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 drugs 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
amounts of the identical active ingredient. Example: the ester of the same therapeutic moiety identical same salt or

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 same height and weight) years,

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 b. Lungs c. Digestive Tract d. Bloodstream

2. Distribution = Most drugs enter the bloodstream; many are then distributed to cells of various organs a. Bone b. Nerves c. Muscles d. Brain e. Glands f. Heart g. Cells 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 b. Saliva c. Tears 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 FDAs 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 2. Binders 3. 4. 5. 6. Coatings Disintegrating Agents Lubricants Suspending Agents 7. Surface Active Agents 8. Flavoring Agents 9. Coloring Agents 10. Preservative Agents 11. Stabilizing 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 Analgesics

Examples Aspirin, meperidine, Pentazocine

Propoxyphene
Antianginal Antiarrhythmics Beta-adrenergic Nitroglycerin Lidocaine Labetolol, Metoprolol, Propranolol

blockers
Calcium channel blockers Sympathomimetic Isoproterenol Verapamil

amines
Tricyclic antidepressants Desipramine, Imipramine, Nortriptyline

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

1. Acetaminophen Conjugation 2. Amoxapine Acetaminophen glucuronide (inactive) 8-hydroxy-amoxaphine (active)

Oxidation

(active)
3. Procainamide (active) 4. Nitroglycerin Hydrolysis

(inactive)
p-Aminobenzoic acid (inactive) 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 oral peroral (per os, p.o.) mouth gastrointestinal tract via mouth SITE

sublingual
parenteral intravenous intraarterial

under the tongue

other than GIT (by injection) vein artery

intracardiac
intraspinal/intrathecal intraosseous intraarticular

heart
spine bone joint

intrasynovial
intracutaneous/intradermal subcutaneous intramuscular

joint-fluid area
skin beneath the skin muscle

Routes Of Drug Administration

TERM

SITE

epicutaneous (topical) transdermal conjunctival intraocular intranasal aural intrarespiratory rectal vaginal urethral

skin surface skin surface conjunctiva eye nose ear lung rectum vagina urethra

DOSAGE FORM/DRUG DELIVERY SYSTEM APPLICATION

Route Of Administration

Primary Dosage Forms

oral

tablets, capsules, solutions, syrups elixirs, suspensions,magmas, gels and powders

tablets, troches or lozenges solutions, suspensions

sublingual parenteral

epicutaneous/transdermal

ointments, creams, infusion pumps pastes, plasters, powders, aerosols lotions, transdermal patches, discs
contact lens inserts, ointments solutions, suspensions solutions, sprays, inhalants, oint. aerosols

conjunctival intraocular/intraaural intranasal Intrarespiratory

DOSAGE FORM/DRUG DELIVERY SYSTEM APPLICATION

Route Of Administration

Primary Dosage Forms

rectal
vaginal urethral

solutions, ointments, suppositories

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

Factors That Determine A Dosage Regimen

Activity, Toxicity
Minimum therapeutic dose Toxic Dose Therapeutic index

Pharmacoknetics
Absorption Distribution Metabolism
Dosage Regimen

Side effects
Dose-response relationship

Excretion

Clinical Factors Clinical State of patient

Condition being treated

Other Factors

Management of Therapy
Convenience of regimen Pharmacogeneticsidiosyncrasy

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

Existence of other disease states Compliance of patient

Drug interactions