Characterization and optimization of albendazole loaded ternary polymeric microparticles

AGUSTINA GARCÍA; DARIO LEONARDI; MARIA C. LAMAS

Antalaya

Simposio; 18th International Symposium on Microencapsulation; 2011

Characterization and optimization of albendazole loaded ternary polymeric microparticles. Agustina Garcíaa, Dario Leonardia,b, María C. Lamasa,b. aIQUIR ? CONICET, bArea Técnica Farmacéutica, Facultad de Ciencias Bioquímicas y Farmacéuticas, UNR, Suipacha 531, S2002LRK Rosario, Argentina. E mail: mlamas@fbioyf.unr.edu.ar Introduction Albendazole (ALB), methyl (5-[propylthio]-1H-benzimidazol-2-yl) carbamate is poorly soluble in water. This drug is a benzimidazole derivative with a broad antihelmintic spectrum used for the treatment of neurocysticercosis, echinococcosis, giardiasis and filariasis [1-3]. Its poor bioavailability, cause an unpredictable therapeutic response in some parasitic infections [4,5]. ALB microparticles based on ternary polymeric systems have been formulated by Chitosan (CH), Pectin (P) and Sodium Carboxymethylcellulose (CMC Sodium) to increase the dissolution rate and to improve the bioavailability parameters. These polymers formed a polielectrolitic complex (PEC) matrix for drug delivery. P is an anionic polysacaride widely explored as a drug transporter [2-7]. CH is a cationic polymer soluble in dilute acid solutions which presents excellent biocampatibility, complete biodegradability and low toxicity among other properties [7-9]. The methodology applied for microparticles formulation was the spray drying process. Physico-chemical parameters such as yield, encapsulation efficacy (EE), size and morphology of the microparticles were evaluated. In adition, it was carried out dissolution profiles and bioavailability studies in male wistar rats. The main goal of this work was to optimize the formulation parameters using experimental desing (Design Expert ®). The polymer concentrations were optimized to obtain maximum yield, EE, Q30, Q60 and Q360. Materials and methods Microparticles were obtained by spray drying method (Buchi Mini dyrer B-290). The process parameters were set up under these conditions: 1. inlet temperature: 130 ºC, 2. outlet temperature: 60 ºC, 3. aspirator rate: 100 %, 4. air flow: 38 m3/h, 5. feed flow: 5 mL/min. The polymer solutions were prepared as folow: ALB (100 mg) was solubilizated in 30 mL of acetic acid under magnetic stirring and 70 mL of water was added. CH was dispersed in the same solution and stirred for 60 minutes. CMC and P solutions were prepared by dissolving in 100 mL of water with stirring for a fixed time (2 h). The concentrations of the polymer solutions depended on the experimental design. The polymer solutions were heated (45ºC) and then the binary system CMC-P was dropped slowly over CH-ALB solution, avoiding the aggregates formation. Afterwards the polymeric systems were sprayed under the conditions previously described. Results and Discussion A satisfactory microparticle formulation depends on many factors, and therefore an expanded Plackett?Burman design was built for estimating the main factors affecting its properties. The analyzed factors were polymer concentrations: CH, P and CMC. In both phases of the experimental design (Plackett Burman and optmization) were checked the following tendecies: 1. Yield increased with the decrease of P and CMC concentrations and when CH concentration was high. 2. An increment in the EE % was observed increasing P and CMC concentrations; the opposite situation was observed increasing the CH concentration. 3. When the concentration of CMC was low, the responses Q30, Q60 and Q360 were increased with decreasing concentrations of CMC and P. The dissolution profiles for a formulation obtained in the selected conditions (run 9) were contrasted against ALB without any treatment. As can be seen, the microparticles formulation showed an enhanced drug dissolution rate, in comparison with the drug alone. Table 1: Central composite design used for the optimization of the responses Run CH % w/v P % w/v CMC % w/v Yield % EE % Q30 Q60 Q360 1 0.60 0.25 0.11 63.8 88.5 40.2 63.3 86.5 2 1.00 0.40 0.20 61.6 97.5 43.2 66.7 87.4 3 1.00 0.10 0.01 85.6 80.0 56.6 79.3 87.3 4 0.20 0.40 0.20 59.9 92.5 21.4 29.5 55.8 5 0.60 0.25 0.26 63.7 101.1 49.4 72.2 87.7 6 0.10 0.25 0.11 66.9 95.3 27.4 37.7 69.0 7 0.60 0.00 0.11 78.7 81.3 56.0 76.9 91.2 8 0.60 0.25 0.11 73.9 88.1 43.5 66.2 88.2 9 1.00 0.10 0.20 72.3 95.9 49.4 68.1 85.4 10 0.60 0.50 0.11 65.0 95.9 31.4 48.9 76.3 11 0.60 0.25 0.11 69.9 88.8 35.4 55.4 87.0 12 0.60 0.25 0.00 78.2 88.4 50.7 73.9 92.3 13 0.20 0.40 0.01 63.4 87.3 50.0 72.3 98.9 14 0.20 0.10 0.20 67.6 97.6 21.3 28.2 55.5 15 0.20 0.10 0.01 62.3 87.5 76.6 89.5 92.5 16 1.27 0.25 0.11 74.0 85.2 41.5 67.5 88.2 17 1.00 0.40 0.01 67.3 95.6 52.6 69.2 92.5 Conclusions This work demonstrates the properties of ALB- microparticles can be improved by rationally analyzing the influence of different parameters in the formulation. The procedure is composed of the following phases: (1) screening the influential factors with a Plackett?Burman design, (2) building a response surface model and (3) finding the optimal conditions. This methodology has been proved to be very efficient in increasing the drug dissolution rate, the EE and yield. Acknowledgements The authors express their gratitude to National University of Rosario (UNR), and the National Council Research (CONICET). References [1] Zongde Z.;Xingping L.;Xiaomei W.;Hong Z.;Yanping S.; Liren C. and Yong Ming L. Analytical and semipreparative resolution of enatiomers of albendazole sulfoxide by HPLC on amylose tris (3,5-dimethylphenylcarbamate) chiral stationary phases. J. Biochem. Biophys. Methods. 2005, 62, 69-79. [2]. Rowe R. C.; Sheskey P. J.; Owen S.C. Handbook of pharmaceutical excipients. Pharm. Press. 2006. 507-508 [3]. Simi S.P.; Saraswathi R.;Krisshman P.N.;Dilip C.; Ameena K. Formulation and evaluation of Albendazole microcapsule for colon delivery. Asian Pacific J. of Trop. Med. 2010. 374-378 [4]. Kitzman D.; Cheng K.; Fleckenstein L. HPLC assay for albendazole and metabolites in human plasma for clinical pharmacokietic studies. J. Pharmaceut. Biomed. 2002. 30, 801-813. [5] Dayan A.D. Albendazole, mebendazole and praziquantel. Rewiew of non-clinical toxicity and pharmacokinetics. Acta Trop. 2003. 86,141-159 [6] Cui-Yun Y.; Bo-Cheng Y.; Wei Z.; Si-Xue C.; Xian-Zheng Z.; Ren-Xi Z. Composite microparticle drug delivery systems based on chitosan, alginate and pectic with improve pH-sensitive drug release property. Colloids Surface B. 2009. 68, 245-249 [7] Dash M.; Chiellini F.; Ottenbrite R.M.; Chiellini E. Chitosan- A versatile semi-synthetic polymer in biomedical applications. Prog. Polym. Sci. .2011. 36, 981?1014. [8]. Palomares-Alonso F.; Rivas González C.; Bernad-Bernad M. J.; Castillo Montiel M. D.; Palencia Hernández G.; González-Hernández I.; Castro-Torres N.; Pinzón Estrada E.; Jung-Cook H. Two novel ternary albendazole?cyclodextrin?polymer systems: Dissolution, bioavailability and efficacy against Taenia crassiceps cysts. Acta Trop. 2010. 113, 56-60. [9]. Pillai C. K. S.; Paul W.; Sharma C.P. Chitin and chitosan polymers: Chemistry, solubility and fiber formation. Prog. Polym. Sci. 2009. 34, 641-678