A drug-loaded gel based on polyelectrolyte complexes of poly (acrylic acid) with poly (vinylpyrrolidone) and chitosan

Materials Chemistry and Physics 123 (2010) 463–470

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Materials Chemistry and Physics journal homepage: www.elsevier.com/locate/matchemphys

A drug-loaded gel based on polyelectrolyte complexes of poly (acrylic acid) with poly (vinylpyrrolidone) and chitosan Shuping Jin a , Mingzhu Liu b,∗ , Shilan Chen c , Chunmei Gao b a b c

Key Laboratory of Resources and Environmental Chemistry of West China, Department of Chemistry, Hexi University, Zhangye 734000, PR China Department of Chemistry and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China Department of Chemistry, Chongqing University of Science and Technology, Chongqing 401331, PR China

a r t i c l e

i n f o

Article history: Received 24 August 2009 Received in revised form 26 April 2010 Accepted 30 April 2010 Keywords: Polyelectrolyte complexes Ionic-crosslinked chitosan Controlled release Release mechanism

a b s t r a c t A drug-loaded gel (CSPP) based on ionic crosslinked chitosan (CS) and polyelectrolyte complexes of poly (acrylic acid) (PAA) with poly (vinylpyrrolidone) (PVP) was prepared by dropping CS solution containing suitable amount of PVP into PAA and trisodium citrate co-existing gelling solution. The surface and crosssection morphology of the gel was observed using scanning electron microscopy, and the observation showed that the CSPP gel had more compact structure than CS gel. In vitro release profiles of model drug from the CSPP gel, which was prepared under different conditions, were investigated in simulative gastric fluid (pH 1.8) using an UV/vis spectrophotometer. The results showed that the rapid release of the model was restrained due to the complex of PVP and PAA, and the CSPP gel could serve as a suitable candidate in drug delivery system such as the site-specific controlled release of the drug in stomach. In addition, the release mechanism of drug was analyzed by fitting the amount of drug released into Peppa’s potential equation. © 2010 Elsevier B.V. All rights reserved.

1. Introduction Chitosan (CS) is currently receiving a great deal of attention for medical and pharmaceutical applications. This increasing interest is undoubtedly due to several favorable characters of CS, such as antiulcer, preventing bacterium, biodegradability and biocompatibility [1–3]. It is reported that CS hydrogel used for oral carrier–drug systems can reduce or prevent the stimulation on stomach mucosa [4,5]. CS hydrogel can be formed through covalent crosslinking or ionic crosslinking. Covalently crosslinked gel is the only system characterized by a permanent network structure, due to its irreversible chemical links. However, most of the crosslinkers used thus are either known to be relatively toxic or their dim fate in the human body, and there is a lack of data concerning their biocompatibility. Compared with covalently crosslinked hydrogel, ionically crosslinked CS hydrogels are generally thought to be well-tolerated and their potential medical and pharmaceutical applications are numerous because ionic crosslinkers are often biocompatible. So ionically crosslinked chitosan hydrogels offer more possibilities as drug delivery systems compared to covalently crosslinked hydrogels [6]. Moreover, ionic crosslinking is

∗ Corresponding author. Tel.: +86 931 8912387; fax: +86 931 8912582. E-mail address: [email protected] (M. Liu). 0254-0584/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.matchemphys.2010.04.042

an extremely simple and mild method for preparing hydrogels [7]. Hari and Prabaharan et al. reported delivery systems for hydrophobic or macromolecules drug, which have slow drug release rate mainly due to the hydrophobic property of drug as well as the large size of drug molecule that brings about an entanglement of drug with polymer matrix [8,9]. In our previous work [10], a polymer matrix has been reported, in which the drug molecule was covalently bonded on it, and its release was significantly controlled via the slow hydrolysis of covalent bond. We have also reported a special drug release matrix for hydrophilic small molecule drug, in which the complex film between CS and poly (methacrylic acid) (PMAA) through electrostatic attraction can suppress the rapid swelling and disintegration of CS gel in simulative gastric fluid [11]. Poly (acrylic acid) (PAA) and PMAA are polyelectrolytes with the H-donating carboxyl, which can form interpolymer complexes (IPC) with H-accepting neutral polymers such as poly(ethylene oxide) (PEO) and poly (vinylpyrrolidone) (PVP) [12,13]. Formation and properties of PAA/PVP complexes have been studied in detail [13–21]. These pH-sensitive materials have also been tested for applications in pH-controlled drug delivery system [22,23], ocular drug formulation [24], synthesis of mucoadhesive microsphere [25], and fabrication of polymer–ceramic composite [26]. In the present work, we aim to develop another special drug release matrix using in stomach for hydrophilic small molecule drugs that offer the stimulation on stomach mucosa. We prepared

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drug-loaded semi-interpenetrating polymer networks composed of CS gel crosslinked by trisodium citrate, PVP and PAA linear chains (CS/PVP–PAA, CSPP), which shows slow drug release behavior in simulative gastric fluid by exploiting the interpolymer complex between PAA and PVP at low pH. The effect of various preparation parameters on the release performance of model drug was investigated. The drug release mechanism was analyzed as well. 2. Experimental 2.1. Materials CS was obtained from Zhejiang Biochemistry Ltd. (China), deacetylation degree is 90.8% and viscosity is 142 mPa s. Aspirin, selected as a model drug, was purchased from the National Institute for the Control of Pharmaceutical and Biological Products (China), and used without further purification. Acrylic acid (AA) and N-vinylpyrrolidone (NVP) were distilled under vacuum prior to use. 2,2 azobisisobutyronitrile (AIBN) was purified by recrystallization with 95% ethanol. Poly (acrylic acid) (PAA) was prepared by free radical polymerization using AIBN as an initiator in anhydrous methanol, and then was purified by multiple dissolutions (3×) in anhydrous methanol followed by precipitation into anhydrous diethyl ether. Poly (N-vinylpyrrolidone) (PVP) was prepared by free radical polymerization using AIBN as an initiator in distilled water, and then was precipitated into acetone, purified in triplicate. Then, both PAA and PVP were dried under vacuum at room temperature to constant weight. The viscosity average molecular weight (M␩ ) was estimated from intrinsic viscosity of the polymer in 2 mol l−1 NaOH aqueous solution for PAA and in distilled water for PVP at constant temperature of 25 ± 0.10 ◦ C, using the Mark–Houwink–Sakurada (MHS) equation [] = kM˛ (k = 42.2 × 10−3 ml g−1 , ˛ = 0.64 for PAA, and k = 1.4 × 10−4 ml g−1 , ˛ = 0.7 for PVP) [20]. Trisodium citrate and other chemicals are analytical grade and used as received.

Fig. 1. FTIR spectrum of CS.

2.6. In vitro drug release Release test of model drug was carried out as follows. The release medium in vitro was HCl aqueous solution (simulative gastric pH 1.8, ionic strength 0.1 mol l−1 ). Suitable amount of gels were immersed into the buffer solution with the proportional mass of gels to the mass of solution about 1:1000, and the system was maintained at 37 ± 0.5 ◦ C under gentle stirring throughout the study. 3 ml release medium was collected at appropriate intervals and the absorbance of drug released was determined using UV/vis spectrometer at 297 nm. A fraction of drug released was calculated by the following expression:

2.2. Drug-loaded Gels preparation Fraction of drug released = Drug-loaded CS/PVP–PAA (CSPP) gels were prepared by extrusion of CS solution containing aspirin and PVP into trisodium citrate aqueous solution at room temperature. A solution was prepared by a mixing of CS (0.4000 g), aspirin (the mass percent of aspirin accounting for 37.5% of CS) and citric acid aqueous solution, which contained suitable amount of PVP (the mass ratio of PVP to CS is 25%), under magnetic stirring. It was placed for 2 h to eliminate the bubbles. Then it was extruded through a needle with a diameter of 0.9 mm into a gently stirred trisodium citrate aqueous solution (20 ml) containing suitable amount of PAA at a flow rate of 1 ml min−1 , and gel formed instantaneously due to the electrostatic attraction between NH3 + on CS and COO− on citrate. At the same time, the interpolymer complex between PAA and CS would form owing to the electrostatic attraction too. The pH of trisodium citrate aqueous solution was adjusted by HCl or NaOH and measured by pHS-3B Model pH meter (China). The ionic strength of trisodium citrate aqueous solution was adjusted by NaCl. After 30 min, gels were separated and then rinsed with distilled water to remove excess drug on the surface. These gels were placed in atmosphere for 12 h and then dried under vacuum for 48 h at room temperature. Gel without incorporating drug was prepared by the same process. 2.3. Encapsulation efficiency The loading capacity (milligram of aspirin entrapped per 100 milligram of dried drug-loaded gels, %) of CSPP gels was determined as follow: the drug-loaded CSPP gels was ground to fine power and known amount of it was immersed into 100 mL HCl aqueous solution for 24 h under magnetic stirring. Then the solution was filtered and detected by PerkinElmer Lambda 35 UV/vis Spectrophotometer at 297 nm to determine the absorbance (A) of the drug contained in it. A quantitative calibration curve was obtained based on the absorbance of the drug in various concentration standard solutions at 297 nm, Beer–Lamberts relationship upon which calibration curve can be written as A = kC, where k is slope of the curve, C is the concentration of standard solution. The amount of drug entrapped can then be calculated. The average loading capacity of the CSPP gel obtained from the measurements was about 5.8 mg aspirin per 100 mg CSPP gels (5.8%).

Ct C∞

where Ct and C∞ are the concentration of drug released at time t and that of drug released completely, respectively. According to Beer-–Lamberts relationship A = kC, the Fraction of drug released can then be expressed as: At /k At Ct = = C∞ A∞ A∞ /k Here At and A∞ are the absorbance of drug released at time t and that of drug released completely, respectively.

3. Results and discussion 3.1. Crosslinking of CS with trisodium citrate In our previous study [11], the gel fraction of CS crosslinked using trisodium citrate as a crosslinker for distinct durations were investigated. CS dropped into trisodium citrate aqueous solution was shaped immediately owing to the electrostatic interaction between citrate and CS, and then the ionic-crosslinker diffused from outside into the core of the gel gradually, that is to say, the gel was crosslinked from the surface to the center step by step. The gel fraction increased with an increase in crosslinking time within 30 min. After crosslinking for more than 30 min, there was no obvious difference in the gel fraction. This indicates that the crosslinking of CS would be completed within 30 min. 3.2. Polymers–drug and polymer–polymer interaction analysis using FTIR

2.4. Morphology observation All of the CS and CSPP gels obtained from different conditions had been freezedried for 15 h using LABCONCO Freeze-dried system (England) after freezing by liquid nitrogen to avoid the collapse of the porous structure. Then the surface and cross-section morphology of the gel were examined using a scanning electron microscopy (JSM-5600LV SEM, Japan) at an accelerating voltage of 20 kV. 2.5. FTIR measurement Fourier transform infrared spectroscopy (FTIR) was measured using Nicolet NEXUS 670 FTIR Spectrometer. The samples were dried completely and ground to fine power, then mixed with KBr dried powder and pressed into a pellet.

In the present work, aspirin-loaded CSPP gel was composed of aspirin, CS, PAA, PVP, and trisodium citrate used as a crosslinker. An attempt was made to detect the eventual existence and type of interaction among the polymers and aspirin using FTIR spectroscopy. FTIR spectrum of CS (shown in Fig. 1) is characterized by absorptions around 1657.07 cm−1 (amide I, C O stretching mode conjugated with N–H deformation mode), 1598.07 cm−1 (bending vibration of NH2 groups) and 1260.71 cm−1 (stretching vibration band of C–N groups). Characteristics for its saccharide structure are

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Fig. 2. FTIR spectra of aspirin (a) and drug-loaded CS gels (b).

absorption bands at 1157.39 cm−1 (asymmetric stretching vibration of the C–O–C bridge), 1087.66 and 1032.08 cm−1 (skeletal vibration involving C–O stretching) [27,28]. The band appearing at about 3423 cm−1 belongs to the stretching vibrations of the O–H and N–H groups. By compared with the spectrum of the CS, a part of the bending vibration of NH2 groups has a shift from 1598.07 cm−1 to about 1578.57 (Fig. 3a) and 1578.30 cm−1 (Fig. 2b) accompanied with an increase of intensity in the spectra of CS gel crosslinked by trisodium citrate shown in Figs. 2 and 3, respectively. This shift and strengthen may be ascribed to the interaction between trisodium citrate and CS. The interaction between aspirin and CS was investigated as shown in Fig. 2. Compared with FTIR spectrum of aspirin (Fig. 2a), the absence of characteristic absorption bands of aspirin at 1685.96 cm−1 (the stretching vibration of C O from the aromatic acid), 1605.69 and 1457.96 cm−1 (the stretching vibration of C = C from benzene), 1187.08 and 916.49 cm−1 (the bending vibration absorption of C–H in the different sites on the benzene) as well as 750.10 cm−1 (the stretching vibration of four adjacent CH groups on the benzene) in the spectrum of aspirin-loaded CS gel (Fig. 2b) may be explained by the low aspirin concentration (5.8%). Drug binding is mainly through hydrogen bond between –OCOCH3 , –COOH on aspirin and OH, NH on CS. Evidences for this come from a major intensity decrease of the infrared bands at 1578.57 cm−1 as well as a shift of the stretching vibration of C O from the ester group on aspirin, and skeletal vibration involving C–O stretching on saccharide from 1755.31, 1087.66 and 1032.08 cm−1 to 1732.15, 1069.85 and 1024.88 cm−1 , respectively. This negative shift signi-

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Fig. 4. FTIR spectra of PAA (a), PVP (b) and PAA/PVP interpolymer complex (c).

fies that intermolecular hydrogen bond did occur between aspirin and CS. Fig. 3 displays FTIR spectra of CS (a) and CSPP gel (b) with a mass ratio 2.5:1:0 of CS:PAA:PVP. In comparison with Fig. 3a and b, it is shown that important changes did take place in the spectra of CS and CSPP gels. The characteristic absorption band at 1713.17 cm−1 and stronger, wider absorption band at 3400–2500 cm−1 may be assigned to the stretching vibration of C O and O–H from PAA, respectively. Meanwhile, two peaks at 1393.72 and 1555.00 cm−1 can be observed due to the symmetrical and asymmetrical stretching of COO− groups from PAA in Fig. 3b, respectively, while the peak at 1628.60 cm−1 is attributed to the NH3 + from CS. These results reveal that electrostatic interaction presents between the anionic COO− and the cationic NH3 + . Similar electrostatic interaction was observed by Anh et al. [29–32]. PAA and PVP are known to form a complex in aqueous solution. In the present work, the FTIR spectra of PAA, PVP and the residue of CSPP after CS matrix disintegrate completely in simulative gastric fluid [11,33] are shown in Fig. 4. As shown in Fig. 4a, the PAA alone has a band at about 1704.43 cm−1 assigned to C O due to intramolecular hydrogen bond. However, some of it will be broken when PAA and PVP form an interpolymer complex, since new hydrogen bonds formed between the carboxyl groups on PAA and the carbonyl groups on PVP. Therefore, the carboxyl absorption band of PAA would shift from 1704.43 (Fig. 4a) to 1737.17 cm−1 (Fig. 4c) [24,34]. Meanwhile, the carbonyl absorption band on PVP shifts from 1657.18 (Fig. 4b) to 1623.70 cm−1 (Fig. 4c). The complex between PAA and PVP via hydrogen bond is further confirmed by a positive shift in the carboxyl absorption bands of PAA [23] and a negative shift in the carbonyl absorption bands of PVP in FTIR spectra [35]. In addition, there are not characteristic absorption peaks for CS saccharide structure appearing in the spectrum. This confirms the complete dissolution of CS in agreement with the literature [11,33]. 3.3. Effect of complex between PAA and PVP on drug release behavior

Fig. 3. FTIR spectra of CS (a) and CSPP gel (b) with a mass ratio 2.5:1:0 of CS:PAA:PVP.

Fig. 5 shows the release profile of model drug, aspirin, from CSPP gel in simulative gastric fluid. From this figure, it can be found that the CSPP gel presents a suitable controlled release profile. After 40 min less than 80% of the drug was released from CSPP gel but about 95% from CS gel. The release of the model drug may be attributed to the disintegration of the CS matrix. However, the complex between PVP and PAA retarded it by suppressing the diffusion rate of solvent and drug molecules, which results in a lower rate of swelling and disintegration of the CS matrix. With the further disintegration of CS, the hydrogen bond between PAA and

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Fig. 5. In vitro release profiles of model drug in simulative gastric fluid from CS gels () and CSPP gel (: CPAA = 0.011 g mol−1 , MPAA = 6 × 103 g mol−1 ) at 37 ◦ C.

Fig. 7. Effect of pH of trisodium citrate aqueous solution on drug release behavior of CSPP gel in simulative gastric fluid at 37 ◦ C (: pH 4.41; ♦: pH 5.35; 䊉: pH 6.26).

PVP becomes more and more strong at pH 1.8, and then a complex hydrogel formed, which further retard the diffusion of drug molecules into simulative gastric fluid. So, it is expected that the interpolymer complex prolongs effectively drug release at gastric pH, which would reduce physiological toxicity resulting from fast release of drug.

3.5. Effect of pH of trisodium citrate solution on drug release behavior

3.4. Effect of the molecular size of PAA on drug release behavior In order to obtain information about the influence of the length of polymer chain on drug release behavior, we investigated the variation of the fraction release of aspirin from CSPP gel with PAA42 (the molecular weight is 10,000 times the numerical index used for the sample designation, for example, PAA42 means M␩ of PAA is 4.2 × 105 g mol−1 ), PAA1.6 and PAA0.6 , respectively, at pH 1.8, and the results have been illustrated in Fig. 6. It is found that the length of PAA affects significantly the drug release rate. CSPP gel holding the longest length of PAA (PAA42 ) shows faster drug release rate than that with the shortest length of PAA (PAA0.6 ). This may be explained by the fact that the interpolymer complex as well as the entrance and diffusion of PAA are strongly dependent on the molecular size of PAA. In the case of CSPP gel with PAA0.6 , the complex would be strong and be expected to prolong the drug release process.

Fig. 6. Effect of molecular weight of PAA on drug release behavior of CSPP gel in simulative gastric fluid at 37 ◦ C (: MPAA = 4.2 × 105 g mol−1 ; 䊉: MPAA = 1.6 × 104 g mol−1 ; ♦: MPAA = 6 × 103 g mol−1 ).

The charge density of citrate, CS and PAA is mainly controlled by the pH value of solution. It could be speculated that the ionic bond between NH3 + groups on CS and its counter ions depends on the pH value of the medium [33]. Fig. 7 displays the drug release behavior of CSPP gel prepared from solutions with various pH values. From these we can seen that the drug release rate of CSPP gel, which was prepared at pH 5.35, is slightly slower than those prepared both at pH 4.41 and 6.26. It is known that the dissociated constant, pKa of CS is about 6.3; pKa,2 and pKa,3 of citric acid are 4.76 and 6.4, respectively. At pH 4.41, which is lower than pKa,2 of citric acid, ionization degree of citric acid is low leading to weak electrostatic interaction between citrate and CS. On the contrary, at pH 6.26, which is close to pKa of CS, protonization degree of NH2 on CS is low resulting in weak electrostatic interaction too. However, both CS and citrate have relatively high ionization degree at pH 5.35 known from reference [33]. This means that a high crosslinking density results in a slightly slower drug release rate. In addition, it could not be neglected that a better complex of CS with PAA is formed at pH ranging from 4.5 to 5.8 [30]. Over this range, CS and PAA are partly ionized and form compact polyelectrolyte complexes by ionic interaction, which also results in a slightly slower drug release rate.

Fig. 8. Effect of ionic strength of trisodium citrate aqueous solution on drug release behavior of CSPP gel in simulative gastric fluid at 37 ◦ C (: CNaCl = 0.0 mol l−1 ; 䊉: CNaCl = 0.5 mol l−1 ; ♦: CNaCl = 1.0 mol l−1 ).

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Fig. 9. SEM photos of surface morphology of CS (a: the crosslinking time is 30 min) and CSPP gel (b: the crosslinking time is 30 min, MPAA = 1.6 × 104 g mol−1 ; c: the crosslinking time is 12 h, MPAA = 1.6 × 104 g mol−1 ; d: the crosslinking time is 30 min, MPAA = 4.2 × 105 g mol−1 ).

3.6. Effect of ionic strength of the gelling solution on drug release behavior Fig. 8 shows the influence of ionic strength of trisodium citrate solution on the release of aspirin from CSPP gel. As shown in this figure, the release rate decreases with an increase of NaCl concentration (CNaCl ) from zero to 0.5 mol l−1 . However, a further increase of that, such as 1 mol l−1 , would cause a dramatic increase of the release rate of aspirin. It is well known that PAA is a weak polyelectrolyte, and its aqueous solution would be stabilized through the competition of the electrostatic repulsion and attraction, but the electrostatic equilibrium would be destroyed by the presence of NaCl when the concentration of NaCl runs up to a certain value, the coupling–coupling attraction increases, accompanied by a decrease of the electrostatic repulsion. That results in a change of the conformation of PAA from a relatively loose coil to a hypercoil form, which is favorable for the entrance and diffusion of PAA because the reducing of the physical entanglement among polymer chains. This would lead to a dramatic decrease in release rate of aspirin. Ionic strength is also an important factor for influencing electrostatic interaction, and salt usually has a significant shielding effect on the weaker ionic interaction between citrate and CS, and hence reduces the crosslinking density, which leads to a quicker release of aspirin from CSPP gel when the concentration of NaCl is 1 mol l−1 . 3.7. Morphology of CS and CSPP gels Macroscopic observation shows that CSPP gel has a spherical shape and smooth surface. In general, the diameter of wet CSPP gel is about 3.0–3.1 mm. The gel has a firm texture and its diameter is

only 0.9–1.0 mm after drying. Fig. 9 displays the surface morphology of CS and CSPP gel. The view of CS shows a highly rough surface (Fig. 9a). In contrast, it is relatively smooth for CSPP (Fig. 9b), and even smoother when the crosslinking time is long enough (12 h) (Fig. 9c) or the molecular size of PAA is large enough (Fig. 9d). The cross-section morphology of CS is shown in Fig. 10a. The view of CS depicts a highly porous cross-section structure, the mean pore size is increasing from surface to core because the gel was crosslinked from surface to core step by step, and these regular pores connect with each other to form channels, which would accelerate the swelling and drug release from CS gel. The cross-section structures of CSPP gel after crosslinking at different times are shown in Fig. 10b and c, respectively. From these we can see that CSPP has a more compact structure than CS gel as a result of the interpolymer complex between PAA and CS as well as PAA and PVP. Moreover, the compactness increases with an increase in crosslingking time. From these we would understand why the drug release capacity of CSPP is distinct from that of CS in simulative gastric solution. However, the view of CSPP gel holding PAA42 (Fig. 10d) shows a less compact structure and the compactness is decreasing from surface to core, for the gel was crosslinked from surface to center step by step as well as the largest molecular size of PAA. Indeed, in this case only a more compact film layer out of CS gel is formed by interpolymer complex between PAA and CS. 3.8. Macroscopic observation of the release process of drug-loaded CSPP in simulative gastric fluid After immersing in simulative gastric fluid for durations varying from 10 to 180 min, CSPP gel was observed and the observations

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Fig. 10. SEM photos of the cross-section morphology of CS (a: the crosslinking time is 30 min) and CSPP gel (b: the crosslinking time is 30 min, MPAA = 1.6 × 104 g mol−1 ; c: the crosslinking time is 12 h, MPAA = 1.6 × 104 g mol−1 ; d: the crosslinking time is 30 min, MPAA = 4.2 × 105 g mol−1 ).

are displayed in Fig. 11. CSPP was compact gel and did not swell at the primary stage within 10 min. Then it began to disintegrate gradually owing to the dissolution of the electrostatic interaction of CS with citrate. However, the hydrogen bond between PAA and PVP was so strong at pH 1.8 that a shell stemming from the interpolymer complex of PAA with PVP formed surrounding the disintegrating center core. The shell would retard significantly the diffusion of aspirin into the simulative gastric fluid and suppress the release rate, which is one of the major problems related to carriers in controlled release [36]. CS disintegrated completely accompanying by the formation of a swelling physical hydrogel within 180 min. The hydrogel would be a hollow or solid closely related with the molecular size of PAA as discussed above. In any case, they would retard effectively the diffusion of drug in the subsequent stage. Finally, if the latter time is longer than 3 h, the swelling complex hydrogel would collapse because of phase separation at pH 1.8 (not shown). If the gel goes into the intestine, at higher pH value (about 7.2), the hydrogen bond would be destroyed, PAA/PVP complex decomposes [20] resulting in complete release of drug, and the linear polymers are excreted with the metabolism. Another major problem related to carriers in controlled release is incomplete unloading of encapsulated drug, however, that is resolved in present study by the destruction of hydrogen bond between PAA and PVP. So, the behavior demonstrates that CSPP may be beneficial to site-specific drug delivery in stomach. 3.9. Drug release mechanism of CSPP gel To investigate more precisely the release behavior of aspirin from CSPP gel (optimum conditions: CS concentration is 3% (w/v), trisodium citrate concentration is 0.1 mol l−1 , pH 5.35, NaCl con-

centration is 0.5 mol l−1 , MPAA = 1.6 × 104 g mol−1 ), the fraction of drug released date during release process were normalized to fit to the Peppa’s potential equation [37]: Mt = kt n M∞ where Mt and M∞ are the amount of drug released cumulatively at time t and that of drug released completely, respectively. k is the apparent release rate and n is the diffusion exponent, which characterizes the diffusion mechanism. A value of n = 0.43 signifies the Fickian diffusion mechanism. In this case the diffusion of drug molecules plays an important role during release process [38,39]. A value of n = 0.85 indicates a swelling-controlled release mechanism. That is to say, the release process of drug is limited by the expanding of the polymer segment to accommodate penetration, i.e., the viscoelastic properties of polymer matrix become important [40]. In the case of 0.43 < n < 0.85, the diffusion mechanism is non-Fickian, where both drug diffusion and polymer relaxation control the overall rate of drug release. Plots of ln(Mt /M∞ ) against ln(t) are shown in Fig. 12 for the CSPP gel obtained under optimum conditions. The profile is linear in the early stage (r2 = 0.99805; r, correlation coefficient), and the slope of this line is 0.54 assigned to the diffusion exponent, n, which shows that the drug release from CSPP gel is a mechanism of combined diffusion of drug with relaxation of polymer matrix [37,41]. Namely, the drug release kinetics of the controlled release matrix can be determined by diffusion process of drug partially through the water-filled pores and channels in the polymer network, as well as the erosion of CS matrix [11]. However, the release begins to deviate from the non-Fickian mechanism revealed by a significant curvature at the sequential

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Fig. 11. Macroscopic photos of CSPP gel during the release process in simulative gastric fluid: (a: 10 min; b: 30 min; c: 100 min; d: 160 min).

The results of drug release in vitro indicate that the release of model drug from CSPP gel takes place through three steps as depicted in Fig. 13. The surface-adhered drug dispersed firstly (Fig. 13, step 1), then the inner drug is released accompanied by an erosion of CS matrix from outside to inside. The release rate is governed simultaneously by the diffusion ability of drug molecule and the disintegration of CS gel (Fig. 13, step 2). At the last stage, the drug molecule dispersed through the water-filled pores and channels in the network of the interpolymer complex between PAA and PVP (Fig. 13, step 3).

4. Conclusions

Fig. 12. ln(Ct /C∞ ) versus time ln(t) for the CSPP gel.

stage (after 30 min). The diffusion exponent is estimated about 0.33 (r2 = 0.99769). In this instance the drug dispersed molecularly into the polymer-rich diffusion layer. However, the viscosity of the layer is so large that drug diffusion is very slow. Consequently, the diffusion of molecules becomes the rate-limiting step to the release of drug.

We develop a new pH-sensitive material, ionic-crosslinked CS exploiting the interpolymer complex of PAA with PVP under mild conditions. The release experiments indicate that this system seems to be a very promising vehicle for the administration of hydrophilic drugs in the gastric cavity due to its pH-sensitive property. The drug release rate can be substantially slowed by the interpolymer complex, which acts as a shield retarding the diffusion of drug molecule and solvent. In addition, the interpolymer complex would be destroyed in the intestine, so, major problems about carriers, which are burst release and incomplete unloading of encapsulated drug, are resolved in present study.

Acknowledgement Fig. 13. Schematic of the drug release process for CSPP gel ( : CS gel; : linear : deintegrating CS; : PAA/PVP complex; : drug molecule). PAA and PVP;

The authors are grateful to the Special Doctoral Program Funds of the Ministry of Education of China (20030730013).

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