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PHARMACEUTICAL INDUSTRY
Drug Discovery- natural sources, synthesis/modification
Preclinical Studiesbiological properties- pharmacology, pharmacokinetics
preformulation- chem/phys properties- analytical assaysFormulation
development of dosage form large-scale manufacturing
Clinical Trials Approval for Distribution
Post-Marketing Surveillance
B. Amsden CHEE 440
Definitions
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 animalsb) restoring, correcting or modifying organic functions in humans or animalsc) “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
Introduction
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
Excipients
B. Amsden CHEE 440
Routes of Administration
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
Bioavailability
extent of absorption and the rate at which an administered dose reaches systemic circulation in its active form
drug in dosage form liver
tissue, lymph
blood plasmabound free
site of action
excretion
metabolism
intravenous
oral
B. Amsden CHEE 440
Absorption
Affected by:
1. Physiological factors route of administration drug distribution
2. Drug chemical physical properties dissolution rate (solids) hydrophilicity/hydrophobicity
B. Amsden CHEE 440
Oral
B. Amsden CHEE 440
Oral Absorption
B. Amsden CHEE 440
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
B. Amsden CHEE 440
Drug Absorptionoral administration plasma concentration time profile
plasmaconc’n
time after administration
absorptionphase elimination phase
B. Amsden CHEE 440
B. Amsden CHEE 440
therapeutic response is dependent on drug achieving an
adequate plasma concentration (Cp)
Cp
time after administration
Therapeutic WindowTherapeutic Window
Oral
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
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
Buccal and Sublingual
Avoids exposure to GIT.
B. Amsden CHEE 440
Parenteral
i.v.
plasmaconc’n
time after administration
B. Amsden CHEE 440
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
B. Amsden CHEE 440
Transdermal
rate limiting step is diffusion through stratum corneum
B. Amsden CHEE 440
Transdermal
Factors affecting absorption
B. Amsden CHEE 440
Transdermal
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
Transdermally Delivered Drugs
B. Amsden CHEE 440
Nasal
external naris
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
B. Amsden CHEE 440
Pulmonary
- large contact surface (surface area > 30 m2 )- extensive blood supply (2000 km of capillaries)- thin membrane separating air from blood
B. Amsden CHEE 440
Conventional Dosage Forms
B. Amsden CHEE 440