Cell Membranes, Epithelial Barriers and Drug Absorption p. 1 Introduction p. 2 The Plasma Membrane p. 2 The phospholipid bilayer p.

Transcription

1 Cell Membranes, Epithelial Barriers and Drug Absorption p. 1 Introduction p. 2 The Plasma Membrane p. 2 The phospholipid bilayer p. 3 Dynamic behaviour of membranes p. 4 Modulation of membrane fluidity by sterols p. 5 Models of cell membranes p. 5 Membrane proteins p. 7 Membrane asymmetry p. 7 Epithelia p. 7 Cell junctions p. 8 Transport Across Cell Membranes p. 12 Passive diffusion p. 12 Facilitated and carrier mediated diffusion p. 14 Cotransport p. 14 Uptake of macromolecules and particles p. 15 Intercellular Routes of Absorption p. 16 Persorption p. 16 Mucus p. 17 Conclusions p. 18 References p. 18 Parenteral Drug Delivery p. 19 Introduction p. 20 Intravenous Delivery p. 20 Physiology p. 20 Advantages and disadvantages of intravenous delivery p. 21 Formulation considerations p. 23 Devices and technologies p. 23 Injected particulates p. 24 Intravenous oxygen carriers p. 25 Intramuscular Delivery p. 26 Physiology p. 26 Pharmacokinetics p. 26 Formulation considerations p. 28 Subcutaneous Delivery p. 28 Physiology p. 28 Subcutaneous colloidal delivery systems p. 29 Tissue Damage and Biocompatability p. 29 Drug Distribution Following Parenteral Administration p. 30 Protein Binding p. 31 The Blood-Brain Barrier p. 32

2 Physiology p. 32 Uptake by diffusion p. 32 Receptor-mediated transport p. 33 Colloidal delivery p. 33 References p. 34 Drug Delivery to the Oral Cavity or Mouth p. 37 Anatomy and Physiology p. 38 The oral cavity p. 38 The palate p. 38 The tongue p. 39 The teeth p. 39 Organisation of the oral mucosa p. 39 Functions of the oral mucosa p. 41 Salivary secretion p. 41 Migration and Clearance of Substances from the Oral Cavity p. 43 Absorption of Drugs across the Oral Mucosa p. 44 Disadvantages of oral mucosal delivery p. 44 Effect of position on drug delivery p. 45 Gingival penetration p. 46 Improving penetration through the mucosa p. 47 Measurement of Oral Mucosal Drug Absorption p. 48 Dosage Forms for the Oral Cavity p. 48 Chewable formulations p. 49 Fast-dissolving dosage forms p. 50 Bioadhesive dosage forms p. 51 Dental systems p. 53 Drugs Administered Via the Oral Mucosa p. 53 Nitrates p. 53 Steroids p. 53 Analgesics p. 54 Antibiotics p. 54 Antifungals p. 54 Others p. 55 Conclusions p. 55 References p. 55 Oesophageal Transit p. 59 Introduction p. 60 Anatomy and Physiology p. 60 Oesophagus p. 60 Gastro-oesophageal junction or cardia p. 61 Motility of the Oesophagus p. 61

3 Oesophageal Transit of Dosage Forms p. 63 Measurement p. 63 Typical transit times p. 64 Oesophageal Adhesion of Dosage Forms p. 65 Factors predisposing formulations to adhere p. 66 Consequences of Adhesion of Dosage Forms p. 67 Delay in drug absorption p. 67 Oesophageal damage p. 67 Effect of Ageing p. 68 Patient Preference and Ease of Swallowing p. 69 Effect of Diseased States on Transit p. 69 Targeting the Oesophagus p. 70 Conclusions p. 71 References p. 71 The Stomach p. 75 Anatomy and Physiology p. 76 Organisation of the stomach p. 76 Gastric secretion p. 80 Digestion and absorption p. 82 Gastric ph p. 83 Circadian rhythm of acidity p. 84 ph and gender p. 85 ph and age p. 85 ph and smoking p. 85 Gastric Motility p. 85 The fasted state p. 85 The fed state p. 86 Physiological factors which influence gastric emptying p. 92 Effect of disease on gastric emptying p. 93 Dispersion of Dosage Forms in the Stomach p. 94 Hard gelatin capsules p. 94 Soft gelatin capsules p. 94 Gastric Emptying of Dosage Forms p. 95 Time of dosing relative to a meal p. 98 Retention of formulations in the stomach p. 98 Posture effects p. 101 Drug-induced effects on gastric emptying p. 102 Gastric ph and Enteric Coatings p. 102 Drug/Formulation Induced Ulceration p. 102 Animal Models for Gastric Emptying p. 103 References p. 103

4 Drug Absorption from the Small Intestine Anatomy and Physiology of the Small Intestine p. 109 Gross morphology p. 110 Mucosa p. 110 Organisation of the mucosa p. 111 The gastrointestinal circulation p. 113 The lymphatic system p. 114 Secretions into the small intestine p. 116 Secretion and absorption of water p. 117 Digestion and absorption of nutrients p. 118 Patterns of Motility in the Small Intestine p. 120 Stagnation at the ileocaecal junction p. 121 Small Intestinal Transit Times p. 122 Methods for measuring small intestinal transit p. 122 Small intestinal transit times of food p. 123 Physiological and pathophysiological effects on small bowel transit p. 123 Small intestinal transit time of dosage forms p. 124 Density and small intestinal transit p. 127 Absorption of Drugs p. 127 Absorption and delivery of macromolecules p. 128 Intestinal ph p. 129 Solvent drag and intestinal permeability p. 129 P-glycoprotein p. 130 Cytochrome P450 3A4 (CYP3A4) p. 131 Intestinal reserve length p. 132 Interaction with food p. 133 First-pass metabolism p. 134 Relationship Between Drug Absorption and Position of Dose Form p. 135 Radio controlled capsule p. 135 Absorption of drugs and foreign substances through the lymphatic system p. 136 Drug Induced Damage p. 136 References p. 137 Drug Delivery to the Large Intestine and Rectum p. 143 Introduction p. 144 Anatomy and Physiology of the Colon p. 144 Interspecies differences in structure p. 145 Colonic structure p. 146 Gut wall metabolism p. 147 Blood supply p. 147 Nervous and humoral control p. 148 Colonic environment p. 149

5 Colonic motility p. 151 Drug absorption from the colon p. 157 Drug Delivery p. 157 Transit p. 158 Dietary factors p. 161 Temporal factors p. 161 Targeting the proximal colon p. 161 Effect of disease and co-medication on colonic drug absorption p. 165 Rectal Administration of Drugs p. 166 Drug absorption and avoidance of first-pass metabolism p. 166 Dosage forms for rectal delivery p. 167 Adjuvants and enhancers p. 167 Spreading of rectal dosage forms p. 168 Therapeutic agents administered rectally p. 169 Rectal irritation and damage p. 173 Conclusions p. 174 References p. 174 Transdermal Drug Delivery p. 181 Introduction p. 182 Structure of the Skin p. 182 Epidermis p. 183 Dermis p. 184 Subcutaneous fat layer p. 184 Hair and nails p. 184 Sebaceous glands p. 185 Eccrine sweat glands p. 185 Surface characteristics p. 185 Passage of Drug Through the Skin p. 185 Model systems for skin p. 185 Routes of absorption p. 186 Advantages and disadvantages of transdermal delivery p. 187 Factors Affecting Percutaneous Absorption p. 188 Individual variation p. 188 Age p. 188 Site p. 188 Occlusion p. 188 Temperature p. 188 Race p. 189 Disease p. 189 Vehicles and Devices p. 189 Penetration Enhancers p. 191

6 Iontophoresis p. 192 Electroporation p. 193 Sonophoresis p. 194 Conclusions p. 194 References p. 195 Nasal Drug Delivery p. 199 Anatomy and Physiology p. 200 Nasal epithelia p. 201 Nasal lymphatic system p. 202 Nasal secretions p. 202 The nasal cycle p. 203 Mucociliary clearance of inhaled particles p. 203 Pathological effects on mucociliary function p. 204 External factors affecting mucociliary clearance p. 206 Chemical-induced changes p. 207 Intranasal Administration of Drugs p. 208 Drugs administered for local action p. 208 Drugs administered for systemic effect p. 209 Drug Delivery Systems and Deposition Patterns p. 210 Mechanisms to increase nasal residence time of formulations p. 212 Excipient and drug effects on clearance p. 213 Effect of formulation ph p. 214 Interspecies Comparisons p. 216 Conclusions p. 216 References p. 217 Pulmonary Drug Delivery p. 221 Structure and Function of the Pulmonary System p. 222 The lung p. 222 Upper airway p. 222 Structure of the tracheo-bronchial tree p. 223 Epithelium p. 225 Lung permeability p. 227 Lung mucus p. 227 Lung defenses p. 228 Lung surfactant p. 228 Blood supply p. 229 Lymphatic system p. 229 Nervous control p. 229 Biochemical processes which occur in the lung p. 230 Breathing p. 230 Respiratory disease p. 230

7 Dosage Forms for Pulmonary Drug Delivery p. 232 Pressurized inhalation aerosols p. 232 Dry powder inhalers p. 234 Nebulizers p. 235 Spacer devices and ancillary equipment p. 236 Assessment of Deposition by Gamma Scintigraphy p. 237 Choice of radiolabel p. 237 Labeling inhalation formulations p. 238 Labeling dry powder inhalers p. 239 Validation p. 239 Factors Affecting Particle Deposition in the Lung p. 239 Physicochemical properties p. 239 Deposition patterns from different dose forms p. 241 Physiological variables p. 241 Drug Absorption p. 242 Pharmacokinetics p. 243 Drugs Administered Via the Pulmonary Route p. 243 Anti-allergy agents p. 243 Beta receptor agonists p. 243 Adrenocorticosteroids p. 244 Leukotriene inhibitors p. 244 Other bronchodilating agents p. 244 Mucolytics p. 244 Systemically-absorbed drugs p. 245 References p. 245 Ocular Drug Delivery p. 249 Introduction p. 250 Structure of the Eye p. 251 The cornea p. 251 The conjunctiva and sclera p. 252 The choroid and retina p. 252 The aqueous humor p. 252 The eyelids p. 253 The precorneal tear film p. 253 Blood-eye barriers p. 256 Factors Affecting Drug Permeation p. 257 Ionization and ph p. 257 Protein binding p. 258 Pigmentation and drug effects p. 258 Drug distribution in the eye p. 259 Drug penetration through the sclera and conjunctiva p. 259

8 Factors Influencing Drug Retention p. 260 Proper placement of the eyedrops p. 260 Influence of instilled volume p. 261 Preservatives p. 261 Effect of systemically administered drugs p. 262 Routes of Drug Administration p. 262 Topical administration p. 262 Intraocular drug delivery p. 266 Systemic administration p. 268 Conclusions p. 269 References p. 269 Vaginal and Interuterine Drug Delivery p. 271 Anatomy and Physiology p. 272 Mucosa p. 273 Blood and nerve supply p. 275 Uterine and vaginal fluid p. 275 ph p. 275 Enzymatic activity p. 276 Mucus p. 276 Menstruation p. 276 Menopause p. 277 Disorders of the vagina p. 277 Drug Absorption Through the Vagina/Uterus p. 277 Drug Delivery p. 277 Vaginal p. 277 Intrauterine Devices p. 279 Conclusion p. 280 References p. 280 Glossary p. 283 Index p. 299 Table of Contents provided by Blackwell's Book Services and R.R. Bowker. Used with permission.