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(外文)海藻酸钠壳聚糖钠双氯芬酸钠释放微粒系统

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(外文)海藻酸钠壳聚糖钠双氯芬酸钠释放微粒系统 International Journal of Pharmaceutics 232 (2002) 225–234 Alginate/chitosan particulate systems for sodium diclofenac release M.L. Gonza´lez-Rodrı´guez a,*, M.A. Holgado a, C. Sa´nchez-Lafuente a, A.M. Rabasco a, A. Fini b a Departamento de Farmacia y Tecnologı´...
(外文)海藻酸钠壳聚糖钠双氯芬酸钠释放微粒系统
International Journal of Pharmaceutics 232 (2002) 225–234 Alginate/chitosan particulate systems for sodium diclofenac release M.L. Gonza´lez-Rodrı´guez a,*, M.A. Holgado a, C. Sa´nchez-Lafuente a, A.M. Rabasco a, A. Fini b a Departamento de Farmacia y Tecnologı´a Farmacace´utica, Facultad de Farmacia, C/Profesor Garcia Gonzalez s/n, Uni�ersidad de Se�illa, 41012 Se�illa, Spain b Istituto di Scienze Chimiche, Uni�ersita` di Bologna, 40127 Bologna, Italy Received 25 June 2001; received in revised form 8 October 2001; accepted 11 October 2001 Abstract Alginate/chitosan particles were prepared by ionic gelation (Ca2+ and Al3+) for the sodium diclofenac release. The systems were characterized by electron microscopy and differential scanning calorimetry. The ability to release the active substance was examined as a function of some technological parameters and pH of dissolution medium. The release of sodium diclofenac is prevented at acidic pH, while is complete in a few minutes when pH is raised up to 6.4 and 7.2. The alginate/chitosan ratio and the nature of the gelifying cation allow a control of the release rate of the drug. The release mechanism was briefly discussed. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Alginate/chitosan beads; Ca2+ and Al3+ ions; Sodium diclofenac; Alginate/chitosan ratio; Dissolution profiles www.elsevier.com/locate/ijpharm 1. Introduction The use of biodegradable polymeric carriers for the drug delivery systems has gained a wide interest, mainly for their biocompatibility and, among the microparticulate systems, microspheres show a spe- cial importance for providing local (Lorenzo- Lamosa et al., 1998; Hari et al., 1996) as well as temporal controlled release of the drug (Donbrow, 1992). Different types of polymers are encountered in the literature used to this purpose. In the case of the release of diclofenac are available: poly-3- caprolactone (Alonso et al., 2000), poly-/vinylalco- hol (Chawla et al., 2000), poly-lactide-co-glycolide (Tuncay et al., 2000a,b). Also natural polymers found their application in this field: albumin (Tun- cay et al., 2000a,b), alginate (Gursoy and Cevik, 2000; Acikgoz et al., 1995), carboxymethyl-cellu- lose (Arica et al., 1996), chitosan (Lim et al., 1997; McLaughlin et al., 1998). The preparation and characterization of the samples are quite similar in most cases. The anti-inflammatory drug (as sodium salt) is dissolved in an aqueous solution containing the soluble polymer and, in the case of carboxylate- containing polymers (alginate, carboxymethyl cellulose), the formation of microspheres was * Corresponding author. E-mail address: rabasco@fafar.us.es (A.M. Rabasco). 0378-5173/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved. PII: S0378 -5173 (01 )00915 -2 M.L. Gonza´lez-Rodrı´guez et al. / International Journal of Pharmaceutics 232 (2002) 225–234226 obtained by the addition of Ca2+ or Al3+: the hydrophilic colloids interact with metal ions to form crosslinked insoluble complexes, that precip- itate incorporating the drug. In this paper, we prepared microspheres of alginate containing sodium diclofenac and exam- ined the different influence of Ca2+ or Al3+ ions on the microsphere morphology and the influence of different amounts of chitosan on the release of diclofenac. Among polyanionic polymers alginate has been widely studied and applied for its possi- bility to modulate the release, according to the properties of its carboxyl groups as well as its biodegradability and absence of toxicity. Also chi- tosan finds wide applications in pharmaceutical technology as tablet disintegrant, for the produc- tion of controlled release solid dosage forms (Miyazaky et al., 1994; Kas, 1997; Illum, 1998; Sezer and Akbuga, 1999) or for improvement of drug dissolution (Felt et al., 1998; Gupta and Ravi Kumar, 2000). Diclofenac is a suitable candidate for incorpo- ration into microspheres (Hosny et al., 1998; Go- hel and Amin, 1999) to minimize its adverse effect after oral administration; in fact, alginate micro- spheres containing diclofenac start to release the drug after the pH of the environment increases above 7 (Sabnis et al., 1997), by-passing the gas- tric environment and avoid direct contact between the drug and the gastric mucosa. 2. Materials and methods 2.1. Materials The following materials were obtained from the indicated suppliers and used as received: sodium alginate (low viscosity; viscosity of 2% solution 25 °C, �250 cps), chitosan (Practical grade from crab shell; Sigma, Barcelona, Spain). Calcium chloride hexahydrate, aluminum chloride hexahy- drate (Sigma, Barcelona, Spain), di-sodium hy- drogen phosphate anhydrous, potassium di-hydrogen phosphate, hydrochloride acid 35% and acetic acid glacial 100% (Merck, Barcelona, Spain), were of the highest purity level available. Sodium diclofenac was of pharmaceutical degree (Farchemia, Italy). 2.2. Preparation of microspheres Sodium diclofenac (0.25% w/v) was added to aqueous solutions of sodium alginate (1.2% w/v) and stirred up to complete dissolution. This solu- tion was dropped using an hypodermic syringe into a second solution, containing Ca2+ (or Al3+) ions (1.3% w/v) and chitosan, previously dissolved in acetic solution (0.5% v/v). Microspheres formed immediately and were left into the original solution for 24 h to ensure internal gelification also. Then they were filtered, washed and dried at room temperature. The whole preparation was carried out at room temperature. Table 1 lists the formulations prepared. 2.3. Loading and yield of the process To evaluate the amount of the drug inside the microspheres, an indirect method was used (Fer- na´ndez-Herva´s et al., 1998). Aliquots from the filtered solutions remaining after removal of the beads were assayed spectrophotometrically at 276 nm. The amount of sodium diclofenac entrapped was calculated from the difference between the total amount of drug added and the sodium di- clofenac found in the filtered solution. 2.4. Thermal analysis Thermograms were obtained using differential scanning calorimeter (Mettler FP89HT), to evalu- ate the state of the active agent inside the micro- sphere of possible degradation. All the samples were run at a scanning rate of 10 °C/min from 30 to 300 °C. 2.5. Scanning electron microscopy Micrographs of the external surface were ob- tained by SEM (Philips XL 30), depositing on the sample a thin film of carbon. The shape and size of the beads were determined using an image analysis system (Scion Image) which was con- nected to the microscope. The following parameters were selected to char- acterize the sodium diclofenac microspheres: M.L. Gonza´lez-Rodrı´guez et al. / International Journal of Pharmaceutics 232 (2002) 225–234 227 � area (A), it is the selected surface; � perimeter/length (l), it is the length around the outside of the selection, or line length for line selections; � diameter of the equivalent area circle (ECD), this is an equivalent diameter that is calculated as follows: Dcirl=2 �A � where A is the area of the closed boundary of the particle. � shape factor (s), this parameter is used to measure object complexity, namely contour complexity. The more the variation of the con- tour, the more the shape factor parameter is elevated. The value of s is determined as follows: s= L2 4�A where L and A are the perimeter and the area of the closed boundary of the particle, respectively. 2.6. Release tests Dissolution assays were carried out in triplicate for 6 h at 37�0.5 °C. For the first 2 h, pH of the dissolution medium was buffered at pH 1.2 (HCl/ NaCl, to mimic the gastric district). pH was then raised up to 6.6 (phosphate buffer) and main- tained at this value for further 2 h. Finally, a little higher pH (7.4) was used up to the end of the experiment. The tests were performed into an apparatus as described in USP 23 (Turu Grau, mod. D-6). At prefixed time (15 min), 3 ml of solution were withdrawn and spectrophotometrically assayed for the diclofenac content (�=276 nm) (Hitachi, mod. U-2000). Dissolution tests were carried out taking into account the following parameters: type of gelify- ing ion and alginate/chitosan ratio. 3. Results and discussion Side effects, mainly at the gastric level, are well known, following oral administration of an NSAID. Therefore the efforts of many researchers have been concerned to solve these problems, through a variety of techniques of protection of the gastric mucosa or alternatively to prevent the NSAID release in this district. In this paper we evaluate the potential utility of natural materials, such as alginate and chitosan in inhibiting sodium diclofenac release in the gastric environment. And since among the microparticulate systems, micro- spheres have a special interest as carriers for NSAID, mainly to extend the duration period of the dosage form, we aimed to investigate the Table 1 Composition of the different formulations used for the preparation of sodium diclofenac microspheres Alginate/chitosanSodium alginate (%)Chitosan (%)CationBatch L1 0.1Ca2+ 1.2 12 0.1Ca2+L2 151.5 Ca2+ 0.2L3 1.2 6 L4 Ca2+ 7.51.50.2 1.2 1.2Ca2+ 1L5 Al3+ 0.1 1.2 12L6 L7 1.5Al3+ 150.1 L8 1.2Al3+ 60.2 7.51.50.2L9 Al3+ 1.2 1L10 Al3+ 1.2 Al3+ 0.6L11 1.2 2 31.20.4L12 Al3+ Al3+ 0 1.2 0L13 M.L. Gonza´lez-Rodrı´guez et al. / International Journal of Pharmaceutics 232 (2002) 225–234228 Table 2 Encapsulation efficiency (EE) and shape parameters of the different formulations; ECD, equivalent circular diameter Area (mm2) Perimeter (mm)Batch Shape factorEE (%) ECD (mm) 99.65�5.28L1 11.35�2.10 10.82�3.03 0.825�0.03 3.80�0.52 11.98�3.58 10.94�2.8599.63�7.99 0.798�0.05L2 3.91�0.99 99.66�7.21L3 9.30�5.81 10.21�4.11 0.897�0.01 3.44�1.01 99.63�10.02L4 10.51�2.78 10.54�4.08 0.847�0.05 3.66�0.21 8.70�3.13 10.10�3.6698.82�5.21 0.938�0.03L5 3.33�0.09 99.87�4.11L6 14.37�9.54 11.62�3.85 0.752�0.01 4.28�0.24 14.41�4.51 11.62�2.10L7 0.749�0.0299.85�10.32 4.28�0.54 12.99�5.41 11.40�5.9299.68�7.41 0.801�0.05L8 4.07�0.65 99.72�3.33L9 13.14�5.99 11.56�5.21 0.813�0.02 4.09�0.54 10.01�2.10 9.10�2.45 0.662�0.01L10 3.57�0.8199.07�6.52 10.22�5.47 9.09�2.6699.3�11.45 0.648�0.03L11 3.61�0.77 10.30�2.33 9.32�1.48 0.675�0.05L12 3.62�0.6399.49�7.41 10.04�4.10 9.20�3.21 0.675�0.0499.76�5.23 3.58�0.41L13 possible applicability of chitosan treated alginate beads as a controlled release system for soluble salts. We prepared microspheres containing sodium diclofenac starting from natural polysac- charides by ionotropic gelation method and exam- ined the effects of various factors (alginate/chitosan ratio, electrolyte concentration and nature of bead). 3.1. Microsphere characterization 3.1.1. Morphology Alginate/chitosan microspheres containing sodium diclofenac were evaluated for particle size, yield and encapsulation efficacy and surface mor- phology. The ionic gelation method gave beads with a high diameter ranging from 2 to 4 mm (Table 2). The drug encapsulation yield was more than 98% in all the cases, and the efficacy was neither affected by the alginate amount nor the crosslinking ion used. So, this method is useful to encapsulate ionic drugs with a high water solubility. Although the encapsulation of the drug was approximately 100% in all the formulations, the use of different ions, such as calcium or alu- minum, determines the mechanical properties of alginate gels and the egg-box structure of the beads, which gives it the spherical morphology. Fig. 1 shows a microsphere prepared adding Ca2+, exhibiting acceptable sphericity and a nota- ble surface porosity, with a shape factor greater than 0.80 in all the cases. This morphology was found independent of the starting composition, provided that Ca2+ ions were the gelifying agent. Due to the adhesive properties of chitosan, micro- spheres tend to agglomerate (Lim et al., 1997; Ganza-Gonza´lez et al., 1999; Murata et al., 1999). The aspect and morphology of the particulates prepared with Al3+ ions is different: no formula- tion enabled the formation of a spherical mor- phology; on the contrary, the particles are flattened, disk-shaped with a collapsed center. The surface appears smooth and little porous (Fig. 2), with a shape factor less than 0.80. The trivalent ions cause more points of aggregation between two contiguous alginate chains, binding them so strictly and quickly that, as a consequence, there is no time to get spherical forms, during their formation. Fig. 3 recalls the feature of a drop touching a water surface, suggesting that instantaneous gelifi- cation blocks the situation of the very first contact between the two solutions, the one containing alginate and the other one the inorganic ions. 3.1.2. Differential scanning calorimetry Thermograms of both types of microspheres do not offer clear peaks of identification (Figs. 4 and 5) (Ford and Timmins, 1989). Calcium chloride shows two endotherm peaks in the temperature range 180–220 °C; while M.L. Gonza´lez-Rodrı´guez et al. / International Journal of Pharmaceutics 232 (2002) 225–234 229 Fig. 1. Scanning electron micrographs of sodium diclofenac microspheres formulated with calcium chloride. sodium alginate decomposes at about 240 °C with a broad exotherm. Peaks of the single com- ponents are not visible when combined into a microsphere, whose thermogram shows only a broad and small endotherm, probably related to dehydration, present at a temperature about 120 °C. The same applies to Al-microspheres: in this case the endotherm peak present in the ther- mogram of AlCl3·6H2O is also absent. This can be interpreted as follows: that a chemical reaction occurred in solution, modifying the starting reagents and that a strong interaction is present among all the compounds inside the formulation; this fact additionally acts as a stabilizer, since degradation endotherms both for alginate and sodium diclofenac are absent at the highest tem- peratures of the thermogram. 3.1.3. Effect of the ion on the release process For the preparation of chitosan treated alginate beads containing sodium diclofenac, we dissolved sodium diclofenac in the aqueous solution of sodium alginate. The addition of the divalent (or trivalent) ions produced (Kondo, 1979) a partial neutralization of carboxylate groups present on the alginate chain, forming an insoluble (but per- meable) transitory thin gelatinous film: 2nNaAlginate + nCa2+ � nCa(Alginate)2 + 2nNa+ Ionic gelation is the result of the formation of an ‘egg box’ between facing units of two different chains and depends on the inorganic ion/alginate ratio. When the solution has a polycationic chain (e.g. protonated chitosan) this acts as a crosslink- ing thus improving the microsphere hardness. Fig. 2. Scanning electron micrographs of sodium diclofenac microspheres formulated with aluminum chloride. M.L. Gonza´lez-Rodrı´guez et al. / International Journal of Pharmaceutics 232 (2002) 225–234230 Fig. 3. Scanning electron micrographs of the structure formed from a drop touching a water surface, during the microsphere fabrication process. These sodium diclofenac microspheres were formulated with aluminum chloride. On the addition of inorganic cations into the solution containing anions (alginate and diclofe- nac) two different reactions can start: the gelation of alginate chain and the (possible) precipitation of an insoluble diclofenac salt. However, the pre- cipitation of diclofenac as an insoluble salt should make its recovery difficult during the dissolution test, even at varying pH. On the contrary, when the experimental conditions are favorable, diclofe- nac is released from the microspheres and appears in solution. Therefore it can be assumed that diclofenac is still present in a soluble form inside the microsphere, as a sodium salt or as a complex with the polycation chitosan readily available. In fact, since inorganic ions were added dropwise, they were always present in the solution in highly deficit concentrations with respect to the alginate anion units. At the composition used, alginate carboxylate groups strongly exceed those present in diclofenac; furthermore, the polyanion rapidly reacts with each cation blocking it into a thermo- dynamically very stable ‘egg box’. This capture of inorganic ions prevents competition towards di- clofenac anion, which could not react with Ca2+ or Al3+ and form insoluble products. The mutual neutralization between oppositely charged algi- nate and chitosan decreases the solubility of the whole system; the same could occur in the forma- tion of a complex between chitosan cations and diclofenac anions. Therefore the driving force for the microsphere formation is a decrease of solu- bility. This mechanism explains the high efficiency of the microsphere formation in depleting diclofe- nac from the solution, irrespective of the different experimental conditions examined. The precipitate inside a microsphere has a complex composition and structure. The alginate/chitosan microsphere represent an efficient system for controlling the release of di- clofenac (Yotsuyanagi et al., 1991). At acidic pH, the release is low for 2 h: the amount of the released diclofenac did not exceed 6–7%, indepen- dent of the microsphere size. At acidic pH, algi- nate is protonated into the insoluble form of the alginic acid: this displays properties of swelling that explains the low aliquot of the release. In this case the release is hindered by chitosan: its posi- tively charged groups strongly interact with algi- M.L. Gonza´lez-Rodrı´guez et al. / International Journal of Pharmaceutics 232 (2002) 225–234 231 nate and diclofenac ions, both reducing swelling and release and, possibly, the protonation of their carboxylated groups. At pH 6.4 a rapid increase of the release rate was observed up to 100%. The deprotonation of the alginic acid causes the disin- tegration of the microsphere systems and the com- plete release of diclofenac as soluble ions. At increasing pH, the increasing deprotonation of chitosan weakens the extent of the interactions inside the microsphere; moreover, diclofenac is soluble as anions and can be brought into the solution. The release is complete in a few minutes. The role of the phosphate anions present in the buffer of the dissolution medium in sequestering the Ca2+ ions and taking away a factor for the insolubility of alginate chains cannot be excluded. This aspect should, however, play differently in the presence of Ca2+ or Al3+ ions, even though the release profiles overlap perfectly in both cases. All the formulations examined show a dissolution profile as that reported in Fig. 6. 3.1.4. Effect of alginate/chitosan ratio on the release process The case of the alginate/chitosan ratio is differ- ent. The presence of chitosan increases the control of the release from the microsphere, since, at increasing concentration, it can form a network of bondings between the two polymer chains. This was expected, since at increasing chitosan amount into the formulations, interactions be- tween the two polymers should have been in- Fig. 4. Thermograms corresponding to the sodium diclofenac microspheres with calcium chloride. M.L. Gonza´lez-Rodrı´guez et al. / International Journal of Pharmaceutics 232 (2002) 225–234232 Fig. 5. Thermograms corresponding to the sodium diclofenac microspheres with aluminum chloride. creased, forming a closer network, which should decrease the diffusion of the drug outwards of the bead. Therefore, to deeper examine this parameter the alginate/chitosan ratio was changed to value 1, 2 and 3 w/w. In these cases, differences were more evident. At the ratio 1:1, while Ca2+ offered a dissolution profile as the previous ones, in the case of Al3+ microspheres, the release is lowered below 50%. This result confirms what was re- ported in the literature that increasing chitosan concentrations decr
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