Thermo-sensitive Polymers for Controlled-release Drug Delivery Systems

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International Journal of Pharmacology 2 (5): 513-519, 2006 ISSN 1811-7775 2006 Asian Network for Scientific Information Thermo-sensitive Polymers for Controlled-release Drug Delivery Systems Li Jun, Wang Bochu and Wang Yazhou Key Laboratory for Biomechanics and Tissue Engineering under the State Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, People's Republic of China Abstract: In recent years, thermo-sensitive polymer as a novel carrier for controlled-release drug delivery systems has been widely concerned by researchers. With respect to thermo-sensitive polymer, Researchers study on its properties in controlled-release drug delivery systems, such as biodegradation, biocompatibility. Lower Critical Solution Temperature (LCST), biotoxicity, etc. In this study, we mainly review the characteristics of thermo-sensitive polymer, its present research state and further study tendency. Key words: Thermo-sensitive polymer, drug delivery systems, biocompatibility, lower critical solution Lemperature INTRODUCTION Over the past several decades increasing attention has focused on designing new drug dosage forms in order to increase the effectiveness and decrease the side effect. of existing medications. As the meaning of ‘drug delivery* expands to the targeting drug at the proper time or the proper site, stimuli-sensitive drug delivery (Sahoo et al., 1998; Ganorkar et al. 1999; Sinha and Kumria, 2001; Qiu and Park, 2001, Miyata et al., 2002, Murdan, 2003; Kopecek, 2003) has been required depending on changes in physiological signals in the body. Body temperature often deviates from normal Lemperature (37°C) owing to the presence of pathogens or pyrogens. This temperature change may be a useful stimulus that can modulate the delivery of therapeutic drugs for discases with accompanying fever. In addition, temperature can also be easily controlled by manpower in the human body. Therefore, extensive research has been performed in the design of temperature-sensitive drug delivery systems (Bae et al., 1987; Hayashi et al., 1996; Chacona et al., 2000; Kim et al., 2000; Makino et al., 2001; Hsiue et al., 2002: Eeckman et al., 2003; Cohn et al., 2003; Fujimori et al., 2005; Zhang et al., 2005). Among them, the use of thermo-sensitive polymers has been successfully carried out. With these polymers, it is possible to administer the formulation as a solution, which undergo a temperature-induced reversible gel-sol transition upon heating or cooling of the aqueous solution. Aqueous solutions of thermo-sensitive polymerS show an inverse dissolution behavior, their phase diagrams presenting a Lower Critical Solution Temperature (LCST). The solutions are homogenous at low temperature and a phase separation appears when the temperature exceeds a critical value called the cloud point. The LCST is the lowest cloud point of the system; i.e. The minimum of the phase diagram. The polymers solutions are regular at temperatures below the LCST. However, when the temperature is raised above the LCST, polymer chains that swelled previously could contract and result. in phase separation. rww Thermo-sensitive polymers, also called intelligent polymers, have met with an increasing interest, particularly the field of controlled-release drug delivery systems (Hayashi et al., 1996; Kim et al., 2000; Hsiue et al., 2002; Cohn et al., 2003; He et al., 2001; Eeckman et al., 2004; Fujimori et al., 2005; Lin et al., 2005; Na et al., 2006), based on their intelligent and reversible behavior in response to temperature variation. By utilizing thermo-sensitive polymers, a temperature-controlled on-off drug delivery system could be achieved. At present these thermo-sensitive polymers mainly include PNIPAA, PEO-PPO-PEO, PEG-PLGA-PEG, PMPA. PNVCL, EPG and PLGA-PEG-PLGA. All UNDERLYING REQUIREMENTS OF THERMO-SENSITIVE POLYMERS TN CONTROLLED-RELEASE DRUG DELIVERY SYSTEMS For themo-sensitive polymers intended controlled-release drug delivery systems in contact with Corresponding Author: Li Jin, Key Laboratory for Biomechanics and Tissue Engineering under the State Ministry of Education. College of Bioengineering, Chongqing University, Chongqing, 100011. People's Republic of China Tel/Fax: 86-23-65122300 513

Intl. J. Pharmacol., 2 (5): 513-519, 2006 living systems must meel. certain criteria and regulatory requirements. The minimum requirements include the following: firstly, the mechanical and physical properties of these polymers, such as strength, elasticity, durability, etc., must be appropriate for the intended application: secondly, these polymers must be biodegradable. biocompatible and nontoxic and the significant one is that Lower Critical Solution Temperature (LCST) of these polymers should around the normal body temperature (37°C). SOME DOMINANT THERMO-SENSITIVE POLYMERS Poly (N-isopropylacrylamide) (PNIPAAM): Poly (N-isopropylacrylamide) (PNIPAAM), a typical thermo-sensitive polymer, has been widely studied. chielly because of its phase transition. which occurs al about 32-37°C (Heskins et al., 1968; Boutris et al., 1997; Eeckman et al., 2003; Erbil et al., 2001; Kuckling et al., 2004; Gao et al., 2006), thus near the ambient temperature. Aqueous solutions of PNTPAAm exhibit a phase separation phenomenon, showing a very rapid and reversible hydration-dehydration process in response to small temperature changes. At temperatures below the LCST, PNIPAM chains are hydrated and expanded random-coil conformations in water. Above the LCST. PNIPAM chains become dehydrated and collapse into tightly packed globular conformation. That effect is due to the dual character of PNIPA Am whose structure contains both a hydrophobic isopropylic group and a hydrophilic amide group. Moreover, the LCST of PNIPAAm aqueous solutions can be easily modified by copolymerization (Chen et al., 1999; Masci et al., 2002; Zhu et al., 2002; Eeckman et al., 2001; Hirata et al., 2001; Guilherme et al., 2004; Gao et al., 2005; Zhao et al., 2005) or by addition of salts (Ecckman et al., 2002, Gao et al., 2006) or surfactants (Beckman et al., 2003). That interesting feature makes almost every desired LCST value available. Up to now, great interest has focused on the study of PNIPAAM, however, the toxicity of PNIPAAM in the body is unknown and one great limitation of it is the lack of compatibility with cells and blood, thus its application in drug delivery systems may be extremely restricted. PEO-PPO-PEO: Poly (ethylene oxide-b-propylene oxide-b-ethylene oxide) (PEO-PPO-PEO), which consists of at least two blocks with different affinities, i.e.. hydrophilic and hydrophobic has been widely studied for pharmaceutical and biomedical applications (Gaisford et al., 1998; Ivanova et al., 2001; Su et al., 2002; Liu et al., 2003; Sosnik and Cohn, 2001; Wang et al., 2005). Its aqueous solution undergoes phase transitions from sol to gel at 5-30°C and gel to sol at 35-50°C. Due to their amphiphilic character, the PEO-PPO-PEO block copolymers exhibit the unique property of amphiphiles in general to self-organize in supermolecular structure in solutions or al interfaces. These polymers, which are often referred to by the trade name Plutonic, are watersoluble and exhibit low toxicity. Because of low toxicity, they also have specialized applications in drug- controlled release (Liaw and Lin 2000; He et al., 2004). PluronicⓇ F127 is an important member of the family of triblock copolymers of PEO-PPO-PEO. It exhibits thermo-reversible gelation and has therefore generaled considerable interest as a novel method for controlled-release drug delivery (Bohorquez et al., 1999; Scherlund et al., 2000; Desai et al., 2001; Matthew et al., 2002; Sharma and Bhatia, 2004). Pluronic drug delivery applications often rely on a transition from liquid to gel occurring at a specific temperature. Aqueous F127 solutions display a liquid-to-gel transition at physiological temperatures; this is referred to as the gelation transition or the lower gel phase boundary. Al higher temperatures the systems liquefy again and refer to as the gel-to-liquid transition, degelation, or the upper gel phase boundary. Both transitions can be influenced by the presence of hydrophobic drug solutes in the formulation. It is worthwhile to indicate that Pluronic has been approved by FDA as biomaterials used in human body. However, because of the dissolution of micelle in aqueous solution the integrity of PEO-PPO-PEO can only maintain a short time. thus, PEO-PPO-PEO is not applicable for sustained drug delivery. PEG-PLGA-PEG: A thermo-sensitive triblock copolymer poly (ethylene glycol-b-(DL-lactic acid-co-glycolic acid)b-ethylene glycol) (PEG-PLGA-PEG) has been widely researched over the past few years (Anderson and Shive, 1997; Joong et al., 1999a. 2000; Lee et al. 2006). With monotonically increasing temperature, its aqueous solutions undergoes sol to gel transition (lower transition) in the range of 30-35°C and gel to sol transition (upper transition) in the range of 40-70°C. The transition temperatures depend on the concentration of polymers. Between the two transitions, a gel phase exists. In particular, the sol to gel transition temperature and their degradability could make this system ideal for an injectable drug delivery system that can be formulated at room temperature which forms a gel at body temperature. In addition to biodegradability of the polymers, the in situ formed gel maintains its integrity for more than 1 month in rats (Jeong et al., 2000a), while the known gelling polymer, Poloxamer, is not biodegradable and the 514

Intl. J. Pharmacol., 2 (5): 513-519, 2006 formed gel is dissolved in a few zhidays al most. Therefore, the PEG-PLGA-PEC system is applicable for injectable long-term drug delivery (Jeong et al., 1999b; Jeong et al., 2000b; Kan et al., 2005). Poly (methyl 2-propionamidoacrylate) (PMPA): A thermo-sensitive polymer. poly (methyl 2propionamidoacrylate) (PMPA) was reported. (Okamura et al., 2002), which has two substituted group at -carbon of each monomer unit. Each of the two groups consists of hydrophilic (ester and amide bonds) and hydrophobic moieties (methyl and ethyl groups) in a suitable balance. II. was found that PMPA shows the Lower Critical Solution Temperature (LCST) at 50.6°C sharply. The LCST of PMPA was almost independent of the polymer concentration above 40 g 1.−1, while, below 40 g 1.-'. it. decreased with the increasing polymer concentration. The effect of salt addition (NaCl, NaBr and Na₂O₁) on the LCST was also studied. The LCST of PMPA linearly decreased with the increasing concentration of each salt. In addition, it was found that the dependence of LCST on the salt concentration is related to the hydrophilicity of polymers; therefore, we can get almost every desired LCST value available around body temperature. However, few have been reported about the toxicity, biodegradation and biocompatibility of the thermosensitive polymer. Poly (N-vinylcaprolactam) (PNVCL): Recently, there has been much interest in the thermo-sensitive polymer Poly (N-vinyl caprolactam)(PNVCL) (Mamytbekov et al., 1999; Lozinsky et al., 2000; Makhaeva et al., 2000; Chen et al., 2002; Boyko et al., 2003; Vihola et al., 2005), which stands out based on the fact that it is not only nonionic. water-soluble, nontoxic and thermo-sensitive but also biocompatible. If the amide bond in the side group is hydrolysed in harsh strongly acidic conditions a polymeric carboxylic acid builds up. Moreover, the LCST of PNVCI is in the range of physiological temperature (32-34°C). These properties make PNVCL suitable for use in some biotechnology, especially in drug delivery system (Vihola et al., 2002). Considering the high biocompatible of PNVCL, it might be a novel thermo-sensitive polymer as a carrier for controlled-release drug delivery system. Eudragit RS and PEG 400 blend polymers (EPG): The Eudragit RS and polyethylene glycol 400 (PEG 400) blend polymer (EPG), a novel thermo-sensitive polymer, was researched (Fujimoric et al., 2005) by the solvent casting method. The EPG membranes containing 2.5-10% PEG 100 (2.5-10% EPG) show the lower critical solution temperature (LCST) around the body temperature (32-12°C). In the water uptake study for the 10% EPG membrane, the degree of the swelling for the membrane tended to increase with increasing temperature above the LCST of the membrane and the thermo-sensitive permeation mechanism for the EPG membranes may be based on the structure change of the membranes caused by the phase transition. Because of the high biological safety of Eudragil. RS and PEG 100 and the LCST of its aqueous solutions can be easily modified by modulating the proportion of Eudragit RS and PEG 100 (Fig. 1), so we can make almost every desired LCST value available, the EPG membranes might be used to develop a novel thermo-sensitive drug delivery system. PLGA-PEG-PLGA: Chen et al. (2005) synthesized a novel thermo-sensitive triblock polymer (PLGA-PEG-PLGA) by ring-opening polymerization of D,L-lactide and glycolide with polyethylene glycol (PEG) in the presence of stannous octoate. Different phase diagrams can be achieved depending on the block length and he copolymer concentration (Zentner et al., 2001). By adjusting the PLGA-PEG-PLGA triblock copolymer compositions ankl concentrations, Themo-sensitive polymer delivery systems may be used for controlledrelease drug delivery systems for an extended period of time. Due to high biodegradation and biocompatibility (Anderson and Shive. 1997) of PLGA-PEG-PLGA and the LCST of its aqueous solutions is around the body normal temperature (37°C) (Fig. 2). Thus, the biodegradable thermal thermo-sensitive polymer holds high potential as injectable, long-term drug delivery systems. Endothermic Eudragit Its membrane 2.5% EPG membrane 5% EPG membrane Fig. 1: 10% KPG membrane 20 30 40 50 60 70 80 Temperature (°C) DSC curves of Eudragit RS membrane and various membranes prepared by Eudragit RSPEG 400 blend polymer (EPG). Healing Tale. 20°C/min (Fujimorie et al., 2005) 51.5

(a) Intl. J. Pharmacol., 2 (5): 513-519, 2006 (b) Fig. 2: Sol-gel transition of PLGA-PEG-PLGA triblock copolymers at different temperatures. (a) At room temperature or below (<25°C) and (b) at body temperature (37°C) (Chen et al., 2005) Table 1: Characteristics of these seven thermo-sensitive polymers Biocompatibility PNIPA Am PEO-PPO-PEO PEG-PLGA-PEG Lack Unknown PMPA PNVCL EPG PLGA-PEG-PLGA High Unknown High High High Biodegradation High Biotoxicity Unknown LCST(°C) 32-37 High Low High Unknown 5-30 30-35 Unknown Unknown 50.6 High Unknown High Low Low Unknown 32-341 32-42 37 CONCLUSION AND FUTURE PERSPECTIVES In contrast to the conventional thermo-sensitive polymers, they have to overcome some limitations (Table 1), such as lack of biocompatibility and biodegradation, biotoxicity, lower critical solution temperature (LCST) besides the body temperature and a broad thermo-sensitive range. In addition, thermosensitive polymers offer a new attractive carrier for drug delivery systems: a temperature-controlled on-off drug delivery system. Indeed, their performance has still to be improved. Also, their behaviors in the body and their toxicity have to be clarified. However, rational design of thermo-sensitive polymer may lead to a new technology, which achieves accurate controlled-release drug delivery. Although many researchers have done much about the biological effect of these thermo-sensitive polymers, the knowledge about them is superficial. Because we should develop a new drug delivery concept making thermo-sensitive polymers suitable for an effective application in vivo, which seems quite difficult to be achieved by classical means. Moreover, the object aimed at requires that the LCST of the thermo-sensitive polymer should be around the body normal temperature (37°C), which is also difficult to be achieved. It is a procedure with mutually linked and relatively independent phases. It needs co-research of more disciplines, such as polymer science, engineering, pharmaceutics, biochemistry and molecular biology. REFERENCES Anderson, J.M. and M.S. Shive, 1997. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv. Drug Deliv. Rev., 28: 5-24. Bae, Y.H., T. Okano and R. Hsu et al., 1987. Thermosensitive polymers as on-off switches for drug release. Die Makromolekulare Chemie, Rapid Commun., 8: 481-485. Bohorquez, M., C. Koch and T. Trygstadet et al., 1999. A Study of the Temperature-Dependent Micellization of Pluronic F127. J. Colloid Interface Sci., 216: 34-40. Boutris, C., E.G. Chatzi and C. Kiparissides et al., 1997. Characterization of the LCST behaviour of aqueous poly (N-isopropylacrylamide) solutions by thermal and cloud point techniques. Polymer, 38: 2567-2570. Boyko, V., A. Pichb and Y. Lue et al., 2003. Thermosensitive poly (N-vinylcaprolactam-coacetoacetoxyethyl methacrylate) microgels: 1synthesis and characterization. Polymer, 44: 7821-7827. 516

Intl. J. Pharmacol., 2 (5): 513-519, 2006 Chen, S.C., W. Feng and II. Pastrikin et al., 2002. Radiation polymerization of thermo-sensitive poly (N-vinylcaprolactam). Radiat. Phys. Chem., 63: 517-519 Chen, S.B. R.Pieper and D.C. Webster et al., 2005. Triblock copolymers: synthesis, characterization and delivery of a model protein. Intl. J. Pharm., 288: 207-218. Chacona, D., Y.L.Hsicha and M.J. Kurthh et al., 2000. Swelling and protein absorption/desorption of thermo-sensitive lactitol-based polyether polyol hydrogels. Polymer, 41: 8257-8262. Cheon, J., Y. Jeong and C.S. Cho et al., 1999. Effects of temperature on diblock copolymer micelle composed of poly (g-benzyl L-glutamate) and poly (Nisopropylacrylamide). Polymer, 40: 2041-2050, Cohn, D., A. Sosnik and A. Levy et al., 2003. Improved reverse Thermo-responsive polymeric systems. Biomaterials. 21: 3707-3711. Desai, P.R., N.J. Jain and R.K. Sharma et al., 2001. Effect of additives on the micellization of PEO/PPO/PEO block copolymer F127 in aqueous solution. Colloids Surf. A: Physicochem. Eng. Aspects, 178: 57-69. Eeckman, F., A.J. Moes and K. Amighi, 2002. Evaluation of a new controlled-drug delivery concept based on the use of thenoresponsive polymers. Int. J. Phan, 241: 113-125. Leckman, F., A.J. Moes and K. Amighi, 2003. Surfactant induced drug delivery based on the use of thermosensitive polymers. J. Control. Release, 88: 105-116. Eeckman, F. et al., 2001. Synthesis and characterization of thermosensitive copolymers for oral controlled drug delivery. Eur. Polym. J., 40: 873-881. Erbil, C.. E. Kazaneyoglu and N. Uyanýk, 2004 Synthesis. characterization and thermoreversible behaviours of poly(dimethylsiloxane poly(N-isopropyl acrylamide) semi-interpenetrating networks. Eur. Polym. J., 40: 1145-1154. Fujimori, J., Y. Yoshihashi and E. Yonemochi et al., 2005. Application of Eudragit RS to thermo-sensitive drug delivery systems II. Effect of temperature on drug permeability through membrane consisting of Eudragit RS/PEG 100 blend polymers. J. Control. Release, 102: 19-57. Gaisford, S., A.E. Beezer and J.C. Mitchell et al., 1998. Temperature induced aggregation in aqueous solution of a series of PEO-PPO-PEO copolymers. Intl. J. Pharm., 171: 39-16. Ganorkar, C.R., F. Liu and M. Baudys et al., 1999. Modulating insulin-release profile from pH/ thenosensitive polymeric beads through polymer molecular weight. J. Control. Release, 59: 287-298. Gao, C.Y, H. Mohwald and J. Shen et al., 2005. Thermosensitive poly(allylamine)-g-poly(Nisopropylacrylamide): Synthesis, phase separation and particle formation. Polymer. 46: 4088-4097. Gao, C.Y., B. Chen and II. Mohwald et al., 2006. Thermosensitive Ixily (allylamine)-g-poly(\isopropylacrylamide) copolymers: Salt-tuned phase separation, particle formation and their applicability on curved surface. Colloids Surf, A: Physicochem. Eng. Aspects, 272: 203-210. Guilherme, M.R., R. da Silva and A.F. Rubira et al., 2004. Thermo-sensitive hydrogels membranes from PAAM networks and entangled PNIPAAM: Effect of Temperature, cross-linking and PNTPAAm contents on the water uptake and permeability. React. Funct. Polym., 61: 233-243. Hayashi, H., K. Kono and T. Takagishi et al., 1996. Temperature-controlled release property of phospholipid vesicles bearing a thermo-sensitive polymer. Biochim. Biophy. Acta, 1280: 127-134. Ile, II.Y., X. Cao and L.J. Lee et al., 2004. Design of a novel hydrogel-based intelligent system controlled drug release. J Controlled Release, 95: 391-402. Heskins, M. et al., 1968. Solution properties of poly (Nisopropylacrylamide). J. Macromol. Sci. Chem. A, 2: 1441-1455. Hirata, I., M. Okazakia and H. Iwata et al., 2001. Simple method for preparation of ultra-thin poly(Nisopropylacrylamide) hydrogel layers and characterization of their thermo-responsive properties. Polymer, 45: 5569-5578. Hsiue. G.H., S.H. Hsub and C.C. Yang et al., 2002. Preparation of controlled release ophthalmic drops, for glaucoma therapy using thermosensitive poly-Nisopropylacrylamide. Biomaterials, 23: 157-162. Ivanova, R., B. Lindmana and P. Alexandridis et al., 2001. Modification of the lyotropic liquid crystalline microstructure of amphiphilic block copolymers in the presence of cosolvents. Adv. Colloid Interface Sci.. 89-90: 351-382. Jeong, B., Y.II. Bae and S.W. Kim et al., 1999a. Biodegradable thermosensitive micelles of PEGPLGA-PEG triblock copolymers. Colloids and Surfaces B: Biointerfaces, 16: 185-193. Jeong, B., Y.K. Choi and Y.H. Bac et al., 1999h. New biodegradable polymers for injectable drug delivery Systems. J. Control. Release, 62: 109-114. Jeong, B., Y.H. Bac and S.W. Kim et al, 2000a. In situ gelation of PEG-PLOA-PEC triblock copolymer aqueous solutions and degradation thereof. J. Biomed. Mater. Res., 50: 171-177. 517

Intl. J. Pharmacol., 2 (5): 513-519, 2006 Jeong, B., Y.H. Bac and S.W. Kim et al., 2000b. Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers. J. Control. Release, 63: 155-163. Kan, P., XZ. Lin and M.F. Hsieh et al., 2005. Thermogelling Emulsions for Vascular Embolization and Sustained Release of Drugs. J. Biomed. Mater Res. Part B: Appl. Biomater, 75B: 185-192. Kim, S.Y., J.C. Ha, Y. and M. Lee et al., 2000. Poly(ethylene oxide)-poly(propylene oxide)poly(ethyleneoxide) poly(e-caprolactone) (PCL) amphiphilic block copolymeric nanospheres II. Thermo-responsive drug release behaviors. J. Control. Release, 65: 345-358. Kopecck, J., 2003. Smart and genetically engineered biomaterials and drug delivery systems. Eur. J. Pharm. Sci., 20: 1-16. Kuckling, D., T. Schmidt and G. Filipcsei et al., 2004. Preparation of filled temperature-sensitive poly (Nisopropylacrylamide) Gel Beads. Macromol. Symp. 210: 369-376. Lee, S.J., B.R. Han and S. Y. Park et al., 2006. Sol-Gel Transition behavior of biodegradable three-arm and four-am star-shaped PLGA-PEG block copolymer aqueous solution. J. Polym. Sci. Part A: Polym. Chem., 11: 888-899. Liaw, J.H. and Y.C. Lin, 2000. Evaluation of poly (ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) gels as a release vehicle for percutaneous fentanyl. J. Controlled Release, 68: 273-282. Lin, C.L., W. Y. Chiu and C.F. Lee et al., 2005. Thermal/pHsensitive core-shell copolymer latex and its potential for targeting drug carrier application. Polymer, 46: 10092-10101 Liu, S.H., X.F. Qian and J. Yin et al., 2003. Room temperature synthesis of PbS nanocrystals with different morphologies in PEO-PPO-PEO uriblock copolymers. Mater. Sci. Eng., B100: 314-317. Lozinsky. V.I., L.A. Simenel and E. A. Kurskaya et al., 2000. Synthesis of N-vinylcaprolactam polymers in watercontaining media. Polymer, 41: 6507-6518. Makhaeva, E.E., H. Tenhub and A.R. Khokhlova et al., 2000. Behaviour of poly (N-vinylcaprolactam) macromolecules in the presence of organic compounds in aqueous solution. Polymer, 41: 9139-9145. Makino, K., Y. Fujita and K. Takao et al., 2001. Preparation and properties of thermosensitive hydrogel microcapsules. Colloids Surf B Biointerfaces, 21: 259-263. Marybekov, G., K. Bouchala and M. Ilavsky et al., 1999. Phase Iransition in swollen gels 26. Feel of charge concentration on temperature dependence of swelling and mechanical behaviour of poly(\vinylcaprolactam) gels. Eur. Polym. J., 35: 1925-1933. Masci, G.D. Bontempo and V. Crescenzi et al., 2002. Synthesis and characterization of thermoresponsive N-isopropylacrylamide/methacrylated pullulan hydrogels. Polymer, 13: 5587-5593. Matthew, J.E., Y.L. Nazario and S.C. Roberts et al., 2002. Effect of mammalian cell culture medium on the gelation properties of Pluronics F127. Biomaterials, 23: 4615-4619. Miyata, T., T. Uragami and K. Nakamae et al., 2002. Biomolecule-sensitive hydrogels. Adv. Drug Deliv. Rev. 54: 79-98. Murdan, S., 2003. Electro-responsive drug delivery from hydrogels. J. Control. Release, 92: 1-17. Na, K., K.H. Lee and D.H. Lee, 2006. Biodegradable thermo-sensitive nanoparticles from poly(L-lactic acid)/poly(ethylene glycol) alternating multi-block copolymer for potential anti-cancer drug carrier. Eur. J. Pharm. Sci., 27: 115-122. Okamura, H., T. Mori and K. Minagawa et al., 2002. A novel thermosensitive polymer, poly (methyl 2propionamidoacrylate), with geminal substituents. Polymer, 13: 3825-3828. Qiu, Y. and K. Park, 2001. Environment-sensitive hydrogels for drug delivery. Adv. Drug Deliv. Rev.. 53: 321-339. Sahoo, S.K.. T.K. De and P.K. Ghosh et al. 1998. pH and thermo-sensitive hydrogel nanoparticles. J. Colloid Interface Sci., 206: 361-368. Scherlund M., M. Malmsten and P. Holmqvist et al., 2000. Thermosetting microemulsions and mixed micellar solutions as drug delivery systems for periodontal anesthesia. Int. J. Pharm., 194: 103-116. Sharma, P.K. and S.R. Bhatia, 2004. Effect of antiinflammatories on Pluronic® F127: micellar assembly, gelation and partitioning. Intl. J. Pharm., 278: 361-377. Sinha, V.R. and R. Kumria, 2001. Polysaccharides in colonspecific drug delivery. Intl. J. Pharm., 224: 19-38. Sosnik, A. and D. Cohn, 2001. Ethoxysilane-capped PLOPPO-PEO triblocks: A new family of reverse thermoresponsive polymers. Biomaterials, 25: 2851-2858. Su, Y.L., J. Wang and H.Z. Liu et al., 2002. Melt, hydration and micellization of the PEO-PPO-PEO block copolymer studied by FTIR spectroscopy. J. Colloid Interface Sci., 251: 417-423. 518

Intl. J. Pharmacol., 2 (5): 513-519, 2006 Viola, H., A. Laukkanen and J. Hirvonen et al., 2002. Binding and release of drugs into and from thermosensitive poly (N-vinylcaprolactam) nanoparticles. Eur. J. Pharm. Sci., 16: 69-74. Vihola, II., A. Laukkanen and L. Valtola et al., 2005. Cytotoxicity of thermosensitive polymers poly(Nisopropylacrylamide), poly(N-vinyleaprolactam) and amphiphilically modified poly(N-vinylcaprolactam). Biomaterials, 26: 3055-3064. Wang, F., G. Xu and Z.Q. Zhang et al., 2005. Morphology control of barium sulfate by PEO-PPO-PEO as crystal growth modifier. Colloids and Surfaces A: Physicochem. Eng. Aspects, 259: 51-154. Zentner, G.M., R. Rahia and C. Shih et al, 2001. Biodegradable block copolymers for delivery of proteins and water-insoluble drugs. J. Control. Release, 72: 203-21.5. Zhang, Y., W. Zhu and B.B. Wang et al., 2005. A novel microgel and associated post-fabrication encapsulation technique of proteins. J. Control. Release, 105: 260-268. Zhao, C.R., Q. Wang and J.W. Meng et al., 2005. A new thermosensitive polymer as nonadhesive liquidl embolism material. Curr. Applied Phys., 5: 197-500. Zhu, L.Y, G.L. Zhu and M.Z. Li et al., 2002. Thermosensitive aggregates self-assembled by an asymmetric block copolymer of dendritic polyether and poly (N-isopropylacrylamide). Eur. Polym. J., 38: 2503-2506. 519