CHEE 440 1

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

CHEE 440 2

OralOral

CHEE 440 3

Oral AbsorptionOral Absorption

CHEE 440 4

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

CHEE 440 5

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

CHEE 440 6

ParenteralParenteral

i.v., i.m., s.c.» bypass hepatic first-pass

CHEE 440 7

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

CHEE 440 9

TransdermalTransdermal

keratohyalin

desmosome

cell nucleus

stratum corneum

granular layer

spinous layer

basal layer

basal lamina

lipid granules

keratinocytes

EPIDERMIS

CHEE 440 10

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

CHEE 440 11

TransdermalTransdermal

time

pseudo-steady state

lag time

Lag Time

CHEE 440 12

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

CHEE 440 13

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

CHEE 440 14

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

CHEE 440 15

Buccal and SublingualBuccal and Sublingual

avoids exposure to GIT

CHEE 440 16

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

CHEE 440 18

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

CHEE 440 19

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

CHEE 440 20

PulmonaryPulmonary

CHEE 440 21

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