Eun Seok Park

Advanced spray-dried design, physicochemical characterization, and aerosol dispersion performance of vancomycin and clarithromycin multifunctional controlled release particles for targeted respiratory delivery as dry powder inhalation aerosols.

Respirable microparticles/nanoparticles of the antibiotics vancomycin (VCM) and clarithromycin (CLM) were successfully designed and developed by novel organic solution advanced spray drying from methanol solution. Formulation optimization was achieved through statistical experimental design of pump feeding rates of 25% (Low P), 50% (Medium P) and 75% (High P). Systematic and comprehensive physicochemical characterization and imaging were carried out using scanning electron microscopy (SEM), hot-stage microscopy (HSM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Karl Fischer titration (KFT), laser size diffraction (LSD), gravimetric vapor sorption (GVS), confocal Raman microscopy (CRM) and spectroscopy for chemical imaging mapping. These novel spray-dried (SD) microparticulate/nanoparticulate dry powders displayed excellent aerosol dispersion performance as dry powder inhalers (DPIs) with high values in emitted dose (ED), respirable fraction (RF), and fine particle fraction (FPF). VCM DPIs displayed better aerosol dispersion performance compared to CLM DPIs which was related to differences in the physicochemical and particle properties of VCM and CLM. In addition, organic solution advanced co-spray drying particle engineering design was employed to successfully produce co-spray-dried (co-SD) multifunctional microparticulate/nanoparticulate aerosol powder formulations of VCM and CLM with the essential lung surfactant phospholipid, dipalmitoylphosphatidylcholine (DPPC), for controlled release pulmonary nanomedicine delivery as inhalable dry powder aerosols. Formulation optimization was achieved through statistical experimental design of molar ratios of co-SD VCM:DPPC and co-SD CLM:DPPC. XRPD and DSC confirmed that the phospholipid bilayer structure in the solid-state was preserved following spray drying. Co-SD VCM:DPPC and co-SD CLM:DPPC dry powder aerosols demonstrated controlled release of antibiotic drug that was fitted to various controlled release mathematical fitting models. The Korsmeyer-Peppas model described the best data fit for all powders suggesting super case-II transport mechanism of controlled release. Excellent aerosol dispersion performance for all co-SD microparticulate/nanoparticulate DPIs was higher than the SD antibiotic drugs suggesting that DPPC acts as an aerosol performance enhancer for these antibiotic aerosol dry powders. Co-SD VCM:DPPC DPIs had higher aerosol dispersion parameters compared to co-SD CLM:DPPC which was related to differences in the physicochemical properties of VCM and CLM.

Albumin-Coated Porous Hollow Poly(Lactic-co-Glycolic Acid) Microparticles Bound with Palmityl-Acylated Exendin-4 as a Long-Acting Inhalation Delivery System for the Treatment of Diabetes

ABSTRACTPurposeTo study the development of porous poly(lactic-co-glycolic acid) microparticles (PLGA MPs) coated initially with albumin and then with palmityl-acylated exendin-4 (Pal-Ex4) as an inhalation system for treating diabetes.MethodsPorous PLGA MPs were prepared by w/o/w double emulsification using hydroxypropyl-β-cyclodextrin and poly(ethylene-alt-maleic anhydride). Albumin was covalently attached to the MPs using EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide); Pal-Ex4 was then bound on the albumin surface. Albumin-binding degree and aerosolization efficiency were investigated. Deposition of the MPs after insufflations into the lungs of ICR mice was observed by image monitoring, and pulmonary hypoglycemic efficacies were examined in db/db mice. Cytotoxicity and histopathology induced by MPs were examined in Calu-3 and A549 cells and in the lungs of db/db mice, respectively.ResultsAlbumin-coating and Pal-Ex4-binding to porous MP were performed with acceptable efficiencies. Pal-Ex4-bound albumin-coated MPs (Pal-Ex4/HSA-PLGA MP) were of high porosity and had appropriate aerodynamic sizes. Furthermore, this MP was efficiently deposited throughout mouse lungs, and exhibited a prolonged hypoglycemia and no significant lung tissue damage in db/db mice.ConclusionPal-Ex4/HSA-PLGA MP demonstrated many meaningful pharmaceutical advantages for the treatment of diabetes, in terms of aerosolization efficiency, drug loading, sustained drug-release, and hypoglycemic duration in vivo.

Liquid chromatography-electrospray lonization tandem mass spectrometric determination of lornoxicam in human plasma

A rapid, sensitive and selective liquid chromatography-electrospray ionization tandem mass spectrometric (LC-ESI-MS/MS) method for the determination of lornoxicam in human plasma was developed. Lornoxicam and isoxicam (internal standard) were extracted from human plasma with ethyl acetate at acidic pH and analyzed on a Sunfire C18 column with the mobile phase of methanol:ammonium formate (10 mM, pH 3.0) (70:30, v/v). The analyte was detected using a mass spectrometer, equipped with electrospray ion source. The instrument was set in the multiple-reaction-monitoring mode. The standard curve was linear (r = 0.9998) over the concentration range of 0.50-500 ng/mL. The coefficient of variation and relative error for intra-and inter-assay at four QC levels were 0.7 to 4.2% and -4.5 to 5.0%, respectively. The recoveries of lornoxicam and isoxicam were 87.8% and 66.5%, respectively. The lower limit of quantification for lornoxicam was 0.50 ng/mL using a 200 μL plasma sample. This method was successfully applied to a pharmacokinetic study of lornoxicam after oral administration of lornoxicam (8 mg) to humans.

Phase behavior of itraconazole–phenol mixtures and its pharmaceutical applications

The aims of this study were to examine the phase behavior of itraconazole-phenol mixtures and assess the feasibility of topical formulations of itraconazole using eutectic mixture systems. Itraconazole-phenol eutectic mixtures were characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy, (1)H-nuclear magnetic resonance, and powder X-ray diffractometry. The skin permeation rates of itraconazole-phenol eutectic formulations were determined using Franz diffusion cells fitted with excised hairless mouse skins. Itraconazole can form eutectic compounds with phenol, and the hydrogen-bonding interactions between the carbonyl group in the itraconazole and hydroxyl group in phenol play a major role in itraconazole-phenol eutectic formation. Despite its high molecular weight and hydrophobicity, the drug (i.e., itraconazole) can be permeated through excised hairless mouse skins from itraconazole-phenol eutectic formulations. The findings of this study emphasize the capabilities of the topical application of itraconazole via external preparations.

A new formulation of controlled release amitriptyline pellets and itsIn Vivo/In Vitro assessments

Controlled-release amitriptyline pellets (ATP) were formulated and its oral bioavailability was assessed in human volunteers after oral administration under fasting conditions. Core pellets were prepared using a CF granulator by two different methods (powder layering and solvent spraying) and coated with Eudragit RS or RL 100. Physical characteristics and dissolution rates of core pellets and coated pellets were evaluated to optimize the formulation. Powder layering method resulted in a better surface morphology than solvent spraying method. However, physical properties of the products were poorer when prepared by powder layering method with respect to hardness, friability and density. The dissolution profile of amitriptyline coated with Eudragit RS 100 was comparable to that of commercially available amitriptyline enteric-coated pellets (Saroten® retard). After the oral administration of both products at the dose of 50 mg, the mean maximum concentrations (Cmax) were 36.4 and 29.7 ng/mL, and the mean areas under the concentration-time curve (AUC0-96) were 1180.2 and 1010.7 ng.h/mL for ATP and Saroten retard, respectively. The time to reach the maximum concentrations (Tmax) was 6 h for both formulations. Statistical evaluation suggested that ATP was bioequivalent to Saroten retard.

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. The quantitative effects of the different formulation factors on the response factors were accurately predicted using the equations of best fit and a strong linearity was observed between the predicted and actual values of the response factors. The optimized bilayer tablet was obtained using a numeric optimization technique and was characterized compared with a control (Twynsta®) by using various physical evaluations and in vivo pharmacokinetic parameters. The physical stability of Telmiduo® was greater than that of Twynsta® owing to the improvement of formulation factors. The in vivo pharmacokinetic parameters suggested that Telmiduo® might have pharmaceutical equivalence and bioequivalence with Twynsta®. Therefore, the bilayer tablet that consisted of telmisartan and amlodipine besylate could be produced using a more economical and simpler method than that used to produce Twynsta®. Moreover, the suitability of QbD for effective product development in the pharmaceutical industry was shown.

Effects of Aloe, Aloesin, or Propolis on the Pharmacokinetics of Benzo[a]Pyrene and 3-OH-Benzo[a]Pyrene in Rats

This study was conducted to examine the effects of aloe and aloesin on the weight gain and blood chemistry as well as the pharmacokinetics of benzo[a]pyrene (BaP) and 3-OH-BaP in rats. The rats treated with multiple doses of aloe and aloesin (100 mg/kg every 12 h for 14–19 d) did not show any significant changes in the weight gain and blood biochemical parameters. In addition, the effects of oral treatment with aloe, aloesin, and propolis on the absorption and pharmacokinetics of benzo[a]pyrene (BaP) and its metabolite, 3-OH-BaP, were studied in rats. The treatment with a single oral dose (200 mg/kg) of aloe, aloesin, and propolis did not alter the concentration–time profiles of BaP and 3-OH-BaP after iv and oral administration of BaP. At higher oral doses (500 mg/kg), the biliary excretion of BaP and the urinary excretion of 3‐OH-BaP were significantly increased, but the urinary excretion of BaP and the fecal excretion of 3-OH-BaP remained unaltered. Whether high doses of aloe increase the overall elimination of BaP deserves further investigation.

Altered Oral Absorption of Alcohol by Combined Aqueous Extracts of Four Herbal Plants in Rats

This study examined the effect of combined aqueous extracts (BHR) of Ginko biloba, Mentha arvensis var. piperascens, Citrus unshiu, and Pueraria lobata var. chinensis on oral absorption of alcohol in rats. The rats were pretreated with BHR, placebo solution identical to BHR without the herbal extract, and isotonic saline. Alcohol was administered orally at 1- and 3-g/kg doses and the absorption profiles were compared. After oral administration of 1-g/kg doses, mean area under the curve (AUC) and Cmax values were significantly reduced in BHR-treated rats (16.1 ± 10.0 and 0.3 ± 0.1 mg/ml, respectively) as compared with saline-treated (37.9 ± 14.4 and 0.7 ± 0.7 mg/ml, respectively) and placebo solution-treated (63.0 ± 46.4 and 0.7 ± 0.4 mg/ml, respectively) rats. Similarly, after administration of 3-g/kg doses, mean AUC and Cmax values in BHR-treated rats (188.1 ± 119.7 mg.min/ml and 1.0 ± 0.4 mg/ml) were significantly reduced over those in saline-treated rats (571.4 ± 512.4 mg.min/ml and 1.8 ± 0.9 mg/ml, respectively). The relative oral bioavailability of alcohol calculated as the ratio of AUCBHR/AUCSaline was 42.5% and 32.9% at 1- and 3-g/kg doses, respectively. The reduced serum alcohol levels as well as the reduced AUC and Cmax after pretreatment with BHR appear to be a result of a reduced systemic absorption not due to an increased metabolic clearance.

Early formulation development of CKD-519, a new CETP inhibitor, for phase 1 clinical study based on in vitro and in vivo evaluation

Graphical abstract Figure. No Caption available. Abstract CKD‐519, a potent cholesteryl ester transfer protein (CETP) inhibitor, is a clinical candidate being developed for the treatment of dyslipidemia. It is considered a Biopharmaceutical Classification System II compound with low solubility and high permeability. The objective of this study was to develop early formulations focusing on the dissolution rate of the compound to achieve dose‐dependent exposure. High performance formulation strategies including solid dispersion (SD) and a self‐microemulsifying drug delivery system (SMEDDS) were investigated and their in vivo and in vitro correlations were also evaluated in monkeys along with dose optimization in human volunteers. The SD granules were prepared in a fluid bed granulator using microcrystalline cellulose and mannitol as carriers. Poloxamer 407 and Eudragit E PO were each found to be a suitable solubilizing agent and polymer for the improvement of the CKD‐519 dissolution rate. Pharmacokinetic studies in monkeys showed that the SD tablets exhibited better absorption than the SMEDDS in a dose‐dependent manner from 1.5 mg to 100 mg. The mannitol‐based SD tablet formulations were bioequivalent. However, pharmacokinetics studies in humans showed that the dose was saturable above 100 mg of CKD‐519. This study was performed to determine how to develop early formulations for clinical studies and to identify rational formulation development strategies for CKD‐519 to establish the pharmaceutical proof‐of‐concept in humans.