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Ibuprofen release from hydrophilic ceramic-polymer composites
Biomoteriols 16(1997)1~35-1~4~ 0 1997 Elsevier Science Limited Printed in Great Britain. All rights reserved PII:
ELSEVIER
SO142-9612
(97)
00054-9
0142-9612/97/517,00
Ibuprofen release fcom hydrophilic ceramic-polymer composites D. Arcos*, M.V. Cab&as*, J. San Romcin*+
C.V. Ragel”, M. Vallet-Regi* and
‘Departamento de Quimica lnorgenica y BioinorgBnica, Faculfad de Farmacia, UCM, 28040 Madrid, Spain; tlnstifuto de Ciencia y Tecnologia de Polimeros, CSIC, Juan de /a Cierva, 3, 28006 Madrid, Spain
Two composite systems composed of a-A1203/poly(methyl methacrylate) (PMMA)/poly(vinyl pyrrolidone) (PVP)/ibuprofen or cr-A1203/PMMA/co-vinyl pyrrolidone-methyl methacrylate/ibuprofen were prepared by free radical polymerization. These systems were characterized by spectroscopic techniques and thermogravimetric and differential thermal analyses. The hydration behaviour of composites with different hydrophilic characters was analysed after the immersion of the composites in buffered solution at pH 7.4 and 37°C. The swelling of the composites depends strongly on the content of the hydrophilic component and is controlled by the presence of the ceramic component. The release of the anti-inflammatory drug, ibuprofen, from the composites in buffered solution was followed by UV spectroscopy and the results obtained indicated that the components of the composites influenced the rate of release of the drug, without the classical ‘burst’ effect observed frequently with hydrophilic systems. 0 1997 Elsevier Science Limited. All rights reserved Keywords:
Ceramic-polymer
composites,
hydrophilic
composites,
vinyl pyrrolidone,
ibuprofen,
drug
release
Received 11 November 1996; accepted 11 March 1997
Organic-inorganic c:omposites represent a family of materials which have several applications in the field of biomaterials. In these heterogeneous systems, the morphology and the characteristics of the interface are critical to determine the properties of the composites1-3. Polymers such as poly(methy1 methacrylate) (PMMA)4,5, and poly(viny1 poly(N,N-dimethylacrylamide)5 pyrrolidone) (PVP)5*6 have been shown to stabilize hydrogen bonding with hydroxyl-functional components and silicate compounds. This results in an effective control of phase separation and stability of the interphase. PVP and copolymers of vinyl pyrrolidone (VP) with other vinyl and acrylic monomers have been used as hydrogels and pa&cularly as support matrices for controlled drug re.lease7-“. In these systems, the polymer support usually displays an asymmetric bellshaped release profile, sometimes characterized by an initial large ‘burst’ effect’0”3S14. PVP is a hydrophilic polymer with excellent biocompatibility, but very soluble in water and physiological fluids13. Although the solubility of polymeric systems based on VP can be controlled by copolymerization with other hydrophobic monomers, in general their mechanical properties and therefore the delivery potency is controlled with some difficulty. In addition, the pyrrolidone ring interacts strongly with polar groups such as carboxylic acids, hydroxyl or even inorganic salts and oxides14-1g. Ceramics exhibit unique physical and chemical
properties not shown by organic supports. For example, alumina, zirconia or titanium dioxide present structural stability without swelling and are resistant to environmental chemical reactions. In addition, if there are physico-chemical interactions between the stable bioceramics and the polymeric components, composite s stems with specific properties can be prepared’&’ Y. Therefore, the present paper deals with the preparation and analysis of composite systems based on PMMA, PVP or copolymers of VP-methyl methacrylate (MMA) and a-alumina, as well as their use as support matrices for the controlled release of ibuprofen (IB), a non-steroid anti-inflammatory agent. These implants could be used for implantation in bone tissue or as ingredients for the preparation of bone or dental cements.
MATERIALS AND METHODS Reagents and products The ceramic component, alumina (a-A1203), was nitrate prepared by decomposition from A1(N0&9Hz0 treated at 400°C (12 h), 900°C (24 h) and finally at 1250°C (33 h). The reaction product was characterized by X-ray diffraction (XRD) on a Philips X’Pert MPD diffractometer (CuK, radiation). All reflections on the XRD pattern could be indexed on the basis of an a-A1203 phasez3 and no extra peaks were observed.
Correspondence to Dr Ivl. Vallet-Regi. 1235
Biomaterials
1997,
Vol. 16 No. 18
Ibuprofen
1236
The morphology of the ceramic obtained was analysed by scanning electron microscopy (SEM) using a Jeol JSM 6400 microscope. The powder so obtained is formed by agglomerated particles with irregular morphology. Figure la shows one of these aggregates, characteristic of this ceramic material, obtained by nitrate decomposition, Each one of these aggregates is formed by several sintered particles, as a consequence of the applied thermal treatment. Figure lb shows a magnification of the aggregate surface shown in Figure la; the unions between particles and their rounded contours become evident; this aspect is a consequence of the sintering process. PVP was prepared by the free radical polymerization of VP in isopropanol solution using azobisisobutyronitrile (AIBN) as the free radical initiator at 60°C. The polymer obtained was precipitated in excess diethyl ether, filtered, washed and finally dried at low pressure until constant weight. The average molecular weight of the polymer was determined by size exclusion chromatography (SEC) using dimethylformamide as solvent and calibration with polystyrene standards (Polymer Laboratories). The values obtained were fi, = 36 000 and &l, = 98 000, with a polydispersity index of I&,/I&, = 2.72. A copolymer of VP with MMA, co-VP-MMA, was obtained by the free radical polymerization of a
release
from
ceramic-polymer
composites:
D. Arcos
et al.
with an average mixture of both monomers composition 70 wt% VP and 30 wt% MMA, using AIBN as initiator at 60°C during 6 h. The copolymer was isolated by precipitation in cool diethyl ether, washed and dried under vacuum until a constant weight was obtained. The molecular weight of the purified sample was determined by SEC, giving values of I$, = 32 000 and &&, = 104 000, with a polydispersity index of i&lfi,, = 3.25. Composites of A1203/PMMA/PVP (system I) or A1203/PMMA/co-VP-MMA (system II) charged with different amounts of IB as the pharmacologically active component were prepared by the free radical polymerization of a mixture of c(-A1203, MMA and PVP or co-VP-MMA using 0.5 wt% benzoyl peroxide as initiatorZ4. Cylindrical specimens (6 mm diameter, 1Omm length) were obtained by using Teflon moulds at a polymerization temperature of 60°C for 1 h and subsequently at 80°C for 24 h. In order to study the influence of each component in vitro, different series of composites were prepared with the compositions described in Table 1. We consider series for both systems with the same composition in VP units as analogous, independent of the nature of the polymeric chains, i.e. PVP for system I and co-VP-MMA for system II.
Characterization The composites synthesized were characterized by thermogravimetric and differential thermal analysis (TG-DTA), proton nuclear magnetic resonance (lHNMR) spectroscopy, XRD and Fourier transform infrared spectroscopy (FTIR). Thermal studies, TG and DTA, were carried out on a TG-DTA 320 Seiko thermobalance, with a heating rate of 10°C min-l in the range of 25-600°C under flow of air (50ml mini’). IH-NMR spectra were registered, after extraction of the organic components from the composite specimens with deuterated chloroform, using a Varian XL300 NMR spectrometer. X-ray data were obtained, using CuK, radiation, with a Philips X’Pert MPD diffractometer equipped with a multipurpose sample holder for non-destructive analysis of samples, which allows the study of the crystalline components of the cylinders. Infrared spectra were recorded on a Nicolet-520 FTIR spectrophotometer. The spectra were registered with KBr pellets.
Swelling hehaviour
and drug release
Composites in the form of cylinders were immersed in lOm1 of a phosphate-buffered solution (KH,PO,/ K2HP04) at pH 7.4 and a temperature of 37°C. The swelling of the samples studied was monitored by measuring the water intake gravimetrically as a function of time during 5 days. The amount of swelling (H) was determinedz5 using the following equation: H (%) =
Figure 1 a, SEM photograph of obtained. b, Detailed area of SEM xl0000 magnification. Biomaterials
1997. Vol. 18 No. 18
c+A1203 sample asphotograph taken at
w - wox
w
100
0
where W, is the weight of the cylinder after immersion in water and W, is the initial weight. The release of IB in the buffered solution was followed by UV spectroscopy, using a Perkin-Elmer
Ibuprofen
release
Table 1
System Series
from
Composition
ceramic-polymer
composites:
(wt%) of composites
synthesized
D. Amos et a/.
1237
a-A1203 Exp.’ (theor.)
PMMA Exp..t (theor.)
PVP Exp.t (theor.)
IB Expt (theor.)
35 (30) 27 (27) 30 (25)
44 (49) 43 (45) 33 (41)
21 (21) 20 (19) 18 (17)
lo (9) 19 (17)
I A,
Series
B,
26 (27) 26 (25)
31 (32) 26 (29)
34 (32) 33 (29)
9 (9) 15 (17)
Series
C, D
58 (64) 52 (58) 57 (64)
30 (27) 30 (25) -
12 (9) 18 (17)
Series
31 (27) 26 (25)
51 (58)
-
32 (30)
39 (40)
31 (27) 26 (25)
33 (37) 33 (33)
coVP-MMA+ 29 (30) 27 (27) 25 (25)
System II Series A,
12 (9) 23 (17) 9 (9) 16 (17)
Series
B2
28.5 (27) 26.5 (25)
19.5 (18.5) 16.5 (16.5)
45 (45.5) 41 (41.5)
7 (9) 16 (17)
Series
C2
-
54 (52.5) 45 (47.5)
38 (38.5) 37 (35.5)
8 (9) 18 (17)
*Determined by TG analysis. ‘Determined by ‘H-NMR spectroscopy.
PMMA
554 spectrophotometer. The amount of IB released in the buffer was measured at i = 264nm. A calibration curve obtained with pure IB was used to determine the concentration of drug released. The UV spectra of PVP solutions showed an absorption at the same wavelength (A = 264nm), with much lower intensity than that of the IB at the concentrations of reagents used in this work. Therefore, the contribution of PVP was taken into consideration, in all the cases, by the analysis of parallel formulations and the correspondi:ng subtraction of the contribution due to the PVP complonent.
(OCH,,
we
:k-
RESULTS AND DISCUSSION The free radical polymerization of mixtures or dispersions in the form of slurries of ceramic, polymers and monomers could be used to fabricate biomaterials for filling hard tissues with controlled delivery properties of specific drugs and growth factors. In the case of Al,O,/PVP/MMA or Al,03/co-VP-MMAIMMA the polymerization reaction described above can be used to fabricate hard cylindrical composites. The actual percentage of a-A1203 in the composites was obtained by TG analysis. The results obtained for the different series prepared are shown in Table I. In all the cases, the percentage of ceramic is slightly higher than the corresponding theoretical value. This is due to the partial volatilization of MMA monomer during the preparation of composites. Data obtained by the analysis of portions taken from different sections of the composite cylinders gave the same results within experimental error (~2 wt%), which indicates that the ceramic component is distributed homogeneously in the bulk composite. The actual content of organic components was obtained from the analysis of the ‘H-NMR spectra. Figure 2 shows the ‘H-NMR spectrum of the organic fraction of a composite of system I (series A1 with 17% IB). The comparison, of the integrated intensities of
Figure 2 ‘H-NM!? spectrum (series A, with 17wt% of IB).
of a composite
of system
I
signals assigned in Figure 2 provided the molar fraction of each component (PVP, PMMA and IB) in the composite specimens. The weight percentage of these components was calculated taking into consideration the total weight of the sample and the cr-AlzOB percentage obtained by TG. Results are shown in Table 1. The organic fraction of samples of system II give ‘H-NMR spectra similar to that shown in Figure 2, but in this case the contribution to the NMR signal the of 0-CH3 groups (3.6 ppm) corresponds to MMA units of the co-VP-MMA as well as those of the side CH3-0 groups formed by the free radical polymerization of the monomer. However, it is possible to calculate the average percentage of each component (CO-VP-MMA, PMMA and IB) assuming that the composition of the coVP-MMA is not modified by the free radical reaction. The XRD patterns of the composites of series A, B and C of both systems showed diffraction maxima characteristic of a-A120Sz3, distributed in an amorphous matrix (associated with the polymeric components). Biomaterials
1997,
Vol. 18 No. 18
Ibuprofen release from ceramic-polymer composites: D. Amos et al.
1238
Series C XRD patterns are characteristic of amorphous materials. In all cases diffraction maxima due to IB were absent, which indicated that this component appears to be in an amorphous form or was in the form of very small crystallites not detectable by XRD. Recent studies carried out on cc-A120Jpoly(lactic acid)/PMMA/IB composites’” demonstrated that IB crystallized only when cr-A120s and poly(lactic acid) crystallites were incorporated in the composites. However, if any of these components were not present, the IB remained amorphous. These results indicate that both crystalline phases are necessary to promote the crystallization of IB. Thus, the unique presence of A1203 in the composites of the present work was not enough to induce the crystallization of IB. Thus, the IB remained in an amorphous state in the composites prepared with PVP or co-VPMMA. Figure 3 shows the TC-DTA diagrams for three representative composites of system I with different compositions. The characteristic diagrams for samples containing IB (Figure 3a, b) do not show any melting peaks at TO-75°C (the melting point of pure IB is i?YC), which supports the fact that IB does not crystallize during the preparation of the composites. On the other hand, the appearance of a relatively sharp peak around 366°C for all the samples was associated with oxidative decomposition of the organic components. However, only the systems containing PVP and IB (Figure 3~) gave a new sharp peak around 475°C. Similar results were obtained for samples of system II. It is well known that PVP, according to its chemical structure, forms molecular complexes with a great number of pharmacologically active compounds1G18. The data obtained by DTA support the formation of a complex between IB and PVP. In system II, the complex could be formed by the interactions of the IB molecules with the VP units distributed along the copolymer chains. Molecular complexes can be studied easily by spectroscopic techniques like FTIR. We have detected the formation of complexes between IB and PVP by FTIR analysis of mixtures of IB/PVP. Figure 4 shows the FTIR spectra of pure IB, PVP and that of an equimolecular mixture of IB/PVP after thermal treatment at 80°C for 24 h. The spectrum of the mixture shows a sharp peak at 1640 cm-‘, in the carbonyl stretching region, which does not appear in the spectra of IB or PVP. The intensity of this peak changes with the composition of the system and can be assigned to complexed species through the carboxylic group of IB with the carbonyl group or the nitrogen of the PVP chains. This trend has been described for other systems which form complexes through hydrogen bonds2792*. Therefore, the data obtained by FTIR and by DTA support complex formation between IB and VP. Swelling bebaviour and drug release The composites of systems I and II present different behaviours due to the swelling process and delivery of IB. This is a consequence of the presence of PVP (soluble polymer in the hydrated medium) in system I, Biomaterials
1997.
Vol. 18 No. 18
30
315
000
T “C Figure 3 TG-DTA curves of different composites constituted by: a, ct-A12031PVPIPMMAII13; b, u-A1203/PMMA/IB; c, a-A12031PVPIPMMA.
or co-VP-MMA, which forms a highly hydrated but in soluble gel, in system II. Figure 5 shows the variation of the degree of hydration (Ef) with the time of immersion in the buffered solution at pH 7.4 for both systems. For all the compositions of system I (Figure ~a), prepared with PVP, the samples analysed reached the equilibrium of the swelling process in a short time (about 3 h), but the value of the maximum degree of hydration changed drastically with the composition. Samples without PVP (series D) showed a maximum degree of hydration of 3.5%, characteristic of PMMA bone cements, whereas the series prepared with PVP (series Al, B1 and C,) reached equilibrium degrees of hydration between 13 and 18%, depending on the
Ibuprofen release from ceramic-polymer
composites:
D. Amos et al.
w 4000
2800
1600
400
U (cm-l) Figure 4 FTIR spectra of: a, IB; b, PVP; c, a mixture of IB and PVP.
bf+----4 30 s 'C !! 0 20 I"
I
l
10
ow
6b
Time
6b
,
I
100
120
(hours)
Figure 5 Swelling behaviour of composites 9wt% IB: a, system I; b!, system II.
containing
1239
content of PVP. According to the actual compositional data reported in the fourth column of Table 1, it seems that there is a linear variation of the degree of swelling with the fraction of PVP in the composition interval studied (ZO-35% of PVP). It is necessary to consider that, in this series, both the PVP and the IB are soluble in the buffered solution, and therefore the values represented in Figure 5a would be slightly higher than those obtained by gravimetry, but the influence of the hydrophilic polymer in the swelling behaviour of the composites is clear. In the case of system II, which corresponds to composites prepared with co-VP-MMA (70:30), insoluble in the hydrated medium but with a high capacity for water absorption, the maximum swelling is reached after 25 h of immersion in the buffered solution (Figure 5b). Series Bz, with a relatively high content of co-VP-MMA (4Owt%) and a co-VP-MMAI PMMA ratio = 2.4 (see Table z), reached the highest degree of hydration (54% in 25 h). Series AZ and CZ correspond to more hydrophobic composites, with a co-VP-MMAIPMMA ratio of 0.8, giving degrees of hydration lower than samples Bz (14 and 34%, respectively) after 25 h of treatment. The difference between series AZ and CZ is the presence of the ceramic in series AZ, which is responsible for the relatively low degree of hydration reached, indicating the strong influence of AlzO, in the hydration process, probably through interactions of the surface of the A1,03 particles with the side carboxylic ester groups of the methacrylate units in co-VP-MMA. The differences in the swelling process for systems I and II are important, since the gel character in system II is due to co-VP-MMA, in contrast to the soluble PVP in system I. These differences markedly affect the release of IB from both systems. Figure 6 shows the cumulative percentage of IB released over time from the various composites containing the same amount of IB (9%). As expected, samples of series D (Figure 6a) show a very slow release of IB. In 5 days, lOmol% IB was delivered without any burst effect. In contrast, in series Al, B1 and C1, IB was released in a relatively fast manner (ca 20mol%) during the initial 2 h and then in a controlled manner during the rest of the experimental period. Differences in the release of IB from composites prepared with and without A1,03 were not significant. From these results it is clear that PVP affects the mechanism of delivery of IB in such a way that the PVP hydrophilic polymer acts as a carrier of IB and is solubilized as a molecular complex. The PVP-IB complex is more soluble than the IB itself13. This is clear by comparing these results with the behaviour of samples D, in which the release of IB is produced only by diffusion from a hydrophobic composite or with other A1203polymer composites prepared with biodegradable polymers like poly(lactic acid)26. Figure 6b shows the cumulative release of IB from the composites of system II. In all cases the rate of release depends strongly of the co-VP-MMAIPMMA ratio in the composites (see Table 2). Series BZ, with a ratio of 2.5, presents the highest delivery percentage. In this system, the presence of the ceramic seems to slightly favour the release of IB, Biomaterials
1997, Vol. 18 No. 18
Ibuprofen
1240 Table 2
Composition
(wt%) of composites
after immersion
release
from
for 5 days in the buffered
ceramic-polymer
composites:
D. Arcos et al.
solution
c(-AI~O~* After (before)
PMMA+ After (before)
PVP+ After (before)
IB+ After (before)
37 (35) 39 (27) 44 (30)
47 (44) 47 (43) 37.5 (33)
16 (21) 12.4 (20) 13.5 (18)
-
35.6 (26) 41.5 (26)
39 (31) 35.5 (26)
24 (34) 22 (33)
1.4 (9) 1 (15)
Series C,
-
72.7 (58) 73 (52)
25 (30) 25 (30)
2.3 (12) 2 (18)
Series
35 (31) 28 (26)
54.2 (57) 51.3 (51)
-
36 (32) 40 (31) 44 (26)
37 (39) 31 (33) 30.2 (33)
coVP-MMAi 27 (29) 27 (27) 21.5 (25)
40 (28.5) 40.5 (26.5)
18 (19.5) 17 (16.5)
41.5 (45) 39.3 (41)
1.5 (7) 3.2 (16)
-
61 (54) 53 (45)
36.5 (38) 42 (37)
2.5 (8)
System I Series A,
Series
B,
D
System II Series A2
Series
B2
Series C2
‘Determined ‘Determined
1.6 (10) 2 (19)
10.8 (12) 20.7 (23)
2 (9) 4.3 (16)
5 (18)
by TG analysis. by ‘H-NMR spectroscopy
chains (system II) and from homopolymers (system I). The major difference is the solubility of the complexed species, since PVP-IB complex is readily soluble in the hydrated medium, whereas the IB-VP complex from copolymer chains is insoluble in the medium and remains as a highly hydrated gel. This means that the complexed IB in the highly hydrated gel is not released until the interactions between IB and water compensate for the interactions between IB and VP, and only free IB is incorporated in the buffer. This is probably the reason why a small percentage of IB is not released from system II after 5 days of study. After the swelling and release experiments, the composites were analysed by TG-DTA and ‘H-NMR. The results obtained are presented in Table 2. There is a good agreement between the IB data obtained after the analysis of the samples by NMR and the concentration of IB released in the phosphate buffer (Figure 6). Figure 7 shows the TG-DTA curve of a composite of system I (Figure 7~) and system II (Figure 7b). The TG diagrams show a weight loss in the interval SO-100°C
Time
(hours)
Figure 6 9wt%
IB release (mol%) from composites containing IB versus immersion time: a, system I; b, system II.
mainly beyond 20 h. However, it is necessary to stress that the percentage of IB released from this system is lower than that of system I and that the rate of IB release for both systems is higher when PVP is incorporated in the composite. These variations are due to the differences between the VP-IB complex formed from hydrated copolymer Biomaterials
1997, Vol. 18
No.
18
associated with water absorption during the swelling process. These data are similar to those obtained by gravimetry for system II (Figure 5b), but slightly higher for system I (Figure ~a). This is expected since the PVP-IB complex is readily solubilized in the medium during the swelling process. With respect to the DTA diagrams, samples of system I (Figure 7~) show only one sharp exothermic peak around 390°C. This peak was postulated to be due to thermo-oxidative degradation of the polymeric matrix. However, the characteristic peak around 475°C due to the molecular PVP-IB complex (Figure 3~) in original composites before the immersion in buffered solution is not present in the DTA diagram. However, the DTA curve of a composite of system II (Figure 7b), in addition to the peak at 3%Y’C, shows an exothermic peak assigned to the VP-IB complex.
Ibuprofen
release from ceramic-polymer
composites:
D. Arcos et al.
a TG
4. * 88% 5.
6.
7. 8.
9.
10.
11.
12.
T OC Figure7 TG-DTA curves of the composites containing 9wt% I6 after immersion during 5 days in the buffered solution: a,c(-A12031PVP!PMMAIIB; b, co-VP-MMAIPMMAIIB.
13.
According to the explanation suggested for the release of IB, PVP in system I has to decrease with time and co-VP-MMA in system II has to remain constant. The analys(is by ‘H-NMR spectroscopy of samples obtained after the release experiment supports the above interpretation (see Table 2). These results confirm that the incorporation of IB in the polymer-drug complex has a significant effect on the release of IB in phosphate buffer. System I, consisting of PVP-IB complex, releases IB as a complex of PVP, while system II releases free IB molecules in the buffered solution.
15.
14.
16.
17.
18.
ACKNOWLEDGEMENTS 19.
We acknowledge the financial support of CICYT (Spain) through Research Project MAT96-0919. 20.
REFERENCES 1.
2.
3.
Murray, C. A., In Bond Orientational Order in Condensed Matter Systems, ed. K. J. Strandburg. Springer, New York, 1992, p. 317. Garetz, B.A., Balsana, N.P., Dai, H. J., Wang, Z., Newstein, M. C. and Majundar, B., Orientation correlations in lamellar block copolymers. Macromolecules, 1996, 29, 467546’79. Landry, C. J.T., Coltrain, B. K., Teegarden, D., Long, T. E. and Long, V. K., Use of organic copolymers as
21.
22.
1241 compatibilizers for organic-inorganic composites. Macromolecules, 1996, 29, 47124721. Landry, C. J.T., Coltrain, B.K. and Brady, B. K., In situ polymerization of tetraethoxysilane in poly(methy1 methacrylate): morphology and dynamic mechanical properties. Polymer, 1992, 33,1486-1495. Landry, C. J. T., Coltrain, B. K., Wesson, J. A., Lippert, J. L. and Zumbulyadis, N., In situ polymerization of tetraethoxysilane in polymers: chemical nature of interactions. Polymer, 1992, 33, 1496-1506. Toki, M., Chow, T.Y., Ohnaka, T., Samura, H. and Saegusa, T., Structure of poly(viny1 pyrrolidone)-silica hybrid. Polym. Bull., 1992, 29, 653-660. Peppas, N. A. (ed.), Hydrogels in Medicine and Pharmacy, Vols 1-3.CRC Press, Boca Raton, FL, 1987. Davis, T. P. and Huglin, M. B., Studies on copolymeric hydrogels of N-vinyl-2-pyrrolidone with 2hydroxyethyl methacrylate. Macromolecules, 1989, 22, 2824-2829. Davis, T. P. and Huglin, M. B., Effect of composition on properties of copolymeric N-vinyl-2-pyrrolidone/ methyl methacrylate hydrogels and organogels. Polymer, 1990, 31,513-519. Kuzma, P., Moo-Young, A. J., Moro, D., Quandt, H., Bardin, C. W. and Schlegel, P.H., Subcutaneous hydrogel reservoir system for controlled drug delivery. Macromolec. Symp., 1996, 109,15-26. Okano, T., Yui, N., Yokoyama, M. and Yoshida, R., Polymeric Systems for Drug Delivery. Gordon and Sciences, Switzerland, 1993,p. 67. Peppas, N. A. and Sahlin, J. J., Hydrogels as mucoadhesive and bioadhesive materials: a review. Biomaterials, 1996,17,1553-1561. Biihler, V., Poly(vmy1 Pyrrolidone) for the Pharmaceutical Industry, 2nd edn. BASF, Germany, 1993. Nicholson, J. and Anstice, M., The development of modified glass-ionomer cements for dentistry. Trends Polym. Sci., 1994, 2, 272-276. Keszler, B., Kennedy, J. P., Ziats, N. P. et al., Amphiphilit networks: polar/nonpolar surface characteristics, protein adsorption from human plasma and cell adhesion. Polym. Bull., 1992, 29, 681-688. Keipert, S., Voigt, R. and Schwarz, K.H., Interactions between macromolecular adjuvants and drugs, 29: Propipocaine-polyvinylpyrrolidone associates. Pharmazie, 1980,35, 3540. Zaharieva, E. I., Georgiev, G. G. and Konstantinov, C. I., Coated reactive carriers based on copolymers of Nvinyl-2-pyrrolidone and maleic anhydride for immobilization of enzymes. Biomaterials, 1996, 17,1609-1613. Plaizier-Vercammen, J. H. and De Neve, R. E., Interactions of povidone with aromatic compounds III: Thermodynamics of the binding equilibria and interaction forces in buffer solutions at varying pH values and varying dielectric constant. J. Pharm. Sci., 1982, 71,552-556. Abdel Azin, A. A., Tenhu, H., Maerta, J. and Sundholm, F., Flexibility and hydrodynamic properties of poly(vinyl pyrrolidone) in non-ideal solvents. Polym. Bull., 1992,29,461-467. Zhang, Y., Kennedy, J. F. and Knill, C. J., Kinetic analysis of ethanol production from glucose fermentation by yeast cells immobilized onto ceramic supports. J. Biomater. Sci., Polym. Edn, 1996,7,1119-1126. Papirer, E., Perrin, J.M., Nanse, G. and Fioux, P., Adsorption of poly(methy1 methacrylate) on a-alumina: evidence of formation of surface carboxylate bonds. Eur. Polym. J., 1994, 30, 985-991. Romero, M. A., Chabert, B. and Domard, A., IR spectroscopy approach for the study of interactions between an oxidized aluminium surface and a poly(propyleneg-acrylic acid) film. J. Appl. Polym. Sci., 1993, 47, 543554. Biomaterials 1997, Vol. 18 No. I8
1242 23. 24.
25.
26.
Ibuprofen release from ceramic-polymer X-Ray Powder Data File, ASTM 43-1484, 1991. Rodriguez-Lorenzo, L. M., Salinas, A. J., Vallet-Regi, M. and San Roman, J., Composite biomaterials based on ceramic-polymers. I. Reinforced systems based on A1203/PLLA/PMMA. J. Biomed. Mater. Res., 1996, 30, 515-522. Pefia, J., Vallet-Regi, M. and San Roman, J., TiOzpolymer composites for biomedical applications. J. Biomed. Mater. Res., 1997, 35, 129-134. Vallet-Regi, M., Granado, S., Arcos, D. et al., Selective release of R ( - ) and S ( + ) stereoisomers of ibuprofen from composites of A1203/PLLA/PMMA
Biomaterials
1997,
Vol.
18 No. 18
27.
28.
composites:
D. Arcos et al.
for orthopaedic surgery. Communication to the Fifth World Biomaterials Congress, Toronto, Canada, 1996, 11770. Lichkus, A., Painter, P. C. and Coleman, M. M., Hydrogen bonding in polymer blends. 5. Blends involving polymers containing methacrylic acid and oxazoline groups. Macromolecules, 1988,21,2636-2641. Meaurio, E., Velada, J. L., Cesteros, L.C. and Katime, I., Blends and complexes of poly(monomethy1 itaconate) with polybases poly(N,N-dimethylacrylamide) and poly(ethyloxazoline). Association and thermal behavior. Macromolecules, 1996, 29,4598-4604.
ELSEVIER
SO142-9612
(97)
00054-9
0142-9612/97/517,00
Ibuprofen release fcom hydrophilic ceramic-polymer composites D. Arcos*, M.V. Cab&as*, J. San Romcin*+
C.V. Ragel”, M. Vallet-Regi* and
‘Departamento de Quimica lnorgenica y BioinorgBnica, Faculfad de Farmacia, UCM, 28040 Madrid, Spain; tlnstifuto de Ciencia y Tecnologia de Polimeros, CSIC, Juan de /a Cierva, 3, 28006 Madrid, Spain
Two composite systems composed of a-A1203/poly(methyl methacrylate) (PMMA)/poly(vinyl pyrrolidone) (PVP)/ibuprofen or cr-A1203/PMMA/co-vinyl pyrrolidone-methyl methacrylate/ibuprofen were prepared by free radical polymerization. These systems were characterized by spectroscopic techniques and thermogravimetric and differential thermal analyses. The hydration behaviour of composites with different hydrophilic characters was analysed after the immersion of the composites in buffered solution at pH 7.4 and 37°C. The swelling of the composites depends strongly on the content of the hydrophilic component and is controlled by the presence of the ceramic component. The release of the anti-inflammatory drug, ibuprofen, from the composites in buffered solution was followed by UV spectroscopy and the results obtained indicated that the components of the composites influenced the rate of release of the drug, without the classical ‘burst’ effect observed frequently with hydrophilic systems. 0 1997 Elsevier Science Limited. All rights reserved Keywords:
Ceramic-polymer
composites,
hydrophilic
composites,
vinyl pyrrolidone,
ibuprofen,
drug
release
Received 11 November 1996; accepted 11 March 1997
Organic-inorganic c:omposites represent a family of materials which have several applications in the field of biomaterials. In these heterogeneous systems, the morphology and the characteristics of the interface are critical to determine the properties of the composites1-3. Polymers such as poly(methy1 methacrylate) (PMMA)4,5, and poly(viny1 poly(N,N-dimethylacrylamide)5 pyrrolidone) (PVP)5*6 have been shown to stabilize hydrogen bonding with hydroxyl-functional components and silicate compounds. This results in an effective control of phase separation and stability of the interphase. PVP and copolymers of vinyl pyrrolidone (VP) with other vinyl and acrylic monomers have been used as hydrogels and pa&cularly as support matrices for controlled drug re.lease7-“. In these systems, the polymer support usually displays an asymmetric bellshaped release profile, sometimes characterized by an initial large ‘burst’ effect’0”3S14. PVP is a hydrophilic polymer with excellent biocompatibility, but very soluble in water and physiological fluids13. Although the solubility of polymeric systems based on VP can be controlled by copolymerization with other hydrophobic monomers, in general their mechanical properties and therefore the delivery potency is controlled with some difficulty. In addition, the pyrrolidone ring interacts strongly with polar groups such as carboxylic acids, hydroxyl or even inorganic salts and oxides14-1g. Ceramics exhibit unique physical and chemical
properties not shown by organic supports. For example, alumina, zirconia or titanium dioxide present structural stability without swelling and are resistant to environmental chemical reactions. In addition, if there are physico-chemical interactions between the stable bioceramics and the polymeric components, composite s stems with specific properties can be prepared’&’ Y. Therefore, the present paper deals with the preparation and analysis of composite systems based on PMMA, PVP or copolymers of VP-methyl methacrylate (MMA) and a-alumina, as well as their use as support matrices for the controlled release of ibuprofen (IB), a non-steroid anti-inflammatory agent. These implants could be used for implantation in bone tissue or as ingredients for the preparation of bone or dental cements.
MATERIALS AND METHODS Reagents and products The ceramic component, alumina (a-A1203), was nitrate prepared by decomposition from A1(N0&9Hz0 treated at 400°C (12 h), 900°C (24 h) and finally at 1250°C (33 h). The reaction product was characterized by X-ray diffraction (XRD) on a Philips X’Pert MPD diffractometer (CuK, radiation). All reflections on the XRD pattern could be indexed on the basis of an a-A1203 phasez3 and no extra peaks were observed.
Correspondence to Dr Ivl. Vallet-Regi. 1235
Biomaterials
1997,
Vol. 16 No. 18
Ibuprofen
1236
The morphology of the ceramic obtained was analysed by scanning electron microscopy (SEM) using a Jeol JSM 6400 microscope. The powder so obtained is formed by agglomerated particles with irregular morphology. Figure la shows one of these aggregates, characteristic of this ceramic material, obtained by nitrate decomposition, Each one of these aggregates is formed by several sintered particles, as a consequence of the applied thermal treatment. Figure lb shows a magnification of the aggregate surface shown in Figure la; the unions between particles and their rounded contours become evident; this aspect is a consequence of the sintering process. PVP was prepared by the free radical polymerization of VP in isopropanol solution using azobisisobutyronitrile (AIBN) as the free radical initiator at 60°C. The polymer obtained was precipitated in excess diethyl ether, filtered, washed and finally dried at low pressure until constant weight. The average molecular weight of the polymer was determined by size exclusion chromatography (SEC) using dimethylformamide as solvent and calibration with polystyrene standards (Polymer Laboratories). The values obtained were fi, = 36 000 and &l, = 98 000, with a polydispersity index of I&,/I&, = 2.72. A copolymer of VP with MMA, co-VP-MMA, was obtained by the free radical polymerization of a
release
from
ceramic-polymer
composites:
D. Arcos
et al.
with an average mixture of both monomers composition 70 wt% VP and 30 wt% MMA, using AIBN as initiator at 60°C during 6 h. The copolymer was isolated by precipitation in cool diethyl ether, washed and dried under vacuum until a constant weight was obtained. The molecular weight of the purified sample was determined by SEC, giving values of I$, = 32 000 and &&, = 104 000, with a polydispersity index of i&lfi,, = 3.25. Composites of A1203/PMMA/PVP (system I) or A1203/PMMA/co-VP-MMA (system II) charged with different amounts of IB as the pharmacologically active component were prepared by the free radical polymerization of a mixture of c(-A1203, MMA and PVP or co-VP-MMA using 0.5 wt% benzoyl peroxide as initiatorZ4. Cylindrical specimens (6 mm diameter, 1Omm length) were obtained by using Teflon moulds at a polymerization temperature of 60°C for 1 h and subsequently at 80°C for 24 h. In order to study the influence of each component in vitro, different series of composites were prepared with the compositions described in Table 1. We consider series for both systems with the same composition in VP units as analogous, independent of the nature of the polymeric chains, i.e. PVP for system I and co-VP-MMA for system II.
Characterization The composites synthesized were characterized by thermogravimetric and differential thermal analysis (TG-DTA), proton nuclear magnetic resonance (lHNMR) spectroscopy, XRD and Fourier transform infrared spectroscopy (FTIR). Thermal studies, TG and DTA, were carried out on a TG-DTA 320 Seiko thermobalance, with a heating rate of 10°C min-l in the range of 25-600°C under flow of air (50ml mini’). IH-NMR spectra were registered, after extraction of the organic components from the composite specimens with deuterated chloroform, using a Varian XL300 NMR spectrometer. X-ray data were obtained, using CuK, radiation, with a Philips X’Pert MPD diffractometer equipped with a multipurpose sample holder for non-destructive analysis of samples, which allows the study of the crystalline components of the cylinders. Infrared spectra were recorded on a Nicolet-520 FTIR spectrophotometer. The spectra were registered with KBr pellets.
Swelling hehaviour
and drug release
Composites in the form of cylinders were immersed in lOm1 of a phosphate-buffered solution (KH,PO,/ K2HP04) at pH 7.4 and a temperature of 37°C. The swelling of the samples studied was monitored by measuring the water intake gravimetrically as a function of time during 5 days. The amount of swelling (H) was determinedz5 using the following equation: H (%) =
Figure 1 a, SEM photograph of obtained. b, Detailed area of SEM xl0000 magnification. Biomaterials
1997. Vol. 18 No. 18
c+A1203 sample asphotograph taken at
w - wox
w
100
0
where W, is the weight of the cylinder after immersion in water and W, is the initial weight. The release of IB in the buffered solution was followed by UV spectroscopy, using a Perkin-Elmer
Ibuprofen
release
Table 1
System Series
from
Composition
ceramic-polymer
composites:
(wt%) of composites
synthesized
D. Amos et a/.
1237
a-A1203 Exp.’ (theor.)
PMMA Exp..t (theor.)
PVP Exp.t (theor.)
IB Expt (theor.)
35 (30) 27 (27) 30 (25)
44 (49) 43 (45) 33 (41)
21 (21) 20 (19) 18 (17)
lo (9) 19 (17)
I A,
Series
B,
26 (27) 26 (25)
31 (32) 26 (29)
34 (32) 33 (29)
9 (9) 15 (17)
Series
C, D
58 (64) 52 (58) 57 (64)
30 (27) 30 (25) -
12 (9) 18 (17)
Series
31 (27) 26 (25)
51 (58)
-
32 (30)
39 (40)
31 (27) 26 (25)
33 (37) 33 (33)
coVP-MMA+ 29 (30) 27 (27) 25 (25)
System II Series A,
12 (9) 23 (17) 9 (9) 16 (17)
Series
B2
28.5 (27) 26.5 (25)
19.5 (18.5) 16.5 (16.5)
45 (45.5) 41 (41.5)
7 (9) 16 (17)
Series
C2
-
54 (52.5) 45 (47.5)
38 (38.5) 37 (35.5)
8 (9) 18 (17)
*Determined by TG analysis. ‘Determined by ‘H-NMR spectroscopy.
PMMA
554 spectrophotometer. The amount of IB released in the buffer was measured at i = 264nm. A calibration curve obtained with pure IB was used to determine the concentration of drug released. The UV spectra of PVP solutions showed an absorption at the same wavelength (A = 264nm), with much lower intensity than that of the IB at the concentrations of reagents used in this work. Therefore, the contribution of PVP was taken into consideration, in all the cases, by the analysis of parallel formulations and the correspondi:ng subtraction of the contribution due to the PVP complonent.
(OCH,,
we
:k-
RESULTS AND DISCUSSION The free radical polymerization of mixtures or dispersions in the form of slurries of ceramic, polymers and monomers could be used to fabricate biomaterials for filling hard tissues with controlled delivery properties of specific drugs and growth factors. In the case of Al,O,/PVP/MMA or Al,03/co-VP-MMAIMMA the polymerization reaction described above can be used to fabricate hard cylindrical composites. The actual percentage of a-A1203 in the composites was obtained by TG analysis. The results obtained for the different series prepared are shown in Table I. In all the cases, the percentage of ceramic is slightly higher than the corresponding theoretical value. This is due to the partial volatilization of MMA monomer during the preparation of composites. Data obtained by the analysis of portions taken from different sections of the composite cylinders gave the same results within experimental error (~2 wt%), which indicates that the ceramic component is distributed homogeneously in the bulk composite. The actual content of organic components was obtained from the analysis of the ‘H-NMR spectra. Figure 2 shows the ‘H-NMR spectrum of the organic fraction of a composite of system I (series A1 with 17% IB). The comparison, of the integrated intensities of
Figure 2 ‘H-NM!? spectrum (series A, with 17wt% of IB).
of a composite
of system
I
signals assigned in Figure 2 provided the molar fraction of each component (PVP, PMMA and IB) in the composite specimens. The weight percentage of these components was calculated taking into consideration the total weight of the sample and the cr-AlzOB percentage obtained by TG. Results are shown in Table 1. The organic fraction of samples of system II give ‘H-NMR spectra similar to that shown in Figure 2, but in this case the contribution to the NMR signal the of 0-CH3 groups (3.6 ppm) corresponds to MMA units of the co-VP-MMA as well as those of the side CH3-0 groups formed by the free radical polymerization of the monomer. However, it is possible to calculate the average percentage of each component (CO-VP-MMA, PMMA and IB) assuming that the composition of the coVP-MMA is not modified by the free radical reaction. The XRD patterns of the composites of series A, B and C of both systems showed diffraction maxima characteristic of a-A120Sz3, distributed in an amorphous matrix (associated with the polymeric components). Biomaterials
1997,
Vol. 18 No. 18
Ibuprofen release from ceramic-polymer composites: D. Amos et al.
1238
Series C XRD patterns are characteristic of amorphous materials. In all cases diffraction maxima due to IB were absent, which indicated that this component appears to be in an amorphous form or was in the form of very small crystallites not detectable by XRD. Recent studies carried out on cc-A120Jpoly(lactic acid)/PMMA/IB composites’” demonstrated that IB crystallized only when cr-A120s and poly(lactic acid) crystallites were incorporated in the composites. However, if any of these components were not present, the IB remained amorphous. These results indicate that both crystalline phases are necessary to promote the crystallization of IB. Thus, the unique presence of A1203 in the composites of the present work was not enough to induce the crystallization of IB. Thus, the IB remained in an amorphous state in the composites prepared with PVP or co-VPMMA. Figure 3 shows the TC-DTA diagrams for three representative composites of system I with different compositions. The characteristic diagrams for samples containing IB (Figure 3a, b) do not show any melting peaks at TO-75°C (the melting point of pure IB is i?YC), which supports the fact that IB does not crystallize during the preparation of the composites. On the other hand, the appearance of a relatively sharp peak around 366°C for all the samples was associated with oxidative decomposition of the organic components. However, only the systems containing PVP and IB (Figure 3~) gave a new sharp peak around 475°C. Similar results were obtained for samples of system II. It is well known that PVP, according to its chemical structure, forms molecular complexes with a great number of pharmacologically active compounds1G18. The data obtained by DTA support the formation of a complex between IB and PVP. In system II, the complex could be formed by the interactions of the IB molecules with the VP units distributed along the copolymer chains. Molecular complexes can be studied easily by spectroscopic techniques like FTIR. We have detected the formation of complexes between IB and PVP by FTIR analysis of mixtures of IB/PVP. Figure 4 shows the FTIR spectra of pure IB, PVP and that of an equimolecular mixture of IB/PVP after thermal treatment at 80°C for 24 h. The spectrum of the mixture shows a sharp peak at 1640 cm-‘, in the carbonyl stretching region, which does not appear in the spectra of IB or PVP. The intensity of this peak changes with the composition of the system and can be assigned to complexed species through the carboxylic group of IB with the carbonyl group or the nitrogen of the PVP chains. This trend has been described for other systems which form complexes through hydrogen bonds2792*. Therefore, the data obtained by FTIR and by DTA support complex formation between IB and VP. Swelling bebaviour and drug release The composites of systems I and II present different behaviours due to the swelling process and delivery of IB. This is a consequence of the presence of PVP (soluble polymer in the hydrated medium) in system I, Biomaterials
1997.
Vol. 18 No. 18
30
315
000
T “C Figure 3 TG-DTA curves of different composites constituted by: a, ct-A12031PVPIPMMAII13; b, u-A1203/PMMA/IB; c, a-A12031PVPIPMMA.
or co-VP-MMA, which forms a highly hydrated but in soluble gel, in system II. Figure 5 shows the variation of the degree of hydration (Ef) with the time of immersion in the buffered solution at pH 7.4 for both systems. For all the compositions of system I (Figure ~a), prepared with PVP, the samples analysed reached the equilibrium of the swelling process in a short time (about 3 h), but the value of the maximum degree of hydration changed drastically with the composition. Samples without PVP (series D) showed a maximum degree of hydration of 3.5%, characteristic of PMMA bone cements, whereas the series prepared with PVP (series Al, B1 and C,) reached equilibrium degrees of hydration between 13 and 18%, depending on the
Ibuprofen release from ceramic-polymer
composites:
D. Amos et al.
w 4000
2800
1600
400
U (cm-l) Figure 4 FTIR spectra of: a, IB; b, PVP; c, a mixture of IB and PVP.
bf+----4 30 s 'C !! 0 20 I"
I
l
10
ow
6b
Time
6b
,
I
100
120
(hours)
Figure 5 Swelling behaviour of composites 9wt% IB: a, system I; b!, system II.
containing
1239
content of PVP. According to the actual compositional data reported in the fourth column of Table 1, it seems that there is a linear variation of the degree of swelling with the fraction of PVP in the composition interval studied (ZO-35% of PVP). It is necessary to consider that, in this series, both the PVP and the IB are soluble in the buffered solution, and therefore the values represented in Figure 5a would be slightly higher than those obtained by gravimetry, but the influence of the hydrophilic polymer in the swelling behaviour of the composites is clear. In the case of system II, which corresponds to composites prepared with co-VP-MMA (70:30), insoluble in the hydrated medium but with a high capacity for water absorption, the maximum swelling is reached after 25 h of immersion in the buffered solution (Figure 5b). Series Bz, with a relatively high content of co-VP-MMA (4Owt%) and a co-VP-MMAI PMMA ratio = 2.4 (see Table z), reached the highest degree of hydration (54% in 25 h). Series AZ and CZ correspond to more hydrophobic composites, with a co-VP-MMAIPMMA ratio of 0.8, giving degrees of hydration lower than samples Bz (14 and 34%, respectively) after 25 h of treatment. The difference between series AZ and CZ is the presence of the ceramic in series AZ, which is responsible for the relatively low degree of hydration reached, indicating the strong influence of AlzO, in the hydration process, probably through interactions of the surface of the A1,03 particles with the side carboxylic ester groups of the methacrylate units in co-VP-MMA. The differences in the swelling process for systems I and II are important, since the gel character in system II is due to co-VP-MMA, in contrast to the soluble PVP in system I. These differences markedly affect the release of IB from both systems. Figure 6 shows the cumulative percentage of IB released over time from the various composites containing the same amount of IB (9%). As expected, samples of series D (Figure 6a) show a very slow release of IB. In 5 days, lOmol% IB was delivered without any burst effect. In contrast, in series Al, B1 and C1, IB was released in a relatively fast manner (ca 20mol%) during the initial 2 h and then in a controlled manner during the rest of the experimental period. Differences in the release of IB from composites prepared with and without A1,03 were not significant. From these results it is clear that PVP affects the mechanism of delivery of IB in such a way that the PVP hydrophilic polymer acts as a carrier of IB and is solubilized as a molecular complex. The PVP-IB complex is more soluble than the IB itself13. This is clear by comparing these results with the behaviour of samples D, in which the release of IB is produced only by diffusion from a hydrophobic composite or with other A1203polymer composites prepared with biodegradable polymers like poly(lactic acid)26. Figure 6b shows the cumulative release of IB from the composites of system II. In all cases the rate of release depends strongly of the co-VP-MMAIPMMA ratio in the composites (see Table 2). Series BZ, with a ratio of 2.5, presents the highest delivery percentage. In this system, the presence of the ceramic seems to slightly favour the release of IB, Biomaterials
1997, Vol. 18 No. 18
Ibuprofen
1240 Table 2
Composition
(wt%) of composites
after immersion
release
from
for 5 days in the buffered
ceramic-polymer
composites:
D. Arcos et al.
solution
c(-AI~O~* After (before)
PMMA+ After (before)
PVP+ After (before)
IB+ After (before)
37 (35) 39 (27) 44 (30)
47 (44) 47 (43) 37.5 (33)
16 (21) 12.4 (20) 13.5 (18)
-
35.6 (26) 41.5 (26)
39 (31) 35.5 (26)
24 (34) 22 (33)
1.4 (9) 1 (15)
Series C,
-
72.7 (58) 73 (52)
25 (30) 25 (30)
2.3 (12) 2 (18)
Series
35 (31) 28 (26)
54.2 (57) 51.3 (51)
-
36 (32) 40 (31) 44 (26)
37 (39) 31 (33) 30.2 (33)
coVP-MMAi 27 (29) 27 (27) 21.5 (25)
40 (28.5) 40.5 (26.5)
18 (19.5) 17 (16.5)
41.5 (45) 39.3 (41)
1.5 (7) 3.2 (16)
-
61 (54) 53 (45)
36.5 (38) 42 (37)
2.5 (8)
System I Series A,
Series
B,
D
System II Series A2
Series
B2
Series C2
‘Determined ‘Determined
1.6 (10) 2 (19)
10.8 (12) 20.7 (23)
2 (9) 4.3 (16)
5 (18)
by TG analysis. by ‘H-NMR spectroscopy
chains (system II) and from homopolymers (system I). The major difference is the solubility of the complexed species, since PVP-IB complex is readily soluble in the hydrated medium, whereas the IB-VP complex from copolymer chains is insoluble in the medium and remains as a highly hydrated gel. This means that the complexed IB in the highly hydrated gel is not released until the interactions between IB and water compensate for the interactions between IB and VP, and only free IB is incorporated in the buffer. This is probably the reason why a small percentage of IB is not released from system II after 5 days of study. After the swelling and release experiments, the composites were analysed by TG-DTA and ‘H-NMR. The results obtained are presented in Table 2. There is a good agreement between the IB data obtained after the analysis of the samples by NMR and the concentration of IB released in the phosphate buffer (Figure 6). Figure 7 shows the TG-DTA curve of a composite of system I (Figure 7~) and system II (Figure 7b). The TG diagrams show a weight loss in the interval SO-100°C
Time
(hours)
Figure 6 9wt%
IB release (mol%) from composites containing IB versus immersion time: a, system I; b, system II.
mainly beyond 20 h. However, it is necessary to stress that the percentage of IB released from this system is lower than that of system I and that the rate of IB release for both systems is higher when PVP is incorporated in the composite. These variations are due to the differences between the VP-IB complex formed from hydrated copolymer Biomaterials
1997, Vol. 18
No.
18
associated with water absorption during the swelling process. These data are similar to those obtained by gravimetry for system II (Figure 5b), but slightly higher for system I (Figure ~a). This is expected since the PVP-IB complex is readily solubilized in the medium during the swelling process. With respect to the DTA diagrams, samples of system I (Figure 7~) show only one sharp exothermic peak around 390°C. This peak was postulated to be due to thermo-oxidative degradation of the polymeric matrix. However, the characteristic peak around 475°C due to the molecular PVP-IB complex (Figure 3~) in original composites before the immersion in buffered solution is not present in the DTA diagram. However, the DTA curve of a composite of system II (Figure 7b), in addition to the peak at 3%Y’C, shows an exothermic peak assigned to the VP-IB complex.
Ibuprofen
release from ceramic-polymer
composites:
D. Arcos et al.
a TG
4. * 88% 5.
6.
7. 8.
9.
10.
11.
12.
T OC Figure7 TG-DTA curves of the composites containing 9wt% I6 after immersion during 5 days in the buffered solution: a,c(-A12031PVP!PMMAIIB; b, co-VP-MMAIPMMAIIB.
13.
According to the explanation suggested for the release of IB, PVP in system I has to decrease with time and co-VP-MMA in system II has to remain constant. The analys(is by ‘H-NMR spectroscopy of samples obtained after the release experiment supports the above interpretation (see Table 2). These results confirm that the incorporation of IB in the polymer-drug complex has a significant effect on the release of IB in phosphate buffer. System I, consisting of PVP-IB complex, releases IB as a complex of PVP, while system II releases free IB molecules in the buffered solution.
15.
14.
16.
17.
18.
ACKNOWLEDGEMENTS 19.
We acknowledge the financial support of CICYT (Spain) through Research Project MAT96-0919. 20.
REFERENCES 1.
2.
3.
Murray, C. A., In Bond Orientational Order in Condensed Matter Systems, ed. K. J. Strandburg. Springer, New York, 1992, p. 317. Garetz, B.A., Balsana, N.P., Dai, H. J., Wang, Z., Newstein, M. C. and Majundar, B., Orientation correlations in lamellar block copolymers. Macromolecules, 1996, 29, 467546’79. Landry, C. J.T., Coltrain, B. K., Teegarden, D., Long, T. E. and Long, V. K., Use of organic copolymers as
21.
22.
1241 compatibilizers for organic-inorganic composites. Macromolecules, 1996, 29, 47124721. Landry, C. J.T., Coltrain, B.K. and Brady, B. K., In situ polymerization of tetraethoxysilane in poly(methy1 methacrylate): morphology and dynamic mechanical properties. Polymer, 1992, 33,1486-1495. Landry, C. J. T., Coltrain, B. K., Wesson, J. A., Lippert, J. L. and Zumbulyadis, N., In situ polymerization of tetraethoxysilane in polymers: chemical nature of interactions. Polymer, 1992, 33, 1496-1506. Toki, M., Chow, T.Y., Ohnaka, T., Samura, H. and Saegusa, T., Structure of poly(viny1 pyrrolidone)-silica hybrid. Polym. Bull., 1992, 29, 653-660. Peppas, N. A. (ed.), Hydrogels in Medicine and Pharmacy, Vols 1-3.CRC Press, Boca Raton, FL, 1987. Davis, T. P. and Huglin, M. B., Studies on copolymeric hydrogels of N-vinyl-2-pyrrolidone with 2hydroxyethyl methacrylate. Macromolecules, 1989, 22, 2824-2829. Davis, T. P. and Huglin, M. B., Effect of composition on properties of copolymeric N-vinyl-2-pyrrolidone/ methyl methacrylate hydrogels and organogels. Polymer, 1990, 31,513-519. Kuzma, P., Moo-Young, A. J., Moro, D., Quandt, H., Bardin, C. W. and Schlegel, P.H., Subcutaneous hydrogel reservoir system for controlled drug delivery. Macromolec. Symp., 1996, 109,15-26. Okano, T., Yui, N., Yokoyama, M. and Yoshida, R., Polymeric Systems for Drug Delivery. Gordon and Sciences, Switzerland, 1993,p. 67. Peppas, N. A. and Sahlin, J. J., Hydrogels as mucoadhesive and bioadhesive materials: a review. Biomaterials, 1996,17,1553-1561. Biihler, V., Poly(vmy1 Pyrrolidone) for the Pharmaceutical Industry, 2nd edn. BASF, Germany, 1993. Nicholson, J. and Anstice, M., The development of modified glass-ionomer cements for dentistry. Trends Polym. Sci., 1994, 2, 272-276. Keszler, B., Kennedy, J. P., Ziats, N. P. et al., Amphiphilit networks: polar/nonpolar surface characteristics, protein adsorption from human plasma and cell adhesion. Polym. Bull., 1992, 29, 681-688. Keipert, S., Voigt, R. and Schwarz, K.H., Interactions between macromolecular adjuvants and drugs, 29: Propipocaine-polyvinylpyrrolidone associates. Pharmazie, 1980,35, 3540. Zaharieva, E. I., Georgiev, G. G. and Konstantinov, C. I., Coated reactive carriers based on copolymers of Nvinyl-2-pyrrolidone and maleic anhydride for immobilization of enzymes. Biomaterials, 1996, 17,1609-1613. Plaizier-Vercammen, J. H. and De Neve, R. E., Interactions of povidone with aromatic compounds III: Thermodynamics of the binding equilibria and interaction forces in buffer solutions at varying pH values and varying dielectric constant. J. Pharm. Sci., 1982, 71,552-556. Abdel Azin, A. A., Tenhu, H., Maerta, J. and Sundholm, F., Flexibility and hydrodynamic properties of poly(vinyl pyrrolidone) in non-ideal solvents. Polym. Bull., 1992,29,461-467. Zhang, Y., Kennedy, J. F. and Knill, C. J., Kinetic analysis of ethanol production from glucose fermentation by yeast cells immobilized onto ceramic supports. J. Biomater. Sci., Polym. Edn, 1996,7,1119-1126. Papirer, E., Perrin, J.M., Nanse, G. and Fioux, P., Adsorption of poly(methy1 methacrylate) on a-alumina: evidence of formation of surface carboxylate bonds. Eur. Polym. J., 1994, 30, 985-991. Romero, M. A., Chabert, B. and Domard, A., IR spectroscopy approach for the study of interactions between an oxidized aluminium surface and a poly(propyleneg-acrylic acid) film. J. Appl. Polym. Sci., 1993, 47, 543554. Biomaterials 1997, Vol. 18 No. I8
1242 23. 24.
25.
26.
Ibuprofen release from ceramic-polymer X-Ray Powder Data File, ASTM 43-1484, 1991. Rodriguez-Lorenzo, L. M., Salinas, A. J., Vallet-Regi, M. and San Roman, J., Composite biomaterials based on ceramic-polymers. I. Reinforced systems based on A1203/PLLA/PMMA. J. Biomed. Mater. Res., 1996, 30, 515-522. Pefia, J., Vallet-Regi, M. and San Roman, J., TiOzpolymer composites for biomedical applications. J. Biomed. Mater. Res., 1997, 35, 129-134. Vallet-Regi, M., Granado, S., Arcos, D. et al., Selective release of R ( - ) and S ( + ) stereoisomers of ibuprofen from composites of A1203/PLLA/PMMA
Biomaterials
1997,
Vol.
18 No. 18
27.
28.
composites:
D. Arcos et al.
for orthopaedic surgery. Communication to the Fifth World Biomaterials Congress, Toronto, Canada, 1996, 11770. Lichkus, A., Painter, P. C. and Coleman, M. M., Hydrogen bonding in polymer blends. 5. Blends involving polymers containing methacrylic acid and oxazoline groups. Macromolecules, 1988,21,2636-2641. Meaurio, E., Velada, J. L., Cesteros, L.C. and Katime, I., Blends and complexes of poly(monomethy1 itaconate) with polybases poly(N,N-dimethylacrylamide) and poly(ethyloxazoline). Association and thermal behavior. Macromolecules, 1996, 29,4598-4604.