Shigeji Sato

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.

Novel sustained release formulation using collagen as a carrier material. (1)-Dosage form design of interferon minipellet.

We have developed a novel sustained release formulation, minipellet, which is applicable to various kinds of biologically active proteins. In this study, dosage form design of interferon (IFN) minipellet was investigated. First, in order to select suitable carrier material, matrix type formulations were prepared with natural biodegradable polymers, human serum albumin (HSA), gelatin and atelocollagen, and the release profiles of IFN from these polymers were compared. IFN was released slowly from the sample made of atelocollagen but rapidly from the samples made of HSA and gelatin. The release of IFN from the atelocollagen films, prepared by drying the atelocollagen solution, varied with the atelocollagen concentration before drying. This suggested that IFN release was controlled by the density of atelocollagen matrix. So, in order to obtain the higher matrix density of atelocollagen, we newly designed a cylindical dosage formulation prepared by extrusion and air-drying of an atelocollagen solution with high concentration and named minipellet. IFN was constantly released from minipellet in vitro. Pharmacokinetic studies in mice showed that the serum IFN concentration was maintained for a long time with minipellet. To determin the optimal minipellet composition, IFN minipellets containing different amount of HSA were prepared and IFN release profile from them in dogs was evaluated, The IFN concentration increased gradually after the administration of IFN minipellet containing 30% (w/w) HSA, reached Cmax after 24h, and decreased gradually thereafter with a detectable level for 10 days. The IFN minipellet is expected to offer a significant advantage in IFN therapy because the attenuated peak IFN concentrations in serum may reduce the side effects and the sustained release may reduce the frequency of administration.