Physiological Pharmaceutics

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Chapter TwoParenteral Drug DeliveryINTRODUCTIONINTRAVENOUS DELIVERYPhysiologyAdvantages and disadvantages of intravenous deliveryFormulation considerationsDevices and technologiesInjected particulatesIntravenous oxygen carriersINTRAMUSCULAR DELIVERYPhysiologyPharmacokineticsFormulation considerationsSUBCUTANEOUS DELIVERYPhysiologySubcutaneous colloidal delivery systemsTISSUE DAMAGE AND BIOCOMPATABILITYDRUG DISTRIBUTION FOLLOWING PARENTERAL ADMINISTRATIONPROTEIN BINDINGTHE BLOOD-BRAIN BARRIERPhysiologyUptake by diffusionReceptor-mediated transportColloidal deliveryREFERENCES19
20 <strong>Physiological</strong> <strong>Pharmaceutics</strong>INTRODUCTIONThe term parenteral drug delivery covers a number of administration routes, which havelittle in common other than the fact that they generally involve the use of a hypodermicneedle to inject the drug into the body. This route bypasses a number of physiologicalbarriers and hence the constraints on the composition and formulation of the medicine aremuch more rigorous than for less invasive routes such as oral or transdermal delivery.Despite this a surprising range of materials can be injected into various tissues if theappropriate precautions are taken. We will examine the constraints for specific formulationswith respect to the appropriate physiological route, but a number of general principles arecommon to all routes. The most important is that the formulation must be sterile, since themajor defence mechanisms of the body (the skin and mucous membranes) are bypassed, andso any infective agent in the formulation may cause major disease. It is not only necessaryto remove live microorganisms; parts of dead organisms can elicit an immune response, andpolysaccharides from the bacterial cell wall, known as pyrogens, can cause a substantialincrease in body temperature.The most important routes of parenteral delivery are intravenous and intramuscular,with subcutaneous being widely used for small volumes and for vaccination. There are anumber of less important routes, since it is generally possible to inject materials into virtuallyany part of the body in an attempt to gain a rapid local action. Thus we also have relativelyspecialized routes such as intrathecal, intraarticular and intracardiac.INTRAVENOUS DELIVERYPhysiologyIntravenous delivery involves the direct injection of the formulation into the venouscirculation. To understand the behaviour of intravenous drugs it is essential to consider thefunction of the circulatory system. This is shown in diagrammatic form in Figure 2.1.Although the heart is normally described as a pump, it is in fact two pumps, one of whichcirculates the blood around the tissues, and one which circulates it specifically around thelungs in a separate loop. Oxygenated blood is pumped by the left side of the heart throughthe aorta and arteries into a network of capillaries which allow transfer of oxygen andnutrients into the tissues, and remove waste products. The blood is then collected by anetwork of veins and passes into the right side of the heart. It is then passed through thepulmonary circulation into the lungs, where it loses carbon dioxide produced by tissuerespiration, and is reoxygenated. It then passes back to the left side of the heart for the cycleto repeat.Not all of the circulation from the tissues returns directly to the heart. A fraction, inparticular that which perfuses the gastrointestinal tract, is pumped to the liver first. The liverperforms a wide range of metabolic processes, but for drug delivery it can be rather moreof a hindrance since it absorbs a fraction of the drug from the bloodstream and begins thecycle of metabolism and excretion. Consequently drugs which are administered orally willvisit the liver before they have the opportunity to reach the target tissue; this effect is calledfirst pass metabolism and can remove a significant and often unpredictable fraction of thedose. When the drug is injected into a vein it passes directly into the heart, and is carriedto the tissues before passing on to the liver. Consequently first pass metabolism is avoidedand the drug has an opportunity to act on the tissues before it passes to the liver onsubsequent cycles around the circulation.The capillaries are, in general, designed to retain their contents, and so in mosttissues the capillary endothelial cells are in close contact without gaps, and a continuousbasement membrane underlies them. Capillaries of this type can allow only relativelysmall solutes, such as water, low molecular weight drugs, and small proteins (maximum
Page 3 and 4: For Alexander and SarinaWith all ou
Page 5 and 6: First edition 1989Second edition fi
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Page 9 and 10: viiiAcknowledgementsFig 6.5 is repr
Page 11 and 12: Table of Contents1. Cell Membranes,
Page 13 and 14: xiiContentsGASTRIC pH .............
Page 15 and 16: xivContents9. Nasal Drug Delivery .
Page 18 and 19: Chapter OneCell Membranes, Epitheli
Page 20 and 21: Membranes and barriers 3Figure 1.1
Page 22 and 23: Membranes and barriers 5Modulation
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Chapter FiveThe StomachANATOMY AND
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The stomach 77Figure 5.2 Structure
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The stomach 79Gastric glandsThe gas
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The stomach 81Figure 5.7 Mechanism
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The stomach 83absorbed from the sto
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The stomach 85Night-time transient
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The stomach 87particle size indiges
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The stomach 89Figure 5.13 MRI cross
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The stomach 91species and man is po
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The stomach 93Figure 5.15 The effec
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The stomach 95emerged from the shel
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The stomach 97Figure 5.17 The gastr
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The stomach 99In order to improve b
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The stomach 101Figure 5.21—Gastri
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The stomach 103The anatomy and dime
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The stomach 10533:1283-1290.35. Cun
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The stomach 10782. Ingani HM, Timme
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Chapter SixDrug Absorption from the
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Small intestine 111Figure 6.1 Secti
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Small intestine 113are uncommon and
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Small intestine 115underlying tissu
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Small intestine 117Brief periodic b
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Small intestine 119is extremely rap
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Small intestine 121Figure 6.5 Segme
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Small intestine 123Measurements of
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Small intestine 125Figure 6.8 Small
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Small intestine 127Scintigraphy oft
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Small intestine 129It is known that
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Small intestine 131It was soon real
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Small intestine 133colonic absorpti
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Small intestine 135also transform d
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Small intestine 137REFERENCES1. Bry
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Small intestine 13949. Hidalgo IJ,
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Small intestine 14193. Bogentoft C,
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Chapter ElevenOcular Drug DeliveryI
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Ocular drug delivery 251STRUCTURE O
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Ocular drug delivery 253chamber. It
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Ocular drug delivery 255The superfi
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Ocular drug delivery 257Figure 11.7
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Ocular drug delivery 259Figure 11.9
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Ocular drug delivery 261Influence o
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Ocular drug delivery 263SpraysSpray
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Ocular drug delivery 265endothelial
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Ocular drug delivery 267polymers ha
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Ocular drug delivery 269sustained-r
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Chapter TwelveVaginal and Intrauter
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Vaginal and intrauterine drug deliv
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284 GlossaryAntipyrine An analgesic
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286 GlossaryClonazepam An anticonvu
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288 GlossaryEsterase An enzyme whic
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290 Glossaryfound in the synovial f
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294 GlossaryPectoral muscle Chest m
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296 Glossarysize exclusion (gel fil
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298 GlossaryTributyrase An enzyme w
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300 Indexß-glucuronidase 276B cell
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302 IndexDiazoxide 262Dichlorodiphe
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304 IndexGelling polymers 264Gels 1
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306 IndexEpithelium 225Factors affe
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308 IndexOros ® 158Osmotic deliver
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310 IndexAbsorption 186Age 188Disea
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312 IndexDrug absorption 277Fluid 2
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Physiological Pharmaceutics

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