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

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

Preformulation studies (physical and chemical properties of the agent) Formulation studies follows develop initial feature of proposed pharmaceutical product or dosage form

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
Purification needed before use in a drug product

New Chemical Entity (NCE)

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

Drug Product

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

Pharmaceutical industrys discovery of new drugs development into commercial products


Sources of New Drug Variety of natural resources

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

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

Federal Food and Drug Cosmetic Act

Variety of Natural Resources Reserpine (tranquilizer and hypotensive agent)

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

Medicinal chemical isolated by design from the

folklore remedy Rauwolfia serpentina

Periwinkle or Vinca Rosea: for diabetes mellitus Paclitaxel (taxol): for ovarian cancer

Development of pharmaceutical products (result of genetic engineering) Submicroscopic manipulation of the double helix, the spiral DNA chain of life

From an extract of the pacific yew tree

Other plant constituents therapeutically) (inactive or unimportant

Two basic technologies that drive the

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

Similarities of Recombinant DNA and Monoclonal Antibody

Semi synthetically produced

Animals have served human in their search for new drugs: Cattle, sheep and swine from the endocrine gland

Manipulate and produce proteins (building blocks of living matter) Production techniques influence cells in their ability to produce proteins

Hormonal substances: thyroid extract,

insulin, and pituitary hormone (replacement therapy in the human body) Pregnant mares (from urine) Differences 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 and vaccines

Rich source of estrogen

Production of various biological products Serums, antitoxins, (lifesaving)

Smallpox vaccine: pioneering work of

Edward Jenner in England in 1796

Human insulin Hepatitis B vaccine Human growth Interferon


o o o o

Cultures of renal monkey: poliomyelitis vaccines Fluids of chicks embryo: mumps and influenza vaccines Duck embryo: measles) vaccine rubella (German

Conducted within cells of higher animals

(including patient)

Skin of bovine calves inoculated with vaccinia virus: smallpox vaccines

Exploits cell to produce an antibody to combat

the specific agent

Synthesis in the laboratory or molecular manipulation

Change natural chemical to different chemical


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)

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 Treat adenosine deaminase (ADA)

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

Not recognized by experts as safe and effective Change in previously approved drug products
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


Desired effect
Orphan Drug

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 effect

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
Gauchers disease

Lead Compound

Leukemia Cystic fibrosis


Prototype chemical compound Fundamental desired biologic or pharmacologic activity


Metabolic biotransformation of compound after administration to produce desired pharmacologically active compound Inactive prodrug to biochemical cleavage) active compound (enzymatic

Pharmacologic Profile In vitro cultures of cells and enzyme systems In vivo animal models are used Objective: to obtain basic information on the drugs 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

Example: enalapril (enalapril maleae, vasotec) bioactivated to enalaprilat (ACE inhibitor, for hypertension) Used for the following reasons:

Solubility Biostability

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 bodys 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

Todays 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: Cells 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

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

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

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

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

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 drugs absorption potential: Drug solubility

Partition coefficient
Physical form and particle size Affect drugs: 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 Dissolution rate Rate & extent of absorption

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

Dosage forms Route of administration

Patient observations, measurements and tests, etc.

Pre- IND Meetings

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)

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 clinical trial or investigation

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 treatment The 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

Design of a

Data to meet requirements of the next step Filing NDA to gain approval for marketing

FDA Review of an IND Application The FDAs objective in reviewing IND: Protect the safety and right of human subjects Ensure evaluation of the drugs 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 potential

Phases of Product Development of Drug Products Containing NCEs Preclinical stage

Animal pharmacology & toxicology data are

obtained. Determines the safety & efficacy of the drug

Clinical procedures, laboratory tests

Phase I

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

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)

Initial introduction (clinical testing) Subjects: healthy volunteers (20- 100)

Phase II Determines drug tolerance & toxicity (assessing safety)

Controlled clinical studies to several hundred

patients with the disease or condition are treated

Phase V Product development continues after the FDAs market approval of drug product Drug product may be improved due to equipment, regulatory, supply or market demands

Safety measured: determines the therapeutic

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

Post Marketing Reporting of Adverse Drug Experiences

Phase III

disease or condition treated for which the drug was developed (controlled & uncontrolled trails)

Several hundred to several thousand patients with

Large scale, multicenter studies performed: to

determine safety and efficacy

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

Side effects are monitored.

Phase 3A Completed studies sufficient for the NDA

Usual adult dose and starting dose for the patient Amount of drug that produces the desired effect in the majority of adult patient

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

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 drugs potency Necessary when drugs (antibiotics & endocrine products) suitable chemical assay methods are unavailable

Phases of Clinical Investigation

Submission of a new drug application (NDA)

Minimum Effective Concentration (MEC)

Drugs average blood serum concentration Determines minimum concentration expected to produce the drugs desired effects in a patient

Include social agents (tobacco & alcohol)

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

Minimum Toxic Concentration (MTC) 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 the drug

Time drug is administered. Influence dosage

Absorption more rapid Stomach & upper portions of intestinal tract are empty of food

ED 50 or Median Effective Dose

Dosage Form and Route of Administration

Produces the desired intensity of effect in 50% of

the individuals tested

IV or parenteral (injectable)

Median Toxic Dose (MTD) Produces a defined toxic effect in 50% of the individuals tested Oral

Drugs enter blood stream directly and completely Required to achieve the same blood levels or
clinical effects

Therapeutic index

Relationship between drugs desired and

undesired effects 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 Ratio of drugs median toxic dose & median effective dose, TD50/EF50

Rarely or if fully absorbed into the bloodstream

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

Prophylactic dose Protects the patient from contracting illness

Direct placement into the blood stream via

IV injection or absorbed into the venous circulation following oral or other routes of administration Routes 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: Slow drug response

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

Chance of irregular absorption of drugs

(constitutional make-up, amount or type of food present within GIT)

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 5mL

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 Patient is unconscious or incapable of swallowing

3. 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

Bypass the liver Disadvantages: inconvenient; irregular & difficult to predict absorption is

III. 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:

Administered: single, small-volume injection or as large volume, slow IV drip fusion IV fat emulsion-caloric parenteral nutrition) source (receiving

Destroyed or inactivated in GIT

Poorly absorbed to provide satisfactory response Rapid absorption is essential

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

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


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)

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

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 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

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

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.

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:

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

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


Term Oral Peroral (per os) Sublingual Parenteral Intravenous Intraarterial Intracardiac Intraspinal or intrathecal Intraosseous Intraarticular Intrasynovial Intracutaneous, intradermal

Site Mouth GIT via mouth Under the tongue Other than the GIT (by injection) Vein Artery Heart Spine Bone Joint Joint fluid area Skin

Subcutaneous Intramuscular Epicutaneous (topical) Transdermal Conjunctival Intraocular Intranasal Aural Intrarespiratory Rectal Vaginal

Beneath the skin Muscle Skin surface Skin surface Conjunctive Eye Nose Ear Lung Rectum Vagina

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

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

Solutions Ointments Suppositories Vaginal Urethral Solutions Ointments Emulsion foams Gels Tablets Inserts, suppositories, sponge Solutions Suppositories Examples

Drug Class


Analgesic meperidine, pentazocine, propoxyphene Antianginal Antiarrhythmic Beta-adrenergic blocker propanolol Calcium channel blocker Sympathomimetic amine Tricyclic antidepressant nortriptyline Lidocaine

Aspirin, Nitroglycerin

Labetolol, Verapamil Isoproterenol Desipramine,