Chong-Kook Kim

Formulation parameters determining the physicochemical characteristics of solid lipid nanoparticles loaded with all-trans retinoic acid

Solid lipid nanoparticles (SLNs) have gained attention as a colloidal drug carrier, particularly for drugs with limited solubility. The poor aqueous solubility of all-trans retinoic acid (ATRA) has been a limiting factor in its clinical use. This study was undertaken to overcome the solubility limitation of ATRA by loading in SLNs. The physicochemical characteristics of ATRA-loaded SLNs were investigated by particle size analysis, zeta potential measurement, thermal analysis and HPLC determination of ATRA content. The mean particle size of ATRA-loaded SLNs could be reduced (1) by mixing EggPC and Tween 80 as a surfactant and (2) by increasing the total surfactant amount. The smallest mean particle size of SLNs was obtained with 50 mg/g surfactant mixture composed of 54:46% (w/w) EggPC:Tween 80 (154.9 nm). The zeta potential of SLNs could be increased by mixing EggPC, Tween 80 and DSPE-PEG in the surfactant mixture. The zeta potential of SLNs prepared with 50 mg/g surfactant mixture composed of 48:6:46% (w/w) of EggPC:DSPE-PEG:Tween 80 was -38.18 mV. ATRA could be loaded at 2.4% (percentage of lipid matrix) on these SLNs without impairing their physical stability. After freeze-drying, the mean particle size and polydispersity index of ATRA-loaded SLNs were only slightly increased (181.8 vs. 265.2 nm, 0.173 vs. 0.200). Furthermore, no significant change was observed in the SLN-loaded concentration of ATRA and the zeta potential of SLNs after freeze-drying. Taken together, SLN formulation of ATRA with similar characteristics to those of parenteral emulsions could be obtained even after freeze-drying.

Physicochemical characterization and evaluation of a microemulsion system for oral delivery of cyclosporin A

Abstract The purpose of this study was to improve the solubility and enhance the bioavailability of poorly water-soluble cyclosporin A loaded in o/w microemulsion systems. Microemulsions with varying weight ratios of surfactant to cosurfactant were prepared using caprylic/capric triglyceride (Captex 355 ® ) as an oil, polyoxyethylated castor oil (Cremophor EL ® ) as a surfactant, Transcutol ® as a cosurfactant and saline. The area of o/w microemulsion region in pseudo-ternary phase diagram was increased with increasing ratio of Cremophor EL ® to Trancutol ® . The solubility of cyclosporin A in microemulsion systems reached the maximum with 2:1 mixture of Cremophor EL ® and Trancutol ® . The dispersion rate of oil–surfactant–cosurfactant mixture with varying ratios of Cremophor EL ® to Trancutol ® in aqueous media assuming the condition of gastric fluid decreased with the increase of Cremophor EL ® to Trancutol ® weight ratio. The droplet size of microemulsion without cyclosporin A was decreased with the increase of Cremophor EL ® content. The droplet size increased on increasing the incorporation of cyclosporin A. The droplet size of cyclosporin A loaded microemulsion was minimized with microemulsions prepared with 2:1 mixture of surfactant to cosurfactant (Cremophor EL ® :Transcutol ® :Captex 355 ® , 10:5:4). The maximal blood concentration ( C max ) of cyclosporin A and the area under the drug concentration-time curve (AUC) after oral administration of this cyclosporin A loaded microemulsion was 3.5 and 3.3 fold increased compared with Sandimmun ® . No significant difference of C max and AUC was observed between this microemulsion system and Sandimmun Neoral ® . The absolute bioavailability of cyclosporin A loaded in this microemulsion system was increased about 3.3 and 1.25 fold compared with Sandimmun ® and Sandimmun Neoral ® . The enhanced bioavailability of cyclosporin A loaded in this microemulsion system might be due to the reduced droplet size of microemulsion systems.

Development of in situ-gelling and mucoadhesive acetaminophen liquid suppository

Abstract Conventional suppositories are solid forms which often cause discomfort during insertion. The leakage of suppositories from the rectum also gives uncomfortable feelings to the patients. In addition, when the solid suppositories without mucoadhesivity reach the end of the colon, the drugs can undergo the first-pass effect. To solve these problems, we developed a novel in situ-gelling and mucoadhesive acetaminophen liquid suppository with gelation temperature at 30–36°C and suitable gel strength and bioadhesive force. Poloxamer 407 (P407) or/and poloxamer 188 (P188) were used to confer the temperature-sensitive gelation property. The mixtures of P407 (15%) and P188 (15–20%) existed as a liquid at room temperature, but gelled at 30–36°C. Acetaminophen, the active ingredient of the suppositories, slightly increased gelation temperature, but significantly decreased gel strength and bioadhesive force. To modulate the gel strength and the bioadhesive force of acetaminophen liquid suppositories, bioadhesive polymers such as polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), carbopol and polycarbophil were studied. The bioadhesive polymers exerted various impacts on the physicochemical properties of liquid suppositories. The gelation temperature was not significantly affected by PVP, HPMC and HPC, but decreased by carbopol and polycarbophil. Of bioadhesive polymers, carbopol and polycarbophil most significantly enhanced both gel strength and bioadhesive force. The liquid suppositories with carbopol or polycarbophil were inserted into the rectum of rats without difficulty and leakage and retained in the rectum for at least 6 h. These results suggest that in situ-gelling and mucoadhesive liquid suppository for humans can be further developed as a more convenient and effective rectal dosage form.

The controlled release of blue dextran from alginate beads

Abstract The purpose of this paper is to explore the possible applicability of alginate gel beads as an oral controlled release system of macromolecular drugs. Blue dextran (M.W. approx. 2000000) was used as the model of macromolecular drugs. The release of blue dextran from alginate beads was strongly affected by drying time and blue dextran/sodium alginate ratio. However, the release was not particularly affected by the other factors such as sodium alginate concentration, calcium chloride concentration, curing time, and drop size. The drug release from alginate beads at pH 6.8 showed nearly zero-order release rate, which was more rapid than that at pH 1.2. Since the release of blue dextran as the model of macromolecular drugs could be controlled by the regulation of the preparation conditions of alginate beads, the alginate beads may be used for a potential oral controlled release system of such macromolecular drugs as vaccines and polypeptide drugs.

In situ gelling and mucoadhesive liquid suppository containing acetaminophen: enhanced bioavailability

Solutions of poloxamers and bioadhesive polymers were previously reported to undergo a phase transition to bioadhesive gels at body temperature. For the development of a convenient acetaminophen-loaded liquid suppository which gels in situ after rectal administration, we studied the release and pharmacokinetics of acetaminophen delivered by the liquid suppository systems composed of poloxamer P 188, P 407 and a bioadhesive polymer, polycarbophil. The release of acetaminophen was differently affected by the components of liquid suppository such as P 188 and polycarbophil. P 188 showed little effect on the release rates of acetaminophen from liquid suppositories. However, polycarbophil significantly delayed the release kinetics of acetaminophen from a certain concentration due to strong gel strength and bioadhesive force. The release rates of acetaminophen did not significantly differ between no polycarbophil and 0.2% polycarbophil-loaded suppositories, while they began to decrease as the concentrations of polycarbophil increased higher than 0.4%. The analysis of release mechanism showed that the release of acetaminophen was proportional to the square root of time, indicating that acetaminophen might be released from the suppositories by Fickian diffusion. Liquid suppository A [P 407/P 188/polycarbophil/acetaminophen (15:19:0.8:2.5%)], which was strongly gelled and mucoadhesive in the rectum, showed more sustained acetaminophen release profile than did other suppositories and gave the most prolonged plasma levels of acetaminophen in vivo. Liquid suppository A also showed higher bioavailibility of acetaminophen than did the conventional formulation. Moreover, liquid suppository A did not cause any morphological damage to the rectal tissues and remained stable for at least 6 month during storage. These results suggest that mucoadhesive and in situ gelling liquid suppository could be a more effective and convenient rectal delivery system of acetaminophen.

Rheological evaluation of thermosensitive and mucoadhesive vaginal gels in physiological conditions.

The timely gelation and retention of in situ-gelling vaginal formulations would be fundamental to improve the efficacy of drugs. In this study, various rheological properties of clotrimazole gels were evaluated for predicting their performance in vagina. Two kinds of thermosensitive and mucoadhesive formulations were composed of poloxamer 407 (P407, 15%), polycarbophil (0.2%), and different amounts of P188 (15 vs. 20%). Both formulations were Newtonian at 20 degrees C but non-Newtonian at 37 degrees C. Although both liquid formulations gelled below the vaginal temperature, they differed in gelation time and viscoelastic properties in the presence of vaginal fluid simulant. At body temperature, the formulation with 20% of P188 gelled within 35 s but it took two times longer for the other one gelled. Upon dilution with simulated vaginal fluid, the formulation with 20% of P188 retained the rheology of a gel, but the other one lost the viscoelastic properties typical for a gel. Moreover, after dilution with simulated vaginal fluid, the elastic modulus was orders of magnitude higher in the formulations with 20% of P188 relative to the other one. These results indicate that the rheological evaluation at the physiologic conditions needs to be preceded to develop more effective in situ-gelling vaginal formulations.

A new self-emulsifying formulation of itraconazole with improved dissolution and oral absorption.

To enhance the dissolution and oral absorption of poorly water-soluble itraconazole, self-emulsifying drug delivery system (SEDDS) composed of oil, surfactant and cosurfactant for oral administration of itraconazole was formulated, and its physicochemical properties and pharmacokinetic parameters of itraconazole were evaluated. Among the surfactants and oils studied, Transcutol, Pluronic L64 and tocopherol acetate were chosen that showed the maximal solubility to itraconazole. The solubility of itraconazole was further improved by the addition of hydrochloric acid. Droplet size of itraconazole emulsion was kept constant both in simulated gastric fluid without pepsin (pH 1.2) and simulated intestinal fluid (pH 6.8) throughout 120-min incubation period. Itraconazole in the SEDDS rapidly dissolved in every dissolution medium whereas the Sporanox showed different dissolution patterns during the 120-min incubation according to the dissolution media. In fasted and fed normal diet group, AUC(0-->24 h) and the mean maximum plasma level (Cmax) of itraconazole after oral administration of SEDDS in rats were comparable to those of itraconazole after oral dose of Sporanox. However, in fed lipidic diet group, AUC and Cmax after oral administration of SEDDS in rats were 3.7- and 2.8-fold higher, respectively, compared with those of Sporanox. These results demonstrate that the SEDDS of itraconazole composed of Transcutol, Pluronic L64 and tocopherol acetate greatly enhanced the bioavailability of itraconazole after the dose, particularly not influenced by food intake or not. Thus, this system may provide a useful dosage form for oral water-insoluble drug without food effect.

Prolonged antifungal effects of clotrimazole-containing mucoadhesive thermosensitive gels on vaginitis

To develop more effective treatment for vaginal candidasis, clotrimazole (CT) was formulated in mucoadhesive thermosensitive gels (MTG). Several MTG formulations composed of poloxamers (P) 407, 188, and polycarbophil (PC) were prepared. P188 and PC increased the mucoadhesiveness but reduced the syringebility of liquid forms of the gels. Based on the balance between the mucoadhesiveness and syringebility, MTG composed of P407/P188/PC (15/15/0.2 or 15/20/0.2) were further studied. Of the two MTG, the formulation with 15% of P188 gelled at higher temperature and revealed lower elastic modulus. In vitro, sustained release of CT from MTG was observed. In vivo antifungal activity of CT, tested against Candida albicans vaginitis in female rats, was significantly prolonged after vaginal delivery using MTG. At 10 days post-dose, the c.f.u. of C. albicans was more than 10(4)-fold decreased in MTG-treated groups. Moreover, the vaginal delivery of CT in MTG enhanced the viability of epithelial cells without affecting the morphology of vaginal mucosa. These results indicate that CT-containing vaginal MTG might be further developed for safe, convenient, and effective treatment of vaginal candidasis with reduced dosing interval.

Effect of sodium chloride on the gelation temperature, gel strength and bioadhesive force of poloxamer gels containing diclofenac sodium

Liquid suppository systems composed of poloxamers and bioadhesive polymers were easy to administer to the anus and mucoadhesive to the rectal tissues without leakage after the dose. However, a liquid suppository system containing diclofenac sodium could not be developed using bioadhesive polymers, since the drug was precipitated in this preparation. To develop a liquid suppository system using sodium chloride instead of bioadhesive polymers, the physicochemical properties such as gelation temperature, gel strength and bioadhesive force of various formulations composed of diclofenac sodium, poloxamers and sodium chloride were investigated. The mixtures of P 407 (15%) and P 188 (15-20%) existed as a liquid at room temperature, but gelled at physiological temperature. Diclofenac sodium significantly increased the gelation temperature and weakened the gel strength and bioadhesive force, while sodium chloride did the opposite. Furthermore, the poloxamer gels with less than 1.0% of sodium chloride, in which the drug was not precipitated, were inserted into the rectum of rabbits without difficulty and leakage, and retained in the rectum of rats for at least 6 h. Our results suggested that a thermosensitive liquid suppository system with sodium chloride and poloxamers was a more physically stable and convenient rectal dosage form for diclofenac sodium.

Preparation and evaluation of flurbiprofen-loaded microemulsion for parenteral delivery

The purpose of this study was to improve the solubility of flurbiprofen, a poorly water-soluble drug, in an oil-in-water (o/w) microemulsion that is suitable for parenteral administration. Microemulsions with varying ratios of oil to surfactant were prepared with ethyl oleate, Tween 20 and isotonic solution. The effect of formulation variables on the particle size of microemulsion and solubility of flurbiprofen in microemulsion system was investigated. The pharmacokinetic parameters of flurbiprofen after intravenous administration of flurbiprofen-loaded microemulsion were compared with those of a solution of the drug. The mean droplet diameter of microemulsion containing less than 1% (w/w) of flurbiprofen was below 100 nm. The maximum solubility of flurbiprofen in the microemulsion system was found to be 10 mg/ml. However, the mean droplet diameters of flurbiprofen-loaded o/w microemulsions tend to be increased at room temperature. The pharmacokinetic parameters of flurbiprofen after intravenous administration of flurbiprofen-loaded microemulsion to rats were not significantly different from those of flurbiprofen in phosphate-buffered saline solution. It can be concluded that microemulsions of flurbiprofen prepared with ethyl oleate and Tween 20 can be used as a parenteral drug carrier for this and other poorly water-soluble drugs, provided that physical stability can be properly addressed.