Name: Pharmaceutical Dosage
Chapter 2: New Drug Development and Approval Process
Chapter 5: Dosage Form Design: Biopharmaceutical and Pharmacokinetic Considerations
Acronyms
Clinical Drug Materials (CTM)
•
Dosage formulations used for clinical evaluation of a new drugInvestigational New Drug (IND)
•
Protects the right and safety of the subjects•
Ensures investigational plan is sound and designed to achieve the stated objectivesNew Drug Application (NDA)
•
Gains permission to market the drug product Supplemental New Drug Application (SNDA)•
Application by the sponsor of approved NDA to make changesAbbreviated New Drug Application (ANDA)
•
Non-clinical laboratory studies and clinical investigations may be omitted except those pertaining to the drug’s bioavailabilityBiologics 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 areasFactors That Triggered Rapid Drug Development and Production in the United States
•
Pharmaceutical industry’s discovery of new drugs and development into commercial products•
Scientific and biomedical information generated worldwide (research institutes, academic centers and industry)•
Combined efforts in drug discovery and development (chemists, biologists, molecular biologists, pharmacologists, etc.)•
Rapid growth of pharmaceutical industry during WWII•
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•
Preformulation studies (physical and chemical properties of the agent)•
Formulation studies follows develop initial feature of proposed pharmaceutical product or dosage formDrug 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•
Purification needed before use in a drug product New Chemical Entity (NCE)•
Drug substance with unknown clinical, toxicologic, physical and chemical propertiesDrug 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
Plant materials have served as reservoirs of potential new drug
Conversion of botanic folklore remedies into 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•
Periwinkle or Vinca Rosea: for diabetes mellitus•
Paclitaxel (taxol): for ovarian cancer
From an extract of the pacific yew tree•
Other plant constituents (inactive or unimportant therapeutically)
Chemically modified to yield important drug with profound pharmacologic activity
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: Cattle, sheep and swine from the endocrine gland
Hormonal substances: thyroid extract, insulin, and pituitary hormone (replacement therapy in the human body) Pregnant mares (from urine)
Rich source of estrogen Production of various biological products Serums, antitoxins, and vaccines (lifesaving)
Smallpox vaccine: pioneering work of Edward Jenner in England in 1796o
Cultures of renal monkey: poliomyelitisvaccines
o
Fluids of chicks’ embryo: mumps and influenza vaccineso
Duck embryo: rubella (German measles) vaccineo
Skin of bovine calves inoculated with vaccinia virus: smallpox vaccines• Synthesis in the laboratory or molecular manipulation
Change natural chemical to different chemicalstructure
Sources of New Drugs
• Development of pharmaceutical products (result of genetic engineering)
Submicroscopic manipulation of the double helix, the spiral DNA chain of life
Two basic technologies that drive the genetic field of drug development:
Recombinant DNA (rDNA)
Monoclonal antibody products (MoAB) productionSimilarities of Recombinant DNA and Monoclonal Antibody
•
Manipulate and produce proteins (building blocks of living matter)•
Production techniques influence cells in their ability to produce proteinsDifferences of Recombinant DNA and Monoclonal Antibody
• Recombinant
More fundamental
Produce any protein
Gene splicing: genetic material transplanted from higher species (humans) which induce the lower organism (bacterium) to make proteins
Human insulin
Hepatitis B vaccine
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 cellsof cancer
Future: combat disease (lupus erythematosus, juvenile onset diabetes and myasthenia gravis)Sources of New Drug
•
Human gene therapy (promising new technology)
Prevent, treat, cure, diagnose, or mitigate human disease, caused by genetic disorder
First human gene therapy
Treat adenosine deaminase (ADA) deficiency (condition resulting in abnormal functioning of the immune system)Goal Drug
•
Produces:
Desired effect
Administered by the most desired route (orally) at minimal dosage and dosing frequently
Optimal onset and duration of activity
Exhibit no side effects
Eliminated from the body efficiently, completely, and without residual effectLead Compound
•
Prototype chemical compound•
Fundamental desired biologic or pharmacologic activity Prodrug•
Metabolic biotransformation of compound after administration to produce desired pharmacologically active compound•
Inactive prodrug to active compound (enzymatic biochemical cleavage)•
Example: enalapril (enalapril maleae, vasotec) bioactivated to enalaprilat (ACE inhibitor, for hypertension)•
Used for the following reasons:
Solubility
Biostability
Absorption
Prolonged release New Drug • According to FDA:
Not recognized by experts as safe and effective
Change in previously approved drug product’sformulation or method of manufacture
New combination of 2 or more old drugs or change in proportions of drugs
Proposed new use, new dosage regimen, new route of administration or new dosage formOrphan Drug
•
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
Chronic lymphocytes Gaucher’s disease
Leukemia
Cystic fibrosis 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
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 1 st 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•
Performed through the collection and analysis of urine, blood and feces samples, and careful examination of animal tissues and organs upon autopsyToxicology
• 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.
Poorly soluble compounds: incomplete erratic 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: add antioxidant stability agent
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: Dosage forms
Route of administration
•
Clinical supplies or clinical trial materials (CTM) Includes: Proposed new drug
Placebos (non-medicated forms for controlled studies)
Drug products compared to new drug (comparator drugs or drug products) Blinded Studies
• Controlled studies where 1 of the parties is not knowledgeable of which product is being administered Open Label
•
All parties are aware of the products administered. Single Blind Studies• Patient unaware of the: Agent administered Placebo
Investigational drug Comparator drug Double Blind Studies
•
Neither the patient nor the clinician is aware of the agent administered.Parallel Designs
• Applicable to most clinical trials Crossover Designs
•
For comparing different treatments within individuals since the following one treatment a patient is “crossed over” to a different treatmentThe Clinical Protocol
• Part of the IND application
• Submitted to ensure the appropriate design and conduct of investigation
•
Includes: Purpose and objectives Number of patients Dosing plan Investigational plan Subject selection
Clinical procedures, laboratory tests
Patient observations, measurements and tests, etc. Pre- IND Meetings•
FDA advises a sponsor relating to the preparation and submission of IND on: Scientific Technical
Formatting concerns
• Includes:
Advice on the adequacy of data to support an investigational plan
Design of a clinical trial or investigation produces 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
Objections are best met by the accuracy and completeness of the IND submission
Design and conduct of the: Investigational plan Expertise
Diligence of the investigators FDA Drug Classification System
•
Upon receipt and examination of IND or NDA application•
FDA classifies the drug by: Chemical type Therapeutic potentialPhases of Product Development of Drug Products Containing NCEs
• Preclinical stage
Animal pharmacology & toxicology data are obtained. Submission of investigational new drug (IND) application for human testing to the FDA
• Phase I
Initial introduction (clinical testing)
Subjects: healthy volunteers (20- 100) 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 therapeuticindex (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
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: todetermine safety and efficacy
Side effects are monitored. Phase 3A Completed studies sufficient for the NDA Phase 3B
Additional studies are used to gather: 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 Phases of Clinical Investigation
• Submission of a new drug application (NDA)
An NDA is submitted to the FDA for review & approval when clinical trials are completed.• Phase IV
Continual clinical investigation Manufacturing scale-up activities Drug formulation modified slightly
To gather supplemental information (labeling, product advantages, additional indications, prospective post marketing studies)
• 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 Post Marketing Reporting of Adverse Drug Experiences
•
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.Drug Dosage and Terminology
•
Usual adult dose and starting dose for the patient Amount of drug that produces the desired effect in the majority of adult patient
•
Dosage regimen or schedule of dosage• Determined from:
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
Drug’s average blood serum concentration Determines minimum concentration expected to
produce the drug’s desired effects in a patient
• Minimum Toxic Concentration (MTC)
Second level of serum concentration of drug Above the average blood serum level producing
toxic effects
Negates desirable effects of the drug compromising safety of the patient
•
ED 50 or Median Effective Dose
Produces the desired intensity of effect in 50% of the individuals tested•
Median Toxic Dose (MTD) Produces a defined toxic effect in 50% of the individuals tested
• Therapeutic index
Relationship between drug’s desired and undesired effects Ratio of drug’s median toxic dose & median effective dose, TD50/EF50
Terms
• Maintenance dosage
Regularly schedule subsequent administration Initial priming or loading dose required to attain
desired concentration of the drug in the blood of tissues
• Prophylactic dose
Protects the patient from contracting illness
• Therapeutic dose
Administered to the patient after exposure or contraction of the illness
• Drug-drug interaction
Effect of drug modified by prior or concurrent administration of another drug
Chemical or physical interaction between the drugs or alteration of the absorption, distribution, metabolism or excretion patterns of one of the drugs
Include “social” agents (tobacco & alcohol) affecting pharmacokinetics of a number of drugs and alter drug’s usual doseTime and Conditions of Administration
•
Time drug is administered. Influence dosage• Absorption more rapid
Stomach & upper portions of intestinal tract are empty of food
Dosage Form and Route of Administration
•
IV or parenteral (injectable)
Drugs enter blood stream directly and completely
Required to achieve the same blood levels orclinical effects
• Oral
Rarely or if fully absorbed into the bloodstream due to various physical, chemical and biologic barriers to their absorptionRoutes of Administration
• Fundamental considerations in dosage form design: Local effects
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 IV injection or absorbed into the venous circulation following oral or other routes of administrationRoutes of Drug Administration I. Oral Route
• Most taken for systemic effects after absorption from various surfaces along GIT
•
Most natural, uncomplicated, convenient and safe means of administering drugs• Disadvantages:
Chance of irregular absorption of drugs (constitutional make-up, amount or type of food present within GIT)
Destruction of certain acid reaction ofstomach 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 Patient is unconscious or incapable ofswallowing
• Bypass the liver
•
Disadvantages: inconvenient; absorption is irregular & difficult to predictIII. 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 satisfactoryresponse
Rapid absorption is essential
• Advantage:
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)• Example: insulin
2.
Intramuscular injection•
Injected into the skeletal muscles-gluteal or lumbar muscles•
Aqueous, oleaginous solution or suspension•
Drugs injected: those irritating to subcutaneous tissue•
2 to 5mL3.
Intravenous injection•
Aqueous solution injected directly into the veins of the forearm• Advantages:
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 source (receiving parenteral nutrition)4.
Intradermal injection•
Administered into the corium of the skin (arm and back)•
10th of a mL in volume• Use: diagnostic measures
• Example: tuberculin and allergy testing 5. 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, antifungalagents, anti-inflammatory agents, local anesthetic
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 (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 7. 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, solutionsb) 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 applicationDrug 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 informationCompleted 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 applicationFDA 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 AdministrationTerm Site
Oral Mouth
Peroral (per os) GIT via mouth
Sublingual Under the tongue
Parenteral Other than the GIT (by injection)
Intravenous Vein
Intraarterial Artery
Intracardiac Heart
Intraspinal or intrathecal Spine
Intraosseous Bone
Intraarticular Joint
Intrasynovial Joint fluid area
Intracutaneous, intradermal Skin
Subcutaneous Beneath the skin
Intramuscular Muscle
Epicutaneous (topical) Skin surface
Transdermal Skin surface
Conjunctival Conjunctive Intraocular Eye Intranasal Nose Aural Ear Intrarespiratory Lung Rectal Rectum Vaginal Vagina
Route of Administration and Delivery System of Primary Dosage Forms 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
• Contact lens inserts
• Ointments Intraocular, intra-aural • Solutions • Suspensions Intranasal • Solutions • Sprays • Inhalants • Ointments Intrarespiratory • Aerosols Rectal • Solutions • Ointments • Suppositories Vaginal • Solutions • Ointments • Emulsion foams • Gels • Tablets
• Inserts, suppositories, sponge Urethral
• Solutions
• Suppositories
Some Drugs that Undergo Significant Liver Metabolism and Exhibit Low Bioavailability when Administered by First-pass Routes
Analgesic Aspirin, meperidine, pentazocine, propoxyphene
Antianginal Nitroglycerin
Antiarrhythmic Lidocaine
Beta-adrenergic blocker Labetolol, metoprolol, propanolol
Calcium channel blocker Verapamil Sympathomimetic amine Isoproterenol
Tricyclic antidepressant Desipramine, imipramine, nortriptyline
