J. MICROENCAPSULATION,
1992,
VOL.
9,
NO.
4, 4 1 5 4 2 3
Release kinetics of fluphenazine from biodegradable microspheres Z. RAMTOOLAT, 0. I. CORRIGANT and C. J. BARRETTS Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
t Department of Pharmaceutics, School of Pharmacy, Trinity College, 18 Shrewsbury Road, Dublin 4, Ireland $ Elan Corporation plc, Monksland, Athlone, Ireland
(Received 1 August 1991; accepted 19 September 1991)
Fluphenazine-loaded microspheres were prepared using biodegradable lactide and lactide-co-glycolide polymers. Sustained release of fluphenazine was achieved with fluphenazine loadings of up to 30 per cent in both the lactide and lactide-co-glycolide polymers. Fluphenazine release from microspheres was found to increase with increasing drug loading and was most rapid from the polyL-lactide-co-glycolide microspheres. The release profiles showed a ‘lag’ period followed by an accelerating release phase and in some cases a decay period, i.e. the release profiles were sigmoidal and fitted the Prout-Tomkins equation (Prout and Tompkins 1944). Consequently it was considered that polymer degradation, the primary rate-determining step controlling drug release, occurred by a mechanism involving propagation of active sites, drug release reflecting the spread of this degradation throughout the polymer.
Introduction Biodegradable microspheres for the controlled release of drugs have been prepared from emulsion systems (Beck et al. 1979,1983, Fong et al. 1986, Wakiyama et al. 1981). I n general release of macromolecules such as the polypeptides-LHRH, calcitonin and somatostatin-is considered to be degradation-controlled (Maulding 1987). However, various mechanisms have been reported for the lower molecular weight drugs and no clear guidelines seem to be evident to enable prediction of the mechanism and/or rate of drug release. Processing variable such as the drugpolymer ratio, polymer composition and physicochemical properties of the drug have been shown to affect the morphology of these systems, which in turn may affect the release of the drug (Beck et al. 1979, 1983, Fong et al. 1986, Wakiyama et al. 1981). Drug release from these systems may range from purely diffusion-controllbd dissolution from a matrix system, in cases when the polymer has a slow degradation rate and the drug molecule is small, to a degradation-controlled release when the drug molecule is large and its permeability through the polymer is low. With the more rapidly degrading polymers drug release can occur through a combination of diffusion and degradation of the polymer (Tice et al. 1982). T h e release of oxytetracycline base from PLA microcapsules and the release of hydrocortisone from DL-PLA microspheres have been fitted to the Higuchi’s spherical matrix model (Vidmar et al. 1984, Leerasamee et al. 1986). T h e release patterns of local anaesthetics from PLA microspheres have been shown to vary depending of the local anaesthetic used, the P L A molecular weight as well as drug loading. T h e drug release may be proportional to the square root of time, may approach zero-order kinetics or can be through extensive disintegration of the 0265-2048/92 83.00 0 1992 Taylor & Francis Ltd.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
416
Z. Ramtoola et al.
microspheres (Wakiyama et al. 1981, 1982 a, b). Varied release patterns from biodegradable microspheres have also been observed with other bases (tertiary amines) where the presence of the amines accelerated the degradation rate of the polymer (Maulding et al. 1986, Cha and Pitt 1988,1989). T h e ability of these amines to catalyse polymer hydrolysis did not correlate with the pK, or log Po,,of the amines (Cha and Pitt 1989). In this report the release kinetics of fluphenazine from biodegradable microspheres were studied. Three polymers: p o l y - ~ ~ - l a c t i dMW e 2000 (PLA), p o l y - ~ lactide-co-glycolide 50 : 50 of i.v. 0.42 dl/g (LPGLA) and poly-DL-lactide-coglycolide 50 : 50 of i.v. 0.5 dl/g (DLPGLA), were used to prepare microspheres containing up to 30 per cent drug loading.
Materials and methods Preparation and evaluation of microspheres Microspheres were prepared with 10, 20 and 30 per cent fluphenazine HCl as previously described (Ramtoola et al. 1990). T h e polymers used were R104 (PLA), poly-L-lactide-co-glycolide 50 : 50 of i.v. 0.42 dl/g (LPGLA) and RG504 (DLPGLA), Boehringer Ingelheim. T h e fluphenazine content of the microspheres was assayed using a UV spectrophotometer (Shimadzu). T h e surface of the microspheres was examined using scanning electron microscopy (Hitachi SSOO). T h e diameter of the microspheres was measured using a Malvern 3600 particle size analyser. In vitro release studies T h e release of fluphenazine from the microspheres was measured in isotonic phosphate buffer pH 7.4 at 37°C under sink conditions as previously described (Ramtoola et al. 1990).
Results and discussion Characteristics of the microspheres All batches of fluphenazine-loaded microspheres were essentially spherical in shape (figure 1). T h e microspheres produced were below 118pm having a mean diameter in the range of 60-70pm. T h e assayed drug content of the microspheres was in the range 60-80 per cent of the initial loading. In vitro release studies The release profiles in figure 2 show sustained release of fluphenazine from the PLA microspheres. An initial burst of fluphenazine at each drug loading was observed which increased with increasing fluphenazine loading. Following the burst, there was an induction period or ‘lag’ time of 10 days at the 10 per cent fluphenazine loading, after which fluphenazine release rate increased and then decreased giving a sigmoidal release profile. At the higher drug loadings the release rate of fluphenazine increased and then declined with no apparent induction period. T h e percentage fluphenazine released at each sampling time increased with increasing fluphenazine loading of the microspheres.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
Fluphenazine biodegradable microspheres
417
2. Ramtoola et al.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
418
z
2c
s
0 0
I
I
I
I
20
40
60
80
100
Time (days)
Figure 2.
Release profiles of fluphenazinefrom PLA 2K microspheres: 0,10%; W , 20%; 30%.
+,
120
;100 v)
a
al
5
80
al
c
Xa
60
-
40
c al r Q
3
c
20-*
*
+ 10
0
Time
30
40
Figure 3. Release profiles of fluphenazine from LPGLA and DLPGLA microspheres in phosphate buffer pH 7.4: , l o % in LPGLA; 0 , 2 0 % in LPGLA; A , 30% in LPGLA; O , l O % in DLPGLA; A , 20% in DLPGLA.
+
Fluphenazine release from both the LPGLA and DLPGLA microspheres (figure 3) was also sensitive to the drug loading. T h e percentage fluphenazine released increased with increasing drug loading and an initial burst, which increased with increasing drug loading, was also observed. Following the burst there was an induction period of 9-10 days at the 10 per cent loading which shortened as the fluphenazine loading of the microspheres was increased. Little or no difference in
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
Fluphenazine biodegradable microspheres
419
release was observed between the LPGLA and DLPGLA microspheres at corresponding drug loadings. However, the release of fluphenazine from copolymer microspheres was faster than fluphenazine release from the lactide microspheres at the low drug loadings, while at the 30 per cent fluphenazine loading there was little difference in release rate. T h e release of basic drugs has been observed to occur at a slower rate from PLA microspheres than from PGLA microspheres (Cha and Pitt 1988). PGLA is the more rapidly degrading polymer and therefore drugs, the release of which is wholly or partially degradation controlled, will be released at a faster rate from PGLA microspheres than from PLA microspheres. T h e release profiles observed for fluphenazine from both PLA and PGLA microspheres suggest degradation-controlled kinetics which may also be assisted by diffusion of the drug. T h e initial burst in release of fluphenazine, observed in all cases, was associated with drug present at or near the surface which diffused out with water penetration. A triphasic release pattern has been observed with nafarelin acetate from lactide-co-glycolide microspheres. An initial rapid release attributed to drug diffusion from the superficial areas of the microspheres was followed by a second phase of lower drug release before the onset of the major drug release phase (Kent et al. 1984,1987, Sanders et al. 1984). As the drug loading of the microspheres is increased a higher amount of drug is expected to be near the surface; thus resulting in an increase in the burst observed (figures 2 and 3). An induction period then followed, during which the polymer degraded before further drug diffusion. T h e induction period shortened with increasing fluphenazine content. As less polymer material is available for degradation the induction period decreases. T h e degradation of the polymer is reportedly autocatalytic, i.e. catalysed by the generation of COOH groups (Schindler et al. 1977) resulting in enhanced polymer degradation rate with time and an accelerated release of the drug (figures 2 and 3). With time, the loss of drug and the diffusion of the low molecular weight polymer chains from the microspheres will result in a fall in release rate of fluphenazine. Photomicrographs (figure 4) of microspheres at various stages during release show the progressive degradation of the microspheres. It was therefore considered that the release kinetics of fluphenazine HCl after the burst may be described by the Prout-Tompkins equation which has been applied to the autocatalytic decomposition of solids, i.e. the drug acting as a marker of polymer degradation. T h e release profiles in figures 2 and 3 were corrected for the burst effects during the first 24h and were fitted to the Prout-Tompkins equation (1) (figures 5-7): In (x/l - x ) - k
x t+c
(1)
where x is the fraction of drug released at time t , k is the rate constant and c = k x t,,,, t,,, being the time for 50 per cent of the drug to be released. For both PGLA and PLA microspheres, k increased and t,,, decreased with increasing drug loading (table 1 ) . At the low drug loadings the release of fluphenazine from the PLA microspheres was slower than from the PGLA microspheres. T h e differences in both the t,,, and k values decreased as the drug loading was increased. T h e k values observed were more sensitive to the drug loading than to polymer composition, which suggests an increase in polymer permeability and/or catalysis of polymer hydrolysis by fluphenazine.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
420 2. Ramtoola et al.
I-
-
a
f
&
L
W
m
Fluphenazine biodegradable microspheres
42 1
1.00
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
m
0.80
CI W
_I
0.60
K
z 0.40 k-
0
a
LT 0.20
iL
(1.00
TIME (days) Figure 5.
Release profiles of fluphenazine from PLA 2K microspheres fitted to the ProutTomkins equation: 0 , 10%; W , 20%; A , 30% fluphenazine content.
.O
Time (days)
Figure 6. Release profiles of fluphenazine from LPGLA microspheres filled to the ProutTomkins equation: W , 10%; Ai 20%; 0 , 30% fluphenazine loading.
Z . Ramtoola et al.
422 n. m 4 [u
0.80 --
[u
C
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
L L
Time (days)
Figure 7. Release profiles of fluphenazine from DLPGLA microspheres fitted to the ProutTomkins equation: 0 , 10%; W , 20% fluphenazine loading.
Table 1. Values of k and t,,, obtained from equation (1) for fluphenazine-loaded LPGLA, DLPGLA and poly-DL-lactide 2000 (PLA) microspheres.
10 20 30
LPGLA LPGLA LPGLA
22.1 14.2 9.9
0.370 0.383 0.422
10 20
DLPGLA DLPGLA
22.1 13.6
0294 0321
10 20 30
PLA PLA PLA
43.1 19.5 8.2
0.079 0097 0.310
References BECK,L. R., COWSAR, D. R., LEWIS,D. H., COSGROVE, R. J., RIDDLE, C. T., LOWRY, S. L., and EPPERLY,T., 1979, A new long acting injectable microscapsule system for the administration of progesterone. Fertility and Sterility, 31, 545-551. BECK,L. R.,POPE,V. Z., FLOWERS, C. E., COWSAR, D. R., TICE, T. R., LEWIS,D. H., DUNN, R. L., MOORE, A. B., and GILLEY, R. M., 1983, Poly(DL-lactide-coglycolide)/norethisterone microcapsules, Biology of Reproduction, 28, 186-1 95. CHA,Y., and PITT,C. G., 1988, A one-week subdermal delivery system for 1-methadone based on biodegradable microcapsules. Journal of Controlled Release, 7 , 69-78. CHA,Y., and PITT, C. G., 1989, The acceleration of degradation-controlled drug delivery from polyester microspheres. Journal of Controlled Release, 8, 259-265. FONG, J. W., NAZARENO, J. P., PEARSON, J. E., and HAWKINS, V. M., 1986, Evaluation of biodegradable microspheres prepared by a solvent evaporation process using sodium oleate as emulsifier. Journal of Controlled Release, 3, 119-1 30. KENT,J. S., SANDERS, L. M., TICE, T . R., and LEWIS,D. H., 1984, Microencapsulation of the peptide nafarelin acetate for controlled release. Long-Acting Contraceptiwe Deliwery Systems, edited by G. I. Zatuchni, A. Goldsmith, J. D. Shelton and J. J. Sciarra (Harper and Row, Philadelphia), pp. 169-179.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
Fluphenazine biodegradable microspheres
423
KENT,J. S., LEWIS,D. H., SANDERS, L. M., and TICE, T. R., 1987, U.S. Patent 4,675,189. LEELARASAMEE, N., HOWARD, S. A., MALANGA, C. J., LUZZI, L. A., HOGAN, T. F., KANDZARI, S. J., and MA, J. K. H., 1986, Kinetics of drug release from polylactic acidhydrocortisone microcapsules, Journal of Microencapsulation, 3, 171-1 79. MAULDING, H. V., 1987, Prolonged delivery of peptides by microscapsules. Journal of Controlled Release, 6 , 167-1 76. MAULDING, H. V.,TICE, T. R., COWSAR, D. R., FONG,J. W., PEARSON, J. E., and NAZARENO, J. P., 1986, Biodegradable microcapsules: Acceleration of polymeric excipient hydrolytic rate by incorporation of a basic medicament. Journal of Controlled Release, 3, 103117. PROUT,E. G., and TOMPKINS, F. C., 1944, The thermal decomposition of potassium permanganate. Transactions of the Faraday Society, 40, 488498. RAMTOOLA, Z., CORRIGAN, 0. I., and BOURKE, E., 1990, Characterisation of biodegradable microspheres containing dehydro-iso-androsterone. Proceedings of the 9th Pharmaceutical Technology Conference, Veldhoven, Holland, Vol. 2, pp. 375-393. SANDERS, L. M., KENT,J. S., MCRAE,G. I. VICKERY, B. H., TICE,T. R., and LEWIS,D. H., 1984, Controlled release of an LHRH analogue from poly-DL-lactide-co-glycolide microspheres. Journal of Pharmaceutical Science, 73, 1294-1 297. SCHINDLER, A., JEFFCOAT, R., KIMMEL, J. L., PITT,C. G., WALL,M. E., and ZWEIDINGER, R., 1977, Biodegradable polymers for sustained drug delivery. Contemporary Topics in Polymer Science, edited by E. M. Pearce and J. R. Schaefgen, Vol. 2 (Plenum Press, New York), p. 255. TICE, T. R., LEWIS,D. H., DUNN,R. L., MEYERS, W. E., CASPER, R. E., and COWSAR, D. R., 1982, Biodegradation of microscapsules and biomedical devices prepared with resorbable polyesters. Proceedings of the 19th International Symposium on Controlled Release Bioactive materials, 9, 21. VIDMAR, V., SMOLCIC-BULBALO, A., and JALSENJAK, I., 1984, Poly(1actic acid) microencapsulated oxytetracycline: in vitro and in vivo evaluation. Journal of Microencapsulation, 1, 131-136. WAKIYAMA, N., KAZUHIKO, J., and NAKANO, M., 1981, Preparation and evaluation in vitro and in vivo of polylactic acid microspheres containing local anaesthetics. Chemistry and Pharmaceutical Bulletin, 29, 3363-3368. WAKIYAMA, N., KAZUHIKO, J., and NAKANO, M., 1982a, Influence of physicochemical properties of polylactic acid on the characteristics and in vitro release patterns of polylactic acid microspheres containing local anaesthetics. Chemistry and Pharmaceutical Bulletin, 30, 2621-2628. WAKIYAMA, N., KAZUHIKO, J., and NAKANO, M., 1982b, Preparation and evaluation in vitro and in vivo of polylactic acid microspheres containing dibucaine. Chemistry and Pharmaceutical Bulletin, 30, 3719-3727.
1992,
VOL.
9,
NO.
4, 4 1 5 4 2 3
Release kinetics of fluphenazine from biodegradable microspheres Z. RAMTOOLAT, 0. I. CORRIGANT and C. J. BARRETTS Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
t Department of Pharmaceutics, School of Pharmacy, Trinity College, 18 Shrewsbury Road, Dublin 4, Ireland $ Elan Corporation plc, Monksland, Athlone, Ireland
(Received 1 August 1991; accepted 19 September 1991)
Fluphenazine-loaded microspheres were prepared using biodegradable lactide and lactide-co-glycolide polymers. Sustained release of fluphenazine was achieved with fluphenazine loadings of up to 30 per cent in both the lactide and lactide-co-glycolide polymers. Fluphenazine release from microspheres was found to increase with increasing drug loading and was most rapid from the polyL-lactide-co-glycolide microspheres. The release profiles showed a ‘lag’ period followed by an accelerating release phase and in some cases a decay period, i.e. the release profiles were sigmoidal and fitted the Prout-Tomkins equation (Prout and Tompkins 1944). Consequently it was considered that polymer degradation, the primary rate-determining step controlling drug release, occurred by a mechanism involving propagation of active sites, drug release reflecting the spread of this degradation throughout the polymer.
Introduction Biodegradable microspheres for the controlled release of drugs have been prepared from emulsion systems (Beck et al. 1979,1983, Fong et al. 1986, Wakiyama et al. 1981). I n general release of macromolecules such as the polypeptides-LHRH, calcitonin and somatostatin-is considered to be degradation-controlled (Maulding 1987). However, various mechanisms have been reported for the lower molecular weight drugs and no clear guidelines seem to be evident to enable prediction of the mechanism and/or rate of drug release. Processing variable such as the drugpolymer ratio, polymer composition and physicochemical properties of the drug have been shown to affect the morphology of these systems, which in turn may affect the release of the drug (Beck et al. 1979, 1983, Fong et al. 1986, Wakiyama et al. 1981). Drug release from these systems may range from purely diffusion-controllbd dissolution from a matrix system, in cases when the polymer has a slow degradation rate and the drug molecule is small, to a degradation-controlled release when the drug molecule is large and its permeability through the polymer is low. With the more rapidly degrading polymers drug release can occur through a combination of diffusion and degradation of the polymer (Tice et al. 1982). T h e release of oxytetracycline base from PLA microcapsules and the release of hydrocortisone from DL-PLA microspheres have been fitted to the Higuchi’s spherical matrix model (Vidmar et al. 1984, Leerasamee et al. 1986). T h e release patterns of local anaesthetics from PLA microspheres have been shown to vary depending of the local anaesthetic used, the P L A molecular weight as well as drug loading. T h e drug release may be proportional to the square root of time, may approach zero-order kinetics or can be through extensive disintegration of the 0265-2048/92 83.00 0 1992 Taylor & Francis Ltd.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
416
Z. Ramtoola et al.
microspheres (Wakiyama et al. 1981, 1982 a, b). Varied release patterns from biodegradable microspheres have also been observed with other bases (tertiary amines) where the presence of the amines accelerated the degradation rate of the polymer (Maulding et al. 1986, Cha and Pitt 1988,1989). T h e ability of these amines to catalyse polymer hydrolysis did not correlate with the pK, or log Po,,of the amines (Cha and Pitt 1989). In this report the release kinetics of fluphenazine from biodegradable microspheres were studied. Three polymers: p o l y - ~ ~ - l a c t i dMW e 2000 (PLA), p o l y - ~ lactide-co-glycolide 50 : 50 of i.v. 0.42 dl/g (LPGLA) and poly-DL-lactide-coglycolide 50 : 50 of i.v. 0.5 dl/g (DLPGLA), were used to prepare microspheres containing up to 30 per cent drug loading.
Materials and methods Preparation and evaluation of microspheres Microspheres were prepared with 10, 20 and 30 per cent fluphenazine HCl as previously described (Ramtoola et al. 1990). T h e polymers used were R104 (PLA), poly-L-lactide-co-glycolide 50 : 50 of i.v. 0.42 dl/g (LPGLA) and RG504 (DLPGLA), Boehringer Ingelheim. T h e fluphenazine content of the microspheres was assayed using a UV spectrophotometer (Shimadzu). T h e surface of the microspheres was examined using scanning electron microscopy (Hitachi SSOO). T h e diameter of the microspheres was measured using a Malvern 3600 particle size analyser. In vitro release studies T h e release of fluphenazine from the microspheres was measured in isotonic phosphate buffer pH 7.4 at 37°C under sink conditions as previously described (Ramtoola et al. 1990).
Results and discussion Characteristics of the microspheres All batches of fluphenazine-loaded microspheres were essentially spherical in shape (figure 1). T h e microspheres produced were below 118pm having a mean diameter in the range of 60-70pm. T h e assayed drug content of the microspheres was in the range 60-80 per cent of the initial loading. In vitro release studies The release profiles in figure 2 show sustained release of fluphenazine from the PLA microspheres. An initial burst of fluphenazine at each drug loading was observed which increased with increasing fluphenazine loading. Following the burst, there was an induction period or ‘lag’ time of 10 days at the 10 per cent fluphenazine loading, after which fluphenazine release rate increased and then decreased giving a sigmoidal release profile. At the higher drug loadings the release rate of fluphenazine increased and then declined with no apparent induction period. T h e percentage fluphenazine released at each sampling time increased with increasing fluphenazine loading of the microspheres.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
Fluphenazine biodegradable microspheres
417
2. Ramtoola et al.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
418
z
2c
s
0 0
I
I
I
I
20
40
60
80
100
Time (days)
Figure 2.
Release profiles of fluphenazinefrom PLA 2K microspheres: 0,10%; W , 20%; 30%.
+,
120
;100 v)
a
al
5
80
al
c
Xa
60
-
40
c al r Q
3
c
20-*
*
+ 10
0
Time
30
40
Figure 3. Release profiles of fluphenazine from LPGLA and DLPGLA microspheres in phosphate buffer pH 7.4: , l o % in LPGLA; 0 , 2 0 % in LPGLA; A , 30% in LPGLA; O , l O % in DLPGLA; A , 20% in DLPGLA.
+
Fluphenazine release from both the LPGLA and DLPGLA microspheres (figure 3) was also sensitive to the drug loading. T h e percentage fluphenazine released increased with increasing drug loading and an initial burst, which increased with increasing drug loading, was also observed. Following the burst there was an induction period of 9-10 days at the 10 per cent loading which shortened as the fluphenazine loading of the microspheres was increased. Little or no difference in
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
Fluphenazine biodegradable microspheres
419
release was observed between the LPGLA and DLPGLA microspheres at corresponding drug loadings. However, the release of fluphenazine from copolymer microspheres was faster than fluphenazine release from the lactide microspheres at the low drug loadings, while at the 30 per cent fluphenazine loading there was little difference in release rate. T h e release of basic drugs has been observed to occur at a slower rate from PLA microspheres than from PGLA microspheres (Cha and Pitt 1988). PGLA is the more rapidly degrading polymer and therefore drugs, the release of which is wholly or partially degradation controlled, will be released at a faster rate from PGLA microspheres than from PLA microspheres. T h e release profiles observed for fluphenazine from both PLA and PGLA microspheres suggest degradation-controlled kinetics which may also be assisted by diffusion of the drug. T h e initial burst in release of fluphenazine, observed in all cases, was associated with drug present at or near the surface which diffused out with water penetration. A triphasic release pattern has been observed with nafarelin acetate from lactide-co-glycolide microspheres. An initial rapid release attributed to drug diffusion from the superficial areas of the microspheres was followed by a second phase of lower drug release before the onset of the major drug release phase (Kent et al. 1984,1987, Sanders et al. 1984). As the drug loading of the microspheres is increased a higher amount of drug is expected to be near the surface; thus resulting in an increase in the burst observed (figures 2 and 3). An induction period then followed, during which the polymer degraded before further drug diffusion. T h e induction period shortened with increasing fluphenazine content. As less polymer material is available for degradation the induction period decreases. T h e degradation of the polymer is reportedly autocatalytic, i.e. catalysed by the generation of COOH groups (Schindler et al. 1977) resulting in enhanced polymer degradation rate with time and an accelerated release of the drug (figures 2 and 3). With time, the loss of drug and the diffusion of the low molecular weight polymer chains from the microspheres will result in a fall in release rate of fluphenazine. Photomicrographs (figure 4) of microspheres at various stages during release show the progressive degradation of the microspheres. It was therefore considered that the release kinetics of fluphenazine HCl after the burst may be described by the Prout-Tompkins equation which has been applied to the autocatalytic decomposition of solids, i.e. the drug acting as a marker of polymer degradation. T h e release profiles in figures 2 and 3 were corrected for the burst effects during the first 24h and were fitted to the Prout-Tompkins equation (1) (figures 5-7): In (x/l - x ) - k
x t+c
(1)
where x is the fraction of drug released at time t , k is the rate constant and c = k x t,,,, t,,, being the time for 50 per cent of the drug to be released. For both PGLA and PLA microspheres, k increased and t,,, decreased with increasing drug loading (table 1 ) . At the low drug loadings the release of fluphenazine from the PLA microspheres was slower than from the PGLA microspheres. T h e differences in both the t,,, and k values decreased as the drug loading was increased. T h e k values observed were more sensitive to the drug loading than to polymer composition, which suggests an increase in polymer permeability and/or catalysis of polymer hydrolysis by fluphenazine.
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
420 2. Ramtoola et al.
I-
-
a
f
&
L
W
m
Fluphenazine biodegradable microspheres
42 1
1.00
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
m
0.80
CI W
_I
0.60
K
z 0.40 k-
0
a
LT 0.20
iL
(1.00
TIME (days) Figure 5.
Release profiles of fluphenazine from PLA 2K microspheres fitted to the ProutTomkins equation: 0 , 10%; W , 20%; A , 30% fluphenazine content.
.O
Time (days)
Figure 6. Release profiles of fluphenazine from LPGLA microspheres filled to the ProutTomkins equation: W , 10%; Ai 20%; 0 , 30% fluphenazine loading.
Z . Ramtoola et al.
422 n. m 4 [u
0.80 --
[u
C
Journal of Microencapsulation Downloaded from informahealthcare.com by McMaster University on 12/29/14 For personal use only.
L L
Time (days)
Figure 7. Release profiles of fluphenazine from DLPGLA microspheres fitted to the ProutTomkins equation: 0 , 10%; W , 20% fluphenazine loading.
Table 1. Values of k and t,,, obtained from equation (1) for fluphenazine-loaded LPGLA, DLPGLA and poly-DL-lactide 2000 (PLA) microspheres.
10 20 30
LPGLA LPGLA LPGLA
22.1 14.2 9.9
0.370 0.383 0.422
10 20
DLPGLA DLPGLA
22.1 13.6
0294 0321
10 20 30
PLA PLA PLA
43.1 19.5 8.2
0.079 0097 0.310
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