L9 - Formulation considerations & targeted delivery of anticancer drugs

Question 1

What is cancer?

Answer 1

Diseases in which cells divide without control

Question 2

Which method is chemotherapy most commonly delivered by?

Answer 2

Parenteral: IV injection or infusion

Question 3

What are parenteral preparations?

Answer 3

STERILE preparations intended for administration by injection/infusion/implantation into human or animal body

Question 4

What are FOUR advantages of parenteral/injectable formulations?

Answer 4

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)

Question 5

What are THREE disadvantages of parenteral/injectable formulations?

Answer 5

Frequent pain & injection site reactions (may be due to drug or excipients)

Psychological fears (needle)

Incorrect dose difficult to counteract

Question 6

What are FOUR specialised parenteral routes for chemotherapy?

Answer 6

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

Question 7

What are THREE biopharmaceutical problems with chemotherapy?

Answer 7

Poor aqueous solubility

Tissue damage/irritation

Unfavourable pharmacokinetics

• Rapid in vivo breakdown
• Poor distribution/cellular uptake
• Lack of selectivity for target tissues

Question 8

What is ONE pharmacodynamic problem with chemotherapy?

Answer 8

Non-specific targeting
- All proliferating cells are attacked, inc. normal cells

–> Off-target side effects

Question 9

What are THREE implications of poor solubility for chemotherapy?

Answer 9

Difficulty for high dosing

Drug precipitation

Toxicities associated with excipients/solvent [which have been added to improve solubility]

Question 10

What are THREE drug delivery systems to counteract poor solubility for chemotherapy?

Answer 10

Nanosuspension

Nanoencapsulation

Cyclodextrin inclusion/mocular encapsulation

Question 11

What are TWO implications of tissue damage/irritation for chemotherapy?

Answer 11

Inadvertent extravasation of drug into tissue surrounding injection site –> tissue ncecrosis

Pain

Question 12

What are TWO drug delivery systems to counteract tissue damage/irritation for chemotherapy?

Answer 12

Nanoencapsulation

Cyclodextrin inclusion

Question 13

What is the most ideal solvent for formulation?

Answer 13

Water for injection

Question 14

What are THREE ways of improving solubility?

Answer 14

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

Question 15

What is post-injection drug precipitation?

Answer 15

Occurs in poorly water-soluble drugs solubilised in solvent systems/non-physiological pH

Occurs after SC, IM, IV injections

Question 16

How does post-injection drug precipitation occur?

Answer 16

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)

Question 17

What is phlebitis?

Answer 17

Inflammation of vein

Question 18

How does phlebitis occur?

Answer 18

Chemical irritation to endothelial cells

Release of inflammatory mediators

Drug precipitation (large particles) –> deposit on veins –> prolonged drug exposure –> increased irritation

Question 19

What are some strategies to resolve pain on injection, post-injection drug precipitation, decreased solubility?

Answer 19

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

Question 20

What is the implication of rapid in vivo breakdown & rapid clearance for chemotherapy?

Answer 20

High drug doses/continuous infusion required

Question 21

What is a drug delivery system to counteract rapid in vivo breakdown & rapid clearance for chemotherapy?

Answer 21

Controlled/sustained release

Question 22

What are FOUR examples of parenteral controlled release strategies?

Answer 22

Dissolution-controlled depot

Encapsulation

Solidifying depot formulation

Implant or device

Question 23

What is a depot injection?

Answer 23

Slow-release, long-acting form of injectable medication

Question 24

What are TWO examples of dissolution-controlled release?

Answer 24

Nanosuspension

Micronised particles

Question 25

How does dissolution-controlled release work?

Answer 25

Reduce dissolution rate from formulation in tissue fluid | --> Decrease absorption rate

Question 26

What is a clinical example of microsphere-based long-acting depot?

Answer 26

Leuprorelin (LHRH/GnRH agonist) Microspheres are suspended in vehicle --> called "suspension"

Question 27

How does solidifying depots work?

Answer 27

Polymeric formulation in sol form before administration into body --> once administered become gel --> drug released over long period of time

Question 28

Qhat is a clinical example of implant?

Answer 28

Zoladex (goserelin)

Question 29

How does implant work?

Answer 29

Polymer-based implant degrades by hydrolysis | --> Slowed degradation & erosion of polymer results in controlled release

Question 30

What are TWO implications of poor distribution for chemotherapy?

Answer 30

Higher Vd = more drug reaches tissues & need higher dose to reach high plasma concentrations = dose-limiting side effects Cardiac toxicity of free doxorubicin

Question 31

What are TWO drug delivery systems to counteract poor distribution for chemotherapy?

Answer 31

Targeted drug delivery systems Nanoparticles (lower Vd)

Question 32

What is the implication of lack of selectivity for target tissues for chemotherapy?

Answer 32

Low concentration results in suboptimal therapeutic effect --> high dose required

Question 33

What is a drug delivery system to counteract lack of selectivity for target tissues for chemotherapy?

Answer 33

Localised drug delivery systems

Question 34

What are FOUR advantages of liposomes?

Answer 34

Non-toxic & biocompatible --> very similar to own cells Encapsulation of both hydrophilic & hydrophobic drugs High drug loading Easy surface modification --> actively targets tumour

Question 35

What is passive tumour targeting?

Answer 35

Drug permeates through leaky blood vessel walls [tumour angiogenesis] --> likely where tumour cells are

Question 36

What is active tumour targeting?

Answer 36

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

Question 37

How come drugs accumulate in tumours?

Answer 37

Tumours have lymphatic systems that do not work well --> drug not cleared from tumour & accumulates

Question 38

What are THREE important formulation parameters for passive tumour targeting?

Answer 38

Size (100-150nm) Long-circulation --> not cleared by body quickly Drug retention from carriers --> form drug in crystals to reduce drug release

Question 39

What is pegylation?

Answer 39

Form of long-circulation Covalent coupling of non-toxic, hydrophilic PEG to drug --> Prevents recognition/opsonisation & rapid clearance

Question 40

What are FOUR advantages of local drug delivery?

Answer 40

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