Thermosensitive Biodegradable Copolymer

Assignee Industrial Technology Research Institute (Hsinchu, TW) 

A method for increasing the biodegradability of low cytotoxic poly(ethylene glycol-b-(lactide-co-glycolide)) derivatives is described. The block copolymers are thermosensitive and can be easily implanted into the human body through injection for timed release of biologically active agents. 

Preparation of Poly(Ethylene Glycol-b-(Lactide-co-Glycolide)) 

A reaction vessel was heated under nitrogen until the temperature reached 110°C and then treated with lactide (50.0 g), glycolide (11.36g), and methoxypolyethylene glycol (24.02 g). After the monomers had melted, the contents were treated with 0.05% tin octanate while the temperature slowly increased to 160°C for 9 hours the vessel was then cooled to ambient temperature. The solid was dissolved in 80 ml of CH2CI2, then poured into n-hexane/ether, 9 1, respectively, and stirred for 3 hours. The solution was next separated into two phases. The upper liquid was discarded, the bottom liquid was washed three times with n-hexane/diethyl ether, dried, and the product was isolated. 

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Chang [2] prepared the thermosensitive biodegradable block copolymer poly [ethylene glycol-b-(lactide-co-glycolide)] end-capped with cholic acid, (I), using catalytic amounts of Sn ion. The product showed improved biode-gradabUity when implanted into the human body with diminished overall polymer cytotoxicity. 

Synthesis of a thermosensitive, biodegradable hydrogel consisting of blocks of poly(ethylene oxide) and poly(L-lactic acid) was carried out (4). Aqueous solutions of these copolymers exhibited temperature-dependent reversible gel-sol transitions. The hydrogel can be loaded with bioactive molecules in an aqueous phase at an elevated temperature (around 45°C), where they form a solution. In this form, the polymer is injectable. On subcutaneous injection and subsequent rapid cooling to body temperature, the loaded copolymer forms a gel that can act as a sustained release matrix for drugs (4). 

Cha Y, Choi YK, Bae YH. 1997. Thermosensitive biodegradable polymers based on poly(ether-ester) block copolymers. US Patent 5 702-717. 

The use of thermosensitive polymers in drug dehvery and biomedical appHcation is widespread. The application of poly(iV-isopropylacrylamide) [poly(NIPAAm)] and its copolymers is probably the best example. As mentioned above, thermosensitive and biodegradable pol3uners are becoming very important in the development of nontoxic, injectable systems to tackle challenging problems in the dehvery of bioactive agents, as will be discussed in this chapter. 

Kwon YM, Kim SW. Biodegradable triblock copolymer microspheres based on thermosensitive sol-gel transition. Pharm Res 2004 21 339-343. 

Jeong B, Bae YH, Kim SW. Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers. J Contr Rel 2000 63 155-163. 

Despite successful results from in vitro studies, however, the clinical applications of systems that are based on polyNlPAAm may be limited, becanse poly-NIPAAm is nondegradable and insoluble. In addition, a major problem of polyNIPAAm-based drug deUvery systems is that thermal treatment is required for controlled destabilization of the micelles and concurrent drug release, which is not always feasible in clinical situations. Therefore, to overcome the disadvantages of polyNIPAAm, controlled biodegradable systems that use polyester block copolymers as thermosensitive polymers have been investigated. 

Key words biodegradability, sol-gel transition, thermosensitivity, hydrogel, block copolymer, in-situ gelation, drug debvery system. 

Gong, CY Qian, ZY Liu, CB Huang, MJ Gu, YC Wen, YJ et al. A Thermosensitive Hydrogel Based on Biodegradable Amphiphilic Poly(ethylene glycol)-polycaprolactone-poly(ethylene glycol) block Copolymers. Smart Mater Struct, 2007, 16,927-933. 

Liu, CB Gong, CY Pan, YF Zhang, YD Wang, JW Huang, MJ et al. Synthesis and Characterization of a Thermosensitive Hydrogel Based on Biodegradable Amphiphilic PCL-Pluronic(L35)-PCL block Copolymers. Colloids Surfaces A, 2007,302,430-438. 

Jeong, B Bae, YH Kim, SW. Biodegradable thermosensitive micelles of PEG-PLGA-PEG triblock copolymers. Colloid Surface B, 1999, 16, 185-193. 

A block copolymer of poly(A-isopropylacrylamide) (PNI-PAAm) and PLA may combine the thermosensitive property of PNIPAAm and the biodegradable property of PLA. Polymeric micelles from such polymers can improve protein release properties. Temperature change can alter the hydro-philicity and conformation of PNIPAAm, which may affect the physicochemical properties of microspheres of the polymer. Amphiphilic block copolymers of P(NIPAAm-Z -LA) have been prepared by ROP of LA in toluene using Sn(Oct)2 as a catalyst and hydroxyl-terminated PNIPAAm, as depicted in Figure 4.6 [62]. Such copolymers have recently been synthesized by ROP of lactide using the two hydroxyl groups of 5, 5 -bis(2-hydroxyethyl-2 -butyrate)trithiocarbonate (BHBT). PLA-Z -PNIPAAm-Z -PLA was prepared by reversible addition-fragmentation chain transfer (RAFT) polymer-... 

Jeong, B., Bae, Y. H., and Kim, S. W., 2000, Drug Release from Biodegradable Injectable Thermosensitive Hydrogel of PEG-PLGA-PEG Triblock Copolymers. J. Control Rel 63 155-163. 

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