Biodegradable In Situ Gel-Forming Controlled Drug Delivery System Based on Thermosensitive Poly(-caprolactone)-Poly(ethylene glycol)-Poly(-caprolactone) Hydrogel
Traditional drug delivery systems which are based on multiple dosing regimens usually pose many disadvantages such as poor compliance of patients and drug plasma level variation. To overcome the obstacles of traditional drug formulations, novel drug delivery system PCL-PEG-PCL hydrogels have been purposed in this study. Copolymers were synthesized by rapid microwave-assisted and conventional synthesis methods. Polymer characterizations were done using gel permeation chromatography and 1H-NMR. Phase transition behavior was evaluated by inverting tube method and in vitro drug release profile was determined using naltrexone hydrochloride and vitamin B12 as drug models. The results indicated that loaded drug structure and copolymer concentration play critical roles in release profile of drugs from these hydrogels. This study also confirmed that synthesis of copolymer using microwave is the most effective method for synthesis of this kind of copolymer. 1. Introduction Treatment of disease by multiple dosing strategies and using conventional drug formulation poses many drawbacks [1]. Among them are fluctuation of drug plasma concentration, the various side effects due to toxic plasma level of drug, or ineffectiveness treatment because of the lower concentration of drug than its therapeutic index [2, 3]. Another important limitation of multiple dosing regimens is poor patient compliance especially for diseases for which patient must take drugs for a long time such as epilepsy [4, 5] or for some specific drugs such as naltrexone hydrochloride which is used for maintenance abstinence in detoxified addicted persons after withdrawal phase of opioids and alcohol [6, 7]. Nowadays scientists are interested in novel drug delivery systems which are used to direct drugs to the specific site of action and to achieve a controlled release of drug with a desirable release kinetics [1, 8]. Among the most studied of these systems are hydrogels which are insoluble matrices of hydrophilic block copolymers which swell in presence of fluids [9, 10]. Smart hydrogels are the polymeric networks which release drugs in response to the environmental parameters such as temperature [11–13], pH [14, 15], light [16, 17], magnetisms [18, 19]. Thermoresponsive hydrogels are extensively investigated smart hydrogels because of their simple application, low adverse effect on tissues compared with some other stimuli, and the difference between room and body temperature [12, 20]. Amphiphilic triblock copolymers, PCL-PEG-PCL, composed of polyethylene glycol (PEG) and poly (ε-caprolactone) (PCL),
References
[1]
P. Gupta, K. Vermani, and S. Garg, “Hydrogels: from controlled release to pH-responsive drug delivery,” Drug Discovery Today, vol. 7, no. 10, pp. 569–579, 2002.
[2]
A. Sood and R. Panchagnula, “Design of controlled release delivery systems using a modified pharmacokinetic approach: a case study for drugs having a short elimination half-life and a narrow therapeutic index,” International Journal of Pharmaceutics, vol. 261, no. 1-2, pp. 27–41, 2003.
[3]
A. Sandberg, I. Blomqvist, U. E. Jonsson, and P. Lundborg, “Pharmacokinetic and pharmacodynamic properties of a new controlled-release formulation of metoprolol: a comparison with conventional tablets,” European Journal of Clinical Pharmacology, vol. 33, pp. S9–S14, 1988.
[4]
A. J. Claxton, J. Cramer, and C. Pierce, “A systematic review of the associations between dose regimens and medication compliance,” Clinical Therapeutics, vol. 23, no. 8, pp. 1296–1310, 2001.
[5]
J. A. Cramer, M. Glassman, and V. Rienzi, “The relationship between poor medication compliance and seizures,” Epilepsy and Behavior, vol. 3, no. 4, pp. 338–342, 2002.
[6]
R. Gueorguieva, R. Wu, B. Pittman et al., “New insights into the efficacy of naltrexone based on trajectory-based reanalyses of two negative clinical trials,” Biological Psychiatry, vol. 61, no. 11, pp. 1290–1295, 2007.
[7]
J. L. Rothenberg, M. A. Sullivan, S. H. Church et al., “Behavioral naltrexone therapy: an integrated treatment for opiate dependence,” Journal of Substance Abuse Treatment, vol. 23, no. 4, pp. 351–360, 2002.
[8]
C. He, S. W. Kim, and D. S. Lee, “In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery,” Journal of Controlled Release, vol. 127, no. 3, pp. 189–207, 2008.
[9]
C.-C. Lin and A. T. Metters, “Hydrogels in controlled release formulations: network design and mathematical modeling,” Advanced Drug Delivery Reviews, vol. 58, no. 12-13, pp. 1379–1408, 2006.
[10]
L. Klouda and A. G. Mikos, “Thermoresponsive hydrogels in biomedical applications,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 68, no. 1, pp. 34–45, 2008.
[11]
J. W. Lee, F.-J. Hua, and D. S. Lee, “Thermoreversible gelation of biodegradable poly(ε-caprolactone) and poly(ethylene glycol) multiblock copolymers in aqueous solutions,” Journal of Controlled Release, vol. 73, no. 2-3, pp. 315–327, 2001.
[12]
E. Ruel-Gariépy and J.-C. Leroux, “In situ-forming hydrogels—review of temperature-sensitive systems,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 58, no. 2, pp. 409–426, 2004.
[13]
E. Khodaverdi, O. Rajabi, F. Farhadi, A. Jalali, and F. S. Mirzazadeh Tekie, “Preparation and investigation of poly (N-isopropylacrylamide-acrylamide) membranes in temperature responsive drug delivery,” Iranian Journal of Basic Medical Sciences, vol. 13, no. 3, pp. 102–110, 2010.
[14]
E. Khodaverdi, O. Rajabi, M. J. Abdekhodai, and X. Y. Wu, “Heterogenous composite membranes as pH responsive drug delivery systems,” Iranian Journal of Basic Medical Sciences, vol. 11, no. 2, pp. 70–79, 2008.
[15]
B. Albarran, A. S. Hoffman, and P. S. Stayton, “Efficient intracellular delivery of a pro-apoptotic peptide with a pH-responsive carrier,” Reactive and Functional Polymers, vol. 71, no. 3, pp. 261–265, 2011.
[16]
N. ？. Kne？evi？, B. G. Trewyn, and V. S. Y. Lin, “Light- and pH-responsive release of doxorubicin from a mesoporous silica-based nanocarrier,” Chemistry, vol. 17, no. 12, pp. 3338–3342, 2011.
[17]
S. K. Choi, M. Verma, J. Silpe, R. E. Moody, K. Tang, J. J. Hanson, et al., “A photochemical approach for controlled drug release in targeted drug delivery,” Bioorganic & Medicinal Chemistry, vol. 20, no. 3, pp. 1281–1290, 2012.
[18]
S. A. Meenach, J. Z. Hilt, and K. W. Anderson, “Poly(ethylene glycol)-based magnetic hydrogel nanocomposites for hyperthermia cancer therapy,” Acta Biomaterialia, vol. 6, no. 3, pp. 1039–1046, 2010.
[19]
N. S. Satarkar and J. Z. Hilt, “Magnetic hydrogel nanocomposites for remote controlled pulsatile drug release,” Journal of Controlled Release, vol. 130, no. 3, pp. 246–251, 2008.
[20]
X.-Z. Zhang, R.-X. Zhuo, J.-Z. Cui, and J.-T. Zhang, “A novel thermo-responsive drug delivery system with positive controlled release,” International Journal of Pharmaceutics, vol. 235, no. 1-2, pp. 43–50, 2002.
[21]
C. Gong, S. Shi, L. Wu et al., “Biodegradable in situ gel-forming controlled drug delivery system based on thermosensitive PCL-PEG-PCL hydrogel. Part 2: sol-gel-sol transition and drug delivery behavior,” Acta Biomaterialia, vol. 5, no. 9, pp. 3358–3370, 2009.
[22]
X. Wei, C. Gong, M. Gou et al., “Biodegradable poly(ε-caprolactone)-poly(ethylene glycol) copolymers as drug delivery system,” International Journal of Pharmaceutics, vol. 381, no. 1, pp. 1–18, 2009.
[23]
M. Gou, M. Dai, X. Li et al., “Preparation of mannan modified anionic PCL-PEG-PCL nanoparticles at one-step for bFGF antigen delivery to improve humoral immunity,” Colloids and Surfaces B, vol. 64, no. 1, pp. 135–139, 2008.
[24]
M. Gou, L. Zheng, X. Peng et al., “Poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL) nanoparticles for honokiol delivery in vitro,” International Journal of Pharmaceutics, vol. 375, no. 1-2, pp. 170–176, 2009.
[25]
L. Zhang, Y. He, M. Yu, and C. Song, “Paclitaxel-loaded polymeric nanoparticles based on PCL-PEG-PCL: preparation, in vitro and in vivo evaluation,” Journal of Controlled Release, vol. 152, supplement 1, pp. e114–e116, 2011.
[26]
X. Dong, R. Qi, Y. Huang, and X. Jing, “Synthesis of biodegradable dextran-g-(PCL-b-PEG) by combination of ring-opening polymerization and click chemistry,” Journal of Controlled Release, vol. 152, supplement 1, pp. e198–e199, 2011.
[27]
A. Sosnik, G. Gotelli, and G. A. Abraham, “Microwave-assisted polymer synthesis (MAPS) as a tool in biomaterials science: how new and how powerful,” Progress in Polymer Science, vol. 36, no. 8, pp. 1050–1078, 2011.
[28]
C. Gong, S. Shi, P. Dong et al., “Synthesis and characterization of PEG-PCL-PEG thermosensitive hydrogel,” International Journal of Pharmaceutics, vol. 365, no. 1-2, pp. 89–99, 2009.
[29]
C. Y. Gong, S. Shi, P. W. Dong et al., “Biodegradable in situ gel-forming controlled drug delivery system based on thermosensitive PCL-PEG-PCL hydrogel: part 1—synthesis, characterization, and acute toxicity evaluation,” Journal of Pharmaceutical Sciences, vol. 98, no. 12, pp. 4684–4694, 2009.
[30]
Y. N. Kalia and R. H. Guy, “Modeling transdermal drug release,” Advanced Drug Delivery Reviews, vol. 48, no. 2-3, pp. 159–172, 2001.
[31]
T. Higuchi, “Rate of release of medicaments from ointment bases containing drugs in suspension,” Journal of Pharmaceutical Sciences, vol. 50, no. 10, pp. 874–875, 1961.
[32]
S. W. Kim, Y. H. Bae, and T. Okano, “Hydrogels: swelling, drug loading, and release,” Pharmaceutical Research, vol. 9, no. 3, pp. 283–290, 1992.
