Advanced Drug Delivery 6 - Microparticles and Nanoparticles

Question 1

What are Microparticles

Answer 1

Particles in the micro size range, normally between 3-800 µm
Two types: microcapsules, microspheres

Question 2

What is a microsphere

Answer 2

No distinct region
Matrix system

Question 3

What is a microcapsules

Answer 3

Two distinct regions: external wall and central core
A reservoir system since they consist of two parts

Question 4

Answer 4

Microcapsule: has distinct regions
Technically a polynuclear microcapsule because it has multiple nuclei

Question 5

Which one is which: microcapsule, microsphere

Answer 5

Top: microcapsule - distinct regions (external wall, central core), reservoir system
Bottom: microsphere - no distinct region, matrix system

Question 6

Administration routes of Microparticles

Answer 6

IV, directly to specific compartment (e.g. inhalation, local injection, SC)

Question 7

What does body distribution of Microparticles depend on

Answer 7

size, shape, surface charge, surface tension

Question 8

5 requirements of materials used to make Microparticles

Answer 8

chemically inert
non-toxic (not the drug so will not accept any toxicity!)
biocompatible
biodegradable if necessary
easy to sterilise - esp for injections

Question 9

Examples of materials used to make Microparticles

Answer 9

Proteins (e.g. albumin, gelatin)
Polysaccharides (e.g. starch, cellulose, chitosan)
Polyesters (PLA, PGA, PLGA)
Polyanhydrides
Polyvinyl derivatives
Polyacrylates
Others e.g. waxes

Question 10

5 applications of Microparticles

Answer 10

MR
Conversion of liquids into pseudo solids
Protection from external environment
Mask flavour and odour - organoleptic properties
Reduce gastric irritation

Question 11

How to convert liquids into pseudo solids using Microparticles

Answer 11

Encapsulate the liquid API to form a microcapsule, this makes it become a pseudo solid

Question 12

3 Steps to prepare Microparticles

Answer 12

1. Disperse drug in the polymer (constituent) solution
2. Coacervation (or phase separation) - using a trigger that makes polymer precipitate so you can form Microparticles
3. Hardening of coating

Question 13

4 examples of coacervation

Answer 13

Changing temperature of polymer solution
Salting out
Adding non solvent
Inducing a polymer-polymer interacition

Question 14

Ways to harden coating

Answer 14

Promote cross linking or cool the system down

Question 15

Coacervation: changing temperature of polymer solution

Answer 15

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

Question 16

Coacervation: salting out

Answer 16

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

Question 17

Coacervation: adding a non solvent

Answer 17

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

Question 18

Coacervation: inducing polymer-polymer interaction

Answer 18

Add a second polymer to the solution that interacts with the first polymer and makes it precipitate out
Formation of Microparticles

Question 19

Preparation of Microparticles via interfacial polymerisation

Answer 19

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

Question 20

Preparation of microspheres by heat or chemical denaturation

Answer 20

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

Question 21

Spray drying to form Microparticles

Answer 21

1. atomisation of liquid feed ( also containing drug ) into fine droplets
2. mix spray droplets with heated gas system, allowing liquid to evaporate and leave a dried solid
3. dried powder separated from gas stream and collected

Question 22

5 advantages of spray drying to form Microparticles

Answer 22

quick and reproducible
control of particle size
low cost
good yield
applicable to heat sensitive materials

Question 23

limitations of spray drying to form Microparticles

Answer 23

need polymers that give low viscosity solutions
need small droplets
water soluble compounds have poor encapsulation

Question 24

5 ways that drug is released from microspheres

Answer 24

Erosion
Disintegration of microsphere in body to release API
Swelling of microsphere, and API diffuses out
Desportion and diffusion
Ionic exchange

Question 25

Drug release from microspheres: desorption & diffusion

Answer 25

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

Question 26

Drug release from microspheres: ionic exchange

Answer 26

Adsorbed drug is an ion - a charged drug Administer microsphere Many ions present tin body that can interact and swap with the drug

Question 27

What are nanoparticles

Answer 27

Particles in the nano size range: nm Two types: nano capsules and nanospheres

Question 28

Nanocapsules

Answer 28

2 distinct regions so are a reservoir system External wall and central core

Question 29

Nanospheres

Answer 29

Matrix system as they only have a single region

Question 30

Location of API in nanoparticles

Answer 30

API can be dissolved, physically entrapped or adsorbed on the surface No covalent bonds - just interactions

Question 31

3 ways to make nanoparticles

Answer 31

- Some scientists make PDG and from them they make nanoparticles (hybrid system) - Using ready made polymers - Methods that require polymerisation

Question 32

2 polymers most commonly used for nanoparticles

Answer 32

PLA and PLGA

Question 33

Preparation of nanoparticles using solvent evaporation

Answer 33

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

Question 34

Toxicity of Microparticles and nanoparticles

Answer 34

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

Question 35

Biodegradation as a method to eliminate Microparticles and nanoparticles from body

Answer 35

Polymer gets broken down at level of monomer as bonds between monomers are biodegradable e.g. PLGA: ester bonds break down

Question 36

Bioerosion as a method to eliminate Microparticles and nanoparticles form body

Answer 36

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

Question 37

Problems with IV injections of nanoparticles and a solution

Answer 37

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

Question 38

What is ABRAXANE

Answer 38

Nanoparticle on the market contains palictaxel used in cancer therapy for advanced metastatic breast, pancreatic and NSCLC