In vitro release behavior of paclitaxel and carboplatin from poly(l-lactide) microspheres dispersed in thermosensitive biodegradable gel for combination therapy

Anupama Mittal, Phaneendra Kurapati, Deepak Chitkara, Neeraj Kumar


The objective of the current work was to design an injectable, sustained release formulation of a combination of anticancer drugs, carboplatin and paclitaxel, for localized delivery. In this combination formulation, carboplatin was encapsulated into poly(L-lactide) (PLA) microspheres and paclitaxel was dissolved in thermosensitive biodegradable gel of PLGA-PEG-PLGA (poly (DL-lactide-co-glycolide- polyethylene glycol- poly (DL-lactide-co-glycolide)); no external solvent like cremophorEL was used in the formulation, further, these carboplatin microspheres were dispersed in the gel containing paclitaxel to achieve a single delivery system. The combined formulation was assessed for various parameters for sustained release of both the drugs. Release profiles of carboplatin from PLA microspheres; paclitaxel from hydrogel alone and in combination with carboplatin and carboplatin microspheres dispersed in paclitaxel loaded gel were studied. In vitro release of both the drugs from PLGA-PEG-PLGA hydrogel showed that carboplatin was released with 40-50% burst release and paclitaxel was released in biphasic manner for 50-60 days. Initial burst of carboplatin was controlled by incorporating it in PLA microspheres which were then dispersed in paclitaxel loaded hydrogel and the new formulation did not exhibit any burst release of the drug. Release pattern of combination formulations revealed that the two drugs were co-eluting from a single delivery system and the rate of release of each of the individual drugs was significantly affected.Thus, a novel injectable combination formulation for sustained and simultaneous delivery of carboplatin and paclitaxel was developed which provided sustained release of each of the drugs and could be further explored in tumor models.

Keywords: Thermosensitive hydrogels, Microspheres, controlled release, combination chemotherapy.


Thermosensitive hydrogels, Microspheres, controlled release, combination chemotherapy.

Full Text:



Skipper HE, Schabel FM, Mellet LB, Montogomery JA, Wilkoff LJ, Lloyd HH, Brockman RW. Implications of biochemical, cytokinetic, pharmacologic, and toxicologic relationships in the design of optimal therapeutic schedules. Cancer Chemother Rep 1970;54:431-450.

Chabner BA, Amrein PC, Druker BJ, Michaelson MD, Goss PE, Ryan DP. Antineoplastic Agents. In: Brunton AC, Lazo JS,Parker KL, editors. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11 ed. New York: McGraw-Hill; 2006;p.1375-1465.

Dhanikula AB, Panchagnula R. Localized paclitaxel delivery. Int J Pharm 1999;183:85-100.

Laohavinij S, Maoleekoonpairoj S, Cheirsilpa A, Maneechavakajorn J, Sirachainant E, Arpornvivat W, Jaisathaporn K, Ratanatharathorn V. Phase II study of paclitaxel and carboplatin for advanced non-small-cell lung cancer. Lung Cancer 1999;26:175-185.

Stordal B, Pavlakis N, Davey R. A systematic review of platinum and taxane resistance from bench to clinic: An inverse relationship. Cancer Treat Rev 2007;33:688-703.

Perez EA. Carboplatin in Combination Therapy for Metastatic Breast Cancer. The Oncologist 2004;9:518-527.

Coleman KO, Steven WJ, Andre R, Debbie K, James MB, Thomas CH, Robert FO, Peter JO, James MG. Evaluation of carboplatin pharmacokinetics in the absence and presence of paclitaxel. Clin Cancer Res 1996;2:549-552.

Tomoko O, Yasutsuna S, Tomohide T, Yoshinori M, Hiroshi N, Yutaka N, Nagahiro S. Clinical pharmacokinetics and pharmacodynamics of paclitaxel: A 3-hour infusion versus a 24-hour infusion. Clin Cancer Res 1995;1:599-606.

Liggins RT, Hunter WL, Burt HM. Solid-state characterization of paclitaxel. J Pharm Sci 1997;86:1458-1463.

Perdue JD, Seaton PJ, Tyrell JA, DeVido DR. The removal of cremophorEL from paclitaxel for quantitative analysis by HPLC-UV. J Pharm Biomed Anal 2006;41:117-123.

Chen S, Pieper R, Webster DC, Singh J. Triblock copolymers: synthesis, characterization, and delivery of a model protein. Int J Pharm 2005;288:207-218.

Qiao M, Chen D, Ma X, Liu Y. Injectable biodegradable temperature-responsive PLGA-PEG-PLGA copolymers: synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels. Int J Pharm 2005;294:103-112.

Rathi RC, Zenter GM. Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties. US Patent 6201072, Dec 21, 1999.

Choi S, Kim SW. Controlled release of insulin from injectable biodegradable triblock copolymer depot in ZDF rats. Pharm Res 2003;20:2008-2010.

Zentner GM, Rathi R, Shih C, McRea JC, Seo MH, Oh H, Rhee BG, Mestecky J, Moldoveanu Z, Morgan M, Weitman S. Biodegradable block copolymers for delivery of proteins and water-insoluble drugs. J Control Release 2001;72:203-215.

Berchane NS, Carson KH, Rice-Ficht AC, Andrews MJ. Effect of mean diameter and polydispersity of PLG microspheres on drug release: Experiment and theory. Int J Pharm 2007;337:118-126.

Shinoda H, Ohtaguro M. Preparation process for bioabsorbable polyester. US Patent 5041529, Aug 20, 1991.

Mittal A, Chitkara D, Kumar N. HPLC method for the determination of carboplatin and paclitaxel with cremophorEL in an amphiphilic polymer matrix. J Chromatography B 2007;855:211-219.

Chen S, Pieper R, Webster DC, Singh J. Triblock copolymers: synthesis, characterization, and delivery of a model protein. Int. J. Pharm. 2005;288:207-218.


  • There are currently no refbacks.

Copyright (c)

               AR Journals

18K, Street 1st, Gaytri Vihar, Pinto Park, Gwalior, M.P. India (Design) 2009-2021


Follow @arjournals on Twitter