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Controlled release of ionic drug through the positively charged temperature-responsive membranes
Journal of Membrane Science 281 (2006) 491–499
Controlled release of ionic drug through the positively charged temperature-responsive membranes Lei Zhang, Tongwen Xu ∗ , Zhan Lin Laboratory of Functional Membranes, School of Chemistry and Material Science, University of Science and Technology of China (USTC), Hefei 230026, PR China Received 22 November 2005; received in revised form 9 March 2006; accepted 18 April 2006 Available online 27 April 2006
Abstract This work is focused on the investigation of the permeability of the ionic drug through the charged BPPO-g-NIPAAm membrane (CGM) in different release mediums. The CGM has temperature-responsive poly(N-isopropylacrylamide) [poly(NIPAAm)] chains and –N+ (CH2 CH3 )3 ionic groups by means of grafting and then amination to the BPPO membrane (the base membrane). By controlling the amination time, the charged base membranes (CUMs) and CGMs with different ion exchange capacities (IEC) and water contents (WR ) are obtained. Results show that the longer the amination time, the higher the IEC and WR values. However, the CUM gains the higher IEC and WR compared with the CGM even within the same amination time, which is possibly due to the decreased opportunity of replacement reaction as well as the blocking of the poly(NIPAAm) chains on the surface of the membrane. The sodium salicylate (SSA) was used as model drug due to its ionization in deionized water. Permeability coefficient of the drug is measured using side-by-side diffusion cells at various temperatures including 25, 37 and 43 ◦ C. It is shown that the permeability coefficient of the drug markedly increases after the grafted membrane is aminated. When NaCl solution is used as the receptor medium, the increased quantity of drug release through the CGM is much more than that through the uncharged grafted membrane in the same change of temperature. Similar results can be also found in the deionized water. Consequently, it can be concluded that the sensitivity of the grafted membrane to temperature can be promoted by amination. © 2006 Elsevier B.V. All rights reserved. Keywords: Poly(N-isopropylacrylamide); Controlled release; Temperature-responsive; Ionic drug; Ion exchange membrane
1. Introduction Stimuli-responsive (“intelligent”) drug delivery systems have been investigated for their applications in pulsatile delivery of certain hormone drugs. Generally speaking, stimuli-responsive systems consist of temperature, pH, ionic strength and currentresponsive system, and so on [1–6]. Among all studied systems, temperature-responsive delivery system has attracted much attention since some disease states manifest themselves by a change in temperature. Up to now, single temperatureresponsive system has been already studied extensively. Meanwhile, the multifunctional temperature-responsive system has been also gradually developed in order to meet the various demands of drug release. For example, the thermo-sensitive
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0376-7388/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.memsci.2006.04.018
polymer and weak electrolyte are often used in such systems since they can alter their mass transport properties by changing structure and physical properties in simultaneous response to the temperature and pH changes [1]. Among all existing drug delivery systems, it has long been known that ion-exchange membrane is widely used in the release for ionic drugs [7,8]. In order to promote the application of temperature-responsive system to ionic drug release or fast responsive materials, the charged temperatureresponsive systems were developed. In previous studies, the charged temperature-responsive systems were often formed by the copolymerization or blending with the polyelectrolyte or ionic monomer [9,10]. Due to the abundant charges exiting in the polymer matrices, the charged temperature-responsive systems containing high water content are very suitable to apply in biotissue. At the same time, they have excellent potential as bioresponsive polymers, because a change in the charge density or the property of the ionic group in the polymers can control
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the strength of their response to the outer temperature. During the drug delivery and diffusion through the membrane, a large amount of the unbound water in the membrane allows substantive solutes to release or transport. Because of the existing charges, electrostatic interaction between the fixed groups located on the membrane matrices and ionic groups on the drug can influence on the permeability coefficient of the ionic drugs. When the receptor medium is an electrolyte solution, the Donnan dialysis effect should be also taken into account. As known to all, poly(N-isopropylacrylamide) [poly(NIPAAm)] is the well-investigated and most prominent temperature-responsive polymer by far. Crosslinked poly(NIPAAm) has a lower critical solution temperature (LCST) at 32–33 ◦ C. Below that temperature, the gel is swollen, hydrated and hydrophilic; while above the LCST, the gel becomes collapsed, dehydrated and hydrophobic [11]. Furthermore, LCST can be increased by copolymerization/blending with more hydrophilic monomers or decreased by using more hydrophobic monomers [1,12]. Just due to the excellent response properties of poly(NIPAAm) to temperature change, it has been widely studied in the grafting/copolymerization form [13,14], mixed form [15] as well as the single hydrogel [16]. In a previous study of our group, a novel thermo-sensitive switching membrane has been prepared by radiation-induced simultaneous grafting N-isopropylacrylamide (NIPAAm) onto bromomethylated poly(2,6-dimethyl-1,4-phenylene oxide) (BPPO) [17]. The grafting conditions were optimized there by changing different factors such as dose, dose rate, concentration of NIPAAm, concentration of inhibitor Cu2+ , membrane thickness and solvents. This provides a possibility for preparing a positively charged thermo-sensitive membrane by simple quaternary amination of the obtained uncharged thermo-sensitive switching membrane. Therefore, in the present study, the positively charged temperature-responsive membranes will be obtained by means of triethylamine replacement of the bromine atoms on the methyl of the grafted membranes. By controlling the amimnation time, positively charged thermo-sensitive membranes with different charge densities can be obtained; further, their release performance of the ionic drug sodium salicylate (SSA) will be investigated according to different receptor mediums under various temperatures. 2. Materials and methods 2.1. Materials The monomer N-isopropylacrylamide (NIPAAm) (Wako) which was bought from Sigma–Aldrich Inc., was recrystallized in n-hexane before use, and bromomethylated poly (2,6dimethyl-1,4-phenylene oxide) (BPPO) was prepared in our laboratory [18]. The analytical grade solvents such as ethanol, triethlamine, n-hexane, hydrochloric acid, sodium hydroxide and sodium chloride were used as received. Sodium salicylate (SSA) and 1-methyl-2-pyrrolidone were of chemical grade. These chemicals were commercially obtained and used without further purification. Deionized water was used in all experiments.
2.2. Preparation of membranes 2.2.1. Preparation of the BPPO-g-NIPAAm membrane (the grafted membrane) The grafted membrane was prepared as described in literature [17]. Briefly, the prepared BPPO base membranes (ungrafted membranes) were immersed in the NIPAAm aqueous solution containing inhibitor Cu2+ . After irradiated by the Co60 -␥-rays irradiation source for a few hours, the grafted membrane was obtained. After removing the remaining monomer polymer on the surface of the membrane and rinsed by deionized water, the degree of grafting was determined gravimetrically according to the following formula: degree of grafting (%) =
m1 − m0 × 100%. m0
(1)
The weight of ungrafted (m0 ) and grafted membrane (m1 ) in the dry state were determined, respectively, after drying in the oven at 60 ◦ C to a constant weight [19]. In our previous job [17], it was shown that a membrane with grafting degree 5–7% was easily obtained and our preliminary tests also showed that such degree could satisfy with the requests of thermo-sensitive property. Therefore, the grafted membrane with a grafting degree about 5.26% was used as received in the whole experiment hereafter. 2.2.2. Preparation of the charged grafted (BPPO-g-NIPAAm) membrane (CGM) or charged ungrafted (BPPO) membrane (CUM) The ungrafted membranes and the grafted membranes were accurately cut into pieces with circular dimensions about 5.72 cm2 and subjected to amination process by immersing them into triethylamine medium. After a proper time, the membranes were extracted from the solution, then washed with deionized water and equilibrated with 1 M HCl solution to be transformed into the chloride form. The amination degree was controlled by amination time [20]. 2.3. Characterization 2.3.1. Determination of WR and IEC values To investigate the effect of amination degree on the water content of the charged thermo-sensitive membranes (CGMs), the dried membranes were immersed in an excess amount of deionized water at 20 ◦ C until swelling equilibrium was attained. Before measuring the weight of the wet membranes, they should be transformed into the chloride form. The weight of wet sample (Wt ) was determined after removing the surface water by blotting with filter paper. Dry weight (W0 ) was determined after drying the membrane in an oven at 60 ◦ C for 2 h. Then the water content (WR ) was calculated from the following equation: Wt − W 0 × 100%. (2) WR = W0 In addition, the water content of the uncharged base membrane and the uncharged grafted membrane were determined by the same method as the CGM or CUM but without the process of
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Fig. 1. The diffusive process of the SSA (SA− referring to salicylate anion) across a CGM in deionized water.
transforming into the chloride form. The final membranes were conducted to the measurements of ion-exchange capacity (IEC) as described elsewhere [20]. 2.3.2. Morphological observation The morphological details of the BPPO membrane, CUM, CGM were observed by scanning election microscopy SEM (XT30 ESEM-TMP PHILIP) with a common procedure. 2.3.3. Temperature dependent swelling behavior After the grafting and amination reaction, positively charged temperature-responsive membranes (CGMs) were obtained. In order to study the temperature dependent swelling behavior, the CGM (IEC = 0.790 mmol/g) was immersed in an excess amount of deionized water under each predetermined temperature until swelling equilibrium was attained, and then the WR was obtained as mentioned above. Meantime, to compare with the characteristic of CGM, the CUM (IEC = 0.730 mmol/g) was also undergone the same experiment.
5.72 cm2 . During the measurement of the permeability coefficients, the receptor medium (100 ml) in the right-hand side cell (receptor cell) and 1 mM aqueous drug solution (100 ml) in the left-hand side cell (donor cell) were introduced, respectively. The membrane was mounted onto the cells after soaking in the deionized water at room temperature. SSA is water-soluble and can be easily detected by a UV spectrophotometer because of its UV-active benzene ring moiety at 295.5 nm. This makes it possible to quantitatively determine its concentration. A sampled solution (2 ml) was taken at interval of 20 min from the receptor cell and replaced with the same kind and quantity of receptor medium. The measurement of permeability coefficient was carried out for 2 h at a desired temperature. The drug flux J and the permeability coefficient P are related by the following relationship [21]: dCt V Ct − C0 J= = −P (3) dt S d Where V is the volume of the receptor cell, S the effective membrane area, d the membrane thickness, P (cm2 /s) the permeability
2.4. Measurement of the permeability coefficients Due to the existence of poly(NIPAAm) chains on the membrane surface and fixed groups, the release process of the SSA through a membrane is mainly controlled by the outer temperature, the IEC of a membrane as well as the receptor medium. As shown in the Fig. 1, when the temperature exceeds the LCST in the deionized water, the pores in the membranes are open owing to the shrunk poly(NIPAAm) chains. Simultaneously, the positively ionic groups fixed on the surface of membrane recognize the anionic drugs and then allow them to pass through the membrane. Based on the process of the drug release, diffusion experiments were carried out using jacketed side-by-side diffusion cells as shown in Fig. 2, where the temperature was controlled by a water bath. The effective membrane area for permeation is
Fig. 2. Schematic representation of the experimental setup for permeability coefficient measurements.
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coefficient of membrane, Ct the concentration of the receptor side, C0 (=1 mM) the concentration of the drug at the left compartment, and dCt /dt is the concentration variance per unit time. It has been confirmed that the water levels of both compartments does not show any significant change throughout the permeability measurements and thus the osmotic pressure effect can’t disturb diffusion of drug significantly [1,22]. 2.5. Measurements of drug adsorption The CUMs and the CGMs with different IEC were, respectively, immersed into the 0.001 M drug solution (20 ml) at 37 ◦ C for 24 h. Then, each of them was transferred into the deionized water (20 ml) at 37 ◦ C for 36 h after rinsing them to eliminate the unadsorbed drug on the membrane surface. The adsorbed amount was determined from the concentration change in the deionized water by the ultraviolet spectrophotometer. However, in order to avoid the effect of difference in membrane area, the adsorption ability (Wads ) of membrane is characterized by the ratio between the adsorbed drug amount (g) and the dried membrane mass (g). 3. Results and discussion 3.1. Preparation of membranes and their characterizations As seen in Fig. 3, the ungrafted and grafted membranes with different WR were obtained after a proper amination time. It can be found that, for the ungrafted membranes, the WR values of membranes increase with the amination time rising. The trend is reasonable, because with amination time rising the ion exchange capacity increases as shown in Fig. 4, which tends to make the membrane more hydrophilic as discussed in detail in our previous paper [20]. For the grafted membranes, the WR follows an analogous trend to that of the ungrafted membranes in a general way. However, compared with the ungrafted membrane, the water content of grafted membrane is much lower. A possible reason is as the following. When the grafting reaction happens, the crosslinking reaction perhaps occurs simultane-
Fig. 4. The variation of the IEC of both the CUMs and the CGMs with the amination time.
ously due to the active methylenes, which tends to make the membrane more compact and reduce the reactive point (bromomethylated groups) in the membrane matrix, and accordingly leads to the decreased WR of the grafted membrane [23]. In addition, the grafted PNIPAAm on the membrane surface may possibly block the amination reaction (as will be discussed in the next section) and then result in the lower WR . Similarly, the IEC of grafted and ungrafted membrane increase with amination time rising is also observed as shown in Fig. 4. The phenomenon is also in a good agreement with the previous study [20]. Meanwhile, it can be found that the ungrafted membrane obtains higher IEC than the grafted membrane within an equal amination time. As a matter of fact, both the grafting reaction and the amination reaction replace the bromine atoms in the matrices of the base membrane. Obviously, there are less bromine atoms in grafted membrane than in ungrafted ones because of the happening of the grafting reaction which has been intensively discussed in our previous paper [17]. Consequently, the chance of the replacement reaction between triethylamine and bromine atom is also decreased in the grafted membranes. Furthermore, the blocking effect of the poly(NIPAAm) chains on the surface of the grafted membrane can also result in the reduction of the opportunity of the subsequent amination reaction. 3.2. The temperature dependent swelling behavior
Fig. 3. The variation of the WR of both the CUMs and the CGMs with the amination time at 20 ◦ C.
In order to study the temperature dependent swelling behavior of CGM with the PNIPAAm chains, a CGM was fully swollen in the deionized water at various temperatures in the expected range of the LCST phase transition. As shown in Fig. 5, the WR of CGM decreases with temperature increasing from 15 to 50 ◦ C in a general way while the most abruptly decrease in the WR is observed at temperatures between 30 and 40 ◦ C. That’s because below 30 ◦ C (around LCST of PNIPAAm) the CGM membrane contains more water due to the swelling of the PNIPAAm chains on it. When the temperature increases up to 30 ◦ C around, it will result in the deswelling of the PNIPAAm chains, and then the WR decreases abruptly. When the temperature increases to
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Fig. 5. The variation of the WR of both the CGM (IEC = 0.790 mmol/g) and the CUM (IEC = 0.730 mmol/g) with the temperature.
40 ◦ C, most of the PNIPAAm chains have shrunk, as a result, the WR tends to level off though the temperature increases further. As far as the CUM is concerned, the WR slightly decreases at the temperature change from 15 to 50 ◦ C, and does not clearly present the abruptly change as shown as the CGM. The difference between the CGM and the CUM probably results from the PNIPAAm chains on the CGM which is hydrophilic below LCST and then hydrophobic above LCST. From the results above, it can be concluded that the positively charged base membranes as well as their thermo-sensitive ones can be prepared in this manner and their some properties can be controlled by the amination time. Especially, compared with the other charged thermo-sensitive membranes mentioned in the introduction, the new route presents the following advantages: (i) The CGM with positive –N+ (CH2 CH3 )3 groups has the higher mechanical strength and faster response to stimuli than the NIPAAm hydrogel. Generally speaking, the application of NIPAAm hydrogels in the controlled drug delivery is limited by the low mechanical and slow response to temperature change in the order of several hours [1]. This will be evidenced by the permeation results as shown hereafter (c.f. Section 3.4), which will show a fast response to changes in temperature in the order of several minutes. (ii) The CGMs are simply obtained compared with those from copolymerization with polyelectrolyte or ionic monomer, and at the same time the membranes with different charge densities can be obtained by controlling the amination time. (iii) In terms of charge species, the membranes with the positive –N+ (CH2 CH3 )3 groups shows satisfactory ion selectivity among the cationic, anionic and neutral drugs.
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Fig. 6. The variation of permeability coefficient of the CUMs and CGMs with different IEC in the deionized water under 25, 37, 43 ◦ C, respectively.
receptor medium, e.g. pH, ionic strength. In the present studies, the deionized water or the buffer solution is usually chosen as the receptor medium to investigate the diffusive behavior of drugs [4,24,25]. However, owing to sodium chloride solute extensively existing on the surface of skin and in the inner of the organism, thus, when a drug release system is applied in vivo, especially for the charged system, the effect of the sodium chloride solute should not be ignored inconsiderately. Based on the consideration above, in this paper, the effect of not only the deionzed water but also the sodium chloride solute was studied in the vitro experiments as shown in Figs. 6 and 7. In the case of the deionized water as the receptor, the permeability coefficient of the CGM with a specific IEC markedly increases when the temperature changes from 25 to 43 ◦ C, while the trend is not so distinct for the CUM (c.f. Fig. 6). Such results show that the CGM exhibits the thermo-sensitive property. Meanwhile, under every given temperature, the changes in permeability coefficient of the CGMs show the increase with IEC in regular. Due to the electrostatic interaction between the ionic drug and the fixed groups in the matrixes of membrane, the permeability coef-
Therefore, such membranes can be applied into the controlled release of ionic drugs, which will be investigated in the following sections. 3.3. Effect of IEC and receptor medium on the drug release As a rule, the delivery rate of drug through the membrane is significantly influenced by the physicochemical properties of the
Fig. 7. The variation of permeability coefficient of the CUMs and the CGMs with different IEC in the sodium chloride solution (C = 0.001 M) under 25, 37, 43 ◦ C, respectively.
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Fig. 8. The variation of the drug adsorption of the CGMs and CUMs with different IEC at 37 ◦ C.
ficient of ionic drug improves to a certain extent. It indicates that the electrostatic interaction between the ionic drug and the fixed group in the matrixes of membrane plays an important role in the drug delivery process. Such result is consistent with the earlier studies which showed that the cationic drugs permeated the membranes faster in ionized form than in un-ionized form [21,26]. Furthermore, the trend is also reasonable from view-point of theory because when the IEC increases, the WR increases which will produce the more water channels for drug diffusion, and then the permeability coefficient will increase as a result. For the CUM, the permeability coefficient of the ionic drug slightly increases with IEC increasing under a certain temperature but the magnitude is much less than that of the CGM. In addition, the permeability coefficient of the drug through the CUM is much less than that of the CGM even though the IEC of the former is much higher than that of the latter (c.f. Fig. 6). Conventionally, the release process of ionic drug through the charged membrane is considered to occur in three steps: (1) diffusion of ionic drug close to the available surface of membrane and adsorption of ionic drug to the surface by exchange with the counter-ions of fixed groups located in membrane; (2) the ionic drug passing through the pore or matrix of membranes to the outer side of membranes by the concentration gradient; (3) desorption of ionic drug from the outer side of membrane into the receptor medium. Comparing the CGM with the CUM, the latter two steps nearly resemble while the first step distinctly differs a lot because the adsorption of drug on CGM is determined not only by exchange with the counter-ions but also by adsorption of the poly(NIPAAm) chains which can adsorb the large quantities of drug by the imino and carbonyl groups [27]. The result shown in Fig. 8 also illustrates that, due to the poly(NIPAAm) chains on the surface of membrane, which are enriched with the imino and carbonyl groups, the adsorption of CGM is much more than that of CUM. Then, the increased adsorption of drug definitely leads to the drug concentration near the surface layer of membrane rising, which allows the more drugs to move through the membrane. Therefore, the permeability coefficient of the drug through the CGM is much higher than that of the CUM in a general way.
When the 1 mM NaCl solution was chosen as the receptor medium, the similar trend that the variation of permeability coefficient of both CGM and CUM with a change of temperature or IEC is detected (c.f. Fig. 7). Dissimilarly, the permeability coefficient of the SSA in the NaCl solution is 1–3 times faster than that in the deionized water under each predetermined temperature. Furthermore, in the NaCl solution, the permeability of drug across the membrane with the same IEC markedly varies with temperature comparing with that in the deionized water. For instance, the permeability coefficient of the membrane with IEC (0.400 mmol/g) increases from 1.72 × 10−6 cm2 /s at 25 ◦ C to 2.27 × 10−5 cm2 /s at 37 ◦ C and then increases to 2.71 × 10−5 cm2 /s at 43 ◦ C when the drug is permeated in the deionized water. However, it increases from 2.99 × 10−6 to 4.13 × 10−5 cm2 /s and then to 4.87 × 10−5 cm2 /s, respectively, in the NaCl solution. Such a phenomenon implies that the sensitivity to temperature of the membrane can be improved by using the NaCl solution as receptor medium. A possible explanation for these results is as the following. Although the hydrophilic groups introduced in the NIPAAm may lead to a higher LCST, the NaCl solution can make the LCST decrease because of the reduced repulsion of the poly(NIPAAm) chains and the accessibility of water surrounding. Nevertheless, what is the most important is the influence of Donnan dialysis effect on the ionic drug permeating through the membrane. Specifically, because the membrane possesses positive fixed charge, when the salicylate ions pass through the membrane, Cl− preferentially transfer across the membrane, which greatly accelerates the salicylate ions to move through the membrane in order to keep the electroneutrality. On the other hand, the charges effect on drug release through the grafted membrane in both kinds of the receptor mediums is clearly presented in Fig. 9. When the grafted membrane is uncharged, the release profiles slightly distinguish in both kind of the receptor medium under different temperatures, which almost completely depends on the temperature-sensitive property of the NIPAAm polymer chains. However, when the grafted membrane is charged by aminating agent the increased sensitivity to the temperature can be observed in both deionized water and NaCl solution. The only difference is that the permeability coefficient in the NaCl solution is faster than that in the deionized water, which is mainly due to the Donnan dialysis effect. Hence, the permeability coefficient of ionic drug across grafted membrane under a certain temperature, and the sensitivity to the temperature can be improved by making the membrane charged or using the electrolyte solution as receptor medium. Otherwise, according to the species of fixed charge, neutral, cationic and anionic drugs can be released selectively. 3.4. Responsive permeability for a CGM to a successional change in temperature As well known, the quick response of an “intelligent” system to outer stimulus is a prerequisite property for its application to drug delivery. In order to investigate the property of CGM, the diffusive experiment of SSA through the CGM to a successional change in temperature was carried out in the deionized
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Fig. 9. The accumulated permeate concentration profiles of drug through the CGM (IEC = 0.802 mmol/g) and uncharged grafted membranes (IEC = 0) in the deionzed water and the NaCl solution (C = 0.001 M), respectively.
water. Meanwhile, for meeting with the requirement of the reservoir-membrane model during the whole diffusive experiment, the original concentration of drug in the donor cell was chosen as 0.010 M. Fig. 10 shows the accumulatively diffusive concentration of drug permeated through the CGM with IEC = 0.400 mmol/g as a function of time at 25, 37 and 43 ◦ C orderly. Apparently, the slope of the straight lines increases with the temperature. The permeability coefficients, calculated from the slopes of the lines, increase from 6.62 × 10−6 cm2 /s at 25 ◦ C to 1.12 × 10−5 cm2 /s at 37 ◦ C and further to 1.28 × 10−5 cm2 /s at 43 ◦ C. Taking into account that the change in the permeability is detected in a few minutes after a stepwise change of temperature in the grafted thermo-sensitive system with positive charges, this system exhibits a faster response to an instantaneous change in the temperature than single hydrogel system [28].
Fig. 10. The accumulated permeate concentration profile of the responsive permeability of a CGM to a successional change in temperature.
3.5. The close–open gate characteristic of the CGM to drug release Theoretically speaking, the open–close gate concept really depends on the physical structure of the membranes. Only for porous membranes (or other mediums), the grafting of PNIPAAm can occur on the surface of the pores and the chains of PNIPAAm shrink to leave the space for solute diffusion as the temperature is higher than LCST. To show the physical structure, the SEM images were taken for base membrane BPPO, CUM and CGM and the results were shown in Fig. 11. It seemed that whether for original BPPO membranes or CGMs or CUMs, all are of porous structure and thus permit us to investigate the close–open gate characteristic. To verify the close–open gate effect of the poly(NIPAAm) grafted on the surface of the pores in the CGM, release experiments was conducted by alternatively changing the environmental temperature across the LCST. Meantime, to compare with the characteristic of CGM, the CUM was also undergone the same experiment. As shown in Fig. 12, due to the thermo-sensitive property of the poly(NIPAAm), the temperature-dependent permeation behavior of CGM is found to be non-linear. At the temperatures lower than the LCST of PNIPAAm (32–33 ◦ C), the pores in the membranes are closed due to the solvated and stretched poly(NIPAAm) side chains, so the permeability coefficient increases only marginally with the increase in the permeation temperature. On the other hand, at the temperatures higher than the LCST (above 33 ◦ C), the pores are opened owing to the shrunk NIPAAm polymer chains, so the permeability coefficient increases markedly with the increase in the permeation temperature when the temperature ranged from 30 to 40 ◦ C. Above 40 ◦ C, the grafted NIPAAm polymer chains completely shrink, thus the permeability coefficients keep invariable on the whole. As far as the CUM is concerned, the permeability coefficients show a slight change with the increase in temperature from 20 to 45 ◦ C. The small variation of the permeability coefficient with change in temperature mainly results from the thermal movement of molecules or ions. From Figs. 6, 7 and 12, it can be observed that such thermal
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Fig. 12. The permeability coefficients of SSA across the CGM (IEC = 0.400 mmol/g) and the CUM (IEC = 0.673 mmol/g) in response to temperature change between 20 and 45 ◦ C in the deionized water.
good agreement with the characteristic of phase transition of the PNIPAAm, which is also consistent with the results shown in Fig. 5. In summary, the CGMs exhibit the intrinsic and particular temperature-responsive property of the poly(NIPAAm) all the same. In addition, the reason for the higher permeability coefficients of CGM than that of CUM in a general way has been illustrated above. 4. Conclusions
Fig. 11. SEM images of surface of BPPO base membrane (a), CUM (b, IEC = 0.673 mmol/g) and CGM (c, IEC = 0.625 mmol/g).
movement can cause much more appreciable increase in the permeability of drug for grafted membrane when temperature is increased. Obviously, this higher permeability is due to the grafting of PNIPAAm. Theoretically, the temperature-sensitivity of the membrane rises with the increase in grafting degree of the PNIPAAm, the transition shown in Fig. 12 for CGM is not as “abrupt” as that reported in some literatures due to the relatively low grafting degree (5.26% in this case) [19]. Nevertheless, at temperatures between 30 and 40 ◦ C as shown in Fig. 12, the change of the permeability coefficient of CGM is in
Based on the investigations above, the ionic drug release behavior through the charged thermo-sensitive membranes is related to their water content, charge concentration, the temperature dependent swelling behavior as well as the receptor medium. Results show that permeability coefficient of the ionic drug is markedly affected by amination on the grafted membrane, and it increases with increasing of the IEC of the membranes. When the NaCl solution is used as the receptor medium, the effect of amination of the grafted membrane on the ionic drug release is very important due to the Donnan dialysis effect, which can result in the notable increase in the release rate. On the other hand, when in the NaCl solution, the increased quantity of drug release across a CGM is much more than that across an uncharged grafted membrane in the same change of temperature. Similarly, the results can be found in the deionized water. It suggests that the sensitivity of the CGM to temperature can be promoted by amination. Acknowledgements This work was supported in part by the Natural Science Foundation of China (No. 20576130), National Basic Research Program of China (973 program, No. 2003CB615700), and the Special Foundation for Doctoral Discipline of Ministry of Education of China (No. 20030358061).
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Controlled release of ionic drug through the positively charged temperature-responsive membranes Lei Zhang, Tongwen Xu ∗ , Zhan Lin Laboratory of Functional Membranes, School of Chemistry and Material Science, University of Science and Technology of China (USTC), Hefei 230026, PR China Received 22 November 2005; received in revised form 9 March 2006; accepted 18 April 2006 Available online 27 April 2006
Abstract This work is focused on the investigation of the permeability of the ionic drug through the charged BPPO-g-NIPAAm membrane (CGM) in different release mediums. The CGM has temperature-responsive poly(N-isopropylacrylamide) [poly(NIPAAm)] chains and –N+ (CH2 CH3 )3 ionic groups by means of grafting and then amination to the BPPO membrane (the base membrane). By controlling the amination time, the charged base membranes (CUMs) and CGMs with different ion exchange capacities (IEC) and water contents (WR ) are obtained. Results show that the longer the amination time, the higher the IEC and WR values. However, the CUM gains the higher IEC and WR compared with the CGM even within the same amination time, which is possibly due to the decreased opportunity of replacement reaction as well as the blocking of the poly(NIPAAm) chains on the surface of the membrane. The sodium salicylate (SSA) was used as model drug due to its ionization in deionized water. Permeability coefficient of the drug is measured using side-by-side diffusion cells at various temperatures including 25, 37 and 43 ◦ C. It is shown that the permeability coefficient of the drug markedly increases after the grafted membrane is aminated. When NaCl solution is used as the receptor medium, the increased quantity of drug release through the CGM is much more than that through the uncharged grafted membrane in the same change of temperature. Similar results can be also found in the deionized water. Consequently, it can be concluded that the sensitivity of the grafted membrane to temperature can be promoted by amination. © 2006 Elsevier B.V. All rights reserved. Keywords: Poly(N-isopropylacrylamide); Controlled release; Temperature-responsive; Ionic drug; Ion exchange membrane
1. Introduction Stimuli-responsive (“intelligent”) drug delivery systems have been investigated for their applications in pulsatile delivery of certain hormone drugs. Generally speaking, stimuli-responsive systems consist of temperature, pH, ionic strength and currentresponsive system, and so on [1–6]. Among all studied systems, temperature-responsive delivery system has attracted much attention since some disease states manifest themselves by a change in temperature. Up to now, single temperatureresponsive system has been already studied extensively. Meanwhile, the multifunctional temperature-responsive system has been also gradually developed in order to meet the various demands of drug release. For example, the thermo-sensitive
∗
Corresponding author. Tel.: +86 551 3601587; fax: +86 551 3601592. E-mail address: [email protected] (T. Xu).
0376-7388/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.memsci.2006.04.018
polymer and weak electrolyte are often used in such systems since they can alter their mass transport properties by changing structure and physical properties in simultaneous response to the temperature and pH changes [1]. Among all existing drug delivery systems, it has long been known that ion-exchange membrane is widely used in the release for ionic drugs [7,8]. In order to promote the application of temperature-responsive system to ionic drug release or fast responsive materials, the charged temperatureresponsive systems were developed. In previous studies, the charged temperature-responsive systems were often formed by the copolymerization or blending with the polyelectrolyte or ionic monomer [9,10]. Due to the abundant charges exiting in the polymer matrices, the charged temperature-responsive systems containing high water content are very suitable to apply in biotissue. At the same time, they have excellent potential as bioresponsive polymers, because a change in the charge density or the property of the ionic group in the polymers can control
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the strength of their response to the outer temperature. During the drug delivery and diffusion through the membrane, a large amount of the unbound water in the membrane allows substantive solutes to release or transport. Because of the existing charges, electrostatic interaction between the fixed groups located on the membrane matrices and ionic groups on the drug can influence on the permeability coefficient of the ionic drugs. When the receptor medium is an electrolyte solution, the Donnan dialysis effect should be also taken into account. As known to all, poly(N-isopropylacrylamide) [poly(NIPAAm)] is the well-investigated and most prominent temperature-responsive polymer by far. Crosslinked poly(NIPAAm) has a lower critical solution temperature (LCST) at 32–33 ◦ C. Below that temperature, the gel is swollen, hydrated and hydrophilic; while above the LCST, the gel becomes collapsed, dehydrated and hydrophobic [11]. Furthermore, LCST can be increased by copolymerization/blending with more hydrophilic monomers or decreased by using more hydrophobic monomers [1,12]. Just due to the excellent response properties of poly(NIPAAm) to temperature change, it has been widely studied in the grafting/copolymerization form [13,14], mixed form [15] as well as the single hydrogel [16]. In a previous study of our group, a novel thermo-sensitive switching membrane has been prepared by radiation-induced simultaneous grafting N-isopropylacrylamide (NIPAAm) onto bromomethylated poly(2,6-dimethyl-1,4-phenylene oxide) (BPPO) [17]. The grafting conditions were optimized there by changing different factors such as dose, dose rate, concentration of NIPAAm, concentration of inhibitor Cu2+ , membrane thickness and solvents. This provides a possibility for preparing a positively charged thermo-sensitive membrane by simple quaternary amination of the obtained uncharged thermo-sensitive switching membrane. Therefore, in the present study, the positively charged temperature-responsive membranes will be obtained by means of triethylamine replacement of the bromine atoms on the methyl of the grafted membranes. By controlling the amimnation time, positively charged thermo-sensitive membranes with different charge densities can be obtained; further, their release performance of the ionic drug sodium salicylate (SSA) will be investigated according to different receptor mediums under various temperatures. 2. Materials and methods 2.1. Materials The monomer N-isopropylacrylamide (NIPAAm) (Wako) which was bought from Sigma–Aldrich Inc., was recrystallized in n-hexane before use, and bromomethylated poly (2,6dimethyl-1,4-phenylene oxide) (BPPO) was prepared in our laboratory [18]. The analytical grade solvents such as ethanol, triethlamine, n-hexane, hydrochloric acid, sodium hydroxide and sodium chloride were used as received. Sodium salicylate (SSA) and 1-methyl-2-pyrrolidone were of chemical grade. These chemicals were commercially obtained and used without further purification. Deionized water was used in all experiments.
2.2. Preparation of membranes 2.2.1. Preparation of the BPPO-g-NIPAAm membrane (the grafted membrane) The grafted membrane was prepared as described in literature [17]. Briefly, the prepared BPPO base membranes (ungrafted membranes) were immersed in the NIPAAm aqueous solution containing inhibitor Cu2+ . After irradiated by the Co60 -␥-rays irradiation source for a few hours, the grafted membrane was obtained. After removing the remaining monomer polymer on the surface of the membrane and rinsed by deionized water, the degree of grafting was determined gravimetrically according to the following formula: degree of grafting (%) =
m1 − m0 × 100%. m0
(1)
The weight of ungrafted (m0 ) and grafted membrane (m1 ) in the dry state were determined, respectively, after drying in the oven at 60 ◦ C to a constant weight [19]. In our previous job [17], it was shown that a membrane with grafting degree 5–7% was easily obtained and our preliminary tests also showed that such degree could satisfy with the requests of thermo-sensitive property. Therefore, the grafted membrane with a grafting degree about 5.26% was used as received in the whole experiment hereafter. 2.2.2. Preparation of the charged grafted (BPPO-g-NIPAAm) membrane (CGM) or charged ungrafted (BPPO) membrane (CUM) The ungrafted membranes and the grafted membranes were accurately cut into pieces with circular dimensions about 5.72 cm2 and subjected to amination process by immersing them into triethylamine medium. After a proper time, the membranes were extracted from the solution, then washed with deionized water and equilibrated with 1 M HCl solution to be transformed into the chloride form. The amination degree was controlled by amination time [20]. 2.3. Characterization 2.3.1. Determination of WR and IEC values To investigate the effect of amination degree on the water content of the charged thermo-sensitive membranes (CGMs), the dried membranes were immersed in an excess amount of deionized water at 20 ◦ C until swelling equilibrium was attained. Before measuring the weight of the wet membranes, they should be transformed into the chloride form. The weight of wet sample (Wt ) was determined after removing the surface water by blotting with filter paper. Dry weight (W0 ) was determined after drying the membrane in an oven at 60 ◦ C for 2 h. Then the water content (WR ) was calculated from the following equation: Wt − W 0 × 100%. (2) WR = W0 In addition, the water content of the uncharged base membrane and the uncharged grafted membrane were determined by the same method as the CGM or CUM but without the process of
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Fig. 1. The diffusive process of the SSA (SA− referring to salicylate anion) across a CGM in deionized water.
transforming into the chloride form. The final membranes were conducted to the measurements of ion-exchange capacity (IEC) as described elsewhere [20]. 2.3.2. Morphological observation The morphological details of the BPPO membrane, CUM, CGM were observed by scanning election microscopy SEM (XT30 ESEM-TMP PHILIP) with a common procedure. 2.3.3. Temperature dependent swelling behavior After the grafting and amination reaction, positively charged temperature-responsive membranes (CGMs) were obtained. In order to study the temperature dependent swelling behavior, the CGM (IEC = 0.790 mmol/g) was immersed in an excess amount of deionized water under each predetermined temperature until swelling equilibrium was attained, and then the WR was obtained as mentioned above. Meantime, to compare with the characteristic of CGM, the CUM (IEC = 0.730 mmol/g) was also undergone the same experiment.
5.72 cm2 . During the measurement of the permeability coefficients, the receptor medium (100 ml) in the right-hand side cell (receptor cell) and 1 mM aqueous drug solution (100 ml) in the left-hand side cell (donor cell) were introduced, respectively. The membrane was mounted onto the cells after soaking in the deionized water at room temperature. SSA is water-soluble and can be easily detected by a UV spectrophotometer because of its UV-active benzene ring moiety at 295.5 nm. This makes it possible to quantitatively determine its concentration. A sampled solution (2 ml) was taken at interval of 20 min from the receptor cell and replaced with the same kind and quantity of receptor medium. The measurement of permeability coefficient was carried out for 2 h at a desired temperature. The drug flux J and the permeability coefficient P are related by the following relationship [21]: dCt V Ct − C0 J= = −P (3) dt S d Where V is the volume of the receptor cell, S the effective membrane area, d the membrane thickness, P (cm2 /s) the permeability
2.4. Measurement of the permeability coefficients Due to the existence of poly(NIPAAm) chains on the membrane surface and fixed groups, the release process of the SSA through a membrane is mainly controlled by the outer temperature, the IEC of a membrane as well as the receptor medium. As shown in the Fig. 1, when the temperature exceeds the LCST in the deionized water, the pores in the membranes are open owing to the shrunk poly(NIPAAm) chains. Simultaneously, the positively ionic groups fixed on the surface of membrane recognize the anionic drugs and then allow them to pass through the membrane. Based on the process of the drug release, diffusion experiments were carried out using jacketed side-by-side diffusion cells as shown in Fig. 2, where the temperature was controlled by a water bath. The effective membrane area for permeation is
Fig. 2. Schematic representation of the experimental setup for permeability coefficient measurements.
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coefficient of membrane, Ct the concentration of the receptor side, C0 (=1 mM) the concentration of the drug at the left compartment, and dCt /dt is the concentration variance per unit time. It has been confirmed that the water levels of both compartments does not show any significant change throughout the permeability measurements and thus the osmotic pressure effect can’t disturb diffusion of drug significantly [1,22]. 2.5. Measurements of drug adsorption The CUMs and the CGMs with different IEC were, respectively, immersed into the 0.001 M drug solution (20 ml) at 37 ◦ C for 24 h. Then, each of them was transferred into the deionized water (20 ml) at 37 ◦ C for 36 h after rinsing them to eliminate the unadsorbed drug on the membrane surface. The adsorbed amount was determined from the concentration change in the deionized water by the ultraviolet spectrophotometer. However, in order to avoid the effect of difference in membrane area, the adsorption ability (Wads ) of membrane is characterized by the ratio between the adsorbed drug amount (g) and the dried membrane mass (g). 3. Results and discussion 3.1. Preparation of membranes and their characterizations As seen in Fig. 3, the ungrafted and grafted membranes with different WR were obtained after a proper amination time. It can be found that, for the ungrafted membranes, the WR values of membranes increase with the amination time rising. The trend is reasonable, because with amination time rising the ion exchange capacity increases as shown in Fig. 4, which tends to make the membrane more hydrophilic as discussed in detail in our previous paper [20]. For the grafted membranes, the WR follows an analogous trend to that of the ungrafted membranes in a general way. However, compared with the ungrafted membrane, the water content of grafted membrane is much lower. A possible reason is as the following. When the grafting reaction happens, the crosslinking reaction perhaps occurs simultane-
Fig. 4. The variation of the IEC of both the CUMs and the CGMs with the amination time.
ously due to the active methylenes, which tends to make the membrane more compact and reduce the reactive point (bromomethylated groups) in the membrane matrix, and accordingly leads to the decreased WR of the grafted membrane [23]. In addition, the grafted PNIPAAm on the membrane surface may possibly block the amination reaction (as will be discussed in the next section) and then result in the lower WR . Similarly, the IEC of grafted and ungrafted membrane increase with amination time rising is also observed as shown in Fig. 4. The phenomenon is also in a good agreement with the previous study [20]. Meanwhile, it can be found that the ungrafted membrane obtains higher IEC than the grafted membrane within an equal amination time. As a matter of fact, both the grafting reaction and the amination reaction replace the bromine atoms in the matrices of the base membrane. Obviously, there are less bromine atoms in grafted membrane than in ungrafted ones because of the happening of the grafting reaction which has been intensively discussed in our previous paper [17]. Consequently, the chance of the replacement reaction between triethylamine and bromine atom is also decreased in the grafted membranes. Furthermore, the blocking effect of the poly(NIPAAm) chains on the surface of the grafted membrane can also result in the reduction of the opportunity of the subsequent amination reaction. 3.2. The temperature dependent swelling behavior
Fig. 3. The variation of the WR of both the CUMs and the CGMs with the amination time at 20 ◦ C.
In order to study the temperature dependent swelling behavior of CGM with the PNIPAAm chains, a CGM was fully swollen in the deionized water at various temperatures in the expected range of the LCST phase transition. As shown in Fig. 5, the WR of CGM decreases with temperature increasing from 15 to 50 ◦ C in a general way while the most abruptly decrease in the WR is observed at temperatures between 30 and 40 ◦ C. That’s because below 30 ◦ C (around LCST of PNIPAAm) the CGM membrane contains more water due to the swelling of the PNIPAAm chains on it. When the temperature increases up to 30 ◦ C around, it will result in the deswelling of the PNIPAAm chains, and then the WR decreases abruptly. When the temperature increases to
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Fig. 5. The variation of the WR of both the CGM (IEC = 0.790 mmol/g) and the CUM (IEC = 0.730 mmol/g) with the temperature.
40 ◦ C, most of the PNIPAAm chains have shrunk, as a result, the WR tends to level off though the temperature increases further. As far as the CUM is concerned, the WR slightly decreases at the temperature change from 15 to 50 ◦ C, and does not clearly present the abruptly change as shown as the CGM. The difference between the CGM and the CUM probably results from the PNIPAAm chains on the CGM which is hydrophilic below LCST and then hydrophobic above LCST. From the results above, it can be concluded that the positively charged base membranes as well as their thermo-sensitive ones can be prepared in this manner and their some properties can be controlled by the amination time. Especially, compared with the other charged thermo-sensitive membranes mentioned in the introduction, the new route presents the following advantages: (i) The CGM with positive –N+ (CH2 CH3 )3 groups has the higher mechanical strength and faster response to stimuli than the NIPAAm hydrogel. Generally speaking, the application of NIPAAm hydrogels in the controlled drug delivery is limited by the low mechanical and slow response to temperature change in the order of several hours [1]. This will be evidenced by the permeation results as shown hereafter (c.f. Section 3.4), which will show a fast response to changes in temperature in the order of several minutes. (ii) The CGMs are simply obtained compared with those from copolymerization with polyelectrolyte or ionic monomer, and at the same time the membranes with different charge densities can be obtained by controlling the amination time. (iii) In terms of charge species, the membranes with the positive –N+ (CH2 CH3 )3 groups shows satisfactory ion selectivity among the cationic, anionic and neutral drugs.
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Fig. 6. The variation of permeability coefficient of the CUMs and CGMs with different IEC in the deionized water under 25, 37, 43 ◦ C, respectively.
receptor medium, e.g. pH, ionic strength. In the present studies, the deionized water or the buffer solution is usually chosen as the receptor medium to investigate the diffusive behavior of drugs [4,24,25]. However, owing to sodium chloride solute extensively existing on the surface of skin and in the inner of the organism, thus, when a drug release system is applied in vivo, especially for the charged system, the effect of the sodium chloride solute should not be ignored inconsiderately. Based on the consideration above, in this paper, the effect of not only the deionzed water but also the sodium chloride solute was studied in the vitro experiments as shown in Figs. 6 and 7. In the case of the deionized water as the receptor, the permeability coefficient of the CGM with a specific IEC markedly increases when the temperature changes from 25 to 43 ◦ C, while the trend is not so distinct for the CUM (c.f. Fig. 6). Such results show that the CGM exhibits the thermo-sensitive property. Meanwhile, under every given temperature, the changes in permeability coefficient of the CGMs show the increase with IEC in regular. Due to the electrostatic interaction between the ionic drug and the fixed groups in the matrixes of membrane, the permeability coef-
Therefore, such membranes can be applied into the controlled release of ionic drugs, which will be investigated in the following sections. 3.3. Effect of IEC and receptor medium on the drug release As a rule, the delivery rate of drug through the membrane is significantly influenced by the physicochemical properties of the
Fig. 7. The variation of permeability coefficient of the CUMs and the CGMs with different IEC in the sodium chloride solution (C = 0.001 M) under 25, 37, 43 ◦ C, respectively.
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Fig. 8. The variation of the drug adsorption of the CGMs and CUMs with different IEC at 37 ◦ C.
ficient of ionic drug improves to a certain extent. It indicates that the electrostatic interaction between the ionic drug and the fixed group in the matrixes of membrane plays an important role in the drug delivery process. Such result is consistent with the earlier studies which showed that the cationic drugs permeated the membranes faster in ionized form than in un-ionized form [21,26]. Furthermore, the trend is also reasonable from view-point of theory because when the IEC increases, the WR increases which will produce the more water channels for drug diffusion, and then the permeability coefficient will increase as a result. For the CUM, the permeability coefficient of the ionic drug slightly increases with IEC increasing under a certain temperature but the magnitude is much less than that of the CGM. In addition, the permeability coefficient of the drug through the CUM is much less than that of the CGM even though the IEC of the former is much higher than that of the latter (c.f. Fig. 6). Conventionally, the release process of ionic drug through the charged membrane is considered to occur in three steps: (1) diffusion of ionic drug close to the available surface of membrane and adsorption of ionic drug to the surface by exchange with the counter-ions of fixed groups located in membrane; (2) the ionic drug passing through the pore or matrix of membranes to the outer side of membranes by the concentration gradient; (3) desorption of ionic drug from the outer side of membrane into the receptor medium. Comparing the CGM with the CUM, the latter two steps nearly resemble while the first step distinctly differs a lot because the adsorption of drug on CGM is determined not only by exchange with the counter-ions but also by adsorption of the poly(NIPAAm) chains which can adsorb the large quantities of drug by the imino and carbonyl groups [27]. The result shown in Fig. 8 also illustrates that, due to the poly(NIPAAm) chains on the surface of membrane, which are enriched with the imino and carbonyl groups, the adsorption of CGM is much more than that of CUM. Then, the increased adsorption of drug definitely leads to the drug concentration near the surface layer of membrane rising, which allows the more drugs to move through the membrane. Therefore, the permeability coefficient of the drug through the CGM is much higher than that of the CUM in a general way.
When the 1 mM NaCl solution was chosen as the receptor medium, the similar trend that the variation of permeability coefficient of both CGM and CUM with a change of temperature or IEC is detected (c.f. Fig. 7). Dissimilarly, the permeability coefficient of the SSA in the NaCl solution is 1–3 times faster than that in the deionized water under each predetermined temperature. Furthermore, in the NaCl solution, the permeability of drug across the membrane with the same IEC markedly varies with temperature comparing with that in the deionized water. For instance, the permeability coefficient of the membrane with IEC (0.400 mmol/g) increases from 1.72 × 10−6 cm2 /s at 25 ◦ C to 2.27 × 10−5 cm2 /s at 37 ◦ C and then increases to 2.71 × 10−5 cm2 /s at 43 ◦ C when the drug is permeated in the deionized water. However, it increases from 2.99 × 10−6 to 4.13 × 10−5 cm2 /s and then to 4.87 × 10−5 cm2 /s, respectively, in the NaCl solution. Such a phenomenon implies that the sensitivity to temperature of the membrane can be improved by using the NaCl solution as receptor medium. A possible explanation for these results is as the following. Although the hydrophilic groups introduced in the NIPAAm may lead to a higher LCST, the NaCl solution can make the LCST decrease because of the reduced repulsion of the poly(NIPAAm) chains and the accessibility of water surrounding. Nevertheless, what is the most important is the influence of Donnan dialysis effect on the ionic drug permeating through the membrane. Specifically, because the membrane possesses positive fixed charge, when the salicylate ions pass through the membrane, Cl− preferentially transfer across the membrane, which greatly accelerates the salicylate ions to move through the membrane in order to keep the electroneutrality. On the other hand, the charges effect on drug release through the grafted membrane in both kinds of the receptor mediums is clearly presented in Fig. 9. When the grafted membrane is uncharged, the release profiles slightly distinguish in both kind of the receptor medium under different temperatures, which almost completely depends on the temperature-sensitive property of the NIPAAm polymer chains. However, when the grafted membrane is charged by aminating agent the increased sensitivity to the temperature can be observed in both deionized water and NaCl solution. The only difference is that the permeability coefficient in the NaCl solution is faster than that in the deionized water, which is mainly due to the Donnan dialysis effect. Hence, the permeability coefficient of ionic drug across grafted membrane under a certain temperature, and the sensitivity to the temperature can be improved by making the membrane charged or using the electrolyte solution as receptor medium. Otherwise, according to the species of fixed charge, neutral, cationic and anionic drugs can be released selectively. 3.4. Responsive permeability for a CGM to a successional change in temperature As well known, the quick response of an “intelligent” system to outer stimulus is a prerequisite property for its application to drug delivery. In order to investigate the property of CGM, the diffusive experiment of SSA through the CGM to a successional change in temperature was carried out in the deionized
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Fig. 9. The accumulated permeate concentration profiles of drug through the CGM (IEC = 0.802 mmol/g) and uncharged grafted membranes (IEC = 0) in the deionzed water and the NaCl solution (C = 0.001 M), respectively.
water. Meanwhile, for meeting with the requirement of the reservoir-membrane model during the whole diffusive experiment, the original concentration of drug in the donor cell was chosen as 0.010 M. Fig. 10 shows the accumulatively diffusive concentration of drug permeated through the CGM with IEC = 0.400 mmol/g as a function of time at 25, 37 and 43 ◦ C orderly. Apparently, the slope of the straight lines increases with the temperature. The permeability coefficients, calculated from the slopes of the lines, increase from 6.62 × 10−6 cm2 /s at 25 ◦ C to 1.12 × 10−5 cm2 /s at 37 ◦ C and further to 1.28 × 10−5 cm2 /s at 43 ◦ C. Taking into account that the change in the permeability is detected in a few minutes after a stepwise change of temperature in the grafted thermo-sensitive system with positive charges, this system exhibits a faster response to an instantaneous change in the temperature than single hydrogel system [28].
Fig. 10. The accumulated permeate concentration profile of the responsive permeability of a CGM to a successional change in temperature.
3.5. The close–open gate characteristic of the CGM to drug release Theoretically speaking, the open–close gate concept really depends on the physical structure of the membranes. Only for porous membranes (or other mediums), the grafting of PNIPAAm can occur on the surface of the pores and the chains of PNIPAAm shrink to leave the space for solute diffusion as the temperature is higher than LCST. To show the physical structure, the SEM images were taken for base membrane BPPO, CUM and CGM and the results were shown in Fig. 11. It seemed that whether for original BPPO membranes or CGMs or CUMs, all are of porous structure and thus permit us to investigate the close–open gate characteristic. To verify the close–open gate effect of the poly(NIPAAm) grafted on the surface of the pores in the CGM, release experiments was conducted by alternatively changing the environmental temperature across the LCST. Meantime, to compare with the characteristic of CGM, the CUM was also undergone the same experiment. As shown in Fig. 12, due to the thermo-sensitive property of the poly(NIPAAm), the temperature-dependent permeation behavior of CGM is found to be non-linear. At the temperatures lower than the LCST of PNIPAAm (32–33 ◦ C), the pores in the membranes are closed due to the solvated and stretched poly(NIPAAm) side chains, so the permeability coefficient increases only marginally with the increase in the permeation temperature. On the other hand, at the temperatures higher than the LCST (above 33 ◦ C), the pores are opened owing to the shrunk NIPAAm polymer chains, so the permeability coefficient increases markedly with the increase in the permeation temperature when the temperature ranged from 30 to 40 ◦ C. Above 40 ◦ C, the grafted NIPAAm polymer chains completely shrink, thus the permeability coefficients keep invariable on the whole. As far as the CUM is concerned, the permeability coefficients show a slight change with the increase in temperature from 20 to 45 ◦ C. The small variation of the permeability coefficient with change in temperature mainly results from the thermal movement of molecules or ions. From Figs. 6, 7 and 12, it can be observed that such thermal
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Fig. 12. The permeability coefficients of SSA across the CGM (IEC = 0.400 mmol/g) and the CUM (IEC = 0.673 mmol/g) in response to temperature change between 20 and 45 ◦ C in the deionized water.
good agreement with the characteristic of phase transition of the PNIPAAm, which is also consistent with the results shown in Fig. 5. In summary, the CGMs exhibit the intrinsic and particular temperature-responsive property of the poly(NIPAAm) all the same. In addition, the reason for the higher permeability coefficients of CGM than that of CUM in a general way has been illustrated above. 4. Conclusions
Fig. 11. SEM images of surface of BPPO base membrane (a), CUM (b, IEC = 0.673 mmol/g) and CGM (c, IEC = 0.625 mmol/g).
movement can cause much more appreciable increase in the permeability of drug for grafted membrane when temperature is increased. Obviously, this higher permeability is due to the grafting of PNIPAAm. Theoretically, the temperature-sensitivity of the membrane rises with the increase in grafting degree of the PNIPAAm, the transition shown in Fig. 12 for CGM is not as “abrupt” as that reported in some literatures due to the relatively low grafting degree (5.26% in this case) [19]. Nevertheless, at temperatures between 30 and 40 ◦ C as shown in Fig. 12, the change of the permeability coefficient of CGM is in
Based on the investigations above, the ionic drug release behavior through the charged thermo-sensitive membranes is related to their water content, charge concentration, the temperature dependent swelling behavior as well as the receptor medium. Results show that permeability coefficient of the ionic drug is markedly affected by amination on the grafted membrane, and it increases with increasing of the IEC of the membranes. When the NaCl solution is used as the receptor medium, the effect of amination of the grafted membrane on the ionic drug release is very important due to the Donnan dialysis effect, which can result in the notable increase in the release rate. On the other hand, when in the NaCl solution, the increased quantity of drug release across a CGM is much more than that across an uncharged grafted membrane in the same change of temperature. Similarly, the results can be found in the deionized water. It suggests that the sensitivity of the CGM to temperature can be promoted by amination. Acknowledgements This work was supported in part by the Natural Science Foundation of China (No. 20576130), National Basic Research Program of China (973 program, No. 2003CB615700), and the Special Foundation for Doctoral Discipline of Ministry of Education of China (No. 20030358061).
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