The Effect of Polymer-Solvent Interaction on the Swelling of Polymer Matrix Tablets: A Magnetic Resonance Microscopy Study Complemented by Bond Fluctuation Model Simulations.

Polymer matrix tablets are an important drug-delivery system widely used for oral drug administration. Understanding the tablet hydration process, both experimentally and theoretically, is, thus, very important for the development of drug delivery systems that exhibit high drug loading capacity and controlled release potential. In this study, we used magnetic resonance microscopy (MRM) to nondestructively and dynamically analyze the water hydration process of xanthan-based tablets. The swelling process was characterized by well-resolved fronts of erosion, swelling, and penetration. The experimental results were complemented by numerical simulations of the polymer matrix hydration process. In the simulations, the polymer tablet matrix was modeled as an assembly of interacting chains with embedded drug particles, while its hydration process was mediated by interaction with solvent particles. The swelling dynamics were modeled within a Monte Carlo-based bond fluctuation model (BFM) that elegantly accounted for steric and nearest-neighbor interactions. This study provides an efficient experimental-theoretical approach for the study of polymer matrix swelling processes.

MR Study of Water Distribution in a Beech (Fagus sylvatica) Branch Using Relaxometry Methods.

Wood is a widely used material because it is environmentally sustainable, renewable and relatively inexpensive. Due to the hygroscopic nature of wood, its physical and mechanical properties as well as the susceptibility to fungal decay are strongly influenced by its moisture content, constantly changing in the course of everyday use. Therefore, the understanding of the water state (free or bound) and its distribution at different moisture contents is of great importance. In this study, changes of the water state and its distribution in a beech sample while drying from the green (fresh cut) to the absolutely dry state were monitored by 1D and 2D 1H NMR relaxometry as well as by spatial mapping of the relaxation times T1 and T2. The relaxometry results are consistent with the model of homogeneously emptying pores in the bioporous system with connected pores. This was also confirmed by the relaxation time mapping results which revealed the moisture transport in the course of drying from an axially oriented early- and latewood system to radial rays through which it evaporates from the branch. The results of this study confirmed that MRI is an efficient tool to study the pathways of water transport in wood in the course of drying and is capable of determining the state of water and its distribution in wood.

Polyethylene oxide matrix tablet swelling evolution: The impact of molecular mass and tablet composition.

This article describes the designing of matrix tablets composed of polyethylene oxides (PEOs) with relative molecular masses of 1 × 106, 2 × 106, and 4 × 106. Percolation thresholds were determined for all of the selected PEO formulations (18, 16, and 12 %, m/m), taking into consideration excipients and tablet surface area which significantly increased the percolation threshold. Moreover, the robustness of the gel layer in PEO matrix tablets was evaluated by magnetic resonance imaging under various mechanical stresses (no flow, 12 mL min-1, and 64 mL-1 of medium flow). Correlations between the percolation threshold and gel thickness (R2 = 0.86), gel thickness and the erosion coefficient (R2 = 0.96) was detected. Furthermore, small-angle X-ray scattering of the selected PEOs detected differences in polymer molecular complexity at the nanoscale. Finally, the ratio of the heat of coalescence to the heat of fusion has confirmed the PEO molecular mass-dependent percolation threshold.

Magnetic Resonance Methods as a Prognostic Tool for the Biorelevant Behavior of Xanthan Tablets.

Hydrophilic matrix tablets with controlled drug release have been used extensively as one of the most successful oral drug delivery systems for optimizing therapeutic efficacy. In this work, magnetic resonance imaging (MRI) is used to study the influence of various pHs and mechanical stresses caused by medium flow (at rest, 80, or 150 mL/min) on swelling and on pentoxifylline release from xanthan (Xan) tablets. Moreover, a bimodal MRI system with simultaneous release testing enables measurements of hydrogel thickness and drug release, both under the same experimental conditions and at the same time. The results show that in water, the hydrogel structure is weaker and less resistant to erosion than the Xan structure in the acid medium. Different hydrogel structures affect drug release with erosion controlled release in water and diffusion controlled release in the acid medium. Mechanical stress simulating gastrointestinal contraction has no effect on the hard hydrogel in the acid medium where the release is independent of the tested stress, while it affects the release from the weak hydrogel in water with faster release under high stress. Our findings suggest that simultaneous MR imaging and drug release from matrix tablets together provide a valuable prognostic tool for prolonged drug delivery design.

In vivo continuous three-dimensional magnetic resonance microscopy: a study of metamorphosis in Carniolan worker honey bees (Apis mellifera carnica).

Three-dimensional (3D) magnetic resonance microscopy (MRM) is a modality of magnetic resonance imaging (MRI) optimized for the best resolution. Metamorphosis of the Carniolan worker honey bee (Apis mellifera carnica) was studied in vivo under controlled temperature and humidity conditions from sealed larvae until the emergence of an adult. The 3D images were analyzed by volume rendering and segmentation, enabling the analysis of the body, tracheal system and gastrointestinal tract through the time course of volume changes. Fat content sensitivity enabled the analysis of flight muscles transformation during the metamorphosis by the signal histogram and gray level co-occurrence matrix (GLCM). Although the transformation during metamorphosis is well known, MRM enables an alternative insight to this process, i.e. 3D in vivo, which has relatively high spatial and temporal resolutions. The developed methodology can easily be adapted for studying the metamorphosis of other insects or any other incremental biological process on a similar spatial and temporal scale.

Dynamics of water and xanthan chains in hydrogels studied by NMR relaxometry and their influence on drug release.

The dynamic properties of water and polymer molecules in xanthan hydrogels at different polymer mass fractions were investigated through the combination of conventional and fast-field cycling NMR relaxation to obtain the information about dynamics in different time scales. The results showed that water dynamics were faster in diluted than in concentrated hydrogels. However, the type of polymer-chain dynamics did not change for xanthan fractions from 0.1 to 0.5, although they slowed at higher xanthan fractions as the system approached transition to the glass state. The addition of the nonionic small drug molecules pentoxifylline did not change the dynamics in the hydrogels, but they were affected by the medium pH. The water and polymer-chain dynamics were faster in the hydrogels for the neutral than the acid medium. These differences resulted in slower swelling and thinner and more rigid hydrogel layer of the matrix tablet in the acid medium that was less susceptible to erosion. Consequently, pentoxifylline release from xanthan tablets in acid medium is dominated by drug diffusion. At neutral pH, the molecular mobility is greater, which resulted in rapid and extensive swelling of the hydrogel, leading to erosion-dominated drug release.

A study of MR signal reception from a model for a battery cell.

Number of NMR/MRI studies on batteries is rapidly increasing in the past decade. As the test batteries designed for the studies contain metal parts such as electrodes and lead wires as well as other conductive parts (electrolyte), which all present obstacles for good MR signal reception, understanding of the role of battery design and of battery interactions with magnetic field is of a key importance for a successful performance of the experiments. For the study, five different samples mimicking a real battery cell were made. All the samples had two parallel copper electrodes separated by a gel layer, however, they differed in electrode thickness, gel conductivity and separation between the electrodes. The samples were inserted in an MRI magnet in different orientations with respect to magnetic fields B0 and B1 and scanned with the spin-echo and single point imaging methods in 2D and 3D (spin-echo only). The performed experiments confirmed that the main reason for poor MR signal reception from a test battery are RF-induced eddy currents. These were found stronger with the sample with the smaller distance between the electrodes. The effect of RF-induced eddy currents was efficiently suppressed when the sample was oriented with the electrodes parallel to the B1 field. However, in the orientation there were still susceptibility effects that caused a signal voiding in a narrow region near the electrodes. The susceptibility effects were found lower with the sample with thin electrodes and the non-conductive gel. The results of the study can help optimizing test battery and capacitor designs for NMR/MRI experiments.

The Influence of High Drug Loading in Xanthan Tablets and Media with Different Physiological pH and Ionic Strength on Swelling and Release.

The formation of a gel coat around xanthan (Xan) tablets, empty or loaded with pentoxifylline (PF), and its release in media differing in pH and ionic strength by NMR, MR imaging, and two release methods were studied. The T1 and T2 NMR relaxation times in gels depend predominantly on Xan concentration; the presence of PF has negligible influence on them. It is interesting that the matrix swelling is primarily regulated by Xan despite high drug loading (25%, 50%). The gastric pH and high ionic strength of the media do not influence the position of the penetration and swelling fronts but do affect the erosion front and gel thickness. The different release profiles obtained in mixing and nonmixing in vitro methods are the consequence of matrix hydration level and erosion at the surface. In water and in diluted acid medium with low ionic strength, the main release mechanism is erosion, whereas in other media (pH 1.2, µ ≥ 0.20 M), anomalous transport dominates as was found out by fitting of measured data with theoretical model. Besides the in vitro investigation that mimics gastric conditions, mathematical modeling makes the product development more successful.

MR microscopy for noninvasive detection of water distribution during soaking and cooking in the common bean.

Magnetic resonance microscopy (MRM) was used to study water distribution and mobility in common bean (Phaseolus vulgaris) seed during soaking at room temperature (20°C) and during the cooking of presoaked and dry bean seed in near-boiling water (98°C). Two complementary MRI methods were used to determine the total water uptake into the seed: the T2-weighted 3D RARE method, which yielded an increased signal from regions of highly mobile (bulk) water and a suppressed signal from regions of poorly mobile (bound) water; and the 3D SPI method, which yielded an increased signal from regions of water restricted in motion and a suppressed signal from the bulk water regions owing to the short repetition time of the method. Based on these results, it can be concluded that during soaking water enters the bean through the micropyle, migrating below the seed coat. The raphe and hypocotyl are hydrated first, while the cotyledon tissue is hydrated next. It was also observed that the imbibition rate increases with an increasing soaking temperature.

Ferri-liposomes as an MRI-visible drug-delivery system for targeting tumours and their microenvironment.

The tumour microenvironment regulates tumour progression and the spread of cancer in the body. Targeting the stromal cells that surround cancer cells could, therefore, improve the effectiveness of existing cancer treatments. Here, we show that magnetic nanoparticle clusters encapsulated inside a liposome can, under the influence of an external magnet, target both the tumour and its microenvironment. We use the outstanding T2 contrast properties (r2=573-1,286 s(-1) mM(-1)) of these ferri-liposomes, which are ∼95 nm in diameter, to non-invasively monitor drug delivery in vivo. We also visualize the targeting of the tumour microenvironment by the drug-loaded ferri-liposomes and the uptake of a model probe by cells. Furthermore, we used the ferri-liposomes to deliver a cathepsin protease inhibitor to a mammary tumour and its microenvironment in a mouse, which substantially reduced the size of the tumour compared with systemic delivery of the same drug.

Using quantitative magnetic resonance methods to understand better the gel-layer formation on polymer-matrix tablets.

INTRODUCTION: Magnetic resonance imaging is a powerful, non-invasive technique that can help improve our understanding of the hydrogel layer formed on swellable, polymer-matrix tablets, as well as the layer's properties and its influence on drug release. AREAS COVERED: In this paper, the authors review the NMR and MRI investigations of hydrophilic, swellable polymers published since 1994. The review covers NMR studies on the properties of water and drugs within hydrated polymers. In addition, MRI studies using techniques for determining the different moving-front positions within the swollen tablets, the polymer concentration profiles across them, the influence of the incorporated drug, and so on, are presented. Some complementary methods are also briefly presented and discussed. EXPERT OPINION: Using MRI, the formation of a hydrogel along with simultaneous determination of the drug's position within it can be observed non-invasively. However, the MRI parameters can influence the signal's intensity and therefore they need to be considered carefully in order to prevent any misinterpretation of the results. MRI makes possible an in situ investigation of swollen-matrix tablets and provides valuable information that can lead, when combined with other techniques, to a better understanding of polymeric systems and a more effective development of optimal dosage forms.

A new approach combining different MRI methods to provide detailed view on swelling dynamics of xanthan tablets influencing drug release at different pH and ionic strength.

The key element in drug release from hydrophilic matrix tablets is the gel layer that regulates the penetration of water and controls drug dissolution and diffusion. We have selected magnetic resonance imaging (MRI) as the method of choice for visualizing the dynamic processes occurring during the swelling of xanthan tablets in a variety of media. The aims were (i) to develop a new method using MRI for accurate determination of penetration, swelling and erosion fronts, (ii) to investigate the effects of pH and ionic strength on swelling, and (iii) to study the influence of structural changes in xanthan gel on drug release. Two dimensional (2D) MRI and one dimensional single point imaging (SPI) of swollen xanthan tablets were recorded, together with T(2) mapping. The border between dry and hydrated glassy xanthan-the penetration front-was determined from 1D SPI signal intensity profiles. The erosion front was obtained from signal intensity profiles of 2D MR images. The swelling front, where xanthan is transformed from a glassy to a rubbery state (gel formation), was determined from T(2) profiles. Further, the new combination of MRI methods for swelling front determination enables to explain the appearance of the unusual "bright front" observed on 2D MR images in tablets swollen in HCl pH 1.2 media, which represents the position of swelling front. All six media studied, differing in pH and ionic strength, penetrate through the whole tablet in 4h+/-0.3h, but formation of the gel layer is significantly delayed. Unexpectedly, the position of the swelling front was the same, independently of the different xanthan gel structures formed under different conditions of pH and ionic strength. The position of the erosion front, on the other hand, is strongly dependent on pH and ionic strength, as reflected in different thicknesses of the gel layers. The latter are seen to be the consequence of the different hydrodynamic radii of the xanthan molecules, which affect the drug release kinetics. The slowest release of pentoxifylline was observed in water where the thickest gel was formed, whereas the fastest release was observed in HCl pH 1.2, in which the gel layer was thinnest. Moreover, experiments simulating physiological conditions showed that changes of pH and ionic strength influence the xanthan gel structure relatively quickly, and consequently the drug release kinetics. It is therefore concluded that drug release is greatly influenced by changes in the xanthan molecular conformation, as reflected in changed thickness of the gel layer. A new method utilizing combination of SPI, multi-echo MRI and T(2) mapping eliminates the limitations of standard methods used in previous studies for determining moving fronts and improves current understanding of the dynamic processes involved in polymer swelling.

Dynamic contrast enhanced MRI of mouse fibrosarcoma using small-molecular and novel macromolecular contrast agents.

The aim of the study was a comparison of 2 novel macromolecular contrast agents, Gadomer-17 and Polylysine-Gd-DTPA, with commercially available Gd-DTPA in determining the quality of tumor microvasculature by dynamic contrast enhanced MRI. Three groups of 5 mice with SA-1 tumors were studied. To each group of animals one contrast agent was administered; i.e. the first group got Gd-DTPA, the second group Gadomer-17 and the third group Polylysine-Gd-DTPA. To perform dynamic contrast enhanced MRI a standard keyhole approach was used by which consecutive signal intensity change due to contrast agent accumulation in the tumor was measured. From the obtained data, tissue permeability surface area product PS and fractional blood volume BV were calculated on a pixel-by-pixel basis. PS and BV values were calculated for each contrast agent. Based on the values, contrast agents were classified according to their performance in characterizing tumor microvasculature. Results of our study suggest that Gadomer-17 and Polylysine-Gd-DTPA are significantly superior to Gd-DTPA in characterizing tumor microvasculature.

A study of tablet dissolution by magnetic resonance electric current density imaging.

The electric current density imaging technique (CDI) was used to monitor the dissolution of ion releasing tablets (made of various carboxylic acids and of sodium chloride) by following conductivity changes in an agar-agar gel surrounding the tablet. Conductivity changes in the sample were used to calculate spatial and temporal changes of ionic concentrations in the sample. The experimental data for ion migration were compared to a mathematical model based on a solution of the diffusion equation with moving boundary conditions for the tablet geometry. Diffusion constants for different acids were determined by fitting the model to the experimental data. The experiments with dissolving tablets were used to demonstrate the potential of the CDI technique for measurement of ion concentration in the vicinity of ion releasing samples.

Turbulent axially directed flow of plasma containing rt-PA promotes thrombolysis of non-occlusive whole blood clots in vitro.

The rate of thrombolysis markedly decreases after a thrombosed vessel is partly recanalized and the remaining clot poses serious risk for rethrombosis. We studied in vitro how thrombolysis depends on penetration of plasma containing thrombolytic agents - 0.2 micro g/ml rt-PA or 250 IU/ml streptokinase (SK) - and the magnetic resonance contrast agent Gd-DTPA (at 1 mmol/l) into non-occlusive clots under conditions of fast (turbulent) or slow (laminar) axially directed flow. Cylindrical non-retracted (fresh) or retracted (aged) whole blood clots were pierced lengthways and connected to a perfusion system. Dynamical spin-echo MRI was used for measuring the penetration of labeled plasma into clots and for assessing the remaining clot size. In both types of clots fast flow enhanced the penetration of Gd-DTPA-labeled plasma into clots in comparison to slow flow. In non-retracted clots, lysis with rt-PA and to a lesser extent also lysis with SK followed the path of plasma penetration into clots. After 40 minutes of fast axially directed flow rt-PA resulted in almost complete lysis and SK left only about a third of the clot undissolved, whereas with slow flow lysis was much slower (undissolved clot: 86 +/- 5 % with rt-PA and 95 +/- 1 % with SK). In retracted clots, substantial lysis was possible only with rt-PA and rapid flow (53 +/- 28% of the clot undissolved after 60 min), whereas the use of SK or slow flow precluded meaningful lysis. We conclude that rapid (turbulent) axially directed flow of plasma along non-occlusive blood clots causes forceful exchange of serum inside the clot with outer plasma which enhances both fibrin-specific and non-fibrin-specific lysis of fresh clots. Dissolution of non-occlusive retracted (aged) clots occurs only under fibrin-specific conditions combined with adequate transport of rt-PA into clots.

Recording of ENGs from the nerves innervating the pancreas of a dog during the intravenous glucose tolerance test.

Electroneurograms (ENGs) from the vagus nerve (VN), the splanchnic nerve (SN) and the pancreatic nerve (PN) innervating the pancreas of a dog, were recorded with chronically implanted 33-electrode spiral cuffs (cuff) before and after the pancreas were stimulated with intravenously (i.v.) administered glucose. In the cuffs platinum electrodes were arranged in three parallel spiral groups containing 11 electrodes on the inner surface. The cuffs had an inner diameter of 2 mm and a length of 18 mm. In a two-year study, the cuffs were implanted into two Beagle dogs and were also used for pancreatic stimulation, although this is not described in this paper. In the VN, the cuff was installed on the nerve at the neck, whilst in the SN, the cuff was installed on the nerve before the celiac ganglion, and in the PN, the cuff was installed on the nerve just before it enters the pancreas. Six months after implantation, when the model of interpretation of the results was developed, three recordings of ENG in each animal were conducted. The first one was conducted in the unstimulated pancreas while the second and the third were conducted 1 and 8 min after a known amount of glucose was i.v. administered. Since the results obtained in both animals were actually quite similar, we present the results obtained in one animal. To evaluate the changes in superficial activity of the nerves, elicited by the administration of glucose, the power spectra corresponding to ENGs, recorded from the nerves before and after the administration of glucose, were integrated within the band of frequencies ranging from 1 to 5 kHz. Accordingly, the magnitude of the integrated power spectrum (MIPS), corresponding to the ENG recorded from the SN before administration of glucose, was 2.863 au. One minute after glucose was administered the value fell to 2.795 au while 8 min after the administration the value returned to 2.8 au. The MIPS corresponding to the ENG recorded from the PN before the administration of glucose was 3.236 au. One minute after the administration the value fell to 2.901 au while 8 min after the administration the value rose to 3.009 au. The MIPS, corresponding to the ENG recorded from the VN before the administration of glucose, was 3.656 au. One minute after the administration the value fell to 3.565 au. Eight minutes after the administration the value rose to 3.689 au. The results show that 1 min after glucose was administered superficial activity in all three nerves was reduced while 8 min after administration the activity in the nerves returned to the same level of activity before the glucose was administered. This information could be effectively used in a further study of pancreatic innervation and its function. Moreover, the results suggest that cuffs could also be useful in recording the ENGs from other nerves of the autonomic nervous system that innervate various glands and internal organs.

Magnetic resonance imaging of arterial thrombi and its possible correlation to fibrinolytic treament.

For 13 patients with subacute and 4 patients with chronic occlusion, magnetic resonance imaging (MRI) of occlusive arterial thrombi in the superficial femoral artery were performed in vivo. The patients with subacute occlusion were treated with catheter-directed thrombolysis. The frequency of MR signal intensity and its distribution in thrombi were studied for 11 successfully and 2 unsuccessfully treated patients and patients with chronic occlusion. Intra-arterial thrombi were MRI inhomogenous in all of the patients, but the MR signals from lysable and chronic thrombi were significantly different than those from nonlysable ones. The MRI of occlusive arterial thrombi is probably usable to predict the therapeutic outcome of thrombolytic treatment.

Electric current density imaging of tablet dissolution.

The Electric current density imaging technique (CDI) was used to monitor the dissolution of and ion migration from tablets of different acids in agar-agar gel. Conventional MRI cannot monitor these processes, since it can only show changes in the size of the tablet during the dissolving process. CDI traces the dissolved ions thanks to changes in conductivity.