Mesoporous silica materials are promising nanocarriers for the development of drug delivery systems. In this study, the influence of pore size, volume, surface area, and doping the silica framework on the release kinetics of a model drug, metoprolol, has been studied. 20% or 50% wt. therapeutic agent was loaded into the carrier mesopores through incipient wetness impregnation. The carriers and drug-loaded samples have been characterized by small- and wide-angle X-ray diffraction, FT-IR spectroscopy, scanning electron microscopy, and nitrogen adsorption-desorption isotherms. The
The development of novel drug delivery systems (DDS), which can be adjusted to individual needs, is receiving a great deal of attention lately. Such systems must be biocompatible and able to load a significant amount of therapeutic agent and to release it following a predetermined time profile. Mesoporous silica nanomaterials (MSN) are currently studied for drug delivery applications due to their biosafety [
We have investigated the influence of pore size, geometry, and introduction of organic functional groups on the release process of a model drug, metoprolol, in our previous work [
Metoprolol (MTP), the model drug, has a smaller size than the carrier mesopore diameters (estimated at 1.6 by 0.5 by 0.6 nm) and it possesses various functional groups which can participate in carrier-drug supramolecular interactions (hydroxyl, secondary amine, methoxy, and phenoxy). The therapeutic agent is widely used in the treatment of several cardiovascular diseases, acting as a
Tetraethylorthosilicate (TEOS, Fluka), AlMCM-41 (Aldrich), 37% hydrochloric acid solution (HCl, Sigma-Aldrich), poly (ethylene glycol)-
The detailed synthesis and characterization of MCM-41 and SBA-15 supports and metoprolol-loaded materials were reported in our previous publications [
The Al-containing SBA-15 support, denoted as AlSBA-15, was synthesized in acid-free conditions [
Metoprolol was loaded onto the mesoporous matrices through incipient wetness impregnation method. The carriers were added to a 100 gL−1 MTP aqueous solution, homogenized, and then dried under vacuum at 25°C. MTP-loaded materials with 20% (denoted MTP@“Carrier”) and 50% (MTP50%@AlSBA-15) drug content were prepared. The
Small- and wide-angle X-ray diffraction (XRD) was performed on a Bruker D8 Discover diffractometer with Cu K
Both the pristine carriers and drug-loaded samples were characterized in order to determine the relevant properties affecting the drug release process.
Small-angle XRD was used to evidence the ordered mesopore array for both pristine carriers and drug-loaded samples (Figure
Small-angle XRD patterns for SBA-15-type (a) and MCM-41-type (b) mesoporous carriers and drug-loaded samples.
Wide-angle XRD patterns of carriers and drug-loaded samples (a) and FT-IR spectra of mesoporous carriers, drug-loaded materials, and MTP (b).
The FT-IR spectra (Figure
SEM analysis was carried out to assess the morphology of the mesoporous carriers (Figure
Si : Al ratio, drug content, and textural parameters of the samples.
Sample | Si : Al (at.) | MTP (%) |
|
|
|
|
---|---|---|---|---|---|---|
Ads. | Des. | |||||
MCM-41 | NA | 775 | 2.4 | 2.4 | 0.61 | |
AlMCM-41 | 28 | 1000 | 2.6 | 2.6 | 0.75 | |
SBA-15 | NA | 870 | 9.6 | 6.6 | 1.16 | |
AlSBA-15 | 116 | 960 | 9.0 | 6.8 | 1.22 | |
|
||||||
MTP@MCM-41 | NA | 20 | 79 | NA | NA | 0.08 |
MTP@AlMCM-41 | 28 | 20 | 726 | 2.1 | 2.0 | 0.34 |
MTP@SBA-15 | NA | 20 | 334 | 8.1 | 6.3 | 0.61 |
MTP@AlSBA-15 | 116 | 20 | 398 | 8.1 | 6.3 | 0.68 |
MTP50%@AlSBA-15 | 116 | 50 | 111 | 6.8 | 5.1 | 0.19 |
NA: not applicable/could not be determined.
SEM analysis of SBA-15 (a), AlSBA-15 (b), and AlMCM-41 supports (c), AlSBA15 EDX elemental mapping (d), and distribution of Si (e) and Al (f).
The nitrogen adsorption-desorption isotherms of the carriers and AlSBA-15 drug-loaded materials are of type IV with hysteresis, characteristic for mesoporous samples (Figure
Nitrogen adsorption-desorption isotherms of mesoporous carriers and drug-loaded samples. Inset: the corresponding pore size distribution curves.
The metoprolol release profiles were obtained in phosphate buffer solution, pH = 7.4, 37°C for all samples, using the dialysis bag method and compared with the drug diffusion in similar conditions (Figure
Cumulative MTP release profiles, obtained using the dialysis bag method. Symbols denote experimental data, while continuous lines represent fitted data.
In order to gain additional insight regarding the MTP release process, the experimental data was fitted with a three-parameter kinetic model developed by Zeng et al. (Figure
The dissociated molecules are then transported into the release medium through diffusion, also approximated as a 1st-order process, with the rate constant
The MTP release is a two-stage process, consisting of a fast, initial release stage (“burst stage”), which is followed by a more gradual drug release, in the sustained release step. The kinetic parameters of the theoretical model can be used to characterize the drug release process. The rate constant for the diffusion process,
The values of the three rate constants,
Kinetics release parameters for the MTP-loaded samples.
Sample |
|
|
|
|
|
---|---|---|---|---|---|
MTP | 35.6 | 16.0 | 5.4 | 4.65 | 0.9475 |
MTP@MCM-41 | 24.0 | 2.2 | 0.8 | 4.31 | 0.9881 |
MTP@AlMCM-41 | 26.8 | 2.3 | 3.1 | −1.38 | 0.9951 |
MTP@SBA-15 | 35.4 | 3.8 | 1.3 | 4.59 | 0.9838 |
MTP@AlSBA-15 | 29.5 | 6.1 | 6.5 | −0.27 | 0.9784 |
MTP50%@AlSBA-15 | 51.9 | 3.6 | 1.5 | 3.79 | 0.9671 |
The
The release rate during the burst stage is proportional with the diffusion rate constant,
The rate of therapeutic agent release during the sustained release stage is directly proportional to the dissociation rate constant,
A correlation analysis between the kinetics release parameters (
Correlation coefficients between release kinetics parameters and sample textural parameters. Bold values indicate absolute correlation values greater than ±0.75.
Parameters |
|
|
|
|
---|---|---|---|---|
Al/Si | −0.18 | −0.27 | 0.30 | − |
|
0.33 | 0.33 | 0.57 | −0.73 |
|
0.67 |
|
0.29 | 0.21 |
|
0.69 |
|
0.36 | 0.08 |
|
−0.39 | 0.00 | 0.48 | − |
|
0.50 |
|
0.37 | 0.14 |
|
−0.10 |
|
0.66 | −0.34 |
|
0.49 | 0.12 | −0.37 |
|
|
|
−0.12 | −0.31 | 0.30 |
|
|
−0.10 | −0.44 | 0.54 |
The correlation results support the qualitative observations regarding the influence of textural properties of the carriers and MTP-loaded samples on the kinetic parameters. The Al/Si ratio has a strong negative correlation with the
The diffusion rate constant,
The dissociation rate constant,
In this work the possibility of tailoring the drug release kinetics of a model drug, metoprolol, from mesoporous silica and aluminosilicate materials was studied. Two types of mesoporous carriers with hexagonal ordered pore arrays, MCM-41 and SBA-15, were employed. The experimental metoprolol release kinetics were fitted with a three-parameter kinetic model, which consists of an equilibrium between drug adsorption and desorption onto the mesopore surface, followed by transport into the release medium. The influence of doping the silica framework with aluminum was studied by correlating the kinetic parameters of the drug release process with the carriers textural properties.
It was found that all mesoporous carriers could act as drug reservoirs. The larger-pore SBA-15-type carriers could be loaded with up to 50% wt. biologically active molecules. All drug release profiles consist of a two-stage process, with a fast initial drug release in the burst stage, followed by a more gradual release, in the sustained release regime. The whole drug release process is characterized by three kinetic parameters, namely, the metoprolol release rates during the burst and sustained release stages, respectively, and the Gibbs energy of the adsorption/desorption equilibrium. These three parameters are proportional to the rate constant of the transport process, the rate of drug desorption from the pore surface, and the ratio between the amounts of therapeutic agent released in the burst and sustained release stages, respectively.
The drug release rate during the burst stage is directly correlated with the drug-loaded amount and the average pore size of the carriers. The sustained release rate was found to be correlated with the steric crowding of the dissociated molecules inside the support mesopores, with a higher carrier pore volume resulting in faster release rate.
The introduction of Al atoms into the silica framework leads to the decrease of Gibbs energy and consequently of the drug amount released in the burst stage, while not affecting the other kinetic parameters. This effect is explained by the electrostatic interactions arising between the negatively charged pore surface and the positively charged model drug molecules and it also depends on the amount of therapeutic agent loaded into the mesoporous carriers. A higher drug loading leads to a decrease in average electrostatic interaction strength and higher overall Gibbs energy. Doping the silica framework with heteroatoms is therefore a promising strategy towards the rational design of drug release systems which combine both instantaneous and sustained release. In prospective, the heteroatom doping of mesoporous silica could be combined with varying the drug amount and carriers textural properties in order to precisely tailor the release profiles of advanced drug delivery systems.
The authors declare that they have no conflicts of interest.
The authors are grateful for the financial support of the Romanian Project PCCA no. 131/2012.