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

Excipients B. AmsdenCHEE 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. AmsdenCHEE 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 plasma bound  free site of action excretion metabolism intravenous oral B. AmsdenCHEE 440

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

Oral B. AmsdenCHEE 440

Oral Absorption B. AmsdenCHEE 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. AmsdenCHEE 440

Drug Absorption oral administration plasma concentration time profile plasma conc’n time after administration absorption phase elimination phase B. AmsdenCHEE 440

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

Buccal and Sublingual Avoids exposure to GIT. B. AmsdenCHEE 440

Parenteral i.v. plasma conc’n time after administration B. AmsdenCHEE 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. AmsdenCHEE 440

Transdermal rate limiting step is diffusion through stratum corneum B. AmsdenCHEE 440

Transdermal Factors affecting absorption B. AmsdenCHEE 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. AmsdenCHEE 440

Transdermally Delivered Drugs B. AmsdenCHEE 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. AmsdenCHEE 440

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

Conventional Dosage Forms B. AmsdenCHEE 440