Articular Injection Of Thermosensitive Gel Drug Delivery Formulations Studied

During the last decade, thermosensitive polymers-based injectable thermosensitive hydrogels received an increasing attention as controlled drug carriers because of their many advantages such as the convenience of application, high drug loading, no organic solvents, sustained drug release behavior and less systemic toxicity. These drug delivery systems are flowable aqueous solution before administration, but once injected, they rapidly form gel under physiological conditions and hence an in situ "drug depot" forms. In situ gel formation after the topical injection of aqueous solutions of such thermosensitive polymers resulted in a significantly prolonged drug residence time.Inflammatory arthritis diseases such as rheumatoid arthritis (RA) affect an enormous number of individuals. Patients afflicted with the disease may experience pain and loss of joint function with associated deleterious effects on patient activity level and lifestyle habits. Treatment of arthritis disease is achieved through oral, parenteral or intra-articular drugs. The direct drug delivery to an affected joint offers the possibility of reaching high drug concentrations at the action site with limited systemic toxicity. However, the undeniable clinical efficacy of intra-articular injections is somehow restricted either by the rapid efflux of drugs from the joint cavity after injections or by the need of repeated injections, possibly causing joint instability and infections. Retention of drugs in the joints using controlled release delivery system offers an exciting option for intra-articular drug delivery. Researchers thus have tried to encapsulate the drugs into different drug delivery systems such as liposomes, nanoparticles and microparticles.Though more promising than drug suspensions, these systems also faced a major drawback of short retention in the joint due to synovial capillary and lymphatic drainage, which takes place within a few days after injection. To overcome these limitations, many researches have been carried out to find more controlled and prolonged drug delivery to the joint.In this study, we have constructed a biodegradable and injectable in situ gel-forming controlled drug delivery system based on thermosensitive PCL-PEG-PCL hydrogels, which offered a great potential to develop a kind of novel topical articular-administrated drug delivery system. The major contents of this paper are shown as follows:1. Synthesis, characterization of a series of thermosensitive PCL-PEG-PCL triblock copolymers with different PCL and PEG block lengths.A series of thermosensitive PCL-PEG-PCL copolymers with different molecular compositions were synthesized by ring-opening polymerization method, and their structure was characterized via 1H-NMR and GPC techniques. The results calculated from 1H-NMR and GPC indicated that EG/CL ratios were consistent with the initial feed ratios, which offered a strong proof to their compositions and molecular structure.2. Thermosensitivity characterization of PCL-PEG-PCL hydrogels.All synthesized PCL-PEG-PCL triblock copolymers in this study exhibited a temperature-dependent reversible sol-to-gel transition in water. The phase diagrams revealed that the sol-to-gel transition behavior of PCL-PEG-PCL triblock copolymers in aqueous solutions was highly dependent on their chemical compositions and copolymer concentrations:â…°) increasing the length of hydrophobic PCL block with a fixed PEG block length resulted in a lower sol-to-gel transition temperature at a given copolymer concentration.â…±) an increase in the copolymer concentration shifted sol-to-gel transitions to the lower temperature. Furthermore, both the short enough gelation time and in situ gel-forming ability of thermosensitive PCL-PEG-PCL hydrogels were confirmed, which were prerequisite for a promising injectable drug delivery system.3. In vitro drug release behavior of thermosensitive PCL-PEG-PCL hydrogels.In this chapter, the in vitro release behavior of both hydrophilic protein drug (BSA) and hydrophobic chemo drug (Paclitaxel) from thermosensitive PCL-PEG-PCL hydrogels were investigated. The results revealed that the in vitro drug release rate from the PCL-PEG-PCL hydrogels was controllable by altering either the PEG and PCL block lengths or the hydrogel concentrations and initial drug loadings. Besides, a suitable controlled delivery system should be able to release protein in its biologically active form. In protein activity test, the released model protein (HRP) was confirmed to conserve its biological activity by specific enzymatic activity assay. 4. Injectable thermosensitive hydrogels for intra-articular delivery of methotrexateThe in vivo biodegradability study suggested that the synthesized PCL-PEG-PCL hydrogels were able to persist about 45 days and provide an extended drug release period. The in vivo biocompatibility of PCL-PEG-PCL hydrogels was evaluated, indicating no obvious inflammatory infiltrattion occurred in the synovial membrane.Sustained drug release behaviors from thermosensitive methotrexate loaded PCL-PEG-PCL hydrogels in both in vitro and in vivo (intra-articular injection in rats) experiments were observed. The pharmacokinetics data suggested that the methotrexate loaded hydrogel was able to slow down the clearance of methotrexate and control the methotrexate release in the joint cavity.Owing to great thermosensitivity, controllable drug release behaviors, biocompatibility and biodegradability of these PCL-PEG-PCL copolymers, these developed PCL-PEG-PCL hydrogels can be applied as a promising in situ gel-forming controlled drug delivery system for the intra-articular injection and pave a way to improve the therapeutic efficacy of rheumatoid arthritis clinically.