Sustained-release of protein from biodegradable sericin film, gel and sponge.

A silk protein, sericin, contains 18 kinds of amino acids, mostly polar side chains forming a complex of three principal polypeptides. The major polypeptides exhibit hydrophobic characteristics by forming a ß-sheet structure in a hydrate state. As a drug-releasing biomaterial made by an aqueous process without using any cross linker, sericin is expected to form various hydrophobic dosage forms. However, its dosage form, with respect to the molecular weight and concentration of sericin, and its biodegradation behavior has not been studied in detail. In this study, the film, gel and sponge of sericin were prepared and examined to determine the release properties of the charged protein, fluorescein isothiocyanate-albumin (FA). The film and gel, as solid and semisolid forms, respectively, were also evaluated for their biodegradation behavior. For in vitro release, FA was sustained-released from these preparations. The concentration and dosage form markedly affected FA release. For in vivo biodegradation, the sericin preparations implanted subcutaneously in rats gradually decreased in size and weight. Histological examination indicated no marked inflammation at the site. As for in vivo release, FA remained for 3-6 weeks or more in rats. These findings suggest that sericin is suitable for use as a drug-releasing biomaterial.

Use of silk protein, sericin, as a sustained-release material in the form of a gel, sponge and film.

To evaluate the usability of silk protein (sericin, SC) as a sustained-release material, the physicochemical properties of SC and the release profiles of model drugs from SC gel, sponge and film were studied. Heat aids the dissolution of SC. The molecular weight of SC tended to decrease as the heating temperature and heating time increased. The gel and sponge formed by SC were moldable and consisted of high molecular weight SC polymers (250 kDa and about 400 kDa). SC film was easily broken and exhibited elastic distortion. The addition of moisture-retaining plasticizer (glycerin and sorbitol) improved the film-forming characteristics of SC. The results suggested that SC is practical as a moldable gel and sponge, and as a tensible film. To evaluate the release profiles of small molecules, fluorescein isothiocyanate-dextran ((1) FD4, 4 kDa and (2) FD70, 70 kDa) were used as two model drugs with significantly different molecular weights, and fluorescein isothiocyanate-albumin ((3) FA, 66 kDa) was used as a charged drug. Each was formulated in SC gel, sponge and film. In each preparation, the release rate of the model drugs tended to be FA

The preparation of a solid dispersion powder of indomethacin with crospovidone using a twin-screw extruder or kneader.

A solid dispersion (SD) powder of indomethacin (IM) with CrosPVP was prepared continuously using a twin-screw extruder (extruder) or twin-screw kneader (kneader), which made it possible to simultaneously control kneading, mixing, and heating. For the extruder or kneader, IM existed in an amorphous state while it was treated with a screw rotation speed of 15 min(-1) or 50 min(-1), respectively, while being heated to 140 degrees C. IM and CrosPVP interacted to maintain IM in an amorphous state. The solubility of SD powders of IM was improved about four-fold compared to crystalline IM. The retention time of the samples in the machine, screw rotation speed, and heating temperature play important roles in the preparation of SD. Although SD was prepared using a theta composer followed by heating at 125 degrees C for 30 min, it is more useful to be able to continuously prepare powdered SD by heating below the melting point (140 degrees C) in a short time (4 min) using an extruder or a kneader from the viewpoint of manufacturing.

A new agglomerated KSR-592 beta-form crystal system for dry powder inhalation formulation to improve inhalation performance in vitro and in vivo.

A new agglomerated KSR-592 (steroid) beta-form needle-like crystals with lactose system for dry powder inhalation (DPI) was developed to improve inhalation performance with Jethaler. The drug agglomerates were prepared by the method of spherical agglomeration in liquid so as to control the particle size and the mechanical strength of agglomerates by changing the agitation speed of the agglomeration system. The agglomerates mixed with lactose particles for the DPI formulation were effectively disintegrated into respirable fine particle in the milling chamber of the device (Jethaler) when inhaled. The DPI formulation with these agglomerates exhibited ideal fluidity and provided a larger fine particle fraction (FPF: 29.7%) than the formulation with agglomerates consisting of alpha-form (plate-like) crystals (24.5%). The air-flow rate of inhalation had no effect on the disintegration properties of these agglomerates, suggesting a reliable inhalation performance in vivo. Further, an in vivo test of the aerosolized KSR-592 (beta-form) crystals having the same particle size distribution as those in the aerosol produced by Jethaler was conducted by means of a dry powder inhalation testing system using Brown Norway rats. Inhaled KSR-592 (beta-form) crystals were found to be uniformly deposited in the lungs of Brown Norway rat sensitized by ovalbumin (OA) and suppressed the increase in eosinophil number in the lungs after OA challenge.

Improved inhalation behavior of steroid KSR-592 in vitro with Jethaler by polymorphic transformation to needle-like crystals (beta-form).

PURPOSE: The aim of the present study was to improve the dry powder inhalation behavior of steroid KSR-592 with lactose by altering the crystal shape and the particle size of the drug for use in a newly designed inhalation device, Jethaler. METHOD: The shape of the crystals was changed by polymorphic transformation of original crystal (alpha-form) to beta-form by agitating alpha-form crystals in hexane containing 5% ethanol. The inhalation properties of the resultant crystals in vitro were evaluated with a twin impinger and cascade impactor. RESULTS: Needle-like crystals (beta-form) with dimensions of 1.8 microm in width x 41 microm in length were obtained by the polymorphic transformation, the kinetics of which was described by the Avrami equation. The beta-form crystals loaded on lactose particles were easily separated and crushed into fine particles in the airstream produced in the Jethaler, which increased dramatically the respirable fraction (RF) deposited in the twin impinger (43.8%) and the fine particle fraction (FPF) of the cascade impactor (FPF = 39.3%) compared with their values for the original crystals (RF = 5.8%, FPF = 4.7%). CONCLUSION: The dry powder inhalation properties of steroid KSR-592 (platelike crystal, alpha-form) were improved dramatically by changing the crystal shape to a needle-like shape by the polymorphic transformation to the beta-form.