Interaction between a cationic polymethacrylate (Eudragit E100) and anionic drugs
Introduction
Polyelectrolytes (PE) under the form of ionic exchange resins (insoluble PE) or dispersible hydrophilic polymers (soluble PE) have been largely used in pharmaceutical formulations (Guo et al., 1998, Jantzen and Robinson, 1996, Anand et al., 2001).
The unique properties arising from the interaction of PE with inorganic or organic counterions has been exploited for a variety of purposes such as drug delivery modulation (Jimenez-Kairuz et al., 2005, Jimenez-Kairuz et al., 2003, Ramírez Rigo et al., 2006), taste masking (Borodkin and Sundberg, 1971) drug compatibility (Vilches et al., 2002), drug stability improvement (Jimenez-Kairuz et al., 2004), viscosity building (Billany, 2002), metabolite traping (Colestipol, 2004), etc.
Therefore, the knowledge about the factors that determine the interaction between ionic or ionizable drugs and PE is relevant in the design of pharmaceutical dosage forms. Although this point has been addressed by many authors (Kunin and Myers, 1947, Peterson and Gowen, 1953, Kennon and Higuchi, 1956, Sawaya et al., 1987), at present a detailed description about the factors governing such interaction is not fully available.
In this context, we have previously reported results concerning with the properties of aqueous dispersions as well as solid matrices of PE-drug systems. Such results were obtained with acidic PEs like carbomer, alginic acid, carboxymethylcellulose and a variety of drugs having basic groups (Jimenez-Kairuz et al., 2002, Jimenez-Kairuz et al., 2003, Ramírez Rigo et al., 2006).
In this step, we consider of interest to get information about the interaction of basic PE and drugs with acidic groups (AH). Among basic PE, chitosan, chitosan derivatives and cationic polymethacrylates are currently used in pharmaceutical systems (Rowe et al., 2006a). We selected the basic polymethacrylate Eudragit® E (EU) to develop a study with a set of AH in order to know the relevant properties of EU–AH systems.
Eudragit E is a cationic polymer based on dimethylaminoethyl methacrylate and other neutral methacrylic acid esters. It is soluble in gastric fluid, as well as in weakly acidic buffer solutions (up to approximately pH 5). This polymer, in its unprotonated form, is soluble in organic solvents and insoluble in petroleum ether and water. It is currently used as coating in solid pharmaceutical dosage forms (for taste masking and protection; Rowe et al., 2006b). However, some research regarding its use as dissolution modifier has been reported. In this line EU was incorporated in solid dispersions and in physical mixtures to improve the solubility and/or dissolution of drugs with low aqueous solubility. The performance of solid dispersions containing Eudragit and sodium divalproex (Rao et al., 2003), albendazole (Kalaiselvan et al., 2006), piroxicam (Valizadeh et al., 2007) and an experimental anti-inflammatory drug (Horisawa et al., 2000), was evaluated. However, in these articles, little explanation about the polymer–drug interactions was provided. Most of these drugs were non-electrolytes and the observed effect on drug dissolution was attributed to the influence of the polymer on the physical state of the drug. However, more detailed studies on the interaction of the quaternary ammonium polycation trymethylmethacrylate chloride (Konar and Kim, 1997, Khalil and Sallam, 1999) and cationic polysaccharides (Rodríguez et al., 2003a, Rodríguez et al., 2003b) with different drugs were reported.
This work is focalized on the ionic interaction between the protonated amino groups of EU macroion and the anions of a set of acidic drugs (AH) with the aim of evaluating the potentialities of EU–AH systems.
Section snippets
Materials
Poly (butyl methacrylate, (2-dimethyl aminoethyl) methacrylate, methyl metacrilate) 1:2:1 (Eudragit® E100, Pharmaceutical Grade, Rohm, Germany) was a gift from Etilfarma S.A. (Buenos Aires, Argentina). Salicylic acid (S), benzoic acid (B) (Pharmaceutical Grade, Vulcano, Buenos Aires, Argentina), mesalamine (M) (PA grade, Fluka, Sweden), sodium diclofenac (D), indomethacin (Id), furosemide (F) (Pharmaceutical grade, Parafarm, Buenos Aires, Argentina), saccharine (Sa), hydrochloric acid,
Preparation of the complexes
Table 1 reports the set of 7 AH that were selected to prepare EU–AH complexes together with their pKa, intrinsic octanol water partition coefficients (log P) and aqueous solubility of each drug. The set includes drugs with aliphatic and aromatic acid groups that cover a range of 3 pKa units. Besides they cover a log P range from 4.4 for the high hydrophobic drug diclofenac to 0.46 for mesalamine.
Complexes EU–AH50, in which AH neutralizes 50% of the basic groups of the PE, and EU–AH50Cl50 where
Conclusions
The body of information provided has clearly shown the high affinity between the macroion EUH+ and anionic drugs that generates a reversible association in aqueous systems. Such results also support the conclusion that the main contribution to the overall interaction arises from the electrostatic attraction. Although non-electrostatic contributions would also play a role in the association process, present results does not provide insights to evaluate this point.
Aqueous dispersions of EU–AH50
Acknowledgments
Financial support from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), FONCyT Préstamo BID 1201/OC-AR, Proy. N° 05-10954 and SECyT-UNC, is greatly acknowledged. We would like to thank Etilfarma S.A. (Buenos Aires) for the provision of Eudragit E100. Quinteros D.A. thanks SECyT-UNC for a research fellowship.
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