A Refined Thin-Film Model for Drug Dissolution Considering Radial Diffusion - Simulating Powder Dissolution.

PURPOSE: We aim to present a refined thin-film model describing the drug particle dissolution considering radial diffusion in spherical boundary layer, and to demonstrate the ability of the model to describe the dissolution behavior of bulk drug powders. METHODS: The dissolution model introduced in this study was refined from a radial diffusion-based model previously published by our laboratory (So et al. in Pharm Res. 39:907-17, 2022). The refined model was created to simulate the dissolution of bulk powders, and to account for the evolution of particle size and diffusion layer thickness during dissolution. In vitro dissolution testing, using fractionated hydrochlorothiazide powders, was employed to assess the performance of the model. RESULTS: Overall, there was a good agreement between the experimental dissolution data and the predicted dissolution profiles using the proposed model across all size fractions of hydrochlorothiazide. The model over-predicted the dissolution rate when the particles became smaller. Notably, the classic Nernst-Brunner formalism led to an under-estimation of the dissolution rate. Additionally, calculation based on the equivalent particle size derived from the specific surface area substantially over-predicted the dissolution rate. CONCLUSION: The study demonstrated the potential of the radial diffusion-based model to describe dissolution of drug powders. In contrast, the classic Nernst-Brunner equation could under-estimate drug dissolution rate, largely due to the underlying assumption of translational diffusion. Moreover, the study indicated that not all surfaces on a drug particle contribute to dissolution. Therefore, relying on the experimentally-determined specific surface area for predicting drug dissolution is not advisable.

Change in absolute neutrophil count after COVID-19 infection in patients using clozapine versus other antipsychotics.

It was reported that patients who contracted COVID-19 while taking clozapine exhibited a distinct hematological response. However, the absence of control groups made it difficult to attribute it to clozapine. The changes in absolute neutrophil counts (ANCs) during the 4 weeks after COVID-19 infection were compared between the two groups of patients with severe mental illnesses (SMIs) (49 patients using clozapine and 54 using other antipsychotics) using generalized additive modeling. Although the pattern of a transient drop in ANC followed by gradual recovery could be demonstrated in both groups, it was more pronounced in the clozapine group ( P  = 0.00025). Nevertheless, overall ANC remained at a higher level in the clozapine group. The results suggested potential interaction between clozapine and COVID-19 at the level of hematological dynamics. However, it did not necessarily indicate that such interaction is inevitably harmful or dangerous. It was more of a concern that some patients using other antipsychotics exhibited decreased ANC, which did not easily recover. Traditionally, clinicians have been concerned about the worsening of hematological side effects in clozapine patients after COVID-19 infection. However, the obtained result highlighted the necessity of hematological monitoring in patients using any type of antipsychotics for SMIs.

Beagle: a near-edge X-ray absorption fine-structure spectroscopy data processing solution for beamline experiments at Pohang Accelerator Laboratory.

Near-edge X-ray absorption fine-structure (NEXAFS) spectroscopy is a powerful tool for identifying chemical bonding states at synchrotron radiation facilities. Advances in new materials require researchers in both academia and industry to measure tens to hundreds of samples during the available beam time on a synchrotron beamline, which is typically allocated to users. Automated measurement methods, along with analysis software, have been developed for beamlines. Automated measurements facilitate high-throughput experiments and accumulate vast amounts of measured spectral data. The analysis software supports various functions for analyzing the experimental data; however, these analysis methods are complicated, and learning them can be time-consuming. To process large amounts of spectral data, a new analysis software, dedicated to NEXAFS spectroscopy, that is easy to use and can provide results in a short time is desired. Herein, the development of Beagle is described, software calculating molecular orientation from NEXAFS spectroscopy data that can report results in a short time comparable with that required to measure one sample at the beamline. It was designed to progress in a single sequence from data loading to the printing of the results with a `click of a button'. The functions of the software include recognizing the dataset, correcting the background, normalizing the plot, calculating the electron yield and determining the molecular orientation. The analysis results can be saved as {\tt{.txt}} files (spectral data), {\tt{.pdf}} files (graphic images) and Origin files (spectral data and graphic images).

Improved Therapeutic Efficacy of MT102, a New Anti-Inflammatory Agent, via a Self-Microemulsifying Drug Delivery System, in Ulcerative Colitis Mice.

MT-102 is a new anti-inflammatory agent derived from Juglans mandshurica and Isatis indigotica. Its therapeutic potential is hindered by low aqueous solubility, impacting its in vivo efficacy. Therefore, this study aimed to develop a self-microemulsifying drug delivery system (SMEDDS) for MT-102 to enhance its oral efficacy in treating ulcerative colitis. Solubility assessment in different oils, surfactants, and cosurfactants led to a SMEDDS formulation of MT-102 using Capmul MCM, Tween 80, and propylene glycol. Based on a pseudoternary phase diagram, the optimal SMEDDS composition was selected, which consisted of 15% Capmul MCM, 42.5% Tween 80, and 42.5% propylene glycol. The resulting optimized SMEDDS (SMEDDS-F1) exhibited a narrow size distribution (177.5 ± 2.80 nm) and high indirubin content (275 ± 5.58 µg/g, a biomarker). Across an acidic to neutral pH range, SMEDDS-F1 showed rapid and extensive indirubin release, with dissolution rates approximately 15-fold higher than pure MT-102. Furthermore, oral administration of SMEDDS-F1 effectively mitigated inflammatory progression and symptoms in a mouse model of ulcerative colitis, whereas pure MT-102 was ineffective. SMEDDS-F1 minimized body weight loss (less than 5%) without any significant change in colon length and the morphology of colonic tissues, compared to those of the healthy control group. In addition, oral administration of SMEDDS-F1 significantly inhibited the secretion of pro-inflammatory cytokines such as IL-6 and TNF-α. In conclusion, the SMEDDS-F1 formulation employing Capmul MCM, Tween 80, and propylene glycol (15:42.5:42.5, w/w) enhances the solubility and therapeutic efficacy of MT-102.

Effect of Hind- and Fore-Foot Eversion on Positional and Rotational Displacement of the Knee in Standing Posture.

We investigated the effects of hindfoot and forefoot eversion on the knee's positional and rotational displacement, plantar pressure, and foot discomfort in a standing posture, beyond the traditional focus on external knee adduction moments (EKAM) in lateral wedge insoles. Twenty-six healthy participants underwent hindfoot eversion from 0 to 10 degrees in 2-degree increments, and forefoot eversion from 0 degrees to the hindfoot eversion angle in 2-degree increments in a standing posture. At each eversion angle, the knee's medial displacement, EKAM's moment arm decrease, plantar pressure changes, and foot discomfort were obtained and compared across varying angles. Both hindfoot-only and entire-foot eversion led to significant medial knee displacement and the EKAM's moment arm decrease, with more pronounced effects in entire-foot eversion. At each hindfoot eversion angle, increasing forefoot eversion resulted in significant medial knee displacement and EKAM's moment arm decrease. Lower leg rotations were not significantly affected in hindfoot-only eversion but displayed significant medial tilting and internal rotation in entire-foot eversion at specific combinations. Varying eversion angles significantly influenced the forefoot pressure, with heel pressure remaining unaffected. Notably, the lateral forefoot pressure increased significantly as the forefoot eversion angle increased, particularly at higher hindfoot eversion angles. Foot discomfort increased significantly with higher eversion angles, particularly in entire-foot eversion, and also increased significantly as the forefoot eversion angle increased at higher hindfoot eversion angles. Insole configurations incorporating 6-10 degrees of hindfoot eversion and 40-60% forefoot eversion of the hindfoot angle may offer optimized biomechanical support for knee osteoarthritis patients.

A comprehensive evaluation of arginine and its derivatives as protein formulation stabilizers.

Arginine and its derivatives (such as arginine ethyl ester and acetyl arginine) have varying degrees of protein aggregation suppressor effect across different protein solutions. To understand this performance ambiguity, we evaluated the activity of arginine, acetyl arginine, and arginine ethyl ester for aggregation suppressor effect against human intravenous immunoglobulin G (IgG) solution at pH 4.8. Both arginine and its cationic derivative arginine ethyl ester in their hydrochloride salt forms significantly reduced the colloidal and conformational stability (reduced kd and Tm) of IgG. Consequently, the monomer content was decreased with an increase in subvisible particulates after agitation or thermal stress. Furthermore, compared to arginine, arginine ethyl ester with one more cationic charge and hydrochloride salt form readily precipitated IgG at temperatures higher than 25 °C. On the contrary, acetyl arginine, which mostly exists in a neutral state at pH 4.8, efficiently suppressed the formation of subvisible particles retaining a high amount of monomer owing to its higher colloidal and conformational stability. Concisely, the charged state of additives significantly impacts protein stability. This study demonstrated that contrary to popular belief, arginine and its derivatives may either enhance or suppress protein aggregation depending on their net charge and concentration.

Optimization of HPLCCAD method for simultaneous analysis of different lipids in lipid nanoparticles with analytical QbD.

Since lipid nanoparticles (LNP) have emerged as a potent drug delivery system, the objective of this study was to develop and optimize a robust high-performance liquid chromatography with charged aerosol detectors (HPLCCAD) method to simultaneously quantify different lipids in LNPs using the analytical quality by design (AQbD) approach. After defining analytical target profile (ATP), critical method attributes (CMAs) were established as a resolution between the closely eluting lipid peaks and the total analysis time. Thus, potential high-risk method parameters were identified through the initial risk assessment. These parameters were screened using Plackett-Burman design, and three critical method parameters (CMPs)-MeOH ratio, flow rate, and column temperature-were selected for further optimization. Box-Behnken design was employed to develop the quadratic models that explain the relationship between the CMPs and CMAs and to determine the optimal operating conditions. Moreover, to ensure the robustness of the developed method, a method operable design region (MODR) was established using the Monte Carlo simulation. The MODR was identified within the probability map, where the risk of failure to achieve the desired CMAs was less than 1%. The optimized method was validated according to the ICH guidelines (linearity: R2 > 0.995, accuracy: 97.15-100.48% recovery, precision: RSD < 5%) and successfully applied for the analysis of the lipid in the LNP samples. The development of the analytical method to quantify the lipids is essential for the formulation development and quality control of LNP-based drugs since the potency of LNPs is significantly dependent on the compositions and contents of the lipids in the formation.

Microfluidic-Integrated Multimodal Wearable Hybrid Patch for Wireless and Continuous Physiological Monitoring.

Despite extensive advances in wearable monitoring systems, most designs focus on the detection of physical parameters or metabolites and do not consider the integration of microfluidic channels, miniaturization, and multimodality. In this study, a combination of multimodal (biochemical and electrophysiological) biosensing and microfluidic channel-integrated patch-based wireless systems is designed and fabricated using flexible materials for improved wearability, ease of operation, and real-time and continuous monitoring. The reduced graphene oxide-based microfluidic channel-integrated glucose biosensor exhibits a good sensitivity of 19.97 (44.56 without fluidic channels) µA mM-1 cm-2 within physiological levels (10 µM-0.4 mM) with good long-term and bending stability. All the sensors in the patch are initially validated using sauna gown sweat-based on-body and real-time tests with five separate individuals who perspired three times each. Multimodal glucose and electrocardiogram (ECG) sensing, along with their real-time adjustment based on sweat pH and temperature fluctuations, optimize sensing accuracy. Laser-burned hierarchical MXene-polyvinylidene fluoride-based conductive carbon nanofiber-based dry ECG electrodes exhibit low skin contact impedance (40.5 kΩ cm2) and high-quality electrophysiological signals (signal-to-noise ratios = 23.4-32.8 dB). The developed system is utilized to accurately and wirelessly monitor the sweat glucose and ECG of a human subject engaged in physical exercise in real time.

Biophysical characterization of siRNA-loaded lipid nanoparticles with different PEG content in an aqueous system.

Although lipid nanoparticles (LNP) are potential carriers of various pharmaceutical ingredients, further investigation for maintaining their stability under various environmental stressors must be performed. This study evaluated the influence of PEGylation and stress conditions on the stability of siRNA-loaded LNPs with different concentrations of PEG (0.5 mol%; 0.5 % PEG-LNP and 1.0 mol%; 1.0 % PEG-LNP) anchored to their surface. We applied end-over-end agitation, elevated temperature, and repeated freeze and thaw (F/T) cycles as physicochemical stressors of pH and ionic strength. Dynamic light scattering (DLS), flow imaging microscopy (FIM), and ionic-exchange chromatography (IEX) were to determine the degree of aggregation and change in siRNA content. The results indicate that 0.5 % PEG-LNP resisted aggregation only at low pH levels or with salt, whereas 1.0 % PEG-LNP had increased colloidal stability except at pH 4. 0.5 % PEG-LNP withstood aggregation until 71 °C and three cycles of F/T. In contrast, 1.0 % PEG-LNP maintained colloidal stability at 90 °C and seven F/T cycles. Moreover, 1.0 % PEG-LNP had higher siRNA stability under all stress conditions. Therefore, to ensure the stability of LNP and encapsulated siRNA, the PEG concentration must be carefully controlled while considering LNPs' colloidal instability mechanisms under various stress conditions.

Comparative study between a gravity-based and peristaltic pump for intravenous infusion with respect to the generation of proteinaceous microparticles.

Subvisible particles generated during the preparation or administration of biopharmaceuticals might increase the risk of immunogenicity, inflammation, or organ dysfunction. To investigate the impact of an infusion system on the level of subvisible particles, we compared two types of infusion sets based on peristaltic movement (Medifusion DI-2000 pump) and a gravity-based infusion system (Accu-Drip) using intravenous immunoglobulin (IVIG) as a model drug. The peristaltic pump was found to be more susceptible to particle generation compared to the gravity infusion set owing to the stress generated due to constant peristaltic motion. Moreover, the 5-µm in-line filter integrated into the tubing of the gravity-based infusion set further contributed to the reduction of particles mostly in the range ≥ 10 µm. Furthermore, the filter was also able to maintain the particle level even after the pre-exposure of samples to silicone oil-lubricated syringes, drop shock, or agitation. Overall, this study suggests the need for the selection of an appropriate infusion set equipped with an in-line filter based on the sensitivity of the product.

Comparative study of lipid nanoparticle-based mRNA vaccine bioprocess with machine learning and combinatorial artificial neural network-design of experiment approach.

To develop a combinatorial artificial-neural-network design-of-experiment (ANN-DOE) model, the effect of ionizable lipid, an ionizable lipid-to-cholesterol ratio, N/P ratio, flow rate ratio (FRR), and total flow rate (TFR) on the outcome responses of mRNA-LNP vaccine were evaluated using a definitive screening design (DSD) and machine learning (ML) algorithms. Particle size (PS), PDI, zeta potential (ZP), and encapsulation efficiency (EE) of mRNA-LNP were optimized within a defined constraint (PS 40-100 nm, PDI ≤ 0.30, ZP≥(±)0.30 mV, EE ≥ 70 %), fed to ML algorithms (XGBoost, bootstrap forest, support vector machines, k-nearest neighbors, generalized regression-Lasso, ANN) and prediction was compared to ANN-DOE model. Increased FRR decreased the PS and increased ZP, while increased TFR increased PDI and ZP. Similarly, DOTAP and DOTMA produced higher ZP and EE. Particularly, a cationic ionizable lipid with an N/P ratio ≥ 6 provided a higher EE. ANN showed better predictive ability (R2 = 0.7269-0.9946), while XGBoost demonstrated better RASE (0.2833-2.9817). The ANN-DOE model outperformed both optimized ML models by R2 = 1.21 % and RASE = 43.51 % (PS prediction), R2 = 0.23 % and RASE = 3.47 % (PDI prediction), R2 = 5.73 % and RASE = 27.95 % (ZP prediction), and R2 = 0.87 % and RASE = 36.95 % (EE prediction), respectively, which demonstrated that ANN-DOE model was superior in predicting the bioprocess compared to independent models.

Dissipation of Four Typical Insecticides on Strawberries and Effects of Different Household Washing Methods.

The dissipation patterns of chlorfenapyr, cyenopyrafen, indoxacarb, and spirotetramat on strawberries and the effects of different household washing methods were investigated. A risk assessment was also conducted by monitoring the insecticide residues detected. The concentrations ranged from 0.011 to 0.27 mg/kg for chlorfenapyr, 0.064 to 0.99 mg/kg for cyenopyrafen, 0.042 to 0.53 mg/kg for indoxacarb, and from 0.25 to 1.3 mg/kg for spirotetramat, which were all below the maximum residue limits (MRLs) reported. Soaking the fruit in solution and then rinsing with running water (B) led to better residue removal (40.9 ± 23.7%) than only soaking in solution (A) (24.7 ± 22.5%). However, neither method decreased chlorfenapyr concentrations, suggesting that the physical-chemical properties of chlorfenapyr could also affect its removal on strawberries. Regarding the different washing solutions in method B, 3% vinegar (removal efficiency: 48.7%) and 3% salt (45.7%) were the most efficient, followed by 3% green tea (38.9%), and tap water only (24.6%). Additionally, the estimated risk quotients (RQs) for strawberry consumption for women were about 1.5 times higher than those observed for men, but both were lower than 1, suggesting minimal risk to humans.

Evaluation of subvisible particles in human immunoglobulin and lipid nanoparticles repackaged from a multi-dose vial using plastic syringes.

The multi-dose vial (MDV) is widely used for most biopharmaceuticals that are repackaged in plastic syringes before use. However, subvisible particle formation with the use of plastic syringes containing silicone oil (SO syringes) for handling therapeutic proteins can be problematic. This study aimed to evaluate the extent of and trends in microparticle (>1 µm) formation and accumulation in repackaged syringes from MDVs containing human immunoglobulin (IgG) and lipid nanoparticles (LNPs). Light obscuration (LO) and flow imaging (FI) were used to analyze the microparticles. The number of microparticles observed with the use SO syringes was greater than that with SO-free syringes, and the number of microparticles continuously increased as did the number of times of repackaging in syringes for both drugs. However, a large variation was observed across different brands of SO syringes. In contrast, using a different technique of drug withdrawal from the vial significantly reduced the number of microparticles. Furthermore, the use of filter-integrated needles or the inclusion of stabilizers such as acetyl-arginine and Tween 20 into the formulation also helped reduce particle formation.

Accuracy of Seismic Response Evaluation of Two-Dimensional Analysis Model with Rigid Joints for RC Frame Buildings.

Three- or two-dimensional (2D) numerical models are used for the evaluation of the seismic performance of reinforced concrete (RC) buildings. This study examines a 2D numerical model for a specimen used in a full-scale four-story RC shaking-table test and evaluates the accuracy of the seismic response of the 2D numerical model, which is composed of a square fiber section model for the columns, a T-shape fiber section model for the beam and slab, and a rigid joint model for the beam-column joint. A parametric analysis of the effective slab width is performed to analyze its effects on the modal shape and natural period. The results suggest that the primary natural period of the considered model is almost identical to that associated with the experimental results. The applicability of the 2D numerical model for estimating the seismic response of the structure is established. By comparing the results of the seismic analysis and the experiment in the 50% amplitude of the JMA-Kobe wave, which corresponds to slightly exceeding VII on the modified Mercalli intensity scale, the root-mean-square percentage error of the 2D numerical model is 1.03% for the floor acceleration and 4.7% for the inter-story drift. Thus, the analytical model used in this study has sufficient accuracy in evaluating the seismic performance of buildings constructed in regions with a maximum seismic intensity of VII.

Enhanced protein aggregation suppressor activity of N-acetyl-l-arginine for agitation-induced aggregation with silicone oil and its impact on innate immune responses.

Previously, N-acetyl-l-arginine (NALA) suppressed the aggregation of intravenous immunoglobulins (IVIG) more effectively and with a minimum decrease in transition temperature (Tm) than arginine monohydrochloride. In this study, we performed a comparative study with etanercept (commercial product: Enbrel®), where 25 mM arginine monohydrochloride (arginine) was added to the prefilled syringe. The biophysical properties were investigated using differential scanning calorimetry (DSC), dynamic light scattering (DLS), size-exclusion chromatography (SEC), and flow-imaging microscopy (FI). NALA retained the transition temperature of etanercept better than arginine, where arginine significantly reduced the Tm by increasing its concentration. End-over-end rotation was applied to each formulation for 5 days to accelerate protein aggregation and subvisible particle formation. Higher monomeric content was retained with NALA with a decrease in particle level. Higher aggregation onset temperature (Tagg) was detected for etanercept with NALA than arginine. The results of this comparative study were consistent with previous study, suggesting that NALA could be a better excipient for liquid protein formulations. Agitated IVIG and etanercept were injected into C57BL/6J female mice to observe immunogenic response after 24 h. In the presence of silicone oil, NALA dramatically reduced IL-1 expression, implying that decreased aggregation was related to reduced immunogenicity of both etanercept and IVIG.

Enhanced Oral Bioavailability of MT-102, a New Anti-inflammatory Agent, via a Ternary Solid Dispersion Formulation.

This study aimed to develop a solid dispersion (SD) of MT-102, a new anti-inflammatory agent, to improve its oral bioavailability. The ternary SD formulations of MT-102 (a poorly soluble extract of Isatis indigotica and Juglans mandshurica) were prepared using a solvent evaporation method with various drug/excipient ratios. Following that, the effectiveness of various SDs as an oral formulation of MT-102 was investigated using indirubin as a marker component. By forming SDs with hydrophilic polymers, the aqueous solubility of indirubin was significantly increased. SD-F4, containing drug, poloxamer 407 (P407), and povidone K30 (PVP K30) at a 1:2:2 weight ratio, exhibited the optimal dissolution profiles in the acidic to neutral pH range. Compared to pure MT-102 and a physical mixture, SD-F4 increased indirubin's dissolution from MT-102 by approximately 9.86-fold and 2.21-fold, respectively. Additionally, SD-F4 caused the sticky extract to solidify, resulting in improved flowability and handling. As a result, compared to pure MT-102, the oral administration of SD-F4 significantly improved the systemic exposure of MT-102 in rats. Overall, the ternary SD formulation of MT-102 with a blended mixture of P407 and PVP K30 appeared to be effective at improving the dissolution and oral absorption of MT-102.

Nature and Extent of Physical Comorbidities Among Korean Patients With Mental Illnesses: Pairwise and Network Analysis Based on Health Insurance Claims Data.

OBJECTIVE: The nature of physical comorbidities in patients with mental illness may differ according to diagnosis and personal characteristics. We investigated this complexity by conventional logistic regression and network analysis. METHODS: A health insurance claims data in Korea was analyzed. For every combination of psychiatric and physical diagnoses, odds ratios were calculated adjusting age and sex. From the patient-diagnosis data, a network of diagnoses was constructed using Jaccard coefficient as the index of comorbidity. RESULTS: In 1,017,024 individuals, 77,447 (7.6%) were diagnosed with mental illnesses. The number of physical diagnoses among them was 11.2, which was 1.6 times higher than non-psychiatric groups. The most noticeable associations were 1) neurotic illnesses with gastrointestinal/pain disorders and 2) dementia with fracture, Parkinson's disease, and cerebrovascular accidents. Unexpectedly, the diagnosis of metabolic syndrome was only scarcely found in patients with severe mental illnesses (SMIs). However, implicit associations between metabolic syndrome and SMIs were suggested in comorbidity networks. CONCLUSION: Physical comorbidities in patients with mental illnesses were more extensive than those with other disease categories. However, the result raised questions as to whether the medical resources were being diverted to less serious conditions than more urgent conditions in patients with SMIs.

Functional ligands for improving anticancer drug therapy: current status and applications to drug delivery systems.

Conventional chemotherapy lacking target selectivity often leads to severe side effects, limiting the effectiveness of chemotherapy. Therefore, drug delivery systems ensuring both selective drug release and efficient intracellular uptake at the target sites are highly demanded in chemotherapy to improve the quality of life of patients with low toxicity. One of the effective approaches for tumor-selective drug delivery is the adoption of functional ligands that can interact with specific receptors overexpressed in malignant cancer cells. Various functional ligands including folic acid, hyaluronic acid, transferrin, peptides, and antibodies, have been extensively explored to develop tumor-selective drug delivery systems. Furthermore, cell-penetrating peptides or ligands for tight junction opening are also actively pursued to improve the intracellular trafficking of anticancer drugs. Sometimes, multiple ligands with different roles are used in combination to enhance the cellular uptake as well as target selectivity of anticancer drugs. In this review, the current status of various functional ligands applicable to improve the effectiveness of cancer chemotherapy is overviewed with a focus on their roles, characteristics, and preclinical/clinical applications.

New long-acting injectable microspheres prepared by IVL-DrugFluidic™ system: 1-month and 3-month in vivo drug delivery of leuprolide.

The microspheres for 1-month (PLGA-based) and 3-month (PLA-based) drug releases of leuprolide were manufactured using an IVL-DrugFluidic™ system and their morphology, particle size and distribution, and encapsulation efficiency were compared with the commercialized products. In vivo test was also conducted to monitor the amount of leuprolide and testosterone in plasma after a single subcutaneous injection in male Sprague-Dawley (SD) rats and male Beagle dogs. The median diameter, span value, drug loading, and encapsulation efficiency of PLGA-based microspheres (63.29 µm, 0.26, 13.15%, and 78.90%, respectively) and PLA-based microspheres (80.28 µm, 0.21, 14.42%, and 86.50%, respectively) demonstrated narrow particle size distribution (monodispersed) and efficient drug loading/encapsulation efficiency. Both the microspheres exhibited a desired time-dependent drug release profile and reduced initial burst release by 16-fold in SD rats and 240-fold in Beagle dogs compared to Leuplin DPS®. Moreover, the testosterone level in plasma was suppressed to < 0.50 ng/mL after 28 days with a steady plasma drug concentration. The results suggested that newly developed leuprolide-loaded microspheres produced by the IVL-DrugFluidic™ system could provide extended drug release with advantages such as reduced initial burst release and testosterone level suppression, along with steady plasma drug concentration, over the existing products.

Correlation of Solubility Thermodynamics of Glibenclamide with Recrystallization and In Vitro Release Profile.

The solubility of glibenclamide was evaluated in DMSO, NMP, 1,4-dioxane, PEG 400, Transcutol® HP, water, and aqueous mixtures (T = 293.15~323.15 K). It was then recrystallized to solvate and compressed into tablets, of which 30-day stability and dissolution was studied. It had a higher solubility in 1,4-dioxane, DMSO, NMP (Xexp = 2.30 × 103, 3.08 × 104, 2.90 × 104) at 323.15 K, its mixture (Xexp = 1.93 × 103, 1.89 × 104, 1.58 × 104) at 298.15 K, and 1,4-dioxane (w) + water (1-w) mixture ratio of w = 0.8 (Xexp = 3.74 × 103) at 323.15 K. Modified Apelblat (RMSD ≤ 0.519) and CNIBS/R-K model (RMSD ≤ 0.358) suggested good comparability with the experimental solubility. The minimum value of ΔG° vs ΔH° at 0.70 < x2 < 0.80 suggested higher solubility at that molar concentration. Based on the solubility, it was recrystallized into the solvate, which was granulated and compressed into tablets. Among the studied solvates, the tablets of glibenclamide dioxane solvate had a higher initial (95.51%) and 30-day (93.74%) dissolution compared to glibenclamide reference (28.93%). There was no stability issue even after granulation, drying, or at pH 7.4. Thus, glibenclamide dioxane solvate could be an alternative form to improve the molecule's properties.