Chulhun Park

Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs.

Over 40% of active pharmaceutical ingredients (API) in development pipelines are poorly water-soluble drugs which limit formulation approaches, clinical application and marketability because of their low dissolution and bioavailability. Solid dispersion has been considered one of the major advancements in overcoming these issues with several successfully marketed products. A number of key references that describe state-of-the-art technologies have been collected in this review, which addresses various pharmaceutical strategies and future visions for the solubilization of poorly water-soluble drugs according to the four generations of solid dispersions. This article reviews critical aspects and recent advances in formulation, preparation and characterization of solid dispersions as well as in-depth pharmaceutical solutions to overcome some problems and issues that limit the development and marketability of solid dispersion products.

Optimization of erythritol production by Candida magnoliae in fed-batch culture

A two-stage fed-batch process was designed to enhance erythritol productivity by the mutant strain of Candida magnoliae. The first stage (or growth stage) was performed in the fed-batch mode where the growth medium was fed when the pH of the culture broth dropped below 4.5. The second stage (or production stage) was started with addition of glucose powder into the culture broth when the cell mass reached about 75 g dry cell weight l−1. When the initial glucose concentration was adjusted to 400 g l−1 in the production stage, 2.8 g l−1 h−1 of overall erythritol productivity and 41% of erythritol conversion yield were achieved, which represented a fivefold increase in erythritol productivity compared with the simple batch fermentation process. A high glucose concentration in the production phase resulted in formation of organic acids including citrate and butyrate. An increase in dissolved oxygen level caused formation of gluconic acid instead of citric acid. Journal of Industrial Microbiology & Biotechnology (2000) 25, 100–103.

New method and characterization of self-assembled gelatin–oleic nanoparticles using a desolvation method via carbodiimide/N-hydroxysuccinimide (EDC/NHS) reaction

In this study, we investigated a new method for the preparation of gelatin-oleic conjugate (GOC) as an amphiphilic biomaterial to load model anti-cancer drugs into self-assembled nanoparticles (NPs). Oleic acid (OA) was covalently bound to gelatin via carbodiimide/N-hydroxysuccinimide (EDC/NHS) reaction in water-ethanol cosolvent to form a GOC. Fourier transform infrared (FT-IR) spectroscopy and proton nuclear magnetic resonance ((1)H NMR) clearly indicated the successful synthesis of GOC. The percentage of gelatin amino groups reacted with OA was up to 50% as determined using the 2,4,6-trinitrobenzene sulfonic acid (TNBS) method. Subsequently, gelatin-oleic nanoparticles (GONs) were prepared using a desolvation method with glutaraldehyde or genipin used as a crosslinker for comparison. Irinotecan hydrochloride (IRT) was used as a model drug to load into GONs using incubation or an in-process adding method for comparison. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) data showed that the sizes of GONs and IRT-loaded GONs (IRT-GONs) were below 250 nm. The zeta potentials of the GONs and irinotecan-loaded IRT-GONs were below -20 mV, which was found to be stable in suspension against the aggregation process. The incubation method was more suitable for drug loading because it did not affect the process of GON formation and thus did not increase their size much compared to the change in size with the in-process adding method. The lipophilic property of the oleic moiety in the GOC increased the affinity between GOC molecules, thus reducing the amount of crosslinking agents needed to stabilize GONs compared to gelatin nanoparticles (GNs). As novel approaches for the synthesis of protein-fatty acid complexes, chemical reaction has been suggested for the synthesis of GOC. The above results show that GOC synthesized via new method is a promising biomaterial based upon preparation of nanoparticles.

Effect of biomimetic shear stress on intracellular uptake and cell-killing efficiency of doxorubicin in a free and liposomal formulation

Shear stress could be considered in the context of cellular uptake and cell-killing efficiency. Thus, mimicking the dynamic characteristics of in vivo environment is important in targeted drug delivery. We investigated the intracellular uptake and cell-killing efficiency of doxorubicin (DOX) in a free and liposomal form (Doxil(®)) under biomimetic shear stress to mimic in vivo environment. In this dynamic environment, cells demonstrated significantly higher fluorescence intensity than that of the static environment, and fluorescence microscopy images indicated increased intracellular uptake of DOX in the presence of fluidic shear stress. In cells treated with free DOX and liposomal Doxil(®), cell-killing efficiency was affected by shear stress. Taken together, shear stress, affecting drug uptake and cell-killing efficiency, is important in intracellular drug targeting.

Fattigation-platform nanoparticles using apo-transferrin stearic acid as a core for receptor-oriented cancer targeting

A major hurdle in cancer treatment is the precise targeting of drugs to the cancer site. As many cancer cells overexpress the transferrin receptor (TfR), the transferrin (Tf)-TfR interaction is widely exploited to target cancer cells. In this study, novel amphiphilic apo-Tf stearic acid (TfS) conjugates were prepared and characterized by Fourier transform infrared (FTIR) spectroscopy, matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry, and trinitrobenzenesulfonic acid (TNBS) assay. The prepared TfS conjugates were readily self-assembled in water to form nanoparticles (NPs), consisting of TfS as a core of NPs, whose sizes and zeta potentials were determined by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and a particle size analyzer. Hydrophilic water-soluble doxorubicin (DOX) was chosen as a model drug. DOX-loaded TfS NPs (NP+DOX), prepared by the adsorption of DOX on the NP surface via the incubation method, were analyzed for their cell targeting and killing efficiencies in TfR-overexpressing A549 and HCT116 cell lines by MTT assay, confocal microscopy, and fluorescence assisted cell sorting (flow cytometry). The data showed that NP+DOX exhibited improved cancer cell targeting and killing properties compared to that reported for free DOX. Further, the cytotoxic efficiency of NP+DOX was comparable to that of PEGylated liposomal product, Doxil®, while its cellular uptake was higher than that of Doxil®. Thus, this novel receptor-based TfS NP drug delivery system has great potential to target TfR-overexpressing cancer cells without off-target effects.

Design and evaluation of clickable gelatin-oleic nanoparticles using fattigation-platform for cancer therapy

ABSTRACT The principles of bioorthogonal click chemistry and metabolic glycoengineering were applied to produce targeted anti‐cancer drug delivery via fattigation‐platform‐based gelatin‐oleic nanoparticles. A sialic acid precursor (Ac4ManNAz) was introduced to the cell surface. Gelatin and oleic acid were conjugated by 1‐(3‐dimethylaminopropyl)‐3‐ethylcarbodiimide hydrochloride/N‐hydroxysuccinimide (EDC/NHS) chemistry with the subsequent covalent attachment of dibenzocyclooctyne (DBCO) in a click reaction on the cell surface. The physicochemical properties, drug release, in vitro cytotoxicity, and cellular uptake of DBCO‐conjugated gelatin oleic nanoparticles (GON‐DBCO; particle size, ˜240nm; zeta potential, 6mV) were evaluated. Doxorubicin (DOX) was used as a model drug and compared with the reference product, Caelyx®. A549 and MCF‐7 cell lines were used for the in vitro studies. GON‐DBCO showed high DOX loading and encapsulation efficiencies. In A549 cells, the IC50 value for GON‐DBCO‐DOX (1.29&mgr;g/ml) was six times lower than that of Caelyx® (10.54&mgr;g/ml); in MCF‐7 cells, the IC50 values were 1.78&mgr;g/ml and 2.84&mgr;g/ml, respectively. Confocal microscopy confirmed the click reaction between GON‐DBCO and Ac4ManNAz on the cell surface. Flow cytometry data revealed that the intracellular uptake of GON‐DBCO‐DOX was approximately two times greater than that of GON‐DOX and Caelyx®. Thus, the newly designed GON‐DBCO‐DOX provided a safe and efficient drug delivery system to actively target the anticancer agents.

Biomimetic shear stress and nanoparticulate drug delivery

Fluidic shear stress generated by fluid flow in human body contributes to the interactions between nanoparticles (NPs) and cells and may affect cellular distribution and delivery of NPs. Furthermore, different NPs properties may differently influence the cellular delivery and targeting of NPs under the in vivo dynamic environments. Thus, we reviewed and discussed how fluidic shear stress affects to drug delivery and cellular distribution of diverse NPs under the biomimetic microfluidic shear stress. Among different physicochemical properties of NPs, size, shape, material type and surface functionality, and surface charge of NPs are critical factors to cellular uptake in presence of fluidic shear stress in dynamic cellular environment. From previous studies, it suggested that fluidic shear stress stimulated specific endocytosis and prompted cell signaling pathway. The cellular interactions between NPs and cells in drug delivery should be carefully investigated in presence of shear stress which is one of critical factors to show the difference of in vitro and in vivo drug distribution and therapy. The shear-activated drug delivery using NPs were also the scope of this review.

Design of fixed dose combination and physicochemical characterization of enteric-coated bilayer tablet with circadian rhythmic variations containing telmisartan and pravastatin sodium

The aim of this study was to investigate a fixed dose combination (FDC) of telmisartan (TEL) and pravastatin sodium (PRA) in enteric-coated bilayer tablets, which was designed for once-daily bedtime dose in order to match circadian rhythmic variations of hypertension and cholesterol synthesis and optimize the patient friendly dosing treatment. Due to the poor aqueous solubility of TEL, ternary solid dispersions (SD) consisting of TEL, polyethylene glycol 6000 (PEG 6000) and magnesium oxide (MgO) were designed to enhance its dissolution rate in intestinal fluid. MgO was added as an effective alkalizer to maintain the high microenvironmental pH of the saturated solution in the immediate vicinity of TEL particles because TEL is known to be ionizable but poorly soluble in intestinal fluid. In contrast, PRA is known to be very unstable in low pH conditions. In the SD system, TEL was present in an amorphous structure and formed an intermolecular hydrogen bonding with MgO, giving complete drug release without precipitation in intestinal fluid. In addition, the amount of hydrophilic carrier (PEG 6000) was also a factor. In the design of tablet formulation, the diluents and superdisintegrants could play a key role in release profiles. Then, to fulfill the unmet needs of the two model drugs and match circadian rhythmic variations of hypertension and cholesterol synthesis, enteric-coated bilayer tablet consisting of TEL SD and PRA was finally prepared using Acryl-EZE® as an enteric coating material. Prior to enteric coating, a seal coating layer (Opadry®, 2% weight gains) was firstly introduced to separate the core bilayer tablet from the acidic enteric coating polymers to avoid premature degradation. Dissolution profiles of finished tablets revealed that enteric-coated bilayer tablets with 6% weight gains remained intact in acidic media (pH 1.0) for 2h and then released drugs completely within 45min after switching to the intestinal media (pH 6.8). It was observed that enteric-coated bilayer tablets were stable during 3 month under the accelerated condition of 40°C/75% RH. The delayed drug release and bedtime dosage regimen using enteric-coated bilayer tablet containing TEL and PRA, matching the circadian rhythms of hypertension and hyperlipidemia can provide therapeutic benefits for elderly patients in terms of maximizing the therapeutic effects.

Modulation of microenvironmental pH for dual release and reduced in vivo gastrointestinal bleeding of aceclofenac using hydroxypropyl methylcellulose-based bilayered matrix tablet

&NA; This study was designed to develop a once‐daily controlled‐release matrix tablet of aceclofenac 200 mg (AFC‐CR) with dual release characteristics and to investigate the role of an alkalizer in enhancing drug solubility and reducing the occurrence of gastroduodenal mucosal lesions. Two formulation approaches were employed, namely a monolithic matrix tablet and a bilayered tablet. In vitro dissolution studies of AFC‐CR tablets were carried out in simulated intestinal fluid (pH 6.8 buffer). The in vivo pharmacokinetic studies and drug safety of the immediate‐release reference tablet Airtal® 100 mg (Daewoong Co., Korea) and the optimized AFC‐CR tablet were compared in beagle dogs under fasted condition. The optimally selected AFC‐CR formulation displayed the desired dual release characteristics in simulated intestinal fluid with satisfactory micromeritic properties. The swelling action of the optimal matrix tablet, which was visualized by near‐infrared (NIR) chemical imaging, occurred rapidly following hydration. Incorporation of sodium carbonate (Na2CO3) was found to enhance the release rate of the AFC‐CR bilayered tablets at early stages and increase the microenvironmental pH (pHM). A pharmacokinetic study in beagle dogs indicated a higher drug plasma concentration and a sustained‐release pattern for the AFC‐CR tablet compared to the Airtal® tablet. AFC‐CR was also superior to Airtal® in terms of in vivo drug safety, since no beagle dog receiving AFC‐CR experienced gastrointestinal bleeding. The significant enhancement of drug safety was attributed to the size reduction and the increase of pHM of drug particles by means of incorporation of the alkalizer. These findings provide a scientific rationale for developing a novel controlled‐release matrix tablet with enhanced patient compliance and better pain control. Graphical abstract Reduced gastrointestinal bleeding obtained in the alkalizer‐containing controlled‐release matrix tablet of aceclofenac tablet Figure. No caption available.

New blends of hydroxypropylmethylcellulose and Gelucire 44/14: physical property and controlled release of drugs with different solubility

New blends of hydroxypropylmethylcellulose (HPMC, 4000 cps) and Gelucire®44/14 (GE) were utilized to modulate the solubility and release rate of poorly water-soluble drug in a controlled manner. HPMC was used as sustained release polymer while GE was blended as a solubilizing carrier. The binary blends of HPMC and GE with proportional ratios (0, 25, 50, 70, 100%) were prepared by three different preparation methods: simple physical mixing, solvent evaporation and hot-melting. The physical properties such as surface morphology, thermal behavior and crystallinity pattern of the binary blends without loading drugs were then characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD), respectively. Finally, the ternary solid dispersions (SD) were prepared by dispersing model drugs in a binary blend. Two model drugs, water-soluble acetaminophen (AAP) and poorly water-soluble pranlukast (PLK) were applied to the binary blends. In case of AAP, HPMC retarded release rate but GE had no significant solubilizing effect due to the high AAP solubility, In contrast, the release rate of PLK was efficiently modulated release rate in a controlled manner with an aid of HPMC and GE. Surely, GE could play a key role in enhancing the dissolution rate while HPMC efficiently controlled release rate of drugs without losing drug crystallinity.