International Journal of Pharmaceutics最新文献_第3页

A finasteride patch for the treatment of androgenetic alopecia: A study of promoting permeability strategy using synthetic novel O-acylmenthols combined with ion-pair 用于治疗雄激素性脱发的非那雄胺贴片：利用合成的新型 O-酰基薄荷醇结合离子对促进渗透性策略的研究。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-04 DOI: 10.1016/j.ijpharm.2024.124802

Currently, finasteride (FIN) is approved to treat androgenetic alopecia only orally, and the application of FIN in transdermal drug delivery system (TDDS) has introduced a new approach for treating the disease. This study was aimed to develop a FIN transdermal patch for the treatment of androgenetic alopecia（AGA） by combing ion-pair and O-acylmenthols (AM) as chemical permeation enhancers (CPEs). The formulation of patch was optimized though single-factor investigation and Box-Behnken design. The pharmacokinetics and androgenetic alopecia pharmacodynamics of the patch were evaluated. Additionally, the permeability enhancement mechanisms of ion-pair and AMs were explored at both the patch and skin levels. The effects of ion-pair and AMs on the patch were characterized by rheology study, FTIR, and molecular docking, and the effects on the skin were assessed through ATR-FTIR, Raman study, DSC, CLSM and molecular dynamics. The finalized formulation of FIN patches was consisted of 5 % (w/w) synthetic FIN-CA (Citric Acid), 6 % MT-C6 as CPEs, 25-AAOH as a pressure-sensitive adhesive (PSA), with a patch thickness of 80 ± 5 μm. The final Q_{24 h} is 78.22 ± 5.18 μg/cm². Based on the high FIN permeability, the pharmacokinetic analysis revealed that the FIN patch group exhibited a slower absorption rate (t_max = 7.3 ± 2.7 h), lower peak plasma concentration and slower metabolic rate (t_1/2 = 6.2 ± 0.8 h, MRT_0-t = 26.0 ± 7.8 h) compared to the oral group. Moreover, the FIN patch also demonstrated the same effect as the oral group in promoting hair growth in AGA mice. The results indicated that both FIN-CA and AMs could enhance the fluidity of the PSA and weaken the interaction between FIN-CA and PSA, thereby promoting the release of the FIN from the patch. The interaction sites on the skin for ion-pair and the four AMs were found in the stratum corneum (SC) of the skin, disrupting the tight arrangement of stratum corneum lipids. This study serves as a reference for the multi-pathway administration of FIN and the combination of ion-pair with AMs to enhance drug permeation.

目前，非那雄胺（FIN）仅被批准用于口服治疗雄激素性脱发，而将非那雄胺应用于透皮给药系统（TDDS）则为治疗该疾病提供了一种新方法。本研究的目的是通过离子对和OPO的结合，开发一种治疗雄激素性脱发（AGA）的FIN透皮贴片。将离子对和O-酰基薄荷醇（AM）结合起来作为化学渗透促进剂（CPE）。通过单因素考察和盒-贝肯设计对贴片配方进行了优化。对贴片的药代动力学和雄激素性脱发的药效学进行了评估。此外，还从贴片和皮肤两个层面探讨了离子对和 AMs 的渗透性增强机制。离子对和 AMs 对贴片的影响通过流变学研究、傅立叶变换红外光谱和分子对接进行了表征，对皮肤的影响则通过 ATR-傅立叶变换红外光谱、拉曼研究、DSC、CLSM 和分子动力学进行了评估。FIN 贴片的最终配方由 5 %（重量比）合成 FIN-CA（柠檬酸）、6 % MT-C6 作为 CPE、25-AAOH 作为压敏胶（PSA）组成，贴片厚度为 80 ± 5 μm。最终的 Q24 h 值为 78.22 ± 5.18 μg/cm2。基于 FIN 的高渗透性，药代动力学分析表明，与口服组相比，FIN 贴片组的吸收速率较慢（tmax = 7.3 ± 2.7 h），血浆峰浓度较低，代谢速率较慢（t1/2 = 6.2 ± 0.8 h，MRT0-t = 26.0 ± 7.8 h）。此外，FIN 贴片在促进 AGA 小鼠毛发生长方面也表现出与口服组相同的效果。结果表明，FIN-CA 和 AMs 都能增强 PSA 的流动性，削弱 FIN-CA 和 PSA 之间的相互作用，从而促进 FIN 从贴片中释放出来。离子对和四种 AMs 在皮肤上的相互作用位点位于皮肤的角质层（SC），破坏了角质层脂质的紧密排列。这项研究为 FIN 的多途径给药以及将离子对与 AMs 结合以增强药物渗透性提供了参考。

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引用次数: 0

Novel natural lipids based NLC containing finasteride improved androgenetic alopecia treatment in rats 含有非那雄胺的新型天然脂基 NLC 可改善大鼠雄激素性脱发的治疗效果。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-04 DOI: 10.1016/j.ijpharm.2024.124804

Androgenetic alopecia (AGA) is the most common hair loss disorder, affecting millions of men and women worldwide. Current formulations used to treat this condition often lead to a wide variety of side effects, ranging from allergies to sexual disfunction, especially when those drugs are administered orally. In this study, we developed and tested unique formulations containing nanostructured lipid carriers (NLC) composed of lipids extracted from fruit seeds, carrying finasteride to enhance efficacy of AGA treatment. By stabilizing the hydrophobic compounds in the solid matrix, three formulations of NLC were engineered and successfully prepared. Further an in vivo model of AGA was induced in rats by the administration of testosterone, as a platform to evaluate the efficiency of the formulations. The chosen formulation exhibited high bioavailability, medium size of 124.5 nm and PdI of 0.143, without systemic absorption. In addition, it promoted efficient and significant follicle restoration in AGA induced rats by increasing number of active bulbs and showed to be a safe formulation for topical application. The results of this research indicate that the presented formulation has significant potential to yield improved outcomes in AGA treatment.

雄激素性脱发（AGA）是最常见的脱发疾病，影响着全球数百万男性和女性。目前用于治疗这种疾病的制剂往往会导致各种各样的副作用，从过敏到性功能障碍，尤其是在口服给药的情况下。在这项研究中，我们开发并测试了含有纳米结构脂质载体（NLC）的独特配方，该载体由从水果种子中提取的脂质组成，并携带非那雄胺，以提高 AGA 的治疗效果。通过将疏水性化合物稳定在固体基质中，成功制备了三种 NLC 配方。此外，还通过给大鼠注射睾酮诱发了 AGA 的体内模型，以此作为评估制剂功效的平台。所选制剂具有较高的生物利用度、124.5 纳米的中等尺寸和 0.143 的 PdI，不会被全身吸收。此外，它还通过增加活性球的数量，促进了 AGA 诱导的大鼠高效、显著的毛囊恢复，并显示出这是一种可用于局部应用的安全配方。这项研究的结果表明，所介绍的制剂在改善 AGA 治疗效果方面具有巨大潜力。

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引用次数: 0

Novel sodium tauroursodeoxycholate-based multifunctional liposomal delivery system for encapsulation of oleanolic acid and combination therapy of type 2 diabetes mellitus 基于牛磺脱氧胆酸钠的新型多功能脂质体递送系统，用于包裹齐墩果酸并联合治疗 2 型糖尿病。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-04 DOI: 10.1016/j.ijpharm.2024.124803

Liposomes have demonstrated great potential for drug delivery and diabetes treatment. However, hydrolysis by enzymes and emulsification by endogenous bile salts make liposomes unstable in the gastrointestinal tract. In this study, sodium tauroursodeoxycholate (TUDCNa)-based multifunctional bilosomes were designed to address the deficiencies of conventional liposomes. In the designed bilosomes, cholesterol was replaced by TUDCNa, which served as both a membrane stabilizer and an antidiabetic drug. Oleanolic acid (OA) was encapsulated in both conventional liposomes (OA-Ch-Lip) and bilosomes (OA-Tu-Bil) to compare their properties. Firstly, OA-Tu-Bil exhibited similar encapsulation efficiency and drug loading compared to OA-Ch-Lip, but with a smaller particle size. Secondly, OA-Tu-Bil showed better stability than OA-Ch-Lip. Thirdly, bilosomes exhibited prolonged intestinal retention time and improved permeability and oral bioavailability. Fourthly, in type 2 diabetes mellitus (T2DM) mice model, TUDCNa synergized with OA to exhibit the strongest therapeutic effect. In conclusion, TUDCNa have demonstrated the ability to substitute cholesterol in conventional liposomes, it provided a new approach for oral delivery of hypoglycemic drugs, and offered an innovative strategy for combination therapy.

脂质体在药物输送和糖尿病治疗方面具有巨大潜力。然而，酶的水解作用和内源性胆盐的乳化作用使得脂质体在胃肠道中不稳定。本研究设计了基于牛磺脱氧胆酸钠（TUDCNa）的多功能双体，以解决传统脂质体的不足。在设计的双糖体中，胆固醇被 TUDCNa 取代，TUDCNa 既是一种膜稳定剂，又是一种抗糖尿病药物。将齐墩果酸（OA）包裹在传统脂质体（OA-Ch-Lip）和双糖体（OA-Tu-Bil）中，比较它们的特性。首先，与 OA-Ch-Lip 相比，OA-Tu-Bil 的封装效率和载药量相似，但粒径更小。其次，OA-Tu-Bil 比 OA-Ch-Lip 表现出更好的稳定性。第三，双糖体延长了肠道滞留时间，提高了渗透性和口服生物利用度。第四，在 2 型糖尿病（T2DM）小鼠模型中，TUDCNa 与 OA 协同发挥了最强的治疗效果。总之，TUDCNa 具有替代传统脂质体中胆固醇的能力，为降糖药物的口服给药提供了一种新方法，并为联合治疗提供了一种创新策略。

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引用次数: 0

Bacterial ghosts engineered with lipidated antigens as an adjuvant-free vaccine for Chlamydia abortus 用脂质抗原设计的细菌幽灵作为流产衣原体无佐剂疫苗。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-04 DOI: 10.1016/j.ijpharm.2024.124801

Bacterial ghosts (BGs) provide novel vaccine delivery platforms because of their inherent adjuvant properties and efficient antigen delivery capabilities. However, effective engineering strategies are required to modify them for different antigens. In this study, the Escherichia coli (E. coli) ghost was modified by using a lpp’-ompA chimera, a widely used bacterial surface display vector, with a protective antigen macrophage infectivity potentiator (MIP) of Chlamydia abortus (C. abortus), and its protective effect was evaluated in a mouse model. The MIP fusion protein accumulated at 1.2% of the ghost total protein mass and a significant portion of the protein was modified into lipoproteins upon translocation to the BG surface. Lipidated MIP-modified recombinant E. coli ghosts (rECG-lpp’-MIP) effectively promoted antigen-presenting cells (APCs) uptake of antigens and stimulated APCs activation in vivo and in vitro. Immunization with rECG-lpp’-MIP and no adjuvant induced intense specific humoral responses as well as Th1-biased cellular immune responses, which significantly improved the efficiency of C. abortus infection clearance in mice and reduced pathological damage to the uterus. In summary, this study demonstrates that recombinant E. coli ghosts modified with lipidated antigens could help to develop an effective C. abortus vaccine and aid in the development of a universal adjuvant-free vaccine platform.

细菌幽灵（BGs）因其固有的佐剂特性和高效的抗原递送能力而成为新型疫苗递送平台。然而，要针对不同的抗原对其进行改造，需要有效的工程策略。本研究利用广泛使用的细菌表面展示载体 lpp'-ompA 嵌合体对大肠杆菌鬼臼毒素（E. coli）进行了改造，将其与流产衣原体（C. abortus）的保护性抗原巨噬细胞感染性增效剂（MIP）进行了融合，并在小鼠模型中对其保护效果进行了评估。MIP 融合蛋白的累积量占鬼魂总蛋白质量的 1.2%，而且在转运到 BG 表面时，相当一部分蛋白被修饰成脂蛋白。脂化的MIP修饰重组大肠杆菌鬼蛋白（rECG-lpp'-MIP）能有效促进抗原递呈细胞（APCs）摄取抗原，并在体内和体外刺激APCs活化。使用rECG-lpp'-MIP和无佐剂免疫可诱导强烈的特异性体液反应和Th1型细胞免疫反应，从而显著提高小鼠流产葡萄球菌感染的清除率并减少子宫的病理损伤。总之，本研究证明了用脂质化抗原修饰的重组大肠杆菌鬼臼毒素有助于开发有效的流产葡萄球菌疫苗，并有助于开发通用的无佐剂疫苗平台。

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引用次数: 0

The molecular design of novel phospholipid-inspired ionic liquid transdermal penetration enhancers: Innovative insights on the action mode and mechanism 新型磷脂离子液体透皮渗透增强剂的分子设计：对作用模式和机制的创新见解。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-04 DOI: 10.1016/j.ijpharm.2024.124805

Ionic liquid transdermal penetration enhancers (IL@TPEs) as new enhancement methods have significant advantages in the transdermal drug delivery system. However, the scientific frameworks for the design of efficient IL@TPEs and their applications in transdermal formulations were still lack. So, a series of novel biomimetic phospholipid-inspired IL@TPEs (PIL@TPEs) were designed and synthesized. The developed QSARs proved that enhancement efficacy of PIL@TPEs depended on pKa of drugs and M.W., Polar., and pKa of cations. Surprisingly, the PIL@TPEs dissociated during transdermal process, and skin penetration amounts of acidic drugs was inversely proportional to skin retention amounts of cations, which showed that action modes of PIL@TPEs were different from conventional enhancers. The novel mechanisms of PIL@TPEs were elucidated by quantitative determination of dynamic interaction among cations, anions, drugs, and skins. The PIL@TPEs with high enhancement efficiency owned strong interactions with drugs determined by ATR-FTIR, Raman and NOESY. Moreover, the PIL@TPEs owning better stability in skin ensured the production of strong interactions with lipids and keratins characterized by ATR-FTIR, ¹H NMR and CLSM. The good safety of optimized PIL@TPEs was proved by determining cytotoxicity, apoptosis, inflammatory cells, and cytokines. In conclusion, this project will make an important contribution to the design and application of IL@TPEs.

离子液体透皮渗透增强剂（IL@TPEs）作为新的增强方法在透皮给药系统中具有显著优势。然而，目前仍缺乏设计高效离子液体透皮渗透促进剂及其在透皮制剂中应用的科学框架。因此，我们设计并合成了一系列新型仿生物磷脂IL@TPEs（PIL@TPEs）。所开发的 QSARs 证明，PIL@TPEs 的增效作用取决于药物的 pKa 和阳离子的 M.W.、Polar. 和 pKa。令人惊讶的是，PIL@TPEs在透皮过程中发生了解离，酸性药物的皮肤渗透量与阳离子的皮肤保留量成反比，这表明PIL@TPEs的作用模式不同于传统的增强剂。通过定量测定阳离子、阴离子、药物和皮肤之间的动态相互作用，阐明了PIL@TPEs的新机制。通过ATR-傅立叶变换红外光谱、拉曼光谱和NOESY光谱测定，具有高增强效率的PIL@TPEs与药物之间具有很强的相互作用。此外，PIL@TPE 在皮肤中具有更好的稳定性，可确保与脂质和角蛋白产生强烈的相互作用，ATR-FTIR、1H NMR 和 CLSM 对其进行了表征。通过测定细胞毒性、细胞凋亡、炎症细胞和细胞因子，证明了经过优化的 PIL@TPEs 具有良好的安全性。总之，该项目将为 IL@TPEs 的设计和应用做出重要贡献。

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引用次数: 0

Doxorubicin and 4-nitrochalcone loaded in beeswax-based nanostructured lipid carriers: In vitro antitumoral screening and evaluation of synergistic effect on HepG-2 cells 将多柔比星和 4-硝基查尔酮载入蜂蜡基纳米结构脂质载体：体外抗肿瘤筛选以及对 HepG-2 细胞协同作用的评估。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-03 DOI: 10.1016/j.ijpharm.2024.124788

Cancer is the second most deadly disease worldwide, and the most traditional approaches such as chemotherapy still face limitations associated to drug dosage and off-target side effects. To address these issues, we propose the simultaneous administration of 4-Nitrochalcone (4NC) and Doxorubicin (DOX) using beeswax based nanostructured lipid carriers (NLCs). The co-encapsulation of 4NC and DOX in the beeswax based NLCs was performed using the water/oil/water double emulsion technique in association with the melt dispersion approach. The system composed by semi-spherical NLCs with an average diameter around 200 nm and narrow size distribution, displayed colloidal stability before and after redispersion, keeping the zeta potential below −30 mV. The antitumor activity of the nanoparticles was screened on different tumor cell lines, and the induced cellular death and internal ROS levels were analyzed on hepatocarcinoma cells, which were found to be more affected by the combination of 4NC and DOX. The results indicated that 4NC + DOX-NCLs could promote cytotoxicity and oxidative damage-mediated apoptosis in a HepG-2 cell line.

癌症是全球第二大致命疾病，而化疗等最传统的方法仍然面临着药物剂量和脱靶副作用的限制。为了解决这些问题，我们提出了使用蜂蜡基纳米结构脂质载体（NLCs）同时给药 4-硝基查尔酮（4NC）和多柔比星（DOX）的方案。采用水/油/水双乳液技术和熔融分散方法，在蜂蜡基纳米脂质载体中实现了 4NC 和 DOX 的共包囊。该体系由平均直径约为 200 nm 的半球形 NLC 组成，粒度分布较窄，在再分散前后均表现出胶体稳定性，zeta 电位保持在 -30 mV 以下。在不同的肿瘤细胞系上对纳米颗粒的抗肿瘤活性进行了筛选，并对肝癌细胞的诱导细胞死亡和内部 ROS 水平进行了分析，发现 4NC 和 DOX 的组合对肝癌细胞的影响更大。结果表明，4NC + DOX-NCLs 可促进 HepG-2 细胞系的细胞毒性和氧化损伤介导的细胞凋亡。

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引用次数: 0

Development of a high-fidelity digital twin using the discrete element method for a continuous direct compression process. Part 2. Validation of calibration workflow 使用离散元素法开发用于连续直接压缩过程的高保真数字孪生模型。第 2 部分。校准工作流程的验证。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-03 DOI: 10.1016/j.ijpharm.2024.124797

This paper is the second in a series of two that describes the application of discrete element method (DEM) and reduced order modeling to predict the effect of disturbances in the concentration of drug substance at the inlet of a continuous powder mixer on the concentration of the drug substance at the outlet of the mixer. In the companion publication, small-scale material characterization tests, a careful DEM parameter calibration and DEM simulations of the manufacturing process were used to develop a reliable RTD models. In the current work, the same calibration workflow was employed to evaluate the predictive ability of the resulting reduced-order model for an extended design space. DEM simulations were extrapolated using a relay race method and the cumulative RTD was accurately parameterized using the n-CSTR model. By performing experiments and simulations, a calibrated DEM model predicted the response of a continuous powder mixer to step changes in the inlet concentration of an API. Thus, carefully calibrated DEM models was used to guide and reduce experimental work and to establish an adequate control strategy. In addition, a further reduction in the computational effort was obtained by using the relay race method to extrapolate results. The predicted RTD curves were then parameterized to develop reduced order models and used to simulate the process in a matter of seconds. Overall, a control strategy evaluation tool based on high-fidelity DEM simulations was developed using material-sparing small-scale characterization tests.

本文是两篇系列论文中的第二篇，介绍了应用离散元素法（DEM）和降阶建模预测连续粉末混合器入口处药物浓度的干扰对混合器出口处药物浓度的影响。在相关出版物中，通过小规模材料表征测试、仔细的 DEM 参数校准和制造过程的 DEM 模拟，开发出了可靠的 RTD 模型。在当前工作中，采用了相同的校准工作流程，以评估由此产生的降阶模型对扩展设计空间的预测能力。使用接力赛法对 DEM 模拟进行了外推，并使用 n-CSTR 模型对累积 RTD 进行了精确参数化。通过进行实验和模拟，校准后的 DEM 模型预测了连续式粉末混合器对原料药入口浓度阶跃变化的响应。因此，经过仔细校准的 DEM 模型可用于指导和减少实验工作，并建立适当的控制策略。此外，通过使用中继赛跑法推断结果，进一步减少了计算工作量。然后，对预测的热电阻曲线进行参数化，以建立减阶模型，并用于在几秒钟内对过程进行模拟。总之，通过使用节省材料的小规模表征试验，开发出了基于高保真 DEM 模拟的控制策略评估工具。

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引用次数: 0

Zein nanoparticles extend lifespan in C. elegans and SAMP8 mice Zein 纳米粒子可延长秀丽隐杆线虫和 SAMP8 小鼠的寿命。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-02 DOI: 10.1016/j.ijpharm.2024.124798

Empty zein nanoparticles (NP) have been shown to lower glycemia in rats by stimulating the secretion of endogenous GLP-1. This study evaluated the effect of these nanoparticles on the lifespan of two animal models: C. elegans fed with a glucose-rich diet and the senescence accelerated mouse-prone 8 (SAMP8 mice). In C. elegans, NP increased the mean lifespan of worms by 7 days (from 17.1 for control to 24.5 days). This observation was in line with the observed significant reductions of glucose and fat contents, lipofuscin accumulation, and ROS expression. Furthermore, NP supplementation led to an upregulation of the expression of daf-16 and skn-1 genes. DAF-16 (orthologue of the FOXO family) and SKN-1 (orthologue of mammalian Nrf/CNC proteins) are implicated in activating detoxification mechanisms against oxidative damage. In SAMP8, oral administration of NP also extended the mean lifespan of mice (by 28 % compared to controls), corroborating the protective effect of these nanoparticles.

空玉米蛋白纳米颗粒（NP）已被证明能通过刺激内源性 GLP-1 的分泌来降低大鼠的血糖。本研究评估了这些纳米颗粒对两种动物模型寿命的影响：这两种动物模型分别是以富含葡萄糖的食物喂养的优雅小鼠和易衰老加速小鼠 8（SAMP8 小鼠）。在 elegans 中，NP 使蠕虫的平均寿命延长了 7 天（从对照组的 17.1 天延长到 24.5 天）。这一观察结果与所观察到的葡萄糖和脂肪含量、脂质褐素积累和 ROS 表达的显著减少相一致。此外，补充氮磷导致 daf-16 和 skn-1 基因表达上调。DAF-16（FOXO 家族的直系同源物）和 SKN-1（哺乳动物 Nrf/CNC 蛋白的直系同源物）与激活抗氧化损伤的解毒机制有关。在 SAMP8 中，口服 NP 还延长了小鼠的平均寿命（与对照组相比延长了 28%），证实了这些纳米粒子的保护作用。

引用次数: 0

Development of a high-fidelity digital twin using the discrete element method for a continuous direct compression process. Part 1. Calibration workflow 使用离散元素法为连续直接压缩过程开发高保真数字孪生模型。第 1 部分：校准工作流程。校准工作流程。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-02 DOI: 10.1016/j.ijpharm.2024.124796

In this work, a high-fidelity digital twin was developed to support the design and testing of control strategies for drug product manufacturing via direct compression. The high-fidelity digital twin platform was based on typical pharmaceutical equipment, materials, and direct compression continuous processes. The paper describes in detail the material characterization, the Discrete Element Method (DEM) model and the DEM model parameter calibration approach and provides a comparison of the system’s response to the experimental results for stepwise changes in the API concentration at the mixer inlet. A calibration method for a cohesive DEM contact model parameter estimation was introduced. To assure a correct prediction for a wide range of processes, the calibration approach contained four characterization experiments using different stress states and different measurement principles, namely the bulk density test, compression with elastic recovery, the shear cell, and the rotating drum. To demonstrate the sensitivity of the DEM contact parameters to the process response, two powder characterization data sets with different powder flowability were applied. The results showed that the calibration method could differentiate between the different material batches of the same blend and that small-scale material characterization tests could be used to predict the residence time distribution in a continuous manufacturing process.

在这项工作中，开发了一个高保真数字孪生系统，以支持设计和测试通过直接压缩生产药品的控制策略。高保真数字孪生平台基于典型的制药设备、材料和直接压缩连续工艺。论文详细描述了材料表征、离散元素法（DEM）模型和 DEM 模型参数校准方法，并比较了系统对混合器入口处原料药浓度逐步变化的响应与实验结果。介绍了内聚 DEM 接触模型参数估计的校准方法。为确保对各种过程进行正确预测，校准方法包括使用不同应力状态和不同测量原理的四种特性实验，即松散密度测试、弹性恢复压缩、剪切池和旋转滚筒。为了证明 DEM 接触参数对过程响应的敏感性，应用了两组具有不同粉末流动性的粉末表征数据。结果表明，校准方法可以区分同一混合物的不同材料批次，小规模材料表征测试可用于预测连续生产过程中的停留时间分布。

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引用次数: 0

A potential cocrystal strategy to tailor in-vitro dissolution and improve Caco-2 permeability and oral bioavailability of berberine 定制体外溶解度、改善小檗碱的 Caco-2 渗透性和口服生物利用度的潜在共晶体策略。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-10-02 DOI: 10.1016/j.ijpharm.2024.124789

Berberine hydrochloride (BER), a promising candidate in treating tumors, diabetes and pain management, has relatively low oral absorption and bioavailability due to its low intestinal permeability. To address these challenges, we developed a BER and lornoxicam cocrystal (BLCC) by a solvent evaporation method and characterized it using X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. Compared with BER, BLCC exhibited an instant release in pH 1.0 HCl and a sustained release up to 24 h in pH 6.8 buffer solutions and water. The Caco-2 permeability of BLCC has shown a remarkable increase compared to that of BER (i.e., P_app(a→b): 50.30 × 10^-7 vs 8.82 × 10^-7 cm/s), which is attributed to the improved lipophilicity of BER (i.e., log P: 1.29 vs −1.83) and the reduced efflux amount of BER (i.e., ER: 1.71 vs 12.11). Furthermore, BLCC demonstrated a relative bioavailability of 410 % in comparison to the original BER, due to notably enhanced intestinal permeability of BLCC and its continuous dissolution in simulated intestinal fluid. BLCC has the potential to tailor the dissolution behavior, improve intestinal permeability, and boost the bioavailability of BER. This indicates that the cocrystal strategy holds promise as an effective approach to improving the oral absorption and bioavailability of active pharmaceutical molecules with low permeability during drug development.

盐酸小檗碱（BER）是治疗肿瘤、糖尿病和疼痛的有望候选药物，但由于其肠道渗透性低，口服吸收率和生物利用度相对较低。为了应对这些挑战，我们采用溶剂蒸发法研制出了盐酸拜耳和洛诺昔康共晶体（BLCC），并利用 X 射线衍射、差示扫描量热法和热重分析对其进行了表征。与 BER 相比，BLCC 在 pH 值为 1.0 的盐酸溶液中可瞬间释放，在 pH 值为 6.8 的缓冲溶液和水中可持续释放达 24 小时。与 BER 相比，BLCC 的 Caco-2 渗透性显著增加（即 Papp（a→b）：50.30×10-7vs8.82×10-7cm/s），这归因于 BER 的亲脂性提高（即 log P：1.29 vs -1.83）和 BER 的外流量减少（即 ER：1.71 vs 12.11）。此外，由于 BLCC 的肠道渗透性明显增强，且能在模拟肠液中持续溶解，与原始 BER 相比，BLCC 的相对生物利用率提高了 410%。BLCC 具有定制溶解行为、改善肠道渗透性和提高 BER 生物利用率的潜力。这表明，在药物开发过程中，共晶策略有望成为改善低渗透性活性药物分子口服吸收和生物利用度的有效方法。

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