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pH-Controlled drug release from mesoporous silica tablets coated with hydroxypropyl methylcellulose phthalate
Materials Research Bulletin 44 (2009) 606–612
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Materials Research Bulletin journal homepage: www.elsevier.com/locate/matresbu
pH-Controlled drug release from mesoporous silica tablets coated with hydroxypropyl methylcellulose phthalate Wujun Xu a,b, Qiang Gao a,b, Yao Xu a,*, Dong Wu a, Yuhan Sun a a b
State Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of Sciences, Number 27, Tao Yuan South Road, Taiyuan, Shanxi 030001, China Graduate University of the Chinese Academy of Sciences, Beijing 100049, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 January 2008 Received in revised form 3 June 2008 Accepted 3 July 2008 Available online 11 July 2008
A simple pH-controlled drug release system was successfully prepared by coating pH-sensitive polymer hydroxypropyl methylcellulose phthalate (HPMCP) on drug-loaded mesoporous SBA-15 tablet. Using famotidine (Famo) as a model drug, the effects of coating times and drying temperature on drug release were studied in detail to optimize the drug release system. In simulated gastric fluid (SGF, pH 1.2), it took only 2 h for Famo to be completely released from mesoporous silica tablet without HPMCP coating. Also in SGF, with the increase of coating times and drying temperature, the release of Famo was greatly delayed by HPMCP coating. For the tablet with twice coating of HPMCP and dried at 80 8C, only 4.0 wt.% of Famo could be released within 4 h. However, in simulated intestinal fluid (SIF, pH 7.4), HPMCP coating did not show obvious effect on the release of Famo. ß 2008 Elsevier Ltd. All rights reserved.
Keywords: A. Nanostructures B. Sol–gel chemistry C. X-ray diffraction
1. Introduction Several attractive features, such as high surface area, large mesoporous pore volume, and well-defined pore size distribution of mesoporous silica materials have made them ideal for hosting molecules of various sizes, shapes, and functionalities [1–4]. Since Vallet-Regi [5] discovered the new property of MCM-41 in drug release, many drug release systems based on mesoporous materials have been studied [6–11], and several methods were reported to adjust the release rate of drug from mesoporous carriers. At first, pore size was an important factor affecting drug release rate. It was found that narrowing of mesopores could delay the release rate of model drug [8–13]. If the mesopore diameter was only two or three times larger than the size of drug molecules, the drug release rate would be very sensitive to the change of pore size. In addition, surface organic functionalization on mesoporous material was also an effective method to regulate drug release rate. Song et al. [7] reported that the adsorption capacity of ibuprofen and the corresponding release rates were highly dependent on the amount of amino groups functionalized onto SBA-15 surface. Tang et al. [14] found that the release of ibuprofen from MCM-41 mesoporous materials could be obviously delayed by surface hydrophobic modification with trimethylsilyl groups. Recently, some environment-sensitive drug release systems,
* Corresponding author. Tel.: +86 351 4049859; fax: +86 351 4041153. E-mail address: [email protected] (Y. Xu). 0025-5408/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.materresbull.2008.07.001
based on mesoporous materials, have been prepared to achieve site-specific drug release [4,15–19]. Lin and co-workers [4] synthesized CdS-capped mesoporous nanospheres for drug release, which could be triggered by disulfide bond-reducing molecules. Shi and co-workers [16] developed a pH-responsive drug release system by coating multilayered polyelectrolytes on hollow mesoporous silica spheres, from which the drug release was obviously slower in the release medium of pH 8.0 than that in the medium of pH 1.4. In the field of traditional medicine, it was difficult to be completely cured for intestinal disease because some of the ingested drug would be adsorbed or digested by stomach before it reached intestine. Therefore, it was very important to develop controlled intestinal drug release systems. In view of this, many researches were reported about intestinal drug release based on Chitosan or other organic matrix [20–22]. However, up to now, only one report has been published by Song et al. [23] about intestinal drug release based on mesoporous silica. In this study, poly(acrylic acid) (PAA) was coated on amino-functionalized mesoporous SBA-15 materials. In the release medium of pH 1.2, only 10.0% bovine serum albumin (BSA) was released from PAA/ SBA-15 within 36 h. The designed drug release system could protect BSA from being degraded by gastric albumin enzymes. Compared with sample without coating, the coating material PAA not only effectively delayed the release of BSA in the release medium of pH 1.2, but to some extent, it also decreased the release rate of BSA in the release medium of pH 7.4. In fact, for an intestinal drug release system, the drug release in stomach should be strictly
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Scheme 1. Illustrations of (a) pH-sensitive drug release system HPMCP/SBA-15 and (b) chemical structure of HPMCP.
controlled. On the other hand, in intestine, the model drug needs to be freely released. Thus, taken the obvious differences in pH value between stomach and intestines into account, a design of pHcontrolled system for intestinal drug release was a good choice. To test the validity of designed intestinal drug release system, the selected model drug must be highly sensitive to the acidity of release medium. In our studies, model drug famotidine (Famo) could dissolve quickly into acidic aqueous solution due to the four NH2 groups in its structure. Therefore, if the designed pHcontrolled release system could effectively delay the release of Famo in simulated gastric fluid (SGF, pH 1.2) and seldom restrict its release in simulated intestinal fluid (SIF, pH 7.4), it might be an ideal candidate for intestinal drug release. As we know, coating technology has been using widely in the field of pharmacy [24–26]. In the present study, hydroxypropyl methylcellulose phthalate (HPMCP) was deposited on drug-loaded mesoporous SBA-15 tablets by dip-coating method to construct a pH-controlled drug release system. The illustrations of this composite system HPMCP/ SBA-15 and chemical structure of HPMCP were shown in Scheme 1. HPMCP is a pH-sensitive polymer with pKa value in the range of 4.5–5.5. It is unsolvable in aqueous solution of pH < 3.5, but can dissolve quickly in aqueous solution of pH > 5.5. Moreover, HPMCP chains have lots of hydroxyl groups that can ensure HPMCP coating to firmly adhere to SBA-15 tablets without any further chemical treatment. To enhance the Famo-loading amount, carboxylfunctionalized SBA-15 was used as drug carrier due to the poor Famo adsorption of pure SBA-15. 2. Experimental 2.1. Mesoporous material synthesis Carboxyl-functionalized mesoporous SBA-15 material was used as drug-loading matrix and it was synthesized as following: 2cyanopropyltriethoxysilane (CPTES) was introduced to HCl solution containing triblock copolymer Pluronic P123 (EO20PO70EO20) under stirring at 40 8C. After being hydrolyzed for 0.5 h, tetraethoxysilane (TEOS) was added into the above solution slowly. The molar composition of the final mixture was 1.0 TEOS:0.15 CPTES:0.017 P123:6.1 HCl:170 H2O. The mixture was stirred at 40 8C for 20 h, followed by aging at 90 8C for 24 h under static conditions. The precipitation was filtrated and dried at 60 8C to collect the solid product. At last, the obtained product was treated following Yang’s method to transform cyano groups into carboxylic groups [27].
2.2. Drug-loading procedure To load Famo into carboxyl-functionalized SBA-15 mesoporous materials, 0.5 g mesoporous solid powder and 0.75 g Famo were added into 500.0 mL mixed solvent of methanol and water (the volume ratio of methanol:water = 1:1) and stirred for 8 h. Then, the drug-loaded SBA-15 powder was filtrated and dried at 70 8C. At last, 2.0 mL filtrate was taken out from the vial and was diluted to 50 mL, with which the residual Famo concentration was analyzed on a UV–vis spectroscopy (Shimadzu UV-3150PC) at 285.0 nm. The amount of Famo loaded in SBA-15 can be calculated by the following equation: wt:% ¼
m1 ð50=vÞCV 100% m2 þ m1 ð50=vÞCV
(1)
where m1 and m2 correspond to the initial mass of Famo and mesoporous materials added into the mixed solution of methanol and water, respectively. C is the concentration of filtrates diluted in 50 mL volumetric flask, v is sampled volume from filtrates, and V is the initial volume of the mixed solution for drug loading. 2.3. Preparation of HPMCP/SBA-15 The pH-sensitive drug release system HPMCP/SBA-15 was prepared as below. 0.15 g drug-loaded mesoporous SBA-15 powder was pressed into a 13 mm 3 mm tablet under 6.0 MPa uniaxial pressure. Simultaneously, some amount of HPMCP was dissolved into a mixed solvent of ethanol and water (the mass ratio of ethanol:water = 8:2) under stirring at room temperature. Then, the drug-loaded mesoporous SBA-15 tablet was dip-coated with HPMCP, and the withdrawal speed was fixed at 18 cm/min. The tablets were repeatedly coated with HPMCP twice or four times and then the HPMCP/SBA-15 tablets were dried in open air at 20 8C for 0.5 h. The obtained samples were assigned to SH2-20 and SH4-20, corresponding to twice and four times coating, respectively. To study the effect of drying temperature on drug release rate, the tablets with twice coating of HPMCP were also dried in open air at 45 8C or 80 8C for 0.5 h. The obtained samples were respectively assigned to SH2-45 and SH2-80. Finally, all the HPMCP/SBA-15 tablets were further dried under vacuum at 20 8C, 45 8C or 80 8C for 12 h to eliminate residual solvent. In addition, the carboxyl-functionalized SBA-15 without polymer coating was used as reference and it was assigned to SH0.
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Fig. 1. SEM (a, b) and TEM (c) images of carboxyl-functionalized SBA-15.
2.4. In vitro drug release study The drug release behaviors were investigated by soaking HPMCP/SBA-15 tablets in different simulated physiological media, including SGF (HCl aqueous solution, pH 1.2) and SIF (phosphate buffer solution, pH 7.4). The release experiments were performed at 37 8C under stirring rate of 100 rpm. 2.0 mL of release fluid was sampled from the studied release system at a predetermined time interval, and another 2.0 mL of fresh release fluid was supplied into it immediately. The concentration of Famo in release medium was measured by UV–vis spectrometer. 2.5. Water uptake experiments The water uptake experiments were processed in SGF according to Refs. [28,29]. At predetermined intervals, samples were taken out and the surface water was wiped carefully with a filter paper. Then, the tablets were immediately weighed. Water uptake was calculated as amount of penetrated water related to dry tablet mass. 2.6. Materials characterization Powder X-ray diffraction (XRD) patterns were collected on a D8-Advance Rigaku diffractometer using Cu Ka radiation. The diffractograms were obtained in a 2u range of 0.5–68 with a step size of 0.028. Nitrogen gas ad/desorption isotherms were measured on a Micromeritics Tristar 3000 sorptometer at liquid nitrogen temperature. Previously, the mesoporous materials were degassed at 333 K for 24 h under vacuum (102 Torr). The specific surface area was calculated using the multiple-point Brunauer–Emmett– Teller (BET) method. The pore size distributions were calculated from the adsorption branch of the ad/desorption isotherms using the Barrett–Joyner–Halenda (BJH) method. Fourier transform infrared (FT-IR) spectrum was obtained on a Nicolet Nexus 470 FT-IR analyzer using the KBr method in the range of
4000–400 cm1. SEM and TEM images of synthesized mesoporous spheres were observed on JSM 6335F and JEOL JEM-2010. The thermogravimetric analyses were carried out between 30 and 700 8C in air with a heating rate of 10 8C/min using a Seiko TG/DTA 320. The Famo concentration in solution was measured on a Shimadzu UV-3501PC UV spectrometer. 3. Results and discussion 3.1. Characterization of mesoporous materials SEM and TEM were respectively used to determine the particle morphology, particle size and pore structure of mesoporous materials. As shown in the SEM images (Fig. 1a and b), the carboxyl-functionalized SBA-15 possessed fiber-like morphology. Some of these SBA-15 fibers were assembled together to form a fiber bundle with the length range from 50 mm to 150 mm. This kind of morphology might be formed by the coupling of rod-like particle [30–32]. The TEM image of functionalized SBA-15 displayed the typical hexagonal arrays of mesopores (Fig. 1c), indicating that the materials still have ordered mesoporous structure after functionalization with carboxyl groups. It was also found that the array of mesopore channels was paralleled with long axis of fibers. Fig. 2 showed the XRD patterns of carboxyl-functionalized SBA15 before and after loading drug. Both of them had three wellresolved peaks, which could be indexed as (1 0 0), (1 1 0) and (2 0 0) diffractions of 2D hexagonal mesoporous structure [33]. Compared with unloaded SBA-15 (Fig. 2a), the XRD reflection of drug-loaded SBA-15 (Fig. 2b) was a little weaker, which might result from the different pore density after loading organic drug molecules in mesopores [14]. N2 ad/desorption method was also applied to characterize the samples before and after loading drug. The obtained results were shown in Fig. 3. The more detailed texture parameters of carboxyl-functionalized SBA-15 and its drug-loading capacity
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Fig. 2. XRD patterns of carboxyl-functionalized SBA-15: (a) before and (b) after loading drug.
Fig. 3. N2 ad/desorption and pore size distribution patterns of carboxylfunctionalized SBA-15: (a) before and (b) after loading drug.
were summarized in Table 1. It could be seen that both samples exhibited type-IV isotherms with a clear H1 hysteresis loops, which was the typical characteristics of ordered mesoporous materials. The results obtained from N2 ad/desorption were consistent with those from TEM and XRD. Compared with the isotherm of unloaded sample, the change of isotherm after loading drug was not obvious. This phenomenon was different from the isotherm of MSU after loading Famo [34]. In Ref. [34], due to the smaller pore size of MSU (about 4.3 nm) than that of SBA-15 (about 6.4 nm), the loaded Famo molecules occupied a large amount of pore space of MSU. So, after loading Famo into carboxylfunctionalized MSU, the hysteresis hoop of isotherm was clearly minished. The pore size distributions of samples before and after loading drug were shown in the insert of Fig. 3. It could be found that both of the samples displayed narrow pore size distributions. And as shown in Table 1, after loading drug, the surface area, pore size, and pore volume of mesoporous SBA-15 distinctly decreased,
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Fig. 4. FT-IR spectra of carboxyl-functionalized SBA-15: (a) before and (b) after loading drug.
indicating that Famo molecules were successfully loaded into the mesopores of carboxyl-functionalized SBA-15. Through analysis by UV–vis spectrometer, the drug-loading capacity of carboxylfunctionalized SBA-15 was about 20.0 wt.%. In our experiments, it was also found that the amount of Famo loaded into pure silica SBA-15 could even be neglected in the same adsorption condition, which was consistent with the previous reports [34,35]. That is to say, pure silica SBA-15 was not suitable to be used as Famo carrier in the present study. This was the reason that we chose the carboxyl-functionalized SBA-15 as Famo carrier. To identify the interactions between Famo molecules and carboxylic groups, FT-IR was used here. Fig. 4 showed the FT-IR spectra of carboxyl-functionalized SBA-15 before and after loading drug. The peak at 1718 cm1 was attributed to the stretching vibration of C O in COOH group. In Fig. 4a, no peak could be found at 2250 cm1 that was of CN groups introduced by CPTES. Accordingly, it could be concluded that all the CN groups had been hydrolyzed into COOH groups after being treated by H2SO4. For drug-loaded sample (see Fig. 4b), an intense carboxylate vibration peak appeared at 1552 cm1, indicating that the proton transfer took place from COOH groups to NH2 groups of Famo [34,36]. These results further confirmed that Famo molecules have been successfully adsorbed into carboxyl-functionalized SBA-15. 3.2. Drug release In vitro release experiments were used to investigate the release of Famo from HPMCP/SBA-15. Figs. 5 and 6 respectively showed the effects of coating times and drying temperature on drug release in SGF. Both increasing coating times and drying temperature were effective methods to delay the release of Famo. Seen from Fig. 5, for SH0, there was a burst release of Famo within 2 h, during which the Famo molecules could be completely released. But, with the increase of coating times, the burst release of Famo could be gradually restrained. Especially, for SH4-20, it almost displayed a linear relationship between release amount of Famo and release time. For SH2-20 and SH4-20, the release amount of Famo decreased to 71.3 wt.% and 27.6 wt.% after 4 h, respectively. When the release time was up to 13 h, the release amount of Famo respectively
Table 1 Texture parameters and drug-loading capacity of functionalized SBA-15 Sample
SBET (m2/g)
Pore volume (cm3/g)
Pore size (nm)
Famo-loading amount (wt.%)
SH0-unloaded SH0-loaded
633.9 469.5
0.864 0.731
6.4 6.2
– 20.0
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Fig. 5. Effect of repeated coating times on Famo release from (a) SH0, (b) SH2-20, and (c) SH4-20 in SGF (pH 1.2).
Fig. 7. Effect of repeated coating times on Famo release from (a) SH0, (b) SH2-20, and (c) SH4-20 in SIF (pH 7.4).
increased to 91.0 wt.% and 65.4 wt.% (see Fig. 5). As shown in Fig. 6, the effect of drying temperature on drug release was also obvious. When drying temperature increased from 20 8C (SH2-20) to 45 8C (SH2-45), the release amount of Famo decreased from 71.3 wt.% to 39.2 wt.% within 4 h. More noticeably, after being dried at 80 8C (SH2-80), the value of released Famo sharply decreased to 4.0 wt.% within the equal time interval. Even though the release time prolonged to 13 h, the amount of Famo released from SH2-80 just reached 12.0 wt.%. In general, the stay time of food in stomach was about 4 h. So, the system SH2-80 could effectively protect the drug molecules adsorbed in mesopores from SGF. Interestingly, when the release medium was changed to SIF, the differences of drug release rates were not obvious whether the drug-loaded SBA-15 tablets coated with HPMCP or not (Fig. 7), and the effect of drying temperature on drug release in SIF was also not detected (Fig. 8). Though there was a little difference among these release profiles in Figs. 7 and 8, these differences were irregular and random. No change law could be summarized from these release profiles in SIF. Therefore, it could be concluded that these differences should be derived from experiment error and the coating material did not restrict the release of drug from HPMCP/ SBA-15 in SIF. As a biocompatible and pH-sensitive polymer, HPMCP was frequently used in drug release system [37,38]. In aqueous
solution, there was a pH-sensitive balance between the repulsion force of charged polymer chains and hydrophobic interactions of polymer chains [39]. In SGF (pH 1.2), the protonated carboxyl groups on HPMCP side chains weakened the electrostatic repulsion forces, and hence the hydrophobic interactions dominated the interactions between the polymer coating and water. In such situation, HPMCP was insoluble in SGF and formed a protective shell on the surface of SBA-15 tablet to prevent drug release. The amount of HPMCP coated on SBA-15 was calculated by thermogravimetrical analysis. The obtained results were shown in Fig. 9. It could be seen that the amount of HPMCP on SH2 was about 3.0 wt.%. And if the coating process was repeated four times (SH4), the amount of HPMCP increased to 5.7 wt.%. So, with the increase of coating times, the protective shell on the surface of tablet would become thicker. It was more difficult for Famo to be released from composite carriers. Thus, in SGF, drug release could be delayed by increasing the times of coating. However, in SIF (pH 7.4), carboxyl groups of HPMCP would be ionized, which enhanced the electrostatic repulsion between polymer chains and gave a driving force for the dissolution of HPMCP in SIF [40]. In our experiments, the HPMCP coating could dissolve quickly in SIF less than 10 min. Therefore, the increase of coating times would not restrict the release of Famo from mesoporous carrier in SIF.
Fig. 6. Effect of drying temperature on Famo release from (a) SH0, (b) SH2-20, (c) SH2-45, and (d) SH2-80 in SGF.
Fig. 8. Effect of drying temperature on Famo release from (a) SH0, (b) SH2-20, (c) SH2-45, and (d) SH2-80 in SIF.
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Fig. 9. Thermogravimetrical analysis profiles of (a) SH0, (b) SH2, and (c) SH4.
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On the other hand, due to the confinement effect of mesopore channels, the mesoporous SBA-15 could act as a good drug carrier. If only HPMCP was used to prepare drug carrier, the loaded drug would be fully released less than 10 min in SIF. That is to say, there must be an obvious burst release of Famo in SIF within 10 min, which could directly weaken the therapeutic effect of drug and might also lead to toxicity to organism because of the high concentration Famo. These phenomena indicated that there was a bug for using mono carrier HPMCP. But, in the system of HPMCP/ SBA-15, this bug could be well avoided because of the confinement effect of mesopore channels. Clearly, this novel HPMCP/SBA-15 system could not only provide large drug-loading capacity, but also effectively prevent drug from quickly releasing in acidic medium (pH < 3.5). It was reasonable to believe that the system HPMCP/ SBA-15 might become a potential drug carrier for intestinal drug release. 4. Conclusions
To discuss the effect of drying temperature on Famo release, water uptake experiments of samples (SH0, SH2-20, SH2-45 and SH2-80) were carried out in SGF. As shown in Fig. 10, with the increase of drying temperature, the water adsorption rate of mesoporous carriers gradually became slow, indicating that the diffusion between release fluid and HPMCP/SBA-15 was restrained. That is to say, after being dried at somewhat higher temperature, such as 45 8C or 80 8C, the coating on HPMCP/SBA-15 became denser [26]. So, it was reasonable that the system SH2-20 exhibited obviously faster drug release rate in SGF than that of SH2-45 (seen in Fig. 6). But in SIF, the ionization of carboxyl groups and the consequent dissolution of HPMCP occurred for all investigated samples. According to the above analysis, the thickness of HPMCP coating was thin (see Fig. 9) and its dissolution rate was very fast (less than 10 min). Therefore, though the HPMCP coating became denser at higher temperature, the effect of drying temperature on Famo release in SIF could be still neglected. At first view, these nearly same behaviors of different HPMCP/SBA-15 tablets in SIF (see Figs. 7 and 8) seemed to be unvaluable. However, an ideal intestinal drug release system should not only avoid a burst release in gastric environment, but also could not restrict the release of drug in the intestinal environment. Thus, the drug release behaviors in SIF were similarly important to their behaviors in SGF. In fact, the good drug release performances of HPMCP/SBA-15 were caused by these advantages inheriting from HPMCP and mesoporous carrier. On one hand, the pH-sensitive HPMCP coating acted as a ‘‘switch’’ of Famo release on the surface of SBA-15 tablet.
Fig. 10. Effect of drying temperature on water uptake into (a) SH0, (b) SH2-20, (c) SH2-45, and (d) SH2-80 in SGF.
A novel pH-sensitive drug release system HPMCP/SBA-15 was successfully prepared by coating HPMCP on drug-loaded mesoporous SBA-15 tablet. This composite system was easily prepared, and showed intelligent performance in the aspect of drug release. Based on the pH-sensitive property of HPMCP, the system could effectively delay the release of Famo in SGF, but showed no influence on Famo release in SIF. Such intelligence of HPMCP/SBA15 well matched the requirements of an intestinal drug release system. We anticipated that this novel drug release system might be a potential candidate for the specific targeting drug-delivery of intestinal diseases. Acknowledgements The financial supports from the National Native Science Foundation (No. 20573128), and Shanxi Native Science Foundation (Nos. 20051025 and 2006021031) were acknowledged. References [1] J.S. Beck, J.C. Vartuli, W.J. Roth, M.E. Leonowicz, C.T. Kresge, K.D. Schmitt, D.H.O.C.T.-W. Chu, E.W. Sheppard, S.B. McCullen, J.B. Higgins, J.L. Schlenkert, J. Am. Chem. Soc. 114 (1992) 10834–10843. [2] J. Zhao, F. Gao, Y. Fu, W. Jin, D. Zhao, Chem. Commun. 7 (2002) 752–753. [3] K. Moller, T. Bein, Chem. Mater. 10 (1998) 2950–2963. [4] C.Y. Lai, B.G. Trewyn, D.M. Jeftinija, K. Jeftinija, S. Xu, S. Jeftinija, V.S.Y. Lin, J. Am. Chem. Soc. 125 (2003) 4451–4459. [5] M. Vallet-Regi, A. Ramila, R.P. del Real, J. Perez-Pariente, Chem. Mater. 13 (2001) 308–311. [6] G. Cavallaro, P. Pierro, F.S. Palumbo, F. Testa, L. Pasqua, R. Aiello, Drug Deliv. 11 (2004) 41–46. [7] S.W. Song, K. Hidajat, S. Kawi, Langmuir 21 (2005) 9568–9575. [8] P. Horcajada, A. Ramila, J. Perez-Pariente, M. Vallet-Regi, Micropor. Mesopor. Mater. 68 (2004) 105–109. [9] T. Heikkila, J. Salonen, J. Tuura, et al. Drug Deliv. 14 (2007) 337–347. [10] F. Qu, G. Zhu, H. Lin, W. Zhang, J. Sun, S. Li, S. Qiu, J. Solid State Chem. 179 (2006) 2027–2035. [11] R. Mellaerts, C.A. Aerts, J.V. Humbeeck, P. Augustijns, G.V. Mooter, J.A. Martens, Chem. Commun. 13 (2007) 1375–1377. [12] J.C. Doadrio, E.M.B. Sousa, I. Izquierdo-Barba, A.L. Doadrio, J. Perez-Pariente, M. Vallet-Regi, J. Mater. Chem. 16 (2006) 462–466. [13] J. Andersson, J. Rosenholm, S. Areva, M. Linden, Chem. Mater. 16 (2004) 4160– 4167. [14] Q.L. Tang, Y. Xu, D. Wu, Y.H. Sun, J. Wang, J. Xu, F. Deng, J. Control. Release 114 (2006) 41–46. [15] N.K. Mal, M. Fujiwara, Y. Tanaka, Nature 421 (2003) 350–353. [16] Y.F. Zhu, J.L. Shi, W.H. Shen, X.P. Dong, J.W. Feng, M.L. Ruan, Y.S. Li, Angew. Chem. Int. Ed. 44 (2005) 5083–5087. [17] H.J. Kim, H. Matsuda, H.S. Zhou, I. Honma, Adv. Mater. 18 (2006) 3083–3088. [18] Q. Fu, G.V.R. Rao, L.K. Ista, Y. Wu, B.P. Andrzejewski, L.A. Sklar, T.L. Ward, G.P. Lo´pez, Adv. Mater. 15 (2003) 1262–1266. [19] S. Zhu, Z. Zhou, D. Zhang, Chem. Phys. Chem. 8 (2007) 2478–2483. [20] M. Ramdas, K.J. Dileep, Y. Anitha, W. Paul, C.P. Sharma, J. Biomater. Appl. 13 (1999) 290–296.
612
W. Xu et al. / Materials Research Bulletin 44 (2009) 606–612
[21] C.J.H. Porter, C.W. Pouton, J.F. Cuine, Adv. Drug Deliv. Rev. 60 (2008) 673–691. [22] F. Tugcu-Demiroz, F. Acarturk, S. Takka, Eur. J. Pharm. Biopharm. 67 (2007) 491– 497. [23] S.-W. Song, K. Hidajat, S. Kawi, Chem. Commun. 42 (2007) 4396–4398. [24] F. Siepmanna, J. Siepmann, M. Walther, R.J. MacRae, R. Bodmeier, J. Control Release 105 (2005) 226–239. [25] E. Karavas, E. Georgarakis, D. Bikiaris, Eur. J. Pharm. Biopharm. 64 (2006) 115–126. [26] Z. Wu, Y. Jiang, T. Kim, K. Lee, J. Control Release 119 (2007) 215–221. [27] C. Yang, Y. Wang, B. Zibrowius, F. Schuth, Phys. Chem. Chem. Phys. 6 (2004) 2461– 2467. [28] S. Stru¨bing, H. Metz, K. Ma¨der, Eur. J. Pharm. Biopharm. 66 (2007) 113–119. [29] H. Kim, H. Matsuda, H. Zhou, I. Honma, Adv. Mater. 18 (2006) 3083–3088. [30] K. Kosuge, T. Sato, N. Kikukawa, M. Takemori, Chem. Mater. 16 (2004) 899–905. [31] C. Yu, J. Fan, B. Tian, D. Zhao, G.D. Stucky, Adv. Mater. 14 (2002) 1742–1745.
[32] X. Wang, Y. Tseng, J.C.C. Chan, S. Cheng, Micropor. Mesopor. Mater. 85 (2005) 241–251. [33] J. Lei, J. Fan, C. Yu, L. Zhang, S. Jiang, B. Tu, D. Zhao, Micropor. Mesopor. Mater. 73 (2004) 121–128. [34] Q. Tang, Y. Xu, D. Wu, Y. Sun, J. Solid State Chem. 179 (2006) 1512–1519. [35] Q. Tang, N. Yu, Z. Li, D. Wu, Y. Sun, Stud. Surf. Sci. Catal. 156 (2005) 649–655. [36] B. Munoz, A. Ramila, J. Perez-Pariente, I. Diaz, M. Vallet-Regi, Chem. Mater. 15 (2003) 500–503. [37] Il.H. Kim, J.H. Park, I.W. Cheong, J.H. Kim, J. Control Release 89 (2003) 225– 233. [38] G. Sertsou, J. Butler, A. Scott, J. Hempenstall, T. Rades, Int. J. Pharm. 245 (2002) 99– 108. [39] E.S. Gil, S.M. Hudson, Prog. Polym. Sci. 29 (2004) 1173–1222. [40] Y. Qiu, K. Park, Adv. Drug Deliv. Rev. 53 (2001) 321–339.
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pH-Controlled drug release from mesoporous silica tablets coated with hydroxypropyl methylcellulose phthalate Wujun Xu a,b, Qiang Gao a,b, Yao Xu a,*, Dong Wu a, Yuhan Sun a a b
State Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of Sciences, Number 27, Tao Yuan South Road, Taiyuan, Shanxi 030001, China Graduate University of the Chinese Academy of Sciences, Beijing 100049, China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 January 2008 Received in revised form 3 June 2008 Accepted 3 July 2008 Available online 11 July 2008
A simple pH-controlled drug release system was successfully prepared by coating pH-sensitive polymer hydroxypropyl methylcellulose phthalate (HPMCP) on drug-loaded mesoporous SBA-15 tablet. Using famotidine (Famo) as a model drug, the effects of coating times and drying temperature on drug release were studied in detail to optimize the drug release system. In simulated gastric fluid (SGF, pH 1.2), it took only 2 h for Famo to be completely released from mesoporous silica tablet without HPMCP coating. Also in SGF, with the increase of coating times and drying temperature, the release of Famo was greatly delayed by HPMCP coating. For the tablet with twice coating of HPMCP and dried at 80 8C, only 4.0 wt.% of Famo could be released within 4 h. However, in simulated intestinal fluid (SIF, pH 7.4), HPMCP coating did not show obvious effect on the release of Famo. ß 2008 Elsevier Ltd. All rights reserved.
Keywords: A. Nanostructures B. Sol–gel chemistry C. X-ray diffraction
1. Introduction Several attractive features, such as high surface area, large mesoporous pore volume, and well-defined pore size distribution of mesoporous silica materials have made them ideal for hosting molecules of various sizes, shapes, and functionalities [1–4]. Since Vallet-Regi [5] discovered the new property of MCM-41 in drug release, many drug release systems based on mesoporous materials have been studied [6–11], and several methods were reported to adjust the release rate of drug from mesoporous carriers. At first, pore size was an important factor affecting drug release rate. It was found that narrowing of mesopores could delay the release rate of model drug [8–13]. If the mesopore diameter was only two or three times larger than the size of drug molecules, the drug release rate would be very sensitive to the change of pore size. In addition, surface organic functionalization on mesoporous material was also an effective method to regulate drug release rate. Song et al. [7] reported that the adsorption capacity of ibuprofen and the corresponding release rates were highly dependent on the amount of amino groups functionalized onto SBA-15 surface. Tang et al. [14] found that the release of ibuprofen from MCM-41 mesoporous materials could be obviously delayed by surface hydrophobic modification with trimethylsilyl groups. Recently, some environment-sensitive drug release systems,
* Corresponding author. Tel.: +86 351 4049859; fax: +86 351 4041153. E-mail address: [email protected] (Y. Xu). 0025-5408/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.materresbull.2008.07.001
based on mesoporous materials, have been prepared to achieve site-specific drug release [4,15–19]. Lin and co-workers [4] synthesized CdS-capped mesoporous nanospheres for drug release, which could be triggered by disulfide bond-reducing molecules. Shi and co-workers [16] developed a pH-responsive drug release system by coating multilayered polyelectrolytes on hollow mesoporous silica spheres, from which the drug release was obviously slower in the release medium of pH 8.0 than that in the medium of pH 1.4. In the field of traditional medicine, it was difficult to be completely cured for intestinal disease because some of the ingested drug would be adsorbed or digested by stomach before it reached intestine. Therefore, it was very important to develop controlled intestinal drug release systems. In view of this, many researches were reported about intestinal drug release based on Chitosan or other organic matrix [20–22]. However, up to now, only one report has been published by Song et al. [23] about intestinal drug release based on mesoporous silica. In this study, poly(acrylic acid) (PAA) was coated on amino-functionalized mesoporous SBA-15 materials. In the release medium of pH 1.2, only 10.0% bovine serum albumin (BSA) was released from PAA/ SBA-15 within 36 h. The designed drug release system could protect BSA from being degraded by gastric albumin enzymes. Compared with sample without coating, the coating material PAA not only effectively delayed the release of BSA in the release medium of pH 1.2, but to some extent, it also decreased the release rate of BSA in the release medium of pH 7.4. In fact, for an intestinal drug release system, the drug release in stomach should be strictly
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Scheme 1. Illustrations of (a) pH-sensitive drug release system HPMCP/SBA-15 and (b) chemical structure of HPMCP.
controlled. On the other hand, in intestine, the model drug needs to be freely released. Thus, taken the obvious differences in pH value between stomach and intestines into account, a design of pHcontrolled system for intestinal drug release was a good choice. To test the validity of designed intestinal drug release system, the selected model drug must be highly sensitive to the acidity of release medium. In our studies, model drug famotidine (Famo) could dissolve quickly into acidic aqueous solution due to the four NH2 groups in its structure. Therefore, if the designed pHcontrolled release system could effectively delay the release of Famo in simulated gastric fluid (SGF, pH 1.2) and seldom restrict its release in simulated intestinal fluid (SIF, pH 7.4), it might be an ideal candidate for intestinal drug release. As we know, coating technology has been using widely in the field of pharmacy [24–26]. In the present study, hydroxypropyl methylcellulose phthalate (HPMCP) was deposited on drug-loaded mesoporous SBA-15 tablets by dip-coating method to construct a pH-controlled drug release system. The illustrations of this composite system HPMCP/ SBA-15 and chemical structure of HPMCP were shown in Scheme 1. HPMCP is a pH-sensitive polymer with pKa value in the range of 4.5–5.5. It is unsolvable in aqueous solution of pH < 3.5, but can dissolve quickly in aqueous solution of pH > 5.5. Moreover, HPMCP chains have lots of hydroxyl groups that can ensure HPMCP coating to firmly adhere to SBA-15 tablets without any further chemical treatment. To enhance the Famo-loading amount, carboxylfunctionalized SBA-15 was used as drug carrier due to the poor Famo adsorption of pure SBA-15. 2. Experimental 2.1. Mesoporous material synthesis Carboxyl-functionalized mesoporous SBA-15 material was used as drug-loading matrix and it was synthesized as following: 2cyanopropyltriethoxysilane (CPTES) was introduced to HCl solution containing triblock copolymer Pluronic P123 (EO20PO70EO20) under stirring at 40 8C. After being hydrolyzed for 0.5 h, tetraethoxysilane (TEOS) was added into the above solution slowly. The molar composition of the final mixture was 1.0 TEOS:0.15 CPTES:0.017 P123:6.1 HCl:170 H2O. The mixture was stirred at 40 8C for 20 h, followed by aging at 90 8C for 24 h under static conditions. The precipitation was filtrated and dried at 60 8C to collect the solid product. At last, the obtained product was treated following Yang’s method to transform cyano groups into carboxylic groups [27].
2.2. Drug-loading procedure To load Famo into carboxyl-functionalized SBA-15 mesoporous materials, 0.5 g mesoporous solid powder and 0.75 g Famo were added into 500.0 mL mixed solvent of methanol and water (the volume ratio of methanol:water = 1:1) and stirred for 8 h. Then, the drug-loaded SBA-15 powder was filtrated and dried at 70 8C. At last, 2.0 mL filtrate was taken out from the vial and was diluted to 50 mL, with which the residual Famo concentration was analyzed on a UV–vis spectroscopy (Shimadzu UV-3150PC) at 285.0 nm. The amount of Famo loaded in SBA-15 can be calculated by the following equation: wt:% ¼
m1 ð50=vÞCV 100% m2 þ m1 ð50=vÞCV
(1)
where m1 and m2 correspond to the initial mass of Famo and mesoporous materials added into the mixed solution of methanol and water, respectively. C is the concentration of filtrates diluted in 50 mL volumetric flask, v is sampled volume from filtrates, and V is the initial volume of the mixed solution for drug loading. 2.3. Preparation of HPMCP/SBA-15 The pH-sensitive drug release system HPMCP/SBA-15 was prepared as below. 0.15 g drug-loaded mesoporous SBA-15 powder was pressed into a 13 mm 3 mm tablet under 6.0 MPa uniaxial pressure. Simultaneously, some amount of HPMCP was dissolved into a mixed solvent of ethanol and water (the mass ratio of ethanol:water = 8:2) under stirring at room temperature. Then, the drug-loaded mesoporous SBA-15 tablet was dip-coated with HPMCP, and the withdrawal speed was fixed at 18 cm/min. The tablets were repeatedly coated with HPMCP twice or four times and then the HPMCP/SBA-15 tablets were dried in open air at 20 8C for 0.5 h. The obtained samples were assigned to SH2-20 and SH4-20, corresponding to twice and four times coating, respectively. To study the effect of drying temperature on drug release rate, the tablets with twice coating of HPMCP were also dried in open air at 45 8C or 80 8C for 0.5 h. The obtained samples were respectively assigned to SH2-45 and SH2-80. Finally, all the HPMCP/SBA-15 tablets were further dried under vacuum at 20 8C, 45 8C or 80 8C for 12 h to eliminate residual solvent. In addition, the carboxyl-functionalized SBA-15 without polymer coating was used as reference and it was assigned to SH0.
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Fig. 1. SEM (a, b) and TEM (c) images of carboxyl-functionalized SBA-15.
2.4. In vitro drug release study The drug release behaviors were investigated by soaking HPMCP/SBA-15 tablets in different simulated physiological media, including SGF (HCl aqueous solution, pH 1.2) and SIF (phosphate buffer solution, pH 7.4). The release experiments were performed at 37 8C under stirring rate of 100 rpm. 2.0 mL of release fluid was sampled from the studied release system at a predetermined time interval, and another 2.0 mL of fresh release fluid was supplied into it immediately. The concentration of Famo in release medium was measured by UV–vis spectrometer. 2.5. Water uptake experiments The water uptake experiments were processed in SGF according to Refs. [28,29]. At predetermined intervals, samples were taken out and the surface water was wiped carefully with a filter paper. Then, the tablets were immediately weighed. Water uptake was calculated as amount of penetrated water related to dry tablet mass. 2.6. Materials characterization Powder X-ray diffraction (XRD) patterns were collected on a D8-Advance Rigaku diffractometer using Cu Ka radiation. The diffractograms were obtained in a 2u range of 0.5–68 with a step size of 0.028. Nitrogen gas ad/desorption isotherms were measured on a Micromeritics Tristar 3000 sorptometer at liquid nitrogen temperature. Previously, the mesoporous materials were degassed at 333 K for 24 h under vacuum (102 Torr). The specific surface area was calculated using the multiple-point Brunauer–Emmett– Teller (BET) method. The pore size distributions were calculated from the adsorption branch of the ad/desorption isotherms using the Barrett–Joyner–Halenda (BJH) method. Fourier transform infrared (FT-IR) spectrum was obtained on a Nicolet Nexus 470 FT-IR analyzer using the KBr method in the range of
4000–400 cm1. SEM and TEM images of synthesized mesoporous spheres were observed on JSM 6335F and JEOL JEM-2010. The thermogravimetric analyses were carried out between 30 and 700 8C in air with a heating rate of 10 8C/min using a Seiko TG/DTA 320. The Famo concentration in solution was measured on a Shimadzu UV-3501PC UV spectrometer. 3. Results and discussion 3.1. Characterization of mesoporous materials SEM and TEM were respectively used to determine the particle morphology, particle size and pore structure of mesoporous materials. As shown in the SEM images (Fig. 1a and b), the carboxyl-functionalized SBA-15 possessed fiber-like morphology. Some of these SBA-15 fibers were assembled together to form a fiber bundle with the length range from 50 mm to 150 mm. This kind of morphology might be formed by the coupling of rod-like particle [30–32]. The TEM image of functionalized SBA-15 displayed the typical hexagonal arrays of mesopores (Fig. 1c), indicating that the materials still have ordered mesoporous structure after functionalization with carboxyl groups. It was also found that the array of mesopore channels was paralleled with long axis of fibers. Fig. 2 showed the XRD patterns of carboxyl-functionalized SBA15 before and after loading drug. Both of them had three wellresolved peaks, which could be indexed as (1 0 0), (1 1 0) and (2 0 0) diffractions of 2D hexagonal mesoporous structure [33]. Compared with unloaded SBA-15 (Fig. 2a), the XRD reflection of drug-loaded SBA-15 (Fig. 2b) was a little weaker, which might result from the different pore density after loading organic drug molecules in mesopores [14]. N2 ad/desorption method was also applied to characterize the samples before and after loading drug. The obtained results were shown in Fig. 3. The more detailed texture parameters of carboxyl-functionalized SBA-15 and its drug-loading capacity
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Fig. 2. XRD patterns of carboxyl-functionalized SBA-15: (a) before and (b) after loading drug.
Fig. 3. N2 ad/desorption and pore size distribution patterns of carboxylfunctionalized SBA-15: (a) before and (b) after loading drug.
were summarized in Table 1. It could be seen that both samples exhibited type-IV isotherms with a clear H1 hysteresis loops, which was the typical characteristics of ordered mesoporous materials. The results obtained from N2 ad/desorption were consistent with those from TEM and XRD. Compared with the isotherm of unloaded sample, the change of isotherm after loading drug was not obvious. This phenomenon was different from the isotherm of MSU after loading Famo [34]. In Ref. [34], due to the smaller pore size of MSU (about 4.3 nm) than that of SBA-15 (about 6.4 nm), the loaded Famo molecules occupied a large amount of pore space of MSU. So, after loading Famo into carboxylfunctionalized MSU, the hysteresis hoop of isotherm was clearly minished. The pore size distributions of samples before and after loading drug were shown in the insert of Fig. 3. It could be found that both of the samples displayed narrow pore size distributions. And as shown in Table 1, after loading drug, the surface area, pore size, and pore volume of mesoporous SBA-15 distinctly decreased,
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Fig. 4. FT-IR spectra of carboxyl-functionalized SBA-15: (a) before and (b) after loading drug.
indicating that Famo molecules were successfully loaded into the mesopores of carboxyl-functionalized SBA-15. Through analysis by UV–vis spectrometer, the drug-loading capacity of carboxylfunctionalized SBA-15 was about 20.0 wt.%. In our experiments, it was also found that the amount of Famo loaded into pure silica SBA-15 could even be neglected in the same adsorption condition, which was consistent with the previous reports [34,35]. That is to say, pure silica SBA-15 was not suitable to be used as Famo carrier in the present study. This was the reason that we chose the carboxyl-functionalized SBA-15 as Famo carrier. To identify the interactions between Famo molecules and carboxylic groups, FT-IR was used here. Fig. 4 showed the FT-IR spectra of carboxyl-functionalized SBA-15 before and after loading drug. The peak at 1718 cm1 was attributed to the stretching vibration of C O in COOH group. In Fig. 4a, no peak could be found at 2250 cm1 that was of CN groups introduced by CPTES. Accordingly, it could be concluded that all the CN groups had been hydrolyzed into COOH groups after being treated by H2SO4. For drug-loaded sample (see Fig. 4b), an intense carboxylate vibration peak appeared at 1552 cm1, indicating that the proton transfer took place from COOH groups to NH2 groups of Famo [34,36]. These results further confirmed that Famo molecules have been successfully adsorbed into carboxyl-functionalized SBA-15. 3.2. Drug release In vitro release experiments were used to investigate the release of Famo from HPMCP/SBA-15. Figs. 5 and 6 respectively showed the effects of coating times and drying temperature on drug release in SGF. Both increasing coating times and drying temperature were effective methods to delay the release of Famo. Seen from Fig. 5, for SH0, there was a burst release of Famo within 2 h, during which the Famo molecules could be completely released. But, with the increase of coating times, the burst release of Famo could be gradually restrained. Especially, for SH4-20, it almost displayed a linear relationship between release amount of Famo and release time. For SH2-20 and SH4-20, the release amount of Famo decreased to 71.3 wt.% and 27.6 wt.% after 4 h, respectively. When the release time was up to 13 h, the release amount of Famo respectively
Table 1 Texture parameters and drug-loading capacity of functionalized SBA-15 Sample
SBET (m2/g)
Pore volume (cm3/g)
Pore size (nm)
Famo-loading amount (wt.%)
SH0-unloaded SH0-loaded
633.9 469.5
0.864 0.731
6.4 6.2
– 20.0
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Fig. 5. Effect of repeated coating times on Famo release from (a) SH0, (b) SH2-20, and (c) SH4-20 in SGF (pH 1.2).
Fig. 7. Effect of repeated coating times on Famo release from (a) SH0, (b) SH2-20, and (c) SH4-20 in SIF (pH 7.4).
increased to 91.0 wt.% and 65.4 wt.% (see Fig. 5). As shown in Fig. 6, the effect of drying temperature on drug release was also obvious. When drying temperature increased from 20 8C (SH2-20) to 45 8C (SH2-45), the release amount of Famo decreased from 71.3 wt.% to 39.2 wt.% within 4 h. More noticeably, after being dried at 80 8C (SH2-80), the value of released Famo sharply decreased to 4.0 wt.% within the equal time interval. Even though the release time prolonged to 13 h, the amount of Famo released from SH2-80 just reached 12.0 wt.%. In general, the stay time of food in stomach was about 4 h. So, the system SH2-80 could effectively protect the drug molecules adsorbed in mesopores from SGF. Interestingly, when the release medium was changed to SIF, the differences of drug release rates were not obvious whether the drug-loaded SBA-15 tablets coated with HPMCP or not (Fig. 7), and the effect of drying temperature on drug release in SIF was also not detected (Fig. 8). Though there was a little difference among these release profiles in Figs. 7 and 8, these differences were irregular and random. No change law could be summarized from these release profiles in SIF. Therefore, it could be concluded that these differences should be derived from experiment error and the coating material did not restrict the release of drug from HPMCP/ SBA-15 in SIF. As a biocompatible and pH-sensitive polymer, HPMCP was frequently used in drug release system [37,38]. In aqueous
solution, there was a pH-sensitive balance between the repulsion force of charged polymer chains and hydrophobic interactions of polymer chains [39]. In SGF (pH 1.2), the protonated carboxyl groups on HPMCP side chains weakened the electrostatic repulsion forces, and hence the hydrophobic interactions dominated the interactions between the polymer coating and water. In such situation, HPMCP was insoluble in SGF and formed a protective shell on the surface of SBA-15 tablet to prevent drug release. The amount of HPMCP coated on SBA-15 was calculated by thermogravimetrical analysis. The obtained results were shown in Fig. 9. It could be seen that the amount of HPMCP on SH2 was about 3.0 wt.%. And if the coating process was repeated four times (SH4), the amount of HPMCP increased to 5.7 wt.%. So, with the increase of coating times, the protective shell on the surface of tablet would become thicker. It was more difficult for Famo to be released from composite carriers. Thus, in SGF, drug release could be delayed by increasing the times of coating. However, in SIF (pH 7.4), carboxyl groups of HPMCP would be ionized, which enhanced the electrostatic repulsion between polymer chains and gave a driving force for the dissolution of HPMCP in SIF [40]. In our experiments, the HPMCP coating could dissolve quickly in SIF less than 10 min. Therefore, the increase of coating times would not restrict the release of Famo from mesoporous carrier in SIF.
Fig. 6. Effect of drying temperature on Famo release from (a) SH0, (b) SH2-20, (c) SH2-45, and (d) SH2-80 in SGF.
Fig. 8. Effect of drying temperature on Famo release from (a) SH0, (b) SH2-20, (c) SH2-45, and (d) SH2-80 in SIF.
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Fig. 9. Thermogravimetrical analysis profiles of (a) SH0, (b) SH2, and (c) SH4.
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On the other hand, due to the confinement effect of mesopore channels, the mesoporous SBA-15 could act as a good drug carrier. If only HPMCP was used to prepare drug carrier, the loaded drug would be fully released less than 10 min in SIF. That is to say, there must be an obvious burst release of Famo in SIF within 10 min, which could directly weaken the therapeutic effect of drug and might also lead to toxicity to organism because of the high concentration Famo. These phenomena indicated that there was a bug for using mono carrier HPMCP. But, in the system of HPMCP/ SBA-15, this bug could be well avoided because of the confinement effect of mesopore channels. Clearly, this novel HPMCP/SBA-15 system could not only provide large drug-loading capacity, but also effectively prevent drug from quickly releasing in acidic medium (pH < 3.5). It was reasonable to believe that the system HPMCP/ SBA-15 might become a potential drug carrier for intestinal drug release. 4. Conclusions
To discuss the effect of drying temperature on Famo release, water uptake experiments of samples (SH0, SH2-20, SH2-45 and SH2-80) were carried out in SGF. As shown in Fig. 10, with the increase of drying temperature, the water adsorption rate of mesoporous carriers gradually became slow, indicating that the diffusion between release fluid and HPMCP/SBA-15 was restrained. That is to say, after being dried at somewhat higher temperature, such as 45 8C or 80 8C, the coating on HPMCP/SBA-15 became denser [26]. So, it was reasonable that the system SH2-20 exhibited obviously faster drug release rate in SGF than that of SH2-45 (seen in Fig. 6). But in SIF, the ionization of carboxyl groups and the consequent dissolution of HPMCP occurred for all investigated samples. According to the above analysis, the thickness of HPMCP coating was thin (see Fig. 9) and its dissolution rate was very fast (less than 10 min). Therefore, though the HPMCP coating became denser at higher temperature, the effect of drying temperature on Famo release in SIF could be still neglected. At first view, these nearly same behaviors of different HPMCP/SBA-15 tablets in SIF (see Figs. 7 and 8) seemed to be unvaluable. However, an ideal intestinal drug release system should not only avoid a burst release in gastric environment, but also could not restrict the release of drug in the intestinal environment. Thus, the drug release behaviors in SIF were similarly important to their behaviors in SGF. In fact, the good drug release performances of HPMCP/SBA-15 were caused by these advantages inheriting from HPMCP and mesoporous carrier. On one hand, the pH-sensitive HPMCP coating acted as a ‘‘switch’’ of Famo release on the surface of SBA-15 tablet.
Fig. 10. Effect of drying temperature on water uptake into (a) SH0, (b) SH2-20, (c) SH2-45, and (d) SH2-80 in SGF.
A novel pH-sensitive drug release system HPMCP/SBA-15 was successfully prepared by coating HPMCP on drug-loaded mesoporous SBA-15 tablet. This composite system was easily prepared, and showed intelligent performance in the aspect of drug release. Based on the pH-sensitive property of HPMCP, the system could effectively delay the release of Famo in SGF, but showed no influence on Famo release in SIF. Such intelligence of HPMCP/SBA15 well matched the requirements of an intestinal drug release system. We anticipated that this novel drug release system might be a potential candidate for the specific targeting drug-delivery of intestinal diseases. Acknowledgements The financial supports from the National Native Science Foundation (No. 20573128), and Shanxi Native Science Foundation (Nos. 20051025 and 2006021031) were acknowledged. References [1] J.S. Beck, J.C. Vartuli, W.J. Roth, M.E. Leonowicz, C.T. Kresge, K.D. Schmitt, D.H.O.C.T.-W. Chu, E.W. Sheppard, S.B. McCullen, J.B. Higgins, J.L. Schlenkert, J. Am. Chem. Soc. 114 (1992) 10834–10843. [2] J. Zhao, F. Gao, Y. Fu, W. Jin, D. Zhao, Chem. Commun. 7 (2002) 752–753. [3] K. Moller, T. Bein, Chem. Mater. 10 (1998) 2950–2963. [4] C.Y. Lai, B.G. Trewyn, D.M. Jeftinija, K. Jeftinija, S. Xu, S. Jeftinija, V.S.Y. Lin, J. Am. Chem. Soc. 125 (2003) 4451–4459. [5] M. Vallet-Regi, A. Ramila, R.P. del Real, J. Perez-Pariente, Chem. Mater. 13 (2001) 308–311. [6] G. Cavallaro, P. Pierro, F.S. Palumbo, F. Testa, L. Pasqua, R. Aiello, Drug Deliv. 11 (2004) 41–46. [7] S.W. Song, K. Hidajat, S. Kawi, Langmuir 21 (2005) 9568–9575. [8] P. Horcajada, A. Ramila, J. Perez-Pariente, M. Vallet-Regi, Micropor. Mesopor. Mater. 68 (2004) 105–109. [9] T. Heikkila, J. Salonen, J. Tuura, et al. Drug Deliv. 14 (2007) 337–347. [10] F. Qu, G. Zhu, H. Lin, W. Zhang, J. Sun, S. Li, S. Qiu, J. Solid State Chem. 179 (2006) 2027–2035. [11] R. Mellaerts, C.A. Aerts, J.V. Humbeeck, P. Augustijns, G.V. Mooter, J.A. Martens, Chem. Commun. 13 (2007) 1375–1377. [12] J.C. Doadrio, E.M.B. Sousa, I. Izquierdo-Barba, A.L. Doadrio, J. Perez-Pariente, M. Vallet-Regi, J. Mater. Chem. 16 (2006) 462–466. [13] J. Andersson, J. Rosenholm, S. Areva, M. Linden, Chem. Mater. 16 (2004) 4160– 4167. [14] Q.L. Tang, Y. Xu, D. Wu, Y.H. Sun, J. Wang, J. Xu, F. Deng, J. Control. Release 114 (2006) 41–46. [15] N.K. Mal, M. Fujiwara, Y. Tanaka, Nature 421 (2003) 350–353. [16] Y.F. Zhu, J.L. Shi, W.H. Shen, X.P. Dong, J.W. Feng, M.L. Ruan, Y.S. Li, Angew. Chem. Int. Ed. 44 (2005) 5083–5087. [17] H.J. Kim, H. Matsuda, H.S. Zhou, I. Honma, Adv. Mater. 18 (2006) 3083–3088. [18] Q. Fu, G.V.R. Rao, L.K. Ista, Y. Wu, B.P. Andrzejewski, L.A. Sklar, T.L. Ward, G.P. Lo´pez, Adv. Mater. 15 (2003) 1262–1266. [19] S. Zhu, Z. Zhou, D. Zhang, Chem. Phys. Chem. 8 (2007) 2478–2483. [20] M. Ramdas, K.J. Dileep, Y. Anitha, W. Paul, C.P. Sharma, J. Biomater. Appl. 13 (1999) 290–296.
612
W. Xu et al. / Materials Research Bulletin 44 (2009) 606–612
[21] C.J.H. Porter, C.W. Pouton, J.F. Cuine, Adv. Drug Deliv. Rev. 60 (2008) 673–691. [22] F. Tugcu-Demiroz, F. Acarturk, S. Takka, Eur. J. Pharm. Biopharm. 67 (2007) 491– 497. [23] S.-W. Song, K. Hidajat, S. Kawi, Chem. Commun. 42 (2007) 4396–4398. [24] F. Siepmanna, J. Siepmann, M. Walther, R.J. MacRae, R. Bodmeier, J. Control Release 105 (2005) 226–239. [25] E. Karavas, E. Georgarakis, D. Bikiaris, Eur. J. Pharm. Biopharm. 64 (2006) 115–126. [26] Z. Wu, Y. Jiang, T. Kim, K. Lee, J. Control Release 119 (2007) 215–221. [27] C. Yang, Y. Wang, B. Zibrowius, F. Schuth, Phys. Chem. Chem. Phys. 6 (2004) 2461– 2467. [28] S. Stru¨bing, H. Metz, K. Ma¨der, Eur. J. Pharm. Biopharm. 66 (2007) 113–119. [29] H. Kim, H. Matsuda, H. Zhou, I. Honma, Adv. Mater. 18 (2006) 3083–3088. [30] K. Kosuge, T. Sato, N. Kikukawa, M. Takemori, Chem. Mater. 16 (2004) 899–905. [31] C. Yu, J. Fan, B. Tian, D. Zhao, G.D. Stucky, Adv. Mater. 14 (2002) 1742–1745.
[32] X. Wang, Y. Tseng, J.C.C. Chan, S. Cheng, Micropor. Mesopor. Mater. 85 (2005) 241–251. [33] J. Lei, J. Fan, C. Yu, L. Zhang, S. Jiang, B. Tu, D. Zhao, Micropor. Mesopor. Mater. 73 (2004) 121–128. [34] Q. Tang, Y. Xu, D. Wu, Y. Sun, J. Solid State Chem. 179 (2006) 1512–1519. [35] Q. Tang, N. Yu, Z. Li, D. Wu, Y. Sun, Stud. Surf. Sci. Catal. 156 (2005) 649–655. [36] B. Munoz, A. Ramila, J. Perez-Pariente, I. Diaz, M. Vallet-Regi, Chem. Mater. 15 (2003) 500–503. [37] Il.H. Kim, J.H. Park, I.W. Cheong, J.H. Kim, J. Control Release 89 (2003) 225– 233. [38] G. Sertsou, J. Butler, A. Scott, J. Hempenstall, T. Rades, Int. J. Pharm. 245 (2002) 99– 108. [39] E.S. Gil, S.M. Hudson, Prog. Polym. Sci. 29 (2004) 1173–1222. [40] Y. Qiu, K. Park, Adv. Drug Deliv. Rev. 53 (2001) 321–339.