Lecture 9: Lipid Based Drug Delivery Systems Flashcards
What is a coarse dispersion?
- droplet sizes > 200 nm
- unstable
- scatter light resulting in opaque appearance
- can be seen under light microscopy
What are the two types of systems that can be formed with an oil, water and surfactant mixture?
Coarse dispersion and colloids
What is a colloidal system?
- Drop size < 200 nm
- do not scatter light so appear transparent
- can only be seen under electron microscope
What is an example of a coarse dispersion?
Macroemulsion - normal emulsion
What is an example of a colloidal system?
Microemulsions
Liquid crystals
Liposomes
SEDDS and SMEDDS
What are microemulsions?
They are a thermodynamically stable, transparent or translucent system with the dispersed droplet sizes < 200nm.
They are either
O/w
W/o
Bicontinuous
What are the components of microemulsions?
- Water
- Oil
- Surfactant
- Co-surfactant
What oils are used in microemulsions?
Mineral oils,
Vegetable oils
Tri and di glycerides
Fatty acid esters
What surfactants are used in microemulsions?
Non-ionic
Zwitterionic
Anionic and cationic are less commonly used
What co surfactants are used in microemulsions?
Short and medium chain alcohols
What are the general advantages of microemulsions ?
- ease of preparation
- clarity
- long term stability
- ability to be filtered
- vehicle for drugs of different lipophilicities
- low viscosity
What are the general disadvantages of microemulsions?
-biological incompatibility of surfactant and/or co surfactants used such as cationic, anionic surfactants, short chain alcohols etc.
What are the specific advantages of w/o microemulsions?
- protection of water soluble drugs
- sustained release of water soluble drugs
- increased bioavailability
What are the specific advantages of o/w microemulsions?
- increased solubility of lipophilic drugs
- increased bioavailability
What are the specific advantages of a bicontinuous microemulsion?
Promising for topical (epidermal and ocular) drug delivery due to good spreading and wetting properties to skin
How is a microemulsion prepared?
By first constructing a pseudo-ternary phase diagram to determine the amount of each component to add.
This varies depending on the properties of each ingredient
Different quantities can result in different types of colloidal systems, hence the formulation is made, and via visual observations, phase contrast and polarising light microscopy, we can determine what sort of colloidal system has been formed and plot a pseudo-ternary phase diagram.
What sort of tests are used in the physical chemical characterisation of microemulsionS?
- Visual examination for phase separation
- Phase contrast and polarised light microscopy
- Freeze fracture transmission electron microscopy
- Electrical conductivity measurements
- Viscosity measurements
- Dye solubilisation
- Stability
- In vitro release study
How can visual examination for phase separation characterise a ME?
ME should be transparent,
If the product is cloudy, it indicates that either phase separation has occurred, or the product is actually a liquid crystalline system or a coarse emulsion
How can phase contrast polarised light microscopy characterise a ME?
Under a microscope, the dispersed phase and the dispersion medium can be seen. A coarse emulsion will appear to have equal distribution of droplets and size of droplets whereas an unstable emulsion will show droplets of multiple different sizes
A polarised microscope can also show birefringence exhibited by liquid crystals. This would not be apparent in a ME
How can freeze fracture transmission electron microscopy characterise a ME?
Can observe microemulsion droplets in fine detail and check they are in the <200nm range
How can electrical conductivity experiments help to characterise a ME?
If a ME sample conducts well this indicates the external phase is water.
A bicontinuous ME will also exhibit high conductance
How can viscosity measurements help to characterise a ME?
All ME systems exhibit Newtonian flow
An increase in oil weight ratio decreases viscosity and a lower viscosity is desireable for drug delivery and pharmaceutical development
A ME has a lower viscosity than a LC
What are liposomes?
Vesicles that are made up of one or more lipid bilayers surrounding the internal aqueous compartment
The most common used lipid is the phospholipid which forms the backbone of the bilayer
What are the 5 main groups of phospholipids that are available that can be used for liposome preparation?
1) phospholipids from natural sources
2) phospholipid modified from natural sources
3) semi-synthetic phospholipid
4) fully synthetic phospholipid
5) phospholipid with non-natural head groups
What are the commonly used phospholipids for liposome preparation?
Phosphatidylcholine (most common)
Phosphatidylenolamine
Phosphatidylserine
What is phisphatidylcholine ?
The most commonly used phospholipid in liposome formation.
-amphiphatic molecule (contains hydrophilic and hydrophobic groups linked by a glycerol bridge
What is the hydrophilic portion of phosphatidylcholine?
Phosphocholine hydrophilic head group
What is the hydrophobic portion of phosphatidylcholine?
A pair of hydrophobic acyl hydrocarbon chains
What are some properties which affect choice of lipid or lipid composition of liposomes and why?
Number of bilayers
Size of lipid
Surface charge of lipid
These properties will affect the drug delivery characteristics of liposomes
What are the different types of liposomes?
Small unilaminar vesicles Large unilaminar vesicles Multimellar vesicles Oligolamellar vesicles Multivesicular vesicles
What is the diameter size and the number of lipid bilayers of SUV?
20-100nm, one lipid bilayer
What is the diameter size and number of lipid bilayers of LUV?
> 100nm, one lipid bilayer
What is the diameter size and number of lipid bilayers of MLV?
> 0.5μm, about 5 to 20 lipid bilayers
What is the diameter size and number of lipid bilayers of an OLV?
Diameter of 0.1-1μm, approx 5 lipid bilayers
What is the diameter size and number of lipid bilayers of MMV?
Diameter of > 1μm, a multicompartmental structure
What are the advantages of liposomes as vehicles for drug delivery?
- accommodates water soluble and lipid soluble drugs in the same system
- protects susceptible water soluble molecules (proteins and peptides)
- controls the release
- allows drug targeting
What are the disadvantages of liposomes as vehicles for drug delivery?
- susceptibility of phospholipids to dehydration and oxidation
- preparation is tedious as it requires multiple steps and sonication
- size variation
- variation in drug loading as a result of drug content
Why is phisphatidylcholine preferred for liposome formulation?
In the aqueous media, PC molecules will align themselves in a planar bilayer sheet to minimise unfavourable interactions between bulk aqueous phase and long hydrocarbon fatty acid chains while normal detergents with a polar head and single chain will preferentially form a micelle structure
Why are liposomes used as a delivery system?
- low toxicity profile
- ability to incorporate both hydrophilic and hydrophobic drugs
- protection of drug from inactivation in blood stream
- variability in size to incorporate larger or smaller drug molecules
- possibility of controlled delivery
- e.g. Ambisome, doxil
What is drug loading?
Incorporating drugs into the liposome,
Polar drugs are entrapped in the internal Aqueous compartment and lipophilic drugs are intercalated into liposome membrane
The water solubility of polar drugs is an important determinant of efficient incorporation into the liposome
What does liposomal drug delivery depend on?
Physicochemical properties of the drug
Lipid composition of the drug
What does the maximal incorporation of drug loading capacity for lipophilic drugs depend on?
The concentration of the lipid
What does the size and shape of liposomes depend on?
The method of preparation
The lipid composition
The ionic strength of the medium
The pH
What are the three main classes of liposomes?
Multilaminar vesicles
Small unilaminar vesicles
Large unilaminar vesicles
What are multi-lamellar vesicles?
- most common preparation
- onion like shape
- size is relatively heterogenous with diameter ranging from 400-3500nm
- each vesicle generally consist of 5 or more lamellae
- advantage is easy preparation with minimal euipment
- disadvantage is low encapulation capacity
what are small unilamellar vesicles?
- spherical in shape,
- optically clear
- size about 25-50nm diameter
- major advantage: relatively homogenous population
- disadvantages: low encapsulation efficiency, asymmetric distribution of various lipids between the inner and outer oolayer
What are large unilamellar vesicles?
- high aqueous space-to-lipid ratio
- size is about 20-1000nm
- advantage: high encapsulation of water soluble drugs, economy of lipid, reproducibility of drug release
- disadvantage: heterogenicity
how are multilaminar vesicles formed?
several vesicles in a multivesicular structure will form one inside the other in diminishing size, creating a multilamellar structure of concentric phospholipid spheres separated by layers of water
what is a bioadhesive system?
-system which facilitates attachment to tissus. e.g. mucoadhesive systems for the treatment of IBD
What are intelligent polymers?
polymers which are sensitive to stimuli such as pH, temerature, UV etc.
What re polymeric micelles?
where a drug is incorporated into a hydrophobic core, to be targeted locally to a tumour
What is a self regulated delivery system?
systems which release drug in response to physiological stimuli e.g. insulin/glucose
what is a cell delivery system?
systems which deliver cells producing the drug e.g islet cells/insulin
what are pharmacy on a chip systems?
where several drugs are released at various times imbedded on a ‘chip’
what are magnetically controlled drug delivery systems?
here the drug release is controlled by the application of a magnetic field
what are targeted polymeric systems (aka active targeting))?
delivery by targeting specific receptors (e.g. liver, asialoglycoprotein receptors)
what are self-emulsifying-drug-delivery-systems?
SEDDS of SMEDDS are isotropic mixtures of natural or synthetic oils, solid or liquid surfactants, or alternatively, on or more hydrophilic solvents and coslvents/surfactants
what are the main components of SEDDS?
oil + surfactant (upon aq. dilution)
what are the main components of SMEDDS?
oil + surfactant cosolvent/cosurfactant (upon aq dilution) forms a microemulsion or fine emulsion
what is the main structural difference between SEDDS and SMEDDS?
SMEDDS contains cosurfactant which ensures flexibility of the interfacial layer resulting in reduction of interfacial tension
what are the applications are SEDDS and SMEDDS?
- improved bioavailability of poorly soluble/absorbed drugs
- improving stability of oxygen/light sensitive drugs
- improving content uniformity of highly potent drugs
- controlled release
- ease of handling
