Theories and Applications of Chem. Eng., 2002, Vol. 8, No. 1

화학공학의 이론과 응용 제8권 제1호 2002년

PLA-PEO-PLA 블록 공중합체의 합성 및 수용액상태에서의

열가역적 전이거동에 관한 연구

이두성, 이형탁

성균관대학교 고분자공학과

Thermoresponsive Phase Transition of PLA-bl-PEO-bl-PLA

Triblock Stereocopolymers in Aqueous Solution

Doo Sung Lee, Hyung Tak Lee

Dept. of Polymer Sci. and Eng., Sungkyunkwan University.

Introduction

Thermo-responsive gelation of synthetic polymers has been extensively investigated for medical applications in the past decades.[1-3] Commercially available block copolymers, such as poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide)(PEO-PPO-PEO), poly(butylene oxide)-block-poly(ethylene oxide)(PBO-PEO, Dow Chem), Pluronics(BASF) and Poloxamers(ICI) undergo  gel-sol transitions in aqueous solution as increasing temperature because of micelle aggregation or packing when the polymer concentration is above a critical value. However, these synthetic polymers were reported to be non-biodegradable and possible to induce the toxicity in body. For example, Poloxamer 407(P-407) have been found to cause toxic hypertriglyceridemia and hypercholesterolemia in rodent experiment.[4, 5] So it is very important to synthesize polymers with biocompatibility, biodegradability and safety for medical applications.

In this study, the poly(D,L-co-L)LA-poly(ethylene glycol)-poly(D,L-co-L)LA (PLA-PEO-PLA) triblock stereo-copolymers with varying poly(D,L-co-L)LA block composition and block length were synthesized. The thermo-responsive phase transition behavior of these triblock copolymers in water was investigated in detail. These novel thermo-responsive hydrogel will contribute to drug delivery system as the carriers of proteins or other pharmaceuticals for long-term delivery.

Experimental

1. Synthesis : The synthesis of PLA-PEO-PLA triblock copolymers with different PLA/PEO and L-lactide/D,L-lactide (L-/DL-LA) ratios was carried out through a ring-opening copolymerization using PEO as the initiatior.

2. Characterization : FT-IR spectrometer (UNICAM Mattson 5000) and 1H-NMR spectrometer (Varian Unity Inova 500 instrument, 500MHz) were used to determine the structures and compositions of triblock copolymers. Molecular weight distribution (MWD) of these triblock copolymers were determined by gel permeation chromatography (GPC) on a Waters Model 410 apparatus equipped with four-styragel columns from 500 □ to 10 □ in series at a flow rate of 1.2ml/min (eluent: THF, 36℃, polystyrene as standard).

3. Phase diagram : Block copolymer aqueous solutions (0.5g) with various concentrations were prepared by dissolving the copolymers at 2℃ in 4ml vials with inner diameter of 11mm. The phase transition of sol(flow)-gel(no flow) of this solution was recorded using the inverting test method at each 2℃ temperature interval.

Results and Discussion

Table 1 shows all the triblock stereo-copolymers composed of a central PEO (Mn, 1500) bearing two PLA blocks with molecular weight over about 1875 were insoluble in water, while all the triblock stereo-copolymers with PLA blocks molecular weight under about 1350 were soluble without sol-gel transition in water. These phenomenons can be interpreted by the hydrophobicity difference of triblock copolymers with the variation of PLA block length. Only those triblock copolymers with PLA blocks molecular weight in the range of 1575 to 1727  and with L-/DL-LA ratio under 0.8 showed a thermo-responsive sol-gel transition, as listed in a thick line framed box in Table 1.

Table 1. Sol-gel transition region of PLA-PEO-PLA triblock copolymers in water

L-LA/D,L-LA (wt/wt) PLA/PEO (wt/wt)	0.8/1	0.6/1	0.4/1	0.2/1	0/1 (only DL-LA)
2.5/1 (1875-1500-1875)	I	I	I	I	I
2.3/1 (1727-1500-1727)	I	A-1	B-1	C-1	D-1
2.1/1 (1575-1500-1575)	~	A-2	B-2	C-2	D-2
1.8/1 (1350-1500-1350)	~	S	S	S	S

Note : I = insoluble; S = soluble; black line-framed zone, sol-gel; *-*, sample code

Sol-gel transitions of PLA-PEO-PLA triblock stereo-copolymers as concentration and temperature change, were represented by phase diagrams in Figure 1~4. The phase diagrams show a critical concentration (CGC) and two critical gelation temperature (CGT) curves. The lower CGT curves mean transition temperature from sol to gel, while the upper CGT curves means transition temperature from gel to precipitation. Taking PLA-PEO-PLA (1692-1500-1692, A-1) as an example in Figure 1, the lower CGT is 25℃ at 10wt%, 24℃ at 15wt% 23℃ at 20wt%, respectively. The lower CGT changes only a few degrees with variation of concentration. On the other hand, when the CGC is under 10wt%, the phase diagram is similar as that of PLGA-PEO-PLGA triblock copolymer.[6] As can be expected from the structure, two hydrophobic PLA blocks can easily locate different micelles, leading to bridging connections, which facilitate the aggregation of micelles. The phase-separation to dehydrate from hydrogel(precipitation) appears at upper CGTs, which is different from gel to sol transition at upper CGTs in PLGA-PEO-PLGA system. The difference may be induced by that PLA blocks is more hydrophobic than PLGA blocks.

Fiure 1 displays phase diagrams of PLA-PEO-PLA triblock stereo-copolymers with varying L-/DL-LA ratios and similar PLA/PEO molecular weight ratio (2.3/1). It shows the lower CGTs of the 15% copolymer concentration water solution decrease from 30 to 23℃ by varying the L-/DL-LA ratios from 0/1(D-1) to 0.6/1(A-1). But upper CGTs hardly change by

varying the L-/DL-LA ratios. If the L-/DL-LA ratio of PLA is increase, stereo-regularity of PLA is increase because of increment of LL bonds (bond between L-lactyl unit and L-lactyl

unit) and decrement of DL bonds (bond between D-lactyl unit and L-lactyl unit). The stereo-regularity increment of PLA induces PLA blocks to be more hydrophobic. As PLA blocks become more hydrophobic, micelles are easily associated by bridging connections between micelles. Therefore, as L-/DL-LA ratio in PLA blocks increases, lower CGTs and CGC decrease gradually. In other word, the gel range in the phase diagram becomes larger with increasing L-/DL-LA ratio in PLA blocks.

Figure 2 displays the phase diagrams of PLA-PEO-PLA triblock stereo-copolymers with different PLA/PEO ratios and comparable L-/DL-LA ratio. In Figure 2, CGC and lower CGTs of A-1(PLA/PEO=2.25/1, L-/DL-LA=0.6/1) are lower than those of A-2(PLA/PEO=2.06/1, L-/DL-LA=0.6/1). This indicates that gel range becomes large as the length of PLA blocks increases. Longer PLA blocks in the triblock copolymers induce stronger hydrophobic interaction, leading to an increase in the association tendency.

Diagram of PLA-PEO1000-PLA (1049-1000-1049, PLA/PEO=2.09/1, L-/DL-LA=0.4/1, E-1) and PLA-PEO1500-PLA (1556-1500-1556, PLA/PEO=2.07/1, L-/DL-LA=0.4/1, B-2) was compared in Figure 3. E-1 has the similar PLA/PEO and L-/DL-LA ratio to B-2 with the exception of the total molecular weight. The phase diagram of E-1 was shifted to low temperature without the change of gel range. This indicates that the strength of gel depends on a balance of hydrophobic and hydrophilic part.

The phase diagram of C-2 (in Table 1) vertically shifts without influencing gel range when different additives such as PEO1000 (Mn=1000) and NaSCN(2% in solution respectively) were added to copolymer solution in Figure4.NaSCN known as water structure breaking salt decreases hydrogen bond interaction between water molecules, resulting in increment of the copolymer solubility in water.[7, 8] This effect induces gelation at higher temperature, raising the phase diagram. Whereas, Adding a small amount of PEO1000 shifts phase diagram to lower temperature. The free PEO1000 in aqueous solution plays a role of bridging connections due to interaction between PEO1000 molecules and PEO block of copolymer. Therefore, PEO1000 molecules in solution can increase interaction between micelles and make micelles better pack, which induces gelation at lower temperature in accordance with the observation of PEO-PLGA-PEO triblock aqueous solution.[9]

References

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3. Guenet J. M.: "Thermoreversible Gelation of Polymers and Biopolymers",□ Academic press, New York, (1992).

4. Wout Z., Pec E. A. and Maggiore J. A.: □J. Parenteral Sci. & Tech., 46(6), 192(1992).

5. Palmer W. K., Emeson E. E. and Johston T. P.:□Atherosclerosis, 136, 115(1998).

6. Shim M. S., Lee H. T., Shim W. S., Park I. S., Lee H. J., Chang T. H., Kim S. W. and Lee D. S.: J. Biomedical Materials Research, in press

7. Zaslavsky B. Y.: "Aqueous Two Phase Partitioning", Marcel Dekker, New York(1995).

8. Finch C. A.: "Chemistry and technology of water-soluble polymers", Plenum Press, New York(1983).

9. Jeong B. M., Bae Y. H. and Kim S. W.: Macromolecules, 32, 7064(1999).