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).

Control Strategy for Excipient Variability in the Quality by Design Approach Using Statistical Analysis and Predictive Model: Effect of Microcrystalline Cellulose Variability on Design Space.

Although various quality by design (QbD) approaches have been used to establish a design space to obtain robust drug formulation and process parameters, the effect of excipient variability on the design space and drug product quality is unclear. In this study, the effect of microcrystalline cellulose (MCC) variability on drug product quality was examined using a design space for immediate-release tablets of amlodipine besylate. MCC variability was assessed by altering the manufacturer and grade.

A formulation development strategy for dual-release bilayer tablets: An integrated approach of quality by design and a placebo layer.

Although dual-release mechanism bilayer tablets containing one drug in both immediate- and sustained-release layers are widely used to improve therapeutic efficiency, studies quantitatively analyzing the drug amount released from each layer and the mutual effect of each layer's mechanical properties on drug product quality are limited. Here, the formulation of a dual-release bilayer tablet containing sarpogrelate HCl was optimized with a placebo layer and quality by design (QbD) approach. The placebo layer was developed to replace the active pharmaceutical ingredient and its mechanical properties were evaluated.

Development of a Robust Control Strategy for Fixed-Dose Combination Bilayer Tablets with Integrated Quality by Design, Statistical, and Process Analytical Technology Approach.

Control strategy and quality by design (QbD) are widely used to develop pharmaceutical products and improve drug quality; however, studies on fixed-dose combination (FDC) bilayer tablets are limited. In this study, the bilayer tablet consisted of high-dose metformin HCl in a sustained-release layer and low-dose dapagliflozin l-proline in an immediate-release layer. The formulation and process of each layer were optimized using the QbD approach.

Off-label use of plastic syringes with silicone oil for intravenous infusion bags of antibodies.

The formation of particulates in post-manufacture biopharmaceuticals continues to be a major concern in medical treatment. This study was designed to evaluate the content of micro-sized particles using flow imaging of antibodies in intravenous infusion bags. Intravenous immunoglobulin (IVIG) and Avastin® were selected as model drugs and plastic syringes with and without silicone oil (SO) were used to transfer the drugs into the bags (0.

Process Analytical Technology Tools for Monitoring Pharmaceutical Unit Operations: A Control Strategy for Continuous Process Verification.

Various frameworks and methods, such as quality by design (QbD), real time release test (RTRT), and continuous process verification (CPV), have been introduced to improve drug product quality in the pharmaceutical industry. The methods recognize that an appropriate combination of process controls and predefined material attributes and intermediate quality attributes (IQAs) during processing may provide greater assurance of product quality than end-product testing. The efficient analysis method to monitor the relationship between process and quality should be used.

Pharmacokinetics of eperisone following oral administration in healthy Korean volunteers.

Eperisone is an oral muscle relaxant used to treat musculoskeletal diseases, which exhibits high pharmacokinetic (PK) variability in bioequivalence studies. The aim of this study was to characterize the PKs of eperisone following its oral administration to Korean volunteers through the conduct of a noncompartmental and population analysis. A total of 360 concentration-time measurements collected on two separate occasions from 15 healthy volunteers during a bioequivalent study of eperisone 50 mg (Murex ) were used in the PK analysis.

Enhanced Oral Bioavailability of Resveratrol by Using Neutralized Eudragit E Solid Dispersion Prepared via Spray Drying.

In this study, we designed amorphous solid dispersions based on Eudragit E/HCl (neutralized Eudragit E using hydrochloric acid) to maximize the dissolution of -resveratrol. Solid-state characterization of amorphous solid dispersions of -resveratrol was performed using powder X-ray diffraction, scanning electron microscopy, and particle size measurements. In addition, an in vitro dissolution study and an in vivo pharmacokinetic study in rats were carried out.

Control Strategy for Process Development of High-Shear Wet Granulation and Roller Compaction to Prepare a Combination Drug Using Integrated Quality by Design.

In this study, we developed a control strategy for a drug product prepared by high-shear wet granulation and roller compaction using integrated quality by design (QbD). During the first and second stages, we optimized the process parameters through the design of experiments and identified the intermediate quality attributes (IQAs) and critical quality attributes (CQAs) relationship, respectively. In the first stage, we conducted an initial risk assessment by selecting critical process parameters with high impact on IQAs and CQAs and confirmed the correlation between control and response factors.

Model-Based Scale-Up Methodologies for Pharmaceutical Granulation.

In the pharmaceutical industry, it is a major challenge to maintain consistent quality of drug products when the batch scale of a process is changed from a laboratory scale to a pilot or commercial scale. Generally, a pharmaceutical manufacturing process involves various unit operations, such as blending, granulation, milling, tableting and coating and the process parameters of a unit operation have significant effects on the quality of the drug product. Depending on the change in batch scale, various process parameters should be strategically controlled to ensure consistent quality attributes of a drug product.

Effects of granulation process variables on the physical properties of dosage forms by combination of experimental design and principal component analysis.

The current study was to understand how process variables of high shear wet granulations affect physical properties of granules and tablets. The knowledge gained was intended to be used for Quality-by-Design based process design and optimization. The variables were selected based on the risk assessment as impeller speed, liquid addition rate, and wet massing time.

New Preclinical Development of a c-Met Inhibitor and Its Combined Anti-Tumor Effect in c-Met-Amplified NSCLC.

c-Met is a receptor tyrosine kinase with no commercially available product despite being a pivotal target in cancer progression. Unlike other c-Met inhibitors that fail clinically, ABN401 is a newly synthesized c-Met inhibitor that is not potentially degraded by aldehyde oxidase (AO) in human liver cytosol. This study aimed to determine the physicochemical stability, pharmacokinetics in beagle dogs, and therapeutic effect of ABN401 in a c-Met-amplified non-small-cell lung cancer (NSCLC) patient-derived xenograft (PDX) model.

Development of a Resveratrol Nanosuspension Using the Antisolvent Precipitation Method without Solvent Removal, Based on a Quality by Design (QbD) Approach.

The purpose of this study was to develop a resveratrol nanosuspension with enhanced oral bioavailability, based on an understanding of the formulation and process parameters of nanosuspensions and using a quality by design (QbD) approach. Particularly, the antisolvent method, which requires no solvent removal and no heating, is newly applied to prepare resveratrol nanosuspension. To ensure the quality of the resveratrol nanosuspensions, a quality target product profile (QTPP) was defined.

Pharmacokinetic Study of a Soft Gelatin Capsule and a Solid-Supersaturatable SMEDDS Tablet of Dutasteride in Beagle Dogs.

Background And Objective: Dutasteride, an analog of testosterone, a 5α-reductase inhibitor is widely used in the treatment of moderate to severe symptomatic benign prostatic hyperplasia. The aim of this study was to compare the pharmacokinetic characteristics of dutasteride in beagle dogs after oral administration of a conventional soft gelatin capsule (Avodart) and a novel solid-supersaturatable soft-microemulsifying drug delivery system (SMEDDS) tablet.

Methods: In this comparative dissolution study, the dissolution of dutasteride was pH-independent for both formulations.

Preparation and Evaluation of Resveratrol-Loaded Composite Nanoparticles Using a Supercritical Fluid Technology for Enhanced Oral and Skin Delivery.

We created composite nanoparticles containing hydrophilic additives using a supercritical antisolvent (SAS) process to increase the solubility and dissolution properties of -resveratrol for application in oral and skin delivery. Physicochemical properties of -resveratrol-loaded composite nanoparticles were characterized. In addition, an in vitro dissolution-permeation study, an in vivo pharmacokinetic study in rats, and an ex vivo skin permeation study in rats were performed.

Application of the Discrete Element Method for Manufacturing Process Simulation in the Pharmaceutical Industry.

Process simulation using mathematical modeling tools is becoming more common in the pharmaceutical industry. A mechanistic model is a mathematical modeling tool that can enhance process understanding, reduce experimentation cost and improve product quality. A commonly used mechanistic modeling approach for powder is the discrete element method (DEM).

Scale-Up Strategy in Quality by Design Approach for Pharmaceutical Blending Process with Discrete Element Method Simulation.

An approach combining quality by design (QbD) and the discrete element method (DEM) is proposed to establish an effective scale-up strategy for the blending process of an amlodipine formulation prepared by the direct compression method. Critical process parameters (CPPs) for intermediate critical quality attributes (IQAs) were identified using risk assessment (RA) in the QbD approach. A Box-Behnken design was applied to obtain the operating space for a laboratory-scale.

Comprehensive Study of Intermediate and Critical Quality Attributes for Process Control of High-Shear Wet Granulation Using Multivariate Analysis and The Quality by Design Approach.

A robust manufacturing process and the relationship between intermediate quality attributes (IQAs), critical quality attributes (CQAs), and critical process parameters (CPPs) for high-shear wet granulation was determined in this study. Based on quality by the design (QbD) approach, IQAs, CQAs, and CPPs of a telmisartan tablet prepared by high-shear wet granulation were determined and then analyzed with multivariate analysis (MVA) to evaluate mutual interactions between IQAs, CQAs, and CPPs. The effects of the CPPs on the IQAs and CQAs were quantitatively predicted with empirical models of best fit.

Quality by Design (QbD) approach to optimize the formulation of a bilayer combination tablet (Telmiduo) manufactured via high shear wet granulation.

A bilayer tablet, which consisted of telmisartan and amlodipine besylate, was formulated based on a Quality by Design (QbD) approach. The control and response factors were determined based on primary knowledge and the target values of the control tablet (Twynsta). A D-optimal mixture design was used to obtain the optimal formulations in terms of D-mannitol, crospovidone, and MCC for the telmisartan layer, and CCM-Na, PVP K25, and Prosolv for the amlodipine layer.

A new lignan and a new alkaloid, and α-glucosidase inhibitory compounds from the grains of Echinochloa utilis Ohwi & Yabuno.

A new lignan, utilisin (1), and a new alkaloid, echinoutilin (2), together with eleven known compounds 3-13 were isolated from the grains of Echinochloa utilis Ohwi & Yabuno. Their structures were identified through the analysis of spectroscopic data. The absolute configuration of 2 was determined by Mosher's method.

Formulation Optimization and in Vitro Characterization of Orally Disintegrating Films Using a Factorial Design and Mathematical Modeling for Drug Release.

Even though experimental designs are becoming popular especially for conventional dosage forms, limited studies have been performed to optimize formulations of orally disintegrating films (ODFs). This study aimed to evaluate sildenafil citrate-loaded ODFs for a controlled release with hydroxypropyl methylcellulose as a film-forming polymer. A factorial design was utilized for optimization with three control factors: ethanol ratio, plasticizer ratio, and the type of plasticizer.

A novel experimental design method to optimize hydrophilic matrix formulations with drug release profiles and mechanical properties.

To investigate the effects of hydrophilic polymers on the matrix system, an experimental design method was developed to integrate response surface methodology and the time series modeling. Moreover, the relationships among polymers on the matrix system were studied with the evaluation of physical properties including water uptake, mass loss, diffusion, and gelling index. A mixture simplex lattice design was proposed while considering eight input control factors: Polyethylene glycol 6000 (x1 ), polyethylene oxide (PEO) N-10 (x2 ), PEO 301 (x3 ), PEO coagulant (x4 ), PEO 303 (x5 ), hydroxypropyl methylcellulose (HPMC) 100SR (x6 ), HPMC 4000SR (x7 ), and HPMC 10(5) SR (x8 ).

Bioequivalence of tacrolimus formulations with different dynamic solubility and in-vitro dissolution profiles.

This study was to evaluate the pharmacokinetics and bioequivalence of two tacrolimus formulations which had different in vitro drug release profiles. Dynamic solubility, in vitro dissolution profiles of the two formulations, and their influence on pharmacokinetics were examined. The male volunteers were randomly assigned to receive a single 1-mg capsule of the test or reference formulation and pharmacokinetic parameters were determined using a noncompartmental method.

Comprehensive evaluation of layer separation tendency of novel three-layered tablets with geometric and mechanical properties.

The layer separation tendency of a novel three-layered matrix tablet was investigated according to various physical properties and novel experiments. Even though layer separation did not occur during manufacturing process and storage, it was observed during a dissolution test depending on the mid-layer formulation. According to the powder properties of the mid-layer substances, Form A, which had higher porosity and lower density than Form B, displayed a tendency of layer separation.