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Applied Clay Science
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Intercalation of drugs in layered double hydroxides and their controlled release: A review
Vicente Rives ⁎, Margarita del Arco, Cristina Martín
GIR-QUESCAT, Departamento de Química Inorgánica, Universidad de Salamanca, 37008 Salamanca, Spain
a r t i c l e
i n f o
a b s t r a c t
The intercalation of different drugs in layered double hydroxides with the hydrotalcite-like structure is reviewed. The intercalation processes are carried out following different routes (direct synthesis, coprecipitation, anion exchange) and the advantages and disadvantages of these methods are described for the speciﬁc drug/LDH system studied. Characterisation of the intercalation compounds is also studied, to determine the way the guest molecules are intercalated between the layers of the layered double hydroxide. The controlled release (in some cases also the kinetics analysis) is also studied. We conclude that layered double hydroxides are very suitable materials to host different families of drugs and in the controlled release they show beneﬁtial properties, on comparing with the effect of the bulk drug. It should be also stressed that these are almost the unique materials (in addition to layered hydroxy salts) able to host drugs in the anionic form, so nicely completing the studies carried out so far on the suitability of cationic clays to host cationic or neutral drugs. © 2013 Elsevier B.V. All rights reserved.
Article history: Received 16 August 2013 Received in revised form 28 November 2013 Accepted 2 December 2013 Available online 28 December 2013 Keywords: Layered double hydroxide Drug intercalation Controlled delivery Organic–inorganic intercalation compounds Hydrotalcite
1. Introduction Among the few families of layered compounds with positively charge layers, the so-called layered double hydroxides (LDHs), also known very often as hydrotalcite-like systems, have deserved a lot of attention. Hydrotalcite is a natural occurring hydroxycarbonate of Mg and Al discovered in Sweden in 1842. The structure of hydrotalcite is similar to that of brucite, Mg(OH)2, an hexagonal close packing of hydroxyl groups, where magnesium cations ﬁll all octahedral holes every two layers. Isomorphic, partial, Mg/Al substitution gives rise to development of a positive charge in the layers, which is balanced by hydrated carbonate anions located in the interlayers which originally were empty in brucite. A scheme is depicted in Fig. 1. The brucite-like layers can be stacked in different ways leading to different structures (Drits and Bookin, 2001; Evans and Slade, 2006), the most common ones being rhombohedral (3R symmetry) and hexagonal (2H symmetry). Probably, one proof of the increasing interest in these solids can be the continuous publication of reviews and monographs on their preparation, characterisation, properties and applications (Costantino et al., 2013; Duan and Evans, 2006; Forano et al., 2013; Rives, 2001; Wypych and Satyanarayana, 2004; Zumreoglu-Karan and Ay, 2012). The cations in the layers can be substituted by many others, such as Zn, Co, Ni, Mn, Fe (divalents), and Cr, Co, Fe, V, Y, Mn, Ga, lanthanides (trivalents) and also the interlayer anion can be substituted by a great variety of simple or complex anions, e.g., simple inorganic anions (Constantino and Pinnavaia, 1995), organic anions (Jaubertie et al.,
⁎ Corresponding author. Tel.: +34 923 294489; fax: +34 923 294574. E-mail address: firstname.lastname@example.org (V. Rives). 0169-1317/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clay.2013.12.002
2006; Newman and Jones, 1998; San Román et al., 2006), coordination compounds (Bhattacharjee and Anderson, 2006; Del Arco et al., 2003; Rives and Ulibarri, 1999), polyoxometalates (Carriazo et al., 2006a,b; Del Arco et al., 2004a,b; Hu and Li, 2004; Rives and Ulibarri, 1999), biomolecules or even DNA (Choy et al., 1999, 2001; Desigaux et al., 2006), etc. Concerning the layer cations, their ionic radii are always close to that of Mg2+ (0.72 Å), except that of Al3+ (0.50 Å), as distortions arise for larger cations. Regarding the anions, their size/charge ratio is important, as large anions with low charge are unable to balance homogeneously the positive charge of the layers. A compromise should be reached between the layer charge density and the dimensions of guests species in the interlayer. For non-spherical anions, and very specially when the anions contain long chains (e.g., carboxylates or sulfonates with long alkyl chains), several arrangements in the interlayer are possible, namely, a monolayer parallel to the layers, a parallel bilayer or tilted monolayers or bilayers. This versatility in the chemical composition leads to many and different potential applications. The current interest in LDHs is founded on several properties: They are basic materials and the mixed oxides formed upon thermal decomposition show even a larger basicity, related to the oxide anions; intercalation of acidic anions provides systems with unique acid–base properties. They show the so-called memory effect (Chibwe and Jones, 1989; Kwon and Pinnavaia, 1989), i.e., the ability to recover their original layered structure when mixed oxides (previously prepared by calcination of some LDHs at moderate temperatures) are put in contact with solutions containing anions. They also show anion exchange capacity (AEC), usually larger than that shown by cationic clays, ranging between 2 and 4 mEq/g.
V. Rives et al. / Applied Clay Science 88–89 (2014) 239–269
Fig. 1. Idealised structure of a layered double hydroxide, with interlayer carbonate anions. Reprinted from Coordination Chemistry Reviews, Vol. 181. Vicente Rives and Maria Angeles Ulibarri, Layered double hydroxides (LDH) intercalated with metal coordination compounds and oxometalates, pp. 61–120. Copyright (1999), with permission from Elsevier.
mixed oxides formed upon calcination can be used to scavenge anions from solutions on recovering the layered structure (Forano, 2004; Goh et al., 2008; Ulibarri and Hermosín, 2001). The intercalation of sodium alginate in ZnAl and MgAl LDHs gave rise to an increase in the adsorption capacity of the intercalated systems – above those shown by alginate or the clay used individually – for water treatment, such as removal of ﬂuorine ions or Orange II dye (Mandal et al., 2012). - Materials science mainly as additives to organic polymers; the composite formed exhibits enhanced mechanical properties, mainly related to the aspect ratio of the lamellar particles of the hydrotalcite (Kaluskova et al., 2004; Leroux and Besse, 2004; Wang and Zhang, 2004); they also act as ﬂame retardants (Chen and Qu, 2003; Pereira et al., 2009) and possess barrier effects (Sorrentino et al., 2005). - Catalysis. Original LDHs exhibit strong basic properties and can be used as heterogeneous catalysts, to avoid environmental problems when using soluble basic catalysts (Jinesh et al., 2010; Rives et al., 2003). They can be also used as catalyst supports or catalyst precursors. Several reviews have reported on the catalytic properties of different families of LDHs (Albertazzi et al., 2004; Basile and Vaccari, 2001; Cavani et al., 1991; Centi and Perathoner, 2008; Costantino et al., 2013; Figueras, 2004; Monzón et al., 2001; Rives et al., 2010; Seis et al., 2001; Tichit and Coq, 2003). - Medicine. Biologically-active molecules are also among the different sorts of molecules which can be intercalated between the brucitelike layers of LDHs, a property which has opened their applications in Medicine and Pharmacy. One of the ﬁrst reviews on this subject was published in 2001 by Costantino and Nocchetti (2001), which has been followed by the works by Xu and Lu (2006), Choy et al. (2007), Ladewig et al. (2009), Jakubiková and Kovanda (2010), Chakraborty et al. (2010a,b), Cunha et al. (2010), Wang and O'Hare (2012) and Costantino et al. (2009, 2013). The applicability of LDHs in this ﬁeld is based mainly on three properties: increased solubility of the drug, basicity of the LDH matrix, and ability for drug controlled release. The addition of LDHs usually improves the solubility of the drugs (Perioli and Pagano, 2012; Perioli et al., 2013) without modifying their chemical structure and thus their pharmacological activity. On the other hand, the intrinsic basicity of the LDH structure provides these materials with antacid properties (Parashar et al., 2012.), which are dependent on the route followed to prepare the Mg,Al hydrotalcite. Finally, it is generally observed that on suspending a drug–LDH intercalation compound in aqueous solutions, release of the drug follows a two step process. First a rapid release, and secondly a maintained, slow release, usually related to anionic exchange with anions of the medium. In this scenario, our aim in this work has been to provide a broad description of the interactions between several drugs and layered double hydroxides. We have excluded the interaction of LDHs with non-steroidal antiinﬂammatory drugs, which has been recently reviewed elsewhere (Rives et al., 2013). Our work summarises the information published roughly from 2000 and we have organised the work attending to the pharmacological properties shown by the different drugs. We have given priority importance to the preparation procedures, as many of the papers reviewed have undoubtedly demonstrated that the ability for drug insertion and the release process is dependent on the preparation method followed, probably because of the different physicochemical properties (particle size, crystallinity, etc.) shown by the same compound, when prepared following different routes. Where available, data on the release of the drug are also included. 2. Antibiotics Encapsulation of penicillin in an inorganic host and the use of such encapsulation composites as sustained-release medications have been scarcely studied in the literature. Li et al. (2006) have reported the intercalation of phenoxymethylpenicillin (PMP), a member of the penicillin
Among the many ways proposed to prepare these solids (De Roy et al., 2001; Forano et al., 2013; He et al., 2006; Kanezaki, 2004), the main routes most frequently followed are: - Coprecipitation, consisting of the slow addition of a solution of the metal cations into a reactor containing the anion to be intercalated; increasing the pH by addition of a base or urea hydrolysis that leads to precipitation of the LDH. - Anionic exchange of anions originally existing in the interlayer of a LDH prepared usually by coprecipitation. Chloride or nitrate is preferred as the original anions, as the exchange is easier than for multicharged anions. The reaction is usually carried out by stirring the LDH precursor in a solution containing an excess of the anion to be intercalated; application of ultrasounds speeds up the exchange process (Kooli et al., 1997). - The reconstruction method is based on the memory effect (Chibwe and Jones, 1989; Kwon and Pinnavaia, 1989) shown by the product formed upon mild calcination (ca. 500 °C under dynamic inert gas atmosphere (Del Arco et al., 1994; Rocha et al., 1999)) of a LDH (usually in the nitrate or carbonate form), i.e., the ability to recover a layered structure when the mixed oxide is immersed in a solution of the anions to be intercalated. - Hydrothermal and microwave treatments are often applied to improve the crystallinity and other properties of the LDHs (Benito et al., 2006a,b,c, 2008a,b, 2009; Herrero et al., 2007a,b, 2009). Layered double hydroxides or the homogeneously dispersed mixed oxides formed upon their calcination ﬁnd applications in different ﬁelds: - Water decontamination; based on the large AEC, hydrotalcites can be used to adsorb polluting anions from aqueous solutions, while the
V. Rives et al. / Applied Clay Science 88–89 (2014) 239–269
family (Foye et al., 1995), in a Mg,Al hydrotalcite. First a reference Mg, Al–CO3 material, with a molar Mg/Al ratio of 3, was prepared by coprecipitation at pH 9.0 and ageing at 100 °C for 24 h; the composite (HTP) was prepared by reconstruction, starting from the parent Mg, Al–CO3 hydrotalcite calcined in air at 500 °C for 5 h, immersed in a PMP aqueous solution. These authors consider that for biomedical applications, the reconstruction method, based on the well known “memory effect” of hydrotalcites (Chibwe and Jones, 1989; Kwon and Pinnavaia, 1989), is much better than anion exchange from hydrotalcites containing chloride or nitrate in the interlayer, because of blood overpressure in the ﬁrst case, and because of reduction of nitrate anions to nitrite ones (able to cause many kinds of cancers) by microorganisms in the living bodies in the second one if exchange of chloride or nitrate anions was not complete. The composite consisted of thin ﬂakes (as seen by SEM, Fig. 2) with a rough thickness around 30 nm and size ranging from 100 to 300 nm; the PXRD pattern indicated a d spacing of 18.7 Å, thus suggesting formation of an interdigited monolayer of PMP between the hydrotalcite layers. The mass percentage of PMP was 33%. Upon incubation at 27 °C overnight it was found that HTP was active against bacteria, while the hydrotalcite was inactive. Soaking of HTP at various pH values, followed by the addition of the solution to an Oxford cup placed on the surface of the culture medium (Staphyloloccus aureaus) in the Petri dish, and treated at 27 °C overnight, clearly demonstrated an increase in the area of the inhibition zone with time and the decrease of the initial pH. The lowest pH tested was 2.9 (reaching ﬁnally a value of 5.5, thus further demonstrating also the ability of hydrotalcite systems to reduce acidity), but clearly this should lead to an almost complete dissolution and destruction of the basic layered structure. These authors concluded that oral administration of HTP would lead to major dissolution of the inorganic structure and release of the drug in the stomach (pH from 0.9 to 1.5), while in the small intestine − (pH 6–7.5) release would arise from anion exchange with HCO− 3 or Cl anions existing in the small intestine.
Fig. 2. Scanning electron micrograph of the HTP sample. Reprinted from Journal of Chemical Technology and Biotechnology, Vol. 81. Wen-Zhuo Li, Jun Lu, Jie-Sheng Chen, Guo-Dong Li, Yu-Sheng Jiang, Lian-Sheng Li, and Bai-Qu Huang, Phenoxymethylpenicillin-intercalated hydrotalcite as a bacteria inhibitor, pp. 89 – 93. Copyright (2005) Society of Chemical Industry.
Trikeriotis and Ghanotakis (2007) have studied the intercalation and controlled release of four antibiotics, two hydrophobic (gramicidin D and amphotericin B) and two hydrophilic (ampicillin and nalidixic acid) in LDHs. Intercalation was achieved by anion exchange from a parent Mg,Al-NO3 hydrotalcite (Mg/Al molar ratio 2) prepared under CO2free conditions and aged for 1 day at room temperature in the mother liquor. As gramicidin is hydrophobic and cannot be intercalated directly via anion exchange, it was ﬁrst solubilised in a solution of sodium cholate (a negatively charged micelle) and this was then intercalated via anion exchange. The d-spacing measured (35.3 Å) for a sample containing 2.2% (w/w) of antibiotic showed the formation of a bilayer of cholate molecules in the interlayer space; this value was very similar to that measured for a hydrotalcite–cholate system (33.9 Å), and so it is probable that the gramicidin molecules were hosted in a bilayer of cholate molecules forming a sort of artiﬁcial membrane in the interlayer space. Due to its chemical nature, gramicidin was not released in water, but was completely released in ethanol in merely 2 min; a slow release proﬁle was measured in a solution containing dodecyl maltoside micelles; these authors concluded that using this intercalation compound in a controlled release system would lead to speciﬁc release of the drug in biological membranes. Amphotericin B was intercalated following two routes: ﬁrst same as gramicidin, via the micelle method (reaching an antibiotic content of 2.7%), or via direct anion exchange (9.7% antibiotic content), as the gramicidin molecule contains a carboxylate group. The behaviour observed for the ﬁrst sample was similar to that above commented for the LDH–cholate–gramicidin system, i.e., the antibiotic molecules were hosted in the intercalated cholate bilayer (d-spacing 35.9 Å) without aggregation of the antibiotic molecules, as conﬁrmed by FT-IR and Vis–UV spectroscopy; in the second case (d-spacing 34 Å, 9.7% w/w drug) a strong contamination by unexchanged nitrate existed. Release was not observed in water or in several organic solvents, but the antibiotic was released speciﬁcally in biological membranes and not in the bulk solution. Ampicillin and nalidixic acid were intercalated by mixing antibiotic solutions and LDH suspensions; almost complete exchange (corresponding to 51.7 and 40% w/w of the drug, respectively) was achieved. Despite the molecular size of ampicillin is larger than that of nalidixic acid, the d-spacing in the former case (20.6 Å) was smaller than in the second one (22.3 Å), pointing to formation of a bilayer in the second case. Spectroscopy measurements indicated that ampicillin was intercalated unaltered as an anion, while for nalidixic acid the UV–vis spectrum suggested the simultaneous presence of anionic and neutral forms. Release was achieved by simply suspending the intercalation compounds in water containing NaCl or in plain water at pH 7, probably by anion exchange with chloride anions; the release was faster for ampicillin. These authors assumed that this was due to the large amount of intercalated ampicillin, and the fact that in plain water it was more extensive for nalidixic acid was claimed to be due to the presence of both neutral and anionic species. However, molecular size calculations to check the room available in the interlayer are lacking and so it is also possible that some of the antibiotic molecules were simply adsorbed on the external surface of the inorganic host, so being easily released in aqueous suspensions. San Román et al. (2012) have reported the intercalation of chloramphenicol within the interlayer space of Zn,Al and Zn,Mg,Al LDHs, prepared by coprecipitation. The divalent/Al3+ molar ratio was close to 2 in both cases; a solution of the salts was dropwise added to a solution of the succinate salt of the drug in decarbonated water at pH 9 and the suspension stirred for 24 h at room temperature in a nitrogen atmosphere. The interlayer spacing, as measured by X-ray diffraction, was ca. 12 Å. Minor signals due to the sodium salt of chloramphenicol succinate (probably adsorbed on the external surface of the crystallites) were also recorded in the powder X-ray diffraction diagram; a minimum amount of a nitrate-containing phase was also detected, of which presence was conﬁrmed by FT-IR spectroscopy. From the lattice parameters of the
9 Å for the nitrate precursor to 18 Å for the cefazolin-containing solid after exchange. which have been related to the fast dissolution of sodium cefazolin (both in water and the NaCl solution). Characterisation of Diclofenac. it also shows several drawbacks. 1989. followed by a much slower process. Beatriz Salinas. (2009) have intercalated amoxicillin – a hydrophylic antibiotic of the penicillin group used to treat many different bacterial infections – in a Zn. fast step where a small amount of the drug was released. Cefazolin is a broad spectrum β-lactamic antibiotic with a high activity against gram positive and gram negative bacteria. (2007) have prepared a new polymer composite with chloramphenicol succinate intercalated in a Mg.Al-LDH by rehydration of a calcined LDH precursor.55 Å.. The thermal stability and the kinetic degradation of the drug were deeply dependent on the preparation method followed. the authors suggested that although a monolayer of drug molecules was formed. Vicente Rives. anion exchange and reconstruction. The PXRD diagrams recorded were typical of well crystallized hydrotalcites.5 Å for planes (003). Copyright (2012).242 V. It should be stressed that cefazolin was recovered unaltered in both cases. associated to the presence of magnetite particles dispersed between the hydrotalcite crystallites. as concluded from thermal analysis studies (TG and DTA). (2010) have used ionic exchange to intercalate cefazolin in a Zn. aureus ATCC 25923 (108 UFC/mL). María Soledad San Román. the so-called “ memory effect ” (Chibwe and Jones. From these results. as thermogravimetric analysis has shown that its oxidative decomposition took place at 700 °C instead of 562 °C. 2006).Al hydrotalcites by direct synthesis. probably because the presence of chloride ions in the medium favoured the anion exchange. suggesting that magnetite was undetectable because it was highly dispersed in the form of very small crystallites. these authors concluded formation of a 62°-tilted.4). Fig. and intercalation was further conﬁrmed by FTIR spectroscopy.8% (w/w) NaCl aqueous solution.08 g of Zn. The powder X-ray diffraction diagram of the Zn.Al-nitrate LDH which had been previously prepared by coprecipitation at pH 7 under a nitrogen atmosphere to exclude carbon dioxide from the reaction medium. Sketch of the possible location of chloramphenicol succinate anions in the interlayer space of ZnAl layered double hydroxides. which showed a swelling of the layers from 8. as bands of the hydrotalcite host and of the guest drug molecules were recorded in the spectrum of the intercalation compound.8% NaCl solution used for the release studies. The former showed a swelling up to 12. Fig. Intercalation was assessed by PXRD. Vol. Release of the drug showed a rather interesting behaviour. Complete dissolution was attained for the physical mixture after 30 min. also improving the antibacterial performance of cefazolin. combustion taking place around 440 °C. Release studies have been carried out at 37 °C in a phosphate buffer (pH 7. (2008) have incorporated chloramphenicol in Mg. and the interlayer water molecules and the brucite-like sheets. María Jesús Holgado. and covered by a polymer ﬁlm (ε-polycaprolactone).Al hydrotalcite prepared by ion-exchange. Kwon and Pinnavaia. with a basal spacing of 7.Al and Zn. the time-dependent solubilisation of the intercalation compound. it was concluded that the molecules in the interlayer were oriented parallel to the brucite-like layers. intercalated.41 Å).05 g amoxicillin and 0. while in water only 25% of the drug was released after 90 min. Frunza et al. Reprinted from Applied Clay Science. These results further conﬁrmed the suitability of these intercalated systems for controlled release of this drug. The parent LDH had been prepared by the coprecipitation method in a suspension containing Fe3O4 (Zn2+/Fe2+ molar ratio = 30) at pH 10 and at 65 °C. Ketoprofen or Chloramphenicol Succinate encapsulated in layered double hydroxides with the hydrotalcite-type structure. Ryu et al. leading to 37% of cefazolin incorporation.35 Å for the basal spacing of planes (003). 3. From the gallery height (13. Magnetic studies revealed that the intercalation compound displayed a paramagnetic behaviour at room temperature. The PXRD diagram conﬁrmed intercalation of the drug without decomposition. Wang et al. Rives et al. comparing the results with those obtained with a physical mixture of 0. while with the intercalated sample only 85% of drug was released after 2 h. Despite its advantages if compared to penicillin and other cefalosporins. Tammaro et al. to obtain a magneticallyfunctionalized LDH.2 Å ) and the size of the intercalated drug. / Applied Clay Science 88–89 (2014) 239–269 solid. both in water and in a 0.Al LDH (San Román et al. this could be checked also by performing the study in a basic medium. on one side. using a cefazolin:LDH ratio of 2:1. Intercalated amoxicillin was thermally more stable than in the bulk form. intercalation also gave rise to an increase in the decomposition temperature of the drug. and stirred for 24 h at room temperature under a nitrogen atmosphere. it is very important to develop matrices suitable to prepare controlled release composites to protect the drug and to increase its efﬁcacy. 1989). 66% was released after merely 39 min in the NaCl solution. this was tilted 37°. and stirring for 24 h under a nitrogen atmosphere. The intercalation compound was prepared by dissolving cefazolin (in its sodium form) in an Fig. 2010) concluded that LDHs behave as very suitable inorganic matrices. 4. where drug/hydroxyl exchange could have taken place. Large differences were observed in the zones of bacterial inhibition for sodium cefazolin and the cefazolin– LDH intercalation compound. using distilled water and the same 0. ethanol:water mixture (70:30). on the other. These properties represented an important advantage of these compounds for transport and vectorization of drugs. with a ﬁrst. as previously reported for lactate anions intercalated in a Mg. pp. Release of the drug was studied by HPLC. as these intercalation compounds could be . It can be easily denaturalized by hydrolysis and decomposes at 65 °C. This LDH was calcined at 400 °C for 24 h and then it was added to an aqueous solution of sodium amoxicillin. which corresponded to a gallery height of 7. it needs to be supplied frequently to maintain required therapeutic levels. 158 – 163. The antibacterial activity of cefazolin and of the intercalation compound has been studied in vitro by programmed diffusion from the disc. the microorganism to be inhibited was S. probably because of the strong interactions developing between the intercalated molecules. probably the ﬁrst release corresponded to desorption from the surface of the crystallites.Al-CO3 LDH. vs. double layer of drug molecules. Insertion of the amoxicillin anion in the interlayer was conﬁrmed both from PXRD and FT-IR spectroscopy experiments.Al-LDH precursor showed only the signals due to the LDH. with permission from Elsevier. the authors (Ryu et al. Concerning its medical use.. 3. due to the strong electrostatic interactions between the drug and the layers. For these reasons. 55. slightly shorter than the length of the amoxicillin molecule (9. related to its chemical stability and medical use. while the second one corresponded to release of intercalated chloramphenicol.
Wang and Zhang (2012) have intercalated several antibiotics within a Mg. (2009) have reported a detailed study of the interaction of tetracycline (TC) with hydrotalcite. Sui et al. Calcined HTs (CHT) showed markedly higher adsorption capacities for aqueous TC than hydrotalcites and were dependent on both reconstruction of layer structures (by the memory effect of CHT) and adsorption on MgO surfaces. Valarezo et al. Release studies indicated that an anion exchange process holds diffusion through the particles being the rate determining step. antibacterial (chloramphenicol hemisuccinate).V. Jin-Ho Choy. and the TC molecules were oriented parallel to the brucite-like layers. 685–688. Copyright (2010). and 4). 4. Zones of bacterial inhibition of (a) LDH. As concluded from PXRD studies. especially for low mass weight drugs.Al hydrotalcite. rapidly concentrated in pathological cells by application of a magnetic ﬁeld. these authors have highlighted that the drug should be intercalated prior to encapsulation for controlled delivery of the drug. Russo and Lamberti. 3. the presence of Sn4 + decreased both parameters. benzylpenicillin (BP). At high TC equilibrium concentrations. Following the ion exchange method. however. Seung-Jin Ryu. (2012) have intercalated norﬂoxacin (NOR) in LDHs with different Mg/Al ratios (2.8% NaCl solution. Costantino et al. (b) cefazolin sodium.Al LDHs into poly(ε-caprolactone) by electrospinning (Frunza et al.. Vol.Al and Zn. Jae-Min Oh. Reprinted from The Journal of Physics and Chemistry of Solids. 71. Jin-Kyu Lee. These authors have studied samples with different Mg/Al ratios (2. namely. the results were compared to those obtained for uncalcined hydrotalcite and with MgO treated under similar conditions. Formation of the corresponding drug–LDH systems has been conﬁrmed by PXRD and FT-IR spectroscopy. 2008. in order to determine their effect on the adsorption ability of the matrix for the drug. Xu et al. with permission from Elsevier. and antiﬁbrinolytic (tranexamic acid) agents in Mg. Layered double hydroxide as novel antibacterial drug delivery system. (2013) encapsulated amoxicillin-intercalated Zn. and ticarcillin (TCC) anions. the layered structure was only partially restored from CHT. . hydrothermal treatment at 120 °C for 24 h. Rives et al. higher TC adsorption capacities were related to higher Mg/Al ratios in CHT. benzoate (BZ). which then can be easily killed. 3. whereas BZ and BP anions were accommodated in the interlayer region as a bilayer. 2011). chloride) in the interlayer and after adding also Sn4 + to the brucite-like layers. and then calcination. and (c) cefazolin–LDH nanohybrid in (A) water and (B) a 0. succinate (SU). (2012) have published a review collecting the patents recently published on the intercalation of anti-inﬂammatory (diclofenac). pp.Al LDHs. / Applied Clay Science 88–89 (2014) 239–269 243 Fig. different anions (carbonate. to remove the antibiotic from water. and 4) prepared by coprecipitation. Those samples with larger Al3+ content and chloride as the interlayer anion showed a larger adsorption capacity and rate of NOR release. Hyun Jung. A Freundlich model ﬁtted well with the adsorption equilibrium data. SU and TCC anions were intercalated in a monolayer arrangement.
in a Mg.. 6.9 Å. but these calculations were not reported in this study. Schematic for nanobiohybrid design.2 without requiring an anion exchange process.2. The d-spacing increased from 8. CPT was released in several minutes both at pHs 4. The difference might be due to the neutral nature of CPT. the limiting step being diffusion through the particles. and 7. which also showed a larger CPT loading (5. Reprinted from The Journal of Controlled Release. forming an end-to-end bilayer (34. Such a difference was due to different release mechanisms: at acidic pHs the inorganic layers were dissolved. As HCPT was only very scarcely soluble in water. 5. while controls (e. / Applied Clay Science 88–89 (2014) 239–269 3. The differences were attributed to a restricted motion within the interlayer space and the drug–layer electrostatic interactions. surfactant. this conclusion was conﬁrmed from TEM observation of solids exposed to different pH environments.Al LDH in its nitrate form was intercalated with sebacate anions by a co-precipitation method. Sucrose aspartate surfactant (SAS) or sodium cholate (SC) were dispersed in water or chloroform. Fig. while at and above pH 7 release was through exchange with anions existing in the medium from the buffer solution.6%). when the positive charge of the layer is lower.9 Å). Pang et al. the release rate and amount released being somewhat lower for sample W-2 (t1/2 values were 12 min for sample W-1 and 52 min for sample W-2). The alkyl chains of the sebacate anions in the interlayer provided a hydrophobic medium. namely. and the LDH slurry was injected in the micelle mixture. via anion exchange. Direct intercalation of CPT in a Mg. Inhibition was less effective with intercalation compounds based on SC than on SAS. with 16.8–7.Al-NO3 (Mg/Al molar ratio ca. Al LDH. Nitrate anions from the original metal salts were also intercalated together with hydroxyl groups. Nanobiohybrids as delivery vehicles for camptothecin. Carmine (a bright-red pigment used as a food additive) was directly intercalated in the LDH by mixing the slurry and an aqueous solution of carmine. However. with permission from Elsevier. with the terminal ring easily converting between the lactone (biologically active) under acidic conditions (pH b 5). A Mg. Copyright (2004).5 showed also a ﬁrst. an antimetabolic drug extensively used in cancer chemotherapy. while the anionic nature of carmine demanded such an exchange process in order to be released.7 Å for intercalation compounds with CPT loaded micelles of SAS and SC. ﬂat-oriented nitrate anions led to a spacing of 7. at 70 °C under hydrothermal conditions (Z-2). has been reported by Wang et al. suitable for intercalation of the drug. Three samples were prepared. which could be released at pH 7. the LDH– HCPT intercalation compounds were prepared by a secondary intercalation method. which negative charge allows intercalation of the composite between the layers of a LDH.9 Å). LDH. probably because of the more efﬁcient encapsulating ability of the latter. Tyner et al. when a large concentration of nitrate is required in the interlayer to balance a large positive charge of the layer for a Mg/Al ratio around 2. 2) LDH was prepared by coprecipitation at pH 10.03 (sample W-2) % (w/w) drug loadings. release was completed in 10 min from a CPT–LDH physical mixture.8 Å for the (003) spacing due to a nitrate-containing sample.9 Å for sample W-2. Intercalation compounds containing CPT inhibited growth of 9L glioma cells as efﬁciently as the pure drug. The diffraction maxima due to planes (003) were recorded at 7. Moreover. respectively. These authors claim that the three maxima were due to three different orientations of the CPT molecule in the interlayer space. molecular size calculations would permit to determine if the interlayer space was large enough to admit ﬂat-oriented CPT molecules. to the carboxylate form at pH N 8. a Zn. Rives et al. (2004) have encapsulated CPT in an anionic micelle derived from a biocompatible surfactant. on the basis of a value of 8. in a Zn.Al (molar ratio 2) LDH prepared by the reconstruction method from a carbonate precursor calcined at 500 °C for 4 h.9 Å). and adding glycerol to the synthesis medium Fig. 501–514. Kinetics studies of HCPT release from the nanocomposites could be ﬁtted to a pseudo-second-order kinetic model. it became anionic under alkaline conditions. pp.72 (sample W-1) and 26. Intercalation of 5 ﬂuorouracil (5-FU). second one.Al (molar ratio ca.8 and 7. aged for 2–5 days at 70 °C to minimize crystal aggregates and kept as a slurry. Anticancer agents Camptothecin (CPT) is a pentacyclic indol alkaloid. 10-hydroxycamptothecin (HCPT). 5. 500 × 10 nm. However. Katherine M Tyner. Carmine was completely released after 40 min at pH 4. (2008b). and HCPT was then intercalated by hydrophobic interaction in an ethanol medium. 95. CPT release at pH 7. Although the molecule was neutral and only weakly acidic.g. with the concomitant poor dispersion in physiological solutions. water) showed no inhibition.8 Å for the nitrate precursor to 29. (2005).8. it should be remembered that such a spacing was related to the presence of nitrate anions in an upward orientation. 3) LDH by coprecipitation without encapsulation in micelles has been reported by Liu et al. Fig. Scott R Schiffman. and thus it could be intercalated in a LDH host. Emmanuel P Giannelis. respectively. observation by TEM showed formation of hexagonal shaped particles ca.244 V. and so these authors were able to study two samples. ﬂat and parallel to the inorganic layers (7. fast step. First. Contrary to carmine. for larger Mg/Al ratios.2.9 (intense) and 34. The release followed a pseudo-ﬁrst order kinetics. stabilized through π–π interactions between CPT molecules. at 60 °C (sample Z-1). followed by a slower. but 70 days were required at pH 7. The lactone phase is only very slightly soluble in water.9 Å for sample W-1. but with adverse side effects due to its toxicity.9 (intense) and 23. and the diffusion of HCPT through the LDH particles played an important role in controlling the drug release.8 and 32. and an interdigitized bilayer (23. compatible with the presence of chloride (from the Trizma buffer used) in the interlayer. which in addition showed a d-spacing of 8 Å. Vol. . (2013) have intercalated a hydrophobic anticancer drug derived from camptothecin. and the encapsulated HCPT could keep the biologically active lactone form.
Its release was more effective under simulated intracellular lysosomal conditions (pH 4. three different orientations were claimed to explain these three spacing values.6 Å) and bilayer (12. following the Ritger– Fig. Suppression of tumour cell (Saos-2) was achieved with MTX and MTX–LDH (pure LDH was inactive) in both time and concentration dependent manners. On the other hand..1 and 19. UV–vis spectra showed the bands expected for these molecules. but never as fast as reported for other drugs.. 2010a). However. Similar effects were observed in the MG-63 cell culture line. as MTX required an induction period of 48 h to reach the maximum value. 6. The observed increase in the anticancer efﬁcacy of MTX when intercalated in a LDH has been also studied varying the drug concentration and the incubation time (Oh et al. as expected. since the neutral charge of the inorganic surface did not induce any repulsive interaction against the negatively charged cell membrane.4). Intercalation of methotrexate (MTX) in Mg. but did not provide quantitative analysis results nor determined the gases evolved to conﬁrm their assumptions about the decompositions processes: dehydration at ca. and development of bands characteristic of the drug molecules. The MTX–LDH intercalation compound showed 5000 times better drug efﬁcacy than MTX itself in terms of drug concentration. Copyright (2005). no molecular size calculation was reported to support this ascription. Similarly to the results by Liu et al. while MTX–LDH intercalation compounds did it through endocytosis. 2010b) by coprecipitation at pH 9. 1994). monolayer (10. ﬂat (8 Å). and increased accumulation in target tumour tissue. probably also because of the difference in cell membrane permeation effects. Methotrexate was intercalated also by coprecipitation (Kim et al. Rives et al. (2008b) for CPT. (2012) have studied the intercalation of MTX in a Mg.. isotropic growth at pH close to the isoelectric point produced particles in the 25–290 nm range. Up to 76% of loaded MTX was released at pH 7. whereas MTX–LDH at about 0.4 Å for the nitrate precursor) for the folinic and MTX -containing intercalation compounds. The cellular uptake of MTX was higher in MTX–LDH-treated cells than in MTX-treated ones. the inhibition of the cell cycle was greater for MTX–LDH than for MTX only. Chakraborty et al. 2004). Schematic illustration of the orientation of 5-FU intercalates. These authors also reported a thermal analysis of the samples. only a maximum at 8 Å was recorded for sample Z-2. FT-IR spectra also showed that 5-FU was intercalated. In addition the study further conﬁrmed that the LDH inorganic matrix is biocompatible so that it does not harm the healthy cells. 2006b). The FT-IR spectra for the exchanged samples showed complete removal of the bands due to nitrate species. to assist in swelling of the layers to facilitate intercalation of the organic molecule (Ulibarri et al. from a Mg. These ﬁndings indicated that one of the main drawbacks of MTX for practical use (toxicity) could be overcome by using the intercalation compound instead of the bulk drug.Al LDH prepared by coprecipitation.Al LDH has been also used to intercalate 5-FU to overcome its toxicity.. to verify the drug delivery efﬁciency of the intercalated system. and complete release was achieved within 120 h.Al LDHs (Mg/Al molar ratio 2) was attained by ion exchange from a nitrate LDH precursor by stirring a suspension of the LDH in an aqueous solution of MTX at 60 °C for 3 days under a nitrogen atmosphere (Choy and Son.. pp.01 μg/mL.5) than simulated body ﬂuid (pH 7. 736 –741. Lin Xu. suggesting a tilted intercalation of the molecules in the interlayer space (tilting angle 50 and 46° for folinic acid and MTX. with permission from Elsevier.5 under nitrogen purging. / Applied Clay Science 88–89 (2014) 239–269 245 (sample Z-3). prolonged drug half-life. and intracelular retention (Choi et al. Synthesis and properties of Mg 2Al layered double hydroxides containing 5-ﬂuorouracil. suggesting an effective release in lysosomes. that at equilibrium only 87% (pH 4) and 74% (pH 7) of drug has been released. The anticancer efﬁcacy of the intercalation compound was larger than that of free MTX. The intercalation compounds were prepared by anion exchange at 60 °C for 4 days under N2 atmosphere. Reprinted from The Journal of Solid State Chemistry. Such a difference was probably due to the easier permeation of the cell membrane by MTX–LDH than MTX itself. but also with transferrin (Oh et al. without any observed change in the functionality of the drug. and the intercalation compound showed a higher efﬁciency: MTX showed 75% of cell viability at 500 μg/mL dosage. . The 5-FU–LDH system was prepared (Choi et al. Lei Gao. conﬁrming that no denaturation of the drug molecules had taken place. in its anionic form. Intracellular LDHs (internalized via clathrin-mediated endocytosis) was highly located both with typical endocytic proteins. A Mg. inmunogenecity and poor integration capacity. It is generally assumed that the MTX molecules entered the cytosol via reduced folate carriers (RFC) mediated transport. conﬁrming that stabilisation in the interlayer took place via electrostatic interactions with the layers. and a shift to 12. Vol..Al-NO3 (Mg/Al molar ratio 2) precursor prepared by coprecipitation. on the other hand. respectively). The efﬁcacy of MTX–LDH intercalation compounds and MTX on two different kinds of cancer cell culture lines has been studied. It showed favourable blood clearance proﬁles compared to unintercalated 5-FU. Folinic acid was intercalated similarly. showing high effectivity in wild-type HOS cells and MTX-resistant HOS/MTX cells in terms of inhibition of cancer cell proliferation. It should be noticed. the action of MTX–LDH was faster. namely. including sustained drug release.9 Å (8. although again.4 at 27 °C. the LDH nanoparticles were also rapidly excreted from the body after administration. These authors found a dependence of the particle size on the pH during the synthesis: while at pH 9 the size was in the 10–100 nm range. probably because of the interaction with the layers. Again a dissolution mechanism was claimed at pH 4 and an anion exchange one (with phosphate anions from the medium) at pH 7. Drug release was larger and faster at pH 4 than at pH 7. as it permitted lower doses. 178.4 Å was observed for sample Z-3. 240 °C and 5-FU decomposition and host dehydroxylation between 300 and 600 °C. cellular uptake. Sample Z-1 showed two (003) d-spacings of 8 (rather weak) and 10. respectively. element chemical analysis and FT-IR spectra ruled out the presence of other anions in the interlayer. however. and moreover the former exhibited 48 h faster efﬁcacy compared to the latter. The basal spacings after intercalation were 19.6 Å. 2007).4 Å). Zhongliang Wang. Thermal analyses showed that decomposition of the organic molecules took place at somewhat higher temperatures than the isolated drugs.V. The MTX–LDH system is also able to overcome drug resistance. Enbo Wang. 2006a).
The d-spacing of the (003) planes decreased from 19. suggesting a similar mechanism for these reconstructed samples. 3762–3771. with permission from Elsevier... 2011b). Another effect of the preparation conditions was on the particle morphology: samples prepared at pH 7. Pan et al. were intercalated by anion exchange. The differences may also arise from the lower crystallinity of the latter sample. The different conﬁguration of the DFUR molecules in the interlayer also determined the DFUR loading. a ﬁrst fast step and a second. Dengke Pan. and then alternative routes (e. Hui Zhang. Reprinted from Chemical Engineering Science. Surfactants. a conclusion also reached from solid UV–vis spectroscopy studies. The performance decreased in the order MTX–LDH N MTX N Dox N 5-FU–LDH N 5-FU in all cell lines. Ting Zhang. which maximum value (42% w/w) was reached in the sample prepared at pH 7. the drug loading in this sample was markedly lower than in the others. 2009b). one of them being the formal charge of the layers.. pp. Fig. but not in a Li/Al LDH.7. 60% DFUR was released in 3 h at pH 6. 65. ion exchange. Intercalation of drug molecules depended on many different factors. respectively. The release process could be ﬁtted to the Bhaskar equation (Bhaskar et al. 7. as concluded from the increase in the gallery height. but also the great potential of MTX–LDH as a cancer chemotherapy agent. namely. They have prepared a 5-ﬂuorouracil (5-FU)–LDH system by coprecipitation and after characterisation.2 was much slower than from a drug–LDH physical mixture. probably with a different arrangement of the DFUR species in the interlayer. Controlled release at pH 4. Samples prepared by ion exchange and submitted to hydrothermal treatment showed a particle size around 350 nm for. t1/2 values were 10 and 15 min. with 96% DFUR released after 6 and 2 h. However. / Applied Clay Science 88–89 (2014) 239–269 Peppas kinetics model. ifosfamide (IFO) Fig. samples with lower Mg/Al ratios prepared at high pH showed much smaller irregular plate-like particles and discontinuous plate– plate stacking. for the pH 7.Al-CO3 precursor calcined at 500 °C for 4 h. one of the most effective chemotherapy agents against a variety of cancers. slower one. Copyright (2010). 2011a). The drug was successfully intercalated also in a Zn.246 V.1 to 16. Vol. and which relative concentration increased as pH ageing did. When the intercalation compounds were dispersed in deionized water. and the modiﬁed Freundlich model. at the highest pH tested. The in vitro release proﬁles of DFUR in a solution simulating gastrointestinal and intestinal ﬂuid at pH 7. but an additional phase with d(003) equal to 8. absorption bands at 208 and 269 nm conﬁrmed the existence of pyrimidine (π–π transition) but. If this is too large.5 Å as the molar Mg/Al ratio was increased. These data. (2008) have reported a comparative study to evaluate the potential of drug-LDH intercalation compounds as cancer chemotherapy agents. direct synthesis and hydrothermal treatment after exchange. 7.4. however. even higher than Dox. such as dodecyl sulfate (SDS) or dodecylbenzene sulfonate (SDBS) in their sodium forms.2 in 2 h. Xue Duan. while particles with a narrow particles size distribution around 40 nm with a lower aspect ratio were obtained by coprecipitation. indicating that the encapsulated system was stable under acidic conditions. these differences probably also affecting the release rate of the drug from the interlayer. demonstrating a diffusion controlled process. respectively. but decreasing when the ﬂoxuridine concentration was increased.2 with Mg/Al = 1. total release of the drug being achieved after 100–150 min. 1986) corresponding to diffusion within the interlayer being the rate determining step. suggested a bilayer arrangement in the interlayer for the high loaded sample.Al-CO3 phase (identiﬁed by a FT-IR band at 1365 cm− 1) was observed. with an encapsulating efﬁciency of 88.2 Å was identiﬁed. probably at the high pH values used absorption of atmospheric CO2 in the reaction medium was favoured. Floxuridine has been also intercalated by coprecipitation (Li et al. a fast one followed by a slower one.. which describes the release behaviour from the ﬂat surface from the heterogeneous sites by an ion exchange diffusion process. The FT-IR spectra indicate also that DFUR was intercalated in its conjugated. So. 2010a.8.6%. but due to its side effects (diarrhoea. . Dispersed microspheres with a particle size in the 17–20 μm range and a smooth surface were obtained. the LDH–DFUR compounds were also encapsulated in Eudragit® L100. The drug molecules were oriented in an upward orientation forming a bilayer. A novel organic–inorganic microhybrids containing anticancer agent doxiﬂuridine and layered double hydroxides: Structure and controlled release properties. a dependence of the particle size was also observed (Chakraborty et al. they studied MTX–LDH. In order to model DFUR release in the colon. and following a second-order kinetics. a band at 223 nm for the highest loaded sample suggested a possible conjugation of DFUR anions in the interlayer region. in addition.2 and low (1. different Mg/Al values (ranging from 1. Nie and Hou (2012) have recently reported the preparation of ifosfamide-surfactant–LDH intercalation compounds. When different synthetic routes were tested. monoionized form. This indicated not only the high efﬁcacy of drug–LDH intercalation compounds. Synthesis strategy for DFUR–LDH hybrids.7) Mg/Al molar ratio showed a spherical shape (500–700 nm diameter) with a wormlike morphology. MTX–LDH was the most effective. Only 6% DFUR was released at pH 1. its effectivity in inhibition of cancer cells has been studied. cis-[Pt(NH3)2(5′-GMP)]2 (5′GMP = guanosine 5′-monophosphate) can be intercalated in a Zn. Doxiﬂuridine (DFUR) shows more effective and less toxic properties than other ﬂuoropyrimidines. with a larger layer charge density. and an equilibrium release of 72% was observed at pH 7. also an important contamination by a Mg. doxorubicin (Dox)–LDH and the bulk drugs..AlNO3 (Zn/Al molar ratio 2) LDH.7 to 2. together with molecular size calculations for the DFUR molecule.45 without pancreatine (phosphate buffered solution) indicated that release occurred in two consecutive steps. the strong electrostatic interactions between the layers and the interlayer anion inhibited swelling and anion/drug substitution. In any case. (2010) have reported its intercalation by reconstruction from a Mg. such as 5-ﬂuorouracil and ﬂoxuridine. direct coprecipitation or reconstruction from calcined precursors) should be tested. Al LDH by ion exchange (Chakraborty et al. nausea and mucositis) by oral administration its application in cancer treatment is somewhat limited.2 to 10) were tested.8 and 7.2 and 10 samples.g. 2005). Choi et al. but a monolayer for samples was prepared at high pH and larger Mg/Al ratio. This phenomenon was quite similar to that previously reported for LDHs with inorganic anions in the interlayer growing on a MgO/Al2O3 mixture upon hydrothermal treatment (Xu and Lu. Rives et al. However.9) and pH during ageing (from 7. release proceeded in two steps. Yang and Guo (2003) have shown that a cis-platin-DNA model adduct.
A short review on the intercalation and delivery of anticancer drugs in and from LDHs has been recently published by Riaz and Ashaf (2013). although it was hardly difﬁcult to measure exactly the amount of vitamin released.. up to 82–92% of the amount initially intercalated was released after 24%. 33 Å.0 M NaOH) for a further exchange process to intercalate the drug.5.Fe–VC).1 and 60. Concerning sample LDH–VA. high temperature. protecting them from degradation and. when the coprecipitation method was used.1 g LDH. Gasser (2009) has intercalated vitamin C by adsorption in the chloride forms of Zn. No explanation was. microemulsions (water-in-oil or oil-in-water) and liquid crystals. was formed. only nitrate was intercalated (while VC remained adsorbed on the external surface of the crystallites) into the MgFe matrix. Hwang et al.8%. following an ion exchange process (type L curve). and enhanced the apoptotic process of tumour cells..001 mol LDH/0. the experimental conditions were as follows: 0. decomposition of the anion took place around 350 °C. Thermogravimetric analysis revealed that in both samples (LDH–VE and LDH–VC) the total mass loss reached a value of 50% upon calcination at 600 °C. the cellular uptake and “in vivo” antitumor inhibition of PPT–LDHs.Fe matrices. Layered double hydroxides being compatible with living organisms may fulﬁl a dual role: on one side. Deintercalation studies were carried out under different conditions.8 Å. Pharmacokinetics studies showed a prolonged circulation time and an increased bioavailability of PPT– LDH than PPT. and secondly the freshly prepared Tyr–LDH suspension was added to a 0. (2007) have intercalated L-ascorbic acid (VC) into MgAl. 1999. Qin et al. consequently. etc. is rather limited because of their easy degradation under light. Vitamins The use of vitamins as active components of cosmetics. 2002). although a lower value was obtained at lower temperatures for sample LDH–VE because of the hydrophobic properties of the vitamin E molecule. 10. [vitamin] / [Al3+] = 2).Fe LDHs. and drug–LDHs can be widely applied in future anti-tumour chemotherapy. while they were parallel to the brucite-like layers in the samples prepared by coprecipitation.. an aqueous carbonate solution was used for sample LDH–VC. So. ﬁnding larger interlayer spacing values in these last cases. provided for this different behaviour. the former facilitated the oxidation of the intercalation molecule. and 53. MgFe. several studies to encapsulate or to immobilise them using liposomes. The amount of vitamin . stability tests against these factors have been also carried out by these authors (Aisawa et al. food. PPT–LDH showed a long-term suppression effect on the tumour growth. relative amount of LDH.1 M podophyllotoxin solution (pH previously adjusted to 12 with 1. In order to diminish this lack of stability. Aisawa et al. for vitamins A.5 Å (Mg. 62° with respect to the brucite-like layers.Fe–VC) and 11. it is very important to develop matrices for protecting vitamins from degradation. 2004. mostly in the reduced state. C and E. to host the vitamins in the interlayer space. Fig. while up to 40% VC was incorporated into the Mg.. As VC was easily oxidized in air under light or heat. 8.5 and 25 °C.Al-LDH–tyrosine intercalation compound was prepared by coprecipitation in a basic medium and inert atmosphere. 10 mL of vitamin C aqueous solution (200 mg/L). The method followed determined the amount of VC intercalated and the orientation of the molecules in the interlayer space. stirring at 75 rpm and at room temperature. (2001) on comparing the d(003) values for LDH–vitamin samples and those for the layered solids prepared with basic zinc salts containing the same vitamins. in both cases the release of the vitamin was slow. when using the reconstruction method. to facilitate their slow delivering by anionic exchange with the anions in the medium. but intercalation was observed for MgAl and ZnAl (the amount of VC intercalated being larger for ZnAl than for MgAl). while for LDH–VE a bilayer. the type of anion and the layer charge density. Deintercalation has been studied by exchange with carbonate. and washing the precipitate thus formed with water and ethanol.3 mV. Rives et al. On the contrary. ascorbic acid (vitamin C) and α-tocophenol acid succinate (vitamin E) in the interlayer space of Zn.. 4. respectively.V.Fe and Mg. resulting in a large interlayer separation. however. the reaction variables studied were pH of the starting solution. a VC/Zn coordination compound was formed for the Zn. Intercalation of the vitamins in the interlayer space was conﬁrmed by the values measured for the basal spacing by X-ray diffraction. on the other hand. They concluded that the interlayer space provided a stabilizer effect and thus the molecule was mostly in the reduced state. swing to its anionic charge density bulk molecules like retinoate adopted a parafﬁne-like bilayer stacking between the hydroxide layers in order to overcome large steric restrictions. Yamamoto et al. The intercalation compounds were prepared by a two-step method: ﬁrst a Mg. these authors suggested that the height of the gallery.. monolayers of vitamins parallel to the basal planes of the LDH were intercalated in the ﬁrst case. but both an excess or a shortage of vitamins leads to undesired effects on the living organism. drugs..8. Semenzato et al. have been carried out (Austria et al.Al and Mg. Studies “in vivo” showed a lower toxicity than PPT alone. 1995.. These studies led to the conclusion that LDH nanoparticles can be considered as one of the ideal carriers for anti-tumour drugs. Gallarte et al. 2001. Hwang et al. 2001). (2010) have intercalated the anticancer drug podophyllotoxin (PPT) and have investigated the “in vitro” cytotoxicity to tumour cells. depending on the speciﬁc nature of the intercalated vitamin. These authors pointed out the integrity and stability of the vitamin molecules in the interlayer space. The role played by the layer charge density on the values calculated for the basal spacing of systems with intercalated vitamins has been studied by Hwang et al. was used as the precursor to incorporate vitamin C by anion exchange (0. As the matrices containing Mg2+ are stronger bases than the ZnAl one. this value has been calculated from the shift of the absorption maxima in the UV–vis spectra of free and intercalated vitamin E. these values suggesting that the reaction proceeded by anionic exchange without damaging the layered structure. exceeds the molecular length of retinoate and the hydroxide layer has its limit in accommodating guest species.Al hydrotalcites. by applying the Kasha formula. due to its immediate oxidation upon release by oxygen dissolved in the carbonate solution. In these samples prepared by coprecipitation the molecules were vertically oriented in the interlayer. pH = 7. Spiclin et al. and a 50% ethanol solution for sample LDH–VE (no deintercalation studies were reported for vitamin A). 2007).Al system. 37. respectively (Choy and Son.003 mol ascorbic acid) at pH = 7 and constant stirring for 48 h at 0 °C (sample named by these authors as LDH–VC). The mass loadings of vitamin were 23. / Applied Clay Science 88–89 (2014) 239–269 247 being intercalated in a second step. and vitamin C concentration in the solution. 1997. for LDH–VC and LDH–VE. and ZnAl LDHs (M2+/M3+ molar ratio 3) by coprecipitation and by reconstruction.0.8 Å (Zn. The human body needs only minor amounts of vitamins for physiological functioning. The basal spacings measured by X-ray diffraction were 10. while the release rate could be controlled via the nature of the solvent.5. The in vitro cytotoxicity experiments indicated that PPT–LDH nanoparticles showed better anti-tumour efﬁcacy than PPT and were more readily taken up by HeLa cells. (2004b) have intercalated retinoic acid (vitamin A). tilted ca. The particle size was in the 80–90 nm range and the zeta potential measured was 20. The release rate was much slower than from samples prepared by simply mixing the drug and the inorganic matrix at pH 7. (2001) and Choy et al. the presence of oxygen or small amounts of alkaline metal cations. Formation of the intercalation compounds after the second exchange process was deﬁnitively conﬁrmed by different experimental techniques. However. the systems with intercalated vitamin E (LDH–VE) and vitamin A (LDH–VA) were prepared by direct synthesis (Zn/Al molar ratio 3. while permitting also their controlled delivery. A sample of the hydrotalcite in its nitrate form. with a nominal Zn/Al molar ratio of 2.
and 17.Fe–VC.2 Å at 150 °C (related to destruction of hydrogen bonding as a result of dehydration). Such an incomplete intercalation was in agreement with the data previously reported by Whilton et al.0 Å. incorporating 98% of the initial amount of vitamin C when using 0.. a solution of Al3 + and M2 + nitrates (M2 +/Al3 + molar ratio 2:1) was slowly added to a solution of NaOH and L-Tyr. a dye and a colour ﬁxant. 1999a. Racemization was almost Fig. is one of the major pharmaceuticals for treatment of the main symptoms of Parkinson's disease (Lai and Yu. respectively. 1982).Al-LDH. Adverse properties of L-Tyr include racemization and oxidation to quinone (Luthra et al. showing that dehydration and dehydroxylation were complete at ca. H.5 and an initial vitamin C concentration of 200 mg/L). Hirahara. (2002) by molecular dynamics..8 Å at 350 °C. Nakayama. its oxidation. 2005). 35. 1997). (2010b) have also reported intercalation of different active molecules in different LDHs. L-Tyrosine (L-Tyr) is a non-essential amino acid normally synthesized in the body from phenylalanine. Molecules of vitamin L1 were oriented as an intertwined bilayer. 8. dyes. L-Dopa (L dyhydroxy phenyl alanine). Intercalation behavior of L -ascorbic acid into layered double hydroxides. and so its intercalation in LDHs has been studied. vitiligo (Chakraborty et al. Rives et al. the d(003) spacing decreased in two steps. (1999b) and slightly different to those determined by Newman et al.41 mg/g for Zn.Fe–VC. etc. and 10 mL of the vitamin C solution. 2005). as the intercalated species could be recovered very rapidly.2 or 0. the release rate was slower for sample Mg. in order to reduce the rate of racemization and its oxidation (Wei et al.AL-LDH. and (b) coprecipitation method. fragances. and some of their optical activity is readily lost by racemization under even relatively mild conditions (Patel et al. for the L-Tyr and L-Phe samples.Fe–VC and Mg. 1994).9.5) solution of aluminium nitrate containing also sodium carbonate. with permission from Elsevier. 40 and 53% of the initial vitamin amount were released from Zn.14 g Zn. these authors thus concluding that this sample resulted more effective for this sort of application. The samples were prepared by coprecipitation. respectively.Al-LDH. Zn) has been studied. fragrances.Fe–Cl.0–6. the maximum concentration tested was 500 mg/L (for which a larger loading of vitamin C was reached). in any case.1. Intercalation of L-Tyr in M. vitamins. The technique has been also applied to follow the thermal decomposition of the intercalation compound. however. although they could be used for storage purposes. the diffraction lines of NiO were evidenced at 400 °C. The adsorption isotherms followed a Langmuir adsorption model. and then to 13. it is also used for treatment of dementia (Growdon et al. related to dehydroxylation.Al-LDH. exchange was achieved at pH 8 and at 60 °C. its deﬁciency has been associated to depression and diet supplements are usually needed. the case of thalidomide is unfortunately well known. the similarities suggested an arrangement corresponding to an interdigitated bilayer of the monovalent anion (since ionization of the phenolic proton is not favoured at the pH of synthesis). Release was studied in physiologic serum. Chakraborty et al.Al-LDH sample. Narita. in good agreement with the values reported by Fudala et al. drugs. following a pseudo-ﬁrst order mechanism. with Q0 values of 18. this process being more evident at 250 °C. Vol. suggesting that this matrix was not adequate to prepare controlled release systems with these vitamins. (1999b). Takahashi. including agrochemicals. as well as a change in the interaction between the guest moiety and the layers around 150 °C (the symmetry of the carboxylate group changes). The adsorption equilibrium was reached merely after 1 h. (1997) and by Aisawa et al.1 to 15. Mg.. and its enantiomer D-dopa has toxic properties. 18. different water content in the interlayer and the presence of traces of intercalated nitrate. FT-IR spectroscopy conﬁrmed intercalation of the monovalent anion. and Zn. 1999). / Applied Clay Science 88–89 (2014) 239–269 5. Khan et al. pp. 16.b) and L-phenylalanine (L-Phe) was reported by Fudala et al. the other has no activity or has even negative effects. from 17. Higashiyama. Deintercalation studies were followed by UV–vis spectroscopy (λ = 265 nm) and carried out in 0. respectively. so being able to be intercalated in LDHs. These authors did not report results concerning release of the amino acids from the interlayer space. H.2 Å for Ni. with vigorous agitation under a nitrogen atmosphere and ageing at 70 °C for 24 h.. the differences were probably due to the different metal molar ratios. The basal spacings were 17. 450 °C. as well as vitamins L1 (anthranilic acid) and B5 (pantothenic acid) in a Li. D. it was very fast in both cases.87 and 28. it was difﬁcult to assess the orientation of the B5 molecules. it is very common that while one enantiomer is therapeutically active. C adsorbed increased with pH and the initial concentration of vitamin C. namely. Ikematsu. (a) reconstruction method. H. application of the Weber and Morris models did not lead to good ﬁttings for any of the samples at the temperatures tested. N. The (003) basal spacings measured were 17. however. (2001). so its presence in the drug or its formation should be strongly avoided. S. The samples were prepared by ion exchange. and can be protonated to cations (thus being intercalated in clays) or deprotonated to anions.248 V. Kondo. due to its ﬂexibility. A Zn. Amino acids and peptides Intercalation of amino acids is important since these molecules are amphoteric. from the chloride precursor. On heating the Ni. Moreover. In order to maintain the efﬁcacy of drugs.Al LDHs (M = Mg. E.Fe–Cl. Reprinted with permission from Applied Clay Science. after 180 min. (2009) have reported an extensive study on the intercalation of key drugs. 146 – 154. 1996). Schematic illustrations of ASA/LDHs. These authors assumed formation of a bilayer of organic guest anions in the interlayer. However. in order to reduce the rate of racemization and its oxidation (Wei et al. respectively.5 M aqueous solutions of carbonate at pH 9. respectively. for the B5 and L1 samples. 1997)... The strength of the interactions developing between the drug and the inorganic matrix has been claimed as the responsible for the different release rate and amount of drug released. Aisawa. . with the benzenic ring parallel to the brucite-like layers and the carboxylate groups directly pointing to them. with strong interactions of the carboxylate groups with the layers. with t90 values of 4 and 10 min. Ni. derived from amino acid L-tyrosine. Many pharmaceutical agents are chiral.Fe–Cl and Mg. S.Fe–Cl and Mg. The intercalation of L-tyrosine (L-Tyr) (Fudala et al. Copyright (2007).0 Å. it is necessary to develop strategies and systems to inhibit the rate of racemization..AlNO3 LDH was prepared by addition of zinc nitrate solution to a slightly acidic (pH 6.5 and 18. decomposition and racemization occur even under rather mild conditions. respectively. and stress (Kelly. The rate constant slightly increased when the reaction temperature was increased from 15 to 40 °C (at pH 7.
. and have also reported density functional theoretical calculations to prove the mechanism of racemization and the effect of LDH on its rate. the decrease after treatment up to 200 °C was 40% for pristine L-dopa. L-dopa was intercalated by two consecutive anion exchange steps at pH 7.4 and 7. Further insight on the stability of intercalated L-dopa was concluded from racemization studies under sunlight. but only 6% if intercalated. and a slower release (up to 92 and 65% of the initial amount of drug. Copyright (2008) American Chemical Society. as conﬁrmed by mass spectrometry monitoring of the evolved gases. The thermal stability of intercalated L-dopa has been also investigated by these authors (Wei et al. the speciﬁc optical rotation decreasing less than 0.6).3 Å. from the pKa's values for L-dopa and bearing in mind the experimental conditions during synthesis (pH 7. as deﬁned by these authors. as the speciﬁc optical rotation (measured at 589.4 (typical values for small intestine and ascending colon.12 Å. UV light and heat treatment. The formula thereof calculated from these results and element chemical analysis was [Mg2. but only 11% for the intercalated phase. Incorporation of the drug led to an increase of the (003) spacing from 8. in other words... Jian Guo. it was concluded that the drug was mostly in its monovalent state. was 8.Al-NO3 LDH by a conventional method at 70 °C and pH 10 under a nitrogen atmosphere. due to dehydroxylation of the layers. even a smaller decrease (less than 4%) was observed under UV light after 80 h exposure.2° upon intercalation. Jing He.6 and 6. 5169–5180. sharp resonance at 170 ppm. Wei et al. The results indicated a dramatic difference: Concerning sunlight effect. the absence of bands due to nitrate (indicating a total anion exchange). Vol. 2003).. which became the rate determining step (Wang et al. Both at pH 7. despite the cautions taken during synthesis. Despite the cautions taken. it has been found that a steady shrinkage exists up to 200 °C.Al LDH aiming to disclose the precise nature of the host–guest interactions. 25 h under UV radiation or thermal treatment at 180 °C. at pH 6. The 13C NMR spectrum also remained mostly unaltered. 9. 2006).73H2O. The host–guest interactions in the galleries of the LDH in some sort of way inhibited racemization.. the shift was not observed upon intercalation.V. As upon intercalation the carboxylate group became involved in strong interactions with the hydroxyl layers. 8 ppm was observed for the C\OH carbon atoms. Kong et al. The dipeptide glycine–tyrosine (GlyTyr) is an important source of tyrosine for animal and humans. racemization or decomposition even under rather mild conditions (Luthra et al. / Applied Clay Science 88–89 (2014) 239–269 249 unappreciable after 50 h under sunlight. racemization rate is markedly inhibited upon intercalation. Fig. and hydrogen bonding between the layers.e.8° to − 12.60(CO3)0. while the decrease for pristine L-dopa was ca. The (003) spacing was reduced to 8. Moreover. as decomposition takes place at a ca. Evans.38°). in addition to the shielding effect of the layers to radiation.. respectively). 9. Feng Li. (2008) have studied the intercalation of L-dopa. with simultaneous evolution of H2O and CO2 (MS signals at m/e 18 and 44. respectively. First. the experimental results found showed cointercalation of a small amount of carbonate.5° from the value for pristine L-Tyr (10. and smoothing the adverse effects of stress. in a Mg. However. 100 °C higher temperature. it can undergo oxidation.32 Å. 1998). hypertension and dementia (Peter. the host– guest interactions corresponded to electrostatic attractions between the negative anions and the positively charged layers. Min Pu.12](C9H11NO4)0. Chemistry of Materials. 40% after 22 h for pristine L-dopa. and so racemization was left as the only origin for the changes observed. respectively). Rives et al. and Xue Duan.4 Å). Jingbin Han. release of the drug from the L-dopa–LDH intercalation compound took place with a fast release during the ﬁrst 15 min (reaction in the external parts of the particle. they have also prepared GlyTyr–LDH ﬁlms by a solvent evaporation method to explore the potential of this alternative controlled release formulation for drugs. the GlyTyr–LDH was prepared by coprecipitation under a nitrogen atmosphere and ageing at 65 °C for 24 h at pH 9.7 for 48 h at 20 °C. as measured from the PXRD diagram. which was ascribed to removal of interlayer water molecules. The gallery height. In this way. A reference Mg. as the position of the signal due to diffraction by (110) planes remained unaltered. The FT-IR spectrum showed typical bands of L-dopa.0. GlyTyr–LDH ﬁlms were prepared by suspending the GlyTyr–LDH in water and ultrasound-treatment under a nitrogen .Al-NO3 LDH was ﬁrst prepared by the hydrothermal method (Bontchev et al. 13C NMR studies revealed that the chemical structure of L-dopa remained unaltered after these treatments. UV–vis.3 nm and 18 °C in 1 M HCl solution) changed only from − 11. those also existing in an LDH environment) formed a dark-coloured compound (Findrik et al.20·1. applied to treat renal failure. and decomposition (combustion) of the interlayer guest. and developing of an additional band at 483 nm (both due to the quinone form). (2010a) have intercalated GlyTyr in a Mg. originated by a shift of an original absorption band at 280 nm (due to the phenolic structure) for the unaltered drug to 303 nm. α decreased ca.4 Å at 300 °C. Computational studies showed that racemization of L-dopa in the solid state took place via an enol intermediate formed by hydrogen transfer from the chiral carbon atom to the nearby carboxylate group. thus restricting its use and encouraging to look for appropriate vehicles for its delivery. absent in the spectrum of pure L-dopa. due to diffusion through the particle.AlLDH to assess the suitability of this intercalation compound to avoid the problems above-mentioned.7). Relationship between d(003) basal spacing of L-dopa–LDH and temperature. racemization did not occur.. All these results conﬁrmed that the integrity of the L-dopa molecule was preserved in the interlayer space. collapsing of the layered structure was observed at 400 °C. 20. 1994). FT-IR and 13C NMR spectroscopies were used to check the stability of the intercalated drug. the presence of carbonate was conﬁrmed by a weak. 2008) from the variable temperature PXRD patterns. vertically orienting the carboxylate group of alternate anions to the upper and lower hydroxide layers. pp. but a weak band at 1363 cm− 1 due to the antisymmetric mode of intercalated carbonate. which may be attributed to the effect of hydrogen bonding between the hydroxyl group and the interlayer water molecules. following the changes in the speciﬁc optical rotation (α). Oxidation of pristine L-dopa under alkaline conditions (i. it was concluded that the thermal stability is signiﬁcantly enhanced upon intercalation. 2005. providing an effective way to avoid racemization. the guest anions and the interlayer water molecules. On comparing the decomposition pattern of LDH–L-dopa and of the pristine drug. 2007). they prepared a Mg. the LDH acting as a sort of “molecular container”.06Al(OH)6.25 Å (for the nitrate precursor) to 13. 38%. Reprinted with permission from Intercalation of L-Dopa Into Layered Double Hydroxides: Enhancement of Both Chemical and Stereochemical Stabilities of a Drug Through Host–Guest Interactions. Fig. while a decrease of 4–5° was observed when unintercalated. anion exchange with phosphate anions from the buffer solution). Min Wei. very close to the length of the L-dopa anion (8. without altering the layers. David G. Yang et al. and only a downﬁeld shift of ca. ﬁnally amounting 2. it was no longer available to act as a hydrogen receptor and thus racemization was inhibited.
the anions and the interlayer water molecules. rather weak. together with changes due to the decomposition processes. while the slow second process should be due to an anion exchange process. some high angle reﬂections (h. Two kinds of conﬁguration for Phe in the interlayer space were concluded from PXRD data for basal spacings: a vertical orientation for Mn. Al. and the suspension was aged for 24 h at 65 °C and the ﬁltered solid dried at 70 °C. as conﬁrmed from the analysis of the solid after the study. corresponding to gallery heights of 6. Nakayama et al. Xue Duan.5–12. indicating its major presence in the interlayer. Asn.Al LDH. indicating an improvement in the thermal stability of intercalated GlyTyr. The FT-IR and FT-IR–ATR spectra conﬁrmed that the chemical structure of GlyTyr remained unaltered in the GlyTyr–LDH powder and in the ﬁlm samples. and 1208 cm− 1. namely.Cr. 2000). Shuxian Shi. a further decrease up to 305 °C has been attributed to a condensation reaction of GlyTyr anions.L-Tyrosine intercalated layered double hydroxide ﬁlm and its in vitro release behavior. Ni. Whilton et al. with developing of diffraction signals due to MgO. Element chemical analysis and FT-IR spectroscopy results suggested that the guest molecules existed as dianions. 1997).3%. intercalation by anion exchange seems to be extremely difﬁcult. and Zn. Rives et al. the distribution coefﬁcient of the monovalent anion was calculated to be 77.Cr LDHs. probably because the amino acids existed as zwitterions in the interlayer of LDH and were electrically neutral at pH 7. consistently with the high alkaline conditions used during the synthesis (pH 12).4). Mn.250 V. aiming to study the polymerization of the intercalated species. with a (003) basal spacing of 13. with permission from Elsevier. for aspartate and glutamate.Al. total collapsing being observed at 465 °C. the pH of the solution was ﬁxed according to Ksp for the monohydroxides of the corresponding metal cations. as a result of the host–guest interactions (electrostatic ones and hydrogen bonding). Preparation of Glycy.. The decomposition process was also followed by FT-IR spectroscopy. Intercalation of GlyTyr led to layered solids with the hydrotalcitelike structure. 598 –604. Asp and Glu was due to formation of a bilayer structure in the interlayer space. The authors concluded that hydrotalcites . these authors (Kong et al. Coprecipitation of Phe was maximum for the Ni. Further conﬁrmation of the unaltered intercalation was concluded from solid state 13C NMR: compared to pristine GlyTyr. Electroneutrality was attained by simultaneous intercalation of carbonate and/or hydroxyl groups.Al. in agreement with the presence of intercalated phosphate from the buffer solution (Costantino et al. The PXRD patterns showed broad (003) diffraction peaks at Fig. Pro. probably because of a partitioning between the solid and the Mg2 +and Al3 + complexes of the amino acid dianions. as well as hydrogen bonding among the layers.Al.Al LDH by coprecipitation. Zn. Release proﬁle of Gly Tyr from Gly Tyr–LDH ﬁlms in PBS solution (pH 7. The ﬁrst one can be attributed to release of GlyTyr species adsorbed on the external surface of the crystallites. 10. Fig. analysis of evolved gases has not been reported. In situ PXRD patterns were recorded at increasing temperatures to insight in the thermal stability of the samples.Al-LDH. / Applied Clay Science 88–89 (2014) 239–269 atmosphere.9 and 1. Removal of interlayer water (and the corresponding shrinkage of the layers) was observed at 185 °C.8 for the Asp–LDH and Glu–LDH samples. Aisawa et al. The values were in agreement with an arrangement of the intercalated amino acids with the carboxylate anions bridging adjacent layers of the inorganic host. Fengjie Zhu. (2001) reported a classical study on the intercalation of amino acid phenylalanine (Phe) within the interlayer space of LDHs differing in the nature of the layer cations. 10. k ≠ 0) were absent for the ﬁlm sample.Al sample in the pH range 6–10. the suspension was dropped onto quartz substrates and dried under vacuum at 70 °C for 24 h.. 4 ppm downﬁeld. but the (110) reﬂection showed no shift. The speciﬁc optical rotation of GlyTyr did not signiﬁcantly change upon intercalation. The samples were prepared by coprecipitation from the corresponding nitrates at 40 °C under a nitrogen atmosphere. and Zn.Al.. 5 h. Xianggui Kong.8 Å for the nitrate-containing sample). after ﬁltration. (1997) reported some years ago the intercalation of aspartate and glutamate (anions of aspartic and glutamic amino acids) in a Mg. but at 205 °C (a gradual mass loss is observed in the TG curve) for GlyTyr–LDH. According to the species existing at the experimental conditions used to prepare these solids.1 Å. however the other amino acids and oligoglycine formed a single layer parallel to the brycite-like layers. In vitro release in PBS solution (pH 7.L-Aspartic and D-glutamic acids were dissolved in a NaOH solution under nitrogen. So. Jingbin Han.3 Å (8.Al. Vol. 2010a). respectively. Copyright (2010). probably because a difference in the interlayer water content between the powder and the ﬁlm samples existed. and 91% was released after ca. Except for Lys. evidencing a well c-oriented assembly of LDH platelets in the ﬁlm (Adachi-Pagano et al. Thr. 2010a) proposed its intercalation as a monolayer. a minor amount of nitrate had been also intercalated. indicating a lack of racemization. but a horizontal one for the Mg. D. it should be noticed that bands at 1330 and 1230 cm− 1 due to condensation were recorded at 185 °C (an exothermic DTA effect was recorded at 172 °C) for pristine GlyTyr. characteristic FT-IR GlyTyr bands were recorded for the powder sample at 1668. The amount of amino acid (or oligoglycine) incorporated was in the 0. Release studies were carried out in an aqueous solution of K2CO3 and it was a very easy process because the interaction between the intercalated zwitterion and the positive LDH layers was only by hydrogen bonding.7 mmol/g range. therefore. Ser. the amide bands at 1653 and 1543 cm− 1 were recorded in the FT-IR–ATR spectrum of the ﬁlm sample. The intercalation process has been followed by PXRD and solid state NMR. which conﬁrmed that the layered structure had not been destroyed. at pH 11. all the resonances in the spectrum of GlyTyr–LDH were shifted only ca. unfortunately. from the mixture of amorphous Mg and Al oxides. Gly. indicating a swelling of the layers without signiﬁcant change in the nature of the LDH host layers. Despite the initial Mg/Al molar ratio was 2.3 and 7. with the carboxylate groups of individual anions alternatively pointing to the upper and lower hydroxide layers (interdigitation). with no band which could be ascribed to nitrate. 157. the experimental values were 1.19 and 11. However. pp.9–2. Min Wei. Reprinted from Chemical Engineering Journal. but the interlayer space of the (003) planes was 8.9 Å. Arg and the different peptides tested. Mg. Zn.4) from the ﬁlm samples has been studied (Kong et al. giving rise to electrostatic interactions between the interlayer anions and the positively charged layers. the (003) reﬂection was recorded at a somewhat higher diffraction angle. 1420. The results showed that the swelling observed upon intercalation of Ala. respectively.. to which another solution containing Mg2+ and Al3+ nitrates was added. 11. a fast release (up to 30%) was observed in the ﬁrst 25 min. (2004) have studied the intercalation of several amino acids and peptides (oligoglycine) into a Mg.8 Å. the other amino acids have been intercalated exclusively by the reconstruction method. Gln.
while the conformation of intercalated ﬂuvastatin molecules was similar as that in the free state. the ﬂuva–LDH solid exhibited a hydrophobic behaviour. Element chemical analysis showed that the drugs content were 30% for both drugs. Vol. from the corresponding nitrates under a nitrogen atmosphere at pH 8. The Journal of Physical Chemistry B. Treatment with aqueous M2CO3 (M = Li or Na) led to quantitative release of the drug. (b) 3D image of panel a. Overcoming these problems is attained by dispersing them in biodegradable polymers. which showed bands for pravastatin (238 nm) and ﬂuvastatin (236 and 305 nm) in the same positions as for the pristine drugs. (2009) have reported a study on the intercalation of these two drugs in a Mg.AlCO3 LDH.100. The C_O stretching vibration was not altered upon intercalation. probably because of steric repulsions between adjacent bulky hydrophobic tails. but multilayers for prava–LDH. Tapping mode AFM image of (a) 2D image of Mg/Al–ﬂuva LDHs. which affects their solubility and can potentially modify their bioavailability. When a phosphate buffer was used (pH 7 or 4) the release curve showed that complete release was achieved within ca. but where ordered inclusion of Li+ cations in the layers that required intercalation of charge-balancing anions. this was further conﬁrmed by UV–vis spectroscopy studies. The authors did not mention the other expected band for the carboxylate group (both a symmetric and an antisymmetric related bands should be recorded). R. 11. Unfortunately. 1583 and 1576 cm− 1. Thermal analysis studies showed that adsorbed and crystalline water were released below 150 °C. On dispersing in water. Instability leading to pharmaceutically unactive forms (lactones) is also a problem. Bahadur. Copyright (2009) American Chemical Society.090–15. indicated formation of a bilayer arrangement of the organic molecules. elevated cholesterol level is a primary risk factor for coronary artery disease.V. together with layer dehydroxylation around 340 °C. These values corresponded to single monolayers (single sandwich) for ﬂuva–LDH. although they could be used as reservoir and adsorbents.9 and 15. Statin family drugs such as pravastatin (prava) and ﬂuvastatin (ﬂuva) are highly effective for reducing cholesterol level in bloodstream. Rives et al. conﬁrming that the guest–host interaction took place mostly through the carboxylate groups. 11. respectively. Panda et al. Anticardiovascular agents Khan et al. and (d) 2D image of Mg/Al–prava LDHs. while the prava–LDH one was hydrophilic. respectively. Panda. formally derived from Al(OH)3. and gemoﬁbrozil was incorporated by ion exchange.Al layered double hydroxide. respectively. for LDH–prava and LDH–ﬂuva. . 6. 113. a drug used to reduce lipid levels. for the prava and ﬂuva LDHs. 15. a major problem in developed countries. Srivastava. indicating its hydrophobic properties. Reprinted with permission from In Vitro Release Kinetics and Stability of Anticardiovascular Drugs-Intercalated Layered Double Hydroxide Nanohybrids. and D.5–9. and that the structure of the drug was retained upon intercalation. (c) Section analysis spectra of image a. (2001) reported in a pioneering work the ability of LDHs to intercalate and readily release gemﬁbrozil. The measured spacings for the (003) basal planes were 14. 30 min. the value was 86° for ﬂuva– LDH. forming a ﬁrst stage intercalation compound (all originally empty interlayers occupied by anions).5 Å. and stabilize undergoing a conformation change. respectively. In this case they used a Li. shifted from the values recorded for the corresponding sodium salts. while the value was 24° for a reference Mg. it was concluded that pravastatin adopted a tilted conﬁguration. AFM micrographs showed that the particle diameter was around 65 and 16 nm. as concluded from PXRD interlayer spacing (23. these drugs are generally unstable because of their hygroscopic nature.2 Å). pp. On comparing with the molecular dimensions of these drugs. S. but this increases their price. It should be noticed that the PXRD pattern of ﬂuva–LDH remained unchanged (diffraction lines in the same positions) even after keeping the sample for Fig. for prava–LDH and ﬂuva–LDH. Fig. The solid was used in its chloride form. Swelling of the layers. The FT-IR spectra showed a carboxylate-related band at 1576 or 1561 cm− 1. / Applied Clay Science 88–89 (2014) 239–269 251 were not suitable matrices for a controlled release of these substances. and degradation took place at 160–300 °C. H. Contact angles of water suspensions were also measured. This shift has been related to a decrease of the C\O bond because of the electronegativity effect of Mg and Al cations. Al LDH (2:1 molar ratio) by direct coprecipitation. showing its hydrophilic nature. the suspension was aged at 65 °C for 24 h and the precipitate repeatedly centrifuged and ﬁltered.
2 (gastric juice pH) in the presence of NaCl..4 permitted the establishment of a therapeutic dose in a short period of time. 2002). Fibrates such as bezaﬁbrate (BZF) and cloﬁbric acid (CF) are a class of lipid-regulating drugs that have been used in the therapy in many forms of hyperlipoproteinemia (Remick et al. from these values these authors claimed that the drug molecules were located in the interlayer as a monolayer in a staggered inter-digitated arrangement through aromatic ring π–π interaction. respectively. and 8). 2005). Fig. 73.5 and 16. 2008). The solution rates for the BZF– LDH and CF–LDH systems were smaller than for the corresponding bula drugs.5 (HCl buffer) and simulated intestinal body ﬂuids. 7.4 (phosphate buffer). the patterns for the physical mixtures were simply the superimposition of the curves for the single components. Its effectiveness requires a rapid gastrointestinal absorption. to the liberation of the drug in a molecular form. 43% drug loading). while for the hydrophilic system it was interparticle diffusion. and also to its low solubility in the gastric ﬂuid because of its weak acidity (pKa = 5. it shows a good tolerability and low hypoglycaemia. When the tests were carried out at pH 3. in contrast with the hydrophilic character of pravastatin. The interlayer spaces calculated from the PXRD diagrams were 23. major decomposition was observed. probably the hydrophobic tails enhanced water repulsion.762Al0. (2010) have used the coprecipitation method to intercalate BFZ and CF in a Mg. Summarising. 12. while the subsequent sustained release allowing maintenance of this dose over a long period of time. Berber et al. / Applied Clay Science 88–89 (2014) 239–269 12 days at 37 °C and 75 ± 10% relative humidity.4 (phosphate buffer) at 37 °C. 2008). and sulfonyl (from 1335 and 1164 cm− 1 for the antisymmetric and symmetric modes. 1994). namely. The FT-IR spectra did not show absorption bands due to nitrate. 4. secretion and signalling (Hajo and Wolfgang. then decreasing to the same values reached on dissolving crystalline GLI.0 Å. Release studies were carried out at pH 7. Thermogravimetric studies showed a mass loss at ca. A Zn. accounting for the stability of the system (the pattern changed dramatically for sodium ﬂuvastatin salt under the same experimental conditions). 180 °C due to removal of intercalated water and two further mass losses due to thermal degradation of the drug.66H2O (ca. Fig. Computer generated model of HTlc–GLI (some Al ions are substituted by Cr ions in the ratio of HTlc–GLI formula). were reached. both at 37 °C.Al. Effect of gliclazide immobilization into layered double hydroxide on drug release. 12. Similar results were observed for prava–LDH. CF [2-(4-Chloro phenoxy)-2-methylpropanoic acid] is the active metabolite of the blood lipid regulator colﬁbrate. The chemical stability of the host–guest systems was studied by UV– vis spectroscopy upon dispersing the solids in water at pH 7.2 after 5 min was ﬁve times larger than that of the crystalline powder. conﬁrming the intercalation. The structural model. Copyright (2009). the TG analysis of the samples kept under these humid conditions further conﬁrmed no change in their structure nor stability. The higher apparent solubility during the ﬁrst 20 min is due. . Studies in solution on these systems as well as on the bula drugs have been carried out at different pHs (2. storage. Nocchetti.252 V. Vol. and clinical studies have demonstrated that Zn2+ is involved in insulin synthesis. probably heterogeneous diffusion via anionic exchange played a major role for the hydrophobic intercalation compound.Al. respectively.4. Rives et al.. and were determined by the different afﬁnity of the LDH for the anions existing in the buffer medium. the intercalation of GLI in a Zn. To overcome these problems. with respect to the crystalline powder. M. ionic exchange with phosphate anions of the buffer was observed. The DSC trace of pristine GLI showed an endothermic effect around 170 °C due to melting of the drug. which was absent for the LDH–GLI sample.8) and its hydrophobic nature (Winters et al. The amount of chromium was calculated to be equivalent to the chromium daily supplement. (2009). the shifts observed for important groups of the molecule. V. Concentration of GLI at pH 1. the solid was ﬁltered. suggested that the GLI anions form a monolayer of partially superimposed species. Probably the layers provided the alkaline medium necessary to stabilize the drug. washed and degassed under nitrogen atmosphere.Cr-LDH has been studied by Ambrogi et al.. the layers were dissolved and the molecularly dispersed anion was solubilised much faster than crystalline pristine GLI. indicating a complete anionic exchange. The experimental data ﬁtted a dissolution–diffusion kinetics model. while both function as antioxidants (Rostan et al. The formula determined for the solid was [Zn0. pp. drug loadings of 54 and 45%. Rossi. C. 2004). 6. followed by a relatively slower release for ﬂuvastatin at pH 7.231Cr0. and at pH 3. V. Despite statin drugs are unstable in acidic media and stable in alkaline media (pH 8–13). The fast release at pH 7. Diabetes Gliclazide (GLI) is a sulfonylurea derivative widely used for treatment of type II diabetes mellitus. These authors chose these cations because Cr3+ and Zn2+ are directly involved in the performance of insulin: Cr3+ is an essential nutrient. carbonyl (from 1710 to 1665 cm− 1).Al hydrotalcite. as it was observed at pH 1. Reprinted from The European Journal of Pharmaceutics and Biopharmaceutics.007(OH)2][GLI]0. An early fast release (4% prava and 20% ﬂuva) was observed. Solubility studies were carried out at pH 1. with this arrangement the π–π interactions between two benzene rings of GLI and the electrostatic interactions between the C_O (formally supporting the negative charge) and the positively charged LDH layers are enhanced. Perioli. GLI was simultaneously dissolved in degassed acetone/water and converted to its anionic form by adding 0. the byproduct being a lactone.. The slow absorption rate shown by GLI has been related to the poor permeability across the gastrointestinal membrane. The PXRD pattern of the solid prepared showed a basal spacing increase from 8. with permission from Elsevier. Ambrogi.and intra-molecular interactions between the drug molecules.3 Å. the NH ureidic group band at 3265 cm− 1 was also absent. 285–291. but it has been also suggested that in enhances insulin binding (Cefalu and Hu.238·0.2. probably because of its hydrophobic character. to 1371 and 1146 cm− 1) were in agreement with the presence of the GLI anion. L. a larger concentration of GLI was measured during the ﬁrst hour. Physical mixtures of GLI and the LDH in its nitrate or chloride forms were also prepared (Ambrogi et al.. but increased as the pH did. BZF (2-[4-(2-[4chlorobenzamindo] ethyl)-phenoxy]-2-methyl-propanoic acid) is a well-known antihyperlipidaemic agent that lowers elevated blood serum lipid concentrations (cholesterol and triglycerides) (Ayaori et al.9 (nitrate precursor) to 15. the stability was considerably improved upon their intercalation in the LDH host.Cr-LDH in the carbonate form was ﬁrst prepared by urea hydrolysis and then it was changed to the nitrate form by treatment with 1 N HNO3 (pH 5). Solubilisation of the drugs was very limited at pH 2.1 M NaOH. Ciarnelli. 2009). further conﬁrming formation of the GLI anion. for BZF–LDH and CF–LDH. the observed stable behaviour was due to the electrostatic interactions with the host (as concluded from the FT-IR studies) and the inter. respectively. a portion of the solid was added to this solution and stirred at room temperature for 24 h and washed under a nitrogen atmosphere.
PCL.65Al0. A similar effect was observed at pH 3 in the presence of NaCl. followed by anion exchange. and was ascribed to anionic exchange between Cpl and phosphate anions of the buffer solution. Trx (trans-4-(aminoethyl)cyclohexane carboxylic acid). quite surprisingly.45 the release was very slow. The TG curve of sample LDH–Trx showed two mass losses centred around 50 and 280 °C. Rives et al.35(OH)2] Trx0. the TG curves for the nanocomposites showed a single mass loss effect which midpoint is some 100 °C lower than that for PCL (402 °C). In water it is deprotonated in two steps related to release of the proton from the carboxylic group (pKa1 = 3. it was concluded that Cpl formed four disulﬁde metabolites with a S\S bond. as experimentally measured. however. The PXRD data demonstrated that the interlayer height after intercalation was almost twice the size of the drug molecule (5.5H2O. and the drug was released via anion exchange with chloride anions of the solution.24 (CO3)0. corresponding to basal spacings of 17. Copyright (2009). which presence suggested intercalation of the polymeric chains in the galleries of the inorganic ﬁller. Fraction of drug released in the physiological solution from the polymeric matrix of PCL–HTrx10. followed by a slower release.45. Due to the lack of chromophores in Trx. 9. as well as the dispersion of the intercalation compound thus formed in poly(ε-caprolactone). 13.V. once an equilibrium pH was reached (pH 5) the layers were no longer dissolved. As a ﬁnal prove of formation of the intercalation compound. and is used in surgery and dental extractions for people suffering from haemophilia. decreasing the release rate. pp. The thermal stability of Cpl was improved upon intercalation. the larger chloride concentration when NaCl was added favours release by an ion exchange process. and complete release was never reached. Incorporation of active nano-hybrids into poly(ε-caprolactone) for local controlled release: Antiﬁbrinolytic drug. if compared to that of pristine Cpl. Antihypertensives Another family of drugs which have been encapsulated in anionic clays to diminish their side effects has been antihypertensive ones.1 M at pH 5 to convert it to the chloride form. Nocchetti.e. from atmospheric CO2. due to drug molecules anchored in the inorganic lamellae lying on the surface of the ﬁlm. The melting point of PCL (62 °C) decreased to 60 °C for the intercalation compounds. up to 95% of the total amount of intercalated drug could be released at both pHs. showed a double diffraction maxima. and. nevertheless. due to removal of intercalated water.06) under nitrogen at pH 10. which increased the pH from 3 to 5. according to FT-IR and Raman spectra. probably because of partial removal of intercalated water molecules. is a synthetic derivative of lysine. and is used as delivery for biomedical applications (Hu and Dorset. was in the 56–62% range for pristine PLC and for the composites.8 and 7. the band did not shift upon formation of the nanocomposites. calculated from the DSC curves. U. Fig. 8. 28. 350–356.5. / Applied Clay Science 88–89 (2014) 239–269 253 whereas the following decrease in the apparent solubility is due to destruction of the LDH matrix.1 Å. together with release of carbon dioxide from intercalated carbonate species.6 and 7. the composites..1 Å upon equilibration with P4O10. in this case. containing a small amount of intercalated carbonate anions. was followed by a slow release extending up to 200 days (only 43% drug had been released).7) and from the thiol group (pKa2 = 9. However. but only 59% at the same pH in the absence of NaCl. probably because the pH increase due to layers' dissolutions avoided further destruction of the layers.. However.Al LDH has been studied by Tammaro et al. but in this case only 30–35% was released. Fig. it should be also stressed that the development of a broad diffraction line centred at ca. These authors reported a release of 72% under these experimental conditions.055·1. and also in the ﬁrst 30 min at pH 3. Antiﬁbrinolytic agents Tranexamic acid. 43. 1990). i. Zhang et al. M. Vittoria. with properties as antiﬁbrinolytic and haemostatic. faster than from crystalline GLI or a physical mixture.7°.1 Å. decreasing to 15. From a chemical point of view it is a mercapto derivative of proline. Further equilibration with a solution of the tranexamic sodium salt led to the ﬁnal product. 13. FTIR spectroscopy was used to monitor Trx release from the PCL matrix as a function of time. Combustion of Trx led to a third mass loss between 280 and 800 °C.2. with the formula C9H15NO3S. Tammaro. with the formula [Zn0. with permission from Elsevier.5 Å. ZnO and the ZnAl2O4 spinel were identiﬁed as the solid residues after thermal treatment at 800 °C. In vitro release was studied also at different pH values. suggesting the presence of both. and the slurry aged at 25 °C for 48 h. and the crystallinity degree of PCL. An initial fast release. The release rate and the amount of released drug decreased as the pH was increased.1 and 15. it did not change upon formation of the intercalation compounds. probably because the base catalysed hydrolysis of the ester bonds. an angiotensinconverting enzyme inhibitor as a model drug to be intercalated in a Mg. only the slow ion exchange (with phosphate anions of the buffer solution) was observed.8). Its intercalation in a Zn. acting also against breakdown of clots. very fast at pH 1. L. A basic solution of Cpl was added to an aqueous solution of Mg2+ and Al3+ nitrates (molar Mg/Al ratio 2. the hydrated and dehydrated forms. both Cr3 + and Zn2 + were also released to the solution.Al LDH by a coprecipitation method. In addition to diffractions at 2θ = 21. Drug release was observed at pH 1. LDH–Trx. due to drugs from inside of the matrix. the fast release in the ﬁrst minutes of the reaction was due to dissolution of the LDH layers and free release of the drug molecules. probably because of a change in the release mechanism: dissolution took place at pH 4. with the carboxylate groups hydrogen bonded to the brucite-like layers. and ﬁlms were prepared by moulding the powder at 70 °C. respectively). The basal PXRD spacing for the intercalation compound was 17. 1998) and titrated with HCl 0.6 at the ﬁrst stages of the studies. Costantino. Powder composites (PCL–LDH–Trx) were prepared by milling mixtures of PCL and LDH–Trx at 850 rpm for 1 h. (2009). Release studies in vitro have been carried out at pH 4. vertically oriented between the layers. Obviously. (Costantino et al. Vol.2 (only 5 or 10 min was needed for total release of Cr3 + and Zn2 +. the FTIR spectrum of LDH–Trx showed a band at 1535 cm− 1 due to the antisymmetric mode of the COO− group. an aliphatic polyester which is biodegradable and biocompatible. This shrinkage underwent with simultaneous development of a diffraction maximum due to intercalated carbonate. (2006) have chosen captopril (Cpl). Reprinted from Applied Clay Science. as a function of time (days).3° and 23. due to crystalline PCL. When pH was further increased to 6. and water derived from dehydroxylation of the layers. .2. At pH 7.26 Å). The LDH was prepared in its carbonate form by the urea method. conﬁrming Trx was intercalated in its anionic form. V. from which the nitrate one was obtained upon equilibration for 24 h at room temperature with a NaNO3 solution.
45.-R. When using the 0. its intercalation took place in different orientations: ramipril and captopril anions were forming a tilted bilayer between the hydrotalcite layers.254 V. encapsulation with the 3% solution gave rise to a protection of 40% during at least 8 h. Sierakowski. DPH). Nakayama et al. Encapsulation was attained by adding the enalaprilate–LDH intercalation compound to both solutions. between the layer cations and the intercalated anions. Wypych. the fast release at this pH should be related to a (at least) partial destruction of the layered structure. but using zinc nitrate instead of magnesium nitrate. Intercalation was attempted by anionic exchange (an originally containing nitrate LDH was used) with a chloroform solution of phospholipids. by anionic exchange.7 mmol/g. Xyloglucan was extracted by an exhaustive aqueous process at 25 °C of pooled and milled seeds of Hymenaea courbaril.Al hydrotalcite. As for captopril studies reported by Zhang et al. Cyclodextrin (CD) is the only oligosaccharide with a hydrophobic cavity where organic molecules can be introduced and stabilized. loaded with a neutral lipophilic ﬂuorescence probe (1. parallel to the brucite-like layers. Complete release of enalapril and lisinopril (forming a monolayer in the interlayer) required longer periods of time than release of captopril and ramipril.3. to avoid the use of organic solvents. in a Zn.5 and 7. for the other drugs. enalapril. Copyright (2009). due to the “liquid” behaviour of xyloglucan.Al LDH (Mg/Al molar ratio 2) by anionic exchange from an LDH in the nitrate form. By controlling the concentration of CD in the intercalation compound. (●) LDH–Enal–XG(3). 367. the interlayer was highly crowded and a steric barrier prevented a fast prazosin release. FT-IR was very useful to assess that the layer–drug interaction was through hydrogen bonding. The drug could be hosted well before or after intercalation of the CD. afterwards a maintained slower release was observed. These ﬁndings are of paramount importance. in addition to electrostatic interactions. This value suggested location of the cyclodextrin molecules forming a monolayer. in other words. In the last case the reconstructed layered material contained intercalated chloride anions (from the reaction medium) and so this method was discarded. C. ACEIs). similarly to the method described by Zhang et al. and also the thermal stability was enhanced upon intercalation. containing respectively 0. Release was very fast in the absence of xyloglucan. while enalapril and lisinopril formed a single vertically oriented layer. pp. As the amount of DMPG was increased.03). non-soluble antihypertensive drug) from LDH–cyclodextrin intercalation compounds. X-ray diffraction lines at low angles were recorded for the samples prepared by anionic exchange. specially in Mg. especially taking into account the large amounts of drugs usually taken by hypertensive individuals. On interacting an anionic clay and a cyclodextrin a balance between the positive charge of the former and the hydrophobicity of the latter is attained. Liposomes present an important drawback for drug delivery. Fig. 10. Release of the drug was measured at pH 5 (phosphate buffer) and 37 °C. thus obtaining a new class of intercalation compounds affording protection and stabilisation of the bilayer and of the drug over a long period of time. (2008) have studied the controlled release of prazosin (a positively-charged. G. lisinopril. kinetics data follow the Higuchi and ﬁrst order models. the interlayer spacing increasing from 8. depending on the precise nature of the drug.5% solution. F. and thus can be potentially used for sustained release. Liposomes As mentioned elsewhere. Ribeiro. M. Release proﬁles of enalaprilate from simulation of the gastrointestinal tract: (■) LDH–Enal. Enalapril was incorporated by coprecipitation. (2006). whichever the concentration used.Al ones.8 to 21. so leading to a ﬁne tuning of the release of the drug encapsulated in the cyclodextrin. probably the faster release at pH 4. and (▲) Enal–XG(3). which were forming a tilted bilayer. the release rate of the drug could be controlled. Bégu et al. and the method using an aqueous medium was preferred. Reprinted from The International Journal of Pharmaceutics. probably. at both pH values.5 Å. the encapsulation did not improve the protection of the intercalation compounds. with permission from Elsevier.C. (2009) have used xyloglucan. (2009) have studied the intercalation of lipophilic drug-loaded phospholipid bilayers between the layers of a Mg. especially at pH 7. a polysaccharide found in the primary cell walls of non-graminaceous (monocotyledons) and in the cotyledon of some dicotyledon seeds. (2006). able to be decomposed under strong acidic conditions (pH 1. as they are unstable in physiological media. 14. respectively. Nanocomposites coated with xyloglucan for drug delivery: In Vitro studies. which are stable under such pH conditions (the Zn. They studied the intercalation of enalaprilate (the pharmacologically active metabolite of enalapril maleate) in a Mg. Release studies at pH 4. several authors have proposed to encapsulate the LDH–drug intercalation compounds. but this can be overcome by intercalating them in LDHs.Al-NO3 LDH (molar Zn/Al ratio 2. Arizaga.Al (Mg/Al molar ratio 2) LDH. and those . To overcome this problem.2) in the stomach. Fig. and thus this sample could be used for a slow release of the drug.2-dimyristoyl-sn-glycero-3-phosphate monosodium salt (DMPG). the diffraction lines below 5° were enhanced.G. 14. especially when submitted to the action of the gastrointestinal tract. Vol. An important release was observed. this last orientation enhanced the thermal stability in a larger extent than for the two ﬁrst drugs. captopril and ramipril.45 showed a steady release of the drug anions. / Applied Clay Science 88–89 (2014) 239–269 Xia et al. one of the main advantages of supporting drugs in LDHs is that the unstability of the drug in physiological media can be avoided. as concluded from PXRD and FT-IR studies. Total nitrate/cyclodextrin exchange was reached after 24 h.5-hexatriene. The sustained release after subcutaneous application was also studied. By using this controlled release system. Ribeiro et al. anionic exchange with the liposome suspension. These authors have intercalated sulfobutyl ether β-cyclodextrin (SBE7-β-CD) into a Mg. However. mimicking a lipophilic drug. (2008) have intercalated a series of antihypertensive drugs (also known as angiotensin-converting enzyme inhibitors. Two aqueous solutions of xyloglucan were obtained.5 and 3% of the polysaccharide. individuals can decrease the amount of ingested drugs. 204–210. namely. Both methods demonstrated to be effective to intercalate these drugs.Al analogues are stable at more acidic pH). during the ﬁrst minutes. Lipid bilayers originating from liposomes were made from 1. reducing the stress factor and improving their quality life.6diphenyl-1. and reconstruction of the calcined (450 °C) LDH precursor with the liposome suspension. deprotonation of the thiol group was also observed. the ﬁrst one behaving as a typical liquid and the second one showing a viscoelastic behaviour. anionic exchange at pH 5 from the nitrate form of the LDH was used.5 was related to the instability of the hydrotalcite-type structure at this rather low pH value. However. One of the drawbacks of anionic clays to be used as matrices for controlled drug release is that they are basic compounds and thus. Rives et al. Prolonged release of prazosin was observed when the CD uptake was 0.
intercalated DMPG decomposed at a lower temperature than pristine DMPG (325 °C). well because of the high hydrophobic character of DPH or well because a large disorder of the alkyl chain. and this temperature decreased as the DMPG loading increased. this could be related to different conformations of the molecule in the pristine or intercalated phase. These changes were assumed to demonstrate intercalation of 5-FC. being lower at pH 7.30 × 0. and a small amount of nitrate was also intercalated.5°. As the molecular dimensions of 5-FC are 0. although it may correspond to a multistep process or adsorption of the liposome on the external brucite-like layers of the LDH particles. and their electrostatic interactions with the layers. basal spacing 0. 2005) and dyes (Tian et al. Regarding release studies. This would ﬁt with the experimental height of the gallery assuming a tilting angle of 41. as the compounds were prepared at pH 7.Pouêssel. more related to surface charge of the layers than to conventional volumetric problems.5 in a Na2HPO4–NaH2PO4 buffer solution. As expected. Zhao and Nagy. probably by anionic exchange with phosphate anions of the buffer solution.48 nm. the morphology of the particles (TEM) changed with the drug/LDH ratio. . This value was lower that the repeat distances (47. suggesting the presence of cointercalated carbonate. Release of the drug under controlled conditions was also studied. a conformational change. from hexagonal plates exclusively to hexagonal plates mixed with threadlike particles and unitary threadlike particles. It should be noted that. decreasing to 90 nm after 36 h.92 nm developed when the intercalated amount was increased. Quite surprisingly.4 Å. conﬁrming the organisation of the phospholipids into bilayers.33 to 0.00.15 M. Copyright (2009) American Chemical Society.9 and 47.96 nm) to the brucite-like layers. release was slower from the intercalation compound and it was also pH-dependent. A depolarization curve was observed only after 24 h. the presence of DMPG was followed spectrophotometrically after leaving the solid in suspension with a physiological medium (NaCl 0. corresponding to a gallery height of 41.48 nm (Wang et al. 2005.50 and to 0. very close to the values reported for analogous systems.41 nm).5% of the originally existing DMPG was extracted after 7 days. 2004c. 2004). probably because of sterical hindrance. which has been intercalated in a Zn.5 °C. Sylvie Bégu. Del Arco et al. which could help to ascertain the nature of the intercalated anions. above a high-order transition at 31.e. no infrared spectroscopy data. (2008a) have. pH 7. but the C/P ratio was in the range of 34. Wang et al. Unfortunately. 50°) (Guo et al.. where the Mg.Al LDH by coprecipitation. a new maximum at 0.7 °C (Tajima et al. as the drug/LDH ratio was increased from 0. 2005). (d) DMPG – 100 – Mg/Al. 11. but a restricted motion of the drug entities at pH above 7. the Mg/Al molar ratio did not change upon intercalation of DMPG. with 5-FC anions parallel (gallery 0. Anne Aubert. Chemistry of Materials. 15. was reported in this study. but carrying the originally encapsulated lipophilic drug. The precipitate thus formed was aged at 40 °C in the mother liquour Fig.5 Å) reported for two different conformations of DMPG bilayers. 15. i. however. and 6% after 14 days. corresponding to a rotation of the terminal glycerol groups of DMPG. PXRD patterns showed the presence of nitrate (gallery height 0. A new maximum at 0. Reprinted with permission from New Layered Double Hydroxides/Phospholipid Bilayer Hybrid Material with Strong Potential for Sustained Drug Delivery System. DTG proﬁles in the temperature range from 30 to 800 °C of (a) DMPG. basal spacing 0. intercalation of 5-FC led to splitting or shift of the (003) diffraction. data conﬁrmed that a single phospholipid bilayer was intercalated. although the nature of the solid after release was not investigated. prepared the anionic conjugate base in an alkaline medium.. Almost 100% was released at pH 4. Only 1. to decrease its potential toxicity a controlled release system should be used. Rives et al. The actual Zn/Al molar ratio decreased as the pH during synthesis was increased. the insertion mechanism is not known. The FT-IR spectra of the intercalated systems showed the disappearance of the band at 1682 cm− 1 due to the C_O stretching mode of the neutral 5-FC molecule upon intercalation. Antimycotic agents The antifungal drug 5-ﬂuorocytosine (5-FC) was originally developed as an anticancer drug.. took place. in addition to nitrate. however. on increasing the amount of intercalated drug..3 – Mg/Al. Liu et al.. respectively. Dan A. The difference could be explained assuming a tilting of the chains in the constrained interlayer space of the LDH host.5 than at pH 4.8. Fig. 2000). Vol. and Didier Tichit. 2007) upon intercalation in the LDH galleries.76 nm) or perpendicular (gallery 0.V.12–40. Lerner. Fig. 21. nitrate was expelled and another biphasic system. Ramona Polexe. The spacing for the (003) diffraction of the DMPG intercalation compound was 46. A QLS (quasi-elastic light scattering) analysis revealed the presence of spherical particles (average diameter 154 nm) after 24 h.4. these authors concluded formation of a biphasic material for low drug loadings. the intercalated phospholipids rearranged forming liposomes after being released. larger than in pristine DMPG (34). The differences found between the release behaviour at different pHs could be due to a partial dissolution of the layers under acidic conditions. but. Both pristine 5-FC and a 5-FC mixture with the nitrate form of the LDH released 5-FC quickly (complete after 5 min) at pH 7.67.4). it can be hardly intercalated in LDHs. 16. They started from Zn2+ and Al3+ nitrates (molar ratio 2:1) under a N2 atmosphere. below and above their transition temperature..76 nm developing. but was found to be valuable against Candida spp. Jean-Marie Devoisselle.. Contrary to the usual increase in thermal stability of several biopolymers (Darder et al. corresponding to the spontaneous formation of liposomes.28 nm. Cryptococcus neoformans and Chromomycosis spp. drugs (Choy and Son. with a tilting angle between 29 and 31°. the drug was dissolved in aqueous ammonia and the pH adjusted using 2 M NaOH or 2 M HCl. 2679–2687. leading to a stretched conformation forming a bilayer with a thickness of 55.Al is very stable.8 in 60 min. (c) DMPG – 20 – Mg/Al. the mechanism of this change remains unknown. A maximum of 87% of the AEC is reached for DMPG.6 Å. 2005). one with nitrate anions and another with 5-FC anions parallel to the brucite-like layers... Kinetic studies revealed the importance of diffusion through the LDH particle in controlling drug release.5 Å. Fluorescence experiments showed a less compact arrangement of the lipids. 23. and then peptized at 60 °C for 24 h. and (e) LDH. (b) DMPG – 13. / Applied Clay Science 88–89 (2014) 239–269 255 due to the phase with intercalated nitrate weakened. pp. Release took place through ion exchange with the phosphate anions from the buffer solution. but these values were lower than those reported for dodecyl sulfate intercalated in LDHs (ca. As the exchange process was carried out at 40 °C. in any case. Unfortunately.. 2004. The drug being a neutral weak acid. 2009. Eliska Leitmanova.
suggesting that HEDP existed as a monovalent anion in the interlayer. The uptake rate was lower through the reconstruction method. Concerning the chloride form.256 V.. as the initial fast release quickly allowed establishment of a therapeutic dose. however. Fig.4) showed a biphasic release shape. abdominal discomfort. exchange at 25 °C or above gave rise to partial dissolution of the layers (the Mg/Al molar ratio was markedly lower than in the original solid).0 Å for the chloride and LMWH forms. Anticoagulants According to WHO (World Health Organization). so. where HEDP existed mostly as the divalent anion. slightly smaller than the thickness of the LMWH (11 Å) molecules when they adopt a helix oriented parallel to the basal planes of the LDH. and so the exchange method starting from the LDH-Cl was identiﬁed as the most suitable one. 1792–1797. The discrepancy probably came from an effect caused by the conﬁned environment within the brucite-like layers. short half-life. for treating from a broad point of view this sort of diseases. 1996). Fig. Gu et al. indicating a lack of crystallinity.8 mmol/g (ca. with the long axis of the molecule perpendicular to the layers. the difference could be attributed to the strong electrostatic interactions between the LMWH and the layers. The PXRD diagrams showed a swelling of the layers from 7. In addition. mainly: 1420 cm− 1 (symmetric C_O stretching). Al–Cl LDH by coprecipitation from the metal chloride salts.Al LDHs. SEM images showed a change from hexagonal to ellipse-shaped particles. The main interest was on overcoming the pharmaceutical limitations of heparin. 16.7 Å to 14. Release in a buffer phosphate solution (pH 7. / Applied Clay Science 88–89 (2014) 239–269 Fig. 17. intercalation at low temperature was essential to avoid dissolution of the inorganic host and for obtaining the intercalation compound as a single phase. and the subsequent sustained release allowed maintenance of this dose over a long period of time. many studies have dealt with the use of anticoagulants. low efﬁciency of cellular delivery and lack of oral absorption. 3 mmol/g. because of dissolution of the layers.5 mmol/g). implying the presence of a quasi free-like anion in the interlayer space. Wanguo Hou. This release rate was much slower than that from a physical drug–LDH mixture (80% in 30 min). leading to undesirable side-effects (e. 13. namely. IEC) was observed. as determined experimentally from the swelling of the layers upon intercalation. Synthesis and characterization of 5-ﬂuorocytosine intercalated Zn–Al layered double hydroxide.Al LDH. the multinegative charge of LMWH permitted an easy and strong interaction with the brucite-like layers. 190 to ca. Reprinted from The Journal of Solid State Chemistry. and above 7 the uptake also decreased. This was undoubtedly an important ﬁnding (as in most of the systems here reported). 12. Samples with different LMWH (10 to 100% substitution of interlayer chloride) were also prepared by coprecipitation under nitrogen atmosphere. 25% of the initial amount of drug released after 24 h and 40–45% after 120 h. and a shift and splitting of the signals due to solid state effects were merely observed. thus requiring usually two daily injections. Shaojie Liu. but no chemical analysis of sodium was reported. Osteoporosis Biphosphonates containing P\C\P bonds inhibit bone resorption and are used for the treatment of osteoporosis (Lin. The authors prepared a reference Mg. depending on the drug loading (the larger the loading. 90 nm. Vol. this was also in agreement with the space requirements (48 Å2/molecule for parallel arrangement and . with ca. 50% of the LDH ionic exchange capacity. Intercalation was thus carried out at pH 4–6. Molecular packing modelling conﬁrmed the orientation of the molecules within the interlayer space.2 Å. The difference between the positions of the S_O stretching bands (190 cm− 1) was very close to that in the sodium salt (210 cm− 1). They disappear rapidly in plasma and so large doses are usually administrated. and the calcined carbonate for reconstruction studies at pH 6. 18. (2008) have studied the intercalation and release of low molecular weight heparin (LMWH) into a Mg. among other drugs. thus.g. because upon deprotonation an increased chelating ability of HEDP developed. although the diffraction maxima for the LMWH samples were rather broad. the lateral dimension decreasing from ca. the experimental results indicated an uptake of ca. with permission from Elsevier. due to the chelating ability of HEDP. Analysis of the solid residue after drug release showed intercalation of phosphate species from the buffer solution. Copyright (2008). for which a maximum uptake of 1. and 1230 and 1040 cm− 1 (antisymmetric and symmetric S_O stretching. probably because of the strong drug–layers interactions when intercalated. cardiovascular diseases have been the ﬁrst cause of death globally. The FT-IR spectra showed the bands corresponding to the anionic form of LMWH.1-diphosphonic acid (HEDP) in Mg. as in the LMWH sodium salt. Lifang Li. respectively. Yan Li. pp. Chunxia Liu. Contrary to usual reports. Rives et al. (2003) have reported intercalation and release studies of 1-hydroxyethylidene-1. The gallery height for the 100% LMWH containing sample was 9. nausea and diarrhoea). 31P MAS NMR spectra showed intercalation without decomposition. Uptake at pH b 3 was low. Schematic structure representation of 5-FC/LDHs nanohybrids with different intercalated amounts of 5-FC. these authors have used commercial hydrotalcites containing chloride (LDH-Cl) or carbonate (LDH-CO3) for ion exchange preparations. the release kinetics model could be adjusted to surface diffusion and bulk diffusion of the loaded LMWH. the uptake of HEDP by the carbonate LDH was rather low. These authors also suggested the cointercalation of Na+ cations to explain this discrepancy. respectively). Nakayama et al. when the LMWH content was increased the particles became less regularly shaped. a value rather close to that determined from the Langmuir plot for the exchange (3. due to the multianionic nature of the drug (20 sulfonate and 10 carboxylate groups per molecule). SEM images showed formation of compact nonporous crystallites with a hexagonal plate-like shape. As expected. the lesser the amount released). 181. meeting the size for administration by injection.
6%. “50” and “100” in the names of the samples stand for the percentage of LMWH exchanged for chloride. Zi Gu. 20. 14. Rives et al. 8. only 1% release was observed in buffer solutions irrespective of their pH. respectively. The powder X-ray diffraction patterns indicated a swelling of the LDH layers from 8. The pH dependence of (●) the uptake of HEDP in LDH(Cl) at 0 °C.1 Å for the carnosine and gallic acid derivatives. Vol. remaining up to Fig. Reprinted with permission from In Vitro Sustained Release of LMWH from MgAl-layered Double Hydroxide Nanohybrids. Julie H. Copyright (2008) American Chemical Society. (d) LMWH100–LDH.1-diphosphonic acidintercalated layered double hydroxide and its physicochemical properties. 92. a 6% release was observed in artiﬁcial intestinal juice (according to Japanese Pharmacopoeia JP XIII 2nd ﬂuid. Vol. gallic acid was intercalated by coprecipitation by simultaneous addition of aqueous NaOH.V. pp. However. the suspension was protected from sunlight and aged for 24 h at 40 °C. 3715–3722. These problems can be diminished by using antioxidants such as carnosine and gallic acid (3.5 under nitrogen atmosphere for 48 h at 70 °C. 18. Carnosine was intercalated by ion exchange with a LDH-nitrate precursor at pH 9. Koji Takeshita. Hirokazu Nakayama. Mitsutomo Tsuhako. Copyright (2003) Wiley-Liss. respectively. a mixed solution of Mg2+ and Al3+ nitrates (molar ratio ca. However. 24 Å2/molecule for perpendicular arrangement) and electric density charge of the layers (26 Å2/charge). carnosine is easily hydrolyzed in the blood and gallic acid has a short half-life in plasma. 2419–2426. Campbell. Preparation of 1-hydroxyethylidene-1. and (❍) the solubility of LDH(Cl). conﬁrming the anion exchange mechanism for exchange. (2010b) have intercalated these molecules in Mg. pH = 6. in other words. Reprinted from The Journal of Pharmaceutical Sciences. (b) LMWH20–LDH.36 mg of LDH(Cl).8 Å for the nitrate precursor to 15. decreasing their biofunctionality. Kong et al.0) to a gallic solution under nitrogen atmosphere and vigorous stirring at pH ca.6 and 95. Immediate release was observed only from HEDP and LDH physical mixtures.8) solutions. the results were rather negative as the release rates and the amounts released were not at satisfactory levels. “20”. both can be oxidized under mild conditions and are pHsensitive.1 Å and 10. as well as to accelerate the ageing process of the cells and trigger several diseases. Antioxidants Free radicals are able to cause damage to nucleic acids. probably because of the lower afﬁnity of the buffer anions (monovalent chloride and acetate) than HEDP for the interlayer space. 2. Drug release (30% of the drug loading) was complete within 2 h in an aqueous K2CO3 solution and nil in degassed water. The N/C ratios for both samples were larger than for both pristine drugs. Chemistry of Materials. / Applied Clay Science 88–89 (2014) 239–269 257 Fig.4. (c) LMWH50–LDH. indicating the simultaneous presence of a small amount of intercalated nitrate. and Gao Qing (Max) Lu. Anita C.5-trihydroxybenzoic acid). One milligramme of Al corresponds to 9. FT-IR and UV–vis spectra showed the stability of the anionic forms of both species upon intercalation. SEM images of (a) Cl–LDH. 17. the molar percentages of carnosine and gallic acid were 80. Zhi Ping Xu. .Al LDHs. Inc. proteins and membrane lipids. Thomas. pp.
Li et al. Min Wei. the slurry was aged above room temperature for several hours and the product ﬁltered and washed. 3. Rives et al. 2009a). Antioxidant drugs intercalated into layered double hydroxide: Structure and in Vitro release. microspheres or microemulsions has been tested as alternative routes to overcome these problems (Brown et al. the process followed a nonFickian diffusion model.51. although no complete release was attained. (poly(tert-butyl acrylate-co-ethyl acrylate-co-methacrylic acid) – (Y. 43% in the ﬁrst 110 min and a relatively slow second step (71% released in 750 min). encapsulation in micelles. the carboxylate groups interacting electrostatically with the Al3+ cations. and 4. 15. (2009) and Y.Al LDHs (Zn/Al molar ratio 2).. i. and this effect was even more pronounced for the Zn/Al = 2/1 sample. Li et al. suggesting that incorporation of Fig. drug anions on the external surface of the LDH particles diffused into the solution via anion exchange. maintaining their bioactivity and achieving a controlled release of the antioxidant drugs. releasing ca.. 19. . respectively. respectively.e. Antioxidant 3-(3. was similar to that shown by the pure drug. 2007. the presence of the monovalent anions was expected in both cases. and the rate determining step in the second stage would be the diffusion of the drug anions from the interlayer space to the external surface of the crystallites. as studied by UV–vis spectroscopy. pp.4 indicated a larger release at pH 2 (probably because an easy dissolution of the layers). From the height of the gallery. In vitro release at pH 2 and 7. the GA molecules are oriented parallel to the layers. and then the PNSloaded micelle was intercalated in a Mg.. Release into buffer (phosphate) solutions did not show the usual burst release phenomenon.. These values were in agreement with a zig–zag orientation of the VA molecules. The amount of antioxidant incorporated into the LDH did not depend on the preparation method followed and was in the 36. maximizing intermolecular π–π interactions. The FT-IR spectra (compared to those of VA and its sodium salt) conﬁrmed development of electrostatic interactions between anionic VA and the positively charged layers. for VA-containing LDHs and Zn/Al molar ratios of 2. The solid residues after release showed PXRD patterns typical of LDHs with intercalated phosphate anions. these LDH– drug intercalation compounds could be successfully used for storing the pharmaceutical agents. F. Vol. with an electrostatic interaction of the carboxylate groups with the layers. / Applied Clay Science 88–89 (2014) 239–269 100% corresponding to nitrate.8 nm. and protection of the drug. the ﬁrst one could be adjusted to a modiﬁed Freundlich model and the second. Xianggui Kong. an increase in water solubility. much slower.53. This behaviour was rather interesting from the therapeutical point of view. and the subsequent sustained release maintains this dose over a long period of time. PXRD diagrams conﬁrmed insertion between the layers. Release in water and 0. Fig. a fast stage followed by a slow one. Intercalation of vanillic acid had been previously reported by Hong et al. with d(003) = 2. obtaining a sample (slightly contaminated with carbonate species) with 55% (w/w) loading of the drug. fast. and so it is poorly dispersed in physiological ﬂuids. a similar trend was observed for gallic acid.. with permission from Elsevier. In vitro release curves of (a) carnosine from carnosine–LDH and (b) GA from GA– LDH. Liu et al. on taking both steps separately.Al LDHs as an alternative delivery route using two different encapsulating agents.. Silion et al. The drug release in the whole release range could not be satisfactorily ﬁtted to a single kinetics model. although the large size of the anions modiﬁed the growing pattern of the hydroxide layers. 49. Lan Jin. but again the Zn/Al = 2/1 sample approached also a ﬁrst order diffusion process. Li et al.2diphenyl-1-picrylhydrazyl) followed a similar trend as that of drug release. which expanded to 1.9% NaCl aqueous media showed a rapid burst until 10 min and partial dissolution of the layers in a neutral aqueous medium. (2013) in a Mg. in agreement with the chemical formula calculated. added to a PTBEM or sodium cholate solution. and stirred under nitrogen until the organic solvent was evaporated.258 V. (2008) by direct synthesis in a Zn.. The release data ﬁtted a Freundlich mechanism. in agreement with formation of a tilted bilayer. 2009a) or dissolved in chloroform (F. Karpela et al.. 2009) or PTBEM – an anionic micelle derived from a biocompatible surfactant. (2009a) have carried out a study on the encapsulation of prednisone in micelles and their intercalation in Mg.5-di-tert-butyl-4 hydroxy-phenyl)-propionic acid (BHPPA) has been intercalated by Lonkar et al.52 nm. to a parabolic diffusion process. The spacing of the (003) basal reﬂection of the PNS/PTBEM–LDH system (Y. indicating that it proceeded via an anion exchange process. Once the micelles were formed (as conﬁrmed by a ﬂuorescence probe technique). From the height of the interlayer space and the molecular dimensions of the drugs. 19. Li et al.33 Å. 2007.Al LDH following the reconstruction method. Copyright (2010). leading to problems in efﬁcient delivery. The use of micelles (combining hydrophilic and hydrophobic segments) has some advantages. step. 324–329. a small amount of nitrate being detected by PXRD in the samples prepared by anion exchange. 100 °C and the antioxidant ability of the intercalated species. it was concluded that carnosine anions form bilayers and gallate anion monolayers. Li et al. a solution containing Mg2 + and Al3 + nitrates (Mg/Al molar ratio 2) was added under nitrogen atmosphere at pH 10 (NaOH aqueous solution). According to the dissociation constants of these polyacids and the experimental conditions during synthesis. with the carboxylate groups alternatively pointing to one brucite layer or another. and so the process could be described as follows: surface diffusion was the rate determining step in the ﬁrst stage.4.85 nm. 2001). these authors concluded that the VA molecules form a monolayer perpendicular to the brucitelike layers. step. Carnosine was released in a twostep process at pH 7. SEM studies conﬁrmed that after reconstruction the hexagonal shape of the particles is preserved. probably because of the larger afﬁnity of the exchangeable anions in the media (hydroxyl or chloride) for solids with a higher positive charge. 1. After the ﬁrst. Prednisone was encapsulated in cholate (F.Al LDH under nitrogen atmosphere. Li et al. namely. Intercalation increased the thermal stability of the drug by ca. thus preserving its activity during transport to the precise target. hereafter VA) by coprecipitation and anion exchange in Zn. (2012) have intercalated gallic acid (GA) and vanillic acid (4-hydroxy-3methoxy benzoic acid. the release was higher in a NaCl medium. respectively. Li et al. and 1. Prednisone was dispersed in acetone (Y. but it is scarcely soluble in water.. however. Xue Duan. The d(003) spacing for a reference nitrate sample prepared under similar conditions was 0. therefore. Immunosuppressant corticosteroids Prednisone (PNS) is a steroidal antiinﬂammatory drug.7–43. However.7 (w/w) range. as the initial fast release rapidly provides a therapeutic dose. The scavenging of the free radical DPPH (2.Al LDH by coprecipitation. Reprinted from Applied Clay Science. 2009a) was 29. 2009). centrifugation and washing with decarbonated water.
indicating that.4).6. Copyright (2009).. respectively (F.1. Li et al.8 the drug release mechanism depended on the combination behaviour control. which was 38.8 and 4. GMP..6 and 9. cytidine-5′-monophosphate (CMP) and herring testis DNA. The PNS bands were hardly recorded in the spectra of the intercalation compounds. 2008. including dissolution of the composite.0 ± 0. a burst release was observed at low pH.... 2002. the band was recorded very close to that of pristine PNS.1 Å) for the LDH–DNA intercalation compound corresponded to the thickness of the DNA molecule adopting a double helix shape parallel to the basal plane of the LDH. Hong Li. and combination of diffusion through the matrix and degradation of the micelles at pH 4. 2009a) cm− 1.. while for the cholate system the release proﬁle ﬁtted to the Rigter–Peppas (RP) equation (Scott and Peppas. but after 105 min at pH 6.. and 100% at pH 4.4 Å (F. pp.5 Å. it is more probably due to the fact that the lowest pH tested in these studies (4. corresponding to a gallery height of 3. The authors concluded about the suitability of the two systems tested. 150 min at pH 7. Y. Rives et al. probably because of the restricted movements of the drug within the micelle core. nor its intercalation in the LDH.. 2009) Broadening of the other diffraction lines has been attributed to the disordered stacking of the layers. Li et al. 1999.6 release was controlled by drug diffusion. The percentage of PNS released was 40.8 or 4.7 Å for AMP. 90 h. assignation of some bands was different in one paper or another (F.4. FT-IR spectroscopy was also applied for further characterisation of these systems. The ν(C_O) was related to bands at 1700 (F. in the ascending colon (6.2.8. 13. Serra et al.0) which had been prepared at pH 10. 2009. The interlayer space (19. Circular dichroism spectra showed a weakening of the CD band at ca. a LDH sample with intercalated micelle. Drug release was dependent on the nature of the micelle and on the pH. Nucleosides Choy et al.. 20. and CMP. 2009a). 20. guanosine-5′-monophosphate (GMP). corresponding to a thickness of a monolayer. a band at 1660 cm− 1 was assigned to the ν(C_C) mode (F. release was faster in the ﬁrst 10 h.e. ion exchange and diffusion of prednisone. 2009). 2009a) the band was recorded at 1612 cm− 1. starting from the nitrate form (Mg/Al ratio 2..8) is not low enough to dissolve the basic LDH layers. Schematic representation for the drug release processes of PNS from PNS/PTBEM–LDH nanocomposite in a buffer solution.. and 7.8. Differences in the value of the n parameter were found depending on the pH. Li et al. Yong Li. 65. thereafter slowering down and equilibrium was reached after ca... encapsulation and intercalation did not change the properties of the prednisone molecule.. encapsulation in PTBEM led to a red shift up to 260 nm. slightly larger than that for a cholate–LDH (i. 2001. probably because of J-aggregation of PNS in the micelle core. Wei et al.4 ± 0. 6. For neither of the system.. . which were related to the release mechanism: at pH 7. Li et al. nor none of the pH tested. 2004. Hussein et al. / Applied Clay Science 88–89 (2014) 239–269 259 the micelle had been achieved. Concerning the cholate system. 2004).7 Å (which increased to 12. Tronto et al. Concerning the cholate system. In vitro drug release was studied for both systems at three different pHs. Khan et al. Li et al. While encapsulation in cholate. Although this can be attributed to the double protecting action of the micelle and of the LDH. release was fast during the ﬁrst 40 min. Jun Lu.). Li et al. pH-Responsive composite based on prednisone-block copolymer micelle intercalated inorganic layered matrix: Structure and in vitro drug release. equilibrium being achieved after ca. probably with the phosphate groups pointing towards the hydrotalcite layers to maximize the electrostatic interactions. but without the PNS molecule). led to no shift in the position of the PNS band. anomalous transport at pH 6. (2001) described for the ﬁrst time the intercalation of nucleoside monophosphates and DNA between the layers of a Mg. Based on the basal spacings of the (003) planes and the molecular size of the intercalated species. 2009). thus releasing the intercalated anion.5 ± 0. The biomolecules were intercalated at pH 7 by dispersing the nitrate LDH in a deaereated aqueous solution containing an excess of adenosine-5′-monophosphate (AMP). For the PTBEM system. a schematic supramolecular structure of the PNS–cholate–LDH composite was proposed (F. Upon release from the PNS/PTBEM–LDH nanocomposite. 16. upon intercalation the band was recorded at 249 nm. 2006). in both cases. as in other cases described in the literature (Gu et al. Fig. 359–366. 151. respectively). and stirring for 48 h. while at pH 6. The PXRD pattern of the nitrate precursor indicated a basal spacing of 8. Reprinted from Chemical Engineering Journal. Vol. with permission from Elsevier.. and in the distal colon (7. Mathematical modelling of the drug release has shown that for the TPBEM system the mechanism could be described by a Fickian diffusion at pH 7. Min Wei. 2008. while in (Y. neither sodium cholate nor PTBEM showed any absorption band in the 200–400 nm range. close to those existing in the small intestine (7. and then slowered. Quite surprisingly. 2009).6).8. Several spectroscopies were used to check if encapsulation and intercalation had led to any change in the chemical nature of PNS. 2009) or 1712 and 1657 (Y.2. Li et al.5 Å for the (003) planes. So. The UV–vis spectrum of prednisone showed an absorption band at 244 nm due to a π → π transition of the drug. Lan Jin.V.Al LDH by ionic exchange at pH 7.7) (Li et al. Fig.4. or to its low loading.. Li et al. Li et al. taking advantage of the applicability in a wide pH range and almost complete release. the spacing was 39.
Gray. 48. 21. but increased on developing new systems with improved properties. HL-60 cells in a culture treated with LDH– As-myc exhibited time dependent inhibition of proliferation.Al LDH (molar ratio 3) was prepared by coprecipitation and hydrothermally treated at 100 °C for 16 h. Probably this was a consequence of the lower solubility at low temperature. indicating that the system is pH-sensitive (a so low pH simply destroys the mostly basic layers) and can be used as a gene reservoir. indicating the family of drugs and the speciﬁc drug inserted. The particle size distribution showed a maximum at 100 nm with low dispersity index. water added and incubated at 37 °C for 10 min with light agitation (350 rpm). pp. Zhi Ping Xu. 3 mg/mL of LDH nanoparticles. Controlled preparation of layered double hydroxide nanoparticles and their application as gene delivery vehicles. Even so. in this sense we can point out the use of layered hydroxide salts (LHSs). Rives et al. in agreement with the molecular dimensions. 21.. while an increase in hydrothermal time and/or temperature increased the peak particle size. 2002). i. but not CHO-S cells. These solids showed a gallery height (from PXRD diagrams) of 19. by using LDHs or LHSs the opportunities given widens and provides a quite interesting scenario for this research. Acknowledgements Financial support from MICINN (grant MAT2009-08526) and ERDF is greatly acknowledged. The plasmids were wrapped around LDH individual particles. 2002). 2012) aiming to use them in ﬁlm sensors. supersaturation was readily reached and crystal nucleation occurred rapidly. / Applied Clay Science 88–89 (2014) 239–269 275 nm. DNA could be released without any degradation by suspending the LDH– DNA intercalation compound in an aqueous solution at pH below 2. (2010) have reported the interaction of DNA plasmids (larger than DNA fragments which intercalation into LDHs had been previously reported) with LDHs. As the size of the plasmid increased. Al LDH by anion exchange following a method similar to that described above. The DNA:LDH ratio never approached the ion exchange capacity of the LDH. The infrared spectra showed rather broad (because of the biomolecule–layer interactions) bands due to phosphate species. but no ﬂuorescence was observed when pristine FITC was used. The Mg.0. and with the molecules (except for DNA. Reprinted from Applied Clay Science. More intense ﬂ uorescences were observed when the concentration of LDH–FITC was increased. the chemical composition of the layers (metal cations). similar to that observed for DNA in a highly concentrated salt solution. guanine and cytosine groups. FITC could be partially released by ion exchange under physiological salt conditions. and the UV–vis spectra showed the expected absorption bands due to the adenosine..) shown by these systems. less plasmid was associated to the LDH particles. homogeneous suspension containing ca.000 rpm) for 30 min.3 Å. 14. forming a larger number of smaller crystals. their importance has not decreased. the preparation method followed and an indication of the availability of release data. as cells could not take FITC even at high concentrations. Cellular uptake of the LDH–FITC intercalation compound was concluded from laser scanning confocal microscopy experiments. loading. Probably in the next years research will continue along these lines (some papers have actually been published on this same topic while this manuscript was under review) and we will be surely witness of the application of other materials as matrices to support anionic drugs. probably because of the different physicochemical properties (mainly related to particle size. the particles of the intercalation compounds showed considerable transfection efﬁciency when Fig. Table 1 summarises most of the papers here reviewed. Marcus Niebert. 17. . As Khan and O'Hare anticipated (Khan and O'Hare. Gao Qing (Max) Lu.. Hydrothermal treatment deaggregated the product and tailor the size via an Ostwald ripening effect. Plasmid size vs. 2007). Dispersions of LDH–FITC were added to NIH3T3. a further proof of antisense oligonucleotides entering into the cells and participating in cell division processes (Kwak et al. 280–289. with permission from Elsevier. etc. indicating that the molecules preserved their integrity upon intercalation. “ … LDHs … to be used as part of a sophisticated drug or gene delivery system in patient care or therapy”. LDH and plasmids were mixed in various mass ratios. These authors have also studied the transfer of LDH–biomolecules systems into mammalian cells (Choy et al. which structure is also a modiﬁcation of the brucite structure (Carbajal Arizaga et al. obtaining a transparent. When lower synthesis temperatures were used smaller particles were formed.260 V. leading to their aggregation. with 65% growth inhibition compared to the untreated cells. It can be also concluded that the preparation method followed modiﬁed the ﬁnal pharmacological behaviour of the drug– LDH system. For an easy location of the systems studied. respectively. Conclusions and further studies The review here reported collects the information in open literature on the interaction of more than 15 families of drugs with layered double hydroxides. the mixture incubated at 25 or 60 °C with light agitation (350 rpm) and then centrifuged (15. The ﬂuorophores were detected in the cells after 1 h incubation and the ﬂuorescence intensity increased continuously up to 8 h incubation (longer times were not tested). ﬂuoresceine-5-isothiocyanate (FITC) and c-myc antisense oligonucleotide (As-myc) were intercalated into a Mg. DNA/LDH ultrathin ﬁlms have been also prepared via a layer-bylayer method using exfoliated LDH nanosheets (Zhao et al. In the authors' opinion.1. 2000).. An aliquot of the LDH suspension was mixed with a plasmid (pDNA) stock solution. indicating an efﬁcient neutralization (by the positively charged layers) of the DNA phosphate groups. TEM showed formation of regularly shaped hexagonal particles. aiming to use these intercalation compounds as gene delivery vehicles. The versatility of LDHs to intercalate different drugs has been shown. and 12.6. adenosine triphosphate (ATP). despite the drug–LDH systems have been being studied for more than ﬁfteen years. uptake and how variation of conditions can improve the “uptake”. probably because of the formation of LDH:DNA aggregates which deposited on the adherent cells. but not on the CHO-S cells. Fig. 14. the zeta potential of the particles was 36 mV. way of intercalation. Herring testis DNA. Peter P. other samples were prepared by changing the synthesis temperature and the time and temperature of the hydrothermal treatment. transfecting adherent cell lines. Ladewig et al. see above) oriented towards the layer planes to maximize the electrostatic interactions.. Katharina Ladewig.e. Copyright (2010). Vol.
Al.Al Micelle method ion exchange Yes Trikeriotis and Ghanotakis (2007) Ampicillin Mg. (2004) Aspartate Mg. (1997) L-Dopa Mg.Al Coprecipitation Nakayama et al. (2004) Costantino et al.Al Coprecipitation Coprecipitation Yes Yes Nakayama et al.b) Oligoglycine Peptides: Gly–Tyr Mg. (1997). Wang et al. (1999a.Al Ion exchange Yes Wang and Zhang (2012) Benzoate Mg. Wei et al. (1999b). … Formula LDH matrix Preparation Release studies Yes Reference 261 Mg.Al. (2001). Kong et al. (2010) (continued on next page) .Al Ion exchange Yes Wang and Zhang (2012) Cefazolin Zn.Cr Ion exchange coprecipitation Fudala et al. Aisawa et al.Al Ion exchange Yes Trikeriotis and Ghanotakis (2007) Benzilpenicillin Mg. Ser. (2005) L-Phenylalanine Zn.Al. Zn. / Applied Clay Science 88–89 (2014) 239–269 Table 1 Summary of studies on insertion of drugs in layered double hydroxides. Al.Al Coprecipitation Whilton et al. Ni.Al Coprecipitation Whilton et al.b) Antibiotics Amoxicillin Zn.Al Coprecipitation ion exchange Fudala et al.Al. Drug or action Amino acids and peptides Amino acids: Ala. Mn. (2009) Amphotericin B Mg. Yang et al.Al Coprecipitation Yes Ryu et al. (2008).Al Mg.Al Reconstruction Yes Wang et al. (2005) L-Tyrosine Mg.Al Ion exchange Yes Wei et al. Ni. Gly. (2007).V. (2010a. Zn. Tyr. Rives et al. Pro. (1997) Glutamate Mg.
Al.Al Reconstruction Xu et al.b) Ifosfamide Mg. Tammaro et al. Liu et al. (2008). (2010). Rives et al. 2010a. Mg.Al Reconstruction coprecipitation Micelle method coprecipitation yes Wang et al.b) Camptothecin Mg.Sn Ion exchange Yes Sui et al. (2007) Trikeriotis and Ghanotakis (2007) Trikeriotis and Ghanotakis (2007) Gramicidin D Nalidixic acid Protein C99H140N20O17 Mg. Li et al.Al A secondary intercalation method Yes Nie and Hou (2012) .Al. (2012) Phenoxymethylpenicillin Mg. (2009) Ticarcillin Mg. (2006) Succinate Mg. (2009).b) Tyner et al.Al Coprecipitation reconstruction Reconstruction hydrotermal treatment Yes Yang and Guo (2003) Pan et al. Y.Al A secondary intercalation method Yes Pang et al. (2004).Mg.Al Ion exchange Yes Wang and Zhang (2012) Tetracycline Mg.Al. / Applied Clay Science 88–89 (2014) 239–269 LDH matrix Preparation Release studies Yes Reference Zn. Xu and Lu (2005) Floxuridine Mg.Al Mg.Al Yes cis-Platin-DNA Doxiﬂuridine Zn. Li et al.262 Table 1 (continued) Drug or action Antibiotics Chloramphenicol Formula V. (2008.Al Yes Yes Norﬂoxacin Mg.Al Reconstruction Yes Li et al. Zn. Choi et al. (2005). Frunza et al.Al Coprecipitation Yes F.Al Coprecipitation ion exchange reconstrution Micelle method Ion exchange San Román et al. (2009a. (2008a.Al Mg.Al Ion exchange Yes Wang and Zhang (2012) Anticancer agents 10-Hydroxy Camptothecin Zn. (2012). (2013) 5-Fluorouracil Mg.
Al Coprecipitation Yes Panda et al. (2010) Fluvastatin Mg. (2009) Gemﬁbrozil Li.Al Ion exchange Yes Khan et al.Al Coprecipitation Yes Berber et al. 2011a.b.Al Ion exchange Yes Qin et al. (2010a. (2001) Pravastatin Mg. / Applied Clay Science 88–89 (2014) 239–269 Table 1 (continued) Drug or action Anticancer agents Methotrexate Formula LDH matrix Preparation Release studies Yes Reference 263 Mg. (2009) Anticoagulants Heparin Mg. Zn. 2012) Podophyllotoxin Mg.V. Kim et al. Chakraborty et al.Al Coprecipitation Yes Panda et al. (2010) Cloﬁbric acid Mg.Al. (2008) (continued on next page) .Al Coprecipitation Yes Berber et al. (2010) Anticardiovascular Bezaﬁbrate Mg. Rives et al.Al Ion-exchange coprecipitation and hidrothermal treatment Choy and Son (2004).Al Coprecipitation Yes Gu et al. (2007).b.
(2010a. Mg. (2008) Prazosin Mg. 2010b) Vanillic acid Zn. (2008). (2008a. (2009) Antihypertensives Captopril Mg. Rives et al.b) Gallic acid Zn. (2008) Enalapril Zn.Al Coprecipitation Yes Liu et al. / Applied Clay Science 88–89 (2014) 239–269 LDH matrix Preparation Release studies Yes Reference Zn. (2008) Ramipril Zn. (2008) Antimycotic 5-Fluorocytosine Zn. (2006).Al.Al Coprecipitation ion exchange Yes Zhang et al. Kong et al.Al Ion exchange Yes Kong et al.Al Ion exchange Yes Nakayama et al. Xia et al. (2012) .Al Ion exchange Yes Xia et al.Al Ion exchange Tammaro et al.Al Ion exchange coprecipitation Yes Silion et al. (2010a.Al Reconstruction Lonkar et al.Al Coprecipitation ion exchange Yes Xia et al.Al Mg. (2012). Zn. Ribeiro et al.b) Antioxidant BHPPA Mg.Al.264 Table 1 (continued) Drug or action Antiﬁbrinolytic Tranexamic acid Formula V.Al Ion exchange coprecipitation Yes Silion et al. (2009) Lisinopril ZnAl Ion exchange Yes Xia et al. (2013) Carnosine Mg.
Y.Al Ion exchange hydrothermal coprecipitation Choy et al. (2001) DNA Mg. Li et al. / Applied Clay Science 88–89 (2014) 239–269 Table 1 (continued) Drug or action Diabetes Gliclazide Formula LDH matrix Preparation Release studies Yes Reference 265 Zn. (2009) Immunosuppressant corticosteroids Prednisone Mg.Al Mg. (2010) (continued on next page) .V.Al. (2009a) Liposomes DMPG Mg.Cr Ion exchange Ambrogi et al. (2000) Nucleosides Guanosine-5′-monophosphate Mg.Al Ion exchange Choy et al. (2000) Cytedine-5′-monophosphate Mg. Ladewig et al.Al Coprecipitation Yes F. (2001) Adenosine triphosphate Mg.Al Ion exchange Yes Choy et al. Li et al.Al Ion exchange Ion exchange Choy et al.Al Ion exchange Yes Bégu et al. (2009).Al Ion exchange Choy et al. (2000) Choy et al. (2001) c-Myc antisense oligonucleotide Fluorsceine-5-isothiocyanate Mg.Al Ion exchange Choy et al. Rives et al. (2009) Nucleosides Adenosine-5′-monophosphate Mg. 2001). (2000.
Hirahara. 59–66. F. Layered hydroxide salts: synthesis. D. Anticancer drug encapsulated in inorganic lattice can overcome drug resistance. J. J.P. Novel method to evaluate diffusion controlled release of drug from resinate.. I−. Solid State Chem. Layered double hydroxides based ceramic nanocapsules as reservoir and carrier of functional anions.. Thermal evolution of a MgAl hydrotalcite-like material intercalated with hexaniobate. A. Chem.. P. Mitra. 107. E. H.. Mater. Tarak. S. D. D. Aisawa. Microporous Mesoporous Mater.... Chakraborty. Choy.P. D. Biopharm. 27... Psychiatry. W. Choy.H. A. F.. J. C.A. Benito.. H.. F. Carriazo.R...A.. Pure Appl. Labajos. Basu. 15. A. Bhaskar. (Ed.. Dasgupta. A.. L.. Vaccari.M. 1996.. J.. Perathoner.. Zn. 2008. M. In: Rives. J. A: Chem. D. 2741–2751.. Intercalation behavior of L-ascorbic acid into layered double hydroxides. M. A. Ceram. Growth Des.... T. F. Higashiyama. Commun. Soc. 52–62. Structural characteristics and thermal properties of PE-g-MA/Mg.. Misra. Rives. S. Pharm. Dasgupta.. D.. Nenoff. Microwave-assisted reconstruction of Ni–Al hydrotalcite-like compounds. pp.G.. Ayaori. Ambrogi.Al..M.. 38.. Ghosh.H. Rocha. R. I.. Sci. Bontchev. 2439–2445.. Triﬁrò. Benito. Dasgupta. 2009. 1997. S. Choi. T. S.. Rives.. C.. B. Vitiligo. Chen. Chakraborty. Rives.. Mori. Jones. J.. 9463–9469. S. Bose. 2 ≥ x ≥ 0) derivatives.K. Ghosh. Chakraborty. 148–158. Bhattacharjee. 15. Rives. Pharm. properties and potential applications. 2394–2401. H. (2001). F. J. 2007. Forano. Frol.. Solid State Chem. Soc. P.. Bose.. Phys. M. Chakraborty. J. Al-LDH exfoliation nanocomposites synthetized by solution intercalation. Basu. 285–291. Solids 69.. F. / Applied Clay Science 88–89 (2014) 239–269 LDH matrix Preparation Release studies Yes Reference Mg.5-cyclooctadiene over LDH hosted Fe and Mn sulfonato– salen complexes.. Martín. 2007. Mishra. D. Benito... Solid State Chem. Hafez... Rossi. pp.. Nanocomposite formulation system of lipid-regulating drugs based on layered double hydroxide: synthesis. Inorg. Mandal.. 15. Aisawa. F. Eur. M.. Basu.. C. F. S. 9. 94. Aisawa et al. R. F.B. Aubert-Pouëssel. W.. 2010. S. Ind.. Inorg.. Dasgupta. Effect of process variatons on anticancerous drug intercalation in ceramic based delivery system.P.1diphosphonic acid Formula V.M.. K. Ikematsu. Carriazo. S. Chakaborty. M. D. Devoisselle.. M. Br−. Oh. Martín. 2001. Chakraborty. Sawada.. C. 173–301. Impact of levetiracetam on mood and cognition during prednisone therapy. F. Elsevier. Vaccari..E. Diabetes Care 27... Barriga.. Chem.. Liu. S. Mater. J.. V...G.. Ogasawara. C. Labajos. Khan.D. D. J. Chem. 2008. 6. psoralen. Res. W. 249. Delamination of layered double hydroxides by use of surfactants. Mater.. Trans. Krumhansl.. J. Rives. Z. J. Polexe. Ceram.. 181.R..A.. E.). 2006a. (2003) Vitamin Vitamins A.. Benito. Cefalu. G... D. Sengupta. Roy. and ion exchange properties of hydrotalcite Mg6Al2(OH)16(A)x(A−)2 − x·4H2O (A.M. V. Momiyama. Inﬂuence of microwave radiation on the textural properties of layered double hydroxides. Voigt. M.Fe Ion exchange coprecipitation reconstruction Yes Choy et al. Comparison of the epoxidation of cyclohexene. Basile. 107–116.. Soundrapandian.M. 20. Stability of vitamin C derivatives in solution and topical formulations. S.. 146–154. Park. 69. Intercalation of organic and inorganic anions into layered double hydroxides. S. Benito. D. Austria.. S. 987–996. Albertazzi. Eur.. C. V. Brown.. 229–234.M. Satyanarayana. (2009) References Adachi-Pagano... Synthesis. A. Mg. Ohsuzu. 21.. Choi... J... Data. Biomed. 3669–3675. (2004). In: Wypych. Solids 72. 47.. P. A. (Eds.. Appl.. Hu.J... Basu.H. Fe.. Pharm.. Chem. Tanaka. Fayad. 2008a. Oh.T. Anal. Today 11.. Layered Double Hydroxides: Present and Future.L. Chem. P. Nagata. Bret. Viswanathan..S. W.. Mitra. A. 795–801. J. Ind. characterization and drug release properties. V. J. Bégu. Umetsu. P. K. Minagawa. Chakraborty. 2006a. Carbajal Arizaga. D.. Narita.... 1243–1251. Catalytic properties of hydrotalcite-type anionic clays. J.. 35.L. Vaccari. Labajos. 2003.. Soc. Benito. 941–949. Nakayama. P. S. Rives. 2010b. T. E. 2003.. Tanaka.. Wypych. 2010a. Chem... 779–783. New York.K. Satyanarayana. Takahashi. Commun. R. C. Chem. Clay Sci.. Layered double hydroxide: inorganic organic conjugate nanocarrier for methotrexate. 1991.Al Ion exchange Yes Khan et al. Applications of hydrotalcite-type anionic clays (layered double hydroxides) in catalysis. S. 2006c..Al Ion exchange reconstruction Nakayama et al. Cryst.. J. 926–927.. Sengupta. P. Domingo. Microwave-treated layered double hydroxides containing Ni2+ and Al3+: the effect of added Zn. Nayaka. Inc. A. T. Effect of gliclazide immobilization into layered double hydroxide on drug release.C. 69.. Int.. P. Taniguchi.E.. 2006b. 448–452. Labajos. Y.. Eur. Labajos. Role of chromium in human health and in diabetes. M. Takahashi. J. 153–163..... Atherosclerosis 196.. Chem. Solid State Chem. Ogura. C. M. Nakamura. 103–111. Y. A facile synthetic strategy for Mg–Al layered double hydroxide material as nanocarrier for methotrexate. 2004. 3784–3797...J. Anticancer drug-layered hydroxide nanohybrids as potent cancer chemotherapy agents. J.M. Int. S. B.. H. 2004. Mg. Herrero. K. and NO− 3 . Qu. 2008. Miglani. . Al-layered double hydroxide. 496–546..). Centi. Pub. Chakraborty... 2011b... Clay Surfaces: Fundamentals and Applications.J. Semenzato. 162.. Gasser (2009).. N. F. E Zn. J. J.. Choi. Tichit. Catal. Guinea. K.. Berber. 2010a. 179. Manoj. M.. Leitmanova. 2008b. Ceram. Basile. Mandal. properties and applications. R. Chibwe. 1459–1471. Effect of bezaﬁbrate therapy on atherosclerotic aortic plaques detected by MRI in dyslipidemic patients with hypertriglyceridemia. Chem. Mitra. Basu. V. S.J. Chakraborty. Chakraborty. 73. E. Microwave-assisted homogeneous precipitation of hydrotalcites by urea hydrolysis. V. Ciarnelli. Chakraborty. S. 81.M.. S. Besse.S... Shilpa. Ghosh. M. 3–15. K. S. R. Chem. G. 2007. B. Narita. Kusuhara. Y. Microwaves and layered double hydroxides: a smooth understanding. Catalysis by layered materials: a review..K... Kihara. Mater. 22. V. G. Murthy. characterization.. Pharm. 2012.. A′ = Cl−. 4608–4615. J. J. F. 2001.. 285–321.. I. 22... V. 3208–3213. M. 28. 425–433.J.. K.. Solid State Ionics 178. M. Noccheti. F. Labajos. J. D. Kondo..K. Pigment Cell Res. 2009. Anderson. dicyclopentadiene and 1. Perioli. J. T. 1989. Larkin. 45. Rives et al. 2679–2687. M. M. 2009. Oh. Methotrexate intercalated Zn.... 184. Phys. M. 2006. 5453–5463.Al Ion exchange Yes Khan et al. Mol. Hydrotalcite-type anionic clays: preparation. (2009) Vitamin B5 Li. P. V... M.. 1986. 2000. Uniform fast growth of hydrotalcite-like compounds..A. M. V.. Ohmori. Lerner.. T. F. S. 1. G..M. Inorg. 1528–1532. and melanogenesis: some observations and understanding. M. Rives..G. Structural and texture evolution with temperature of layered double hydroxides intercalated with paramolybdate anions. J. 1961–1966.. Nova. 1143–1162. 2011a... Rives. Cavani. Trans... Bettero. Chem. 91–92. J.M.266 Table 1 (continued) Drug or action Osteoporosis 1-Hydroxyethylidene-1.. R. J. Catal.B. A.Al.. Direct intercalation of amino acids into layered double hydroxides by coprecipitation.. Microporous Mesoporous Mater. Chem. H. J.. Hwang et al.. 2006b. A. Yonemura. Chakraborty. Amsterdam. M. N. New layered double hydroxides/phospholipid bilayer hybrid material with strong potential for sustained drug delivery system.. Chem. S. Mandal. V. (2007) Vitamin L1 Li.
Kong. Son. In: Duan. B. Z. P. Zhu.M. (Ed. N. Nanosize cobalt oxide-containing catalysts obtained through microwave assisted methods. S. New York. List. Stabilization of Co2+ in layered double hydroxides (LDHs) by microwave-assisted ageing. Léone.. J. Zhang. Ed. In: Wypych. (Ed. Kannan. Solid State Ionics 97. 1439–1446. vol. pp.... 3114–3121. O'Hare. Handbook of Clay Science. Layered Double Hydroxides. W. Choy.P. A. 36. 29.. Surf. V. In: Wypych. Environmental remediation involving layered double hydroxides.. 2009.. Casciola. Evans. Fernández.Q. R. 465–470.L. G. Rives.. Clay Sci.... Oh.. 2001. X. Desigaux.. Richard. Eng. C.J. J. C. A. U.. M. Logue. Marmottini..J. Mater... M. Inorganic layered double hydroxides as ascorbic acid (vitamin C) delivery system—intercalation and their controlled release properties.. Inorg.. Y. F. New synthetic routes to hydrotalcite-like compounds—characterisation and properties of the obtained materials. 199–204.... Degrad.Z.). 538–544. U. Biochem.. Kang. Catal.. Chem. 4th ed. An FT-IR study of the − adsorption and reactivity of ethanol on systems derived from Mg2Al-W7O6 24 layered double hydroxides.. U... G. Norquist. Intercalation of functional organic molecules with pharmaceutical.. Sci..c. Elsevier.. Duan.G. Nova Sci.M. Rives. V. A. A.S. M. 2009. Cellular uptake behavior of [gamma-P-32] labeled ATP–LDH nanohybrids. J. O'Hare. Phys. Xu. M.. Yahaya. Eur. Angew. R. Findrik. vol. Nutritional and botanical interventions to assist with the adaptation to stress.. 1999. 2007a. Li. Vittoria. M. Oh. Gutierrez.. 2010.. U. P. Leroux. On the stability of ascorbic acid in emulsiﬁed systems for topical and cosmetic use.G.. 373–379. Crystal structure and X-ray identiﬁcation of layered double hydroxides. M. biochemical and life sciences. Foye. 42.S. Choy. Goh.. V..J. Williams..H.. E. Ferreira..E. 17.R. 417–427.J. 2009.. Zhao. pp. Rives..H. 42... Rives.. 178. F.M. P. Rives. J. P.J. Preparation of double layered hydroxides. San Román. Nocchetti. 5. Preparation and characterization of hybrid organic– inorganic composite materials using the amphoteric property of amino acids: amino acid intercalated layered double hydroxide and montmorillonite. K. C.. Besee. 4940. Layered Double Hydroxides: Present and Future..C. Appl.... Fong.G. Clay Surfaces: Fundamentals and Applications. Gasser. D. 203–212. Inorg. Nocchetti. 180.R. 18. 2010a..... Li. T.I. S.. Dunbar.T.. Rives.... Cellier... Oh. J. J. J. 2003.. Martín. M. Y. Lemke.. S. Intercalation of vitamer into LDH and their controlled release properties. Ind. Shi. 4604–4607. Chem. Vymazal. Effects of oral L -tyrosine administration on CSF tyrosine and homovanillic acid levels in patients with Parkinson's disease.. Geueke. De Roy. Jin. J.. M.M. Choy. J.. Mg. J. G. Evans. V. D. Amino acid-pillared layered double hydroxide and montmorillonite —thermal characteristics. Park. J. 2001. Am. F. 30. A. Costantino. D. Nova... 3715–3722. Park. Labajos.. Water Res. 129–137. Novota. Melamed. Valim.W. 275–286. Holgado.. Encapsulation of ﬂavor molecules. Z.E. pp... Markland. M.). Lisa. V.M. Jaubertie.H.J. Costantino...H.S. Med..H. TaviotGuého. Fudala. pp. V. Amsterdam. Herrero.H. Lett. Surface and textural properties of hydrotalcitelike materials and their decomposition products. Kiricsi.I.. Appl. J.. Dorset. Nanotechnol. J. Evans.. Lei.. Top. 2004. Soc. Williams & Wilkins. He. E. 2005. F. Elsevier. 345–373. Y. BioMetals 18. J. J. 2004. Biomaterials 25.. 10. Jeong. Rives et al. 224.Y. 1671–1674. O. pp.. M.. J. characterization and pharmacological study. 1–87.M. G. Vivani. 2004. Catal. V. Modiﬁed hydrotalcite-like compounds as active ﬁllers of biodegradable polymers for drug release and food packaging applications. (Eds. Al layered double hydroxide.. Lagaly. J.).. 10196–10205.. 4653–4658. Kristallogr. 43. Res. Ruiz-Hitzky. L. 218–230. Han. Hong... A. Structural characterisation and delamination of lactate-intercalated Zn.. S.. Elsevier. S. Nocchetti.. Satyanarayana. Pinnavaia. Palinko. J. M. 2004. 2nd edition. Handbook of Clay Science. 2006. M. Inc.. Khan. 2002. I. 5018–5021. 2010. K.. Gutiérrez. J. Sisani. M.). Costantino.. Structure and Bonding.. hydroxide. 2008. 2006. Chem. 27.. (Eds. 2007. 375–384. A. 6. Layered Double Hydroxides: Present and Future. F. Forano. Park. V. Cario. Hajo.. Del Arco.. O'Hare. 180–196. M. Amsterdam. Recent progress in the synthesis and application of organically modiﬁed hydrotalcites.A. M. F. Hwang. pp. 2001. I.. Duan. Altern.. 2009. J. M. 1999b. pp. 1995. Sci. M.. Z.. 12. J. Duan. S..L. S. Growdon. 2006. Jinesh. (Eds. Self-assembly and characterization of layered double hydroxide/DNA hybrids.H. M. Nanosci. 317–322. Int. V. Jung. Chem... B.G.. Modelling of L-DOPA enzymatic oxidation catalyzed by L-amino acid oxidase from Crotalus adamanteus and Rhodococcus opacus. Fe-hydrotalcites. .. (Ed. chemical.. J. Solid State Chem. M. 25. Y.. Clay Surfaces: Fundamentals and Applications. M. Commun. 2005.. Appl. B 73... Lopez-Blanco. J.M. 598–604. S... V. M. S.. Layered double hydroxides: synthesis and postsynthesis modiﬁcation.. Springer.). M. 765–791. Costantino..L. V. Amsterdam. New York. 2nd edition. Hummel.. Lutskyg. Preparation of layered double hydroxides. B. In: Bergaya. Del Arco..J. 2004b. C.). B. 2007b. Chem. 119. A. Choy. S. C. J. 2004a. Rives.. Prévot.Y. Popa.. Nanotechnol. Chem. 38. 1995. J. Park. Baltimore.G.G. Wei. 20. Berlin. U.). into layered inorganic nanoparticles for controlled release of ﬂavor.J. G. Al layered double hydroxides with intercalated indomethacin: synthesis.. Chem.. D. Rives...S. Chem. (Eds. Anal. Oh. Kim. Principles of Medicinal Chemistry.G. 42.. L. Thomas. Chem.. Synthesis and characterization of new Mg2Al-paratungstate layered double hydroxides.).. D.Y... 1019–2021. Structure and Bonding. Pub. Elsevier. L. 1969–1977... C. Cunha... Z. Choi. J. Sci. 22. Rives. Kanezaki.. W.. Del Arco. Al-layered double hydroxides. D. 1399–1400....... Miron.. Choy. 103–109. C.. X. F. C.S. Y. C. Calorim.. Clay Sci. V. Tronto.. Chen. Eng. 1999a.R..D. Intercalation a controlled release of pharmaceutically active compounds from a layered double hydroxide..A. Costantino.. Choi. 628–637.. Han. Recent Pat. 157. 273–281. Hu. (Eds. A. S. Nocchetti.. Solid State Chem. 324–329. Del Arco. J. Nanosci.H.. Leroux. M. 4-hydroxy-3methoxy benzoic acid.G. C. J. Clay Surfaces: Fundamentals and Applications.. Satyanarayana. T. Clay Sci.... R. Evans.. Hefti.). K. D.. X. Wurtman. Carriazo. Y. Chem. Mater. J.. Pharm. S.. R. C. Hu. Gu. Elsevier... C. A. Labajos. D. T. J. Macromolecules 23. D. Inorg. 827–832. 1649–1658. D. Utilization of layered double hydroxides in medical applications. Bull. Bull.. K.P. 233–241. Rocha. Pub. Jakubiková. 2004.J. Gutiérrez. Constantino. M. Control.. F. S. Bookin. Lu.M. F.L. Martín. Int. Release studies of different NSAIDs encapsulated in Mg. Layered Double Hydroxides. 2006. D... T. Therm. Vivani. chloride and sulphate anions. (Eds. J. Chem. In ﬂuence of copper on the isomerization of eugenol for as-synthetized NiCuAl ternary hydrotalcites: an understanding through physicochemical study. 2008. Respir. F. Crystal structure of poly(ε-caprolactone). Antonyraj. 1999. 119. 87. M... Del Arco.. 2004c. T. F. J.J..J. 5. Nayakb. M. α-naphthaleneacetate from the lamella of Zn–Al-layered double hydroxide nanocomposite. J. I. Structural aspects of layered double hydroxides. pp. Fishf. O'Brien. D. Choy. Layered Double Hydroxides: Present and Future.J. M. Rives. A. Han. Kiricsi. Chem. Duan. Part B: Techniques and Applications. 6.. Choy. Springer. Colloids Surf. 2013. Bovo. 873–884. Belkacem.. Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants. 4041–4045. Forano. LDH in physical. In: Rives. Carriazo. Benito. 2005. M. / Applied Clay Science 88–89 (2014) 239–269 Choi. 1–37. Nanosci. Layered double hydroxides (LDH). Nanotechnol. 903–909.S. Preparation of glycy-l-tyrosine intercalated layered double hydroxide ﬁlm and its in vitro release behavior. Gutiérrez. Nano Lett. D.. V. W. Wei. 2913–2916. Fudala. Palinko. 1982. Stab.S. L... 121.H. Nova.. Wolfgang.. Pharm. Evans. Nistor.. Darder. Pitard.K. Inc. Oh. X. M.. Chem.H. Polym. 2010b. Catal.A. Aranda. Campbell. Chem.. 159–171. Rives.... C. Mater.. L. Inorg.B. 507–515. V. Appl..I. Inhaled mometasone furoate reduces oral prednisone usage and improves lung function in severe persistent asthma. T. Vasıc-Racki. C. 2006... D. Khan.Y.. 2006. Vivani. pp. Dong.. C.. 93. J. Y. Drits. A. Z. E. R. F. 2002. Craigd. Hussein. H. Developments in Clay Science. Evans. 267 Frunza. U. 425–458. Portier. Choy.H.V. E.. 85.. Herrero.. 2004. Intercalation and grafting of hydrogen phosphates and phosphonates into synthetic hydrotalcites and a. 2008. Synthesis and characterization of Cd–Cr and Zn–Cd–Cr layered double hydroxides intercalated with dodecyl sulphate. In vitro sustained release of LMWH from MgAl-layered double hydroxide nanohybrids. 101..H.. Tammaro. Kerwine. X. Figueras.. H.. Mousty.. J. Karpela.. 188. Constantino.. M. Xu. F. Sevilla.. 1343–1368.. Amsterdam. In: Bergaya.D. A. Investigation of thermal stabilization of poly(vinyl chloride) by lead stearate and its combination with synthetic hydrotalcite..). cosmeceutical and nutraceutical functions into layered double hydroxides and zinc basic salts.. X. Del Arco. Base catalysis in the synthesis of ﬁne chemicals. F. V.J. Sci. Choy. Lagaly.G. 3059–3064... 49. Trujillano. U. Chem. Li.. In: Rives.G.. 510–518. J. 2007.. B. V..G. Korean Chem.B. Korean Chem.-conductivity of the compounds there by obtained. J. M. Clay Sci. 4232–4240.. Kelly. 1997.. 2009. Lim.H. Carlotti. 93.). 3191–3198. Basic properties of Mg2+1 − xAl3+x layered double hydroxides intercalated by carbonate. Layered Double Hydroxides. L..J. J. 2342–2343.O. Nova 33.. Kwak.. Cebadera. 2000.. C.. Mater. 2012.. Catal.. In: Rives. M.. S. Pub..M. Antioxidant drugs intercalated into layered double hydroxide: structure and in vitro release. M. 1830–1836. 89–119. B.C. 374–402.. Therm. 10. Application of layered double hydroxides for removal od oxyanions: a review.. 11. Sh. Clay minerals and layered double hydroxides for novel biological applications. Martín. J. 3700–3705. Williams. J. L. 337–342.C. Inc. 1998. Lumryc. (Eds. X. 134. Thermogravimetric analysis of layered double hydroxides with chloramphenicol and salicylate in the interlayer space. Ragavan. In: Wypych. A. 1–234. Anal.I. Berlin. Martín. Bionanocomposites based on layered double hydroxides. Carriazo. pp.. Intercalation chemistry of layered double hydroxides: recent development and applications... 333–338. 2010.J. Massinelli. E. Z.J. Part A: Fundamentals. Chem.. Jeong.. Wei. 2007. Kong. 122–132. 383–411. Soc. Intercalative nanohybrids of nucleoside monophosphates and DNA in layered metal hydroxide. X. T. Quim. 2013. Kovanda. M. Benito.. Hidróxidos duplos lamelares: Nanpartículas inorgánicas para armazenamento e liberaçao de espécies de interesse biologico e terapêutico (in Portuguese). In: Duan. Developments in Clay Science. 6. Phys. Al. M. P. 2010b. Today 128.. pp. Recent developments in the use of layered double hydroxides as host materials for the storage and triggered release of functional. Kwak. 2001. J. Nocchetti. Zainal. Release 82. Martín. 8. 2008. 48.. 7. Stud. Mater. Y. 1990. H. (Eds.. V.. Guo. X. Chem. Layered double hydroxide as an efﬁcient drug reservoir for folate derivatives. Med. M.H. T.. Anticancer drug-inorganic nanohybrid and its cellular interaction. V.. Polyoxometalate complexes of layered double hydroxides. R. Forano. Satyanarayana. J.M. Costantino.B. 249–265. Jeong. New York. Taviot Gueho. D. Kwak.. 2001... Layered double hydroxides and their intercalation compounds in photochemistry and in medicinal chemistry. Berlin.H. 745–782. Kang.. 39–92. Nocchetti. Chem. Jeong. Calorim. Trotta. S.. Montero. Size control and optimisation of intercalated layered double hydroxides.. 34. 1994.A. Kaluskova.. Park. I. M. Amsterdam. V. Springer. G. Rev.H.. 56. Z... Intercalation of [Cr(C2O4)3]3 − complex in Mg.. Gallarte. Soc. J. 1999. Biocompatible nanoparticles intercalated with anticancer drug for target delivery: pharmacokinetic and biodistribution study. Controlled release of a plant growth regulator.T. D. M. Foo. Eng. Hrivnak. Park.P. Choy.. L. J.M.. Costantino. 906–912.. Duan. B. 42. J. F. 39.. 883–892. Herrero. Khan.S... Slade.. Labajos. F. D. Inorg. Life Sci.. 2004. 104. Leroux. Nanotechnol...H. D. Inorganic layered double hydroxide as nonviral vectors.... R. M. 2001. J. M.. J. J. V. 122–126.
Niebert. 417–423. 158. 339–345. D. Tortora. Catal. F.Q.J. Jung. Tammaro. Int.A.. Kim. Tsuhako. Carriazo. 2004. Biocatalytic synthesis of some chiral drug intermediates by oxidoreductases.. V. Kuwano. F. 71. Vittoria. New York.. 939–946. 71–75. Offenbacher. Soc. 181. Nanobiohybrids as delivery vehicles for camptothecin. Synthesis and characterization of camptothecin intercalated into Mg/Al layered double hydroxide.. Marenzi. Phys.M. S. Choy. M. 75–85. Park. Layered double hydroxide as novel antibacterial drug delivery system.. 55. J. Dopamine.. 280–289.. 907–922..X.. 22. Kwak. 61–120. 522–529. R.J. Springer. Oil Chem. Int. Zhang.P. V. L. 287. M.F.... Chem. Nocchetti.Al hydrotalcite-like compounds.. T. Riaz... 222. Synthesis and controlled release properties of prednisone intercalated Mg–Al layered double hydroxide composite. 2009. Setton. Cristina. 88. 2012... N. 28–39. 267–276. M. J.A. L. Macromolecules 32. J.. G. Kim. Effects of oxidative stress and antioxidative factors. Chem. Eng.. 2010.S.A.D. Chem. 2009. Qin. Silion. Ma.Y. characterization and release kinetic studies. 48.. Fisher. Popa..I. Sharma. / Applied Clay Science 88–89 (2014) 239–269 Pereira. M. Zhou. 2010. 1999. Dispersion Sci.G. 2933–2939..T. Layered double hydroxides (LDH) intercalated with metal coordination compounds and oxometalates.. Chem. 2001... L...268 V. Chem. Mutascio. Layered double hydroxide/polymer nanocomposites. J.. H. Kooli... Lonkar. K. (Eds. W. 2006. S. Layered double hydroxides as drug carriers and for controlled release of non-steroidal antiinﬂammatory drugs (NSAID): a review.L.. Herrero. Chem.P. Panda. J. A. 48.E.. Sci. Luthra. D.G.. B. M. 1559–1572. 2008. Release 95. 93. Porous. D. Kinetics of copolymerization of PEG containing multiacrylates with acrylic acid. J. S.. G. H. 2003.. J. 2009. Eng.. Jung.. J. Lin. J... Heinrich.G... Li. V.. J.. Cellular uptake mechanism of an inorganic nanovehicle and its drug conjugates: enhanced efﬁcacy due to clathrin-mediated endocytosis. V. Koshinuma..S. 2009. Marchetti. M. Degrad. Lu. J. Wang.. Ulibarri. D..H.C. Mater. Semenzato. 2499–2503.. 10. Bio-LDH nanohybrid for gene therapy. Balasubramanian. 2009a.. Chem. J. F. Racemization of tyrosine in the insoluble protein fraction of brunescent aging human lenses. Peppas.N. Pang. V. L. 9. W. J. Y. D. 25.X.. 13.G.. Nakayama. 1792–1797. Mini. Elsevier. Oh. Solid State Chem. M. Heterogeneous Catalysis by PolyoxometalateIntercalated Layered Double Hydroxides. Seis. Inorg.Q. Lisa.. M. S... V. Kmetec. R. A novel organic–inorganic microhybrids containing anticancer agent doxiﬂuridine and layered double hydroxides: structure and controlled release properties. Adsorption of norﬂoxacin in aqueous solution by Mg–Al layered double hydroxides with variable metal composition and interlayer anions. L.. de Vos.D.G. G. D. Sierakowski. Y. Weintraub.. L. Mater. Sheng. Holgado. Med. Nanohybrids for controlled antibiotic release in topical applications.... S. 43. R. Takeshita.. L.. 93–95. 2002.. 158–163. 2008a.. Dermatol.H.. Bochner. Mater. 2008. B. New York. X. Synthesis and characterization of 10hydroxycamptothecin – sebacate – layered double hydroxide nanocomposites. R. Control.. M.. Huang. 2012.. 161–171. Serra. S. Rives. Stab. 105–111. 1998.. 2008b. Zheng.. X. C.).. Besse. X. 2013. Zhu. Enteric-coated layered double hydroxides as a controlled release drug delivery system.. Sci.. ketoprofen or chloramphenicol succinate encapsulated in layered double hydroxides with the hydrotalcite-type structure. Nova Sci. 2006b. 204–210.. S. Am. Jacobs. Valim. In: Rives.. Mater.. Xu. Schiffmanb. Rapid synthesis of hydrotalcite with high antacid activity. Solids 69. In vitro release of citrate anions intercalated in magnesium aluminium layered double hydroxides.. Ulibarri. Li... B. Sun.S. Y. J.. Characterisation of diclofenac. Lai.. 206–217. J.... G. Marques.. Mastrangelo. L. Allergy Clin. Li. Synthesis and characterization of 5ﬂuorocytosine intercalated Zn–Al layered double hydroxide. Eng. H. Jiang. J. K. J.. 2012.F. Gray. Solids 65.. Solids 67. Prieto. X. A. K.S. Patil. Y... Mater... 2012. 2010.. Li. Kannan. Chem. Schwartzbard. 53. Technol.J. Biotechnol. Pharm. 459–495. Chem.. F. 151. 2005. Lee.. Biol. A. Technol. 2419–2426. Ind. A. J..J. A. Phys. Dall'Aglio. High-performance liquid chromatographic determination of ionic compounds in cosmetic emulsions: application to magnesium ascorbyl phosphate. V. Silvério. An alternative route to polyoxometalateexchanged layered double hydroxides: the use of ultrasounds. P. Proud.S. V.. E. Rives...R. C. Inc.. R.. 29–38. U. Pub. Appl. 2004. Choy.H. Agents 29.. 385–389. A.. del Arco. 156–166. D.. B.. Li. Ranganathan. W. Stability of ascorbyl palmitte in topical microemulsions. Tsuhako. Rev. 363–372. J.Q. Choi. J. Solid State Ionics 151. Chem. J. Hritcu. Ghanotakis.M... Chem. C. Chem.. 271–279. J. Evidence supporting zinc as an important antioxidant for skin.. P. Lichtenstein. Pharmacol.T. B..A.. Y.. Li. Hou.. Coord... characterisation and delamination behaviour of lactate-intercalated Mg. M. S. Incorporation of active nanohybrids into poly(ε-caprolactone) for local controlled release: antiﬁbrinolytic drug. 2013.A. Pharm. Chem. J. M. Microporous Mesoporous Mater.H. J.. Agarwal. M.. Wypych. W. Int. Jin... 2012.. Rocha. Chin.C. Polymer 46. Madey.. 319–397. D.C.S.. P.. J.. Lu. 2013. 269.. 122. Phenoxymethylpenicillinintercalated hydrotalcite as a bacteria inhibitor. Costantino. Nakayama. Preparation of 1-hydroxyethylidene-1. Z.. Mater... Califano. Jaubertie. Cardiol. Xu.... Schleimer.. Russo. Pharm. 92. Tronto. J.). Sci. Int. W.H.. 2001.R. Incorporation of Mg–Al hydrotalcite into a biodegradable poly(ε-caprolactone) by high energy ball milling. pp. S...M.. Expert Opin. Romeo.. Ladewig.. W.. pp. J. W.. Duan. 16. J. Layered Double Hydroxides: Present and Future. CATTECH 7.Z. A. Jones. 128.Y. L. Sui. V. Chem. Ranganathan. Control.... 1997. N. Jones. Vittoria.P.. Pharm. A.F. Chin.. Hou.. A. Nakayama. M. S.... Synthesis and characterization of ifosfamide intercalated layered double hydroxides. K. M. 2001. 181.M.. J.T. D.. E.. Drug transport mechanisms and release kinetics from molecularly designed poly (acrylic acid-g-ethylene glycol) hydrogels.and L-beta-3. Hydrogenation catalysys by mixed oxides prepared from LDHs.. Vittoria. Rives et al.. Patel.. M. M..X. 1998. Int..1diphosphonic acid-intercalated layered double hydroxide and its physicochemical properties. F. J. 1806–1810. 2013. 381–383. Rives. Hydrotalcite-like anionic clays in catalytic organic reactions. 2009. In: Wypych. 1994. K.H. Imai. G. Pub. Choy. Clay Sci. J. M. L. R. Catalysis by hydrotalcites and related materials. 1024–1027. K. J.. Dos Reis. Int. D. In: Gil. 89–93. T. W. 2007. S. A. 2006. Newman. H. F. 475–480.. 79–97.. H. 2004. Nanocomposites coated with xyloglucan for drug delivery: in vitro studies. Adv.. Colloid Interface Sci. characterization and application studies. F. F... M. 2003. Wei.. Calignanoe... B 113. 74. 5440–5451. G. Alginate and hydrotalcite-like anionic clay composite systems: synthesis. J. Padella. U. C. 74. Costantino. Liu. Solid State Sci. Duan. Pharm... Controlled release of drug from cyclodextrinintercalated layered double hydroxide. 1995. T. Lett. Lett.. Jin. Wada.B. Li.A. 1.4-dihydroxyphenylalanine hydrochloride (L-Dopa)-induced cytotoxicity towards catecholaminergic neuroblastoma SH-SY5Y cells. S. 2010.M. Solids 71. Han.H. Efﬁcient delivery of anticancer drug MTX through MTX–LDH nanohybrid system. Pharm. U. C. P.J. Langmuir 18.. 22678–22682. Li..P.. V.. 1333–1341. Evans. M. 108.. L.. New hybrid materials based on layered double hydroxides and antioxidant compounds.C. characterization and applications of layered double hydroxides containing organic guests. Richhariya. 1997. J. B. 269. Vicente. Drug Deliv. 3762–3771.T. The in vitro and in vivo anti-tumor effect of layered double hydroxides nanoparticles as delivery for podophyllotoxin. Clay Surfaces: Fundamentals and Applications. Gorrasi... Rives. Sorrentino. Reconstruction of layered double hydroxides from calcined precursors: a powder XRD and 27Al MAS NMR study.A. Arizaga. 606–611. Rives. A. Gasperlin. pH-Responsive composite based on prednisoneblock copolymer micelle intercalated inorganic layered matrix: structure and in vitro drug release.. Tyner. Xue. Polym... Szarka.. 789–796. D. Duan. Freidhoff. S.G. Mayadevi. Hou. Molecular dynamics simulation of cationic and anionic clays containing amino acids.... 241–246. 65.. Synthesis. 1997. Liu.S. 2002.. R. Kwon. J. Pagano. Polym. Appl. 451–460. Lu. 1552–1555. Kang. Nova. N. 8–14. Res. Pan.P. Breslin. Lett.. Wang. V.G. N. S. Nanohybrids of phenolic antioxidant intercalated into MgAl-layered double hydroxide clay. Hou. Lu. Drug Deliv.. Appl. Pinnell. Chromatogr.R. 6149–6158.J.... P. J. Hanson. Coveney. Li. Mandal. Rives.. C.. Xu... Dubey. R. Remick. J. Newman. M.. 2001. J. Holgado. Perioli.. Rev. J. H. Chen. V. 1996. Old and new substrates in clinical nutrition. Z. Chem.. T.G.M.C. New J. San Román..M. R. Oh. Antimicrob.Q. del Arco.. Electrospinning of drug-loaded polymer systems: preparation and drug release. Pillaring of a layered double hydroxide by polyoxometalates with Keggin-ion structures. M. L.J. Tajima. A. San Román. Res.. 129–141. Hubbard. Chem. Eng.M. J. H. 176–184.... Ulibarri. G.). Kutlu. 2013. Intercalation of amino acids and peptides into Mg–Al layered double hydroxide by reconstruction method. F. J. J..J... Leroux. Ryu... Rev.S. Sci. A.. J. Sci. 2002. G. L. Lamberti. J.. Y..J. Tammaro. Ch. 2007.. Jones. Sun. 350–356.. Y. 2000. Rives. Solid State Sci. Bettero. Liu. Intercalation of hydrophilic and hydrophobic antibiotics in layered double hydroxides.S. Zhang. Li. J.. V. Marchi. 2009b. Leuteritz.A. Layered double hydroxide nanoparticles in gene and drug delivery. M. Biochem. Nutr. L. Costantino. C. 43. DeBuys.P. 223–230. Perioli. Liu. 2003. W.. G. Hou. J. Pharm.T.. Li. Synergistic effect in the hydroxylation of phenol over CoNiAl ternary hydrotalcites. Banerjee.. Ribeiro. F. 16. 2007.. Clay Sci. Phys.. Layered Double Hydroxides: Present and Future. Martín. M. Release 169. 443–488.. Pharm. H. Bahadur.. Catal. Inorganic matrices: an answer to low drug solubility problem.. Choy. K.. 2011.. J. 359–366. M...R. Nakamura. Evans. 323–382. Labajos.G.P. Chem. 1411–1417. V. Ladewig. Immunol. Tian. Tetè.. Bolognese.. V.. H. S. The inﬂuence of the nanocomposite MgAl–HTlc on gastric absorption of drugs: in vitro and ex vitro studies. O. C. J. Martín.L.. Thermal transitions in the bilayer assembly of dimyristoylphosphatidylglycerol sodium salt dispersion in water: a new phase transition through an intermediate state.. 2004. 2006a. He. Jeong. 3551–3556. Rives. 41. Rives. V. V... Monzón. E. B..... J. Clay Sci. Marmottini. J. Stealey. (Ed. Scott. Phys. 81. Double layered hydroxides as potential anti-cancer drug delivery agents.. L. 1999. Preparation.. F. Expert Opin.. 17. E. V.. G. Nie. Peppas.A.J. A. X. pp. 2012... M. S. J. V. Preparation and properties of new ﬂame retardant unsaturated polyester nanocomposites based on layered double hydroxides. J.F. 9. J. 19. H. L.. 1662–1666. Li. 2006. 30. C.M. D.P... Balbo. M. B.. U.. J. 1601–1608.. 2012. . Spiclin.Q.. Pagano. W. 5590–5597. M. Sci. Li. R. C. Inc.. 229–234. Fibrate therapy: an update. Wang. Zhang.. In-vitro release kinetics and stability of anticardiovascular drugs-intercalated layered double hydroxide nanohybrids. Technol.M. H. 16. 469–478. Peter. J. Austria. P. B. Giannelis. Controlled preparation of layered double hydroxide nanoparticles and their application as gene delivery vehicles. Zhang. M. Rostan. Rives. Domenech.. F.K. (Ed. Y.F.. 27–29. Int.D. Effects of prednisone on the cellular responses and release of cytokines and mediators after segmental allergen challenge of asthmatic subjects. Synthesis and characterization of ﬂoxuridine-layered double hydroxide nanohybrid. Int. M. Salinas. Park. L. D. New York. Y. Amsterdam. 210. 33.. 1999.. 1345–1360. Oh. 15090–15100. Y.B. B. Phys. Pinnavaia. Satyanarayana. 6. Parashar. Trujillano. Bioconjugate Chem. 89–95. J. Rev.. A 705. Korili. 26. Schroeder. S. 61. 2010. S.. 2009..V. M. C. Srivastava. Li. 220. Wei. S.A. G. Li.. Chem. J. Trikeriotis. Biomaterials 27. 2001. J.... Ashaf. J. W.P. Biphosphonates: a review of their pharmacokinetics properties. 2124–2128. (Eds.. 1989. M.. Yu. Synthesis..J. 388. Coq. Li. 501–514. 2004. D. Tichit. 685–688.. Xiao.. Bone 18... S. Sammartino. D. 332.X. Appl. Synthesis and thermo-optical stability of omethyl red-intercalated Ni–Fe layered double hydroxide material. 367. M.). Tsuhako. D..
H. J. as skin antioxidants. Chin. J. Xia. P. J. F. Hwang. Li. 62–65. Xu. sustained release properties of magnetically functionalized organic–inorganic materials: amoxicillin anions intercalated magnetic layered double hydroxides via calcined precursors at room temperature. (Eds. Rev. Sci. I. characterization. Labajos. D. Xu. Wang. J. Whilton. 2005. Pap. T. P. Duan. J.. Z.. G. Y. S. Synthesis. Layered double hydroxides as supports for intercalation and sustained release of antihypertensive drugs. 20. Chem. Sasaki. Environ. Evans. Wei. Choy. 2008. D. 3185–3194. Solid State Sci.A..P. Okazaki.. 2012. vol.. Jiang. Colloid Interface Sci. Z. P.M. D. Med... / Applied Clay Science 88–89 (2014) 239–269 Ulibarri. M. 1597–1601. Comparative study of the synthesis and properties of vanadate-exchanged layered double hydroxides.A. Pharm. Zhao. 2002. Layered solids as a “molecular container” for pharmaceutical agents: l-tyrosine-intercalated layered double hydroxides.Q.. Zhang. A. Z. 53. Solid State Chem. 6-O-acyl-2-O-alphaD-glucopyranosyl-L-ascorbic acids. S. 673–677. F. A... 2006. Dodecyl sulfate–hydrotalcite nanocomposites for trapping chlorinated organic pollutants in water. 4124–4155. Z. Park. W. K. B. Elsevier – Academic Press. Mater. 38. Lett. Yang... 45. 2008.J. 2592–2599. W... and controlled release antibacterial behaviour of antibiotic intercalated Mg–Al layered double hydroxides.). mechanical properties. 300–3004. Clay Surfaces: Fundamentals and Applications.. K.. pp. 1771–1779.. Qi.H. Hermosín. 2012. Guo. Recent advances in the synthesis and application of layered double hydroxide (LDH) nanosheets. Jing.. N. Int. Hu. Q. Wang.. Q. Rives et al. 181. Qual. Kagunya... 1302–1310. 251–284. O'Hare. M. Z... Interface Science and Technology. Layered Double Hydroxides: Present and Future.. Q. 19. M. On the adsorption of tetracycline by calcined magnesium–aluminum hydrotalcites. 613–624. Xue Duan.. 1994. Chem. Solid-state properties and crystal structure of gliclazide. Ma. F. Vickers. 179.. He. Zhang. Mater... thermal property and in vitro release of captoprilintercalated Mg–Al-layered double hydroxides. X.. S. Q. 11. 78. X. X. Vittoria. M. Ni.. Lu. Mater. Z.. 1997.. Selection of inorganic layered double hydroxide materials for intercalation of a cisplatin-guanosine adduct.. J.. .N. Evans. 2005. M. New York. Inorg. M.. Chem. Ay. Effect of hydrotalcite on the thermal stability. Y.G. R. 104–109. Wei. J.P. E.. Inorg. D. K. Synthesis and properties of Mg2Al layered double hydroxides containing 5-ﬂuorouracil.. Xu... Valarezo. Shields.. T.. 33. Z. rheology and ﬂame retardance of poly(vinyl chloride).. Appl. Wang.. J. Wei.G. J.. Layer-by-layer assembly and morphological characterizations of DNA/layered double hydroxide thin ﬁlms. 72.. Rives.and polyamino acid intercalated layered double hydroxides. Satyanarayana. Mater. Mater. 1994. P. Tammaro. New inorganic-based drug delivery system of indole-3-acetic acid-layered metal hydroxide nanohybrids with controlled release rate... Han. Ulibarri. Yin.J... 1. Wang. Gao. Amsterdam.. J.. Xu.L. Guo. 2005.V. K. Tai. Chem. 2009.C.... L.. Nanostructural drug-inorganic clay composites: structure. Sh. Pure Appl. Yang. J.... Clay Sci. In: Rives.. 269 Winters. 78.. Polym... 1792–1801. Han. L. C. B. Mann. 462–468. J. V. 2007. Z. (Ed... Hydrothermal synthesis of layered double hydroxides (LDHs) from mixed MgO and Al2O3: LDH formation mechanism. 1–10.. 47. M.. Res. Chem. Solid State Chem. J.. Zheng. Hu. 33.. F. Jones. S. Chem... Zumreoglu-Karan.. Fan. NOVA Sci. M. D. 2001.Z.. Yang.B. Zhang. Layered double hydroxide nanomaterials as potential cellular drug delivery agents. Z. J.M.G.. 1197–1203. H. S. Liu. Layered double hydroxides in water decontamination. 66. Q. Park.. Chem. Duan.. 15. Chem. Malagón.. O. X. Chem. Solid State Chem. Layered double hydroxides —multifunctional nanomaterials. pp. V. L.. Fabrication and sustained release properties of poly (ε-caprolactone) electrospum ﬁbers loaded with layered double hydroxide nanoparticles intercalated with amoxicillin. Wang. Xu. Timmins. 2012. G.T. 2004.. J. Mater. Fujinami. 17. X. 2013. Wypych. Wang. Chem. G. 112. Bioinorganic clays: synthesis and characterization of amino..J. S... Bull. Wang. 178. 5169–5180. 2004. 7. Zhang.. Zou. E.X. Z. Z. Lu. J. Y. Zhang. Pu. 2006. 2610–2619. Mater. 1–553. Gonzalez. 698–707. Zhang.. 274. Inc.. S. H.. 1055–1062. 736–741..S... Li. 2004. J. Liu.. Chem. Nagy.). York. Yuan. D. Zhao. 19. Pub. Yamamoto. Trujillano. Synthesis and characterization of a series of novel monoacylated ascorbic acid derivatives.J. 2679–2685... 2003. V. Xu. Guo. M. L. Synthesis. 2012. 1623–1629. Y. Intercalation of l-dopa into layered double hydroxides: enhancement of both chemical and stereochemical stabilities of a drug through host–guest interactions... 2009..S. J..
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