Preparation of Roxithromycin-Loaded Poly(l-lactic Acid) Films with

Nov 2, 2011 - Preparation of Roxithromycin-Loaded Poly(l-lactic Acid) Films with ... For a more comprehensive list of citations to this article, users...
0 downloads 0 Views 825KB Size
ARTICLE pubs.acs.org/IECR

Preparation of Roxithromycin-Loaded Poly(l-lactic Acid) Films with Supercritical Solution Impregnation Jin-Peng Yu, Yi-Xin Guan,* Shan-Jing Yao, and Zi-Qiang Zhu Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, People's Republic of China ABSTRACT: Supercritical solution impregnation (SSI) was applied to prepare drug-loaded biodegradable films where poly(l-lactic acid) (PLLA) was used as the matrix and roxithromycin as the model drug. The effects of impregnation time, operating temperature, and pressure on drug loading capacity (DLC) of roxithromycin into PLLA matrix were investigated. With the extension of impregnation time, DLC increased gradually to an equilibrium value. DLC was also affected by impregnation temperature and pressure. At the optimal condition, i.e., impregnating at 70 °C and 300 bar for 2 h, the maximal DLC was approximately 10.5%. After SSI process, the PLLA film was still transparent. The SEM images showed that the morphologies of PLLA film did not change with the SSI process. The DSC data and XRD spectra demonstrated that roxithromycin molecules were dispersed into the PLLA film in an amorphous state and the SCCO2 processed PLLA film had a lower crystal degree than raw PLLA film. The residual dichloromethane due to the PLLA film preparation could be removed effectively during the SSI process and meet the Chinese Pharmacopoeia limit. In vitro release of roxithromycin consisted of two stages: initial rapid release and a following slow release. The SSI process is expected to be a promising technique to prepare a drug-loaded biodegradable polymer surface and matrix for antibacterial therapeutic implants.

1. INTRODUCTION Supercritical carbon dioxide (SCCO2) is considered as an environmentally friendly and nontoxic substitute for organic solvents in many polymer processing technologies such as polymerization,1 micronization,2,3 foaming,4 and impregnation,5 and so forth. The impregnation of polymer with SCCO2 is termed as supercritical solution impregnation (SSI) and widely used in textile dyeing and polymer blending.5,6 In recent decades, the application of an SSI process in preparation of sustained- and controlled-release drug delivery systems (SCRDDS) is attracting great attention, especially in ophthalmic7 9 and anti-inflammatory10 12 pharmaceutical formulations. In the SSI process, at least three components are involved: active substance, SCCO2, and polymer matrix.5,6 First, SCCO2 swells the polymer matrix, thus increasing the free volume among polymer molecules, which could facilitate active substance diffusion into the polymer matrix, followed by the sorption of substance molecules into the polymer matrix. After depressurization, SCCO2 evaporates and exhausts from the polymer matrix with no residual. Meanwhile, the active substance is trapped in the polymer matrix to achieve the production of SCRDDS. If the affinity between active substance and polymer is strong enough, then the polymer matrix would be loaded with a mass of active substance to satisfy the demand of the SCRDDS.10,11 At present, bacterial infection at the site of implanted medical devices such as catheters and artificial prostheses is a serious problem in the biomedical field. The average infection rate of implants embedded into the human body is approximately 4% in the United States, and the estimate of direct medical costs associated with such infections is above 3 billion dollars annually in the U.S. alone.13,14 Infections in implantations result from bacterial adhesions to a biomaterial surface and subsequently from formation of bacterial biofilms on the surface of the matrix. r 2011 American Chemical Society

The organisms in the biofilms exhibit extreme resistance to antibiotics, resulting in inefficiency of conventional therapy including injection and oral administration.15 An effective approach to reduce the bacterial adhesions is using SCRDDS, which is based on the loading of drugs into the implants that actively and continuously release antibacterial reagents including antibiotics16 and anti-infective silvers,17 etc. There are two common methods to load antibiotics onto the surface of (or into) the implants. One method is to immerse implants into the antibiotic solution for a certain period to load the antibiotics into the implants;16 the other method is to coat the implants with a solution of drug blended with polymer.17 After the evaporation of the solvent, the polymer that contains the drug would form a film on the surface of the implants. Considering the first method, the drug loaded into the implants is limited, thus it could not achieve continuous release for a long period. The second method employs an organic solvent to dissolve the polymer, which requires further procedures to remove the residual organic solvent. Compared with the above methods, the SSI process could load drugs into a polymer matrix more effectively due to polymer swelling by SCCO2 and high diffusivity of SCCO2, meanwhile it affords the advantages of decreasing the risk of organic solvent residual in implants.18 Poly(l-lactic acid) (PLLA) and other poly(α-hydroxy acid) are widely applied in controlled/sustained release drug delivery systems due to their biocompatibility and biodegradability.10,11,19,20 The drug-loaded poly(lactic acid) or poly((lactic-co-glycolic acid) with an SSI process have been prepared as SCRDDS for Received: June 17, 2011 Accepted: November 2, 2011 Revised: October 26, 2011 Published: November 02, 2011 13813

dx.doi.org/10.1021/ie201294u | Ind. Eng. Chem. Res. 2011, 50, 13813–13818

Industrial & Engineering Chemistry Research the treatment of cancer10 and inflammation,11 and so forth. Roxithromycin, a semisynthetic macrolide antibiotic, is mostly used to treat respiratory tract, urinary and soft tissue infections from Gram-positive cocci,21 but its application in SCRDDS is rarely reported. In this work, PLLA and roxithromycin will be used as polymer matrix and model drug, respectively. The aim of this work is to investigate the loading of roxithromycin into PLLA films with an SSI process. The effect of operating conditions on the SSI process will be examined to obtain the proper drug loading capacity. Furthermore, the PLLA film properties are characterized to demonstrate the maintenance of polymer structures after SSI processing. Finally, the in vitro release behavior of drug-loaded PLLA films is evaluated to indicate the potential of the SSI process in the preparation of antibacterial implants.

2. MATERIALS AND METHODS 2.1. Materials. Poly(l-lactic acid) (PLLA, Mw = 11.3 kDa,

Tg = 58.6 °C, Tm = 169.3 °C) was the product of Toshiba Co. Ltd. (Japan). Roxithromycin (99.5% purity) was purchased from Fubang Pharmaceutical Co. Ltd. (Jiangsu, P.R. China). Dichloromethane (A. R.) was provided by Hangzhou Dafang Chemical Reagent Co. Ltd. (Zhejiang, P.R. China). Carbon dioxide (99.9% purity) was supplied by Hangzhou Jingong Gas Co. Ltd. (Zhejiang, P.R. China). All other reagents were of analytical grade and available commercially. 2.2. Analytical Method. The content of roxithromycin was determined by a UV vis spectrophotometer (Utrospec 3300 pro, GE Healthcare). A volume of 5 mL roxithromycin sample was mixed with 5 mL sulfuric acid solution of 75% to produce a color reaction and the absorbance of the reaction solution was analyzed at 482 nm. The drug mass could be obtained from the absorbance calibration curve. 2.3. PLLA Film Preparation. PLLA film was prepared by solvent casting22 with the procedure described below. First, PLLA powder was dissolved into dichloromethane and the final concentration was 4% (w/v, g/mL). Then 10 mL of the PLLA solution was poured onto a glass Petri dish (I.D. = 9.0 cm). After the dichloromethane in the solution evaporated, PLLA film was obtained. The film thickness was approximately 50 μm. Finally, the obtained film was vacuum-dried at 40 °C for 24 h and cut into sector pieces with 15 cm2 for later use. 2.4. Supercritical Solution Impregnation Process. The flowsheet of the supercritical solution impregnation process is schematically represented in Figure 1. The equipment mainly consisted of a cylindrical high pressure stainless steel cell (100 mL) with an electrical heater controlled by a programmed system. The temperature in the cell was measured by a digital thermometer with a deviation of (1 °C. The impregnation pressure in the cell was adjusted by the high pressure pump equipped with a pressure-feedback module and measured with an online pressure transducer. The stirrer with a rotating speed of 60 rpm was equipped to enhance the drug dissolving into CO2. In the SSI process, CO2 was first liquefied through a cooling unit and compressed to the operating pressure using a high pressure pump. The drug, i.e., roxithromycin, was loaded at the bottom of the cell, while the PLLA film (0.05 0.20 g) wrapped in a filter paper pocket was fixed in the center of the cell to avoid direct contact with the drug. The amount of the drug should be predetermined in order to saturate the CO2 at the operational condition. CO2 was allowed to flow through the cell to purge the air from the system. Then, valve 10 was closed and the cell was

ARTICLE

Figure 1. Schematic diagram of the experimental apparatus in the supercritical solution impregnation process: (1) CO2 reservoir; (2), (6), (10) valves; (3) heat exchanger; (4) flow meter; (5) high pressure pump; (7) preheater; (8) stirrer; (9) high pressure cell; (11) heater; (12) temperature controller; (13) digital thermometer; and (14) pressure transducer.

loaded with CO2. After the desired pressure and temperature were attained, the system was maintained under constant conditions during the impregnation experiments. Three main factors affecting the drug loading capacity of the PLLA film including the impregnation time, pressure, and temperature in the cell were investigated in detail. At the end of the impregnation period, the system was depressurized to atmospheric pressure in 10 min, and the samples were stored in a desiccator. 2.5. Drug Loading Capacity. A fraction of film sample prepared in Section 2.4 was dissolved into a 5 mL mixed solvent of ethyl acetate and dimethylformamide (volume ratio of 1:1) at 60 °C. Subsequently, 5 mL ethanol was added into the solution as the antisolvent of PLLA, thus PLLA precipitated from solution. After centrifugation at 6000 rpm for 20 min, the supernatant was analyzed for roxithromycin content as described in Section 2.2. The drug loading capacity was defined as the drug mass in the sample divided by the polymer mass after impregnation process. In this work, all experiments and measurements were carried out in triplicate, and the averages were adopted in the data analysis. 2.6. Characterization of Drug-Loaded Films. A scanning electron microscope (Sirion, FEI, Netherlands) was employed to analyze the surface and cross-section morphologies of the film samples. The samples were fixed onto the copper stub using double-sided adhesive carbon tape and then coated with a thin layer of gold by a sputter coater to render them electrical conductivity. Differential scanning calorimeter (DSC7, PerkinElmer, U.S.) was used to test Tm and Tg of the film samples. A sample of 10 mg was loaded on a nonhermetic aluminum disk and heated from 30 to 200 °C with a rate of 10 °C/min, where nitrogen was used as the purge gas at a flow rate of 50 mL/min. The film samples and roxithromycin powder were also tested by X-ray diffractometer (X’Pert RPD, PANalvital, Netherlands) to know the crystallization of drug in the PLLA film. The conditions were as follows: Ni-filtered Cu Kα radiation, target at 40 kV and 40 mA, 2θ angle ranging from 10° to 60°. 2.7. Solvent Residual in Drug-Loaded Films. The residual dichloromethane in film samples was analyzed by gas chromatography (6894N, Agilent Technologies, U.S.) equipped with a chromatograph column (HP-Innowax), headspace sampler (7694E) and FID detector. Sample of 0.06 g was dissolved into 3 mL mixed solvent of ethyl acetate and dimethylformamide (volume ratio of 1:1) in a 20 mL sample bottle. The solution was equilibrated on the headspace sampler at 70 °C for 30 min. The temperature program was as follows: isothermal at 40 °C for 2 min, then raised to 160 °C at 10 °C/min and held for 2 min. 13814

dx.doi.org/10.1021/ie201294u |Ind. Eng. Chem. Res. 2011, 50, 13813–13818

Industrial & Engineering Chemistry Research

ARTICLE

Figure 2. Effect of impregnation time on drug loading capacity of PLLA film in SSI process.

Figure 3. Effect of impregnation temperature on drug loading capacity of PLLA film in SSI process (impregnation time of 2 h).

2.8. In Vitro Release Behavior. The drug-loaded film was immersed in 10 mL phosphate buffer (0.01 M, pH 7.6) at 37 °C and roxithromycin molecules in the film would diffuse into the buffer. In order to maintain constant release conditions, the whole buffer was freshly replaced while the solution sample was taken. The samples were determined for roxithromycin content as described in Section 2.2.

The effect of impregnation temperature on DLC is shown in Figure 3. When the operating pressure was above 120 bar, DLC increased with temperature. On the contrary, DLC decreased with temperature when the operating pressure was below 120 bar. However, at the operating pressure of 120 bar, the relationship between DLC and impregnation temperature became complicated, which first increased ranging from 40 to 50 °C, while inverting to decrease from 50 to 70 °C. The drug concentration in CO2 phase is one of important factors to influence DLC. Usually, the temperature could affect the solubility of drug in SCCO2 in two aspects.26,27 First, the increasing of the temperature reduced the density of CO2, which might cause the decreasing of the solubility. Second, the temperature also affected sublimation pressure (PS) of drug, and usually PS increased with the rising of the temperature, leading to the higher solubility. The interactions between the two aspects complicated the relationship between the temperature and the DLC. When the pressure approached the critical point, a tiny change of temperature might result in a large variation of CO2 density. Thus the first aspect played the important role and the DLC decreased with increased temperature (below 120 bar); while when the pressure deviated from the critical point, the latter was dominant and the DLC rose with increased temperature (above 120 bar). In addition, the high temperature could facilitate drug molecules sorption into polymer phase, which is favorable to SSI process. Effect of Operating Pressure on DLC. The effect of impregnation pressure on DLC is described in Figure 4(a). It could also be easily transformed into Figure 4(b), where the density of CO2 was calculated using Peng Robinson equation. From Figure 4(a),(b), we know that DLC increased with the elevation of the impregnation pressure or CO2 density for each isotherm curve. The correlation between DLC and density of CO2 was approximately linear. Usually, the elevation of pressure would increase the density of CO2, thus enhance the solubility of drug in SCCO2,26,27 which resulted in the increase of DLC. In addition, crossover area of DLC could be easily observed in Figure 4(a), which was caused by temperature effect. As shown in Figure 3, the slope of DLC shifted from negative value to positive in the range of 100 160 bar, hence crossover area of DLC occurred. It should be emphasized that the pressure and temperature could greatly influence the DLC. Especially, when the operation conditions approached the critical point, a tiny change of temperature or pressure led to a large variation of CO2 density

3. RESULTS AND DISCUSSION 3.1. Supercritical Solution Impregnation Process. The drug release behavior of SCRDDS lies mostly on the drug loading capacity (DLC). Hence, the suitable DLC of PLLA films should be determined in the SSI process. Usually, the DLC is affected by the properties of polymer and drug, also closely related with the operation conditions of SSI process.5,6 The SSI process could be considered as four simultaneous steps:5 the CO2 diffusing into the polymer matrix, the drug molecules dissolving into the CO2, diffusing into the polymer, and adsorption by polymer molecular chains. Through these four steps, the DLC changes with the operating conditions including impregnation time, temperature, and pressure of CO2 in the impregnation vessel. Effect of Impregnation Time on DLC. The impregnation time is a key factor in the diffusion processes. The effect of the impregnation time on DLC is shown in Figure 2, where the impregnation temperature ranged from 40 to 70 °C and impregnation pressure from 80 to 300 bar. While the impregnation time was prolonged, the DLC increased and slowly approached to a definite value which was based on partition equilibrium of the drug between the polymer phase and the CO2 phase.5,6 From Figure 2, it can be seen that the period to reach partition equilibrium was closely related with the pressure and temperature of CO2. With the increase of pressure, the sorption of CO2 into polymer rises,23 which will result in the enhancement of drug diffusion rate in polymer film.24,25 As shown in Figure 2, the DLC could rapidly reach the equilibrium within 30 min at higher pressure (300 bar), but it took about 2 h at relatively low pressures (80 100 bar). The equilibrium of DLC could be achieved even more quickly at higher temperature (70 °C) because molecular movement of drug is intensified and the drug diffusion rate expedites with the increase of temperature. Thus, the impregnation time was ascertained as 2 h to make sure that the equilibrium was reached in following experiments. Effect of Operating Temperature on DLC. The DLC was measured at different conditions with the impregnation time of 2 h.

13815

dx.doi.org/10.1021/ie201294u |Ind. Eng. Chem. Res. 2011, 50, 13813–13818

Industrial & Engineering Chemistry Research

Figure 4. Effect of impregnation pressure (a) and CO2 density (b) on drug loading capacity of PLLA film in SSI process (impregnation time of 2 h).

and DLC accordingly. In this experimental range of pressure (80 300 bar) and temperature (40 70 °C), the DLC increased about 110 times from 0.092% up to 10.5%, which showed high tunable ability of SSI process. Kazarian et al.28 proposed two mechanisms in the SSI process. The first mechanism corresponded to a simple deposition of compounds when the fluid leaves the swollen matrix. In this case, even a solute with low affinity with the polymer could be trapped in the matrix. However, this method might result in the recrystallization of substances in the polymer matrix without formation of the molecularly dispersed formulation. The second mechanism utilized the high affinity between substances and a certain polymer matrix. Specific interactions between the solute and matrix could prevent self-association of solute molecules and result in solute molecularly dispersed in the polymer matrix. In this work, the DLC of roxithromycin into PLLA film was quite high compared with results reported,7 12 which implied that roxithromycin had high affinity with PLLA and accorded well with the second mechanism. The interactions between the polymer and drug could be reflected from the difference between their solubility parameters (δ).11,29 The δ of PLLA was 23.3 MPa1/2 from literature,11 and δ of roxithromycin was 24.2 MPa1/2 calculated using the group contribution method.30 The small Δδ between PLLA and roxithromycin indicated high affinity between PLLA and roxithromycin,28 leading to a high DLC up to 10.5% at 70 °C and 300 bar. 3.2. Characterization of Drug-Loaded Films. Scanning Electron Microscopy. The surface and cross-sectional morphologies

ARTICLE

Figure 5. SEM graphs of the PLLA film cross sections and surfaces with different operation process. (a) Prepared PLLA film; (b) drug-loaded PLLA film using SSI at 40 °C and 80 bar for 2 h; and (c) drug-loaded PLLA film using SSI at 70 °C and 300 bar for 2 h.

of film samples under different processes were investigated by SEM and the photos are shown in Figure 5, where (a) is the prepared PLLA film; (b) and (c) drug-loaded PLLA films at different experimental conditions. In total, all of the three samples were transparent and no obvious morphological changes were observed, implying that no foaming formed after the SSI was processed. PLLA was a semicrystal polymer and did not easily foam when processed by SCCO2.31 Furthermore, the operation temperatures in all experiments were not higher than 70 °C, far below Tm of PLLA (169.3 °C), which also prevented the foaming of PLLA with SCCO2.31 For the antibacterial implanted device, the drug in the polymer matrix should be released continuously for a long period.13 Foaming of the matrix that could lead to the explosive release of the drug from the polymer matrix should be avoided and SSI process could satisfy this demand. Differential Scanning Calorimetry. The DSC data for different samples, including (a) prepared PLLA film; (b) roxithromycin powder; (c) physical mixture of PLLA film and roxithromycin (w/w, 10/1); and (d) drug-loaded PLLA film using SSI, are presented in Figure 6. As shown in parts (a) and (b), melting peaks of PLLA film and roxithromycin were located at 169.3 and 120.8 °C, respectively. Mixture (c) had both melting peaks of roxithromycin and PLLA film. However, the drugloaded PLLA film (d) had only one melting peak, indicating that roxithromycin dispersed into the PLLA film in an amorphous 13816

dx.doi.org/10.1021/ie201294u |Ind. Eng. Chem. Res. 2011, 50, 13813–13818

Industrial & Engineering Chemistry Research

ARTICLE

Table 1. Residual Dichloromethane in Film Samples Using Different Methods mass ratio of residual samples prepared PLLA film PLLA film immersed in pure

dichloromethane (%) 0.305 0.0195

SCCO2 at 40 °C and 200 bar for 2 h PLLA film vacuum-dried at 60 °C for 24 h

0.0198

Figure 6. DSC data of different processing samples. (a) Prepared PLLA film; (b) roxithromycin powder; and (c) physical mixture of prepared PLLA film and roxithromycin (w/w, 10/1); (d) drug-loaded PLLA film using SSI at 70 °C and 300 bar for 2 h.

Figure 8. In vitro release curve of roxithromycin from the drug-loaded PLLA film at 37 °C.

Figure 7. The XRD spectra of different processing samples. (a) roxithromycin powder; (b) prepared PLLA film; (c) PLLA film prepared with pure SCCO2 at 70 °C and 300 bar for 2 h; and (d) drug-loaded PLLA film using SSI at 70 °C and 300 bar for 2 h.

state, which also demonstrated that roxithromycin molecules had affinity with PLLA molecules. Therefore, the SSI process of roxithromycin into PLLA accorded with the second mechanism proposed by Kazarian et al.,28 and the roxithromycin might be molecularly dispersed into PLLA film. X-ray Diffraction. The XRD spectra of samples, including (a) roxithromycin powder; (b) prepared PLLA film; (c) PLLA film processed with pure SCCO2 with the absence of roxithromycin; and (d) drug-loaded PLLA film, are presented in Figure 7. The comparisons among parts (a), (c), and (d) indicated that roxithromycin was dispersed into PLLA film in an amorphous state, which agrees with DSC data. In addition, the differences among parts (b), (c), and (d) showed that the SCCO2 processed PLLA film had a lower crystal degree than raw PLLA film, which was attributed to two reasons. One was that the SCCO2 could diffuse into the PLLA crystal region to destroy the crystal structure; the other was that the existence of the drug molecules in the matrix would prevent the recrystallization of PLLA molecules. The crystals of both polymer and drug molecules in the film might result in the heterogeneity of drug dispersion. Therefore, the drug-loaded films with low crystal degrees obtained by the SSI process were beneficial to the drug uniform release for SCRDDS. 3.3. Solvent Residual in Drug-Loaded Films. The residual dichloromethane in film samples with different methods was

analyzed and the results are listed in Table 1. The dichloromethane content in prepared PLLA film was 0.305%, beyond the limit of Chinese Pharmacopoeia (0.06%, 2005 edition). After the SSI process, the residual dichloromethane dropped greatly to 0.0195%, which could well meet the standard. As contrast, PLLA film was vacuum-dried for 24 h with the temperature increasing to 60 °C. As a result, the residual dichloromethane also dropped to a lower value, while softening of the film was observed because the temperature was above Tg of PLLA (58.6 °C). Compared with the traditional method, an SSI process could remove residual organic solvents more effectively, which took only 2 h. The similar conclusion was also reported by Koegler et al.18 3.4. In Vitro Release Behavior. The drug-loaded PLLA film prepared with an SSI process at 70 °C and 300 bar for 2 h was employed in drug release experiment which contained 10.5% roxithromycin. As shown in Figure 8, the release curve included two stages: initial rapid release and a following slow release period. The initial rapid release drug was surface adsorbed roxithromycin, and the following slow release drug was in the interior. Average drug release rate of initial 6 h was 0.695 μg/(h 3 cm2), while the release rate decreased to 2.37 ng/ (h 3 cm2) after 4 d. For implanted medical devices embedded into the body, the initial 6 h had a high possibility of being infected by bacteria, and the high drug concentration could reduce this risk.13 However, after the implant integrates into the surrounding tissues, the low drug concentration would be mild to the body. The two-stage release curve indicated that drug-loaded PLLA films prepared with the SSI process could be used as the matrix for antibacterial therapeutic implants.

4. CONCLUSIONS An SSI process was successfully applied to prepare drugloaded PLLA films. When the impregnation time was above 2 h, 13817

dx.doi.org/10.1021/ie201294u |Ind. Eng. Chem. Res. 2011, 50, 13813–13818

Industrial & Engineering Chemistry Research the DLC of PLLA films increased to an equilibrium value. The DLC of PLLA films went up with the increasing density of SCCO2 and the maximal DLC was approximately 10.5% under the optimal conditions of impregnating at 70 °C and 300 bar for 2 h. The PLLA films were transparent and had no visible changes in morphology after the SSI process. The solid characterization indicated that roxithromycin dispersed into the PLLA was amorphous and the SCCO2 processed PLLA film had a lower crystal degree than raw PLLA film. The chromatographic analysis showed that the SSI process could remove residual dichloromethane in the polymer preparation more effectively than the traditional method. The in vitro release curve of roxithromycin presented the possibility of the SSI process to prepare implanted devices with antibiotics to prevent the associated infections. Compared with the conventional drug-loading methods, SSI offers individual advantages: avoiding the use of organic solvents and high productivity.

’ AUTHOR INFORMATION Corresponding Author

*Tel.: +86-571-87951982. Fax: +86-571-87951982. E-mail: guanyx @zju.edu.cn.

’ ACKNOWLEDGMENT The authors are grateful for financial support provided by the National Natural Science Foundation of China (21076185). ’ REFERENCES (1) Temtem, M.; Casimiro, T.; Mano, J. F.; Aguiar-Ricardo, A. Green Synthesis of a Temperature Sensitive Hydrogel. Green Chem. 2007, 9, 75. (2) Wang, Q.; Guan, Y. X.; Yao, S. J.; Zhu, Z. Q. Microparticle Formation of Sodium Cellulose Sulfate Using Supercritical Fluid Assisted Atomization Introduced by Hydrodynamic Cavitation Mixer. Chem. Eng. J. 2010, 159, 220. (3) Alessi, P.; Cortesi, A.; Kikic, I. Particle Production of Steroid Drugs Using Supercritical Fluid Processing. Ind. Eng. Chem. Res. 1996, 35, 4718. (4) Xu, Z. M.; Jiang, X. L.; Liu, T.; Hu, G. H.; Zhao, L.; Zhu, Z. N.; Yuan, W. K. Foaming of Polypropylene with Supercritical Carbon Dioxide. J. Supercrit. Fluids 2007, 41, 299. (5) Kikic, I.; Vecchione, F. Supercritical Impregnation of Polymers. Curr. Opin. Solid State Mater. Sci. 2003, 7, 399. (6) Kikic, I. Polymer-Supercritical Fluid Interactions. J. Supercrit. Fluids 2009, 47, 458. (7) Duarte, A. R. C.; Simplicio, A. L.; Vega-Gonzalez, A.; SubraPaternault, P.; Coimbra, P.; Gil, M. H.; de Sousa, H. C.; Duarte, C. M. M. Supercritical Fluid Impregnation of a Biocompatible Polymer for Ophthalmic Drug Delivery. J. Supercrit. Fluids 2007, 42, 373. (8) Braga, M. E. M.; Vaz Pato, M. T.; Costa Silva, H. S. R.; Ferreira, E. I.; Gil, M. H.; Duarte, C. M. M.; de Sousa, H. C. Supercritical Solvent Impregnation of Ophthalmic Drugs on Chitosan Derivatives. J. Supercrit. Fluids 2008, 44, 245. (9) Ya~nez, F.; Martikainen, L.; Barga, M. E. M.; Alvarez-Lorenzo, C.; Concheiro, A.; Duarte, C. M. M.; Gil, M. H; de Sousa, H. C. Supercritical Fluid-Assisted Preparation of Imprinted Contact Lenses for Drug Delivery. Acta Biomater. 2011, 7, 1019. (10) Guney, O.; Akgerman, A. Synthesis of Controlled-Release Products in Supercritical Medium. AIChE J. 2002, 48, 856. (11) Liu, H.; Finn, N.; Yates, M. Z. Encapsulation and Sustained Release of a Model Drug, Indomethacin, Using CO2-Based Microencapsulation. Langmuir 2005, 21, 379.

ARTICLE

(12) Gong, K.; Darr, J. A.; Rehman, I. U. Supercritical Fluid Assisted Impregnation of Indomethacin into Chitosan Thermosets for Controlled Release Applications. Int. J. Pharm. 2006, 315, 93. (13) Hetrick, E. M.; Schoenfisch, M. H. Reducing Implant-Related Infections: Active Release Strategies. Chem. Soc. Rev. 2006, 35, 780. (14) Darouiche, R. O. Treatment of Infections Associated with Surgical Implants. N. Engl. J. Med. 2004, 350, 1422. (15) Costerton, J. W.; Stewart, P. S; Greenberg, E. P. Bacterial Biofilms: A Common Cause of Persistent Infections. Science 1999, 284, 1318. (16) Cormio, L.; La Forgia, P.; La Forgia, D.; Siitonen, A.; Ruutu, M. Bacterial Adhesion to Urethral Catheters: Role of Coating Materials and Immersion in Antibiotic Solution. Eur. Urol. 2001, 40, 354. (17) Multanen, M.; Talja, M.; Hallanvuo, S.; Siitonen, A.; Valimaa, T.; Tammela, T. L. J.; Seppala, J.; Tormala, P. Bacterial Adherence to Silver Nitrate Coated Poly-l-lactic Acid Urological Stents in Vitro. Urol. Res. 2000, 28, 327. (18) Koegler, W. S.; Patrick, C.; Cima, M. J.; Griffith, L. G. Carbon Dioxide Extraction of Residual Chloroform from Biodegradable Polymers. J. Biomed. Mater. Res., Part A 2002, 63, 567. (19) Liu, R.; Ma, G. H; Meng, F. T; Su, Z. G. Preparation of Uniform-Sized PLA Microcapsules by Combining Shirasu Porous Glass Membrane Emulsification Technique and Multiple Emulsion-Solvent Evaporation Method. J. Controlled Release 2005, 103, 31. (20) Fu, Y. J; Shyu, S. S.; Su, F. H; Yu, P. C. Development of Biodegradable co-poly(D,L-lactic/glycolic acid) Microspheres for the Controlled Release of 5-FU by the Spray Drying Method. Colloids Surf., B 2002, 25, 269. (21) Biradar, S. V.; Patil, A. R.; Sudarsan, G. V.; Pokharkar, V. B. A Comparative Study of Approaches Used to Improve Solubility of Roxithromycin. Powder Technol. 2006, 169, 22. (22) Natu, M. V.; Gil, M. H.; de Sousa, H. C. Supercritical Solvent Impregnation of Poly (ε- caprolactone)/poly (oxyethylene-b-oxypropylene-b-oxyethylene) and Poly (ε-caprolactone)/poly (ethylene-vinyl acetate) Blends for Controlled Release Applications. J. Supercrit. Fluids 2008, 47, 93. (23) Oliveira, N. S.; Dorgan, J.; Coutinho, J. A. P.; Ferreira, A.; Daridon, J. L.; Marrucho, I. M. Gas Solubility of Carbon Dioxide in Poly(lactic Acid) at High Pressures. J. Polym. Sci., Part B: Polym. Phys. 2006, 44, 1010. (24) Duarte, A. R. C.; Martins, C.; Coimbra, P.; Gil, M. H. M.; de Sousa, H. C.; Duarte, C. M. M. Sorption and Diffusion of Dense Carbon Dioxide in a Biocompatible Polymer. J. Supercrit. Fluids 2006, 38, 392. (25) Sicardi, S.; Manna, L.; Banchero, M. Diffusion of Disperse Dyes in PET Films during Impregnation with a Supercritical Fluid. J. Supercrit. Fluids 2000, 17, 187. (26) Burgos-Solorzano, G. I.; Brennecke, J. F.; Stadtherr, M. A. Solubility Measurements and Modeling of Molecules of Biological and Pharmaceutical Interest with Supercritical CO2. Fluid Phase Equilib. 2004, 220, 57. (27) Gong, X. Y.; Cao, X. J. Measurement and Correlation of Solubility of Artemisinin in Supercritical Carbon Dioxide. Fluid Phase Equilib. 2009, 284, 26. (28) Kazarian, S. G.; Martirosyan, G. G. Spectroscopy of Polymer/ drug Formulations Processed with Supercritical Fluids: in situ ATR IR and Raman Study of Impregnation of Ibuprofen into PVP. Int. J. Pharm. 2002, 232, 81. (29) Park, M. W.; Bae, H. K. Dye Distribution in Supercritical Dyeing with Carbon Dioxide. J. Supercrit. Fluids 2002, 22, 65. (30) Krevelen, D. W. Y. Properties of Polymers, Fourth ed.; Elsevier: Amsterdam, 2009. (31) Kiran, E. Foaming Strategies for Bioabsorbable Polymers in Supercritical Fluid Mixtures. Part I. Miscibility and Foaming of Poly (l-lactic acid) in Carbon Dioxide + Acetone Binary Fluid Mixtures. J. Supercrit. Fluids 2010, 54, 296.

13818

dx.doi.org/10.1021/ie201294u |Ind. Eng. Chem. Res. 2011, 50, 13813–13818