(M1230-02-09) Comparison of Controlled-Release Performance between Carrageenan and Several Other Hydrophilic Polymers

Purpose: Hydrophilic matrix is the most frequently used technology for controlled release (CR) tablets. Many swellable hydrophilic polymers, such as hydroxypropyl methylcellulose (HPMC), carrageenan, sodium alginate, polyethylene oxide (PEO), hydroxypropyl cellulose (HPC) and xanthan gum, are applied as matrix polymers in CR tablets. Carrageenan is a sulfated poly-galactose with the ester-sulfate content between 15% and 40% (w/w). It is formed by alternate units of d-galactose and 3,6-Anhydro-galactose (3,6-AG) joined by α-1,3 and β-1,4-Glycosidic linkage ^[1]. The commonly used commercial types of carrageenan in pharmaceuticals are kappa (containing 18-25% ester-sulfate and about 34% 3,6-AG), iota (containing 25-34% ester-sulfate and about 30% 3,6-AG) and lambda (containing 30-40% ester-sulfate and none 3,6-AG). This study is to compare the controlled-release performance of carrageenan with several other hydrophilic polymers in metformin hydrochloride CR tablets and theophylline CR tablets.

Methods: The swelling and erosion performance of polymers were investigated by putting the pure polymer tablets in different dissolution media. Polymer tablets were put about 1 cm under different solution mediums and photographed at different time points to investigate their swelling and erosion behaviors. Metformin hydrochloride CR tablets and theophylline CR tablets were prepared by direct compaction respectively with different polymers (lambda carrageenan Viscarin® GP-209; iota carrageenan Gelcarin® GP-379 and kappa carrageenan Gelcarin® GP-911, HPMC METHOCEL^TM K4M, PEO POLYOX^TM WSR 301 and sodium alginate Protanal® CR 8223). Drug release was determined, and the release mechanism was analyzed by the equation derived by Ritger et al ^[2-3]. Release exponent, n, was used to illustrate the 3 probable mechanisms for drug release. 1) n < 0.45, Fickian diffusion mechanism. 2) 0.45< n < 0.89, non-Fickian diffusion, which is a combination of diffusion and erosion mechanism. 3) n >0.89, super case II transport mechanism, which is known as an erosion-dominated mechanism.

Results: The swelling and erosion performance of pure polymer tablets is shown in Figure 1. Viscarin® GP-209 tablet absorbed dissolution media quickly due to its high hydrophilicity. The viscous layer formed quickly onto tablet surface to become a barrier for drug release. Gelcarin® GP-379 tablet swelled to a very large volume quickly in pH6.8 phosphate buffer and pH1.2 HCl solution, indicating a risk of fast disintegration of tablets. Gelcarin® GP-911 tablet swelled rapidly before gel formation in pH6.8 and pH1.2 HCl solution, and the tablets completely disintegrated in several minutes. In a comparison of the two types of sodium alginate, CR8223 had a slower erosion rate in all media due to higher molecular weight. Both types of sodium alginate form insoluble gels in pH1.2 HCl solution which make them control drug release better in the acidic solution. POLYOX™ tablet absorbed media and swelled faster than METHOCEL™ (HPMC) did. This phenomenon is attributed to better hydrophilicity of POLYOX™ polymers characterized by flexible and linear molecular chains and free ending hydroxy groups. As shown in Figure 2, for highly soluble drugs like metformin hydrochloride, Viscarin® GP-209 showed very good control on drug release, with a similar or slower release rate than METHOCEL™ K4M and POLYOX™ WSR301,and the drug-release mechanism was a combination of diffusion and erosion. Gelcarin® GP-379 only showed good CR effects in pH 6.8 phosphate buffer. Gelcarin® GP-911 swelled rapidly and disintegrated in pH 6.8 and pH 1.2 media, and metformin tablets demonstrated typical immediate release behavior. Protanal® CR 8133 showed the slowest drug release in pH 1.2 HCl medium due to the formation of an insoluble gel in acidic conditions. As shown in Figure 3, for slightly soluble drugs like theophylline, Gelcarin® GP-379 exhibited stronger CR effects than METHOCEL™ K4M did at early stage of drug release and more complete drug release at final stage of drug release. The drug release mechanism was erosion dominated. Gelcarin® GP-911 based tablets showed an immediate release effect in pH 6.8 medium.

Conclusion: For a highly soluble API like metformin hydrochloride, Viscarin® GP-209 (lambda carrageenan) could achieve good CR effects in all three media. For a slightly soluble API like theophylline, Gelcarin® GP-379 (iota carrageen) could enable near-zero-order drug release in all three media. Gelcarin® GP-911 is not considered to be suitable as a CR matrix polymer alone due to its rapid swelling and disintegration behaviors in pH 6.8 and pH 1.2 dissolution media.

References: [1] Nercas J, Bartosikova L, Carrageenan: a review. Vet Med, 2013, 58(4): 187–205
[2] Ritger PL and Peppas NA. A simple equation for description of solute release II. Fickian and anomalous release from swellable devices. Control. Release. 1987, 5:37-42.
[3] Korsmeyer, RW, Gumy, R, Doelker E, et al. Mechanisms of solute release from porous hydrophilic polymers. Inr. J. Pharm., 1983, 15: 23-35.

Figure 1 The swelling and erosion performance of pure polymer tablets in different media

Figure 2 Drug release of metformin from CR tablets with different polymers in different media

Figure 3 Drug release of theophylline from CR tablets with different polymers in different media