Jong-Dal Rhee

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.

Terfenadine–β-Cyclodextrin Inclusion Complex with Antihistaminic Activity Enhancement

Terfenadine, an antihistaminic drug, has relatively low bioavailability after oral administration due to its limited solubility in water. To enhance the antihistaminic activity of terfenadine, the terfenadine–β-cyclodextrin (1 : 2) inclusion complex was prepared by the neutralization method. The solubility and dissolution of the inclusion complex were carried out, and its antihistaminic activity was then evaluated and compared with terfenadine powder by the passive subcutaneous anaphylaxis method in rats. The formation constant of the inclusion complex was higher at lower pH, while its formation ratio was 1 : 2 irrespective of pH. For terfenadine, it improved the solubility 200 times and the dissolution rate 5 times. It gave a low histamine level at 30 min, followed by a sustained low level until 60 min, while terfenadine powder gave a low histamine level at 60 min, suggesting that it had faster and more effective antihistaminic activity than terfenadine powder in rats due to fast dissolution and absorption of terfenadine. It is concluded that this inclusion complex enhanced the antihistaminic activity of terfenadine following the enhanced solubility and dissolution of terfenadine.

Effect of sodium chloride on the release, absorption and safety of diclofenac sodium delivered by poloxamer gel

Poloxamer solutions prepared with poloxamers and sodium chloride were previously reported to undergo a phase transition to bioadhesive gels at body temperature. For the development of a thermosensitive diclofenac sodium-loaded poloxamer gel, here we investigated the effect of sodium chloride on the release, safety and rectal absorption in rats of diclofenac sodium delivered by the poloxamer gels. P 188 delayed the release rates of diclofenac sodium from poloxamer gels. However, sodium chloride showed no significant effect on the release rates of diclofenac sodium from poloxamer gels. Release mechanism analysis showed the release of diclofenac sodium was proportional to the time. The initial plasma concentrations of diclofenac sodium in the rectal formulation [diclofenac sodium/poloxamer 407 (P 407)/poloxamer 188 (P 188)/sodium chloride (2.5/15/17/0.8%)] were significantly higher compared with those in semi-solid suppository. Furthermore, it gave significantly faster Tmax of diclofenac sodium than did semi-solid suppository, indicating that the diclofenac sodium from poloxamer gel could be absorbed faster than that from semi-solid one in rats. It did not cause any morphological damage to the rectal tissues. These results suggested that poloxamer gel with sodium chloride could be a more effective and safe rectal delivery system of diclofenac sodium.

Physicochemical Characterization and Evaluation of Buccal Adhesive Tablets Containing Omeprazole

The objective of this study was to develop an effective omeprazole buccal adhesive tablet with excellent bioadhesive force and good drug stability in human saliva. The omeprazole buccal adhesive tablets were prepared with various bioadhesive polymers, alkali materials, and croscarmellose sodium. Their physicochemical properties, such as bioadhesive force and drug stability in human saliva, were investigated. The release and bioavailability of omeprazole delivered by the buccal adhesive tablets were studied. As bioadhesive additives for the omeprazole tablet, a mixture of sodium alginate and hydroxypropylmethylcellulose (HPMC) was selected. The omeprazole tablets prepared with bioadhesive polymers alone had bioadhesive forces suitable for a buccal adhesive tablet, but the stability of omeprazole in human saliva was not satisfactory. Among alkali materials, only magnesium oxide could be an alkali stabilizer for omeprazole buccal adhesive tablets due to its strong waterproofing effect. Croscarmellose sodium enhanced the release of omeprazole from the tablets; however, it decreased the bioadhesive forces and stability of omeprazole tablets in human saliva. The tablet composed of omeprazole/sodium alginate/HPMC/magnesium oxide/croscarmellose sodium (20/24/6/50/10 mg) could be attached on the human cheek without disintegration, and it enhanced the stability of omeprazole in human saliva for at least 4 h and gave fast release of omeprazole. The plasma concentration of omeprazole in hamsters increased to a maximum of 370 ng/ml at 45 min after buccal administration and continuously maintained a high level of 146–366 ng/ml until 6 h. The buccal bioavailability of omeprazole in hamsters was 13.7% ± 3.2%. These results demonstrate that the omeprazole buccal adhesive tablet would be useful for delivery of an omeprazole that degrades very rapidly in acidic aqueous medium and undergoes hepatic first-pass metabolism after oral administration.

Retarded dissolution of ibuprofen in gelatin microcapsule by cross-linking with glutaradehyde

Ibuprofen-loaded gelatin microcapsule, a solid form of microcapsules simultaneously containing ethanol and ibuprofen in water-soluble gelatin shell was previously reported to improve the dissolution of drug. In this study, to retard the initial high dissolution of ibuprofen from gelatin microcapsule, the ibuprofen-loaded cross-linked gelatin microcapsule was prepared by treating an ibuprofen-loaded gelatin microcapsule with glutaraldehyde and its dissolution was evaluated compared to ibuprofen powder and gelatin microcapsule. The ibuprofen-loaded cross-linked microcapsule treated with glutaraldehyde for 10 and 60 sec gave significantly higher dissolution rates than did ibuprofen powder. Furthermore, the dissolution rate of ibuprofen from the cross-linked microcapsule treated for 10 sec was similar to that from gelatin microcapsule. However, the dissolution rate of ibuprofen from the cross-linked microcapsule treated for 60 sec decreased significantly compared to gelatin microcapsule, suggesting that the treatment of gelatin microcapsule with glutaraldehyde for 60 sec could cross-link the gelatin microcapsule. Furthermore, the cross-linking of gelatin microcapsule markedly retarded the release rate of ibuprofen in pH 1.2 simulated gastric fluid compared to gelatin microcapsule. However, the cross-linking of gelatin microcapsule with glutaraldehyde hardly changed the size of gelatin microcapsules, ethanol and ibuprofen contents encapsulated in gelatin microcapsule. Thus, the ibuprofen-loaded cross-linked gelatin microcapsule could retard the initial high dissolution of poorly water-soluble ibuprofen.

Physicochemical Characterization of Diclofenac Sodium-Loaded Poloxamer Gel as a Rectal Delivery System with Fast Absorption

Abstract Rectal poloxamer gel systems composed of poloxamers and bioadhesive polymers were easy to administer to the anus and were mucoadhesive to the rectal tissues without leakage after the dose. However, a poloxamer gel containing diclofenac sodium could not be developed using bioadhesive polymers, since the drug was precipitated in this preparation. To develop a poloxamer gel 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. Furthermore, the pharmacokinetic study of diclofenac sodium delivered by the poloxamer gel was performed. Diclofenac sodium significantly increased the gelation temperature and weakened the gel strength and bioadhesive force, while sodium chloride did the opposite. The poloxamer gels with less than 1.0% sodium chloride, in which the drug was not precipitated, were inserted into the rectum without difficulty and leakage, and were retained in the rectum of rats for at least 6 hr. Furthermore, poloxamer gel gave significantly higher initial plasma concentrations and faster Tmax of diclofenac sodium than did solid suppository, indicating that drug from poloxamer gel could be absorbed faster than that from the solid one in rats. Our results suggested that a rectal poloxamer gel system with sodium chloride and poloxamers was a more physically stable, convenient, and effective rectal dosage form for diclofenac sodium.

Enhanced oral bioavailability of ibuprofen in rats by poloxamer gel using poloxamer 188 and menthol

To improve the oral bioavailability of poorly water-soluble ibuprofen with poloxamer and menthol, the effects of menthol and poloxamer 188 on the aqueous solubility of ibuprofen were investigated. The dissolution and pharmacokinetic study of ibuprofen delivered by the ibuprofen-loaded preparations composed of poloxamer 188 and menthol were then performed. In the absence of poloxamer, the solubility of ibuprofen increased until the ratio of menthol to ibuprofen increased from 0:10 to 4:6 followed by an abrupt decrease in solubility above the ratio of 4:6, indicating that four parts menthol formed eutectic mixture with six parts ibuprofen. In the presence of poloxamer, the solutions with the same ratio of menthol to ibuprofen showed an abrupt increase in the solubility of ibuprofen. The poloxamer gel with menthol/ibuprofen ratio of 1:9 and higher than 15% poloxamer 188 showed the maximum solubility of ibuprofen, 1.2 mg/mL. The simultaneous addition of menthol and poloxamer 188 significantly improved the dissolution rates of ibuprofen from aqueous solution due to the ibuprofen solubility-improving effect of menthol in the presence of poloxamer. Furthermore, the ibuprofen-loaded preparation with menthol and poloxamer 188 gave significantly higher initial plasma concentrations, Cmax, and AUC of ibuprofen than did the preparation without menthol and poloxamer 188, indicating that the simultaneous addition of menthol and poloxamer 188 could improve the oral bioavailability of ibuprofen in rats. In modern pain management it is always desirable for the ibuprofen-loaded preparation with poloxamer 188 and menthol to show a rapid onset of action with a minimal phase of lag time to feel the decreased pain. From an industry point of view, it is more desirable for a formulation to be fast acting, easy to use, and cost effective. Thus, the ibuprofen-loaded preparation with poloxamer 188 and menthol was a more effective oral dosage form for poorly water-soluble ibuprofen.

Improved Solubility and In Vitro Dissolution of Ibuprofen from Poloxamer Gel Using Eutectic Mixture with Menthol

To improve the solubility and in vitro dissolution of poorly water-soluble ibuprofen with poloxamer and menthol, the effects of menthol and poloxamer 188 on the aqueous solubility of ibuprofen were investigated. The dissolution study of ibuprofen delivered by poloxamer gels composed of poloxamer 188 and menthol were performed. In the absence of poloxamer, the solubility of ibuprofen increased until the ratio of menthol to ibuprofen increased from 0:10 to 4:6, followed by an abrupt decrease in solubility above the ratio of 4:6, indicating that 4 parts of ibuprofen formed eutectic mixture with 6 parts of menthol. In the presence of poloxamer 188, the solutions with the same ratio of menthol to ibuprofen showed abrupt increase in the solubility of ibuprofen. Furthermore, the solution with ratio of 4:6 showed more than 2.5- and 6-fold increase in the solubility of ibuprofen compared with that without poloxamer and that without menthol, respectively. The poloxamer gel with menthol/ibuprofen ratio of 1:9 and higher than 15% poloxamer 188 showed the maximum solubility of ibuprofen, 1.2 mg/ml. Menthol improved the dissolution rates of ibuprofen from poloxamer gels. Dissolution mechanism showed that the dissolution rate of ibuprofen from the poloxamer gels without menthol was independent of the time, but the drug might be dissolved from the poloxamer gels with menthol by Fickian diffusion. Thus, the poloxamer gels developed using eutectic mixture with menthol, which gave the improved solubility and dissolution of drug, are potential candidates for ibuprofen-loaded transdermal and rectal delivery system.

Physicochemical Characterization of Rutaecarpine-Loaded Microemulsion System

To develop an o/w microemulsion system containing poorly water-soluble rutaecarpine, the solubility of rutaecarpine in water, ethanol, various oils, and surfactants were investigated. Among the surfactants and oils tested, Tween 20/PEG 400 and castor oil were chosen as the surfactant system and oil phase of the microemulsion, as rutaecarpine was most soluble in them, respectively. Pseudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant, and cosurfactant for microemulsion formation, and the stability test of rutaecarpine delivered by microemulsion formation was then evaluated. Pseudoternary phase diagrams show that the areas of microemulsion appeared at those with 0–20% Smix (PEG 400/Tween80 = 60/40), 64–81% water, and 10–20% oil. The rutaecarpine (300 µg/g)-loaded microemulsion composed of 10.8% PEG 400, 7.2% Tween 80, 20% caster oil, and 72% water was physically and chemically stable for at least 6 months. Thus, the microemulsion system composed of castor oil, PEG 400, Tween 80, and water could be a stable dosage form for rutaecarpine.

Trials of novel13C-urea-containing capsule for more economic and sensitive diagnosis ofHelicobacter pylori infection in human subjects

To develop a13C-urea-containing capsule for more economic and sensitive diagnosis ofHelicobacter pylori infection, the13C-urea-containing capsules were prepared with various additives such as polyethylene glycol, microcrystalline cellulose, sodium lauryl sulfate and citric acid. Their dissolution test and13C-urea Breath Test in human volunteers were then performed. Polyethylene glycol increased the initial dissolution rates of urea and difference δ13C values from13C-urea, while microcrystalline cellulose and sodium lauryl sulfate decreased them. Irrespective of addition of citric acid, the compositions with polyethylene glycol showed higher values from13C-urea compared to a commercial 76 mg13C-urea-containing capsule due to higher initial dissolution rate. The capsules with 38 mg13C-urea and 1.9 mg polyethylene glycol, which showed higherHelicobacter pylori-positive value of about 8%. at 10 min, improved the sensitivity of13C-urea in human volunteers. Thus, the13C-urea-containing capsule with polyethylene glycol would be a more economical and sensitive preparation for diagnosis ofHelicobacter pylori infection.