Pharmaceutics 2 -Physical and Chemical Properties of Drugs and Excipients for Formulation Flashcards
What is a problem that cancer drug formulation must overcome?
The properties that allow drugs to act on their target are often an obstacle to their delivery
What are the problems with etoposide chemistry for formulation?
Etoposide has;
a tendency to crystalline or precipitate
binds strongly to plasma proteins (up to 94% bound in plasma proteins).
How does the orientation of drug and salicylate affect aqueous solubility in etoposide? What does this improve in the formulation?
Planar orientation of drug and salicylate improve (aq) solubility.
Improved bioavailavility; reduced plasma protein binding, reduced precipitation
Increased solubility that leads to lower volume of injection (better tolerate) and better formulation stability.
What are the advantages to etoposide phosphate formulation?
As a prodrug; better solubility in water compared to OG formulation, can be infused over 5 minutes to 3.5 hours (+flexible and less exposure to risk of infection), easier to formulate and handle, less in vitro toxicity because not active metabolite until in vivo, less protein binding as phosphate.
What caution is needed when administering Etopophos™? (Etoposide Phosphate)
Caution in administering with drugs known to inhibit phosphatase activates
What is the self-assembly problem associated with doxorubicin?
Doxorubicin can undergo self-assembly that leads to the formation of stacked dimers. This complex has strong pie pie interactions betwee aromatic rings (also important in DNA binding) and this creating polymeric aggregates that can precipitate and cause embolism.
How can aromatic stacking be avoided in doxorubicin?
Parabens (p-hydroxybenzoic acid esters) can complex with doxorubicin and this disrupts the self-assembly.
What are the benefits to avoiding self-assembly / stacking of dimers in doxorubicin?
Enables rapid dissolution from lyophilised formulation, enhanced bioavailability and more predictable dosing
What are the benefits to doxorubicin HCl?
More soluble in salt form
Fast running infusion over minutes
Why should contact of doxorubicin with alkaline solutions be avoided?
The deprotonation of doxorubicin would reduce the solubility of the drug
Why should doxorubicin not be mixed with Heparin or 5-FU?
Precipitates may form due to the negative charges
How does bevacizumab (Avastin) act?
Malignant tumours rely on blood vessels for growth. The blood vessels require Vascular Endothelial Growth Factor (VEGF).
Bevacizumab binds to VEGF and forms a non-active complex that can be metabolised and excreted
What are the benefits of using bevacizumab (biological agent) in treatment of cancer?
No direct cell killing, so no associated toxicity (although side effect profile still relevant). The target for protein drugs such as Bevacizumab is extracellular so no need to cross membranes
What is the half life of bevacizumab and how does it vary between patients?
-20 days
Male patients and those with higher tumour burden have higher clearances of bevacizumab.
What are the formulation considerations for protein formualtions such as bevacizumab?
Viscosity (aggregation risk) Self-aggregation Precipitation Oral degradation, so route of administration Formulation with minimal excipients such as buffers, tonicity agents, stabilisers Sterility pH neutral to avoid stinging Stable at high protein concentrations
