Chapter 5

Dosage Form Design: Biopharmaceutical and

Pharmacokinetic Considerations

Biopharmaceutic Considerations

Biopharmaceutics is the area of the study embracing the relationship between physical, chemical and biological sciences as they apply to drug and to drug action

ADME

Bioavailability - describe the rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a

drug product and becomes available at the site of the drug action.

Bioequivalence - refers to the comparison of bioavailabilities of different formulations, drug products, or batches of the same drug product.

Bioavailability Data are used to determine:

1. The amount or proportion of drug absorbed from a formulation or dosage form

2. The rate at which the drug was absorbed

3. The duration of the drug’s presence in the biologic fluid or tissue; and, when correlated with patient response

4. The relationship between drug blood levels and clinical efficacy and toxicity

Terms Used To define The Type or Level Of “Equivalency” Between Drug Products

Pharmaceutical Equivalents -are drug products that contain identical amounts of the identical active ingredient.

Example: the same salt or ester of the same therapeutic moiety

Pharmaceutical Alternatives - are drug products that contain the identical therapeutic moiety, or its precursor, but not necessarily in the same amount or dosage form or as the same salt or ester.

Bioequivalent Drug Products - are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption

do not show a significant difference when administered at the same molar dose of the therapeutic moiety under similar experimental conditions, either single dose or multiple dose.

Therapeutic Equivalent - has been used to indicate pharmaceutical equivalent which, when administered to the same individuals in the same dosage regimens, will provide essentially the same therapeutic effect.

The most common experimental plan to compare the bioavailability of two drug products is the

simple crossover design study.

(12 to 14 individuals, males between 18 to 40 years, same height and weight)

How A Drug Passes Through The Body

1. Absorption = The site at which a drug enters the body affects its rates of absorption

a. Skin c. Digestive Tract

b. Lungs d. Bloodstream

2. Distribution = Most drugs enter the bloodstream; many are then distributed to

cells of various organs

a. Bone e. Glands

b. Nerves f. Heart

c. Muscles g. Cells

d. Brain h. Other organs

3. Metabolism = A drug is partially broken down, usually in the liver, before or after distribution

a. Liver

4. Elimination = Finally, a drug is eliminated, mainly via kidneys, but also in stools

and tears or through breathing

a. Breast milk c. Tears

b. Saliva d. Sweat

APPROVAL REQUIREMENTS FOR GENERIC DRUG PRODUCTS

1. Contain the same active ingredients as the pioneer drug (inert ingredient may vary)

2. Be identical in strength, dosage form, and route of administration

3. Have the same indications and precautions for use and other labeling instructions

4. Be bioequivalent

5. Meet the same batch to batch requirements for identity, strength, purity, and quality

6. Be manufactured under the same strict standards of FDA’s CGMP regulations as required for pioneer products.

Some Factors Which Can influence The Bioavailability Of Orally Administered Drugs

I. Drug Substance Physiochemical Properties

II. Pharmaceutical Ingredients and Dosage Form Characteristics

III. Physiologic Factors and Patient Characteristics

Some Factors Which Can influence The Bioavailability Of Orally Administered Drugs

I. Drug Substance Physiochemical Properties

A. Particle Size

B. Crystalline or Amorphous Form

C. Salt Form

D. Hydration

E. Lipid/Water Solubility

F. pH and pKa

Some Factors Which Can influence The Bioavailability Of Orally Administered Drugs

II. Pharmaceutic Ingredients and Dosage Form Characteristics

A. Pharmaceutical Ingredients

1. Fillers 7. Surface Active Agents

2. Binders 8. Flavoring Agents

3. Coatings 9. Coloring Agents

4. Disintegrating Agents 10. Preservative Agents

5. Lubricants 11. Stabilizing Agents

6. Suspending Agents

Some Factors Which Can influence The Bioavailability Of Orally Administered Drugs

B. Disintegration Rate (Tablets)

C. Dissolution Time of Drug in Dosage Form

D. Product Age and storage Conditions

III. Physiologic Factors and Patient Characteristics

A. Gastric Emptying Time

B. Intestinal Transit Time

C. Gastrointestinal Abnormality or Pathologic Condition

D. Gastric Contents

1. Food

2. Other Drugs

3. Fluid

E. Gastrointestinal pH

F. Drug Metabolism (gut and during first passage through liver)

Examples Of Drugs That Undergo Significant Liver Metabolism and Exhibit Low Bioavailability when Administered by First-pass Routes

Drug Class Examples

Analgesics Aspirin, meperidine, Pentazocine

Propoxyphene

Antianginal Nitroglycerin

Antiarrhythmics Lidocaine

Beta-adrenergic Labetolol, Metoprolol, Propranolol

blockers

Calcium channel Verapamil

blockers

Sympathomimetic Isoproterenol

amines

Tricyclic Desipramine, Imipramine,

antidepressants Nortriptyline

Several Examples of Biotransformations occurring within the body are as follows:

1. Acetaminophen Conjugation Acetaminophen glucuronide(active) (inactive)

2. Amoxapine Oxidation 8-hydroxy-amoxaphine

(active) (inactive)

3. Procainamide Hydrolysis p-Aminobenzoic acid

(active) (inactive)

4. Nitroglycerin reduction 1-2 and 1-3 dinitroglycerol

(active) (inactive)

Some compound under full, partial no biotransformation

1. Lisinopril (zestril) - does not go metabolism, excreted unchanged

2. Verapamil (Calan) - 12 metanolites, the most prevalent is norverapamil

3. Diltiazem (Cardizem) - partially metabolized to desacetyldiltiazem

4. Indomethacin (Indocin) - metabolized in part to desmethyl, desbenzoyl, and

desmethylbenzoyl

5. Propoxypehene napsylate (Darvon N) - metabolized to norpropoxyphene

Routes Of Drug Administration

TERM SITE

oral mouth

peroral (per os, p.o.) gastrointestinal tract via mouth

sublingual under the tongue

parenteral other than GIT (by injection)

intravenous vein

intraarterial artery

intracardiac heart

intraspinal/intrathecal spine

intraosseous bone

intraarticular joint

intrasynovial joint-fluid area

intracutaneous/intradermal skin

subcutaneous beneath the skin

intramuscular muscle

Routes Of Drug Administration

TERM SITE

epicutaneous (topical) skin surface

transdermal skin surface

conjunctival conjunctiva

intraocular eye

intranasal nose

aural ear

intrarespiratory lung

rectal rectum

vaginal vagina

urethral urethra

DOSAGE FORM/DRUG DELIVERY SYSTEM APPLICATION

Route Of Administration Primary Dosage Forms

oral tablets, capsules, solutions, syrupselixirs, suspensions,magmas, gels

and powders

sublingual tablets, troches or lozenges

parenteral solutions, suspensions

epicutaneous/transdermal ointments, creams, infusion pumpspastes, plasters, powders, aerosolslotions, transdermal patches, discs

conjunctival contact lens inserts, ointments

intraocular/intraaural solutions, suspensions

intranasal solutions, sprays, inhalants, oint.

Intrarespiratory aerosols

DOSAGE FORM/DRUG DELIVERY SYSTEM APPLICATION

Route Of Administration Primary Dosage Forms

rectal solutions, ointments, suppositories

vaginal solutions, ointments, emulsion foams, tablets, inserts, suppositories, sponge

urethral solutions, suppositories

Factors That Determine A Dosage Regimen

Activity, Toxicity Pharmacoknetics

Minimum therapeutic dose Absorption

Toxic Dose Distribution

Therapeutic index Metabolism

Side effects Excretion

Dose-response relationship

Clinical Factors Other Factors

Clinical State of patient Management of Therapy

Age, weight, urine pH Multiple drug therapy Tolerance-dependence

Condition being treated Convenience of regimen Pharmacogenetics- idiosyncrasy

Existence of other disease states Compliance of patient Drug interactions

DosageRegimen