(M1430-08-50) HPC vs HPMC – A Mechanistic Investigation on Bioadhesion via Swelling and Rheological Data

Purpose: When formulating bioadhesive formulations (e.g., eye drops, gastro retentive products) characterization of bioadhesive properties are of great interest. Due to short interaction times following characteristics of bioadhesive formulations are of great interest: (i) easy penetration of the mucin chains into the polymer layer (ii) fast gel recovery, (iii) fast interaction between the mucin and polymer chains (iv) fast formation of gel layers for solids. In this work various analytical techniques (scanning electron microscope (SEM), texture analyzer (TA), oscillating rheology) are employed to analyze the bioadhesive behavior of neat HPC and HPMC as well as 65% DL metformin tablets containing HPC or HPMC.

Methods: HPC-VH FP, HPC-M FP (Nippon Soda, Japan), Benecel K4M DC (Ashland), Metformin HCl (Aarti Drug Ltd.), Magnesium Stearate (Peter Greven, Nederland C.V.). Metformin HCl was milled and passed through a 500 µm sieve and subsequently mixed with the polymers at a drug load of 65%. A Styl’one classic, mimicking the compaction of a Fette 102i equipped with biplanar round 8 mm tooling was used to produce the tablets (neat polymers and 65% DL). To decrease the influence of porosity on swelling properties or bioadhesion, all tablets were compressed to a fixed solid fraction of 0.88. Bioadhesion was determined using a texture analyzer equipped with a 3D printed tablet holder. The tablet was placed in the holder, immersed in 0.1 N HCl for 30 seconds and pressed against an artificial mucin layer (5% (w/w) mucin /phosphate buffer) for 180s adapted after Wong et al.[1] To compare the bioadhesion of the tablets the peak detachment force and the total work of adhesion was used. The swelling kinetics (diffusion + swelling layer) were determined after 15 min, 30 min, 60 min and 120 min of immersion in dissolution medium (0.1 N HCl) using a TA and SEM without agitation. The distance from gel surface until the probe hit the dry center (characterization of swelling kinetics) and the AUC from 0 s up to this point (characterization of texture of the gel) were determined. The SEM images were acquired from freeze dried tablets after dissolution. To compare gel attributes during and after the swelling process additional oscillatory rheologic experiments were performed using 4% (w/w) and 10% (w/w) gels as surrogates.

Results: Bioadhesion measurements showed similar bioadhesion for the neat polymers but tablets containing 35% HPC/HPMC and 65% metformin HCl demonstrated higher bioadhesion for the HPC containing tablets than HPMC. Tablets containing either HPC grade showed similar swelling kinetics, fast swelling at the beginning (15 and 30 min) and slower swelling after 30 minutes compared to the HPMC tablet. HPC-VH FP swelled the fastest and strongest. The AUC, characterizing the integrity of the gel against movement, was the highest for HPMC, followed by HPC-VH FP and HPC-M FP. The SEM images of the tablets revealed different ratios of the swelling to gel layers and a greater amount of air bubbles in the inner swelling layer of the HPC tablets. HPMC tablets exhibited a pronounced thinner swelling layer compared to HPC tablets at similar gel layer thickness. Rheology measurements revealed a higher viscosity in the linear viscoelastic section for the 10% HPMC gel but a stronger reduction of G’ (storage modulus) when reducing the concentration to 4%, leading to a liquid like behavior under shear. For HPC-VH FP both 4% and 10% gels showed a gel like structure over the entire LVE section (G’ > G’’). The HPC-M FP gel behaved liquid like at both concentrations. To explain the higher bioadhesion of HPC, the penetration theory of bioadhesion and two aspects have to be taken into account [2]. First, the faster building of a gel/swelling layer of HPC. As the swelling layer was able to contain air bubbles, the gel has to be formed faster, before the air can diffuse out of the gel. This is confirmed by the faster swelling kinetic shown in the SEM and TA data. Second the lower AUC during the TA experiments was another strong indication for the higher bioadhesion of HPC-M FP and HPC-VH FP, as the O-glycosylated proteins of the mucin layer are able to penetrate easier into the gel. The higher reduction in ∆G when reducing polymer concentration and different viscosities from 10% to 4% HPC or HPMC, respectively seemed to have little impact on the bioadhesion and could not confirm the found easier penetration of the TA probe into the swollen layers.

Conclusion: Bioadhesion of HPC or HPMC depended highly on swelling/diffusion kinetics of the tablet and properties of the forming gel. HPC tablets showed higher bioadhesion due to (i) faster building of gel and swelling layer and (ii) easier penetration of the mucin chains into the polymer layer. The lower molecular weight HPC-M FP showed better bioadhesion than HPC-VH FP as the penetration of the mucin chains into the gel layer seems simpler.

References: [1] C.F. Wong, K.H. Yuen, K.K. Peh, An in-vitro method for buccal adhesion studies: importance of instrument variables, Int. J. Pharm. 180 (1999) 47–57.
[2] Y. Huang, W. Leobandung, A. Foss, N.A. Peppas, Molecular aspects of muco- and bioadhesion: Tethered structures and site-specific surfaces, J. Controlled Release (2000).

Figure 1 Bioadhesion of HPC and HPMC tablets at 65% DL Metformin HCl

Figure 2 SEM Image of HPC-VH FP(A) vs Benecel K4M (B) after 30 minutes in KH2PO4 K2HPO4 buffer, shock frozen, freez dried, cross section. Determination of different visible layers (swelling layer (red), gel layer (green))

Figure 3 Swelling distance of HPC-VH FP (blue), HPC-M FP (green), Benecel K4M (red), determined by texture analyzer