**5. Conclusions**

370 New Advances in the Basic and Clinical Gastroenterology

they formed a eutectic mixture (Roh et al., 2004). The phase behavior of monoolein and triglycerides could be explained by the classical binary eutectic phase diagram of two

We could conclude from the DSC data that monoolein and tricaprylin do not mix below *ca.* 30 C where monoolein exists as lamellar crystalline phase. Monoolein and Tween 80 did not mix in this temperature range either. Above 30 C, however, all three ingredients, tricaprylin, monoolein and Tween 80 existed as liquid and mixed homogeneously. Two important things to note were that paclitaxel precipitates were not observed even at 0 C by microscopy in any of the oral formulations and that the formulations could be heated and cooled in cycles between -20 and 40 C without compromising the effectiveness of the drug. These results are significant in that the oral formulation (possibly in a soft capsule) can be stored in the shelf and orally administered in the phase-separated form, but transforms into a homogenous liquid

In our oral formulations, monoolein was included due to its well-known mucoadhesive property (Nielsen et al., 1998). Monoolein and other monoglycerides have been used in oral drug delivery formulations since they can enhance absorption of small molecules and even proteins through the epithelial cells (Ganem-Quintanar et al., 2000; Chung et al., 2002). The absorption enhancing mechanism is not clearly known. Nanopore induction or the membrane perturbation (Anderson, 2005), and the intermediate phases formed in the intestine (Kossena et al., 2005) were considered important. *In vitro* study showed that monoglycerides can enhance the cellular absorption of drugs by inhibition of Pglycoproteins (Konishi et al., 2004). Further studies are required to explain the absorption

In the previous study, we administered intravesically the dispersion of DHP107 in water to experimental rabbits and observed that the formulation adhered tightly to the bladder mucosa, and paclitaxel penetrated through the physical barrier imposed by the uroepithelium (S. J. Lee et al., 2005). Histological examination of the bladder and other

Oral administration of formulations containing different triglycerides showed that those with tricaproin, tricaprylin and tricaprin had higher AUC values than others. The formulation with tricaproin had the highest AUC value. We must note that paclitaxel was mixed directly with the vehicles and sonicated for 30 s to obtain the formulations in Table 2. When the preparation process was changed to add and to remove methylene chloride in turn in order to solubilize crystalline as well as amorphous paclitaxel, the AUC value of tricaprylin/monoolein/Tween 80/paclitaxel formulation (G2, DHP107) increased from 8.9 to 11.0 μgh/ml, which was similar to that of tricaproin/monoolein/Tween 80/paclitaxel formulation in Table 2 (T6) statistically. We proceeded with the tricaprylin/monoolein/Tween 80/paclitaxel formulation for further experiments because the toxicity of tricaprylin (LD50 = 3700 mg/kg; intravenous and 26600 mg/kg; oral) was much lower than that of tricaproin (LD50 = 122 mg/kg; intravenous) for mice according to the Material Safety Data Sheets for tricaprylin (T9126) and tricaproin (T4137)

We also performed the pharmacokinetic study with the formulations having different contents of the drug, under fasting or non-fasting conditions, by changing the commercial source of paclitaxel, with or without the emulsifier, Tween 80 and in the form of dispersions

immiscible solid phases and a completely miscible melt.

enhancing mechanism of monoolein unequivocally.

provided by Sigma (www.sigma-aldrich.com).

tissues did not reveal any local or systemic toxicity to the rabbits.

solution by the body heat while traveling inside the gastrointestinal tract.

In conclusion, we prepared oral paclitaxel formulations that do not contain P-glycoprotein inhibitors as active pharmaceutical ingredients. The formulations are liquid at body temperature and can solubilize paclitaxel effectively. The oral bioavailability of paclitaxel was 14 ~ 20 % when compared to the intravenous Taxol® formulation without concomitant administration of P-glycoprotein inhibitors. Preclinical efficacy study on mice showed that the tumor size was reduced significantly for the human non-small cell lung carcinoma. In separate studies, we have determined the tissue distribution of paclitaxel after oral administration (manuscript in preparation) and performed pre-clinical antitumor efficacy studies in mice with several tumor types (manuscript in preparation). Regulatory preclinical experiments to initiate the clinical evaluations of DHP107 have also been carried out.
