Drug Delivery System Using Injectable Polymeric Sheets
Authors: Kondo Taro , Nezhad Zhaleh Kashikouli , Suzuki Jin , Nagai Nobuhiro , Nishizawa Matsuhiko , Abe Toshiaki , Kaji Hirokazu 
Published: February 2020

Introduction
Designing drug-delivery systems (DDS) targeting a local specific organ in the body, e.g., the bladder and the subretinal structure, is one of the most challenging tasks. Ideally, DDS devices are to be less-invasive as much as possible. Given the conventional DDS devices, DDS microspheres are superior in terms of less-invasive by injection but they cannot be located at the affected area. On the other hand, sheet-type DDS devices require surgical procedure to be retained in the body while they can delivery drug for long-term at affected area. Therefore, development of DDS devices that can be injected and located at the affected area for long-term drug release would bring significant benefits. In this study, we report on an injectable sheet-type DDS device by embedding DDS microspheres in polymeric sheets. The developed device was characterized in vitro and also evaluated in vivo by implanting it into rat eyes.
Material and Method
Collagen microspheres (COLs) were prepared by water-in-oil emulsion method. Next, COLs were immersed in solution of a model drug FITC-dextran (FD-40). The devices were made by photopolymerization with UV light of mixtures of polyethylene glycol dimethacrylate (PEGDM), a photopolymerization initiator and COLs. The devices were observed by SEM and fluorescence microscope to examine the distribution of COLs in PEGDM. In vitro release study was carried out to reveal release characteristics. To estimate the amounts of FD-40 that had diffused out of the devices, the devices were immersed in 3 mL of PBS and incubated at 37 C. The fluorescent intensities of the PBS solutions were measured spectrofluorometrically. PEGDM sheets of different thickness were photopolymerized with UV light. They were rounded several times around a glass cylindrical shape and the deployment times were measured in water in order to examine self-deployment characteristics. For in vivo experiments, Sprague-Dawley rats (SLC) weighing 250-300 g were used. After the rats were anesthetized with ketamine hydrochloride and xylazine hydrochloride, the FITC-albumin-loaded device was implanted on the sclera of rats and the fluorescence distribution at the posterior segment of the eye was evaluated.
Result and Discussion
A sheet type DDS device that consists of COLs and PEGDM sheet was fabricated. COLs were uniformly distributed in the device and a part of COLs was exposed on the surface of the device. The density of COLs in the device was proportional to the concentration of COLs in the corresponding unpolymerized PEGDM/COL mixture. In vitro release study confirmed that devices could release FD-40 continuously over 4 weeks, though the release of FD-40 could not be observed from PEGDM sheets in which FD-40 was directly loaded without the use of COLs. The results indicate that the drug diffuses through interconnected COLs in the device. PEGDM sheets showed a linear relationship between deployment time and the number of turns of the sheet. Also, the device could be injected in water through a syringe needle and then fully expanded. In vivo experiments showed that the device adhered on the sclera without suturing. Also, the fluorescence could still be detected in the sclera and retina even 4 weeks after the implantation of the device, indicating the transscleral delivery of the drug to the retina.
Conclusion
We developed an injectable sheet type DDS device consisting of COLs and PEGDM sheet, which can continuously release a model drug over 4 weeks. The device could implanted on the sclera of rat eyes and indicated the possibility of the transscleral delivery of the drug to the retina.