Journal of pharmaceutical sciences最新文献

{"title":"Investigating the effect of permeation enhancers on oral absorption of a BCS IV compound, ombitasvir, utilizing animal models.","authors":"Anura S Indulkar, Layan Hanouch, Nathan Gignac, Thomas Borchardt, Kennan Marsh","doi":"10.1016/j.xphs.2025.103851","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103851","url":null,"abstract":"<p><p>Discovery of complex biological targets and novel treatment modalities have led to an increase in the number of compounds with poor permeability. Generally, formulation design and development are primarily focused on overcoming poor solubility. Improving oral bioavailability by utilizing permeation enhancers for poorly permeable new chemical entities (NCEs) has not been widely explored. Therefore, in this work the effect of permeation enhancers on a poorly soluble and poorly permeable compound, ombitasvir (OBT), was investigated. Structurally diverse permeation enhancers (PEs) with good safety profile-labrasol® ALF, lauroyl L- and palmitoyl L-carnitine, salcaprozoate sodium (SNAC), and sodium caprate-were tested. To study the impact of solid form and formulation, OBT was dosed as crystal form and as amorphous formulations. To avoid the influence of preclinical in vitro/ex vivo method artifacts on data interpretation, studies were conducted in whole animal models (rat and dog). OBT was dosed at 2 mg/kg and PEs were dosed at 20 mg/kg by peroral route. In rats, OBT was administered as an amorphous colloidal suspension. Only the carnitines showed meaningful enhancement (∼2X) in oral bioavailability. In dogs, OBT was dosed in enteric capsules as crystal form, a slow dissolving 15% drug load (DL) amorphous solid dispersion (ASD) that slowly reached amorphous solubility, and a rapidly dissolving 5% DL ASD that reached amorphous solubility and formed amorphous nanoprecipitates, with and without PEs. OBT was not detected in the blood upon dosing of neat crystalline solid. However, when co-dosed with PEs significantly high oral bioavailability (11-17%) was observed. 15% DL ASD alone showed a meaningful increase in oral bioavailability (∼4%) relative to the crystal form; and combination with PEs further increased the bioavailability by 2-5 fold. All the PEs showed enhancement in oral bioavailability when combined with the crystal form and 15% DL ASD. The enhancement in bioavailability due to SNAC was attributed to dissolution rate enhancement whereas, that due to lauroyl L-carnitine and labrasol was attributed to both dissolution and permeability enhancement. 5% DL ASD by itself increased the oral bioavailability to ∼8% which was attributed to its rapid dissolution. A massive increase in the oral bioavailability to 78% (∼10-fold enhancement) was observed with lauroyl L-carnitine. In contrast to the crystal form and 15% DL ASD groups, other PEs, were found to be ineffective when combined with the 5% DL ASD. Physicochemical characterization including solubility determination in presence of PEs, dissolution performance of the forms/formulations and particle size distribution of the amorphous precipitated phase (for 5% DL ASD) in presence of PEs was performed to understand in vivo results. It was concluded that the dissolution rate of the form/formulation, the amount of drug concomitantly available with PE at the site of absorption, the association of PE ","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103851"},"PeriodicalIF":3.7,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of silicone oil on the structure, stability, and aggregation of a therapeutic antibody.","authors":"Vaibhav Upadhyay, Sudipta Panja, Yogita Krishnamachari, Sarita N Mittal, Hanmi Xi, Wei Xu, Jing Song, Guangli Hu, Yongchao Su, Krishna Mg Mallela","doi":"10.1016/j.xphs.2025.103848","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103848","url":null,"abstract":"<p><p>Silicone oil is commonly used as a coating in prefilled syringes of protein therapeutics to facilitate the smooth operation of the syringe plunger. The presence of silicone oil droplets in formulations has often been associated with increased aggregation of proteins, which is undesirable for protein-based therapeutics. To ensure the safety and efficacy of protein therapeutics, it is essential to understand the mechanism of adsorption of proteins to silicone oil and subsequent structural transitions leading to aggregation. We have used a model protein dupilumab (commercially known as Dupixent) that is marketed in a prefilled syringe coated with an emulsion of dimethicone silicone oil. The binding interactions between protein and silicone oil were characterized using isothermal titration calorimetry (ITC). The structural and stability changes in the protein were characterized using circular dichroism, intrinsic protein fluorescence, and nuclear magnetic resonance (NMR) spectroscopy. Front-face fluorescence was used to obtain the fluorescence spectra from turbid samples containing silicone oil emulsions. Silicone oil droplets and protein aggregates were characterized with flow imaging techniques and dynamic light scattering (DLS). ITC results revealed a weak binding interaction between silicone oil and dupilumab with a millimolar affinity mediated by hydrophobic interactions. Tryptophan fluorescence, near-UV CD, and 2D ¹³. C-¹H NMR spectroscopy indicated no effect of silicone oil on the structure and conformational stability of the protein. However, silicone oil accelerated protein aggregation under thermal stress conditions, potentially due to a decrease in colloidal stability or partial unfolding of the protein adsorbed to silicone oil droplets.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103848"},"PeriodicalIF":3.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Which Unbound Fraction Should We Use in the Well-Stirred Model for More Accurately Predicting Hepatic Clearance of Drugs for Humans?","authors":"Patrick Poulin","doi":"10.1016/j.xphs.2025.103827","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103827","url":null,"abstract":"<p><p>As the hepatic clearance (CL_H) of drugs becomes independent of hepatic blood flow rate, CL_H depends primarily on intrinsic clearance (CL_int). Incubations of microsomes or hepatocytes are commonly used to generate CL_int. Therefore, CL_int estimates corrected for binding to the in vitro systems and scaled to whole liver, are applied to a well-stirred liver model to obtain CL_H predictions for drugs. In other words, CL_int is extrapolated with the ratio of unbound fraction between the plasma (fu_p) and incubation medium (fu_inc). However, this binding correction resulted to an important underprediction bias of CL_H. Therefore, the approach considering fu_p and fu_inc needs to be better understood for more precisely scaling CL_int. The objective of this study was to explain the underprediction bias of CL_H based on physicochemical properties of drugs. Analysis-ready datasets have been collected so that evaluation of the data generates a mechanistic understanding of the impact of unbound fraction on the prediction of CL_H of human for 128 drugs. Experimental values of fu_inc for liver are quantifying solely the binding to lipids in microsomes or hepatocytes in the absence of plasma proteins in the incubations. However, the experimental values of fu_p for plasma can estimate the binding to lipids and plasma proteins. Therefore, drugs binding primarily to lipids in the liver and plasma showed a less pronounced underprediction bias of CL_H by using the ratios of fu_p/fu_inc in the well-stirred model. In contrast, drugs binding primarily to the plasma proteins in the liver and plasma showed a larger underprediction bias of CL_H. Furthermore, for the ionized drugs, values of fu_p and fu_inc are not covering the pH gradient effect between plasma and hepatocytes, which also impacted the CL_H predictions. For these reasons, a mechanistic approach was proposed to replace the conventional fu_p value with an adjusted fu_p (fu_-adjusted) that accounts for differences in proteins/lipids binding and pH gradient effect between the liver and plasma. Hence, replacing fu_p with fu_-adjusted did provide a universal and mechanisms-based approach removing the underprediction bias for all datasets of drugs. Overall, this study indicates which drug properties generated the largest underprediction bias of CL_H and suggests that the Poulin et al. method referring to fu_-adjusted could be the most proper unbound fraction to reduce that bias with the well-stirred model.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103827"},"PeriodicalIF":3.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determination of absolute bioavailability, absorption, metabolism, and excretion of evogliptin in healthy male subjects using a microtracer method.","authors":"Dae Young Lee, Hee Eun Kang","doi":"10.1016/j.xphs.2025.103847","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103847","url":null,"abstract":"<p><p>Evogliptin, a selective serine protease dipeptidyl peptidase-4 inhibitor, has been approved in Korea for the treatment of type 2 diabetes. In this study, we investigated the absorption, metabolism, and excretion of evogliptin in healthy male subjects. To determine the extent of absolute oral bioavailability (F), one group of six participants received a microtracer intravenous (IV) dose, a 10-min infusion of 20 µg [¹⁴C]-evogliptin (651 nCi) commencing 4 h after administration of a 5 mg oral evogliptin tablet. A second group of six participants received an oral solution of [¹⁴C]-evogliptin (5 mg: 1000 nCi) to determine pharmacokinetics, mass balance recovery, plasma and excreta metabolite profiles, and structural identification of metabolites. The F of the 5 mg evogliptin tablet was 50.2%. Evogliptin exhibited a long elimination half-life of 40-55 h after both the IV and oral doses. Following oral administration of [¹⁴C]-evogliptin, more than 75.3% of the dose was absorbed. An average of 88.9% of the total radioactivity (TRA) dose was recovered in excreta over 240 h, with 46.1% via urine and 42.8% via feces. Evogliptin was metabolised through oxidation to M7 and M8, sulfation to M13, and subsequent glucuronide conjugation of M7 to M16. No single metabolite accounted for more than 10% of the TRA in plasma. The concomitant oral dosing followed by microtracer IV dosing and the microtracer oral dosing enabled a comprehensive description of evogliptin's absorption, metabolism, and excretion in humans. Evogliptin was safe and well tolerated in healthy subjects.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103847"},"PeriodicalIF":3.7,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing GLP-1 expression via IVT mRNA and fusion protein technology for diabetes therapy","authors":"Xiaoying Wu ,&nbsp;Jingtao Qiao ,&nbsp;Fei Xiao ,&nbsp;Lixin Guo","doi":"10.1016/j.xphs.2025.103829","DOIUrl":"10.1016/j.xphs.2025.103829","url":null,"abstract":"<div><h3>Background</h3><div>Diabetes is a chronic metabolic disorder with high incidence and prevalence worldwide. This study explores a novel glucagon-like peptide-1-Fc (GLP-1-Fc) mRNA designed to improve diabetes management by inducing stable and persistent production of GLP-1-Fc protein.</div></div><div><h3>Methods</h3><div>The GLP-1-Fc mRNA was generated using <em>in vitro</em> transcription and fusion protein technology. Protein expression was assessed via western blot and enzyme-linked immunosorbent assay (ELISA) in Human Embryonic Kidney 293T (HEK293T) cells. GLP-1-Fc mRNA and GLP-1-Fc protein (dulaglutide) were administered to C57BL/6J and db/db mice to evaluate protein levels, GLP-1 receptor activity, hypoglycemic effects, and safety using ELISA, lance ultra cAMP assay, blood glucose levels detection, immunofluorescence, and hematoxylin and eosin staining.</div></div><div><h3>Results</h3><div>The designed mRNA fused with the Fc region successfully encoded GLP-1-Fc, showing optimal stability and translation efficiency. The GLP-1-Fc protein levels were significantly higher in the GLP-1-Fc mRNA treatment group than those in the control mice. The GLP-1-Fc mRNA effectively reduced blood glucose levels and increased GLP-1 receptor expression in db/db mice after both single and repeated administrations. Moreover, the GLP-1-Fc mRNA provided prolonged glucose reduction with similar efficacy to GLP-1 protein drug, dulaglutide. Besides, intraperitoneal delivery of GLP-1-Fc mRNA does not induce tissue damage.</div></div><div><h3>Conclusions</h3><div>Compared to conventional peptide-based therapies, GLP-1-Fc mRNA represents a promising strategy for diabetes treatment by enabling sustained <em>in vivo</em> protein expression, achieving effective glycemic control, and offering a streamlined manufacturing process with reduced production complexity.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 7","pages":"Article 103829"},"PeriodicalIF":3.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144090271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein Adsorption of In-line Intravenous Infusion Filter and the Corresponding Mitigation Plans.","authors":"Xing Mu, Yao Tang, Hangting Hu, Zhaowei Jin, Quanmin Chen, Jeremy Guo","doi":"10.1016/j.xphs.2025.103846","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103846","url":null,"abstract":"<p><p>Protein adsorption is one of the most frequently observed incompatibility issues during intravenous (IV) administration of therapeutic proteins, especially at low concentration, leading to a lower-than-expected drug recovery and potential insufficient therapeutic effect. With its porous structure and complex surface physicochemical property, the in-line filter is usually the main component where protein adsorption happens. Thus, comprehending the adsorption mechanism between proteins and filter membranes is essential for designing effective mitigation strategies. In this study, the adsorption behaviors for 4 proteins with different pI (isoelectric point) and hydrophobicity were evaluated after dilution to 5 μg/mL in 5% dextrose (D5W) and 0.9% sodium chloride (saline), respectively. The results showed that in-line filter is the main contributor to protein loss compared with IV bag and infusion line. The adsorption in D5W was dominated by electrostatic attraction between positively charged protein and negatively charged filter membrane. By adjusting the solution pH above the protein pI to have negatively charged protein or using positively charged filter membrane, the adsorption was effectively reduced by reducing the electrostatic attraction, while adding electrolyte solution could be similarly effective by shielding the surface charge to reduce the electrostatic attraction. In addition, adding surfactant could further reduce the adsorption induced by hydrophobic interaction between protein and contacting materials including IV bag, infusion line and in-line filter as well. When saline was used as a diluent, hydrophobic interaction between protein and filter membrane was the main cause for protein with high hydrophobicity. 0.005% (w/v) polysorbate 80 was demonstrated to be effective to elevate the dose recovery to about 100% for all the evaluated proteins. A decision tree was provided to guide the design of proper mitigation plans to reduce the protein adsorption during IV infusion based on the type of diluent, filter membrane and protein pI.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103846"},"PeriodicalIF":3.7,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced anti-tumor efficacy of paclitaxel by the co-amorphous technology with resveratrol","authors":"Ping-fu Huang ,&nbsp;Wen-Min Niu ,&nbsp;Lu-lu Liu ,&nbsp;Guan-qiao Wang ,&nbsp;Jun Chen ,&nbsp;Zhou-xun Dong ,&nbsp;Jia-bing Tong","doi":"10.1016/j.xphs.2025.103844","DOIUrl":"10.1016/j.xphs.2025.103844","url":null,"abstract":"<div><div>Paclitaxel (PTX), categorized as a BCS Class IV anti-tumor agent, is integral to clinical treatment, however, the insolubility of PTX leads to diminished bioavailability. Resveratrol (RES), a bioactive compound present in various dietary sources, has the potential to augment the anti-tumor effectiveness of PTX. This research aims to formulate a co-amorphous system consisting of PTX and RES to enhance the solubility and bioavailability of PTX. The co-amorphous system was synthesized via the solvent evaporation technique and subsequently characterized using powder X-ray diffraction, Fourier-transform infrared spectroscopy, differential scanning calorimetry, Raman spectroscopy, and thermal analysis. Molecular dynamics simulations illustrated the interactions between PTX and RES, which facilitated an increase in apparent solubility and <em>in vitro</em> dissolution rates. Furthermore, <em>in vitro</em> cytotoxicity assays, Caco-2 cell model studies, and <em>in vivo</em> anti-tumor experiments demonstrated that the PTX-RES combination exhibited enhanced anti-tumor efficacy relative to other treatment groups. Pharmacokinetic evaluations revealed that the oral bioavailability of the PTX-RES complex surpassed that of pure PTX. These findings substantiate that the PTX-RES co-amorphous system significantly improves the physicochemical properties and anti-tumor activity of PTX. Additionally, this study presents a promising approach for enhancing the solubility and bioavailability of compounds with poor solubility.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 7","pages":"Article 103844"},"PeriodicalIF":3.7,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analytical Control Strategy for Biologics. Part II: Roadmap for Development and Implementation.","authors":"Krishnan Sampathkumar, Brent S Kendrick, John P Gabrielson, Da Ren","doi":"10.1016/j.xphs.2025.103834","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103834","url":null,"abstract":"<p><p>Biologics therapeutics encompass different modalities with vastly different molecular profiles. However, there are many similarities in the integrated product control strategy development that may be applied across the different modalities, including establishing Quality Target Product Profile (QTPP), drug substance and product development, analytical method development and qualification, process performance qualification, analytical method validation and continuous process verification. Technical and regulatory requirements for biologics development are established in numerous regulatory guidance documents issued by industry experts, ICH, FDA, EMA, and other health authorities. While there is substantial published knowledge on specific studies needed for the development of a product, there is no specific guidance on establishing a comprehensive analytical control strategy as part of an integrated control strategy in alignment with the lifecycle of product development from pre-clinical through commercialization of human biotherapeutics. This commentary is part II of a two-part commentary series on analytical control strategy development and implementation. In part I, we presented the foundations of a well-developed analytical control strategy. In this part, we present a streamlined and stage-appropriate roadmap for developing and implementing the key elements of an analytical control strategy from pre-clinical to commercial launch of therapeutic biologics.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103834"},"PeriodicalIF":3.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Effect of Solvent Polarity Environment Differences in Electrolyte and non-Electrolyte Systems.","authors":"Valeria Briceida Tellez Gallego, Kate Sorg, Rodolfo Pinal","doi":"10.1016/j.xphs.2025.103836","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103836","url":null,"abstract":"<p><p>To address the knowledge gap regarding the polarity of excipient solutions and the impact on biologically relevant systems, a comprehensive exploration of the polarity of solutions is essential. This study explores the solvatochromic response of Reichardt's dye to solvent polarity in aqueous solutions, focusing on structurally similar electrolytes and non-electrolytes at concentrations typically used in pharmaceutical formulations. UV absorbance measurements demonstrated sensitivity to subtle structural differences, such as counterion variations or glycosidic bonds. Here, chloride salts and disaccharides were analyzed and notable polarity differences between similar systems were found. Additionally, unexpected similarities between sodium chloride and trehalose were observed. This investigation underscores the potential of readily accessible solvent polarity and solvatochromic studies to deepen the understanding of aqueous solutions and extend their application to pharmaceutical excipients and their roles in protein formulation.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103836"},"PeriodicalIF":3.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissolvable Microneedles assisted Minimally Invasive Transcleral Delivery of Conjugated Soluplus Nanomicelles targeting Retina in the management of Retinoblastoma.","authors":"Mudassir Ansari, Yogesh A Kulkarni, Kavita Singh","doi":"10.1016/j.xphs.2025.103835","DOIUrl":"https://doi.org/10.1016/j.xphs.2025.103835","url":null,"abstract":"<p><p>The present study focused on delivering sorafenib-loaded conjugated soluplus nanomicelles to the back of the eye targeting retina via dissolvable microneedle-mediated transcleral delivery. The research involved fabricating dissolvable microneedles by melt casting method using a blend of PVA and PVP 90F. Optical and scanning electron microscopy confirmed that the microneedles were sharp, smooth, non-sticky, and non-brittle, exhibiting no cracks. Mechanical testing revealed a hardness cycle of 71.63 g±5.12, with successful penetration into goat sclera, as indicated by blue dots from trypan blue staining. The drug content was consistent with the incorporation amount, measured at 10.04µg±0.67. Following rapid dissolution, the nanomicelles released the complete drug load within four hours. Drug permeation across the goat scleral membrane was estimated at 3.57±0.0.09 µg/cm², with scleral deposition of 4.99±0.13 µg, indicating effective penetration. Ocular tissue distribution analysis (LC-MS/MS) revealed sorafenib concentrations of 69.37±5.19 ng/g in the retina and 4.93±0.53 ng/g in the vitreous humor, confirming successful drug transport to the posterior eye segment. The final formulation remained stable for three months and was non-irritant, establishing a minimally invasive platform technology for the management of retinoblastoma relative to invasive eye injections.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103835"},"PeriodicalIF":3.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}