Pub Date : 2024-11-17DOI: 10.1016/j.ejpb.2024.114580
Petra Záhonyi, Áron Gábor Müncz, Anna Haraszti, Zsombor Kristóf Nagy, István Csontos, György Marosi, Edina Szabó
Electrospinning (ES) is a promising continuous formulation strategy to produce amorphous solid dispersions (ASDs) and thereby improve the dissolution of poorly water-soluble drugs. However, processing the electrospun material into solid dosage forms (e.g. tablets) is challenging due to the poor flow properties. In this research, continuous twin-screw melt granulation was applied to improve the flowability of the fibers and therefore ease the further processing steps. During this work, two ASD compositions were investigated: one containing 60 % poly-vinylpyrrolidone-vinyl acetate 6:4 copolymer and 40 % itraconazole (ITR), and another one containing hydroxypropyl methylcellulose (HPMC) and ITR in the same ratio. Both fiber compositions were granulated with polyethene glycol as the binder material, while the effects of the process parameters were examined. The application of higher granulation temperature and screw configurations with increased shear forces compromised the fibrous structure, induced crystallization of the ASD, and decreased the dissolution. However, the stability of the ITR-HPMC fibers proved to be higher as their granulation at 60 °C led to granules with adequate flow properties and dissolution. Moreover, tablets with fewer excipients were pressed from them, resulting in a 34 % reduction in weight. Consequently, this process can complement ES technology and facilitate its industrial implementation.
电纺丝（ES）是一种很有前景的连续制剂策略，可用于生产无定形固体分散体（ASD），从而改善水溶性差药物的溶解性。然而，由于电纺材料流动性差，将其加工成固体剂型（如片剂）具有挑战性。在这项研究中，采用了连续双螺杆熔融造粒技术来改善纤维的流动性，从而简化进一步的加工步骤。在这项工作中，研究了两种 ASD 组合物：一种含有 60% 的聚乙烯吡咯烷酮-醋酸乙烯酯 6:4 共聚物和 40% 的伊曲康唑（ITR），另一种含有相同比例的羟丙基甲基纤维素（HPMC）和伊曲康唑（ITR）。两种纤维组合物均以聚乙二醇为粘合剂材料进行造粒，同时考察了工艺参数的影响。较高的造粒温度和剪切力增大的螺杆配置破坏了纤维结构，导致 ASD 结晶，并降低了溶解度。然而，事实证明，ITR-HPMC 纤维的稳定性更高，因为它们在 60 °C 下制粒可获得具有适当流动性和溶解性的颗粒。此外，用它们压制出的片剂辅料更少，重量减轻了 34%。因此，该工艺可作为 ES 技术的补充，并促进其工业化应用。
{"title":"Continuous twin-screw melt granulation of drug-loaded electrospun fibers.","authors":"Petra Záhonyi, Áron Gábor Müncz, Anna Haraszti, Zsombor Kristóf Nagy, István Csontos, György Marosi, Edina Szabó","doi":"10.1016/j.ejpb.2024.114580","DOIUrl":"https://doi.org/10.1016/j.ejpb.2024.114580","url":null,"abstract":"<p><p>Electrospinning (ES) is a promising continuous formulation strategy to produce amorphous solid dispersions (ASDs) and thereby improve the dissolution of poorly water-soluble drugs. However, processing the electrospun material into solid dosage forms (e.g. tablets) is challenging due to the poor flow properties. In this research, continuous twin-screw melt granulation was applied to improve the flowability of the fibers and therefore ease the further processing steps. During this work, two ASD compositions were investigated: one containing 60 % poly-vinylpyrrolidone-vinyl acetate 6:4 copolymer and 40 % itraconazole (ITR), and another one containing hydroxypropyl methylcellulose (HPMC) and ITR in the same ratio. Both fiber compositions were granulated with polyethene glycol as the binder material, while the effects of the process parameters were examined. The application of higher granulation temperature and screw configurations with increased shear forces compromised the fibrous structure, induced crystallization of the ASD, and decreased the dissolution. However, the stability of the ITR-HPMC fibers proved to be higher as their granulation at 60 °C led to granules with adequate flow properties and dissolution. Moreover, tablets with fewer excipients were pressed from them, resulting in a 34 % reduction in weight. Consequently, this process can complement ES technology and facilitate its industrial implementation.</p>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":" ","pages":"114580"},"PeriodicalIF":4.4,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675569","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}
Pub Date : 2024-11-13DOI: 10.1016/j.ejpb.2024.114579
Amir Hossein Farhadian, Maedeh Mollaei
Pharmaceutical tablets need to have a homogenous chemical structure, especially in cases where the patient may divide the tablet in half prior to consumption. This work aims to demonstrate the viability of using laser induced breakdown spectroscopy (LIBS) for analyzing the homogeneity and determining the chemical composition of losartan potassium tablets. This was accomplished by obtaining the spectra of 10 tablet points in 30 successive laser pulses, which revealed four main peaks (C, H, N, and O) as well as a high concentration of calcium and potassium in the core tablets and titanium in the coating-all of which are excellent analytical objectives for LIBS. It is possible to say that the generated plasma meets the minimum requirement for local thermodynamic equilibrium because the physical parameters of the plasma, including temperature (T) and electronic density (Ne), were calculated throughout the Boltzmann plot and Stark broadened line, respectively, and the McWhirter criterion was met. In addition, T and Ne changes have been used for homogeneity analysis. Different peak comparisons cannot provide us with further data because the major structural components are similar, making it challenging to differentiate between them. So relative standard deviation (RSD) and principal component analysis (PCA) were used to comprise the whole spectra, which showed that the homogeneity of the tablet's core is better than that of the coating and is acceptable.
{"title":"Homogeneity analysis of medicine tablets by laser induced breakdown spectroscopy combined with multivariate methods.","authors":"Amir Hossein Farhadian, Maedeh Mollaei","doi":"10.1016/j.ejpb.2024.114579","DOIUrl":"https://doi.org/10.1016/j.ejpb.2024.114579","url":null,"abstract":"<p><p>Pharmaceutical tablets need to have a homogenous chemical structure, especially in cases where the patient may divide the tablet in half prior to consumption. This work aims to demonstrate the viability of using laser induced breakdown spectroscopy (LIBS) for analyzing the homogeneity and determining the chemical composition of losartan potassium tablets. This was accomplished by obtaining the spectra of 10 tablet points in 30 successive laser pulses, which revealed four main peaks (C, H, N, and O) as well as a high concentration of calcium and potassium in the core tablets and titanium in the coating-all of which are excellent analytical objectives for LIBS. It is possible to say that the generated plasma meets the minimum requirement for local thermodynamic equilibrium because the physical parameters of the plasma, including temperature (T) and electronic density (N<sub>e</sub>), were calculated throughout the Boltzmann plot and Stark broadened line, respectively, and the McWhirter criterion was met. In addition, T and N<sub>e</sub> changes have been used for homogeneity analysis. Different peak comparisons cannot provide us with further data because the major structural components are similar, making it challenging to differentiate between them. So relative standard deviation (RSD) and principal component analysis (PCA) were used to comprise the whole spectra, which showed that the homogeneity of the tablet's core is better than that of the coating and is acceptable.</p>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":" ","pages":"114579"},"PeriodicalIF":4.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638707","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}
Pub Date : 2024-11-10DOI: 10.1016/j.ejpb.2024.114578
Sabrina S. Snyder, Crystal A. Rock, Nancy J. Millenbaugh
Invasive fungal infections have high mortality rates, and many current antimycotics are limited by host toxicity and drug resistance. Recent experiments in our laboratory have demonstrated the antifungal activity of dKn2-7, a synthetic peptide, against Candida albicans. The purpose of the current study was to develop a wound dressing capable of dKn2-7 release for extended periods to help combat fungal infection in wounds. dKn2-7 was incorporated into calcium alginate microfibers, an excipient with known wound healing and hemostatic properties. dKn2-7 release rates from the fibers were dependent on drug loading, but all formulations exhibited a burst release with 41–71 % of total theoretical release in the first 15 min and 84–96 % release by 24 h. Calcium release at 15 min was similar to that of a commercial hemostatic dressing, indicating dKn2-7 loading would not adversely affect the hemostatic capability of the alginate fibers. In vitro antifungal studies indicated a dose dependent effect with fibers loaded at ≥20 µg/mg causing significant planktonic killing and ≥30 µg/mg causing significant biofilm killing. Viable fungal counts in biofilms grown on ex vivo porcine skin declined by 99 % following 500 µg/mg fiber treatment. Skin histology indicated no significant differences in tissue damage between treatment groups and controls. Results confirm calcium alginate microfibers are capable of binding and subsequently releasing dKn2-7 over a 24-h period when rehydrated. Furthermore, dKn2-7 released from the fibers was able to significantly reduce biofilms in an ex vivo model with minimal toxicity, indicating these dKn2-7-loaded fiber dressings may be effective at controlling C. albicans biofilm infections in vivo.
{"title":"Antifungal peptide-loaded alginate microfiber wound dressing evaluated against Candida albicans in vitro and ex vivo","authors":"Sabrina S. Snyder, Crystal A. Rock, Nancy J. Millenbaugh","doi":"10.1016/j.ejpb.2024.114578","DOIUrl":"10.1016/j.ejpb.2024.114578","url":null,"abstract":"<div><div>Invasive fungal infections have high mortality rates, and many current antimycotics are limited by host toxicity and drug resistance. Recent experiments in our laboratory have demonstrated the antifungal activity of dKn2-7, a synthetic peptide, against <em>Candida albicans</em>. The purpose of the current study was to develop a wound dressing capable of dKn2-7 release for extended periods to help combat fungal infection in wounds. dKn2-7 was incorporated into calcium alginate microfibers, an excipient with known wound healing and hemostatic properties. dKn2-7 release rates from the fibers were dependent on drug loading, but all formulations exhibited a burst release with 41–71 % of total theoretical release in the first 15 min and 84–96 % release by 24 h. Calcium release at 15 min was similar to that of a commercial hemostatic dressing, indicating dKn2-7 loading would not adversely affect the hemostatic capability of the alginate fibers. <em>In vitro</em> antifungal studies indicated a dose dependent effect with fibers loaded at ≥20 µg/mg causing significant planktonic killing and ≥30 µg/mg causing significant biofilm killing. Viable fungal counts in biofilms grown on <em>ex vivo</em> porcine skin declined by 99 % following 500 µg/mg fiber treatment. Skin histology indicated no significant differences in tissue damage between treatment groups and controls. Results confirm calcium alginate microfibers are capable of binding and subsequently releasing dKn2-7 over a 24-h period when rehydrated. Furthermore, dKn2-7 released from the fibers was able to significantly reduce biofilms in an <em>ex vivo</em> model with minimal toxicity, indicating these dKn2-7-loaded fiber dressings may be effective at controlling <em>C. albicans</em> biofilm infections <em>in vivo</em>.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114578"},"PeriodicalIF":4.4,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617176","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}
Pub Date : 2024-11-09DOI: 10.1016/j.ejpb.2024.114577
Ji Li , Ziyun Xia , Minzhi Yu , Anna Schwendeman
Multivesicular liposomes (DepoFoam® technology) are distinctive lipid-based sustained release drug delivery systems. Their non-concentric structure differentiates them from unilamellar and multilamellar liposomes. Several products using DepoFoam® technology have been successfully developed and translated into clinical and commercial applications. The unique composition and structure of these particles result in large drug-trap volumes, diverse loading capacities, variable release rates, and different administration routes. With all these advantages, DepoFoam® based products can achieve sustained release pharmacokinetics and significantly improved half-life in various subject species. However, the complexity of constituents and the manufacturing process, as well as the complicated structure and release mechanism, pose challenges to the translation and application of DepoFoam® technology. This review aims to summarize current approved commercial products based on DepoFoam® technology, their structures and components, large-scale manufacturing processes, release characteristics, in vivo pharmacokinetics and clinical outcomes. Challenges in the development and approval of multivesicular liposomes are also highlighted. The persistent academic and industrial research will be needed to overcome the difficulties in developing this unique drug delivery system and pave the path for successful DepoFoam® applications in the future.
{"title":"Challenges in the development of long acting injectable multivesicular liposomes (DepoFoam® technology)","authors":"Ji Li , Ziyun Xia , Minzhi Yu , Anna Schwendeman","doi":"10.1016/j.ejpb.2024.114577","DOIUrl":"10.1016/j.ejpb.2024.114577","url":null,"abstract":"<div><div>Multivesicular liposomes (DepoFoam® technology) are distinctive lipid-based sustained release drug delivery systems. Their non-concentric structure differentiates them from unilamellar and multilamellar liposomes. Several products using DepoFoam® technology have been successfully developed and translated into clinical and commercial applications. The unique composition and structure of these particles result in large drug-trap volumes, diverse loading capacities, variable release rates, and different administration routes. With all these advantages, DepoFoam® based products can achieve sustained release pharmacokinetics and significantly improved half-life in various subject species. However, the complexity of constituents and the manufacturing process, as well as the complicated structure and release mechanism, pose challenges to the translation and application of DepoFoam® technology. This review aims to summarize current approved commercial products based on DepoFoam® technology, their structures and components, large-scale manufacturing processes, release characteristics, <em>in vivo</em> pharmacokinetics and clinical outcomes. Challenges in the development and approval of multivesicular liposomes are also highlighted. The persistent academic and industrial research will be needed to overcome the difficulties in developing this unique drug delivery system and pave the path for successful DepoFoam® applications in the future.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114577"},"PeriodicalIF":4.4,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617181","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}
Pub Date : 2024-11-09DOI: 10.1016/j.ejpb.2024.114576
Grzegorz S. Czyrski, Mikkel K. Frese Hjort, Thomas Rades, Andrea Heinz
Transdermal delivery of therapeutic molecules is often hindered by the properties of the skin, with the stratum corneum serving as the primary permeation barrier. To overcome this barrier, the integrity of the stratum corneum can be modified by chemical permeation enhancers, such as deep eutectic solvents (DESs), or by mechanically impairing the skin with microneedles (MNs). However, a systematic comparison between these strategies is currently lacking. Hence, this study examined the potential of DESs and MNs to promote the permeation and retention of drugs with varying lipophilicities – specifically, the hydrophilic drug metronidazole (logP ∼ 0), the moderately lipophilic drug lidocaine (logP ∼ 2.3), and the highly lipophilic drug clotrimazole (logP ∼ 5). A mixture of menthol and thymol was selected as a model terpene-based DES and delivery vehicle, while a DermaPen equipped with solid MNs was used to mechanically impair the skin. Permeation rates of model drugs applied to the skin with either DES, MNs, or both were compared to the rates determined for the drugs applied in control vehicles. Both strategies were found to compromise the skin barrier function, but their permeation-enhancing effect was dependent on the lipophilicity of tested model drug. The DES was most effective for the hydrophilic drug metronidazole, while the MNs were more effective in increasing the permeation of the highly lipophilic drug clotrimazole. For the moderately lipophilic drug lidocaine, neither the DES nor MNs increased its permeation rate, as the drug permeated through the skin well on its own. Notably, the combination of both enhancement strategies did not result in significantly better permeation rates of the drugs compared to the individual approaches. In conclusion, both the terpene-based DES and solid MNs are effective strategies to enhance drug permeation through the skin, but our results suggest that the choice of strategy should be dictated by the drug’s lipophilicity. Moreover, from a permeation-enhancing perspective, there is no benefit in combining these two strategies.
治疗分子的透皮给药通常受到皮肤特性的阻碍，而角质层是主要的渗透屏障。为了克服这一障碍，可以通过化学渗透促进剂（如深共晶溶剂（DES））或微针（MN）机械损伤皮肤来改变角质层的完整性。然而，目前还缺乏对这些策略的系统比较。因此，本研究考察了 DESs 和 MNs 促进不同亲脂性药物渗透和保留的潜力，特别是亲水性药物甲硝唑（logP ∼ 0）、中等亲脂性药物利多卡因（logP ∼ 2.3）和高亲脂性药物克霉唑（logP ∼ 5）。薄荷醇和百里酚的混合物被选为基于萜烯的 DES 和输送载体模型，而装有固体 MNs 的 DermaPen 则用于机械损伤皮肤。将使用 DES、MNs 或两者的皮肤模型药物渗透率与使用对照载体的药物渗透率进行了比较。结果发现，这两种方法都会损害皮肤屏障功能，但它们的渗透增强效果取决于被测模型药物的亲脂性。DES 对亲水性药物甲硝唑最有效，而 MN 对增加高亲脂性药物克霉唑的渗透更有效。对于中等亲脂性药物利多卡因，DES 和微针都不能提高其渗透率，因为这种药物本身就能很好地透过皮肤。值得注意的是，与单独使用两种方法相比，两种增强策略的结合并没有明显提高药物的渗透率。总之，基于萜烯的 DES 和固体 MNs 都是增强药物在皮肤中渗透的有效策略，但我们的研究结果表明，策略的选择应取决于药物的亲脂性。此外，从促进渗透的角度来看，将这两种策略结合使用并无益处。
{"title":"Comparing effects of terpene-based deep eutectic solvent and solid microneedles on skin permeation of drugs with varying lipophilicity","authors":"Grzegorz S. Czyrski, Mikkel K. Frese Hjort, Thomas Rades, Andrea Heinz","doi":"10.1016/j.ejpb.2024.114576","DOIUrl":"10.1016/j.ejpb.2024.114576","url":null,"abstract":"<div><div>Transdermal delivery of therapeutic molecules is often hindered by the properties of the skin, with the stratum corneum serving as the primary permeation barrier. To overcome this barrier, the integrity of the stratum corneum can be modified by chemical permeation enhancers, such as deep eutectic solvents (DESs), or by mechanically impairing the skin with microneedles (MNs). However, a systematic comparison between these strategies is currently lacking. Hence, this study examined the potential of DESs and MNs to promote the permeation and retention of drugs with varying lipophilicities – specifically, the hydrophilic drug metronidazole (logP ∼ 0), the moderately lipophilic drug lidocaine (logP ∼ 2.3), and the highly lipophilic drug clotrimazole (logP ∼ 5). A mixture of menthol and thymol was selected as a model terpene-based DES and delivery vehicle, while a DermaPen equipped with solid MNs was used to mechanically impair the skin. Permeation rates of model drugs applied to the skin with either DES, MNs, or both were compared to the rates determined for the drugs applied in control vehicles. Both strategies were found to compromise the skin barrier function, but their permeation-enhancing effect was dependent on the lipophilicity of tested model drug. The DES was most effective for the hydrophilic drug metronidazole, while the MNs were more effective in increasing the permeation of the highly lipophilic drug clotrimazole. For the moderately lipophilic drug lidocaine, neither the DES nor MNs increased its permeation rate, as the drug permeated through the skin well on its own. Notably, the combination of both enhancement strategies did not result in significantly better permeation rates of the drugs compared to the individual approaches. In conclusion, both the terpene-based DES and solid MNs are effective strategies to enhance drug permeation through the skin, but our results suggest that the choice of strategy should be dictated by the drug’s lipophilicity. Moreover, from a permeation-enhancing perspective, there is no benefit in combining these two strategies.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114576"},"PeriodicalIF":4.4,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617257","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}
Pub Date : 2024-11-07DOI: 10.1016/j.ejpb.2024.114574
Kiramat Ali Shah , Anam Razzaq , Bengang You , Amos Dormocara , Haroon Iqbal , Jing-Hao Cui
The study investigates the effect of pulmonary surfactant (PS) coating on the performance of lysozyme-loaded poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs). The NPs were fabricated using a double emulsification technique and optimized using the Box-Behnken experimental design (BBED). The NPs were assessed for size, polydispersity index (PDI), zeta potential, drug loading (DL%), and encapsulation efficiency (EE%). In addition, the optimized PLGA NPs were modified with either a neutral dipalmitoylphosphatidylcholine DPPC or an anionic dipalmitoyl phosphatidylglycerol (DPPG) with different molar ratios of PS to PLGA (PS: PLGA = 1:2, 1:1 and 2:1). These NPs were assessed for biological activity, drug release, mucus adhesion, mucus penetration, cellular uptake, toxicity, and in vivo destiny after intratracheal (IT) instillation to mice. Results showed a bi-phasic drug release, with no significant effect of PS on the release and biological activities of PLGA NPs. The PS@PLGA NPs improved mucus adhesion, decreased mucus penetration, and increased cellular internalization of PLGA NPs. In addition, ex vivo experiments demonstrated that DPPC@PLGA NPs and DPPG@PLGA NPs could adhere to mucus. These NPs created a thicker layer at the interface of the airway compared to unmodified PLGA NPs. Moreover, interaction of PS@PLGA NPs with BALF suggested improved mucoadhesive characteristics. Finally, the in vivo studies confirmed the precise distribution of all NPs in the lungs after IT administration. The study presents empirical evidence and scientific guidance for developing a lung surfactant-modified nanocarrier system for lung drug delivery.
{"title":"Unveiling the potential of pulmonary surfactant-based nanocarriers for protein inhalation therapy","authors":"Kiramat Ali Shah , Anam Razzaq , Bengang You , Amos Dormocara , Haroon Iqbal , Jing-Hao Cui","doi":"10.1016/j.ejpb.2024.114574","DOIUrl":"10.1016/j.ejpb.2024.114574","url":null,"abstract":"<div><div>The study investigates the effect of pulmonary surfactant (PS) coating on the performance of lysozyme-loaded poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs). The NPs were fabricated using a double emulsification technique and optimized using the Box-Behnken experimental design (BBED). The NPs were assessed for size, polydispersity index (PDI), zeta potential, drug loading (DL%), and encapsulation efficiency (EE%). In addition, the optimized PLGA NPs were modified with either a neutral dipalmitoylphosphatidylcholine DPPC or an anionic dipalmitoyl phosphatidylglycerol (DPPG) with different molar ratios of PS to PLGA (PS: PLGA = 1:2, 1:1 and 2:1). These NPs were assessed for biological activity, drug release, mucus adhesion, mucus penetration, cellular uptake, toxicity, and in vivo destiny after intratracheal (IT) instillation to mice. Results showed a bi-phasic drug release, with no significant effect of PS on the release and biological activities of PLGA NPs. The PS@PLGA NPs improved mucus adhesion, decreased mucus penetration, and increased cellular internalization of PLGA NPs. In addition, ex vivo experiments demonstrated that DPPC@PLGA NPs and DPPG@PLGA NPs could adhere to mucus. These NPs created a thicker layer at the interface of the airway compared to unmodified PLGA NPs. Moreover, interaction of PS@PLGA NPs with BALF suggested improved mucoadhesive characteristics. Finally, the in vivo studies confirmed the precise distribution of all NPs in the lungs after IT administration. The study presents empirical evidence and scientific guidance for developing a lung surfactant-modified nanocarrier system for lung drug delivery.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114574"},"PeriodicalIF":4.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617262","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}
Pub Date : 2024-11-06DOI: 10.1016/j.ejpb.2024.114573
Sidra Altaf, Mahira Zeeshan, Hussain Ali, Ahmed Zeb, Iqra Afzal, Ayesha Imran, Danish Mazhar, Salman Khan, Fawad Ali Shah
{"title":"Corrigendum to \"pH-Sensitive Tacrolimus loaded nanostructured lipid carriers for the treatment of inflammatory bowel disease\" [Eur. J. Pharm. Biopharm. 204 (2024) 114461].","authors":"Sidra Altaf, Mahira Zeeshan, Hussain Ali, Ahmed Zeb, Iqra Afzal, Ayesha Imran, Danish Mazhar, Salman Khan, Fawad Ali Shah","doi":"10.1016/j.ejpb.2024.114573","DOIUrl":"https://doi.org/10.1016/j.ejpb.2024.114573","url":null,"abstract":"","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":" ","pages":"114573"},"PeriodicalIF":4.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603736","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}
Pub Date : 2024-11-06DOI: 10.1016/j.ejpb.2024.114575
Shiva Vanukuru , Fraser Steele , Natalia N. Porfiryeva , Alejandro Sosnik , Vitaliy V. Khutoryanskiy
Mucoadhesive polymers are crucial for prolonging drug retention on mucosal surfaces. This study focuses on synthesising and characterising novel derivatives by reacting chitosan with crotonic and methacrylic anhydrides. The structure of the resulting derivatives was confirmed using proton-nuclear magnetic resonance spectroscopy and Fourier-transform infrared spectroscopy. It was established that the degree of substitution plays a crucial role in the pH-dependent solubility profiles and electrophoretic mobility of the chitosan derivatives. Spray-drying chitosan solutions enabled preparation of microparticles, whose mucoadhesive properties were evaluated using fluorescence flow-through studies and tensile test, demonstrating improved retention on sheep nasal mucosa for modified derivatives. Acute toxicity studies conducted in vivo using planaria and in vitro using MTT assay with the Caco-2 cell line, a model of the mucosal epithelium in vitro, showed that the novel derivatives are not cytotoxic. These findings emphasise the potential of tailored chitosan chemical modifications for enhancing transmucosal drug delivery.
{"title":"Functionalisation of chitosan with methacryloyl and crotonoyl groups as a strategy to enhance its mucoadhesive properties","authors":"Shiva Vanukuru , Fraser Steele , Natalia N. Porfiryeva , Alejandro Sosnik , Vitaliy V. Khutoryanskiy","doi":"10.1016/j.ejpb.2024.114575","DOIUrl":"10.1016/j.ejpb.2024.114575","url":null,"abstract":"<div><div>Mucoadhesive polymers are crucial for prolonging drug retention on mucosal surfaces. This study focuses on synthesising and characterising novel derivatives by reacting chitosan with crotonic and methacrylic anhydrides. The structure of the resulting derivatives was confirmed using proton-nuclear magnetic resonance spectroscopy and Fourier-transform infrared spectroscopy. It was established that the degree of substitution plays a crucial role in the pH-dependent solubility profiles and electrophoretic mobility of the chitosan derivatives. Spray-drying chitosan solutions enabled preparation of microparticles, whose mucoadhesive properties were evaluated using fluorescence flow-through studies and tensile test, demonstrating improved retention on sheep nasal mucosa for modified derivatives. Acute toxicity studies conducted <em>in vivo</em> using planaria and <em>in vitro</em> using MTT assay with the Caco-2 cell line, a model of the mucosal epithelium <em>in vitro</em>, showed that the novel derivatives are not cytotoxic. These findings emphasise the potential of tailored chitosan chemical modifications for enhancing transmucosal drug delivery.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114575"},"PeriodicalIF":4.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603737","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}
Pub Date : 2024-10-30DOI: 10.1016/j.ejpb.2024.114572
Akashni Rajoo , Sangeetaprivya P. Siva , Chin Siew Sia , Eng-Seng Chan , Beng Ti Tey , Liang Ee Low
Cosmeceuticals, focusing on enhancing skin health and appearance, heavily rely on emulsions as one of the common mediums. These emulsions pose a challenge due to their dependence on surfactants which are essential for stability but are causing concerns about environmental impact as well as evolving consumer preferences. This has led to research focused on Pickering emulsions (PEs), which are colloidal particle-based emulsion alternatives. Compared to conventional emulsions, PEs offer enhanced stability and functionality in addition to serving as a sustainable alternative but still pose challenges such as rheological control and requiring further improvement in long-term stability, whereby the limitations could be addressed through the introduction of a hydrogel network. In this review, we first highlight the strategies and considerations to optimize active ingredient (AI) absorption and penetration in a PE-based formulation. We then delve into a comprehensive overview of the potential of Pickering-based cosmeceutical emulsions including their attractive features, the various Pickering particles that can be employed, past studies and their limitations. Further, PE hydrogels (PEHs), which combines the features between PE and hydrogel as an innovative solution to address challenges posed by both conventional emulsions and PEs in the cosmeceutical industry is explored. Moreover, concerns related to toxicity and biocompatibility are critically examined, alongside considerations of scalability and commercial viability, providing a forward-looking perspective on potential future research directions centered on the application of PEHs in the cosmeceutical field.
{"title":"Transitioning from Pickering emulsions to Pickering emulsion hydrogels: A potential advancement in cosmeceuticals","authors":"Akashni Rajoo , Sangeetaprivya P. Siva , Chin Siew Sia , Eng-Seng Chan , Beng Ti Tey , Liang Ee Low","doi":"10.1016/j.ejpb.2024.114572","DOIUrl":"10.1016/j.ejpb.2024.114572","url":null,"abstract":"<div><div>Cosmeceuticals, focusing on enhancing skin health and appearance, heavily rely on emulsions as one of the common mediums. These emulsions pose a challenge due to their dependence on surfactants which are essential for stability but are causing concerns about environmental impact as well as evolving consumer preferences. This has led to research focused on Pickering emulsions (PEs), which are colloidal particle-based emulsion alternatives. Compared to conventional emulsions, PEs offer enhanced stability and functionality in addition to serving as a sustainable alternative but still pose challenges such as rheological control and requiring further improvement in long-term stability, whereby the limitations could be addressed through the introduction of a hydrogel network. In this review, we first highlight the strategies and considerations to optimize active ingredient (AI) absorption and penetration in a PE-based formulation. We then delve into a comprehensive overview of the potential of Pickering-based cosmeceutical emulsions including their attractive features, the various Pickering particles that can be employed, past studies and their limitations. Further, PE hydrogels (PEHs), which combines the features between PE and hydrogel as an innovative solution to address challenges posed by both conventional emulsions and PEs in the cosmeceutical industry is explored. Moreover, concerns related to toxicity and biocompatibility are critically examined, alongside considerations of scalability and commercial viability, providing a forward-looking perspective on potential future research directions centered on the application of PEHs in the cosmeceutical field.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114572"},"PeriodicalIF":4.4,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564135","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}
Investigating the structural stability of poorly-soluble luteolin (LuT) after encapsulation within cyclodextrins (CDs) is crucial for unlocking the therapeutic potential of LuT bioactive molecule. Herein, native and modified β-CD were employed to investigate LuT inclusion complex formation. Molecular mechanics (MM) and quantum mechanics (QM) were utilized for structural dynamics analysis. Microsecond timescale MD simulations yielded insights into LuT-CD interactions. The binding affinity between LuT and selected β-CDs was assessed by calculating the binding free energy using MM-PBSA and umbrella sampling simulations. The MM-PBSA results indicated that Heptakis-O-(2-hydroxypropyl)-β-CD (HP-β-CD) (−82.59+/-11.67 kJ/mol) and Di-O-methyl-β-CD (DM-β-CD) (−54.01+/-11.07 kJ/mol) exhibited good binding affinity for LuT. Subsequently, derivative screening of HP-β-CD revealed that only 2-HP-β-CD (HP-β-CD-1)/LuT (−21.38 kJ/mol) displayed a superior binding free energy (obtained from umbrella sampling) than HP-β-CD/LuT (−16.55 kJ/mol) inclusion complex. We conducted QM calculations on the top three inclusion complexes namelly HP-β-CD, DM-β-CD, and HP-β-CD-1 employing wB97X-D/6–311 + G(d,p) model chemistry to strengthen the MM results. The computational analysis aligns with experimental findings (phase solubility analysis), validating HP-β-CD-1 as most effective cavitand molecule for improving the solubility of LuT. This study offers critical structural insights for developing novel HP-β-CD derivatives with enhanced host capacity to encapsulate guest molecules efficiently.
{"title":"Computational and experimental analysis of Luteolin-β-cyclodextrin supramolecular complexes: Insights into conformational dynamics and phase solubility","authors":"Pramod Kumar , Vijay Kumar Bhardwaj , Pravin Shende , Rituraj Purohit","doi":"10.1016/j.ejpb.2024.114569","DOIUrl":"10.1016/j.ejpb.2024.114569","url":null,"abstract":"<div><div>Investigating the structural stability of poorly-soluble luteolin (LuT) after encapsulation within cyclodextrins (CDs) is crucial for unlocking the therapeutic potential of LuT bioactive molecule. Herein, native and modified β-CD were employed to investigate LuT inclusion complex formation. Molecular mechanics (MM) and quantum mechanics (QM) were utilized for structural dynamics analysis. Microsecond timescale MD simulations yielded insights into LuT-CD interactions. The binding affinity between LuT and selected β-CDs was assessed by calculating the binding free energy using MM-PBSA and umbrella sampling simulations. The MM-PBSA results indicated that Heptakis-O-(2-hydroxypropyl)-β-CD (HP-β-CD) (−82.59+/-11.67 kJ/mol) and Di-O-methyl-β-CD (DM-β-CD) (−54.01+/-11.07 kJ/mol) exhibited good binding affinity for LuT. Subsequently, derivative screening of HP-β-CD revealed that only 2-HP-β-CD (HP-β-CD-1)/LuT (−21.38 kJ/mol) displayed a superior binding free energy (obtained from umbrella sampling) than HP-β-CD/LuT (−16.55 kJ/mol) inclusion complex. We conducted QM calculations on the top three inclusion complexes namelly HP-β-CD, DM-β-CD, and HP-β-CD-1 employing wB97X-D/6–311 + G(d,p) model chemistry to strengthen the MM results. The computational analysis aligns with experimental findings (phase solubility analysis), validating HP-β-CD-1 as most effective cavitand molecule for improving the solubility of LuT. This study offers critical structural insights for developing novel HP-β-CD derivatives with enhanced host capacity to encapsulate guest molecules efficiently.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"205 ","pages":"Article 114569"},"PeriodicalIF":4.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557408","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}
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