ペプチド・蛋白質性薬物の大腸デリバリーシステム

Abstract

The advances in biotechnology and medicinal chemistry in 1980s made it possible to produce large amount of useful peptide/protein drugs. However, their clinical use is limited to parenteral route. Among them, we selected recombinant human granulocyte-colony stimulating factor (rhG-CSF) as a representative peptide/protein drug. For the sake of the QOL of patients, non-parenteral, especially oral, preparation is needed now. For the development of oral peptide/protein preparations, colon delivery system has attracted the interests of many scientists. The most important reason is the lower hydrolytic enzyme activities in the colon than in the small intestine. We have developed two colon delivery capsules (CDC). One is intestinal inner pressure-controlled CDC (PCDC) and the other is release time-controlled CDC. As PCDC does not receive the effect of food on the delivery efficiency of drugs to the colon, PCDC was used for the preparation of oral rhG-CSF. At first, the colon delivery ability of PCDC was ascertained by administering 5-aminosalicylic acid (5-ASA), a drug for inflammatory bowel disease, in PCDC. After oral administration of 5-ASA in PCDC to beagle dogs, plasma 5-ASA levels vs. time curves were analyzed. The first appearance time of 5-ASA into the systemic circulation was approximately 4hr which corresponds to the colon arrival time in the beagle dogs. Based on these results, rhG-CSF was formulated into the PCDC and was orally administered to beagle dogs, 25 μg/kg. Blood samples were collected consecutively for 96 hr and blood total leukocyte counts (BTLC) were measured. At 8 hr after administration, BTLC increased to 1.3 times higher than the pre-dose level and thereafter declined gradually to the normal level at 96 hr. These results support the usefulness of PCDC for designing the oral delivery system of peptide/protein drugs.