Drug Targeting Organ-Specific Strategies

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Water insoluble polymer membrane (Ethylcellulose) Sucrose bead Drug layer Swelling agent layer (low substituted Hydoxypropylcellulose) compartment. Micropores in the outer semi-permeable film allow a sustained drug release after dissolution and extrusion of the underlying delay coat. For an erosion-induced drug delivery system compactable cellulose ethers are suitable polymers [103]. Drug release, which is controlled by the erosion/dissolution of these polymeric layers, may be pH-dependent if an acid or basic polymer is used. In summary, the lag time of drug release may be controlled by the rate at which water penetrates through the coating or shell, the rate of fluid absorption of the polymer layer, the osmotic activity of salts and osmopolymers, the erosion and dissolution rate of the polymer layers and the thickness of the layers or coatings. 6.4.4 Pressure-controlled Drug Release 6.4 Approaches to Colon-specific Drug Delivery 167 Hydrophobic surfactant layer (wax, Polysorbate 80, Hydroxypropylmethylcellulose) Enteric coating Tablet core Eudragit ® S (optional) Hydroxypropylmethylcellulose (high viscosity) Figure 6.4. Swelling-induced time-controlled drug delivery systems. Eudragit ® L Drug core Pressure-controlled delivery systems take advantage of the temporary increase in intra-luminal pressure in the colon in the event of a peristaltic wave.A drug formulation relying on the resulting destructive force has been developed and consists of a conventional hard gelatin capsule with a thick inner layer of ethylcellulose [104,105]. The rupture of the ethylcellulose shell with subsequent drug release is induced by an increase in the intra-luminal pressure and subsequent destructive force. Drug absorption from this formulation has been investigated in vivo in dogs and humans with mesalazine, carbamazepine [105,106] and caffeine [104] as the model drugs. The capsule contains the drug in solution because otherwise there may be insufficient fluid available in the distal portion of the colon for the drug to dissolve in.
168 6 A Practical Approach in the Design of Colon-specific Drug Delivery Systems 6.5 Concluding Remarks All the methods for colon-specific drug delivery presented in this overview are more or less susceptible to changes in the physiological environment (diet, disease state, medication, etc.). This may affect reliability and reproducibility of the delivery systems. However, most of the systems described have already been investigated in vivo with regard to colon specificity. Methods such as planar γ-scintigraphy [86,97,107] and three-dimensional magnetic marker monitoring [108,109] appear to be the methods of choice for dynamic visualization of the dosage form in the GI tract and the determination of the location and time of onset of drug release. In animal models, the measurement of blood and intestinal tissue concentrations of the perorally administered drug in order to quantify the reduction in the systemic exposure, is an additional approach [110]. However, most formulations are tested in healthy humans or animals in spite of the fact, that pathological conditions such as inflammatory bowel disease may have a significant influence on gut physiology.As yet, little is known regarding the effect of disease states on the intestinal transit time, GI tract motility, luminal pH, intra-luminal colonic pressure and composition of colonic microflora. It appears that time-controlled drug release systems, which rely on a constant transit time through the small intestine, are the most promising colon-specific delivery systems, as this transit time is only marginally influenced by pathological events in the GI tract. pH-controlled systems are reliable only if there is a significant difference in the luminal pH between the small and the large intestine. Under physiological conditions this pH difference is often too small. In certain pathological conditions such as inflammatory bowel disease however, a significant decrease in pH in the affected GI tract regions may be observed, and this has led to the development of novel pH-controlled delivery systems. Enzyme-controlled delivery systems are dependent on the activity of the microbial enzymes in the large intestine, which are susceptible to many environmental factors, particularly diet and medication. The reliability of pressure-controlled delivery systems is expected to be highly dependent on variations in intestinal peristalsis despite promising in vivo data. References [1] Simon GL, Gorbach SL, Gastroenterology 1984, 86, 174–193. [2] Drasar BS, Hill MJ, In: Human Intestinal Flora, pp. 103-123. Academic Press, London, 1974. [3] Bragger JL, Yazaki E, Evans DF, Pharm. Res. 1997, 14 (11 Suppl.), S656–S657. [4] Mitsuoka T, Intestinal Bacteria and Health. Harcourt Brace Jovanovich, Tokyo, 1978. [5] Evans DF, Pye G, Bramley R, Clark AG, Dyson TJ, Hardcastle JD, Gut 1988, 29, 1035–1041. [6] Shameem M, Katori N, Aoyagi N, Kojima S, Pharm. Res. 1995, 12, 1049–1054. [7] Haeberlin B, Friend DR, In: Oral Colon-Specific Drug Delivery (Ed. Friend DR), pp. 1–43. CRC Press, Boca Raton, 1992. [8] Zeitz M, Digestion 1997, 58 (Suppl. 1), 59–61. [9] Bhatti MA, Hodgson HJF, Int. J. Exp. Pathol. 1995, 76, 309–315. [10] Morteau O, Bueno L, Gastroenterol. Clin. Biol. 1995, 19, 204–214. [11] Warren BF, Watkins PE, J. Pathol. 1994, 172, 313–316. [12] Pories SE, Ramchurren N, Summerhayes I, Steele G, Arch. Surg. 1993, 128, 647–653. [13] Fix JA, J. Pharm. Sci. 1996, 85, 1282–1285. [14] Ashford M, Fell JT, Attwood D, Woodhead PJ, Int. J. Pharm. 1993, 91, 241–145. [15] Ashford M, Fell JT, Attwood D, Sharma H, Woodhead PJ, Int. J. Pharm. 1993, 95, 193–199. [16] Dew MJ, Ryder REJ, Evans N, Evans BK, Rhodes J, Br. J. Clin. Pharmacol. 1983, 16, 185–187.
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Drug Targeting Organ-Specific Strat
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Preface Drug Targeting Organ-Specif
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Foreword Drug Targeting Organ-Speci
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X List of Contributors Henderik W.
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XII List of Contributors Grietje Mo
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Contents Drug Targeting Organ-Speci
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Contents XVII 3 Pulmonary Drug Deli
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Contents XIX 5.2.1.6 Identification
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Contents XXI 7.5 In Vitro Technique
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Contents XXIII 9.4 Tumour Vasculatu
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Contents XXV 12.8. Tissue Slices fr
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Dexa dexamethasone DIVEMA divinyl e
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LRP lung resistance related protein
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ROS reactive oxygen species RSV res
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Index a ADEPT 217, 224, 268, 291 ad
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e E. coli expression system 292 eff
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polymers, soluble 4, 218 - dendrime
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2 1 Drug Targeting: Basic Concepts
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24 2 Brain-Specific Drug Targeting
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54 3 Pulmonary Drug Delivery: Deliv
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4 Cell Specific Delivery of Anti-In
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The sinusoids are lined by the disc
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4.2.2.2 Phagocytosis and Transcytos
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ther inflammatory cells or accessor
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4.3 Hepatic Inflammation and Fibros
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process is not yet available. Sever
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this carrier to the KCs.When the ma
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e taken up rapidly by mannose recep
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y the transcriptional regulatory pr
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4.8 Testing Liver Targeting Prepara
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4.8 Testing Liver Targeting Prepara
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4.9 Targeting of Anti-inflammatory
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4.9 Targeting of Anti-inflammatory
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Page 153 and 154: References 117 [50] Coleman DL, Eur
Page 155 and 156: References 119 [133] Cronstein BN,
Page 157 and 158: 5 Delivery of Drugs and Antisense O
Page 159 and 160: 5.1 Introduction 123 convoluted tub
Page 161 and 162: treatment of the targeted cell and
Page 163 and 164: CL uptake (ml/min/g) centration pro
Page 165 and 166: 5.2.1.4 Specific Binding of Alkylgl
Page 167 and 168: 5.2 Renal Delivery Using Pro-Drugs
Page 169 and 170: 5.2 Renal Delivery Using Pro-Drugs
Page 171 and 172: 5.3 Renal Delivery Using Macromolec
Page 181 and 182: 5.4 Renal Delivary of Antisense Oli
Page 183 and 184: 5.4 Renal Delivery of Antisense Oli
Page 185 and 186: 5.4.8 Benefits and Limitations of A
Page 187 and 188: via reabsorption from the luminal s
Page 189 and 190: References 153 [66] Franssen EJF, M
Page 191 and 192: References 155 [145] Van Zwieten PA
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Page 235 and 236: 8.2.2 Histogenesis The traditional
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Monomethoxy-polyethylene glycol CH
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e efficiently loaded into the lipos
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8.6 Clinical Studies 223 Table 8.5.
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8.6.3 (Synthetic) (co)Polymers Solu
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8.8 Conclusions and Future Perspect
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References 229 [43] Chaouchi NA, Va
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References 231 [126] Czuczman MS, G
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234 9 Tumour Vasculature Targeting
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256 10 Phage Display Technology for
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11 Development of Proteinaceous Dru
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carrier is an homogenous product. I
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11.3 The Homing Device 11.3 The Hom
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malian cell lines that have acquire
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jugates for the delivery of other a
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11.5 The Linkage Between Drug and C
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actions are directed towards these
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11.5 The Linkage Between Drug and C
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homing potential if the antigen rec
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ly used promoters include T7 RNA po
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the baculovirus expression vector,
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11.8 Recombinant DNA Constructs 297
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11.8 Recombinant DNA Constructs 299
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toxic activity. Anthrax and tetanus
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11.9 Recombinant Domains as Buildin
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References 305 [16] Milstein C, Wal
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References 307 [99] Verma R, Boleti
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12 Use of Human Tissue Slices in Dr
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are also extensively used in a vari
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Meanwhile many incubation systems h
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12.3 Incubation and Culture of Live
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to investigate the effect of differ
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The mechanisms of uptake and excret
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12.6 The Use of Liver Slices in Dru
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12.7 Efficacy Testing of the Drug T
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NO x µM 80 60 40 20 * * 12.7 Effic
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TNFα ng/ml 1.5 1 0.5 0 * Human (n=
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References 329 [33] Ikejima K, Enom
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References 331 [109] Dutt A, Priebe
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334 13 Pharmacokinetic/Pharmacodyna
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372 14 Drug Targeting Strategy: Scr
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374 14 Drug Targeting Strategy: Scr
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