Pharmaceutics Final

• 1.) Food & Drug Act (1906): Strength & Purity
• 2.)Food, Drug, & Cosmetic Act (1938):Safe
• 3.) Durham-Humphrey Amendment (1951): Seperate Rx from Non
• 4.) Kefauver-Harris Amendment (1962): Efficous & Adverse Rxns Required
• 5.) Orphan Drug Act (1983): D Affects Fewer People
• 6.) Drug Price Competition & Patent Term Restoration Act (1984): Generic markets Faster & Extend D Patent to 7 yr
• 7.) Rx D User Fee Act (PDUFA): D Co. pays FDA for Quicker Review for Approval
• 8.) Food & Drug Administration Modernization Act (1997): Extend Patent for Pediatric Studies on D

• Discovery
• Developement
• Marketing

• Universities, Research Institutions, & Pharmaceutical Companies
• Isolate Active Ingredient from Traditional Remedies
• Serendipitous (by chance) Discovery: ex. Flemming's Penicillin from Bacteria on Petri
• New Molecule w/ Desired Biological Activity
• Structural Changes/Modeling
• Opt: Physio-Chemical/ADME Properties

Phases 1-3 (sometimes 4)

• 20-100 Healthy Humans
• Single Dose
• Start Low then Increase
• Not Blinded
• ~ 1 yr
• Goals: Acute Safety & ADME
• Adverse Effects & Safe Dosage Range

• 100-300 w/ Disease
• Double-Blinded & Randomized (sometimes Cross Over)
• ~ 2 yr
• Goals: Efficacy

• 1,000-3,000 w/ Disease
• Diverse (age, sex, health, etc.)
• ~ 3 yr
• Goal: Efficay & Safety
• Risk v. Benefit, Dosing, etc.

• D's Entire Life on Market
• Office of D Safety (ODS) in Center for Drug Evaluation & Research (CDER)
• Adverse Event/Problem--> Label Change, Box Warning, Recall, Medical & Safety Alerts

• Report to ODS
• Voluntary for all Except Pharmaceutical Co.

After D in Use; Long Term EffectsInteractions, Alternate Dosing, Response to Specific Sub Populations (age, ethnicity, etc.)Co. may conduct Post Approval Studies (^ Indications, Optimize Dosing Schedules, New Info to Label)Better Marketing (fewer Adverse Effects & better Efficacy/Cost Effectiveness than competitor)

• IV: Start @ Top then go down
• Require Absorption: Down Up Down

• Tpk: Time @ which Cpk is highest )how fast D works); Less Sensitive Measure of Rate of Absorption
• Curve Shows how Long D works
• Cpk: Max Conc; Rate of Absorption
• AUC: Measure of Extent of Absorption

• Rate of Absorption Depends on how Fast D Dissentigrates
• Fast: ^ & Early Tpk, ^ Cpk (on graph)
• Slow: Wider Tpk, Lower Cpk

the longer it takes to Absorb to Reach and Effective Conc the slower D works but stays in system longer

• Rate & Extent to which Active Ingredient in Pharmaceutical Equivalents become Available @ Site of D Action
• Quality of D Reaching System or Extent of Drug Absorption Circulation/Quantity of D Administered

• Disintegration & Dissolution of D from Dosage Form
• Absorption Characteristics of D
• Dosage Form
• RoA
• Stability of A Ingredient @ Absorption Site
• Extent of Biotransformation prior to Reaching System Circulation

• D is Biotransformed by Enzymes Prior to Reachign Systemic Circulation
• Decreases BioAvailability
• Sites: Liver & GI

Ds that are Extensively & Efficiently Metabolized

• RoA/[AUC (IV)]
• AUC (ex. Oral)/AUC (IV)

• RoA/Most BioAvaible RoA
• AUC (ex. tablet)/AUC (ex. liquid)

Everytime (unless IV RoA BioAvailability is Not Available)

Only if IV RoA BioAvailability is Not Available (then use most BioAvailable)

Food & Drug ActFederal Food, D, & Cosmetic Act (FFDCA)Kefauver-Harris Amendments to FFDCAAbbreviated New D Application (ANDA)Maximum Allowable Cost Program (MAC)Orange BookWaxman-Hatch Act (D Price Competition & Patent Term Restoration Act)

• Orange Book
• Waxman-Hatch Act (D Price Competition & Patent Term Restoration Act)

• 1906
• Strength & Purity

• Federal Food, D, & Cosmetic Act
• 1938
• New D Application (NDA)
• New D referred to A Ingredient
• Safety

• 1962
• Efficacy
• D Efficacy Study Implementation (DESI): review for Ds b/t 1938-1962
• New D referred to Entire Dosage form

• Abbreviated New D Application
• 1970
• originally for Ds b/t 1938-1962

• Maximum Allowable Cost program
• 1975
• DHHS (US Dept. of Human & Health Services) Established for Reimbursement of Selected Generic Ds in Medicaid Program

• 1980
• Approved D Products w/ Therapeutic Equivalence Evaluations

• D Price Competition & Patent Term Restoration Act
• 1984
• Applied ANDA process to Ds Marketed after 1962

• Approved by FDA as Safe & Effective
• ~No Ds b/f 1938
• ~No Ds Marketed b/t 1938-1962 which are Safe ~But Not Approved as Effective
• Adequately Labeled
• Manufactured in Compliance w/ FDA GMP (good manufacturing practice) Regulations
• Must be Pharmaceutically Equivalent & Bioequivalent

• Require Same:
• ~Amounts
• ~Active Ingredient
• ~Dosage Form
• ~RoA

• (in order)
• Pharmacokinetic (PK) Studies
• Pharmacodynamic (PD) Studies
• Comparative Clinical Trials
• In vitro Trials

• 1st Letter:
• ~A: D Product Considered Therapeutically Equivalent to Other Pharmaceutically Equivalent Products
• ~B: Not Equivalent
• *BD: Active Ingredients & Dosage Forms w/ Documented BioEquivalence Problems
• *BP: Potential
• *BX: Data Reviewed by FDA is Insufficient to Determine Therapeutic Equivalence
• 2nd Letter:
• ~AA: No Bioequivalency Problems (No BioEquivalency Testing comparing Innovator & Generic)
• ~AB: Meets Necessary BioEquivalent Requirements But Actual or Potential BioEquivalency problem Solved thru Appropriate Scientific Testing
• 3rd #:
• ~more than 1 Referenced Product of Same Strength Exists (generic proves equivalent to 1 or more products)

• Limits of Dating System:
• ~Lacks Data (Comparatie BioEquivalence Data, Pre-1938 D, DESI Ds)
• ~Difference in D Release Dosage Forms
• ~Serious Disease (Dr. only used Brand Manufacturer--they're only/most accountable)
• ~Narrow Therapeutic Range (NTI)
• *D w/ Small DIff. b/t Therapeutic & Toxic Range
• *n% of Potential Diff. could be HUGE (even if small) When giving Patient Generic Use Same 1 Every Time)
• Only way to Assure Patient Receives Same P each time is Write for Trade Name w/ No Sub

• Extent to which Dosage Form Retains, w/i Specific Limits & throughout its Storage & Use, the Same Properties & Characteristics that it Possessed @ Time of Manufacture
• Expressed in terms of Shelf-Life

D Degrades too quickly

• Visually Evident
• *1 D Not of Suitable Composition be Combined w/ Another Excipient/Dye (D alone is not instable, just can't be mixed w/ other things)
• *Manifests as Change in Physical State
• * IV D (ex. w/ Saline-->forms Chrystals, Precipitation, etc.)
• Ex. Antiobiotics or Dilante 5% Dextrose?

• 1.) Chemical Degredation (irreversible)
• 2.)Physical Visual Apperance (Color or Clarity)
• *Predicts Factors Affecting Chemical & Physical Stability: Temp, Moisture, pH, & Oxidation
• 3.) Microbiological: sterility or resistence to microbial growth
• 4.) Therapeutic: D Potency Doesn't Change
• 5.)Toxicological: no ^ in Toxicity
• 6.) Aesthetic: Visually Acceptable

• 3 Factors:
• 1.)Dry Formulation (D+Excipients)
• 2.)Environmental Conditions (heat/temp/moisture)
• 3.)Packaging

• Loss of Active
• *D P or Active Ingredient Drop b/l Label Content
• ^ Active Conc
• *Volatile Solvent (ex. Alburterol Alcohol Evaporates, ^ D Conc.)
• BioAvailability Alteration
• *Active-->Inactive D, decreases BioAvailability decreasing amount Available to be Absorbed
• Form Toxic Degredation P
• *Rare (ex. exposure to light)
• Lose Content Uniformity
• *Physical Instabilities
• Lose Pharmaceutical Elegane & Patient Acceptability

• C (conc of reactants)-->P (products)
• -dC/dt (Reactants Decrease as)-->+dP/dt (^ P)
• Reactant Conc influences Rate of Chemical Rxn

• Half Life
• Time Required for 1/2 Initial Conc of Reactants-->P

• Stabilize D in its Dosage Form
• Assign Shelf-Life

• Most Common in Pharmacy
• Loss of D is Directly Proportional to Remaining Conc w/ Respect to Time
• Amount Removed Each Time Decreases
• Fraction of D Removed Remains Constant

• Loss of D is Independent of Conc of Reactants & Constant w/ Respect to Time
• Same Amount of D Removed Each Time

• 1st Order
• *Tablets: Paracetanel? (Acetaminophen)
• *Soln: Omeprazole
• *Eye Drops: Sulfacetamide
• 0 Order
• *Suspension: Aspirin?

• 1.) Temp
• *RoR
• 2.)Solvolysis
• *Active D decomposes in Presense of Solvent (usually H2O)
• 3.)pH & Hydrolysis
• *Rate of Hydrolysis vary w/ pH
• 4.)Oxidation
• *Autooxidation: Rxn w/ Atmospheric O2 under Ambient Conditions
• * Ps are more Electronically Conjugated
• *Solution to Problem: ^ Stability by 1. Replace O2 w/ N2 or inert gas? 2. + Anti-Oxidant
• 5.)Photolysis
• *L (sun or room) provides E for Degredation
• 6.)Racemization
• *Enantiomers (mirror image) have diff. ADME properties & differ in Pharmacological Actions
• 7.)Vaporization
• *Some Ds & Excipients have ^VP @ RT; Volatilization thru Container-->Major D Loss
• 8.)Adsorption
• *Drug-plastic Interactions becoming Potential Problems

Ea (Activation E): there must be enough E present to overcome repulsive forces b/t molecules & Allow Bonds to Break & New Bonds to Form (--> New P)