Dosage - Chapter 2 and Chapter 5

Name:

•

Preformulation studies (physical and chemical properties of the agent)

•

Formulation studies follows develop initial feature of proposed pharmaceutical product or dosage form

Pharmaceutical Dosage Chapter 2: New Drug Development and Approval Process Chapter 5: Dosage Form Design: Pharmacokinetic Considerations

Biopharmaceutical

and

Acronyms Clinical Drug Materials (CTM) • Dosage formulations used for clinical evaluation of a new drug Investigational New Drug (IND) • Protects the right and safety of the subjects • Ensures investigational plan is sound and designed to achieve the stated objectives New Drug Application (NDA) • Gains permission to market the drug product Supplemental New Drug Application (SNDA) • Application by the sponsor of approved NDA to make changes Abbreviated New Drug Application (ANDA) • Non-clinical laboratory studies and clinical investigations may be omitted except those pertaining to the drug’s bioavailability Biologics License Application (BLA) • Manufacture of biologicals (blood products, vaccines, and toxins) International Conference on Harmonization (ICH) • Brings together regulatory requirements • Establishes (long range goal) a uniform set of standards for drug registration within a geographic areas

Drug Substance

•

Active ingredients or components that produce the pharmacologic activity

•

Produced by:

 Chemical synthesis  Recovery from a natural product  Recombinant DNA technology  Fermentation  Enzymatic reaction  Combination of these processes •

New Chemical Entity (NCE)

•

•

Pharmaceutical industry’s discovery of new drugs development into commercial products

•

Scientific and biomedical information generated worldwide (research institutes, academic centers and industry)

•

and

Drug substance with unknown clinical, toxicologic, physical and chemical properties

Drug Product

Factors That Triggered Rapid Drug Development and Production in the United States

•

Purification needed before use in a drug product

Finished dosage form (containing the drug substances and other excipients or inert substances)

Sources of New Drug •

Variety of natural resources

 Serendipity or result of tireless pursuit

Combined efforts in drug discovery and development (chemists, biologists, molecular biologists, pharmacologists, etc.)

 Plant materials have served as reservoirs of

•

Rapid growth of pharmaceutical industry during WWII

 Conversion of botanic folklore remedies into

•

Development of other antibiotics

•

Postwar drug with the development of many new agents

Federal Food and Drug Cosmetic Act

•

New drug be approved by the Food and Drug Administration (FDA) before legally introduced in interstate commerce

potential new drug

modern wonder drugs •

Synthesis in the laboratory

Variety of Natural Resources •

Reserpine (tranquilizer and hypotensive agent)

 Medicinal chemical isolated by design from the folklore remedy Rauwolfia serpentina

1

•

Periwinkle or Vinca Rosea: for diabetes mellitus

•

Paclitaxel (taxol): for ovarian cancer

•

Development of pharmaceutical products (result of genetic engineering) 

 From an extract of the pacific yew tree •

Other plant constituents therapeutically)

(inactive

or

Submicroscopic manipulation of the double helix, the spiral DNA chain of life

 Two basic technologies that drive the

unimportant

genetic field of drug development:

 Chemically modified to yield important drug with profound pharmacologic activity



Recombinant DNA (rDNA)



Monoclonal antibody products (MoAB) production

 Example: species of Dioscorea (Mexican yams)  Rich in the chemical steroids structure: cortisone and estrogens

 Semi synthetically produced •

Animals have served human in their search for new drugs: 

Similarities of Recombinant DNA and Monoclonal Antibody

•

Manipulate and produce proteins (building blocks of living matter)

•

Production techniques influence cells in their ability to produce proteins

Cattle, sheep and swine from the endocrine gland

 Hormonal substances: thyroid extract, insulin, and pituitary hormone (replacement therapy in the human body) 

Differences of Recombinant DNA and Monoclonal Antibody •

Pregnant mares (from urine)

 More fundamental

 Rich source of estrogen 

 Produce any protein

Production of various biological products 

Recombinant

Serums, antitoxins, (lifesaving)

and

 Gene splicing: genetic material transplanted from higher species (humans) which induce the lower organism (bacterium) to make proteins

vaccines

 Human insulin

 Smallpox vaccine: pioneering work of Edward Jenner in England in 1796

o o

Fluids of chicks’ embryo: mumps and influenza vaccines

o

Duck embryo: measles) vaccine

o •

rubella

(German

Skin of bovine calves inoculated with vaccinia virus: smallpox vaccines

Synthesis in the laboratory or molecular manipulation

 Change natural chemical to different chemical structure

 Hepatitis B vaccine

Cultures of renal monkey: poliomyelitis vaccines

 Human growth  Interferon •

MoAB

 Conducted within cells of higher animals (including patient)

 Exploits cell to produce an antibody to combat the specific agent

 Used in home pregnancy testing products  In medicine: to stage and localize malignant cells of cancer

Sources of New Drugs

 Future: combat disease (lupus erythematosus, juvenile onset diabetes and myasthenia gravis)

2

 Absorption Sources of New Drug

•

 Prolonged release

Human gene therapy (promising new technology)

 Prevent, treat, cure, diagnose, or mitigate human disease, caused by genetic disorder

New Drug •

According to FDA:

 First human gene therapy

 Not recognized by experts as safe and effective

 Treat adenosine deaminase (ADA)

 Change in previously approved drug product’s

deficiency (condition resulting in abnormal functioning of the immune system)

formulation or method of manufacture

 New combination of 2 or more old drugs or change in proportions of drugs Goal Drug

•

 Proposed new use, new dosage regimen, new route of administration or new dosage form

Produces:

 Desired effect Orphan Drug

 Administered by the most desired route (orally) at minimal dosage and dosing frequently

•

Treatment IND are sought for to target small numbers of patients with rare conditions or diseases (orphan diseases) where there are no satisfactory alternative treatments.

•

Orphan Disease: rare disease or condition affecting fewer than 200,000 people

 Optimal onset and duration of activity  Exhibit no side effects  Eliminated from the body efficiently, completely, and without residual effect

 Chronic lymphocytes 

Lead Compound

Gaucher’s disease

 Leukemia

•

Prototype chemical compound

 Cystic fibrosis

•

Fundamental desired biologic or pharmacologic activity



Prodrug

•

Metabolic biotransformation of compound after administration to produce desired pharmacologically active compound

•

Inactive prodrug to biochemical cleavage)

•

Example: enalapril (enalapril maleae, vasotec) bioactivated to enalaprilat (ACE inhibitor, for hypertension)

•

active

Used for the following reasons:

 Solubility

compound

(enzymatic

AIDS

Pharmacologic Profile • In vitro cultures of cells and enzyme systems • In vivo animal models are used • Objective: to obtain basic information on the drug’s effect that may be used to predict safe and effective use in humans Molecular Graphics • Use of computer graphics to present and manipulate the structure of the drug molecule to fit the stimulated molecular structure of the receptor site • Complementary tool in drug molecule design Methods of Drug Discovery • Random or non-targeted screening  Testing of large numbers of systematic organic compound or substance of natural origin for biologic activity

 Biostability 3

Detects unknown activity of test compound or identifies compromising compounds to be studied to determine specific activity  Ex. bioassays  Detects and evaluates biologic activity  Differentiates the effect and potency of test agent compared with controls of known action or effect Molecular modification  Chemical alteration of organic compound frequently a lead compound to:  Enhance its usefulness as a drug  Enhancing specificity for a body’s target site  Increasing potency  Improving rate and extent of absorption  Modifying time course in the body  Reducing toxicity  Change of physical or chemical properties to provide desired pharmaceutical features Mechanism-based drug design  Drug design that interferes with the known or suspected biochemical pathway of mechanism of a disease process  Intention: interaction of a drug with:  Specific cell receptors  Enzyme systems  Metabolic processes of the pathogens or tumor cells  Resulting in: blocking, disruption, reversal of the disease process 

•

•

Non Proprietary Names • For single agents Proprietary or Trademark Names • Associated with a single chemical entity or with a mixture of chemicals constituting a specific proprietary product Pharmacology • Embraces:  Physical and chemical properties  Biochemical and physiological effects  Mechanisms of action, absorption, distribution, biotransformation, excretion, therapeutic and other uses of drugs • Concerned with drugs, their sources, appearance, chemistry, action, and uses • Comes from the Latin word “pharmaco” (drugs) and “logos” (study of) Sub Area of Pharmacology • Pharmacodynamics  Study of the biochemical and physiological effect of drugs and their mechanism of action • Pharmacokinetics  Deals with the absorption, distribution, metabolism or biotransformation, and excretion (ADME) of the drug • Clinical pharmacology  Applied pharmacologic principle to the study of the effects and action of drugs in human

Today’s Emphasis in Development of New Drugs • Identifying the cause and process of a disease • Designing drug molecules capable of interfering with that process • Precise cause of each disease: not yet known • Known in most diseases arising from:  Biochemical imbalance abnormal proliferation of cells  Endogenous deficiency  Exogenous chemical toxin or invasive pathogen Quantity of Drug Will Influence its Effectivity • There is a relationship of drug molecules for interaction and the capacity of the specific receptor site. • Following a dose of drug and its transit to the site of action:  Cell’s receptors may or may not become fully saturated with interacting drug  Receptors fully saturated: effects of the specific interaction are maximized  Additional drug present and not participating in the interaction serve as a reservoir to replace drug molecules that become releases from the complex 2 Drugs in a Biologic System • Compete for the same binding sites • Drug with stronger bonding attraction for the site prevails • Bound molecules of the more weakly bound drug • May be replaced from the binding site • Let free in the circulation as unbound drug Biologic Characterization • Drug metabolism: series of animal studies of a proposed drug ADME are undertaken to determine:  Extent and rate of drug absorption from various routes of administration including human use  Rate of distribution of drug through the body and the site or sites and the duration of drug residence  Rate, primary and secondary sites, and the mechanism of the drug metabolism in the body and the chemistry and pharmacology of any metabolism  The proportion of administered dose eliminated from the body and its rate and route of elimination Specific and Non-specific Enzymes • Participate in drug metabolism (liver, kidneys, lungs, and GIT) Drugs Following Oral Administration that Enter the Hepatic Circulation after Absorption from GIT • Exposed to rapid drug metabolism 1st Pass Effect • Transit through the liver and exposure to the hepatic enzyme system • To be avoided: other routes of administration (buccal and rectal) may be used to absorb drug into the systemic circulation through blood vessels other than hepatic ADME Studies

4

•



Performed through the collection and analysis of urine, blood and feces samples, and careful examination of animal tissues and organs upon autopsy

 Poorly soluble compounds: incomplete erratic

Toxicology • Area of pharmacology that deals with the adverse or undesired effects of drugs Different Studies in Toxicological Profile • Acute or short-term toxicity studies  Toxic effect of a test compound when administered in single dose or in multiple dose over short period, usually a single day  Test compound administered at various dose levels, with toxic signs observed  Doses are ranged to find dose not to produce toxic effect, severe toxic effect, and intermediate toxic level • Subacute or subchronic studies  Considered: the relationship to projected human clinical studies for safety  Animal toxicity studies (minimum of 2 weeks of daily drug administration at 3 or more dosage levels to 2 animal species) are required to support the initial administration of a single dose in human clinical testing • Chronic toxicity studies  Drugs intended to be given to humans for a week or more, animal studies of 90 to 180 days in length must demonstrate safety  For chronic human illness, long-term animal studies for 1 year or longer • Carcinogenicity studies  For limited number of rat and mouth strains: there is reasonable information on spontaneous tumor incidence  Long term studies (18 to 24 months) with surviving animals killed and studied at defined weeks during the test period  Component of chronic testing, undertaken when the compound has shown sufficient promise as a drug to enter human clinical trials • Reproduction studies  Reveals any effect of an active ingredient on mammalian reproduction  Evaluated for anatomical abnormalities, growth and development: maternal parent, fetus, neonates, and weaning offspring • Genetoxicity or mutagenecity studies  Determines whether test compound affects gene mutation or cause chromosome or DNA damage  Used in assays to detect mutations: strains of Salmonella typhimurium Different Properties of Drug Substance Included in Pre-formulation Studies Preformulation Studies •

Drug Solubility

Drug substance must possess some aqueous solubility for system absorption and therapeutic response.

and/or slow absorption producing minimum response at desired dosage •

Partition coefficient 

Drug molecules must first cross a biologic membrane of protein and lipid to produce a pharmacologic response, which acts as a lipophilic barrier to many drugs.

 Measure of its distribution in a lipophilic or hydrophilic phase system, and is indicative of its ability to penetrate biologic multiphase system. •

Dissolution rate

 Speed, rate, at which a drug substance dissolves in a medium 

Provide indication of drug’s absorption potential: 

Drug solubility

 Partition coefficient •

Physical form and particle size 

•

Affect drug’s: 

Dissolution rate



Rate & extent of absorption

Stability 

Tests: various temperatures, conditions of relative humidity and environments of light, air and packaging



Critical in preparing a successful pharmaceutical product, alone and when combined with formulation components



Drugs susceptible to: 

Oxidative decomposition: antioxidant stability agent

add



Hydrolysis: processing and packaging required

Initial Product Formulation and Clinical Trial Materials (CTM)

•

Product formulated (per formulation studies as basis) for the clinical studies and for the new drug with consideration of: 

Dose

5

•



Dosage forms



Route of administration

Clinical supplies or clinical trial materials (CTM) 

 Patient observations, measurements and tests, etc. Pre- IND Meetings

•

Includes: 

Proposed new drug



Placebos (non-medicated forms for controlled studies)



Drug products compared to new drug (comparator drugs or drug products)

•



Scientific



Technical



Formatting concerns

Includes: 

Blinded Studies • Controlled studies where 1 of the parties is not knowledgeable of which product is being administered

Advice on the adequacy of data to support an investigational plan

 Design of a

clinical trial or investigation

produces

Open Label • All parties are aware of the products administered. Single Blind Studies • Patient unaware of the:  Agent administered  Placebo  Investigational drug  Comparator drug

FDA advises a sponsor relating to the preparation and submission of IND on:



Data to meet requirements of the next step



Filing NDA to gain approval for marketing

FDA Review of an IND Application •

The FDA’s objective in reviewing IND: 

Protect the safety and right of human subjects



Ensure evaluation of the drug’s safety and effectiveness

Parallel Designs • Applicable to most clinical trials



Objections are best met by the accuracy and completeness of the IND submission

Crossover Designs • For comparing different treatments within individuals since the following one treatment a patient is “crossed over” to a different treatment



Design and conduct of the:

Double Blind Studies • Neither the patient nor the clinician is aware of the agent administered.

The Clinical Protocol



Investigational plan



Expertise



Diligence of the investigators

•

Part of the IND application

•

Submitted to ensure the appropriate design and conduct of investigation

•

Upon receipt and examination of IND or NDA application

•

Includes:

•

FDA classifies the drug by:

FDA Drug Classification System



Purpose and objectives



Chemical type



Number of patients



Therapeutic potential



Dosing plan



Investigational plan



Subject selection

 Clinical procedures, laboratory tests

Phases of Product Development of Drug Products Containing NCEs •

Preclinical stage

 Animal pharmacology & toxicology data are obtained. 

Determines the safety & efficacy of the drug

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 •

Phase I

 An NDA is submitted to the FDA for review & approval when clinical trials are completed. •

Phase IV

 Initial introduction (clinical testing)



Continual clinical investigation

 Subjects: healthy volunteers (20- 100)



Manufacturing scale-up activities



Drug formulation modified slightly



To gather supplemental information (labeling, product advantages, additional indications, prospective post marketing studies)

 •

Submission of investigational new drug (IND) application for human testing to the FDA

Determines drug tolerance & toxicity (assessing safety)

Phase II

 Controlled clinical studies to several hundred patients with the disease or condition are treated

•

 Safety measured: determines the therapeutic

Phase V 

Product development continues after the FDA’s market approval of drug product



Drug product may be improved due to equipment, regulatory, supply or market demands

index (ratio of toxic dose to effective dose) 

•

Final drug formulation developed bioequivalent (same rate & extent of drug absorption to the brand drug product) to the dosage form

Phase III

Post Marketing Reporting of Adverse Drug Experiences

•

 Several hundred to several thousand patients with disease or condition treated for which the drug was developed (controlled & uncontrolled trails)

 Large scale, multicenter studies performed: to determine safety and efficacy

 Side effects are monitored. 



Drug Dosage and Terminology

•

Phase 3A 

Completed studies sufficient for the NDA

Additional studies are used to gather: 

Dosage regimen or schedule of dosage

•

Determined from:

Supplemental information to support certain labeling requests



Information on patients’ quality of life issues



Product advantages over already marketed competing drugs



Evidence in support of possible additional drug indications



Other clues for prospective post marketing studies

Submission of a new drug application (NDA)

Amount of drug that produces the desired effect in the majority of adult patient

•

•

Phases of Clinical Investigation •

Usual adult dose and starting dose for the patient 

Phase 3B 

A drug sponsor is required to report to the FDA each adverse drug experience that is both serious (life threatening or fatal) and unexpected (not contained in the approved drug product labeling) regardless of the source of the information within 15 working days of receipt information.

•



Clinical investigation



Inherent duration of action



Pharmacokinetics



Characteristics of the dosage form

Units of activity 

Derived from biological assay methods



Reflects drug’s potency



Necessary when drug’s (antibiotics & endocrine products) suitable chemical assay methods are unavailable

Minimum Effective Concentration (MEC)

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•



Drug’s average blood serum concentration



Determines minimum concentration expected to produce the drug’s desired effects in a patient

•



Second level of serum concentration of drug



Above the average blood serum level producing toxic effects Negates desirable effects of compromising safety of the patient

affecting pharmacokinetics of a number of drugs and alter drug’s usual dose Time and Conditions of Administration

Minimum Toxic Concentration (MTC)



•

 Include “social” agents (tobacco & alcohol)

the

 •

ED 50 or Median Effective Dose



•

•

IV or parenteral (injectable)

 Drugs enter blood stream directly and completely

Median Toxic Dose (MTD)

 Required to achieve the same blood levels or

Produces a defined toxic effect in 50% of the individuals tested

clinical effects •

Therapeutic index

Oral

 Rarely or if fully absorbed into the bloodstream

 Relationship between drug’s desired and

due to various physical, chemical and biologic barriers to their absorption

undesired effects 

Ratio of drug’s median toxic dose & median effective dose, TD50/EF50

Routes of Administration •

Terms •

•

Regularly schedule subsequent administration



Initial priming or loading dose required to attain desired concentration of the drug in the blood of tissues

 Direct application of the drug to desired site of action (eye, nose, ears) 

Systemic effects

 Entrance of drug into circulatory system and transport to cellular site of its action

 Direct placement into the blood stream via

Protects the patient from contracting illness

IV injection or absorbed into the venous circulation following oral or other routes of administration

Therapeutic dose 

•

Local effects

Prophylactic dose 

•

Fundamental considerations in dosage form design: 

Maintenance dosage 

Stomach & upper portions of intestinal tract are empty of food

Dosage Form and Route of Administration

the individuals tested



Influence dosage

Absorption more rapid

drug

 Produces the desired intensity of effect in 50% of •

Time drug is administered.

Administered to the patient after exposure or contraction of the illness

Drug-drug interaction

Routes of Drug Administration I.

Oral Route •

Most taken for systemic effects after absorption from various surfaces along GIT

 Chemical or physical interaction between the

•

drugs or alteration of the absorption, distribution, metabolism or excretion patterns of one of the drugs

Most natural, uncomplicated, convenient and safe means of administering drugs

•

Disadvantages:

 Effect of drug modified by prior or concurrent administration of another drug



Slow drug response

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•

 Chance of irregular absorption of drugs (constitutional make-up, amount or type of food present within GIT)

2. Intramuscular injection

 Destruction of certain acid reaction of stomach or GIT enzymes II.

Rectal Route

•

Suppositories, solutions, or ointments

•

For systemic action preferred for drugs:

 Destroyed or inactivated by the stomach and intestine environments 

III.

Bypass the liver

•

Disadvantages: inconvenient; irregular & difficult to predict

absorption

•

Injected into the skeletal muscles-gluteal or lumbar muscles

•

Aqueous, oleaginous solution or suspension

•

Drugs injected: those irritating to subcutaneous tissue

•

2 to 5mL

3. Intravenous injection

Patient is unconscious or incapable of swallowing

•

•

Aqueous solution injected directly into the veins of the forearm

•

Advantages:

is

Parenteral Route •

Injected into the body using a fine needle at various sites and depths

•

Routes: subcutaneous, IM, IV, intracardiac and intraspinal

•

Preferred for drugs:

 Destroyed or inactivated in GIT

•

•



Poorly absorbed to provide satisfactory response



Rapid absorption is essential

Advantage: 

Example: insulin

Treating patients who are uncooperative, unconscious, unable to accept oral medication

Disadvantage:

 Once drug is injected, there is no retreat.

1. Subcutaneous (hypodermic) injection •

Injected through layers of skin into the loose subcutaneous tissue

•

Aqueous solution or suspension (2mL or less)



Rate commensurate with efficiency, safety, comfort to the patient



Desired duration of drug response



Useful in emergency situations where immediate drug response is desired

•

Administered: single, small-volume injection or as large volume, slow IV drip fusion

•

IV fat emulsion-caloric parenteral nutrition)

source

(receiving

4. Intradermal injection • Administered into the corium of the skin (arm • • • 5.

and back) 10th of a mL in volume Use: diagnostic measures Example: tuberculin and allergy testing

Epicutaneous route • Applied topically to the skin (for action at site of application or systemic drug effects)  Transdermal delivery systems (adhesive disc/patch)  Slowly releases medication for percutaneous absorption  Examples: nitroglycerin (antianginal), nicotine (smoking cessation), estradiol (estrogenic hormone), clonidine (antihypertensive), scopolamine (antinausea)  For local action:  Prolonged local contact with minimal absorption  Antiseptics, antifungal agents, anti-inflammatory agents, local anesthetic

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

•

agents, skin emollients and protectants Creams, ointments, powders, aerosol sprays, lotions, solutions

• • •

• • • • •

6. Ocular, oral and nasal routes • For eye, ear and mucous membranes of the nose

7.

(not for systemic effect)  Ophthalmic preparations:  Solutions, suspensions and ointments  Nasal preparations:  Solutions or suspensions by drops as fine mist from a nasal spray container  Otic or ear preparations  Viscid to soften ear wax, relieve earache or combat an ear infection Other routes • Lungs  Administered of gases and aerosol sprays  Should attain proper drug particle size and ensure uniformity for consistent penetration • Drugs inserted into the: a) Vagina  Tablet, suppositories, ointments, emulsion, foams, gels, solutions b) Urethra  Suppositories or solutions

Treatment IND or Treatment Protocol • Use of an investigational drug in the life-treating disease in lieu of no satisfactory alternative therapy • Makes promising new drug available to desperately ill patient, early as possible in the drug development process Withdrawal or Termination of an IND • By the sponsor any time ending all clinical investigation

• • •

Stock of clinical supplies returned to the sponsor or otherwise destroyed If withdrawn because of safety reasons, must advice: FDA, IRB, and all investigators FDA may terminate an IND for safety, efficiency, or regulatory compliance issue.

The New Drug Application (NDA) • Filed by the sponsor with the FDA if:  Three phases of clinical testing demonstrates sufficient drug safety and therapeutic effectiveness • Preceded by pre-NDA meeting between the sponsor and FDA to discuss:  The consent and format of the new-drug application Drug Product Labeling • Description of the product • Clinical pharmacology

Indication and usage Contraindications Warning Precaution Adverse reaction Drug abuse and dependence Over dosage Dosage and administration How supplied

Drug Product Labeling • According to federal regulation, includes:  Label placed on an immediate container

 Information on the packaging, in package insert and in •

company literature, advertising, and promotion materials The package insert required to contain the summary information

Completed New Drug Application • Reviewed by the FDA, decides:

 To allow the sponsor to market the drug  To disallow marketing  To require additional data before rendering a judgment •

FDA respond within 180 days (review clock) of receipt of an application

FDA Review and “Action Letters” • Approvable letter  Specific additional data or other requested material is submitted or specific conditions are met  Pertains to development or wording of the final product labeling • Approval letter  Approval of the application permitting marketing • New approval letter  One or more deficiencies ICH

• •

Harmonizing or bringing together regulatory requirements with long-range goal of drug registration within these geographic areas Focused on 3 general areas:

 Quality topics  Stability, light stability, analytical validation, 

impurities and biotechnology Safety topics

 

Carcinogenicity, genotoxicity, toxicokinetics, reproduction toxicity and single and repeat dose toxicity Efficacy topics



Population exposure, managing clinical trials, clinical study reports, dose response, ethnic factors, good clinical practices and geriatrics

Routes of Drug Administration

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Term

Site

Subcutaneous

Beneath the skin

Oral

Mouth

Intramuscular

Muscle

Peroral (per os)

GIT via mouth

Epicutaneous (topical)

Skin surface

Sublingual

Under the tongue

Transdermal

Skin surface

Parenteral

Other than the GIT (by injection)

Conjunctival

Conjunctive

Intravenous

Vein

Intraocular

Eye

Intraarterial

Artery

Intranasal

Nose

Intracardiac

Heart

Aural

Ear

Intraspinal or intrathecal

Spine

Intrarespiratory

Lung

Intraosseous

Bone

Rectal

Rectum

Intraarticular

Joint

Vaginal

Vagina

Intrasynovial

Joint fluid area

Intracutaneous, intradermal

Skin

Oral • Tablets • Capsules • Solutions • Syrups • Elixir • Suspensions • Magmas • Gels • Powders Sublingual • Tablets • Troches, lozenges • Drops (solutions) Parenteral • Solutions • Suspensions Epicutaneous, transdermal • Ointments • Creams • Infusion pumps • Pasters • Plasters • Powders • Aerosols • Lotions • Transdermal patches, discs, solutions Conjunctival

Route of Administration and Delivery System of Primary Dosage Forms • Contact lens inserts • Ointments Intraocular, intra-aural • Solutions • Suspensions Intranasal • Solutions • Sprays • Inhalants • Ointments Intrarespiratory • Rectal

Aerosols

• Solutions • Ointments • Suppositories Vaginal • • • • • • Urethral • •

Solutions Ointments Emulsion foams Gels Tablets Inserts, suppositories, sponge Solutions Suppositories

Drug Class

Examples

Some Drugs that Undergo Significant Liver Metabolism and Exhibit Low Bioavailability when Administered by First-pass Routes

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Analgesic meperidine, pentazocine, propoxyphene

Aspirin,

Antianginal

Nitroglycerin

Antiarrhythmic

Lidocaine

Beta-adrenergic blocker propanolol

Labetolol,

Calcium channel blocker

Verapamil

Sympathomimetic amine

Isoproterenol

Tricyclic antidepressant nortriptyline

Desipramine,

metoprolol,

imipramine,

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