Drug delivery Flashcards
What are 3 ways to increase solubility of a poorly water soluble drug?
- Ionisation of a weak base or acid into a water soluble salt
- Change crystal structure- amorphous, polymorphs
- Decrease particle size- increase SA available for dissolution
How do solid dispersions increase dissolution?
Solid dispersing are form when poorly soluble drugs are mixed with a water soluble carrier in liquid state which form a solid via cooling or evaporating.
Advantages:
Molecular dispersions stabilise high energy crystals that have high aqueous solubility
When dissolved forms a supersaturated solution
Even if precipitation occurs, these are very small particles that have high dissolution rates
Water soluble carries: PEG melts, PVP
What are other methods in making a drug more soluble?
Surfactants
Using lipid based formulations- take advantage of lipid digestion SMEDD/SEDD
What are SEDDS and how do they work?
Self emulsifying drug delivery systems
Usually capsules that are filled with a isotropic mix of oil contain drug and surfactants
When the capsule dissolves, the fill makes contact with water and instantaneously forms a emulsion
What properties must a drug display to utilise lymphatic transport?
High Log P and high lipid solubility
The drug needs to avoid being taken up into the vascular endothelium and need to associated with lipoproteins and taken up into the lymphatic system
if administered with a high lipid meal- can stimulate more lymphocytes
Why is it an advantage to use specific drug delivery?
Improves therapeutic window for the drug at the specific site
Reduces side effects at non target sites
Can improve absorption at specific sites
What are some ways to achieve targeted delivery?
Use of agents (buccal, ocular, topical) that are site specific
Oral meds like sulfasalazine- target colon
Intra articular
IV - little specificity but can be increased by drug conjugation
6 types of targeting agents?
- Viruses
- Mircrospheres
- Liposomes
- Linear polymers- drug conjugates
- Dendritic polymers
- PEGylation
What is passive targeting? EPR
Targets tumours
Tumours have a ‘leaky’ vasculature and decrease in lymphatic drainage, this can help accumulate the drug
Large macromolecules also increased circulation time
How does Caelyx work?
Pegylated liposome formulation of doxorubicin
Increase half life
EPR
S/E- accumulation in soles or feet and hand leading to inflammation (hand foot syndrome)
Alternative - non PEGylated liposome doxorubicin
Difference between keratinised and non keratinised?
Keratinised - keratin filled cells and intercellular lipids are more ordered and non polar
Non- keratinised - less ordered (amorphous) and polar
Why is it tough for drugs to access CNS?
BBB- TJ lipophilic
Efflux transports
Need good pharmacokinetics
Ways to penetrate CNS?
RMT CMT Osmotic disruption Chemical modification- lipidisation Efflux transporter inhibitors
How can RMT be used to increase drug uptake into the CNS?
Trojan horse approach (Transferrin receptor)
Drug is attached onto a monoclonal antibody which has affinity for receptors on the BBB
This allows it to be recognised and taken into the CNS via endocytosis
4 barriers of DNA delivery?
- Physicochemical- large MW, anionic charged, very polar
- Biochemical- endogenous nucleases hydrolyse DNA
- Cellular- target cell walls are difficult for large, highly polar molecules to penetrate
- Intracellular- lysosomal encapsulation
