Drug-Delivery-Strategien zur gezielten Behandlung von chronisch-entzündlichen Darmerkrankungen

Zusammenfassung

Chronisch-entzündliche Darmerkrankungen (CED) sind häufig auftretende Erkrankungen bei jungen Erwachsenen, die mit rezidivierender oder chronisch-entzündlicher Krankheitsaktivität einhergehen. Die Therapie ist bislang geprägt durch die Gabe von antiinflammatorischen oder immunsuppressiven Wirkstoffen, die die intestinale Entzündung begrenzen und entsprechend Krankheitssymptome lindern. Derzeitige CED-Behandlungsstrategien zeichnen sich aber durch eine begrenzte therapeutische Effizienz und dem potenziellen Auftreten schwerer unerwünschter Nebenwirkungen aus. Dieser Übersichtsartikel fasst sog. „Drug-Delivery-Strategien“ zur Behandlung von CED zusammen. Dazu werden etablierte „Intestine-Targeting-Strategien“ vorgestellt, die gezielt Wirkstoffe in den entsprechenden Darmabschnitt an den Ort der Entzündung liefern, wie z. B. Prodrugs und Formulierungen mit pH-/zeitkontrollierter Wirkstofffreisetzung. Zusätzlich werden auch zukunftsorientierte „Disease-Targeting-Strategien“ diskutiert, die selektiv Wirkstoffe im Bereich der intestinalen Entzündung freisetzen, wie z. B. mikro-/nanoskalige synthetische und biologische Wirkstoffträger. Dadurch kann die therapeutische Effizienz in der Behandlung von CED erhöht und das Risiko von unerwünschter Arzneimittelnebenwirkung minimiert werden.

Abstract

Inflammatory bowel disease (IBD) is a frequently occurring disease in young people, which is characterized by chronic inflammation of the gastrointestinal tract. The therapy of IBD is dominated by the administration of anti-inflammatory and immunosuppressive agents, which suppress the intestinal inflammatory burden and improve the disease-related symptoms. Present treatment strategies are characterized by a limited therapeutical efficacy and the occurrence of adverse drug reactions. The development of novel disease-targeted drug delivery strategies is preferable for a more effective therapy and thus demonstrates the potential to address unmet medical needs. This review gives an overview about drug delivery strategies for the treatment of IBD. Therefore, established intestine-targeting strategies for a selective drug release into the diseased part of the gastrointestinal tract will be presented, including prodrugs, and dosage forms with pH-/time-dependent drug release. Furthermore future-oriented disease-targeting strategies for a selective drug release into the intestinal inflammation will be described, including micro-/nanosized synthetic and biologic drug carriers. This novel therapeutic approach may enable a more effective anti-inflammatory treatment of IBD with reduced risks of adverse reactions.

Schlüsselwörter

chronisch-entzündliche Darmerkrankung - Morbus Crohn - Colitis ulcerosa

Key words

chronic inflammatory bowel disease - Crohn's disease - ulcerative colitis

• Literatur

• 1 Solberg IC, Vatn MH, Hoie O et al. Clinical course in Crohn's disease: results of a Norwegian population-based ten-year follow-up study. Clin Gastroenterol Hepatol 2007; 5: 1430-1438
• 2 Solberg IC, Lygren I, Jahnsen J et al. Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study). Scand J Gastroenterol 2009; 44: 431-440
• 3 Munkholm P, Langholz E, Davidsen M et al. Frequency of glucocorticoid resistance and dependency in Crohn's disease. Gut 1994; 35: 360-362
• 4 Faubion Jr WA , Loftus Jr EV , Harmsen WS et al. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001; 121: 255-260
• 5 Bokemeyer B, Helwig U, Teich N et al. P337 TNF-alpha as induction therapy for Crohn's disease: a comparison of adalimumab and infliximab–a prospective observational study in Germany. J Crohns Colitis 2014; 8: S205
• 6 Gross V, Andus T, Caesar I et al. Oral pH-modified release budesonide versus 6-methylprednisolone in active Crohn's disease. German/Austrian Budesonide Study Group. Eur J Gastroenterol Hepatol 1996; 8: 905-909
• 7 Sandborn WJ, Feagan BG, Rutgeerts P et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med 2013; 369: 711-721
• 8 Feagan BG, Rutgeerts P, Sands BE et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369: 699-710
• 9 Strebhardt K, Ullrich A. Paul Ehrlich's magic bullet concept: 100 years of progress. Nat Rev Cancer 2008; 8: 473-480
• 10 Collnot EM, Ali H, Lehr CM. Nano- and microparticulate drug carriers for targeting of the inflamed intestinal mucosa. J Control Release 2012; 161: 235-246
• 11 Lautenschlager C, Schmidt C, Fischer D et al. Drug delivery strategies in the therapy of inflammatory bowel disease. Adv Drug Deliv Rev 2013; Epub Date 2013/10/26
• 12 Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative treatments in ulcerative colitis: a meta-analysis. Gut 1997; 40: 775-781
• 13 Harris MS, Lichtenstein GR. Review article: delivery and efficacy of topical 5-aminosalicylic acid (mesalazine) therapy in the treatment of ulcerative colitis. Aliment Pharmacol Ther 2011; 33: 996-1009
• 14 Gionchetti P, Rizzello F, Venturi A et al. Comparison of mesalazine suppositories in proctitis and distal proctosigmoiditis. Aliment Pharmacol Ther 1997; 11: 1053-1057
• 15 Safdi M, DeMicco M, Sninsky C et al. A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis. Am J Gastroenterol 1997; 92: 1867-1871
• 16 Mulder CJ, Fockens P, Meijer JW et al. Beclomethasone dipropionate (3 mg) versus 5-aminosalicylic acid (2g) versus the combination of both (3 mg/2g) as retention enemas in active ulcerative proctitis. Eur J Gastroenterol Hepatol 1996; 8: 549-553
• 17 Romkens TE, Kampschreur MT, Drenth JP et al. High mucosal healing rates in 5-ASA-treated ulcerative colitis patients: results of a meta-analysis of clinical trials. Inflam Bow Dis 2012; 18: 2190-2198
• 18 Svartz N. Salazopyrin, a new sulfanilamide preparation. A. Therapeutic Results in Rheumatic Polyarthritis. B. Therapeutic Results in Ulcerative Colitis. C. Toxic Manifestations in Treatment with Sulfanilamide Preparations. Acta Med Scand 1942; 110: 577-598
• 19 Rafii F, Franklin W, Cerniglia CE. Azoreductase activity of anaerobic bacteria isolated from human intestinal microflora. Appl Environ Microbiol 1990; 56: 2146-2151
• 20 Doell RG, Kretchmer N. Studies of small intestine during development I. Distribution and activity of fl-galactosidase. Biochim Biophys Acta 1962; 62: 353-362
• 21 Englyst H, Hay S, Macfarlane G. Polysaccharide breakdown by mixed populations of human faecal bacteria. FEMS Microbiol Lett 1987; 45: 163-171
• 22 Klotz U. Clinical pharmacokinetics of sulphasalazine, its metabolites and other prodrugs of 5-aminosalicylic acid. Clin Pharmacokinet 1985; 10: 285
• 23 Lim WC, Hanauer S. Aminosalicylates for induction of remission or response in Crohn's disease. The Cochrane database of systematic reviews 2010;
• 24 Wen H, Park K. Oral controlled release formulation design and drug delivery: theory to practice. Hoboken, N. J.: Wiley; 2010
• 25 Horst SN, Kane S. Multi-Matrix System (MMX(R)) mesalamine for the treatment of mild-to-moderate ulcerative colitis. Expert Opin Pharmacother 2012; 13: 2225-2232
• 26 Feagan BG, Macdonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. The Cochrane database of systematic reviews 2012; 10 CD000544
• 27 Israeli E, Goldin E, Fishman S et al. Mo1211 Oral Administration of Non-Absorbable Delayed Release 6-Mercaptopurine is Locally Active in the Gut, Exerts a Systemic Immune Effect and Alleviates Crohn's Disease With Low Rate of Side Effects: Results of Double Blind Phase II Clinical Trial. Gastroenterology 2014; 146: 587
• 28 Burmester GR, Panaccione R, Gordon KB et al. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann Rheum Dis 2012;
• 29 Garcia-Vidal C, Rodriguez-Fernandez S, Teijon S et al. Risk factors for opportunistic infections in infliximab-treated patients: the importance of screening in prevention. Eur J Clin Microbiol Infect Dis 2009; 28: 331-337
• 30 Soler D, Chapman T, Yang LL et al. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther 2009; 330: 864-875
• 31 Thomas S, Baumgart DC. Targeting leukocyte migration and adhesion in Crohn's disease and ulcerative colitis. Inflammopharmacology 2012; 20: 1-18
• 32 Rutgeerts PJ, Fedorak RN, Hommes DW et al. A randomised phase I study of etrolizumab (rhuMAb beta7) in moderate to severe ulcerative colitis. Gut 2013; 62: 1122-1130
• 33 Vermeire S, O'Byrne S, Keir M et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. The Lancet 2014; 384: 309-318
• 34 Smith MA, Mohammad RA. Vedolizumab: An alpha4beta7 Integrin Inhibitor for Inflammatory Bowel Diseases. Ann Pharmacother 2014;
• 35 Danese S, Panés J. Development of Drugs to Target Interactions Between Leukocytes and Endothelial Cells and Treatment Algorithms for Inflammatory Bowel Diseases. Gastroenterology 2014; 147: 981-989
• 36 McGuckin MA, Eri R, Simms LA et al. Intestinal barrier dysfunction in inflammatory bowel diseases. Inflam Bow Dis 2009; 15: 100-113
• 37 Schmitz H, Barmeyer C, Fromm M et al. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology 1999; 116: 301-309
• 38 McAlindon ME, Gray T, Galvin A et al. Differential lamina propria cell migration via basement membrane pores of inflammatory bowel disease mucosa. Gastroenterology 1998; 115: 841-848
• 39 Tonelli F, Giudici F, Asteria CR. Effectiveness and safety of local adalimumab injection in patients with fistulizing perianal Crohn's disease: a pilot study. Dis Colon Rectum 2012; 55: 870-875
• 40 Maggi L, Capone M, Giudici F et al. CD4+CD161+ T lymphocytes infiltrate Crohn's disease-associated perianal fistulas and are reduced by anti-TNF-alpha local therapy. Int Arch Allergy Immunol 2013; 161: 81-86
• 41 Schmidt C, Lautenschlaeger C, Collnot EM et al. Nano-and microscaled particles for drug targeting to inflamed intestinal mucosa – A first in vivo study in human patients. J Control Release 2013; 165: 139-145
• 42 Lautenschläger C, Schmidt C, Lehr CM et al. PEG-functionalized microparticles selectively target inflamed mucosa in inflammatory bowel disease. Eur J Pharm Biopharm 2013; 85: 578-586
• 43 Steidler L, Neirynck S, Huyghebaert N et al. Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10. Nat Biotechnol 2003; 21: 785-789
• 44 Foligne B, Dessein R, Marceau M et al. Prevention and treatment of colitis with Lactococcus lactis secreting the immunomodulatory Yersinia LcrV protein. Gastroenterology 2007; 133: 862-874
• 45 Vandenbroucke K, Hans W, Van Huysse J et al. Active delivery of trefoil factors by genetically modified Lactococcus lactis prevents and heals acute colitis in mice. Gastroenterology 2004; 127: 502-513
• 46 Ricci S, Macchia G, Ruggiero P et al. In vivo mucosal delivery of bioactive human interleukin 1 receptor antagonist produced by Streptococcus gordonii. BMC Biotechnol 2003; 3: 15
• 47 Watterlot L, Rochat T, Sokol H et al. Intragastric administration of a superoxide dismutase-producing recombinant Lactobacillus casei BL23 strain attenuates DSS colitis in mice. Int J Food Microbiol 2010; 144: 35-41
• 48 Steidler L, Hans W, Schotte L et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 2000; 289: 1352-1355
• 49 Akin D, Sturgis J, Ragheb K et al. Bacteria-mediated delivery of nanoparticles and cargo into cells. Nat Nanotechnol 2007; 2: 441-449
• 50 Dietrich G. Bioengineering: Bacteria give nanoparticles a ride. Nat Nanotechnol 2007; 2: 394-395
• 51 Kudela P, Paukner S, Mayr UB et al. Bacterial ghosts as novel efficient targeting vehicles for DNA delivery to the human monocyte-derived dendritic cells. J Immunother 2005; 28: 136
• 52 Paukner S, Kudela P, Kohl G et al. DNA-loaded bacterial ghosts efficiently mediate reporter gene transfer and expression in macrophages. Mol Ther 2005; 11: 215-223
• 53 Haslberger A, Kohl G, Felnerova D et al. Activation, stimulation and uptake of bacterial ghosts in antigen presenting cells. J Biotechnol 2000; 83: 57-66
• 54 Lubitz W. Bacterial ghosts as carrier and targeting systems. Expert Opin Biol Ther 2001; 1: 765-771
• 55 Eko FO, Schukovskaya T, Lotzmanova EY et al. Evaluation of the protective efficacy of Vibrio cholerae ghost (VCG) candidate vaccines in rabbits. Vaccine 2003; 21: 3663-3674
• 56 Mayr UB, Haller C, Haidinger W et al. Bacterial ghosts as an oral vaccine: a single dose of Escherichia coli O157: H7 bacterial ghosts protects mice against lethal challenge. Infect Immun 2005; 73: 4810
• 57 Talwar N, Jain N. Erythrocytes as carriers of metronidazole: in-vitro characterization. Drug Dev Ind Pharm 1992; 18: 1799-1812
• 58 Mishra P, Jain N. Surface modified methotrexate loaded erythrocytes for enhanced macrophage uptake. J Drug Target 2000; 8: 217-224
• 59 Hamidi M, Tajerzadeh H, Dehpour AR et al. In vitro characterization of human intact erythrocytes loaded by enalaprilat. Drug Delivery 2001; 8: 223-230
• 60 Annese V, Latiano A, Rossi L et al. Erythrocytes-mediated delivery of dexamethasone in steroid-dependent IBD patients-a pilot uncontrolled study. Am J Gastroenterol 2005; 100: 1370-1375
• 61 Bossa F, Latiano A, Rossi L et al. Erythrocyte-mediated delivery of dexamethasone in patients with mild-to-moderate ulcerative colitis, refractory to mesalamine: a randomized, controlled study. Am J Gastroenterol 2008; 103: 2509-2516
• 62 Goldman P, Peppercorn MA. Sulfasalazine. N Engl J Med 1975; 293: 20-23
• 63 Ragunath K, Williams J. Balsalazide therapy in ulcerative colitis. Aliment Pharmacol Ther 2001; 15: 1549-1554
• 64 Hetzel D, Shearman D, Labrooy J et al. Olsalazine in the treatment of active ulcerative colitis: a placebo controlled clinical trial and assessment of drug disposition. Scand J Gastroenterol 1988; 23: 61-69
• 65 Jung YJ, Lee JS, Kim HH et al. Synthesis and evaluation of 5-aminosalicyl-glycine as a potential colon-specific prodrug of 5-aminosalicylic acid. Arch Pharm Res 1998; 21: 174-178
• 66 Jung YJ, Lee JS, Kim YM. Synthesis and in vitro/in vivo evaluation of 5‐aminosalicyl‐glycine as a colon‐specific prodrug of 5‐aminosalicylic acid. J Pharm Sci 2000; 89: 594-602
• 67 Nakamura A. Glycoside prodrug of 5-aminosalicylic acid. In: Google Patents; 2005
• 68 Friend DR, Chang GW. A colon-specific drug-delivery system based on drug glycosides and the glycosidases of colonic bacteria. J Med Chem 1984; 27: 261-266
• 69 Haeberlin B, Rubas W, Nolen III HW et al. In vitro evaluation of dexamethasone-β-D-glucuronide for colon-specific drug delivery. Pharm Res 1993; 10: 1553-1562
• 70 Zou MJ, Cheng G, Okamoto H et al. Colon-specific drug delivery systems based on cyclodextrin prodrugs: In vivo evaluation of 5-aminosalicylic acid from its cyclodextrin conjugates. World J Gastroenterol 2005; 11: 7457
• 71 Yano H, Hirayama F, Kamada M et al. Colon-specific delivery of prednisolone-appended [alpha]-cyclodextrin conjugate: alleviation of systemic side effect after oral administration. J Control Release 2002; 79: 103-112
• 72 Jung YJ, Lee JS, Kim HH et al. Synthesis and properties of dextran-5-aminosalicylic acid ester as a potential colon-specific prodrug of 5-aminosalicylic acid. Arch Pharm Res 1998; 21: 179-186
• 73 Ertl B, Heigl F, Wirth M et al. Lectin-mediated bioadhesion: preparation, stability and caco-2 binding of wheat germ agglutinin-functionalized Poly (D, L-lactic-co-glycolic acid)-microspheres. J Drug Target 2000; 8: 173-184
• 74 Yin YS, Chen DW, Qiao MX et al. Lectin-conjugated PLGA nanoparticles loaded with thymopentin: ex vivo bioadhesion and in vivo biodistribution. J Control Release 2007; 123: 27-38
• 75 Arbos P, Arangoa M, Campanero M et al. Quantification of the bioadhesive properties of protein-coated PVM/MA nanoparticles. Int J Pharm 2002; 242: 129-136
• 76 Haltner E, Easson J, Russel-Jones G et al. A rapid assay for bioadhesion of lectin-functionalized nano-particles to Caco-2 cell monolayers. J Control Release 1996; 41: S3
• 77 Montisci MJ, Giovannuci G, Duchene D et al. Covalent coupling of asparagus pea and tomato lectins to poly (lactide) microspheres. Int J Pharm 2001; 215: 153-161
• 78 Madgulkar AR, Kshirsagar SJ, Bhalekar MR et al. Design and development of pH sensitive budesonide-chitosan mucoadhesive beads for ileo-ceacal targeting. J Pharm Sci 2011; 6: 8-17
• 79 Mladenovska K, Raicki R, Janevik E et al. Colon-specific delivery of 5-aminosalicylic acid from chitosan-Ca-alginate microparticles. Int J Pharm 2007; 342: 124-136
• 80 Mura C, Nacher A, Merino V et al. N-Succinyl-chitosan systems for 5-aminosalicylic acid colon delivery: In vivo study with TNBS-induced colitis model in rats. Int J Pharm 2011;
• 81 Crcarevska MS, Dodov MG, Petrusevska G et al. Bioefficacy of budesonide loaded crosslinked polyeletrolyte microparticles in rat model of induced colitis. J Drug Target 2009; 17: 788-802
• 82 Tahara K, Samura S, Tsuji K et al. Oral nuclear factor-[kappa] B decoy oligonucleotides delivery system with chitosan modified poly (d, l-lactide-co-glycolide) nanospheres for inflammatory bowel disease. Biomaterials 2011; 32: 870-878
• 83 Behrens I, Pena AIV, Alonso MJ et al. Comparative uptake studies of bioadhesive and non-bioadhesive nanoparticles in human intestinal cell lines and rats: the effect of mucus on particle adsorption and transport. Pharm Res 2002; 19: 1185-1193
• 84 Tang BC, Dawson M, Lai SK et al. Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc Natl Acad Sci USA 2009; 106: 19268-19273
• 85 Cu Y, Saltzman WM. Controlled surface modification with poly (ethylene) glycol enhances diffusion of PLGA nanoparticles in human cervical mucus. Mol Pharm 2008; 6: 173-181
• 86 Vila A, Gill H, McCallion O et al. Transport of PLA-PEG particles across the nasal mucosa: effect of particle size and PEG coating density. J Control Release 2004; 98: 231-244
• 87 Uwiera R, Romancyia D, Wong J et al. Liposomes targeted to deliver antisecretory agents to jejunal mucosa. Can J Vet Res 1992; 56: 249
• 88 Tirosh B, Khatib N, Barenholz Y et al. Transferrin as a luminal target for negatively charged liposomes in the inflamed colonic mucosa. Mol Pharm 2009; 6: 1083-1091
• 89 Jubeh TT, Barenholz Y, Rubinstein A. Differential adhesion of normal and inflamed rat colonic mucosa by charged liposomes. Pharmaceutical research 2004; 21: 447-453
• 90 Awasthi V, Goins B, McManus L et al. [99mTc] liposomes for localizing experimental colitis in arabbit model. Nucl Med Biol 2003; 30: 159-168
• 91 Awasthi V, Goins B, Klipper R et al. Accumulation of PEG-liposomes in the inflamed colon of rats: potential for therapeutic and diagnostic targeting of inflammatory bowel diseases. J Drug Target 2002; 10: 419-427
• 92 Castro M, Rossi L, Papadatou B et al. Long-term treatment with autologous red blood cells loaded with dexamethasone 21-phosphate in pediatric patients affected by steroid-dependent Crohn disease. J Pediatr Gastroenterol Nutr 2007; 44: 423
• 93 Bossa F, Latiano A, Rossi L et al. Erythrocyte-mediated delivery of dexamethasone in patients with mild-to-moderate ulcerative colitis, refractory to mesalamine: a randomized, controlled study. Am J Gastroenterol 2008; 103: 2509-2516
• 94 Annese V, Latiano A, Rossi L et al. Erythrocytes-mediated delivery of dexamethasone in steroid-dependent IBD patients – a pilot uncontrolled study. Am J Gastroenterol 2005; 100: 1370-1375
• 95 Annese V, Latiano A, Rossi L et al. The polymorphism of Multi-Drug Resistance 1 gene (MDR1) does not influence the pharmacokinetics of Dexamethasone loaded into autologous erythrocytes of patients with inflammatory bowel disease. Eur Rev Med Pharmacol Sci 2006; 10: 27
• 96 Braat H, Rottiers P, Hommes DW et al. A phase I trial with transgenic bacteria expressing internot_foundleukin-10 in Crohn's disease. Clin Gastroenterol Hepatol 2006; 4: 754-759
• 97 Ricci S, Macchia G, Ruggiero P et al. In vivo mucosal delivery of bioactive human interleukin 1 receptor antagonist produced by Streptococcus gordonii. BMC Biotechnol 2003; 3: 15
• 98 Grangette C, Nutten S, Palumbo E et al. Enhanced antiinflammatory capacity of a Lactobacillus plantarum mutant synthesizing modified teichoic acids. Proc Natl Acad Sci U S A 2005; 102: 10321
• 99 Palffy R, Behuliak M, Gardlik R et al. Oral in vivo Bactofection in Dextran Sulfate Sodium Treated Female Wistar Rats. Folia Microbiol 2010; 3: 171-176
• 100 Palffy R, Gardlik R, Behuliak M et al. Salmonella-mediated gene therapy in experimental colitis in mice. Exp Biol Med 2011; 236: 177-183
• 101 Rochat T, Bermúdez-Humarán L, Gratadoux JJ et al. Anti-inflammatory effects of Lactobacillus casei BL23 producing or not a manganese-dependant catalase on DSS-induced colitis in mice. Microb Cell Fact 2007; 6: 22
• 102 Castagliuolo I, Beggiao E, Brun P et al. Engineered E. coli delivers therapeutic genes to the colonic mucosa. Gene Ther 2005; 12: 1070-1078