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
- 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)
- Hardening of coating
Coacervation
The process by which a polymer solution separates into two phases
4 factors of coacervation
- Changing temperature of polymer solution
- Salting out
- Adding non-solvent
- Inducing a polymer-polymer interaction
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 non-solvent
- Will cause polymer to become less soluble and associate with each other
- Forms a dense liquid phase (coacervate) and a dilute liquid phase (supernatant)
- 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 links 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
- Desorption 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 depends on 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 from body e.g. by biodegradation and bioerosion
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
