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

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Excipients

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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

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Absorption

Affected by:

1. Physiological factors route of administration drug distribution

2. Drug chemical physical properties dissolution rate (solids) hydrophilicity/hydrophobicity

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Oral

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Oral Absorption

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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

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Drug Absorptionoral administration plasma concentration time profile

plasmaconc’n

time after administration

absorptionphase elimination phase

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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

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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

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Buccal and Sublingual

Avoids exposure to GIT.

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Parenteral

i.v.

plasmaconc’n

time after administration

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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

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Transdermal

rate limiting step is diffusion through stratum corneum

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Transdermal

Factors affecting absorption

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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

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Transdermally Delivered Drugs

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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

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Pulmonary

- large contact surface (surface area > 30 m2 )- extensive blood supply (2000 km of capillaries)- thin membrane separating air from blood

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Conventional Dosage Forms

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