Advanced Drug Delivery 6 - Microparticles and Nanoparticles Flashcards
What are Microparticles
Particles in the micro size range, normally between 3-800 µm
Two types: microcapsules, microspheres
What is a microsphere
No distinct region
Matrix system
What is a microcapsules
Two distinct regions: external wall and central core
A reservoir system since they consist of two parts
Microcapsule: has distinct regions
Technically a polynuclear microcapsule because it has multiple nuclei
Which one is which: microcapsule, microsphere
Top: microcapsule - distinct regions (external wall, central core), reservoir system
Bottom: microsphere - no distinct region, matrix system
Administration routes of Microparticles
IV, directly to specific compartment (e.g. inhalation, local injection, SC)
What does body distribution of Microparticles depend on
size, shape, surface charge, surface tension
5 requirements of materials used to make Microparticles
chemically inert
non-toxic (not the drug so will not accept any toxicity!)
biocompatible
biodegradable if necessary
easy to sterilise - esp for injections
Examples of materials used to make Microparticles
Proteins (e.g. albumin, gelatin)
Polysaccharides (e.g. starch, cellulose, chitosan)
Polyesters (PLA, PGA, PLGA)
Polyanhydrides
Polyvinyl derivatives
Polyacrylates
Others e.g. waxes
5 applications of Microparticles
MR
Conversion of liquids into pseudo solids
Protection from external environment
Mask flavour and odour - organoleptic properties
Reduce gastric irritation
How to convert liquids into pseudo solids using Microparticles
Encapsulate the liquid API to form a microcapsule, this makes it become a pseudo solid
3 Steps to prepare Microparticles
- Disperse drug in the polymer (constituent) solution
- Coacervation (or phase separation) - using a trigger that makes polymer precipitate so you can form Microparticles
- Hardening of coating
4 examples of coacervation
Changing temperature of polymer solution
Salting out
Adding non solvent
Inducing a polymer-polymer interacition
Ways to harden coating
Promote cross linking or cool the system down
Coacervation: changing temperature of polymer solution
Materials have different solubilities at different temperatures
There is a dispersion of the drug in the polymer solution - polymer is dissolved
Change to a temperature at which polymer is no longer soluble so that it precipitates out and you form Microparticles
Coacervation: salting out
Drug is disperse in a solution of a polymer
Add an inorganic salt (contains anions + cations)
Water molecules will preferentially interact with the charged ions
Polymer will precipitate out, Microparticles will form
Coacervation: adding a non solvent
Polymer is solubilised in solvent A
Add solvent B which is miscible (can be mixed) in solvent A
Solvent B needs to be a poor solvent for the polymer (polymer is insoluble in this)
Polymer will precipitate out
Microparticles will form
Coacervation: inducing polymer-polymer interaction
Add a second polymer to the solution that interacts with the first polymer and makes it precipitate out
Formation of Microparticles
Preparation of Microparticles via interfacial polymerisation
Start with a monomer and make the polymerisation in situ
Polymer is formed at the interface between two immiscible liquids: organic phase and aqueous phase + dissolved drug
By addition, you can obtain microspheres
By Condensation, you can form microCapsules
Preparation of microspheres by heat or chemical denaturation
Good way to make Microparticles when material is protein
Oil phase, add an aqueous solution of protein + drug
Mix the two to form emulsion: water in oil
Need a trigger to denature protein so that Microparticles can form
Chemical: add glutharaldehyde or butadiene which cross slinks protein and it will precipitate out
Physical: heat system 100-170C to denature and precipitate protein out
Spray drying to form Microparticles
- atomisation of liquid feed ( also containing drug ) into fine droplets
- mix spray droplets with heated gas system, allowing liquid to evaporate and leave a dried solid
- dried powder separated from gas stream and collected
5 advantages of spray drying to form Microparticles
quick and reproducible
control of particle size
low cost
good yield
applicable to heat sensitive materials
limitations of spray drying to form Microparticles
need polymers that give low viscosity solutions
need small droplets
water soluble compounds have poor encapsulation
5 ways that drug is released from microspheres
Erosion
Disintegration of microsphere in body to release API
Swelling of microsphere, and API diffuses out
Desportion and diffusion
Ionic exchange
Drug release from microspheres: desorption & diffusion
In the microsphere, some of the drug could be inside and some could be adsorbed on surface via interactions
Once administered, there is a change in environment
Adsorbed drug may come off and diffuse into the body fluids
Drug release from microspheres: ionic exchange
Adsorbed drug is an ion - a charged drug
Administer microsphere
Many ions present tin body that can interact and swap with the drug
What are nanoparticles
Particles in the nano size range: nm
Two types: nano capsules and nanospheres
Nanocapsules
2 distinct regions so are a reservoir system
External wall and central core
Nanospheres
Matrix system as they only have a single region
Location of API in nanoparticles
API can be dissolved, physically entrapped or adsorbed on the surface
No covalent bonds - just interactions
3 ways to make nanoparticles
- Some scientists make PDG and from them they make nanoparticles (hybrid system)
- Using ready made polymers
- Methods that require polymerisation
2 polymers most commonly used for nanoparticles
PLA and PLGA
Preparation of nanoparticles using solvent evaporation
Two beakers: polymer + drug and water +emulsifying agent
Mix the two to form an oil water emulsion
Droplets of solvent contain the polymer + drug
Solvent evaporation to form nanoparticles
Nanoparticles will precipitate and can be collected
Toxicity of Microparticles and nanoparticles
Generally acute toxicity is low as it depends on materials used and they are no toxic
Toxicity depend son size and number of particles injected
Longer term toxicity:
- consider possibility of material starting to accumulate in body
- need to ensure material is being eliminated form body e.g. by degradation and bioerosion
Biodegradation as a method to eliminate Microparticles and nanoparticles from body
Polymer gets broken down at level of monomer as bonds between monomers are biodegradable
e.g. PLGA: ester bonds break down
Bioerosion as a method to eliminate Microparticles and nanoparticles form body
Points of junctions in polymer get broken down
Don’t end up with individual monomers, but smaller components of the polymer
These are small enough for body to degrade them
Problems with IV injections of nanoparticles and a solution
Nanoparticles can be endocytosed by macrophages of the reticular endoplasmic system (RES)
This is good if we are targeting the liver or spleen
This is bad if it reaches other tissues because it won’t be effective
Strategy: PEG-coated nanoparticles to mask them from macrophages
What is ABRAXANE
Nanoparticle on the market
contains palictaxel
used in cancer therapy for advanced metastatic breast, pancreatic and NSCLC
