Cha 1990
Cha 1990
Cha 1990
Blends of poly(s-caprolactone) (PCL) and poly(L-lactic acid) (PM) with polyglycolic acid-co-l-lactic acid
(PGLA) were prepared by three methods: compression moulding, coprecipitation, and solvent evaporation
of a methylene chloride-in-water emulsion of the polymers. The rates of hydrolytic chain scission of each
component of the blends were determined by deconvolution of GPC traces of samples maintained in
phosphate buffer, pH 7.4,37%, for up to 3000 h. The observed rates were dependent on the method of
blending. For compression moulded blends, the rate of chain scission of PGLA was decreased and that of
PC1 and PLlA increased. A corresponding delay in the onset of weight loss was also observed. There was
no evidence of blend miscibility.
Keywords: Biodegradation, poly(e-caprolactone), poly(L-lactic acid), polyglycolic acid-co-L-lactic acid. polymer blends. hydrolysis,
gel permeation chromatography
Aliphatic polyesters derived from glycolic acid, DL- and 140°C for 18 h in an evacuated glass vessel in the presence
L-lactic acid, and c-caprolactone have found frequent appli- of stannous octoate4, 5. The polymers were purified by
cation as biodegradable matrices for prosthetics’ and precipitation from methylene chloride with methanol and
controlled drug delivery’. 3. The optimization of the key dried in vacua. The sample of PGLA was determined to
properties of these biomaterials, i.e. the permeability, the contain 83 mol% of lactide by ’ H-n.m.r. spectroscopy (CDCI,
rate of biodegradation, and the tensile properties, has solvent) using a Bruker Model Wm-250 Supercon spectro-
generally been achieved by copolymerization4-6. Blending of meter. Blends were prepared by casting common solutions
the homo- and copolymers represents an alternative but less of the polymers in methylene chloride, then compression
exploited means of tailoring the material properties. The moulding the cast films to a thickness of 0.6 mm in a Carver
changes in the permeability of polyesters effected by press for 2 min at 2000 p.s.i. then 1.5 min at 20 000 p.s.i.
blending are predictable and have already been used to tailor at elevated temperatures: PGLA 1 OO”C, PGLA-PCL and PCL
the rate and duration of drug delivery systems. For example, 125-l 3O”C, PGLA-PLLA 190-200°C. Discs, diameter
blending poly(s-caprolactone) (PCL) or its copolymers with 0.64 cm, approx. 20 mg, were punched from the moulded
increasing amounts of poly(L-lactic acid) (PLLA)‘, cellu- films. Precipitated blends of PCL and PGLA were prepared
loses*,’ or other glassy polymers permits a systematic by dissolution of a 1 g mixture of the two polymers in
reduction in the permeability of the polymer matrix. In methylene chloride (6 ml), concentration of the continuously
contrast to these diffusion studies, the biodegradation of mixed solutionin vacua at 35”C, and addition of an excess of
blends is largely unexplored. Several recent publications7. lo methanol. The precipitated mass was dried in vacua, and cut
suggest that blending may be used to manipulate the rates of into 3 mm3 pieces (about 20 mg). Microspheres were
biodegradation-controlled delivery of drugs, but the prepared by the solvent evaporation method” at ambient
mechanism of the process is not known. We report here the pressures. Typically, a solution of the polyesters (300 mg) in
effect of blending on the rates of hydrolytic degradation of CH,CI, (4 ml) was poured rapidly into 20 ml of water
the above polyesters and show that, despite the incompati- containing 0.4 wt%of poly(vinyl alcohol) (/VI, 25 000; 88%
bility of the blends, the rate of hydrolytic chain scission of hydrolysed). The mixture was stirred with a magnetic stirrer
each component is significantly modified by the presence of to form an emulsion; stirring was continued at 37°C until the
the second polymer. CH,CI, had evaporated. The microspheres were separated,
washed with deionized water, and dried in vacua.
Polymer hydrolysis was measured by immersing
METHODS
samples in 40 ml of 0.1 M phosphate buffer at pH 7.4 and
37°C. Duplicate samples were withdrawn at different time
PCL, PLLA and polyglycolic acid-co-L-lactic acid (PGLA)
intervals and weight loss was determined gravimetrically
were prepared by bulk polymerization of redistilled
after drying for 24 h in vacua. Molecular weights were
c-caprolactone or recrystallized L-dilactide and diglycolide at
determined by gel permeation chromatography (GPC) in
Correspondence to Dr C.G. Pitt. chloroform using a set of five p-Styragel columns (Waters
The authors are presently at Amgen Inc.. Thousand Oaks, CA 9 1320. USA Assoc.) with nominal pore sizes of 1 05, 1 04, 1 03, 1 02, and
5 X 10’ nm, and an eluent flow rate of 1 ml/min. The GPC 600 -7
Table 2 Weight loss (%) of PGLA and its blends with PCL as a function of
time in phosphate buffer, pH 7.4, 37°C
PGLAa 4 9 41 53 69 -
PCL:PGLA (1:3) 0 0 0 0 28 -
PCL:PGLA (1:2) 0 0 0 0 4.5 -
PCL:PGLA (1:l) 0 0 0 0 4 17
PCLb 0 0 0 0 0 0
TIME(HRS)
domains exist. However, despite the apparent lack of
miscibility, the large perturbation of the rates of chain
Figure 3 The change in the molecular weights (M,) of unblended and
scission suggested that there must be a strong interaction of
compression moulded It1 blends of PGLA and PLLA in phosphate buffer,
pH 7.4, 37°C. The initial M, of the unblended sample of PLLA was slightly
the polymers or a significant change in their morphology on
smaller than that used to prepare the blend. Symbols: unblended PLLA (U), blending.
PGLA:PCL blend (0). precipitation (0); and solvent evaporation of an The importance of the morphology of the polymers
emulsion (X). was examined by comparing the rates of hydrolysis of
PCL:PGLA blends prepared by two additional methods.
hydrolytic chain cleavage of PGLA in PCL-PGLA blends was These were: coprecipitation from a common solution with a
accompanied by an increase in the induction period before non-solvent and solvent evaporation of an emulsion in water.
weight loss. The weight losses of 1: 1, I:2 and 1:3 blends The latter procedure is a common method of preparation of
during a period of 4000 h are listed in Table 2. The greater microspheres for drug delivery. The result of these changes
the proportion of PCL, the slower the onset and extent of in sample preparation was a reduction in the rate of
hydrolysis of unblended PGLA (Figure 4). as well as a change
Table 1 Rate constants (X 1O4 h-‘) derived from initial slopes (first in the behaviour of the blends (figures5 6).The initial rateof
1000 h) of semilog plots of the molecular weights (M,) of polyesters and hydrolysis of PGLA microspheres was approximately one-
their blends versus time in phosphate buffer, pH 7.4, 37°C
third of the rate of compression moulded PGLA discs.
Blend ratio Moulded Precipitated Solvent evaporated
However, the rate increased with time and after 1500 h was
of polymers comparable to that of compression moulded PGLA. The rate
PCL PGLA PCL PGLA PCL PGLA of hydrolysis of precipitated PGLAwas intermediate in value.
The hydrolysis of PCL was less affected by the method of
1a 1.7 - 2.1 - 1.4 -
preparation, and the changes in molecular weight were
1:l 3.8 4.4
1:2 6.2 8.2 2.5 4.9 1.7 7.0 small. The rates of hydrolysis of PCL in coprecipitated 1 :2
1:3 11 8.8 2.7 3.3 2.1 6.4 and 1 :3 blends with PGLA were the same and significantly
0:l 31 - 24 - 9.7 lower than those observed with compression moulded
PLLA PGLA blends (Table 7). The rates of hydrolysis of PGLA in
microsphere blends with PCL were similar to the rates of
1 :o 2.8 - compression moulded blends and slightly greater than the
1:l 5.0 9.5
rates of coprecipitated blends.
0:l 31
No correlation between hydrolysis rates and the
v_ . . _~
+- PCL
5
G
0 PGLA
Lu 108
g
0 500 1000
TIME(HAS)
1500 2000 lo2w- TIME(HAS)
2000
Figure 4 The change in the molacolar weights (M,j of PGlA in phosphate figtire 6 The change in the molecular werghts (NI,j oioobleoded (0) PCL
buffer. pH 7.4,3 7°C Samples were prepared& compression moolding (Oj, and PGL/L and lt2 (X) and 1:3 (0) blends of the same polymers, in
compression moulding as a 3: 1 PGLAPCL blend (Oj, precipitation (0). and phosphate buffer, pH 7.4, 37°C. Samples were prepared by solvent
solvent evaporation of an emulsion IXJ. evaporation of a methylene chlorrde solution of the polymers emulsified rn
aqueous po/y(vinyl akohol).
ACKNOWLEDGEMENTS
REFERENCES