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Dexketoprofen and aceclofenac release from layered double hydroxide and SBA-15 ordered mesoporous material
Applied Clay Science 121–122 (2016) 9–16
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Dexketoprofen and aceclofenac release from layered double hydroxide and SBA-15 ordered mesoporous material Soledad San Román, Gonzalo Nuno Almeida, Margarita del Arco ⁎, Cristina Martín ⁎ Departamento de Química Inorgánica, Facultad de Farmacia, Universidad de Salamanca, Avda. Campo Charro s/n, 37007 Salamanca, Spain
a r t i c l e
i n f o
Article history: Received 27 May 2015 Received in revised form 2 December 2015 Accepted 8 December 2015 Available online xxxx Keywords: Layered double hydroxide SBA-15 Dexketoprofen Aceclofenac Controlled release
a b s t r a c t Two non-steroidal anti-inflammatory drugs, dexketoprofen (Dx) and aceclofenac (Ac), were incorporated in two different matrixes, layered double hydroxide and ordered mesoporous silica, SBA-15. The matrixes and the samples were characterized by different techniques, PXRD, SEM, TEM, FT-IR, N2 adsorption at −196 °C and the drug release speed was also measured. The total amount of incorporated drug to the different matrixes was higher in the LDH than in mesoporous silica. The release studies showed a higher drug release speed from the layered double hydroxide than from the ordered mesoporous silica, but even so slower than the one found for the pure drugs, what shows that these solids can be used as drug controlled release matrixes. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Several studies have shown the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) in pain and inflammation treatment in all age range; these are the most consumed drugs around the world (Fosbol et al., 2008). For these drugs the oral administration route is more effective than the topical route (Bjordal et al., 2007) and their toxicity is similar through the different routes: oral, parenteral or intravenous. As all other drugs, NSAIDs have some side effects, being the most common ones are those with gastrointestinal, cardiovascular and renal origins, being also those potentially more severe, so these drugs should be given in the lower effective dose possible and in short periods of time. One of the pharmaceutical industry challenges is to search compounds that can be used as matrixes for controlled release that could avoid side effects and dangerous drug interactions. Many compounds have been tested as release matrixes: polymers, cyclodextrins, clays, etc., (Patrick et al., 1997; Langer, 1998; Vallet-Regí et al., 2007; Costantino et al., 2008) to prepare appropriate materials for each application, following the biocompatibility and biodegradability requests. In the last decade, some inorganic compounds like ordered mesoporous silica (Vallet-Regí et al., 2001) and layered double hydroxides (LDHs), also called hydrotalcites (De Sousa et al., 2013; Rives et al., 2013, 2014) have received special attention to prepare controlled release ⁎ Corresponding authors at: Departamento de Química Inorgánica, Facultad de Farmacia, 37007 Salamanca, Spain. E-mail addresses: [email protected] (S.S. Román), [email protected] (G.N. Almeida), [email protected] (M. del Arco), [email protected] (C. Martín).
http://dx.doi.org/10.1016/j.clay.2015.12.006 0169-1317/© 2015 Elsevier B.V. All rights reserved.
systems and bio-separation systems (Huang et al., 2012; Arcos and Vallet-Regí, 2013; Colilla et al., 2013). There are several different families of ordered mesoporous silica (OMS) that due to the uniformity of their pores are suitable for storage and delivery of small therapeutic molecules with problematic bioavailability (Athens et al., 2009; Manzano et al., 2009; Pasqua et al., 2009; Garcia-Bennet, 2011; Vialpando et al., 2011). Among OMS it can be found SBA-15, prepared by Zhao et al. (1998); this solid presents a regular pore size of approximately 30 nm and is characterized by a hexagonal organization of parallel cylindrical pores. Bui et al. (2011) have used SBA-15 as an adsorbent of some drugs (diclofenac, ibuprofen, ketoprofen among others) in order to analyze if this material could be used to eliminate the small quantities of these drugs that passes to the residual waters of their producing industries. These authors observed that the adsorption kinetics is really fast, achieving the stationary state in less than 15 min and that between 75.2 and 89.3% of the drug is adsorbed. In the study made with mesoporous silica of different structures, Yuan et al. (2009) indicated that the total amount of drug incorporated in the matrix pores depended on several factors such as: solvent used in the impregnation process, pH, drug concentration, among others, and that the release kinetic was related to the pore size and the interactions established between the drug and the matrix. To achieve the desired drug release all these parameters must be taken into account. The drug solubility has been studied by Van Speybroeck et al. (2009), who found that the drug solubility increases by incorporating them to SBA-15, also increasing their bioavailability. Layered double hydroxides (LDH), also known as hydrotalcites type solids, have great interest because of their easy and cheap preparation and their enormous applications (Rives, 2001). These are layered
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materials where the layers have a positive charge, being the charge balanced by the negative charges of the anions existing in the interlayer space, together with water molecules; they can be described by the following formula: [M2x + M′31 +− x(OH)2][An−]x/n·n H2O. In the fields of Medicine and Pharmacy these compounds show a huge number of applications because of their use as additives and as host matrixes to improve the drug solubility and therefore its bioavailability (Ambrogi et al., 2003; Del Arco et al., 2008). Moreover, the unwanted drug side effects can be decreased if they are hosted in the interlayer, acting this system as a controlled release system (Del Arco et al., 2004a). Two recently published articles summarize the utilization of these systems as matrixes to incorporate different drugs used to treat several pathologies (Rives et al., 2013, 2014). The current study was developed to evaluate the possibility of using LDH and mesoporous silica SBA-15 as host matrixes to hold broadly used non-steroidal anti-inflammatory drugs such as dexketoprofen (Dx) and aceclofenac (Ac) and to try to develop new pharmaceutical formulations. These systems were chosen because they present low bio-toxicity, easy synthesis, they are cheap and can be stored with high stability. 2. Experimental 2.1. Materials MgCl2·6H2O, AlCl3·6H2O, Tetraethyl orthosilicate (TEOS), Pluronic 123, HCl, butyl alcohol and KOH were all of analytical purity and were purchased from Sigma Aldrich. The drugs were supplied by Menarini (Dx) and Almirall (Ac) and used without additional purification. 2.2. Preparation of the samples 2.2.1. Synthesis of drug/mesoporous solids SBA-15 was prepared following the procedures described by Zhao et al. (1998); a portion of 8 g of pluronic 123 was dissolved in 250.5 g of water and 49.3 g of HCl (35%); the resultant solution was maintained with vigorous stirring during 6 h at 50 °C. Then 17 g of TEOS was added to the solution and kept, with the same stirring and same temperature, during 20 h. The suspension was then left without stirring for ageing for 36 h at 95 °C (a reflux refrigerant was used to avoid evaporation of the solvent). The obtained solid was washed with demineralised water, filtered, dried at 110 °C during 2 h, and calcined at 550 °C for 6 h under ambient atmosphere to remove the triblock copolymer. The sample was designated as SBA-15. Drug incorporation (dexketoprofen or aceclofenac) into the matrix was carried out by the impregnation method: 1 g of SBA-15 was added to a butyl alcohol solution of Dx or Ac (1 g/20 ml) and this suspension was kept at 60 °C for 24 h with stirring in a covered flask. The suspension was then filtered and dried in an oven at 80 °C; the samples obtained have been designated as SBA-Dx, and SBA-Ac, and were stored under a dry atmosphere. 2.2.2. Synthesis of LDH/drug Sample preparation has been performed by two different methods: a) ion exchange and b) coprecipitation. For the samples synthesized by ion exchange the precursor used was sample LDH-Cl. This sample was prepared by coprecipitation in a N2 atmosphere (to avoid incorporation of carbonate from atmospheric Table 1 Formulae of the samples prepared. Sample
Formulae
Drug (%)
MgAlCl C-Dx I-Dx
[Mg0.674Al0.326 (OH)2]Cl0.32·n H2O [Mg0.662Al0.338 (OH)2] (Dx)0.338·n H2O [Mg0.671Al0.329 (OH)2] (Dx)0.31 X0.019·n H2O
– 51.8 49.4
Table 2 Textural and structural properties of the SBA-15 (SM) and the samples of SBA-15 with incorporated drug (SM-Ac and SM-Dx) and amount of drug incorporated. Sample
SBET (m2·g−1)
dp(Ab.) (nm)
Vp (cm3·g−1)
Vmicrop (cm3·g−1)
Drug (%)
SM SM-Ac SM-Dx
737 308 248
8.9 8.2 8.3
1.1 0.7 0.5
0.06 0.0 0.0
– 11.5% 14.5%
carbon dioxide) from aqueous solutions of MgCl2·6H2O and AlCl3·6H2O at pH = 9, using 2 M NaOH and a MII/MIII molar ratio of 2. The suspension was aged for 24 h at 70 °C and simultaneous stirring (Carriazo et al., 2007). Drug incorporation was achieved by adding 0.71 g (0.028 mol) of drug dissolved in 3 mL of butyl alcohol and KOH at pH = 8. The resultant solution was added to 50 mL of the LDH-Cl aqueous suspension (1.14 g). The entire mixture was kept at 100 °C (a reflux refrigerant was used to avoid evaporation of the solvent) and N2 atmosphere for 3 days. The suspension was then centrifuged, washed with decarbonated water and dried in a desiccator; the samples were designated as LDH-Dxi and LDH-Aci. To prepare the samples by the co-precipitation method, LDH-Dxc and LDH-Acc, the starting salt solutions were prepared by adding 0.73 g (0.003 mol) of AlCl3·6H2O and 1.2 g de MgCl2·6H2O (0.006 mol) to 50 mL of decarbonated water. This solution was slowly added over the basic solution of each drug, 0.54 g (0.0021 mol) of Dx and 0.75 g (0.021 mol) of Ac dissolved in 50 mL of water with a couple of drops of butanol and the sufficient amount of KOH (1 M) to obtain pH = 9. The remaining solution was kept at 70 °C under N2 atmosphere during 48 h. The resultant samples were washed, centrifuged and dried. To avoid carbonation of the samples all the experiments were performed using CO2-free water, which was previously prepared by boiling distilled water while bubbling N2. 2.3. Characterization techniques Element chemical analysis of Mg and Al for LDH-drug samples was carried out by atomic absorption in Servicio General de Análisis Químico Aplicado (University of Salamanca) in a MARK 2 ELL-240 apparatus after dissolving the samples in nitric acid solution. The amount of drugs incorporated in the matrix in the different samples was determined by UV–Vis spectroscopy (Perkin Elmer Lambda 35® spectrophotometer, optical path of 1 cm) using a quartz cell at λ = 260 nm for Dx and λ = 275 nm for Ac after adding the samples to a solution of NaOH 0.1 M. Before measuring one calibration line was calculated for each drug by using different drug concentrations (4·10−5–3·10−4 M) in basic solution. The powder X-ray diffraction patterns (PXRD) of the LDH samples were collected in a Siemens D-500 diffractometer using Cu Kα radiation (λ = 1.5405 Å) from 2° to 70°, the scanning rate was of 1°/min and step = 0.05°. In the case of SBA samples they were collected in a Philips X'Pert PRO MPD (λ = 1.5406 Å) equipment from 0.5° to 10°, scanning rate of 0.3°/min and step = 0.0167°. The Fourier-Transform Infrared spectra (FT-IR) were recorded in a Perkin-Elmer BX FT-IR instrument in the wavenumber region from 4000 to 350 cm−1, using the KBr pellet technique with a of sample/KBr mass ratio of 1/50; 100 scans were averaged to improve the signal-to-noise ratio, at a nominal resolution of 4 cm−1. The textural properties were studied from the N2 adsorption– desorption isotherms, recorded at − 196 °C, in a Gemini instrument from Micromeritics. The samples were previously de-gassed at 120 °C for 2 h under nitrogen flow before nitrogen adsorption. Scanning Electron Micrographs (SEM) were obtained in a model 940 Digital scanning-microscope from Zeiss. Transmission electron microscopy (TEM) pictures were obtained in a Zeiss-902 instrument equipped with a digital camera; the samples were prepared on a copper grid by evaporating a drop of water-dispersed sample at an accelerating voltage = 120–200 keV.
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Fig. 1. Powder X-ray diffraction of the samples indicated (the diagrams have been vertically displaced).
2.4. In vitro release assays The release assays were performed in a Selecta Unitronic 320OR® thermostatic bath and a vertical overhead Velp Scientifica DLH® stirring device. The solution temperature was kept at 37 ± 0.5 °C and the stirring speed at 60 rpm. All release assays were performed following the conditions described in USP30-NF25, using a solution of phosphate buffer at pH = 7.4 (405 mL of Na2HPO4 0.2 M + 95 mL of NaH2PO4·H2O 0.2 M). Once achieved a constant bath temperature, the samples compressed in tablets with 12–13 mm diameter with a pressure of 1 MPa, were added to 500 mL of the phosphate solution. In all cases the samples contained 50 mg of drug. 3 mL of solution was withdrawn with a syringe at fixed times, filtered with Millex HV Millipore®, (Φ =0.45 μm) and, in order to keep the volume constant, an equal volume of the buffer solution was immediately replaced. The amount of drug released from the samples was monitored by UV–Vis spectrophotometry be applying the Lambert–Beer equation. Tests were made in triplicate, the averaged values were reported and the error was expressed as standard deviation.
the total amount of drug, determined as explained in the previous paragraph. The Mg/Al molar ratio of the starting solution remained similar to values in samples LDH-Dxc and LDH-Dxi and in the precursor sample, LDH-Cl. The amount of intercalated Dx was similar to that reported by other authors with other NSAIDs (Ambrogi et al., 2003; Del Arco et al., 2004b; Li et al., 2005). The total amount of drug incorporated into sample LDH-Dxi was somewhat lower than that required to attain the electro-neutrality of the sample, due to incomplete anion exchange of Cl− or co-intercalation of OH− or carbonate species. The amount of Ac incorporated into the interlayer was quite small by both synthesis methods used because part of the Ac was decomposed during the synthesis process, as demonstrated by the PXRD results. This finding can be explained by the high intrinsic pH of the LDH, showing that this matrix is not suitable to incorporate this drug under the conditions here used. The amount of drug incorporated to SBA-15 was 14.5% and 11.5% for the samples SBA-Dx and SBA-Ac, respectively, Table 2. The PXRD patterns of the LDH-drug samples and its precursor LDHCl are included in Fig. 1. All of them are characteristic of rather well
3. Results and discussion 3.1. Characterization of materials The LDH-Dx sample formulae included in Table 1 were obtained starting from the mass percentage of the corresponding elements and
Fig. 2. Molecular dimensions of the free drug, as determined with the CS Chem 3D Pro programme.
Fig. 3. Powder X-ray diffraction of the samples indicated (the diagrams have been vertically displaced).
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Fig. 4. FTIR spectra of the dexketoprofen, LDH-Dxi and LDH-Dxc.
crystallized layered materials with the LDH-type structure; for the drugcontaining solids the reflections due to planes (003), (006), and (009) are recorded at spacings much larger than those for LDH-Cl precursors, such as swelling of the layers being due to the intercalation of the drug molecules. Sample LDH-Dxi has a very acute reflection due to diffraction by planes (009) due to the partial chloride-drug exchange that produces an overlapping of the reflections due to planes d003 of the sample LDHCl and planes d009 of the sample LDH-Dxi. The reflections at 0.153 and 0.15 nm, due to the diffraction by planes (110) and (113), respectively, appear better defined for the samples synthesized by exchange than those prepared by coprecipitation; this fact suggests that there is a better overlapping in the first samples. Reflections due to the presence of the LDH-Ac and LDH-Cl phases are recorded in the diffractograms of samples LDH-Aci and LDH-Acc, together with several non-identified diffraction lines, and that must
correspond to Ac decomposition products, these effects are larger for the LDH-Aci sample due to the longer contact time between Ac and the basic medium. The interlayer spacing was determined from the basal spacing measured from the position of the first intense reflection peak at low diffraction angle, after subtracting the thickness of a brucite-type layer, 0.48 nm (Drezdzon, 1988), obtaining values in the range 2.01– 1.97 nm for samples with Dx and of 1.93 nm for the samples with Ac. These values are larger than those calculated (Chem.3d Office Ultra 8.0 2004) for the length and width of the drugs, Fig. 2, so in agreement with other authors (Ambrogi et al., 2003), both drugs must be found in the interlayer space slightly tilted forming bi-layers with the carboxylate groups pointing towards the brucite-like layers. The PXRD patterns recorded for samples SBA-15 and SBA-drugs are included in Fig. 3. The diffractogram of the SBA-15 sample recorded at
Fig. 5. FTIR spectra of the drugs and sample SBA-drug.
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Fig. 6. Scheme of interactions of hydroxyls group with the drug.
low angle (0.5–2θ(°)) shows three perfectly defined reflection lines at 11.4, 6.1 and 5.3 nm that correspond to the reflections produced by (100), (110) and (200) planes, respectively; these reflections and their good definition are characteristic of a well ordered 2D hexagonal structure. In the high angle zone no reflection could be found, but only a broad band due to the characteristic amorphous pore wall. Drug incorporation into the matrix did not significantly change the diffractogram, indicating that the ordered hexagonal structure remained stable. No crystalline drug outside the pores was found by a high angle diffractogram (5–70° range) (Sawant Harshada et al., 2011; Banchero et al., 2013), indicating that all drug is incorporated into the SBA-15 mesoporous. FT-IR spectra of the LDH samples with intercalated Dx, LDH-Dxc and LDH-Dxi, are included in the Fig.4a and b, together with the spectra of pure Dx and of the LDH-Cl precursor. The spectra of the pure drugs showed many intense sharp absorption bands, due to the different functional groups existing in the molecule. The characteristic bands due the stretching vibration of ν(CH) and ν(OH) groups were recorded in the 4000 and 2500 cm−1 range. The signals due to the ν(CO) stretching vibration in the carboxylic acid and in the cetone groups were recorded at 1725 and 1654 cm− 1, respectively. The bands due to the ν(C–H) vibration of the aromatic rings were recorded between 1700 and 1450 cm− 1 (Bellamy, 1975; Kloprogge and Frost, 2001). Due to the large number of signals it is extremely difficult to assign all of them. The spectra of the LDH-Dxc and LDH-Dxi samples are similar to each other, and show that only small bands slightly shifted, depending on the method of synthesis. As a consequence of the intercalation of the drug in LDH, the ν(CO) band characteristic of the carboxylic acid disappears and new bands due to the carboxylate group, at 1556 and 1398 cm−1, corresponding to the vibrations νas(COO) and νs(COO), respectively, are recorded. The other bands due to the drug are recorded in similar
Fig. 7. N2 adsorption–desorption isotherms of different samples.
Fig. 8. Pore distributions of the samples indicated.
positions as those shown by the pure drug, but they have lower intensity because they are overlapped with the bands of the LDH. The bands corresponding to the (Mg/Al–OH) vibrations within the brucitelike layers (Kloprogge and Frost, 2001) are recorded in the low wavenumbers region, below 500 cm−1. The bands at 445 and 393 cm−1 were sharp and intense. In the spectra of the samples with Ac, not shown, new bands assigned to products from the partial degradation of the drug, are recorded, together with the bands due to the drug and the LDH, so their ascription can be hardly done. The spectra of samples SBA-Dx and SBA-Ac are included in Fig. 5; for comparison, the spectra of silica and of the pure drug are also included. The spectra for sample SBA-Dx show the characteristic bands of mesoporous silica: the bands at wavenumbers larger than 2500 cm−1 correspond to the stretching mode of hydroxyl (OH) groups of absorbed or molecular water and three peaks at 450, 800 and 1100 cm−1 corresponding to rocking modes of the oxygen atoms bridging silicon atoms in (Si–O–Si) units, and to symmetric vibrations of silicon atoms in (Si–O–Si) units, respectively. The peak at 950 cm−1 is due to silanol (Si–OH) stretching vibrations (Fidalgo and Ilharco, 2001). In addition, most of the characteristic bands of Dx are recorded, except that corresponding to the stretching vibration ν(CO) from the carboxylic group (1727 cm−1) that disappears those bands due to the carboxylate group between 1500 and 1300 cm− 1, due to the νas(COO) and νs(COO) vibrations, respectively, are recorded. This is the result of the acid–base reaction, Fig. 6, produced between the carboxylic group and the silanol groups, Si–OH, (Yada et al., 1996) existing in the mesoporous wall. The FT-IR spectrum recorded for sample SBA-Ac is almost identical to that recorded for sample SBA-Dx, showing bands due to the aceclofenac functional groups. The pure drug shows bands at 1771, 1717, 1589 and 1056 cm−1 corresponding to the stretching vibrations of the CO, COOH, NH and δ(OH), respectively. As for dexketoprofen, the stretching vibration of (CO) of the carboxylic acid disappears, and those due to the carboxylatre group are recorded. The nitrogen adsorption–desorption isotherms recorded at −196 °C for SBA-15 and for sample SBA-drugs are shown in Fig. 7, and the specific surface area, pore total volume, micro-pore volume and pore size values for each of the samples are included in Table 2. All isotherms can be included in type-IV according to the IUPAC classification (Sing et al., 1985), characteristic of adsorption on mesoporous solids, with an initial uptake due to the monolayer adsorption; the typical step of these isotherms corresponds to N2 condensation inside of mesoporous, and is recorded between 0.4 and 0.8 relative pressure. They also show a H1 type hysteresis loop, characteristic of mesoporous solids with a
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Fig. 9. TEM micrographs of sample SM.
relatively tiny pores distribution and characteristic of materials formed by uniform shape and size particles (Leofanti et al., 1998). After drug incorporation the isotherm shape remains unchanged, but the adsorption capacity decrease. The pore size distribution curves are included in Fig. 8, showing one single narrow peak for all samples. For the SBA-15 sample the maximum is centred at 8.9 nm (diameter) and after the drug incorporation the diameter of this maximum decreases, as well as its intensity; this decrease is responsible of the reduction of pore volume from 1.1 to 0.7 or 0.5 cm3 g−1, Table 2. Upon drug incorporation the specific surface also decreases, from 737 m2 g− 1 to 248 m2 g− 1 and 380 m2 g− 1 for SBA-Dx and SBA-Ac, respectively. Sample SBA-Dx shows a larger decrease because of the larger incorporation of drug. SBA-15 has a hexagonal distribution and presents a small amount of micropores in its mesoporous walls. The calculated micropore volume was 0.06 cm3 g− 1. The pore shape and curvature is very important because the molecular diffusion through the structure and its adsorption capacity depends on these parameters (Fan et al., 2003). It seems that the polyoxyethylene (PEO), the surfactant source, is responsible for the presence of micropores in these compounds, being the hydrophilic part of pluronic 123 (Zheng et al., 1999; Ruthestein et al., 2003) and the polyoxypropylene (PPO) as the hydrophobic part directs the mesoporous structure (Zheng et al., 1999; Imperor-Clerc et al., 2000;
Fig. 10. Release profiles of dexketoprofen and aceclofenac from different materials.
Ruthestein et al., 2003). Changing the PEO length it is possible to modify the micropores concentration and size of their walls, and changing the PEO/PPO ratio the mesophase structure (laminar, hexagonal, cubic,…) can be modified as well (Kipkembol et al., 2001; Maynem et al., 2009). The decrease of pore size, pore volume and specific surface area indicates that the drugs are within the pores. The morphology and particles size of SBA-15 can be observed in the micrographs, Fig. 9. In these micrographs stick-shaped nanoparticles with an average size of 200 nm and a very uniform pore distribution can be observed. The drug incorporation just slightly changes the solid's morphology.
3.2. In vitro release assays The release curves have been obtained following the protocol described above and the results are collected in Fig. 10. When the pure drugs (Ac and Dx) were used the release was very fast, all drug being dissolved in 10 min. The incorporation of the drugs into the different matrices produces an increase of the drug release time with respect to the pure drug. Among the samples prepared using LDH, only sample LDH-Dxc corresponded to a single crystallographic phase. Dx release from this sample was slower than that measured for the pure drug; 30 min after the beginning of the essay 73% of Dx had been released and after 300 min one 77% has been released. On these samples the release process corresponded to exchange between the anionic form of the drug and the phosphate anions from the solution medium, giving place to a biphasic system formed by two phases: LDH-Dxc and LDH-Phosphate. Once the drugs were incorporated into SBA-15, a clear increase of the release time was observed, achieving the 100% release of dexketoprofen at 410 min for sample SBA-Dx and at 240 min for release of aceclofenac from sample SBA-Ac. The huge amount of papers concerning drug release from mesoporous matrices indicate that the release time is related to the pore size, drug content, presence of OH groups in the pore walls and drug crystallinity (Yada et al., 1996; Costa and Sousa-Lobo, 2001; Sminova et al., 2003; Das et al., 2009; Carriazo et al., 2010a, 2010b; Shen et al., 2011). Sminova et al. (2003) indicated that on increasing the pore size, more drug will be incorporated into the matrix and its release speed will be slower, due to the higher hydrophobicity created inside the pores that obstructs the entrance of solvent. Shen et al. (2011) relate the ibuprofen release speed with the drug crystallinity inside the mesoporous of MCM-41 and SBA-15, independently of the pore size. These authors indicated that the release speed decreased with the drug crystallinity increment; once the drug
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was in an amorphous state in the matrix channel it could be quickly dissolved. In this study the release time differences can be related to the different percentages of incorporated drug into the SBA-15 and, as it has been mentioned before, the release time increased with the increased drug incorporation due to the hydrophobicity increment inside the pores. The observed differences on the release speed from the matrixes, LDH and SBA-15, are related to the release process. While in the LDH samples the drug gets out of the matrix by an exchange process between the drug anion and phosphate existing in the buffer (Del Arco et al., 2009), in the case of SBA-15 it is carried out by a diffusion process throughout the pore structure, being much slower than the exchange process. 4. Conclusions The results show that LDH can be used for intercalated drugs as Dx, but not for intercalation of Ac because it decomposes in basic medium. More dexketoprofen was incorporated into hydrotalcite than into the mesoporous silica; the low content of drug in sample SBA-Dx is not a problem because the larger activity of isomer S(+) (Dx) makes that the amount of drug required for a patient can be reduce by 50% in comparison with the racemic mixture. The release studies showed that both matrices (LDH and ordered mesoporous silica SBA-15) can be used to prepare controlled release systems. The release was slower when silica was used as a matrix because this process takes place by diffusion, instead of interchange as occurs in the LDH. Acknowledgments The authors wish to acknowledge the assistance of the Menarini and Almirall laboratories for supplying dexketoprofen and aceclofenac samples, respectively. References Ambrogi, V., Fardella, G., Grandolini, G., Nochetti, M., 2003. Effect of hydrotalcite-like compounds on the aqueous solubility of some poorly water-soluble drugs. J. Pharm. Sci. 92, 1407–1418. Arcos, D., Vallet-Regí, M., 2013. Bioceramics for drug delivery. Acta Mater. 61, 890–911. Athens, G.L., Shayib, R.M., Chmelka, B.F., 2009. Functionalization of mesostructured inorganic–organic and porous inorganic materials. Curr. Opin. Colloid Interface 14, 281–292. Banchero, M., Ronchetti, S., Manna, L., 2013. Characterization of ketoprofen/methyl-βcyclodextrin complexes prepared using supercritical carbon dioxide. J. Chem. N. Y. 2013, 583952. Bellamy, L.J., 1975. The Infrared Spectra of Complex Molecules. Chapman & Hall, London. Bjordal, J.M., Klovning, A., Ljunggren, A.E., Slordal, L., 2007. Short-term efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: a meta-analysis of randomized placebo-controlled trials. Eur. J. Pain 11, 125–138. Bui, T.X., Kang, S.Y., Lee, S.H., Choi, H., 2011. Organically functionalized mesoporous SBA-15 as sorbents for removal of selected pharmaceuticals from water. J. Hazard. Mater. 193, 156–163. Carriazo, D., Del Arco, M., Martín, C., Fernández, A., Rives, V., 2010b. Inclusion and release of fenbufen in mesoporous silica. J. Pharm. Sci. 99, 3372–3380. Carriazo, D., Del Arco, M., Martín, C., Ramos, C., Rives, V., 2010a. Influence of the inorganic matrix nature on the sustained release of naproxen. Microporous Mesoporous Mater. 130, 229–238. Carriazo, D., Del Arco, M., Martín, C., Rives, V., 2007. A comparative study between chloride and calcined carbonate hydrotalcites as adsorbents for Cr(VI). Appl. Clay Sci. 37, 231–239. Colilla, M., González, B., Vallet-Regí, M., 2013. Mesoporous silica nanoparticles for the design of smart delivery nanodevices. Biomater. Sci. 1, 114–134. Costa, P., Sousa-Lobo, J.M., 2001. Modeling and comparison of dissolution profiles. Eur. J. Pharm. Sci. 13, 123–133. Costantino, U., Abrogi, V., Nocchetti, M., Perioli, L., 2008. Hydrotalcite-like compounds: versatile layered hosts of molecular anions with biological activity. Microporous Mesoporous Mater. 107, 149–160. Das, S.K., Kapoor, S., Yamada, H., Bhattacharyva, A.J., 2009. Effects of surface acidity and pore size of mesoporous alumina on degree of loading and controlled release of ibuprofen. Microporous Mesoporous Mater. 118, 267–272. De Sousa, L.A., Figueiras, A., Veiga, F., Mendes de Freitas, R., Cunha, L.C., Cavalcanti, E., Da Silva, C.M., 2013. The systems containing clays and clay minerals from modified drug release: a review. Colloids Surf. B 103, 642–651.
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Del Arco, M., Cebadera, E., Gutiérrez, S., Martín, C., Montero, M.J., Rives, V., Rocha, J., Sevilla, M.A., 2004b. Mg,Al layered double hydroxides with intercalated indomethacin: synthesis, characterization, and pharmacological study. J. Pharm. Sci. 93, 1649–1658. Del Arco, M., Fernández, A., Martín, C., Rives, V., 2008. Solubility and release of fenamates intercalated in layered double hydroxides. Clay Miner. 43, 255–265. Del Arco, M., Fernández, A., Martín, C., Rives, V., 2009. Release studies of different NSAIDs encapsulated in Mg,Al,Fe-hydrotalcites. Appl. Clay Sci. 42, 538–544. Del Arco, M., Gutiérrez, S., Martín, C., Rives, V., Rocha, J., 2004a. Synthesis and characterization of layered double hydroxides (LDH) intercalated with non-steroidal antiinflammatory drugs (NSAID). J. Solid State Chem. 177, 3954–3962. Drezdzon, M.A., 1988. Synthesis of isopolymetalate-pillared hydrotalcite via organicanion-pillared precursors. Inorg. Chem. 27, 4628–4632. Fan, J., Ley, L., Wang, I., Yu, C., Tu, B., Zhao, D., 2003. Rapid and high-capacity immobilization of enzymes based on mesoporous silicas with controlled morphologies. Chem. Commun. 17, 2140–2141. Fidalgo, A., Ilharco, L.M., 2001. The defect structure of sol–gel-derived silica/ polytetrahydrofuram hybrid films by FTIR. J. Non-Cryst. Solids 283, 144–154. Fosbol, E.L., Gislason, G.H., Jacobsen, S., Abildstron, S.Z., Hansen, M.L., Schramm, T.K., Folke, F., Sorensen, R., Rasmussen, J.N., Kober, L., Madsen, M., Torp-Pedersen, C., 2008. The pattern of use of non-steroidal anti-inflammatory drugs (NSAIDs) from 1997 to 2005: a nationwide study on 4.6 million people. Pharmacoepidemiol. Drug Saf. 17, 822–833. Garcia-Bennet, A.E., 2011. Synthesis, toxicology and potential of ordered mesoporous materials in nanomedicine. Nanomedicine 6, 867–877. Huang, S., Li, C., Cheng, Z., Fan, Y., Yang, P., Zang, C., Yang, K., Lin, J., 2012. Magnetic Fe3O4@ mesoporous silica composites for drug delivery and bioadsorption. J. Colloid Interface Sci. 376, 312–321. Imperor-Clerc, M., Davidson, P., Davidson, A., 2000. Existence of a microporous corona around the mesopores of silica-based SBA-15 materials templated by triblock copolymers. J. Am. Chem. Soc. 122, 11925–11938. Kipkembol, P., Fodgen, A., Alfredsson, V., Flodstrom, K., 2001. Triblock copolymers as templates in mesoporous silica formation: structural dependence on polymer chain length and synthesis temperature. Langmuir 17, 5398–5402. Kloprogge, J.T., Frost, R.L., 2001. Infrared and Raman spectroscopic studies of layered double hydroxides (LDHs). In: Rives, V. (Ed.), Layered Double Hydroxides: Present and Future. Nova Sci Pub., Inc., New York, pp. 139–192. Langer, R., 1998. Drug delivery and targeting. Nature 30, 5–10. Leofanti, G., Padovan, M., Tozzola, G., Venturelli, B., 1998. Surface area and pore texture of catalysts. Catal. Today 41, 207–219. Li, B., He, J., Ewans, D.G., Duan, X., 2005. Inorganic layered double hydroxides as a drug delivery system-intercalation and in vitro release of fenbufen. Appl. Clay Sci. 27, 199–207. Manzano, M., Colilla, M., Vallet-Regi, M., 2009. Drug delivery from ordered mesoporous matrices. Expert. Opin. Drug Deliv. 6, 1383–1400. Maynem, V., Cool, P., Vansant, E.F., 2009. Verified synthesis of mesoporous materials. Microporous Mesoporous Mater. 125, 170–223. Pasqua, L., Chundari, S., Ceresa, C., Cavaletti, G., 2009. Recent development, applications, and perspectives of mesoporous silica particles in medicine and biotechnology. Curr. Med. Chem. 16, 3054–3063. Patrick, B., O'Donnell, B., McGinity, J.W., 1997. Preparation of microspheres by the solvent evaporation technique. Adv. Drug Deliv. Rev. 28, 25–42. Rives, V. (Ed.), 2001. Layered Double Hydroxides: Present and Future. Nova Sci. Pub., Inc., New York. Rives, V., Del Arco, M., Martín, C., 2013. Layered double hydroxides as drug carriers and for controlled release of non-steroidal antiinflammatory drugs (NSAIDs): a review. J. Control. Release 169, 28–39. Rives, V., Del Arco, M., Martín, C., 2014. Intercalation of drugs in layered doublé hydroxides and their controlled release: a review. Appl. Clay Sci. 88-89, 239–269. Ruthestein, S., Frydman, V., Kababya, S., Landan, M., Goldfarb, D., 2003. Study of the formation of the mesoporous material SBA-15 by EPR spectroscopy. J. Phys. Chem. 107, 1739–1748. Sawant Harshada, H., Mhatre Vivek, K., Tekade Bharat, W., Thakare Vinod, M., Patil Vijai, R., 2011. Formulation, evaluation and characterization of aceclofenac modified release microcapsules. Int. J. Pharm. Sci. 3, 221–228. Shen, S.C., Ng, W.K., Chia, L., Hu, J., Tan, R.B.H., 2011. Physical state and dissolution of ibuprofen formulated by co-spray drying with mesoporous silica: effect of pore and particle size. Int. J. Pharm. Sci. 410, 188–195. Sing, K.S.W., Everett, D.H., Haul, R.A.W., Moscou, L., Pierotti, R., Ruquerol, J., Sieminiewska, T., 1985. Reporting physisorption data for gas solid systems vith special reference to the determination of surface-area and porosity (recommendations 1984). Pure Appl. Chem. 57, 603–619. Sminova, I., Mamic, J., Arlt, W., 2003. Adsorption of drugs on silica aerogels. Langmuir 26, 8521–8525. Vallet-Regí, M., Balas, F., Arcos, D., 2007. Mesoporous materials for drug delivery mesoporous materials for drug delivery. Angews. Chem. Int. Ed. 46, 7523–7534. Vallet-Regí, M., Ramila, A., Del Real, P.P., Pérez-Pariente, J., 2001. A new property of MCM41: drug delivery system. Chem. Mater. 13, 308–311. Van Speybroeck, M., Barillaro, V., Thi, T.D., Mellaerts, R., Martens, J., Van Humbeeck, J., Vermant, J., Annaert, P., Van den Mooter, G., Augustijns, P., 2009. Ordered mesoporous silica material SBA-15: a broad-spectrum formulation platform for poorly soluble drugs. J. Pharm. Sci. 98, 2648–2658. Vialpando, M., Martens, J.A., Van den Mooter, G., 2011. Potential of ordered mesoporous silica for oral delivery of poorly soluble drugs. Ther. Deliv. 2, 1079–1091. Yada, M., Machida, M., Kijima, T., 1996. Synthesis and deorganization of an aluminiumbased dodecyl sulfate mesophase with a hexagonal structure. Chem. Commun. 769–770.
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Yuan, X., Xing, W., Zhuo, S.P., Han, Z., Wang, G., Gao, X., Yan, Z.F., 2009. Preparation and application of mesoporous Fe/carbon composites as a drug carrier. Microporous Mesoporous Mater. 117, 678–684. Zhao, D., Feng, J., Huo, Q., Melosh, N., Fredrickson, G.H., Chmelka, B.F., Stucky, G.D., 1998. Triblock copolymer syntheses of mesoporous silica with periodic 50 to 300 angstrom pores. Science 279, 548–552.
Zheng, Y., Won, Y.Y., Bates, F.S., Davis, G.T., Scriven, L.E., Talmon, Y., 1999. Directly resolved core-corona structure of block copolymer micelles by cryo-transmission electron microscopy. J. Phys. Chem. B 103, 10331–10334.
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Dexketoprofen and aceclofenac release from layered double hydroxide and SBA-15 ordered mesoporous material Soledad San Román, Gonzalo Nuno Almeida, Margarita del Arco ⁎, Cristina Martín ⁎ Departamento de Química Inorgánica, Facultad de Farmacia, Universidad de Salamanca, Avda. Campo Charro s/n, 37007 Salamanca, Spain
a r t i c l e
i n f o
Article history: Received 27 May 2015 Received in revised form 2 December 2015 Accepted 8 December 2015 Available online xxxx Keywords: Layered double hydroxide SBA-15 Dexketoprofen Aceclofenac Controlled release
a b s t r a c t Two non-steroidal anti-inflammatory drugs, dexketoprofen (Dx) and aceclofenac (Ac), were incorporated in two different matrixes, layered double hydroxide and ordered mesoporous silica, SBA-15. The matrixes and the samples were characterized by different techniques, PXRD, SEM, TEM, FT-IR, N2 adsorption at −196 °C and the drug release speed was also measured. The total amount of incorporated drug to the different matrixes was higher in the LDH than in mesoporous silica. The release studies showed a higher drug release speed from the layered double hydroxide than from the ordered mesoporous silica, but even so slower than the one found for the pure drugs, what shows that these solids can be used as drug controlled release matrixes. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Several studies have shown the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) in pain and inflammation treatment in all age range; these are the most consumed drugs around the world (Fosbol et al., 2008). For these drugs the oral administration route is more effective than the topical route (Bjordal et al., 2007) and their toxicity is similar through the different routes: oral, parenteral or intravenous. As all other drugs, NSAIDs have some side effects, being the most common ones are those with gastrointestinal, cardiovascular and renal origins, being also those potentially more severe, so these drugs should be given in the lower effective dose possible and in short periods of time. One of the pharmaceutical industry challenges is to search compounds that can be used as matrixes for controlled release that could avoid side effects and dangerous drug interactions. Many compounds have been tested as release matrixes: polymers, cyclodextrins, clays, etc., (Patrick et al., 1997; Langer, 1998; Vallet-Regí et al., 2007; Costantino et al., 2008) to prepare appropriate materials for each application, following the biocompatibility and biodegradability requests. In the last decade, some inorganic compounds like ordered mesoporous silica (Vallet-Regí et al., 2001) and layered double hydroxides (LDHs), also called hydrotalcites (De Sousa et al., 2013; Rives et al., 2013, 2014) have received special attention to prepare controlled release ⁎ Corresponding authors at: Departamento de Química Inorgánica, Facultad de Farmacia, 37007 Salamanca, Spain. E-mail addresses: [email protected] (S.S. Román), [email protected] (G.N. Almeida), [email protected] (M. del Arco), [email protected] (C. Martín).
http://dx.doi.org/10.1016/j.clay.2015.12.006 0169-1317/© 2015 Elsevier B.V. All rights reserved.
systems and bio-separation systems (Huang et al., 2012; Arcos and Vallet-Regí, 2013; Colilla et al., 2013). There are several different families of ordered mesoporous silica (OMS) that due to the uniformity of their pores are suitable for storage and delivery of small therapeutic molecules with problematic bioavailability (Athens et al., 2009; Manzano et al., 2009; Pasqua et al., 2009; Garcia-Bennet, 2011; Vialpando et al., 2011). Among OMS it can be found SBA-15, prepared by Zhao et al. (1998); this solid presents a regular pore size of approximately 30 nm and is characterized by a hexagonal organization of parallel cylindrical pores. Bui et al. (2011) have used SBA-15 as an adsorbent of some drugs (diclofenac, ibuprofen, ketoprofen among others) in order to analyze if this material could be used to eliminate the small quantities of these drugs that passes to the residual waters of their producing industries. These authors observed that the adsorption kinetics is really fast, achieving the stationary state in less than 15 min and that between 75.2 and 89.3% of the drug is adsorbed. In the study made with mesoporous silica of different structures, Yuan et al. (2009) indicated that the total amount of drug incorporated in the matrix pores depended on several factors such as: solvent used in the impregnation process, pH, drug concentration, among others, and that the release kinetic was related to the pore size and the interactions established between the drug and the matrix. To achieve the desired drug release all these parameters must be taken into account. The drug solubility has been studied by Van Speybroeck et al. (2009), who found that the drug solubility increases by incorporating them to SBA-15, also increasing their bioavailability. Layered double hydroxides (LDH), also known as hydrotalcites type solids, have great interest because of their easy and cheap preparation and their enormous applications (Rives, 2001). These are layered
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materials where the layers have a positive charge, being the charge balanced by the negative charges of the anions existing in the interlayer space, together with water molecules; they can be described by the following formula: [M2x + M′31 +− x(OH)2][An−]x/n·n H2O. In the fields of Medicine and Pharmacy these compounds show a huge number of applications because of their use as additives and as host matrixes to improve the drug solubility and therefore its bioavailability (Ambrogi et al., 2003; Del Arco et al., 2008). Moreover, the unwanted drug side effects can be decreased if they are hosted in the interlayer, acting this system as a controlled release system (Del Arco et al., 2004a). Two recently published articles summarize the utilization of these systems as matrixes to incorporate different drugs used to treat several pathologies (Rives et al., 2013, 2014). The current study was developed to evaluate the possibility of using LDH and mesoporous silica SBA-15 as host matrixes to hold broadly used non-steroidal anti-inflammatory drugs such as dexketoprofen (Dx) and aceclofenac (Ac) and to try to develop new pharmaceutical formulations. These systems were chosen because they present low bio-toxicity, easy synthesis, they are cheap and can be stored with high stability. 2. Experimental 2.1. Materials MgCl2·6H2O, AlCl3·6H2O, Tetraethyl orthosilicate (TEOS), Pluronic 123, HCl, butyl alcohol and KOH were all of analytical purity and were purchased from Sigma Aldrich. The drugs were supplied by Menarini (Dx) and Almirall (Ac) and used without additional purification. 2.2. Preparation of the samples 2.2.1. Synthesis of drug/mesoporous solids SBA-15 was prepared following the procedures described by Zhao et al. (1998); a portion of 8 g of pluronic 123 was dissolved in 250.5 g of water and 49.3 g of HCl (35%); the resultant solution was maintained with vigorous stirring during 6 h at 50 °C. Then 17 g of TEOS was added to the solution and kept, with the same stirring and same temperature, during 20 h. The suspension was then left without stirring for ageing for 36 h at 95 °C (a reflux refrigerant was used to avoid evaporation of the solvent). The obtained solid was washed with demineralised water, filtered, dried at 110 °C during 2 h, and calcined at 550 °C for 6 h under ambient atmosphere to remove the triblock copolymer. The sample was designated as SBA-15. Drug incorporation (dexketoprofen or aceclofenac) into the matrix was carried out by the impregnation method: 1 g of SBA-15 was added to a butyl alcohol solution of Dx or Ac (1 g/20 ml) and this suspension was kept at 60 °C for 24 h with stirring in a covered flask. The suspension was then filtered and dried in an oven at 80 °C; the samples obtained have been designated as SBA-Dx, and SBA-Ac, and were stored under a dry atmosphere. 2.2.2. Synthesis of LDH/drug Sample preparation has been performed by two different methods: a) ion exchange and b) coprecipitation. For the samples synthesized by ion exchange the precursor used was sample LDH-Cl. This sample was prepared by coprecipitation in a N2 atmosphere (to avoid incorporation of carbonate from atmospheric Table 1 Formulae of the samples prepared. Sample
Formulae
Drug (%)
MgAlCl C-Dx I-Dx
[Mg0.674Al0.326 (OH)2]Cl0.32·n H2O [Mg0.662Al0.338 (OH)2] (Dx)0.338·n H2O [Mg0.671Al0.329 (OH)2] (Dx)0.31 X0.019·n H2O
– 51.8 49.4
Table 2 Textural and structural properties of the SBA-15 (SM) and the samples of SBA-15 with incorporated drug (SM-Ac and SM-Dx) and amount of drug incorporated. Sample
SBET (m2·g−1)
dp(Ab.) (nm)
Vp (cm3·g−1)
Vmicrop (cm3·g−1)
Drug (%)
SM SM-Ac SM-Dx
737 308 248
8.9 8.2 8.3
1.1 0.7 0.5
0.06 0.0 0.0
– 11.5% 14.5%
carbon dioxide) from aqueous solutions of MgCl2·6H2O and AlCl3·6H2O at pH = 9, using 2 M NaOH and a MII/MIII molar ratio of 2. The suspension was aged for 24 h at 70 °C and simultaneous stirring (Carriazo et al., 2007). Drug incorporation was achieved by adding 0.71 g (0.028 mol) of drug dissolved in 3 mL of butyl alcohol and KOH at pH = 8. The resultant solution was added to 50 mL of the LDH-Cl aqueous suspension (1.14 g). The entire mixture was kept at 100 °C (a reflux refrigerant was used to avoid evaporation of the solvent) and N2 atmosphere for 3 days. The suspension was then centrifuged, washed with decarbonated water and dried in a desiccator; the samples were designated as LDH-Dxi and LDH-Aci. To prepare the samples by the co-precipitation method, LDH-Dxc and LDH-Acc, the starting salt solutions were prepared by adding 0.73 g (0.003 mol) of AlCl3·6H2O and 1.2 g de MgCl2·6H2O (0.006 mol) to 50 mL of decarbonated water. This solution was slowly added over the basic solution of each drug, 0.54 g (0.0021 mol) of Dx and 0.75 g (0.021 mol) of Ac dissolved in 50 mL of water with a couple of drops of butanol and the sufficient amount of KOH (1 M) to obtain pH = 9. The remaining solution was kept at 70 °C under N2 atmosphere during 48 h. The resultant samples were washed, centrifuged and dried. To avoid carbonation of the samples all the experiments were performed using CO2-free water, which was previously prepared by boiling distilled water while bubbling N2. 2.3. Characterization techniques Element chemical analysis of Mg and Al for LDH-drug samples was carried out by atomic absorption in Servicio General de Análisis Químico Aplicado (University of Salamanca) in a MARK 2 ELL-240 apparatus after dissolving the samples in nitric acid solution. The amount of drugs incorporated in the matrix in the different samples was determined by UV–Vis spectroscopy (Perkin Elmer Lambda 35® spectrophotometer, optical path of 1 cm) using a quartz cell at λ = 260 nm for Dx and λ = 275 nm for Ac after adding the samples to a solution of NaOH 0.1 M. Before measuring one calibration line was calculated for each drug by using different drug concentrations (4·10−5–3·10−4 M) in basic solution. The powder X-ray diffraction patterns (PXRD) of the LDH samples were collected in a Siemens D-500 diffractometer using Cu Kα radiation (λ = 1.5405 Å) from 2° to 70°, the scanning rate was of 1°/min and step = 0.05°. In the case of SBA samples they were collected in a Philips X'Pert PRO MPD (λ = 1.5406 Å) equipment from 0.5° to 10°, scanning rate of 0.3°/min and step = 0.0167°. The Fourier-Transform Infrared spectra (FT-IR) were recorded in a Perkin-Elmer BX FT-IR instrument in the wavenumber region from 4000 to 350 cm−1, using the KBr pellet technique with a of sample/KBr mass ratio of 1/50; 100 scans were averaged to improve the signal-to-noise ratio, at a nominal resolution of 4 cm−1. The textural properties were studied from the N2 adsorption– desorption isotherms, recorded at − 196 °C, in a Gemini instrument from Micromeritics. The samples were previously de-gassed at 120 °C for 2 h under nitrogen flow before nitrogen adsorption. Scanning Electron Micrographs (SEM) were obtained in a model 940 Digital scanning-microscope from Zeiss. Transmission electron microscopy (TEM) pictures were obtained in a Zeiss-902 instrument equipped with a digital camera; the samples were prepared on a copper grid by evaporating a drop of water-dispersed sample at an accelerating voltage = 120–200 keV.
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Fig. 1. Powder X-ray diffraction of the samples indicated (the diagrams have been vertically displaced).
2.4. In vitro release assays The release assays were performed in a Selecta Unitronic 320OR® thermostatic bath and a vertical overhead Velp Scientifica DLH® stirring device. The solution temperature was kept at 37 ± 0.5 °C and the stirring speed at 60 rpm. All release assays were performed following the conditions described in USP30-NF25, using a solution of phosphate buffer at pH = 7.4 (405 mL of Na2HPO4 0.2 M + 95 mL of NaH2PO4·H2O 0.2 M). Once achieved a constant bath temperature, the samples compressed in tablets with 12–13 mm diameter with a pressure of 1 MPa, were added to 500 mL of the phosphate solution. In all cases the samples contained 50 mg of drug. 3 mL of solution was withdrawn with a syringe at fixed times, filtered with Millex HV Millipore®, (Φ =0.45 μm) and, in order to keep the volume constant, an equal volume of the buffer solution was immediately replaced. The amount of drug released from the samples was monitored by UV–Vis spectrophotometry be applying the Lambert–Beer equation. Tests were made in triplicate, the averaged values were reported and the error was expressed as standard deviation.
the total amount of drug, determined as explained in the previous paragraph. The Mg/Al molar ratio of the starting solution remained similar to values in samples LDH-Dxc and LDH-Dxi and in the precursor sample, LDH-Cl. The amount of intercalated Dx was similar to that reported by other authors with other NSAIDs (Ambrogi et al., 2003; Del Arco et al., 2004b; Li et al., 2005). The total amount of drug incorporated into sample LDH-Dxi was somewhat lower than that required to attain the electro-neutrality of the sample, due to incomplete anion exchange of Cl− or co-intercalation of OH− or carbonate species. The amount of Ac incorporated into the interlayer was quite small by both synthesis methods used because part of the Ac was decomposed during the synthesis process, as demonstrated by the PXRD results. This finding can be explained by the high intrinsic pH of the LDH, showing that this matrix is not suitable to incorporate this drug under the conditions here used. The amount of drug incorporated to SBA-15 was 14.5% and 11.5% for the samples SBA-Dx and SBA-Ac, respectively, Table 2. The PXRD patterns of the LDH-drug samples and its precursor LDHCl are included in Fig. 1. All of them are characteristic of rather well
3. Results and discussion 3.1. Characterization of materials The LDH-Dx sample formulae included in Table 1 were obtained starting from the mass percentage of the corresponding elements and
Fig. 2. Molecular dimensions of the free drug, as determined with the CS Chem 3D Pro programme.
Fig. 3. Powder X-ray diffraction of the samples indicated (the diagrams have been vertically displaced).
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Fig. 4. FTIR spectra of the dexketoprofen, LDH-Dxi and LDH-Dxc.
crystallized layered materials with the LDH-type structure; for the drugcontaining solids the reflections due to planes (003), (006), and (009) are recorded at spacings much larger than those for LDH-Cl precursors, such as swelling of the layers being due to the intercalation of the drug molecules. Sample LDH-Dxi has a very acute reflection due to diffraction by planes (009) due to the partial chloride-drug exchange that produces an overlapping of the reflections due to planes d003 of the sample LDHCl and planes d009 of the sample LDH-Dxi. The reflections at 0.153 and 0.15 nm, due to the diffraction by planes (110) and (113), respectively, appear better defined for the samples synthesized by exchange than those prepared by coprecipitation; this fact suggests that there is a better overlapping in the first samples. Reflections due to the presence of the LDH-Ac and LDH-Cl phases are recorded in the diffractograms of samples LDH-Aci and LDH-Acc, together with several non-identified diffraction lines, and that must
correspond to Ac decomposition products, these effects are larger for the LDH-Aci sample due to the longer contact time between Ac and the basic medium. The interlayer spacing was determined from the basal spacing measured from the position of the first intense reflection peak at low diffraction angle, after subtracting the thickness of a brucite-type layer, 0.48 nm (Drezdzon, 1988), obtaining values in the range 2.01– 1.97 nm for samples with Dx and of 1.93 nm for the samples with Ac. These values are larger than those calculated (Chem.3d Office Ultra 8.0 2004) for the length and width of the drugs, Fig. 2, so in agreement with other authors (Ambrogi et al., 2003), both drugs must be found in the interlayer space slightly tilted forming bi-layers with the carboxylate groups pointing towards the brucite-like layers. The PXRD patterns recorded for samples SBA-15 and SBA-drugs are included in Fig. 3. The diffractogram of the SBA-15 sample recorded at
Fig. 5. FTIR spectra of the drugs and sample SBA-drug.
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Fig. 6. Scheme of interactions of hydroxyls group with the drug.
low angle (0.5–2θ(°)) shows three perfectly defined reflection lines at 11.4, 6.1 and 5.3 nm that correspond to the reflections produced by (100), (110) and (200) planes, respectively; these reflections and their good definition are characteristic of a well ordered 2D hexagonal structure. In the high angle zone no reflection could be found, but only a broad band due to the characteristic amorphous pore wall. Drug incorporation into the matrix did not significantly change the diffractogram, indicating that the ordered hexagonal structure remained stable. No crystalline drug outside the pores was found by a high angle diffractogram (5–70° range) (Sawant Harshada et al., 2011; Banchero et al., 2013), indicating that all drug is incorporated into the SBA-15 mesoporous. FT-IR spectra of the LDH samples with intercalated Dx, LDH-Dxc and LDH-Dxi, are included in the Fig.4a and b, together with the spectra of pure Dx and of the LDH-Cl precursor. The spectra of the pure drugs showed many intense sharp absorption bands, due to the different functional groups existing in the molecule. The characteristic bands due the stretching vibration of ν(CH) and ν(OH) groups were recorded in the 4000 and 2500 cm−1 range. The signals due to the ν(CO) stretching vibration in the carboxylic acid and in the cetone groups were recorded at 1725 and 1654 cm− 1, respectively. The bands due to the ν(C–H) vibration of the aromatic rings were recorded between 1700 and 1450 cm− 1 (Bellamy, 1975; Kloprogge and Frost, 2001). Due to the large number of signals it is extremely difficult to assign all of them. The spectra of the LDH-Dxc and LDH-Dxi samples are similar to each other, and show that only small bands slightly shifted, depending on the method of synthesis. As a consequence of the intercalation of the drug in LDH, the ν(CO) band characteristic of the carboxylic acid disappears and new bands due to the carboxylate group, at 1556 and 1398 cm−1, corresponding to the vibrations νas(COO) and νs(COO), respectively, are recorded. The other bands due to the drug are recorded in similar
Fig. 7. N2 adsorption–desorption isotherms of different samples.
Fig. 8. Pore distributions of the samples indicated.
positions as those shown by the pure drug, but they have lower intensity because they are overlapped with the bands of the LDH. The bands corresponding to the (Mg/Al–OH) vibrations within the brucitelike layers (Kloprogge and Frost, 2001) are recorded in the low wavenumbers region, below 500 cm−1. The bands at 445 and 393 cm−1 were sharp and intense. In the spectra of the samples with Ac, not shown, new bands assigned to products from the partial degradation of the drug, are recorded, together with the bands due to the drug and the LDH, so their ascription can be hardly done. The spectra of samples SBA-Dx and SBA-Ac are included in Fig. 5; for comparison, the spectra of silica and of the pure drug are also included. The spectra for sample SBA-Dx show the characteristic bands of mesoporous silica: the bands at wavenumbers larger than 2500 cm−1 correspond to the stretching mode of hydroxyl (OH) groups of absorbed or molecular water and three peaks at 450, 800 and 1100 cm−1 corresponding to rocking modes of the oxygen atoms bridging silicon atoms in (Si–O–Si) units, and to symmetric vibrations of silicon atoms in (Si–O–Si) units, respectively. The peak at 950 cm−1 is due to silanol (Si–OH) stretching vibrations (Fidalgo and Ilharco, 2001). In addition, most of the characteristic bands of Dx are recorded, except that corresponding to the stretching vibration ν(CO) from the carboxylic group (1727 cm−1) that disappears those bands due to the carboxylate group between 1500 and 1300 cm− 1, due to the νas(COO) and νs(COO) vibrations, respectively, are recorded. This is the result of the acid–base reaction, Fig. 6, produced between the carboxylic group and the silanol groups, Si–OH, (Yada et al., 1996) existing in the mesoporous wall. The FT-IR spectrum recorded for sample SBA-Ac is almost identical to that recorded for sample SBA-Dx, showing bands due to the aceclofenac functional groups. The pure drug shows bands at 1771, 1717, 1589 and 1056 cm−1 corresponding to the stretching vibrations of the CO, COOH, NH and δ(OH), respectively. As for dexketoprofen, the stretching vibration of (CO) of the carboxylic acid disappears, and those due to the carboxylatre group are recorded. The nitrogen adsorption–desorption isotherms recorded at −196 °C for SBA-15 and for sample SBA-drugs are shown in Fig. 7, and the specific surface area, pore total volume, micro-pore volume and pore size values for each of the samples are included in Table 2. All isotherms can be included in type-IV according to the IUPAC classification (Sing et al., 1985), characteristic of adsorption on mesoporous solids, with an initial uptake due to the monolayer adsorption; the typical step of these isotherms corresponds to N2 condensation inside of mesoporous, and is recorded between 0.4 and 0.8 relative pressure. They also show a H1 type hysteresis loop, characteristic of mesoporous solids with a
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Fig. 9. TEM micrographs of sample SM.
relatively tiny pores distribution and characteristic of materials formed by uniform shape and size particles (Leofanti et al., 1998). After drug incorporation the isotherm shape remains unchanged, but the adsorption capacity decrease. The pore size distribution curves are included in Fig. 8, showing one single narrow peak for all samples. For the SBA-15 sample the maximum is centred at 8.9 nm (diameter) and after the drug incorporation the diameter of this maximum decreases, as well as its intensity; this decrease is responsible of the reduction of pore volume from 1.1 to 0.7 or 0.5 cm3 g−1, Table 2. Upon drug incorporation the specific surface also decreases, from 737 m2 g− 1 to 248 m2 g− 1 and 380 m2 g− 1 for SBA-Dx and SBA-Ac, respectively. Sample SBA-Dx shows a larger decrease because of the larger incorporation of drug. SBA-15 has a hexagonal distribution and presents a small amount of micropores in its mesoporous walls. The calculated micropore volume was 0.06 cm3 g− 1. The pore shape and curvature is very important because the molecular diffusion through the structure and its adsorption capacity depends on these parameters (Fan et al., 2003). It seems that the polyoxyethylene (PEO), the surfactant source, is responsible for the presence of micropores in these compounds, being the hydrophilic part of pluronic 123 (Zheng et al., 1999; Ruthestein et al., 2003) and the polyoxypropylene (PPO) as the hydrophobic part directs the mesoporous structure (Zheng et al., 1999; Imperor-Clerc et al., 2000;
Fig. 10. Release profiles of dexketoprofen and aceclofenac from different materials.
Ruthestein et al., 2003). Changing the PEO length it is possible to modify the micropores concentration and size of their walls, and changing the PEO/PPO ratio the mesophase structure (laminar, hexagonal, cubic,…) can be modified as well (Kipkembol et al., 2001; Maynem et al., 2009). The decrease of pore size, pore volume and specific surface area indicates that the drugs are within the pores. The morphology and particles size of SBA-15 can be observed in the micrographs, Fig. 9. In these micrographs stick-shaped nanoparticles with an average size of 200 nm and a very uniform pore distribution can be observed. The drug incorporation just slightly changes the solid's morphology.
3.2. In vitro release assays The release curves have been obtained following the protocol described above and the results are collected in Fig. 10. When the pure drugs (Ac and Dx) were used the release was very fast, all drug being dissolved in 10 min. The incorporation of the drugs into the different matrices produces an increase of the drug release time with respect to the pure drug. Among the samples prepared using LDH, only sample LDH-Dxc corresponded to a single crystallographic phase. Dx release from this sample was slower than that measured for the pure drug; 30 min after the beginning of the essay 73% of Dx had been released and after 300 min one 77% has been released. On these samples the release process corresponded to exchange between the anionic form of the drug and the phosphate anions from the solution medium, giving place to a biphasic system formed by two phases: LDH-Dxc and LDH-Phosphate. Once the drugs were incorporated into SBA-15, a clear increase of the release time was observed, achieving the 100% release of dexketoprofen at 410 min for sample SBA-Dx and at 240 min for release of aceclofenac from sample SBA-Ac. The huge amount of papers concerning drug release from mesoporous matrices indicate that the release time is related to the pore size, drug content, presence of OH groups in the pore walls and drug crystallinity (Yada et al., 1996; Costa and Sousa-Lobo, 2001; Sminova et al., 2003; Das et al., 2009; Carriazo et al., 2010a, 2010b; Shen et al., 2011). Sminova et al. (2003) indicated that on increasing the pore size, more drug will be incorporated into the matrix and its release speed will be slower, due to the higher hydrophobicity created inside the pores that obstructs the entrance of solvent. Shen et al. (2011) relate the ibuprofen release speed with the drug crystallinity inside the mesoporous of MCM-41 and SBA-15, independently of the pore size. These authors indicated that the release speed decreased with the drug crystallinity increment; once the drug
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was in an amorphous state in the matrix channel it could be quickly dissolved. In this study the release time differences can be related to the different percentages of incorporated drug into the SBA-15 and, as it has been mentioned before, the release time increased with the increased drug incorporation due to the hydrophobicity increment inside the pores. The observed differences on the release speed from the matrixes, LDH and SBA-15, are related to the release process. While in the LDH samples the drug gets out of the matrix by an exchange process between the drug anion and phosphate existing in the buffer (Del Arco et al., 2009), in the case of SBA-15 it is carried out by a diffusion process throughout the pore structure, being much slower than the exchange process. 4. Conclusions The results show that LDH can be used for intercalated drugs as Dx, but not for intercalation of Ac because it decomposes in basic medium. More dexketoprofen was incorporated into hydrotalcite than into the mesoporous silica; the low content of drug in sample SBA-Dx is not a problem because the larger activity of isomer S(+) (Dx) makes that the amount of drug required for a patient can be reduce by 50% in comparison with the racemic mixture. The release studies showed that both matrices (LDH and ordered mesoporous silica SBA-15) can be used to prepare controlled release systems. The release was slower when silica was used as a matrix because this process takes place by diffusion, instead of interchange as occurs in the LDH. Acknowledgments The authors wish to acknowledge the assistance of the Menarini and Almirall laboratories for supplying dexketoprofen and aceclofenac samples, respectively. References Ambrogi, V., Fardella, G., Grandolini, G., Nochetti, M., 2003. Effect of hydrotalcite-like compounds on the aqueous solubility of some poorly water-soluble drugs. J. Pharm. Sci. 92, 1407–1418. Arcos, D., Vallet-Regí, M., 2013. Bioceramics for drug delivery. Acta Mater. 61, 890–911. Athens, G.L., Shayib, R.M., Chmelka, B.F., 2009. Functionalization of mesostructured inorganic–organic and porous inorganic materials. Curr. Opin. Colloid Interface 14, 281–292. Banchero, M., Ronchetti, S., Manna, L., 2013. Characterization of ketoprofen/methyl-βcyclodextrin complexes prepared using supercritical carbon dioxide. J. Chem. N. Y. 2013, 583952. Bellamy, L.J., 1975. The Infrared Spectra of Complex Molecules. Chapman & Hall, London. Bjordal, J.M., Klovning, A., Ljunggren, A.E., Slordal, L., 2007. Short-term efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: a meta-analysis of randomized placebo-controlled trials. Eur. J. Pain 11, 125–138. Bui, T.X., Kang, S.Y., Lee, S.H., Choi, H., 2011. Organically functionalized mesoporous SBA-15 as sorbents for removal of selected pharmaceuticals from water. J. Hazard. Mater. 193, 156–163. Carriazo, D., Del Arco, M., Martín, C., Fernández, A., Rives, V., 2010b. Inclusion and release of fenbufen in mesoporous silica. J. Pharm. Sci. 99, 3372–3380. Carriazo, D., Del Arco, M., Martín, C., Ramos, C., Rives, V., 2010a. Influence of the inorganic matrix nature on the sustained release of naproxen. Microporous Mesoporous Mater. 130, 229–238. Carriazo, D., Del Arco, M., Martín, C., Rives, V., 2007. A comparative study between chloride and calcined carbonate hydrotalcites as adsorbents for Cr(VI). Appl. Clay Sci. 37, 231–239. Colilla, M., González, B., Vallet-Regí, M., 2013. Mesoporous silica nanoparticles for the design of smart delivery nanodevices. Biomater. Sci. 1, 114–134. Costa, P., Sousa-Lobo, J.M., 2001. Modeling and comparison of dissolution profiles. Eur. J. Pharm. Sci. 13, 123–133. Costantino, U., Abrogi, V., Nocchetti, M., Perioli, L., 2008. Hydrotalcite-like compounds: versatile layered hosts of molecular anions with biological activity. Microporous Mesoporous Mater. 107, 149–160. Das, S.K., Kapoor, S., Yamada, H., Bhattacharyva, A.J., 2009. Effects of surface acidity and pore size of mesoporous alumina on degree of loading and controlled release of ibuprofen. Microporous Mesoporous Mater. 118, 267–272. De Sousa, L.A., Figueiras, A., Veiga, F., Mendes de Freitas, R., Cunha, L.C., Cavalcanti, E., Da Silva, C.M., 2013. The systems containing clays and clay minerals from modified drug release: a review. Colloids Surf. B 103, 642–651.
15
Del Arco, M., Cebadera, E., Gutiérrez, S., Martín, C., Montero, M.J., Rives, V., Rocha, J., Sevilla, M.A., 2004b. Mg,Al layered double hydroxides with intercalated indomethacin: synthesis, characterization, and pharmacological study. J. Pharm. Sci. 93, 1649–1658. Del Arco, M., Fernández, A., Martín, C., Rives, V., 2008. Solubility and release of fenamates intercalated in layered double hydroxides. Clay Miner. 43, 255–265. Del Arco, M., Fernández, A., Martín, C., Rives, V., 2009. Release studies of different NSAIDs encapsulated in Mg,Al,Fe-hydrotalcites. Appl. Clay Sci. 42, 538–544. Del Arco, M., Gutiérrez, S., Martín, C., Rives, V., Rocha, J., 2004a. Synthesis and characterization of layered double hydroxides (LDH) intercalated with non-steroidal antiinflammatory drugs (NSAID). J. Solid State Chem. 177, 3954–3962. Drezdzon, M.A., 1988. Synthesis of isopolymetalate-pillared hydrotalcite via organicanion-pillared precursors. Inorg. Chem. 27, 4628–4632. Fan, J., Ley, L., Wang, I., Yu, C., Tu, B., Zhao, D., 2003. Rapid and high-capacity immobilization of enzymes based on mesoporous silicas with controlled morphologies. Chem. Commun. 17, 2140–2141. Fidalgo, A., Ilharco, L.M., 2001. The defect structure of sol–gel-derived silica/ polytetrahydrofuram hybrid films by FTIR. J. Non-Cryst. Solids 283, 144–154. Fosbol, E.L., Gislason, G.H., Jacobsen, S., Abildstron, S.Z., Hansen, M.L., Schramm, T.K., Folke, F., Sorensen, R., Rasmussen, J.N., Kober, L., Madsen, M., Torp-Pedersen, C., 2008. The pattern of use of non-steroidal anti-inflammatory drugs (NSAIDs) from 1997 to 2005: a nationwide study on 4.6 million people. Pharmacoepidemiol. Drug Saf. 17, 822–833. Garcia-Bennet, A.E., 2011. Synthesis, toxicology and potential of ordered mesoporous materials in nanomedicine. Nanomedicine 6, 867–877. Huang, S., Li, C., Cheng, Z., Fan, Y., Yang, P., Zang, C., Yang, K., Lin, J., 2012. Magnetic Fe3O4@ mesoporous silica composites for drug delivery and bioadsorption. J. Colloid Interface Sci. 376, 312–321. Imperor-Clerc, M., Davidson, P., Davidson, A., 2000. Existence of a microporous corona around the mesopores of silica-based SBA-15 materials templated by triblock copolymers. J. Am. Chem. Soc. 122, 11925–11938. Kipkembol, P., Fodgen, A., Alfredsson, V., Flodstrom, K., 2001. Triblock copolymers as templates in mesoporous silica formation: structural dependence on polymer chain length and synthesis temperature. Langmuir 17, 5398–5402. Kloprogge, J.T., Frost, R.L., 2001. Infrared and Raman spectroscopic studies of layered double hydroxides (LDHs). In: Rives, V. (Ed.), Layered Double Hydroxides: Present and Future. Nova Sci Pub., Inc., New York, pp. 139–192. Langer, R., 1998. Drug delivery and targeting. Nature 30, 5–10. Leofanti, G., Padovan, M., Tozzola, G., Venturelli, B., 1998. Surface area and pore texture of catalysts. Catal. Today 41, 207–219. Li, B., He, J., Ewans, D.G., Duan, X., 2005. Inorganic layered double hydroxides as a drug delivery system-intercalation and in vitro release of fenbufen. Appl. Clay Sci. 27, 199–207. Manzano, M., Colilla, M., Vallet-Regi, M., 2009. Drug delivery from ordered mesoporous matrices. Expert. Opin. Drug Deliv. 6, 1383–1400. Maynem, V., Cool, P., Vansant, E.F., 2009. Verified synthesis of mesoporous materials. Microporous Mesoporous Mater. 125, 170–223. Pasqua, L., Chundari, S., Ceresa, C., Cavaletti, G., 2009. Recent development, applications, and perspectives of mesoporous silica particles in medicine and biotechnology. Curr. Med. Chem. 16, 3054–3063. Patrick, B., O'Donnell, B., McGinity, J.W., 1997. Preparation of microspheres by the solvent evaporation technique. Adv. Drug Deliv. Rev. 28, 25–42. Rives, V. (Ed.), 2001. Layered Double Hydroxides: Present and Future. Nova Sci. Pub., Inc., New York. Rives, V., Del Arco, M., Martín, C., 2013. Layered double hydroxides as drug carriers and for controlled release of non-steroidal antiinflammatory drugs (NSAIDs): a review. J. Control. Release 169, 28–39. Rives, V., Del Arco, M., Martín, C., 2014. Intercalation of drugs in layered doublé hydroxides and their controlled release: a review. Appl. Clay Sci. 88-89, 239–269. Ruthestein, S., Frydman, V., Kababya, S., Landan, M., Goldfarb, D., 2003. Study of the formation of the mesoporous material SBA-15 by EPR spectroscopy. J. Phys. Chem. 107, 1739–1748. Sawant Harshada, H., Mhatre Vivek, K., Tekade Bharat, W., Thakare Vinod, M., Patil Vijai, R., 2011. Formulation, evaluation and characterization of aceclofenac modified release microcapsules. Int. J. Pharm. Sci. 3, 221–228. Shen, S.C., Ng, W.K., Chia, L., Hu, J., Tan, R.B.H., 2011. Physical state and dissolution of ibuprofen formulated by co-spray drying with mesoporous silica: effect of pore and particle size. Int. J. Pharm. Sci. 410, 188–195. Sing, K.S.W., Everett, D.H., Haul, R.A.W., Moscou, L., Pierotti, R., Ruquerol, J., Sieminiewska, T., 1985. Reporting physisorption data for gas solid systems vith special reference to the determination of surface-area and porosity (recommendations 1984). Pure Appl. Chem. 57, 603–619. Sminova, I., Mamic, J., Arlt, W., 2003. Adsorption of drugs on silica aerogels. Langmuir 26, 8521–8525. Vallet-Regí, M., Balas, F., Arcos, D., 2007. Mesoporous materials for drug delivery mesoporous materials for drug delivery. Angews. Chem. Int. Ed. 46, 7523–7534. Vallet-Regí, M., Ramila, A., Del Real, P.P., Pérez-Pariente, J., 2001. A new property of MCM41: drug delivery system. Chem. Mater. 13, 308–311. Van Speybroeck, M., Barillaro, V., Thi, T.D., Mellaerts, R., Martens, J., Van Humbeeck, J., Vermant, J., Annaert, P., Van den Mooter, G., Augustijns, P., 2009. Ordered mesoporous silica material SBA-15: a broad-spectrum formulation platform for poorly soluble drugs. J. Pharm. Sci. 98, 2648–2658. Vialpando, M., Martens, J.A., Van den Mooter, G., 2011. Potential of ordered mesoporous silica for oral delivery of poorly soluble drugs. Ther. Deliv. 2, 1079–1091. Yada, M., Machida, M., Kijima, T., 1996. Synthesis and deorganization of an aluminiumbased dodecyl sulfate mesophase with a hexagonal structure. Chem. Commun. 769–770.
16
S.S. Román et al. / Applied Clay Science 121–122 (2016) 9–16
Yuan, X., Xing, W., Zhuo, S.P., Han, Z., Wang, G., Gao, X., Yan, Z.F., 2009. Preparation and application of mesoporous Fe/carbon composites as a drug carrier. Microporous Mesoporous Mater. 117, 678–684. Zhao, D., Feng, J., Huo, Q., Melosh, N., Fredrickson, G.H., Chmelka, B.F., Stucky, G.D., 1998. Triblock copolymer syntheses of mesoporous silica with periodic 50 to 300 angstrom pores. Science 279, 548–552.
Zheng, Y., Won, Y.Y., Bates, F.S., Davis, G.T., Scriven, L.E., Talmon, Y., 1999. Directly resolved core-corona structure of block copolymer micelles by cryo-transmission electron microscopy. J. Phys. Chem. B 103, 10331–10334.