Han-Gon Choi

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.

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.

Effect of additives on the physicochemical properties of liquid suppository bases

To investigate the effects of additives on the physicochemical properties of in situ gelling and mucoadhesive liquid suppository base, gelation temperature, gel strength and bioadhesive force of liquid suppository base, poloxamer 407 (P 407) and poloxamer 188 (P 188) (15/15%) were evaluated in the presence of following additives: solvent (ethanol, propylene glycol, glycerin), ionic strength-controlling agent (sodium chloride) and pH-controlling agent (hydrochloric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate). Among the additives studied, sodium chloride, sodium monohydrogen phosphate and sodium dihydrogen phosphate increased to a great extent the gel strength and the bioadhesive force of P 407/P 188 (15/15%) with a decrease in gelation temperature. Glycerin slightly decreased the gelation temperature and slightly increased the gel strength and bioadhesive force. However, the addition of 1% of sodium chloride, sodium monohydrogen phosphate or sodium dihydrogen phosphate caused a greater than 60-fold increase in gel strength and over a tenfold increase in bioadhesive force with 2-4 degrees C decrease of gelation temperature within optimal range, compared with P 407/P 188 (15/15%) alone. On the other hand, ethanol, propylene glycol and hydrochloric acid increased the gelation temperature and slightly decreased the gel strength and the bioadhesive force. Taken together, these findings indicate that the effect of additives on the physicochemical properties of liquid suppository bases depends on their bonding capacities, in that additives such as sodium chloride, sodium monohydrogen phosphate and sodium dihydrogen phosphate having strong cross-linking bonds with the components of liquid suppository base increase the strength and bioadhesive force of a gel compared to liquid suppository base alone, while additives such as ethanol, propylene glycol and hydrochloric acid having weaker hydrogen bonding result in a weaker response. Thus, sodium chloride and sodium phosphates appear to be promising additives for in situ gelling and mucoadhesive liquid suppository base, if used in adequate amounts.

Formulation and in vivo evaluation of omeprazole buccal adhesive tablet

For the development of omeprazole buccal adhesive tablets, we studied the release and bioavailability of omeprazole delivered by buccal adhesive tablets composed of sodium alginate, hydroxypropylmethylcellulose (HPMC), magnesium oxide and croscarmellose sodium. Croscarmellose sodium enhanced the release of omeprazole from the tablets. The analysis of the release mechanism showed that croscarmellose sodium changed the release profile of omeprazole from first- to zero-order release kinetics by forming porous channels in the tablet matrix. However, it decreased the bioadhesive forces and stability of omeprazole tablets in human saliva. The tablet is composed of omeprazole-sodium alginate-HPMC-magnesium oxide-croscarmellose sodium (20:24:6:50:10 mg). It may be attached to the human cheek without collapse and it enhanced the stability of omeprazole in human saliva for at least 4 h, giving a fast release of omeprazole. The plasma concentration of omeprazole in hamsters increased to reach a maximum of 370 ng/ml at 45 min after buccal administration and remained at the high level of 146-366 ng/ml for 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 to deliver omeprazole which degrades very rapidly in acidic aqueous medium and undergoes hepatic first-pass metabolism after oral administration.

Development of a thermo-reversible insulin liquid suppository with bioavailability enhancement

The purpose of this work is to develop a thermo-reversible insulin liquid suppository, which undergoes a phase transition to bioadhesive gels at body temperature and enhances the bioavailability of insulin. The effects of insulin and sodium salicylate on the physicochemical properties of a liquid suppository composed of poloxamer P 407, P 188 and polycarbophil were investigated. The pharmacodynamic study and quantitative histological assessment of the rectal mucosa of rats were carried out after the dose of insulin-loaded liquid suppositories with different amounts of sodium salicylate into streptozotocin-treated rats. Only thermo-reversible insulin liquid suppository [insulin/P407/P188/polycarbophil/sodium salicylate (100 (IU/g)/15/20/0.2/10%)] showed the optimal physicochemical properties and good safety in rats. It gave significantly lower plasma glucose levels, AUC(0-->4h) (the area below basal glucose level) and C(nadir) (the plasma glucose levels at the nadir) than did the solid and liquid suppositories without sodium salicylate in rats, indicating that the insulin from liquid suppository with sodium salicylate could be well absorbed in rats due to the absorption enhancing effect of sodium salicylate. It is concluded that thermo-reversible insulin liquid suppository [insulin/P 407/P 188/polycarbophil/sodium salicylate (100 (IU/g)/15/20/0.2/10%)], which was easy to administer without any pain during insertion and remained at the administered sites, could have a potential to be developed as a more convenient, safe and effective rectal delivery system of insulin.

Development of omeprazole buccal adhesive tablets with stability enhancement in human saliva

To develop an omeprazole buccal adhesive tablet, the absorption of omeprazole solutions from human oral cavity was evaluated and the physicochemical properties such as the bioadhesive forces of various omeprazole tablet formulations composed of bioadhesive polymers and alkali materials, and the stability of omeprazole tablets in human saliva were investigated. About 23% of the administered dose was absorbed from the oral cavity at 15 min after the administration of omeprazole solutions (1 mg/15 ml). A mixture of sodium alginate and HPMC was selected as the bioadhesive additive for the omeprazole tablet. Omeprazole tablets prepared with bioadhesive polymers alone had the bioadhesive forces suitable for buccal adhesive tablets, but the stability of omeprazole in human saliva was not satisfied. Among alkali materials, only magnesium oxide could be an alkali stabilizer for omeprazole buccal adhesive tablets due to its strong waterproofing effect. Two tablets composed of [omeprazole/sodium alginate/HPMC/magnesium oxide (20/24/6/50, mg/tab)] and [(20/30/0/50, mg/tab)] were suitable for omeprazole buccal adhesive tablets which could be attached to human cheeks without collapse and could be stabilized in human saliva for at least 4 h. It was concluded that these two formulae were potential candidates for the subject of further study for the development of omeprazole buccal adhesive tablets.

Bioavailability of cyclosporin A dispersed in sodium lauryl sulfate-dextrin based solid microspheres

The purpose of this work was to develop a solid dispersion system containing cyclosporin A (CsA) in order to improve the bioavailability of poorly water-soluble CsA. Solid dispersion systems that are spherical in shape (CsA-microspheres) were prepared with varying ratios of CsA/sodium lauryl sulfate/dextrin using a spray-drying technique. The effects of sodium lauryl sulfate (SLS) and dextrin on the dissolution of CsA dispersed in SLS-dextrin based solid microspheres were investigated. The bioavailability of CsA-microspheres was compared with CsA powder alone and commercial Sandimmun in dogs. SLS significantly enhanced the dissolution of CsA from microspheres, while dextrin did not affect this. The CsA-microspheres at the CsA/SLS/dextrin ratio of 1/3/1, which gave the highest dissolution rate of CsA among the formula treated, was selected as an optimal formula for oral delivery. This formula gave significantly higher blood levels, area under the drug concentration-time curve (AUC) and maximum blood concentration of drug (Cmax) of CsA in dogs compared with the CsA powder alone. The AUC, Cmax and time to reach maximum blood concentration (Tmax) of CsA with CsA-microspheres was not significantly different from those after oral administration of Sandimmun, suggesting the similar bioavailability to Sandimmun in dogs. Our study demonstrates that the CsA-microspheres prepared with SLS and dextrin, with improved bioavailability of CsA, would be useful to deliver a poorly water-soluble CsA and could be applicable to other poorly water-soluble drugs.

Trials of in situ-gelling and mucoadhesive acetaminophen liquid suppository in human subjects

For the development of in-situ gelling and mucoadhesive acetaminophen liquid suppository prepared with poloxamers (P 407. P 188) and sodium alginate, the physicochemical characteristics of liquid suppositories [acetaminophen 407/P 188/sodium alginate (5/15/19/0-1.0%)] were evaluated. Furthermore, a pharmacokinetic study of acetaminophen from liquid and conventional solid suppositories in human subjects was carried out. The results showed that acetaminophen liquid suppository [acetaminophen/P 407/P 188/sodium alginate (5/15/19/0.6%)] with optimal gelation temperature, gel strength and bioadhesive force had a similar release pattern to conventional suppository. The area under the drug concentration-time curve (AUC), mean residence time (MRT), biological half-life (t 1/2 ) and apparent elimination rate constant (K e1 ) of acetaminophen from liquid suppository were not significantly different from those from conventional suppository. However, liquid suppository gave significantly faster the time to reach the maximum plasma concentration (T max ) and higher the maximum plasma concentration of drug (C max ) of acetaminophen than conventional suppository (p <0.05). It is concluded that in situ gelling and mucoadhesive acetaminophen liquid suppository, which was easy to administer to the anus and showed faster absorption of acetaminophen in human subjects than conventional suppository, was more comfortable for the patients and therefore, is thought to be a favorable anti-pyretic and analgesic dosage form for infants and children.

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.