Physical and Chemical properties of Drugs and Excipients relevant to Formulation Flashcards
What negative feedback loop exists re. the properties that allow drugs to act on their targets vs. their delivery?
Negative feedback loop between drug properties (solubility, BCS type, stability) and ability to formulate into an injectable system
What formulation parallels exist between Amphotericin B (antifungal) and many anticancer drugs?
- AmB has a v. hydrophobic long oily chain; non-soluble, hence need to develop formulations:
> Amphotericin B lipid complex (ABLC)
> Liposomal amphotericin B (L-AmB)
> Amphotericin B colloidal dispersion (ABCD; also contains lipids)
What are the formulation problems of the anti-cancer drug, Etopside?
- Contains planar, aromatic components
- This leads to solubility issues (due to hydrophobicity/oily); low solubility of 0.98 g.L^-1
- Thus tendency to crystallise or precipitate (aromaticity)
How are the formulation problems of Etopside overcome?
- Solution containing sodium salicylate (salt)
- Planar orientation of drug and salicylate salt improves solubility in aqueous solution
- Reduced precipitation
- Reduced protein binding
- Enhanced bioavailability
- Increased solubility leads to:
> Lower volume of injection
> Better formulation stability
(improving tolerability for patient)
What are the pharmacokinetic issues with standard Etoposide Injection USP? What issues surround precipitation and MTD?
- High inter-individual variation (differences in protein binding)
- Rapidly distributed; concentrations in plasma fall in biphasic manner, with terminal t1/2 of 4 to 11 hours.
- Practically insoluble in water
- Given by slow IV infusion > 30 minutes
- Concentration of infusion: 200 - 400 micrograms/mL
»> Precipitation may occur at higher concentrations
> But want to dose patient at MTD for efficacy
Why must Etoposide OG be kept at neutral or weakly acid pH?
Lactone ring epimerises in alkaline pH, losing activity.
What is etoposide phosphate (Etopophos), and how does it compare with Etoposide OG?
- Pro-drug of etoposide; addition of phosphate group
- Confers greater water solubility (up to 20mg/mL, compared to 0.98mg/mL)
- Available as dry powder for dilution, or pre-formed solution (convenient for hospital)
- Can be infused over minute to 3.5 hours (flexibility in dosing schedule compared to just 30mins+)
- Less protein binding as pro-drug (phosphate form), but upon conversion, binding ratio correlates directly w/serum albumin
»> Easier to formulate and to handle
»> In vitro cytotoxicity for etoposide phosphate significantly less than etoposide
What precautions need to be considered when considering the pro-drug formulation of Etoposide, Etoposide phosphate?
- Pro-drug; requires dephosphorylation in vivo by phosphatase enzyme to etoposide
- Caution co-administering w/drugs known to inhibit phosphatase activities e.g. levamisole HCL
What are the formulation issues with Doxorubicin?
- Dox can form stacked dimers and polymeric self-assembly aggregates (aromatic stacking)
- Due to strong p-p interactions between aromatic rings (which are also important in Dox-DNA binding)
- Aggregates can precipitate
How are the formulation issues with Dox overcome w/Parabens?
- Parabens (p-hydroxybenzoic acid esters) is a surfactant
- In complex with Dox, it disrupts self-assembly (the aromatic stacking) of the drug
- Enables rapid dissolution from lyophilised formulation
- Enhanced bioavailability (no precipitation)
- More predictable dosing (good for therapeutic dosing)
Why is doxorubicin OG given via a fast-running infusion of NaCl 0.9%/Glucose 5% over 3 minutes or more?
(Why is rate of administration dependent on size of vein and dosage?)
- Dox forms stacked dimers and polymeric aggregates, w/strong p-p interactions between aromatic rings
- Fast-running infusion to minimise aggregation/chance for Dox to be in contact with itself = less precipitation
- Size of vein; larger the faster (less space for Dox to self-aggregate)
Why should contact w/alkaline solutions be avoided w/doxorubicin OG?
As deprotonation would render Dox less stable (precipitation?)
Why should Doxo.HCl not be mixed w/heparin or 5-FU?
Precipitates may form; due to the negative charges on heparin, (aromaticity of 5FU?)
What are the advantages of protein/biotechnology-based anticancer agents?
Targeting specific, molecular target for cancer:
- Non cytotoxic agents, specific anti-malignant agents
How does Bevacizumab (Avastin) demonstrate how protein-based therapy can solve the anticancer drug problem?
- Bevacizumab binds VEGF to form non-active complex; metabolised and excreted
- Mechanism is not via direct cell kill
- No S/Es due to direct toxicity as a result (but still some due to inhibiting angiogenesis)
- Target for protein drug is extracellular; no need to cross membranes as opposed to TKIs
