Journal of pharmaceutical sciences最新文献_第3页

Improved properties of glass vials for primary packaging with atomic layer deposition 利用原子层沉积技术改善初级包装用玻璃瓶的性能。

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.09.007

Ilkka Manninen , Riina Ritasalo , Samuli Hirsjärvi

Novel pharmaceuticals and drug delivery devices may require better performance from the packaging material e.g., in terms of extractables and leachables, and unwanted interactions. To address this, we applied atomic layer deposition (ALD) to build nanometer-range SiO₂, ZrO₂ and Al₂O₃-TiO₂ films on primary packaging glass. Controlled modification of the surface also enabled creation of functionality without affecting visual appearance of the material. ALD-coated Type I borosilicate vials were compared to uncoated ones, and tailored functionality was presented by appropriate measurements. The tested ALD coatings formed a barrier on glass against extractables and leachables, from the vial and the coating alike. A good ALD coating prevents any leakage into the stored drug product. Hydrolytic resistance results improved by 85–92 %, and these results correlated well with straightforward water conductivity measurements. Opposite to uncoated borosilicate glass vials, no extracted elements could be detected from the extracts of the coated vials with stable ALD films. Improved surface integrity was observed with electron microscopy as well. ALD films increased hydrophilicity of the surface and tuning the ALD film thickness and composition allowed precise blocking of UV light wavelengths, without affecting transparency. As a conclusion, ALD is a versatile method to create barrier and functional films on primary packaging materials.

新型药品和给药装置可能需要包装材料具有更好的性能，例如在可萃取性、可浸出性和不需要的相互作用方面。为此，我们采用原子层沉积（ALD）技术，在初级包装玻璃上形成纳米范围的二氧化硅、二氧化锆和氧化铝-二氧化钛薄膜。在不影响材料视觉外观的前提下，通过对表面进行可控改性，还实现了功能性的创造。ALD 镀膜的 I 型硼硅玻璃瓶与未镀膜的玻璃瓶进行了比较，并通过适当的测量显示了量身定制的功能。测试的 ALD 涂层在玻璃上形成了一道屏障，防止玻璃瓶和涂层中的可萃取物和可浸出物。良好的 ALD 涂层可防止药物泄漏到储存的产品中。耐水解性结果提高了 85-92%，这些结果与直接的水传导性测量结果密切相关。与未镀膜的硼硅酸盐玻璃瓶相反，镀有稳定 ALD 膜的玻璃瓶提取物中检测不到任何萃取元素。电子显微镜也观察到了表面完整性的改善。ALD 膜增加了表面的亲水性，调整 ALD 膜的厚度和成分可精确阻挡紫外线波长，而不影响透明度。总之，ALD 是一种在初级包装材料上制造阻隔膜和功能膜的多功能方法。

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引用次数: 0

Microparticles incorporating dual apoptotic factors to inhibit inflammatory effects in macrophages 含有双重凋亡因子的微颗粒可抑制巨噬细胞的抗炎作用。

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.05.030

Sean R. Simpson , Denzel D. Middleton , Nicole Rose Lukesh , Md Jahirul Islam , Stephen A. Ehrenzeller , Eric M. Bachelder , Kristy M. Ainslie

New approaches to treat autoimmune diseases are needed, and we can be inspired by mechanisms in immune tolerance to guide the design of these approaches. Efferocytosis, the process of phagocyte-mediated apoptotic cell (AC) disposal, represents a potent tolerogenic mechanism that we could draw inspiration from to restore immune tolerance to specific autoantigens. ACs engage multiple avenues of the immune response to redirect aberrant immune responses. Two such avenues are: phosphatidylserine on the outer leaflet of the cell and engaging the aryl hydrocarbon receptor (AhR) pathway. We incorporated these two avenues into one acetalated dextran (Ace-DEX) microparticle (MP) for evaluation in vitro. First phosphatidylserine (PS) was incorporated into Ace-DEX MPs and evaluated for cellular association and mediators of cell tolerance including IL-10 production and M2 associated gene expression when particles were cultured with peritoneal macrophages (PMacs). Further PS Ace-DEX MPs were evaluated as an agent to suppress LPS stimulated PMacs. Then, AhR agonist 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) was incorporated into Ace-DEX MPs and expression of M2 and IL-10 genes was evaluated in PMacs. Further the ITE and PS Ace-DEX MPs (PS/ITE MPs) were evaluated for suppression of T cell priming and Th1 polarization. Our results indicate that the PS/ITE-MPs stimulated anti-inflammatory cytokine expression and suppressed inflammation following LPS stimulation of PMacs. Moreover, PS/ITE MPs induced the anti-inflammatory enzyme IDO1 and suppressed macrophage-mediated T cell priming and Th1 polarization. These findings suggest that PS and ITE-loaded Ace-DEX MPs could be a promising therapeutic tool for suppressing inflammation.

我们需要治疗自身免疫性疾病的新方法，我们可以从免疫耐受机制中得到启发，以指导这些方法的设计。吞噬细胞介导的凋亡细胞（AC）处理过程--吞噬细胞吞噬作用是一种有效的耐受机制，我们可以从中获得灵感，恢复对特定自身抗原的免疫耐受。凋亡细胞参与免疫反应的多种途径，以重定向异常免疫反应。其中两个途径是：细胞外叶上的磷脂酰丝氨酸和芳基烃受体（AhR）途径。我们将这两种途径整合到一个乙缩醛葡聚糖（Ace-DEX）微颗粒（MP）中进行体外评估。首先，我们将磷脂酰丝氨酸（PS）加入 Ace-DEX MPs 中，并在颗粒与腹腔巨噬细胞（PMacs）一起培养时，对其细胞关联性和细胞耐受性介质（包括 IL-10 的产生和 M2 相关基因的表达）进行了评估。此外，还对 PS Ace-DEX MPs 作为抑制 LPS 刺激 PMacs 的药物进行了评估。然后，在 Ace-DEX MPs 中加入 AhR 激动剂 2-（1'H-吲哚-3'-羰基）噻唑-4-羧酸甲酯（ITE），并评估 PMacs 中 M2 和 IL-10 基因的表达。此外，还评估了 ITE 和 PS Ace-DEX MPs（PS/ITE MPs）对 T 细胞启动和 Th1 极化的抑制作用。我们的研究结果表明，PS/ITE-MPs 能刺激抗炎细胞因子的表达，并能在 LPS 刺激 PMacs 后抑制炎症。此外，PS/ITE-MPs 还能诱导抗炎酶 IDO1，抑制巨噬细胞介导的 T 细胞启动和 Th1 极化。这些研究结果表明，PS和ITE负载的Ace-DEX MPs可能是一种很有前景的抑制炎症的治疗工具。

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引用次数: 0

Predicting plasma protein binding of drugs in special populations: Are all models wrong, but can some be recalibrated, refined, and become more useful? 预测特殊人群血浆蛋白与药物的结合：是否所有模型都是错误的，但有些模型可以重新校准、改进并变得更有用？

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.08.020

Guo-Fu Li, Guo Yu, Ming-Feng Li

引用次数: 0

A new ciprofibrate calcium salt with improved solubility and intrinsic dissolution rate 一种新的环丙贝特钙盐，其溶解度和内在溶解速率均有所提高。

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.08.025

Bruno Arantes Borges , Kassius de Souza Reis , Camila Batista Pinto , Javier Ellena , Antônio Carlos Doriguetto , Rudy Bonfilio

Ciprofibrate (CIP) is an active pharmaceutical ingredient (API) classified as class II on the basis of biopharmaceutical classification system (BCS), what indicates that it has low solubility in aqueous solvents. The use of API salts has attracted attention due to their improvements in solubility, tolerability, higher rate and extent of absorption, and faster onset of the therapeutic effect. In this work, a new crystalline CIP monohydrated calcium salt (Ca(CIP)₂.H₂O) was successfully obtained and its crystal structure determined by single crystal X-ray diffraction analysis (SCXRD). Additionally, Ca(CIP)₂.H₂O was widely characterized by powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and submitted to solubility, intrinsic dissolution and accelerated stability studies. Ca(CIP)₂.H₂O exhibited higher solubility and dissolution rate than CIP-free form and was stable up to 6 months at 40 °C (75 %RH). Therefore, Ca(CIP)₂.H₂O may be a viable alternative for use in solid dosage forms.

环丙贝特（CIP）是一种活性药物成分（API），根据生物制药分类系统（BCS）被归为第二类，这表明它在水性溶剂中的溶解度较低。由于原料药盐具有更好的溶解性、耐受性、更高的吸收率和吸收范围以及更快的治疗效果，其使用已引起人们的关注。在这项研究中，我们成功获得了一种新型结晶的 CIP 一水钙盐 (Ca(CIP)2.H2O)，并通过单晶 X 射线衍射分析 (SCXRD) 确定了其晶体结构。此外，还通过粉末 X 射线衍射 (PXRD)、傅立叶变换红外光谱 (FTIR)、差示扫描量热法 (DSC)、热重分析 (TGA) 对 Ca(CIP)2.H2O 进行了广泛表征，并对其进行了溶解度、内在溶解度和加速稳定性研究。与不含 CIP 的形式相比，Ca(CIP)2.H2O 表现出更高的溶解度和溶解速率，并且在 40°C （75%RH）条件下可稳定长达 6 个月。因此，Ca(CIP)2.H2O 可以作为固体制剂的一种可行替代品。

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引用次数: 0

An unexpected degradation pathway of N-hydroxy-5-methylfuran-2-sulfonamide (BMS-986231), a pH sensitive prodrug of HNO, in a prototype formulation solution N-羟基-5-甲基呋喃-2-磺酰胺（BMS-986231）（一种对 pH 值敏感的 HNO 原药）在原型制剂溶液中的意外降解途径。

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.08.027

Yande Huang , Amy Sarjeant , Roger Sommer , Dhaval Patel , Qinggang Wang , Dilbir Bindra , Scott A. Miller

N-hydroxy-5-methylfuran-2-sulfonamide (BMS-986231, Cimlanod) was being developed as a pH-sensitive prodrug of HNO (nitroxyl) for the treatment of acute decompensated heart failure. During a stressed study of Cimlanod in a prototype formulation solution (pH 4.5) at 40°C, a predominant unknown degradant along with three previously identified degradants were observed. The unknown degradant was isolated from the stressed solution via preparative HPLC but totally decomposed during freeze-drying. LC-HRMS analysis of the isolated unknown degradant, prior to freeze-drying, revealed an empirical formula equivalent to the adduct of Cimlanod with SO₂ even though SO₂ was not added in the prototype formulation solution. The unknown degradant was synthesized from Cimlanod and DABSO ((1,4-diazabiscyclo[2,2,2]octane bis(sulfur dioxide) adduct) and isolated as a crystalline DABCO (1,4-diazabiscyclo[2,2,2]octane) salt for single crystal X-ray structure elucidation. The degradation of Cimlanod increased when the solution was exposed to air, as compared to N₂ atmosphere. A plausible mechanism was postulated for the unexpected degradation pathway of Cimlanod. This study provided in-depth stability knowledge of Cimlanod, which will be beneficial to the subsequent stability indicating method development and validation as well as the registrational applications on the content and qualification of impurities in new drug products.

N-羟基-5-甲基呋喃-2-磺酰胺（BMS-986231，Cimlanod）是一种对 pH 值敏感的硝化氢原药，用于治疗急性失代偿性心力衰竭。在对 40°C 下原型制剂溶液（pH 值为 4.5）中的 Cimlanod 进行压力研究期间，观察到了一种主要的未知降解剂和三种先前确定的降解剂。通过制备型 HPLC 从受压溶液中分离出了未知降解剂，但在冷冻干燥过程中完全分解。对冷冻干燥前分离出的未知降解剂进行的 LC-HRMS 分析表明，尽管原型配方溶液中没有添加二氧化硫，但其经验公式相当于辛拉诺与二氧化硫的加合物。未知降解剂是由辛拉诺和 DABSO（1,4-二氮杂双环[2,2,2]辛烷二（二氧化硫）加合物）合成的，并分离出结晶的 DABCO（1,4-二氮杂双环[2,2,2]辛烷）盐，用于单晶 X 射线结构解析。与氮气环境相比，当溶液暴露在空气中时，辛辣诺的降解速度加快。研究人员推测了辛辣诺意外降解的合理机制。这项研究提供了关于辛辣诺稳定性的深入知识，有利于后续稳定性指示方法的开发和验证，以及新药中杂质含量和合格性的注册应用。

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引用次数: 0

Study of leachable compounds in hospital pharmacy-compounded prefilled syringes, infusion bags and vials 医院药房配制的预灌封注射器、输液袋和药瓶中可浸出化合物的研究。

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.08.004

William Bello , Julian Pezzatti , Serge Rudaz , Farshid Sadeghipour

Hospital pharmacy compoundings are crucial for maintaining patient care. They are time- and cost-effective in hospital pharmacy settings because they prevent waste, preparation errors, dosage errors, microbial contamination and breakage due to handling. Unfortunately, the drawbacks of hospital pharmacy compounding include the selection of inappropriate medical devices (MDs) for long-term storage, which could directly impact patients.

In this study, three important hospital pharmaceutical compoundings, vancomycin in prefilled syringes (PFSs) made of polypropylene (PP) material, paediatric parenteral nutrition (PN) in ethylene vinyl acetate (EVA) bags and diluted insulin in cyclic olefin copolymer (COC) vials, were selected for leachate study and risk assessment. These compounds were studied via a semiquantitative screening approach by means of an ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) with postcolumn infusion and an in-house built database. 17 leachable compounds for the PFS, 25 for the PN, and 10 for the vial were identified, and their concentrations were estimated for toxicological assessments.

In conclusion, all MDs used in hospital pharmacy compoundings were observed suitable thanks to risk assessments. However, suitable MDs recommended for long-term storage would remain with polymers like COC, for higher safety when exposed to frail and vulnerable patients like neonates and infants.

医院药房复方制剂对维持病人护理至关重要。在医院药房环境中，复方制剂既省时又经济，因为它可以防止浪费、制剂错误、剂量错误、微生物污染和因操作造成的破损。遗憾的是，医院药房复方制剂的缺点包括选择不合适的医疗器械（MD）进行长期储存，这可能会直接影响患者。在这项研究中，我们选择了三种重要的医院药剂复方制剂，即用聚丙烯（PP）材料制成的预充式注射器（PFS）中的万古霉素、用乙烯-醋酸乙烯（EVA）袋装的儿科肠外营养品（PN）和用环烯烃共聚物（COC）瓶装的稀释胰岛素，进行浸出物研究和风险评估。通过柱后输液的超高效液相色谱-高分辨质谱法（UHPLC-HRMS）和内部建立的数据库，对这些化合物进行了半定量筛选研究。确定了 PFS 中的 17 种可浸出化合物、PN 中的 25 种可浸出化合物和小瓶中的 10 种可浸出化合物，并估算了它们的浓度，以便进行毒理学评估。总之，根据风险评估，医院药房配制中使用的所有 MD 都是合适的。不过，建议用于长期储存的适当 MD 仍应使用 COC 等聚合物，以便在接触新生儿和婴儿等体弱和易受伤害的患者时具有更高的安全性。

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引用次数: 0

Synthesis of thiomer/nanoclay nanocomposites as a potential drug carrier: Evaluation of mucoadhesive and controlled release properties 作为潜在药物载体的硫代物/纳米黏土纳米复合材料的合成：黏附性和控释性能评估

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.08.030

Alexander Sepúlveda-Córdova, Tomás Fernández-Martínez, Víctor H. Campos-Requena

Novel thiomer/nanoclay nanocomposites based on a thiomer and montmorillonite (MMT) were prepared in order to obtain a mucoadhesive material with controlled release properties for its potential use as drug carrier. The thiomer was synthesized by immobilization of L-cysteine in alginate mediated by carbodiimide reaction and further characterized by FT-IR and Ellman's reaction. Nanocomposites with growing concentrations of thiomer and MMT were prepared and analyzed by XRD, TGA and TEM. Rheological behavior of nanocomposite in contact with mucin and intestinal mucus were studied as in vitro and in situ mucoadhesion approach, showing until ∼10-fold increasing in the complex viscosity and ∼27-fold in elastic modulus when the amount of thiomer is increased. Higuchi and Korsmeyer-Peppas kinetic models were evaluated in order to study the release of deltamethrin from nanocomposite films. Release profiles showed a retard in the migration of the drug influenced by the amount of MMT (P < 0.05). Diffusion coefficient (D) showed a significant decrease (P < 0.0001) when concentration of MMT is increased reaching D = 4.18 × 10^–7 m² h^–1, which resulted ∼7-fold lower in comparison with formulation without MMT. This hybrid nanocomposite can be projected as a potential mucoadhesive drug carrier with controlled release properties.

为了获得一种具有控释特性的粘液粘附材料并将其用作潜在的药物载体，本研究制备了基于硫代物和蒙脱石（MMT）的新型硫代物/纳米粘土纳米复合材料。硫代物是通过碳二亚胺反应将 L-半胱氨酸固定在海藻酸盐中合成的，并通过傅立叶变换红外光谱和埃尔曼反应对其进行了进一步表征。制备了硫代物和 MMT 浓度不断增加的纳米复合材料，并通过 XRD、TGA 和 TEM 进行了分析。研究了纳米复合材料与粘蛋白和肠粘液接触时的流变学行为，结果表明，当硫单体的用量增加时，复合粘度增加 10 倍，弹性模量增加 27 倍。为了研究溴氰菊酯从纳米复合薄膜中的释放，对 Higuchi 和 Korsmeyer-Peppas 动力学模型进行了评估。释放曲线显示，药物的迁移速度受 MMT 含量的影响而减慢（P < 0.05）。当 MMT 的浓度增加时，扩散系数（D）显著降低（P < 0.0001），达到 D = 4.18 × 10-7 m2 h-1，与不含 MMT 的配方相比降低了 7 倍。这种混合纳米复合材料有望成为一种具有控释特性的粘液粘附药物载体。

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引用次数: 0

Early clinical drug product shelf-life setting using accelerated predictive stability and metabolite data for impurity qualification: A case study 利用加速预测稳定性和代谢物数据进行杂质鉴定，确定早期临床药物产品的保质期：案例研究。

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.08.010

Jenny E. Ottosson , Angela Ku , Magnus Fransson , Carina Leandersson , Lars Weidolf , Jufang Wu Ludvigsson , Magnus Klarqvist

This case study demonstrates how knowledge of degradation products together with predictions can establish a lean stability strategy using the accelerated predictive stability (APS) principles. Applying all available data for AZD4831, (R)-1-(2-(1-aminoethyl)-4-chlorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrrolo[3,2-d]pyrimidin-4(5H)-one, a reliable predictive model was developed despite minor differences in technical batch tablet compositions. Early forced degradation studies were performed to map potential degradation pathways. The insights from these studies guided the design of an APS study, which in turn inform on a suitable clinical stability program, initial specification and shelf-life. The use of APS predictions of degradants as well as total impurities highlighted at an early stage, when designing the clinical stability program, the opportunity to identify which degradation product that would be shelf-life limiting. Hence, it was possible to guide the development stability activities and set an initial shelf-life of a tablet formulation. The presented study displays the importance of combining several sources of information in drug development, e.g., potential degradation pathways, accelerated stability, stability program design, metabolite data, and specification limits.

本案例研究展示了降解产物知识和预测如何利用加速预测稳定性（APS）原理建立精益稳定性策略。应用 AZD4831（(R)-1-(2-(1-氨基乙基)-4-氯苄基)-2-硫酮-2,3-二氢-1H-吡咯并[3,2-d]嘧啶-4(5H)-酮）的所有可用数据，建立了一个可靠的预测模型，尽管技术批次片剂成分略有不同。为绘制潜在降解途径图，进行了早期强制降解研究。这些研究为 APS 研究的设计提供了指导，而 APS 研究又为合适的临床稳定性计划、初始规格和保质期提供了信息。在设计临床稳定性方案的早期阶段，使用 APS 预测降解剂和杂质总量，可以确定哪种降解产物会对货架期产生限制。因此，有可能指导开发稳定性活动并设定片剂制剂的初始保质期。本研究显示了在药物开发过程中结合多种信息来源的重要性，例如潜在降解途径、加速稳定性、稳定性方案设计、代谢物数据和规格限值。

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引用次数: 0

Rapid communication: A simple, non-invasive, cost-effective technique to monitor ice nucleation in GMP freeze-drying 快速交流：一种监测 GMP 冻干过程中冰核形成的简单、无创、经济高效的技术。

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.07.011

Jean-René Authelin , Evgenyi Shalaev

引用次数: 0

Drug delivery from a ring implant attached to intraocular lens: An in-silico investigation 眼内透镜环形植入物的药物输送：模拟研究

IF 3.7 3区医学 Q2 CHEMISTRY, MEDICINAL

Journal of pharmaceutical sciences

Pub Date : 2024-11-01 DOI: 10.1016/j.xphs.2024.09.001

Pawan Kumar Pandey , Manish Jain , Prateek K. Jha

Multiple iterations required to design ocular implants, which will last for the desired operational period of months or even years, necessitate the use of in-silico models for ocular drug delivery. In this study, we developed an in-silico model to simulate the flow of Aqueous Humor (AH) and drug delivery from an implant to the Trabecular Meshwork (TM). The implant, attached to the side of the intraocular lens (IOL), and the TM are treated as porous media, with their effects on AH flow accounted for using the Darcy equation. This model accurately predicts the physiological values of Intraocular Pressure (IOP) for both healthy individuals and glaucoma patients, as reported in the literature. Results reveal that the effective diffusivity of the drug within the implant is the critical parameter that can alter the bioavailability time period (BTP) from a few days to months. Intuitively, BTP should increase as effective diffusivity decreases. However, we discovered that with lower levels of initial drug loading, BTP declines when effective diffusivity falls below a specific threshold. Our findings further reveal that, while AH flow has a minimal effect on the drug release profile at the implant site, it significantly impacts drug availability at the TM.

眼部植入物的设计需要多次反复，才能达到预期的几个月甚至几年的使用期限，因此有必要使用用于眼部给药的室内模型。在这项研究中，我们开发了一个硅内模型来模拟水液（AH）的流动以及药物从植入体到小梁网状结构（TM）的输送。植入体连接到眼内晶状体（IOL）的一侧，而小梁网被视为多孔介质，它们对 AH 流的影响通过达西方程来计算。根据文献报道，该模型能准确预测健康人和青光眼患者的眼压（IOP）生理值。结果显示，药物在植入体内的有效扩散率是关键参数，可改变生物利用度时间段（BTP），从几天到几个月不等。从直观上看，随着有效扩散率的降低，生物利用时间应该会延长。然而，我们发现，在初始药物负载水平较低的情况下，当有效扩散率低于特定阈值时，生物利用度时间段就会缩短。我们的研究结果进一步表明，虽然 AH 流量对植入部位的药物释放曲线影响甚微，但却对 TM 的药物可用性产生了重大影响。

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引用次数: 0