Biodegradable systems are interesting for pharmaceuti-cal applications for a number of reasons. In particular, the degradation can be used in order to control the release rate of the drug, but it may also be valuable for protecting the drug from degradation, to reduce the risk for accumulation-related diseases, to control the biologi-cal responses to the active substances, etc. By the use of biodegradable chemical links, it is possible to make par-ticles, gels, surface coatings, self-assemblied structures, etc., which degrade with half-lifes which are orders of magnitude in difference.
The degradation is affected by a number of factors, most notably the nature of the unstable link, compo-sition, pH and temperature. A particular emphasis in this area over the last decade or so has been placed on polyester (co)polymers, and particularly those con-sisting of polylactides and/or polyglycolides. Through control of the copolymer composition, the degradation
% Released
Time (h)
Figure 1.17. Release rate of nicotine from a negatively charged resin (Amberlite IRC50) at pH 7.4 at ionic strengths of 0.11 M (triangles), 0.22 M (squares) and 0.44 M (diamonds) (data from ref. (224))
rate may be controlled to quite some extent (232, 233).
Analogous to low-molecular-weight esters, the degrada-tion of polyesters is accellerated at low and high pH (234-236). This makes them interesting regarding oral administration, since a biodegradable drug carrier may be used in order to protect the active substance in the stomach, which is particularly important if the latter is sensitive to hydrolysis, after which it is released after passage through the stomach. Since the degradation rate is quite low at neutral pH or in the dried formulation, on the other hand, one could expect the storage stabilities for such systems to be good.
7.1 Solid systems
Biodegradable particles and other solid systems are probably the types which have been most extensively investigated in this context. In particular, emphasis in these studies have been placed on biodegradation as a means of controlling the drug release rate. It has been found in some cases that there is a close correlation between the degradation and the drug release rate. For example, Domb and Langer investigated the degradation of discs composed of poly(carbophenoxyvaleric acid), as well as the release of p-nitroaniline for these, and were able to demonstrate that the release occurs as a consequence of the degradation (Figure 1.18(a)) (237).
Since the degradation rate may be controlled over orders of magnitude through the choice of copolymer composition, the drug release rate may be widely controlled with some accuracy. Furthermore, a drug release sustained over extremely long times may be achieved by using this approach.
It is important to note, however, that the drug release from biodegradable polymer systems may be signifi-cantly more complex than this. In particular, both the polymer degradation and the drug physico-chemical properties are frequently of importance for the drug release. For example, Sung et al. studied the effects on the drug release rate of both the drug physico-chemical properties, notably the hydrophobicity, and the copoly-mer composition for a series of nalbuphine prodrugs and polylactide-polyglycolide copolymers of different compositions (238). As can be seen in Figure 1.18(b), the drug release rate decreases with an increasing drug hydrophobicity, thus indicating that the drug partition-ing is important to the release rate. On the other hand, these investigators also found in the same study that the release rate increases with increasing polyglycolide con-tent in the copolymer, thus indicating that the faster the degradation/erosion, then the faster the release.
In fact, the relation between degradation, drug par-titioning and drug release may be even more complex than this, since the drug may also affect the degradation rate. For example, basic drugs may behave as base cata-lysts, which may enhance the degradation rate and hence also the release rate. On the other hand, basic drugs may also neutralize the polymer terminal carboxyl residues of polyesters, thereby reducing the autocatalysis due to the acidic end-groups, and therefore also the degradation rate and the release rate (238-241).
An area where biodegradable particulate drug carriers have been found promising is in the development of oral vaccines (242-258). Because most infectious species enter the body through mucosal surfaces, immunization involving these surfaces can be expected to be an
% Degradation Higuchi rate constant (% released/d1/2 )
Time (d) Prodrug solubility (|ig/ml)
Figure 1.18. (a) In vitro release of /?-nitroaniline (circles) from a poly(carbophenoxyvaleric acid) matrix, as well as the fractional degradation of the matrix (triangles) (data from ref. 237). (b) Relationship between the release rate and the aqueous solubility of various nalbuphine prodrugs (data from ref. (238))
efficient approach for vaccination. The gastrointestinal tract has been mainly investigated in this context, although in addition, other mucosal surfaces, e.g. the pulmonary, genitourinary and nasopharyngal surfaces are all coated with mucus-containing immunoglobulins, notably IgA, and could therefore be of interest in this respect.
From a delivery point of view, particle encapsulation is an interesting route to facilitate a successful vaccina-tion through the oral route. One reason for this is the harsh conditions prevalent in the stomach, which cause rapid degradation of the material used for immunization, e.g. peptides, proteins, cells, viruses, etc. By encapsu-lation, on the other hand, degradation of the species provoking the immune-response may be reduced or eliminated. Furthermore, in analogy to parenteral immu-nization, particles may also be beneficial for immuniza-tion by acting as adjuvants (259). Thirdly, since orally administered particles are typically taken up by Peyer's patches, which constitute one of the main immune sys-tems in the gastrointestinal tract, a beneficial localization effect may also occur. In fact, considering the key role played by Peyer's patches, the successful use of par-ticles in oral vaccines seems to depend extensively on the uptake of the latter in these patches. This uptake, in turn, has been found to depend on a number of factors, notably particle size, hydrophobicity and charge, as well as the feeding state of the patient.
Although a number of different particle systems may be used for oral vaccination, biodegradable polylac-tides and polyglycolides, or their copolymers, are par-ticularly interesting in this context, e.g. since they are taken up very efficiently by Peyer's patches, as they are readily biodegradable, and since the resulting degra-dation products are essentially non-toxic and readily resorbable. A number of groups have investigated the use of these types of particles in oral vaccination, and stimulation of both mucosal (slgA antibodies) and sys-temic (IgG antibodies) have been observed (see, e.g.
ref.121). For example, Elridge et al. studied the immune response resulting from Staphylococcal enterotoxin B encapsulated in poly(DL-lactide-C(?-glycolide) particles, and found that particles in the size range 1-10 urn were efficient as carriers for this antigen (256). In contrast, the soluble antigen was relatively ineffec-tive (Figure 1.19). Furthermore, Elridge and co-workers demonstrated that particles of different sizes can be co-administered in order to provoke a biphasic immune response (246). Similarly, Nellore et al. investigated the performance of microparticles with hepatitis B surface antigen vaccine and found enhanced antibody responses (255), while Stevens et al. investigated biodegradable
Immunization
Figure 1.19. Plasma anti-toxin antibody levels of the IgM, IgA and IgG isotypes induced following oral immunizations with 100 ug doses of staphylococcal enterotoxin B vaccine either encapsulated (a) or free (b) (data from ref. (256))
microparticles in vaccination for fertility control, and found promising results (260). Biodegradable particles have also been found useful for provoking immune responses to viruses, including parainfluenza virus (244) and influenza virus (248).
Another area where biodegradable polymer systems are of interest is in drug delivery to the lymphatic system (121). This, in turn, is interesting since transport via the intestinal lymphatics circumvents first-pass metabolism through the liver and may enhance the drug bioavail-ability. Furthermore, uptake in the GALT constitutes an access route to the lymphatic system, and the success-ful use of this may provide an absorption pathway for encapsulated drug molecules (e.g. peptides and proteins) which are otherwise subject to luminal degradation. As discussed above, the uptake in Peyer's patches depends on the particle size, generally decreasing with increasing
Prebleed Primary Secondary Tertiary Soluble toxoid 1/log2 Anti-toxin titre
Microencapsulated toxoid
Prebleed Primary Secondary Tertiary
particle size. Furthermore, it has been found that the surface characteristics of paniculate drug carriers affect the uptake of the latter in the lymphatic system. For example, more hydrophilic particles are less effectively retained in the regional lymph nodes than hydrophobic particles.
7.2 Polymer gels
Biodegradable polymer gels are interesting, e.g. for oral, buccal, topical, ocular, nasal and vaginal drug delivery. Such systems are frequently preferred due to suitable rheological properties, bioadhesion, optical clarity, etc. Biodegradation of such systems, in turn, offers advantages related to ease of removal or lack of need of removal, sustained release, etc. Considering the advantageous properties of PEO and PEO-containing copolymers in many drug delivery applications, as well as the advantages of biodegradable systems in general, the possibility of producing biodegradable gels from functional PEOs, as discussed previously, e.g. by Zhao and Harris (261) and by Singh et al. (262), is certainly interesting.
An area where biodegradable gels are of particu-lar interest is in colon drug delivery (196). The main reason for this is that the fermentation of polysaccha-ride carriers caused by microbial enzymes in the large intestine may be used, together with the inherent ten-dency for such systems to display sustained release of solubilized drugs, to obtain efficient controlled release formulations, e.g. for the treatment of Crohn's disease, ulcerative colitis, spastic colon, constipation and colon cancer. Moreover, colon administration is also inter-esting for systemic absorption of, e.g. peptides and proteins, which are extensively degraded in the gas-trointestinal tract. Naturally, a number of systems are of interest in this context, e.g. coatings of by amy-lose, cyclodextrins, galactomannan or pectin, as well as matrices formed by, e.g. chondroitin sulfate, dextran, pectin or galactomannan. Just to provide one illustra-tive example, Figure 1.20 shows the results obtained by Rubinstein and Sintov on the release of indomethacin from a calcium pectate gel in the absence and pres-ence of pectinolytic enzyme (known to be present in the colonic region) (263). As can be seen from this figure, essentially no release is observed in the absence of digestive enzymes, whereas a significant release was observed in the presence of such enzymes. Therefore, the release to the colon may be controlled by the sta-bility of the matrix to enzymatic degradation, and, more importantly, a specific targeting to the large intestine can be obtained by this approach.
Time (h)
Figure 1.20. Cumulative release of indomethacin from a cal-cium pectate gel in citrate buffer in the presence (circles) and absence (squares) of pectinolytic enzyme (data from ref. (263))
7.3 Surface coatings
Biodegradable surface coatings of drug carriers could be expected to be of interest in a number of pharmaceutical applications, but particularly so in relation to parenteral drug delivery of colloidal drug carriers. As discussed above in relation to liposomes, sterically stabilized, and particularly PEO-modified colloidal drug carriers, are quite interesting due to prolonged bloodstream circulation times, a comparably even tissue distribution, reduced toxicity effects, etc. Even with PEO-modified particles or surface coatings, however, the bloodstream circulation time is generally of the order of a couple of days at most, and hence a PEO-based surface coating needs to be stable over that particular time only. After this, the fairly good chemical stability of PEO has no advantage, and indeed it may even be detrimental to the degradation and excretion of this substance.
As discussed above, the origin of the advantageous effects of PEO-containing coatings of colloidal drug car-riers in intravenous drug delivery is the low serum pro-tein adsorption caused by the PEO chains. On biodegra-dation, on the other hand, the PEO chains are released and the serum proteins can adsorb once more. For example, Muller et al. have previously investigated the adsorption of a number of PEO-polylactide copolymers at hydrophobic methylated silica surfaces, as well as the adsorption of fibrinogen, a well-known opsonin (8) at such surface coatings, e.g. before and after degradation of the polylactide anchoring block (264). It was found that when the polylactide moiety is intact, the polymer is strongly anchored at the hydrophobic surface, and pre-vents the protein from adsorbing. On degradation of the polylactide block, however, the polymer does not adsorb
% Cumulative release
as extensively and strongly at the surface, and hence it is no longer capable of reducing the protein adsorption.
Analogous to this, Kirpotin et al. investigated the properties of lipsomes with detachable polymer coatings through incorporation of a disulfide-linked PEO-phospholipid conjugate (distearoyl phosphatidy-lethanolamine-dithiopropionyl (DTP)-PE02ooo) in dio-leoyl phosphatidylethanolamine (DOPE) liposomes (265). It was found that the liposomes in the absence of such a conjugated lipid, but in the presence of not readily degradable DOPE/mPEO-distearoyl phosphatidylethanolamine, displayed a long circulation time in the bloodstream, stability to flocculation, and a slow release of an entrapped fluorescence marker. On the other hand, the stability of the liposomes decreased drastically on degradation of the carbamate links.
Moreover, modifying pH-sensitive DOPE/cholesterol hemisuccinate liposomes with mPEO-DTP-distearoly phosphatidyl ethanolamine (DSPE) resulted in a decrease in the pH-sensitivity. After cleavage, on the other hand, the pH-sensitivity was restored. Such degradable surface coatings therefore seem feasible.