CHEE 440 Physiologic Factors Physiologic Factors consider systemic delivery routes of administration » oral (peroral » parenteral (s.c., i.v., i.m.) » transdermal » buccal and sublingual » nasal » rectal » pulmonary
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Physiologic FactorsPhysiologic Factors
consider systemic delivery routes of administration
» oral (peroral» parenteral (s.c., i.v., i.m.)» transdermal» buccal and sublingual » nasal» rectal» pulmonary
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OralOral
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Oral AbsorptionOral Absorption
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OralOral
gastric emptying volume of gastric contents determines [drug] time dosage form/drug spends in stomach
influences absorption liquids emptied faster than solids acids slow gastric emptying natural triglycerides inhibit gastric motility eating influences transit
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OralOral
intestinal transit material moved by peristalsis presence of food retards absorption transit time is consistent among individuals
blood flow GIT is well vascularized hepatic first-pass effect
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ParenteralParenteral
i.v., i.m., s.c.» bypass hepatic first-pass
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ParenteralParenteral
i.m. and s.c. not all drugs fully absorbed tissue more acidic than most tissues blood flow is important good supply of capillaries drug absorption function of diffusion rate
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TransdermalTransdermal
rate limiting step is diffusion through stratum corneum
stratum corneumviable epidermissebaceous glandlymph vesselhair shaftsweat glandcapillaryvascular networknerve endingshair follicledermis
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TransdermalTransdermal
keratohyalin
desmosome
cell nucleus
stratum corneum
granular layer
spinous layer
basal layer
basal lamina
lipid granules
keratinocytes
EPIDERMIS
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TransdermalTransdermal
diffusion
diffusionpartitionbinding
metabolismpartition
diffusion
diffusion
metabolism
binding
pharmacologic receptor
pharmacologic receptor
partitioncirculation
stratum corneum
viable epidermis
dermis
lymph or blood vessel
drug reservoir
membraneadhesive
partition
Factors Affecting Transport
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TransdermalTransdermal
time
pseudo-steady state
lag time
Lag Time
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TransdermalTransdermal
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
0 1 2 3 4 5
NSAIDSsalicylatescurve fit
log (Ko/w
)
Optimum Ko/w
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TransdermalTransdermal
Limitations drug must be potent drug must be effective when delivered slowly over a long
period of time benefits over existing methods?
qualifications narrow therapeutic window subject to extensive first-pass degradation taken many times/day unpleasant side-effects
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TransdermalsTransdermalsdrug MW
(g/mol)pKa m.p.
(˚C)log
(Ko/w)efficaciousblood level
(ng/mL)
scopolamine 303 7.8 59 1.24 0.04
clonidine 230 8.2 140 0.83 0.2-2.0
nitroglycerin 227 13.5 2.05 1.2-11.0
estradiol 272 176 2.49 0.04-0.06
fentanyl 337 8.4 83 2.93 1
nicotine 162 6.16 < -80 10-30
testosterone 288 153 3.31 10-100
progesterone 314 131 3.57 1-3
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Buccal and SublingualBuccal and Sublingual
avoids exposure to GIT
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NasalNasal
frontal sinus
external naris
sinus
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NasalNasal mucus
» moderately viscous, glycoprotein» protects nasal mucosa and traps particulate matter» contains many enzymes» pH 5.5-6.5, low buffering capacity
advantageous for drugs poorly absorbed orally» for some peptides and small molecules» bioavailability comparable to injections
drugs » lypressin, desmopressin, vitamin B-12, progesterone, insulin,
calcitonin, propanolol
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Rectal, Vaginal, UrethralRectal, Vaginal, Urethral
rectal lined with one or more layers of epithelial cells
» luminal side covered with mucus layer» contains a small amount (1-3 ml) of fluid» fluid has low buffering capacity» abundantly vascularized
drug absorption primarily by passive diffusion» avoids some first pass clearance
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PulmonaryPulmonary
large contact surface (surface area > 30 m2 ) extensive blood supply (2000 km of
capillaries) thin membrane separating air from blood disadvantages
small proportion of the drug reaches the site
» e.g., disodium cromoglycate: 8% Variability in dose Lack of Compliance
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PulmonaryPulmonary
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SummarySummary
Route Advan tage Conc erns
IV Direct and complete BA Inconvenience, costIM/SC Good BA; avoids gut exposure Inconvenience, costInhalation convenience Erratic BA, limited
applicationDermal convenience Limited applicationRectal Better BA than po; portion avoid first
hepatic 1st passInconvenience, Erratic
absorptionBuccal Good BA; avoids gut and hepatic 1st
passInconvenience, Size
limitationNasal Good BA; avoids gut and hepatic 1st
passInconvenience, Size
limitation