Article pubs.acs.org/IECR
Drug Release from Poly(dimethylsiloxane)-Based Matrices: Observed and Predicted Stabilization of the Release Rate by Three-Layer Devices Dimitrios N. Soulas, Kyriaki G. Papadokostaki, Athanasia Panou, and Merope Sanopoulou* Institute of Physical Chemistry, National Centre for Scientific Research “Demokritos”, 15310 Ag. Paraskevi Attikis, Athens, Greece ABSTRACT: Realistic mathematical modeling can greatly facilitate the optimum design of matrix-controlled release (MCR) devices. Here, we present a practical example of a relevant methodology, based on a previously developed model for symmetrical, three-layer MCR devices. The experimental system is based on PDMS matrices incorporating 10% of poly(ethylene glycol) and loaded with theophylline. The matrices were either single-layer devices uniformly loaded with theophylline or symmetrical threelayer devices with a uniformly loaded inner layer and theophylline-free outer layers. The theophylline loads, and the geometrical characteristics of the multilayer matrices, were chosen according to general guidelines for improved uniformity of rate, previously formulated by model calculations. As anticipated, these devices were found to effectively stabilize the rate of release, as compared to the corresponding single-layer system. The main kinetic characteristics of the experimental systems were then successfully reproduced theoretically by a set of input parameters (pertaining to the transport properties of the polymer−solute−solvent system), derived mainly from the release experiments in monolithic matrices. Finally, the same input parameters were used for exploring theoretically the range of the three-layer device parameters that are expected to preserve the observed improved performance of the experimental systems.
1. INTRODUCTION Siloxanes are ideal materials for biomedical applications, due to their biocompatibility, chemical inertness, and good mechanical properties. Among other applications, they have been used as matrices for controlled release devices of lipophilic bioactive compounds such as various steroids,1−3 the anticancer drug 1,3bis(2-chloroethyl)-1-nitrosourea,4 vitamin D3,5 and metronidazole as a model antibacterial drug.6 In general, a lipophilic drug exhibits adequate solubility in siloxanes and is released mainly by diffusive transport through the polymer matrix. On the other hand, incorporation of osmotically active excipients is considered a simple method to overcome the highly hydrophobic nature of siloxanes, in order to facilitate the release of relatively hydrophilic drugs or proteins, or to accelerate the release of lipophilic ones.5,7−9 High osmotic pressure excipients, such as inorganic salts in the form of particles, result in microscopic cracks due to the osmotically induced water. These cracks eventually form an interconnecting network filled with water, through which the drug is released.10−15 Compounds of milder osmotic action, such as sugars16 and poly(ethylene glycols),17,18 have also been used as excipients, while in certain cases the drug itself may present an osmotic action,19−22 facilitating its own release from the hydrophobic matrix. A most important aspect in the design of matrix controlled release (MCR) systems is the uniformity of release rate.23,24 Simple monolithic devices, operating by diffusion-controlled release kinetics (t1/2 kinetics), are characterized by a continuously declining dose rate. More complex release mechanisms (such as crack formation, operating mainly in the case of excipient particles of strong osmotic action) result in deviations from Fickian diffusion kinetics, thus exhibiting a more uniform rate of release. In general, the optimum design of © 2012 American Chemical Society
MCR devices requires (i) achievement of a delivery rate within specified limits (the “therapeutic range”), and (ii) maximization of the fractional amount of embedded solute which can be delivered within these limits. A method to stabilize the rate of MCR systems is the construction of multilayer devices with layers differing in solute load and/or material properties.14,25−30 Multilayer systems may also be used for the parallel or sequential release of more than one bioactive compounds.31 Optimization of the design of matrix MCR systems can be facilitated by mathematical modeling.32−43 Such models, to be able to realistically simulate the performance of a broad range of practical MCR systems, must take into account several factors such as the drug loadings above or below the saturation limit in the matrix, the ingress of the aqueous medium during the release of the drug, and the interdependence of those two fluxes. Even for simple diffusional transport (i.e., in the absence of relaxation effects of the swelling polymer44,45) in a homogeneously loaded matrix, the said effects may alter the release kinetics in various ways, affording thus the possibility of adjusting or optimizing the release profile according to the needs of specific applications. Thus, realistic modeling of MCR systems may be used: (i) to provide general guidelines on the effect of individual design parameters on the rate and kinetics of release, or (ii) for the predictive evaluation of the performance of specific MCR designs. Here, we present a practical example of applying a model for MCR systems,37,38 outlined in the following section, as a tool in Received: Revised: Accepted: Published: 7126
February April 23, April 27, April 27,
29, 2012 2012 2012 2012
dx.doi.org/10.1021/ie300540x | Ind. Eng. Chem. Res. 2012, 51, 7126−7136
Industrial & Engineering Chemistry Research
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loaded with solute at CN0i. The outer (A) layers of the device may consist of the same or of different polymeric material than that of the inner (B) layer and thus are characterized by the same or by different transport properties (Si, Di) for both solute and solvent. The expression of the diffusion equation (eqs 1 and 2) in terms of activity (instead of concentration) gradients permits the representation of thermodynamic and kinetic interactions of the two diffusing species through functional dependences of the relevant diffusion and solubility coefficients on solvent and/or solute concentration.47 In particular, the sorption behavior of water is represented by:
various steps of the design of a specific experimental system. The matrices consist of poly(dimethylsiloxane) (PDMS) containing 10% w/w poly(ethylene glycol) (PEG) of Mw = 3000 and loaded at two different concentrations of theophylline, a drug with a narrow therapeutic window, most safely and effectively administered through controlled release systems.46 Physical mixtures of PDMS with PEG were used as a matrix instead of pure PDMS, because the incorporation of the hydrophilic compound is a simple method for adjusting the capacity of water uptake of the matrix. The matrices were either monolithic (single-layer) uniformly loaded with theophylline, or three-layer, symmetrical ABA matrices with uniformly loaded inner B layer and theophylline-free outer A layers. The first objective of this work was to effectively stabilize the rate of drug release from the PDMS/PEG matrix by the use of three-layer ABA systems. For this, the theophylline loads and the geometrical characteristics of the ABA multilayer systems were chosen according to general guidelines for improved uniformity of rate, previously formulated by model calculations.37,38 Second, it is shown that parametrization of the said model, based mainly on the release experiments from the monolithic matrices, can successfully reproduce the performance of the experimental multilayer systems. This justifies further calculations to explore the range of the ABA system’s parameters that are expected to preserve the improved performance of the experimental ABA matrices.
S Wi = C Wi /aW
where the activity of water aW is equated to the relative humidity, which would be at equilibrium with concentration CWi. In the absence of solute-induced osmotic effects (i.e., enhancement of SW in the presence of the solute), the sorption isotherm of the polymer−water system, CWi = F(aW), defines the degree of hydration of the layer at any aW. The equilibrium water concentration of the fully hydrated layer (aW = 1) is denoted by CoWi. Both the solubility (SNi) and the diffusivity (DNi) of the solute are dependent on the water uptake of the layer. The solubility coefficient of solute in the hydrated layer is defined as SNi = CNSi/aN, where CNSi represents the concentration of dissolved (mobile) solute in layer. The activity aN is equated to the fractional saturation cNS/coNS, where cNS is the concentration of an aqueous solution of the solute, which would be at equilibrium with CNSi, and coNS is the aqueous solubility of the solute. Thus:
2. MODEL FOR MCR SYSTEMS For solvent-activated symmetrical ABA devices of the type shown in Figure 1, one-dimensional diffusive transport of
o S Ni = C NSi /aN = ksiC WiVw̅ c NS
⎛ ⎞ B N1i D Ni = D NS exp⎜ − ⎟ ⎝ B N2i + C Wi ⎠
solvent (usually water, subscript W) and solute (subscript N) along the x-direction at t ≥ 0 is given by:37,38 (1)
∂C Ni ∂a ⎞ ∂ ⎛ ⎜D Ni S Ni N ⎟ = ∂t ∂x ⎝ ∂x ⎠
(2)
(4)
where V̅ W is the molar volume of water and ksi is defined in such a way that it reduces to unity if the solute dissolves primarily in the sorbed water (i.e., the polymer is relatively inert to solute).47 Equation 4 shows that SNi is an increasing function of CWi. The solubility limit of the solute in the fully swollen matrix (aW = 1, CW = CoWi) is denoted by CoNSi. The value of CoNSi in relation to the initial concentration of embedded solute CN0i in layer i determines whether the layer is initially (a) “unsaturated” or “saturated” (CN0i ≤ CoNSi), with the entire solute load in a mobile state, or (b) “supersaturated” (CN0i > CoNSi), in which case part of the solute load (CN0i − CoNSi) is in the “dispersed” or “immobile” state. The rate of diffusion of dissolved solute is strongly dependent on the extent to which the matrix is swollen by the solvent. In particular, the diffusion coefficient of solute DNi in each layer I is given by:47−49
Figure 1. Schematic representation of a three-layer ABA matrix of thickness 2L. Because of symmetry, the matrix may be represented by two layers of thickness L (L = LA + LB). In the experimental system studied here, both A and B layers are made from the same material, and the outer A layers are solute-free.
∂C Wi ∂a ⎞ ∂ ⎛ ⎜D Wi S Wi W ⎟ = ∂t ∂x ⎝ ∂x ⎠
(3)
(5)
where DNS is the aqueous diffusion coefficient of the solute, and BN1i, BN2i are positive input constants (and BN2i may be zero). The value of DNi in the fully swollen matrix (CW = CoWi) is denoted as DNEi. The model, briefly outlined above, can be parametrized on the basis of data pertaining to the fundamental sorption and diffusion properties of the polymer−solute−solvent system, derived from literature or independent experimental measurements. In this way, it has been successfully applied to experimental data of model three-layer matrices consisting of
where Ci (x,t) denotes the concentration of water or solute in layer i (i = A or B) and 0 ≤ a(x,t) ≤ 1 is the activity of the diffusing species in the matrix. Si and Di are the relevant sorption (or solubility) and (thermodynamic) diffusion coefficients, respectively. Each layer i (i = A or B) is uniformly 7127
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Industrial & Engineering Chemistry Research
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curing. The thickness of the individual layers of the ABA matrices was determined during the preparation procedure by measuring the resulting thickness after each curing step, at five points at least, with a micrometer reading to ±1 μm. The relative thickness of the layers in each ABA system was also verified by SEM microscopy (Leo 440 SEM, Leo, Germany). The two A layers of the ABA-7 matrices differed in thickness (LA) by less than 2%, while in ABA-15 matrices the said differences were ∼10%. The geometrical characteristics of each type of matrices studied are summarized in Table 1. As was also
inner cellulose layers loaded with sodium chloride and solutefree outer layers of cellulose or cellulose acetate.50 The cellulosic layers were loaded by equilibration to salt solutions, and release performance was studied under conditions of initially fully swollen matrices. The system studied here concerns drug loadings above saturation and is more complex, mainly because release experiments from initially dry matrices are studied, and thus ingress of water occurs concurrently to drug release.
3. MATERIALS AND METHODS Poly(dimethylsiloxane) (PDMS) (RTV 615 type), kindly supplied by Momentive (U.S.) in a two-component silicone kit, consists of a vinyl-terminated prepolymer with high molecular weight (part a) and a cross-linker, containing several hydride groups on shorter PDMS chains (part b). Curing of the PDMS occurs via Pt-catalyzed hydrosilylation reaction resulting in a densely cross-linked polymer network, forming freestanding films. Other common methods of curing PDMS involve a condensation reaction between OH-terminated PDMS and tetraalkyl orthosilicates, catalyzed by tin compounds such as stannous octoate, and thermal cross-linking of poly(dimethylsiloxane-co-methylvinyl siloxane), in the presence of a peroxide catalyst.51 PEG of molecular weight Mw = 3000 g/ mol was purchased by Merck (Germany). Theophylline C7H8N4O2 (1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurine, of 99% purity, Mw = 180.14 g/mol) in the form of granules of particle size 2−8 μm was purchased from Acros Organics (Belgium). Dichloromethane of analytical reagent grade (Aldrich) was used. All matrices studied here were prepared with a w/w PDMS:PEG ratio = 90:10. Neat (theophylline-free) PDMS/ PEG matrices were prepared by first mixing the RTV615 components (5.0 and 0.5 g of parts a and b, respectively) under stirring for 1 h. Next, 0.6 g of PEG, dissolved in 1 mL of dichloromethane, was added, and the new mixture was stirred for another 30 min. After evaporation of the solvent, the polymeric mixture was cast on a poly(propylene)-coated glass plate by means of an adjustable doctor knife blade, followed by curing for 1 h at 100 °C. Drug-loaded matrices were similarly prepared by adding to the, prior to curing, polymeric mixture appropriate amounts of theophylline. As said in the Introduction, the theophylline loads studied, as well as the geometrical characteristics of the ABA matrices, were chosen on the basis of previous model calculations.37,38 In particular, the said parametric study indicated that the key to success in terms of rate uniformity is highly loaded, supersaturated B layers with LA/L ≈ 1/2. An estimate of the solubility limit of theophylline in the fully swollen PDMS/PEG matrix was determined by equilibration of neat films to theophylline aqueous solutions and was found to be 0.011 ± 0.001 g/g of dry polymer matrix. Accordingly, the two loads used were well above this limit, that is, 0.07 and 0.15 g/g. The single-layer loaded matrices with initial concentrations CN0 = 0.07 and 0.15 g/g are designated as B-7 and B-15, respectively. The symmetrical multilayer ABA matrices (Figure 1) consisted of an inner drug-loaded layer containing theophylline at 0.07 or 0.15 g/g (layer B) and two outer, drug-free, layers (layers A) and will be designated as ABA-7 and ABA-15, respectively. They were prepared by casting successively, on top of an already cured drug-free A layer, the drug-containing polymer fluid, followed by curing and then casting a second drug-free polymer mixture, followed by a new
Table 1. Geometrical Characteristics of Experimental B and ABA Matrices Single-Layer B Matrices matrix thickness, 2LB B-7 B-15
ABA-7 ABA-15
231 ± 3 308 ± 6 Three-Layer ABA Matrices
matrix thickness, 2L
inner layer thickness, 2LB
LA/L
380 ± 6 455 ± 4
221 ± 4 300 ± 7
1/2.40 1/2.87
shown in the representative SEM photos of Figure 2, the outer layers of the composite structures remain tightly connected to the inner layer both before (a and b) and after (c and d) the release of the drug. The release experiments, in all cases, were performed by mounting the matrix on stirring rods, rotating at 50 rpm, in known volumes of distilled water thermostatted at 25 ± 0.1 °C. The amount of drug released was measured at suitable times t and at t→∞ (denoted as QNt and QN∞ respectively) by means of a UV/vis spectrophotometer (V-630 Jasco, Japan) at 271 nm. In the case of the multilayer systems, each sample’s perimeter was covered with silicone (Sista Silicone 5, Henkel, Düsseldorf, Germany) to avoid any leakage of the drug from the rims of the samples. Finally, the concurrent variation of the water content of B-7 and B-15 matrices (QWt at time t and QW∞ at t→∞) was determined by weighing the blotted films at suitable time intervals and by taking into account the amount of drug that has been released. All experiments were performed in duplicate or triplicate.
4. EXPERIMENTAL RESULTS Experimental release data from monolithic B-7 and B-15 matrices are shown in Figure 3. The results are plotted as functional amount of drug released (QNt/QN∞) versus t1/2/L scale. In the same plot, the kinetics of the fractional amount of concurrent water uptake (QWt/QW∞) is also presented. The amount of water uptake QW∞ at the end of the release process from B-7 and B-15 matrices was 1.02 ± 0.15 g of H2O/g of dry matrix, The significant water absorbability of these matrices is attributed to the presence of hydrophilic PEG in the mixed matrix, because pure PDMS is known to absorb less than 1% w/w of water.52,53 The drug-depleted B-7 and B-15 matrices, after being in contact with the eluting medium for approximately 45 and 55 days, respectively (see Figure 4 below), were dried in a vacuum until constant weight. The estimated weight losses of the PDMS−PEG matrix during the eluting period were in all cases low enough (
