Stereocomplexes of Enantiomeric Lactic Acid and Sebacic Acid Ester

Biomacromolecules 2002, 3, 754-760

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Stereocomplexes of Enantiomeric Lactic Acid and Sebacic Acid Ester-Anhydride Triblock Copolymers Raia Slivniak and Abraham J. Domb* Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel Received January 28, 2002; Revised Manuscript Received May 2, 2002

A systematic study on the synthesis, characterization, degradation, and drug release of d-, l-, and dl-poly(lactic acid) (PLA)-terminated poly(sebacic acid) (PSA) and their stereocomplexes is reported. PLA-terminated sebacic acid polymers were synthesized by melt condensation of the acetate anhydride derivatives of PLA oligomers and sebacic anhydride oligomers to yield ABA triblock copolymers of molecular weights between 3000 and 9000 that melt at temperatures between 35 and 80 °C. Pairs of the corresponding enantiomeric ABA copolymers composed of l-PLA-PSA-l-PLA and d-PLA-PSA-d-PLA were solvent mixed to form stereocomplexes. The formed stereocomplexes exhibited higher crystalline melting temperature than the enantiomeric polymers, which indicate stereocomplex formulation. The PLA terminals had a significant effect on the polymer degradation and drug release rate. PSA with up to 20% w/w of PLA terminals degraded and released the incorporated drug for more than 3 weeks as compared with 10 days for PSA homopolymer. Introduction The delivery of drugs from polyanhydrides has been extensively studied.1,2 Polyanhydrides are useful bioabsorbable materials for controlled drug release. They hydrolyze to dicarboxylic acid monomers when placed in aqueous medium. It has been reported that drug release and degradation of polyanhydrides can be altered by using various composites of hydrophobic and hydrophilic monomers.3 d-, l-, and dl-poly(lactic acid) are good candidates for the preparation of biodegradable copolymers with polyanhydrides. Biodegradable polymer blends of polyanhydrides and polyesters have been investigated as drug carriers. In general, polyanhydrides of different structures form uniform blends with a single melting temperature.4-6 Low molecular weight poly(lactic acid) (PLA), poly(hydroxybutyrate) (PHB), and poly(caprolactone) (PCL) are miscible with polyanhydrides, while high molecular weight polyesters (MW > 10 000) are not miscible with polyanhydrides. Thus, copolymerization may form a uniform polymer. It was discovered in recent years that d and l enantiomers of lactic acid form stable stereocomplexes, with physical and chemical properties different from the original polymers.7-12 Stereocomplexes were formed from the interaction between chemically identical polymers with different chiral configurations, forming a physical complex with altered physical properties compared to the parent compounds. Syndiotactic and isotactic poly(methyl methacrylate) were the first reported pair of polymers to form a stereocomplex, * Corresponding author. Tel: 972-2-6757573. Fax: 972-2-6758959. E-mail: [email protected]. Affiliated with the David. R. Bloom Center for Pharmacy at the Hebrew University and the Alex Grass Center for Drug Design and Synthesis, The Hebrew University of Jerusalem.

in acetone or tetrahydrofuran (THF).13 Lacking possibilities for electrostatic interactions or hydrogen bridge formation, the main force favoring the complexation was thought to come forth from stereospecific van der Waals interactions.14 Examples of stereocomplexes consisting of opposite isotactic polymers are (R)- and (S)-poly(γ-benzylglutamate),15 poly(R-methyl-R-ethyl-β-propiolactone),16 poly(tert-butylethylene oxide and sulfide),17 poly(2,3-dimethyltartaric acid),18 Rmethylbenzyl methacrylate,19 and poly(lactic acid).7-9,20 The discovery of the stereocomplex formation between d- and l-poly(lactic acid) (d- and l-PLA) is significant as these polymers are widely used in various medical applications.21 Stereocomplexes are also formed upon mixing di- and triblock copolymers, if the stereoregular lactic acid sequences are of sufficient length.22-23 Copolymerization of PLA blocks with another clinically approved compounds can provide additional modifications that might be used effectively in medicine. For example, hydrogels were prepared by stereocomplexation of watersoluble triblock copolymers of PEO and l- or d-lactide solutions in water.24 Water-soluble triblock copolymers containing polylactide (PLA) blocks can be prepared by initiating lactide polymerizations with appropriate poly(ethylene glycol) (PEG).25 We hypothesized that block copolymerization of enantiomeric PLA oligomers with a polyanhydride may result in low melting biodegradable polyanhydrides that form stereocomplexes with different drug release and degradation properties. These new polyanhydrides can control the release of drugs and polymer degradation by changing the percent of stereocomplexed PLA in the copolymer. These stereocomplex compositions are expected to form microparticles upon complex formation.

10.1021/bm0200128 CCC: $22.00 © 2002 American Chemical Society Published on Web 06/08/2002

Stereocomplexes of Enantiomeric Triblock Copolymers

We report here on a systematic study on the synthesis, characterization, degradation, and drug release of PLAterminated PSA polyanhidrides and their stereocomplexes. Experimental Section Materials. Sebacic acid (SA) was purchased from Aldrich (Milwaukee, WI), d-Lactide was purchased from Purac Biochem (Gorinchem, Netherlands); l-lactic acid (l-LA) and dl-lactic acid (dl-LA) were purchased from J. T. Baker (Deventer, Netherlands). Reagent lactate was purchased from Sigma (St. Louis, MO). D-Lactic acid was prepared from the hydrolysis of d-lactide in water. All solvents and salts were analytical grade from Aldrich or Frutarom (Haifa, Israel). Triamcinalone was a gift from Taro Ind. (Haifa). Instrumentation. Infrared (IR) spectroscopy (PerkinElmer System 2000 FT-IR) was performed on monomer, prepolymer, and polymer samples cast on NaCl plates from chloroform solutions. Ultraviolet spectroscopy was performed using a Kontron Instruments Uvicon model 930 (Msscientific, Berlin, Germany). Thermal analysis was determined on a Mettler TA 4000-DSC differential scanning calorimeter (Mettler-Toledo, Schwerzzenbach, Schweiz), calibrated with Zn and In standards, at a heating rate of 10 °C/min under nitrogen atmosphere. Average sample weight was 5-20 mg. Melting temperatures of the polyanhydrides were determined by a Fisher Scientific melting point apparatus (USA). Molecular weights of the polyanhydrides was estimated on a gel permeation chromatography (GPC) system consisting of a Spectra Physics (Darmstadt, Germany) P 1000 pump with refractive index (RI) (Waters, MA) detection, a Rheodyne (Coatati, CA) injection valve with a 20 µL loop, and a Spectra Physics Data Jet integrator. Samples were eluted with chloroform through a linear Styrogel column, 500-pore size (Waters, MA) at a flow rate of 1 mL/min. The molecular weights were determined relative to polystyrene standards (Polyscience, Warrington, PA) with a molecular weight range of 400-10000 using a WINner/286 computer program. 1H NMR and 13C NMR spectra (CDCl3) were obtained on a Varian 300 MHz spectrometer using TMS as internal standart (Varian Inc., Palo Alto, CA). Optical rotations of polymers were determined by an Optical Activity LTD polarimeter (Cambridgeshire, England) in 1 mg/mL polymer solution in chloroform. Scanning electron microscopy (SEM) was conducted using a Philips 505 scanning electron microscope (20 kV) after dried stereocomplex microparticles were fixed on a stub and gold coated using Polarone E5100. Prepolymer Synthesis. Sebacic acid prepolymer was prepared from the purified diacid monomer by refluxing in excess acetic anhydride for 30 min and evaporating the solvent to dryness. The hot clear viscous residue was dissolved in an equal volume of dichloromethane and precipitated in a mixture of ether/petroleum ether (1:1 v/v). The white precipitate was collected by filtration and dried in vacuo at room temperature. Low molecular weight d-PLA, l-PLA, and dl-PLA were prepared from the corresponding lyophilized lactic acids by condensation reaction at 150 °C. The hot light brown clear viscous residue was dissolved in an equal volume of chloroform and precipitated in a mixture

Biomacromolecules, Vol. 3, No. 4, 2002 755

of diisopropyl ether/petroleum ether (9:1 v/v). The white precipitate was collected by filtration and dried in vacuo at room temperature. The oligomers were characterized by GPC, 1H NMR, and IR analysis. The NMR for l-PLA: 1H NMR (CDCl3/TMS, δ) 1.5 (CH3 due to the hydroxyl terminal of the 2-hydroxypropionate unit), 1.6 (CH3 for the l-lactate unit), 4.4 (CH due to the hydroxyl terminal of the 2-hydroxypropionate unit), 5.2 (CH for the l-lactate unit). From the integral ratio of the methyne signal at δ ) 4.4 ppm relative to that at δ ) 5.2 ppm, the degree of polymerization was found to be 30, and the number average molecular weight was about 2200 g/mol, supported by GPC. Acetyl-terminated and symmetric poly(lactic acid) anhydrides were prepared by refluxing a solution of low molecular weight PLA in excess acetic anhydride for 30 min and evaporating the solvent to dryness. Polymer Synthesis. PLA-PSA triblock copolymers were prepared by melt condensation of acetate anhydride PLA and PSA oligomers at 150 °C under a vacuum of 0.3 mmHg for 1 h. Both prepolymers were placed in a 50-mL round-bottom flask equipped with a magnetic stirrer and a vacuum-line port. The activated oligomers were melt before connecting the system to a vacuum line. The polymerization was followed by GPC analysis of samples withdrawn during polymerization. Stereocomplex Preparation. Stereocomplexes were prepared by mixing the solutions of the enantiomers and evaporating the solvent to form the complexes. In a typical experiment, l-PLA-PSA 70:30 (120 mg) having a number average molecular weight of 4800 and d-PLA-PSA 70:30 (120 mg) having a number average molecular weight of 5300 were dissolved separately in dichloromethane (0.5 mL). The solutions were mixed and poured onto a glass Petri dish to allow solvent evaporation. A fine white powder of the stereocomplex was obtained. When a drug was added, triamcinalone solution (13 mg in 0.2 mL of ethanol/ dichloromethane 1:1 mixture) was added to the polymer solution and mixed well until a clear solution was obtained. In Vitro Hydrolytic Degradation of Polymers. The hydrolysis of the polymers was evaluated by placing rectangular samples of polymer (prepared by melt cast) (3 × 5 × 5 mm, 100 mg) in 10 mL of 0.1 M phosphate buffer, pH 7.4, at 37 °C with continuous shaking (100 rpm). At each time point, a polymer sample was taken out of the buffer and dried in vacuo at room temperature overnight. The hydrolysis of the polymer was monitored by (a) weight loss of the sample, (b) disappearance of the anhydride bonds by IR spectroscopy, (c) changes in polymer molecular weight as determined by GPC, and (d) lactic acid release by reagent lactate. This reagent acts as follows: Lactic acid is converted to pyruvate and hydrogen peroxide (H2O2) by lactate oxidase. In the presence of the H2O2 formed, peroxidase catalyzes the oxidative condensation of chromogen precursors to produce a colored dye with an absorption maximum at 540 nm. The increase in absorbance at 540 nm is proportional to lactate concentration in the sample.26,27 The hydrolysis of the stereocomplexes was evaluated similarly using 7 mm diameter tablets prepared by compres-

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Slivniak and Domb

Scheme 1. Synthesis of PLA-PSA Copolymers

Figure 1. Determination of the anhydride and ester bond ratio of PLA-PSA copolymers using FT-IR. Polymer samples cast on NaCl plates from chloroform solutions. Relative amount of ester and anhydride bonds in original copolymers according to relative absorbance at 1748 cm-1 and at 1810 cm-1: ([) % ester bonds; (9) % anhydride bonds, respectively.

sion of stereocomplex powder prepared by solvent evaporation method. All experiments were carried out in triplicates. In Vitro Drug Release. Triamcinalone (5 wt %) was incorporated in the polymer by mixing the drug in the polymer melt and then casting the homogeneous melt into cubic shapes (3 × 3 × 3 mm, 50 mg). In the case of stereocomplexes, 5% triamcinalone was loaded into stereocomplex microparticles of a uniform particle size of 5-7 µm, by the solvent evaporation method. Drug release studies were conducted by placing each polymer or stereocomplex sample (50 mg) in 50 mL of phosphate buffer (0.1 M, pH 7.4) at 37 °C with continuous shaking (100 rpm). At each time point, the solution was replaced with a fresh buffer and kept for drug analysis. Triamcinalone concentration in the solution was determined by UV detection at 238 nm. All experiments were done in triplicate. Results and Discussion Polymer Synthesis. Enantiomeric PLA-PSA-PLA triblock copolymers of different block length and PLA to PSA weight ratio were synthesized by melt condensation of the corresponding acetate anhydride oligomers to yield off-white materials (Scheme 1). The polymers were soluble in dichloromethane or chloroform and insoluble in acetone or acetonitrile. It should be noted that PLA alone has good solubility both in acetone and in chloroform, while PSA dissolves properly only in chloroform or dichloromethane. The solubility of the reaction products only in chloroform and dichloromethane indicates a uniform product where PLA is incorporated within PSA. Physical mixtures of PSA and PLA are partially soluble in acetone. All polymers possess typical IR absorption at 1748 and 1810 cm-1 corresponding to symmetrical and asymmetrical

Figure 2. Molecular weight of PLA-PSA copolymers: (2) l-PLAPSA; (0) d-PLA-PSA; ([) dl-PLA-PSA. Molecular weight was determined by GPC.

anhydride carbonyl stretching bands, where the absorption at 1748 cm-1 corresponds also to the ester carbonyl stretching bands. The 1H NMR spectra of the polymers fit their composition. For example, the NMR for l-PLA-PSA 60:40 is as follows: 1H NMR (CDCl3/TMS,δ) 1.5 (CH3 due to the hydroxyl terminal of the 2-hydroxypropionate unit), 1.6 (CH3 for the l-lactate unit), 4.4 (CH due to the hydroxyl terminal of the 2-hydroxypropionate unit), 5.2 (CH for the l-lactate unit) for PLA terminals, and 1.32 for (4H) -COOCO-CH2CH2-, 2.3-2.5 for (2H) -COOCO-CH2-CH2- for sebacic acid. The integration of the peaks fit the polymer composition. The quantitative relation between PLA and PSA in the copolymer was reflected in the IR spectra (Figure 1). As can be seen, as the PLA content in the copolymer increases, so does the absorbance at 1748 cm-1, while the absorbance at 1810 cm-1 is decreasing. There is a good linear fit between PLA content and percent of ester or anhydride bonds in the copolymer, respectively. The molecular weight and melting temperatures of PLAPSA-PLA triblock copolymers as a function of PLA content in the polymer in the range between 10% and 90 wt % of poly(lactic acid) are given in Figures 2 and 3, respectively. Polymers with molecular weights in the range of 30009000 were obtained (Figure 2). The molecular weights of



Figure 5. Scanning electron micrographs of microparticles prepared by stereocomplexation.

Figure 3. Melting temperatures of PLA-PSA copolymers as determined by Fisher visual melting point apparatus: (4) l-PLA-PSA; (9) dl-PLA-PSA; ([) d-PLA-PSA.

Figure 6. DSC thermogram (10 °C/min) of l- and d-PLA-PSA stereocomplex (lower thermogram) (6:4 PLA to PSA) (1:1 l-PLAPSA to d-PLA-PSA) and the original (upper thermogram) l-PLAPSA copolymer.

Figure 4. Optical rotation of PLA-PSA copolymers: (4) l-PLA-PSA; (9) d-PLA-PSA; (b) dl-PLA-PSA, determined in 1 mg/mL chloroform solution.

the polymers with poly(lactic acid) decreased with the increase in the content of the PLA blocks that act as chain terminator. As shown in previous studies, sebacic acid is responsible for the growth of the molecular weight during the polymerization, and polymerization is limited by the PLA:PSA ratio. Under the reaction conditions, the PLA blocks did not change in length, and the polymerization affected only the poly(sebacic acid) anhydride blocks. All triblock copolymers completely liquefy at temperatures between 35 and 80 °C, which make them suitable for drug incorporation by the melt molding process. From about 50% w/w of poly(lactic acid) terminals, the triblock melting range was influenced by the lactic acid blocks (Figure 3). The highest melting temperature, 80 °C, was obtained for copolymers with 50% w/w of enantiomeric blocks whereas racemic copolymers with 50% w/w of poly(dl-lactic acid) blocks melted at a significantly lower temperature. Above 50% w/w PLA content the melting temperature reduced significantly to as low as 35 °C. The optical rotation of the copolymers is given in Figure 4. It can be seen that the copolymerization process did not affect the optical purity of the d- and l-PLA enantiomer blocks. Linear dependence between the quantity of chiral PLA in the copolymer and its optical rotation was observed

for both d and l enantiomers, which fit the calculated rotation degree. Stereocomplex Formation and Characterization. Stereocomplexes were prepared by the solvent evaporation technique. The stereocomplexes had different physical properties with respect to solubility, film-forming properties, and melting temperature. The stereocomplexes are powdery crystalline materials formed spontaneously upon mixing in melt or solution and do not form films. Scanning electron micrographs of the powders are shown in Figure 5. Uniform porous spherical particles were formed with a uniform particle size of 5-7 µm. All stereocomplexes were insoluble in common organic solvents where the individual enantiomeric copolymers are highly soluble in chloroform, dichloromethane, tetrahydrofuran, dioxane, dimethylformamide, and dimethyl sulfoxide. Stereocomplex formation was determined by differential scanning calorimetry (DSC). Stereocomplexes possess a melting temperature that is significantly higher than the melting temperature of the corresponding enantiomers. As shown in Figure 6, the stereocomplex segments melt at temperatures between 180 and 200 °C, which is about 50 °C above the melting temperature of the corresponding enantiomers. In Vitro Hydrolysis of Copolymers and Stereocomplexes. The hydrolysis of the PLA-terminated triblock copolymers and their stereocomplexes was studied in vitro under physiological conditions (phosphate buffer pH 7.4 at 37 °C) following the weight loss, hydrolysis of anhydride

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Figure 7. Hydrolysis of PLA-PSA stereocomplexes monitored by weight loss. Hydrolysis was conducted in phosphate buffer pH 7.4 at 37 °C: (9) [l-PLA-PSA 20:80 + d-PLA-PSA 20:80] 1:1 stereocomplex; (2) [l-PLA-PSA 40:60 + d-PLA-PSA 40:60] 1:1 stereocomplex; (b) [l-PLA-PSA 60:40 + d-PLA-PSA 60:40]1:1 stereocomplex; (/) [l-PLA-PSA 80:20 + d-PLA-PSA 80:20] 1:1 stereocomplex.

Figure 8. Hydrolysis of PLA-PSA copolymers and stereocomplexes monitored by anhydride bond degradation. Hydrolysis was conducted in phosphate buffer of pH 7.4 at 37 °C. Anhydride degradation was determined by IR from the peak size ratio: υ1810(anhydride)/υ1810 + υ1748(ester+anhydride) + υ1700(acid). ([) d-PLA-PSA 80:20; (9) d-PLAPSA 20:80; (2) [l-PLA-PSA 80:20 + d-PLA-PSA 80:20] 1:1 stereocomplex; (×) [l-PLA-PSA 20:80 + d-PLA-PSA 20:80] 1:1 stereocomplex.

bonds, lactic acid release, and change in polymer molecular weight during hydrolysis. Weight loss of PLA-PSA stereocomplexes with different PLA:PSA ratios are shown in Figure 7. Hydrolysis was conducted in 0.1M phosphate buffer pH 7.4 at 37 °C. As shown in Figure 7 the higher the PLA content in the stereocomplex the lower the rate of its weight loss. The weight loss during hydrolysis of (l-PLA-PSA 20:80 + d-PLA-PSA 20:80) 1:1 stereocomplex and (l-PLA-PSA 80:20 + d-PLA-PSA 80:20) 1:1 stereocomplex is significantly different. As shown in Figure 7, (l-PLA-PSA 20:80 + d-PLA-PSA 20:80) 1:1 stereocomplex lost more than 60% of its weight in 8 days, whereas (l-PLA-PSA 80:20 + d-PLA-PSA 80:20) 1:1 stereocomplex loses less than 30% of its weight at the same time. The 20% and 40% PLA content complexes degraded nearly the same, but faster than the 60% content complexes. The slowest degradation rate was of 80% PLA content stereocomplex. The disappearance of the anhydride bonds as a function of time in the copolymers and stereocomplexes is shown in Figure 8. The anhydride peaks at 1748 and 1810 cm-1 diminished with time while the acid peak at 1700 intensified.

Slivniak and Domb

Figure 9. Ester and anhydride bond ratio after 8 days of degradation of PLA-PSA. Hydrolysis was conducted in phosphate buffer pH 7.4 at 37 °C, monitored by FT-IR. ([) relative amount of ester bonds; (9) relative amount of anhydride bonds.

Figure 10. Molecular weight decrease during hydrolytic degradation: ([) l-PLA-PSA 20:80; (9) d-PLA-PSA 20:80; (2) d-PLA-PSA 80:20. Mn was determined by GPC of the chloroform soluble fraction of the polymer. Hydrolysis was conducted in phosphate buffer pH 7.4 at 37 °C.

Copolymers and stereocomplexes rich with anhydride bonds (80% PSA) lost 50% of the anhydride bonds in 2 days. Copolymers and stereocomplexes poor with anhydride bonds (20% PSA) lost, at the same time, all the anhydride bonds. The amount of anhydride and ester bonds of the PLAPSA series, after 8 days of degradation is given in Figure 9. The 20% and 40% PLA content polymers still maintain 30% and 10% of anhydride bonds, respectively. Copolymers with more then 40% PLA content lost all their anhydride bonds in less than 8 days. These data indicate that the PLA component is more accessible to water absorption than the PSA component; thus increase in the PLA component enhances the degradation of the anhydride bonds. The number average molecular weight of the degraded samples was monitored by GPC (Figure 10). Only solid residue of degraded sample of each time point was monitored. The samples were extracted in chloroform and filtered before injection into GPC, so only the chloroform-soluble part of the copolymer molecular weight was determined. A sharp decrease in molecular weight was observed during the first 3 days, followed by a slow degradation phase which kept the number average molecular weight of the chloroform soluble part of the sample at ∼2800 and ∼4000 for the copolymers containing 20% and 80% PLA for over 50 days, respectively.



Figure 11. Lactic acid release from PLA-PSA copolymers during hydrolysis. Hydrolysis was conducted in phosphate buffer pH 7.4 at 37 °C. (b) l-PLA-PSA 80:20; (2) l-PLA-PSA 20:80; (9) [l-PLAPSA 80:20 + d-PLA-PSA 80:20] 1:1 stereocomplex; ([) [l-PLAPSA 20:80 + d-PLA-PSA 20:80] 1:1 stereocomplex. Figure 13. In vitro release of triamcinalone from stereocomplex microparticles prepared by two different formulations. Triamcinalone release was conducted in phosphate buffer pH 7.4 at 37 °C. (1) Stereocomplex microparticles prepared by evaporation of solutions of the polymers in dichloromethane, particle size of 5-7 µm. ([) [d-PLA-PSA 50:50 + l-PLA-PSA 50:50] 1:1; (]) [d-PLA + l-PLAPSA 50:50] 30:70; (2) [d-PLA-PSA 60:40 + l-PLA-PSA 60:40] 1:1; (4) [d-PLA-PSA + l-PLA-PSA 60:40] 30:70; (b) [d-PLA-PSA 70: 30 + l-PLA-PSA 70:30] 1:1; (O) [d-PLA + l-PLA-PSA 70:30] 30: 70; (9) [d-PLA-PSA 80:20 + l-PLA-PSA 80:20] 1:1; (0) [d-PLA + l-PLA-PSA 80:20] 30:70; (×) [d-PLA + l-PLA 30:70] 1:1; (×) [d-PLA + l-PLA 30:70] 30:70. (2) Stereocomplex microparticles (particle size of 5-7 µm) prepared from dichloromethane/ethanol solution 4:3 respectively: (9) [d-PLA-PSA 70:30 + l-PLA-PSA 70:30] 1:1; (2) [d-PLA + l-PLA] 1:1; (b) [d-PLA + l-PLA-PSA 70:30] 30:70. Figure 12. In vitro release of triamcinalone from PLA-PSA copolymers. Cubic shapes (3 × 3 × 3 mm, 50 mg) prepared by melt cast of polymer containing 5% w/w triamcinalone. Triamcinalone release was conducted in phosphate buffer pH 7.4 at 37 °C. (b) l-PLA-PSA 40:60; ([) l-PLA-PSA 20:80; (2) dl-PLA-PSA 20:80; (-) dl-PLAPSA 50:50.

Lactic acid release from copolymers was monitored by UV spectrophotometer after reaction with reagent lactate (Figure 11). There is no difference in the rate of lactic acid release from stereocomplexes and copolymers. Only ∼30% of total lactic acid was released as monomer-free l-lactic acid after 50 days; apparently there are PLA-soluble oligomers in the buffer solution that do not react with reagent lactate. In Vitro Drug Release from Polymers. The drug release characteristic from PLA-terminated copolymers and stereocomplexes were determined using triamcinalone as representative hydrophobic drug. Triamcinalone is a slightly water-soluble drug that is used to reduce the instance of inflammatory reactions. The in vitro release of triamcinalone from PLA-PSA 20:80 and 40:60 copolymers and stereocomplexes was studied. Incorporation of the drug into the polymer was by melt mixing for the enantiomeric block copolymers and by the solvent evaporation method for the stereocomplexes. The stereocomplexes formed microparticles with particle size of 5-7 µm. Triamcinalone was constantly released from the copolymers for about 2 weeks (Figure 12). Triamcinalone was released for 1 week from stereocomplex particles, depending on the formulation method. The slowest triamcinalone release was obtained for stereocomplex microparticles prepared from l-PLA-PSA copolymers with 30% d-PLA content, by dichloromethane evaporation.

Stereocomplex microparticles with incorporated drug was prepared by solvent evaporation (Figure 13). Although it is not proper to compare the drug release from devices prepared by melt, PLA-PSA block copolymers, and stereocomplex devices prepared by compression molding of powder because of the significant difference in surface area, the drug release profiles are quite similar (Figures 12 and 13). Both devices released the drug for about 1 week. Summary This report describes the synthesis of PLA-PSA-PLA block copolymers where enantiomeric d- and l-PLA, and racemic dl-PLA blocks were used. Unlike the enantiomeric PLA homopolymers, which melt at 180 °C, the block copolymers melt at temperatures between 35 and 80 °C depending on the PLA to PSA ratio. These block copolymers spontaneously formed stereocomplexes by solvent or melt mixing in a form of microspheres. When triamcinalone was mixed with the enantiomers during complex formation, the drug was entrapped and released for over 7 days when placed in buffer solution at 37 °C. These polymers have a potential use as drug carriers for sustained release applications. References and Notes (1) Domb, A. J.; Amselem, S.; Langer, R.; Maniar, M. In Biomedical Polymers; Shalaby, S., Ed.; Carl Hauser Verlag: Munchen, 1994; p 69. (2) Domb, A. J.; Elmalak, O.; Shastry, V. R.; Ta-Shma, Z.; Masters, D. M.; Ringel, I.; Teomim, D.; Langer, R. In Handbook of Biodegradable Polymers; Domb, A. J., Kost, J., Weiseman, D. M., Eds.; Hardwood Academic Publisher: Amsterdam, 1997; p 135.

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BM0200128

Stereocomplexes of Enantiomeric Lactic Acid and Sebacic Acid Ester

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