- Email: [email protected]
Chitosan-based drug delivery systems
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx 1
Contents lists available at SciVerse ScienceDirect
European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb
2
Short review (expert opinion)
3
Chitosan-based drug delivery systems
4 5 6 7 9 2 1 10 11 12 13 14 15 16 17 18 19 20
Q1
Andreas Bernkop-Schnürch ⇑, Sarah Dünnhaupt Department of Pharmaceutical Technology, University of Innsbruck, Innsbruck, Austria
a r t i c l e
i n f o
Article history: Received 16 November 2011 Accepted in revised form 16 April 2012 Available online xxxx Keywords: Chitosan Drug delivery Mucoadhesion Permeation enhancement Controlled release
a b s t r a c t Within the past 20 years, a considerable amount of work has been published on chitosan and its potential use in drug delivery systems. In contrast to all other polysaccharides having a monograph in a pharmacopeia, chitosan has a cationic character because of its primary amino groups. These primary amino groups are responsible for properties such as controlled drug release, mucoadhesion, in situ gellation, transfection, permeation enhancement, and efflux pump inhibitory properties. Due to chemical modifications, most of these properties can even be further improved. Within this review, an overview on the advantages of chitosan for various types of drug delivery systems is provided. Ó 2012 Published by Elsevier B.V.
22 23 24 25 26 27 28 29
30 31 32
1. Introduction
33
Since chitosan has entered the pharmaceutical arena in the early 1990s, it has inspired academic and industrial research teams to generate novel more effective therapeutic systems based on it. Apart from applications such as slimming, wound dressing, and tissue engineering, chitosan showed promising features as auxiliary agent in drug delivery. In contrast to all other biodegradable polymers having a monograph in a pharmacopoeia, chitosan is the only one exhibiting a cationic character rendering it unique among all others. This cationic character being based on its primary amino groups is responsible for various properties and subsequently for its use in drug delivery systems. In the following, these properties are highlighted in more detail.
34 35 36 37 38 39 40 41 42 43 44
45
2. Properties of chitosan
46
2.1. Controlled drug release
47
When sustained drug release cannot be provided by making use of a simple drug dissolution process, by diffusion, by erosion, by membrane control, or by osmotic systems, retardation mediated by ionic interactions is often the ultimate ratio. Such a controlled release can be achieved for cationic drugs by using anionic polymeric excipients such as polyacrylates, sodium carboxymethylcellulose, or alginate. In case of anionic drugs, however, chitosan is the
48 49 50 51 52 53
⇑ Corresponding author. Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold–Franzenz–University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Tel.: +43 512 507 58600; fax: +43 512 507 58699. E-mail address: [email protected] (A. Bernkop-Schnürch).
only choice. Bhise et al. [1], for instance, designed sustained release systems for the anionic drug naproxen using chitosan as drug carrier matrix. Using polyanionic drugs, the interactions between chitosan and the therapeutic agent are more pronounced, and based on an ionic cross-linking in addition, even stable complexes are formed from which the drug can be released even over a more prolonged time period. Sun et al. [2], for instance, designed enoxaparin/chitosan nanoparticulate delivery systems, providing very stable complexes that led to a significantly improved drug uptake. In addition, chitosans can be homogenized with anionic polymeric excipients such as polyacrylates, hyaluronic acid, alginate, pectin, or carrageenan, resulting in comparatively stable complexes of high density. Mainly based on diffusion and erosion processes, incorporated drugs are released in a sustained manner from such complexes [3]. Alternative to anionic polymers, multivalent inorganic anions such as tripolyphosphate or sulfate can be used in order to achieve the same effect [4].
54
2.2. Mucoadhesive properties
71
The mucoadhesive properties are likely also based on its cationic character. The mucus gel layer exhibits anionic substructures in the form of sialic acid and sulfonic acid substructures. Based on ionic interactions between the cationic primary amino groups of chitosan and these anionic substructures of the mucus, mucoadhesion can be achieved. In addition, hydrophobic interactions might contribute to its mucoadhesive properties. In comparison with various anionic polymeric excipients such as carbomer, polycarbophil, and hyaluronic acid, however, its mucoadhesive properties are weak [5]. Furthermore, in order to achieve high mucoadhesive properties, the polymer needs to exhibit also high cohesive
72
0939-6411/$ - see front matter Ó 2012 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ejpb.2012.04.007
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70
73 74 75 76 77 78 79 80 81 82
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 2
A. Bernkop-Schnürch, S. Dünnhaupt / European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx
112
properties as the adhesive bond otherwise fails within the mucoadhesive polymer rather than between the mucus gel layer and the polymer. In case of chitosans, however, these cohesive properties are also comparatively weak. Although they can be strongly improved by the formation of complexes with multivalent anionic drugs, multivalent anionic polymeric excipients, and multivalent inorganic anions, this strategy is only to a quite limited extent effective, as the cationic substructures of chitosan being responsible for mucoadhesion via ionic interactions with the mucus are in this way blocked. Lueßen et al., for instance, demonstrated a significantly improved oral bioavailability of buserelin when being administered with mucoadhesive polymers such as chitosan and carbomer to rats. This effect, however, could not be observed anymore when chitosan was combined with the polyanionic carbomer in the same formulation [6]. Trimethylation of the primary amino group of chitosan provides an even more cationic character of the polymer. When trimethylated chitosan (TMC) is additionally PEGylated, its mucoadhesive properties are even up to 3.4-fold improved [7]. Due to the immobilization of thiol groups on chitosan, its mucoadhesive properties can also be strongly improved, as the thiolated polymer is capable of forming disulfide bonds with mucus glycoproteins of the mucus gel layer, placing it among the most mucoadhesive polymers known so far [8]. In addition, as inter- and intrachain disulfide bonds are also formed within chitosan itself, thiolated chitosan exhibits substantially improved cohesive properties. Recently, the mucoadhesive properties of thiolated chitosans were even significantly further improved by the preactivation of thiol groups on chitosan via the formation of disulfide bonds with mercaptonicotinamide [Dünnhaupt et al., unpublished results].
113
2.3. In situ gelling properties
114
129
In case of hydrogels, chitosan offers the advantage of in situ gelling properties when its pH-dependent hydratability is addressed properly from the formulation point of view. Gupta et al., for instance, developed an in situ gelling delivery system by the combination of polyacrylic acid and chitosan. The resulting formulation was in liquid state at pH 6.0 and underwent rapid transition into the viscous gel phase at physiological pH of 7.4 [9]. These in situ gelling properties can even be further improved by thiolation. Due to access to oxygen on mucosal surfaces such as the ocular or nasal mucosa after having been applied in liquid form out of for instance oxygen-free single unit dosage forms, a cross-linking process via disulfide bond formation takes place resulting in a strong increase in viscosity. Utilizing this cross-linking mechanism, Sakloetsakun et al., for instance, could show an even 16,500-fold increase in viscosity within 20 min. of an aqueous 1% (m/v) chitosan–thioglycolic acid conjugate [10].
130
2.4. Transfection enhancing properties
131
In contrast to small molecules, where a controlled release of anionic drugs can be achieved as described above, comparatively large polyanionic molecules such as DNA-based drugs and siRNA form stable complexes with chitosan. In this way, nanoparticles exhibiting a positive zeta potential can be formed, when the ratio of the cationic polymer is sufficiently high. Because of this positive net charge and the small size of these particles, endocytosis can be achieved in particular when these particles are below 100 nm in size [11]. As chitosan is comparatively less toxic than other cationic polymers such as polyethyleneimine, polylysine, or polyarginine [12], it is therefore a promising excipient for non-viral gene delivery systems. In addition, chitosan–DNA-based drug complexes protect at least to some extend towards degradation by DNAses in this way improving the bioavailability of DNA-based drugs delivered
83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111
115 116 117 118 119 120 121 122 123 124 125 126 127 128
132 133 134 135 136 137 138 139 140 141 142 143 144
into the body [13]. As the transfection efficiency of conventional chitosans is generally found to be low, the polysaccharide was modified following different strategies in order to improve its properties. Malmo et al. [14] investigated the self-branching of chitosans as a strategy to improve its gene transfer properties without compromising its safety profile. Self-branched and selfbranched trisaccharide-substituted chitosans with molecular mass of 11–71 kDa were synthesized, characterized, and compared with their linear counterparts with respect to transfection efficiency, showing that self-branched chitosans can yield gene expression levels two and five times higher than those of Lipofectamine and Exgen, respectively. Following another approach, Martien et al. [15] stabilized chitosan/plasmid nanoparticles by utilizing thiolated chitosan forming intrachain disulfide bonds within the complex. In this way, a higher stability towards nucleases was achieved. In addition, the plasmid was mainly released in the target cells, as due to the reducing conditions of the cytoplasma, the disulfide bonds were mainly cleaved there leading to the release of the plasmid at the target site. The transfection rate of thiolated chitosan/ plasmid nanoparticles was in this connection demonstrated to be five times higher than that of unmodified chitosan/pDNA nanoparticles. This strategy could even be further improved by raising the cationic character of thiolated chitosan due to trimethylation of the remaining primary amino groups [16]. Furthermore, PEGylated chitosan and chitosan/cyclodextrin nanoparticles were identified as promising tools for DNA-based drug delivery [17,18].
145
2.5. Permeation enhancing properties
171
The mechanism being responsible for the permeation enhancing effect of chitosan is also based on the positive charges of the polymer, which seems to interact with the cell membrane resulting in a structural reorganization of tight junction-associated proteins [19]. A more pronounced cationic character being achieved by trimethylation of the primary amino group, however, did not lead to further improved permeation enhancing properties, suggesting that the underlying mechanism described above is obviously more complex than assumed [20]. Schipper et al. [21] could demonstrate that the structural properties of chitosan, that is, molecular mass and degree of deacetylation, dictate the permeation enhancing properties and toxicity to a large extent. Chitosans of high degree of deacetylation and of high molecular mass exhibit the comparatively highest increase in epithelial permeability. This increase in permeation enhancing effect with increasing molecular mass could also be observed for other permeation enhancing polymers such as polyacrylates [22], providing another piece for the overall puzzle of the underlying mechanism. As these parameters determining permeation enhancement do not correlate with those determining toxicity, chitosans with maximal permeation enhancing effect and minimal toxicity are available. The comparatively high permeation enhancing properties of chitosan seen on Caco-2 cell monolayers, however, are in the presence of the mucus layer much lower, as chitosan cannot reach the epithelium because of size-limited diffusion and competitive charge interactions with mucins. Nevertheless, this permeation enhancing effect could be confirmed by various in vivo studies. Shah et al., for instance, could demonstrate a 2-fold improved oral bioavailability of ganciclovir due to the co-administration of chitosan. As the polysaccharide acts in a completely different way than most other permeation enhancers, it can be combined with them leading to an additive or even synergistic effect. Following this strategy, the oral bioavailability of ganciclovir was even 4-fold improved using a combination of chitosan and sodium dodecylsulfate, although sodium dodecylsulfate led just to a 2-fold improvement when being co-administered without chitosan [23]. Recently, it was shown that chitosan nanoparticles exhibit only in the first segment of the duodenum a
172
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170
173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 A. Bernkop-Schnürch, S. Dünnhaupt / European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx
214
permeation enhancing effect for small peptides, whereas due to the addition of cyclodextrin, this permeation enhancing effect was enlarged over the entire duodenum [24]. Furthermore, due to thiolation, the permeation enhancing properties of chitosan on certain mucosal membranes can be even more than 30-fold further improved [25,26].
215
2.6. Efflux pump inhibitory properties
216
231
In 2002, Carreno-Gomez and Duncan demonstrated efflux pump inhibitory properties for various polysaccharides [27]. Although they did not evaluate chitosan in their studies, it was quite obvious that this polysaccharide will exhibit the same effect. A proof-of-principle for this theory was then provided by Föger et al. [28], demonstrating a significantly improved oral uptake of the P-gp substrate rhodamine 123 due to the co-administration of (thiolated) chitosan in rats. Results are illustrated in Fig. 1. Although this effect is in comparison with other efflux pump inhibitors not that pronounced, it seems, nevertheless, useful to improve the mucosal uptake of various efflux pump substrate drugs. In case of permeation enhancement, the effect of chitosan increased with increasing molecular mass of the polymer, whereas in case of efflux pump inhibition, a molecular mass in the range of 150 kDa led at least for a chitosan derivative to the most pronounced inhibition [29].
232
2.7. Colon targeting
233
In the same way as numerous other polysaccharides, chitosan is degraded in the colon. By making use of this colon-specific degradation, chitosan has been discovered as useful coating in order to guarantee a site specific delivery. Radiolabelled (99mTc) tablets coated with a combination of pectin/chitosan/hydroxypropyl methylcellulose (3 + 1 + 1), for instance, were administered orally to human volunteers [30]. Within this study, gamma scintigraphy was used to evaluate the gastrointestinal transit of these tablets, showing that they remain intact through the stomach and small intestine. In the colon, the bacteria degraded the coat, and thus, the tablets disintegrated. In another study, our own research group developed a sustained dosage form for alpha-lipoic acid making use of ionic interactions between this anionic drug and chitosan used as carrier matrix. Studies in human volunteers showed a release maximum once the formulation had reached the colon [31].
209 210 211 212 213
217 218 219 220 221 222 223 224 225 226 227 228 229 230
234 235 236 237 238 239 240 241 242 243 244 245 246 247
Fig. 1. Plasma curves of Rho-123 (ng/ml) after oral administration of 1.5 mg Rho123 in solution (white triangles), in chitosan tablets (black squares), or thiolated tablets (white squares). Indicated values are means (±SD) of five experiments; 1,2,3,4 differ from chitosan tablets, p < 0.01; p < 0.003; p < 0.001; p < 0.005, respectively. Adapted from Föger et al. [28].
3
3. Chitosan drug delivery systems
248
These properties of chitosan resulted in the development of numerous drug delivery systems for various application sites, which are described in more detail below.
249
3.1. Oral drug delivery
252
As liquid formulations are not favored by patients, and storage stability problems of drugs such as peptide drugs have to be overcome, solid dosage forms are the delivery systems of choice. Apart from capsules, tablets are therefore the likely most favorable dosage form. As tablets provide an accurate dosage and are easy to manufacture and handle, numerous drug delivery systems comprising chitosan are based on this type of dosage form [32–34]. The drug can thereby be homogenized with chitosan and directly compressed to tablets. As chitosan precipitates at pH above 6.5, it loses its mucoadhesive and permeation enhancing properties in distal segments of the intestine. This effect reduces its applicability to drugs having their absorption window in the proximal segment of the GI tract. Dhaliwal et al. [35], for instance, could improve the oral bioavailability of acyclovir 3-fold and 4-fold due to the incorporation of this drug in chitosan and thiolated chitosan, respectively. Within this study, a prolonged residence time in particular of thiolated chitosan microparticles in duodenal and jejunum regions was observed. These data need to be confirmed in human volunteers. So far, an improved oral bioavailability of various model drugs could be shown in human volunteers for mucoadhesive formulations likely because of an intimate contact of the delivery system with the absorption membrane and a prolonged mucosal residence time of the delivery systems [36]. Such studies, however, have not yet been performed with chitosans. A hint that such systems based on chitosan might work also in humans was at least provided by Säkkinen et al. [37], demonstrating the adhesion of chitosan granules to the distal esophageal mucosa for almost two hours. Chitosan derivatives of comparatively higher cationic character such as trimethylated chitosans [38], chitosan–thiobutylamidine conjugates [39], or chitosan–thioethylamidine conjugates [40], however, do not precipitate anymore within the whole pH range of the GI-tract. Thanou et al. [41], for instance, demonstrated that intraduodenally applied buserelin results in 0.8% absolute bioavailability in rats, whereas co-administrations with trimethylated chitosans resulted in average bioavailability values between 6% and 13%. In contrast, chitosan HCl did not significantly increase the intestinal absorption at pH 7.2. In case of nanoparticulate delivery systems, chitosan is in most cases ionically cross-linked. Precipitation at higher pH is therefore not anymore an issue at all, as the polymer is already ‘‘co-precipitated’’ with the multivalent anionic cross-linker. Although precipitated and homogenized with a polyanion blocking, its cationic groups to a high extend such nanoparticulate delivery systems exhibit surprisingly still potential. Sarmento et al. [42], for instance, showed a significant decrease in the blood glucose level of diabetic rats, when insulin was given orally in chitosan/alginate nanoparticles. Explanations might be given by the mucoadhesive properties of nanoparticulate formulations per se diffusing at least to some extent in the mucus gel layer and the protective effect of such formulations towards proteases.
253
3.2. Ocular drug delivery
303
Due to its nontoxic character, permeation enhancing properties, and physicochemical characteristics, chitosan is a suitable material for the design of ocular drug delivery systems. Chitosan-based formulations used for ophthalmic drug delivery are hydrogels [43],
304
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
250 251
254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302
305 306 307
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 4
A. Bernkop-Schnürch, S. Dünnhaupt / European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx
336
nanoparticles [44], and coated colloidal systems [45]. Chitosanbased systems have the potential for improving the retention and biodistribution of drugs applied topically onto the eye. Making use of its in situ gelling properties, chitosan can be applied and distributed on the ocular surface in almost liquid form thereafter transforming into the gel status. In this way, a prolonged ocular residence time and an improved therapeutic efficacy can be achieved [9,43]. De Campos et al. [46] demonstrated the potential of chitosan nanoparticles with incorporated cyclosporine A in improving the delivery of drugs to the ocular mucosa. Furthermore, chitosan-based colloidal systems were found to work as transmucosal drug carriers, either facilitating the transport of drugs to the inner eye or their accumulation into the corneal epithelia. The use of chitosan-based colloidal suspensions in vivo showed a significant increase in ocular drug bioavailability [45,47]. Calvo et al. [45], for instance, combined the features of polycaprolactone nanocapsules as ocular carriers with the advantages of the cationic mucoadhesive chitosan and poly-L-lysine (PLL) coating. Even though PLL and chitosan displayed a similar positive surface charge, only chitosan-coated nanocapsules enhanced the ocular penetration of indomethacin with respect to uncoated nanocapsules as shown in Fig. 2. The authors suggested that an undetermined property of chitosan was responsible for this enhanced uptake. Genta et al. [47] indicated that acyclovir-loaded chitosan microspheres offer significantly sustained ocular drug release in vivo. According to the authors in addition to its mucoadhesive properties, chitosan is effective in retarding the rate of drug release. Overall, each particulate system represents a useful approach to increase the ocular bioavailability of drugs.
337
3.3. Nasal drug delivery
338
Due to nasal obstacles such as low membrane permeability, a short local residence time, and high turnover rate of a secretion in nasal cavities, the bioavailability of nasally administered drugs is often comparatively poor [48]. The likely most promising approach to improve nasal drug absorption is the use of permeation enhancers and mucoadhesive nasal delivery systems. They can provide a prolonged contact between drug formulation and absorptive sites in the nasal cavity by delaying the mucociliary clearance of the formulation. Such mucoadhesive systems can be in the form of powders as well as liquids or liquid in situ gelling systems such as described above. Mainly because of its mucoadhesive and permeation enhancing properties, chitosan has been investigated as auxiliary agent in nasal drug delivery systems
308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335
339 340 341 342 343 344 345 346 347 348 349 350
Fig. 2. Indomethacin concentrations attained in the cornea following the topical application, in rabbits, of indomethacin-loaded carriers and control solution. Mean values ± SD (n = 3–4) are shown. Adapted from Calvo et al. [45].
[49,50]. Na et al. [51], for instance, could demonstrate significantly improved nasal uptake of isosorbide dinitrate due to the co-administration of chitosan in rats. In the same study, they showed a minor cilio-inhibiting effect of the polymer. Furthermore, chitosan particles or polyelectrolyte complexes have been studied for nasal delivery of therapeutic proteins [52–54]. It was found that insulinloaded chitosan nanoparticles enhance nasal drug absorption to a greater extent than relevant chitosan solutions. In addition, Fisher et al. [55] developed fentanyl nasal spray formulations with pectin, chitosan, and chitosan–poloxamer 188 for clinical evaluation to provide rapid absorption and subsequently increased bioavailability. The study was conducted in 18 healthy adult volunteers and revealed significantly increased systemic exposure as well as reduced times to peak plasma values for all formulations compared with oral transmucosal fentanyl citrate lozenge as illustrated in Fig. 3.
351
3.4. Vaginal drug delivery
367
El-Kamel et al. [56] prepared chitosan-based vaginal tablets containing metronidazole by direct compressing the polymer, loosely cross-linked with glutaraldehyde, together with sodium alginate with or without microcrystalline cellulose. Tablets showed adequate release properties in pH 4.8 and 7 and gave low values of swelling index. These tablets showed also comparatively good adhesive properties. In another study, Sandri et al. [57] evaluated the mucoadhesive and permeation enhancing properties of four different chitosan derivatives: 5-methyl-pyrrolidinone chitosan, two low molecular mass chitosans, and a partially re-acetylated chitosan via the vaginal and buccal mucosa using acyclovir as model drug. Methyl-pyrrolidinone chitosan showed the highest mucoadhesive and permeation enhancing properties in both vaginal and buccal environments. The capability of enhancing the permeation/ penetration of acyclovir was decreased by partial depolymerization of chitosan and disappeared after partial re-acetylation. The antimicrobial properties of chitosan, however, might have a negative impact on the vaginal microflora [58]. Its vaginal use for treatment of chronic diseases has therefore to be seen with caution.
368
3.5. Buccal drug delivery
387
By avoiding hepatic first-pass metabolism and degradation in stomach and small intestine, the buccal route is an alternative choice to deliver drugs to the application site. In addition, this route shows high acceptance by patients. An ideal buccal delivery system should stay in the oral cavity for hours and release the drug in a controlled way. Mucoadhesive polymers prolong the residence time of the drug in the oral cavity [59]. Based on its mucoadhesive as well as absorption enhancement properties, chitosan is a promising polymer to be used for buccal delivery. Sandri et al. [60], for instance, could show that trimethylated chitosans seem to be promising exipients for drug delivery systems intended for buccal mucosa applications to enhance the absorption of hydrophilic macromolecules. In another study, the potential of thiolated chitosan for peptide delivery systems via the buccal mucosa was investigated in pigs [25]. The therapeutic peptide PACAP was applied to pigs, and its bioavailability was determined in order to facilitate the treatment of type 2 diabetes. Due to its strong permeation enhancing properties, tablets based on thiolated chitosan raised continuously the plasma level of this peptide drug, allowing for therapeutic range levels to be maintained over the whole period of application. Furthermore, buccal bilayered devices with a mixture of nifedipine and propranolol as well as chitosan displayed promising potential for use in controlled delivery in the oral cavity [61].
388
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
352 353 354 355 356 357 358 359 360 361 362 363 364 365 366
369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386
389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 A. Bernkop-Schnürch, S. Dünnhaupt / European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx
5
Fig. 3. Mean values ± SD of plasma concentration time following single-dose administration of 100 lg FChNS = fentanyl chitosan nasal spray (n = 18), 100 lg FChPNS = fentanyl in chitosan–poloxamer 188 nasal spray (n = 18), 100 lg FPNS = fentanyl pectin nasal spray (n = 18), 200 lg OTFC = oral transmucosal fentanyl citrate lozenge (n = 18). Insert provides 0–2-h profile (without error bars). Adapted from Fisher et al. [55]. 412
3.6. Parenteral drug delivery
413
431
As highly purified low molecular mass chitosan was shown neither to be toxic nor hemolytic when given intravenously [62], its use in injectable preparations has received considerable attention within the last years. In controlled release technology, biodegradable polymeric carriers offer potential advantages for prolonged release of low-molecular-weight compounds to macromolecular drugs [63,64]. The susceptibility of chitosan to lysozyme makes it biodegradable [65]. Pharmacokinetic and tissue-distribution studies were performed in mice using fluorescent glycol–chitosan and N-succinyl-chitosan. Both chitosans demonstrated a good retention in blood circulation and a slight accumulation in tissues, suggesting that chitosan is an effective carrier for drugs that are excreted rapidly [66]. In another study, Kim et al. [67] synthesized hydrophobically modified glycol chitosan with 5-b-cholanic acid groups, which was subsequently used to prepare nanoparticles with incorporated RGD peptide (Arg-Gly-Asp). Intratumoral administration of RGD-loaded chitosan nanoparticles demonstrated a substantially decreased tumor growth as compared to the RGD peptide administered intravenously.
432
3.7. Intravesical drug delivery
433
441
Barthelmes et al. [68] investigated mucoadhesive properties of chitosan and thiolated chitosan nanoparticles on the intravesical mucosa in order to prolong the residence time of instilled drugs in urinary bladders. It was shown that thiolated chitosan nanoparticles might be a useful tool for local intravesical drug delivery, which increases the residence time of the drug and enables sustainable delivery for an extended period of time. Evidence for this theory could at least be provided by in vivo studies in rats [Barthelmes et al., unpublished results].
442
3.8. Vaccine delivery
443
Although chitosan was already shown in the early 1990s to stimulate IgM production of human lymphocytes in serum-free
414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430
434 435 436 437 438 439 440
444
culture [69], it took several years until first vaccine delivery systems were developed. Jabbal-Gill et al. [70] were likely the first providing evidence for a successful nasal immunization against Bordetella pertussis in mice combining different antigens with chitosan. In the following, various chitosan-based carriers have been designed and evaluated for nasal delivery of antigens showing valid levels of both systemic and local immune response [71– 76]. Utilizing trimethylated chitosan nanoparticles for nasal administration led even to an increased immune response that could be further improved by the incorporation of certain immunopotentiators [77]. In the following, also oral vaccine delivery systems based on chitosan were developed. Van der Lubben et al. [74], were the first who could demonstrate the uptake of chitosan microparticles by the epithelium of the murine Peyer’s patches. Similar to nasal vaccine delivery systems also in case of oral delivery trimethylated-chitosan exhibiting in contrast to unmodified chitosan, an intrinsic adjuvant effect on dentritic cells showed comparatively greater potential [78].
445
4. Conclusion
463
Due to its cationic character, chitosan exhibits mucoadhesive, permeation enhancing, in situ gelling, and efflux pump inhibitory properties. In addition, by making use of ionic interactions, also a controlled drug release can be achieved, and nanoparticulate delivery systems for DNA-based drugs and siRNA can be formed. Most of these effects of chitosan, however, are comparatively weak providing simply not enough added values that would justify product developments based on it. Consequently, only very few studies in humans are done with chitosan, and there are currently no products on the market making use of certain properties of this polymer from the drug delivery point of view. Due to derivatization, almost all properties of chitosan, however, can be strongly improved, and this trend will certainly hold on resulting in even more potent chitosan derivatives. The authors are therefore convinced that it is just a question of time when products being based on potent chitosan derivatives will enter the market, and in fact, the initial step in this direction has already been taken. The very first product
464
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462
465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 6
A. Bernkop-Schnürch, S. Dünnhaupt / European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx
containing a chitosan derivative (hydroxypropyl–chitosan) has already been registered, being meanwhile commercially available 483 under the brand name CiclopoliÒ and various compounds further 484 Q3 will certainly follow. 481 482
485
References
486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562
[1] K. Bhise, R. Dhumal, A. Paradkar, S. Kadam, Effect of drying methods on swelling, erosion and drug release from chitosan–naproxen sodium complexes, AAPS PharmSciTech 9 (2008) 1–12. [2] W. Sun, S. Mao, Y. Wang, V.B. Junyaprasert, T. Zhang, L. Na, J. Wang, Bioadhesion and oral absorption of enoxaparin nanocomplexes, Int. J. Pharm. 386 (2010) 275–281. [3] C. Tapia, V. Corbalán, E. Costa, M.N. Gai, M. Yazdani-Pedram, Study of the release mechanism of diltiazem hydrochloride from matrices based on chitosan alginate and chitosan carrageenan mixtures, Biomacromolecules 6 (2005) 2389–2395. [4] G. Shavi, U. Nayak, M. Reddy, A. Karthik, P. Deshpande, A. Kumar, N. Udupa, Sustained release optimized formulation of anastrozole-loaded chitosan microspheres: in vitro and in vivo evaluation, J. Mater. Sci. Mater. Med. 22 (2011) 865–878. [5] V. Grabovac, D. Guggi, A. Bernkop-Schnürch, Comparison of the mucoadhesive properties of various polymers, Adv. Drug Deliv. Rev. 57 (2005) 1713–1723. [6] H.L. Lueßen, B.J. de Leeuw, M.W.E. Langemeÿer, A.G. de Boer, J.C. Verhoef, H.E. Junginger, Mucoadhesive polymers in peroral peptide drug delivery. VI. Carbomer and chitosan improve the intestinal absorption of the peptide drug buserelin in vivo, Pharm. Res. 13 (1996) 1668–1672. [7] A. Jintapattanakit, V.B. Junyaprasert, T. Kissel, The role of mucoadhesion of trimethyl chitosan and PEGylated trimethyl chitosan nanocomplexes in insulin uptake, J. Pharm. Sci. 98 (2009) 4818–4830. [8] M. Werle, A. Bernkop-Schnürch, Thiolated chitosans: useful excipients for oral drug delivery, J. Pharm. Pharmacol. 60 (2008) 273–281. [9] S. Gupta, S.P. Vyas, Carbopol/chitosan based pH triggered in situ gelling system for ocular delivery of timolol maleate, Sci. Pharm. 78 (2010) 959–976. [10] D. Sakloetsakun, J. Hombach, A. Bernkop-Schnürch, In situ gelling properties of chitosan–thioglycolic acid conjugate in the presence of oxidizing agents, Biomaterials 30 (2009) 6151–6157. [11] S. Mao, W. Sun, T. Kissel, Chitosan-based formulations for delivery of DNA and siRNA, Adv. Drug Deliv. Rev. 62 (2010) 12–27. [12] H. Yu, X. Chen, T. Lu, J. Sun, H. Tian, J. Hu, Y. Wang, P. Zhang, X. Jing, Poly(Llysine)-graft-chitosan copolymers: synthesis, characterization, and gene transfection effect, Biomacromolecules 8 (2007) 1425–1435. [13] D. Lee, S.S. Mohapatra, Chitosan nanoparticle-mediated gene transfer, in: J.M. Doux (Ed.), Gene Therapy Protocols, Humana Press, 2008, pp. 127–140. [14] J. Malmo, K.M. Vrum, S.P. Strand, Effect of chitosan chain architecture on gene delivery: comparison of self-branched and linear chitosans, Biomacromolecules 12 (2011) 721–729. [15] R. Martien, B. Loretz, M. Thaler, S. Majzoob, A. Bernkop-Schnürch, Chitosan– thioglycolic acid conjugate: an alternative carrier for oral nonviral gene delivery?, J Biomed. Mater. Res. A 82 (2007) 1–9. [16] A.K. Varkouhi, R.J. Verheul, R.M. Schiffelers, T. Lammers, G. Storm, W.E. Hennink, Gene silencing activity of siRNA polyplexes based on thiolated N,N,N-trimethylated chitosan, Bioconjugate Chem. 21 (2010) 2339–2346. [17] D. Teijeiro-Osorio, C. Remuñán-López, M.J. Alonso, Chitosan/cyclodextrin nanoparticles can efficiently transfect the airway epithelium in vitro, Eur. J. Pharm. Biopharm. 71 (2009) 257–263. [18] M. Malhotra, C. Lane, C. Tomaro-Duchesneau, S. Saha, S. Prakash, A novel method for synthesizing PEGylated chitosan nanoparticles: strategy, preparation, and in vitro analysis, Int. J. Nanomed. 6 (2011) 485–494. [19] N.G.M. Schipper, S. Olsson, J.A. Hoogstraate, A.G. deBoer, K.M. Vårum, P. Artursson, Chitosans as absorption enhancers for poorly absorbable drugs. 2: Mechanism of absorption enhancement, Pharm. Res. 14 (1997) 923–929. [20] A.F. Kotzé, H.L. Lueßen, B.J. de Leeuw, B.G. de Boer, J. Coos Verhoef, H.E. Junginger, Comparison of the effect of different chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2), J. Control. Release 51 (1998) 35–46. [21] N.G.M. Schipper, K.M. Vårum, P. Artursson, Chitosans as absorption enhancers for poorly absorbable drugs. 1: Influence of molecular weight and degree of acetylation on drug transport across human intestinal epithelial (caco-2) cells, Pharm. Res. 13 (1996) 1686–1692. [22] C.E. Kast, A. Bernkop-Schnürch, Influence of the molecular mass on the permeation enhancing effect of different poly(acrylates), STP Pharm. Sci. 6 (2002) 351–356. [23] P. Shah, V. Jogani, P. Mishra, A.K. Mishra, T. Bagchi, A. Misra, Modulation of ganciclovir intestinal absorption in presence of absorption enhancers, J. Pharm. Sci. 96 (2007) 2710–2722. [24] A. Trapani, A. Lopedota, M. Franco, N. Cioffi, E. Ieva, M. Garcia-Fuentes, M.J. Alonso, A comparative study of chitosan and chitosan/cyclodextrin nanoparticles as potential carriers for the oral delivery of small peptides, Eur. J. Pharm. Biopharm. 75 (2010) 26–32. [25] N. Langoth, H. Kahlbacher, G. Schöffmann, I. Schmerold, M. Schuh, S. Franz, P. Kurka, A. Bernkop-Schnürch, Thiolated chitosans: design and in vivo evaluation of a mucoadhesive buccal peptide drug delivery system, Pharm. Res. 23 (2006) 573–579.
[26] N. Langoth, A. Bernkop-Schnürch, P. Kurka, In vitro evaluation of various buccal permeation enhancing systems for PACAP (pituitary adenylate cyclaseactivating polypeptide), Pharm. Res. 22 (2005) 2045–2050. [27] B.B. Carreno-Gomez, R.W. Duncan, Compositions with Enhanced oral Bioavailability, US Patent 20030211072, 2003. [28] F. Föger, T. Schmitz, A. Bernkop-Schnürch, In vivo evaluation of an oral delivery system for P-gp substrates based on thiolated chitosan, Biomaterials 27 (2006) 4250–4255. [29] T.F. Palmberger, J. Hombach, A. Bernkop-Schnürch, Thiolated chitosan: development and in vitro evaluation of an oral delivery system for acyclovir, Int. J. Pharm. 348 (2008) 54–60. [30] G.S. Macleod, J.T. Fell, J.H. Collett, H.L. Sharma, A.-M. Smith, Selective drug delivery to the colon using pectin:chitosan:hydroxypropyl methylcellulose film coated tablets, Int. J. Pharm. 187 (1999) 251–257. [31] A. Bernkop-Schnürch, E. Reich-Rohrwig, M. Marschütz, H. Schuhbauer, M. Kratzel, Development of a sustained release dosage form for a-lipoic acid. II. Evaluation in human volunteers, Drug Dev. Ind. Pharm. 30 (2004) 35–42. [32] P. Mura, N. Zerrouk, N. Mennini, F. Maestrelli, C. Chemtob, Development and characterization of naproxen–chitosan solid systems with improved drug dissolution properties, Eur. J. Pharm. Sci. 19 (2003) 67–75. [33] C. Kose-Ozkan, A. Savaser, C. Tas, Y. Ozkan, The development and in vitro evaluation of sustained release tablet formulations of benzydamine hydrochloride and its determination, Comb. Chem. High Throughput Screening 13 (2010) 683–689. [34] S. Mutalik, K. Manoj, M. Reddy, P. Kushtagi, A. Usha, P. Anju, A. Ranjith, N. Udupa, Chitosan and enteric polymer based once daily sustained release tablets of aceclofenac: in vitro and in vivo studies, AAPS PharmSciTech 9 (2008) 651–659. [35] S. Dhaliwal, S. Jain, H. Singh, A. Tiwary, Mucoadhesive microspheres for gastroretentive delivery of acyclovir: in vitro and in vivo evaluation, AAPS J. 10 (2008) 322–330. [36] Y. Akiyama, N. Nagahara, E. Nara, M. Kitano, S. Iwasa, I. Yamamoto, J. Azuma, Y. Ogawa, Evaluation of oral mucoadhesive microspheres in man on the basis of the pharmacokinetics of furosemide and riboflavin, compounds with limited gastrointestinal absorption sites, J. Pharm. Pharmacol. 50 (1998) 159–166. [37] M. Säkkinen, J. Marvola, H. Kanerva, K. Lindevall, A. Ahonen, M. Marvola, Scintigraphic verification of adherence of a chitosan formulation to the human oesophagus, Eur. J. Pharm. Biopharm. 57 (2004) 145–147. [38] A.B. Sieval, M. Thanou, A.F. Kotze´, J.C. Verhoef, J. Brussee, H.E. Junginger, Preparation and NMR characterization of highly substituted N-trimethyl chitosan chloride, Carbohydr. Polym. 36 (1998) 157–165. [39] A. Bernkop-Schnürch, M. Hornof, T. Zoidl, Thiolated polymers–thiomers: synthesis and in vitro evaluation of chitosan-2-iminothiolane conjugates, Int. J. Pharm. 260 (2003) 229–237. [40] K. Kafedjiiski, A.H. Krauland, M.H. Hoffer, A. Bernkop-Schnürch, Synthesis and in vitro evaluation of a novel thiolated chitosan, Biomaterials 26 (2005) 819– 826. [41] M. Thanou, B.I. Florea, M.W.E. Langemeÿer, J.C. Verhoef, H.E. Junginger, Ntrimethylated chitosan chloride (TMC) improves the intestinal permeation of the peptide drug buserelin in vitro (caco-2 cells) and in vivo (rats), Pharm. Res. 17 (2000) 27–31. [42] B. Sarmento, A. Ribeiro, F. Veiga, P. Sampaio, R. Neufeld, D. Ferreira, Alginate/ chitosan nanoparticles are effective for oral insulin delivery, Pharm. Res. 24 (2007) 2198–2206. [43] H. Gupta, T. Velpandian, S. Jain, Ion- and pH-activated novel in-situ gel system for sustained ocular drug delivery, J. Drug Targeting 18 (2010) 499–505. [44] A.M. De Campos, A. Sánchez, M.a.J. Alonso, Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporin A, Int. J. Pharm. 224 (2001) 159–168. [45] P. Calvo, J.L. Vila-Jato, M.a.J. Alonso, Evaluation of cationic polymer-coated nanocapsules as ocular drug carriers, Int. J. Pharm. 153 (1997) 41–50. [46] A.M. De Campos, A. Sánchez, M.J. Alonso, Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporin A, Int. J. Pharm. 224 (2001) 159–168. [47] I. Genta, B. Conti, P. Perugini, F. Pavanetto, A. Spadaro, G. Puglisi, Bioadhesive microspheres for ophthalmic administration of acyclovir, J. Pharm. Pharmacol. 49 (1997) 737–742. [48] L. Illum, Nasal drug delivery – possibilities, problems and solutions, J. Control. Release 87 (2003) 187–198. [49] R.J. Soane, M. Frier, A.C. Perkins, N.S. Jones, S.S. Davis, L. Illum, Evaluation of the clearance characteristics of bioadhesive systems in humans, Int. J. Pharm. 178 (1999) 55–65. [50] L. Ilium, Chitosan and its use as a pharmaceutical excipient, Pharm. Res. 15 (1998) 1326–1331. [51] L. Na, S. Mao, J. Wang, W. Sun, Comparison of different absorption enhancers on the intranasal absorption of isosorbide dinitrate in rats, Int. J. Pharm. 397 (2010) 59–66. [52] D. Teijeiro-Osorio, C. Remuñán-López, M. José Alonso, New generation of hybrid poly oligosaccharide nanoparticles as carriers for the nasal delivery of macromolecules, Biomacromolecules 10 (2008) 243–249. [53] X. Zhang, H. Zhang, Z. Wu, Z. Wang, H. Niu, C. Li, Nasal absorption enhancement of insulin using PEG-grafted chitosan nanoparticles, Eur. J. Pharm. Biopharm. 68 (2008) 526–534. [54] R. Fernández-Urrusuno, P. Calvo, C. Remuñán-López, J.L. Vila-Jato, M. José Alonso, Enhancement of nasal absorption of insulin using chitosan nanoparticles, Pharm. Res. 16 (1999) 1576–1581.
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 A. Bernkop-Schnürch, S. Dünnhaupt / European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686
[55] A. Fisher, M. Watling, A. Smith, A. Knight, Pharmacokinetic comparisons of three nasal fentanyl formulations; pectin, chitosan and chitosan–poloxamer 188, Int. J. Clin. Pharmacol. Ther. 48 (2010) 138–145. [56] A. El-Kamel, M. Sokar, V. Naggar, S. Al Gamal, Chitosan and sodium alginatebased bioadhesive vaginal tablets, AAPS J. 4 (2002) 224–230. [57] G. Sandri, S. Rossi, F. Ferrari, M.C. Bonferoni, C. Muzzarelli, C. Caramella, Assessment of chitosan derivatives as buccal and vaginal penetration enhancers, Eur. J. Pharm. Sci. 21 (2004) 351–359. [58] D. Raafat, H.-G. Sahl, Chitosan and its antimicrobial potential – a critical literature survey, Microb. Biotechnol. 2 (2009) 186–201. [59] K. Aiedeh, M.O. Taha, Synthesis of iron-crosslinked chitosan succinate and iron-crosslinked hydroxamated chitosan succinate and their in vitro evaluation as potential matrix materials for oral theophylline sustainedrelease beads, Eur. J. Pharm. Sci. 13 (2001) 159–168. [60] G. Sandri, S. Rossi, M.C. Bonferoni, F. Ferrari, Y. Zambito, G. Di Colo, C. Caramella, Buccal penetration enhancement properties of N-trimethyl chitosan: influence of quaternization degree on absorption of a high molecular weight molecule, Int. J. Pharm. 297 (2005) 146–155. [61] S.M. Upadrashta, P.R. Katikaneni, N.O. Nuessle, Chitosan as a tablet binder, Drug Dev. Ind. Pharm. 18 (1992) 1701–1708. [62] S.W. Richardson, H.J. Kolbe, R. Duncan, Potential of low molecular mass chitosan as a DNA delivery system: biocompatibility, body distribution and ability to complex and protect DNA, Int. J. Pharm. 178 (1999) 231–243. [63] C.G. Pitt, The controlled parenteral delivery of polypeptides and proteins, Int. J. Pharm. 59 (1990) 173–196. [64] B.C. Thanoo, M.C. Sunny, A. Jayakrishnan, Cross-linked chitosan microspheres: preparation and evaluation as a matrix for the controlled release of pharmaceuticals, J. Pharm. Pharmacol. 44 (1992) 283–286. [65] R.J. Nordtveit, K.M. Vårum, O. Smidsrød, Degradation of fully water-soluble, partially N-acetylated chitosans with lysozyme, Carbohydr. Polym. 23 (1994) 253–260. [66] H. Onishi, Y. Machida, K. Kamiyama, Pharmacokinetics and tissue distribution properties of glycol–chitosan and N-succinyl–chitosan in mice, in: Proceedings of the Controlled Release Society, 1996, pp. 645–646. [67] J.-H. Kim, Y.-S. Kim, K. Park, E. Kang, S. Lee, H.Y. Nam, K. Kim, J.H. Park, D.Y. Chi, R.-W. Park, I.-S. Kim, K. Choi, I. Chan Kwon, Self-assembled glycol chitosan nanoparticles for the sustained and prolonged delivery of antiangiogenic small peptide drugs in cancer therapy, Biomaterials 29 (2008) 1920–1930.
7
[68] J. Barthelmes, G. Perera, J. Hombach, S. Dünnhaupt, A. Bernkop-Schnürch, Development of a mucoadhesive nanoparticulate drug delivery system for a targeted drug release in the bladder, Int. J. Pharm. 416 (2011) 339–345. [69] M. Maeda, H. Murakami, H. Ohta, M. Tajima, Stimulation of IgM production in human–human hybridoma HB4C5 cells by chitosan, Biosci., Biotechnol., Biochem. 56 (1992) 427–431. [70] I. Jabbal-Gill, A.N. Fisher, R. Rappuoli, S.S. Davis, L. Illum, Stimulation of mucosal and systemic antibody responses against Bordetella pertussis filamentous haemagglutinin and recombinant pertussis toxin after nasal administration with chitosan in mice, Vaccine 16 (1998) 2039–2046. [71] R. Garmise, H. Staats, A. Hickey, Novel dry powder preparations of whole inactivated influenza virus for nasal vaccination, AAPS PharmSciTech 8 (2007) 2–10. [72] R.C. Read, S.C. Naylor, C.W. Potter, J. Bond, I. Jabbal-Gill, A. Fisher, L. Illum, R. Jennings, Effective nasal influenza vaccine delivery using chitosan, Vaccine 23 (2005) 4367–4374. [73] A. Bacon, J. Makin, P.J. Sizer, I. Jabbal-Gill, M. Hinchcliffe, L. Illum, S. Chatfield, M. Roberts, Carbohydrate biopolymers enhance antibody responses to mucosally delivered vaccine antigens, Infect. Immun. 68 (2000) 5764–5770. [74] I.M. van der Lubben, J.C. Verhoef, A.C. van Aelst, G. Borchard, H.E. Junginger, Chitosan microparticles for oral vaccination: preparation, characterization and preliminary in vivo uptake studies in murine Peyer’s patches, Biomaterials 22 (2001) 687–694. [75] A. Vila, A. Sánchez, K. Janes, I. Behrens, T. Kissel, J.L.V. Jato, M.J. Alonso, Low molecular weight chitosan nanoparticles as new carriers for nasal vaccine delivery in mice, Eur. J. Pharm. Biopharm. 57 (2004) 123–131. [76] O. Borges, A. Cordeiro-da-Silva, J. Tavares, N. Santarém, A. de Sousa, G. Borchard, H.E. Junginger, Immune response by nasal delivery of hepatitis B surface antigen and codelivery of a CpG ODN in alginate coated chitosan nanoparticles, Eur. J. Pharm. Biopharm. 69 (2008) 405–416. [77] S.M. Bal, B. Slütter, R. Verheul, J.A. Bouwstra, W. Jiskoot, Adjuvanted, antigen loaded N-trimethyl chitosan nanoparticles for nasal and intradermal vaccination: adjuvant- and site-dependent immunogenicity in mice, Eur. J. Pharm. Sci. 45 (2012) 475–481. [78] B. Slütter, L. Plapied, V. Fievez, M. Alonso Sande, A. des Rieux, Y.-J. Schneider, E. Van Riet, W. Jiskoot, V. Préat, Mechanistic study of the adjuvant effect of biodegradable nanoparticles in mucosal vaccination, J. Control. Release 138 (2009) 113–121.
687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
No. of Pages 7, Model 5G
2 May 2012 European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx 1
Contents lists available at SciVerse ScienceDirect
European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb
2
Short review (expert opinion)
3
Chitosan-based drug delivery systems
4 5 6 7 9 2 1 10 11 12 13 14 15 16 17 18 19 20
Q1
Andreas Bernkop-Schnürch ⇑, Sarah Dünnhaupt Department of Pharmaceutical Technology, University of Innsbruck, Innsbruck, Austria
a r t i c l e
i n f o
Article history: Received 16 November 2011 Accepted in revised form 16 April 2012 Available online xxxx Keywords: Chitosan Drug delivery Mucoadhesion Permeation enhancement Controlled release
a b s t r a c t Within the past 20 years, a considerable amount of work has been published on chitosan and its potential use in drug delivery systems. In contrast to all other polysaccharides having a monograph in a pharmacopeia, chitosan has a cationic character because of its primary amino groups. These primary amino groups are responsible for properties such as controlled drug release, mucoadhesion, in situ gellation, transfection, permeation enhancement, and efflux pump inhibitory properties. Due to chemical modifications, most of these properties can even be further improved. Within this review, an overview on the advantages of chitosan for various types of drug delivery systems is provided. Ó 2012 Published by Elsevier B.V.
22 23 24 25 26 27 28 29
30 31 32
1. Introduction
33
Since chitosan has entered the pharmaceutical arena in the early 1990s, it has inspired academic and industrial research teams to generate novel more effective therapeutic systems based on it. Apart from applications such as slimming, wound dressing, and tissue engineering, chitosan showed promising features as auxiliary agent in drug delivery. In contrast to all other biodegradable polymers having a monograph in a pharmacopoeia, chitosan is the only one exhibiting a cationic character rendering it unique among all others. This cationic character being based on its primary amino groups is responsible for various properties and subsequently for its use in drug delivery systems. In the following, these properties are highlighted in more detail.
34 35 36 37 38 39 40 41 42 43 44
45
2. Properties of chitosan
46
2.1. Controlled drug release
47
When sustained drug release cannot be provided by making use of a simple drug dissolution process, by diffusion, by erosion, by membrane control, or by osmotic systems, retardation mediated by ionic interactions is often the ultimate ratio. Such a controlled release can be achieved for cationic drugs by using anionic polymeric excipients such as polyacrylates, sodium carboxymethylcellulose, or alginate. In case of anionic drugs, however, chitosan is the
48 49 50 51 52 53
⇑ Corresponding author. Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold–Franzenz–University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Tel.: +43 512 507 58600; fax: +43 512 507 58699. E-mail address: [email protected] (A. Bernkop-Schnürch).
only choice. Bhise et al. [1], for instance, designed sustained release systems for the anionic drug naproxen using chitosan as drug carrier matrix. Using polyanionic drugs, the interactions between chitosan and the therapeutic agent are more pronounced, and based on an ionic cross-linking in addition, even stable complexes are formed from which the drug can be released even over a more prolonged time period. Sun et al. [2], for instance, designed enoxaparin/chitosan nanoparticulate delivery systems, providing very stable complexes that led to a significantly improved drug uptake. In addition, chitosans can be homogenized with anionic polymeric excipients such as polyacrylates, hyaluronic acid, alginate, pectin, or carrageenan, resulting in comparatively stable complexes of high density. Mainly based on diffusion and erosion processes, incorporated drugs are released in a sustained manner from such complexes [3]. Alternative to anionic polymers, multivalent inorganic anions such as tripolyphosphate or sulfate can be used in order to achieve the same effect [4].
54
2.2. Mucoadhesive properties
71
The mucoadhesive properties are likely also based on its cationic character. The mucus gel layer exhibits anionic substructures in the form of sialic acid and sulfonic acid substructures. Based on ionic interactions between the cationic primary amino groups of chitosan and these anionic substructures of the mucus, mucoadhesion can be achieved. In addition, hydrophobic interactions might contribute to its mucoadhesive properties. In comparison with various anionic polymeric excipients such as carbomer, polycarbophil, and hyaluronic acid, however, its mucoadhesive properties are weak [5]. Furthermore, in order to achieve high mucoadhesive properties, the polymer needs to exhibit also high cohesive
72
0939-6411/$ - see front matter Ó 2012 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ejpb.2012.04.007
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70
73 74 75 76 77 78 79 80 81 82
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 2
A. Bernkop-Schnürch, S. Dünnhaupt / European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx
112
properties as the adhesive bond otherwise fails within the mucoadhesive polymer rather than between the mucus gel layer and the polymer. In case of chitosans, however, these cohesive properties are also comparatively weak. Although they can be strongly improved by the formation of complexes with multivalent anionic drugs, multivalent anionic polymeric excipients, and multivalent inorganic anions, this strategy is only to a quite limited extent effective, as the cationic substructures of chitosan being responsible for mucoadhesion via ionic interactions with the mucus are in this way blocked. Lueßen et al., for instance, demonstrated a significantly improved oral bioavailability of buserelin when being administered with mucoadhesive polymers such as chitosan and carbomer to rats. This effect, however, could not be observed anymore when chitosan was combined with the polyanionic carbomer in the same formulation [6]. Trimethylation of the primary amino group of chitosan provides an even more cationic character of the polymer. When trimethylated chitosan (TMC) is additionally PEGylated, its mucoadhesive properties are even up to 3.4-fold improved [7]. Due to the immobilization of thiol groups on chitosan, its mucoadhesive properties can also be strongly improved, as the thiolated polymer is capable of forming disulfide bonds with mucus glycoproteins of the mucus gel layer, placing it among the most mucoadhesive polymers known so far [8]. In addition, as inter- and intrachain disulfide bonds are also formed within chitosan itself, thiolated chitosan exhibits substantially improved cohesive properties. Recently, the mucoadhesive properties of thiolated chitosans were even significantly further improved by the preactivation of thiol groups on chitosan via the formation of disulfide bonds with mercaptonicotinamide [Dünnhaupt et al., unpublished results].
113
2.3. In situ gelling properties
114
129
In case of hydrogels, chitosan offers the advantage of in situ gelling properties when its pH-dependent hydratability is addressed properly from the formulation point of view. Gupta et al., for instance, developed an in situ gelling delivery system by the combination of polyacrylic acid and chitosan. The resulting formulation was in liquid state at pH 6.0 and underwent rapid transition into the viscous gel phase at physiological pH of 7.4 [9]. These in situ gelling properties can even be further improved by thiolation. Due to access to oxygen on mucosal surfaces such as the ocular or nasal mucosa after having been applied in liquid form out of for instance oxygen-free single unit dosage forms, a cross-linking process via disulfide bond formation takes place resulting in a strong increase in viscosity. Utilizing this cross-linking mechanism, Sakloetsakun et al., for instance, could show an even 16,500-fold increase in viscosity within 20 min. of an aqueous 1% (m/v) chitosan–thioglycolic acid conjugate [10].
130
2.4. Transfection enhancing properties
131
In contrast to small molecules, where a controlled release of anionic drugs can be achieved as described above, comparatively large polyanionic molecules such as DNA-based drugs and siRNA form stable complexes with chitosan. In this way, nanoparticles exhibiting a positive zeta potential can be formed, when the ratio of the cationic polymer is sufficiently high. Because of this positive net charge and the small size of these particles, endocytosis can be achieved in particular when these particles are below 100 nm in size [11]. As chitosan is comparatively less toxic than other cationic polymers such as polyethyleneimine, polylysine, or polyarginine [12], it is therefore a promising excipient for non-viral gene delivery systems. In addition, chitosan–DNA-based drug complexes protect at least to some extend towards degradation by DNAses in this way improving the bioavailability of DNA-based drugs delivered
83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111
115 116 117 118 119 120 121 122 123 124 125 126 127 128
132 133 134 135 136 137 138 139 140 141 142 143 144
into the body [13]. As the transfection efficiency of conventional chitosans is generally found to be low, the polysaccharide was modified following different strategies in order to improve its properties. Malmo et al. [14] investigated the self-branching of chitosans as a strategy to improve its gene transfer properties without compromising its safety profile. Self-branched and selfbranched trisaccharide-substituted chitosans with molecular mass of 11–71 kDa were synthesized, characterized, and compared with their linear counterparts with respect to transfection efficiency, showing that self-branched chitosans can yield gene expression levels two and five times higher than those of Lipofectamine and Exgen, respectively. Following another approach, Martien et al. [15] stabilized chitosan/plasmid nanoparticles by utilizing thiolated chitosan forming intrachain disulfide bonds within the complex. In this way, a higher stability towards nucleases was achieved. In addition, the plasmid was mainly released in the target cells, as due to the reducing conditions of the cytoplasma, the disulfide bonds were mainly cleaved there leading to the release of the plasmid at the target site. The transfection rate of thiolated chitosan/ plasmid nanoparticles was in this connection demonstrated to be five times higher than that of unmodified chitosan/pDNA nanoparticles. This strategy could even be further improved by raising the cationic character of thiolated chitosan due to trimethylation of the remaining primary amino groups [16]. Furthermore, PEGylated chitosan and chitosan/cyclodextrin nanoparticles were identified as promising tools for DNA-based drug delivery [17,18].
145
2.5. Permeation enhancing properties
171
The mechanism being responsible for the permeation enhancing effect of chitosan is also based on the positive charges of the polymer, which seems to interact with the cell membrane resulting in a structural reorganization of tight junction-associated proteins [19]. A more pronounced cationic character being achieved by trimethylation of the primary amino group, however, did not lead to further improved permeation enhancing properties, suggesting that the underlying mechanism described above is obviously more complex than assumed [20]. Schipper et al. [21] could demonstrate that the structural properties of chitosan, that is, molecular mass and degree of deacetylation, dictate the permeation enhancing properties and toxicity to a large extent. Chitosans of high degree of deacetylation and of high molecular mass exhibit the comparatively highest increase in epithelial permeability. This increase in permeation enhancing effect with increasing molecular mass could also be observed for other permeation enhancing polymers such as polyacrylates [22], providing another piece for the overall puzzle of the underlying mechanism. As these parameters determining permeation enhancement do not correlate with those determining toxicity, chitosans with maximal permeation enhancing effect and minimal toxicity are available. The comparatively high permeation enhancing properties of chitosan seen on Caco-2 cell monolayers, however, are in the presence of the mucus layer much lower, as chitosan cannot reach the epithelium because of size-limited diffusion and competitive charge interactions with mucins. Nevertheless, this permeation enhancing effect could be confirmed by various in vivo studies. Shah et al., for instance, could demonstrate a 2-fold improved oral bioavailability of ganciclovir due to the co-administration of chitosan. As the polysaccharide acts in a completely different way than most other permeation enhancers, it can be combined with them leading to an additive or even synergistic effect. Following this strategy, the oral bioavailability of ganciclovir was even 4-fold improved using a combination of chitosan and sodium dodecylsulfate, although sodium dodecylsulfate led just to a 2-fold improvement when being co-administered without chitosan [23]. Recently, it was shown that chitosan nanoparticles exhibit only in the first segment of the duodenum a
172
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170
173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 A. Bernkop-Schnürch, S. Dünnhaupt / European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx
214
permeation enhancing effect for small peptides, whereas due to the addition of cyclodextrin, this permeation enhancing effect was enlarged over the entire duodenum [24]. Furthermore, due to thiolation, the permeation enhancing properties of chitosan on certain mucosal membranes can be even more than 30-fold further improved [25,26].
215
2.6. Efflux pump inhibitory properties
216
231
In 2002, Carreno-Gomez and Duncan demonstrated efflux pump inhibitory properties for various polysaccharides [27]. Although they did not evaluate chitosan in their studies, it was quite obvious that this polysaccharide will exhibit the same effect. A proof-of-principle for this theory was then provided by Föger et al. [28], demonstrating a significantly improved oral uptake of the P-gp substrate rhodamine 123 due to the co-administration of (thiolated) chitosan in rats. Results are illustrated in Fig. 1. Although this effect is in comparison with other efflux pump inhibitors not that pronounced, it seems, nevertheless, useful to improve the mucosal uptake of various efflux pump substrate drugs. In case of permeation enhancement, the effect of chitosan increased with increasing molecular mass of the polymer, whereas in case of efflux pump inhibition, a molecular mass in the range of 150 kDa led at least for a chitosan derivative to the most pronounced inhibition [29].
232
2.7. Colon targeting
233
In the same way as numerous other polysaccharides, chitosan is degraded in the colon. By making use of this colon-specific degradation, chitosan has been discovered as useful coating in order to guarantee a site specific delivery. Radiolabelled (99mTc) tablets coated with a combination of pectin/chitosan/hydroxypropyl methylcellulose (3 + 1 + 1), for instance, were administered orally to human volunteers [30]. Within this study, gamma scintigraphy was used to evaluate the gastrointestinal transit of these tablets, showing that they remain intact through the stomach and small intestine. In the colon, the bacteria degraded the coat, and thus, the tablets disintegrated. In another study, our own research group developed a sustained dosage form for alpha-lipoic acid making use of ionic interactions between this anionic drug and chitosan used as carrier matrix. Studies in human volunteers showed a release maximum once the formulation had reached the colon [31].
209 210 211 212 213
217 218 219 220 221 222 223 224 225 226 227 228 229 230
234 235 236 237 238 239 240 241 242 243 244 245 246 247
Fig. 1. Plasma curves of Rho-123 (ng/ml) after oral administration of 1.5 mg Rho123 in solution (white triangles), in chitosan tablets (black squares), or thiolated tablets (white squares). Indicated values are means (±SD) of five experiments; 1,2,3,4 differ from chitosan tablets, p < 0.01; p < 0.003; p < 0.001; p < 0.005, respectively. Adapted from Föger et al. [28].
3
3. Chitosan drug delivery systems
248
These properties of chitosan resulted in the development of numerous drug delivery systems for various application sites, which are described in more detail below.
249
3.1. Oral drug delivery
252
As liquid formulations are not favored by patients, and storage stability problems of drugs such as peptide drugs have to be overcome, solid dosage forms are the delivery systems of choice. Apart from capsules, tablets are therefore the likely most favorable dosage form. As tablets provide an accurate dosage and are easy to manufacture and handle, numerous drug delivery systems comprising chitosan are based on this type of dosage form [32–34]. The drug can thereby be homogenized with chitosan and directly compressed to tablets. As chitosan precipitates at pH above 6.5, it loses its mucoadhesive and permeation enhancing properties in distal segments of the intestine. This effect reduces its applicability to drugs having their absorption window in the proximal segment of the GI tract. Dhaliwal et al. [35], for instance, could improve the oral bioavailability of acyclovir 3-fold and 4-fold due to the incorporation of this drug in chitosan and thiolated chitosan, respectively. Within this study, a prolonged residence time in particular of thiolated chitosan microparticles in duodenal and jejunum regions was observed. These data need to be confirmed in human volunteers. So far, an improved oral bioavailability of various model drugs could be shown in human volunteers for mucoadhesive formulations likely because of an intimate contact of the delivery system with the absorption membrane and a prolonged mucosal residence time of the delivery systems [36]. Such studies, however, have not yet been performed with chitosans. A hint that such systems based on chitosan might work also in humans was at least provided by Säkkinen et al. [37], demonstrating the adhesion of chitosan granules to the distal esophageal mucosa for almost two hours. Chitosan derivatives of comparatively higher cationic character such as trimethylated chitosans [38], chitosan–thiobutylamidine conjugates [39], or chitosan–thioethylamidine conjugates [40], however, do not precipitate anymore within the whole pH range of the GI-tract. Thanou et al. [41], for instance, demonstrated that intraduodenally applied buserelin results in 0.8% absolute bioavailability in rats, whereas co-administrations with trimethylated chitosans resulted in average bioavailability values between 6% and 13%. In contrast, chitosan HCl did not significantly increase the intestinal absorption at pH 7.2. In case of nanoparticulate delivery systems, chitosan is in most cases ionically cross-linked. Precipitation at higher pH is therefore not anymore an issue at all, as the polymer is already ‘‘co-precipitated’’ with the multivalent anionic cross-linker. Although precipitated and homogenized with a polyanion blocking, its cationic groups to a high extend such nanoparticulate delivery systems exhibit surprisingly still potential. Sarmento et al. [42], for instance, showed a significant decrease in the blood glucose level of diabetic rats, when insulin was given orally in chitosan/alginate nanoparticles. Explanations might be given by the mucoadhesive properties of nanoparticulate formulations per se diffusing at least to some extent in the mucus gel layer and the protective effect of such formulations towards proteases.
253
3.2. Ocular drug delivery
303
Due to its nontoxic character, permeation enhancing properties, and physicochemical characteristics, chitosan is a suitable material for the design of ocular drug delivery systems. Chitosan-based formulations used for ophthalmic drug delivery are hydrogels [43],
304
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
250 251
254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302
305 306 307
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 4
A. Bernkop-Schnürch, S. Dünnhaupt / European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx
336
nanoparticles [44], and coated colloidal systems [45]. Chitosanbased systems have the potential for improving the retention and biodistribution of drugs applied topically onto the eye. Making use of its in situ gelling properties, chitosan can be applied and distributed on the ocular surface in almost liquid form thereafter transforming into the gel status. In this way, a prolonged ocular residence time and an improved therapeutic efficacy can be achieved [9,43]. De Campos et al. [46] demonstrated the potential of chitosan nanoparticles with incorporated cyclosporine A in improving the delivery of drugs to the ocular mucosa. Furthermore, chitosan-based colloidal systems were found to work as transmucosal drug carriers, either facilitating the transport of drugs to the inner eye or their accumulation into the corneal epithelia. The use of chitosan-based colloidal suspensions in vivo showed a significant increase in ocular drug bioavailability [45,47]. Calvo et al. [45], for instance, combined the features of polycaprolactone nanocapsules as ocular carriers with the advantages of the cationic mucoadhesive chitosan and poly-L-lysine (PLL) coating. Even though PLL and chitosan displayed a similar positive surface charge, only chitosan-coated nanocapsules enhanced the ocular penetration of indomethacin with respect to uncoated nanocapsules as shown in Fig. 2. The authors suggested that an undetermined property of chitosan was responsible for this enhanced uptake. Genta et al. [47] indicated that acyclovir-loaded chitosan microspheres offer significantly sustained ocular drug release in vivo. According to the authors in addition to its mucoadhesive properties, chitosan is effective in retarding the rate of drug release. Overall, each particulate system represents a useful approach to increase the ocular bioavailability of drugs.
337
3.3. Nasal drug delivery
338
Due to nasal obstacles such as low membrane permeability, a short local residence time, and high turnover rate of a secretion in nasal cavities, the bioavailability of nasally administered drugs is often comparatively poor [48]. The likely most promising approach to improve nasal drug absorption is the use of permeation enhancers and mucoadhesive nasal delivery systems. They can provide a prolonged contact between drug formulation and absorptive sites in the nasal cavity by delaying the mucociliary clearance of the formulation. Such mucoadhesive systems can be in the form of powders as well as liquids or liquid in situ gelling systems such as described above. Mainly because of its mucoadhesive and permeation enhancing properties, chitosan has been investigated as auxiliary agent in nasal drug delivery systems
308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335
339 340 341 342 343 344 345 346 347 348 349 350
Fig. 2. Indomethacin concentrations attained in the cornea following the topical application, in rabbits, of indomethacin-loaded carriers and control solution. Mean values ± SD (n = 3–4) are shown. Adapted from Calvo et al. [45].
[49,50]. Na et al. [51], for instance, could demonstrate significantly improved nasal uptake of isosorbide dinitrate due to the co-administration of chitosan in rats. In the same study, they showed a minor cilio-inhibiting effect of the polymer. Furthermore, chitosan particles or polyelectrolyte complexes have been studied for nasal delivery of therapeutic proteins [52–54]. It was found that insulinloaded chitosan nanoparticles enhance nasal drug absorption to a greater extent than relevant chitosan solutions. In addition, Fisher et al. [55] developed fentanyl nasal spray formulations with pectin, chitosan, and chitosan–poloxamer 188 for clinical evaluation to provide rapid absorption and subsequently increased bioavailability. The study was conducted in 18 healthy adult volunteers and revealed significantly increased systemic exposure as well as reduced times to peak plasma values for all formulations compared with oral transmucosal fentanyl citrate lozenge as illustrated in Fig. 3.
351
3.4. Vaginal drug delivery
367
El-Kamel et al. [56] prepared chitosan-based vaginal tablets containing metronidazole by direct compressing the polymer, loosely cross-linked with glutaraldehyde, together with sodium alginate with or without microcrystalline cellulose. Tablets showed adequate release properties in pH 4.8 and 7 and gave low values of swelling index. These tablets showed also comparatively good adhesive properties. In another study, Sandri et al. [57] evaluated the mucoadhesive and permeation enhancing properties of four different chitosan derivatives: 5-methyl-pyrrolidinone chitosan, two low molecular mass chitosans, and a partially re-acetylated chitosan via the vaginal and buccal mucosa using acyclovir as model drug. Methyl-pyrrolidinone chitosan showed the highest mucoadhesive and permeation enhancing properties in both vaginal and buccal environments. The capability of enhancing the permeation/ penetration of acyclovir was decreased by partial depolymerization of chitosan and disappeared after partial re-acetylation. The antimicrobial properties of chitosan, however, might have a negative impact on the vaginal microflora [58]. Its vaginal use for treatment of chronic diseases has therefore to be seen with caution.
368
3.5. Buccal drug delivery
387
By avoiding hepatic first-pass metabolism and degradation in stomach and small intestine, the buccal route is an alternative choice to deliver drugs to the application site. In addition, this route shows high acceptance by patients. An ideal buccal delivery system should stay in the oral cavity for hours and release the drug in a controlled way. Mucoadhesive polymers prolong the residence time of the drug in the oral cavity [59]. Based on its mucoadhesive as well as absorption enhancement properties, chitosan is a promising polymer to be used for buccal delivery. Sandri et al. [60], for instance, could show that trimethylated chitosans seem to be promising exipients for drug delivery systems intended for buccal mucosa applications to enhance the absorption of hydrophilic macromolecules. In another study, the potential of thiolated chitosan for peptide delivery systems via the buccal mucosa was investigated in pigs [25]. The therapeutic peptide PACAP was applied to pigs, and its bioavailability was determined in order to facilitate the treatment of type 2 diabetes. Due to its strong permeation enhancing properties, tablets based on thiolated chitosan raised continuously the plasma level of this peptide drug, allowing for therapeutic range levels to be maintained over the whole period of application. Furthermore, buccal bilayered devices with a mixture of nifedipine and propranolol as well as chitosan displayed promising potential for use in controlled delivery in the oral cavity [61].
388
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
352 353 354 355 356 357 358 359 360 361 362 363 364 365 366
369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386
389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 A. Bernkop-Schnürch, S. Dünnhaupt / European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx
5
Fig. 3. Mean values ± SD of plasma concentration time following single-dose administration of 100 lg FChNS = fentanyl chitosan nasal spray (n = 18), 100 lg FChPNS = fentanyl in chitosan–poloxamer 188 nasal spray (n = 18), 100 lg FPNS = fentanyl pectin nasal spray (n = 18), 200 lg OTFC = oral transmucosal fentanyl citrate lozenge (n = 18). Insert provides 0–2-h profile (without error bars). Adapted from Fisher et al. [55]. 412
3.6. Parenteral drug delivery
413
431
As highly purified low molecular mass chitosan was shown neither to be toxic nor hemolytic when given intravenously [62], its use in injectable preparations has received considerable attention within the last years. In controlled release technology, biodegradable polymeric carriers offer potential advantages for prolonged release of low-molecular-weight compounds to macromolecular drugs [63,64]. The susceptibility of chitosan to lysozyme makes it biodegradable [65]. Pharmacokinetic and tissue-distribution studies were performed in mice using fluorescent glycol–chitosan and N-succinyl-chitosan. Both chitosans demonstrated a good retention in blood circulation and a slight accumulation in tissues, suggesting that chitosan is an effective carrier for drugs that are excreted rapidly [66]. In another study, Kim et al. [67] synthesized hydrophobically modified glycol chitosan with 5-b-cholanic acid groups, which was subsequently used to prepare nanoparticles with incorporated RGD peptide (Arg-Gly-Asp). Intratumoral administration of RGD-loaded chitosan nanoparticles demonstrated a substantially decreased tumor growth as compared to the RGD peptide administered intravenously.
432
3.7. Intravesical drug delivery
433
441
Barthelmes et al. [68] investigated mucoadhesive properties of chitosan and thiolated chitosan nanoparticles on the intravesical mucosa in order to prolong the residence time of instilled drugs in urinary bladders. It was shown that thiolated chitosan nanoparticles might be a useful tool for local intravesical drug delivery, which increases the residence time of the drug and enables sustainable delivery for an extended period of time. Evidence for this theory could at least be provided by in vivo studies in rats [Barthelmes et al., unpublished results].
442
3.8. Vaccine delivery
443
Although chitosan was already shown in the early 1990s to stimulate IgM production of human lymphocytes in serum-free
414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430
434 435 436 437 438 439 440
444
culture [69], it took several years until first vaccine delivery systems were developed. Jabbal-Gill et al. [70] were likely the first providing evidence for a successful nasal immunization against Bordetella pertussis in mice combining different antigens with chitosan. In the following, various chitosan-based carriers have been designed and evaluated for nasal delivery of antigens showing valid levels of both systemic and local immune response [71– 76]. Utilizing trimethylated chitosan nanoparticles for nasal administration led even to an increased immune response that could be further improved by the incorporation of certain immunopotentiators [77]. In the following, also oral vaccine delivery systems based on chitosan were developed. Van der Lubben et al. [74], were the first who could demonstrate the uptake of chitosan microparticles by the epithelium of the murine Peyer’s patches. Similar to nasal vaccine delivery systems also in case of oral delivery trimethylated-chitosan exhibiting in contrast to unmodified chitosan, an intrinsic adjuvant effect on dentritic cells showed comparatively greater potential [78].
445
4. Conclusion
463
Due to its cationic character, chitosan exhibits mucoadhesive, permeation enhancing, in situ gelling, and efflux pump inhibitory properties. In addition, by making use of ionic interactions, also a controlled drug release can be achieved, and nanoparticulate delivery systems for DNA-based drugs and siRNA can be formed. Most of these effects of chitosan, however, are comparatively weak providing simply not enough added values that would justify product developments based on it. Consequently, only very few studies in humans are done with chitosan, and there are currently no products on the market making use of certain properties of this polymer from the drug delivery point of view. Due to derivatization, almost all properties of chitosan, however, can be strongly improved, and this trend will certainly hold on resulting in even more potent chitosan derivatives. The authors are therefore convinced that it is just a question of time when products being based on potent chitosan derivatives will enter the market, and in fact, the initial step in this direction has already been taken. The very first product
464
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462
465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 6
A. Bernkop-Schnürch, S. Dünnhaupt / European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx
containing a chitosan derivative (hydroxypropyl–chitosan) has already been registered, being meanwhile commercially available 483 under the brand name CiclopoliÒ and various compounds further 484 Q3 will certainly follow. 481 482
485
References
486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562
[1] K. Bhise, R. Dhumal, A. Paradkar, S. Kadam, Effect of drying methods on swelling, erosion and drug release from chitosan–naproxen sodium complexes, AAPS PharmSciTech 9 (2008) 1–12. [2] W. Sun, S. Mao, Y. Wang, V.B. Junyaprasert, T. Zhang, L. Na, J. Wang, Bioadhesion and oral absorption of enoxaparin nanocomplexes, Int. J. Pharm. 386 (2010) 275–281. [3] C. Tapia, V. Corbalán, E. Costa, M.N. Gai, M. Yazdani-Pedram, Study of the release mechanism of diltiazem hydrochloride from matrices based on chitosan alginate and chitosan carrageenan mixtures, Biomacromolecules 6 (2005) 2389–2395. [4] G. Shavi, U. Nayak, M. Reddy, A. Karthik, P. Deshpande, A. Kumar, N. Udupa, Sustained release optimized formulation of anastrozole-loaded chitosan microspheres: in vitro and in vivo evaluation, J. Mater. Sci. Mater. Med. 22 (2011) 865–878. [5] V. Grabovac, D. Guggi, A. Bernkop-Schnürch, Comparison of the mucoadhesive properties of various polymers, Adv. Drug Deliv. Rev. 57 (2005) 1713–1723. [6] H.L. Lueßen, B.J. de Leeuw, M.W.E. Langemeÿer, A.G. de Boer, J.C. Verhoef, H.E. Junginger, Mucoadhesive polymers in peroral peptide drug delivery. VI. Carbomer and chitosan improve the intestinal absorption of the peptide drug buserelin in vivo, Pharm. Res. 13 (1996) 1668–1672. [7] A. Jintapattanakit, V.B. Junyaprasert, T. Kissel, The role of mucoadhesion of trimethyl chitosan and PEGylated trimethyl chitosan nanocomplexes in insulin uptake, J. Pharm. Sci. 98 (2009) 4818–4830. [8] M. Werle, A. Bernkop-Schnürch, Thiolated chitosans: useful excipients for oral drug delivery, J. Pharm. Pharmacol. 60 (2008) 273–281. [9] S. Gupta, S.P. Vyas, Carbopol/chitosan based pH triggered in situ gelling system for ocular delivery of timolol maleate, Sci. Pharm. 78 (2010) 959–976. [10] D. Sakloetsakun, J. Hombach, A. Bernkop-Schnürch, In situ gelling properties of chitosan–thioglycolic acid conjugate in the presence of oxidizing agents, Biomaterials 30 (2009) 6151–6157. [11] S. Mao, W. Sun, T. Kissel, Chitosan-based formulations for delivery of DNA and siRNA, Adv. Drug Deliv. Rev. 62 (2010) 12–27. [12] H. Yu, X. Chen, T. Lu, J. Sun, H. Tian, J. Hu, Y. Wang, P. Zhang, X. Jing, Poly(Llysine)-graft-chitosan copolymers: synthesis, characterization, and gene transfection effect, Biomacromolecules 8 (2007) 1425–1435. [13] D. Lee, S.S. Mohapatra, Chitosan nanoparticle-mediated gene transfer, in: J.M. Doux (Ed.), Gene Therapy Protocols, Humana Press, 2008, pp. 127–140. [14] J. Malmo, K.M. Vrum, S.P. Strand, Effect of chitosan chain architecture on gene delivery: comparison of self-branched and linear chitosans, Biomacromolecules 12 (2011) 721–729. [15] R. Martien, B. Loretz, M. Thaler, S. Majzoob, A. Bernkop-Schnürch, Chitosan– thioglycolic acid conjugate: an alternative carrier for oral nonviral gene delivery?, J Biomed. Mater. Res. A 82 (2007) 1–9. [16] A.K. Varkouhi, R.J. Verheul, R.M. Schiffelers, T. Lammers, G. Storm, W.E. Hennink, Gene silencing activity of siRNA polyplexes based on thiolated N,N,N-trimethylated chitosan, Bioconjugate Chem. 21 (2010) 2339–2346. [17] D. Teijeiro-Osorio, C. Remuñán-López, M.J. Alonso, Chitosan/cyclodextrin nanoparticles can efficiently transfect the airway epithelium in vitro, Eur. J. Pharm. Biopharm. 71 (2009) 257–263. [18] M. Malhotra, C. Lane, C. Tomaro-Duchesneau, S. Saha, S. Prakash, A novel method for synthesizing PEGylated chitosan nanoparticles: strategy, preparation, and in vitro analysis, Int. J. Nanomed. 6 (2011) 485–494. [19] N.G.M. Schipper, S. Olsson, J.A. Hoogstraate, A.G. deBoer, K.M. Vårum, P. Artursson, Chitosans as absorption enhancers for poorly absorbable drugs. 2: Mechanism of absorption enhancement, Pharm. Res. 14 (1997) 923–929. [20] A.F. Kotzé, H.L. Lueßen, B.J. de Leeuw, B.G. de Boer, J. Coos Verhoef, H.E. Junginger, Comparison of the effect of different chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2), J. Control. Release 51 (1998) 35–46. [21] N.G.M. Schipper, K.M. Vårum, P. Artursson, Chitosans as absorption enhancers for poorly absorbable drugs. 1: Influence of molecular weight and degree of acetylation on drug transport across human intestinal epithelial (caco-2) cells, Pharm. Res. 13 (1996) 1686–1692. [22] C.E. Kast, A. Bernkop-Schnürch, Influence of the molecular mass on the permeation enhancing effect of different poly(acrylates), STP Pharm. Sci. 6 (2002) 351–356. [23] P. Shah, V. Jogani, P. Mishra, A.K. Mishra, T. Bagchi, A. Misra, Modulation of ganciclovir intestinal absorption in presence of absorption enhancers, J. Pharm. Sci. 96 (2007) 2710–2722. [24] A. Trapani, A. Lopedota, M. Franco, N. Cioffi, E. Ieva, M. Garcia-Fuentes, M.J. Alonso, A comparative study of chitosan and chitosan/cyclodextrin nanoparticles as potential carriers for the oral delivery of small peptides, Eur. J. Pharm. Biopharm. 75 (2010) 26–32. [25] N. Langoth, H. Kahlbacher, G. Schöffmann, I. Schmerold, M. Schuh, S. Franz, P. Kurka, A. Bernkop-Schnürch, Thiolated chitosans: design and in vivo evaluation of a mucoadhesive buccal peptide drug delivery system, Pharm. Res. 23 (2006) 573–579.
[26] N. Langoth, A. Bernkop-Schnürch, P. Kurka, In vitro evaluation of various buccal permeation enhancing systems for PACAP (pituitary adenylate cyclaseactivating polypeptide), Pharm. Res. 22 (2005) 2045–2050. [27] B.B. Carreno-Gomez, R.W. Duncan, Compositions with Enhanced oral Bioavailability, US Patent 20030211072, 2003. [28] F. Föger, T. Schmitz, A. Bernkop-Schnürch, In vivo evaluation of an oral delivery system for P-gp substrates based on thiolated chitosan, Biomaterials 27 (2006) 4250–4255. [29] T.F. Palmberger, J. Hombach, A. Bernkop-Schnürch, Thiolated chitosan: development and in vitro evaluation of an oral delivery system for acyclovir, Int. J. Pharm. 348 (2008) 54–60. [30] G.S. Macleod, J.T. Fell, J.H. Collett, H.L. Sharma, A.-M. Smith, Selective drug delivery to the colon using pectin:chitosan:hydroxypropyl methylcellulose film coated tablets, Int. J. Pharm. 187 (1999) 251–257. [31] A. Bernkop-Schnürch, E. Reich-Rohrwig, M. Marschütz, H. Schuhbauer, M. Kratzel, Development of a sustained release dosage form for a-lipoic acid. II. Evaluation in human volunteers, Drug Dev. Ind. Pharm. 30 (2004) 35–42. [32] P. Mura, N. Zerrouk, N. Mennini, F. Maestrelli, C. Chemtob, Development and characterization of naproxen–chitosan solid systems with improved drug dissolution properties, Eur. J. Pharm. Sci. 19 (2003) 67–75. [33] C. Kose-Ozkan, A. Savaser, C. Tas, Y. Ozkan, The development and in vitro evaluation of sustained release tablet formulations of benzydamine hydrochloride and its determination, Comb. Chem. High Throughput Screening 13 (2010) 683–689. [34] S. Mutalik, K. Manoj, M. Reddy, P. Kushtagi, A. Usha, P. Anju, A. Ranjith, N. Udupa, Chitosan and enteric polymer based once daily sustained release tablets of aceclofenac: in vitro and in vivo studies, AAPS PharmSciTech 9 (2008) 651–659. [35] S. Dhaliwal, S. Jain, H. Singh, A. Tiwary, Mucoadhesive microspheres for gastroretentive delivery of acyclovir: in vitro and in vivo evaluation, AAPS J. 10 (2008) 322–330. [36] Y. Akiyama, N. Nagahara, E. Nara, M. Kitano, S. Iwasa, I. Yamamoto, J. Azuma, Y. Ogawa, Evaluation of oral mucoadhesive microspheres in man on the basis of the pharmacokinetics of furosemide and riboflavin, compounds with limited gastrointestinal absorption sites, J. Pharm. Pharmacol. 50 (1998) 159–166. [37] M. Säkkinen, J. Marvola, H. Kanerva, K. Lindevall, A. Ahonen, M. Marvola, Scintigraphic verification of adherence of a chitosan formulation to the human oesophagus, Eur. J. Pharm. Biopharm. 57 (2004) 145–147. [38] A.B. Sieval, M. Thanou, A.F. Kotze´, J.C. Verhoef, J. Brussee, H.E. Junginger, Preparation and NMR characterization of highly substituted N-trimethyl chitosan chloride, Carbohydr. Polym. 36 (1998) 157–165. [39] A. Bernkop-Schnürch, M. Hornof, T. Zoidl, Thiolated polymers–thiomers: synthesis and in vitro evaluation of chitosan-2-iminothiolane conjugates, Int. J. Pharm. 260 (2003) 229–237. [40] K. Kafedjiiski, A.H. Krauland, M.H. Hoffer, A. Bernkop-Schnürch, Synthesis and in vitro evaluation of a novel thiolated chitosan, Biomaterials 26 (2005) 819– 826. [41] M. Thanou, B.I. Florea, M.W.E. Langemeÿer, J.C. Verhoef, H.E. Junginger, Ntrimethylated chitosan chloride (TMC) improves the intestinal permeation of the peptide drug buserelin in vitro (caco-2 cells) and in vivo (rats), Pharm. Res. 17 (2000) 27–31. [42] B. Sarmento, A. Ribeiro, F. Veiga, P. Sampaio, R. Neufeld, D. Ferreira, Alginate/ chitosan nanoparticles are effective for oral insulin delivery, Pharm. Res. 24 (2007) 2198–2206. [43] H. Gupta, T. Velpandian, S. Jain, Ion- and pH-activated novel in-situ gel system for sustained ocular drug delivery, J. Drug Targeting 18 (2010) 499–505. [44] A.M. De Campos, A. Sánchez, M.a.J. Alonso, Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporin A, Int. J. Pharm. 224 (2001) 159–168. [45] P. Calvo, J.L. Vila-Jato, M.a.J. Alonso, Evaluation of cationic polymer-coated nanocapsules as ocular drug carriers, Int. J. Pharm. 153 (1997) 41–50. [46] A.M. De Campos, A. Sánchez, M.J. Alonso, Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporin A, Int. J. Pharm. 224 (2001) 159–168. [47] I. Genta, B. Conti, P. Perugini, F. Pavanetto, A. Spadaro, G. Puglisi, Bioadhesive microspheres for ophthalmic administration of acyclovir, J. Pharm. Pharmacol. 49 (1997) 737–742. [48] L. Illum, Nasal drug delivery – possibilities, problems and solutions, J. Control. Release 87 (2003) 187–198. [49] R.J. Soane, M. Frier, A.C. Perkins, N.S. Jones, S.S. Davis, L. Illum, Evaluation of the clearance characteristics of bioadhesive systems in humans, Int. J. Pharm. 178 (1999) 55–65. [50] L. Ilium, Chitosan and its use as a pharmaceutical excipient, Pharm. Res. 15 (1998) 1326–1331. [51] L. Na, S. Mao, J. Wang, W. Sun, Comparison of different absorption enhancers on the intranasal absorption of isosorbide dinitrate in rats, Int. J. Pharm. 397 (2010) 59–66. [52] D. Teijeiro-Osorio, C. Remuñán-López, M. José Alonso, New generation of hybrid poly oligosaccharide nanoparticles as carriers for the nasal delivery of macromolecules, Biomacromolecules 10 (2008) 243–249. [53] X. Zhang, H. Zhang, Z. Wu, Z. Wang, H. Niu, C. Li, Nasal absorption enhancement of insulin using PEG-grafted chitosan nanoparticles, Eur. J. Pharm. Biopharm. 68 (2008) 526–534. [54] R. Fernández-Urrusuno, P. Calvo, C. Remuñán-López, J.L. Vila-Jato, M. José Alonso, Enhancement of nasal absorption of insulin using chitosan nanoparticles, Pharm. Res. 16 (1999) 1576–1581.
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007
563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648
EJPB 11125
No. of Pages 7, Model 5G
2 May 2012 A. Bernkop-Schnürch, S. Dünnhaupt / European Journal of Pharmaceutics and Biopharmaceutics xxx (2012) xxx–xxx 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686
[55] A. Fisher, M. Watling, A. Smith, A. Knight, Pharmacokinetic comparisons of three nasal fentanyl formulations; pectin, chitosan and chitosan–poloxamer 188, Int. J. Clin. Pharmacol. Ther. 48 (2010) 138–145. [56] A. El-Kamel, M. Sokar, V. Naggar, S. Al Gamal, Chitosan and sodium alginatebased bioadhesive vaginal tablets, AAPS J. 4 (2002) 224–230. [57] G. Sandri, S. Rossi, F. Ferrari, M.C. Bonferoni, C. Muzzarelli, C. Caramella, Assessment of chitosan derivatives as buccal and vaginal penetration enhancers, Eur. J. Pharm. Sci. 21 (2004) 351–359. [58] D. Raafat, H.-G. Sahl, Chitosan and its antimicrobial potential – a critical literature survey, Microb. Biotechnol. 2 (2009) 186–201. [59] K. Aiedeh, M.O. Taha, Synthesis of iron-crosslinked chitosan succinate and iron-crosslinked hydroxamated chitosan succinate and their in vitro evaluation as potential matrix materials for oral theophylline sustainedrelease beads, Eur. J. Pharm. Sci. 13 (2001) 159–168. [60] G. Sandri, S. Rossi, M.C. Bonferoni, F. Ferrari, Y. Zambito, G. Di Colo, C. Caramella, Buccal penetration enhancement properties of N-trimethyl chitosan: influence of quaternization degree on absorption of a high molecular weight molecule, Int. J. Pharm. 297 (2005) 146–155. [61] S.M. Upadrashta, P.R. Katikaneni, N.O. Nuessle, Chitosan as a tablet binder, Drug Dev. Ind. Pharm. 18 (1992) 1701–1708. [62] S.W. Richardson, H.J. Kolbe, R. Duncan, Potential of low molecular mass chitosan as a DNA delivery system: biocompatibility, body distribution and ability to complex and protect DNA, Int. J. Pharm. 178 (1999) 231–243. [63] C.G. Pitt, The controlled parenteral delivery of polypeptides and proteins, Int. J. Pharm. 59 (1990) 173–196. [64] B.C. Thanoo, M.C. Sunny, A. Jayakrishnan, Cross-linked chitosan microspheres: preparation and evaluation as a matrix for the controlled release of pharmaceuticals, J. Pharm. Pharmacol. 44 (1992) 283–286. [65] R.J. Nordtveit, K.M. Vårum, O. Smidsrød, Degradation of fully water-soluble, partially N-acetylated chitosans with lysozyme, Carbohydr. Polym. 23 (1994) 253–260. [66] H. Onishi, Y. Machida, K. Kamiyama, Pharmacokinetics and tissue distribution properties of glycol–chitosan and N-succinyl–chitosan in mice, in: Proceedings of the Controlled Release Society, 1996, pp. 645–646. [67] J.-H. Kim, Y.-S. Kim, K. Park, E. Kang, S. Lee, H.Y. Nam, K. Kim, J.H. Park, D.Y. Chi, R.-W. Park, I.-S. Kim, K. Choi, I. Chan Kwon, Self-assembled glycol chitosan nanoparticles for the sustained and prolonged delivery of antiangiogenic small peptide drugs in cancer therapy, Biomaterials 29 (2008) 1920–1930.
7
[68] J. Barthelmes, G. Perera, J. Hombach, S. Dünnhaupt, A. Bernkop-Schnürch, Development of a mucoadhesive nanoparticulate drug delivery system for a targeted drug release in the bladder, Int. J. Pharm. 416 (2011) 339–345. [69] M. Maeda, H. Murakami, H. Ohta, M. Tajima, Stimulation of IgM production in human–human hybridoma HB4C5 cells by chitosan, Biosci., Biotechnol., Biochem. 56 (1992) 427–431. [70] I. Jabbal-Gill, A.N. Fisher, R. Rappuoli, S.S. Davis, L. Illum, Stimulation of mucosal and systemic antibody responses against Bordetella pertussis filamentous haemagglutinin and recombinant pertussis toxin after nasal administration with chitosan in mice, Vaccine 16 (1998) 2039–2046. [71] R. Garmise, H. Staats, A. Hickey, Novel dry powder preparations of whole inactivated influenza virus for nasal vaccination, AAPS PharmSciTech 8 (2007) 2–10. [72] R.C. Read, S.C. Naylor, C.W. Potter, J. Bond, I. Jabbal-Gill, A. Fisher, L. Illum, R. Jennings, Effective nasal influenza vaccine delivery using chitosan, Vaccine 23 (2005) 4367–4374. [73] A. Bacon, J. Makin, P.J. Sizer, I. Jabbal-Gill, M. Hinchcliffe, L. Illum, S. Chatfield, M. Roberts, Carbohydrate biopolymers enhance antibody responses to mucosally delivered vaccine antigens, Infect. Immun. 68 (2000) 5764–5770. [74] I.M. van der Lubben, J.C. Verhoef, A.C. van Aelst, G. Borchard, H.E. Junginger, Chitosan microparticles for oral vaccination: preparation, characterization and preliminary in vivo uptake studies in murine Peyer’s patches, Biomaterials 22 (2001) 687–694. [75] A. Vila, A. Sánchez, K. Janes, I. Behrens, T. Kissel, J.L.V. Jato, M.J. Alonso, Low molecular weight chitosan nanoparticles as new carriers for nasal vaccine delivery in mice, Eur. J. Pharm. Biopharm. 57 (2004) 123–131. [76] O. Borges, A. Cordeiro-da-Silva, J. Tavares, N. Santarém, A. de Sousa, G. Borchard, H.E. Junginger, Immune response by nasal delivery of hepatitis B surface antigen and codelivery of a CpG ODN in alginate coated chitosan nanoparticles, Eur. J. Pharm. Biopharm. 69 (2008) 405–416. [77] S.M. Bal, B. Slütter, R. Verheul, J.A. Bouwstra, W. Jiskoot, Adjuvanted, antigen loaded N-trimethyl chitosan nanoparticles for nasal and intradermal vaccination: adjuvant- and site-dependent immunogenicity in mice, Eur. J. Pharm. Sci. 45 (2012) 475–481. [78] B. Slütter, L. Plapied, V. Fievez, M. Alonso Sande, A. des Rieux, Y.-J. Schneider, E. Van Riet, W. Jiskoot, V. Préat, Mechanistic study of the adjuvant effect of biodegradable nanoparticles in mucosal vaccination, J. Control. Release 138 (2009) 113–121.
687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725
Please cite this article in press as: A. Bernkop-Schnürch, S. Dünnhaupt, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm. (2012), http:// dx.doi.org/10.1016/j.ejpb.2012.04.007