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Chapter 1 Introduction. New Drug Development Procedures (FDA):. What is the “new drug”?. According to FDA’s Definition: A new drug need not be a new chemical entity to be considered new. It can be any drug with the following considerations:
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Chapter 1 Introduction New Drug Development Procedures (FDA): What is the “new drug”? • According to FDA’s Definition: • A new drug need not be a new chemical entity to be considered new. It can be any drug with the following considerations: • A change in a previously approved drug product’s formulation or method of manufacture • A combination of two or more old drugs • A change in the usual proportions of drugs in an established combination product • A proposed new use of an established drug • A new dosage schedule or regimen • A new route of administration • A new dosage form Abbreviated New Drug Application (ANDA)
FDA Drug Classification System What is prodrug? It requires metabolic biotransformation after administration to produce the desired pharmacologically active compound.
Dosage Forms • Solid: • Tablet (tab.): 裸錠(uncoated)、糖衣錠(sugar coated, S.C.)、舌下錠(sublingual)、口含錠(喉錠，lozenge；bucal) 、內服錠(oral)、腸溶錠(enteric, EN)、陰道錠(vaginal) • Capsule (cap.): gelatin • Granule: Vitamins • Powders: antibiotics • Spray (Aerosol): Nasal Spray 、Inhaled Spray
Liquid:溶液劑(solution)、糖漿劑(syrup)、懸液劑(suspension)、乳劑(emulsion)、洗劑(lotion)、含漱劑(gargle)、灌腸劑(enema)Liquid:溶液劑(solution)、糖漿劑(syrup)、懸液劑(suspension)、乳劑(emulsion)、洗劑(lotion)、含漱劑(gargle)、灌腸劑(enema) • Paste: • 軟膏劑(solution): transdermal， topical • 栓塞劑(suppository): rectal， vaginal • 霜劑(cream) • 乳劑(patch) • Sterile Injectable (Ampoule):靜脈輸注液(infusion)、注射劑(injection)、懸液注射劑(suspension injection)、乾粉注射劑(powder for injection) • Ophthalmic Form (Ocular): Eye drop，Ophthalmic Ointment
Common Terms in Prescription Administration Frequency of Drug in Prescription Dosage Forms of Drug Administration in Prescription
Common Terms in Prescription Administration Routes of Drug in Prescription Other Terms in Prescription
Drug Effectiveness MTC: Minimum Toxic Concentration MEC: Minimum Effective Conc. Therapeutic Index = LD50 / ED50 • Questions: • How long is the action period? • How long is the lag time?
Dosage Forms on Drug Effectiveness • What is the advantage of an extended release dosage forms? • What is the definition of an extended dosage form?
Drug Effectiveness -- LD50 & ED50 MTC Therapeutic Window MEC What is the goal of the prolonged release? • LD50: Lethal Dose (50% of Test Objects) • ED50: Effective Dose (50%) • Therapeutic Index (safety margin) = LD50/ ED50 Potent Toxic
Factors Determining Dosage Regimen ADME stands for Absorption, Distribution, Metabolism and Excretion.
Route of Drug Intake ADME stands for Absorption, Distribution, Metabolism and Excretion.
Effect of Administration Route on Drug Efficacy What is the first-pass effect? How to survive the first-pass?
Time Course of Drug in Body ADME stands for Absorption, Distribution, Metabolism and Excretion.
An ADME Example of Drug In-vivo data (drug: lidocaine) Simulated distribution of drug in various organs
Anatomy – Circulation • Circulating Body Fluids: • Blood: major (systemic) circulation and lesser (pulmonary) system. • Blood volume is about 8% of the body weight. • 55 % of blood by volume is plasma. • Lymphatic circulation: lymph & lymphocytes (production of immunity); 2 – 4 L/day • Cerebral Circulation: Cerebrospinal fluid; 150 mL & 550 mL/day. Splanchnic circulation
Anatomy – Enteric Route & Circulation Mean lengths of Various Segments of the Gastrointestinal Tract (by Intubation) • Other estimates: • Intestine ~ 10 to 14 ft; • Colon ~ 4 to 5 ft
Cell Structures and Functions Mitochondria; Ribosomes; Nucleus; Membrane; Cytoplasm; Golgi apparatus Model of Cell Membrane:
Digestion and Adsorption of Lipids Inside Mucosal Cell • Bile salt (Cholic acid-Deoxycholic acid sodium salt 50%/50% mixture) • Pancreatic Lipase
Passage of Drug Across Cell Membranes • Passive Diffusion: Most common Blood-brain barrier: hydrophilic drug could not diffuse through cell membrane to brain • Carrier-Mediated Transport: • Active Transport • Facilitated Diffusion • Carrier-mediated Intestinal Transport • Vesicular Transport: pinocytosis, phagocytosis, endocytosis, exocytosis • Pore (convective) Transport • Ion-Pair Formation
Interaction of Drug and Receptor – Molecular Medicine Simple Model of Ligand Binding to Cell Surface: Drug, Bacteria … Drug + Receptor Complexes Effectiveness • Receptor Agonist: must have both affinity and intrinsic activity • Receptor Antagonist: competition between active sites (receptors) • Antihistamine • Enzyme Inhibitor: aspirin, some antibiotics • Metabolic antagonist: AZT • Ion channel blockers: procaine
Bioavailability And Bioequivalence Requirements: (CFR TITLE 21--PART 320 -- Bioavailability And Bioequivalence Requirements) Definitions: (a) Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bio-availability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action. (b) Drug product means a finished dosage form, e.g., tablet, capsule, or solution, that contains the active drug ingredient, generally, but not necessarily, in association with inactive ingredients. (c) Pharmaceutical equivalents means drug products in identical dosage forms that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified release dosage forms that require a reservoir or overage or such forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates.
Bioavailability And Bioequivalence Requirements: (d) Pharmaceutical alternatives means 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. Each such drug product individually meets either the identical or its own respective compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates. (e) Bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Where there is an intentional difference in rate (e.g., in certain extended release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action. This applies only if the difference in the rate at which the active ingredient or moiety becomes available at the site of drug action is intentional and is reflected in the proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug. (f) Bioequivalence requirement means a requirement imposed by the Food and Drug Administration for in vitro and/or in vivo testing of specified drug products which must be satisfied as a condition of marketing. [42 FR 1634, Jan. 7, 1977, as amended at 42 FR 1648, Jan. 7, 1977; 57 FR 17997, Apr. 28, 1992; 67 FR 77672, Dec. 19, 2002]
