首页 > 最新文献

European Journal of Pharmaceutics and Biopharmaceutics最新文献

英文 中文
Formulation and clinical evaluation of carbidopa/levodopa oral solution for the treatment of sepiapterin reductase deficiency 用于治疗sepiapterin还原酶缺乏症的卡比多巴/左旋多巴口服溶液的配方和临床评估。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-07 DOI: 10.1016/j.ejpb.2024.114429

Background

sepiapterine reductase deficiency (SRD) is a rare levodopa (L-dopa)-responsive disorder treated with a combination therapy of controlled-release L-dopa and carbidopa. The currently available formulation of controlled-release carbidopa/L-dopa does not entirely meet the requirements for the long-term therapy in pediatric patients. In fact, administration of a manufactured tablet at a dose intended for adults necessitates its adjustment to the child’s needs, as the splitting of the tablet into smaller portions or its dilution in water. It’s essential to emphasize that tablets must not be crushed, as this can compromise the controlled-release mechanism and affect the efficacy of the medication. At the moment, commercial liquid formulations are not available. Given these limitations, in house drug preparation in hospitals and community pharmacies is a valid option to ensure the proper therapeutic management of these patients.

Materials and methods

we described sample preparation, physical and microbiological analyses, taste testing, and tolerability of a 1:10 ratio carbidopa/L-dopa flavored (mint, raspberry, cacao, berries) and unflavored oral formulation (no sweetening agents were added). We also reported long-term follow-up of two pediatric patients with SRD.

Results

we documented the stability for 28 days at 25 °C of the liquid solution. All formulations were well-tolerated, and no adverse events were observed during or after assessing taste and tolerability. The long-term follow up of two patients was characterized by effective symptom control and optimal treatment adherence and compliance.

Conclusions

in-house liquid drug formulations can be a valid option for pediatric patients with SRD. Given the significant impact of taste on medication adherence, the use of flavoring agents in the development of liquid formulations of L-dopa/carbidopa results a very useful strategy to obtain optimal adherence in the pediatric population.

背景:sepiapterine还原酶缺乏症(SRD)是一种罕见的左旋多巴(L-多巴)反应性疾病,可通过控释左旋多巴和卡比多巴联合疗法进行治疗。目前可用的卡比多巴/左旋多巴控释制剂并不完全符合儿童患者长期治疗的要求。事实上,如果按成人剂量服用已制成的药片,就必须根据儿童的需要进行调整,如将药片分成小份或用水稀释。必须强调的是,药片不能压碎,否则会破坏控释机制,影响药效。目前还没有商业液体制剂。材料和方法:我们介绍了 1:10 比例的卡比多巴/多巴风味(薄荷、覆盆子、可可、浆果)和无味口服制剂(未添加甜味剂)的样品制备、物理和微生物分析、口味测试和耐受性。我们还报告了对两名患有SRD的儿童患者的长期随访结果:我们记录了液体溶液在25°C下28天的稳定性。所有制剂的耐受性都很好,在评估口感和耐受性期间或之后均未发现不良反应。对两名患者的长期随访显示,他们的症状得到了有效控制,治疗的依从性和顺应性也达到了最佳水平。鉴于口感对服药依从性的重要影响,在开发左旋多巴/卡比多巴液体制剂时使用调味剂是一项非常有用的策略,可使儿科患者获得最佳的服药依从性。
{"title":"Formulation and clinical evaluation of carbidopa/levodopa oral solution for the treatment of sepiapterin reductase deficiency","authors":"","doi":"10.1016/j.ejpb.2024.114429","DOIUrl":"10.1016/j.ejpb.2024.114429","url":null,"abstract":"<div><h3>Background</h3><p>sepiapterine reductase deficiency (SRD) is a rare levodopa (L-dopa)-responsive disorder treated with a combination therapy of controlled-release L-dopa and carbidopa. The currently available formulation of controlled-release carbidopa/L-dopa does not entirely meet the requirements for the long-term therapy in pediatric patients. In fact, administration of a manufactured tablet at a dose intended for adults necessitates its adjustment to the child’s needs, as the splitting of the tablet into smaller portions or its dilution in water. It’s essential to emphasize that tablets must not be crushed, as this can compromise the controlled-release mechanism and affect the efficacy of the medication. At the moment, commercial liquid formulations are not available. Given these limitations, in house drug preparation in hospitals and community pharmacies is a valid option to ensure the proper therapeutic management of these patients.</p></div><div><h3>Materials and methods</h3><p>we described sample preparation, physical and microbiological analyses, taste testing, and tolerability of a 1:10 ratio carbidopa/L-dopa flavored (mint, raspberry, cacao, berries) and unflavored oral formulation (no sweetening agents were added). We also reported long-term follow-up of two pediatric patients with SRD.</p></div><div><h3>Results</h3><p>we documented the stability for 28 days at 25 °C of the liquid solution. All formulations were well-tolerated, and no adverse events were observed during or after assessing taste and tolerability. The long-term follow up of two patients was characterized by effective symptom control and optimal treatment adherence and compliance.</p></div><div><h3>Conclusions</h3><p>in-house liquid drug formulations can be a valid option for pediatric patients with SRD. Given the significant impact of taste on medication adherence, the use of flavoring agents in the development of liquid formulations of L-dopa/carbidopa results a very useful strategy to obtain optimal adherence in the pediatric population.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cationic pH-sensitive liposome-based subunit tuberculosis vaccine induces protection in mice challenged with Mycobacterium tuberculosis 对 pH 值敏感的阳离子脂质体结核亚单位疫苗能在受到结核分枝杆菌挑战的小鼠体内产生保护作用。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-07 DOI: 10.1016/j.ejpb.2024.114437

Tuberculosis (TB) has been and still is a global emergency for centuries. Prevention of disease through vaccination would have a major impact on disease prevalence, but the only available current vaccine, BCG, has insufficient impact. In this article, a novel subunit vaccine against TB was developed, using the Ag85B-ESAT6-Rv2034 fusion antigen, two adjuvants – CpG and MPLA, and a cationic pH-sensitive liposome as a delivery system, representing a new TB vaccine delivery strategy not previously reported for TB.

In vitro in human dendritic cells (DCs), the adjuvanted formulation induced a significant increase in the production of (innate) cytokines and chemokines compared to the liposome without additional adjuvants. In vivo, the new vaccine administrated subcutaneously significantly reduced Mycobacterium tuberculosis (Mtb) bacterial load in the lungs and spleens of mice, significantly outperforming results from mice vaccinated with the antigen mixed with adjuvants without liposomes. In-depth analysis underpinned the vaccine’s effectiveness in terms of its capacity to induce polyfunctional CD4+ and CD8+ T-cell responses, both considered essential for controlling Mtb infection. Also noteworthy was the differential abundance of various CD69+ B-cell subpopulations, which included IL17-A-producing B-cells. The vaccine stimulated robust antigen-specific antibody titers, further extending its potential as a novel protective agent against TB.

几个世纪以来,结核病(TB)一直是全球的紧急疾病,现在依然如此。通过接种疫苗预防疾病将对疾病的流行产生重大影响,但目前唯一可用的疫苗卡介苗效果不佳。本文利用 Ag85B-ESAT6-Rv2034 融合抗原、两种佐剂(CpG 和 MPLA)以及阳离子 pH 敏感脂质体作为递送系统,开发了一种新型结核病亚单位疫苗,这是一种以前从未报道过的结核病疫苗递送策略。在体外人树突状细胞(DCs)中,与不添加佐剂的脂质体相比,添加佐剂的配方诱导产生的(先天性)细胞因子和趋化因子显著增加。在体内,皮下注射新疫苗可显著减少小鼠肺部和脾脏中的结核分枝杆菌(Mtb)细菌量,明显优于接种抗原与佐剂混合但不含脂质体的小鼠。深入分析证实了疫苗在诱导多功能 CD4+ 和 CD8+ T 细胞反应方面的有效性,而这两种细胞反应都被认为是控制 Mtb 感染的关键。同样值得注意的是,各种 CD69+ B 细胞亚群的丰度不同,其中包括产生 IL17-A 的 B 细胞。疫苗激发了强大的抗原特异性抗体滴度,进一步扩大了其作为新型结核病保护剂的潜力。
{"title":"Cationic pH-sensitive liposome-based subunit tuberculosis vaccine induces protection in mice challenged with Mycobacterium tuberculosis","authors":"","doi":"10.1016/j.ejpb.2024.114437","DOIUrl":"10.1016/j.ejpb.2024.114437","url":null,"abstract":"<div><p>Tuberculosis (TB) has been and still is a global emergency for centuries. Prevention of disease through vaccination would have a major impact on disease prevalence, but the only available current vaccine, BCG, has insufficient impact. In this article, a novel subunit vaccine against TB was developed, using the Ag85B-ESAT6-Rv2034 fusion antigen, two adjuvants – CpG and MPLA, and a cationic pH-sensitive liposome as a delivery system, representing a new TB vaccine delivery strategy not previously reported for TB.</p><p><em>In vitro</em> in human dendritic cells (DCs), the adjuvanted formulation induced a significant increase in the production of (innate) cytokines and chemokines compared to the liposome without additional adjuvants. <em>In vivo</em>, the new vaccine administrated subcutaneously significantly reduced <em>Mycobacterium tuberculosis</em> (Mtb) bacterial load in the lungs and spleens of mice, significantly outperforming results from mice vaccinated with the antigen mixed with adjuvants without liposomes. In-depth analysis underpinned the vaccine’s effectiveness in terms of its capacity to induce polyfunctional CD4<sup>+</sup> and CD8<sup>+</sup> T-cell responses, both considered essential for controlling Mtb infection. Also noteworthy was the differential abundance of various CD69<sup>+</sup> B-cell subpopulations, which included IL17-A-producing B-cells. The vaccine stimulated robust antigen-specific antibody titers, further extending its potential as a novel protective agent against TB.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002637/pdfft?md5=1a1aa331630a54c5190dd72437be78fc&pid=1-s2.0-S0939641124002637-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141912304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Rationalisation of the purification process for a phage active pharmaceutical ingredient 噬菌体活性药物成分纯化过程的合理化。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-05 DOI: 10.1016/j.ejpb.2024.114438

The resurgence of phage therapy, once abandoned in the early 20th century in part due to issues related to the purification process and stability, is spurred by the global threat of antibiotic resistance. Engineering advances have enabled more precise separation unit operations, improving overall purification efficiency. The present review discusses the physicochemical properties of impurities commonly found in a phage lysate, e.g., contaminants, phage-related impurities, and propagation-related impurities. Differences in phages and bacterial impurities properties are leveraged to elaborate a four-step phage purification process: clarification, capture and concentration, subsequent purification and polishing. Ultimately, a framework for rationalising the development of a purification process is proposed, considering three operational characteristics, i.e., scalability, transferability to various phages and duration. This guide facilitates the preselection of a sequence of unit operations, which can then be confronted with the expected impurities to validate the theoretical capacity of the process to purify the phage lysate.

20 世纪初,噬菌体疗法曾一度被放弃,部分原因是与纯化过程和稳定性相关的问题,而抗生素耐药性的全球性威胁则刺激了噬菌体疗法的复苏。工程技术的进步使分离装置的操作更加精确,从而提高了整体纯化效率。本综述讨论了噬菌体裂解物中常见杂质的理化性质,如污染物、噬菌体相关杂质和繁殖相关杂质。利用噬菌体和细菌杂质特性的差异,阐述了噬菌体纯化的四个步骤:澄清、捕获和浓缩、后续纯化和抛光。最后,考虑到三个操作特性,即可扩展性、对各种噬菌体的可移植性和持续时间,提出了一个合理开发纯化过程的框架。该指南有助于预先选择单元操作序列,然后与预期的杂质对抗,以验证该过程纯化噬菌体裂解物的理论能力。
{"title":"Rationalisation of the purification process for a phage active pharmaceutical ingredient","authors":"","doi":"10.1016/j.ejpb.2024.114438","DOIUrl":"10.1016/j.ejpb.2024.114438","url":null,"abstract":"<div><p>The resurgence of phage therapy, once abandoned in the early 20th century in part due to issues related to the purification process and stability, is spurred by the global threat of antibiotic resistance. Engineering advances have enabled more precise separation unit operations, improving overall purification efficiency. The present review discusses the physicochemical properties of impurities commonly found in a phage lysate, e.g., contaminants, phage-related impurities, and propagation-related impurities. Differences in phages and bacterial impurities properties are leveraged to elaborate a four-step phage purification process: clarification, capture and concentration, subsequent purification and polishing. Ultimately, a framework for rationalising the development of a purification process is proposed, considering three operational characteristics, i.e., scalability, transferability to various phages and duration. This guide facilitates the preselection of a sequence of unit operations, which can then be confronted with the expected impurities to validate the theoretical capacity of the process to purify the phage lysate.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002649/pdfft?md5=c735cdb388314a96724b855a75e9e09a&pid=1-s2.0-S0939641124002649-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dissolution profiles of BCS class II drugs generated by the gastrointestinal simulator alpha has an edge over the compendial USP II method 胃肠道模拟器 alpha 生成的 BCS II 类药物溶解曲线优于药典 USP II 方法。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-05 DOI: 10.1016/j.ejpb.2024.114436

The poor water solubility of orally administered drugs leads to low dissolution in the GI tract, resulting to low oral bioavailability. Traditionally, in vitro dissolution testing using the compendial dissolution apparatuses I and II has been the gold-standard method for evaluating drug dissolution and assuring drug quality. However, these methods don’t accurately represent the complex physiologies of the GI tract, making it difficult to predict in vivo behavior of these drugs. In this study, the in vivo predictive method, gastrointestinal simulator alpha (GIS-α), was used to study the dissolution profiles of commercially available BCS Class II drugs, danazol, fenofibrate, celecoxib, and ritonavir. This biorelevant transfer method utilizes multiple compartments alongside peristaltic pumps, to effectively model the transfer of material in the GI tract. In all cases, the GIS-α with biorelevant buffers gave superior dissolution profiles. In silico modeling using GastroPlusTM yielded better prediction when utilizing the results from the GIS-α as input compared to the dissolution profiles obtained from the USP II apparatus. This gives the GIS-α an edge over compendial methods in generating drug dissolution profiles and is especially useful in the early stages of drug and formulation development. This information gives insight into the dissolution behavior and potential absorption patterns of these drugs which can be crucial for formulation development, as it allows for the optimization of drug delivery systems to enhance solubility, dissolution, and ultimately, bioavailability.

口服药物的水溶性差,导致其在消化道内的溶解度低,从而造成口服生物利用度低。传统上,使用药典溶出度仪 I 和 II 进行体外溶出度测试是评估药物溶出度和确保药物质量的黄金标准方法。然而,这些方法并不能准确反映消化道的复杂生理结构,因此很难预测这些药物在体内的表现。在本研究中,使用了体内预测方法胃肠道模拟器α(GIS-α)来研究市售 BCS II 类药物达那唑、非诺贝特、塞来昔布和利托那韦的溶出曲线。这种生物相关转移方法利用蠕动泵和多个隔室,有效地模拟了胃肠道内的物质转移。在所有情况下,带有生物相关缓冲液的 GIS-α 都能提供出色的溶解曲线。在使用 GastroPlusTM 进行硅建模时,如果将 GIS-α 的结果作为输入,则预测结果优于从 USP II 仪器获得的溶出曲线。这使得 GIS-α 在生成药物溶出曲线方面比药典方法更具优势,在药物和制剂开发的早期阶段尤其有用。这些信息有助于深入了解这些药物的溶解行为和潜在的吸收模式,这对配方开发至关重要,因为它可以优化给药系统,以提高溶解度、溶出度和最终的生物利用度。
{"title":"Dissolution profiles of BCS class II drugs generated by the gastrointestinal simulator alpha has an edge over the compendial USP II method","authors":"","doi":"10.1016/j.ejpb.2024.114436","DOIUrl":"10.1016/j.ejpb.2024.114436","url":null,"abstract":"<div><p>The poor water solubility of orally administered drugs leads to low dissolution in the GI tract, resulting to low oral bioavailability. Traditionally, in vitro dissolution testing using the compendial dissolution apparatuses I and II has been the gold-standard method for evaluating drug dissolution and assuring drug quality. However, these methods don’t accurately represent the complex physiologies of the GI tract, making it difficult to predict in vivo behavior of these drugs. In this study, the in vivo predictive method, gastrointestinal simulator alpha (GIS-α), was used to study the dissolution profiles of commercially available BCS Class II drugs, danazol, fenofibrate, celecoxib, and ritonavir. This biorelevant transfer method utilizes multiple compartments alongside peristaltic pumps, to effectively model the transfer of material in the GI tract. In all cases, the GIS-α with biorelevant buffers gave superior dissolution profiles. In silico modeling using GastroPlus<sup>TM</sup> yielded better prediction when utilizing the results from the GIS-α as input compared to the dissolution profiles obtained from the USP II apparatus. This gives the GIS-α an edge over compendial methods in generating drug dissolution profiles and is especially useful in the early stages of drug and formulation development. This information gives insight into the dissolution behavior and potential absorption patterns of these drugs which can be crucial for formulation development, as it allows for the optimization of drug delivery systems to enhance solubility, dissolution, and ultimately, bioavailability.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Investigating experimental vs. Predicted pKa values for PET radiotracer 研究 PET 放射性示踪剂的实验 pKa 值与预测 pKa 值。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-03 DOI: 10.1016/j.ejpb.2024.114430

The prediction of central nervous system (CNS) active pharmaceuticals and radiopharmaceuticals has experienced a boost by the introduction of computational approaches, like blood–brain barrier (BBB) score or CNS multiparameter optimization values. These rely heavily on calculated pKa values and other physicochemical parameters. Despite the inclusion of various physicochemical parameters in online data banks, pKa values are often missing and published experimental pKa values are limited especially for radiopharmaceuticals. This comparative study investigated the discrepancies between predicted and experimental pKa values and their impact on CNS activity prediction scores. The pKa values of 46 substances, including therapeutic drugs and PET imaging radiopharmaceuticals, were measured by means of potentiometry and spectrophotometry. Experimentally obtained pKa values were compared with in silico predictions (Chemicalize/Marvin). The results demonstrate a considerable discrepancy between experimental and in silico values, with linear regression analysis showing intermediate correlation (R2(Marvin) = 0.88, R2(Chemicalize) = 0.82). This indicates that if one requires an accurate pKa value, it is essential to experimentally assess it. This underscores the importance of experimentally determining pKa values for accurate drug design and optimization. The study’s data provide a valuable library of reliable experimental pKa values for therapeutic drugs and radiopharmaceuticals, aiding researchers in the field.

血脑屏障(BBB)评分或中枢神经系统多参数优化值等计算方法的引入推动了中枢神经系统(CNS)活性药物和放射性药物的预测。这些方法在很大程度上依赖于计算得出的 pKa 值和其他理化参数。尽管在线数据库中包含了各种理化参数,但 pKa 值往往缺失,而且公布的实验 pKa 值也很有限,尤其是放射性药物的 pKa 值。这项比较研究调查了预测 pKa 值与实验 pKa 值之间的差异及其对中枢神经系统活性预测得分的影响。通过电位测定法和分光光度法测量了 46 种物质的 pKa 值,其中包括治疗药物和 PET 成像放射性药物。实验获得的 pKa 值与硅学预测值(Chemicalize/Marvin)进行了比较。结果表明,实验值与硅学预测值之间存在相当大的差异,线性回归分析显示出中等相关性(R2(Marvin) = 0.88,R2(Chemicalize) = 0.82)。这表明,如果需要准确的 pKa 值,就必须进行实验评估。这强调了实验确定 pKa 值对于准确设计和优化药物的重要性。这项研究的数据为治疗药物和放射性药物提供了一个宝贵的可靠实验 pKa 值库,为该领域的研究人员提供了帮助。
{"title":"Investigating experimental vs. Predicted pKa values for PET radiotracer","authors":"","doi":"10.1016/j.ejpb.2024.114430","DOIUrl":"10.1016/j.ejpb.2024.114430","url":null,"abstract":"<div><p>The prediction of central nervous system (CNS) active pharmaceuticals and radiopharmaceuticals has experienced a boost by the introduction of computational approaches, like blood–brain barrier (BBB) score or CNS multiparameter optimization values. These rely heavily on calculated pK<sub>a</sub> values and other physicochemical parameters. Despite the inclusion of various physicochemical parameters in online data banks, pK<sub>a</sub> values are often missing and published experimental pK<sub>a</sub> values are limited especially for radiopharmaceuticals. This comparative study investigated the discrepancies between predicted and experimental pK<sub>a</sub> values and their impact on CNS activity prediction scores. The pK<sub>a</sub> values of 46 substances, including therapeutic drugs and PET imaging radiopharmaceuticals, were measured by means of potentiometry and spectrophotometry. Experimentally obtained pK<sub>a</sub> values were compared with <em>in silico</em> predictions (Chemicalize/Marvin). The results demonstrate a considerable discrepancy between experimental and <em>in silico</em> values, with linear regression analysis showing intermediate correlation (R<sup>2</sup><sub>(Marvin)</sub> = 0.88, R<sup>2</sup><sub>(Chemicalize)</sub> = 0.82). This indicates that if one requires an accurate pK<sub>a</sub> value, it is essential to experimentally assess it. This underscores the importance of experimentally determining pK<sub>a</sub> values for accurate drug design and optimization. The study’s data provide a valuable library of reliable experimental pK<sub>a</sub> values for therapeutic drugs and radiopharmaceuticals, aiding researchers in the field.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S093964112400256X/pdfft?md5=9520f0e4ca8c940dfd6bd6ed92e620c2&pid=1-s2.0-S093964112400256X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Improved therapeutic index of the liposomal docetaxel-glutathione prepared by active click loading 通过主动点击加载法制备的多西他赛-谷胱甘肽脂质体提高了治疗指数。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-03 DOI: 10.1016/j.ejpb.2024.114435

The clinical usage of docetaxel (DTX) is severely hindered by the dose-limiting neutropenia and peripheral neurotoxicity of polysorbate 80-solubilized DTX injection, and there are no alternative formulations until now. In this study, we developed a new liposomal formulation of DTX to reduce its toxicities, accompanying with the greatly improved antitumor activity. The DTX was encapsulated into liposomes in the form of hydrophilic glutathione (GSH)-conjugated prodrugs using a click drug loading method, which achieved a high encapsulation efficiency (∼95 %) and loading capacity (∼30 % wt). The resulting liposomal DTX-GSH provided a sustained and efficient DTX release (∼50 % within 48 h) in plasma, resulting in a greatly improved antitumor activities as compared with that of polysorbate 80-solubilized DTX injection in the subcutaneous and orthotopic 4T1 breast tumor bearing mice. Even large tumors > 500 mm3 could be effectively inhibited and shrunk after the administration of liposomal DTX-GSH. More importantly, the liposomal DTX-GSH significantly decreased the neutropenia and peripheral neurotoxicity as compared with that of polysorbate 80-solubilized DTX injection at the equivalent dose. These data suggested that the liposomal DTX-GSH might become a superior alternative formulation to the commercial DTX injection.

多西他赛(DTX)的临床应用严重受限于多山梨醇酯 80 溶解型 DTX 注射剂的剂量限制性中性粒细胞减少症和外周神经毒性,迄今为止尚无替代制剂。在这项研究中,我们开发了一种新的 DTX 脂质体制剂,以减少其毒性,同时大大提高抗肿瘤活性。通过点击载药法,DTX以亲水性谷胱甘肽(GSH)共轭原药的形式被包裹到脂质体中,实现了较高的包裹效率(∼95 %)和载药量(∼30 % wt)。所制备的脂质体 DTX-GSH 能在血浆中持续高效释放 DTX(48 小时内释放量达 50%),与多聚山梨醇酯 80 溶剂 DTX 相比,大大提高了皮下注射和正位 4 T1 乳腺肿瘤小鼠的抗肿瘤活性。服用脂质体 DTX-GSH 后,即使大于 500 立方毫米的大肿瘤也能得到有效抑制和缩小。更重要的是,与同等剂量的聚山梨醇酯 80 溶剂 DTX 注射液相比,脂质体 DTX-GSH 能显著减少中性粒细胞减少症和外周神经毒性。这些数据表明,脂质体 DTX-GSH 可能会成为商用 DTX 注射剂的一种优质替代制剂。
{"title":"Improved therapeutic index of the liposomal docetaxel-glutathione prepared by active click loading","authors":"","doi":"10.1016/j.ejpb.2024.114435","DOIUrl":"10.1016/j.ejpb.2024.114435","url":null,"abstract":"<div><p>The clinical usage of docetaxel (DTX) is severely hindered by the dose-limiting neutropenia and peripheral neurotoxicity of polysorbate 80-solubilized DTX injection, and there are no alternative formulations until now. In this study, we developed a new liposomal formulation of DTX to reduce its toxicities, accompanying with the greatly improved antitumor activity. The DTX was encapsulated into liposomes in the form of hydrophilic glutathione (GSH)-conjugated prodrugs using a click drug loading method, which achieved a high encapsulation efficiency (∼95 %) and loading capacity (∼30 % wt). The resulting liposomal DTX-GSH provided a sustained and efficient DTX release (∼50 % within 48 h) in plasma, resulting in a greatly improved antitumor activities as compared with that of polysorbate 80-solubilized DTX injection in the subcutaneous and orthotopic 4T1 breast tumor bearing mice. Even large tumors &gt; 500 mm<sup>3</sup> could be effectively inhibited and shrunk after the administration of liposomal DTX-GSH. More importantly, the liposomal DTX-GSH significantly decreased the neutropenia and peripheral neurotoxicity as compared with that of polysorbate 80-solubilized DTX injection at the equivalent dose. These data suggested that the liposomal DTX-GSH might become a superior alternative formulation to the commercial DTX injection.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Therapeutic targeting of siRNA/anti-cancer drug delivery system for non-melanoma skin cancer. Part I: Development and gene silencing of JAK1siRNA/5-FU loaded liposome nanocomplexes 针对非黑色素瘤皮肤癌的 siRNA/抗癌药物输送系统。第一部分:JAK1siRNA/5-FU 脂质体纳米复合物的开发与基因沉默。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-02 DOI: 10.1016/j.ejpb.2024.114432

Non-melanoma skin cancer (NMSC) is one of the most prevalent cancers, leading to significant mortality rates due to limited treatment options and a lack of effective therapeutics. Janus kinase (JAK1), a non-receptor tyrosine kinase family member, is involved in various cellular processes, including differentiation, cell proliferation and survival, playing a crucial role in cancer progression. This study aims to provide a more effective treatment for NMSC by concurrently silencing the JAK1 gene and administering 5-Fluorouracil (5-FU) using liposome nanocomplexes as delivery vehicles. Utilizing RNA interference (RNAi) technology, liposome nanocomplexes modified with polyethylene imine (PEI) were conjugated with siRNA molecule targeting JAK1 and loaded with 5-FU. The prepared formulations (NL-PEI) were characterized in terms of their physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, and stability. Cell cytotoxicity, cell uptake and knockdown efficiency were evaluated in human-derived non-melanoma epidermoid carcinoma cells (A-431). High contrast transmission electron microscopy (CTEM) images and dynamic light scattering (DLS) measurements revealed that the nanocomplexes formed spherical morphology with uniform sizes ranging from 80-120 nm. The cationic NL-PEI nanocomplexes successfully internalized within the cytoplasm of A-431, delivering siRNA for specific sequence binding and JAK1 gene silencing. The encapsulation of 5-FU in the nanocomplexes was achieved at 0.2 drug/lipid ratio. Post-treatment with NL-PEI for 24, 48 and 72 h showed cell viability above 80 % at concentrations up to 8.5 × 101 µg/mL. Notably, 5-FU delivery via nanoliposome formulations significantly reduced cell viability at 5-FU concentration of 5 µM and above (p < 0.05) after 24 h of incubation. The NL-PEI nanocomplexes effectively silenced the JAK1 gene in vitro, reducing its expression by 50 %. Correspondingly, JAK1 protein level decreased after transfection with JAK1 siRNA-conjugated liposome nanocomplexes, leading to a 37 % reduction in pERK (phosphor extracellular signal-regulated kinase) protein expression. These findings suggest that the combined delivery of JAK1 siRNA and 5-FU via liposomal formulations offers a promising and novel treatment strategy for targeting genes and other identified targets in NMSC therapy.

非黑色素瘤皮肤癌(NMSC)是发病率最高的癌症之一,由于治疗方案有限且缺乏有效的治疗方法,导致死亡率居高不下。Janus 激酶(JAK1)是一种非受体酪氨酸激酶家族成员,参与各种细胞过程,包括分化、细胞增殖和存活,在癌症进展中起着至关重要的作用。本研究旨在利用脂质体纳米复合物作为给药载体,在沉默JAK1基因的同时给药5-氟尿嘧啶(5-FU),从而更有效地治疗NMSC。利用RNA干扰(RNAi)技术,用聚乙烯亚胺(PEI)修饰的脂质体纳米复合物与靶向JAK1的siRNA分子共轭,并装载5-FU。所制备的制剂(NL-PEI)在理化性质、形态、包封效率、体外药物释放和稳定性方面均具有特征。在人源非黑色素瘤表皮样癌细胞(A-431)中评估了细胞毒性、细胞摄取和基因敲除效率。高对比度透射电子显微镜(CTEM)图像和动态光散射(DLS)测量结果表明,纳米复合物呈球形,大小均匀,范围在 80-120 nm 之间。阳离子 NL-PEI 纳米复合物成功地在 A-431 细胞质中内化,输送 siRNA 以实现特定序列结合和 JAK1 基因沉默。在药物/脂质比为0.2的情况下,5-FU被包裹在纳米复合物中。经 NL-PEI 处理 24、48 和 72 小时后,细胞存活率超过 80%,浓度高达 8.5 × 101 µg/mL。值得注意的是,在 5-FU 浓度为 5 µM 及以上时,通过纳米脂质体制剂递送 5-FU 会显著降低细胞活力(p
{"title":"Therapeutic targeting of siRNA/anti-cancer drug delivery system for non-melanoma skin cancer. Part I: Development and gene silencing of JAK1siRNA/5-FU loaded liposome nanocomplexes","authors":"","doi":"10.1016/j.ejpb.2024.114432","DOIUrl":"10.1016/j.ejpb.2024.114432","url":null,"abstract":"<div><p>Non-melanoma skin cancer (NMSC) is one of the most prevalent cancers, leading to significant mortality rates due to limited treatment options and a lack of effective therapeutics. Janus kinase (JAK1), a non-receptor tyrosine kinase family member, is involved in various cellular processes, including differentiation, cell proliferation and survival, playing a crucial role in cancer progression. This study aims to provide a more effective treatment for NMSC by concurrently silencing the JAK1 gene and administering 5-Fluorouracil (5-FU) using liposome nanocomplexes as delivery vehicles. Utilizing RNA interference (RNAi) technology, liposome nanocomplexes modified with polyethylene imine (PEI) were conjugated with siRNA molecule targeting JAK1 and loaded with 5-FU. The prepared formulations (NL-PEI) were characterized in terms of their physicochemical properties, morphology, encapsulation efficiency, <em>in vitro</em> drug release, and stability. Cell cytotoxicity, cell uptake and knockdown efficiency were evaluated in human-derived non-melanoma epidermoid carcinoma cells (A-431). High contrast transmission electron microscopy (CTEM) images and dynamic light scattering (DLS) measurements revealed that the nanocomplexes formed spherical morphology with uniform sizes ranging from 80-120 nm. The cationic NL-PEI nanocomplexes successfully internalized within the cytoplasm of A-431, delivering siRNA for specific sequence binding and JAK1 gene silencing. The encapsulation of 5-FU in the nanocomplexes was achieved at 0.2 drug/lipid ratio. Post-treatment with NL-PEI for 24, 48 and 72 h showed cell viability above 80 % at concentrations up to 8.5 × 10<sup>1</sup> µg/mL. Notably, 5-FU delivery via nanoliposome formulations significantly reduced cell viability at 5-FU concentration of 5 µM and above (p &lt; 0.05) after 24 h of incubation. The NL-PEI nanocomplexes effectively silenced the JAK1 gene <em>in vitro</em>, reducing its expression by 50 %. Correspondingly, JAK1 protein level decreased after transfection with JAK1 siRNA-conjugated liposome nanocomplexes, leading to a 37 % reduction in pERK (phosphor extracellular signal-regulated kinase) protein expression. These findings suggest that the combined delivery of JAK1 siRNA and 5-FU via liposomal formulations offers a promising and novel treatment strategy for targeting genes and other identified targets in NMSC therapy.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Plasma, brain and spinal cord concentrations of caffeine are reduced in the SOD1G93A mouse model of amyotrophic lateral sclerosis following oral administration SOD1G93A肌萎缩性脊髓侧索硬化症小鼠口服咖啡因后,血浆、大脑和脊髓中咖啡因的浓度会降低。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-02 DOI: 10.1016/j.ejpb.2024.114434

Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114–120 male and female SOD1G93A mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the ex vivo intestinal permeability of caffeine were assessed. The area under the plasma concentration–time curves (AUCplasma) of digoxin and sulfasalazine were not significantly different between SOD1G93A and WT mice for both sexes. However, the AUCplasma of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1G93A compared to WT mice, which was associated with lower AUCbrain (female: 0.76-fold, male: 0.80-fold) and AUCspinal cord (female: 0.81-fold, male: 0.82-fold). The AUCstomach of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1G93A compared to WT mice, suggesting reduced gastric emptying in SOD1G93A mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and ex vivo intestinal permeability of caffeine (0.52-fold) in male SOD1G93A compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1G93A mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range.

众所周知,肌萎缩性脊髓侧索硬化症(ALS)是运动神经元病(MND)家族中的一种神经退行性疾病,在该病的症状期,小肠和肝脏会发生变化。这些改变如何影响药物的口服吸收和药代动力学仍是未知数。在这项研究中,代表不同肠道转运机制的模型药物(被动扩散的咖啡因、P-糖蛋白外流的地高辛和乳腺癌抗性蛋白外流的柳氮磺胺吡啶)通过口服灌胃给出生后第 114-120 天的雌雄 SOD1G93A 小鼠(家族性 ALS 模型)和野生型(WT)同窝小鼠服用。在给药后 15、30、60 或 180 分钟采集血液、大脑和脊髓样本。此外,还评估了异硫氰酸荧光素-右旋糖酐(FITC-右旋糖酐)的体内胃排空和咖啡因的体外肠道渗透性。SOD1G93A 小鼠和 WT 小鼠的地高辛和柳氮磺胺吡啶的血浆浓度-时间曲线下面积(AUCplasma)没有显著差异。然而,与 WT 小鼠相比,SOD1G93A 小鼠的咖啡因血浆浓度曲线(AUCplasma)明显较低(雌性:0.79 倍,雄性:0.76 倍),这与较低的脑浓度曲线(AUCbrain)(雌性:0.76 倍,雄性:0.80 倍)和脊髓浓度曲线(AUCspinal cord)(雌性:0.81 倍,雄性:0.82 倍)有关。与 WT 小鼠相比,SOD1G93A 小鼠胃中咖啡因的 AUC 明显更高(雌性:1.5 倍,雄性:1.9 倍),这表明 SOD1G93A 小鼠的胃排空能力降低。此外,与 WT 小鼠相比,雄性 SOD1G93A 小鼠 FITC-葡聚糖的胃排空(0.66 倍)和咖啡因的体外肠道渗透性(0.52 倍)显著降低。因此,SOD1G93A 小鼠全身和脑/脊髓接触咖啡因的减少可能是由于胃排空和小肠渗透性发生了改变。因此,某些治疗 ALS 的药物可能需要特定的剂量要求,以确保其保持在安全有效的浓度范围内。
{"title":"Plasma, brain and spinal cord concentrations of caffeine are reduced in the SOD1G93A mouse model of amyotrophic lateral sclerosis following oral administration","authors":"","doi":"10.1016/j.ejpb.2024.114434","DOIUrl":"10.1016/j.ejpb.2024.114434","url":null,"abstract":"<div><p>Modifications to the small intestine and liver are known to occur during the symptomatic disease period of amyotrophic lateral sclerosis (ALS), a member of the motor neuron disease (MND) family of neurodegenerative disorders. How these modifications impact on oral absorption and pharmacokinetics of drugs remains unknown. In this study, model drugs representing different mechanisms of intestinal transport (caffeine for passive diffusion, digoxin for P-glycoprotein efflux, and sulfasalazine for breast cancer resistance protein efflux) were administered via oral gavage to postnatal day 114–120 male and female SOD1<sup>G93A</sup> mice (model of familial ALS) and wild-type (WT) littermates. Samples of blood, brain and spinal cord were taken at either 15, 30, 60 or 180 min after administration. In addition, the in vivo gastric emptying of 70 kDa fluorescein isothiocyanate-dextran (FITC-dextran) and the <em>ex vivo</em> intestinal permeability of caffeine were assessed. The area under the plasma concentration–time curves (AUC<sub>plasma</sub>) of digoxin and sulfasalazine were not significantly different between SOD1<sup>G93A</sup> and WT mice for both sexes. However, the AUC<sub>plasma</sub> of caffeine was significantly lower (female: 0.79-fold, male: 0.76-fold) in SOD1<sup>G93A</sup> compared to WT mice, which was associated with lower AUC<sub>brain</sub> (female: 0.76-fold, male: 0.80-fold) and AUC<sub>spinal cord</sub> (female: 0.81-fold, male: 0.82-fold). The AUC<sub>stomach</sub> of caffeine was significantly higher (female: 1.5-fold, male: 1.9-fold) in SOD1<sup>G93A</sup> compared to WT mice, suggesting reduced gastric emptying in SOD1<sup>G93A</sup> mice. In addition, there was a significant reduction in gastric emptying of FITC-dextran (0.66-fold) and <em>ex vivo</em> intestinal permeability of caffeine (0.52-fold) in male SOD1<sup>G93A</sup> compared to WT mice. Reduced systemic and brain/spinal cord exposure of caffeine in SOD1<sup>G93A</sup> mice may therefore result from alterations to gastric emptying and small intestinal permeability. Specific dosing requirements may therefore be required for certain medicines in ALS to ensure that they remain in a safe and effective concentration range.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002601/pdfft?md5=e2cf0e874064372a6370d29ef3f4efa3&pid=1-s2.0-S0939641124002601-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Investigation of keratolytic impact of synthetic bolalipids on skin penetration of a model hydrophilic permeant 合成栓脂对模型亲水性渗透剂皮肤渗透的角质溶解影响研究
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-02 DOI: 10.1016/j.ejpb.2024.114433

Synthetic single-chain bolalipids (SSCBs) are novel excipients in drug delivery, with potential as stabilizers or solubilizers. However, their impact on skin barrier function has not been comprehensively studied. Therefore, two SSCBs (PC-C24-PC and PC-C32-PC) were studied in aqueous systems for their impact on penetration of a model permeant into porcine skin. Concentrations of 0.05 – 5 % w/w were tested; PC-C24-PC formulations were low-viscosity liquids while PC-C32-PC formed viscous dispersions to gels at room temperature. Formulations were compared for their ability to enhance sodium fluorescein penetration (SF, 0.1 % w/w) into skin via tape stripping. Using NIR-densitometry, the effect of SSCB formulations on corneocyte cohesion was evaluated. Data were compared with phospholipid mixture Lipoid S-75, sodium dodecyl sulfate (SDS), and polyethylene glycol 12-hydroxystearate (PEG-HS), and distilled water as negative control. Contrary to the hypothesis, both SSCBs failed to increase SF penetration into the stratum corneum, but rather showed a significant decrease in penetration depth compared to water. Both SSCBs exhibited a keratolytic effect at 5 % w/w, leading to substantial removal of proteins from the skin surface. Consequently, SSCBs may not enhance penetration of hydrophilic drugs into skin, but could be used as keratolytic agents.

合成单链硼烷脂(SSCBs)是一种新型给药辅料,具有稳定剂或增溶剂的潜力。然而,它们对皮肤屏障功能的影响尚未得到全面研究。因此,我们在水性体系中研究了两种 SSCB(PC-C24-PC 和 PC-C32-PC)对模型渗透剂渗入猪皮肤的影响。测试的浓度为 0.05 - 5 % w/w;PC-C24-PC 配方为低粘度液体,而 PC-C32-PC 则在室温下形成粘稠的分散体至凝胶体。通过胶带剥离,比较了这些配方增强荧光素钠(SF,0.1 % w/w)渗透皮肤的能力。使用近红外密度计评估了 SSCB 配方对角质细胞凝聚力的影响。数据与磷脂混合物 Lipoid S-75、十二烷基硫酸钠(SDS)和聚乙二醇 12-羟基硬脂酸酯(PEG-HS)以及作为阴性对照的蒸馏水进行了比较。与假设相反,两种 SSCB 都未能增加 SF 对角质层的渗透,与水相比,渗透深度反而显著下降。两种 SSCB 在 5% w/w 浓度下都具有角质溶解作用,导致皮肤表面的蛋白质大量脱落。因此,SSCB 可能不会增强亲水性药物对皮肤的渗透,但可用作角质分解剂。
{"title":"Investigation of keratolytic impact of synthetic bolalipids on skin penetration of a model hydrophilic permeant","authors":"","doi":"10.1016/j.ejpb.2024.114433","DOIUrl":"10.1016/j.ejpb.2024.114433","url":null,"abstract":"<div><p>Synthetic single-chain bolalipids (SSCBs) are novel excipients in drug delivery, with potential as stabilizers or solubilizers. However, their impact on skin barrier function has not been comprehensively studied. Therefore, two SSCBs (PC-C24-PC and PC-C32-PC) were studied in aqueous systems for their impact on penetration of a model permeant into porcine skin. Concentrations of 0.05 – 5 % w/w were tested; PC-C24-PC formulations were low-viscosity liquids while PC-C32-PC formed viscous dispersions to gels at room temperature. Formulations were compared for their ability to enhance sodium fluorescein penetration (SF, 0.1 % w/w) into skin via tape stripping. Using NIR-densitometry, the effect of SSCB formulations on corneocyte cohesion was evaluated. Data were compared with phospholipid mixture Lipoid S-75, sodium dodecyl sulfate (SDS), and polyethylene glycol 12-hydroxystearate (PEG-HS), and distilled water as negative control. Contrary to the hypothesis, both SSCBs failed to increase SF penetration into the stratum corneum, but rather showed a significant decrease in penetration depth compared to water. Both SSCBs exhibited a keratolytic effect at 5 % w/w, leading to substantial removal of proteins from the skin surface. Consequently, SSCBs may not enhance penetration of hydrophilic drugs into skin, but could be used as keratolytic agents.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002595/pdfft?md5=d30fb352ac7df7ebaf8fb0d55041104d&pid=1-s2.0-S0939641124002595-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Directional freezing and thawing of biologics in drug substance bottles 定向冷冻和解冻药物瓶中的生物制剂。
IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-31 DOI: 10.1016/j.ejpb.2024.114427

Biological drug substance (DS) is typically stored frozen to increase stability. However, freezing and thawing (F/T) of DS can impact product quality and therefore F/T processes need to be controlled. Because active F/T systems for DS bottles are lacking, freezing is often performed uncontrolled in conventional freezers, and thawing at ambient temperature or using water baths.

In this study, we evaluated a novel device for F/T of DS in bottles, which can be operated in conventional freezers, generating a directed air stream around bottles. We characterized the F/T geometry and process performance in comparison to passive F/T using temperature mapping and analysis of concentration gradients. The device was able to better control the F/T process by inducing directional bottom-up F/T. As a result, it reduced cryo-concentration during freezing as well as ice mound formation. However, freezing with the device was dependent on freezer performance, i.e. prolonged process times in a highly loaded freezer were accompanied by increased cryo-concentrations. Thawing was faster compared to without the device, but had no impact on concentration gradients and was slower compared to thawing in a water bath.

High-performance freezers might be required to fully exploit the potential of directional freezing with this device and allow F/T process harmonization and scaling across sites.

生物药物 (DS) 通常采用冷冻储存,以提高稳定性。然而,DS 的冷冻和解冻 (F/T) 会影响产品质量,因此需要对 F/T 过程进行控制。由于缺乏用于 DS 瓶的主动 F/T 系统,冷冻通常在传统冷冻箱中不受控制地进行,而解冻则在环境温度下或使用水浴进行。在这项研究中,我们评估了一种用于瓶中 DS 的 F/T 的新型装置,该装置可在传统冷冻箱中运行,在瓶子周围产生定向气流。与被动式 F/T 相比,我们利用温度分布图和浓度梯度分析确定了 F/T 的几何形状和工艺性能。该装置能够通过自下而上的定向 F/T 来更好地控制 F/T 过程。因此,它减少了冷冻过程中的低温浓缩以及冰丘的形成。不过,使用该装置进行的冷冻取决于冷冻室的性能,即在高负荷冷冻室中延长处理时间会导致低温浓度增加。与不使用该装置相比,解冻速度更快,但对浓度梯度没有影响,而且与水浴解冻相比速度更慢。要充分利用该装置的定向冷冻潜力,并实现 F/T 过程的协调和跨站点扩展,可能需要高性能的冷冻机。
{"title":"Directional freezing and thawing of biologics in drug substance bottles","authors":"","doi":"10.1016/j.ejpb.2024.114427","DOIUrl":"10.1016/j.ejpb.2024.114427","url":null,"abstract":"<div><p>Biological drug substance (DS) is typically stored frozen to increase stability. However, freezing and thawing (F/T) of DS can impact product quality and therefore F/T processes need to be controlled. Because active F/T systems for DS bottles are lacking, freezing is often performed uncontrolled in conventional freezers, and thawing at ambient temperature or using water baths.</p><p>In this study, we evaluated a novel device for F/T of DS in bottles, which can be operated in conventional freezers, generating a directed air stream around bottles. We characterized the F/T geometry and process performance in comparison to passive F/T using temperature mapping and analysis of concentration gradients. The device was able to better control the F/T process by inducing directional bottom-up F/T. As a result, it reduced cryo-concentration during freezing as well as ice mound formation. However, freezing with the device was dependent on freezer performance, i.e. prolonged process times in a highly loaded freezer were accompanied by increased cryo-concentrations. Thawing was faster compared to without the device, but had no impact on concentration gradients and was slower compared to thawing in a water bath.</p><p>High-performance freezers might be required to fully exploit the potential of directional freezing with this device and allow F/T process harmonization and scaling across sites.</p></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0939641124002534/pdfft?md5=c285bfef17e8e9fbdc617a851090fde8&pid=1-s2.0-S0939641124002534-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
European Journal of Pharmaceutics and Biopharmaceutics
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1