Myoung Jin Ho

Enhanced dissolution and oral absorption of tacrolimus by supersaturable self-emulsifying drug delivery system

A new Soluplus (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer)-based supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to enhance oral absorption of tacrolimus (FK506) with minimal use of oil, surfactant, and cosurfactant. A high payload supersaturable system (S-SEDDS) was prepared by incorporating Soluplus, as a precipitation inhibitor, to SEDDS consisting of Capmul MCM, Cremophor EL, and Transcutol (FK506:vehicle:Soluplus =1:15:1). In vitro dissolution profile and in vitro pharmacokinetic aspect of S-SEDDS in rats were comparatively evaluated with those of conventional SEDDS formulas containing four times greater content of vehicle components (FK506:vehicle =1:60). Both formulations formed spherical drug-loaded microemulsion <70 nm in size when in contact with aqueous medium. In an in vitro dissolution test in a nonsink condition, the amphiphilic polymer noticeably retarded drug precipitation and maintained >80% of accumulated dissolution rate for 24 hours, analogous to that from conventional SEDDS. Moreover, pharmacokinetic parameters of the maximum blood concentration and area under the curve from S-SEDDS formula in rats were not statistically different (P>0.05) than those of conventional SEDDS. The results suggest that the Soluplus-based supersaturable system can be an alternative to achieve a comparable in vitro dissolution profile and in vivo oral absorption with conventional SEDDS, with minimal use of vehicle ingredients.

Improved oral absorption of tacrolimus by a solid dispersion with hypromellose and sodium lauryl sulfate

A novel surfactant-incorporated hydroxypropyl methylcellulose (HPMC) solid dispersion (SD) system was constructed in order to facilitate the release rate and oral absorption of tacrolimus (FK506), a poorly water-soluble immunosuppressant. Several emulsifiers including sodium lauryl sulfate (SLS), as drug release promotors, were employed with HPMC to fabricate SD using the solvent wetting method. The solid state characteristics using differential scanning calorimetry and X-ray powder diffraction, revealed that FK506 was molecularly distributed within all dispersions in amorphous form. The dissolution rates of FK506 in SLS-incorporated SDs were much higher than those in SDs prepared with HPMC alone, and even with stearoyl polyoxyl-32 glycerides or tocopheryl polyethylene glycol 1000 succinate. In particular, the greatest dissolution enhancement was obtained from the SD consisting of the drug, HPMC, and SLS in a weight ratio of 1:1:3, providing a 50-fold higher drug concentration within 15 min, compared with HPMC SD. In vivo absorption study in rats demonstrates that the optimized formula remarkably increased the oral absorption of FK506, providing about 4.0-fold greater bioavailability (p<0.05) compared with the marketed product (Prograf®, Astellas Pharma). These data suggest that a novel SLS/HPMC SD may be an advantageous dosage form of FK506, boosting the dissolution and absorption in gastrointestinal tract.

Cationic PLGA/Eudragit RL nanoparticles for increasing retention time in synovial cavity after intra-articular injection in knee joint.

Positively surface-charged poly(lactide-co-glycolide) (PLGA)/Eudragit RL nanoparticles (NPs) were designed to increase retention time and sustain release profile in joints after intra-articular injection, by forming micrometer-sized electrostatic aggregates with hyaluronic acid, an endogenous anionic polysaccharide found in high amounts in synovial fluid. The cationic NPs consisting of PLGA, Eudragit RL, and polyvinyl alcohol were fabricated by solvent evaporation technique. The NPs were 170.1 nm in size, with a zeta potential of 21.3 mV in phosphate-buffered saline. Hyperspectral imaging (CytoViva®) revealed the formation of the micrometer-sized filamentous aggregates upon admixing, due to electrostatic interaction between NPs and the polysaccharides. NPs loaded with a fluorescent probe (1,1′-dioctadecyl-3,3,3′,3′ tetramethylindotricarbocyanine iodide, DiR) displayed a significantly improved retention time in the knee joint, with over 50% preservation of the fluorescent signal 28 days after injection. When DiR solution was injected intra-articularly, the fluorescence levels rapidly decreased to 30% of the initial concentration within 3 days in mice. From these findings, we suggest that PLGA-based cationic NPs could be a promising tool for prolonged delivery of therapeutic agents in joints selectively.

Increased localized delivery of piroxicam by cationic nanoparticles after intra-articular injection.

Piroxicam (PRX), a potent nonsteroidal anti-inflammatory drug, is prescribed to relieve postoperative and/or chronic joint pain. However, its oral administration often results in serious gastrointestinal adverse effects including duodenal ulceration. Thus, a novel cationic nanoparticle (NP) was explored to minimize the systemic exposure and increase the retention time of PRX in the joint after intra-articular (IA) injection, by forming micrometer-sized electrostatic clusters with endogenous hyaluronic acid (HA) in the synovial cavity. PRX-loaded NPs consisting of poly(lactic-co-glycolic acid), Eudragit RL, and polyvinyl alcohol were constructed with the following characteristics: particle size of 220 nm, zeta potential of 11.5 mV in phosphate-buffered saline, and loading amount of 4.0% (w/w) of PRX. In optical and hyperspectral observations, the cationic NPs formed more than 50 μm-sized aggregates with HA, which was larger than the intercellular gaps between synoviocytes. In an in vivo pharmacokinetic study in rats, area under the plasma concentration–time curve (AUC0–24 h) and maximum plasma concentration (Cmax) of PRX after IA injection of the cationic NPs were <70% (P<0.05) and 60% (P<0.05), respectively, compared to those obtained from drug solution. Moreover, the drug concentration in joint tissue 24 h after dosing with the cationic NPs was 3.2-fold (P<0.05) and 1.8-fold (P<0.05) higher than that from drug solution and neutrally charged NPs, respectively. Therefore, we recommend the IA cationic NP therapy as an effective alternative to traditional oral therapy with PRX, as it increases drug retention selectively in the joint.

Microsuspension of fatty acid esters of entecavir for parenteral sustained delivery

&NA; Entecavir (EV), an anti‐viral agent for hepatitis B infection, should be administered under fasted state, as intestinal absorption of this hydrophilic compound is markedly decreased under post‐prandial conditions. Herein, in order to improve therapeutic adherence, a parenteral sustained delivery system was constructed, by synthesizing water‐insoluble ester prodrugs of the nucleotide analogous with fatty acids. EV‐3‐palmitate (named EV‐P), exhibited the lowest solubility in phosphate buffered saline (pH 7.4, 1.1 &mgr;g/ml), with extended release profile compared with EV, EV‐3‐myristate, and EV‐3‐stearate, was selected as a candidate to formulate drug suspension. The crystalline suspension was fabricated using anti‐solvent crystallization technique, with a mean particle size of 7.7 &mgr;m. After subcutaneous (SC) injection in beagle dogs (0.43 mg/kg as EV), the plasma concentrations of EV were markedly protracted with lowered maximum plasma concentration (Cmax, 4.7 ng/ml), extended time required to reach Cmax (Tmax, 9.0 days), and lengthened elimination half‐life (T1/2, 129.3 h) compared with those after oral administration (0.0154 mg/kg, Cmax, 15.4 ng/ml; Tmax, 0.01 days; T1/2, 4.1 h). The systemic exposure of the lipidic prodrug was below 0.1% compared with that of EV following SC injection, denoting that EV‐P was rapidly converted into the parent compound in blood. Therefore, SC delivery of EV‐P microsuspension can be an alternative to oral EV therapy, offering prolonged pharmacokinetic profile after single injection. Graphical abstract Figure. No caption available.

A Polyvinylpyrrolidone-Based Supersaturable Self-Emulsifying Drug Delivery System for Enhanced Dissolution of Cyclosporine A

A novel supersaturable self-emulsifying drug delivery system (S-SEDDS) of cyclosporine A (CyA)—a poorly water-soluble immunosuppressant—was constructed in order to attain an apparent concentration–time profile comparable to that of conventional SEDDS with reduced use of oil, surfactant, and cosolvent. Several hydrophilic polymers, including polyvinylpyrrolidone (PVP), were employed as precipitation inhibitors in the conventional SEDDS, which consists of corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil, ethanol, and propylene glycol. PVP-incorporated pre-concentrate (CyA:vehicle ingredients:PVP = 1:4.5:0.3 w/v/w) spontaneously formed spherical droplets less than 120 nm within 7 min of being diluted with water. In an in vitro dialysis test in a biorelevant medium such as simulated fed and/or fasted state intestinal and/or gastric fluids, PVP-based S-SEDDS exhibited a higher apparent drug concentration profile compared to cellulose derivative-incorporated S-SEDDS, even displaying an equivalent concentration profile with that of conventional SEDDS prepared with two times more vehicle (CyA:vehicle ingredients = 1:9 w/v). The supersaturable formulation was physicochemically stable under an accelerated condition (40 °C/75% RH) over 6 months. Therefore, the novel formulation is expected to be a substitute for conventional SEDDS, offering a supersaturated state of the poorly water-soluble calcinurin inhibitor with a reduced use of vehicle ingredients.

Colon-targeted delivery of solubilized bisacodyl by doubly enteric-coated multiple-unit tablet

&NA; A doubly enteric‐coated multiple‐unit tablet (DET) of bisacodyl (BD) was formulated to selectively deliver the stimulant laxative to the large intestine. Solubilized BD in surfactants was adsorbed into the porous carrier and primarily coated with different combinations of pH‐sensitive polymers (Eudragit S and Eudragit L) and time‐dependent release polymer (Eudragit RS). BD‐loaded granules were compressed into tablets and coated again with pH‐sensitive polymers (Eudragit S:Eudragit L = 1:1). The multiple‐unit tablet was optimized with respect to the granular coating compositions (Eudragit S:Eudragit L:Eudragit RS = 5:1:4) and coating level (12.5%), and coating level on the tablet (25%), by evaluating in vitro release profile in continuous dissolution medium. Drug release from the optimized tablet was effectively retarded in the simulated gastric and small intestinal fluids (below 7%), but profound drug liberation was attained in the colonic fluid (over 50%). On the other hand, drug release from the marketed product (Dulcolax®, Boehringer Ingelheim Pharma), a reference drug, in the gastric and small intestinal fluids was reached to 30%, while that in the colonic fluid was only 7%. In an in vivo efficacy study in loperamide‐induced constipated rabbits, a remarkable recovery in fecal secretion was observed in the DET‐treated group 24 h post‐dosing, compared to vehicle‐treated (p < 0.05) and the marketed product‐treated groups (p < 0.05). Moreover, pharmacokinetic evaluation in the constipated rabbits revealed that the DET system significantly lowered the systemic exposure compared with the marketed product (p < 0.05), by hindering drug release in the upper intestine, a preferential absorption site. Therefore, the novel colon‐targeted delivery system may be an alternative for boosting pharmacological responses in the colon, while diminishing the intestinal irritation and/or systemic adverse effect of the stimulant laxative. Graphical abstract Figure. No caption available.

Synthesis and Physicochemical Evaluation of Entecavir-Fatty Acid Conjugates in Reducing Food Effect on Intestinal Absorption

The oral bioavailability of entecavir (EV), an anti-viral agent commonly prescribed to treat hepatitis B infections, is drastically reduced under a post-prandial state. This is primarily due to its low permeability in the gastrointestinal tract. To reduce the food effect on the intestinal absorption of the nucleotide analogue, four lipidic prodrugs were synthesized via the esterification of the primary alcohol of EV with fatty acids (hexanoic acid, octanoic acid, decanoic acid, and dodecanoic acid). EV-3-dodecanoate (or EV-C12) exhibited high solubility in a fed state simulated intestinal fluid (78.8 μg/mL), with the acceptable calculated logP value (3.62) and the lowest hydrolysis rate (22.5% for 12 h in simulated gastric fluid, pH 1.2). Therefore, it was chosen as a candidate to improve intestinal absorption of EV, especially under a fed state condition. Physical characterization using scanning electron microscopy, a differential scanning calorimeter, and X-ray powder diffraction revealed that EV-C12 had a rectangular-shaped crystalline form, with a melting point of about 170 °C. In a release test in biorelevant media, such as fasted and fed state-simulated intestinal and/or gastric fluid, more than 90% of the prodrug was released within 2 h in all media tested. These data suggest that this lipidic prodrug might have the potential to alleviate the negative food effect on the intestinal absorption of EV with increased therapeutic efficacy and patient compliance.

Formulation and in vivo pharmacokinetic evaluation of ethyl cellulose-coated sustained release multiple-unit system of tacrolimus

A novel once-a-day sustained-release (SR) system of tacrolimus (FK506), a poorly water-soluble immunosuppressive agent, was designed employing ethyl cellulose (EC) polymer as release retardant. Drug (5 mg) was layered onto sugar spheres (518.3 mg) with hypromellose (5 mg), to transform the drug from a crystalline to an amorphous form. Subsequently, the drug-layered pellets were recoated with EC polymer (0.5-1.5 mg) using a fluid bed granulator. Drug release from the reservoir-type pellets was markedly impeded by the outer EC-based coating layer (EC 1 mg), displaying about 60% of drug release after 8 h, regardless of the acidity of the media. In an in vivo pharmacokinetic study in fasted Cynomolgus monkeys, the drug level in blood was gradually increased over 4.7 h and high drug concentration was maintained until 24 h, with an elimination half-life of 16.6 h. There were no statistical differences between the novel SR pellets and the recently marketed SR capsule (Advagraf®, Astellas Pharma, Japan) in terms of maximum blood concentration, area under the curve, and half-life values, in both fasted and fed states. Therefore, the novel EC-coated pellets are expected to be bioequivalent to the commercial SR capsule, providing a once-daily dosing regimen in patients with allogenic rejection.

Design and in vivo evaluation of entecavir-3-palmitate microcrystals for subcutaneous sustained delivery

ABSTRACT The objectives of this study were to formulate microcrystals of entecavir‐3‐palmiate (EV‐P), a palmitic acid ester of entecavir (EV), and evaluate the influence of particle size on its pharmacokinetic behavior following subcutaneous (SC) injection. Systemic toxicity and local tolerability of the hepatitis B anti‐viral suspension were further evaluated in normal rats. EV‐P microcrystals possessing median diameters of 2.1, 6.3, and 12.7&mgr;m were fabricated using anti‐solvent crystallization technique with polysorbate 20 and polyethylene glycol 4000 as steric stabilizer. Dissolution rate of EV‐P microcrystals was controlled by adjusting the particle size, under sink condition. Pharmacokinetic profiles of 2.1&mgr;m‐sized and 6.3&mgr;m‐sized EV‐P microcrystals were quite comparable (1.44mg/kg as EV), over 46days in rats. The absorption rate and extent of EV after SC injection of 12.7&mgr;m‐sized microcrystals were significantly retarded, due to its slower dissolution rate in aqueous media. No single‐dose systemic toxicity was observed after SC injection of high dose of EV‐P microcrystal suspension (30–300mg/kg as EV). The microcrystals were tolerable in the injected site, showing mild inflammatory responses at a dose of 30mg/kg. Therefore, the novel microcrystal system with median particle size of below 6.3&mgr;m is expected to be a unique long‐acting system of the anti‐viral agent, improving patient’s compliance with chronic disease.