MN 552 MIDTERM QUESTIONS AND ANSWERS
What is Modified Release? - Answers - 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 - Answers - - 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 - Answers - - 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 - Answers - - multiple doses of immediate release drug units with
intermittent dosing
- Such as repeat-action tablets and capsules
Extended, Sustained, Long-Acting, Prolonged, Controlled Release - Answers - -
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 - Answers - - 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? - Answers - - 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 - Answers - - 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).
Improving Patient Compliance - Answers - 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 - Answers - Reduction of side effects
- Anticancer drugs
--> Cytosine arabinoside- Dpocyt®
- Anti-fertility Agents
- Anti-inflammatory drugs
Site Specific Drug Action or Drug Targeting - Answers - - 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
The Goal of Modified Drug Delivery - Answers - 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? - Answers - - 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
Routes of Administration - Answers - 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 - Answers - a. Stents
- XIENCE PRIMETM coronary artery disease
b. Implants
- dental
c. Inserts
- NuvaRing ® IUD Contraceptive
Variables to Consider - Answers - 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 - Answers - 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 - Answers - - 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? -
Answers - 3 * 325mg = 975 mg (the total dosage size is small enough, under 1 g)
Biological Variables to Consider - Answers - - short half-life is ideal because
What is Modified Release? - Answers - 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 - Answers - - 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 - Answers - - 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 - Answers - - multiple doses of immediate release drug units with
intermittent dosing
- Such as repeat-action tablets and capsules
Extended, Sustained, Long-Acting, Prolonged, Controlled Release - Answers - -
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 - Answers - - 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? - Answers - - 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 - Answers - - 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).
Improving Patient Compliance - Answers - 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 - Answers - Reduction of side effects
- Anticancer drugs
--> Cytosine arabinoside- Dpocyt®
- Anti-fertility Agents
- Anti-inflammatory drugs
Site Specific Drug Action or Drug Targeting - Answers - - 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
The Goal of Modified Drug Delivery - Answers - 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? - Answers - - 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
Routes of Administration - Answers - 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 - Answers - a. Stents
- XIENCE PRIMETM coronary artery disease
b. Implants
- dental
c. Inserts
- NuvaRing ® IUD Contraceptive
Variables to Consider - Answers - 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 - Answers - 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 - Answers - - 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? -
Answers - 3 * 325mg = 975 mg (the total dosage size is small enough, under 1 g)
Biological Variables to Consider - Answers - - short half-life is ideal because
