3D cubic mesoporous silica microsphere as a carrier for poorly soluble drug carvedilol

Abstract

The present work was proposed not only to exploit the potential of 3D cage-like mesoporous silica SBA-16 with a well-defined spherical morphology as a carrier for poorly soluble drugs, but also to compare the drug loading and release properties of 3D cubic SBA-16 with that of classic 2D hexagonal MCM-41. SBA-16 microsphere with highly ordered mesostructures was synthesized by a facile method using block co-polymer F127 as template, cetyltrimethylammonium bromide (CTAB) as co-template and tetraethyl orthosilicate (TEOS) as silica source. Carvedilol (CAR), an antihypertensive agent, was used as a model drug and loaded into mesoporous silica via solvent deposition method at drug–silica ratio of 1:3. In vitro dissolution was performed in both simulated intestinal fluid (SIF, pH 6.8) and simulated gastric fluid (SGF, pH 1.2). Of particular interest was that in SIF both MCM-41 and SBA-16 samples exhibited promoted dissolution profile for CAR as compared to its corresponding crystalline form which exhibited poor dissolution behavior. This dissolution-enhancing effect might be due to the non-crystalline state and increased surface area of confined CAR as well as the hydrophilic nature of silica. In comparison with MCM-41, SBA-16 displayed a more rapid release profile in both SIF and SGF, which may be ascribed to the 3D interconnected pore networks and the highly accessible surface areas. The suitability of the utilization of SBA-16 microsphere as carriers will open new avenues for the formulation of poorly soluble drugs.

Introduction

Since the discovery of the new family of mesoporous silica M41S in 1992 [1], there has been ever increasing attention and effort in synthesis and application of mesoporous silica materials, owing to their tunable pore size, high surface areas, versatile possibilities of surface functionalization as well as diversity in composition, structure, and morphology [2], [3], [4]. Among these mesoporous silica, SBA-series have attracted considerable interest for various applications because of their large pore size and pore volume, thick pore walls, high thermal and hydrothermal stabilities [5]. In particular, SBA-16 is considered to be one of the most interesting mesostructures. It has a 3D cubic pore structure corresponding to Im3m space group. In this body-centered cubic arrangement each pore is connected with its eight nearest neighbors via apertures to form a multidirectional system of mesoporous network [6], [7]. This type of highly interconnected 3D mesostructured porous silica is expected to be superior to 2D hexagonal structures with 1D channel, because it facilitates mass transfer, is less susceptible for pore blockage and ensures the accessibility of pores from any direction [8], [9]. It is noteworthy that the environmentally friendly and commercially available triblock copolymer poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (F127) has been mostly used for the synthesis of SBA-16, thus a combined micropore and mesopore networks could be obtained due to the presence of PEO and PPO chains in F127 [5]. The above-mentioned interesting features, combined with this dual porosity system, make cage-like SBA-16 very promising materials for applications in adsorption, catalysis and separations as well as for immobilization of biomolecules [7], [8], [9], [10], [11].

It was firstly Vallet-Regi et al. in 2001 who proposed the use of mesoporous silica as drug carriers by loading ibuprofen into MCM-41 silica material [12]. Since then, more and more researchers have focused on drug delivery application of mesoporous silica [13], [14], [15], [16], [17], [18]. So far, the most extensively investigated mesoporous silica as drug carrier has been the channel-like MCM-41 and SBA-15, typically featuring a very uniform pore structure of unidirectional channels. And the focus of mesoporous silica materials as drug vehicles has been mainly on the sustained/controlled drug release, with few reports published involving the dissolution enhancement of water-insoluble drugs by mesoporous silica [19], [20], [21], [22], [23], [24], [25]. With respect to the unique structures of SBA-16, it can be expected that this highly ordered 3D interconnected structure offers a great many opportunities for drug delivery applications. Surprisingly, there has been very limited work dealing with the employment of 3D cubic SBA-16 materials as drug carriers. To the best of our knowledge, there is only one paper describing mesoporous silica nanoparticles (MSNs) with cubic Im3m structures as carriers for carbamazepine and oxcarbazepine [26], wherein rapid release profiles were observed within 3 h. However, the release profile of pure crystalline drugs or commercial products was not supplied in that work, therefore the rapid release profile was not so convincing based on the fact that the comparison between drug loaded MSN and raw crystal drug was lack. Besides, it was speculated that the produced MSNs will be difficult to recovered by filtration or centrigation after the aging procedure due to the extremely fine particles of 120 nm dispersed in the diluted solutions. Taking all the above mentions into account, it is highly desirable to undertake a more systematic and detailed investigations to exploit the potential of SBA-16 materials with 3D cubic pore arrangement as drug carriers.

For practical purposes, the morphology of a mesoporous material is a necessary consideration in combination with its internal pore structures. From the view point of drug delivery applications, a regular morphology is anticipated to be preferred as a vehicle for poorly soluble drugs as far as reproducible drug loading and release profile were concerned. It has also been reported that the morphology of mesoporous silica particle is an important factor influencing drug release profiles [27], [28], [29] as well as cellular uptake and cell functions [30], [31]. Despite significant progress in the textural and structural modification of SBA-16 [32], [33], it seems difficult to control the macroscopic morphology of SBA-16 [34], [35], [36], [37] and in most cases irregular or aggregated particles are obtained [4], [32]. In the present study, spherical particles of mesoporous SBA-16 with cubic Im3m structure were successfully prepared in a simple way using Pluronic F127 as template and TEOS as silica source in the presence of cetyltrimethylammonium bromide (CTAB) as co-template. Notably, the synthesis time by this method was shortened (usually 2 days by conventional method) and the synthesis process was simplified since only one-step heating was necessary. This well-defined morphology of SBA-16 by this method is speculated to be more preferred and advantageous as drug carriers than the irregular or aggregated particles. Moreover, it will be of particular interest to compare drug loading and release characteristics between the most investigated 2D channel-like mesoporous MCM-41 and 3D cubic mesoporous SBA-16, especially as to our knowledge, the comparison between these two types of materials has not been reported yet.

Carvedilol (CAR), an anti-hypertensive agent with nonselective β-adrenergic blocking and α1-blocking activities, which is sparingly soluble in water and shows limited bioavailability after oral administration, is used as model drug [38], [39]. Apart from being an antihypertensive agent, CAR is also used in other cardiovascular disorders such as cardiac arrhythmias, angina pectoris and myocardial infarction. Due to these therapeutic effects CAR has become one of the important and promising drugs for cardiovascular diseases [40].