850

Controlled drug release from implantable matrices based on hydrophobic polymers* Giacomo Di Co10 Institute of Pharmaceuticel Chemists, Universi~ of P&a, Via Bo~a~no 6, 56126 P&a, Italy Reports on the controlled release of drugs, including macromolecular drugs, from silicone elastomers and ethylene-vinyl acetate copolymers, based on the formation of channels and cracks in the polymer, are reviewed. Aqueous interconnected pores are produced by osmotically active additives or by using loads of water-soluble drugs exceeding the percolation threshold. The release is generally proportional to the square root of time (t”*). Nevertheless, pseudozeroorder release kinetics can be obtained by adequately controlling the formulation variables. The factors controlling the release pattern and rate are discussed. In vivo applications of these types of systems are also considered. Keywords: Received

Drug delivery,

30 September

hydfopho&jc

1992; revised 3 December

The concept of long-term, continuous drug administration through sub-cutaneously implanted systems is not new. In fact, biocompatible polymers were first used for the construction of controlled drug delivery implants about 25 yr ago, so the advantages offered by these systems for control of the therapeutic response are now well known and need not be illustrated here. Early polymers studied were of the non-degradable type, such as silicone polymer (PDMS). Much research has since concerned the controlled release of lipophilic drugs from this polymer, and some implantable devices, such as Norplant@, a contraceptive reservoir/membrane system releasing levonorgest~l for 5 yr, and Compudose~, a matrix system releasing 17 ,f?-estradiol for 200-400 d cattle growth promotion, have now reached the market. Another successful non-degradable polymer is ethylenevinyl acetatecopolymer (EVAc), the biocompatibility of which was used to develop progestasert@, an intrauterine reservoir/membrane system releasing progesterone for up to 1 yr. On the other hand, water-soluble drugs have long been considered inadequate for administration by controlled release systems based on hy~phobic polymers, because of a poor diffusivity of these drugs in such polymers. However, in the 198Os, release mechanisms different from molecular diffusion through the polymer were described, demonstrating that well-established biomaterials such as PDMS and EVAc may also be apt to release water-soluble drugs and proteins. Correspondence

to Professor F. Di Colo.

*Paperpresented at the 18th International Symposium on Controlled Release of Bioactive Materials, Amsterdam, Biomaterials

1992. Vol. 13 NO. 12

polymers,

8-12 Juiy 1991.

ethylene-vf~yf

1991; accepted

acetate copolymer

28 January

1992

The general approach was to provide the drug dispersed in matrix with aqueous paths, by either ~ofo~ulating with osmotic agents or using drug loads beyond the percolation threshold. Such concepts have been put into practice in a variety of experiments, and many of the conclusions drawn about the releasecontrolling factors are linked to the particular system studied, This paper attempts to put in a logical order the more significant results of the research carried out in the past decade on controlled release polymeric systems based on the above concepts, and to sort out conclusions of general impo~ance, to provide straightfo~ard information on the mechanistic features and the potential applications of the type of matrices under discussion. The reader is referred to the references for experimental techniques, details and in-depth discussion of each system.

WATER ABSORPTION INTO HYDROPHOBIC POLYMERS BY MEANS OF OSMOSIS 1 shows a photomicrograph, reported by Fedor?, which was obtained by incorporating small crystals of a water-soluble salt into a transparent PDMS, totally immersing the rubber in water, and observing the system microscopically. Since water can diffuse in the interchain space of PDMS, the salt crystals are dissolved by means of osmosis, giving rise to growing cavities in the polymer, which are clearly visible in the figure. Since the crystals have an irregular shape, the volume increase produces

Figure

0 1992 Butterworth-Heinemann 0142-9612/92/120650-07

Ltd

Drug release

from hydrophobic

polymers:

G. Di Co/o

851 1.6

1.4

1.2

1.0 -E -Y p

0.8

< 2 0.6

Figure 1 Development of disc-shaped cracks in rubber containing irregularly shaped solute particles. Reproduced from Fedors, R.F. Osmotic effects in water absorption by polymers, Polymer 1980, 21, 207-212, by permission of the publishers, Butterworth-Heinemann Ltd. 0

very high local stresses which lead to the formation of cracks in the polymer, extending several times the length of the initial crystal size. Indeed, the development of disc-shaped cracks is apparent in Figure 3. On this basis, it is reasoned that if a sufficiently high volume fraction of a solid osmotic agent is dispersed in a PDMS’matrix, the system, once immersed in an aqueous medium, will gradually change from a dispersion of discrete particles, via a dispersion of growing cavities and cracks, and ending in a network of water-filled cracks and cavities. These changes are expected to promote the release of drugs which partition preferentially in water rather than in the polymer.

0.4

0.2

a

t’,

hf

1.8

EFFECT OF WATER-SOLUBLE ADDITIVES ON DRUG RELEASE FROM MATRICES BASED ON HYDROPHOBIC POLYMERS Either solid or liquid water carriers have been used to promote the release of numerous drugs of very different physico-chemical nature’-“j, including proteins71 lo, from matrices based on PDMS. The data in Figure 2 show the effect of such a strong solid osmotic agent as sodium chloride on the release of a drug model, sulphanilamide (SAM], from a PDMS-based disc-shaped matrix to an isotonic buffer3. The matrixswelling profile, plotted in Figure 26 against the square root of time (tl”), goes through a sharp maximum, in compliance with the aforesaid hypothesis that the osmotic agent would cause the development of a network of water-filled cracks and cavities in matrix. Indeed, since sodium chloride cannot permeate through PDMS, the shrinking portion of the swelling profile can only be explained by the leaching of osmotic agent through interconnecting aqueous pathways. Drug release, which is plotted in Figure 2% is strikingly enhanced over the control as a consequence of a preferential partitioning of SAM in the pore, rather than the rubber phase. In the same work, a number of liquid agents, such as

1.0 1 0

b

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20

t+, hf

Figure2 Influence of sodium chloride (11.5% w/w) on the drug release and swelling properties of PDMS discs (1 cm diameter, 0.1 cm thick) containing SAM at 4% w/w loading doses. a, Amount of drug released per unit initial surface area (Q/A) versus t”*; b, matrix swellin degree (u = ratio of swollen to dry matrix weights) versus t3‘*. A, sodium chloride; , control. Reproduced from Reference 3 with permission.

glycerin, ethylene glycol, PEG 200 and PEG 400 were also tested for their potential as drug-release enhancers3. All of these additives produced a significant matrix swelling. The drug release was proportional to t”’ and the rate constant, i.e. the slope of the release versus square root time plot, could be modulated over a range of values by varying the additive-polymer ratio3. These liquid water carriers were less effective than sodium chloride in promoting SAM release from matrix. This Biomaterials

1992, Vol. 13 No. 12

852

Drug release from hydrophobic

polymers:

G. Di Co/o

Figure 3 Photomicrographs of a PDMS-based matrix containing 1% w/w of indomethacin and 20% w/w of glycerin, before leaching, a, and after leaching, b. Reproduced from Ref. 6 by courtesy of Marcel Dekker Inc.

was due to a lesser osmotic power of the liquid agents. Also, with liquid osmotic agents the cavities created in polymer by the dispersed agent droplets are expected to be rather round shaped, so the swelling stress is better distributed and, therefore, the polymer cracking is more strongly resisted than with irregularly shaped particles of solid osmotic agents. The microstructure of PDMS-based matrix containing 1% w/w of indomethacin and 20% w/w of glycerin was investigated by Hsieh and Chien”. Figure 3 shows the photomicmgraphs of the device before leaching (Figure 3a) and after leaching and drying (Figure 3b). In Figure 3a numerous vesicles filled with glycerin are visible, which appear to be round. On the other hand, interconnected cracks can hardly be assessed in the spongy structure seen in Figure 3b. It should be considered, however, that such cracks, present in the water-swollen polymer might not be detectable through SEM in the shrunken dry polymer. These results obtained with SAM matrices seem to be contradicted by a further study where the same liquid osmotic agents and sodium chloride were used in the same additive-polymer ratio as with the previous SAM systems, to enhance the release of prednisolone (PDN) from PDMS-based matrices’. In this case, indeed, the liquid agents, especially glycerin, turned out to be more effective release promoters than sodium chloride and, also, sodium chloride was the only agent to produce a significant matrix swelling. An analysis of these systems by differential scanning calorimetry (DSC) indicated that the liquid osmotic agents in matrix were rapidly replaced by the elution medium, without any matrix swelling being producedg, Apparently, small volumes of water drawn in from the environment were sufficient to start a system of cracks in the polymer, giving rise to interconnected pores large enough to prevent matrix swelling. The reason for the greater polymer cracking effectiveness of the liquid agents with respect to sodium chloride in the present case may reside in the possibility of these agents being adsorbed to the excess surface of the solid drug particles. Indeed, the PDN loading dose was considerably increased with respect to the previous SAM systems (20% versus 4%) and the drug powder was micmnized. Another cause may be the low ,water solubility of PDN. In such a situation, indeed, the stress at the polymerparticle interface would be highly localized. It can be concluded that liquid osmotic agents can be stronger polymer crackers than solid agents of even Biomaterials

1992, Vol.

13 No. 12

higher osmotic competence, if the former are adsorbed at the surface of solid particles having a low water solubility. The drug-release mechanism for the PDN systems being discussed was investigated by DSC. As shown in Figure 4, the release is biphasic: in the first stage, drug particles completely surrounded by the pore fluid are released with a diffusion-controlled mechanism; in the second stage, drug particles either partially or totally su~und~ by the polymer are released with a dissolutiondiffusion-controlled mechanism. Of the agents tested, glycerin exerted the strongest release accelerating effect. The release profile was linear with respect to t”’ up to around 90% of PDN released. The drug load and the glycerin-polymer ratio were used to modulate the release rate constant.

SELF=PROMO~D

RELEASE

SYSTEMS

When a drug is water-soluble and its load in a hydrophobic polymer is increased beyond the percolation threshold, the drug particles form clusters which span the matrix thickness and are converted into a continuous aqueous pathway, following direct dissolution of drug by the penetrating elution medium. Based on this rationale, a notable work on protein release from EVAc monolithic matrices has been carried out’7-25. Predictive mathematical models of the diffusion process, based on a modified percolation theory, and microstructural descriptions of systems were developed20-25. At the lower loads (S%, 2070,)most of the drug particles remain trapped within the polymer and only a few are connected to the releasing surface. These are dissolved early, then the release virtually stops. At around 30% protein load both the release rate and the total fraction released increase sharply, in accord with a percolation process. At 40% the drug particles are almost entirely connected to the releasing surface and, with this protein load and at 50%~~the total release is virtually 100% and release is linear versus t”’ up to 80% released. The release was found to be faster and more complete with larger particles 24. Indeed, theo~tically, for a given volume fraction of solute and a limited thickness of matrix the percolation threshold is lower for a larger particle size of the solute. With the present self-promoted systems, protein

Drug

release

from

hydrophobic

Polymer

polymers:

Aqueous

853

G. Di Co/o

pore

Sink

ink

1st Stage

Figure 4 surrounded surrounded

2nd

Stage

Schematic representation of glycerin-promoted PDN release from PDS-based matrices. a, Particles completely by pore fluid; released in the 1st stage with a diffusion-controlled mechanism.-, Particles partially or totally by polymer; released in the 2nd stage with a dissolution-diffusion-controlled mechanism.

release is supposed to be carried by molecular diffusion within the aqueous pores. However, the apparent diffusion coefficients of proteins are orders of magnitude smaller than their diffusion coefficients in water*‘. It was demonstrated through mathematical modelling that the main retardation factor was the diffusion of the protein molecules through constrictions connecting large pore,?. During release, the matrices underwent significant swelling, in analogy with some of the osmotically actuated PDMS systems discussed earlier in this report. Such a similarity in swelling behaviour, however, does not imply a similar swelling mechanism. In fact, the swelling of the present systems is explained by admitting that the constrictions which connected the cavities containing the dissolving particles acted like diffusional barriers, through which water would diffuse into the cavities much more rapidly than the protein would out of themlg. Due to the elastic force of the polymer the matrix shrank when a large protein fraction had leached out. The drug-release kinetics could be affected by the interaction between the restrictive force of the polymer and the swelling pressure of the drugIs.

PSEUDOZERO-ORDER

RELEASE

SYSTEMS

The release with the systems dealt with so far has been kinetics are generally linear with the tl”. Zero-order preferred in order to avoid the initial burst, typical of the t I” pattern. In fact, apparent zero-order kinetics have been observed for the release of some osmotically active drug salts from monolithic systems, based on either EVAc or PDMSz6-“. The time-independent release of pilocarpine nitrate, epinephrine bitartrate and tetracycline hydrochloride from monolithic EVAc slabs was analysed by a model, assuming that osmotic imbibition of water produced a serial rupturing of the polymer encapsulating succeeding drug particlesz7. Here, the major determinant of the drugrelease rate is the osmotic imbibition of water into capsules that have ruptured, but still contain solid drug, which results in the pumping of saturated drug solution across the network of ruptured capsules into the surrounding environment. No bulk swelling of these matrices has been reported. It was later found that clonidine hydrochloride (CHC), a drug salt with effective osmotic activity, was released from PDMS monoliths with pseudozero-order kinetics”. Figure 5 shows CHC release and matrix swelling data for disc-shaped matrices of different thickness, or cylinder-

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Figure 5

Representative data on 20% w/w CHC release from PDMS discs 0.05 cm thick, A, or 0.1 cm thick, n , or cylindrical pellets (0.6 cm diameter, 0.3 cm height), 0, to phosphate buffer pH 7.4, and corresponding matrix swelling (y, ratio of swollen to dry matrix weights). Data from Ref. 29.

shaped matrices, all based on PDMS”. Water is taken up in all cases until a maximum is reached. Drug release in the matrix swelling course is of pseudozero-order, after a short burst effect: after maximum swelling is attained, the release rate tails off. By this time c. 50-607~ of the initial drug load has been released. Such a linear release pattern is explained by the effect of matrix swelling in progressively increasing the polymer perviousness to the drug. This effect is best interpreted in terms of polymer cracking. The stationary release rate was significantly higher with the thinner disc (218 + 17 pg d-‘) than with the thicker one (128 + 6pg d-l). This finding suggests that the serial rupturing model mentioned above, which implies a thickness-independent release ratez7, does not apply to the present PDMS systems. Since the initial surface area of the two discs is Biomaterials

1992. Vol. 13 No. 12

Drug release from hydrophobic

854 Table 1 Influence of matrix geometry, drug particle size and polymer reinforcing filler on the pattern of CHC release in the matrix swelling course Matrix geometry

Drug load W)

Drug particle size range (pm)

Filler WI

Drug release pattern

Disc 10 x 0.5 mm Disc 10 X 0.5 mm Disc 10xlmm Cylinder 8X3mm Cylinder 6X3mm Cylinder 6X3mm

20

50-l 50

20

Linear

20

50-l 50

0

20

50-l 50

20

Upward curve Linear

20-40

50-150

20

Linear

20,25

1O-50

20

30

1O-50

20

Upward curve Linear

practically equal, then the inverse dependence of release rate on disc thickness points to an inverse effect of matrix volume on the rate of crack development in polymer. From Table 3, which shows the influence of drug particle size and polymer reinforcing filler on the pattern of CHC release, such a pattern appears to shift from linearity to an upward curve, if an elastomer weakened by the absence of the filler or a finer drug These findings suggest that the powder is used”. pseudozero-order release pattern with these PDMS systems depends on a proper balance between cracking promoting and cracking resisting factors, to produce an appropriate pattern of crack development over time in the whole matrix volume. The possibility of obtaining a constant-rate release of water-soluble macromolecular drugs from PDMS-based matrices was subsequently tested3’. Bovine serum albumin (BSA) was used as a model drug, and sodium chloride as the osmotic agent. A PDMS elastomer with particularly high tensile strength and elongation was chosen as the matrix material. To control particle size and optimize drug contact with the aqueous pathways produced by means of osmosis, BSA was made into osmotically active particles by granulating it with sodium chloride. The pattern of BSA release from matrices was controlled to a pseudozero-order through osmotic agent fraction in granules, matrix surfacevolume ratio, granule load in matrix and granule size. An increase of one or more of these variables produces an increment of the cracking effectiveness. A release pattern similar to that seen for CHC before was achieved with a BSA-NaCl weight ratio (in granules) of 35:65, and with various matrix geometries, granule loads and granule sizes. The pseudozero-order rate could be modulated through the granule load and size, or the matrix surface-volume ratio3’, from 36 to 5000 fig d-‘. The concept of granulating a drug which has little osmotic power with sodium chloride to obtain osmotically active particles to construct PDMS-based matrices with a controlled constant-rate release was also applied successfully to papaverine hydrochloride3’, which means that this is probably applicable to any drug substance having moderate-to-high water solubility. The physicochemical properties of the candidate substance can nevertheless influence the width of the range of conditions Biomaterials

1992, Vol. 13 No. 12

polymers:

G. Di Co/o

in which the pseudozero-order pattern exists, and the range of values over which the release rate can be modulated. The approach to release kinetics control with these systems has been exclusively experimental, as mathematical modelling has seemed too complex to be practicable. However, the experimental procedure through which knowledge and control of the system can be achieved has proved rather simple.

IN WV0 APPLICATIONS The studies in vitro aimed at extending the knowledge of the factors governing release and evaluating the potentialities of the systems being discussed have been matched by applications in animals’z-‘6~ 32-34, Glycerin was found to enhance the delivery to mice of pineal and steroidal hormones, such as melatonin and estradiol, and of indomethacin from PDMS-based subdermal implants”, 13, When ewes were treated with such implants containing 25% w/w of melatonin for up to 49 d, blood levels above the target level of 450-966~mol/l were achieved” and maintained for at least 35 d. According to a Japanese patent14, drug release from silicone rubber in sustained-release formulations is controlled with glycine, lysine hydrochloride and sodium chloride. These formulations, when implanted subdermally in animals, release drugs such as bleomycin over l-4 wk. An intriguing method for implanting a sustainedrelease dosage form was reported in mice”. The liquid mixture of the drug (3’,5’-fluoro-2’-deoxyuridine), the release promoter (L-alanine), and the chemically reactive silicone components was injected intraperitoneally and let to vulcanize in vivo. Before treatment, the mice were inoculated with murine lymphoma cells. The antitumour activity of the sustained-release preparation was shown to be higher than that of single injections of drug, and not significantly different from that of a continuous injection. Release experiments in vitro with solidified sheets of the preparation had shown an initial burst effect on day 1, followed by a downward release curve up to day 23. Applications of matrices based on PDMS or EVAc, releasing water-soluble medicaments, such as ethylenehydroxydiphosponate or lidocaine hydrochloride, for the treatment of cardiovascular diseases, were recently reviewed3’. A small macroporous matrix implant supplying therapeutic levels of a LH-RH analogue at a constant rate for 1 yr was described34. The implant is indicated for oestrus or male sexual behaviour suppression, or for the treatment of sex hormone-dependent diseases in the canine or feline. The system contains 41% of watersoluble drug dispersed in PDMS. This percentage exceeds the percolation threshold, so the in vitro release mechanism is of the self-promoted type, with a timedecreasing rate, and a time scale33 of around 35 d. Such discrepancies between in vitro and in vivo results suggested that some in vivo mechanisms may contribute to the control of drug release from these implants34. Povidone (PVP) was used as a hydrophilic component to control the release of salicylic acid from PDMS matrices implanted subdermally in mice16. Strong

Drug release

from hydrophobic

polymers:

G. Di Co/o

correlation was found between in viva and in vitro drugrelease rates, both of which were proportional to PVP concentration. All release-rate profiles displayed t”’ relationships.

855 7

8

CONCLUSION The foregoing examples demonstrate that the release mechanisms discussed have increased the potential for inert hydrophobic polymers to be used as basic materials for implantable matrices. An important advantage over the classical polymeric implants, where the release of the drug occurs by diffusion through the polymer, is that the present matrices can release macromolecular drugs provided with a fair aqueous solubility. The mechanism of progressive polymer cracking realized by means of osmosis may help overcome the limit of a release rate decreasing over time, inherent in monolithic systems. Nevertheless, some shortcomings are connected with this mechanism, such as the initial burst effect, which is increasingly important the larger the size of the osmotically active particles and the greater the matrix surface-volume ratio, or the fact that, with the PDMS systems, no more than c. 50% of the initial drug dose is generally released at a constant rate. The strong dependence of the release rate on the drug-loading dose, which is another important characteristic of these systems, may be an advantage in terms of control of the release rate by means of the load, but reduces the possibility of modulating the release term by means of the load. Indeed, a low dose is needed to obtain a low rate, whilst a high dose is bound to be released at a high rate. In fact, the case of the PDMS system releasing clonidine hydrochloride for longer than 5 months, seen in Figure 5, is unique. In none of the other cases reviewed here could a constant release rate in vitro be sustained for longer than 1 month. Further effort towards prolonging the time-scale of the zero-order release with these systems is warranted by the simplicity of their preparation.

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REFERENCES Fedors, R.F., Osmotic effects in water absorption by polymers, Polymer 1980, 21, 207-212 McGinity, SW., Hunke, L.A. and Combs, A.B., Effect of water-soluble carriers on morphine sulfate release from a silicone polymer, J Pbarm. Sci. 1979, 66, 662-664 Di Colo, G., Carelli, V., Nannipieri, E., Serafini, M.F., Vitale, D. and Bottari, F., Effect of different watersoluble additives on the sustained release of sulfanilamide from silicone rubber matrices, Zl Farmaco, Ed. Pr. 1982, 37, 377-389 Carelli, V. and Di Colo, G., Effect of different watersoluble additives on water sorption into silicone rubber, 1. Pharm. Sci. 1983, 72, 316-317 Hsieh, D.S.T., Mann, K. and Chien, Y.W., Enhanced release of drugs from silicone elastomers (I): Release kinetics of pineal and steroidal hormones, Drug Dev. Znd. Pharm. 1985, 11, 1391-1410 Hsieh, D.S.T. and Chien, Y.W., Enhanced release of drugs from silicone elastomers [II): Induction of swelling and changes in microstructure, Drug Dev. Znd. Pharm. 1985, l&1411-1432

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Hsieh, D.S.T., Chiang, CC. and Desai, D.S., Controlled release of macromolecules from silicone elastomer, Pbarm. Technol. 1985, 9, 39-49 Di Colo, G., Carelli, V., Nannipieri, E., Serafini, M.F. and Vitale, D., Effect of water-soluble additives on drug release from silicone rubber matrices. II. Sustained release of prednisolone from non-swelling devices, Znt. J. Pharm. 1986, 39, l-7 Carelli, V., Di Colo, G. and Nannipieri, E., Effect of water-soluble additives on drug release from silicone rubber matrices. III. A study of release mechanism by differential scanning calorimetry, Znt. J Pharm. 1986,30, 9-16 Kim, S.H. and Kim, S.W., Heparin release from hydrophobic polymers (I): In vitro studies, Arcbiv. Pbarmacol Res. 1986, 9, 193-199 Kim, S.H. and 0, IX., Controlled release of progesterone from polyethylene oxide-silicone rubber matrix, Archiv. Pharmacol Res. 1989, 12, 191-195 Hsieh, D.S.T. and Chien, Y.W., Controlled release of drugs from silicone elastomers [III): Subcutaneous controlled administration of melatonin for early onset of estrus cycles in ewes, Drug Dev. Znd. Pbarm. 1985, 11, 1433-1446 Hsieh, D.S.T., Mason, P. and Chien, Y.W., Enhanced release of drugs from silicone elastomers [IV): Subcutaneous controlled release of indomethacin and in vivolin vitro correlations, Drug Dev. Znd. Pharm. 1985, 11, 1447-1466 Nippon Kayaku, Japanese Patent, 5,944,310, 1984 Imasaka, K., Ueda, H., Azuma, T., Kawaguchi, T. and Nagai, T., Application of new silicone gel to sustained release dosage form of antitumor drug, Drug Design Deb. 1989, 4, 237-246 Tarantino, R., Adair, D. and Bolton, S., In vitro and in vivo release of salicylic acid from povidone/polydimethylsiloxane matrices, Drug Dev. Znd. Pharm. 1990, 16, 1217-1231 Rhine, W.D., Hsieh, D.S.T. and Langer, R., Polymers for sustained macromolecule release: Procedures to fabricate reproducible delivery systems, and control release kinetics, I. Pbarm. Sci. 1980, 69, 265-270 Siegel, R.A. and Langer, R., Controlled release of polypeptides and other macromolecules, Pbarm. Res. 1984, 1, Z-10 Hsu, T.T. and Langer, R., Polymers for the controlled release of macromolecules: Effect of molecular weight of ethylene-vinylacetate copolymer, I. Biomed. Mater. Res. 1985, 10, 445-460 Miller, E.S., Peppas, N.A. and Winslow, D.N., Morphological changes of ethylene-vinyl acetate-based controlled delivery systems during release of watersoluble solutes, I, Membr. Sci. 1983, 14, 79-92 Bawa, R., Siegel, R.A., Marasca, B., Karel, M. and Langer, R., An explanation for the controlled release of macromolecules from polymers, 1. Conk Rel. 1985, 1, 259-267 Saltzman, W.M., Pasternak, S.H. and Langer, R., Quantitative image analysis for developing microstructural descriptions of heterogeneous materials, Cbem. Eng. Sci. 1987, 42,1989-2004 Siegel, R.A., Kost, J. and Langer, R., Mechanistic studies of macromolecular drug release from macroporous polymers. I. Experiments and preliminary theory concerning completeness of drug release, 1, Conk. Rel. 1989, 6, 223-236 Saltzman, W.M. and Langer, R., Transport rates of proteins in porous materials with known microgeometry, Biophys. J. 1989, 55,163-171 Siegel, R.A. and Langer, R., Mechanistic studies of

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Drug release from hydrophobia polymers: G. Di Co/o macromolecular drug release from macroporous polymers. II. Models for the slow kinetics of drug release, J. Contr. Rel. 1990,14,153-167 Gale, R., Chandrasekaran, SK., Swanson, D. and Wright, J., Use of osmotically active therapeutic agents in monolithic systems, I; Membr. Sci. 1980,7, 319 Wright, J., Chandrasekaran, SK., Gale, R. and Swanson, D., A model for the release of osmotically active agents from monolithic polymeric matrices, AIChE Symp. Ser. 1981, 77(206), 62-66 Di Colo, G., Campigli, V., Carelli, V., Nannipieri, E., Serafini, M.F. and Vitale, D., Release of osmotically active drugs from silicone rubber matrixes, fl Farmaco, Ed. Pr. 1984, 39, 310-319 Carelli, V., Di Colo, G. and Nannipieri, E., Factors in zeroorder release of clonidine hydrochloride from monolithic polydimethylsiloxane matrices, Int. J. Pharm. 1987, 35, 21-28 Carelli, V., Di Colo, G., Guerrini, C. and Nannipieri, E.,

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Drug release from silicone elastomer through controlled polymer cracking: an extension to macromolecular drugs, Int J. Pharm. 1989, 30, 181-188 Care116 V., Di Colo, G. and Nannipieri, E., Zero-order drug release from monolithic polydimethylsiloxane matrices through controlled polymer cracking, Xl Farmaco, Ed. Pr. 1988,43,121-135 Levy, R.J., Johnston, T.P., Sintov, A. and Golomb, G., Controlled release implants for cardiovascular disease, J, Conk Rel. 1990, 11,245-254 Burns, R., Peterson, K. and Sanders, L., A one year controlled release implant for the luteinizing hormone releasing hormone superagonist RS-49947. I, Implant characterization and analysis of in vitro results, J, Contr. Rel. 1990,14,221-232 Burns, R., McRae, G. and Sanders, L., A one year controlled release implant for the luteinizing hormone releasing hormone superagonist RS-49947. II. Clinical performance results, J. Conk Rel. 1990, 14,233-241

Controlled drug release from implantable matrices based on hydrophobic polymers.

Reports on the controlled release of drugs, including macromolecular drugs, from silicone elastomers and ethylene-vinyl acetate copolymers, based on t...
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