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دانلود کتاب Physiological Pharmaceutics

Physiological Pharmaceutics
Barriers to drug absorption
Second Edition
Neena Washington, Clive Washington and
Clive G.Wilson

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1. Cell Membranes, Epithelial Barriers and Drug Absorption............................................ 1
INTRODUCTION .................................................................................................................... 2
THE PLASMA MEMBRANE ................................................................................................... 2
The phospholipid bilayer ................................................................................................. 3
Dynamic behaviour of membranes .................................................................................. 4
Modulation of membrane fluidity by sterols .................................................................. 5
Models of cell membranes ............................................................................................... 5
Membrane proteins .......................................................................................................... 7
Membrane asymmetry ..................................................................................................... 7
EPITHELIA ............................................................................................................................... 7
Cell junctions ................................................................................................................... 8
TRANSPORT ACROSS CELL MEMBRANES ...................................................................... 12
Passive diffusion ............................................................................................................ 12
Facilitated and carrier mediated diffusion ..................................................................... 14
Cotransport .................................................................................................................... 14
Uptake of macromolecules and particles ....................................................................... 15
INTERCELLULAR ROUTES OF ABSORPTION .................................................................. 16
PERSORPTION ...................................................................................................................... 16
MUCUS ................................................................................................................................... 17
CONCLUSIONS ..................................................................................................................... 18
REFERENCES ......................................................................................................................... 18
2. Parenteral Drug Delivery .............................................................................................. 19
INTRODUCTION ................................................................................................ 20
INTRAVENOUS DELIVERY ................................................................................ 20
Physiology ..................................................................................................... 20
Advantages and disadvantages of intravenous delivery................................. 21
Formulation considerations........................................................................... 23
Devices and technologies .............................................................................. 23
Injected particulates ...................................................................................... 24
Intravenous oxygen carriers .......................................................................... 25
INTRAMUSCULAR DELIVERY .......................................................................... 26
Physiology ..................................................................................................... 26
Pharmacokinetics .......................................................................................... 26
Formulation considerations........................................................................... 28
SUBCUTANEOUS DELIVERY .............................................................................. 28
Physiology ..................................................................................................... 28
Subcutaneous colloidal delivery systems ....................................................... 29
TISSUE DAMAGE AND BIOCOMPATABILITY ................................................. 29
DRUG DISTRIBUTION FOLLOWING PARENTERAL ADMINISTRATION .... 30
PROTEIN BINDING ............................................................................................ 31
THE BLOOD-BRAIN BARRIER .......................................................................... 32
Physiology ..................................................................................................... 32
Uptake by diffusion ...................................................................................... 32
Receptor-mediated transport ......................................................................... 33
Colloidal delivery .......................................................................................... 33
REFERENCES ....................................................................................................... 34
Contents xi
3. Drug Delivery to the Oral Cavity or Mouth ................................................................ 37
ANATOMY AND PHYSIOLOGY ......................................................................................... 38
The oral cavity ............................................................................................................... 38
The palate ...................................................................................................................... 38
The tongue ..................................................................................................................... 39
The teeth ........................................................................................................................ 39
Organisation of the oral mucosa ................................................................................... 39
Functions of the oral mucosa ........................................................................................ 41
Salivary secretion ........................................................................................................... 41
MIGRATION AND CLEARANCE OF SUBSTANCES FROM
THE ORAL CAVITY .......................................................................................................... 43
ABSORPTION OF DRUGS ACROSS THE ORAL MUCOSA .............................................. 44
Disadvantages of oral mucosal delivery ........................................................................ 44
Effect of position on drug delivery ............................................................................... 45
Gingival penetration ...................................................................................................... 46
Improving penetration through the mucosa .................................................................. 47
MEASUREMENT OF ORAL MUCOSAL DRUG ABSORPTION ........................................ 48
DOSAGE FORMS FOR THE ORAL CAVITY ...................................................................... 48
Chewable formulations .................................................................................................. 49
Fast-dissolving dosage forms ......................................................................................... 50
Bioadhesive dosage forms .............................................................................................. 51
Dental systems ............................................................................................................... 53
DRUGS ADMINISTERED VIA THE ORAL MUCOSA ....................................................... 53
Nitrates .......................................................................................................................... 53
Steroids .......................................................................................................................... 53
Analgesics ...................................................................................................................... 54
Antibiotics ...................................................................................................................... 54
Antifungals ..................................................................................................................... 54
Others ............................................................................................................................ 55
CONCLUSIONS ..................................................................................................................... 55
REFERENCES ......................................................................................................................... 55
4. Oesophageal Transit ..................................................................................................... 59
INTRODUCTION .................................................................................................................. 60
ANATOMY AND PHYSIOLOGY ......................................................................................... 60
Oesophagus .................................................................................................................... 60
Gastro-oesophageal junction or cardia .......................................................................... 61
MOTILITY OF THE OESOPHAGUS .................................................................................... 61
OESOPHAGEAL TRANSIT OF DOSAGE FORMS .............................................................. 63
Measurement ................................................................................................................. 63
Typical transit times ...................................................................................................... 64
OESOPHAGEAL ADHESION OF DOSAGE FORMS .......................................................... 65
Factors predisposing formulations to adhere ................................................................ 66
CONSEQUENCES OF ADHESION OF DOSAGE FORMS ................................................. 67
Delay in drug absorption .............................................................................................. 67
Oesophageal damage ..................................................................................................... 67
EFFECT OF AGEING ............................................................................................................ 68
PATIENT PREFERENCE AND EASE OF SWALLOWING .................................................. 69
EFFECT OF DISEASED STATES ON TRANSIT ................................................................... 69
TARGETING THE OESOPHAGUS ....................................................................................... 70
CONCLUSIONS ..................................................................................................................... 71
REFERENCES ......................................................................................................................... 71
5. The Stomach ................................................................................................................ 75
ANATOMY AND PHYSIOLOGY ......................................................................................... 76
Organisation of the stomach ......................................................................................... 76
Gastric secretion ............................................................................................................ 80
Digestion and absorption .............................................................................................. 82
xii Contents
GASTRIC pH .......................................................................................................................... 83
Circadian rhythm of acidity .......................................................................................... 84
pH and gender ............................................................................................................... 85
pH and age .................................................................................................................... 85
pH and smoking ............................................................................................................ 85
GASTRIC MOTILITY ............................................................................................................ 85
The fasted state .............................................................................................................. 85
The fed state .................................................................................................................. 86
Physiological factors which influence gastric emptying ................................................ 92
Effect of disease on gastric emptying ............................................................................ 93
DISPERSION OF DOSAGE FORMS IN THE STOMACH .................................................. 94
Hard gelatin capsules .................................................................................................... 94
Soft gelatin capsules ...................................................................................................... 94
GASTRIC EMPTYING OF DOSAGE FORMS ..................................................................... 95
Time of dosing relative to a meal ................................................................................. 98
Retention of formulations in the stomach .................................................................... 98
Posture effects .............................................................................................................. 101
Drug-induced effects on gastric emptying ................................................................... 102
GASTRIC pH AND ENTERIC COATINGS ........................................................................ 102
DRUG/FORMULATION INDUCED ULCERATION .......................................................... 102
ANIMAL MODELS FOR GASTRIC EMPTYING .............................................................. 103
REFERENCES ....................................................................................................................... 103
6. Drug Absorption from the Small Intestine
ANATOMY AND PHYSIOLOGY OF THE SMALL INTESTINE ..................................... 109
Gross morphology ....................................................................................................... 110
Mucosa ........................................................................................................................ 110
Organisation of the mucosa ........................................................................................ 111
The gastrointestinal circulation ................................................................................... 113
The lymphatic system .................................................................................................. 114
Secretions into the small intestine ............................................................................... 116
Secretion and absorption of water .............................................................................. 117
Digestion and absorption of nutrients......................................................................... 118
PATTERNS OF MOTILITY IN THE SMALL INTESTINE ................................................ 120
Stagnation at the ileocaecal junction ........................................................................... 121
SMALL INTESTINAL TRANSIT TIMES ............................................................................ 122
Methods for measuring small intestinal transit ........................................................... 122
Small intestinal transit times of food .......................................................................... 123
Physiological and pathophysiological effects on small bowel transit ......................... 123
Small intestinal transit time of dosage forms .............................................................. 124
Density and small intestinal transit ............................................................................. 127
ABSORPTION OF DRUGS .................................................................................................. 127
Absorption and delivery of macromolecules ............................................................... 128
Intestinal pH ................................................................................................................ 129
Solvent drag and intestinal permeability ..................................................................... 129
P-glycoprotein .............................................................................................................. 130
Cytochrome P450 3A4 (CYP3A4) .............................................................................. 131
Intestinal reserve length ............................................................................................... 132
Interaction with food ................................................................................................... 133
First-pass metabolism .................................................................................................. 134
RELATIONSHIP BETWEEN DRUG ABSORPTION AND
POSITION OF DOSE FORM ........................................................................................... 135
Radio controlled capsule ............................................................................................. 135
Absorption of drugs and foreign substances through the lymphatic system .............. 136
DRUG INDUCED DAMAGE ............................................................................................... 136
REFERENCES ....................................................................................................................... 137
Contents xiii
7. Drug Delivery to the Large Intestine and Rectum ...................................................... 143
INTRODUCTION ................................................................................................................ 144
ANATOMY AND PHYSIOLOGY OF THE COLON ........................................................ 144
Interspecies differences in structure ............................................................................. 145
Colonic structure ......................................................................................................... 146
Gut wall metabolism ................................................................................................... 147
Blood supply ................................................................................................................ 147
Nervous and humoral control ..................................................................................... 148
Colonic environment ................................................................................................... 149
Colonic motility ........................................................................................................... 151
Drug absorption from the colon ................................................................................. 157
DRUG DELIVERY ................................................................................................................ 157
Transit .......................................................................................................................... 158
Dietary factors ............................................................................................................. 161
Temporal factors .......................................................................................................... 161
Targeting the proximal colon ...................................................................................... 161
Effect of disease and co-medication on colonic drug absorption ............................... 165
RECTAL ADMINISTRATION OF DRUGS ......................................................................... 166
Drug absorption and avoidance of first-pass metabolism ........................................... 166
Dosage forms for rectal delivery ................................................................................. 167
Adjuvants and enhancers ............................................................................................. 167
Spreading of rectal dosage forms ................................................................................ 168
Therapeutic agents administered rectally .................................................................... 169
Rectal irritation and damage ....................................................................................... 173
CONCLUSIONS ................................................................................................................... 174
REFERENCES ....................................................................................................................... 174
8. Transdermal Drug Delivery ........................................................................................ 181
INTRODUCTION ................................................................................................................ 182
STRUCTURE OF THE SKIN ............................................................................................... 182
Epidermis ..................................................................................................................... 183
Dermis.......................................................................................................................... 184
Subcutaneous fat layer ................................................................................................. 184
Hair and nails .............................................................................................................. 184
Sebaceous glands ......................................................................................................... 185
Eccrine sweat glands .................................................................................................... 185
Surface characteristics .................................................................................................. 185
PASSAGE OF DRUG THROUGH THE SKIN .................................................................... 185
Model systems for skin................................................................................................ 185
Routes of absorption ................................................................................................... 186
Advantages and disadvantages of transdermal delivery .............................................. 187
FACTORS AFFECTING PERCUTANEOUS ABSORPTION ............................................... 188
Individual variation ..................................................................................................... 188
Age ............................................................................................................................... 188
Site ............................................................................................................................... 188
Occlusion ..................................................................................................................... 188
Temperature ................................................................................................................. 188
Race ............................................................................................................................. 189
Disease ......................................................................................................................... 189
VEHICLES AND DEVICES .................................................................................................. 189
PENETRATION ENHANCERS ........................................................................................... 191
IONTOPHORESIS ................................................................................................................ 192
ELECTROPORATION ......................................................................................................... 193
SONOPHORESIS .................................................................................................................. 194
CONCLUSIONS ................................................................................................................... 194
REFERENCES ....................................................................................................................... 195
xiv Contents
9. Nasal Drug Delivery ................................................................................................... 199
ANATOMY AND PHYSIOLOGY ....................................................................................... 200
Nasal epithelia ............................................................................................................. 201
Nasal lymphatic system ............................................................................................... 202
Nasal secretions ........................................................................................................... 202
The nasal cycle ............................................................................................................ 203
Mucociliary clearance of inhaled particles .................................................................. 203
Pathological effects on mucociliary function............................................................... 204
External factors affecting mucociliary clearance ......................................................... 206
Chemical-induced changes ........................................................................................... 207
INTRANASAL ADMINISTRATION OF DRUGS ............................................................... 208
Drugs administered for local action ............................................................................ 208
Drugs administered for systemic effect........................................................................ 209
DRUG DELIVERY SYSTEMS AND DEPOSITION PATTERNS ........................................ 210
Mechanisms to increase nasal residence time of formulations ................................... 212
Excipient and drug effects on clearance ...................................................................... 213
Effect of formulation pH ............................................................................................. 214
INTERSPECIES COMPARISONS ........................................................................................ 216
CONCLUSIONS ................................................................................................................... 216
REFERENCES ....................................................................................................................... 217
10. Pulmonary Drug Delivery ......................................................................................... 221
STRUCTURE AND FUNCTION OF THE PULMONARY SYSTEM ................................. 222
The lung ....................................................................................................................... 222
Upper airway ............................................................................................................... 222
Structure of the tracheo-bronchial tree ....................................................................... 223
Epithelium .................................................................................................................... 225
Lung permeability ........................................................................................................ 227
Lung mucus ................................................................................................................. 227
Lung defenses .............................................................................................................. 228
Lung surfactant ............................................................................................................ 228
Blood supply ................................................................................................................ 229
Lymphatic system......................................................................................................... 229
Nervous control ........................................................................................................... 229
Biochemical processes which occur in the lung .......................................................... 230
Breathing ...................................................................................................................... 230
Respiratory disease ...................................................................................................... 230
DOSAGE FORMS FOR PULMONARY DRUG DELIVERY .............................................. 232
Pressurized inhalation aerosols .................................................................................... 232
Dry powder inhalers .................................................................................................... 234
Nebulizers .................................................................................................................... 235
Spacer devices and ancillary equipment ...................................................................... 236
ASSESSMENT OF DEPOSITION BY GAMMA SCINTIGRAPHY .................................... 237
Choice of radiolabel .................................................................................................... 237
Labeling inhalation formulations ................................................................................ 238
Labeling dry powder inhalers ...................................................................................... 239
Validation..................................................................................................................... 239
FACTORS AFFECTING PARTICLE DEPOSITION IN THE LUNG ................................. 239
Physicochemical properties .......................................................................................... 239
Deposition patterns from different dose forms ........................................................... 241
Physiological variables ................................................................................................. 241
DRUG ABSORPTION .......................................................................................................... 242
PHARMACOKINETICS ....................................................................................................... 243
DRUGS ADMINISTERED VIA THE PULMONARY ROUTE ........................................... 243
Anti-allergy agents ....................................................................................................... 243
Beta receptor agonists .................................................................................................. 243
Contents xv
Adrenocorticosteroids .................................................................................................. 244
Leukotriene inhibitors ................................................................................................. 244
Other bronchodilating agents ...................................................................................... 244
Mucolytics ................................................................................................................... 244
Systemically-absorbed drugs ........................................................................................ 245
REFERENCES ....................................................................................................................... 245
11. Ocular Drug Delivery ............................................................................................... 249
INTRODUCTION ................................................................................................................ 250
STRUCTURE OF THE EYE ................................................................................................. 251
The cornea ................................................................................................................... 251
The conjunctiva and sclera .......................................................................................... 252
The choroid and retina ................................................................................................ 252
The aqueous humor ..................................................................................................... 252
The eyelids ................................................................................................................... 253
The precorneal tear film .............................................................................................. 253
Blood-eye barriers ........................................................................................................ 256
FACTORS AFFECTING DRUG PERMEATION ................................................................. 257
Ionization and pH ....................................................................................................... 257
Protein binding ............................................................................................................ 258
Pigmentation and drug effects ..................................................................................... 258
Drug distribution in the eye ........................................................................................ 259
Drug penetration through the sclera and conjunctiva ................................................ 259
FACTORS INFLUENCING DRUG RETENTION .............................................................. 260
Proper placement of the eyedrops ............................................................................... 260
Influence of instilled volume ....................................................................................... 261
Preservatives ................................................................................................................. 261
Effect of systemically administered drugs.................................................................... 262
ROUTES OF DRUG ADMINISTRATION .......................................................................... 262
Topical administration ................................................................................................. 262
Intraocular drug delivery ............................................................................................. 266
Systemic administration ............................................................................................... 268
CONCLUSIONS ................................................................................................................... 269
REFERENCES ....................................................................................................................... 269
12. Vaginal and Interuterine Drug Delivery .................................................................... 271
ANATOMY AND PHYSIOLOGY ....................................................................................... 272
Mucosa ........................................................................................................................ 273
Blood and nerve supply ............................................................................................... 275
Uterine and vaginal fluid ............................................................................................. 275
pH ................................................................................................................................ 275
Enzymatic activity ........................................................................................................ 276
Mucus ..........................................................................................................................276
Menstruation ............................................................................................................... 276
Menopause ................................................................................................................... 277
Disorders of the vagina ............................................................................................... 277
DRUG ABSORPTION THROUGH THE VAGINA/UTERUS ............................................. 277
DRUG DELIVERY ................................................................................................................ 277
Vaginal ......................................................................................................................... 277
Intrauterine Devices ..................................................................................................... 279
CONCLUSION ..................................................................................................................... 280
REFERENCES ....................................................................................................................... 280
GLOSSARY ........................................................................................................................... 283
INDEX .....................................................................................................