MN 552 QUIZ, MIDTERM EXAM AND FINAL EXAM What is Modified Release? - The term modified -release is used to describe dosage forms that alter the timing and/or the rate of release of a conventional drug product/dosage form - FDA does define this Some Modified Release Systems - - some of these have overlap 1. Delayed release 2. Repeated Release or Repeat Action 4. Extended, Sustained, Long -Acting, Prolonged, Controlled Release 5. Targeted Release Delayed -release - - dosage forms release the drug at a later time than an immediate dose system - Delayed -release can include enteric -coated tablets, where timed release is achieved by a barrier coating - takes more time to release drug; doesn't start dissolving until a certain point of time Repeat -release - - multiple doses of immediate release drug units with intermittent dosing - Such as repeat -action tablets and capsules Extended, Sustained, Long -Acting, Prolonged, Controlled Release - - Extended, Sustained -release systems slowly release the drug over an extended period of time - Rate and duration are not always designed to a particular profile - If the system can maintain predictable levels of drug in the target tissue or cells, it is considered controlled - release. (Examples: XL,SR,CR) - Controlled release systems are also called extended or sustained (prolonged) release - dissolves and continues dissolving for a longer time Targeted Release - - Site-specific or targeting refers to concentrated drug release at a certain site such as a tissue, organ, receptor, or cell - A form of controlled release - very difficult to achieve - trying to control distribution of drug to target area What is Controlled Release? - - Controlled Drug Delivery attempts to deliver the precise amount of a therapeutic agent (drug), to a specific site (site of action), for a specific time (duraterm -5tion of treatment) - OR Achieve both spatial (targeted) and/or temporal "control" of the drug - a lot of prediction involved, very precise, and targeted - The Drug Delivery System attempts to control the drug concentration at the target tissue Disadvantages of Conventional Delivery - - Inconvenient because pt can forget to take dose - Difficult to monitor - Overdosing possible - Large amounts of drug can be "lost" when it does not get to the target organ because has to distribute to the whole body - Drug goes to non -target cells and can cause damage - Expensive (using more drug than necessary) The Goal of Modified Drug Delivery - To Alter and Control - Absorption - Distribution - includes Cellular Uptake - Metabolism (reduce it so more drug available) - Elimination (reduce how fast eliminated to prolong effect of drug) - Toxicity (reduce it) What is Sustained Drug Action? - - ideal dosage form - pt only has to take one time rather than multiple times - minimize side effects by delivering API to site of action (target receptors, cells, tissues, or area in the body) - re-patenting without new drug development. Improving Patient Compliance - Minimize Plasma fluctuation - Plasma Concentration vs Time - Sustained Release: takes longer to be absorbed and in therapeutic range for longer but eventually eliminated - Controlled: absorbed quickly and in therapeutic range for as long as necessary - the more times you have take a medication day, the lower pt compliance Tries to Achieve: Site Specific Drug Delivery - Reduction of side effects - Anticancer drugs --> Cytosine arabinoside - Dpocyt® - Anti-fertility Agents - Anti-inflammatory drugs Site Specific Drug Action or Drug Targeting - - Targeting or Spatial Delivery - exclusive drug delivery to specific organ, tissues, or cell types - Still in development and difficult - Designed to be directed to a specific organ, tissues, cell or cell compartment - Targets include surface or compartment cell markers, proteins or even nucleic acids - can locally put the drug through patches Routes of Administration - a. Parenteral - Refers to injections and IV - Fast Absorption - No First pass - Painful - Inconvenient b. Transdermal - Easy access - Large surface area - Avoid first pass metabolism - Avoid GI incompatibility of drugs - Good patient compliance - Slow absorption - Transport across skin can be a challenge - Need lipophilic - Low MW drugs c. Ocular - Localized delivery for eye disorders - Good absorption for many drugs - Bypasses certain clearance routes - Problems with loss of drug in tears d. Nasal - Easy administration - Local delivery of drugs - Rapid absorption - Can bypasses certain clearance routes e. Pulmonary - Rapid absorption - Large surface area for absorption - Local delivery of drugs - Can bypasses certain clearance routes when delivered systemically - Particle size determines anatomic placement in respiratory tract - Some drug may be swallowed f. Buccal or Sublingual - No first pass, Thin mucous membrane with a rich blood supply, Good absorption, Mild pH ~6.0, Drug must be potent, Can be swallowed. g. Rectal - Less worries about pH changes or enzymatic degradation as in oral, Good for patients who cannot swallow, Good for Local delivery of drug, Limited systemic absorption, Discomfort. h. Oral -Most common route, Easy to formulate and manufacture, Patient compliance is generally good, Inexpensive dosage form, Tricky due to environment of GI tract because of: First pass, pH degradation, Enzymatic degradation, Intestinal motility - affects residence time, Single patient and patient -to-patient variations, Absorption limitations in stomach. Stents, Implants, Inserts - a. Stents - XIENCE PRIMETM coronary artery disease b. Implants - dental c. Inserts - NuvaRing ® IUD Contraceptive Variables to Consider - includes examples of controlled/sustained oral drug delivery systems because historically, the oral route of administration has been used the most for both conventional and novel drug delivery systems - The types of release systems employed for oral administration include virtually every currently known theoretical mechanism Variables to Consider when designing an Oral Modified/Sustained Drug Delivery System - a. Physiochemical & Drug Properties pKa, Solubility, Log P, Permeability, Stability, Dose size b. Biological - Half-Life (time for 50% of drug to be eliminated) - GI Environment: Absorption, Metabolism, Target site c. Others - Route of delivery - Disease state -acute vs. chronic Physiochemical and Drug Properties Variables to Consider - - pKa, Solubility: Must now also consider delivery system *> 0.01mg/mL Lower Limit* (pH 1 -7.8) - Log P: Must now also consider delivery/carrier system --> if drug is sticks to carrier, it won't release as well - Stability: Drugs that are unstable in the small intestine may have decreased bioavailability in sustained release forms - metabolism increases if enzymes not saturated - Dose size: 1 gram oral, I.M. 2mL --> most people don't like to swallow bigger tablets If a drug must be taken 3 times daily and 325 mg per dose is required, what is the estimated sustained/controlled dose if the Duration of Action needed is 24 hours? - 3 * 325mg = 975 mg (the total dosage size is small enough, under 1 g) Biological Variables to Consider - - short half -life is ideal because
