J. Phys. Chem. B 2004, 108, 10893-10898
10893
Release of Model Compounds from “Plum-Pudding”-Type Gels Composed of Microgel Particles Randomly Dispersed in a Gel Matrix Iseult Lynch* and Kenneth A. Dawson Irish Center for Colloid Science and Biomaterials, Department of Chemistry, UniVersity College Dublin, Belfield, Dublin 4, Ireland ReceiVed: March 23, 2004; In Final Form: April 30, 2004
A novel gel structure called the “plum-pudding” gel was described by us previously.1 The gel was composed of randomly dispersed microgel particles (“plums”) in a conventional hydrogel network. Depending on the preparation conditions, the microgels can be incorporated into the gel as expanded networks or dense collapsed globules. Where the microgel particles exist as collapsed globules, they have the potential to act as reservoirs for hydrophobic solutes, from which the solutes are released very slowly. The release of two model hydrophobic compounds (pyrene and BODIPY) from “plum-pudding” gels composed of 50:50 BAM:NIPAM microgels embedded in NIPA gel films was investigated. The release of pyrene was found to follow Fickian diffusion, while the release of BODIPY was found to be slightly non-Fickian. Thus, we propose that by controlling the attractiveness of the microgel particles to the solutes to be released, a range of release profiles can be obtained from pure-Fickian to almost any conceivable time scale.
Introduction Controlled release has been defined as the permeationmodified transfer of the active material from a reservoir to a target host to maintain a predetermined concentration of the solute for a specified time.2 Conventional methods of drug delivery involve periodic application of the drug in the form of pills, intravenous infusions, aerosols, etc. The main disadvantage of these methods is that they are both uncontrolled and untargeted. The drug is distributed around the body in the bloodstream until it reaches its target site, leading to the possibility of toxic levels building up elsewhere in the body. Administration of a drug in this manner causes an initial sharp concentration peak followed by a decline due to metabolism and excretion. To maintain a therapeutic dose it is thus necessary to administer a second dose, which is costly, inefficient, and increases the risk of side effects due to toxicity. For this reason there has been a concerted effort in recent years to develop alternative drug-release technologies which offer controlled and/ or targeted release. The release behavior of solutes from thermoresponsive gels can be explained using the free volume theory.3,4 The free volume theory makes three assumptions about the system. (1) The effective free volume for solute diffusion corresponds to the free volume of the aqueous phase. (2) The solute diffuses through “fluctuating pores” by successive jumps through “holes” which are larger than the solute. (3) The solute permeates only through aqueous regions, and solute polymer interactions are minimal. According to this theory, the diffusivity of solutes through hydrogel matrices is a function of the activation energy term for diffusion, which is overcome by thermal energy. Thus, release behavior is related to temperature (even in cases where the polymer properties are unaffected by temperature). The * To whom correspondence should be addressed. Present address: Physical Chemistry 1, Lund University, Center for Chemistry and Chemical Engineering, P.O. Box 124, 22100 Lund, Sweden. E-mail: Iseult.Lynch@ fkem1.lu.se.
degree of swelling or hydration of the gel also affects the diffusion of solutes from the gel. The more swollen a gel matrix is, the larger the free volume and hence the more diffusive the solutes. This means that the diffusion behavior of a solute is a function of both temperature and swelling of the gel. In the case of thermosensitive gels, the diffusivity of the solute increases with increasing temperature, but this is balanced by the decrease in the swelling of the gel at this higher temperature. Therefore, the release rate can be controlled by altering the balance between the swelling behavior and the thermal acceleration of diffusivity. Recently we prepared a composite gel matrix, composed of PNIPAM microgel particles enmeshed in a NIPA gel matrix, which we called the “plum-pudding” gel since the microgel particles were shown via confocal microscopy to resemble plums in a traditional plum-pudding.1 It was proposed that the network chains of the NIPA gel matrix pass though the swollen microgel particles, and thus, the microgel particles become constrained within the gel, and the structure was confirmed by pore-size measurements as a function of temperature.1 It was shown that the presence of responsive microgel particles could impart a responsive behavior onto nonresponsive gel matrices.1 Thus, using the plum-pudding gel we proposed a versatile structural motif which enables the separation of the concepts of functionality and mechanical properties, with the microgel particles providing the required functionality (in this case a temperatureresponsive shrinking transition) and the bulk material providing the mechanical or biocompatible properties as desired. To undergo a shrinking transition it is necessary that the microgels be incorporated into the gels at a temperature below their transition temperature. Incorporating microgels into a bulk gel above their transition temperature would result in the microgels being in the dense collapsed state, and as such there would be no enhancement to the overall shrinking rate. On the other hand, an alternative use can be envisioned for the “plumpudding” gels prepared with the microgels as collapsed hydrophobic domains within an expanded hydrophilic gel matrix. In
10.1021/jp0487105 CCC: $27.50 © 2004 American Chemical Society Published on Web 06/26/2004
10894 J. Phys. Chem. B, Vol. 108, No. 30, 2004 this case the “plum-pudding” gel could be used as a slow-release device for hydrophobic drug molecules, with the microgels or “plums” acting as sinks or reservoirs for the solutes from which the solutes diffuse slowly. Here again, the concepts of functionality and bulk issues are separated, with the microgel particles providing the functionality (controlled release) while the bulk properties are provided by the hydrogel matrix. The aim of this paper is to investigate the possibility of using the two-component “plum-pudding” gel matrix with the microgels in the dense globular form to achieve very slow release of model hydrophobic solutes, with near zero-order kinetics. Such a release pattern would show a constant rate of elution and have the advantage of maintaining a therapeutic dose at the target site for a longer period of time than administration by normal routes. The release rate of two model solutes from the twocomponent “plum-pudding” gel was determined, where the microgel particles were incorporated into the gel matrix in the collapsed phase. The bulk gel was composed of N-isopropylacrylamide (NIPA) gel and had a transition temperature of 34 °C, and the “plums” or microgels were copolymers of NIPAM and BAM (50:50). Incorporation of the more hydrophobic monomer N-tert-butylacrylamide (BAM) into the microgels reduces the transition temperature of the microgel particles, making them hydrophobic (collapsed) even at room temperature. Pyrene and BODIPY (4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora3a,4a-diaza-s-indacene) were used as the model compounds, and their release from the “plum-pudding” gels was determined with the aim of achieving continuous, zero-order release kinetics. Experimental Section Materials. N-isopropylacrylamide (NiPAM) monomer (purity > 99%) supplied by Phase Separations Ltd. (Clwyd, U.K.) or Acros Organics Ltd. (Geel, Belgium) was recrystallized twice from hexane. The following chemicals were used as supplied: N-tert-butylacrylamide (BAM) (purity g 97.0%), and N,N1methylene-bisacrylamide (BisAM) (purity > 99.5%) from Fluka (Dorset, England); ammonium peroxydisulfate (APS) (purity 99.99%) from Aldrich (Dorset, England); N,N,N1,N1-tetramethylethylenediamine (TEMED) from Sigma (Dorset, England); pyrene from Aldrich (Steinheim, Germany); and 4,4-difluoro1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY) from Molecular Probes (Leiden, The Netherlands). All water used was doubly-deionized Milli-Q water, and degassed before use. Synthesis of 50:50 BAM:NIPAM Microgels. 50:50 BAM:NIPAM microgels were synthesized by dispersion polymerization according to the method of Li and Bae.5 The monomers, NIPAM (0.1 g), BAM (0.1 g), and BisAm (0.02 g, 3.2 mmol), were dissolved in 36 mL of water. A 1 mL amount of 0.1 wt % Triton 100 solution was added. The solution was heated to 70 °C and degassed by bubbling with N2. APS (0.02 g) was dissolved in 4 mL of water, degassed, and added slowly to the stirring monomer solution under an N2 atmosphere. The reaction was left for 12 h at 70 °C. The resulting 1 wt % microgels in water dispersion was cleaned by dialysis and stored in solution at 4 °C. 100% PNIPAM microgel particles were also prepared for comparison. Transition Temperature of PNIPAM and 50:50 BAM: NIPAM Microgels. The transition temperatures of the microgel particles were determined from the decrease in the transmission by UV using a Pharmacia LKB-Ultrospec UV-vis spectrophotometer at a wavelength of 450 nm. Temperature control was provided by a Neslab RTE-211 water bath, and the heating rate was 0.5 °C/min. The transition temperature was taken to
Lynch and Dawson be the temperature at which transmission was reduced to 50% of its initial value. In all cases a 0.1 wt % microgel solution was used. Loading of 50:50 BAM:NIPAM Microgels with Hydrophobic Fluorescent Dyes. The fluorescent dyes used were pyrene and BODIPY, both of which are hydrophobic and thus have limited solubility in water. For pyrene, a 2 × 10-6 M aqueous standard solution was prepared. For BODIPY, a standard solution of 1 mg in 25 mL ethanol was prepared. An aqueous standard solution was prepared from this by diluting 1 mL of the BODIPY in ethanol solution to 10 mL with water, giving a concentration of 1.5 × 10-5 mg/mL BODIPY. For both pyrene and BODIPY, 5 mL of the standard solution was mixed with 5 mL of the 1 wt % 50:50 BAM:NIPAM microgel solution and shaken at room temperature for 2 h. Solutions were then centrifuged at 10 000 rpm for 30 min, and the supernatant was removed and used to calculate the amount of the fluorophor absorbed into the microgel particles. Water was added to resuspend the microgels, the amount depending on the concentration of microgels required in the subsequent gel. Loading of pyrene resulted in a concentration of 3.12 × 10-3 µg of pyrene in the microgels after centrifugation. Loading of BODIPY resulted in a concentration of 1.44 × 10-3 µg of BODIPY in the microgels after centrifugation. Synthesis of Flat Sheets of Gel Containing 1 wt % Fluorescent Microgels. Flat sheets of gel containing the dyeloaded microgels (physically absorbed pyrene or BODIPY) of 50:50 BAM:NIPAM were prepared according to the method of Kokufuta and Nakaizumi.6 Pregel solutions were prepared as follows. The required amounts of monomer (700 mmol of NIPAM), cross-linker (8.6 mmol of BisAM), and promotor (0.001% v/v of TEMED) were dissolved in 1 mL of water. The microgels were concentrated by centrifugation (to remove excess dye in the cases of pyrene or BODIPY) and resuspended in one-quarter the amount of water they were in initially. A 1 mL amount of the concentrated microgel solution was added to the monomer solution (to give a final concentration of 1 wt % microgel particles). The solution was degassed under vacuum, and initiator (3.5 mmol of ammonium persulfate) was added. The solution was injected between two glass slides separated by 0.15 mm and left to gel overnight at room temperature, i.e., above the transition temperature of the microgel particles, so that they were in the collapsed state. Release of Fluorescent Dyes (Pyrene and BODIPY) from Flat Sheets of Microgel-Containing Gels. The release of hydrophobic dye molecules from thin films containing hydrophobic microgels of 50:50 BAM:NIPAM loaded with the dye molecules was measured by fluorescence spectroscopy. The freshly prepared gel was placed in a beaker containing 30 mL of deionized water and thermostated at 37 °C, which was above the transition temperature of both the microgel particles and the bulk NIPA gel. At regular intervals the water was removed and replaced by fresh water. In all cases the setup represented the release of the drug from a thin gel film in a well-stirred infinite bath. The amount of the fluorophore in the water at each sampling time was determined using a Perkin-Elmer Luminescence Spectrometer LS50B and plotted as the percent release as a function of time. The initial concentration in the microgels was calculated from the loading process. The concentration in the supernatant after shaking and centrifuging is subtracted from the concentration in the solution before shaking. This is the amount of dye loaded into the microgels. For the pyrene experiments the excitation and emission wavelengths were 337
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Figure 1. Transmission curve of 50:50 BAM:NIPAM microgels as a function of temperature.
and 385, respectively, while for the BODIPY experiments they were 493 and 503, respectively. Results The 100% PNIPAM microgels had a transition temperature of 35 °C.1 Microgels composed of 50% N-tert-butylacrylamide (BAM) and 50% NIPAM were found to have a transition temperature of 11.5 ° C, as shown in Figure 1 (taking the transition temperature to be at 50% of the initial transmission). The lower transition temperature is a result of the fact that BAM is more hydrophobic than NIPAM due to the additional -CH2 groups in its structure. Thus, synthesis of the bulk gel at room temperature would result in the microgels being entrapped in the gel matrix as dense collapsed hydrophobic globules. PNIPAM microgels have been shown to absorb large quantities of small molecules and ions.7,8 Generally, the amount absorbed is at a maximum at temperatures below the transition temperature of the microgel particles. For example, PNIPAM microgel particles absorb 20-50 mg of heavy metal nitrates per gram of microgel at 25 °C but release as much as 80% of this when the gel is heated to 50 °C.9 However, in the case of hydrophobic solutes, the amount absorbed increases with increasing temperature (as long as the solute is sufficiently small that it can fit through the smaller pores), as shown by Pankasem et. al. for pyrene.10 They show that increasing the temperature provides a more hydrophobic environment for pyrene and that depending on the microgel concentration as much as 87% of the added pyrene will reside inside the microgel particles at 50 °C.10 Figure 2a shows the fluorescence spectra of pyrene in the 100% NIPAM microgel dispersion at 21 and 50 °C. A significant difference is observed at the different temperatures. In particular, the ratio of the peak at 383.5 nm and the peak at 373 nm changed considerably. This is called the I3/I0 ratio and is a measure of the polarity of the microenvironment of the pyrene. The ratio usually decreases when the polarity of the environment increases.10 The I3/I0 ratio of pyrene fluorescence changes from 0.88 at 21 °C to 0.94 at 50 °C, indicating that the microenvironment for pyrene becomes more hydrophobic at higher temperatures. This is in agreement with the findings of Pankasem et al.,10 who interpreted this change as being a result of the polymers coiling upon themselves with increasing temperature, thereby providing a more hydrophobic environment
Figure 2. (a) Fluorescence spectrum of pyrene in 100% NIPA microgels at 21 and 50 °C showing the change in the I3/I1 ratio. (b) Fluorescence spectra of pyrene in 50:50 BAM:NIPAM microgels at 10 and 50 °C showing that the BAM:NIPAM microgels are extremely polar even when swollen. In both cases, the upper curve was at 50 °C.
for pyrene and allowing a significant amount of pyrene to reside in the polymer compared to the aqueous phase. Figure 2b shows the fluorescence spectra of pyrene in the 50:50 NIPAM:BAM microgel dispersion at 10 and 50 °C. No significant difference is noted. This is evidence that even in the swollen state the 50:50 BAM:NIPAM microgels are extremely hydrophobic and are more hydrophobic than the 100% NIPAM microgels, as expected. Thus, incorporating BAM into the microgels increases the hydrophobicity of the microgels and hence increases the amount of pyrene that migrates into the microgels. The kinetics of solute release from gel matrices have been studied in detail, and release patterns have been observed varying from zero order (continuous release) to first order (two distinct stages of release). Yasuda et al.3 determined an equation for analyzing the release behavior from a polymeric matrix, where the exact release mechanism is unknown
M(t)/M(∞) ) Ktn
(1)
where M(t)/M(∞) is the fraction of drug released at time t, M(t) is the amount of drug released at time t, and M(∞) is the total amount of drug present in the matrix initially. The index n determines the release mechanism. When n < 0.5, the release is by Fickian diffusion of the solute, when 0.5 < n < 1.0 the release is by non-Fickian diffusion, and when n ) 1 there is continuous zero-order release. The index n can be determined by plotting log M(t)/M(∞) against log Ktn and determining the slope of the line obtained
log(M(t)/M(∞)) ) n log(t) + log(K)
(2)
Once the release kinetics for a particular drug from a polymeric film have been established, it is possible to determine the diffusion coefficient for the drug at the temperature used. Where the release kinetics conform to Fickian diffusion (n < 0.5), the diffusion coefficient can be obtained from the following equation
M(t)/M(∞) ) 2(Dt/πl2)
(3)
10896 J. Phys. Chem. B, Vol. 108, No. 30, 2004
Figure 3. Elution profile of pyrene from 150 µm two-component gel at 37 °C.
Lynch and Dawson
Figure 5. Elution profile of BODIPY from 150 µm two-component gel at 37 °C.
Figure 4. Elution profile of pyrene replotted as a log-log plot according to eq 2 to determine the n value, which gives information as to the diffusion process governing the release.
Figure 6. Elution profile of BODIPY replotted as a log-log plot according to eq 2 to determine the n value.
where D is the diffusion constant of the drug and l is the thickness of the gel film. Figure 3 shows a plot of the elution of pyrene from a 150 µm thick gel matrix composed of 2 wt % 50:50 BAM:NIPAM microgels in a 700 mmol NIPA bulk gel as a function of time at 37 °C. Replotting the data according to eq 2 gave a slope (n value) of 0.176 as shown in Figure 4. Since n < 0.5, the diffusion of pyrene from the two-component gel is described by a Fickian diffusion process. The elution profile of BODIPY from an identical gel to that described for pyrene and under identical conditions is shown in Figure 5. Similarly replotting the data from the BODIPY release experiments according to eq 2 gave a slope of 0.568 as shown in Figure 6. Thus, the release behavior of BODIPY from the two-component gels is not fully described by Fickian diffusion, since 0.5 < n < 1.0, and the release is slightly nonFickian. It is interesting to note that the release of pyrene is much faster than that of BODIPY under identical conditions. After
450 h, 60% of the initial pyrene was released, while in the same time period, only 30% of the BODIPY was released. This is in direct relation to the degrees of hydrophobicity of the two dye molecules, with BODIPY being far more hydrophobic than pyrene. Thus, it is postulated that the slower release of BODIPY is due to its greater affinity for the hydrophobic microgels, from which the BOPDIY molecules detach more slowly than the pyrene molecules. The release kinetics of pyrene from 150 µm “plum-pudding” gel films at 37 °C were determined to be Fickian, and so the diffusion coefficient was determined from eq 3. Taking the time where one-half the total amount of the dye has been released, the diffusion coefficient for pyrene was found to be 2.74 × 10-15 m2 s-1. The release kinetics of BODIPY from 150 µm “plum-pudding” gel films at 37 °C were found to be slightly non-Fickian; however, the diffusion coefficient was still determined from eq 3. The point at which one-half of the BOPDIPY was released was estimated by extrapolation of the data. The diffusion coefficient was found to be 9.43 × 10-16 m2 s-1.
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Discussion It can be seen that in both the pyrene and BODIPY elution profiles the first couple of points are nonlinear. This is due to an initial burst of release of dye from the matrix. Two explanations for this phenomenon are possible. The first is that some of the dye molecules may not have been absorbed into the microgels but rather may have been in the bulk matrix and so was able to diffuse into the surrounding water very quickly. Alternatively, the burst effect may have been due to the dissolution of dye crystals, which are known to form on the matrix surface.11 In fact, due to the method by which the dye molecules are incorporated into the microgels, both of these reasons may contribute to the burst effect. To separate the microgels from the dye, the solution was centrifuged at 10 000 rpm for 30 min. In cases where the concentration of dye was very high, this process resulted in dye crystals forming at the bottom of the centrifuge tube which may have been incorporated into the pregel solution when the microgels were resuspended in water. However, during the resuspension of the microgels some of these crystals may have dissolved into the pregel solution and remained in the bulk gel, enabling rapid release due to diffusion once the gel was immersed in water. Studies by Kim et al.12 on the release of hydrophilic and hydrophobic solutes from hydrophilic methacrylate gels found that the diffusion process was significantly different depending on the nature of the solute. The starting point for their discussion was the proposal by Jhon et al.13 that the water in a hydrogel can be divided into three distinct “types”. These include “bound” water, which is strongly associated with the polymer, probably as water hydrating the hydrophilic groups of the polymer; “interfacial” water, which is probably associated with the hydrophobic interactions between the polymer segments; and “bulk” water, which is similar to the water in the aqueous solution. Kim et al.12 found that the mechanism of permeation of hydrophilic solutes through a gel medium is transport through the “bulklike” water regions of the hydrogel film (i.e., free volume diffusion), which probably exists within the porous regions of the gel. For hydrophobic solutes, the permeability coefficients were found to be smaller and the partition coefficients were higher relative to hydrophilic solutes. Diffusion was found to occur mainly by a partition-type mechanism via the polymer matrix, “interfacial” and “bound” water regions of the hydrogels. In the partition diffusion mechanism the solutes permeate by dissolution and diffusion within the macromolecular segments of the polymer backbone.12 The release of pyrene and BODIPY from the two-component gel films was studied at 37 °C, at which temperature both the microgels and the bulk gel are in the collapsed phase. Thus, it is reasonable to assume that there would be some interaction between the solute and the polymer phase. However, this does not appear to be the case with pyrene, which was found to be released by simple Fickian diffusion. However, in the case of the more hydrophobic and structurally complex solute BODIPY, the free volume theory is not sufficient to describe the diffusion process as assumption 3 of the free volume theory (outlined in the Introduction) assumes that the diffusion is via the free or bulk water only. The structures of pyrene and BODIPY are shown in Figure 7, from where it can be seen that such an interaction with the polymer network would be more likely with BODIPY than with pyrene. It is worth mentioning here that there could also be an effect of the different sizes of the two solute molecules on their different release rates, as bigger molecules will diffuse slower than larger molecules; however, molecular or geometric arguments would not be sufficient to
Figure 7. Chemical structures of pyrene and BODIPY.
explain why pyrene has a Fickian-type release profile while BODIPY has a slightly non-Fickian release profile. It seems reasonable to assume that the “partition” mechanism of Kim et al.12 could explain the non-Fickian release behavior observed with BODIPY. Since the entire gel network is collapsed (hydrophobic) at the release temperature, interaction of the hydrophobic solute BODIPY and the gel could occur, enabling the BODIPY molecules to diffuse along the polymer chains. Movement of dissolved molecules within a polymer film occurs by the simple process of Brownian motion, which is basically a random movement. Thus, the release of a solute (or its diffusion from a polymer film) is also primarily by Brownian motion. This means that there is an irrefutable law which is that the rate of release of a drug molecule is a well-defined function of time: D ≈ t1/2. Conventional coatings and films can do absolutely nothing to alter this scaling law, and thus, the rate at which drugs can be released appears to be fixed. However, we show evidence here of a composite gel structure which appears to interfere with the simple Brownian motion of the drug molecules (hence the non-Fickian release observed). Of course it does not actually violate this time dependence of the release. Instead, we postulate that release occurs via a “hopping” mechanism whereby a solute molecule released by one microgel particle gets pulled into another microgel particle, from which it must subsequently be released. Thus, we suggest that the release rate from the “plum-pudding” gel is the sum over the number of particles that the solute encounters. Such a mechanism would be possible given the hydrophobic nature of the microgel particles which act as reservoirs or sinks for the solute, and many of the molecules which are released by one microgel particle could be reabsorbed into adjacent microgel particles as they pass by, slowing down the rate of release. By altering the number of sinks and/or their attractiveness to the molecule being released, the release path could theoretically be tailored to almost any conceivable time scale (since the release will now be summed over several t1/2). Further work is being done to investigate if this is indeed the release mechanism and will be reported separately. Additionally, due to the composite nature of the gels, the release kinetics will consist of two steps: first, release of the solutes from the microgel particles into the bulk gel and then release from the bulk gel into the surrounding solvent. However, due to the much looser network structure of the bulk gel and its lower hydrophobicity (and thus lower attractiveness to the solutes), the release rate from the bulk gel to the solvent will be much faster than the release from the microgels into the bulk gel, and thus, the release from the bulk gel will not have much affect on the observed release rate. Using the concept of separation of functionality and bulk properties and using the microgel particles as reservoirs for solute molecules, a range of potential applications can be envisioned, from release of agricultural products such as pesticides to release of flavorings and nutraceuticals to drug delivery applications. Using a series of microgel particles containing different solute molecules, a range of release profiles can be obtained from a single gel film. By incorporating
10898 J. Phys. Chem. B, Vol. 108, No. 30, 2004 microgel particles which are responsive to different environmental triggers, delivery devices can be prepared where one solute has continual release, another releases in response to, for example, pH changes, and another still is self-regulating and releases only when its concentration in the bulk medium drops below some cutoff point. Work is underway to determine the release of both hydrophobic and charged solutes simultaneously from the composite gels and will be reported separately. Conclusion A “plum-pudding” gel structure, with the microgels incorporated into the gel matrix in the collapsed phase (i.e., above their collapse transition temperature), was prepared which had a large partition affinity for hydrophobic drugs. The microgel particles or “plums” act as reservoirs for solute or drug molecules and can be incorporated into conventional hydrogels at various concentrations to give two-component gel matrices which give controlled release of the solutes. Thus, the required functionality is provided by the microgel particles, while the bulk properties are controlled by the hydrogel matrix. The gels used were 0.15 mm thin films composed of loosely cross-linked NIPA, and the plums were composed of 50% BAM and 50% NIPAM, which were loaded with either pyrene or BODIPY and incorporated into the gel at room temperature. In this initial study the less hydrophobic molecule (pyrene) was found to be released by Fickian diffusion whereas the release of the more hydrophobic solute (BODIPY) was found to be slightly non-Fickian. A suggested mechanism for release is the “partition”-type release mechanism where the solute travels through the interfacial and bound water regions of the gel along
Lynch and Dawson the polymer matrix. Additionally, the increased attractiveness of the microgel particles for the BODIPY molecules could cause them to be reabsorbed into adjacent microgel particles as they pass by, further slowing the release. Further work is underway to test the release mechanism as well as studies on the simultaneous release of two (or more) solutes differing in hydrophobicity and charge. Acknowledgment. This work was funded by grants from Enterprise Ireland and the Health Research Board of Ireland. References and Notes (1) Lynch, I.; Dawson, K. A. J. Phys. Chem. B 2003, 107, 9629. (2) Colombo, I.; Grassi, M.; Fermeglia, M.; Lapasin, R. Y.; Procl, S. Fluid Phase Equilib. 1996, 116, 148. (3) Yasuda, H.; Lamaze, C. E.; Ikenberry, L. D. Makromol. Chem. 1968, 118, 18. (4) Bae, Y. H.; Okano, T.; Hsu, R.; Kim, S. W. Macromol. Chem., Rapid Commun. 1987, 8, 481. (5) Li, Y. D.; Bae, Y. C. J. Appl. Polym. Sci. 1998, 67, 2088. (6) Kokufuta, E.; Nakaizumi, S. Macromolecules 1995, 28, 1704. (7) Snowden, M. J.; Thomas, D.; Vincent, B. Analyst 1993, 118, 1367. (8) Tanaka, T.; Wang, C.; Pande, V.; Grosberg, A. Yu.; English, A.; Masamune, S.; Gold, H.; Levy, R.; King, K. Faraday Discuss. 1996, 102, 210. (9) Snowden, M. J. J. Chem. Soc., Chem. Commun. 1992, 11, 803. (10) Pankasem, S.; Thomas, J. K.; Snowden, M. J.; Vincent, B. Langmuir 1994, 10, 3023. (11) Singhal, R.; Shukla, B.; Mathur, G. N. J. Polym. Mater. 1997, 14, 311. (12) Kim, S. W.; Cardinal, J. R.; Wisniewski, S.; Zentner, G. M. In Water in Polymers; Comstock, M. J., Ed.; ACS Symposium Series 127; American Chemical Society: Washington, D.C., 1980; pp 347-359. (13) Jhon, M. S.; Andrade, J. D. J. Biomed. Mater. Res. 1973, 7, 509.
