Synthesis of pH-responsive mesoporous silica ... - Springer Link

J Sol-Gel Sci Technol (2014) 69:364–369 DOI 10.1007/s10971-013-3228-x

ORIGINAL PAPER

Synthesis of pH-responsive mesoporous silica nanotubes for controlled release Jie Ma • Huiming Lin • Rong Xing • Xiaofeng Li • Chunhui Bian • Di Xiang Wei Guo • Fengyu Qu

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Received: 20 August 2013 / Accepted: 27 November 2013 / Published online: 20 December 2013 Ó Springer Science+Business Media New York 2013

Abstract A novel mesoporous silica tubes (MMT) which possessed pH-sensitive controlled release ability had been fabricated and synthesized by using carbon nanotubes (CNTs) as template. The sample replicated the morphologies of the CNTs successfully. The Brunauer–Emmett– Teller surface area of the materials can reach 1,017 m2 g-1 with the pore size of 3.8 nm. As a model drug, metformin HCl was applied to study the drug loading and control release ability of the materials. MMT possesses higher drug loading ratio (36 %) than that of MCM-41 (27.5 %). The release kinetics were studied in simulated gastric fluid (pH = 1.2) and in simulated proximal intestine fluid (pH = 7. 4), respectively. The result shows that the delivery systems exhibit well pH-sensitive control release ability and the as-synthesized materials have potential application in biomedical field. Keywords Mesoporous silica Carbon nanotubes pH-responsive Controlled release

1 Introduction As a drug host, mesoporous silica materials, such as, MCM-41, MCM-48 and SBA-15 etc., are drawn much attention due to its adjustable pore size, non-toxic nature, good biocompatibility and so on [1–3]. Early, mesoporous silica materials were used as the hosts for drug molecules making the drug release process controlled just by the pore

J. Ma H. Lin R. Xing X. Li C. Bian D. Xiang W. Guo F. Qu (&) College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, People’s Republic of China e-mail: [email protected]

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size and morphology of the host. However, due to the can not keep drug bioactivity, lower loading ratio, shorter release time and so on, the ordinary drug release process can not satisfy the clinical needs [4]. To make sure necessary drug delivery amount and targeted position, the drug controlled release system responding to the internal or external stimulation (e.g., temperature [5], pH [6–9], light [10], magnetism [11, 12] and luminescence [13–15]) can be adopted. The synthesis of stimuli-responsive drug controlled release system based on the functional mesoporous silica materials has been widely investigated and attracted increasing attention [16, 17]. Huang et al. [18] synthesized magnetic mesoporous silica spheres with different morphologies and pore sizes by the S/O/W single-emulsion method,showing the well targeted drug delivery performance. Meng et al. [19] reported a novel mesoporous silica delivery system capable of drug delivery based on the function of—cyclodextrin nanovalves that are responsive to the endosomal acidification conditions in human differentiated myeloid and squamous carcinoma cell lines. Furthermore, they demonstrate how to optimize the surface functionalization of the MSNP so as to provide a platform for the effective and rapid doxorubicin release to the nuclei of KB-31 cells. As we know, human body shows various pH environments in different positions. The pH value of stomach, lintestine, blood and tumor is about 1.5–2, 7.4, 7.35–7.45 and 5.8–7.2 respectively. Therefore pH-sensitive drug release systems play an important role in controlled drug delivery systems. Yang et al. [20] reported an efficient pH-responsive carrier system has been constructed by oppositely charged ionic interaction between carboxylic acid modified SBA-15 silica rods and polyelectrolyte. Xue et al. [21] reported a poly(D,L-lactide-co-glycolide) (PLGA)/mesoporous silica hybrid structure (PS hybrid structure),which was synthesized via a

J Sol-Gel Sci Technol (2014) 69:364–369

novel sol–gel route assisted by single emulsion solvent evaporation. In this paper, mesoporous silica with tube structure was synthesized via a facile one-step sol–gel method with carbon nanotube (CNTs) as the hard template. EudragitS100, a pH sensitive anionic polymer, was coating outside the mesoporous materials, showing the well pH sensitive drug release performance. Metformin HCl (MH) was used as the model drug. The release kinetics of MH from these ES/HMMT was discussed in simulated gastric fluid (SGF, pH = 1.2) and simulated proximal intestine fluid (SIF, pH = 7.4), respectively.

2 Experimental section

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temperature in a sealed vial to prevent the evaporation of the H2O. The drug-loading MMT powder was recovered by vacuum filtration and dried at room temperature. 10 mL filtrate was extracted and properly diluted. And then it was analyzed by UV–vis spectroscopy at a wavelength of 237 nm, to determine the drug-loading with the differential method. And thee sample was named as MMT/MH. The MMT/MH tablets with a diameter of 10 and 0.5 mm in thickness were obtained by pressure on preforming machine at 4 MPa. Then, the EudragitS-100 (5.0 wt%) ethanol solution was dropped on the surface of MMT/MH tablets and dried in air at room temperature. When the ethanol outside the tablets volatilized completely, the pH-sensitive EudragitS-100 was fully coated on the surface of the MMT/MH tablets named as ES/MMT/ MH.

2.1 Materials 2.4 Drug release in vitro All the reagents were analytic reagent grade and purchased from commercial without further purification. Tetraethyl orthosilicate (TEOS, Tiantai Chemical Co., Tianjin), Cetyltrimethylammonium bromide (CTAB), carbon nanotube (CNTs), polyvinylpyrrolidone (PVP), NH3H2O, ethanol (Yongda Chemical Reagent Company, Tianjin), Metformin HCl (MH, Shandongkeyuan, Jinan), EudragitS100 (Shanghai, China). 2.2 Synthesis of mesoporous silica tube (MMT) CNTs (0.2 g) were added into of an ethanol (100 mL) solution including PVP (1.0 g). Then the above solution was stirring 12 h until it became homogeneous at room temperature. The mixture was separated by centrifugation and washed three times with ethanol. The resulting material was dissolved in mixing solution of distilled water, ethanol and ammonia. The solution was continuingly ultrasound for 40 min for producing CNTs disperse in the solution perfectly. After the solution turned uniform, CTAB (0.62 g) was added into above solution. When CTAB was dissolved completely, TEOS (1.05 g) was poured into the solution under vigorous stirring. Stirring was continued for 12 h, and then the resulting solid was collected by centrifugation and washed three times with ethanol and dried in and dried in air at ambient temperature and named CNTs@SiO2. The CNTs@SiO2 was calcined at 550 °C for 6 h to remove the templates. The sample was named as MMT. 2.3 Drug loading Typically, MMT sample (0.206 g) was suspended in H2O (10 mL) solution of MH with a concentration of 0.1 mol L-1. The mixture was stirred for 2 h at room

Briefly, ES/MMT/MH was immersed in beaker with 300 mL of release media (SGF, pH = 1.2 and SBF, pH = 7.4) solution. The beaker was incubated at 37 °C in a thermostat shaker. At appropriate intervals, the release medium (3.0 mL) was taken and immediately replaced with an equal volume of fresh. The 3.0 mL extracted solution was properly diluted to estimate the concentration of drug release. Finally the MH content was analyzed for at 237 nm using UV–vis spectrometer. Calculation of the corrected concentration of the released MH is based on the following equation: Ctorr ¼ Ct þ

t¼1 vX Ct V 0

ð1Þ

where Ctorr is the corrected concentration at time t, Ct is the apparent concentration at time t, v is the volume of sample taken, and V is the total volume of the dissolution medium. 2.5 Characterization The morphologies of the prepared samples were characterized using a scanning electron microscope (SEM, Hitachi S4800) at an accelerating voltage of 20 kV. Powder X-ray diffraction (XRD) data were collected on a Bruker D8 ADVANCE diffractometer at 40 kV and 30 mA, using Cu Ka radiation. The specific surface area of samples was determined using Brunauer–Emmett–Teller (BET) (NOVA 4200E Surface Area and Pore Size Analyzer, Quantachrome, USA). The pore size distributions were calculated from the adsorption branches of the N2 adsorption isotherms using the Barrett–Joyner–Halenda (BJH) model. Fourier transform infrared (FTIR) spectra were recorded on a Perkin–Elmer 580B Infrared Spectrophotometer using the KBr pellet technique. The UV–vis absorbance spectra were

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Fig. 1 SEM images of CNTs (a) and HMMT (b)

(a): CNTs (b): CNTs@SiO2

Intensity

Intensity

(c): HMMT

(c)

(002)

(b) (a)

1

2

3

4

5

6

2theta (degree)

20

25

30

35

40

2theta (degree)

Fig. 2 Low-angle XRD of MMT

Fig. 3 Wide-angle XRD of CNTs (a), CNTs@SiO2 (b), and MMT (c)

measured using a Shimadzu UV-3101PC spectroscope. Transmission electron microscopy (TEM) images were recorded on a FEITecnai F20 instrument.

XRD patterns of CNTs, CNTs@SiO2 and MMT. From Fig. 3, CNTs and CNTs@SiO2 show the diffraction peak at 2h = 26.4°, ascribing to the (002) diffraction of graphite. After calcination, there is not diffraction peak present for MMT, implying the remove of CNTs under high temperature treatment. The TEM images of MMT are exhibited in Fig. 4. It can be seen that MMT retains the tubes structure about 150–200 nm in size from Fig. 4a. The tube wall and cavity is about 50–100 and 50 nm, respectively from Fig. 4b. Furthermore, MMT shows the worm-like mesoporous structure that is corresponding to the result of XRD. The cavity of MMT played an important role to increase the specific surface area of material and drug loading amount. The N2 adsorption–desorption isotherm and the BJH pore size distribution curve of sample were shown in Fig. 5. From Fig. 5a, it exhibits the characteristic type of IV N2 adsorption/desorption patterns, with well-defined steps at relative pressures P/P0 of 0.4–0.6, implying the uniform mesoporous channels. Narrow peak of the samples in the BJH pore size

3 Results and discussion 3.1 Structural characteristics of samples The SEM images of CNTs and MMT are exhibited in Fig. 1. From Fig. 1a, CNTs reveals the typical tube morphology with 50–150 nm in diameter and several microns in long. From Fig. 1b, MMT also shows the tube structure, implying the well replication of the hard templates of CNTs. Figure 2 shows the small angle XRD pattern of MMT. Just only one diffraction peak at 2h = 2.3 can be found in Fig. 2, suggesting the mespororous structure with low ordered degree of the sample. In order to testify the remove of the hard template CNTs, wide angle XRD was used. Figure 3 shows the

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Fig. 4 Low (a) and high (b) TEM images of MMT

(b)

(a) 700

0.4

600

dV/dlog (D),cm3 /g

Volume Adsorbed(cm3/g)

Fig. 5 Nitrogen adsorption– desorption isotherm (a) and pore size distribution curve (b) of MMT

500 400 300

0.3

0.2

0.1

200 0.0 100 0.0

0.2

0.4

0.6

0.8

Relative Pressure(p/p0 )

Table 1 The structure parameters of the MMT Sample

SBET (m2 g-1)

VP (cm3 g-1)

D (nm)

MMT

1,017

0.5

2.6

1.0 5

10

15

20

25

30

Pore size (nm)

was focused on 3.8 nm. The BET surface area and pore volume listed in Table 1. BET surface area and pore volume was 1,017 m2 g-1 and 0.5 cm3 g-1.This decides the MMT possesses the high drug loading ratios (36 %).

Fig. 6 SEM image of MMT/MH and ES/MMT/MH

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80

2.0

Transmittance

1.6

Cumulative Release Rate (Wt%)

MMT\MH:pH=7.4 MH 3177

1.2

956 0.8

MMT

1097

0.4

3190

964

0.0

MMT/MH

1082 4000

3000

2000

1000

70

Es\MMT\MH:pH=7.4 60 50

MCM-41\MH:pH=7.4

40 30 20

Es\MMT\MH:pH=1.2 10 0

0

0

10

20

30

-1

Wave number (cm )

The SEM images of MMT/MH and ES/MMT/MH were offered in Fig. 6. The surface of MMT/MH was rough, but it became smooth when ES coated on their surface, revealing that ES had been coated successfully. The FTIR analysis of MH, MMT and MMT/MH was provided in the Fig. 7. For MMT, it can be seen the obvious absorption bands at about 3,439, 1,090 and 960 cm-1 indexed –OH, Si–O–Si and Si–OH respectively. Meanwhile, from the FTIR spectrum of MMT/MH, the peak located at about 3,200 cm-1 assigned to the stretching vibrations of –NH group can be detected from MH, confirming the successful loading of MH molecules onto the MMT. The release behavior cure of MH from the MMT\MH, Es\MMT\MH, MCM-41\MH in SIF (pH = 7.4) and MH from the SGF (pH = 1.2) at 37 °C is shown in Fig. 8. From the release curve of MCM-41\MH, the MH release slowly and the maximum amount is only 50 % at 24 h. But to the MMT\MH, MH release in simulated SIF appears to be much faster, which can release 69 % at 1 h and it takes 12 h to reach the maximum amount 80 %. With tube structure, MMT shows the uniform tube walls about 50 nm in thickness. The short path of the drug molecule release from the pore into outside makes the fast release performance. However, after the Es grating, the MH release from Es\MMT\MH deduces to 32 % at 1 h in SIF. And it takes 48 h to reach the maximum 70 %. Eudragit-S100 is a typical anionic polymer exhibiting pH-dependent solubility. It can be insoluble in acid medium and dissolves at pH values above 7. The pH-dependent controlled release of Es\MMT\MH was also carried out in SGF (pH = 1.2) as contrast. From the release curve of Es\MMT\MH in SGF (pH = 1.2), after 1 h the release reach 10 %. With the increase to 36 h, the release increase to 19 %. After 70 h,

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50

60

70

80

Time/h

Fig. 8 The release curves of MMT\MH, Es\ MMT\MH, MCM41\MH in SIF (pH = 7.4) and Es\ MMT\MH in the SGF (pH = 1.2)

80

Cumulative Release Rate (Wt%)

Fig. 7 FTIR spectra of MH, MMT and MM/MH

40

70 60 50 40 30 20 10 0 0

2

4

6

8

10

12

14

16

18

20

22

24

Time/h

Fig. 9 The release curves of Es\ MMT\MH in pH 1.2 in the first 2 h and pH 7.4 in the other hours

no more than 20 % was released. While in SIF, the release can reach 70 % at 70 h. In order to further investigate the pH-dependent controlled release of Es\MMT\MH, the release performance in SGF at first 2 h and then in SIF was also shown in Fig. 9. From Fig. 9, Es\MMT\MH release about 11 % at the first 2 h in SGF. When the release medium was changed into SIF, the release rate and amount were increased remarkably. Until 24 h, the release can reach 56 % in SIF. The pH sensitivity was caused by structural change of the polymer associated with ionization of the carboxylic functional group at pH value above 7. In clinical application, Es\MMT system can protect the drug in stomach acid, and make the drug release in intestinal position. From the above, the Es\MMT system shows the potential application on the treatment of intestinal disease.


4 Conclusions In summary, the mesoporous silica with nanotube structure was prepared using a facile sol–gel method by one-step. CNTs were used as the hard template and CTAB as the mesoporous template. The synthesized sample shows large BET surface area 1,017 m2 g-1 and high drug loading amount %. Furthermore, Eudragit-S100, a pH-sensitive polymer, was grafted outside MMT making the systems exhibit well pH-sensitive control release ability. Es\MMT system inhibits the drug release in acid condition, and makes the freely release in natural and alkali condition. That is to say, it can protect the drug in stomach acid, and make the drug release in intestinal position. From the above, the Es\MMT system can be used on the treatment of intestinal disease. Acknowledgments Financial support for this study was provided by the National Natural Science Foundation of China (21171045, 21101046), Natural Science Foundation of Heilongjiang Province of China (ZD201214, B201206), Program for Scientific and Technological Innovation team Construction in Universities of Heilongjiang province (2011TD010), Research Fund for the Doctoral Program of Higher Education of China (20102329110002), Pre-research Found for Technological Development of Harbin Normal University (12XYG-11), Foundation of Education Department of Heilongjiang Province, China (12533037).

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