L9 - Formulation considerations & targeted delivery of anticancer drugs Flashcards
What is cancer?
Diseases in which cells divide without control
Which method is chemotherapy most commonly delivered by?
Parenteral: IV injection or infusion
What are parenteral preparations?
STERILE preparations intended for administration by injection/infusion/implantation into human or animal body
What are FOUR advantages of parenteral/injectable formulations?
Rapid onset & PREDICTABLE effect
Predictable & high bioavailability
Avoid GI tract –> first-pass metabolism, pH degradation
Reliable in very ill/comatose patients (where swallowing not viable)
What are THREE disadvantages of parenteral/injectable formulations?
Frequent pain & injection site reactions (may be due to drug or excipients)
Psychological fears (needle)
Incorrect dose difficult to counteract
What are FOUR specialised parenteral routes for chemotherapy?
Intraarterial chemotherapy via catheter –> deliver chemotherapy directly to tumour, which reduces exposure to healthy tissue
Hyperthermic peritoneal chemotherapy –> deliver chemotherapy directly to lining of abdominal wall cavity during surgery
Intrathecal to CNS
Intravesicular to bladder
What are THREE biopharmaceutical problems with chemotherapy?
Poor aqueous solubility
Tissue damage/irritation
Unfavourable pharmacokinetics
- Rapid in vivo breakdown
- Poor distribution/cellular uptake
- Lack of selectivity for target tissues
What is ONE pharmacodynamic problem with chemotherapy?
Non-specific targeting
- All proliferating cells are attacked, inc. normal cells
–> Off-target side effects
What are THREE implications of poor solubility for chemotherapy?
Difficulty for high dosing
Drug precipitation
Toxicities associated with excipients/solvent [which have been added to improve solubility]
What are THREE drug delivery systems to counteract poor solubility for chemotherapy?
Nanosuspension
Nanoencapsulation
Cyclodextrin inclusion/mocular encapsulation
What are TWO implications of tissue damage/irritation for chemotherapy?
Inadvertent extravasation of drug into tissue surrounding injection site –> tissue ncecrosis
Pain
What are TWO drug delivery systems to counteract tissue damage/irritation for chemotherapy?
Nanoencapsulation
Cyclodextrin inclusion
What is the most ideal solvent for formulation?
Water for injection
What are THREE ways of improving solubility?
Use of organic solvents for solvent-water systems
pH adjustment/salt formation –> eg. decreased pH allows basic drugs to be ionised & therefore more readily absorbed in water
What is post-injection drug precipitation?
Occurs in poorly water-soluble drugs solubilised in solvent systems/non-physiological pH
Occurs after SC, IM, IV injections
How does post-injection drug precipitation occur?
pH neutralisation (eg. tissue acts like buffer)
- -> Drug concentration becomes more than solubility
- -> Drug which was ionised becomes unionised again & precipitates
- -> Poor absorption (IM/SC) or phlebitis (IV)
What is phlebitis?
Inflammation of vein
How does phlebitis occur?
Chemical irritation to endothelial cells
Release of inflammatory mediators
Drug precipitation (large particles) –> deposit on veins –> prolonged drug exposure –> increased irritation
What are some strategies to resolve pain on injection, post-injection drug precipitation, decreased solubility?
Cyclodextrin use (molecular encapsulation)
Micro- or nanocarriers [macro sized particles can only be used in local site injections, not into bloodstream –> may precipitate]
- -> Controlling drug diffusion –> no accumulation of drug
- -> Prevent direct drug exposure to tissue
What is the implication of rapid in vivo breakdown & rapid clearance for chemotherapy?
High drug doses/continuous infusion required
What is a drug delivery system to counteract rapid in vivo breakdown & rapid clearance for chemotherapy?
Controlled/sustained release
What are FOUR examples of parenteral controlled release strategies?
Dissolution-controlled depot
Encapsulation
Solidifying depot formulation
Implant or device
What is a depot injection?
Slow-release, long-acting form of injectable medication
What are TWO examples of dissolution-controlled release?
Nanosuspension
Micronised particles
How does dissolution-controlled release work?
Reduce dissolution rate from formulation in tissue fluid
–> Decrease absorption rate
What is a clinical example of microsphere-based long-acting depot?
Leuprorelin (LHRH/GnRH agonist)
Microspheres are suspended in vehicle –> called “suspension”
How does solidifying depots work?
Polymeric formulation in sol form before administration into body –> once administered become gel –> drug released over long period of time
Qhat is a clinical example of implant?
Zoladex (goserelin)
How does implant work?
Polymer-based implant degrades by hydrolysis
–> Slowed degradation & erosion of polymer results in controlled release
What are TWO implications of poor distribution for chemotherapy?
Higher Vd = more drug reaches tissues & need higher dose to reach high plasma concentrations = dose-limiting side effects
Cardiac toxicity of free doxorubicin
What are TWO drug delivery systems to counteract poor distribution for chemotherapy?
Targeted drug delivery systems
Nanoparticles (lower Vd)
What is the implication of lack of selectivity for target tissues for chemotherapy?
Low concentration results in suboptimal therapeutic effect –> high dose required
What is a drug delivery system to counteract lack of selectivity for target tissues for chemotherapy?
Localised drug delivery systems
What are FOUR advantages of liposomes?
Non-toxic & biocompatible –> very similar to own cells
Encapsulation of both hydrophilic & hydrophobic drugs
High drug loading
Easy surface modification –> actively targets tumour
What is passive tumour targeting?
Drug permeates through leaky blood vessel walls [tumour angiogenesis] –> likely where tumour cells are
What is active tumour targeting?
Drug has receptors added to surface that will bind to specific targets on tumour cells
Requires passive targeting to occur beforehand –> leave bloodstream & find tumour cell first before can bind
How come drugs accumulate in tumours?
Tumours have lymphatic systems that do not work well –> drug not cleared from tumour & accumulates
What are THREE important formulation parameters for passive tumour targeting?
Size (100-150nm)
Long-circulation –> not cleared by body quickly
Drug retention from carriers –> form drug in crystals to reduce drug release
What is pegylation?
Form of long-circulation
Covalent coupling of non-toxic, hydrophilic PEG to drug
–> Prevents recognition/opsonisation & rapid clearance
What are FOUR advantages of local drug delivery?
Reduce systemic side effects
Overcome BBB
Increased drug exposure to tumours
Effectively kill tumour cells due to high drug concentration, usually those left behind after surgery
