Stereoisomeric effect on in vitro drug release ... - Wiley Online Library

POLYMERS FOR ADVANCED TECHNOLOGIES Polym. Adv. Technol. 2008; 19: 671–679 Published online 2 May 2008 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/pat.1140

Stereoisomeric effect on in vitro drug release from injectable poly(lactic acid co castor oil) polyesters Marina Sokolsky-Papkov and Abraham J. Domb* y Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120 Jerusalem, Israel Received 4 March 2008; Accepted 4 March 2008

A systematic study on the influence of lactic acid (LA) conformation on polyester properties, degradation, and drug release profiles is reported. Copolyesters based on L- or DL-LA and castor oil (CO) (triglyceride of ricinoleic acid (RA)) were synthesized by melt condensation. Two feed ratios of LA to CO were used. Copolymers with feed ratio of 60:40 and 50:50 LA to CO were synthesized. P(LA/CO)s 60:40 and 50:50 had weight average molecular weights (Mw) of 4700 and 3700, respectively. All polymers are viscous liquids at room temperature. Copolymer composition and LA conformation had direct effect on polymer properties, degradation rate, and drug release profile. Increase in CO content (hydrophobisity) decreased the degradation and release rates of the polymers. Effect of sample size was also different for all polymers. Choosing polymer composition and LA conformation it is possible to choose desired release profile for the tested drug. Copyright # 2008 John Wiley & Sons, Ltd. KEYWORDS: structure–property relations; polyesters; drug delivery systems; degradation

INTRODUCTION Depot delivery systems can minimize side effects by achieving constant blood levels, especially important for drugs with ‘‘infusion-like’’ narrow therapeutic indices. Chronic drugs delivery by injectable biodegradable polymers can increase the efficacy of therapy and compliance of patients. The following drugs have been investigated in the study: Tamsulosin hydrochloride is a highly selective alpha 1A-adrenoreceptor antagonist that has been used for treatment of lower urinary-tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH). Biodegradable polymers (mainly polyesters and polyanhydrides) are useful materials for controlled drug delivery. They have a hydrophobic backbone with hydrolytically labile anhydride and/or ester bonds that may hydrolyze to dicarboxylic acid and hydroxy acid monomers when placed in an aqueous medium. Fatty acids are suitable candidates for the preparation of biodegradable polymers, as they are natural body components and are hydrophobic, and thus may retain an encapsulated drug for longer time periods when used as drug carriers.1 Mechanical and physical *Correspondence to: A. J. Domb, Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, 91120 Jerusalem, Israel E-mail: [email protected] y Leonyl Jacobson Chair of Medicinal Chemistry, affiliated with the Devid R. Bloom Center for Pharmacy and the Alex Grass Center for Synthesis and Drug Design at The Hebrew University of Jerusalem.

characteristics of these polymers can be manipulated by polymer composition. Previous studies in our laboratory resulted in the synthesis and characterization of polyanhydrides based on sebacic and ricinoleic acid (RA) for local delivery and controlled release of anti-cancer drugs, local prolonged analgesia, peptides, and proteins.2–4 However anhydrydride bonds are extremely sensitive to hydrolysis and therefore exposure to moisture should be avoided during polymer preparation and storage. Polyesters based on lactic and RA were previously synthesized and characterized in our laboratory.5,6 In this study polymers containing L-lactic acid (LA) and RA were synthesized by different methods and evaluated as drug delivery carriers. Stereochemistry plays an important role in determining the physicochemical properties of the polymer. The melting point of stereocomplexes of L-LA and D-LA is higher than the enantiomeric counterparts. These stereocomplexes also exhibit stronger mechanical properties.7,8 The effect of LA stereoconformation was investigated in regard to thermoreversible sol–gel transitions. The hydrogel prepared from poly(L-lactide)-poly(ethylene glycol)-poly(L-lactide) exhibited higher modulus than poly(DL-lactide)-poly(ethylene glycol)-poly(DL-lactide).9 The explanation suggested in this study is that crystallinity is causing the difference. However, poly(L-lactide) has isotactic methyl groups whereas the poly(DL-lactide) has atatic methyl groups.10 When the hydrophobic methyl groups are regularly oriented on the same side along the backbone of PEG/PLLA, the polymers are expected to have a higher tendency to aggregate in water than the PEG/PDLLA that has randomly oriented hydroCopyright # 2008 John Wiley & Sons, Ltd.

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phobic methyl groups along the polymer chain. Joo et al.11 showed that the difference in phase diagram and gel modulus between PEG/PDLLA and PEG/PLLA multiblock copolymer thermogelling system is not caused by the crystallinity of the PEG/PLLA multiblock copolymer. The isotactic attachment of the hydrophobic methyl groups gives the PEG/PLLA multiblock copolymer a strong tendency to aggregate in water due to the cooperative hydrophobic interactions.11 In this study we prepared two sets of polyesters from L-LA and racemic D,L-LA with castor oil (CO). CO is triglyceride of mainly RA (2.7 mol of RA per triglyceride). Each set of the polymers (6:4 and 5:5 feed ratio) possessed similar molecular weight and crystallinity parameters. The influence of LA conformation on polymer characteristics, degradation rates, and in vitro drug release profiles was investigated. Also, the influence of drug load and injected sample weight (size) was monitored.

MATERIALS CO European Pharmacopoeia (Eur Ph) was obtained from Florish (Haifa, Israel). L-LA and DL-LA were purchased from J. T. Baker (Deventer, The Netherlands). Tamsulosin hydrochloride was a gift from Panacea Biotech (India). CDCl3, for NMR, was purchased from Sigma-Aldrich (Rehovot, Israel). All solvents and salts were analytical grade from Aldrich or Biolab (Jerusalem, Israel).

INSTRUMENTATION IR spectra were performed on monomer and polymer samples cast on NaCl plates from dichloromethane solution on Bruker (Vector 22 System FT-IR). UV spectra were taken on 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, Switzerland), calibrated with Zn and In standards, at a heating rate of 108C/min under nitrogen atmosphere. Molecular weights of the co-polyesters were estimated on a gel permeation chromatography (GPC) system consisting of a Waters 1515 Isocratic HPLC Pump, with 2410 Refractive Index detector (RI) (Waters, MA), a Rheodyne (Coatati, CA) injection valve with a 20 ml loop. Samples were eluted with chloroform through a ˚ -pore size (Waters, MA) at a linear Styrogel column, 500 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 500–12,000 using BREEZE 3.20 version, copyright 2000 Waters corporation computer program. 1H NMR spectra

(in CDCl3) were recorded on a Varian 300 spectrometer using TMS as internal standard (Varian Inc., Palo Alto, CA). Optical rotations of polymers were determined by Optical Activity LTD polarimeter (Cambridgeshire, England) in 25 mg/ml polymer in CHCl3 solution. Viscosity of polymers was measured using a Brookfield LVDV-III programmable viscometer coupled to a temperature-controlling unit. Cylindrical spindle LV4 was used. Temperature sensitivity test was performed starting at a temperature of 558C and down to room temperature (258C) by applying constant rotational speed. Detection of rheological behavior was performed by measuring shear stress and/or viscosity at different shear rates, starting at 2.1 sec1 and up to 21 sec1 for 6:4 copolymer and all experiments were performed in triplicate.

SYNTHESIS OF POLY(LACTIC ACID CO CASTOR OIL) Poly (LA co CO) 60:40 designated as p(LA-CO) 6:4 and poly (LA co CO) 50:50 designated as p(LA-CO) 5:5 were prepared using enantiomeric (L) or racemic mixture (DL) LA. All polyesters were synthesized using one neck reaction vessel equipped with a mechanical stirrer on an oil heating bath. LA and CO in appropriate weight ratio were added into the vessel. The catalyst, H3PO4 0.5% w/w was added to the reaction mixture prior to polymerization. During esterification, the temperature was slowly increased up to 1808C and the mixture was stirred for 1.5 hr under constant N2 flow. The reaction vessel was connected to a pump and the reaction was continued under vacuum (15 mbar) for 24 hr. The resulting polymers were evaluated by GPC, IR, and NMR. No further purification steps were taken. P(LLA/CO)60:40; p(DLLA/CO) 6:4; p(LLA/CO) 50:50; and p(DLLA/CO) 50:50 were synthesized. The polymer structure is shown in Scheme 1. Drug loaded formulations were prepared by directly mixing the drug powder in the pasty polymers at room temperature. Tamsulosin hydrochloride (10 and 20% wt/wt) incorporated in pasty p(LA/CO)60:40 and p(LA/ CO)50:50 by trituration. The composition was mixed until a smooth paste was formed. The following formulations were prepared: (1) p(LLA/CO)6:4 containing tamsulosin (10%); (2) p(DLLA/CO)6:4 containing tamsulosin (10 and 20% wt/ wt); (3) p(LLA/CO)5:5 containing tamsulosin (5 and 20% wt/wt); (4) p(DLLA/CO)5:5 containing tamsulosin (5 and 20% wt/wt). All formulations were prepared and filled in syringes at room temperature without heating. The obtained formulations were liquid at room temperature, and are injectable via a 23G needle. In vitro drug release studies were conducted by injecting 60 or 170 mg of the pasty formulation sample in 15 or 45 ml phosphate buffer solution (0.1 M, pH

Scheme 1. Structure of poly(lactic acid co castor oil) synthesized by polycondensation. Copyright # 2008 John Wiley & Sons, Ltd.

Polym. Adv. Technol. 2008; 19: 671–679 DOI: 10.1002/pat

Copyright # 2008 John Wiley & Sons, Ltd.

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b

a

Castor oil/lactic acid wt/wt ratio as calculated from 1H NMR (by the integration ratio of the peaks at 5.15 ppm (one proton of PLA) and the peaks at 4.87 ppm one proton (C12) of PRA). Optical rotations of polymers determined by an Optical Activity Ltd. polarimeter in a 20 mg/ml polymer solution in CHCl3. c Molecular weight determined by gel permeation chromatography. d Viscosity of the copolymers measured using a Brookfield LVDV-III programmable viscometer coupled to a temperature-controlling unit at 298C.

4,300 2,000 14,500 6,600 Mn ¼ 2,600 Mw ¼ 3,670 Mn ¼ 2,800 Mw ¼ 3,800 37 þ9.25 62:38 56:42 12,700 5,500 72,200 37,300 Mn ¼ 3,300 Mw ¼ 4,800 Mn ¼ 3,250 Mw ¼ 4,650 57.3 þ11.25

Specificb optical rotation [R]20D Calculated lactica acid/castor oil ratio

Table 1. Summary of copolymers used in the study

Polymers were synthesized according to Scheme 1. The P(LA/CO)6:4 and 5:5 are summarized in Table 1. In our previous study, series of copolymers from LA and CO were prepared. To produce liquid injectable polymers, CO entre´e should be 40% or higher. P(LA/CO) 6:4 and 5:5 are viscous liquids at room temperature. Since the only possible structure for these polymers is poly(LA) blocks on CO chains (condensation of hydroxyl groups on CO with acid group of LA followed by condensation of LA), the molecular weights of the polymers are limited by LA entry. In the case of p(LA/ Co)6:4, it is possible to synthesize polymers with higher molecular weight (Table 1), but these polymers are too viscous and are not injectable at room temperature. To prepare injectable p(LA/CO) 6:4 polymers, the molecular weight should be closely monitored not to exceed the values shown in Table 1. Molecular weights of p(LA/CO) 5:5 are generally lower than those of p(LA/CO) 6:4. The LA conformation does not affect the possible molecular weight of the polymers. To evaluate the effect of LA conformation, polymers with narrow distribution of molecular weight were synthesized. The reaction was stopped before p(LA/CO)6:4 reached molecular weight which exceed injectability limits. P(LA/CO) 6:4 have molecular weights (Mw) of 4600–4800. P(LA/CO)s 5:5 possess molecular weights (Mw) in the range of 3600–3800. All polymers were analyzed by IR, 1H NMR, and DSC. All polymers possess typical IR absorption at 1748 cm1, which corresponds to the ester carbonyl stretching bands. There is no difference in IR spectrum of all four polymers (Scheme 2). 1H NMR spectra of the polymers fit their composition (Scheme 3(a) and (b) (6:4) and Scheme 4(a) and (b)(5:5)). (RA-ricinoleic acid, LA-lactic acid, GL-glycerol) 1 H NMR (CDCl3, P(LA-CO), d): 5.45–5.30 (2H, m, C9-10, –CH –– CH–, RA), 5.20–5.02 (1H, q, CH–CH3, LA), 4.94–4.86 (1H, m, C12 HC–O–, RA), 4.41–4.21(4H, m, CH, GL) 2.38–2.24 (2H, m, C2 –CH2, and 2H, m, C11 –CH2), 2.01 (2H, m, C8 –CH2), 1.68–1.50 (2H, m, C3 –CH2, 2H, m, C13 –CH2, and

60:40

Polyester synthesis and characterization

Lactic acid conformation

RESULTS AND DISCUSSION

Mn/Mwc

Viscosity at Calculated roomc Viscosity at lactica acid/ Specificb optical temperature (cP) 378Cd (cP) castor oil ratio rotation [R]20D

50:50

To study the polymer degradation, samples (80 mg) of p(LA/ CO)s 6:4 and p(LA/CO)s 5:5 were incubated in 20 ml buffer phosphate solution pH 7.4, 0.1 M at 378C, with orbital shaking (100 rpm). The buffer solution was replaced periodically with fresh buffer solution. At each time point, the polymer sample was taken out of the buffer and weighed wet and after lyophilization. The hydrolysis of the polymer was monitored by weight loss of the sample and changes in molecular weight. All experiments were done in duplicate.

Mn/Mwc

HYDROLYTIC DEGRADATION

55:45 52:48

7.4) at 378C with constant shaking (100 rpm). The pasty formulation hardens to soft solid shortly after addition to the buffer. The release medium was replaced periodically with fresh buffer solution and the drug concentration in the solution was determined by UV absorbtion at 269 nm. Blank polymers were used as control. All experiments were performed in triplicate.

L DL

Viscosity at roomc Viscosity at temperature (cP) 378Cd (cP)

Stereoisomeric effect on in vitro drug release


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Scheme 2. IR spectrum of p(LA/CO)s 6:4 and 5:5. 3H, d, –CH3, LA), 1.34–1.25 (16H, m, C4-7, and C14-17), and 0.868 (3H, t, C18 –CH3) ppm. Copolymer composition was verified and calculated from 1 H NMR by the integration ratio of the peaks at 5.15 ppm (one proton of PLA) and the peaks at 4.87 ppm 2.7 protons (C12) of RA in CO. The difference in physical characteristics between LPLA and DLPLA is attributed to the ability of PLLA to form crystalline domains. In our case, all polymers are completely amorphous, as confirmed by DSC (Scheme 5), probably because the LA segments are too short to create crystalline domains. Rheological behavior (viscosity) is a very important factor then injectable polymers are concert. Measuring viscosity at different shear rates is also important when a material is to be subjected to a variety of shear rates in processing (preparation of polymer loaded with drug by trituration) or use (injecting of the polymer via needle). Viscosity was measured in the temperature range of 25–508C while preheated polymer cooled. Increase in CO content decreased polymers viscosity as expected. For each group, polymers prepared from L-LA had higher viscosity than polymers prepared from DL-LA. P(LLA/CO) 6:4 viscosity is more sensitive to temperature. At high temperature, both poly-mers have same viscosity (2000 cP). Viscosity of p(LLA/ CO) increases rapidly while temperature decreases (58,500 cP at lowest point). For p(DLLA/CO), the increase in viscosity is less significant (29,000 cP at same temperature) (Fig. 1). No such difference can be seen for p(LA/CO)s 5:5 (Fig. 2). Viscosity of p(LLA/CO) is higher at any temperature than p(DLLA/CO)’s. Change in viscosity as a function of temperature is quite similar for both polymers. LA conformation did not affect shear rate/shear stress behavior of the polymers. All polymers behave as Newtonian fluid, showing constant shear rate/shear stress correlation (Figs 3 and 4). Copyright # 2008 John Wiley & Sons, Ltd.

Hydrolytic degradation The next question was if the LA conformation affects degradation rates of these copolymers. Hydrolysis was monitored by weight loss of the specimens (Fig. 5) and changes in polymer molecular weight (Fig. 6). Generally, p(LA/CO)s 6:4 degraded faster due to their lower content of CO and therefore lower hydrophobicity. Both p(LA/CO)s 6:4 degraded in similar rate, losing 60 and 65% of sample weight during 100 days (Fig. 5). However slight difference can be seen in degradation pattern. P(LLA/CO) showed almost zero-order decrease in molecular weight and DL-based polyester showed non-distinct two-phase degradation pattern. For p(LA/Co)5:5 sample weight of the polymers remained constant during 60 days. Only after 75 days slight decrease in molecular weight was observed. The decrease was more significant for p(DLLA/CO) 5:5 which lost 20% of its weight compared to p(LLA/CO) 5:5, which lost only about 5% of its weight. The number average molecular weight (Mn) loss was monitored by GPC (Fig. 6). Mn of P(LA/CO)s 6:4 decreased to about 2000 Da during 100 days of incubation, regardless of the initial molecular weight and polymer composition. During the first 40 days of incubation, no change in molecular weight was observed. The main decrease in molecular weight was observed after 40 days. Little difference in the molecular weight loss was observed for p(LLA/CO) 6:4 and p(DLLA/CO) 6:4. For p(LA/CO) 5:5 the changes in Mn were negligible during the degradation period. During the first 30 days of the study, the samples of P(LA-CO) 6:4 preserved their original shape and did not crumble. After 60 days partial polymer decomposition was observed. The decomposition of the polymer sample was more pronounced for p(LLA/CO). For p(LA/CO) 5:5 decomposition in polymer shape was observed after 75 days of incubation. Polym. Adv. Technol. 2008; 19: 671–679 DOI: 10.1002/pat


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Scheme 3. (a) NMR spectrum of p(LLA/CO) 6:4. (b) NMR spectrum of p(DLLA/CO) 6:4.

In vitro drug release from polymers The drug release characteristics from P(LA-CO)s 6:4 and 5:5 were determined using Tamsulosin hydrochloride as representative hydrophilic drug (sparingly soluble in water). Tamsulosin hydrochloride is a highly selective alpha 1A-adrenoreceptor antagonist that has been used for the treatment of LUTS/BPH. The drug was incorporated into the Copyright # 2008 John Wiley & Sons, Ltd.

polymer by trituration at room temperature. Tamsulosin hydrochloride is constantly released from the copolymers for over 3 weeks up (Figs 7–10). The effect of LA conformation, drug load, and sample size of the formulation was evaluated. The Tamsulosin hydrochloride release from the p(DLLA/ CO) 6:4 was much faster than the release from p(LLA/CO). P(DLLA/CO) 6:4 loaded with 5% Tamsulosin hydrochloride Polym. Adv. Technol. 2008; 19: 671–679 DOI: 10.1002/pat

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Scheme 4. (a) NMR spectrum of p(LLA/CO)5:5. (b) NMR spectrum of p(DLLA/CO)5:5.

released all the drug during the first 15 days of incubation (Fig. 7). Drug released from p(DLLA/CO) 6:4 loaded with 10% was slower and 80% of the drug was released during the first 21 days of incubation (Fig. 7). Although lower drug load affects the release rates and total drug release, the release profile is not affected by drug load. The fast release of drug is almost zero order regardless of the drug load. Sample size affected the release rate only. For 5% loaded formulation Copyright # 2008 John Wiley & Sons, Ltd.

increase in sample size was not significant, 100% of the drug was released during the first 15 days. For 10% loaded formulation increase in size caused decrease in release rate. About 60% of the drug was released during 21 days of incubation. Additional 10% of the drug was released during the following 60 days of the experiment (Fig. 7). Then p(LLA/CO)6:4 was used as a drug carrier; the release profile did not change, but total drug release was lower. A total of Polym. Adv. Technol. 2008; 19: 671–679 DOI: 10.1002/pat


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Scheme 5. DSC traces of p(LA/CO)s 6:4 and 5:5.

Figure 1. Viscosities of P(LA:CO)s 6:4 as a function of temperature at different shear rates.

Figure 2. Viscosities of P(LA:CO)s 5:5 as a function of temperature at different shear rates. 40–60% of the drug was released during the first 21 days, depending on sample size. Similar to p(DL/LA/CO) 6:4 increase in sample size of the formulation reduced the release rate of the drug (Fig. 8). Sample size probably slows the diffusion of the drug from the polymer matrix to the surrounding medium, reducing the release rates. When CO content in polymer is increased to 50% w/w the release rate from p(DLLA/CO) loaded with 5% drug changes slightly, the release is slower, total of 80% of the drug is released Copyright # 2008 John Wiley & Sons, Ltd.

Figure 3. Relationship of shear rate/shear stress p(LA:CO) 6:4. Measurements were performed at 238C.

Figure 4. Relationship of shear rate/shear stress p(LA:CO) 5:5. Measurements were performed at 238C. during the first 21 days (Fig. 9). Although the release pattern is not changed, only 50% of the drug is released during 21 days. For the formulation containing 20% drug the decrease in the release rate is more marked. The total drug release decreases to 60%. Also, the sample size effect is the most significant between all formulations (the total drug release drops to 37%). For p(LLA/CO) the increase in CO content had similar effect (Fig. 10). For polymer loaded with 5% drug release rate was similar to p(LLA/CO) 6:4 loaded Polym. Adv. Technol. 2008; 19: 671–679 DOI: 10.1002/pat

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Figure 5. Hydrolysis of polymers based on lactic acid and castor oil [P(LA:CO)s] 60:40 and 50:50w/w monitored by specimen mass loss. The hydrolysis was conducted in 0.1 M phosphate buffer (pH 7.4) at 378C.

Figure 8. In vitro release of tamsulosin hydrochloride from P(LLA-CO) 60:40 loaded with 10% w/w of the drug. The tamsulosin hydrochlorid release was conducted in a 0.1 M phosphate buffer (pH 7.4) at 378C. Tamsulosin hydrochloride content in the releasing medium was determined by ultraviolet detection at 269 nm. Release medium from unloaded polymer was used as reference.

Figure 6. Hydrolysis of P(LA:CO)s 60:40 and 50:50 w/w monitored by the Mn loss, determined by gel permeation chromatography. The hydrolysis was conducted in 0.1 M phosphate buffer (pH 7.4) at 378C.

Figure 9. In vitro release of tamsulosin hydrochloride from P(DLLA-CO) 50:50 loaded with 5% and 20% w/w of the drug. The tamsulosin hydrochlorid release was conducted in a 0.1 M phosphate buffer (pH 7.4) at 378C. Tamsulosin hydrochloride content in the releasing medium was determined by ultraviolet detection at 269 nm. Release medium from unloaded polymer was used as reference.

Figure 7. In vitro release of tamsulosin hydrochloride from P(DLLA-CO) 60:40 loaded with 5% and 10% w/w of the drug. The tamsulosin hydrochlorid release was conducted in a 0.1 M phosphate buffer (pH 7.4) at 378C. Tamsulosin hydrochloride content in the releasing medium was determined by ultraviolet detection at 269 nm compared to blank polymer.

Figure 10. In vitro release of tamsulosin hydrochloride from P(LLA-CO) 50:50 loaded with 5% and 10% w/w of the drug. The tamsulosin hydrochlorid release was conducted in a 0.1 M phosphate buffer (pH 7.4) at 378C. Tamsulosin hydrochloride content in the releasing medium was determined by ultraviolet detection at 269 nm. Release medium from unloaded polymer was used as reference.




with 10% drug. For this formulation the increase in sample size also decreased the released amount of drug by 10% and release pattern remained unchanged. The formulation containing 20% of the drug released only 50% of the drug in first 21 days. However, in this case, the sample size had little effect on the release rate. The drug release from polyesters depends on various physical and chemical parameters including hydrophobicity of monomers and polymer, crystallinity of polymer, water permeability into the polymer matrix, and the degradation medium and conditions. Drug load can affect the polymer hydrophobicity, which indirectly affects the drug release. In this study all tested polymers are amorphous, which allows water to penetrate and diffuse the drug out. Increase in CO content increases hydrophobicity. Hydrophobicity compensates for lack of crystallinity resulting in a similar degradation rate, causing water rejection and thus slower release than from the polymer. The increase in hydrophobicity explains the general difference between p(LA/CO) 6:4 and 5:5. Still it cannot explain the difference in each group. Generally, the difference is attributed to the ability of L-LA to form crystalline domains, which is impossible in the case of DL-LA. The arrangement of these blocks probably causes the difference in the release profiles. Isotactic attachment of the hydrophobic methyl groups causes L-lactic based polymers to aggregate in water, which reduces water penetration and drug diffusion.

CONCLUSIONS Amorphous pasty copolyesters of L-LA or D,L-LA with CO were synthesized. All polymers were amorphous as confirmed by DSC. The difference in the viscosity of balk polymer, hydrolytic degradation, and drug release profiles suggests that the isotactic attachment of the hydrophobic methyl groups causes the L-LA based polyesters to form different arrangement in balk and in water due to the


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cooperative hydrophobic interactions. The aggregation of L-lactic acid-based polyesters in water slows their degradation rate and drug release due to difficulty of water to penetrate into hydrophobic polymer matrix.

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