controlled delivery of paclitaxel from stent coatings using novel styrene maleic anhydride copolymer...

Controlled delivery of paclitaxel from stent coatings usingnovel styrene maleic anhydride copolymer formulations

Robert Richard, Marlene Schwarz, Ken Chan, Nikolai Teigen, Mark BodenCorporate Research and Advanced Technology, Boston Scientific Corporation, One Boston Scientific Place,Natick, Massachusetts 01760

Received 8 June 2007; revised 30 November 2007; accepted 2 January 2008Published online 18 June 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.a.31969

Abstract: The controlled release of paclitaxel (PTx) fromstent coatings comprising an elastomeric polymer blendedwith a styrene maleic anhydride (SMA) copolymer isdescribed. The coated stents were characterized for mor-phology by scanning electron microscopy (SEM) and atomicforce microscopy (AFM), and for drug release using high-performance liquid chromatography (HPLC). Differentialscanning calorimetry (DSC) was used to measure the extentof interaction between the PTx and polymers in the formu-lation. Coronary stents were coated with blends of poly(b-styrene-b-isobutylene-b-styrene) (SIBS) and SMA contain-ing 7% or 14% maleic anhydride (MA) by weight. SEM ex-amination of the stents showed that the coating did notcrack or delaminate either before or after stent expansion.Examination of the coating surface via AFM after elution ofthe drug indicated that PTx resides primarily in the SMAphase and provided information about the mechanism of

PTx release. The addition of SMA altered the release profileof PTx from the base elastomer coatings. In addition, thepresence of the SMA enabled tunable release of PTx fromthe elastomeric stent coatings, while preserving mechanicalproperties. Thermal analysis reveled no shift in the glasstransition temperatures for any of the polymers at all drugloadings studied, indicating that the PTx is not misciblewith any component of the polymer blend. An in vivo evalu-ation indicated that biocompatibility and vascular responseresults for SMA/SIBS-coated stents (without PTx) are simi-lar to results for SIBS-only-coated and bare stainless steelcontrol stents when implanted in the non-injured coronaryarteries of common swine for 30 and 90 days. � 2008 WileyPeriodicals, Inc. J Biomed Mater Res 90A: 522–532, 2009

Key words: coronary stent; coating; polymer; paclitaxel;drug release

INTRODUCTION

Drug delivering medical devices often utilize poly-meric materials as coatings and matrices for con-trolled release of therapeutic agents. The drug-elut-ing coronary stent is an excellent example of a de-vice-based drug delivery product that relies on apolymeric coating to modulate release of a therapeu-tic material after implantation. Several drug-elutingcoronary stent technologies have been shown to behighly effective at reducing restenosis in controlledclinical trials.1–7 The mechanical requirements of pol-ymers used for drug-eluting stent (DES) applicationsinclude elasticity and toughness to preserve thephysical integrity of the coating during stent expan-sion and deployment. Since these polymer coatingsare exposed to the vascular tissue and flowing blood,they must also exhibit compatibility with the in vivoenvironment.8 Biostable polymers intended for DES

applications must not break down or erode afterimplantation because this could affect the releaserate of the therapeutic agent or introduce inflamma-tory particles or degradants during the life time ofthe implant. Polymers used in DES applications alsomust withstand exposure to sterilization conditionswithout compromising the mechanical integrity orfunction of the coating. In addition, the coatingshould enable release of the therapeutic in a modu-lated fashion to deliver a specific dose of the thera-peutic to the vessel.

The TAXUS1 Express2TM Paclitaxel-Eluting Coro-nary Stent System (Boston Scientific Corporation,Natick, MA) consists of paclitaxel (PTx) and poly(styrene-b-isobutylene-b-styrene) (SIBS) coated on thesurface of a coronary stent. The physical and chemi-cal attributes of the SIBS copolymer are well suitedfor stent coating applications and have been reportedpreviously.9

For hydrophobic drugs like PTx, it has beenshown that release from a stent coating can bemodulated effectively by changing the drug loading,introducing excipients, or through blending with

Correspondence to:M. Boden; e-mail: [email protected]

� 2008 Wiley Periodicals, Inc.

other homopolymers or copolymers.10–12 Conven-tional techniques, such as differential scanning calo-rimetry (DSC), have been used to evaluate potentialdrug-polymer interactions and better understand thecharacteristics of the polymer carrier that control therelease of PTx.13–17

Atomic force microscopy (AFM) is a technique thathas proven useful for examining the morphologyof stent coatings. Correlation of AFM images withspecific drug release profiles has enhanced theunderstanding of the PTx-based stent coating sys-tems.9–12,18 Similar studies with novel polymericdrug-delivery coatings that exhibit different releaseprofiles can expand the understanding of drug dis-tribution, interactions, and subsequent release fromthe coating.

The present work investigated a novel approach tomodulate the in vitro PTx release performance fromcoated coronary stents by blending SIBS with styrenemaleic anhydride copolymers (SMA) containing 7%or 14% maleic anhydride (MA). Previous work eval-uating stent coatings based on poly(butyl methacry-late) (BMA) or poly(b-styrene-b-ethylene-butylene-b-styrene) (SEBS) has demonstrated a similar ability tomodulate the release of PTx.18 To provide under-standing of the release mechanism, PTx-containingSIBS/SMA blends were studied in detail for mor-phology and miscibility.

The usefulness of a polymer such as SMA in bio-medical applications also depends on the in vivoresponse of biological tissue to the material. Studiesusing an alternating SMA copolymer injected intothe vas deferens of rats showed no change in anytoxicity parameters over 6 months.19 A similar studyshowed that behavioral, hematological, biochemicaland histopathological parameters of rhesus monkeysremained comparable to controls 1 year after injec-tion of SMA into the vas deferens.20 In both studiesSMA was dissolved in dimethyl sulfoxide prior toinjection into the lumen at the desired doses.

Other studies have focused on the use of SMA inpro-drug formulations; specifically the SMA acid-half-butyrate copolymer conjugated with neocarzi-nostatin.21,22 However, the drug polymer conjugateis formed from a low molecular weight (�1700 Da)alternating SMA copolymer. The biocompatibleresponse from the contraceptive and prodrug appli-cations of SMA may be vastly different from the vas-cular reaction to a thin stent coating containing ahigh molecular weight (greater than 100,000 Da)SMA copolymer with relative low levels of maleicanhydride (less than 15%).

An in vivo evaluation of the SMA/SIBS blend sys-tem was conducted to investigate the vascular com-patibility of SMA coated stents. Stents coated with aSMA/SIBS blend (no drug) were implanted in thenon-injured coronary arteries of healthy Yorkshire

swine. This model was selected due to the anatomi-cal similarity between the coronary arteries of theporcine and humans.

Patency was assessed using angiography, whereasvascular compatibility of the polymer coating wasdetermined by histological evaluation and scanningelectron microscopy (SEM) examination of the ex-planted vessels. Histology, specifically morphologyand morphometry, was used to indicate the arterialresponse or localized reaction to the stent (i.e.,inflammation and thrombus) and the stability of thevascular wall (i.e., disruption of the laminar or mus-cular layers). SEM examination was also used to pro-vide information on the degree of endothelization ofthe luminal surface. The biocompatibility of the SIBScopolymer coated stents was also examined usingthe same pre-clinical model and methods.

MATERIALS AND METHODS

Materials

The SIBS copolymer containing �17 mol % styrene[130–160 K Mw/1.2–1.5 polydispersity (PDI)] was synthe-sized using known techniques.23–25 Polystyrene (PS) (�200K Mw) and SMA (150–200K Mw/1.7–2.2 PDI) copolymerscontaining 7% or 14% maleic anhydride (MA) by weight(SMA7 and SMA14, respectively) were purchased fromSigma–Aldrich, Milwaukee, WI. Anhydrous crystallinePTx was obtained from Indena, SpA. Milan, Italy, and wasused as received. HPLC grade toluene and tetrahydrofuran(THF), used for sample preparations, were purchased fromSigma–Aldrich, Milwaukee, WI.

Coating solutions of the desired formulations were pre-pared and coated onto the clean surfaces of 8 mmExpress1 and Liberte1 Stents (Boston Scientific Corpora-tion, Natick, MA) using a proprietary process. LiberteStents used during the in vivo analysis to determine vascu-lar compatibility were coated with SMA14/SIBS formula-tions without PTx.

Test methods

SEM

The mechanical integrity of the coated stents was exam-ined using a JEOL JSM-6460 scanning electron microscope(Tokyo, Japan). Coated stents did not require an additionalcoating of a conductive thin layer (e.g., gold or carbon)prior to examination. An accelerating voltage of 1 kV wasused for collecting the secondary electron images. Coatingdurability was confirmed by SEM examination afterexpanding the stents to nominal dimensions in a 378Cwater bath. The stent/balloon catheter assembly wasimmersed in a 378C water bath for 10 s before the balloonwas inflated to its nominal deployment pressure. Follow-ing current DES direction for use (DFUs), the inflation

CONTROLLED DELIVERY OF PACLITAXEL FROM STENT COATINGS 523

Journal of Biomedical Materials Research Part A

pressure was maintained for 30 s to bring the stent to fullexpansion before deflating the balloon.

AFM

The polymer morphology of the coated surface wasdetermined using AFM analysis. A multimode AFM (Digi-tal Instruments/Veeco Metrology, Santa Barbara, CA) con-trolled with NanoScope IIIa and NanoScope Extenderelectronics was used. Stents coated with SIBS and SIBS/SMA14 blends, with and without PTx were analyzed byAFM.

Stent samples were initially examined in the dry stateusing the tapping mode. Subsequently, the stents wereexposed to an excess of the release medium (phosphatebuffered saline (PBS)-Tween 20) at room temperaturewhile mounted in the AFM sample holder. AFM images ofthe stent surface were gathered after 24–27 h of exposureto release medium during which PTx was released fromthe coating.

DSC

DSC analysis was conducted on cast films containingSMA14, SIBS, and PTx at varying ratios. The glass transi-tion temperatures (Tg) of the copolymer blends were deter-mined using a TA Instruments Q1000 (New Castle, DE)differential scanning calorimeter at a heating rate of 208C/min. To provide consistent history, samples for compatibil-ity evaluations were first heated above their Tg, thencooled at 108C/min to eliminate residual solvents and theeffect on Tg, and variations in sample preparation. Datawere collected on the second heating cycle for compatibil-ity analysis. The results presented are the average valuesdetermined from multiple sample runs. All instrumentswere calibrated against indium.

SMA14/SIBS DSC samples were cast from 15% solidssolutions in 85% THF using a doctor blade film formationprocess, followed by oven drying. Formulations with anSMA14/SIBS ratio of 1:1.5 by weight and with levels ofPTx from 0 to 25 weight % (wt %) were prepared in 5%increments, cast, and dried for 1 day at ambient conditionsprior to additional drying at 708C for up to 4 days. Sam-ples of SIBS containing 0%, 10%, and 25% wt % PTx werecast from a 5% solids solution containing 5% THF/90%toluene, into a Teflon dish. The samples were dried at am-bient conditions for 16 h, followed by 24 h at 658C undervacuum.

PTx release

Individual coated stents were analyzed for PTx releasein 1.5 mL of the release medium (PBS-0.05 wt % Tween20) at 378C. The sampling frequency and sample size wereselected to ensure that sink conditions were maintained. Inaddition, complete recovery of PTx was demonstratedusing mass balance evaluation after release. This involveddissolving the stent coating and quantifying the PTx thatremained in the coating. The elution rate of PTx from the

stent coating was determined via high-performance liquidchromatography (HPLC) (Waters 2695 Separation Module,Waters Corporation, Milford, MA) analysis of the releasemedia using a previously published method.9

In vivo evaluation

An in vivo evaluation of the biocompatibility of a stentcoating with a blend of 1:1.5 SMA14/SIBS (40/60 wt %)was conducted in non-injured coronary arteries of healthyYorkshire swine (30 6 5 kg) at MPI Research (Mattawan,MI). All animals were examined and weighed prior to im-plantation. They were pretreated with 325 mg aspirin and75 mg clopidogrel for 3 days prior to surgery, and main-tained on daily doses of 81 mg aspirin and 75 mg clopi-dogrel for the duration of the study. Single SMA/SIBS-coated, SIBS-only-coated or bare metal Liberte1 Stents(2.75 3 16 mm, 3.0 3 16 mm and 3.5 3 16 mm) (BostonScientific Corporation, Natick, MA) were implanted ineither the left anterior descending (LAD), left circumflexcoronary (LCX), and/or the right coronary (RCA) arteriesof the animals. The devices were introduced via carotidartery access and advanced into the coronary arteriesusing a Mach 11, FL3, 7F Guide Catheter (Boston ScientificCorporation, Natick, MA) and a 0.014 IQTM Guide Wire(Boston Scientific Corporation, Natick, MA). The stentswere deployed at a 1.1 (60.05):1 stent to artery ratio withan Encore1 Inflation Device (Boston Scientific Corporation,Natick, MA). Angiographic guidance was performedduring implantation using an OEC9800 (General Electric,Fairfield, CT) fluoroscope. Observations for mortality andmorbidity were conducted twice daily. Clinical observa-tions were conducted weekly. Explantation of stents wasperformed after either 30 or 90 days.

Fluoroscopic images were captured for quantitative cor-onary angiography at stent implant and prior to necropsy.Blood samples for clinical pathology evaluations were alsocollected pre-implant and prior to necropsy. After termina-tion, necropsies were performed and the organs wereexamined for abnormalities. The hearts were removed forhistopathology and SEM evaluation of stented arteries.Stents were excluded from the study if two or more strutswere outside the exterior elastic lamina (EEL), stent dissec-tion, strut mal-apposition, procedural complications, ani-mal condition unrelated to test device that may impactstudy outcome or a tissue processing artifact. The numberof stents explanted and evaluated is shown in Table I.

TABLE INumber of Stents Implanted in the Noninjured Porcine

Coronary Model per Time Point after Exclusions

Device Type

30 Days 90 Days

Histology SEM Histology SEM

SMA/SIBS n 5 8 n 5 2 n 5 6 n 5 2SIBS n 5 7 n 5 2 n 5 11 n 5 2Bare metal n 5 7 n 5 2 n 5 5 n 5 2

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Following a 24-h fixation period in 10% neutral bufferedformalin (10% NBF), stented vessels were embedded inepoxy and cross sectioned at five locations (proximal refer-ence vessel, proximal stent, mid stent, distal stent, anddistal reference vessel). Embedded sections were stainedusing hematoxylin and eosin (H&E) and Masson’s Tri-chrome stains. The following semiquantitative morphologi-cal parameters were assessed: endothelial cell coverage,parastrut leukocytes, luminal thrombus, elastic lamina dis-ruption, and strut tissue coverage. Images of the histologysections were collected using a light microscope and imagecapturing system. Stented vessels designated for SEManalysis were longitudinally sectioned and assessed forendothelial coverage.

Myocardial samples proximal, distal, deep, and lateralto each stented arterial segment were collected for furtherevaluation. The remaining hearts (stented arteries excised)were sectioned for tissue analysis (identification of infarc-tions and/or abnormalities).

RESULTS AND DISCUSSION

SEM

After application of the coating solution and dry-ing to remove residual solvents, a smooth uniformcoating was achieved for all formulations investi-gated. SEM was used to examine the coating qualityand evaluate the level of defects such as webbingacross struts or protrusion and ensure uniform cov-erage. Images of 30% SMA14/45% SIBS (1:1.5 ratio)coatings with 25% PTx are shown in Figure 1. Figure1(a) illustrates that complete coverage of the stentwas achieved without filling the interstitial spacesbetween the struts. Coating durability was confirmedby deploying the stents in 378C water. Duringexpansion of the stent, the polymeric coating under-goes a significant degree of elongation on the inte-rior radii of the struts, and compression on the op-posite sides of the struts. The polymer coating mustexhibit elastomeric properties that allow for elonga-

tion and compression without deformation or crack-ing. SEM images in Figure 1(b,c) clearly demonstratethat the coating covered the entire surface of everystrut including the exterior, interior, and sides of theindividual struts, even after expansion.

AFM

An understanding of the mechanism of PTxrelease from SIBS/SMA coatings was gained by ex-amination of the stent surfaces using AFM. Topogra-phy and phase images were generated after expo-sure of the stents to the PBS release medium, duringwhich time changes in the surface texture of thestent coating were monitored. The topography andphase images shown in Figures 2(a–c) and 3(a–c),respectively, were generated from SIBS or SMA14/SIBS stent coatings containing no drug. Figures 2(d–f) and 3(d–f) show the same polymer formulationswith the addition of 25% PTx after �24 h of PTxelution.

Figures 2(a) and 3(a) show the 2-phase morphol-ogy observed from stents coated with the SIBScopolymer. The thermodynamically incompatibleblocks of the copolymer separated into distinctphases which were visible using AFM. After theaddition of 25% PTx to the formulation, drug par-ticles were observed to be dispersed in the 2-phasemorphology of the SIBS copolymer. During exposureto the release medium, PTx eluted from the matrix,leaving voids in the surface of the SIBS matrix asshown in the topography image in Figure 2(d).

Figures 2(b,c) and 3(b,c) show AFM topographyand phase images, respectively of 13% SMA14/87%SIBS and 40% SMA14/60% SIBS (1:6.5 and 1:1.5SMA14:SIBS ratios). Both blocks of the SIBS copoly-mer are immiscible with SMA14 and several distinctphases were visible, corresponding to each compo-nent in the formulations. These images also show athird phase dispersed within the two-phase SIBS

Figure 1. SEM micrograph of a typical SMA/SIBS/PTx coated stent. Formulation coated on the stents shown is SMA14/SIBS with a 1:1.5 ratio and 25% PTx by weight or 25% PTx/30% SMA14/455 SIBS. (a) unexpanded stent at 340 magnifica-tion (b) 340 magnification of an expanded stent (c) 3200 magnification of an expanded stent.



Figure 2. AFM topography images (2 lm scans) of the surface of coated stents. (a) SIBS only before exposure to releasemedia. (b) 13% SMA14/87% SIBS (1:6.5 ratio) before exposure to release media. (c) 40% SMA14/60% SIBS (1:1.5 ratio)before exposure to release media. (d) 25% PTx/75% SIBS imaged after immersion in release media for about 24 h. (e) 25%PTx/10% SMA14/65% SIBS (1:6.5 SMA14/SIBS ratio) imaged after immersion in release media for about 24 hours and (f)25% PTx/30% SMA14/45% SIBS (1:1.5 SMA14/SIBS ratio) imaged after immersion in release media for about 24 h.

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morphology resulting from the presence of SMA14.It was observed that this phase became larger as theamount of SMA14 increased, verifying that this third

phase was SMA Figures 2(e,f) and 3(e,f) show AFMimages of stents coated with the same copolymerblend ratios as seen in 2b,c and 3b,c, respectively,

Figure 3. AFM phase images (2 lm scans) of the surface of coated stents (a) SIBS only before exposure to release media(b) 13% SMA14/87% SIBS (1:6.5 ratio) before exposure to release media (c) 40% SMA14/60% SIBS (1:1.5 ratio) before expo-sure to release media (d) 25% PTx/75% SIBS imaged after immersion in release media for about 24 h (e) 25% PTx/10%SMA14/65% SIBS (1:6.5 SMA14/SIBS ratio) imaged after immersion in release media for about 24 h and (f) 25% PTx/30%SMA14/45% SIBS (1:1.5 SMA14/SIBS ratio) imaged after immersion in release media for about 24 h.



with 25% by weight PTx added to the formulation.After �24 h of elution in the release medium, thephase attributed to the SMA14 remained visible inthe SIBS matrix. Voids resulting from PTx elutionwere visible in the SMA14 phase of the blend asshown in the topography images in Figure 2(e,f),suggesting that PTx forms a co-continuous phasewith SMA14. It is hypothesized that the increasedaffinity of PTx for the SMA14 phase in the blendsmay be attributed to the increased polarity in theSMA14 phase. It is important to note that the addi-tion of PTx to the copolymer blends resulted in theformation of a fourth phase which was immisciblewith both copolymer phases. This finding is alsosupported by the DSC results described in the nextsection.

DSC

To examine the thermodynamic interactions ofPTx with each polymer phase, films of SIBS/SMAwith various levels of PTx were subjected to DSCanalysis. It was previously reported that DSC studieson SIBS/PTx blends with 0, 10, and 25 wt % PTxindicated that the Tg of each of the copolymer blocksremained unchanged as the amount of PTx in theblend was increased.9 This suggests that PTx is notmiscible in either the PS or PIB phase of the copoly-mer and agrees with the AFM observations of dis-tinct separate PS, PIB, and PTx phases.

Figure 4 shows the DSC curves for blends pre-pared with a constant SMA14/SIBS ratio of 1:6.5 inwhich the PTx amount was increased from 0 to 25wt %, in 5% increments. DSC data for 25% PTx inSIBS are also included for comparison. The SIBS/

PTx data show that three distinct Tgs are evidentwhich can be attributed to isobutylene (2678C), sty-rene (1028C), and Ptx (1518C) domains.9 In theSMA14/SIBS blends, the Tg for each block of SIBSwas detected and found to remain constant as thelevel of PTx in the blend increased. The Tg ofSMA14 can be identified from the formulation with0% PTx at 1338C. The Tg of the SMA phase did notsignificantly change as the amount of PTx in thesample increased. These findings confirm that theSMA is indeed a separate phase from the SIBS, asindicated by AFM. Further, although the PTxappeared to be associated with the SMA domains inthe blends in the AFM images, there is no evidencefrom DSC that it is miscible with the SMA, so theinteraction must be relatively weak. The PTx Tg isnot seen in these samples. The reason is not known,although it is possible that structure of PTx particlesis affected by the copolymer environment or theprocessing method used in these experiments.

PTx release

Figure 5 shows the in vitro cumulative PTx elutionprofile out to 13 days for coating formulations con-taining 25% PTx and 75% of a polymer blend con-sisting of varying ratios of SMA14 and SIBS. Formu-lations containing 25% PTx/75% SIBS typicallyresulted in a small burst of 5–10% of the loaded PTx,followed by a period of low sustained PTx release.Modifying the polymer composition by addingSMA14 resulted in little change to the initial burstrelease. However, after the initial burst, the sus-tained rate of PTx release was greater for SIBS/SMA14 blends than for the corresponding formula-tion with SIBS only. The sustained release rate ofPTx, after the initial burst period, increased as theamount of SMA14 in the blend was increased. Coat-ings prepared with SMA14/SIBS in a 1:1.5 ratio and25% PTx resulted in the release of up to 45% of thePTx over the 13 day in vitro test compared to less

Figure 4. DSC Thermograms SMA14:SIBS films contain-ing 0, 5, 10, 15, 20, and 25% Ptx. SMA14/SIBS ratio washeld constant at 1:1.5.

Figure 5. Release profile generated from coronary stentscoated with 25% PTx/75% polymer. Polymer componentcontains SIBS or a blend of SMA14/SIBS.

528 RICHARD ET AL.


than 5% released for compositions containing 25%PTx/75% SIBS.

One formulation was selected for evaluation of thePTx release over 90 days of testing. Figure 6 showsthe release of PTx from 25% PTx/30% SMA14/45%SIBS (1:1.5 SMA14/SIBS ratio) over 90 days withdata points generated weekly. The initial release ofPTx is rapid, and slightly lower than the releasefrom stents coated with the same formulation shownin Figure 5. The release rate of PTx slows slightlyafter the initial 14 days for testing. However, PTxcontinues to release from the stent coating for theduration of testing reaching a maximum of about65% in 90 days. The plot indicates that the release ofPTx would continue if testing was not terminated.

The in vitro elution profile for coating formulationsin which the loading of PTx was increased from 10to 34% although maintaining a constant 1:6.5SMA14/SIBS ratio are depicted in Figure 7. It wasfound that the amount and rate of PTx eluting from

the coating during the initial (<3 day) portion of thein vitro test increased with PTx loading. It is likelythat the greater initial release is due to higher avail-ability of PTx at or near the surface. The sustained(>4 day) rate of PTx release is relatively low for the10% PTx coating. However, the PTx release ratesfrom coatings with 20–34% PTx are similar andgreater than the rate of release from 10% PTx formu-lations. Once the combined volume fraction of SMAand PTx reaches a threshold value, they form a co-continuous phase as observed using AFM. Abovethis threshold, drug release is controlled by diffusionthrough this co-continuous phase rather thanthrough SIBS. Therefore, increasing the loading ofPTx in the coating leads to increased dosing at earlytime points, but has minimal impact on long-termdaily dose.

Figure 6. Release of PTx generated from coronary stentscoated with 25% PTx/30% SMA14/45% SIBS after 90 daysof in vitro testing.

Figure 7. Release of PTx generated from coronary stentscoated with PTx/SMA14/SIBS; PTx loading varied at aconstant polymer ratio of 1:6.5 SMA14/SIBS.

Figure 8. Release profile generated from 25% PTx/75%polymer blend coronary stent coatings. Polymer componentcontains SIBS or a blend of SMA7 and SIBS.

Figure 9. Release of PTx from coronary stents coatedwith 25% PTx/75% polymer blend or copolymer. Polymercomponent contains 75% SIBS or a blend of either SMA14,SMA7, or PS with SIBS.



An SMA7 copolymer was evaluated to determinehow the level of MA in SMA affected PTx release.The release curves generated from stents coated with25% PTx and 75% of a polymer blend consisting ofvarying ratios of SMA7 and SIBS are shown in Fig-ure 8. It was found that the release rate increased asthe amount of SMA7 in the formulation increased;however, the release curves show constant release ofPTx for �3 days, followed by a gradual decrease toa slightly lower constant release rate.

Data comparing the release of PTx from stentscoated with 25% PTx blended in a 1:2.75 ratio of ei-ther SMA14, SMA7, or a PS homopolymer with SIBSare shown in Figure 9. In general, the overall releaseof PTx in 14 days increased as the amount of MA inthe SMA copolymer increased from 0 to 14%. Therelease of PTx appeared to be independent of thelevel of MA in the copolymer for the first few daysof testing. After the initial constant release, the PSand SMA7 release curves gradually changed to aslower rate of PTx release. It was also found that theSMA14 showed almost zero order PTx release underthese conditions. The time of the initial constant PTxrelease increased as the amount of MA in the styrenecopolymer increased. Similar trends were found for

formulations with ratios of 1:6.5 and 1:1.5 of PS,SMA7, or SMA14 with SIBS.

In vivo animal studies

The SIBS copolymer has been proven to be bio-compatible in a pre-clinical model.9 It also has anexcellent track record in clinical use.1–7 Stents coatedwith SIBS and SMA14/SIBS (1:1.5 ratio by weight)were evaluated in a porcine animal model and com-pared to the same stents with no polymer coating todetermine if the addition of SMA would influencethe biocompatibility. Figure 10 shows representative90-day pre-euthanasia angiographic images of aSMA14/SIBS-coated stent compared to each of thecontrol stents. As seen in the images, all vesselsimplanted with SMA14/SIBS and control stents werefound to be patent 90 days after implantation.

Figure 11 shows the histological cross sections ofrepresentative SIBS, SMA14/SIBS and control stentswith no coating. Histological examination showedno statistically significant differences in the arterialresponse to SMA14/SIBS-coated stents relative toSIBS or bare metal, as determined using a recentlypublished scoring technique.26 In addition, morpho-

Figure 10. Angiographic images of porcine coronary arteries taken immediately prior to animal euthanasia. (a) No coat-ing, (b) SIBS, (c) 40% SMA14/60% SIBS (1:1.5 ratio).

Figure 11. Histological cross sections of the 40% SMA14/60% SIBS (1:1.5 ratio), SIBS coated and the bare metal stentsexplanted after 90 days of implanting in porcine coronary arteries.

530 RICHARD ET AL.


logical evaluations did not reveal any statistically sig-nificant differences between test and control groups.

Scanning electron microscopy of SMA14/SIBS andSIBS-only-coated stents at 30 and 90 days post im-plantation revealed complete endothelialization withlack of thrombus on the stent flow surface, as shownin Figure 12. These images are representative of theremainder of the samples. Endothelial cells are iden-tified by their shape, but no tests were run to deter-mine EC function and barrier properties. The cellsdo appear to be confluent. Myocardial evaluationdid not reveal any infarctions or abnormalities in ei-ther the 30 or 90 day groups. These in vivo resultsindicate that the addition of SMA14 to SIBS does notaffect biocompatibility for the formulation tested.

CONCLUSION

Stent coatings prepared by blending SMA into aformulation containing SIBS and PTx yielded smooth

conformal coatings which maintained their integrityafter expansion as observed using SEM. Examinationof the stent surface coated with SMA/SIBS/PTx sys-tems using AFM showed the 2-phase morphology ofSIBS with an additional inter-dispersed SMA phase.Voids remaining in the SMA component of themulti-phase blend after incubation in release me-dium suggest that the PTx preferentially resided andelutes from the SMA phase of the coating surface.DSC evaluation of the SIBS and SMA blends did notidentify significant miscibility between PTx and anycomponent of the blend. The lack of miscibilitybetween SMA14 and PTx agrees with AFM observa-tions of distinct phases corresponding to PS, PIB,SMA14 and PTx.

Blending SMA with SIBS produced coatings withrelease profiles tunable by varying the formulationand relative levels of PTx, SMA, and SIBS. However,modulation of PTx release by varying the composi-tion cannot be attributed to miscibility between thedrug and polymers. These results suggest that the

Figure 12. SEM images of lengthwise sectioned 40% SMA14/60% SIBS (1:1.5 ratio), SIBS coated and the bare metal stentsexplanted after 90 days of implanting in porcine coronary arteries.



mechanism of enhanced PTx release is primarily dueto the diffusion of the PTx from the co-continuousSMA/PTx phase of the blends.

The vascular response of SMA/SIBS and SIBScoated stents implanted in porcine coronary arterieswas comparable to bare stainless steel stents basedon the histological and SEM evaluation. The stentcoatings were found to be comparable at both 30and 90 day time points. Together these data supportthe safety and vascular compatibility of SMA/SIBS-polymer-coated stents in non-injured coronaryarteries of common swine.

References

1. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C,Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, PopmaJJ, Russell ME. TAXUS-IV investigators. A polymer-based,paclitaxel-eluting stent in patients with coronary artery dis-ease. N Engl J Med 2004;350:221–231.

2. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy, C,Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, PopmaJ. J, Russell ME. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: TheTAXUS-IV trial. Circulation 2004;109:1942–1947.

3. Tanabe K, Serruys PW, Grube E, Smits PC, Selbach G, vander Giessen WJ, Staberock M, de Feyter P, Muller R, Regar E,Degertekin M, Ligthart JMR, Disco C, Backx B, Russell ME.TAXUS III Trial: In-stent restenosis treated with stent-baseddelivery of paclitaxel incorporated in a slow-release polymerformulation. Circulation 2003;107:559–564.

4. Colombo A, Drzewiecki J, Banning A, Grube E, HauptmannK, Silber S, Dudek D, Fort S, Schiele F, Zmudka K, GuagliumiG, Russell ME. Randomized study to assess the effectivenessof slow and moderate release polymer-based paclitaxel-elut-ing stents for coronary artery lesions. Circulation 2003;108:788–794.

5. Grube E, Silber S, Hauptmann KE, Mueller R, Buellesfeld L,Gerckens U, Russell ME. TAXUS I: Six and twelve-monthresults from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions.Circulation 2003;107:38–42.

6. Sousa JE, Serruys PW, Costa MA. New frontiers in cardiol-ogy: Drug-eluting stents. I. Circulation 2003;107:2274–2279.

7. Sousa JE, Serruys PW, Costa MA. New frontiers in cardiol-ogy: Drug-eluting stents. II. Circulation 2003;107:2383–2389.

8. Richard RE, Barry JJ, Kamath K, Miller KL, Ranade SV,Schwarz MC. Controlled release of paclitaxel from a vascularcompatible polymer matrix—The TAXUSTM Express2 pacli-taxel-eluting coronary stent. 31st Annual Meeting of the Con-trolled Release Society, Honolulu, Hawaii, USA, June 12–16,2004.

9. Ranade SV, Miller KM, Richard RE, Chan AK, Allen MJ, Hel-mus MN. Physical characterization of controlled release ofpaclitaxel from the TAXUSTM Express2TM drug eluting stent.J Biomed Mater Res 2004;71A:625.

10. Richard RE, Schwarz MC, Ranade SV, Chan AK, Matyjaszew-ski K, Summerlin BS. Evaluation of acrylate-based blockcopolymers prepared by atom transfer radical polymerization

as matrices for paclitaxel delivery from coronary stents. Bio-macromolecules 2005;6:3410.

11. Cho J, Faust R, Richard R, Boden M, Schwarz M, Ranade S,Chan K. Synthesis, characterization and drug release pro-perties of poly(e-caprolactone-b-isobutylene-b-e-caprolactone).PMSE Prepr 2005;92:664.

12. Laszlo S, Som A, Faust R, Richard RE, Schwarz MC, RanadeSV, Boden M, Chan K. Controlled delivery of paclitaxel fromstent coatings using poly(hydroxystyrene-b-isobutylene-b-hydroxystyrene) and its acetylated derivatives. Biomacromo-lecules 2005;6:2570.

13. Andrews RJ, Grulke EA. Glass transition temperature ofpolymers. In: Brandrup J, Immergut EH, Grulke EA, editors.Polymer Handbook, 4th ed. New York: Wiley; 1999. p 198.

14. Jenquin MR, McGinity JW. Characterization of acrylic resinmatrix films and mechanisms of drug-polymer interactions.Int J Pharm 1994;101:23–34.

15. Li J, Masso JJ, Guertin JA. Prediction of drug solubility in anacrylate adhesive based on the drug–polymer interactionparameter and drug solubility in acetonitrile. J ControlledRelease 2002;83:211–221.

16. Nair R, Nyamweya N, Gonen S, Martinez-Miranda LJ, HoagSW. Influence of various drugs on the glass transition tem-perature of poly(vinylpyrrolidone): A thermodynamic andspectroscopic investigation. Int J Pharm 2001;225:83–96.

17. Puttipipatkhachorn S, Nunthanid J, Yamamoto K, Peck GE.Drug physical state and drug-polymer interaction on drugrelease from chitosan matrix films. J Controlled Release2001;75:143–153.

18. Schwarz MC, Ranade SV, Richard RE. Controlled delivery ofpaclitaxel from stent coatings containing styrene maleic anhy-dride polymer blends. 31st Annual Meeting of the ControlledRelease Society, Honolulu, Hawaii, USA, June 12–16, 2004.

19. Sethi N, Srivastava RK, Singh RK, Nath D. Long-Term toxic-ity studies of styrene maleic anhydride in rats. Biomed Envi-ron Sci 1990;3:452–457.

20. Sethi N, Srivastava RK, Singh RK, Bhatia GS, Sinha N.Chronic toxicity of styrene maleic anhydride, a male contra-ceptive, in rhesus monkeys (Macaca mulatta). Contraception1990;42:337–347.

21. Maeda H, Tomohiro S, Toshimitsu K. Mechanism of tumor-targeted delivery of macromolecular drugs, including theEPR effect in solid tumor and clinical overview of the proto-type polymeric drug SMANCS. J Controlled Release 2001;74:47–61.

22. Maeda H. SMANCS and polymer-conjugated macromoleculardrugs: Advantages in cancer chemotherapy. Adv Drug Rev2001;46:169–185.

23. Fodor Z, Gyor M, Wang HC, Faust R. Living carbocationicpolymerization of styrene in the presence of proton rap. JMSPure Appl Chem 1993;A30:349–363.

24. Gyor M, Fodor Z, Wang HC, Faust R. Polyisobutylene basedthermoplastic elastomers. I. Synthesis and characterization ofPS-B-PIB-B-PS triblock copolymers. JMS Pure Appl Chem 1994;A31:2055–2065.

25. Kaskas G, Puskas J, Kennedy JP, Hager WG. Polyisobutylene-containing block polymers by sequential monomer addition.II. Polystyrene–polyisobutylene–polystyrene triblock polymers:Synthesis, characterization, and physical properties. J Polym SciPolymChem. Ed 1991;29:427–435.

26. Wilson GJ, Polovick JE, Huibregtse BA, Poff BC. Overlappingpaclitaxel-eluting stents: Long-term effects in a porcine coro-nary artery model. Cardiovascular Res 2007;76:361–372.

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