Lec 11- Liposomes (Part 1) Flashcards
1
Q
So what are liposomes
A
- Spherical bilayer constructs built from phospholipids
- Resembles lipid bilayer of mammalian membranes
- Hid drugs in the sphere
- Drugs will not act on the body apart from when released in the active site
- Body is unable to degrade drug= increase F/stability
2
Q
Lipid- a classification system
NOT a question in the exam
A
- Non-polar lipids
- Insoluble in water
- Monolayers at the water-air interface
- Aliphatic and aromatic carbohydrates, paraffin
- Polar lipids
- Surface active
- Class I: Insoluble in water, do not swell in water e.g. triglycerides
- Class II: Insoluble in water, swell in water
- Class III: Some solubility, form micelles- ionic and non-ionic surfactants
- Surface active
3
Q
Types of delivery systems
A
- Class I: emulsions and solid lipid nanoparticles
- Class II: Bilayer vesicles
- Class III: micelles
4
Q
Lipid molecular characteristics dictate construct
A
5
Q
The shape of the lipid may be expressed as its critical packing parameter (p) which can be defined as
A
- v= molecular volumes of the hydrophobic part of the polar lipid
- ao= surface area per molecule at the hydrocarbon-water interface
- Ic= length of the hydrocarbon region
6
Q
Combinations of lipids can create a wide range of structures
A
- For cancer, we want to use SUV <100nm hide from the body
- Niosomes= non-ionic surfactant
- Virosomes- Attenuated virus combined in a liposome
7
Q
Commonly employed lipids in liposomes
A
- Phosphatidylcholine is a commonly used component in liposomes however a range of other lipids are also used
- The lipid head-group dictates the surface charge of the liposomes
- The lipid acyl tail influences the melting point of the lipid bilayer and its permeability and therefore influences drug release rates from liposomes
- The presence of cholesterol within the bilayers can reduce their permeability and drug leakage
8
Q
Phospholipids- headgroup
A
- The headgroup determines the charge
- At neutral pH phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are uncharged (zwitterionic)
- Phosphatidylglycerol (PG) and phosphatidylserine (PS) have 1 net-negative charge per molecule
9
Q
Which of the following could you make liposomes from
A
- Sodium dodecyl sulphate
- Cetyl trimethylammonium
- Phosphatidylcholine- Only one that makes liposomes
- Dioleoyl phosphatidylethanolamine- the size of head group= micelles
- if the molecule has two chains, it forms a liposome
- If it has one, it will form a micelle
10
Q
Bilayer properties- alkyl chain
A
- Transition temperature- where the vesicle membrane forms a gel-like structure, more likely to give up the drug
- We can apply heat to the skin- increase drug release in that area
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11
Q
Phospholipids- tailgroup
A
- Longer carbon chain= increase instability
12
Q
Classification
A
- There are various ways to classify liposomes including classification based on their composition and in vivo application e.g.
- Stealth liposomes which have a polyethyleneglycol (PEG) coat
- PEG hides liposome from MPS
- Immunoliposomes which have an antibody targeting moiety
- Cationic liposomes prepared using positively charged lipids
- Stealth liposomes which have a polyethyleneglycol (PEG) coat
- However, the most widely accepted is to classify liposomes into 3 main types, based on their size and number of bilayers
13
Q
Types of liposomes
A
- Modification of surface properties
- Modification of size
- Multilamellar vesicle (MLV)
- Large unilamellar vesicles (LUV)
- Small unilamellar vesicles (SUV)
14
Q
Types of liposome
MLV vs SUV vs LUV
A
- Can’t put much drug into SUV
- LUV will be thrown out by MPS or Kidneys
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15
Q
Liposomes
A
- Characteristics offered by liposomes
- Can entrap both water-soluble and poorly soluble drugs
- Can protect drugs from degradation in vivo
- Have been shown to be non-toxic
- The structure can be easily manipulated and tailored
- Can target and deliver drugs to required site of action
16
Q
Drug loading and release
Three categories of drug types may be differentiated in terms of their incorporation and retention in liposomes
A
- Hydrophilic drugs (log P <1.7): these are retained well in the aqueous core of liposomes
- Lipophilic drugs (Log P >5): These are easily incorporated and retained within the liposome bilayer
- Intermediate drugs (Log P 1.7-5): these partition between the bilayer and aqueous phase which can result in rapid loss from the liposome
17
Q
Liposomes as medicines
A
- Currently a range of drugs formulated in liposome products on the market
- The majority used in chemotherapy due to their passive targeting
- However, their biphasic nature makes them effective targeting systems for low solubility drugs
18
Q
Liposome-based products
A
- Depocyt (Cytarabine) - these are multivesicle liposomes composed of DOPC, cholesterol, triolein and DPPG
- The vesicles are in size range 3-30 microns (TARGET MPS organs)
- AmBisome (Amphotericin B)- these vesicles are <100nm in size and composed of soy phosphatidylcholine, cholesterol, diasteroyl
19
Q
Depocyte offers sustained release
A
- An injectable, sustained-release formulation
- Gradually releases cytarabine into the cerebral spinal fluid (CSF) and extends the dosing interval to once every two weeks
- Standard intrathecal chemotherapy dosing of 2 times per week
- MLV multiple layers degrade one after another to give controlled release of cytarabine (cytarabine concentrations split between the layers)
20
Q
Improving solubility
A
- Modify molecule
- Salts, pro-drugs, co-solvents
- Physical modification
- Crystal engineering, amorphous systems, particle size (reduction)
- Drug delivery systems
- Inclusion complexes, Emulsions, Lipid-based systems
21
Q
Case studies: Lipid formulations of amphotericin B
A
- Amphotericin B used is comprised of associated adverse side effects
- Lipid formulations of the drug offer a better therapeutic index and there are three commercially available lipid formulations of amphotericin B in clinical use
22
Q
Ambisome: passive targeting
A
- Amphotericin B is incorporated within the liposomal bilayers
- Formulations: 50mg Amphotericin B; 213mg SoyPC; 52mg ChE; 84mg DSPG; 0.64mg a-tocopherol
23
Q
AmBisome
A
- This is a small unilamellar liposome formulation with a well defined size range of ~80nm
- Due to it’s aqueous core this can be described as the only true liposome formulation of the three products
- It is composed to hydrogenated soy PC, ChE, disteroylphosphatidylglycerol and amphotericin B in 2:1:0.8:0.4 molar ratio
- It also contains a-tocopherol as an anti-oxidant
- The drug is intercalated within the liposomal membrane
24
Q
Ambisome: passive targeting
Leishmaniasis
A
- The parasitic disease spread by the bite of infected sandflies
- The most common forms are cutaneous, causing skin sores, and visceral, affecting the spleen, liver and bone marrow
- Advantages of liposomal delivery: Enhanced circulation and targeting of the drug, therefore reduced toxicity profile
25
Q
Passive targeting of liposomes to the MPS
A
- Liposomes, due to their particulate nature are taken up by the MPS
- This allows passive targeting of sites including liver, spleen, bone marrow
26
Q
Abelect
A
- This formulation is composed of Am B, dimyristoyl phosphatidylcholine, and mimyristoyl phosphatidylglycerol in a 1:1 drug to lipid molar ratio, it forms ribbon-like complexes which due to their structure are difficult to size however have been reported to be around 1.6 to 11um in diameter, with 90% of the particles being smaller than 6um
27
Q
Amphotec
A
- This formulation consists of AmB in a complex with cholesteryl sulfate at a 1:1 molar ratio to form stable colloidal disc-like structures with diameters of 100-140nm in size
28
Q
How would you design a liposome with long circulation and good drug retention
A
- Use a high melting point lipid e.g. DSPC- higher transition temperature
- Include ChE
- Make it an SUV (<100nm)
- PEG coating- Avoid opsonisation
