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Drug Controlled Release From Structured Bioresorbable Films Used in Medical Devices—A Mathematical Model Meital Zilberman, Alon Malka Department of Biomedical Engineering, Faculty of Engineering, Tel-Aviv University, Tel-Aviv 69978, Israel Received 13 December 2007; revised 1 April 2008; accepted 17 June 2008 Published online 5 September 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.b.31200 Abstract: A mathematical model for predicting drug release profiles from structured bioresorbable films was developed and studied. These films, which combine good mechanical properties with desired drug release profiles, are designed for use in various biomedical applications. Our structured polymer/drug films are prepared using a promising technique for controlling the drug location/dispersion in the film. The present model was used for predicting drug release profiles from two film types that is films in which the drug is located on the surface (A-type) and films in which the drug is located in the bulk (B-type). The model is based on Fick’s 2nd law of diffusion and assumes that the drug release profile from the films is affected by the host polymer’s characteristics, the drug location/dispersion in the film and the drug’s characteristics. This semiempirical model uses the weight loss profile of the host polymers as well as the change in their degree of crystallinity with degradation. Our study indicates that the model correlates well with in vitro release results, exhibiting a mean error of less than 7% for most studied cases. It also shows that the host polymer’s degradation has a greater effect on the drug release profile than the degree of crystallinity. This new model exhibits a potential for simulating the release profile of bioactive agents from structured films for a wide variety of biomedical applications. ' 2008 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 89B: 155–164, 2009 Keywords: drug release; bioresorbable films; mathematical model; medical device; dexamethasone INTRODUCTION Bioresorbable drug-eluting films can be used as basic elements in various biomedical implants, such as tracheal stents1 and coatings for orthopaedic implants.2 Poly(ahydroxy acid) films loaded with water-soluble and waterinsoluble drugs have been developed and studied for various applications.3–8 For example, tetracycline was released from poly(L-lactic acid) (PLLA) barrier films, and the system was studied for potential use in periodontal therapy,3 gentamicin was released from poly(a-hydroxy acid) films for potential use in local treatment of bone infection,2,4,5 dexamethasone (DM) was released from various poly(ahydroxy acid) films used as basic elements in tracheal films,1 and sirolimus was released from a bilayer PLLAPLGA film in order to simulate its release from a stent.7 Bioactive agents with a relatively high molecular weight, such as albumin and the malaria vaccine (synthetic polypeptide), were released from PLGA films.6,8 New combinations of materials, other than the traditional poly(a-hydroxy Correspondence to: M. Zilberman (e-mail: [email protected]) ' 2008 Wiley Periodicals, Inc. acid), were tried as host polymers9–13 in order to exhibit proper mechanical properties with the desired release profile from polymeric bioresorbable films. For example, a combination of alginate and polyethylene glycol and a graft copolymer of vinyl alcohol and lactic/glycolic acid were tried in paclitaxel eluting films for stent applications,9,10 and segmented poly(ether-ester-amide) films and crosslinked gelatin films were loaded with bioactive agents such as metronidazole for dental applications.11,12 Solution casting of polymers is a well-known method for preparing polymer films. To incorporate drugs by this method, the polymer is dissolved in a solvent and mixed with the drug prior to casting. The solvent is then evaporated and the polymer/drug film is created. We have previously reported a method for controlling drug location/ dispersion in the film.14,15 To review briefly, bioresorbable polymeric films containing drugs were prepared using the solution casting technique, accompanied by a postpreparation isothermal heat treatment. In this process, the solvent evaporation rate determines the kinetics of drug and polymer solidification and thus, the drug dispersion/location within the film. Solubility effects in the starting solution also contribute to the postcasting diffusion processes and occur concomitantly to the drying step. In general, two 155 156 ZILBERMAN AND MALKA Figure 1. Polarized light micrographs of DM-loaded PLLA (semicrystalline) and PDLLA (amorphous) films: upper micrographs, A-type; lower micrographs, B-type. types of polymer/drug film structures were created and studied for all matrix polymer types, as presented in Figure 1 for PLLA and poly(DL-lactic acid) (PDLLA) films loaded with DM: a. A polymer film with large crystalline drug particles located on its surface, as presented in the upper micrographs of Figure 1. This structure, derived from a dilute solution of both polymer and drug, was obtained using the slow solvent evaporation rate, which enables prior drug nucleation and growth on the polymer solution surface. This skin formation is accompanied by a later polymer core formation/solidification. This structure was named the ‘‘A-type.’’ b. A polymer film with small drug particles and crystals distributed within the bulk, as presented in the lower micrographs of Figure 1. This structure, derived from a concentrated solution, was obtained using the fast solvent evaporation rate and resulted from drug nucleation and segregation within a dense polymer solution. Solidification of drug and polymer occurred concomitantly. In semicrystalline-based films, such as PLLA/DM, the drug is located in amorphous domains of a semicrystalline matrix, around the spherulites.14 This structure was named the ‘‘B-type.’’ We have studied the morphology and formation process of these structured films extensively, and a detailed model describing the structuring of these films is described elsewhere.14 Our study indicates that both A-type and B-type structures can be developed for both amorphous and semicrystalline polymeric films loaded with DM and also with other drugs, such as cortisone14 and gentamicin.2 The type of polymer affects the film morphology but has almost no effect on the drug location/dispersion within the polymeric film. The latter is determined mainly by the kinetics of film formation.2,14,15 Mathematical models for controlled release of bioactive agents from bioresorbable matrices are based on diffusion aspects, on the structural characteristics of the matrix polymer and its degradation and swelling, and on the microenvironmental pH changes inside the polymer matrix pores that are due to the degradation products. Prediction of the drug release profile using a model can obviously be very useful in the device’s design phase, as the model enables fast evaluation and tuning of the various parameters for achieving an optimal release profile, while reducing laboratory tasks to a minimum.16,17 Early drug delivery models described either systems based on nondegradable matrices or surface-eroding systems.18 Several more recent models described bulk-eroding systems, in which the drug is physically immobilized. For example, Siepman and Gopferich19 quantified drug release from slab-shaped PLLA and poly(DL-lactic-co-glycolic acid) (PDLGA) matrices. Their model was based on Higuchi’s classical pseudo steady-state equation for oversaturated, planar, nondegrading polymeric films, where the permeability of the drug within the polymer matrix was assumed to increase with time due to cleavage of the polymer’s bonds. Another possibility for simulating the effect of erosion on the diffusion process is to use a diffusion coefficient which increases with time. Various theories, therefore related the drug diffusion coefficient inside a degradable polymer directly to its molecular weight, as Journal of Biomedical Materials Research Part B: Applied Biomaterials DRUG CONTROLLED RELEASE FROM STRUCTURED BIORESORBABLE FILMS 157 Figure 2. The experimental system at the initial point: A-type film and B-type film floated on water in a Petri dish. The diffusion occurs in the Z direction. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] short chains offer less restriction to drug diffusion than long chains. This was one of the main assumptions in the models of Charlier et al.20 for predicting the release rate of Mifepristone from 50/50 PDLGA bulk-eroding films of various molecular weights, and Faisant et al.21 who examined the release rate of 5-fluorouracil from 50/50 PDLGA microspheres. Both used an additional assumption regarding the polymer’s first order degradation kinetics in order to calculate an appropriate time-dependent diffusion coefficient, which they used in Fick’s laws of diffusion. Zhang et al.22 addressed three mechanisms for drug release in a microspheric matrix, namely dissolution of the drug from the polymer matrix, diffusion of the dissolved drug, and erosion of the matrix. However, our promising technique for controlling the drug location/dispersion in the film raised the need for a suitable model which could predict the release profile of various drugs from these structured films, and therefore, shorten the design process of biomedical implants based on these drug-eluting films. This need was the driving force for the current research, in which a suitable mathematical model was developed. The hypotheses of our study were: (1) A model based on Fick’s laws will be able to provide good prediction of the drug release profile from our structured drug-eluting films, and (2) The drug release profile from the films is affected by the host polymer’s characteristics (degradation profile and degree of crystallinity), by the drug location/dispersion in the film, and by the drug characteristics. MATERIALS AND METHODS Case Definition and Model Assumptions A mathematical model for predicting drug release from our structured drug-eluting films was developed in this study, using Matlab 6.1. The release profiles that were predicted Journal of Biomedical Materials Research Part B: Applied Biomaterials using this model were compared with experimental results for certain films loaded with DM. The Experimental System. Polymer films (0.12–0.15 mm thick) consisting of poly(a-hydroxy acid) and DM (5% w/w in each film) were prepared by a three-step solution processing method as follows: The components were mixed in a solvent at room temperature until polymer dissolution. Both dilute and concentrated solutions were prepared for the various polymer/DM systems. The solutions were then cast into Petri dishes, and solvent drying was performed under atmospheric pressure at room temperature. A slow solvent evaporation rate was used for dilute solutions in order to obtain A-type films, whereas a fast solvent evaporation rate was used for concentrated solutions in order to obtain B-type films. Finally, an isothermal heat treatment at a temperature higher than the glass transition temperature of the polymer (60–908C) was performed for 1 h in a vacuum oven. This heat treatment enabled the disposal of residual solvent. The process of film formation is described in greater detail elsewhere.15 The films were immersed in sterile water at 378C for 20 weeks in order to determine the DM release kinetics. Samples of 1.5 mL were collected every week and were replaced with sterile water. A schematic representation of the experimental system is presented in Figure 2. The DM content in each sample was measured using high performance liquid chromatography (HPLC), DX 500 (Dionex Corp., Sunnyvale, CA). An AD-20 ultraviolet detector (Dionex Corp., Sunnyvale, CA) was used to monitor absorbance at 254 nm. Five samples were examined for each film type. The examined films are as follows: Films based on amorphous host polymers: 1. 50/50 PDLGA, A and B types. 2. 85/15 PDLGA, A and B types. 158 ZILBERMAN AND MALKA 2. 3. 4. 5. 6. 7. 8. 9. Figure 3. The time-dependent parameters which affect the diffusion coefficient of the drug in the film: (a) The polymer’s weight loss, (b) The polymer’s degree of crystallinity. The host polymer type is indicated. Films based on semicrystalline host polymers: 1. PLLA, A and B types. 2. Polydioxanone (PDS), B type. 3. 10/90 PDLGA, B type. The weight loss profile of the various host polymers and their degree of crystallinity versus time are presented in Figure 3(a,b, respectively). They were taken from one of our recent publications.15 Assumptions Used When Deriving the Model’s Equations. 1. The drug’s diffusion coefficient within the polymeric film is only time-dependent, and the basic mathematical equation which describes the diffusion behavior is Fick’s 2nd law (partial differential equation). Also, there is no drug concentration profile in the aqueous medium, and there is homogenic distribution of drug on the surface of the film. The diffusion coefficient (D) inside the film is affected by the bulk erosion of the host polymer and its degree of crystallinity (which also changes with time). The weight loss of the polymeric film increases with time, resulting in increasing film porosity and D. In contradistinction, the increase in the polymer’s degree of crystallinity with degradation15 results in a decrease in D. The polymeric chains create a porous film with a homogenous structure. The film’s pore size increases with weight loss, but the structure is homogenous. The size and shape of the drug particles do not change with time. During the advanced stage of polymer degradation, monomers, and oligomers diffuse out. This diffusion occurs in parallel to the drug diffusion. No reciprocal effect exists between the diffusion of the drug particles and the diffusion of the monomers. There is drug flux only toward the film’s interface with water (z direction). The external environment provides perfect sink conditions for the released drug. The drug particles within the film are released only when they find a continuous path to the surface and their release occurs solely by diffusing through the water. The drug particles diffuse out only through amorphous regions and not through dense crystalline regions. Model Equations According to assumption (1), the mathematical equation which describes the diffusion behavior in our system is Fick’s 2nd law of diffusion. The basic form of the equation is: r ðDrCÞ ¼ @C @t ð1Þ where D is the diffusion coefficient (cm2/s), ! is the Laplace operator, C is the drug concentration (mole/cm3) and t is time (s). Using assumption 1 we can simplify Eq. (1) to: D r2 C ¼ @C @t ð2Þ Using assumption 6 and the Laplace operator, the final diffusion equation is: D @ 2 C @C ¼ @Z 2 @t ð3Þ Appropriate initial and boundary conditions should be used in order to solve the diffusion Eq. (3). Assuming an initial uniform drug concentration (C0) in the bulk of the Journal of Biomedical Materials Research Part B: Applied Biomaterials DRUG CONTROLLED RELEASE FROM STRUCTURED BIORESORBABLE FILMS polymeric film or on its surface leads to the following initial condition: C ¼ C0 C ¼ C0 at t ¼ 0; Z ¼ Zfilm for A-type films ð4aÞ at t ¼ 0; 0 Z < Zfilm for B-type films ð4bÞ Second initial condition: there is no drug in the medium (water) at the starting point: at t ¼ 0; Zfilm < Z L C¼0 ð5Þ This is a closed system, and therefore, drug particles cannot leave the system. Hence, the flux at the boundaries is equal to 0, and the boundary conditions are: @C ðt; Z ¼ 0Þ ¼ 0 @Z ð6Þ @C ðt; Z ¼ LÞ ¼ 0 @Z ð7Þ Using the above initial and boundary conditions, the differential Eq. (3) was resolved via the ‘‘pdepe’’ Matlab function, yielding C(Z,t) which describes how the drug concentration changes with time, and how it changes along the Z-axis. The released drug particles reach the surface of the film (Z 5 Zfilm), and the cumulative drug particles can therefore be ‘‘counted’’ as follows: Zt mðtÞ ¼ d CðZ ¼ Zfilm ; t0 ÞAdt0 dt0 159 where Dw is the theoretical diffusion coefficient of a spherical particle in water (cm2/s), KB is Boltzmann’s constant 5 1.38 3 10216 (g cm2/s2 K), T is the absolute temperature (3108K 5 378C), l is the water’s viscosity 5 0.01 (g/ cm s), and R0 is the radius of a spherical particle (cm). In our study, R0 was estimated using light and electron microscopy. In our model we had to slightly change Eq. (11) because of physical restriction on the drug particles’ motion. In A-type films the drug particles sense mainly the water and not the film in the surrounding and the nonideal (nonspherical) shape of the drug particles is therefore the dominant restriction. Equation (13) actually shows how far are the particles from spherical shape. In B-type films, the drug particles sense mainly the polymer chains of the film, which create paths through which the drug particles move. In B-type films, Eq. (14) elucidates the ability of the drug particles to pass through the porous structure. A restriction factor (Fr) was therefore added to Eq. (14) as follows: Dw ¼ KBT 2lR0 Fr ð12Þ where: Fr ¼ ðsurface area of particleÞ=ðsurface area of equivalent sphereÞ in A-type films ð13Þ ð8Þ Fr ¼ average pore size=R0 in B-type films ð14Þ 0 where m(t) is the cumulative drug released (moles), t, t0 — Time (s), CðZ ¼ Zfilm ; t0 Þ—area concentration of drug (mole/cm2), and A is the film area (cm2). Estimation of the Diffusion Coefficient. The diffusion coefficient (D) in our model is divided into two regions, corresponding to the Z-axis division. One region is inside the film at 0 Z Zfilm, where the diffusion coefficient is time depended during the film degradation and can be written as Df(t). The second region is in the water at Zfilm \ Z L, where the diffusion coefficient is constant and can be written as Dw. Hence, D is expressed as follows: D ¼ Df ðtÞ at 0 Z Zfilm D ¼ Dw at Zfilm < Z L ð9Þ ð10Þ Because the diffusion medium in both cases is water, the following theoretical equation for diffusion in water can be used23: Dw ¼ KB T 2lR0 ð11Þ Journal of Biomedical Materials Research Part B: Applied Biomaterials The initial diffusion coefficient inside the film (Df0) is based on Eq. (12), but we should consider the effects of the film characteristics as follows: Df0 ¼ Dw P0 Fs Ft ð15Þ where Df0 is the initial diffusion coefficient inside the film (cm2/s), and P0 is the initial porosity of the film (%). P0 indicates the volume of water inside the film, which was evaluated experimentally and used in our model. Fs is a surface factor ([1) that we used in A-type films. It gives an indication for the initial binding (physical interactions such as hydrogen bonds) between the drug and the film surface. The value of Fs is higher for smaller (weaker) interactions. When there are relatively weak interactions between the host polymer and the drug molecules (in A-type films), the diffusion coefficient is closer to that of the drug in water. Ft is a tortuosity factor (\1) used for B-type films. It indicates the initial tortuosity of the film, which can indicate the ratio of shortest and the actual path of particles. Fs and Ft values were evaluated using our experimental data.15 Ft ¼ L1 =L2 ð16Þ 160 ZILBERMAN AND MALKA TABLE I. Film Types Used for Obtaining the Experimental Data and Their Calculated Factors Used in the Model The Polymer 50/50 PDLGA 85/15 PDLGA PDS 10/90 PDLGA PLLA Film Type Fr Fs Ft A B A B B B A B 2 40 9 30 20 50 7 20 30 – 80 – – – 50 – – 0.33 – 0.67 0.67 0.67 – 0.33 where L1 is the distance between particle location and film surface (Z 5 Zfilm), and L2 is the length of the actual particle path inside the film. The factors Fr, Fs, and Ft for the various films used in this study are presented in Table I. The time-dependent diffusion coefficient in the bulk [Df(t)] starts from its initial value Df0 [calculated in Eq. (15)] and changes with time due to the polymer’s weight loss (bulk erosion) and changes in its degree of crystallin- ity, as stated in assumption 2. Df(t) is evaluated as follows: Df ðtÞ ¼ Df0 þ fðDw Df0 Þ3WðtÞ3ð100% CRSTLðtÞÞg ð17Þ where W(t) is the film’s weight loss (%), and CRSTL(t) is the polymer’s degree of crystallinity (%). Both parameters were measured for all polymers used in this study, and the results are presented in Figure 3. Because diffusion of drug particles occurs through the amorphous regions of the semicrystalline polymer rather than through the dense crystalline regions (assumption 9), we used [100% 2 CRSTL(t)] in Eq. (17). The degree of crystallinity was measured as follows: the heat of fusion (DHm) was determined by differential scanning calorimetry using an indium-calibrated TA Instruments DSC 2010 differential scanning calorimeter (DSC). The measurements were carried out on 10 mg samples under N2 atmosphere, heating the samples from 308C to 2508C (above their melting points), using a heating rate of 108C/min. The analysis was performed using TA Universal Figure 4. DM release profile from amorphous polymer films containing 5% (w/w) DM. The experimental results (mean —— and upper and lower limits -------) are compared with the predicted results (—l—): (a) A-type (85/15 PDLGA)/DM, (b) B-type (85/15 PDLGA)/DM, (c) A-type (50/50 PDLGA)/DM, (d) B-type (50/50 PDLGA)/DM. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] Journal of Biomedical Materials Research Part B: Applied Biomaterials DRUG CONTROLLED RELEASE FROM STRUCTURED BIORESORBABLE FILMS 161 Figure 5. DM release profile from semicrystalline polymer films containing 5% (w/w) DM. The experimental results (mean —— and upper and lower limits -------) are compared with the predicted results (—l—): (a) B-type PDS / DM, (b) B-type (10/90 PDLGA)/DM, (c) A-type PLLA/DM, (d) Btype PLLA/DM. [Color figure can be viewed in the online issue, which is available at www. interscience.wiley.com.] Analysis Software. The degree of crystallinity, CRST(t), was calculated by the relationship: %CRST ¼ DHm 3100 DHF ð18Þ where DHm and DHF are the heats of fusion of the sample (a semicrystalline material) and the perfect crystal, respectively. DHF (PLLA) 5 93.6 J/g,24 DHF (PGA) 5 191.2 J/g and DHF (PDS) 5 141.2 J/g.25 Mean errors for the predicted release profiles were evaluated as follows: for each data point, when the model’s prediction is within the error of the experimental results, the model’s error is considered as 0. When the model’s prediction is not in the range of the experimental’s error, there appears an error (in %) for this point. The average error is the average of the various errors of all points. RESULTS AND DISCUSSION As mentioned earlier, the experimental data used to validate this model were taken from one of our recent studJournal of Biomedical Materials Research Part B: Applied Biomaterials ies.15 Two types of films were used, A-type with drug located on the surface of the polymer film and B-type with drug located in the bulk. Amorphous and semicrystalline polymers were used for both types of drugs (Table I). The predicted DM release profile was compared with the experimental release profile for each type of structured film. The results for the amorphous based films are presented in Figure 4 and the results for the semicrystalline-based films are presented in Figure 5. A very good fit was obtained for all studied films (less than 7% error), except for the 10/90 PDLGA/DM based film, where the predicted DM release during the first 7 weeks was higher than the experimental DM release [Figure 5(b)]. In A-type films the release profile exhibited a burst release of 30% followed by a release profile, which was determined by the degradation rate of the host polymer, whereas the B-type films exhibited a release profile governed by the degradation rate of the host polymer with a low burst release. Our model demonstrated a good fit for both types of films. These results thus support our first hypothesis about the good predictability of a model based on Fick’s laws. The advantage of building a model for drug delivery systems is the ability to elucidate the effect of the system’s 162 ZILBERMAN AND MALKA Figure 6. DM release profile from 85/15 PDLGA films containing 5% (w/w) DM, showing the effect of the host polymer’s weight loss during drug release. The experimental results (mean —— and upper and lower limits -------) are compared with the predicted results (—l—) and with the predicted results when neglecting weight loss (—~—): (a) A-type films, (b) B-type films. [Color figure can be viewed in the online issue, which is available at www.interscience. wiley.com.] for B-type films [Figure 6(b)] than for A-type films [Figure 6(a)]. The degree of crystallinity of the studied semicrystalline polymers as a function of degradation time is presented in Figure 3(b). During the first 12 weeks of degradation, the degree of crystallinity increased significantly as follows: for PDS from 53 to 83%, for 10/90 PDLGA from 43 to 59%, and for PLLA from 53 to 69%. It is widely accepted that poly(a-hydroxy acids) are degraded by simple hydrolysis. Hydrolysis begins in the amorphous phase of the polymer, because of the relatively easy penetration of water into these domains.26 Thus, the overall degree of crystallinity of the polymer film increases during degradation, mainly due to the erosion of amorphous domains. The increase in the degree of crystallinity with time may also occur due to further crystallization of low molecular weight chains. It should be noted that water acts as a softener, giving rise to that additional crystallization. The effect of the host polymer’s degree of crystalliniy on the release profile of DM from B-type PDS film is presented in Figure 7 and is compared with the effect of degradation. When the polymer’s degree of crystallinity and its change with degradation time is not considered, the predicted released quantity of drug is higher than the experimental release or the predicted release when using the full model. These results are reasonable, because the polymeric crystalline domains are dense and do not allow diffusion of drug through them. Therefore, an increase in the degree of crystallinity with degradation time acts as an obstacle for drug release, which slows the rate of diffusion. As mentioned earlier, the polymer’s degree of crystallinity is affected by its degradation, and it is therefore not possible parameters (each one separately) on the release profile of the bioactive agent. In this regard, the effect of the host polymer’s degradation rate and degree of crystallinity (for semicrystalline polymets) were studied. The effect of the degradation rate on the release profile was examined using the measured weight loss profiles of various host polymers [Figure 3(a)]. The results for the 85/15 PDLGA based films are presented as an example, in Figure 6. After the burst release, if degradation of the host polymer is not considered, the predicted amount of drug released is much lower than the experimental release or the predicted release when using the full model. These results are reasonable, because degradation of the host polymer results in higher porosity, which enables a faster drug release rate. The release profiles from the B-type films are affected by degradation more than the release profiles from the A-type films (Figures 4 and 5), because most drug particles are located within the bulk of the former. Indeed, our model shows that the difference between the experimental results and the predicted results (when degradation is neglected) is higher Figure 7. DM release profile from PDS films containing 5% (w/w) DM, showing the effects of the host polymer’s weight loss and degree of crystallinity and its change during drug release. The experimental results (mean —— and upper and lower limits -------) are compared with the predicted results ( ) and with the predicted results when neglecting crystallinity ( ) and when neglecting weight loss ( ). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] Journal of Biomedical Materials Research Part B: Applied Biomaterials DRUG CONTROLLED RELEASE FROM STRUCTURED BIORESORBABLE FILMS to examine the effect of each of these parameters on the drug release profile separately. Our model indicates that the effect of degradation on the drug release profile is more important than the effect of the degree of crystallinity (Figure 7). These results support our second hypothesis that the drug release profile from the films is affected by the host polymer’s degradation profile and its degree of crystallinity and also elucidates the relative contribution of each. 3. 4. 5. SUMMARY AND CONCLUSIONS The aim of this study was to develop a mathematical model for predicting drug release profiles from structured bioresorbable films designed to be used in various biomedical applications. Our structured polymer/ drug films are prepared using a promising technique for controlling the drug location/dispersion within the film and can be loaded with either water-soluble or water-insoluble bioactive agents. Use of the suggested model affords a good and rapid evaluation of the release profile, enabling further economical in vitro/in vivo release studies. The model is based on Fick’s 2nd law of diffusion and assumes that the drug release profile from the films is affected by the host polymer’s characteristics, by the drug’s location/dispersion in the film and by the drug’s characteristics. The model uses the weight loss profile of the host polymers as well as their change in degree of crystallinity. It also uses empirical parameters such as restriction factor, porosity, tortuosity factor, and a surface factor, which gives an indication for possible physical binding between drug molecules and the host polymer. In this study, the model was used for predicting DM release profiles from structured films of both types, with the drug located on the surface of the film (A-type), and with the drug located in the bulk (B-type). We demonstrated that the model correlates well with in vitro release results, exhibiting a mean error of less than 7% for most studied cases. Furthermore, two types of host bioresorbable polymers were used, amorphous, and semicrystalline, and the model demonstrated that the host polymer’s degradation has a greater effect on the drug release profile than the degree of crystallinity. This new model exhibits a potential for simulating the release profile of bioactive agents from structured films for a wide variety of biomedical applications. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. REFERENCES 1. Zilberman M, Eberhart RC, Schwade ND. In-vitro study of drug loaded bioresorbable films and support structures. J Biomater Sci Polym Ed 2002;13:1221–1240. 2. Aviv M, Berdicevsky I, Zilberman M. Gentamicin-loaded bioresorbable films for prevention of bacterial infections associJournal of Biomedical Materials Research Part B: Applied Biomaterials 18. 19. 163 ated with orthopedic implants. J Biomed Mater Res Part A 2007;83:10–19. Park YJ, Lee YM, Park SN, Lee JY, Ku Y, Chung CP, Lee SJ. 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