Use of carboxymethycellulose as release modifier of a medicinal plant extract

LOREANA GALLO; JULIANA PIÑA; BUCALÁ VERÓNICA; ALLEMANDI DANIEL; RAMIREZ RIGO M.VERÓNICA

Bahía Blanca

Simposio; Simposio Argentino de Polimeros; 2011

INTRODUCTION Modified release drug delivery systems (MRS) have been widely studied to improve drug efficiency and patient adherence to treatment as well as to reduce drug toxicity (Aulton, 2004). These systems are particularly useful in the treatment of chronic pathologies because they provide more effective plasma drug concentration-time profile (by keeping constant the plasma drug concentration in the therapeutic window for prolonged time). Due to the numerous technological applications, the hydrophilic polymers play an important role in the design of MRS (Guo et al., 1998). Hydrophilic matrices, for example, have become one of the most popular control release dosage form (Conti et al, 2007). They consist of a compact containing a mixture of one or more active ingredients with one or more hydrophilic polymers (gel forming agents) which retard the drug release. Modified release concepts applied to plant actives and extracts are still in an exploratory stage. A variety of novel herbal formulations that have remarkable advantages over conventional formulations has been reported (Vicentini et al., 2008,). However, several problems related to industrial production and disease treatment need to be solved (Saraf, 2010). In this context, the aim of the present work was to develop a spray dried co-processed material based on Hamamelis virginiana extract, sodium carboxymethylcellulose and colloidal silicon dioxide with good flow properties for direct compression and useful as a modified release system. The spray drying technique gives products with precise quality specifications (moisture content, solubility, bulk density, hygroscopicity) in continuous operation (Souza and Oliveira, 2006). The co-processing of several materials simultaneously allows improving the powders physico-mechanical properties. H. virginiana extract was selected as a model plant extract used in the treatment of the chronic pathology Varicose Vein Disease, which affects one out of two people age 50 and older (http://www.nlm.nih.gov). The tannins presents in H. virginiana leaves have venotonic properties (EMEA, 2009). The development of a matricial system that slowly delivers the extract could improve the security and efficacy of this phytotherapy. MATERIALS AND METHODS The fluid plant extract (FPE) of H. virginiana was prepared by decoction of its leaves in boiling water according to EMEA (2009). The solid residue (SR) content was determined by solvent evaporation up to constant weight. Sodium carboxymethylcellulose (CMC) and colloidal silicon dioxide (CSD) were added to the FPE with different purposes. The polymer is required to modulate the drug release (Rowe et al., 2009). CSD is usually included to improve the flowability, compressibility, and compactability of powder (Souza and Oliveira, 2006). The influence of the CMC grade (ultra high, high and medium viscosity) and concentration (SR:CSD:CMC ratio: 1:1:0.3, 1:1:0.15 and 1:1:0.075) of the atomized aqueous dispersion on the product performance was explored. Aqueous mixtures of different compositions were spray dried in a Mini Spray Dryer Büchi B-290. The experimental conditions were: drying air inlet temperature 150º C, atomization air volumetric flow rate 400 l/h, feed volumetric flow rate 10% (2 ml/min) and drying air volumetric flow rate 100% (about 35-38 m3/h). The dry extract moisture content, process yield, angle of repose and Carr´s Index (flow powder indicators) were determined (Gallo et al., 2011). The obtained products were compacted in a hydraulic press (Delfabro) at 0.5 ton for 5 s. Flat punches with a 12 mm diameter were used. Extract release experiments were carried out in an Apparatus 2 (Erweka) with paddle rotation speed of 50 rpm, using 900 ml of different mediums (distilled water, simulated gastric fluid (SGF) pH 1.2 and simulated intestinal fluid (SIF) pH 6.8) at 37º C. Samples were withdrawn and tannins were spectrophotometrically assayed at 280 nm (Laghi et al., 2010). Finally, the release profiles were compared using the similarity factor, f2 (O’Hara et al., 1998). RESULTS AND DISCUSION The influence of polymer grade on process yield, moisture powder content, and extract release from compacted powder was initially studied. The composition of the tested sprayed aqueous dispersions was SR:CSD:CMC = 1:1:0.3. The powders obtained by spray drying presented light orange color, the typical extract smell, good flow properties for direct compression (repose angle and Carr Index; Gallo et al. 2011) and moisture content between 2.05 and 2.55 %. The process yield achieved for each experiment was in the range 34-76%. The highest value was obtained for the product containing the medium viscosity grade CMC (MV). In vitro extract release experiments in distilled water from compacted powders with CMC of different grades showed no significant differences (the f2 factor was higher than 76 indicating similarity). Consequently, just the matrix containing 1:1:0.3, SR:CSD:CMC MV ratio (previously studied in water medium) was used to analyze the release behavior in biorrelevant media of pH 1.2 and 6.8. The CMC MV matrix did not allowed the complete extract release in SGF and SIF mediums for 8 hours. The same pattern was observed when matrices were immersed in SGF for 2 hours followed by 6 hours in SIF. For this reason, in a second stage, the influence of polymer concentration on process yield, moisture powder content and extract release from compacted powder was evaluated. New co-processed powders containing decreasing proportions of CMC MV were obtained. The corresponding process yields were even better (82-84%), which can be condiser as excellents for lab-scale spray dryers. In addition, the powders exhibited good flow properties. The moisture content was between 2.56 and 2.76%, demonstrating the high efficiency of the drying process. The release study of the compacted powders showed a complete extract release during 8 hours for all the tested media. As an example, Fig. 1 presents the results for the release experiments carried out in SGS for 2 hours, and SIF for the remaining 6 ones. Fig.1. Extract release from matrix systems with different CMC MV concentrations in SGF (the first 2 hours) and SIF (the remaining 6 hours). Both compacts, the 1:1:0.075 and 1:1:0.15, SR:CSD:CMC, were good from a pharmaceutical point of view. Due to its lower CMC MV content, the 1:1:0.075 SR:CSD:CMC powder will be considered for further material characterization and investigation of the release mechanism. CONCLUSIONS The scalable spray drying technology allowed the production of powders containing H. virginiana extract with good flow properties for DC. The CMC MV, at low concentrations, proved to be a suitable polymer for controlling the release of the selected medicinal plant extract from the compacts containing the co-processed spray dried powder.