(M1330-03-16) pH-Independent Modified Release Matrix Tablet of Weakly Basic Drug Using Acidic Ionizable Polymer

Purpose: Modified release of weakly basic drugs with pH-dependent solubility may cause intra- and inter-individual variabilities in absorption, due to variable pH values in gastrointestinal (GI) tract. A common strategy to achieve pH-independent release is using small molecule pH modifiers in hydrophilic matrix tablet. However, small molecule pH modifiers may not maintain their effect on microenvironment pH modulation over time, due to their fast diffusion to the bulk of dissolution media. In this study, we propose to incorporate acidic ionizable polymers in HPMC matrix tablet to attain pH-independent drug release. Three acidic ionizable polymers, HPMCAS, Eudragit L100-55, and polyacrylic acid (PAA), are selected as release modifiers. The acidic ionizable polymer is unionized in pH 1.1 dissolution media and expected to be inert. In pH 6.8 dissolution media, the acidic ionizable polymer is expected to modulate microenvironment pH and increase the erosion rate of matrix tablet to match drug release rate in pH 1.1 media. The release modification effect of acidic ionizable polymer is also expected to maintain throughout the drug dissolution.

Methods: Thiabendazole (THZ, pKa 4.7) with an intrinsic solubility of 80 μg/ml was used as a model drug in this study. 5% THZ, 25% HPMC K750PH, 35% acidic ionizable polymer, and 35% microcrystalline cellulose (MCC) were blended and compressed into 300 mg tablets for dissolution test in USP II apparatus at 75 rpm and 37 °C with 900 ml of either 0.1 N HCl (pH 1.1) or pH 6.8 phosphate buffer. Two control formulations substituted acidic ionizable polymer with either MCC or ethyl cellulose (EC). Thiabendazole concentration was analyzed using HPLC. HPMC concentration was quantitated by measuring UV absorbance at 485 nm based on a phenol-sulfuric acid colorimetry method, in which 1 ml dissolution samples were mixed with 40 μl 80% (w/w) phenol solution and 2.5ml sulfuric acid. The molecular interactions between HPMC and acidic ionizable polymer was analyzed using Raman spectroscopy. Tablets spiked with methyl red (pH indicator, yellow at pH > 6.2, red at pH < 4.4) were also clamped between two Plexiglass discs for dissolution test and image analysis.

Results: Thiabendazole (THZ) release from two control formulations (Figure 1. a and b) at pH 6.8 was significantly slower than its release at pH 1.1. When acidic ionizable polymers were used in formulation, THZ release became slower at pH 1.1 and faster at pH 6.8 than control formulations (Figure 1. c-f). HPMC release was studied as a measure of tablet erosion rate. At pH 1.1, HPMC release from the Eudragdit L and PAA formulations was slower than the HPMC release from MCC control formulation. Carboxylic groups in PAA were found to have strong hydrogen bond interactions with HPMC at pH 1.1 in Raman spectroscopy. The presence of hydrogen bond interactions reduced HPMC release from PAA formulations. High molecular weight PAA almost completely inhibited HPMC release, while low molecular weight PAA partially inhibited HPMC release. Eudragit L was not found forming hydrogen bonds with HPMC. The reduced HPMC release rate from Eudragit L formulation could be attributed to reduced water penetration in tablet due to the hydrophobicity of Eudragit L at pH 1.1. As HPMC release rate in EC control formulation was slower than HPMC release in MCC control formulation, the increased hydrophobicity of tablet matrix could reduce HPMC release. At pH 6.8, HPMC release from the Eudragit L and PAA formulations was faster than the HPMC release from MCC and EC control formulation. As the ionizable polymers were soluble and had low viscosity in pH 6.8, the incorporation of ionizable polymer weakened HPMC gel in pH 6.8 and increased tablet erosion rate. From the images in Figure 2, microenvironment pH, tablet erosion, and water penetration during dissolution in pH 6.8 were assessed. When pH 6.8 dissolution media penetrated the tablet, color changed as methyl red started to dissolve. MCC control formulation showed yellow color, as there was no pH-modulating agent in tablet. Eudragit L and PAA formulations showed red color in tablet, which indicated the ionizable polymer had ability to lower the microenvironment pH and increase THZ solubility in tablet matrix. The fact that the red color maintained after 21 h suggested that the ionizable could modulate the microenvironment pH over the entire period of dissolution.

Conclusion: Acidic ionizable polymers were able to achieve pH-independent release of THZ by modulating drug release mechanism (drug diffusion and matrix erosion) at different pH levels. At 0.1 N HCl, acidic ionizable polymers suppressed matrix erosion by reducing water penetration rate (e.g., Eudragit L) or forming strong hydrogen-bond interactions (e.g., PAA). As a result, THZ release decreased at 0.1 H HCl. At pH 6.8 buffer, acidic ionizable polymers increased THZ diffusion rate by decreasing microenvironmental pH in matrix and also increased matrix erosion rate to facilitate THZ release.

Acknowledgments: The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Deliang Zhou and Yi Huang are former AbbVie employees. Deliang Zhou is currently affiliated with BeiGene and Ye Huang is currently affiliated with InvestisBio and they have no conflicts of interest.

Figure 1. Dissolution profiles of each formulation at either pH 1.1 or pH 6.8 dissolution media. LM indicates low molecular weight and HM indicates high molecular weight.



Figure 2. Images of tablets clamped between two Plexiglass discs. Methyl red was incorporated into tablets. Yellow indicates microenvironment pH over 6.2. Red indicates microenvironment pH under 4.4.