AAPS PharmSciTech最新文献_第8页

Development of a Stable Lyophilized Cyclophosphamide Monohydrate Formulation Using Non-Aqueous Solvents 使用非水溶剂开发稳定的冻干一水环磷酰胺制剂

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-08-28 DOI: 10.1208/s12249-024-02920-9

Shaik Riyaz Ahammad, Damodharan Narayanasamy

To ensure product stability, it is critical to maintain the monohydrate state of cyclophosphamide following lyophilization, as this is the most stable solid form of the Cyclophosphamide. On the other hand, because of their limited aqueous solubility and stability, non-aqueous solvents are preferred for determining the composition and stability of bulk solutions. Hence, the purpose of this study was to use non-aqueous solvents for determining the composition and stability of bulk solutions, and to shorten the lyophilization process by retaining the cyclophosphamide monohydrate. Furthermore, prior to selecting the solvent for the bulk solution consisting of 90:10 tertiary butyl alcohol (TBA) and acetonitrile (ACN), various factors were taken into account, including the freezing point, vapor pressure of solvents, solubility, and stability of cyclophosphamide monohydrate. The concentration of the bulk solution was adjusted to 200 mg/mL in order to optimize the fill volume, enhance sublimation rates at lower temperatures during primary drying, and eliminate the need for secondary drying. The differential scanning calorimetry (DSC) measurements of bulk solution were used to improve the lyophilization cycle. The lyophilization cycle opted was freezing at a temperature of -55 °C with annealing step at -22 °C by which the reconstitution time was significantly reduced. The drying was performed at below − 25 °C while maintaining a chamber pressure of 300 mTorr. The complete removal of non-aqueous solvents was achieved by retaining water within the system. The presence of cyclophosphamide monohydrate was confirmed using X-ray diffraction (XRD). The reduction of lyophilization process time was established by conducting mass transfer tests and evaluating the physicochemical properties of the pharmaceutical product. Using non-aqueous solvents for freeze-drying cyclophosphamide is a viable option, and this study provides significant knowledge for the advancement of future generic pharmaceuticals.

Graphical Abstract

为确保产品的稳定性，在冻干后保持环磷酰胺的一水合物状态至关重要，因为这是环磷酰胺最稳定的固体形式。另一方面，由于环磷酰胺的水溶性和稳定性有限，因此在确定散装溶液的成分和稳定性时，首选非水溶剂。因此，本研究的目的是使用非水溶剂来确定散装溶液的成分和稳定性，并通过保留环磷酰胺一水合物来缩短冻干过程。此外，在选择由 90:10 叔丁醇（TBA）和乙腈（ACN）组成的块状溶液的溶剂之前，考虑了各种因素，包括凝固点、溶剂的蒸汽压、溶解度和一水环磷酰胺的稳定性。散装溶液的浓度调整为 200 毫克/毫升，以优化填充体积，提高一次干燥过程中在较低温度下的升华率，并消除二次干燥的需要。利用散装溶液的差示扫描量热法（DSC）测量来改进冻干周期。所选择的冻干周期是在-55 °C的温度下冷冻，并在-22 °C的温度下退火，从而大大缩短了重组时间。干燥在低于 -25 °C 的温度下进行，同时保持室压为 300 mTorr。通过在系统中保留水，实现了非水溶剂的完全去除。通过 X 射线衍射 (XRD) 确认了环磷酰胺一水合物的存在。通过进行传质测试和评估药品的理化特性，确定了冻干过程时间的缩短。使用非水溶剂冷冻干燥环磷酰胺是一种可行的选择，这项研究为未来非专利药品的发展提供了重要的知识。

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引用次数: 0

Exploring the Dissolution, Solid-state Properties, and Long-term Storage Stability of Cryoprotectant-free Fenbendazole Nanoparticles 探索不含低温保护剂的苯醚甲环唑纳米颗粒的溶解、固态特性和长期储存稳定性。

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-08-28 DOI: 10.1208/s12249-024-02921-8

Giselle Bedogni, Lina Vargas Michelena, Katia Seremeta, Nora Okulik, Claudio Salomon

Fenbendazole is an antiparasitic drug widely used in veterinary medicine to treat parasitic infections caused in animals like cattle, horses, sheep, and dogs. Recently, it has been repositioned as a potential alternative for cancer treatment. However, it is a highly hydrophobic molecule (0.9 ug/mL), which can compromise its dissolution rate and absorption. Thus, this work aimed to apply a nanotechnological approach to improve drug solubility and dissolution performance. Fenbendazole nanoparticles stabilized by different poloxamers were obtained by lyophilization without cryoprotectants. The behavior of the drug in the solid state was analyzed by X-ray diffractometry, differential scanning calorimetry, and infrared spectroscopy. The nanosystems were also evaluated for solubility and dissolution rate. A long-term stability evaluation was performed for three years at room temperature. The yields of the lyophilization ranged between 75 and 81% for each lot. The nanoparticles showed a submicron size (< 340 nm) and a low polydispersity depending on the stabilizer. The physicochemical properties of the prepared systems indicated a remarkable amorphization of the drug, which influenced its solubility and dissolution performance. The drug dissolution from both the fresh and aged nanosystems was significantly higher than that of the raw drug. In particular, nanoparticles prepared with poloxamer 407 showed no significant modifications in their particle size in three years of storage. Physical stability studies indicated that the obtained systems prepared with P188, P237, and P407 suffered certain recrystallization during long storage at 25 °C. These findings confirm that selected poloxamers exhibited an important effect in formulating fenbendazole nanosystems with improved dissolution.

Graphical Abstract

芬苯达唑是一种抗寄生虫药物，广泛应用于兽医领域，治疗牛、马、羊和狗等动物的寄生虫感染。最近，它被重新定位为治疗癌症的潜在替代药物。然而，它是一种高度疏水的分子（0.9 微克/毫升），这可能会影响其溶解率和吸收。因此，这项工作旨在应用纳米技术方法来提高药物的溶解度和溶解性能。在不使用低温保护剂的情况下，通过冻干法获得了由不同多聚酰胺稳定的芬苯达唑纳米颗粒。通过 X 射线衍射仪、差示扫描量热仪和红外光谱分析了药物在固态下的行为。此外，还对纳米系统的溶解度和溶解速率进行了评估。在室温下进行了为期三年的长期稳定性评估。每个批次的冻干产率在 75% 到 81% 之间。根据稳定剂的不同，纳米颗粒显示出亚微米尺寸（< 340 nm）和较低的多分散性。所制备体系的理化性质表明，药物发生了显著的非形态化，这影响了药物的溶解度和溶解性能。新鲜和老化纳米体系的药物溶解度都明显高于生药。尤其是用聚氧乙烯聚酰胺 407 制备的纳米颗粒，在三年的储存过程中粒径没有发生明显变化。物理稳定性研究表明，用 P188、P237 和 P407 制备的系统在 25 °C 长期储存期间会出现一定程度的再结晶。这些研究结果证实，所选的多羟酰胺在配制芬苯达唑纳米系统中具有重要作用，可提高溶解度。

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引用次数: 0

Gastroretentive Delivery Approach to Address pH-Dependent Degradation of (+)- and (-)-Phenserine 解决(+)-和(-)-细辛的 pH 依赖性降解问题的护胃给药方法。

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-08-27 DOI: 10.1208/s12249-024-02903-w

Pratishtha Verma, Leyla Rezaei, Ramprakash Govindarajan, Nigel H. Greig, Maureen D. Donovan

(-)-Phenserine (“phenserine”) and (+)-phenserine (posiphen; buntanetap) are longer-acting enantiomeric analogs of physostigmine with demonstrated promise in the treatment of Alzheimer’s and Parkinson’s diseases. Both enantiomers have short plasma half-lives, and their pharmacokinetics might be improved through the use of either once or twice-daily administration of an extended-release dosage form. Phenserine was observed to form a colored degradation product in near-neutral and alkaline pH environments, and at pH 7, the half-life of posiphen was determined to be ~ 9 h (40 °C). To limit luminal degradation which would reduce bioavailability, a gastroretentive tablet composed of a polyethylene oxide-xanthan gum matrix was developed. When placed in simulated gastric fluid (pH 1.2), approximately 70% of the phenserine was released over a 12 h period, and no degradants were detected in the release medium. In comparison, a traditional hydrophilic-matrix, extended-release tablet showed measurable amounts of phenserine degradation in a pH 7.2 medium over an 8 h release interval. These results confirm that a gastroretentive tablet can reduce the luminal degradation of phenserine or posiphen by limiting exposure to neutral pH conditions while providing sustained release of the drug over at least 12 h. Additional advantages of the gastroretentive tablet include reduced gastric and intestinal concentrations of the drug resulting from the slower release from the gastroretentive tablet which may also limit the occurrence of the dose-limiting GI side effects previously observed with immediate-release phenserine capsules.

Graphical Abstract

(-)-苯海拉明（"phenserine"）和(+)-苯海拉明（posiphen；buntanetap）是作用时间较长的波司的明对映体类似物，在治疗阿尔茨海默氏症和帕金森氏症方面前景看好。这两种对映体的血浆半衰期都很短，通过每天服用一次或两次缓释剂型，可以改善它们的药代动力学。据观察，在接近中性和碱性的 pH 环境中，phenserine 会形成一种有色降解产物，在 pH 值为 7 时，posiphen 的半衰期约为 9 小时（40 °C）。为了限制会降低生物利用率的管腔降解，我们开发了一种由聚乙烯氧化物-黄原胶基质组成的胃保留片剂。在模拟胃液（pH 值为 1.2）中放置 12 小时后，约 70% 的钩藤碱被释放出来，并且在释放介质中未检测到降解物。相比之下，一种传统的亲水基质缓释片在 pH 值为 7.2 的介质中，在 8 小时的释放间隔内，出现了可测量的芬瑟林降解量。这些结果证实，胃复安片剂可以通过限制暴露在中性pH条件下，减少表皮生长因子或泊西芬的腔内降解，同时提供至少12小时的药物持续释放。胃复安片剂的其他优点还包括，由于胃复安片剂的释放速度较慢，降低了药物在胃和肠道中的浓度，这也可以限制以前在表皮生长因子速释胶囊中观察到的剂量限制性胃肠道副作用的发生。

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引用次数: 0

Microbicidal Polymer Nanoparticles Containing Clotrimazole for Treatment of Vulvovaginal Candidiasis 含克霉唑的杀菌聚合物纳米粒子用于治疗外阴阴道念珠菌病

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-08-22 DOI: 10.1208/s12249-024-02914-7

María del Rocío Lara-Sánchez, Adriana Ganem-Rondero, María Guadalupe Nava-Arzaluz, Andrea Angela Becerril-Osnaya, Laura Abril Pérez-Carranza, Sergio Alcalá-Alcalá, Néstor Mendoza-Muñoz, Elizabeth Piñón-Segundo

Vulvovaginal candidiasis (VVC) alters the innate cervicovaginal immunity, which provides an important barrier against viruses and other infections. The incidence of this disease has not decreased in the last 30 years, so effective treatments are still needed. Nanoparticles (NPs) of cellulose acetate phthalate (CAP) and clotrimazole (CLZ) were prepared by the emulsification-diffusion method. NPs were characterized using dynamic light scattering, atomic force microscopy and differential scanning calorimetry; their release profile was determined by the dialysis bag technique and mucoadhesion was evaluated with the mucin-particle method. The growth inhibition study of Candida albicans was carried out using the plate counting technique. Finally, accelerated physical stability tests of NPs were carried out, both in water and in SVF. The CAP-CLZ NPs had an average diameter of 273.4 nm, a PDI of 0.284, smooth surfaces and spherical shapes. In vitro release of CLZ from the CAP NPs was categorized with the Weibull model as a matrix system in which initial release was rapid and subsequently sustained. The inhibition of C. albicans growth by the CAP-CLZ NPs was greater than that of free CLZ, and the CAP-only NPs had a microbicidal effect on C. albicans. The NPs showed poor mucoadhesiveness, which could lead to studies of their mucopenetration capacities. An accelerated physical stability test revealed the erosion of CAP in aqueous media. A nanoparticulate system was developed and provided sustained release of CLZ, and it combined an antifungal agent with a microbial polymer that exhibited antifungal activity against C. albicans.

Graphical Abstract

外阴阴道念珠菌病（VVC）会改变宫颈阴道的先天免疫力，而这种免疫力是抵御病毒和其他感染的重要屏障。在过去的 30 年中，这种疾病的发病率并没有降低，因此仍然需要有效的治疗方法。本研究采用乳化扩散法制备了邻苯二甲酸醋酸纤维素（CAP）和克霉唑（CLZ）的纳米颗粒（NPs）。使用动态光散射、原子力显微镜和差示扫描量热法对 NPs 进行了表征；使用透析袋技术测定了它们的释放曲线，并使用粘蛋白颗粒法评估了粘附性。使用平板计数技术对白色念珠菌的生长抑制进行了研究。最后，在水中和 SVF 中对 NPs 进行了加速物理稳定性测试。CAP-CLZ NPs 的平均直径为 273.4 nm，PDI 为 0.284，表面光滑，呈球形。根据威布尔模型，CAP-CLZ NPs 的体外释放属于基质系统，初始释放迅速，随后持续释放。CAP-CLZ NPs 对白茨菌生长的抑制作用大于游离的 CLZ，而纯 CAP NPs 对白茨菌有杀菌作用。这些 NPs 的粘附性很差，因此需要对其粘液渗透能力进行研究。加速物理稳定性测试显示，CAP 在水介质中会受到侵蚀。该研究开发了一种纳米颗粒系统，可持续释放 CLZ，并将一种抗真菌剂与一种微生物聚合物结合在一起，对白僵菌具有抗真菌活性。

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引用次数: 0

Isolation, Purification of Phenolic Glycoside 1 from Moringa oleifera Seeds and Formulation of Its Liposome Delivery System 从油辣木籽中分离、纯化酚醛苷 1 并配制其脂质体输送系统

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-08-22 DOI: 10.1208/s12249-024-02911-w

Feng Shi, Mingjie Gong, Michael Adu-Frimpong, Xia Jiang, Xiaowen Wang, Qinyang Hua, Tingyuan Li, Jiaying Li, Jiangnan Yu, Elmurat Toreniyazov, Xia Cao, Qilong Wang, Ximing Xu

In this study, N, N '-bis {4- [(α-L- rhamnosyloxy) benzyl]} thiourea (PG-1), a phenolic glycoside compound was purified from Moringa seed. The PG-1 has attracted extensive attention due to its anti-cancer, antioxidant, anti-inflammatory and hypoglycemic properties. However, some of its physicochemical properties such as oral bioavailability has not been studied. Herein, a highly purified PG-1 was extracted and incorporated in multiple layered liposomes (PG-1-L) to avoid its burst release and enhance oral bioavailability. After appropriate characterization, it was discovered that the obtained PG-1-L was stable, homogeneous and well dispersed with the average particle size being 89.26 ± 0.23 nm. Importantly, the in vitro release and in vivo oral bioavailability of PG-1-L were significantly improved compared with PG-1. In addition, MTT results showed that compared with the free PG-1, PG-1-L displayed obvious inhibitory effect on the HepG2 cells, while the inhibitory effect on healthy non-malignant 3T6 and LO-2 cells was not significant, indicating that PG-1-L had high safety. In conclusion, PG-1-L can be used as a promising delivery system and an ideal novel approach to improve the oral bioavailability and anticancer activity of PG-1.

Graphical Abstract

本研究从辣木籽中纯化出一种酚苷化合物 N, N '-bis {4- [(α-L- rhamnosyloxy) benzyl]} thiourea (PG-1)。PG-1 因其抗癌、抗氧化、抗炎和降血糖特性而受到广泛关注。然而，它的一些理化特性（如口服生物利用度）尚未得到研究。本文提取了高度纯化的 PG-1，并将其加入多层脂质体（PG-1-L）中，以避免其猝灭释放并提高口服生物利用度。经过适当的表征后发现，获得的 PG-1-L 稳定、均质、分散性好，平均粒径为 89.26 ± 0.23 nm。重要的是，与 PG-1 相比，PG-1-L 的体外释放和体内口服生物利用度都有显著提高。此外，MTT 结果表明，与游离 PG-1 相比，PG-1-L 对 HepG2 细胞有明显的抑制作用，而对健康的非恶性 3T6 和 LO-2 细胞的抑制作用不明显，表明 PG-1-L 具有较高的安全性。总之，PG-1-L 是一种很有前景的给药系统，是提高 PG-1 口服生物利用度和抗癌活性的理想新方法。

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引用次数: 0

Antipsoriatic Effect of Silymarin NLCs Based Gel: In Vitro and In Vivo Activity 基于水飞蓟素 NLCs 的凝胶的抗银屑病效果：体外和体内活性

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-08-21 DOI: 10.1208/s12249-024-02910-x

Faijmahmad Momin, Vijay Kevlani, Shruti Rawal, Riya Patel, Sheetal Acharya, Shreeraj Shah

Psoriasis is a chronic inflammatory disorder affecting over 100 million people, requires long-term therapy. Current treatments offer only symptomatic relief. However, phytoconstituents-based therapies like Silymarin (SLM) have shown promising effects. The study aims to develop, optimize, and evaluate a novel stable SLM NLC gel to improve anti-psoriatic activity by enhancing its permeability and retention into the dermal layer. SLM NLC formulation was prepared and optimized using 3² full factorial designs. The formulation was evaluated for the particle size, PDI, zeta potential, and % entrapment efficiency, evaluated by Transmission electron microscopy and thermal analysis. The freeze dried and prepared NLC-loaded gel was evaluated for physicochemical parameters, ex-vivo, and in-vivo studies. SLM-loaded NLC shows 624 nm particle size, 0.41 PDI, 92.95% entrapment efficiency, and -31.6 mV zeta potential. The sphere form of NLCs was confirmed using TEM. Controlled drug release was observed in ex vivo studies, low PASI score compared to disease control. Further, the levels of IL-6, TNF-α, and NF-κB were also reduced. The results are supported by histopathology showing minimal parakeratosis indicated in the SLM NLC-treated group. Prepared NLC-based shows enhance topical penetration and decrease the thickness of psoriatic plaques in the in vivo study.

Graphical Abstract

牛皮癣是一种慢性炎症性疾病，影响超过 1 亿人，需要长期治疗。目前的治疗方法只能缓解症状。然而，水飞蓟素（SLM）等基于植物成分的疗法已显示出良好的效果。本研究旨在开发、优化和评估一种新型稳定的水飞蓟素 NLC 凝胶，通过提高其在真皮层的渗透性和滞留性来改善抗银屑病活性。研究采用 32 种全因子设计制备和优化了 SLM NLC 配方。通过透射电子显微镜和热分析，对配方的粒度、PDI、ZETA电位和吸附效率进行了评估。对冷冻干燥和制备的 NLC 负载凝胶进行了理化参数、体外和体内研究评估。SLM负载的NLC粒径为624 nm，PDI为0.41，包埋效率为92.95%，ZETA电位为-31.6 mV。利用 TEM 技术确认了 NLC 的球形结构。在体内外研究中观察到药物的可控释放，与疾病对照组相比，PASI 评分较低。此外，IL-6、TNF-α 和 NF-κB 的水平也有所降低。组织病理学结果表明，SLM NLC 治疗组的角化不全现象极少，这也为上述结果提供了佐证。在体内研究中，制备的 NLC 可增强局部渗透性并减少银屑病斑块的厚度。

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引用次数: 0

Improvement of Bioavailability of Sildenafil Citrate Through Taste Masked Orodispersible Film for Pulmonary Hypertension Management 通过掩味型可发散薄膜提高枸橼酸西地那非的生物利用度，用于肺动脉高压治疗

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-08-21 DOI: 10.1208/s12249-024-02905-8

Vivek Mewada, Jigar Shah, Shery Jacob, Hiral Shah, Sai H. S. Boddu, Anroop B Nair

The oral bioavailability of sildenafil citrate is approximately 43%, primarily limited by the low aqueous solubility and first-pass effect. Considering the drug properties and biopharmaceutical considerations, this study aimed to develop an immediate release, taste masked orodispersible film (ODF) of sildenafil citrate for the efficient management of pulmonary arterial hypertension (PAH). The optimization was done by applying 3² full-factorial design. The drug-loaded film was prepared and evaluated for the physical and mechanical parameters like; thickness, disintegration time, tensile strength, elongation, swelling index, content uniformity, disintegration and in vitro drug release in pH 6.2 stimulated salivary fluid. The FTIR and DSC data proved excellent compatibility between the drug and polymers used. The time taken for disintegration by the optimized film was about 62.66 s, while the drug release was observed ~ 96% in 10 min. Pharmacokinetic studies exhibited better sildenafil plasma level (p < 0.05) and C_max (p < 0.001) of orally disintegrating film which is significantly higher than the oral drug solution. The AUC_0–8 (24874.425 ± 1234.45 ng. h/mL) in the oromucosal application was 1.2-fold more (p < 0.0001) than the control. The presence of sweetening and flavoring agents in the formulation masked the drug bitterness, resulting in a higher intake of the formulation in rats compared to the unmasked drug solution, as observed with in vivo taste masking studies. The importance of ODF as a feasible, effective, and optimal approach for delivering sildenafil citrate via oromucosal administration for the treatment of PAH was successfully highlighted by these results.

Graphical Abstract

枸橼酸西地那非的口服生物利用度约为 43%，主要受限于较低的水溶性和首过效应。考虑到药物特性和生物制药方面的因素，本研究旨在开发一种枸橼酸西地那非速释掩味口崩膜（ODF），用于有效治疗肺动脉高压（PAH）。该研究采用 32 全因子设计进行优化。制备并评估了载药薄膜的物理和机械参数，如厚度、崩解时间、拉伸强度、伸长率、膨胀指数、含量均匀性、崩解度以及在 pH 值为 6.2 的唾液刺激下的体外药物释放。傅立叶变换红外光谱（FTIR）和 DSC 数据证明了药物与所用聚合物之间极佳的相容性。优化薄膜的崩解时间约为 62.66 秒，10 分钟内药物释放量达到 96%。药代动力学研究表明，在口腔黏膜应用中，西地那非的血浆水平（p max，p 0-8，24874.425 ± 1234.45 ng. h/mL）比在口腔黏膜应用中高 1.2 倍（p 0-8，24874.425 ± 1234.45 ng. h/mL）。

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引用次数: 0

A Semi-Mechanistic Physiologically Based Biopharmaceutics Model to Describe Complex and Saturable Absorption of Metformin: Justification of Dissolution Specifications for Extended Release Formulation 描述二甲双胍复杂饱和吸收的半机械生理学模型：缓释制剂溶出度规格的合理性。

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-08-21 DOI: 10.1208/s12249-024-02904-9

Adithya Karthik Bhattiprolu, Sivacharan Kollipara, Rajkumar Boddu, Anand Arumugam, Sohel Mohammed Khan, Tausif Ahmed

Physiologically based pharmacokinetic (PBPK) or physiologically based biopharmaceutics models (PBBM) demonstrated plethora of applications in both new drugs and generic product development. Justification of dissolution specifications and establishment of dissolution safe space is an important application of such modeling approaches. In case of molecules exhibiting saturable absorption behavior, justification of dissolution specifications requires development of a model that incorporates effects of transporters is critical to simulate in vivo scenario. In the present case, we have developed a semi-mechanistic PBBM to describe the non-linearity of BCS class III molecule metformin for justification of dissolution specifications of extended release formulation at strengths 500 mg and 1000 mg. Semi-mechanistic PBBM was built using physicochemical properties, dissolution and non-linearity was accounted through incorporation of multiple transporter kinetics at absorption level. The model was extensively validated using literature reported intravenous, oral (immediate & extended release) formulations and further validated using in-house bioequivalence data in fasting and fed conditions. Virtual dissolution profiles at lower and upper specifications were generated to justify the dissolution specifications. The model predicted literature as well as in-house clinical study data with acceptable prediction errors. Further, virtual bioequivalence trials predicted the bioequivalence outcome that matched with clinical study data. The model predicted bioequivalence when lower and upper specifications were compared against pivotal test formulations thereby justifying dissolution specifications. Overall, complex and saturable absorption pathway of metformin was successfully simulated and this work resulted in regulatory acceptance of dissolution specifications which has ability to reduce multiple dissolution testing.

Graphical Abstract

基于生理学的药代动力学模型（PBPK）或基于生理学的生物药剂学模型（PBBM）在新药和非专利产品开发中都有大量应用。证明溶出度规格和建立溶出度安全空间是此类建模方法的一项重要应用。对于表现出可饱和吸收行为的分子，要证明其溶解规范的合理性，就必须建立一个包含转运体效应的模型，这对模拟体内情况至关重要。在本案例中，我们开发了一种半机制 PBBM 来描述 BCS III 级分子二甲双胍的非线性特性，以证明 500 毫克和 1000 毫克缓释制剂的溶出规格。半机理 PBBM 是利用物理化学特性、溶解度和非线性建立的，在吸收水平上考虑了多转运动力学。该模型利用文献报道的静脉注射、口服（速释和缓释）制剂进行了广泛验证，并利用内部空腹和进食条件下的生物等效性数据进行了进一步验证。生成了较低和较高规格的虚拟溶出曲线，以证明溶出规格的合理性。该模型预测了文献和内部临床研究数据，预测误差可接受。此外，虚拟生物等效性试验预测了与临床研究数据相匹配的生物等效性结果。在将较低和较高规格与关键试验配方进行比较时，该模型预测了生物等效性，从而证明了溶出规格的合理性。总之，该模型成功模拟了二甲双胍复杂而可饱和的吸收途径，并使监管部门接受了溶出度规格，从而减少了多次溶出度测试。

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引用次数: 0

Tailored Sticky Solutions: 3D-Printed Miconazole Buccal Films for Pediatric Oral Candidiasis. 量身定制的粘性解决方案：用于治疗小儿口腔念珠菌病的三维打印咪康唑颊黏膜。

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-08-20 DOI: 10.1208/s12249-024-02908-5

Konstantina Chachlioutaki, Anastasia Iordanopoulou, Orestis L Katsamenis, Anestis Tsitsos, Savvas Koltsakidis, Pinelopi Anastasiadou, Dimitrios Andreadis, Vangelis Economou, Christos Ritzoulis, Dimitrios Tzetzis, Nikolaos Bouropoulos, Iakovos Xenikakis, Dimitrios Fatouros

In this research, 3D-printed antifungal buccal films (BFs) were manufactured as a potential alternative to commercially available antifungal oral gels addressing key considerations such as ease of manufacturing, convenience of administration, enhanced drug efficacy and suitability of paediatric patients. The fabrication process involved the use of a semi-solid extrusion method to create BFs from zein-Poly-Vinyl-Pyrrolidone (zein-PVP) polymer blend, which served as a carrier for drug (miconazole) and taste enhancers. After manufacturing, it was determined that the disintegration time for all films was less than 10 min. However, these films are designed to adhere to buccal tissue, ensuring sustained drug release. Approximately 80% of the miconazole was released gradually over 2 h from the zein/PVP matrix of the 3D printed films. Moreover, a detailed physicochemical characterization including spectroscopic and thermal methods was conducted to assess solid state and thermal stability of film constituents. Mucoadhesive properties and mechanical evaluation were also studied, while permeability studies revealed the extent to which film-loaded miconazole permeates through buccal tissue compared to commercially available oral gel formulation. Histological evaluation of the treated tissues was followed. Furthermore, in vitro antifungal activity was assessed for the developed films and the commercial oral gel. Finally, films underwent a two-month drug stability test to ascertain the suitability of the BFs for clinical application. The results demonstrate that 3D-printed films are a promising alternative for local administration of miconazole in the oral cavity.

本研究制造了三维打印抗真菌口腔薄膜（BFs），作为市售抗真菌口腔凝胶的潜在替代品，主要考虑因素包括易于制造、给药方便、增强药效和适合儿科患者。制造过程包括使用半固态挤压法，将玉米蛋白-聚乙烯吡咯烷酮（玉米蛋白-PVP）聚合物混合物制成 BF，作为药物（咪康唑）和增味剂的载体。生产后发现，所有薄膜的崩解时间均小于 10 分钟。不过，这些薄膜的设计目的是粘附在口腔组织上，确保药物的持续释放。大约 80% 的咪康唑在 2 小时内从 3D 打印薄膜的沸石/PVP 基质中逐渐释放出来。此外，还进行了详细的物理化学表征，包括光谱和热学方法，以评估薄膜成分的固态和热稳定性。此外，还研究了黏附性能和机械评估，而渗透性研究则揭示了与市售口服凝胶制剂相比，薄膜装载的咪康唑通过口腔组织的渗透程度。随后还对处理过的组织进行了组织学评估。此外，还对开发的薄膜和商用口服凝胶进行了体外抗真菌活性评估。最后，对薄膜进行了为期两个月的药物稳定性测试，以确定 BFs 是否适合临床应用。研究结果表明，三维打印薄膜是口腔局部给药咪康唑的理想选择。

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引用次数: 0

Thermally-Induced Supersaturation Approach for Optimizing Drug Loading and Biopharmaceutical Properties of Supersaturated Lipid-Based Formulations: Case Studies with Ibrutinib and Enzalutamide 用热诱导过饱和方法优化过饱和脂质制剂的药物负载和生物制药特性：伊布替尼和恩扎鲁胺的案例研究。

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech

Pub Date : 2024-08-20 DOI: 10.1208/s12249-024-02912-9

Arvind Sirvi, Akash Janjal, Kajal Guleria, Mahesh Chand, Abhay T. Sangamwar

Lipid-based formulations (LbFs) have demonstrated success in pharmaceutical applications; however, challenges persist in dissolving entire doses of the drug into defined liquid volumes. In this study, the temperature-induced supersaturation method was employed in LbF to address drug loading and pill burden issues. Supersaturated LbFs (super-LbF) were prepared using the temperature-induced supersaturation method, where the drug load is above its equilibrium solubility. Further, the influence of the drug’s physicochemical and thermal characteristics on drug loading and their relevance with an apparent degree of supersaturation (aDS) was studied using two model drugs, ibrutinib and enzalutamide. All the prepared LbFs were evaluated in terms of physical stability, dispersion, and solubilization capacity, as well as pharmacokinetic assessments. Drug re-crystallization was observed in the lipid solution on long-term storage at higher aDS values of 2–2.5. Furthermore, high-throughput lipolysis studies demonstrated a significant decrease in drug concentration across all LbFs (regardless of drug loading) due to a decline in the formulation solvation capacity and subsequent generation of in-situ supersaturation. Further, the in vivo results demonstrated comparable pharmacokinetic parameters between conventional LbF and super-LbF. The short duration of the thermodynamic metastable state limits the potential absorption benefits. However, super-LbFs of Ibr and Enz showed superior profiles, with 1.7-fold and 5.2-fold increased drug exposure compared to their respective crystalline suspensions. In summary, this study emphasizes the potential of temperature-induced supersaturation in LbF for enhancing drug loading and highlights the intricate interplay between drug properties, formulation characteristics, and in vivo performance.

Graphical Abstract

脂基制剂（LbFs）在制药应用中取得了成功；然而，将整个剂量的药物溶解到确定的液体体积中仍然存在挑战。在本研究中，LbF 采用了温度诱导过饱和方法来解决药物负载和药丸负担问题。采用温度诱导过饱和法制备了过饱和 LbF（超 LbF），药物载量高于其平衡溶解度。此外，还使用两种模型药物伊布替尼和恩扎鲁胺研究了药物的理化和热特性对药物负载的影响及其与表观过饱和度（aDS）的相关性。对所有制备的 LbFs 的物理稳定性、分散性、增溶能力以及药代动力学进行了评估。在较高的 aDS 值（2-2.5）条件下，长期储存的脂质溶液中出现了药物再结晶现象。此外，高通量脂肪分解研究表明，由于制剂溶解能力下降以及随后产生的原位过饱和，所有脂质溶液的药物浓度都显著下降（与药物负载量无关）。此外，体内研究结果表明，传统 LbF 和超级 LbF 的药代动力学参数相当。热力学稳定状态的持续时间较短，这限制了潜在的吸收优势。不过，Ibr 和 Enz 的超级 LbF 显示出更优越的特征，与各自的晶体悬浮剂相比，药物暴露量分别增加了 1.7 倍和 5.2 倍。总之，本研究强调了温度诱导的超饱和 LbF 在提高药物载量方面的潜力，并突出了药物特性、制剂特征和体内表现之间错综复杂的相互作用。

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引用次数: 0