Drug Discovery
natural sources, synthesis/modification biological properties
- pharmacology, pharmacokinetics Preclinical Studies preformulation
- chem/phys properties
- analytical assays Formulation
 development of dosage form
 large-scale manufacturing
Clinical Trials Approval for Distribution
B. Amsden
Post-Marketing Surveillance
CHEE 440

drug Any substance or mixture of substances manufactured, sold or represented for use in: a) the diagnosis, treatment, mitigation or prevention of a disease, a disorder, an abnormal physical state or the symptoms thereof in humans or animals b) restoring, correcting or modifying organic functions in humans or animals c) “ disinfection ” in premises in which food is manufactured, prepared or kept pharmaceutics the area of study concerned with the formulation, manufacture, stability, and effectiveness of dosage forms pharmacology the science of the properties of drugs and their effects on the body pharmacokinetics the study of the kinetics of absorption, distribution, metabolism, and excretion of drugs and their corresponding pharmacologic response in animals/man clinic a facility or area where ambulatory patients are seen for special study and treatment
B. Amsden CHEE 440

Drugs seldom administered alone
• contain additional ingredients called excipients
Need for dosage forms:
• provide safe and accurate delivery
• protect drug from environmental and in vivo degradation
• provide rate-controlled action
• conceal bitter/salty taste, offensive odor
• allow for administration by the desired route
Objective of dosage form design
• achieve a predictable therapeutic response to a drug included in a formulation which is capable of large scale manufacture with reproducible product quality
B. Amsden CHEE 440

B. Amsden
pH control preservative antioxidant solvent surfactant ointment base flavor
citric acid, NaCO
3
NaBenzoate, phenol ascorbic acid,
NaBisulfite alcohol, sterilized water cetyl alcohol petrolatum, PEG peppermint oil, menthol
CHEE 440

Considering only systemic delivery, wherein the objective is to get the drug into the blood stream. There are essentially two classes of delivery approaches:
 enteral
• oral (peroral), rectal, buccal and sublingual
 parenteral
• injection (s.c., i.v., i.m.)
• transdermal
• nasal
• pulmonary
B. Amsden CHEE 440

 extent of absorption and the rate at which an administered dose reaches systemic circulation in its active form intravenous drug in dosage form oral liver tissue, lymph blood plasma bound  free site of action excretion metabolism
B. Amsden CHEE 440

Affected by:
1. Physiological factors
 route of administration
 drug distribution
2. Drug chemical physical properties
 dissolution rate (solids)
 hydrophilicity/hydrophobicity
B. Amsden CHEE 440

B. Amsden CHEE 440

B. Amsden CHEE 440

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
B. Amsden CHEE 440

oral administration plasma concentration time profile absorption phase elimination phase plasma conc ’ n time after administration
CHEE 440 B. Amsden

 therapeutic response is dependent on drug achieving an adequate plasma concentration (C p
)
C p time after administration
CHEE 440 B. Amsden

advantages
 patient compliance
 cheap compared to other routes
 transit time is consistent among individuals disadvantages
 hepatic first-pass effect
 possible enzymatic degradation/acid degradation
 effect too slow for emergencies
 presence of food retards absorption
 short window of time for absorption
B. Amsden CHEE 440

Rectal route:
 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
B. Amsden CHEE 440

Avoids exposure to GIT.
B. Amsden CHEE 440

i.v.
B. Amsden plasma conc ’ n
CHEE 440 time after administration

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
B. Amsden CHEE 440

rate limiting step is diffusion through stratum corneum
B. Amsden CHEE 440

Factors affecting absorption
B. Amsden CHEE 440

Limitations
 drug must be potent
 drug must be effective when delivered slowly over a long period of time
 benefits over existing methods?
Drug qualifications
 narrow therapeutic window
 subject to extensive first-pass degradation
 taken many times/day
 unpleasant side-effects
B. Amsden CHEE 440

drug scopolamine
M W
(g/mol) pKa m.p.
(˚C) log
(K o/w
)
303 7.8
59 1.24
efficacious blood level
(ng/mL)
0.04
clonidine nitroglycerin
230
227
8.2
140
13.5
0.83
2.05
0.2-2.0
1.2-11.0
estradiol fentanyl nicotine testosterone progesterone
272
288
314
176 2.49
0.04-0.06
337 8.4
83 2.93
162 6.16 < -80
153
131
3.31
3.57
1
10-30
10-100
1-3
CHEE 440 B. Amsden

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 external naris
B. Amsden CHEE 440

- large contact surface (surface area > 30 m 2 )
- extensive blood supply (2000 km of capillaries)
- thin membrane separating air from blood
B. Amsden CHEE 440

B. Amsden CHEE 440