Molecular Pharmaceutics最新文献

{"title":"High-Density Lipoprotein Mimetic Peptide 4F Reduces Toxic Amyloid-Beta Exposure to the Blood-Brain Barrier Endothelium in Alzheimer's Disease Transgenic Mice.","authors":"Zengtao Wang, Rui Zhong, Geoffry L Curran, Paul Min, Val J Lowe, Ling Li, Karunya K Kandimalla","doi":"10.1021/acs.molpharmaceut.4c00633","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00633","url":null,"abstract":"<p><p>Aβ accumulation in the blood-brain barrier (BBB) endothelium, which lines the cerebrovascular lumen, is a significant contributor to cerebrovascular dysfunction in Alzheimer's disease (AD). Reduced high-density lipoprotein (HDL) levels are associated with increased AD risk, and the HDL mimetic peptide 4F has been developed as a promising therapeutic agent to improve cerebrovascular health in AD. In this study, we evaluated the impact of 4F on ¹²⁵I-Aβ₄₂ blood-to-brain distribution using dynamic SPECT/CT imaging in both wild-type and APP/PS1 transgenic mice. Graphical analysis of the imaging data demonstrated that 4F significantly reduced the blood-to-brain influx rate in wild-type mice and the distribution of ¹²⁵I-Aβ₄₂ in the BBB endothelium in APP/PS1 mice. To elucidate the molecular mechanisms underlying the effect of 4F, we evaluated its impact on the p38 pathway and its role in mediating Aβ₄₂ trafficking in human BBB endothelial cell monolayers. Treatment with 4F significantly decreased Aβ₄₂ induced p38 activation in BBB endothelial cells. Furthermore, inhibition of p38 kinase significantly reduced endothelial accumulation of fluorescence-labeled Aβ₄₂ and luminal-to-abluminal permeability across the cell monolayer. While our previous publication has hinted at the potential of 4F to reduce Aβ accumulation in the brain parenchyma, the current findings demonstrated the protective effect of 4F in reducing Aβ₄₂ accumulation in the BBB endothelium of AD transgenic mice. These findings revealed the impact of a clinically tested agent, the HDL mimetic peptide 4F, on Aβ exposure to the BBB endothelium and offer novel mechanistic insights into potential therapeutic strategies to treat cerebrovascular dysfunction in AD.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405719","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}

{"title":"Drug-Drug Cocrystal Alloy and Nanoformulation of Cytarabine: Optimized Biopharmaceutical Property and Synergistic Antitumor Efficacy.","authors":"Yue-Ming Yu, Xue-Jie Li, Fan-Zhi Bu, Zhi-Long Zhao, Zhi-Yong Wu, Yan-Tuan Li","doi":"10.1021/acs.molpharmaceut.4c00733","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00733","url":null,"abstract":"<p><p>An integrated strategy by combining cocrystallization with nanotechnology is developed to optimize in vitro/vivo performances of marine antitumor drug cytarabine (ARA) and further obtain innovative insights into the exploitation of cocrystal alloy nanoformulation. Therein, the optimization of properties and synergistic effects of ARA mainly depends on assembling with uracil (U) and antitumor drug 5-fluorouracil (FU) into the same crystal by cocrystallization technology, while the long-term efficacy is primarily maintained by playing the superiority of nanotechnology. Along this line, the first cocrystal alloy of ARA, <i>viz.</i>, ARA-FU-U (0.6:0.4), is successfully obtained and then transformed into a nanocrystal. Single-crystal X-ray diffraction analysis demonstrates that this cocrystal alloy consists of two isomorphic cocrystals of ARA, namely, ARA-FU and ARA-U, in 0.6:0.4 ratio. An <i>R</i>₂²(8) hydrogen-bonding cyclic system formed by a cytosine fragment of ARA with U or FU can protect and stabilize the amine group on ARA, laying the foundation for regulating its properties. The <i>in vitro</i>/<i>in vivo</i> properties of the cocrystal alloy and its nanocrystals are investigated by theoretical and experimental means. It reveals that both the alloy and nanocrystal can improve physicochemical properties and promote drug absorption, thus bringing to optimized pharmacokinetic behaviors. The nanocrystal produces superior effects than the alloy that helps to extend therapeutic time and action. Particularly, relative to the corresponding binary cocrystal, the synergistic antitumor activity of ARA and FU in the cocrystal alloy is heightened obviously. It may be that U contributes to reducing the degradation of FU, specifically increasing its concentration in tumors to enhance the synergistic effects of FU and ARA. These findings provide new thoughts for the application of cocrystal alloys in the marine drug field and break fresh ground for cocrystal alloy formulations to optimize drug properties.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398656","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}

{"title":"RNA Nanotechnology for Codelivering High-Payload Nucleoside Analogs to Cancer with a Synergetic Effect.","authors":"Xin Li, Kai Jin, You-Cheng Liao, Wen-Jui Lee, Li-Ching Chen, Tzu-Chun Cheng, Yuan-Soon Ho, Peixuan Guo","doi":"10.1021/acs.molpharmaceut.4c00674","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00674","url":null,"abstract":"<p><p>Nucleoside analogs are potent inhibitors for cancer treatment, but the main obstacles to their application in humans are their toxicity, nonspecificity, and lack of targeted delivery tools. Here, we report the use of RNA four-way junctions (4WJs) to deliver two nucleoside analogs, floxuridine (FUDR) and gemcitabine (GEM), with high payloads through routine and simple solid-state RNA synthesis and nanoparticle assembly. The design of RNA nanotechnology for the co-delivery of nucleoside analogs and the chemotherapeutic drug paclitaxel (PTX) resulted in synergistic effects and high efficacy in the treatment of Triple-Negative Breast Cancer (TNBC). The 4WJ-drug complexes were confirmed to have efficient tumor spontaneous targeting and no toxicity because the motility of RNA nanoparticles has been previously shown to enable these RNA-drug complexes to spontaneously accumulate in tumor blood vessels. The negative charge of RNA enables those RNA complexes that are not targeted to tumor vasculature to circulate in the blood and enter the urine through the kidney glomerulus, without accumulating in organs, therefore being nontoxic. Drug incorporation into RNA 4WJ can be precisely controlled with a defined loading amount, location, and ratio. The incorporation of nucleoside analogs into 4WJ only requires one step using nucleoside analogue phosphoramidites during solid-phase RNA synthesis, without the need for additional conjugation and purification processes.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398657","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}

{"title":"Innovative Microencapsulation of Polymyxin B for Enhanced Antimicrobial Efficacy via Coated Spray Drying.","authors":"Amal Yousfan, Arwa Omar Al Khatib, Afrah M H Salman, Mahmoud H Abu Elella, Glyn Barrett, Nicholas Michael, Mohammed Gulrez Zariwala, Hisham Al-Obaidi","doi":"10.1021/acs.molpharmaceut.4c00594","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00594","url":null,"abstract":"<p><p>This study aims to develop an innovative microencapsulation method for coated Polymyxin B, utilizing various polysaccharides such as hydroxypropyl β-cyclodextrin, alginate, and chitosan, implemented through a three-fluid nozzle (3FN) spray drying process. High-performance liquid chromatography (HPLC) analysis revealed that formulations with a high ratio of sugar cage, hydroxypropyl β-cyclodextrin (HPβCD), and sodium alginate (coded as ALG_HCD_HP_L^PM) resulted in a notable 16-fold increase in Polymyxin B recovery compared to chitosan microparticles. Morphological assessments using fluorescence labeling confirmed successful microparticle formation with core/shell structures. Alginate-based formulations exhibited distinct layers, while chitosan formulations showed uniform fluorescence throughout the microparticles. Focused beam reflectance and histograms from fluorescence microscopic measurements provided insights into physical size analysis, indicating consistent sizes of 6.8 ± 1.2 μm. Fourier-transform infrared (FTIR) spectra unveiled hydrogen bonding between Polymyxin B and other components within the microparticle structures. The drug release study showed sodium alginate's sustained release capability, reaching 26 ± 3% compared to 94 ± 3% from the free solution at the 24 h time point. Furthermore, the antimicrobial properties of the prepared microparticles against two Gram-negative bacteria, <i>Escherichia coli</i> and <i>Pseudomonas aeruginosa</i>, were investigated. The influence of various key excipients on the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values was evaluated. Results demonstrated effective bactericidal effects of ALG_HCD_HP_L^PM against both <i>E. coli</i> and <i>P. aeruginosa</i>. Additionally, the antibiofilm assay highlighted the potential efficacy of ALG_HCD_HP_L^PM against the biofilm viability of <i>E. coli</i> and <i>P. aeruginosa</i>, with concentrations ranging from 3.9 to 500 μg/m. This signifies a significant advancement in antimicrobial drug delivery systems, promising improved precision and efficacy in combating bacterial infections.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386419","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}

{"title":"Single-Step Extrusion Process for Formulation Development of Self-Emulsifying Granules for Oral Delivery of a BCS Class IV Drug.","authors":"Vineet R Kulkarni, Santosh Bashyal, Varsha V Nair, Ishaan Duggal, Mohammed Maniruzzaman","doi":"10.1021/acs.molpharmaceut.4c00199","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00199","url":null,"abstract":"<p><p>This study aimed to develop and optimize formulations containinga BCS Class IV drug by improving its solubility and permeability. Herein development of self-emulsifying solid lipid matrices was investigated as carrier systems for a BCS Class IV model drug. Self-emulsifying drug delivery systems (SEDDS) have been extensively investigated for formulating drugs with poor water solubility. However, manufacturing SEDDS is challenging. These systems usually have low drug-loading capacities, and the incorporated drugs tend to recrystallize during storage, which severely impacts the storage stability <i>in vitro</i> and performance <i>in vivo</i>. Moreover, they require greater amounts (>80%) of lipid carriers, cosolvents, surfactants, and other excipients to keep them from recrystallizing. This in turn is again challenging for high-dose drugs as it affects the size of the final drug product (tablets and capsules). Also, the final liquid nature of the formulation affects the handling and processability of the formulation, which poses challenges during the manufacturing and packaging steps. In this work, we have studied the feasibility of a single-step extrusion process to formulate and optimize solid self-emulsifying granules with a relatively higher drug loading of Ritonavir (RTV), a BCS Class IV drug. Further, we have compared the performance of using these granules as the feedstock for direct powder extrusion-based 3D printing as opposed to the use of physical blends. The stability and solubility-permeability advantage of these granules was also evaluated where SEDDS showed about 27 and 20 fold increase in apparent solublity and permeability compared to bulk drug, respectively. Combining the capabilities of HME to form drug-loaded homogeneous granules as a continuous process along with application of direct printing extruiosn (DPE) 3D printing improves the drug delivery prospects for such candidates.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386421","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}

{"title":"Voices in <i>Molecular Pharmaceutics</i>: Meet Dr. Sanjeevini Sanju Babu Reddiar, Who Designs Advanced Drug Delivery Systems for Oral Peptides.","authors":"Sanjeevini Babu Reddiar","doi":"10.1021/acs.molpharmaceut.4c01107","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c01107","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386423","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}

{"title":"Design and Antimalarial Evaluation of Polydopamine-Modified Methyl Artelinate Nanoparticles.","authors":"Qingxia Li, Rongrong Wang, Shuqi Han, Nan Shi, Jiaqi Yang, Canqi Ping, Liqing Chai, Ruili Wang, Bin Zheng, Guolian Ren, Shuqiu Zhang","doi":"10.1021/acs.molpharmaceut.4c00520","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00520","url":null,"abstract":"<p><p>Targeted nanodrug delivery systems are highly anticipated for the treatment of malaria. It is known that <i>Plasmodium</i> can induce new permeability pathways (NPPs) on the membrane of infected red blood cells (iRBCs) for their nutrient uptake. The NPPs also enable the uptake of nanoparticles (NPs) smaller than 80 nm. Additionally, <i>Plasmodium</i> maintains a stable, slightly acidic, and reductive internal environment with higher glutathione (GSH) levels. Based on this knowledge, methyl artelinate (MA, a prodrug-like derivative of dihydroartemisinin) nanoparticles (MA-PCL-NPs) were developed using poly(ethylene glycol)-<i>b</i>-poly(ε-caprolactone) (mPEG-PCL) by a thin-film dispersion method and were further coated with polydopamine (PDA) to obtain MA-PCL@PDA-NPs with a particle size of ∼30 nm. The biomaterial PDA can be degraded in slightly acidic and reductive environments, thereby serving as triggers for drug release. MA could generate reactive oxygen species and decrease GSH levels, consequently causing parasite damage. The in vitro release experiment results indicated that the cumulative release percentage of MA from MA-PCL@PDA-NPs was considerably higher in phosphate buffer with 10 mM GSH at pH 5.5 (88.10%) than in phosphate buffer without GSH at pH 7.4 (16.98%). The green fluorescence within iRBCs of coumarin 6, the probe of NPs (C6-PCL@PDA-NPs), could be reduced significantly after adding the NPP inhibitor furosemide (<i>p</i> < 0.001), which demonstrated that MA-PCL@PDA-NPs could be ingested into iRBCs through NPPs. In vivo antimalarial pharmacodynamics in <i>Plasmodium berghei</i> K173-bearing mice showed that the inhibition ratio of MA-PCL@PDA-NPs (93.96%) was significantly higher than that of commercial artesunate injection (AS-Inj, 63.33%). The above results showed that the developed MA-PCL@PDA-NPs possessed pH-GSH dual-responsive drug release characteristics and targeting efficacy for iRBCs, leading to higher antimalarial efficacy against <i>Plasmodium</i>.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386418","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}

{"title":"Transition Metal (Molybdenum)-Doped Drug-like Conformational Nanoarchitectonics with Altered Valence States (Mn²⁺/Mn⁴⁺ and Mo⁵⁺/Mo⁶⁺) for Augmented Cancer Theranostics.","authors":"Hong-Ying Xia, Ying Zhao, Ruo-Yin Meng, Ai-Zheng Chen, Shi-Bin Wang, Ranjith Kumar Kankala","doi":"10.1021/acs.molpharmaceut.4c00896","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00896","url":null,"abstract":"<p><p>Despite the advancements in cancer therapy, delivering active pharmaceutical ingredients (APIs) using nanoparticles remains challenging due to the failed conveyance of the required drug payload, poor targeting ability, and poor biodistribution, hampering their clinical translation. Recently, the appropriate design of materials with intrinsic therapeutic functionalities has garnered enormous interest in the development of various intelligent therapeutic nanoplatforms. In this study, we demonstrate the fabrication of transition metal (molybdenum, Mo)-doped manganese dioxide (MnO₂) nanoarchitectures, exhibiting diagnostic (magnetic resonance imaging, MRI) and therapeutic (chemodynamic therapy, CDT) functionalities. The facile hydrothermal approach-assisted Mo-doped MnO₂ flower-like nanostructures offered tailorable morphologies in altered dimensions, precise therapeutic effects, exceptional biocompatibility, and biodegradability in the tumor microenvironment. The resultant defects due to doped Mo species exhibited peroxidase and oxidase activities, improving glutathione (GSH) oxidation. The two sets of variable valence metal ion pairs (Mn²⁺/Mn⁴⁺ and Mo⁵⁺/Mo⁶⁺) and their interplay could substantially improve the Fenton-like reaction and generate toxic hydroxyl radicals (^•OH), thus achieving CDT-assisted antitumor effects. As inherent T1-MRI agents, these MnO₂ nanoparticles displayed excellent MRI efficacy <i>in vitro</i>. Together, we believe that these conformational Mo-doped MnO₂ nanoarchitectures with two pairs of variable valence states could potentiate drugless therapy in pharmaceutics.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386422","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}

{"title":"A Practical <i>In Silico</i> Method for Predicting Compound Brain Concentration-Time Profiles: Combination of PK Modeling and Machine Learning.","authors":"Koichi Handa, Daichi Fujita, Mariko Hirano, Saki Yoshimura, Michiharu Kageyama, Takeshi Iijima","doi":"10.1021/acs.molpharmaceut.4c00584","DOIUrl":"10.1021/acs.molpharmaceut.4c00584","url":null,"abstract":"<p><p>Given the aging populations in advanced countries globally, many pharmaceutical companies have focused on developing central nervous system (CNS) drugs. However, due to the blood-brain barrier, drugs do not easily reach the target area in the brain. Although conventional screening methods for drug discovery involve the measurement of (unbound fraction of drug) brain-to-plasma partition coefficients, it is difficult to consider nonequilibrium between plasma and brain compound concentration-time profiles. To truly understand the pharmacokinetics/pharmacodynamics of CNS drugs, compound concentration-time profiles in the brain are necessary; however, such analyses are costly and time-consuming and require a significant number of animals. Therefore, in this study, we attempted to develop an <i>in silico</i> prediction method that does not require a large amount of experimental data by combining modeling and simulation (M&S) with machine learning (ML). First, we constructed a hybrid model linking plasma concentration-time profile to the brain compartment that takes into account the transit time and brain distribution of each compound. Using mouse plasma and brain time experimental values for 103 compounds, we determined the brain kinetic parameters of the hybrid model for each compound; this case was defined as scenario I (a positive control experiment) and included the full brain concentration-time profile data. Next, we built an ML model using chemical structure descriptors as explanatory variables and rate parameters as the target variable, and we then input the predicted values from 5-fold cross-validation (CV) into the hybrid model; this case was defined as scenario II, in which no brain compound concentration-time profile data exist. Finally, for scenario III, assuming that the brain concentration is obtained at only one time point, we used the brain kinetic parameters from the result of the 5-fold CV in scenario II as the initial values for the hybrid model and performed parameter refitting against the observed brain concentration at that time point. As a result, the RMSE/R2-values of the brain compound concentration-time profiles over time were 0.445/0.517 in scenario II and 0.246/0.805 in scenario III, indicating the method provides high accuracy and suggesting that it is a practical method for predicting brain compound concentration-time profiles.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337277","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}

{"title":"Coupled Discrete Phase and Eulerian Wall Film Models for Drug Deposition Efficacy Analysis in Human Respiratory Airways.","authors":"Sameer Kumar Verma, Kishore Singh Patel, B Kiran Naik","doi":"10.1021/acs.molpharmaceut.4c00482","DOIUrl":"https://doi.org/10.1021/acs.molpharmaceut.4c00482","url":null,"abstract":"<p><p>The current study explores the effectiveness of drug particle deposition into human respiratory airways to cure various pulmonary-bound ailments. It has been assumed that drug solutions are inhaled in the form of tiny droplets or mist, which after striking create a thin layer along the inner surface of airways where the virus initially resides to infect the human body. A coupled Eulerian wall film (EWF) and discrete phase model (DPM) based simulation approach is used to capture these dynamics. Here, the Lagrangian DPM technique tracks the dynamics of tiny droplets, while the liquid layer formation after striking is captured using the Eulerian thin film approximations or the EWF model. Previous studies in this field primarily employed only the DPM method, which is inadequate to predict the poststriking dynamics of drug layer deposition and their spread to neutralize the respiratory virus. The drug delivery effectiveness is characterized by three different particle sizes, 1, 5, and 10 μm at the inhalation rates of 15, 30, and 60 L per minute (LPM). It has been found that the size of the drug particles significantly influences drug delivery effectiveness. The film thickness increases monotonically with particle sizes and inhalation rates. However, this increase in averaged film thickness is prominent in the range 5 to 10 μm (≈60%) compared to 1 to 5 μm (≈10%) droplet sizes at generation level 4 (G4). The other deposition parameters, e.g., deposition fraction, deposition density, and area coverage) roughly show similar behavior with the increase in droplet sizes. Therefore, it is recommended to vary the droplet sizes between 5 and 10 μm for better deposition effectiveness. The sizes of more than 10 μm mostly stuck into the oral cavity and cannot reach the targeted generations. In contrast, less than 5 μm may reach much deeper generations than the targeted one.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379455","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}