The Safety and Efficacy of Remimazolam Compared to Dexmedetomidine for Awake Tracheal Intubation by Flexible Bronchoscopy: A Randomized, Double-Blind, Controlled Trial.

Background: Remimazolam is a novel ultra-short-acting benzodiazepine sedative that has the potential to be an alternative for procedural sedation due to its rapid sedation and recovery, no accumulation effect, stable hemodynamics, minimal respiratory depression, anterograde amnesia effect, and specific antagonist. Here, we aimed to compare the safety and efficacy of remimazolam with dexmedetomidine for awake tracheal intubation by flexible bronchoscopy (ATI-FB). Methods: Ninety patients scheduled for ATI-FB were randomly divided into three groups, each consisting of 30 cases: dexmedetomidine 0.6 µg/kg + sufentanil (group DS), remimazolam 0.073 mg/kg + sufentanil (group R1S), or remimazolam 0.093 mg/kg + sufentanil (group R2S). The primary outcome was the success rate of sedation. Secondary outcomes were MOAA/S scores, hemodynamic and respiratory parameters, intubation conditions, intubation time, tracheal intubation amnesia, and adverse events. Results: The success rates of sedation in groups R2S and DS were higher than that in group R1S (93.3%, 86.7%, respectively, vs 58.6%; P = 0.002), and intubation conditions were better than those in group R1S (P < 0.05). Group R2S had shorter intubation times than groups R1S and DS (P = 0.003), and a higher incidence of tracheal intubation amnesia than group DS (P = 0.006). No patient in the three groups developed hypoxemia or hypotension, and there were no significant differences in oligopnea, PetCO2, or bradycardia (P > 0.05). Conclusion: In conclusion, both DS and R2S had higher success rates of sedation, better intubation conditions, and minor respiratory depression, but R2S, with its shorter intubation time, higher incidence of anterograde amnesia, and ability to be antagonized by specific antagonists, may be a good alternative sedation regimen for patients undergoing ATI-FB.

Ultrasound enhanced siRNA delivery using cationic liposome-microbubble complexes for the treatment of squamous cell carcinoma.

Rationale: Microbubble (MB) contrast agents combined with ultrasound targeted microbubble cavitation (UTMC) are a promising platform for site-specific therapeutic oligonucleotide delivery. We investigated UTMC-mediated delivery of siRNA directed against epidermal growth factor receptor (EGFR), to squamous cell carcinoma (SCC) via a novel MB-liposome complex (LPX). Methods: LPXs were constructed by conjugation of cationic liposomes to the surface of C4F10 gas-filled lipid MBs using biotin/avidin chemistry, then loaded with siRNA via electrostatic interaction. Luciferase-expressing SCC-VII cells (SCC-VII-Luc) were cultured in Petri dishes. The Petri dishes were filled with media in which LPXs loaded with siRNA against firefly luciferase (Luc siRNA) were suspended. Ultrasound (US) (1 MHz, 100-µs pulse, 10% duty cycle) was delivered to the dishes for 10 sec at varying acoustic pressures and luciferase assay was performed 24 hr later. In vivo siRNA delivery was studied in SCC-VII tumor-bearing mice intravenously infused with a 0.5 mL saline suspension of EGFR siRNA LPX (7×108 LPX, ~30 µg siRNA) for 20 min during concurrent US (1 MHz, 0.5 MPa spatial peak temporal peak negative pressure, five 100-µs pulses every 1 ms; each pulse train repeated every 2 sec to allow reperfusion of LPX into the tumor). Mice were sacrificed 2 days post treatment and tumor EGFR expression was measured (Western blot). Other mice (n=23) received either EGFR siRNA-loaded LPX + UTMC or negative control (NC) siRNA-loaded LPX + UTMC on days 0 and 3, or no treatment ("sham"). Tumor volume was serially measured by high-resolution 3D US imaging. Results: Luc siRNA LPX + UTMC caused significant luciferase knockdown vs. no treatment control, p<0.05) in SCC-VII-Luc cells at acoustic pressures 0.25 MPa to 0.9 MPa, while no significant silencing effect was seen at lower pressure (0.125 MPa). In vivo, EGFR siRNA LPX + UTMC reduced tumor EGFR expression by ~30% and significantly inhibited tumor growth by day 9 (~40% decrease in tumor volume vs. NC siRNA LPX + UTMC, p<0.05). Conclusions: Luc siRNA LPXs + UTMC achieved functional delivery of Luc siRNA to SCC-VII-Luc cells in vitro. EGFR siRNA LPX + UTMC inhibited tumor growth and suppressed EGFR expression in vivo, suggesting that this platform holds promise for non-invasive, image-guided targeted delivery of therapeutic siRNA for cancer treatment.

Identifying Predictors for Hypoplastic Aortic Arch (HAA) in Pediatric Patients with Complex Coarctation of the Aorta (CoA).

OBJECTIVE: HAA is a significant risk factor in complex CoA patients. We conducted a retrospective study to explore the relationship between HAA and other cardiovascular factors. METHODS: We analyzed 103 patients diagnosed with complex CoA using CT angiography and echocardiography. Aortic diameter was measured at six levels, and severe coarctation was defined as coarctation site to diaphragmatic level ratio (CDR) < 50%. Correlations between non-HAA and HAA groups were assessed. Univariate and multivariate logistic regression identified HAA risk factors. RESULTS: Among 103 children with complex CoA, 55 were in the non-HAA group and 48 in the HAA group. The incidence of PDA (56.3% vs. 32.7%, p < 0.05), severe coarctation (CDR < 50%, 81.3% vs. 34.5%, p < 0.01), and collateral arteries (39.6% vs. 0, p < 0.01) were higher in the HAA group than one in the non-HAA group. The aortic arch size was positively correlated with age and negatively correlated with severe coarctation, VSD, collateral arteries, and left heart dysfunction. Logistic regression results showed that collateral arteries were risk factors for the whole aortic arch (proximal arch OR = 11.458; p < 0.01, distal arch OR = 4.211; p < 0.05, and isthmus OR = 11.744; p < 0.01), severe coarctation (OR = 6.653; p < 0.01), and left heart dysfunction (OR = 5.149; p < 0.01) associated with isthmus hypoplasia. CONCLUSION: This study highlights the prevalence of HAA in complex CoA patients and its associations with various cardiovascular factors. These insights improve diagnosis and treatment approaches.

Cobalt-Catalyzed Carbon-Heteroatom Transfer Enables Regioselective Tricomponent 1,4-Carboamination.

Tricomponent cobalt(salen)-catalyzed carbofunctionalization of unsaturated substrates by radical-polar crossover has the potential to streamline access to broad classes of heteroatom-functionalized synthetic targets, yet the reaction platform has remained elusive, despite the well-developed analogous hydrofunctionalizations mediated by high-valent alkylcobalt intermediates. We report herein the development of a cobalt(salen) catalytic system that enables carbofunctionalization. The reaction entails a tricomponent decarboxylative 1,4-carboamination of dienes and provides a direct route to aromatic allylic amines by obviating preformed allylation reagents and protection of oxidation-sensitive aromatic amines. The catalytic system merges acridine photocatalysis with cobalt(salen)-catalyzed regioselective 1,4-carbofunctionalization that facilitates the crossover of the radical and polar phases of the tricomponent coupling process, revealing critical roles of the reactants, as well as ligand effects and the nature of the formal high-valent alkylcobalt species on the chemo- and regioselectivity.

The long rod-shaped Sr2 MgSi2 O7 :Eu2+ ,Dy3+ with ultrahigh afterglow performance.

The afterglow properties of long afterglow luminescent materials are greatly affected by their defects, which are distributed on the grain surface. Increasing the exposed surface area is an important method to improve the afterglow performance. In this research, long rod-shaped long afterglow materials Sr2 MgSi2 O7 :Eu2+ ,Dy3+ were prepared using the hydrothermal-coprecipitation method. When the reaction time reached 96 h, the length of the afterglow materials could grow to 2 mm, and the sintering temperature was just 1150°C. The emission spectra of all obtained samples upon excitation at 397 nm had a maximum of 465 nm, which belonged to the representative transition of Eu2+ . The initial brightness was 1.35 cd/m2 . The afterglow time could reach 19 h, giving a good afterglow performance. The research on this kind of material has essential significance in the exploration of luminescence mechanisms and their applications.

Feasibility study of multiple-energy Bragg peak proton FLASH on a superconducting gantry with large momentum acceptance.

BACKGROUND: While the Bragg peak proton beam (BP) is capable of superior target conformity and organs-at-risk sparing than the transmission proton beam (TB), its efficacy in FLASH-RT is hindered by both a slow energy switching process and the beam current. A universal range shifter (URS) can pull back the high-energy proton beam while preserving the beam current. Meanwhile, a superconducting gantry with large momentum acceptance (LMA-SC gantry) enables fast energy switching. PURPOSE: This study explores the feasibility of multiple-energy BP FLASH-RT on the LMA-SC gantry. METHOD AND MATERIALS: A simultaneous dose and spot map optimization algorithm was developed for BP FLASH-RT treatment planning to improve the dose delivery efficiency. The URS was designed to be 0-27 cm thick, with 1 cm per step. BP plans using the URS were optimized using single-field optimization (SFO) and multiple-field optimization (MFO) for ten prostate cancer patients and ten lung cancer patients. The plan delivery parameters, dose, and dose rate metrics of BP plans were compared to those of TB plans using the parameters of the LMA-SC gantry. RESULTS: Compared to TB plans, BP plans significantly reduced MUs by 42.7% (P < 0.001) with SFO and 33.3% (P < 0.001) with MFO for prostate cases. For lung cases, the reduction in MUs was 56.8% (P < 0.001) with SFO and 36.4% (P < 0.001) with MFO. BP plans also outperformed TB plans by reducing mean normal tissue doses. BP-SFO plans achieved a reduction of 56.7% (P < 0.001) for prostate cases and 57.7% (P < 0.001) for lung cases, while BP-MFO plans achieved a reduction of 54.2% (P < 0.001) for the prostate case and 40.0% (P < 0.001) for lung cases. For both TB and BP plans, normal tissues in prostate and lung cases received 100.0% FLASH dose rate coverage (>40 Gy/s). CONCLUSIONS: By utilizing the URS and the LMA-SC gantry, it is possible to perform multiple-energy BP FLASH-RT, resulting in better normal tissue sparing, as compared to TB plans.

Human vulnerability assessment based on bullet motion and cavity expansion model with tissue identification.

In human vulnerability assessment, the wound characteristics are derived from a single soft media penetration experiment, and there is a lack of mathematical model or algorithm to accurately describe the bullet motion (consider bullet rolling) and temporary cavity variation during bullet penetration into different soft media. This paper derives a bullet motion and cavity expansion-contraction model for bullet penetration into soft tissue; Established a dynamic wound reconstruction model based on neural networks that considers tissue differences. Assessment of damage to tissues using the Abbreviated Injury Scale; Developed software for assessing human vulnerability based on dynamic wound reconstruction. Research results show that the bullet motion model and the cavity expansion-contraction model can predict the characteristic volume of the wound and the temporary cavity profile changes during bullet penetration more accurately; the maximum temporary cavity diameters of the muscle wound, the cardiac wound, and the muscle-cardiac-muscle coupling wound are 183.6, 158.06, and 174.74 mm respectively, and using the cavity in a single target as the basis for human injury assessment will introduce errors. The process of bullet penetration into soft tissue can be accurately described based on a predictive model that considers tissue differences. This paper provides the model that improves the accuracy of human injury assessment compared to existing penetration models.

Derived the bullet motion model and temporary cavity expansion- contraction model when the projectile penetrates a soft medium.Derived a dynamic wound reconstruction model based on feed-forward neural networks that considers tissue variation.Developed a wound visualization program that is more consistent with experimental phenomena.Analysis of the differences in wound channels when projectile penetrating different tissues shows that using the results of penetrating a single medium as the basis for assessment introduces errors.

Micro-to-Nano Oncolytic Microbial System Shifts from Tumor Killing to Tumor Draining Lymph Nodes Remolding for Enhanced Immunotherapy.

Because the tumor-draining lymph nodes (TDLNs) microenvironment is commonly immunosuppressive, oncolytic microbe-induced tumor antigens aren't sufficiently cross-primed tumor specific T cells through antigen-presenting cells (e.g., dendritic cells (DCs)) in TDLNs. Herein, this work develops the micro-to-nano oncolytic microbial therapeutics based on pyranose oxidase (P2 O) overexpressed Escherichia coli (EcP) which are simultaneously encapsulated by PEGylated mannose and low-concentrated photosensitizer nanoparticles (NPs). Following administration, P2 O from this system generates toxic hydrogen peroxide for tumor regression and leads to the release of tumor antigens. The "microscale" EcP is triggered, following exposure to the laser irradiation, to secrete the "nanoscale" bacterial outer membrane vesicles (OMVs). The enhanced TDLNs delivery via OMVs significantly regulates the TDLNs immunomicroenvironment, promoting the maturation of DCs to potentiate tumor antigen-specific T cells immune response. The micro-to-nano oncolytic microbe is leveraged to exert tumor killing and remold TDLNs for initiating potent activation of DCs, providing promising strategies to facilitate microbial cancer vaccination.

Allograft inflammatory factor-1 enhances inflammation and oxidative stress via the NF-κB pathway of bladder urothelium in diabetic rat model.

OBJECTIVES: To explore the role of allograft inflammatory factor-1 (AIF-1) both in diabetic rat bladder urothelium and in high-glucose-treated human urothelial cell line (SV-HUC-1). METHODS: Inflammation and oxidative stress (OS) promote diabetic cystopathy (DCP), but the mechanisms are not fully understood. The expression level of AIF-1 in diabetic rat bladder urothelium and in the SV-HUC-1 cells treated with high glucose was detected using tissue immunofluorescence, immunohistochemistry and western blot assays. AIF-1 was knocked down and NF-κB was suppressed with the specific inhibitor BAY 11-7082 in high-glucose-treated SV-HUC-1 cells. RESULTS: High-glucose condition induced AIF-1 upregulation in vivo and in vitro. The up-regulated AIF-1 induced the production of inflammatory factors IL-6 and TNF-α and elevation of ROS. Informatics analysis suggested that NF-κB pathway is implicated in DCP. Through knockdown of AIF-1, we confirmed that AIF-1 simulated NF-κB pathway by enhancing the phosphorylation of IκB (p-IκB) and promoting the translocation of NF-κB p65 from cytoplasm into nucleus. Additionally, High-glucose-induced inflammation in SV-HUC-1 cells was attenuated by the addition of NF-κB inhibitor. CONCLUSIONS: This study provides novel information to understand the molecular regulation mechanisms of AIF-1 in DCP.

The fatal effect of shock waves on the head of a person wearing a polyurea-reinforced ballistic helmet.

Ballistic helmets are an important part of personal protective equipment in war and are specifically designed to protect a person's head. The future trend is to improve the protective performance of helmets through the use of lightweight coatings, and polyurea, as one of the hottest elastomeric polymer coating materials in recent years, has excellent physical properties, especially its ability to improve the target's protection against blast shock waves. Therefore, in this study, using a validated head model, a blast impact model under the fluid-solid coupling method was constructed to study the effect of blast wave on the model and to analyse its effect on intracranial pressure and skull deformation. In addition, the effect of the position of the polyurea lightweight protective coating on the bending deformation of the skull under the effect of the blast wave was also investigated. The results showed that the polyurea coating could reduce the skull deformation under the same surface density condition. However, spraying polyurea on the blast surface of the helmet's blast-facing surface does not effectively reduce skull deformation caused by blast waves.

Development of a human glioblastoma model using humanized DRAG mice for immunotherapy.

Glioblastoma (GBM) is the most common and lethal primary brain tumor. The development of alternative humanized mouse models with fully functional human immune cells will potentially accelerate the progress of GBM immunotherapy. We successfully generated humanized DRAG (NOD.Rag1KO.IL2RγcKO) mouse model by transplantation of human DR4+ hematopoietic stem cells (hHSCs), and effectively grafted GBM patient-derived tumorsphere cells to form xenografted tumors intracranially. The engrafted tumors recapitulated the pathological features and the immune cell composition of human GBM. Administration of anti-human PD-1 antibodies in these tumor-bearing humanized DRAG mice decreased the major tumor-infiltrating immunosuppressive cell populations, including CD4+PD-1+ and CD8+PD-1+ T cells, CD11b+CD14+HLA-DR+ macrophages, CD11b+CD14+HLA-DR-CD15- and CD11b+CD14-CD15+ myeloid-derived suppressor cells, indicating the humanized DRAG mice as a useful model to test the efficacy of GBM immunotherapy. Taken together, these results suggest that the humanized DRAG mouse model is a reliable preclinical platform for studying brain cancer immunotherapy and beyond.

Genome-Wide Analysis of Cation/Proton Antiporter Family in Soybean (Glycine max) and Functional Analysis of GmCHX20a on Salt Response.

Monovalent cation proton antiporters (CPAs) play crucial roles in ion and pH homeostasis, which is essential for plant development and environmental adaptation, including salt tolerance. Here, 68 CPA genes were identified in soybean, phylogenetically dividing into 11 Na+/H+ exchangers (NHXs), 12 K+ efflux antiporters (KEAs), and 45 cation/H+ exchangers (CHXs). The GmCPA genes are unevenly distributed across the 20 chromosomes and might expand largely due to segmental duplication in soybean. The GmCPA family underwent purifying selection rather than neutral or positive selections. The cis-element analysis and the publicly available transcriptome data indicated that GmCPAs are involved in development and various environmental adaptations, especially for salt tolerance. Based on the RNA-seq data, twelve of the chosen GmCPA genes were confirmed for their differentially expression under salt or osmotic stresses using qRT-PCR. Among them, GmCHX20a was selected due to its high induction under salt stress for the exploration of its biological function on salt responses by ectopic expressing in Arabidopsis. The results suggest that the overexpression of GmCHX20a increases the sensitivity to salt stress by altering the redox system. Overall, this study provides comprehensive insights into the CPA family in soybean and has the potential to supply new candidate genes to develop salt-tolerant soybean varieties.

Ni isotopes provide a glimpse of Earth's pre-late-veneer mantle.

Moderately siderophile (e.g., Ni) and highly siderophile elements (HSEs) in the bulk silicate Earth (BSE) are believed to be partly or near-completely delivered by late accretion after the depletion caused by metallic core formation. However, the extent and rate of remixing of late-accreted materials that equilibrated with Earth's pre-late-veneer mantle have long been debated. Observing evidence of this siderophile element-depleted pre-late-veneer mantle would provide powerful confirmation of this model of early mantle evolution. We find that the mantle source of the ~3.8-billion-year-old (Ga) Narssaq ultramafic cumulates from Southwest Greenland exhibits a subtle 60Ni/58Ni excess of ~0.05 per mil and contains a clear HSE deficiency of ~60% relative to the BSE. The intermediate Ni isotopic composition and HSE abundances of the ~3.8-Ga Narssaq mantle mark a transitional Eoarchean snapshot as the poorly mixed 3.8-Ga mantle containing elements of pre-late-veneer mantle material transitions to modern Earth's mantle.

Concentration-Dependent Layer Exfoliation of Black Phosphorus by Human Serum Albumin and Its Corresponding Biocompatibility Change.

Layered black phosphorus (LBP) is drawing increasing attention because of its excellent potential in biomedical applications. Properties and bioeffects of LBP depend on its layer number (LN). However, the variation of LN during applications, especially in organisms, is largely unknown. Herein, LBP is found to be exfoliated by human serum albumin (HSA) after the formation of protein coronas. The sorption of HSA on LBP exhibits multiple intermediate equilibrium and size-dependent capacity and is distinguished from traditional multilayer sorption. The loss of LN for LBP increases with the increase of HSA concentrations, e.g., 2, 4, and 6 layers of LBP are exfoliated at 35, 135, and 550 mg/L HSA, respectively. The energy distribution shows that at low HSA concentrations, exfoliation is mainly driven by electrostatic and hydrogen bond interactions. With middle or high HSA concentrations, exfoliation is mainly driven by p-π or hydrophobic interactions, respectively. Layer exfoliation causes the continuous emergence of an unsaturated LBP surface available for adsorbing further HSA, breaking previous sorption saturations. The complete exfoliation of LBP weakens cytotoxicity and promotes internalization to the A-549 cell line compared with pristine or less exfoliated LBP. This finding unveils the exfoliation mechanism of proteins toward LBP and is of benefit to evaluating application performance and biosafety of LBP.

Role of PLGA Variability in Controlled Drug Release from Dexamethasone Intravitreal Implants.

Long-acting injectable formulations based on poly(lactide-co-glycolide) (PLGA) have been commercialized for over 30 years in at least 20 FDA-approved products. These formulations offer several advantages, including reduced dosing frequency, improved patient compliance, and maintenance of therapeutic levels of drug. Despite extensive studies, the inherent complexity of the PLGA copolymer still poses significant challenges associated with the development of generic formulations having drug release profiles equivalent to those of the reference listed drugs. In addition, small changes to PLGA physicochemical properties or the drug product manufacturing process can have a major impact on the drug release profile of these long-acting formulations. This work seeks to better understand how variability in the physicochemical properties of similar PLGAs affects drug release from PLGA solid implants using Ozurdex (dexamethasone intravitreal implant) as the model system. Four 50:50, acid-terminated PLGAs of similar molecular weights were used to prepare four dexamethasone intravitreal implants structurally equivalent to Ozurdex. The PLGAs were extensively characterized by using a variety of analytical techniques prior to implant manufacture using a continuous, hot-melt extrusion process. In vitro release testing of the four structurally equivalent implants was performed in both normal saline and phosphate-buffered saline (PBS), yielding drastically different results between the two methods. In normal saline, no differences in the release profiles were observed. In PBS, the drug release profiles were sensitive to small changes in the residual monomer content, carboxylic acid end group content, and blockiness of the polymers. This finding further underscores the need for a physiologically relevant in vitro release testing method as part of a robust quality control strategy for PLGA-based solid implant formulations.

Manufacturing dexamethasone intravitreal implants: Process control and critical quality attributes.

Over 20 long-acting injectable formulations based on poly(lactide-co-glycolide) (PLGA) have been approved by the FDA to date. PLGA is a biodegradable polymer that can extend drug release from these dosage forms for up to six months after administration. Despite the commercial success of several of these formulations, there are still a limited number of products that utilize PLGA, and there are currently no generic counterparts of these products on the market. Significant technical challenges are associated with preparation of chemically and structurally equivalent formulations that yield an equivalent drug release profile to the reference listed drug (RLD) both in vitro and in vivo. In this work, Ozurdex (dexamethasone intravitreal implant) was used as a model system to explore how the manufacturing process of PLGA-based solid implants impacts the quality and performance of the dosage form. Control of implant structural characteristics, including diameter, internal porosity, and surface roughness, was required to maintain accurate unit dose potency. Implants were prepared by a continuous hot-melt extrusion process that was thoroughly characterized to show the importance of precise feeding control to meet dimensional specifications. Five extruder die designs were evaluated using the same hot-melt extrusion process to produce five structurally-distinct implants. The structural differences did not alter the in vitro drug release profile when tested in both normal saline and phosphate-buffered saline (pH 7.4); however, implant porosity was shown to impact the mechanical strength of the implants. This work seeks to provide insight into the manufacturing process of PLGA-based solid implants to support development of future novel and generic drug products.

Response of exogenous melatonin on transcription and metabolism of soybean under drought stress.

Amino acid metabolism is an important factor in regulating nitrogen source assimilation and source/sink transport in soybean. Melatonin can improve plant stress resistance, but whether it affects amino acid metabolism is not known. Therefore, this study investigated whether exogenous melatonin had an effect on amino acid metabolism of soybean under drought conditions and explored its relationship with yield. The treatments were normal water supply treatment (WW), drought stress treatment (D), drought stress and melatonin treatment group (D + M), sprayed with 100 µmol/L melatonin. The effects of melatonin on amino acid metabolism and grain filling were studied by physiological and omics experiments using Kangxian 9 (drought-sensitive variety) and Suinong 26 (drought-resistant variety) soybean cultivars. The results showed that drought stress decreased the activity of carbon and nitrogen metabolizing enzymes, which inhibited the accumulation of dry matter and protein, and decreased the yield. In the drought-sensitive soybean variety, glycoenzymes and amino acid synthetases synthetic genes were upregulated in melatonin-treated soybeans, hence carbon and nitrogen metabolism enzyme activity increased, increasing the carbohydrate and amino acid contents simultaneously. This resulted in higher dry matter and yield than drought-stressed soybean not treated with melatonin. In the drought-resistant variety, the grain weight per plant increased by 7.98% and 6.57% in 2020 and 2021, respectively, while it increased by 23.20% and 14.07% in the drought-sensitive variety during the respective years. In conclusion, melatonin treatment can enhance the activity of nitrogen and carbon metabolism and amino acid content by upregulating the expression of soybean metabolic pathway and related genes, thus increasing the yield of soybean under drought stress.

Impact of Apparatus and Adapter on In vitro Drug Release of Ophthalmic Semisolid Drug Products.

PURPOSE: In vitro release testing (IVRT) is a widely used tool for evaluating the quality and performance of drug products. However, standardized sample adaptors or drug release apparatus setups for IVRT studies are still lacking for ophthalmic ointments. The aim of this study was to provide a better understanding of the impact of apparatus and sample adaptor setups on IVRT of ophthalmic ointments. METHODS: Dexamethasone (DEX), a steroidal ingredient commonly used in ophthalmic drug products, was selected as a model drug. Ointments were prepared by mixing DEX in white petrolatum using a high shear mixer. A novel two-sided adapter was developed to increase the drug release surface area. DEX ointment was placed in one-sided or two-sided release adaptors coupled with 1.2 µm polyethersulfone membrane, and the drug release was studied in different USP apparatuses (I, II, and IV). RESULTS: The sample adaptor setups had a minimal impact on cumulative drug release amount per area or release rate while USP IV apparatus with agitated flow enhanced drug release rates. The USP apparatus I with a two-sided semisolid adapter, which uses membranes on both sides, showed dramatically higher cumulative drug release and discriminative release profiles when evaluating ophthalmic formulations. CONCLUSIONS: USP apparatuses and sample adaptors are critical considerations for IVRT. Two-sided semisolid adapter provides higher cumulative release, facilitating the discrimination between low drug content ophthalmic ointment formulations with good sensitivity and repeatability without affecting the drug release rate.