dosage form design (3)

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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, whencorrelated 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 orpharmaceutical 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 absorptiona. 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 FormD. 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 Agents3. 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 metabolizedto 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, syrups

elixirs, suspensions,magmas, gels

and powders

sublingual tablets, troches or lozenges

parenteral solutions, suspensions

epicutaneous/transdermal ointments, creams, infusion pumps

pastes, plasters, powders, aerosols

lotions, 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

Dosage

Regimen

dosage form design (3)

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