1. Physiologic Factors consider systemic delivery
routes of administration
oral (peroral
parenteral (s.c., i.v., i.m.)
transdermal
buccal and sublingual
nasal
rectal
pulmonary

2. Oral

3. Oral Absorption

4. Oral 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

5. Oral intestinal transit blood flow 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

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

7. Parenteral 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

8. Transdermal
rate limiting step is diffusion through stratum corneum

9. Transdermal EPIDERMIS
- divided into 4 layers; all cells attached by protein fibres called desmosomes
- cell division occurs only in basal layer - these cells are round
- upon division one cell moves upward while other remains
- as cell migrates upwards and matures, its shape changes to flat, it extrudes lipids into the extracellular space, organelles and nucleus degraded, cytoplasm becomes almost completely filled with dense, crystalline filamentous proteins (keratin and keratohyalin); finally become keratinocytes
stratum corneum
- outermost layer; between cells thick; primarily lipids (20%) and protein (40%) and water (15%)
-cells are organized into a tight fitting interdigitating structure cemented together with extracellular lipids; this structure gives the skin its large resistance to movement through it
- at surface, physiologically inactive, are shedded

10. Transdermal Factors Affecting Transport
rate of transport is dependent on solubility and diffusivity of component through SC

11. Transdermal
Lag Time

12. Transdermal Optimum Ko/w K measures lipo/hydro balance
- usually K given in terms of octanol
- optimum K exists (between 100 and 1000)

13. Transdermal Limitations qualifications 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

14. Transdermals
- recall that drugs need to be of small size, lipophilic, effective at low doses, generally have a narrow therapuetic window, nasty side-effects, required to be taken several times daily
- low melting point is a reflection of tendency of drug to partition into crystalline, ordered structure. - lower Tm means more ready transport through SC
- these are the 7 drugs that are currently marketed as transdermals

15. Buccal and Sublingual
avoids exposure to GIT

16. Nasal frontal sinus external naris sinus nasal cavity (20ml capacity)
large surface area (180 cm2)
hair at entrance act as filters
covered with richly vascularized mucous membrane
mucus constantly being secreted and moved toward pharynx by action of cilia
cilium - approximatetly 5 µm in length and moves at 20 beats/s
microvilli along epithelium provide large surface area
function is to warm and filter air that is entering the lungs
sinus

17. Nasal mucus moderately viscous, glycoprotein
protects nasal mucosa and traps particulate matter
contains many enzymes
pH , 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
foreign bodies such as dust, pollen, bacteria, carried out to pharynx where the mass is swallowed or expectorated
effective ciliary movement depends on the viscosity of the mucus, if too viscous then cilia cannot move it and becomes uncomfortable
some drugs can affect cilia movement as well
% NaCl found to stop ciliary movement - an effect that was difficult to revers
- 0.9% NaCl had no effect
- cocaine - paralyzes cilia

18. Rectal, Vaginal, Urethral
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
useful alternative to oral route (unconscious,pediatric or geriatric)
avoid some first pass metabolism (50%)
preferred for drugs destroyed or upsetting to G.I. tract
when oral route precluded by vomiting
DISADVANTAGES
compliance
erratic and unpredictable absorption
inconvenient

19. Pulmonary 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

20. Pulmonary

21. Summary