Drug Targeting Organ-Specific Strategies

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3.10 In Vitro Particle Size Analysis and Deposition Measurements 79 trast, collection efficiency in vivo decreases with decreasing particle size (deposition mechanism) to a minimum of 20% for particles with an aerodynamic diameter of 0.5 µm (e.g. [8]). The classification by impactors into a small number of classes for the relevant particle sizes (one to seven) may provide insufficient discrimination. For example, the theoretical cut-off (with 50% collection efficiency) for the third stage of the multistage liquid impinger (MSLI) is 3.1 µm at 60 l min –1 for particles with a true density of 1.5 g cm –3 . So, the fraction retained from the fourth impactor stage plus filter is smaller than 3.1 µm. If the MMAD of this fraction is 2 µm, deposition efficiency in the respiratory tract can be nearly 40%. If however, the MMAD of this fraction is only 1 µm, the deposition efficiency is only about 20%, which is twice as low. This difference cannot be judged from the cascade impactor result. Usually, the inspiratory flow through impactors is an on–off function: a (solenoid) valve is opened to allow suction at a pre-set flow rate through the inhalation device over a certain period. Some recent guidelines prescribe a flow rate corresponding with 4 kPa pressure drop for DPIs. Asking and Olsson derived a useful relationship for the effective cut-off diameters for the different stages of the MSLI as function of the flow rate for the range between 30 and 100 l min –1 [123]. Impactors have relatively large volumes and high airflow resistances which confine the range of adjustable PIFR and FIR. Probably the major drawback of cascade impactor analysis is that the technique is extremely laborious and time consuming. Laser diffraction is a fast alternative for analysis of the size distribution of particles in an aerosol cloud.The theory of laser diffraction is well understood [124,125]) but this technique requires special measures to test inhalation devices and to interpret the results correctly. One of the major problems is that flow adjustment through the inhaler is not possible. Furthermore, the presence of carrier particles from adhesive mixtures may disturb the measurement of the fine drug particles and the size distribution obtained is of an unknown delivered mass fraction of the dose.These practical problems and limitations have been solved by the design of a new modular inhaler adapter for the Sympatec laser diffraction apparatus (Figure 3.6). Preseparator Fine particle collector Figure 3.6. Schematic representation of a new inhaler adapter for laser diffraction characterization of the aerosol cloud.
80 3 Pulmonary <strong>Drug</strong> Delivery: Delivery To and Through the Lung The adapter for DPI testing consists of a closed central housing with a pre-separator for large (carrier) particles and a fine particle collector for analysis of the fine particle mass fraction [126].The adapter for nebulizer testing can be tilted in order to fit the angled mouthpieces of this type of inhalation device. The closed system allows accurate control of the inspiratory flow rate through the inhaler without limitations regarding PIFR and FIR. The application of the laser diffraction technique is sometimes questioned because it measures geometric instead of aerodynamic particle diameters. However, the aerodynamic diameter can be calculated when the dynamic shape factor and density are known. Moreover, the dynamic shape factor (χ) of micronized particles will often be only slightly higher than 1 and so is the true particle density (1.0 < ρ P
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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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26 2 Brain-Specific Drug Targeting
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Page 91 and 92: 54 3 Pulmonary Drug Delivery: Deliv
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Page 125 and 126: 4 Cell Specific Delivery of Anti-In
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Page 129 and 130: 4.2.2.2 Phagocytosis and Transcytos
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Page 133 and 134: 4.3 Hepatic Inflammation and Fibros
Page 135 and 136: process is not yet available. Sever
Page 137 and 138: this carrier to the KCs.When the ma
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Page 141 and 142: y the transcriptional regulatory pr
Page 143 and 144: 4.8 Testing Liver Targeting Prepara
Page 145 and 146: 4.8 Testing Liver Targeting Prepara
Page 147 and 148: 4.9 Targeting of Anti-inflammatory
Page 149 and 150: 4.9 Targeting of Anti-inflammatory
Page 151 and 152: with monoclonal and bispecific anti
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
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Page 165 and 166: 5.2.1.4 Specific Binding of Alkylgl
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5.2 Renal Delivery Using Pro-Drugs
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5.2 Renal Delivery Using Pro-Drugs
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5.3 Renal Delivery Using Macromolec
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5.4 Renal Delivary of Antisense Oli
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5.4 Renal Delivery of Antisense Oli
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5.4.8 Benefits and Limitations of A
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via reabsorption from the luminal s
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References 153 [66] Franssen EJF, M
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References 155 [145] Van Zwieten PA
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158 6 A Practical Approach in the D
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172 7 Vascular Endothelium in Infla
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8 Strategies for Specific Drug Targ
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8.2.2 Histogenesis The traditional
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may become obstructed and compresse
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8.5 Strategies to Deliver Drugs to
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8.5 Strategies to Deliver Drugs to
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larly cytotoxic immune effector cel
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contributes to limited tumour penet
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ples onto anti-EGP-2 scFv. Biologic
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In the case of drug-monoclonal anti
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cells, the presence of co-stimulato
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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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Drug Targeting Organ-Specific Strategies

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