Yoshihiro Takada

Novel delivery system for proteins using collagen as a carrier material: the minipellet

It is critical to develop effective delivery systems for biologically active peptides and proteins since most of them are rapidly destroyed by the body. In this study, interferon (IFN) was used as a model protein drug and matrix type formulations were prepared with natural biodegradable polymers, albumin, gelatin and collagen. The release of IFN from albumin and gelatin was much faster than that of collagen in vitro. The release of IFN from the collagen matrix varied with various processing conditions and were explained based on the density of collagen matrix. IFN was constantly released with a cylindrical solid dosage form prepared by extrusion and air-drying of a 30% (w/w) collagen solution of a high concentration in vitro. Pharmacokinetic studies in mice showed that the serum IFN concentration was maintained for a long time with this solid formulation called minipellet. The advantages of the minipellet are ( 1 ) carrier material is a biodegradable natural protein; (2) it is manufactured under mild processing conditions without any organic solvent or heating process; and (3) it is easily administered in the same way as conventional injections. Therefore, it is applicable to various kinds of biologically active peptides and proteins and expected to facilitate their potential therapeutic use.

Long-acting delivery system of interferon : IFN minipellet

Abstract The optimal composition for an interferon (IFN) minipellet which released IFN with a high bioavailability and a long half-life was designed. Minipellets are cylindrical solid dosage forms using collagen as a biodegradable carrier material. A monolithic collagen matrix releases the incorporated drugs over long periods of time. Minipellets of various composition containing IFN were prepared and IFN release from minipellets was examined. Human serum albumin (HSA) added to the collagen matrix was shown to promote and maintain IFN release. In vivo experiments demonstrated that serum IFN concentrations were maintained at elevated levels for 7–10 days after administration of IFN minipellets containing 30% (w/w) HSA in the matrix. Pharmaco-kinetic studies showed that the IFN minipellet had good dose-dependency and reproducibility in serum drug level profiles. The IFN minipellet is expected to offer a significant advantage in IFN therapy because the peak IFN serum concentrations are attenuated, allowing prolonged effective dosing and reducing side effects. The increasing popularity of IFN treatment calls for the development of a formulation and a method of administration that reduces the burden on the patients. Therefore, a long-acting IFN delivery system requiring weekly subcutaneous administrations seems to be highly useful in a clinical setting.

Augmentation of antitumor effect on syngeneic murine solid tumors by an interleukin 2 slow delivery system, the IL-2 mini-pellet

We evaluated the antitumor effect of an interleukin 2 (IL-2) slow delivery system, the IL-2 mini-pellet, in two murine solid tumor models, and also investigated the enhancement of its therapeutic effect by serial administration. The IL-2 mini-pellet contains 1 × 106 units of IL-2 and releases it slowlyin vivo. In our experiment, the IL-2 mini-pellet was administered subcutaneously near the tumor site in combination with the intravenous injection of lymphokine-activated killer (LAK) cells. When this regimen was given on days 8 and 11 after the subcutaneous inoculation of Meth A fibrosarcoma into BALB/c mice, tumor growth was significantly inhibited (p < 0.05) compared to tumor growth in untreated controls. Moreover, the IL-2 mini-pellet alone was also effective in inhibiting tumor growth. In another experiment, MH134 hepatoma was inoculated into C3H/He mice. Both administration of the IL-2 minipellet alone and in combination with LAK cells resulted in complete tumor regression in four of five mice. In a third experiment, serial administration of the IL-2 mini-pellet at 3- or 5-day intervals prolonged the suppression of Meth A fibrosarcoma growth in BALB/c mice. These results suggested that the IL-2 mini-pellet could be applied to cancer immunotherapy and that its antitumor effect could be prolonged by serial administration.