Ldh-buct.com

Ind. Eng. Chem. Res. 2009, 48, 5590–5597
Synthesis and Controlled Release Properties of Prednisone Intercalated Mg-Al
Layered Double Hydroxide Composite

Fusu Li,† Lan Jin,† Jingbin Han,† Min Wei,*,† and Congju Li*,‡
State Key Laboratory of Chemical Resource Engineering, Beijing UniVersity of Chemical Technology,Beijing 100029, P. R. China, and College of Material Science and Engineering, Beijing Institute of FashionTechnology, Beijing 100029, P. R. China A drug-inorganic composite involving prednisone-cholate ion micelles intercalated Mg-Al layered doublehydroxide (LDH) has been assembled by a coprecipitation method. Powder X-ray diffraction (XRD), Fouriertransform infrared (FT-IR), and UV-vis absorption spectroscopy indicate a successful intercalation ofprednisone-containing micelles into galleries of the LDH matrix. The in vitro drug release studies show thatno burst release phenomenon was observed at the beginning of release tests, and the pH value imposes verylittle influence on the release performance of prednisone in the studied pH range 4.8-7.6. It is, therefore,concluded that the MgAl-LDH can be used as an excellent inorganic drug carrier for prednisone in a widerange of pH values. Four kinetic models (first-order equation, Higuchi equation, Bhaskas equation, andRitger-Peppas equation) were chosen to study the release kinetics of prednisone from the LDH carrier, andit was found that this process can be described by the Ritger-Peppas equation satisfactorily based on adirecting Excel-based solver (DEBS). Moreover, the mechanism for drug release was also discussed.
therapeutics such as ibuprofen in controlled release systems.7,8Owing to the intercalation property of LDHs, many LDH Many drugs have poor water solubility, leading to difficulties compounds with intercalated beneficial organic anions, such as in efficient dose delivery and unwanted side effects. An example DNA,9-11 amino acid,12-16 anti-inflammatory drugs17,18 and is prednisone, a drug of adrenocorticotro, which has been plant growth regulators19 have also been prepared. Many reports investigated as a possible therapeutic treatment for several forms were focused on the study of drug-LDH hybrid materials to of cancer. However, systemic drug administration results in increase the bioavailability of poorly water-soluble, negatively distribution of the drug throughout the patient's body through charged, anti-inflammatory drugs. These drugs can be directly blood circulation. This can lead to elevated drug concentrations intercalated into the LDH galleries and then be released in in undesired parts of the body with severe side effects.
molecular form. The composites have high chemical stability Additionally, there are many cases where conventional drug and can be maintained as long as 4 years.20 administration methods do not provide satisfactory pharmaco- Although this scheme provides an interesting route to deliver kinetic profiles because the drug concentration rapidly falls negatively charged drugs based on LDH materials, the delivery below desired levels. Therefore, a drug delivery and controlled of nonionic, poorly water-soluble drugs remains a challenge.
release system is a more sophisticated drug administration Tyner et al., who reported a new method, utilized LDHs to method designed to overcome such problems.1 These systems control nonionic, poorly water-soluble drug delivery.21,22 This utilize carriers that slowly release their contents in order to process involves first encapsulating the hydrophobic molecules maintain drug concentrations at the desired levels for a longer in an anionic micelle derived from a biocompatible surfactant, period of time. At present, much attention has been paid to and then the negative charge on the surfactant allows the uptake polymers or various types of lipid vesicles and liposomes, as of the drug-loaded micelle between the sheets of the LDHs by drug carriers that form micro- or nanoparticles.2-5 an ion exchange process.
Recently, biocompatible inorganic materials, such as layered In the present study, prednisone was selected as a model drug double hydroxides (LDHs), are being used in drug delivery and for nonionic, poorly water-soluble drugs. It was first encapsu- controlled release systems. These materials are more stable and lated in cholate ions micelles and then intercalated into MgAl- less toxic than conventional drug carriers. LDHs consist of layers LDH galleries by the method of coprecipitation. The physi- of magnesium hydroxide, with aluminum isomorphically sub- ological and biological importance of bile salts (sodium cholate, stituted to give the layers a net positive charge. This charge is for instance) lies in their ability in delivery systems for balanced by interlayer hydrated anions, resulting in multiple medicines, to solubilize and emulsify cholesterol, dietary lipids, layers of alternating host layers and gallery anions. There has and fatsoluble vitamins in the gastrointestinal tract.23 In this been interest in the preparation of biomolecule-LDH complexes work, cholate was chosen to form prednisone-containing mi- for delivery systems. This approach has been used to success- celles and then was further intercalated into the LDH matrix as fully deliver pharmaceutically active molecules, such as grami- a drug carrier. X-ray diffraction (XRD), Fourier transform cidin, amphotericin B, ampicillin, and nalidixic acid.6 Similar infrared (FT-IR), and UV-vis spectroscopy indicate a successful systems based on LiAl-LDH have been studied to deliver intercalation of this prednisone-cholate micelles. The releasebehavior of the resulting composite at different pH buffers has * To whom correspondence should be addressed. Phone: +86-10- been studied, demonstrating that this drug-micelle-LDH 64412131. Fax: +86-10-64425385. E-mail: weimin@mail.buct.edu.cn composite can be used as an excellent controlled release (M.W.); clycongjuli@bift.edu.cn (C.L.).
formulation in a wide range of pH values from 4.8 to 7.6.
Beijing University of Chemical Technology.
‡ Beijing Institute of Fashion Technology.
Moreover, four kinetic models (first-order equation, Higuchi 10.1021/ie900043r CCC: $40.75  2009 American Chemical Society Published on Web 05/18/2009 Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009 equation, Bhaskas equation, and Ritger-Peppas equation) were 2.4. Determination of Prednisone Loading. A known
chosen respectively to study the release kinetics of prednisone weight of the LDH-cholate-prednisone composite (typically from LDH carrier, and it was found that this process can be 10 mg) was dissolved by 5.0 mL of 1.0 M HCl solution and described by the Ritger-Peppas equation satisfactorily based then diluted to 10.00 mL by alcohol. The concentration of on a directing Excel-based solver (DEBS). It can be therefore prednisone was measured by UV-vis spectroscopy (λmax: 244 expected that the method in this work provides a potential nm) based on a multipoint working curve. Runs were performed application in the field of controlled release for nonionic and in triplicate.
2.5. In Vitro Drug Release Study. To measure the release
performances of prednisone from LDH-cholate-prednisone, 2. Materials and Methods
0.4 g composite powder was added in 900 mL of phosphate 2.1. Reagents. Prednisone (98% purity) was purchased from
buffer solutions (pH 4.8, 6.8, and 7.6, respectively) and was J&K Chemical Ltd. and used as received; sodium cholate (98% stirred at 37 °C. At specified time intervals, 5 mL of solution purity) was purchased from Shanghai Sangon Biological was removed and filtered through a 0.2 µm syringe filter. The Engineering Technology Co., Ltd. Other inorganic chemicals absorbance of the filtrate, at the λ max of prednisone, was 3)2 6H2O, Al(NO3)3 9H2O, NaOH, etc., were measured and plotted as the relative release percentages of of analytical grade and used without further purification.
Phosphate buffer solutions were used at 37 °C.
prednisone against time.
2.2. Determination of the Critical Micellar Concentra-
2.6. Characterization. Powder X-ray diffraction data were
tion (CMC) Value of Sodium Cholate. The formation of
recorded by a Shimadzu XRD-6000 power X-ray diffractometer micelles was confirmed by using prednisone as a fluorescence using Cu KR radiation (λ ) 0.154 nm) at 40 kV, 30 mA, a probe. Prednisone and sodium cholate were suspended in scanning rate of 10° min-1, and a 2θ angle ranging from 2° to distilled water, and the pH of the stock solution was found to 70°. The sample of LDH-cholate-prednisone was also char- be ∼8. The fluorescence spectra were measured with the acterized on a Rigaku D/MAX2500 VB2+/PC X-ray diffrac- concentration of sodium cholate varying from 8 to 32 mM (the tometer under air condition, using Cu KR radiation (0.154184 prednisone concentration was 1.06 × 10-6 M). The excitation nm) at 40 kV and 200 mA with a scanning rate of 5°/min, a wavelength (λex) is 283 nm.
step size of 0.02°/s, and a 2θ angle ranging from 1.5° to 10°.
2.3. Synthesis of LDH-Cholate-Prednisone Composite.
UV-vis absorption spectra were performed on a Shimadzu UV- Synthesis of LDH-cholate-prednisone by a coprecipitation 2501PC spectrometer. The Fourier transform infrared (FT-IR) method was carried out as follows. Prednisone (30 mg, as a 2 spectra were recorded using a Vector 22 (Bruker) spectropho- mg/mL solution in chloroform) was added to an aqueoussolution (200 mL) of sodium cholate (1.72 g, 20 mM) and stirred tometer using the KBr pellet technique in the range 4000-400 cm-1 with 2 cm-1 resolution. Fluorescence measurements were 2 to allow for the evaporation of chloroform. When the cholate micelles containing prednisone molecules have been carried out with Shimadzu RF-5301PC spectrofluorimeter.
formed, an aqueous solution (25 mL) containing NaOH (0.32 Thermogravimetry and differential thermal analysis (TG-DTA) g) and a solution (25 mL) containing Mg(NO were carried out on a PCT-1A thermal analysis system under 3)3 9H2O (0.500 g) (initial Mg/Al ) 2.0) were ambient atmosphere with a heating rate of 10 °C/ min. Elemental simultaneously added dropwise into the micellar solution under analyses were performed by inductively coupled plasma (ICP) N2 atmosphere with vigorous stirring until the final pH of ca.
atomic emission spectroscopy using solutions prepared by 10 was obtained. The resulting slurry was aged at 70 °C for dissolving the samples in dilute HCl. Carbon, hydrogen, and 60∼70 h. The product was filtered, washed thoroughly with nitrogen analyses were carried out using a Perkin-Elmer CO2-free water, and finally dried at 70 °C for 12 h. The product Elementarvario elemental analysis instrument.
was denoted as LDH-cholate-prednisone.
Figure 1. (A) Emission spectra of prednisone with different concentrations of sodium cholate. (B) Intensity of prednisone at emission maximum (364 nm)
in the emission spectra as a function of concentration of sodium cholate at room temperature. [prednisone] ) 1.06 × 10-6 M; [sodium cholate] ) 8-32 mM;
λ


Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009 Figure 4. UV-vis spectra of (a) prednisone solution, (b) prednisone-cholate
Figure 2. Powder X-ray diffraction patterns for (a) LDH-cholate and (b)
micelle, (c) LDH-cholate-prednisone after dissolution in solution (VHCl: LDH-cholate-prednisone (for clarity, the XRD pattern in the 2θ range of 1:1), and (d) sodium cholate solution.
1.5-10° was displayed in the inset).
Figure 5. UV-vis spectra of the LDH-cholate-prednisone with the
concentration of (a) [cholate] ) 20 mM and (b) [cholate] ) 10 mM.
Figure 3. FT-IR spectra of (a) sodium cholate, (b) prednisone, (c)
3.2. Characterization of the LDH-Cholate-Prednisone
LDH-cholate-prednisone, and (d) LDH-cholate.
Composite. The powder XRD patterns of LDH-cholate and
LDH-cholate-prednisone are shown in Figure 2. The interlayer
3. Results and Discussion
distance d003 value, representing the combined thickness of the 3.1. Determination of CMC Value of Sodium Cholate. The
brucitelike layer (0.48 nm) and the gallery height, is a function formation of cholate ion micelles was verified by a fluorescence of the size and the orientation of intercalated anions.26 Compared probe technique using prednisone.24 Although the reported CMC with the LDH-cholate (Figure 2a, 2θ ) 2.299, d values of sodium cholate range from 10 to 19 mM,24 it is the basal reflection (003) of LDH-cholate-prednisone com- necessary to determine the CMC value for this system first. The posite (Figure 2b, 2θ ) 2.236, d 39.5 Å) shifts to a lower fluorescence emission spectra of prednisone in the presence of 2θ angle. This may indicate the intercalation of prednisone-cholate sodium cholate at a fixed λex of 283 nm are shown in Figure micelle into galleries of LDH, which will be further confirmed 1A. It can be seen that the peak intensity decreases with the in the next section.
increase of the concentration of sodium cholate, especially at364 nm. This is due to the fact that prednisone in water has a Scheme 1. Possible Representation for the Structure of
strong emission peak at 364 nm, which decreases significantly when it transfers into a hydrophobic environment. This phe-nomenon indicates the formation of micelles, which is inagreement with Small's model of micelle formation.25 Figure1B shows the effect of the sodium cholate concentration on theintensity of 364 nm for the emission spectrum. The intersectionpoint of the horizontal line and the bias can be defined as theCMC value, which was found to be 19 mM. As a result it canbe concluded that prednisone-containing cholate micelle isformed in aqueous solution with the CMC value of 19 mM.
Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009 respectively. The spectrum of prednisone (Figure 3b) shows thestretching vibration of CdO at 1700 cm-1 and CdC fromcyclohexadiene at 1660 cm-1. The other absorption bands below1000 cm-1 are attributed to δ(C-H) deformation modes. Thespectrum of LDH-cholate (Figure 3d) displays characteristicbands of sodium cholate at 1584 and 1404 cm-1, confirmingthe intercalation of cholate ions. For the spectrum of LDH-cholate-prednisone (Figure 3c), both of the characteristic bandsof prednisone at 1700 and 1660 cm-1 and those of sodiumcholate at 1584 and 1404 cm-1 were observed. It was foundthat the IR absorption of prednisone is weak for the sample ofLDH-cholate-prednisone composite, which can be attributedto two possible reasons: (1) According to previous reports,27,28the movement of a drug molecule from a micelle core will beslower in comparison to the movement of drug out of core thatis more mobile, which could lead to the low IR absorption ofprednisone.(2)TheactualdrugconcentrationintheLDH-cholate-prednisone composite is low. This will be further discussed Figure 6. Release profiles of prednisone from the composite in buffer
solutions at 37 °C with different pH values.
UV-vis spectroscopy was used to investigate whether The FT-IR spectra of pristine sodium cholate, pristine intercalation of prednisone into the LDH host was associated prednisone, LDH-cholate-prednisone, and LDH-cholate are with any change in its chemical composition or environment.
displayed in Figure 3. For the sake of clarity, only the main Figure 4 shows the UV-vis spectrum of prednisone released absorption bands were listed. In the spectrum of sodium cholate from LDH-cholate-prednisone composite after dissolution in (Figure 3a), the strong absorption bands at 1584 and 1404 cm-1 HCl-ethanol solution (Figure 4c), with the pristine prednisone are characteristic of the stretching vibrations of CdO and OsH, (Figure 4a), prednisone/cholate micelle (Figure 4b), and sodium Figure 7. Plots of different kinetic models for the release of prednisone from the composite at pH 7.6.
Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009 Figure 8. Plots of different kinetic models for the release of prednisone from the composite at pH 6.8.
cholate (Figure 4d) as comparison samples. It can be seen that UV-vis spectroscopy based on a multipoint working curve. This pristine prednisone exhibits a strong absorption band at 244 nm, result is a little higher than other reports6,21 on encapsulating while pristine sodium cholate displays no absorption from 200 hydrophobic drug molecules into LDH. Elemental analysis gave to 400 nm. A band at 244 nm (Figure 4b) is noted for the Mg 8.192%, Al 4.339%, C 48.95%, and H 7.684%. The prednisone/cholate micelle. In the case of prednisone released chemical composition for the LDH-cholate-prednisone com- from the LDH-cholate-prednisone composite, an absorption posite can be obtained: [Mg0.68Al0.32(OH)2](C21H26O5)0.022- band at 245 nm (Figure 4c) was observed. Combined with the 24H39O5 )0.32 0.12H2O, based on the results of elemental results obtained by fluorescence probe technique using pred- analysis, ICP, TG-DTA, and UV-vis spectroscopy.
nisone (3.1 part), the XRD and FT-IR results mentioned above, On the basis of the basal spacing d the UV-vis results indicate that the prednisone-cholate micelle 003 of 39.5 Å for the LDH-cholate-prednisone composite observed by XRD, the gal- was successfully intercalated into the LDH host.
lery height was calculated to be 34.7 Å by subtracting the It should be noted that the micellization of cholate is very thickness of the inorganic layer (4.8 Å). The host-guest important for prednisone to intercalate into LDH. The following interactions for the composite consist of the electrostatic experiments can verify it. For comparison, two composite attraction between the positively charged LDH layers and the samples of LDH-cholate-prednisone were synthesized by the negatively charged micelles, as well as the hydrogen bonding same method with the sodium cholate concentrations of 10 and20 mM, respectively, i.e., one concentration is lower than the formed among the host layers, the guest anions and the interlayer CMC value, and the other is higher than it. Equal weights of water molecules. Taking into account the molecular dimensions two samples were dissolved in solution (V of cholate and prednisone (11.66 and 9.93 Å, respectively, measured by UV-vis spectrometer, respectively (Figure 5). The determined by the ChemWindow 6.0 software) and the existence spectrum of LDH-cholate-prednisone ([cholate] ) 20 mM, of the prednisone-cholate micelle, a schematic supramolecular Figure 5a) displays a band at 245 nm attributed to prednisone, structure of the LDH-cholate-prednisone composite was while it is inconspicuous in the spectrum of LDH-cholate- tentatively proposed and presented in Scheme 1.
prednisone ([cholate] ) 10 mM, Figure 5b). The comparison 3.3. In Vitro Drug Release Behavior. The drug release
study were indicates that the formation of prednisone-cholate properties of prednisone from the LDH-cholate-prednisone micelle is crucial for the preparation of LDH-based drug composite have been investigated at a constant temperature of 37 °C. Figure 6 shows the release profiles of composite in The drug loading for the LDH-cholate-prednisone com- solution at pH 4.8, 6.8, and 7.6, respectively. It was found that posite was determined to be 3.82% (w/w) by the method of the rapid release during the first 40 min is followed by a slower Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009 Figure 9. Plots of different kinetic models for the release of prednisone from the composite at pH 4.8.
release of the drug, and equilibrium was achieved after ca. 150 from the LDH-cholate-prednisone composite is very compli- min. In the case of pH 7.6 (Figure 6a), the released percentages cated and not completely understood. According to the literature, of 65% and 90% were obtained after 40 and 140 min, a first-order equation (eq 1),32 the Higuchi equation (eq 2),33,34 respectively, and prednisone was completely released at ∼175 the Bhaskas equation (eq 3),32 and the Rigter-Peppas (RP) min. For pH 6.8 and 4.8 (Figure 6b and c), the release rates are equation (eq 4)35,36 with modification were chosen to study the a little higher than that of pH 7.6, and complete release of release dynamics of this system: prednisone was observed at ∼105 min. Compared with the release behavior based on LDH-drug composites reported X ) 1 - e k(t-R) previously,21 it is worth noticing that there is no burstphenomenon occurring at the beginning of all the release tests.
X ) k(t - R)1/2 It was also found that the pH value of the medium imposesvery little influence on the release performances of prednisone.
X ) 1 - e k(t - R)0.65 This is rather different from the release behavior of drugintercalated LDHs reported previously, in which lower pH leads X ) k(t - R)n to faster release of pharmaceutically active components fromLDH.19 In this work, prednisone is double protected from the where , t, k, and R are the release percentage, release time, physiological environment in the LDH-cholate-prednisone kinetic constant, and modified parameter, respectively. Here, n composite, first by the organic environment of the micelles and is an exponent, which is normally used to describe different second by the durability of the LDH. Therefore, the release release mechanisms. The value of n < 0.45 corresponds to the process of the LDH-cholate-prednisone is controlled by the drug diffusion control; n > 0.89 is attributed to the dissolution synergistic effect of both the cholate micelle and LDH host, of LDH particles; 0.45 < n < 0.89 is due to the cooperation of demonstrating almost 100% release of prednisone and ap- drug diffusion and LDH dissolution. A directing Excel-based plicability in a wide pH range of 4.8-7.6.
solver (DEBS) was used in this work, and the equations were The drug release based on the LDH-cholate-prednisone evaluated by residual sum of squares (SUM, SUM ) Σ(X - composite could be controlled by any of the following steps: X′)2) and r (coefficient).
(1) dissolution of LDH particles;29,30 (2) ion-exchange reaction On the basis of the four different kinetic models, the fitting between prednisone-containing micelles and phosphate anions results of drug release profiles at pH 7.6, 6.8, and 4.8 are given in buffer solution;31 (3) disaggregation of the cholate micelle in Figures 7, 8, and 9, respectively. The parameters of SUM, and release of prednisone. The release mechanism of prednisone R, n, and r are tabulated in Table 1. It can be seen from Table Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009 Table 1. Fitting Parameters of Drug Release Profiles to Different
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This project was supported by the National Natural Science (25) Stephenson, B. C.; Goldsipe, A.; Beers, K. J.; Blankschtein, D.
Foundation of China, the 111 Project (Grant No.: B07004), the Quantifying the hydrophobic effect. 2. a computer simulation-molecular-thermodynamic model for the micellization of nonionic surfactants in 863 project (Grant no.: 2007AA021900), and the Program for aqueous solution. J. Phys. Chem. B 2007, 111, 1045.
Changjiang Scholars and Innovative Research Team in Uni- (26) Wei, M.; Pu, M.; Guo, J.; Han, J. B.; Li, F.; He, J.; Evans, D. G.; versity (Grant No.: IRT0406).
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La voz de los protagonistas Publicación Oficial de DAECPU Distribución Gratuita Diciembre de 2011 Año 7 Nº 278 Una casa en construcción y de puertas abiertas. / d / José AriSi. 14º Encuentro de Murga Joven / d / Adrián Baseda. Ya están las "reinitas" de Promesas.

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AQUEL QUE NUNCA ME DEJA A fines del siglo XVIII, la oscura conciencia de sí, de su a raíz de la toma de su ciudad por los británicos y que, por otras mo- en las más sobresalientes sensibilidades de la Isla: las de sus poetas. SilvestredeBalboaensudiscutido Espejode paciencia. Se enca- está, claro, la famosa «Oda a la piña», del habanero Manuel de ción de la Sociedad Patriótica, luego Real Sociedad Económica de