macromolecular drugs Flashcards
what therapy can macromolecular drugs be used in
replacement therapy
supplementing therapy
therapeutic antibodies
site-specific carriers
what is the ideal route for administration of macromolecular drugs?
oral
list 8 examples of macromolecular drugs (peptides and protein)
8
Examples:
Colony stimulating factors
Interferons & Interleukins
Enzymes
Hormones
Recombinant protein vaccines
Growth factors
Monoclonal antibodies (diagnostic and therapeutic)
Recombinant soluble receptors
list two macromolecular drug (peptides and protein) growth factors
Tissue/bone growth factors
Neurotropic factors
why does monoclonal antibodies and macromolecular drugs need to be administered in high concentration?
because only a fraction of the administered drug will reach the site of action
what are the problems with having a drug with high concentration
high viscosity
low solubility
aggregation
what are the barriers to manufacturing and delivery of peptide and proteins macromolecular drugs
in-vitro stability barriers
metabolic barriers
absorption barriers
explain in-vitro instability barriers are a problem
peptides and proteins are not very stable also they can undergo enhanced instability due condition used during the manufacturing and storage of the drugs
this instability is caused by three main factors :
Inherent instability due to reactive side chains
Degradation caused by environmental factors
Manufacturing process
explain how Inherent instability due to reactive side chains makes the drug unstable (8)
what is done to avoid this?
why should this be avoided
Transpeptidation Deamination Side-chain hydrolysis Proteolysis Disulfide exchange β-elimination Oxidation Racemization
eg if the drug has oxidative side chains an anti oxidant can be added to make it more stable.
it should be avoided because the reactions could lead to a loss of activity and also an exposure to hydrophobic groups which could lead to aggregation and absorption into containers (eg plastic containers).
explain how Degradation caused by environmental factors causes drug instability
Temperature pH Ionic strength Pressure Detergents
e.g. when the temperature is increased we would have an increase in flexibility of the molecules this allows for more collision between the molecules which can lead to aggregation.
aggregation can also happen with change in pH and ionic strength because pH and ionic strength can lead to neutralization of the charges that are present in the molecules these charges have a very important role to play in solubility. neutralization would therefore cause aggregation of the molecules
detergents are often used in stabilizing and also solubilizes protein and peptides but if they are not used in the correct concentration it can lead to aggregation.
explain how manufacturing process of the drug causes drug instability
processes involved in manufacturing are:
Determine degradation routes
Choose adequate additives (e.g. if the drug is degraded because of oxidation an anti oxidant can be added to make it more stable)
Test stability of the solution ( when the additives required are added to the drug, the stability of the drug is tested, and if the stability of the drug is less than two years we would have to make the drug solid to give it a longer half life)
finally (development of a solid formulation)
in order to prepare solid formulation we use technics that affect peptides and protein which messes with the stability of the drug
when should a drug be made into a solid formulation?
when the stability after adding the adequate additives is less than two years.
what is the most commonly used technic for obtaining powder out of a solution is _______?
lyophilization or freeze drying
what are the steps in lyophilization?
freeze sample (in order to reduce pressure)
sublimation of water (elimination of water througgh vapour)
desorption of bound water
what are the disadvantages of lyophilization
what is done to prevent these disadvantages?
irreversible aggregation
denaturation
solution to disadvantage:
addition of cryoprotectants
addition of other additives
list different cryoprotectants
SUGARS
Sucrose
Sorbitol
Mannitol
POLYMERS
Dextran
PVP
PEG
OTHER
BSA (bubi serum albumin)
Amino acids
name the second techniques used in the development of a solid formulation?
spray drying
when is spray drying used?
this is used when we require a particular particle size.
e.g. in Nasal and pulmonary formulations
Powder with good flow properties and narrow size distribution
what are the steps in spray drying?
the solution is sprayed through a nozzle to form very tiny droplets
these droplets are then collected in a chamber where there is hot air
which induces the evaporation of water, and therefore then the collection of dry powder
