Benchtop-magnetic resonance imaging (BT-MRI) characterization of push–pull osmotic controlled release systems

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Abstract

The mechanism of drug release from push–pull osmotic systems (PPOS) has been investigated by Magnetic Resonance Imaging (MRI) using a new benchtop apparatus. The signal intensity profiles of both PPOS layers were monitored non-invasively over time to characterize the hydration and swelling kinetics. The drug release performance was well-correlated to the hydration kinetics. The results show that (i) hydration and swelling critically depend on the tablet core composition, (ii) high osmotic pressure developed by the push layer may lead to bypassing the drug layer and incomplete drug release and (iii) the hydration of both the drug and the push layers needs to be properly balanced to efficiently deliver the drug. MRI is therefore a powerful tool to get insights on the drug delivery mechanism of push–pull osmotic systems, which enable a more efficient optimization of such formulations.

Introduction

Controlled drug delivery systems for oral applications are widely used clinically to decrease the frequency of administration or to reduce side effects that are related to peak plasma concentrations (Cmax). Many of them are based on matrix tablets. In many cases, their drug release rates are either dependent on pH and / or on shear forces of the local environment leading to a so-called food effect and in vivo variability [1]. A reproducible zero-order release profile of poorly and pH-dependently soluble drugs is a challenge. Osmotic [2], [3], multiparticulate [4], [5] and, more recently, special erosion controlled delivery systems (Egalet™) [6] have been developed to overcome these limitations.

Osmotic pumps also known as oral osmotic systems (OROS™) were reported as suitable to deliver poorly soluble compounds such as nifedipine, isradipine or doxazosin [7]. This controlled release technology was initially developed by Theeuwes and associates in the 1970s as a result of an ultimate simplification of Higuchi–Leeper pump design [8]. Two delivery systems based on OROS technology were mainly developed and marketed [9]. The elementary osmotic pump is based on a single tablet core and suitable for highly soluble drugs. The second type is the push–pull osmotic system (PPOS) based on a bilayer tablet core for poorly soluble compounds (Fig. 1).

The delivery principle of all osmotic systems involves controlled water diffusion through a semipermeable membrane and the drug release through a laser-drilled orifice [2]. Several mathematical hydration models were proposed for single core systems [2], [9] as well as for bilayer PPOS [10]. These approaches were based on the Starling equation (Eq. (1)) describing the flow rate (dV/dt) through a semipermeable membrane as:Vt=A·Lph(σΔπΔP)with the membrane thickness (h) and surface (A), the water permeability (Lp), the difference of hydraulic pressure (ΔP) and the osmotic gradient (σ · Δπ). Eq. (2) was adapted to bilayer PPOS by Wong et al. [11]:Vt=σ·Lph[AP(H)·πp+(AAP(H))πDΔP(H)]with the degree of hydration (H), the layer surfaces (Ax) and the osmotic pressure (πx) of the push and the drug layers indexed with P and D respectively. These models were used to explain the effect of some parameters from a qualitative point of view. However, knowledge of the detailed mechanisms underlying the release process from PPOS is still limited due to a lack of experimental data despite the clinical value and long history of oral osmotically driven drug delivery systems. Therefore, the aim of the present study was to investigate the hydration kinetics of push–pull osmotic systems in more detail. For this purpose, a marketed formulation was compared to several laboratory formulations. The drug layer composition was modified with respect to drug load and polymer grade. The osmotic agent proportion in the push layer and the drug layer/push layer ratio were also varied.

The PPOS hydration behaviour and kinetics was monitored using nuclear magnetic resonance imaging. This non-destructive technique is a well established and powerful method to investigate drug delivery systems in vitro and in vivo [12]. The hydration of various drug delivery systems has been investigated by MRI [12]. Examples include hydrophilic matrix tablets based on hydroxypropylmethylcellulose (HPMC) [13], amylose starch [14] and polyethylene oxide (PEO) [15], film coated tablets [16], Egalet systems [17], [18] and pulsatile systems [19]. However, to the best of our knowledge, only two papers describe MRI measurements on osmotic systems. Fyfe and Blazek-Welsh proposed a technique to follow the hydration kinetics of an elementary osmotic pump during a dissolution test in a flow through cell [13]. The second publication was focused on Dynacirc CR tablets, a marketed PPOS tablet system for the delivery of Isradipine [20]. Unfortunately, the authors of this study performed the whole study with bidistilled water at room temperature within a NMR test tube of 10 or 15 mm diameter. No specification of the water volume was given, but it is clear that the small volume within an unstirred NMR test tube is very artificial and neither reflects USP nor physiological conditions. Compared to standard conditions, a change of the hydration and release kinetics can be expected due to the undefined and changing osmotic pressure of the release medium. At the beginning, the osmotic pressure gradient will be high due to the use of bidistilled water. With time, released material will increase the pressure within the NMR tube. Furthermore, no differentiation of the internal tablet structure such as the push or pull layers was achieved. In addition, no quantitative treatment of the MRI data was done. The authors observed, however, differences in the MRI images between slow and fast releasing tablets.

Until now, superconducting NMR machines have been used as standard MRI equipment. Very recently, benchtop-MRI (BT-MRI) systems have been developed which overcome the main limitation of the MRI applications, namely high installation and running costs of superconducting systems. Working with a permanent magnet which does not require liquid helium, makes such a system more affordable (installation costs are around 1/5 to 1/10). However, the question remains whether or not, BT-MRI can provide sufficient resolution on “standard”-MRI applications, including the monitoring of the hydration of oral dosage forms. Very recently, BT-MRI has been used successfully to characterize floating tablets, including CO2 developing coated [16] and matrix tablets [21]. It was therefore the aim of the current study to obtain new, more detailed and quantitative information on the hydration and release processes of osmotic controlled tablets by means of proton BT-MRI. For this purpose, a commercialized formulation of Isradipine, Dynacirc CR, was compared to four modified formulations with various compositions containing isradipine, a poorly soluble calcium channel blocker drug.

Section snippets

Preparation of the tablets

DynaCirc CR 5-mg tablets (Reliant Pharmaceuticals, United States) were purchased on the US market.

The laboratory formulations were prepared according to the following procedure: A 500 μm mesh sieve was primarily used to sieve the ingredients Isradipine, PEO 200 k, 600 k and 7000 k (Polyox WSR N-80, WSR 205 and WSR 303, Dow Chemical, Midland United States), Natrium Chloride (NaCl, VSR AG, Pratteln Switzerland), indigo blue (FD&C n°2, Univar Ltd, Bradford UK) and magnesium stearate (FACI SRL,

Dynacirc CR hydration kinetics

The hydration kinetics of Dynacirc CR was monitored over time. The signal intensity profiles were calculated on the central cross-section of the Dynacirc CR tablet. Fig. 2 shows that the T1-weighted signal intensity of both the drug and the push layers increased up to 8 h until a uniform hydration plateau with different intensity levels was reached. However, the signal enhancement was higher in the drug layer. The preferential accumulation of water within the drug layer is caused by the

Conclusion

The findings of this study lead to a deeper mechanistic understanding of drug delivery from PPOS. The hydration and swelling behaviours of both layers were non-invasively studied using BT-MRI. The hydration balance between both the drug and the push layers appeared as a key parameter influencing the drug delivery. Incomplete delivery linked to high drug load was observed and linked with an inhomogeneous hydration. Based on MRI, the core formulation was optimized to achieve balanced hydration

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