Advanced Drug Delivery 2 - liposomes Flashcards
What are liposomes and their size
- Microparticulate or colloidal drug carriers
- Vesicular structures composed of one or more lipid bilayers encapsulating a central aqueous core
- The lipid molecules are normally phospholipids
- Size: 0.05 – 5 µm
Chemical structure of phospholipids
- Two fatty acid tails (hydrophobic)
- Phosphate group head (hydrophilic)
- This structural arrangement allows them to form lipid bilayers
Hydrophilic head
Phosphate moiety joined together by an alcohol or glycerol molecule
Characteristics of fatty acids
- fatty = lipophilic
- acid = COOH carboxylic group
What charge is phosphate
Negative
Phosphatidylcholine (PC) derivatives
- Phosphate group is -
- PC is +
- So overall neutral
Phosphatidylethanolamine (PE) derivatives
- Phosphate group is -
- PE is +
- So overall neutral
Phosphatidylserine (PS) derivatives
- Phosphate group is -
- PS has one + and one -
- So overall negative
Phosphatidylglycerol (PG) derivatives
- Phosphate group is -
- PG is -
- So overall negative
Discuss cholesterol in the context of liposomes
- Usually added to liposomes
- Amphiphilic:
Mostly hydrophobic
OH group makes is slightly hydrophilic - This allows cholesterol to insert itself in the bilayer with the OH group close to polar head and hydrophobic part next to lipophilic chains
The presence of OH group and the properties of liposomes
- The OH groups can form hydrogen bonds with other molecules in the liposome membrane
- Increases its stability and rigidity.
- Can impact the solubility and permeability of the liposome
Main transition temperature (TM)
Phospholipid membranes have a parameter called TM
Below the TM:
- cholesterol has a fluidising, disorganising action
- phospholipids bilayer is less fluid, more gel like
Above TM:
- cholesterol has a condensing action
- a lot of energy in system
- bilayer very fluid
Conformation of a lisaphospholipid
- e.g. detergents
- Geometry: like a cone
- Therefore most thermodynamically stable conformation is a micelle
Conformation of double chain phospholipids with LARGE head groups
- e.g. PC
- Large polar head and smaller tails that occupy smaller volume
- Geometry: like truncated cone
- Therefore, most thermodynamically stable conformation is bilayer vesicle
Conformation of double chain phospholipid with SMALL head groups
- e.g. PE
- Geometry: like a cyclinder
- Therefore, most thermodynamically stable conformation is planar bilayer
Conformation of phospholipid with two chains and unsaturation
- e.g. Phosphatidylethanol amine (unsaturated)
- Double bonds = tails spreads wider
- Geometry: Inverted truncated cone
- Therefore, most thermodynamically stable conformation is inverted micelle
Classification of Liposomes
- SUV - small unilamellar vesicles
- LUV - large unilamellar vesicles
- MLV - multilamellar vesicles
- MVV - multi vesicular vesicles
SUV
small unilamellar vesicle (SUV)
LUV
large unilameller vesicles (LUV)
MLV
multilamellar vesicles
MVV
multi vesicular vesicles
- How can liposomes be used as drug carriers?
- Can carry both hydrophobic and hydrophilic drugs
- Encapsulate the drug within the liposome; which protects from degradation and improves solubility in water
- Target specific cells/tissues; improves efficiency of drug and reduce SE
- Liposomes can be designed to release the drug in a controlled manner
Where hydrophobic and hydrophilic drugs inserts themselves in the liposomes
- hydrophobic drugs = hydrophobic tails (middle of bilayer)
- hydrophilic drugs = aqueous core
4 Characteristics of liposomes
- Drug:lipid ratio
- Encapsulation efficiency
- Size
- Lamellarity
Challenge of liposomes
- Bilayers form spontaneously after addition of water to phospholipids.
- The challenge is forming stable vesicles with the desired:
- Size
- Physio-chemical properties
- A high drug encapsulation frequency
What is high drug encapsulation efficiency
- Measure of how efficiently the drug is incorporated into the liposome
- Allowing for less liposomes to be administered (based on efficacy)
Typical methodology of preparing liposomes
- Lipid hydration
- Selection of liposomes based on size
- Remove the non-encapsulated drug
Thin layer evaporation method of preparing liposomes
- Mixture of phospholipids dissolved in organic solvent
- Solvent evaporation leads to phospholipid film in flask
- Add water-based buffer solution into phospholipid film for lipid hydration
- Stirring; temperature > transition temperature
- This causes film hydration under stirring
- Liposome will start forming
Additional methods to form desired lysosome
e.g. Sonification and extrusion
What is sonification
- Prepare a solution of PC in chloroform
- Place it in a round bottom flask and evaporate solvent
- Add an aqueous solution of the drug stirring
- Put liposome mixture in an ultrasound bath to reduce particle size
What is extrusion
- Process carried out through polycarbonate filters
- to control size under pressure by controlling size of pores in filter
Administration routes of liposomes
- Parenteral
- Pulmonary
- Oral
- Topical
Biodistribution of liposomes and PK of the API depend on
- size of vesicles
- composition of bilayer
- fluidity of bilayer
Stability of issues before administration and solution
- Oxidation of lipophilic chains
- Hydrolysis and formation of lysophospholipids
- Tendency to form aggregates
- Solution: freeze drying
Stabilities issues of liposomes after administration and solution
- Captured by macrophages
- Solution: long circulating liposomes (LCL) aka sterically stabilised liposomes (stealth)
- attach PEG chains, macrophages will not recognise them, allowing them to circulate for longer
4 types of liposomes based on composition and application
- Conventional liposomes
- Sterically stabilised (stealth) liposomes
- Immunoliposomes (antibody targeted)
- Cationic liposomes (for gene delivery)
Clinical applications of liposomes
- Abelcet
- AmBisome
- Doxil
What is Abelcet
- Contains amphotericin B
- Anti fungal with good activity BUT nephrotoxic
- Sodium chloride added for tonicity
What is AmBisome
- Amphotericin B encapsulated in conventional liposomes
- Parenteral use
- SUV (small unilamellar vesicles) 50-100nm
- Lower toxicity than normal amphotericin B
What is Doxil
- Liposomal encapsulated doxorubicin
- Anticancer agent that is very cardiotoxic
- Liposomes reduce toxicity
- Contain PEGlyated liposomes (long circulating liposomes)
