Design and development of intraocular polymeric implant systems for long-term controlled-release of clindamycin phosphate for toxoplasmic retinochoroiditis


1 Department of Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

2 Department of Ophthalmology, Eye Research Center, Farabi Eye Hospital, Iran

3 Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran


Background: The release of the anti-toxoplasmosis drug, clindamycin phosphate, from intraocular implants of the biodegradable polymers poly (D, L-lactic acid) (PLA) and poly (D, L-lactide-co-glycolide) (PLGA) has been studied in vitro.
Materials and Methods: The preparation of the implants was performed by a melt-extrusion method. The developed extrudates were characterized and compared in in-vitro release profiles for elucidating the drug release mechanism. The formulations containing up to 40% w/w of drug were prepared. Release data in phosphate buffer (pH 7.4) were analyzed by high performance liquid chromatography. The release kinetics were fitted to the zero-order, Higuchi's square-root, first order and the Korsmeyer-Peppas empirical equations for the estimation of various parameters of the drug release curves. Degradation of implants was also investigated morphologically with time (Scanning Electron Microscopy).
Results: It was observed that, the release profiles for the formulations exhibit a typical biphasic profile for bulk-eroding systems, characterized by a first phase of burst release (in first 24 hrs), followed by a phase of slower release. The duration of the secondary phase was found to be proportional to the molecular weight and monomer ratio of copolymers and also polymer-to-drug ratios. It was confirmed that Higuchi and first-order kinetics were the predominant release mechanisms than zero order kinetic. The Korsmeyer-Peppas exponent (n) ranged between 0.10 and 0.96. This value, confirmed fickian as the dominant mechanism for PLA formulations (n ≤ 0.45) and the anomalous mechanism, for PLGAs (0.45 < n < 0.90).
Conclusion: The implant of PLA (I.V. 0.2) containing 20% w/w of clindamycin, was identified as the optimum formulation in providing continuous efficient in-vitro release of clindamycin for about 5 weeks.


Bourges JL, Bloquel C, Thomas A, Froussart F, Bochot A, Azan F, et al. Intraocular implants for extended drug delivery: Therapeutic applications. Adv Drug Deliv Rev 2006;58:1182-202.  Back to cited text no. 1
Choonara YE, Pillay V, Danckwerts MP, Carmichael TR, du Toit LC. A review of implantable intravitreal drug delivery technologies for the treatment of posterior segment eye diseases. J Pharm Sci 2010;99:2219-39.  Back to cited text no. 2
Eljarrat-Binstock E, Pe'er J, Domb AJ. New techniques for drug delivery to the posterior eye segment. Pharm Res 2010;27:530-43.  Back to cited text no. 3
Del Amo EM, Urtti A. Current and future ophthalmic drug delivery systems. A shift to the posterior segment. Drug Discov Today 2008;13:135-43.  Back to cited text no. 4
Thrimawithana TR, Young S, Bunt CR, Green C, Alany RG. Drug delivery to the posterior segment of the eye. Drug Discov Today 2011;16:270-7.  Back to cited text no. 5
Sobrin L, Kump LI, Foster CS. Intravitreal clindamycin for toxoplasmic retinochoroiditis. Retina 2007;27:952-7.  Back to cited text no. 6
Peyman GA, Charles HC, Liu KR, Khoobehi B, Niesman M. Intravitreal liposome-encapsulated drugs: A preliminary human report. Int Ophthalmol 1988;12:175-82.  Back to cited text no. 7
Paquejt JT, Peyman GA. Intravitreal clindamycin phosphate in the treatment of vitreous infection. Ophthalmic Surg 1974;5:34-9.  Back to cited text no. 8
Soheilian M, Ramezani A, Azimzadeh A, Sadoughi MM, Dehghan MH, Shahghadami R, et al. Randomized trial of intravitreal clindamycin and dexamethasone versus pyrimethamine, sulfadiazine, and prednisolone in treatment of ocular toxoplasmosis. Ophthalmology 2011;118:134-41.  Back to cited text no. 9
Mostafavi N, Ataei B, Nokhodian Z, Monfared LJ, Yaran M, Ataie M, et al. Toxoplasma gondii infection in women of childbearing age of Isfahan, Iran: A population-based study. Adv Biomed Res 2012;1:60.  Back to cited text no. 10
Sallam A, Jayakumar S, Lightman S. Intraocular delivery of anti-infective drugs-bacterial, viral, fungal and parasitic. Recent Pat Antiinfect Drug Discov 2008;3:53-63.  Back to cited text no. 11
Wong R, dell'Omo R, Marino M, Hussein B, Okhravi N, Pavesio CE. Toxoplasma gondii: An atypical presentation of toxoplasma as optic disc swelling and hemispherical retinal vein occlusion treated with intravitreal clindamycin. Int Ophthalmol 2009;29:195-8.  Back to cited text no. 12
Lasave AF, Díaz-Llopis M, Muccioli C, Belfort R Jr, Arevalo JF. Intravitreal clindamycin and dexamethasone for zone 1 toxoplasmic retinochoroiditis at twenty-four months. Ophthalmology 2010;117:1831-8.  Back to cited text no. 13
de-la-Torre A, Stanford M, Curi A, Jaffe GJ, Gomez-Marin JE. Therapy for ocular toxoplasmosis. Ocul Immunol Inflamm 2011;19:314-20.  Back to cited text no. 14
Martínez Castillo S, Gallego-Pinazo R, Francés-Muñoz E, Dolz-Marco R, Vázquez Polo A, Díaz-Llopis M. Macular toxoplasmosis and intravitreal clindamycin: An alternative to oral treatment. Arch Soc Esp Oftalmol 2012;87:93-5.  Back to cited text no. 15
Vukomanoviæ M, Skapin SD, Poljanšek I, Zagar E, Kralj B, Ignjatoviæ N, et al. Poly (D, L-lactide-co-glycolide)/hydroxyapatite core-shell nanosphere. Part 2: Simultaneous release of a drug and a prodrug (clindamycin and clindamycin phosphate). Colloids Surf B Biointerfaces 2011;82:414-21.  Back to cited text no. 16
Rao VS, Peyman GA, Khoobehi B, Vangipuram S. Evaluation of liposome-encapsulated clindamycin in Staphylococcus aureus endophthalmitis. Int Ophthalmol 1989;13:181-5.  Back to cited text no. 17
Uskokoviæ V, Hoover C, Vukomanoviæ M, Uskokoviæ DP, Desai TA. Osteogenic and antimicrobial nanoparticulate calcium phosphate and poly-(D, L-lactide-co-glycolide) powders for the treatment of osteomyelitis. Mater Sci Eng C Mater Biol Appl 2013;33:3362-73.  Back to cited text no. 18
Vukomanoviæ M, Zavašnik-Bergant T, Braèko I, Skapin SD, Ignjatoviæ N, Radmiloviæ V, et al. Poly (D, L-lactide-co-glycolide)/hydroxyapatite core-shell nanospheres. Part 3: Properties of hydroxyapatite nano-rods and investigation of a distribution of the drug within the composite. Colloids Surf B Biointerfaces 2011;87:226-35.  Back to cited text no. 19
Vukomanoviæ M, Skapin SD, Janèar B, Maksin T, Ignjatoviæ N, Uskokoviæ V, et al. Poly (D, L-lactide-co-glycolide)/hydroxyapatite core-shell nanospheres. Part 1: A multifunctional system for controlled drug delivery. Colloids Surf B Biointerfaces 2011;82:404-13.  Back to cited text no. 20
Hascicek C, Rossi A, Colombo P, Massimo G, Strusi OL, Colombo G. Assemblage of drug release modules: Effect of module shape and position in the assembled systems on floating behavior and release rate. Eur J Pharm Biopharm 2011;77:116-21.  Back to cited text no. 21
Kimura H, Ogura Y. Biodegradable polymers for ocular drug delivery. Ophthalmologica 2001;215:143-55.  Back to cited text no. 22
Athanasiou KA, Niederauer GG, Agrawal CM. Sterilization, toxicity, biocompatibility and clinical applications of polylactic acid/polyglycolic acid copolymers. Biomaterials 1996;17:93-102.  Back to cited text no. 23
The United States Pharmacopeia. 35 th ed. (USP 35). United States Pharmacopeial Convention Inc. Rockville: CD-ROM (Insight Publishing Productivity; 2012.  Back to cited text no. 24
Li S, Shen Y, Li W, Hao X. A common profile for polymer-based controlled release and its logical interpretation to general release process. J Pharm Pharm Sci 2006;9:238-44.  Back to cited text no. 25
Ritger PL, Peppas NA. A simple equation for the description of solute release, II: Fickian and anomalous release from swellable devices. J Control Release 1987;5:37-42.  Back to cited text no. 26
Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci 2001;13:123-33.  Back to cited text no. 27
Korsmeyer RW, Gury R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm 1983;15:25-35.  Back to cited text no. 28
Kunou N, Ogura Y, Yasukawa T, Kimura H, Miyamoto H, Honda Y, et al. Long-term sustained release of ganciclovir from biodegradable scleral implant for the treatment of cytomegalovirus retinitis. J Control Release 2000;68:263-71.  Back to cited text no. 29
Birnbaum DT, Kosmala JD, Henthorn DB, Peppas LB. Controlled release of h-estradiol from PLAGA microparticles: The effect of organic phase solvent on encapsulation and release. J Control Release 2000;65:375-87.  Back to cited text no. 30
Fu Y, Kao WJ. Drug release kinetics and transport mechanisms of non-degradable and degradable polymeric delivery systems. Expert Opin Drug Deliv 2010;7:429-44.  Back to cited text no. 31
Frank A, Rath SK, Venkatraman SS. Controlled release from bioerodible polymers: Effect of drug type and polymer composition. J Control Release 2005;102:333-44.  Back to cited text no. 32
Rosenberg RT, Siegel SJ, Dan N. Release of highly hydrophilic drugs from poly (epsilon-caprolactone) matrices. J Appl Polym Sci J 2008;107:3149-56.  Back to cited text no. 33
Siegel SJ, Kahn JB, Metzger K, Winey KI, Werner K, Dan N. Effect of drug type on the degradation rate of PLGA matrices. Eur J Pharm Biopharm 2006;64:287-93.  Back to cited text no. 34
McGinity JW, Koleng JJ, Repka MA, Zhang F. Hot-melt extrusion technology. In: Swarbrick J, Boylan JC, editors. Encyclopedia of pharmaceutical technology. New York: Marcel Dekker; 2001. p. 203-26.  Back to cited text no. 35
Breitenbach J. Melt extrusion: From process to drug delivery technology. Eur J Pharm Biopharm 2002;54:107-17.  Back to cited text no. 36
Albers J, Alles R, Matthée K, Knop K, Nahrup JS, Kleinebudde P. Mechanism of drug release from polymethacrylate-based extrudates and milled strands prepared by hot-melt extrusion. Eur J Pharm Biopharm 2009;71:387-94.  Back to cited text no. 37
Young CR, Koleng JJ, McGinity JW. Production of spherical pellets by a hot-melt extrusion and spheronization process. Int J Pharm 2002;242:87-92.  Back to cited text no. 38
Brabander C, Vervaet C, Remon JP. Development and evaluation of sustained release mini-matrices prepared via hot-melt extrusion. J Control Release 2003;89:235-47.  Back to cited text no. 39
Cheboyina S, Wyandt CM. Wax-based sustained release matrix pellets prepared by a novel freeze pelletization technique II. In vitro drug release studies and release mechanisms. Int J Pharm 2008;359:167-73.  Back to cited text no. 40
Verhoeven E, Siepmann F, De Beer TR, Van Loo D, Van den Mooter G, Remon JP, et al. Modeling drug release from hot-melt extruded mini-matrices with constant and non-constant diffusivities. Eur J Pharm Biopharm 2009;73:292-301.  Back to cited text no. 41
Fukuda M, Peppas NA, McGinity JW. Properties of sustained release hot-melt extruded tablets containing chitosan and xanthan gum. Int J Pharm 2006;310:90-100.  Back to cited text no. 42
Schilling SU, Bruce CD, Shah NH, Malick AW, McGinity JW. Citric acid monohydrate as a release-modifying agent in melt extruded matrix tablets. Int J Pharm 2008;361:158-68.  Back to cited text no. 43
Gurny R, Doelker E, Peppas NA. Modelling of sustained release of water-soluble drugs from porous, hydrophobic polymers. Biomaterials 1982;3:27-32.  Back to cited text no. 44
Higuchi T. Mechanism of sustained action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci 1963;52:1145-9.  Back to cited text no. 45
Di Colo G. Controlled drug release from implantable matrices based on hydrophobic polymers. Biomaterials 1992;13:850-6.  Back to cited text no. 46
Miyajima M, Koshika A, Okada J, Kusai A, Ikeda M. Factors influencing the diffusion-controlled release of papaverine from poly (L-lactic acid) matrix. J Control Release 1998;56:85-94.  Back to cited text no. 47
Ocal H, Arýca-Yegin B, Vural I, Goracinova K, Calýþ S. 5-Fluorouracil-loaded PLA/PLGA PEG-PPG-PEG polymeric nanoparticles: Formulation, in vitro characterization and cell culture studies. Drug Dev Ind Pharm. Epub 2013 Apr 18.  Back to cited text no. 48