Preparation of the Rutin-SBA-16 Drug Delivery System

This study sets out a scheme for a controlled release delivery system using SBA-16 as a carrier matrix and Rutin as a drug (Rutin-SBA-16). Physicochemical characterizations were performed to confirm the structure of the SBA-16 for post-synthesis by scanning electron microscopy (SEM), Transmission Electron Microscopy (TEM) and X-ray Diffraction (XRD). The presence of Rutin-SBA-16 was confirmed by Fourier-transform infrared spectroscopy (FTIR) and Nitrogen adsorption-desorption isotherms at 77 K. The dissolution kinetics was evaluated by the Zero Order, First Order and Higuchi models, and Rutin quantification was carried out by High Performance Liquid Chromatography (HPLC). The best impregnation time, which was 8 hours, adsorbing 284 μg Rutin per mg of silica, and the maximum degree of dissolution occurred in a period of 20 - 25 h. The release kinetics of the Rutin was called Higuchi, and showed high linearity, with a correlation coefficient (R 2 ) of 0.999 compared with 0.905 and 0.980 of the zero order and first order models respectively. The study shows the benefits of Rutin-SBA-16 as a drug delivery system.

Journal of Biomaterials and Nanobiotechnology cas such as MCM ("Mobil Composition of Matter") and SBA ("Santa Barbara Amorphous") silicates have been shown to be good supports because of their large surface area, (i.e. ~1000 m 2 ·g −1 ), adjustable pore sizes (i.e. 2.0 -10.0 nm) and uniform pore size distribution [12] [13]. However, the SBA-16 is regarded as one of the most valuable mesostructures, since it has a cubic 3D arrangement of mesopores in the form of a cage corresponding to a spatial area of Im3m, which have high thermal stability and are generally synthesized in a low pH solution [14] [15]. For this reason, the organized structure of the SBA-16 materials provides them with useful features for several applications, including the matrix in the drug delivery systems.
This study sets out a scheme for a controlled release system using SBA- 16 [16].
The Rutin is known for its multiple pharmacological properties, such as antitumor, antioxidant, anti-inflammatory, anti-depressant and antiviral activity, and cardioprotective mechanisms. It also has a beneficial effect by 1) reducing the concentration of low density cholesterol; 2) taking action to strengthen the structure of the blood vessel wall layers by making the veins more resistant and 3) overcoming problems related to poor blood circulation [17]. Thus, the combination of the essential properties of mesoporous silica with natural products has aroused interest in studies concerned with the spread of these molecules from a controlled release system.

Synthesis, Sample Preparation and Analysis
For the synthesis of mesoporous silica SBA-16, 180 mL of HCl (0.4 mol·L −1 ), 1.40 g of Pluronic F-127 surfactant and 0.16 g of the CTAB co-surfactant were diluted in a beaker with 80.0 mL of deionized water for 20 minutes to form the micelles on a magnetic stirrer (TMA10CF Thelga) [14]. After the complete dissolution of the surfactant, 5.0 mL of the TEOS silica precursor was added, and kept under vigorous stirring with a mechanical stirrer (713 Fisatom), for 5 minutes. The material was then kept for 5 days at 95.0˚C in a thermostated ultrasonic bath The Rutin quantification in the impregnation and dissolution stages was carried out by High Efficiency Liquid Chromatography-HPLC (Thermo Scientific Finnigan Surveyor) equipped with a Phenomenex Gemini column (NX 5 μm, C18 110 Å, 150 × 4.6 mm) and UV-VIS detection system at a wavelength of 254 nm. The mobile phase consisted of acetonitrile and water acidified with 1.0% acetic acid. The mobile phase flow was 1.4 mL per minute. The volume injected was 20.0 μL and the retention time of the routine was 3 minutes. The accuracy of the quantification method by HPLC was determined by carrying out addition and recovery tests for 5.00, 15.00 and 30.00 μg·mL −1 of Rutin in a solution prepared in 1% HCl and 1% DDS to simulate the pH of the stomach (i.e. site of interest of the Rutin release activity) and check any possible interference in the readings. The

Physicochemical and Morphological Characterization
The physicochemical characterizations were performed to confirm the structure of the SBA-

Physicochemical and Morphological Characterization
Through the micrographs shown in Figure 2, it can be observed that the par-Journal of Biomaterials and Nanobiotechnology ticles have a rhombododecahedra morphology that is consistent with the findings of the literature used for the synthesis of this material [14] [15]. The comments in the micrographs obtained by TEM (Figure 3(a) and Figure 3(b)) are in accordance with this structure (SBA-16). Although it does not show the regular and perfect form of a polyhedron, it is possible that the images are becoming similar to those in the pore system [14] [23] [24].   The characterizations were finalized by conducting tests involving the adsorption-desorption isotherm of N 2 to 77 K to calculate the pore diameter and compare the calcined silica and silica impregnated with Rutin (as in Figure 7(a) and Figure 7(b), respectively). The profile of the isotherms did not change after impregnation, and the structural features of the mesoporous synthesized array were preserved [33]. The comparison of the results of the calcined silica with silica impregnated with Rutin provided the measurements of the specific surface area (SBET), pore diameter (DP) and pore volume (VP), which were 732 m 2 ·g −1 , 6.6 nm, 0.55 cm 3 ·g −1 respectively for Rutin-SBA-16. These data demonstrate that there was a reduction in surface area and pore volume, thus confirming the presence of Rutin on silica (i.e. SBET, DP and VP of 806 m 2 ·g −1 , 6.6 nm, 0.60 cm 3 ·g −1 ) to SBA-16 [14] [24]. The comparison between the DP of SBA-16 and Rutin-SBA-16 shows that the pore diameter did not change; this can be explained by the fact that the Rutin is impregnated inside the pores and not necessarily in the walls of the pore, which would not result in a change in the diameter. This might indicate a non-uniform distribution of Rutin within the silica pores [27].   Higuchi, as shown in Table 1.

Kinetic Release Study of Rutin-SBA-16
Kinetic studies are widely used to assist in the development of new formulations, assess the influence of changes in the production process and/or in the formulation, monitor quality control from batch to batch of a particular specialist area, and make an evaluation of pharmaceutical equivalence between the presentations of different manufacturers.
The dissolution profile of Rutin that has been evaluated in this work is shown in Figure 8. It is clear from this that the maximum release occurs between 20 -25 h. The release kinetics of the Rutin are called Higuchi (Table 1)  amount that still remains, and at the same time, the released amount decreases over the course of the testing period [19] [34] [35]. The Higuchi release systems are for uncoated devices which are often used to describe the rate of the controlled release of the drug from a matrix system; this is because the yield of the drug is based on Fick's first law of diffusion which is proportional to the square root of time [2] [35] [36]. In this case, the release of the Rutin-SBA-16 occurs by diffusion of the Rutin through the matrix pores by means of the monolithic system, where the interactions that occur between the silica and the Rutin are of the hydrogen bond type [37].
In light of the study material, someone weighing 70 kg would require the ingestion of approximately 30 mg, (i.e. Rutin-SBA-16 containing 120 μg·kg −1 Rutin) for effective anticancer treatment involving the inhibition of cell proliferation and removal of reactive oxygen species that can cause DNA damage and lead to mutations in a dosage [37]. Although supplementary toxicity tests are needed, the study shows the benefits of Rutin-SBA-16 as a drug delivery system. Since the SBA-16 mesoporous silica of this research represents an interesting carrier matrix for modulating rutin release (Higuchi Model). This ability of silica to modulate release will allow in vivo studies to evaluate different pharmaceutical forms for dose/frequency adequacy of rutin use.

Conclusion
The techniques of characterization provided proof that the array of mesoporous silica (SBA-16) was prepared successfully. Impregnation of Rutin on silica was confirmed from the FTIR techniques and the adsorption/desorption of nitrogen. The kinetic tests showed high linearity, with a correlation coefficient (R 2 ) of 0.999 for the Higuchi model. This was due to the diffusion of Rutin by the pores of the array through the monolithic system, where the interactions that occur between silica and Rutin are of the hydrogen bond type. The Rutin-SBA-16 system released 284 μg of Rutin by mg of silica in a period of 24 h. Moreover, it was able to provide a controlled release of the drug and included an array for future tests of toxicities and in vivo applications.