Controlled release of metoprolol tartrate from nanoporous silica matrices

https://doi.org/10.1016/j.micromeso.2010.03.005Get rights and content

Abstract

A series of nanoporous silica matrices (a silica gel matrix and two ordered mesoporous silica) have been investigated as potential carriers for the controlled release of metoprolol tartrate a selective β1 receptor blocker used in the treatment of several diseases of the cardiovascular system. Particular attention was devoted to the optimisation of a reproducible and fast synthetic procedure. The textural properties, structure and chemical nature of the porous surfaces were characterised by N2 physisorption, X-ray diffraction, HR-TEM and FTIR analyses. The delivery profiles were collected in vitro in physiological solution at pH 7.4.

It has been possible to observe a close correlation between the drug release kinetic and the textural properties of the carriers.

Introduction

The realisation of a new pharmaceutical form involves several steps, among which the selection of the excipients (stabilizing agents, lubricating, binding agents, sweetening, colouring, aromatizing,  ) that both improve and favour the acceptability of the final product by the patient. The choice of the carrier is of fundamental importance as in most cases it affect the transfer modality of the drug to the organism. With traditional formulations the delivery of the active agent is total and immediate: it reaches a maximum value that could be out of the therapeutically range. In the last years many efforts have been devoted to the development of new formulations that can control both rate and period of drug delivery. Using controlled drug delivery systems (DDS) designed for long-term administration, the drug level in the blood is kept constant for long time between the desired maximum and minimum value. Other important advantages of using controlled-delivery systems can include: (i) the need for fewer administrations, (ii) optimal use of the drug at issue, and (iii) increased patient compliance.

An inert, biocompatible and stable matrix has to be adopted in the design of an ideal DDS. The traditional carriers currently employed are either natural or synthetic polymers (such as microcapsules, cells, lipoproteins, liposomes, …), but an increasing number of studies is actually addressed to the development of alternative supports, such as silica-based materials that have attracted a lot of interest [1], [2], [3], [4], [5], [6], [7], [8]. Silica matrices show high biocompatibility–biodegrability [1], [9] (these materials are biodegradable to monosilicic acid (in the long run) in the intestine) and resistance to microbial attack; these systems exhibit higher mechanical strength, enhanced thermal stability, and negligible swelling in organic solvents if compared to most organic polymers. Moreover, physico-chemical and textural properties of silica can be modulated ad hoc by the choice of a tailored synthetic approach. Among the different techniques adopted for silica preparation, the sol–gel process is particularly attractive, as it permits to control the physico-chemical features (textural properties, hydrophilic–hydrophobic character) of the material simply through the proper choice of the synthesis parameters (such as composition of precursors mixture, catalysts, pH range, ageing). The relatively mild processing conditions allow the incorporation of the bioactive molecule into the matrix in a one-step process [10], [11]. In the case of silica-based delivery systems, the kinetic release of the drug is ruled by several factors and an important key-role is played by both physico-chemical nature of silica surface and the interaction between the carrier and the active molecule. These interactions can be of different nature: chemical interaction (hydrogen or electrostatic bond) and/or steric interaction related with the texture of the carrier. This last interaction is very marked in the case of ordered nanoporous silica, like MCM-41, SBA-15 and so on.

Recently we have studied several silica systems as carrier for sustaining the drug release of ibuprofen. We have investigated the behaviour of methyl-modified silica matrix prepared by a sol–gel approach or ordered silica matrices pure and modified with aminopropyl groups [12], [13], [14].

In the present work we have focused the attention on both synthesis and characterisation of silica carriers for the controlled release of metoprolol tartrate (MPT) (see Fig. 1). Several points of novelty are presented in this paper, as reported in the following:

  • (i)

    For the first time, MPT has been used as drug model to develop a DDS by using silica as carrier. Metoprolol is frequently employed to alleviate several diseases of the cardiovascular system and its administration by means of a prolonged DDS is desirable, as confirmed by the controlled release formulations of metropolol present on the market.

  • (ii)

    Two innovative and reliable techniques have been optimised for the synthesis of the investigated drug-silica systems: a one-pot sol–gel approach and an incipient wetness impregnation method. The drug is usually adsorbed on the (silica) carrier by post-synthesis wet impregnation.

  • (iii)

    A thorough comparison between a silica gel and two mesoporous carriers is here reported.

Aim of our work has been the investigation of the effect of both textural and physico-chemical properties of the carriers on the drug delivery behaviour. The target has been pursued through a depth analysis and comparison of three different silica matrices.

Section snippets

Materials

Tetraethoxysilane (TEOS) (Aldrich, 98%), NaOH (Fluka, 97%), EtOH (Fluka, 99%), Tris Buffer Saline (Fluka), HCl (Fluka, 37%), Cetyltrimethyammonium bromide (CTA-Br) (Fluka, 99.5%), Pluronic 123 (Aldrich), Metoprolol Tartrate (MPT, 99%). All reagents have been used as received.

Synthesis

In order to ensure the drug stability after adsorption, all the MPT/Silica composites were prepared by using mild synthesis conditions (room temperature, gentle stirring…) as described in detail in the following sections.

Silica gel

Silica gel

The silica gel samples were prepared by a one-step sol–gel approach: the drug was introduced on the liquid sol with the requested amount of water and, after condensation/drying, transparent, monolithic and homogeneous tablets have been obtained. This optimised process turns out to be an efficient way to obtain, in a relatively short time, a silica/drug composite available for delivery studies. Each capsule contains 80 mg of metoprolol tartrate; this amount has been selected on the basis of the

Conclusions

In this work we have synthesised and studied micro- and mesoporous silica as possible carriers to sustain the release of metoprolol tartrate, a drug used in the treatment of several diseases of the cardiovascular system.

A reliable and reproducible synthetic procedure has been optimized for the preparation of stable silica/drug systems. We have observed a close correlation between the drug release and the textural properties of the matrices.

Among the investigated silica systems, the best

Acknowledgements

The authors want to thank Prof. Giuseppe Cruciani (University of Ferrara) for supplying XRD data and Dr. Andrea Chiminazzo for the excellent technical assistance.

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