Exam 5 Spring 2017 Flashcards
What dosage forms are the only ones that you can use with controlled drug delivery (CDD)?
- tablets
- capsules
What are the types of controlled drug delivery (CDD)?
XL, SR, ER, CR, PA, PL, SA, TR
What are CDD useful for?
to treat chronic diseases
What is dose dumping?
when the CDD fails and delivers the amount of drug in the tablet all at once
Define CDD
drug system that is capable of spatial placement and temporal release of a drug
What does spatial placement pertain to?
release of drug in a particular location
What does temporal placement pertain to?
time release of the drug
What are the ways in which you can maintain sustained plasma levels of the drug?
- multiple dosing
- intermittent infusion
- constant infusion
After how many half lives can we assume that the drug is out of the body?
- four
- some literature use 3.3 because that equals 90%
intermittent infusion
drug is given continually but not continuously
multiple dosing
- requires strict adherence
- cannot tolerate missed doses
- if doses are missed, plasma levels not sustained and may fall below MEC
What is the assumption for CDD?
kinetics of drug release governs drug availability
What are the types of CDD systems?
- osmotically controlled
- swelling controlled
- diffusion controlled
- dissolution controlled
- ion-exchange resin
- complex formation
- magnetically controlled
- electrically controlled
osmotically controlled system
- has a hole in the tablet
- polymer is semi-permeable
- pH independent
With respect to osmotically controlled systems, what does it mean that the polymer is semi-permeable?
water and GI fluids can enter tablet but not permeable to substances coming out of tablet
example(s) of osmotic agents
- mannitol
- xylitol
What is osmotically controlled systems dependent on?
- size of hole
- type of polymer
- type of osmotic agent / osmotic pressure
- saturated solubility of drug
Example(s) of semi-permeable membranes used to regulate osmotic permeation of water
- cellulose derivatives
- polyvinyl chloride
- polyvinyl alcohol
How does the osmotic agent play a role in osmotically controlled systems?
- osmotic agent creates a high osmotic pressure gradient inside the tablet
- fluid enters the tablet (osmosis)
- increase in volume -> drug gets pushed out of hole
swelling controlled system
- polymer and drug tightly packed
- once in GIT, polymer swells to release drug
In a swelling controlled system, what is the release of drug dependent on?
rate of water sorption in polymer
Example(s) of polymers used in swelling controlled systems
- poly acrylic acid
- sodium alginate
- cellulose derivatives
diffusion controlled system
polymer is physical barrier to drug release
In a diffusion controlled system, what is the release of drug dependent on?
- nature of polymer
- thickness of polymer
What are the categories of diffusion controlled systems?
- reservoir
- matrix
describe the reservoir diffusion controlled systems
- drug is coated with water-insoluble polymer
- water penetrate through polymer to reach drug
- drug dissolved to produce saturated solution
- saturated solution diffuses through polymer to outside
If the polymer for reservoir diffusion controlled system is water-insoluble, how does the drug diffuse through it to the outside?
osmotic movement through polyemeric mesh (space between macromolecular chains)
For reservoir diffusion controlled systems, how can release of drug remain constant?
if concentration of drug in the core remains at saturation
describe the matrix diffusion controlled systems
- aka monolithic
- drug dispersed in polymeric matrix
Polymers for diffusion controlled systems
- reservoir’s polymers are water-INsoluble
- matrix’s can be both
fate of polymers for matrix diffusion controlled systems
- erode with tiem
- dissolve
- stay intact as ghost matrix
dissolution controlled system
dissolution of drug is the major role in drug release
ion exchange resin system
drug is resinated and then formulated in it’s respective dosage form
What does it mean for a drug to be resinated?
- cationic / anionic drug passed through ion exchange resin
- cations replace H atoms
- anions replace OH atoms
- drug-resin complex = resinated
complex formation systems
- drug complexes which are slowly soluble in GI fluid; pH dependent
- salts of tannic acid used for this purpose
Characteristics of controlled release systems
- not for all drugs
- not all medical conditions need it
- dissolution and absorption release of drug should be predictable
- rate of drug release is controlled
- rate of drug release = rate of drug elimination
Ideal drug candidates for controlled release systems
- Absorption/elimination rate shoud not be too fast or slow
- Uniformly absorbed form the GI tract
- Effective dose should be small
- Possess good margin of safety
- Used for chronic conditions
Limitations of controlled release systems
- Dose dumping
- Termination of therapy is not easy
- Variable release of drug
- Absorption of released drug may not be constant
- Delayed release = delayed immediate effect of drug
What does modified release refer to?
drug release based on time, course, or location not offered by conventional dosage forms
What are the categories of modified release?
- extended release
- delayed release
extended release
allows a reduction in dosing frequency
delayed release
releases drug at a time other than promptly after administration
What are repeat action tablets?
two layer tablet; one layer is IR and second layer is DR
What are targeted release tablets/capsules?
directed towards a target location in the GI tract
What are the different types of mechanisms of drug degradation?
- hydrolysis
- oxidation
- isomerization
- polymerization
What are the functional groups prone to hydrolysis?
- ester
- amide
- lactone
- lactam
- imide
- carbamate
What is the most common cause of drug degradation?
hydrolysis
hydrolysis
drug molecule + water => breakdown products
oxidation
gaining electronegative atoms or radicals
What functional groups are subject to oxidation?
- phenol
- aromatic amine
- aldehyde
- ether
- unsaturated aliphatic compound
What are examples of drugs that are prone to oxidation?
- morphine
- epinephrine
- dopamine
- steroids
- vitamins
formation of free radicals
- can form in presence of heavy metals, peroxides, or atmospheric oxygen
- generated radicals form more free radicals
What are the factors that affect drug stability?
- temperature
- pH
- solvent
- light
affect on drug stability: temperature
- for every 10°C rise in temp, degradation increases 2-3 times
affect on drug stability: pH
- specific-acid catalytic reaction goes faster at a low pH and a specific-base catalytic reaction goes faster at a high pH
- optimal pH is only possible for liquid solution formulations–NOT solid dosage forms
examples of drug stability with respect to pH
- thiotepa must be reconstituted with basic solution
- thiamine is stable at pH of 2
affect on drug stability: solvent
- increased stability = decreased relative permeability
- can add PEG to stabilize substances prone to solvolysis
affect on drug stability: light
- catalyze oxidation reaction -> radicals
- must be stored in amber vials
What are common stresses when testing stability?
- temperature
- humidity
- light
What is the purpose of liposomes with respect to drug delivery?
- increase efficacy
- reduce dose frequency
- enhance pt compliance
- minimizing unexpected effects
- increased half life
- prepare drugs that are difficult to administer
What are liposomes made up of?
- cholesterol
- phospholipid
T/ F A drug maintains its kinetics properties even inside a liposome.
False; it’s kinetics will depend on liposome properties
What happens with increasing phospholipid carbon?
- increase rigidity
- increasing melting point
How do you load drugs into liposomes?
- passive loading
- active loading (remote loading)
Passive loading
Drug is incorporated while the liposome structure is being formed
Active loading
Drug is loaded after the empty liposome structure is formed
Conditions for active loading: ammonium ion gradient
– Internal medium: 250 mM ammonium sulfate
– External medium: sucrose
Conditions for active loading: hydrogen ion gradient
– Internal pH 4.0 (citrate buffer)
– External pH 7.0 (sodium carbonate buffer)
What are characteristics of liposomes to consider?
- lamellarity
- size
- charge
- amount of drug loaded
- presence / type of surface coating
Lamellarity of liposomes
- Multilamellar vesicles (MLVs): more lipid phase available; multi-lipid-layers
- Unilamellar vesicles (ULVs): more aqueous space; one lipid layer
Desirable liposome size
- 80-300 nm
- nanoparticles = <100nm even more desirable
How is liposome size reduction achieved?
- high shear homogenization
- pushed through pores of defined size
When reducing liposome size, how can you narrow size distribution?
multiple cycles of homogenization or extrusion
Neutral liposomes increase in size. How can we combat against that?
use 5-10% of anionic liposome
How is lipid oxidation combated?
anti-oxidants esp. vit E
How can liposome surface be modified?
long polyethylene glycol chain (hydrophilic substance)
What is the consequence of PEG-lipid?
stability against opsonization and uptake by macrophage
How does PEG stabilize liposome?
PEG is hydrophilic so the body will think that it’s a solvated particle
liposome in cancer therapy
- accumulation in solid tumors
- reduced toxicity
- increased efficacy
- enhanced stability
AmBisome®
- amphotericin B liposomes for i.v. infusion
- lipid bi-layer carries drug
- unilamellar system
Myocet®
- increased size to decrease possibility of uptake by macrophage
- 3 vial system: doxorubicin, buffer, liposome
Doxil®
- doxorubicin liposome
- coated with PEG
