrease the sizes of drug particles to micron range after one minute of focused ultrasound exposure which was superior compared to other milling techniques (e.g., non-focused ultrasound exposure). The addition of milling beads decreased the drug particle sizes even further, thus to a lower degree than other already established milling techniques such as milling by dual centrifugation. This study thereby demonstrated that adaptive focused ultrasonication was a promising method for rapid homogenization and particle size reduction to micron range for different compounds varying in grindability without altering the crystalline structure.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974750","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 : 2024-08-13DOI: 10.1208/s12249-024-02894-8
Nuttawut Supachawaroj, Sucharat Limsitthichaikoon
Local anesthesia is essential in dental practices, particularly for managing pain in tooth socket wounds, yet improving drug delivery systems remains a significant challenge. This study explored the physicochemical characteristics of lidocaine hydrochloride (LH) incorporated into a polyelectrolyte complex and poloxamer thermosensitivity hydrogel, assessing its local anesthetic efficacy in mouse models and its onset and duration of action as topical anesthetics in clinical trials. The thermoresponsive hydrogel exhibited a rapid phase transition within 1-3 minutes and demonstrated pseudo-plastic flow behavior. Its release kinetics followed Korsmeyer-Peppas, with 50% of biodegradation occurring over 48 h. In mouse models, certain thermogels showed superior anesthetic effects, with rapid onset and prolonged action, as evidenced by heat tolerance in tail-flick and hot plate models. In clinical trials, the LH-loaded thermoresponsive hydrogel provided rapid numbness onset, with anesthesia (Ton) beginning at an average of 46.5 ± 22.5 seconds and lasting effectively (Teff) for 202.5 ± 41.0 seconds, ranging from 120 to 240 seconds, indicating sustained release. These results highlight the promising properties of these formulations: rapid onset, prolonged duration, mucoadhesion, biodegradability, and high anesthesia effectiveness. This study demonstrates the potential for advancing local anesthesia across various medical fields, emphasizing the synergy between material science and clinical applications to improve patient care and safety.
{"title":"Lidocaine HCl-Loaded Polyelectrolyte Complex -Poloxamer Thermoresponsive Hydrogel: In Vitro- In Vivo Anesthetic Evaluations for Tooth Socket Wound Delivery.","authors":"Nuttawut Supachawaroj, Sucharat Limsitthichaikoon","doi":"10.1208/s12249-024-02894-8","DOIUrl":"10.1208/s12249-024-02894-8","url":null,"abstract":"<p><p>Local anesthesia is essential in dental practices, particularly for managing pain in tooth socket wounds, yet improving drug delivery systems remains a significant challenge. This study explored the physicochemical characteristics of lidocaine hydrochloride (LH) incorporated into a polyelectrolyte complex and poloxamer thermosensitivity hydrogel, assessing its local anesthetic efficacy in mouse models and its onset and duration of action as topical anesthetics in clinical trials. The thermoresponsive hydrogel exhibited a rapid phase transition within 1-3 minutes and demonstrated pseudo-plastic flow behavior. Its release kinetics followed Korsmeyer-Peppas, with 50% of biodegradation occurring over 48 h. In mouse models, certain thermogels showed superior anesthetic effects, with rapid onset and prolonged action, as evidenced by heat tolerance in tail-flick and hot plate models. In clinical trials, the LH-loaded thermoresponsive hydrogel provided rapid numbness onset, with anesthesia (T<sub>on</sub>) beginning at an average of 46.5 ± 22.5 seconds and lasting effectively (T<sub>eff</sub>) for 202.5 ± 41.0 seconds, ranging from 120 to 240 seconds, indicating sustained release. These results highlight the promising properties of these formulations: rapid onset, prolonged duration, mucoadhesion, biodegradability, and high anesthesia effectiveness. This study demonstrates the potential for advancing local anesthesia across various medical fields, emphasizing the synergy between material science and clinical applications to improve patient care and safety.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974753","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}
The dissolution and bioavailability challenges posed by poorly water-soluble drugs continue to drive innovation in pharmaceutical formulation design. Nintedanib (NDNB) is a typical BCS class II drug that has been utilized to treat idiopathic pulmonary fibrosis (IPF). Due to the low solubility, its oral bioavailability is relatively low, limiting its therapeutical effectiveness. It is crucial to enhance the dissolution and the oral bioavailability of NDNB. In this study, we focused on the preparation of amorphous solid dispersions (ASD) using hot melt extrusion (HME). The formulation employed Kollidon® VA64 (VA64) as the polymer matrix, blended with the NDNB at a ratio of 9:1. HME was conducted at temperatures ranging from 80 °C to 220 °C. The successful preparation of ASD was confirmed through various tests including polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). The in-vitro cumulative release of NDNB-ASD in 2 h in a pH 6.8 medium was 8.3-fold higher than that of NDNB (p < 0.0001). In a pH 7.4 medium, it was 10 times higher (p < 0.0001). In the in-vivo pharmacokinetic experiments, the area under curve (AUC) of NDNB-ASD was 5.3-fold higher than that of NDNB and 2.2 times higher than that of commercially available soft capsules (Ofev®) (p < 0.0001). There was no recrystallization after 6 months under accelarated storage test. Our study indicated that NDNB-ASD can enhance the absorption of NDNB, thus providing a promising method to improve NDNB bioavailability in oral dosages.
{"title":"Preparation, Characterization and Evaluation of Nintedanib Amorphous Solid Dispersions with Enhanced Oral Bioavailability.","authors":"Shuyin Liu, Hui Chen, Feng Zhou, Sandip Tiwari, Kai Zhuang, Yudong Shan, Jiantao Zhang","doi":"10.1208/s12249-024-02902-x","DOIUrl":"10.1208/s12249-024-02902-x","url":null,"abstract":"<p><p>The dissolution and bioavailability challenges posed by poorly water-soluble drugs continue to drive innovation in pharmaceutical formulation design. Nintedanib (NDNB) is a typical BCS class II drug that has been utilized to treat idiopathic pulmonary fibrosis (IPF). Due to the low solubility, its oral bioavailability is relatively low, limiting its therapeutical effectiveness. It is crucial to enhance the dissolution and the oral bioavailability of NDNB. In this study, we focused on the preparation of amorphous solid dispersions (ASD) using hot melt extrusion (HME). The formulation employed Kollidon<sup>®</sup> VA64 (VA64) as the polymer matrix, blended with the NDNB at a ratio of 9:1. HME was conducted at temperatures ranging from 80 °C to 220 °C. The successful preparation of ASD was confirmed through various tests including polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). The in-vitro cumulative release of NDNB-ASD in 2 h in a pH 6.8 medium was 8.3-fold higher than that of NDNB (p < 0.0001). In a pH 7.4 medium, it was 10 times higher (p < 0.0001). In the in-vivo pharmacokinetic experiments, the area under curve (AUC) of NDNB-ASD was 5.3-fold higher than that of NDNB and 2.2 times higher than that of commercially available soft capsules (Ofev<sup>®</sup>) (p < 0.0001). There was no recrystallization after 6 months under accelarated storage test. Our study indicated that NDNB-ASD can enhance the absorption of NDNB, thus providing a promising method to improve NDNB bioavailability in oral dosages.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974754","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 : 2024-08-13DOI: 10.1208/s12249-024-02896-6
Mohamed A Akl, Muhammad Alaa Eldeen, Abdulsalam M Kassem
Transdermal administration techniques have gained popularity due to their advantages over oral and parenteral methods. Noninvasive, self-administered delivery devices improve patient compliance and control drug release. Transdermal delivery devices struggle with the skin's barrier function. Molecules over 500 Dalton (Da) and ionized compounds don't permeate through the skin. Drug encapsulation in phospholipid-based vesicular systems is the most effective skin delivery technique. Vesicular carriers include bi-layered liposomes, ultra-deformable liposomes, ethanolic liposomes, transethosomes, and invasomes. These technologies enhance skin drug permeation by increasing formula solubilization, partitioning into the skin, and fluidizing the lipid barrier. Phospholipid-based delivery systems are safe and efficient, making them a promising pharmaceutical and cosmeceutical drug delivery technique. Still, making delivery systems requires knowledge about the physicochemical properties of the drug and carrier, manufacturing and process variables, skin delivery mechanisms, technological advances, constraints, and regulatory requirements. Consequently, this review covers recent research achievements addressing the mentioned concerns.
{"title":"Beyond Skin Deep: Phospholipid-Based Nanovesicles as Game-Changers in Transdermal Drug Delivery.","authors":"Mohamed A Akl, Muhammad Alaa Eldeen, Abdulsalam M Kassem","doi":"10.1208/s12249-024-02896-6","DOIUrl":"10.1208/s12249-024-02896-6","url":null,"abstract":"<p><p>Transdermal administration techniques have gained popularity due to their advantages over oral and parenteral methods. Noninvasive, self-administered delivery devices improve patient compliance and control drug release. Transdermal delivery devices struggle with the skin's barrier function. Molecules over 500 Dalton (Da) and ionized compounds don't permeate through the skin. Drug encapsulation in phospholipid-based vesicular systems is the most effective skin delivery technique. Vesicular carriers include bi-layered liposomes, ultra-deformable liposomes, ethanolic liposomes, transethosomes, and invasomes. These technologies enhance skin drug permeation by increasing formula solubilization, partitioning into the skin, and fluidizing the lipid barrier. Phospholipid-based delivery systems are safe and efficient, making them a promising pharmaceutical and cosmeceutical drug delivery technique. Still, making delivery systems requires knowledge about the physicochemical properties of the drug and carrier, manufacturing and process variables, skin delivery mechanisms, technological advances, constraints, and regulatory requirements. Consequently, this review covers recent research achievements addressing the mentioned concerns.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974751","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 : 2024-08-13DOI: 10.1208/s12249-024-02887-7
Yang Yang, Jiang Wang, Apipa Wanasathop, Mengmeng Niu, Priyanka Ghosh, Ahmed Zidan, Jianghong Gu, Robert Hunt, Patrick Faustino, Muhammad Ashraf, Xiaoming Xu
Winlevi® (clascoterone) topical cream (1%, w/w) was approved by the U.S. FDA for the treatment of acne vulgaris in patients 12 years of age and older. The active ingredient, clascoterone, is not stable in physiological solutions and can hydrolyze to cortexolone at body temperature. Instability of clascoterone poses a significant challenge in accurately assessing the rate and extent of clascoterone permeation in vitro. Therefore, the purpose of this study was to develop an in vitro skin permeation test (IVPT) method, and a robust analytical method, that can minimize hydrolyzation of clascoterone during the study for quantification of clascoterone. Two IVPT methods, using either vertical diffusion cells or flow-through cells, were developed and compared to evaluate in vitro permeation of clascoterone from Winlevi. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed to monitor the level of clascoterone and cortexolone in the IVPT samples. The analytical method features a 2-min high-throughput analysis with good linearity, selectivity, and showed a lower limit of quantitation (LLOQ) of 0.5 ng/mL for both clascoterone and cortexolone. The in vitro skin permeation of clascoterone and cortexolone was observed as early as 2 h in both IVPT methods. A substantive amount of clascoterone was found to hydrolyze to cortexolone when using the vertical static diffusion cells with aliquot sampling. Conversely, degradation of clascoterone was significantly minimized when using the flow-through diffusion cells with fractional sampling. The data enhanced our understanding of in vitro permeation of clascoterone following topical application of the Winlevi topical cream, 1% and underscores the importance of IVPT method development and optimization during product development.
{"title":"Evaluation of in vitro Skin Permeation of Clascoterone From Clascoterone Topical Cream, 1% (w/w).","authors":"Yang Yang, Jiang Wang, Apipa Wanasathop, Mengmeng Niu, Priyanka Ghosh, Ahmed Zidan, Jianghong Gu, Robert Hunt, Patrick Faustino, Muhammad Ashraf, Xiaoming Xu","doi":"10.1208/s12249-024-02887-7","DOIUrl":"10.1208/s12249-024-02887-7","url":null,"abstract":"<p><p>Winlevi<sup>®</sup> (clascoterone) topical cream (1%, w/w) was approved by the U.S. FDA for the treatment of acne vulgaris in patients 12 years of age and older. The active ingredient, clascoterone, is not stable in physiological solutions and can hydrolyze to cortexolone at body temperature. Instability of clascoterone poses a significant challenge in accurately assessing the rate and extent of clascoterone permeation in vitro. Therefore, the purpose of this study was to develop an in vitro skin permeation test (IVPT) method, and a robust analytical method, that can minimize hydrolyzation of clascoterone during the study for quantification of clascoterone. Two IVPT methods, using either vertical diffusion cells or flow-through cells, were developed and compared to evaluate in vitro permeation of clascoterone from Winlevi. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed to monitor the level of clascoterone and cortexolone in the IVPT samples. The analytical method features a 2-min high-throughput analysis with good linearity, selectivity, and showed a lower limit of quantitation (LLOQ) of 0.5 ng/mL for both clascoterone and cortexolone. The in vitro skin permeation of clascoterone and cortexolone was observed as early as 2 h in both IVPT methods. A substantive amount of clascoterone was found to hydrolyze to cortexolone when using the vertical static diffusion cells with aliquot sampling. Conversely, degradation of clascoterone was significantly minimized when using the flow-through diffusion cells with fractional sampling. The data enhanced our understanding of in vitro permeation of clascoterone following topical application of the Winlevi topical cream, 1% and underscores the importance of IVPT method development and optimization during product development.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974752","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}
Palbociclib and ribociclib an orally bioavailable, potent cyclin-dependent kinase 4/6 inhibitors, with low oral bioavailability due to substrate specificity towards CYP3A and P-glycoprotein. Thus, current research aims to examine the effect of a bioenhancer (naringin), on oral pharmacokinetics of palbociclib and ribociclib. Naringin's affinity for CYP3A4 and P-glycoprotein was studied using molecular docking; its impact on palbociclib/ribociclib CYP3A metabolism and P-glycoprotein-mediated efflux was examined using in vitro preclinical models; and its oral pharmacokinetics in rats were assessed following oral administration of palbociclib/ribociclib in presence of naringin (50 and 100 mg/kg). Naringin binds optimally to both proteins with the highest net binding energy of - 1477.23 and - 1607.47 kcal/mol, respectively. The microsomal intrinsic clearance of palbociclib and ribociclib was noticeably reduced by naringin (5-100 µM), by 3.0 and 2.46-folds, respectively. Similarly, naringin had considerable impact on the intestinal transport and efflux of both drugs. The pre-treatment with 100 mg/kg naringin increased significantly (p < 0.05) the oral exposure of palbociclib (2.0-fold) and ribociclib (1.95-fold). Naringin's concurrent administration of palbociclib and ribociclib increased their oral bioavailability due to its dual inhibitory effect on CYP3A4 and P-glycoprotein; thus, concurrent naringin administration may represent an innovative strategy for enhancing bioavailability of cyclin-dependent kinase inhibitors.
{"title":"Strategy to Improve the Oral Pharmacokinetics of Cyclin-Dependent Kinase 4/6 Inhibitors: Enhancing Permeability and CYP450 Inhibition by a Natural Bioenhancer.","authors":"Prajakta Harish Patil, Mrunal Pradeep Desai, Rajat Radhakrishna Rao, Srinivas Mutalik, Jagadish Puralae Channabasavaiah","doi":"10.1208/s12249-024-02899-3","DOIUrl":"10.1208/s12249-024-02899-3","url":null,"abstract":"<p><p>Palbociclib and ribociclib an orally bioavailable, potent cyclin-dependent kinase 4/6 inhibitors, with low oral bioavailability due to substrate specificity towards CYP3A and P-glycoprotein. Thus, current research aims to examine the effect of a bioenhancer (naringin), on oral pharmacokinetics of palbociclib and ribociclib. Naringin's affinity for CYP3A4 and P-glycoprotein was studied using molecular docking; its impact on palbociclib/ribociclib CYP3A metabolism and P-glycoprotein-mediated efflux was examined using in vitro preclinical models; and its oral pharmacokinetics in rats were assessed following oral administration of palbociclib/ribociclib in presence of naringin (50 and 100 mg/kg). Naringin binds optimally to both proteins with the highest net binding energy of - 1477.23 and - 1607.47 kcal/mol, respectively. The microsomal intrinsic clearance of palbociclib and ribociclib was noticeably reduced by naringin (5-100 µM), by 3.0 and 2.46-folds, respectively. Similarly, naringin had considerable impact on the intestinal transport and efflux of both drugs. The pre-treatment with 100 mg/kg naringin increased significantly (p < 0.05) the oral exposure of palbociclib (2.0-fold) and ribociclib (1.95-fold). Naringin's concurrent administration of palbociclib and ribociclib increased their oral bioavailability due to its dual inhibitory effect on CYP3A4 and P-glycoprotein; thus, concurrent naringin administration may represent an innovative strategy for enhancing bioavailability of cyclin-dependent kinase inhibitors.</p>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141905504","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}