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Adjusting drug diffusivity using miscible polymer blends
Journal of Controlled Release 102 (2005) 679 – 687 www.elsevier.com/locate/jconrel
Adjusting drug diffusivity using miscible polymer blends Su-Ping Lyu*, Randall Sparer, Christopher Hobot, Kiem Dang Medtronic Technology Center LT 140, 710 Medtronic Parkway NE, Minneapolis, MN 55432, USA Received 30 August 2004; accepted 1 November 2004 Available online 2 December 2004
Abstract Tuning the release rates of drugs was accomplished with miscible polymer blends. Dexamethasone (DX) was formulated in a miscible polymer blend composed of two poly(ether urethane)s, one in which DX diffuses relatively quickly and the other in which DX diffuses relatively slowly. Matrices that provide drug diffusion coefficients from 71013 to 31019 cm2/s were obtained by adjusting the blend ratio. Tunable diffusion coefficients were also achieved with partially miscible blends, such as poly(vinyl acetate) (PVAC)/cellulose acetate butyrate (CAB). However, similar tunable diffusion was not observed with an immiscible polymer blend composed of poly(carbonate urethane) (PCU) and polysulfone (PSF). D 2004 Elsevier B.V. All rights reserved. Keywords: Drug release; Diffusivity; Medical device; Miscible; Polymer blend
1. Introduction Combining medical devices with drug therapy is becoming a trend in the medical device industry. The drug-coated stent is one example, in which a thin polymer layer containing a drug is coated on the surface of the stent. The drug-coated stent demonstrates improved efficacy in reducing restenosis after expansion of the narrowed coronary artery. However, controlling drug release from thin polymer layers is in practice more challenging than controlling release
* Corresponding author. Tel.: +1 763 505 4549; fax: +1 763 505 4712. E-mail address: [email protected] (S.-P. Lyu). 0168-3659/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2004.11.007
from thicker polymer devices. In large devices, a drug can be loaded above its solubility limit in polymers as long as the precipitated drug particles do not form percolation channels. However, this may not be feasible for thin coatings (e.g., a stent coating) because if the drug particles have a size comparable to the coating thickness (about 10 Am), the drug will directly dissolve into the dissolution medium from the exposed particles without control by the polymer matrix. This will cause a burst or an initial fast release, followed by diffusion-controlled release of the remaining drug. For the same reason, methods such as those based on reservoirs or osmotic pressure [1] that are used to adjust drug release rates in large devices may not work for thin coatings. Additionally, in the case of drug delivery from implanted medical
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devices, the polymer matrices should be biocompatible and in some cases biostable. Unfortunately, there are not many polymers that meet all of these requirements. A possible solution to these issues is to make blends of two or more implantable polymers, one through which the drug diffuses relatively quickly and one through which it diffuses relatively slowly. By adjusting the composition of these blends, a continuous spectrum of new diffusion coefficients, bounded by those of the two pure polymers, can be achieved. This gives much more flexibility than can be achieved by using the two individual polymers separately. Blending concepts have been used for a long time in drug delivery [2–23]. Park et al. [2] obtained controlled release of bovine serum albumin from blends composed of poly(lactic acid) (PLA)/poly(ethylene oxide-co-propylene oxide-co-ethylene oxide) (PEO–PPO–PEO). The authors explained their results in terms of entanglement of the triblock copolymer surfactant with the PLA amorphous phase. Pitt et al. [3] studied blends composed of poly(vinyl alcohol) (PVA)/poly(glycolic acid-co-lactic acid) (PGLA). The authors found that the release rates of several hydrophilic compounds and proteins were proportional to the water content in hydrated blends that was monotonically related to the blend composition. The authors also reported that there was no significant effect on the release rates by the changes in the morphology of blends as the blends varied from miscible to immiscible. Edlund and Albertsson [4] reported interesting examples of wellcontrolled drug release with a miscible blend composed of poly(d,l-lactic acid) (PDLLA) and poly(1,5-dioxepan-2-one) (PDXO). The authors explained this in terms of the plasticizing effect of PDXO on PDLLA. By comparing this with the results from a blend that was partially miscible and semicrystalline, the authors stressed the importance of morphology of blends in controlling drug release. Uniform adjustment of release rates was also obtained in other polymer blends [17,19–21]. However, in some systems, complicated results were observed by changing the experimental conditions. For example, Lecomte et al. [5] reported that the drug release rate in blends composed of ethyl cellulose and poly(methacrylic acid-co-ethyl acryl-
ate) uniformly changed with blend composition in acidic dissolution solutions. However, the same blends, when tested at pH 7.4, provided a bimodal release pattern in which the drug was released at either a higher rate or a lower rate. Complicated release has been reported in other papers [6–9]. Obviously, more systematic studies are needed to fully understand the relationships between the miscibility, morphology, and controlled release behavior of polymer blends. In this report, three polymer blends (miscible, partially miscible, and immiscible) will be used to clarify the relationship between the miscibility of polymers and the diffusivity of drugs. The polymers used in the present paper have been used for implant applications. Therefore, the present paper also extends the application of implantable biopolymers.
2. Tuning diffusivity of drugs using miscible polymer blends 2.1. Diffusion of drugs in polymers Diffusion rates of drug molecules in polymers depend on three factors: the size and the shape of drug molecules, the mobility of polymer chains, and the interactions between the drug and polymer chains [24,25]. Drug molecules diffuse slower in the polymers that have higher glass transition temperatures (T g) because these polymers have less free volume and the mobility of chains is lower. Diffusion is slower in the polymers that have stronger interactions with drug molecules. Both of these factors are intrinsic properties of the materials and therefore cannot be easily changed. However, when two polymers are miscible, the blends have different glass transition temperatures and different interactions with drugs. The new T g values and interactions are functions of the composition of the blends (and may have linear relationships to composition). Therefore, the diffusion coefficients of drugs in polymer blends can be changed accordingly. There are many theories about the diffusion of small molecules in polymers that are based on either the Arrhenius equation [25] or the Williams Landel Ferry (WLF) equation (time–temperature superposition).
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urethane)s [Tecoplast (TP) and Tecothane75D (TC)], a partially miscible blend of cellulose acetate butyrate (CAB) and poly(vinyl acetate) (PVAC), and an immiscible blend of poly(carbonate urethane) (PCU) and polysulfone (PSF). Dexamethasone (DX), a hydrophobic and low-molecular-weight drug, was used as a model drug for all three blends. All the polymers and the drug were purchased from various commercial sources and listed in Table 1. Polymers and drug were individually dissolved in either anhydrous tetrahydrofuran (THF) or chloroform to make 1 wt.% solutions. TC and PCU cannot be directly dissolved in THF at room temperature. The materials were dried at about 70 8C under vacuum overnight, then were press-molded into sheets at 230 8C. The pressed sheets were easily dissolved into THF at room temperature. Samples for diffusivity tests were made by simply mixing the corresponding polymer solutions and drug (DX) solution. The drug content was about 10 wt.% based on the solid content. The mixed solutions were cast onto surfaces of stainless steel (316 L) shims (0.51.5 in.2) and dried in a glove box filled with nitrogen gas. The thickness of the dried coating was about 5 to 20 Am. Prior to casting the polymer/drug solutions, the shims were cleaned with THF and treated with a primer. The primer was a thin TC coating (0.1 to 1 Am in thickness) that was cast onto the shim surfaces from its THF solution, dried, and annealed at 215 8C for 5 to 10 min. This primer significantly promoted the adhesion between polymer and shim and prevented
2.2. Miscibility of polymers Unfortunately, due to their high molecular weights, most polymers are not miscible although their monomers may be miscible. The critical condition of miscibility can be described by the following equation based on the Flory–Huggins theory [26]: ð1Þ
vN V2
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where v is the Flory–Huggins parameter that measures the polymer–polymer interactions (v is positive for repulsive interactions and negative for attractive ones), N is the degree of polymerization of the two polymers (assuming the two polymers have the same value). Generally, N is a large number, from 102 to 103. Therefore, v has to be very close to zero or even negative for the polymers to be miscible. This could be achieved only when the two polymers are essentially the same or have specific attractive interactions, such as hydrogen bonding. v can be estimated based on solubility parameters of the pure polymers. The solubility parameter can be approximated with group contribution methods [25] or computer simulation [23].
3. Experimental 3.1. Materials and sample preparations Three blends were studied in the present paper. They were a miscible blend of two poly(ether
Table 1 Thermal transition, solubility parameter, solvent, and vendor information about the materials used in the present paper Polymer/drug
T g (8C)a (DSC)
Dexamethasone (DX) Tecothane75D (TC) Tecoplast (TP) Cellulose acetate butyrate (CAB)
N/A 22 72 160
Poly(vinyle acetate) (PVAC) Polysulfone (PSF) Poly(carbonate urethane) (PCU)
40 180 10
a b
Ref. [23]. Hard segment.
Solubility parameter (J1/2/cm3/2)a 23b 23b 22 21
Solvents
Molecular weight (number average, kg/mol)
THF THF THF THF
102 83 65
THF Chloroform THF
334 64 92
Sources and chemistry
Sigma-Aldrich TT-1075D-M, Thermedics TP-470, Thermedics 29.5 wt.% acetyl and 17 wt.% butyryl. Sigma-Aldrich Sigma-Aldrich Udel, BP-Amoco Bionate 75D. Polymer Technology Group
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polymer from delaminating during dissolution testing [27]. The shims were weighed after each step to track the amount of coating added. Samples for miscibility tests contained only the corresponding polymers. 3.2. Miscibility tests Miscibility of polymer blends was assessed by measuring the thermal transition temperatures of various blends with differential scanning calorimetry (DSC; PYRIS 1, PerkinElmer Com). The scanning was programmed from 50 to 220 8C at 40 8C/min. The sample size was about 10 mg. If the signal was too noisy, a second scan was conducted on the same sample. PYRIS software version 5.0 was used to determine the onset of T g transitions. The DSC curves of blends with different compositions were plotted in the same graph by vertically shifting the curves for comparison. 3.3. Dissolution tests The coated shims were cut into pieces. The surface areas were measured for normalization. Each piece was immersed in a vial containing 3 mL of phosphate-buffered saline solution (PBS, pH=7.4). Approximately 2 mg of coating, containing about 200 Ag of DX, and 3 mL of PBS that was preheated to 37 8C were used. The dissolution test was run at 37 8C. The PBS was refreshed and the sampled PBS solutions were analyzed at various times to determine the concentration of DX in each sample. The concentration of DX in PBS was measured with UV-Vis spectroscopy (HP 4152A) at the wavelength of 243 nm or using liquid chromatography (HP 1090. Zorbax Eclipse (5 Am) column) with a UV detector.
4. Results and discussions 4.1. Miscible polymer blends Tecoplast (TP) and Tecothane (TC) both are poly(ether urethane). Both of them contain more hard segments [formed from 4,4V-methylene bis(phenyl isocyanate) and short alcohols, C2 to C6] than soft segments [formed from 4,4V-methylene bis(phenyl isocyanate) and low-molecular-weight poly(tetramethylene oxide)]. For this reason, both polymers are rigid (80D and 75D, Shore D). Both polymers have a single T g (Fig. 1). DSC curves of the two pure polymers and three blends (TP/TC ratio in weight=75/25, 50/50, 25/75) are plotted in Fig. 1. TP had a T g at 72 8C and TC had a T g at 22 8C. All three blends had a single T g that increased with increasing content of TP (the higher T g component). This clearly suggested that all the TP/TC blends had a single phase and therefore were miscible blends. If the blends were immiscible, two T g values would be expected. All the blend samples were as clear as the two pure polymers, further suggesting that the two polymers were miscible. The dissolution of DX from TP/TC blends is plotted in Fig. 2 in the form of cumulative
3.4. Scanning electron microscopy (SEM) images of blend cross-section morphology The cross-section morphology of the PVAC/CAB blends was observed with a SEM (Jeol 5900). The samples were fractured in liquid nitrogen and etched with ethanol to remove the PVAC phase (CAB does not dissolve in ethanol). The etched sample cross section appeared to be porous.
Fig. 1. DSC curves of poly (ether urethane)(TP/TC) blends. The glass transition temperature increased with increasing Tecothane content. The peaks from 80 to 180 8C in the curve of pure TC corresponded to a melt-like transition in polyurethane, but not glass transition.
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Fig. 2. Cumulative percentage release of dexamethasone (DX) from TC/TP blends. The linear relationship between percentage release and square root (SQRT) of time in the early stage (broken line) indicated the release was controlled by a diffusion mechanism. The release rate increased with increasing the TC content.
percentage release as a function of square root of time. As is shown, all five curves are approximately linear for low values of time. DX was released fastest from the pure TC (the lower T g polymer) but slowest from TP (the higher T g polymer). The release rates of DX from these blends increased with increasing content of the fast release matrix TC. This trend is correlated with the relationships between the T g and the blend composition as showed in Fig. 1. These results exactly demonstrated the premise of the present paper that the release rates of drugs could be tuned by blending two miscible polymers. Based on theoretical study, cumulative percentage release f(t) should be linear with square root of time t [28,29], f ðt Þ ¼ 4
Dt px2
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linear, as shown in Fig. 2, it can be concluded that the DX release was controlled by a diffusion mechanism. The diffusion coefficient can be calculated from the slope of the initial linear part of the release curve by using Eq. (2). The slope was calculated by applying least squares fit to the data points ranging from t=0 to a cutoff time that was defined such that the R 2 of fitting was 0.99 to 0.999. The relative error of D was calculated by doubling the sum of the fitting error and the error in sample thickness measurement (this error propagation relationship can be derived from Eq. (2) by differential calculus). TP and TC had a DX diffusion coefficient of 71013 and 31019 cm2/s, respectively. The diffusion coefficients of the other three blends were between these two values. By blending the two polymers together, a broad range of diffusion coefficients was obtained (Fig. 3). Both TP and TC have excellent mechanical properties. A few grades of TC have been used for long-term human being implantation (http://www.thermedicsinc.com/ products/medical/pdf/biocompat.pdf). Therefore, the blending strategy not only allows the creation of polymer matrices with tunable diffusion coefficients but also allows the matrices to be made with polymers that have already been tested for implant applications.
1=2 ð2Þ
where x is the thickness of the film sample, p=3.14. This equation holds for up to 60% of cumulative release for those samples with sufficient thickness. Because the initial rate of release is
Fig. 3. Tuning the diffusion coefficient of dexamethasone (DX) in the blends of poly(ether urethane)s by changing the blend content. As a comparison, the glass transition temperature (T g) was also shown (right axis). The diffusion coefficient decreased as the T g increased.
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4.2. Partially miscible polymer blends As mentioned above, most polymers are not miscible with each other, which puts some practical limits to this miscible blending strategy. However, many polymers can be partially miscible and can be used to tune the diffusivity of drug. This will be demonstrated with a partially miscible blend of cellulose acetate butyrate (CAB)/poly(vinyl acetate) (PVAC). Fig. 4 shows the DSC curves of the two pure polymers, PVAC and CAB, and three blends of them. PVAC had a T g at 40 8C and CAB had a T g at 160 8C. All three blends had two T g values, one at 58 8C and the other at 160 8C or slightly below. Such phenomena are very common for polymer blends. It indicated that PVAC and CAB were not completely miscible; therefore, they could not form a homogeneous phase. Instead, they were partially miscible and formed two distinct phases, one is a PVAC-rich and the other one is a CAB-rich phase. Therefore, there were two new T g values. Dissolution curves of these polymers and blends were plotted in Fig. 5. Interestingly, the release behavior of DX from these blends was very similar to that of the miscible blend TP/TC. The release rate increased with increasing content of PVAC, the fast
Fig. 4. Glass transition temperature of cellulose acetate butyrate/ poly(vinyl acetate) (CAB/PVAC) blends. All the three blends have two glass transitions within the range bounded by that of the pure CAB and PVAC. This indicated that CAB and PVAC were only partially miscible.
Fig. 5. Cumulative release of dexamethasone from various PVAC/ CAB blends with different PVAC contents. It was shown that the release rates were tuned by changing the amount of PVAC of blends.
release matrix. The diffusion coefficient of DX for each blend was calculated in a similar way as that for TC/TP blends and is plotted in Fig. 6. The log(D) followed a nearly linear relationship with the content of PVAC. However, one has to be cautious to interpret the mechanisms of tuning diffusivity of drug with partially miscible blends. Different from the miscible blends that have homogeneous structure, the partially miscible blends had heterogeneous structures composed of two new phases that contained both of the
Fig. 6. Diffusion coefficient of dexamethasone in PVAC/CAB blends increased as a function of the PVAC content of blends.
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Fig. 7. Cross-section SEM of the CAB/PVAC blend film. The samples were prepared by cryo-fracture in liquid nitrogen. The PVAC phase was etched away with ethanol and was shown in the picture as pores. The pore size was about 1 to 5 Am, smaller than the thickness of the dissolution film samples (about 20 Am).
two pure polymers. If the domain size of each phase was smaller than sample size, it may be reasonable to approximate the blends as uniform systems to understand the control mechanism of drug release. Fig. 7 showed the SEM microstructure of PVAC/CAB (50:50) blend. The PVAC-rich domains (pores) were smaller (1 to 5 Am) than the film thickness (5 to 20 Am). This may explain why the partially miscible PVAC/CAB blends could tune the DX diffusivity.
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Fig. 8. Glass transition temperature of poly(carbonate urethane) (PCU) and polysulfone (PSF) and a 50/50 blend. The glass transition was around 40 and 180 8C for PCU and PSF, respectively. Like Tecothane, PCU has melting like peaks around 180 8C that depends on processing and thermohistory. The lower temperature transition of PCU/PSF blend was similar to that of the pure PCU. The higher temperature transition was complicated by the melting like peak of PCU. However, there was no new peak, which suggests there was no new phase formation. Therefore, PCU and PSF are immiscible.
4.3. Immiscible polymer blends
content range. It was noticed that the viscosity of PSF solution was lower than that of PCU; and lower viscosity favors the formation of continuous phase from that component [30]. This speculation needs to be confirmed. However, it is clear that controlling
Poly(carbonate urethane) (PCU) and polysulfone (PSF) were used as an immiscible example. The blends of these two polymers were opaque, indicating the blends were phase-separated and are immiscible. This was confirmed with the DSC results of the two polymers and their blend (Fig. 8). The diffusivity of DX from various blends was estimated based on the dissolution measurements and plotted in Fig. 9. As is shown, the diffusion coefficients of DX increase slowly from pure PSF to the blend with 85 wt.% of PCU. When the matrix changed from 85 wt.% PCU to pure PCU, the diffusion coefficient jumped by almost a factor of 4. Obviously, the diffusion coefficient of DX in PCU/PSF blends was not linear but had a bimodal relationship with the blend composition, indicating the tuning ability of this pair of polymers was poor. There are several possible reasons for the bimodal release. One possibility is that PSF might form a barrier or a continuous phase over a broad
Fig. 9. Diffusivity of DX in the blends composed of poly(carbonate urethane) and polysulfone (PCU/PSF) as a function of blend composition. The two polymers were not miscible. The ability to tune diffusion coefficient was poor: the change in D was slow up to 85 wt.% of PCU, but it was sharp from 85 to 100 wt.%.
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drug release with immiscible blends is more complicated than with miscible ones and adds more variables to application development. Although only the diffusivity was discussed in the present paper, the same idea has also been applied to tuning the solubility of drugs in polymers and to tuning the water swelling ability of polymer matrices (or hydropholicity/hydrophobicity). Detailed discussions can be found in the patent literature [23].
[6]
[7]
[8]
5. Conclusions It has been demonstrated that a broad and continuous spectrum of drug diffusion coefficients could be achieved by blending a few polymers that are miscible or partially miscible. Polymers that are suitable for implant applications may be used. Therefore, this miscible blend approach can provide a rapid method to screen polymer matrices that can be attached to biomedical devices to add the new function of controlled drug release.
[9]
[10]
[11]
[12]
Acknowledgment The authors would like to thank Christopher Deegan, Lori McNamara, Emily Rolfes, Deanna Huehn, Kishore Udipi, Peiwen Cheng, and Michael Benz for technical assistance.
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Adjusting drug diffusivity using miscible polymer blends Su-Ping Lyu*, Randall Sparer, Christopher Hobot, Kiem Dang Medtronic Technology Center LT 140, 710 Medtronic Parkway NE, Minneapolis, MN 55432, USA Received 30 August 2004; accepted 1 November 2004 Available online 2 December 2004
Abstract Tuning the release rates of drugs was accomplished with miscible polymer blends. Dexamethasone (DX) was formulated in a miscible polymer blend composed of two poly(ether urethane)s, one in which DX diffuses relatively quickly and the other in which DX diffuses relatively slowly. Matrices that provide drug diffusion coefficients from 71013 to 31019 cm2/s were obtained by adjusting the blend ratio. Tunable diffusion coefficients were also achieved with partially miscible blends, such as poly(vinyl acetate) (PVAC)/cellulose acetate butyrate (CAB). However, similar tunable diffusion was not observed with an immiscible polymer blend composed of poly(carbonate urethane) (PCU) and polysulfone (PSF). D 2004 Elsevier B.V. All rights reserved. Keywords: Drug release; Diffusivity; Medical device; Miscible; Polymer blend
1. Introduction Combining medical devices with drug therapy is becoming a trend in the medical device industry. The drug-coated stent is one example, in which a thin polymer layer containing a drug is coated on the surface of the stent. The drug-coated stent demonstrates improved efficacy in reducing restenosis after expansion of the narrowed coronary artery. However, controlling drug release from thin polymer layers is in practice more challenging than controlling release
* Corresponding author. Tel.: +1 763 505 4549; fax: +1 763 505 4712. E-mail address: [email protected] (S.-P. Lyu). 0168-3659/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2004.11.007
from thicker polymer devices. In large devices, a drug can be loaded above its solubility limit in polymers as long as the precipitated drug particles do not form percolation channels. However, this may not be feasible for thin coatings (e.g., a stent coating) because if the drug particles have a size comparable to the coating thickness (about 10 Am), the drug will directly dissolve into the dissolution medium from the exposed particles without control by the polymer matrix. This will cause a burst or an initial fast release, followed by diffusion-controlled release of the remaining drug. For the same reason, methods such as those based on reservoirs or osmotic pressure [1] that are used to adjust drug release rates in large devices may not work for thin coatings. Additionally, in the case of drug delivery from implanted medical
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devices, the polymer matrices should be biocompatible and in some cases biostable. Unfortunately, there are not many polymers that meet all of these requirements. A possible solution to these issues is to make blends of two or more implantable polymers, one through which the drug diffuses relatively quickly and one through which it diffuses relatively slowly. By adjusting the composition of these blends, a continuous spectrum of new diffusion coefficients, bounded by those of the two pure polymers, can be achieved. This gives much more flexibility than can be achieved by using the two individual polymers separately. Blending concepts have been used for a long time in drug delivery [2–23]. Park et al. [2] obtained controlled release of bovine serum albumin from blends composed of poly(lactic acid) (PLA)/poly(ethylene oxide-co-propylene oxide-co-ethylene oxide) (PEO–PPO–PEO). The authors explained their results in terms of entanglement of the triblock copolymer surfactant with the PLA amorphous phase. Pitt et al. [3] studied blends composed of poly(vinyl alcohol) (PVA)/poly(glycolic acid-co-lactic acid) (PGLA). The authors found that the release rates of several hydrophilic compounds and proteins were proportional to the water content in hydrated blends that was monotonically related to the blend composition. The authors also reported that there was no significant effect on the release rates by the changes in the morphology of blends as the blends varied from miscible to immiscible. Edlund and Albertsson [4] reported interesting examples of wellcontrolled drug release with a miscible blend composed of poly(d,l-lactic acid) (PDLLA) and poly(1,5-dioxepan-2-one) (PDXO). The authors explained this in terms of the plasticizing effect of PDXO on PDLLA. By comparing this with the results from a blend that was partially miscible and semicrystalline, the authors stressed the importance of morphology of blends in controlling drug release. Uniform adjustment of release rates was also obtained in other polymer blends [17,19–21]. However, in some systems, complicated results were observed by changing the experimental conditions. For example, Lecomte et al. [5] reported that the drug release rate in blends composed of ethyl cellulose and poly(methacrylic acid-co-ethyl acryl-
ate) uniformly changed with blend composition in acidic dissolution solutions. However, the same blends, when tested at pH 7.4, provided a bimodal release pattern in which the drug was released at either a higher rate or a lower rate. Complicated release has been reported in other papers [6–9]. Obviously, more systematic studies are needed to fully understand the relationships between the miscibility, morphology, and controlled release behavior of polymer blends. In this report, three polymer blends (miscible, partially miscible, and immiscible) will be used to clarify the relationship between the miscibility of polymers and the diffusivity of drugs. The polymers used in the present paper have been used for implant applications. Therefore, the present paper also extends the application of implantable biopolymers.
2. Tuning diffusivity of drugs using miscible polymer blends 2.1. Diffusion of drugs in polymers Diffusion rates of drug molecules in polymers depend on three factors: the size and the shape of drug molecules, the mobility of polymer chains, and the interactions between the drug and polymer chains [24,25]. Drug molecules diffuse slower in the polymers that have higher glass transition temperatures (T g) because these polymers have less free volume and the mobility of chains is lower. Diffusion is slower in the polymers that have stronger interactions with drug molecules. Both of these factors are intrinsic properties of the materials and therefore cannot be easily changed. However, when two polymers are miscible, the blends have different glass transition temperatures and different interactions with drugs. The new T g values and interactions are functions of the composition of the blends (and may have linear relationships to composition). Therefore, the diffusion coefficients of drugs in polymer blends can be changed accordingly. There are many theories about the diffusion of small molecules in polymers that are based on either the Arrhenius equation [25] or the Williams Landel Ferry (WLF) equation (time–temperature superposition).
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urethane)s [Tecoplast (TP) and Tecothane75D (TC)], a partially miscible blend of cellulose acetate butyrate (CAB) and poly(vinyl acetate) (PVAC), and an immiscible blend of poly(carbonate urethane) (PCU) and polysulfone (PSF). Dexamethasone (DX), a hydrophobic and low-molecular-weight drug, was used as a model drug for all three blends. All the polymers and the drug were purchased from various commercial sources and listed in Table 1. Polymers and drug were individually dissolved in either anhydrous tetrahydrofuran (THF) or chloroform to make 1 wt.% solutions. TC and PCU cannot be directly dissolved in THF at room temperature. The materials were dried at about 70 8C under vacuum overnight, then were press-molded into sheets at 230 8C. The pressed sheets were easily dissolved into THF at room temperature. Samples for diffusivity tests were made by simply mixing the corresponding polymer solutions and drug (DX) solution. The drug content was about 10 wt.% based on the solid content. The mixed solutions were cast onto surfaces of stainless steel (316 L) shims (0.51.5 in.2) and dried in a glove box filled with nitrogen gas. The thickness of the dried coating was about 5 to 20 Am. Prior to casting the polymer/drug solutions, the shims were cleaned with THF and treated with a primer. The primer was a thin TC coating (0.1 to 1 Am in thickness) that was cast onto the shim surfaces from its THF solution, dried, and annealed at 215 8C for 5 to 10 min. This primer significantly promoted the adhesion between polymer and shim and prevented
2.2. Miscibility of polymers Unfortunately, due to their high molecular weights, most polymers are not miscible although their monomers may be miscible. The critical condition of miscibility can be described by the following equation based on the Flory–Huggins theory [26]: ð1Þ
vN V2
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where v is the Flory–Huggins parameter that measures the polymer–polymer interactions (v is positive for repulsive interactions and negative for attractive ones), N is the degree of polymerization of the two polymers (assuming the two polymers have the same value). Generally, N is a large number, from 102 to 103. Therefore, v has to be very close to zero or even negative for the polymers to be miscible. This could be achieved only when the two polymers are essentially the same or have specific attractive interactions, such as hydrogen bonding. v can be estimated based on solubility parameters of the pure polymers. The solubility parameter can be approximated with group contribution methods [25] or computer simulation [23].
3. Experimental 3.1. Materials and sample preparations Three blends were studied in the present paper. They were a miscible blend of two poly(ether
Table 1 Thermal transition, solubility parameter, solvent, and vendor information about the materials used in the present paper Polymer/drug
T g (8C)a (DSC)
Dexamethasone (DX) Tecothane75D (TC) Tecoplast (TP) Cellulose acetate butyrate (CAB)
N/A 22 72 160
Poly(vinyle acetate) (PVAC) Polysulfone (PSF) Poly(carbonate urethane) (PCU)
40 180 10
a b
Ref. [23]. Hard segment.
Solubility parameter (J1/2/cm3/2)a 23b 23b 22 21
Solvents
Molecular weight (number average, kg/mol)
THF THF THF THF
102 83 65
THF Chloroform THF
334 64 92
Sources and chemistry
Sigma-Aldrich TT-1075D-M, Thermedics TP-470, Thermedics 29.5 wt.% acetyl and 17 wt.% butyryl. Sigma-Aldrich Sigma-Aldrich Udel, BP-Amoco Bionate 75D. Polymer Technology Group
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polymer from delaminating during dissolution testing [27]. The shims were weighed after each step to track the amount of coating added. Samples for miscibility tests contained only the corresponding polymers. 3.2. Miscibility tests Miscibility of polymer blends was assessed by measuring the thermal transition temperatures of various blends with differential scanning calorimetry (DSC; PYRIS 1, PerkinElmer Com). The scanning was programmed from 50 to 220 8C at 40 8C/min. The sample size was about 10 mg. If the signal was too noisy, a second scan was conducted on the same sample. PYRIS software version 5.0 was used to determine the onset of T g transitions. The DSC curves of blends with different compositions were plotted in the same graph by vertically shifting the curves for comparison. 3.3. Dissolution tests The coated shims were cut into pieces. The surface areas were measured for normalization. Each piece was immersed in a vial containing 3 mL of phosphate-buffered saline solution (PBS, pH=7.4). Approximately 2 mg of coating, containing about 200 Ag of DX, and 3 mL of PBS that was preheated to 37 8C were used. The dissolution test was run at 37 8C. The PBS was refreshed and the sampled PBS solutions were analyzed at various times to determine the concentration of DX in each sample. The concentration of DX in PBS was measured with UV-Vis spectroscopy (HP 4152A) at the wavelength of 243 nm or using liquid chromatography (HP 1090. Zorbax Eclipse (5 Am) column) with a UV detector.
4. Results and discussions 4.1. Miscible polymer blends Tecoplast (TP) and Tecothane (TC) both are poly(ether urethane). Both of them contain more hard segments [formed from 4,4V-methylene bis(phenyl isocyanate) and short alcohols, C2 to C6] than soft segments [formed from 4,4V-methylene bis(phenyl isocyanate) and low-molecular-weight poly(tetramethylene oxide)]. For this reason, both polymers are rigid (80D and 75D, Shore D). Both polymers have a single T g (Fig. 1). DSC curves of the two pure polymers and three blends (TP/TC ratio in weight=75/25, 50/50, 25/75) are plotted in Fig. 1. TP had a T g at 72 8C and TC had a T g at 22 8C. All three blends had a single T g that increased with increasing content of TP (the higher T g component). This clearly suggested that all the TP/TC blends had a single phase and therefore were miscible blends. If the blends were immiscible, two T g values would be expected. All the blend samples were as clear as the two pure polymers, further suggesting that the two polymers were miscible. The dissolution of DX from TP/TC blends is plotted in Fig. 2 in the form of cumulative
3.4. Scanning electron microscopy (SEM) images of blend cross-section morphology The cross-section morphology of the PVAC/CAB blends was observed with a SEM (Jeol 5900). The samples were fractured in liquid nitrogen and etched with ethanol to remove the PVAC phase (CAB does not dissolve in ethanol). The etched sample cross section appeared to be porous.
Fig. 1. DSC curves of poly (ether urethane)(TP/TC) blends. The glass transition temperature increased with increasing Tecothane content. The peaks from 80 to 180 8C in the curve of pure TC corresponded to a melt-like transition in polyurethane, but not glass transition.
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Fig. 2. Cumulative percentage release of dexamethasone (DX) from TC/TP blends. The linear relationship between percentage release and square root (SQRT) of time in the early stage (broken line) indicated the release was controlled by a diffusion mechanism. The release rate increased with increasing the TC content.
percentage release as a function of square root of time. As is shown, all five curves are approximately linear for low values of time. DX was released fastest from the pure TC (the lower T g polymer) but slowest from TP (the higher T g polymer). The release rates of DX from these blends increased with increasing content of the fast release matrix TC. This trend is correlated with the relationships between the T g and the blend composition as showed in Fig. 1. These results exactly demonstrated the premise of the present paper that the release rates of drugs could be tuned by blending two miscible polymers. Based on theoretical study, cumulative percentage release f(t) should be linear with square root of time t [28,29], f ðt Þ ¼ 4
Dt px2
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linear, as shown in Fig. 2, it can be concluded that the DX release was controlled by a diffusion mechanism. The diffusion coefficient can be calculated from the slope of the initial linear part of the release curve by using Eq. (2). The slope was calculated by applying least squares fit to the data points ranging from t=0 to a cutoff time that was defined such that the R 2 of fitting was 0.99 to 0.999. The relative error of D was calculated by doubling the sum of the fitting error and the error in sample thickness measurement (this error propagation relationship can be derived from Eq. (2) by differential calculus). TP and TC had a DX diffusion coefficient of 71013 and 31019 cm2/s, respectively. The diffusion coefficients of the other three blends were between these two values. By blending the two polymers together, a broad range of diffusion coefficients was obtained (Fig. 3). Both TP and TC have excellent mechanical properties. A few grades of TC have been used for long-term human being implantation (http://www.thermedicsinc.com/ products/medical/pdf/biocompat.pdf). Therefore, the blending strategy not only allows the creation of polymer matrices with tunable diffusion coefficients but also allows the matrices to be made with polymers that have already been tested for implant applications.
1=2 ð2Þ
where x is the thickness of the film sample, p=3.14. This equation holds for up to 60% of cumulative release for those samples with sufficient thickness. Because the initial rate of release is
Fig. 3. Tuning the diffusion coefficient of dexamethasone (DX) in the blends of poly(ether urethane)s by changing the blend content. As a comparison, the glass transition temperature (T g) was also shown (right axis). The diffusion coefficient decreased as the T g increased.
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4.2. Partially miscible polymer blends As mentioned above, most polymers are not miscible with each other, which puts some practical limits to this miscible blending strategy. However, many polymers can be partially miscible and can be used to tune the diffusivity of drug. This will be demonstrated with a partially miscible blend of cellulose acetate butyrate (CAB)/poly(vinyl acetate) (PVAC). Fig. 4 shows the DSC curves of the two pure polymers, PVAC and CAB, and three blends of them. PVAC had a T g at 40 8C and CAB had a T g at 160 8C. All three blends had two T g values, one at 58 8C and the other at 160 8C or slightly below. Such phenomena are very common for polymer blends. It indicated that PVAC and CAB were not completely miscible; therefore, they could not form a homogeneous phase. Instead, they were partially miscible and formed two distinct phases, one is a PVAC-rich and the other one is a CAB-rich phase. Therefore, there were two new T g values. Dissolution curves of these polymers and blends were plotted in Fig. 5. Interestingly, the release behavior of DX from these blends was very similar to that of the miscible blend TP/TC. The release rate increased with increasing content of PVAC, the fast
Fig. 4. Glass transition temperature of cellulose acetate butyrate/ poly(vinyl acetate) (CAB/PVAC) blends. All the three blends have two glass transitions within the range bounded by that of the pure CAB and PVAC. This indicated that CAB and PVAC were only partially miscible.
Fig. 5. Cumulative release of dexamethasone from various PVAC/ CAB blends with different PVAC contents. It was shown that the release rates were tuned by changing the amount of PVAC of blends.
release matrix. The diffusion coefficient of DX for each blend was calculated in a similar way as that for TC/TP blends and is plotted in Fig. 6. The log(D) followed a nearly linear relationship with the content of PVAC. However, one has to be cautious to interpret the mechanisms of tuning diffusivity of drug with partially miscible blends. Different from the miscible blends that have homogeneous structure, the partially miscible blends had heterogeneous structures composed of two new phases that contained both of the
Fig. 6. Diffusion coefficient of dexamethasone in PVAC/CAB blends increased as a function of the PVAC content of blends.
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Fig. 7. Cross-section SEM of the CAB/PVAC blend film. The samples were prepared by cryo-fracture in liquid nitrogen. The PVAC phase was etched away with ethanol and was shown in the picture as pores. The pore size was about 1 to 5 Am, smaller than the thickness of the dissolution film samples (about 20 Am).
two pure polymers. If the domain size of each phase was smaller than sample size, it may be reasonable to approximate the blends as uniform systems to understand the control mechanism of drug release. Fig. 7 showed the SEM microstructure of PVAC/CAB (50:50) blend. The PVAC-rich domains (pores) were smaller (1 to 5 Am) than the film thickness (5 to 20 Am). This may explain why the partially miscible PVAC/CAB blends could tune the DX diffusivity.
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Fig. 8. Glass transition temperature of poly(carbonate urethane) (PCU) and polysulfone (PSF) and a 50/50 blend. The glass transition was around 40 and 180 8C for PCU and PSF, respectively. Like Tecothane, PCU has melting like peaks around 180 8C that depends on processing and thermohistory. The lower temperature transition of PCU/PSF blend was similar to that of the pure PCU. The higher temperature transition was complicated by the melting like peak of PCU. However, there was no new peak, which suggests there was no new phase formation. Therefore, PCU and PSF are immiscible.
4.3. Immiscible polymer blends
content range. It was noticed that the viscosity of PSF solution was lower than that of PCU; and lower viscosity favors the formation of continuous phase from that component [30]. This speculation needs to be confirmed. However, it is clear that controlling
Poly(carbonate urethane) (PCU) and polysulfone (PSF) were used as an immiscible example. The blends of these two polymers were opaque, indicating the blends were phase-separated and are immiscible. This was confirmed with the DSC results of the two polymers and their blend (Fig. 8). The diffusivity of DX from various blends was estimated based on the dissolution measurements and plotted in Fig. 9. As is shown, the diffusion coefficients of DX increase slowly from pure PSF to the blend with 85 wt.% of PCU. When the matrix changed from 85 wt.% PCU to pure PCU, the diffusion coefficient jumped by almost a factor of 4. Obviously, the diffusion coefficient of DX in PCU/PSF blends was not linear but had a bimodal relationship with the blend composition, indicating the tuning ability of this pair of polymers was poor. There are several possible reasons for the bimodal release. One possibility is that PSF might form a barrier or a continuous phase over a broad
Fig. 9. Diffusivity of DX in the blends composed of poly(carbonate urethane) and polysulfone (PCU/PSF) as a function of blend composition. The two polymers were not miscible. The ability to tune diffusion coefficient was poor: the change in D was slow up to 85 wt.% of PCU, but it was sharp from 85 to 100 wt.%.
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drug release with immiscible blends is more complicated than with miscible ones and adds more variables to application development. Although only the diffusivity was discussed in the present paper, the same idea has also been applied to tuning the solubility of drugs in polymers and to tuning the water swelling ability of polymer matrices (or hydropholicity/hydrophobicity). Detailed discussions can be found in the patent literature [23].
[6]
[7]
[8]
5. Conclusions It has been demonstrated that a broad and continuous spectrum of drug diffusion coefficients could be achieved by blending a few polymers that are miscible or partially miscible. Polymers that are suitable for implant applications may be used. Therefore, this miscible blend approach can provide a rapid method to screen polymer matrices that can be attached to biomedical devices to add the new function of controlled drug release.
[9]
[10]
[11]
[12]
Acknowledgment The authors would like to thank Christopher Deegan, Lori McNamara, Emily Rolfes, Deanna Huehn, Kishore Udipi, Peiwen Cheng, and Michael Benz for technical assistance.
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