Pharmaceutics Flashcards
(39 cards)
Why do we need to formulate cancer drugs?
Existing drugs have a low theraputic window?
Cancer drugs are dosed close to the maximum tolerated dose
biological drugs are degraded if taken orally
Why is it an issue to take Nilotinib with food?
It has a LogP of 4.4 and is therefore lipid soluble so bioavalibility is largely increased and may be to a toxic level
What are the advantages of giving chemo IV?
Accurate, rapid dosing that can be removed instantly if adverse effects are too severe.
It also avoids first pass metabolism and fed or fasting effects on drug don’t apply.
Flexibility of dosing schedule.
Disadvantage of chemo via IV
accurate dosing but increased nausea
What are the stringent requirements for IV formulations?
Sterile production, formulation stability, no preservatives and low excipients as bypassing body’s natural defence barrier
What would we have to consider when formulating a chemo drug for subcutaneous use? (i.e. IM)
Highly vascularised muscles
formulation requirements are less severe
could use implants colloids and suspensions
A high collagen content in the muscle could bind the charged drugs.
Name a topical treatment used for malignant melnoma
Tretonoin
Why would you use etoposide phosphate over etoposide?
Easier to formulate and handle in vitro cytotoxicity is less
Why should alkaline solutions be avoided with doxorubicin?
Promotes hydrolysis
What key properties does etoposide have that make it difficult to formulate IV?
- low solubility in water
- tendency to crystallize or precipitate
- Binds strongly to plasma proteins (e.g. albumin has a hydrophobic binding site) - up to 94% can be found bound in human pasma
What can be done about formulating etoposide?
- co planar orientation of aromatic ring in drug and salicylate salt improves solubility in aqueous solution (net charge negative - charge charge repulsion prevents precipiation and protein binding)
- this all leads to enhanced bioavailability
- Increased solubility leads to: lower volume of injection and better formulation stability
How can etopside be formulated as a prodrug?
- phosphorylated
- water-soluble so available as a dry powder for dilution of pre-formed
- can be infused in 5 minutes
- easier to formulate and handle
- but lower cytotoxicity as needs to be dephosphorylated to pro drug - binding site effected so not as active
- when converted to etoposide it can bin to serum albumin
- caution needed when administering etopophos with drugs which inhibit phosphatase activities (e.g. levamisole hydrochoride)
Key chemistry point regarding doxorubicin?
- dox can form stacked dimers and polymeric self-assembled aggregates
- pi-pi interactions strong between aromatic rings (also important in dox-DNA binding)
- same property but can be blessing or curse
How can we safely formulate doxorubicin?
- formulate with parabens (p-hydroxybenzoic acid esters) - make a complex with dox
- this disrupts self assembly of drug, enables rapid dissolution from lyophilised formulation, enhances bioavailability and gives more predictable dosing
Why can’t doxorubicin be formulated with alkaline or heparin or 5FU?
- precipitates the drug
- due to covalent bonds in dox dimers
What are the formulation demands of proteins?
- rheology (flow of matter)/viscosity
- self-aggregation
- precipitation
- formulated with buffers, tonicity agents, stabilisers, etc
- formulation and excipients must be: sterile, pH close to neutral to avoid stinging, stable even at high protein conc
What can happen when you shake a high concentration of proteins in a vial?
- proteins are amphiphilic
- contains charged amino acids and hydrophobic regions
- if protein is denatured or assembled at the interface, or if shear is created by shaking, association and aggregation can occur
How do we avoid systemic toxicity with dox dosing?
Encapsulate dox into a virus-sized carrier in stacks
What is the criteria for the dox carrier?
- high drug incorporation
- long-circulation time
- stable in circulation
- reisis absorption or plasma proteins
- ability to release drug in tumour
- exploit enhanced permeation and retention effect (EPR)
What are the factors affecting EPR?
Vehicle related: plasma residence time, particle sze (big enough the transpot and not pumped out by efflux pumps), carrier vehicle, polymer architecture
Tumour related: tumour type, microenvironment
External mediators: radiation, bradykinin antagonist, cyclooxygenase inhibitor, nitric oxide scavengers
- note: EPR effect measured mostly in implanted tumours: limited data on epr in metastatic lesions in patients, significant patient and tumour heterogeneity therefore, tumour response alone is not a good predictor of overall survival
What are the other factors that define passive targeting?
- prolonged blood circulation of drug carriers is important: drug carriers delivered to target tissue through bloodstream, extravasation considered to be slow and passie manner
- obstacles to long circulation of partculate or macromolecular carriers: glomerular excretion by the kidney, recognition by reticuloendothelial system (RES) located in the liver, spleen and lung
- Glomerular secretion can be avoided by using carriers (bigger moleculars wont be filtered out - thershold value 42-50 kDa for water soluble polymers)
- RES recognitions: not just size but also shapes
Describe how dox is formulated as liposomal to solve the problems
- Average particle size 90-100nm ~ virus-size
- PEG layer prevents attachment of plasma proteins - entropic stabilisation also prevents aggregation
- Liposomal dox.HCl - half life = 55hrs of 26 hour for HCl salt alone
- lomger duration time allows passive transport to tumour tissue with disrupted vasculature - accumulation in tumour
- reduced binding of dox to plasma proteins as it’s encapsulated in transit to tumours
- total diameter - 200nm = good for transport but limiting factor for drug loading
- liposomes are highly diluted for injection: drug leakeage during transport and balance of stability of liposome and drug release = BAD
- changing pH and counter-ion (Dox.HCl vs NH4SO4) allows high loading of drug and self-association of drug in liposome - gives high conc of fibrous gel in liposome
- may also be a benefit of reduced p\h in solid tumurs - retained liposomes exhibit prolonged time in lower pH environments
- BUT - EPR effect not present for all tumours: also, unwanted accumulation at sites with poor circulation, palmer-palmar syndrome: damage to fingers, toes, peripheral sites
How is Paclitaxel formulated to avoid long infusion times and toxic solvents?
Formulate paclitaxel within a nanoparticle pre-formed from albumin & PTX - details are patented but likely a controlled precipitation of albumin in the presence of PTX
What is tamoxifen?
- endocrine therapy to slow/stop growth of hormone-related cancers
- not cytotoxic = range of administration routes and formulations possible
- weak base: low aqueous solubility, converted to citrate salt to be given orally, originally screened to be a new contraceptive agent
- is a pro-drug: an antagonist of oestrogen receptor in breast via active metabolite (4-hydroxytamoxifen)
- peak plasma conc ~ 4-7 hrs after oral dose
