Nanomedicines: liposomes... Flashcards
1
Q
How big is a nanometer compared to a meter?
A
1 x 10⁻⁹m
2
Q
What is nanomedicine?
A
The medical application of nanotechnology
3
Q
What is nanotechnology in nanomedicine?
A
The engineering and application of nanoscale based materials & their properties to achieve best patient intervention
4
Q
viruses and DNA are in the nanometer range, true or false?
A
true
5
Q
molecule that is capable of interacting with a biological component to illicit some response?
A
drug
6
Q
2 terms for the packaging of a drug that is delivered to a diseased site in the body is as important as the drug itself?
A
vectors or carriers
7
Q
reasons for using DDS?
A
carriers for therapeutic diagnostic molecules to site of action
8
Q
drug molecules should be X,Y and Z at specific sites
A
Packaged, Transported and Released
9
Q
give one reason for encapsulation of drugs in a DDS?
A
reduce side effects
10
Q
packaging drugs reduces drug resistance such as in the case of anti cancer drugs, true or false?
A
true
11
Q
encapsulation alters pharmacokinetic parameters such as delaying clearance etc , true or false?
A
true
12
Q
give some reasons for encapsulation of drugs?
A
reduce side effects,
reduce drug resistance,
enhance specificity and targeting
avoid solubility issues
13
Q
2 main classes of DDS?
A
hard and soft
14
Q
would carbon based and metallic based DDS be hard or soft?
A
hard
15
Q
would lipid based and polymeric based DDS be hard or soft?
A
soft
16
Q
hard and soft drug delivery systems can deliver a range of molecules such as small molecules like cisplatin, proteins and nucleic acid, true or false?
A
true
17
Q
what 2 words make up theranostic?
A
therapeutic and diagnostic
18
Q
What are drug delivery systems (DDS)?
A
nanometre sized particles used as a the vehicle/carrier component of nanomedicines
19
Q
What are DDS made of?
A
natural/synthetic materials; polymers, proteins, lipids
20
Q
can liposomes be hollow, porous or solid interior?
A
all of above
21
Q
What are the 2 ways DDS can carry/deliver drugs?
A
- encapsulation/entrapment: incorporated inside
- adsorption/attachment: on particle surface
22
Q
How do DDS improve drug potency/efficacy?
A
- improved solubility + dissolution
- sustained/controlled drug release
- prolong time in circulation
- protect drug from harsh conditions
- improve transport across biological barriers
- targeted drug delivery
23
Q
what parameters can be modified to improve drug potency and efficacy via improved drug solubility and dissolution ?
A
small carrier size, high surface area to vol ratio
24
Q
why does smaller carrier size thus higher SA:Vol ratio improve drug solublity and dissolution of a DDS?
A
Particle/ DDS made of a polymer, then degraded by an aq medium (subject to hydrolysis)
if aq medium can permeate/ penetrate into small particle more easily -> faster degradation of carrier component. Again impact on drug release
25
TRUE OR FALSE: sustained or controlled drug release will not improve drug efficacy/ potency?
false
26
TRUE OR FALSE: prolonging residence time in systemic ciruclation will not improve drug potency and or efficacy?
false
27
what can help protect drugs from harsh in vivo conditions thus helping diffusion. This is most effective if the drug is...
encapsulation in DDS
28
incorporating a drug into chitosan polymer can aid release across?
nasal epithelia
29
Give an example of how DDS improve transport across biological barriers (nasal epithelium).
chitosan nanoparticles allow for mucoadhesion to nasal epithelia
30
2 pros for using DDS for targeted drug delivery to particular cells or tissues?
increased delivery efficiency and potential decreased tox
31
DDS are Facilitating targeted drug delivery, meaning...
Enhanced delivery to particular cells or tissues. Delivering drug more specifically to site of action
32
What are liposomes?
Closed, spherical vesicles of single or multiple lipid bilayers, enclosing an internal aqueous core
33
What are the lipid bilayers within liposomes called?
lamellae
34
What do liposomes resemble?
the natural structure of biological membranes = advantage!
35
What material are liposomes prepared using?
naturally occurring or synthetic lipids - usually phospholipids
36
Synthetic phospholipids used in marketed products of liposomes drug delivery more often, why?
can control: composition and purity
37
What types of molecules are phospholipids (philicity)?
amphiphilic
38
What are the 2 main components of phospholipids?
- hydrophilic head
- hydrophobic tails
39
how do phospholipids arrange themselves in aq environments spontaneously, w energy input?
bilayer structures → liposome formation
head group exposed to water and hydrophobic fatty acids chains sequestered and hidden from water, inside.
40
when energy is inputted to bilayer structures, what may form?
liposomes
41
Describe the composition of the hydrophilic head of a phospholipid.
- glycerol phosphate
- R group
42
Describe the composition of the hydrophobic tail of a phospholipid.
fatty acid chains which can vary in saturation degree
(unsaturated: C=C, kink in structure)
43
are phospholipids water soluble?
NO but have part that likes water and part that doesnt
44
R group on phospholipid head allows substituent to be bound which may be charged. Can be positive, negative or neutral. If used to make liposomes do these liposomes have an overall surface charge?
yes
45
fully saturated means double bonds or no double bonds?
no double bonds
46
Liposomes are classified based on...
- size + number of lamellae
- surface charge
47
which type of liposome would have multiple bilayers and a size above or equal to 100 nm?
MLV
48
what type of liposome has one bilayer and can be above or equal to 100 nm?
LUV
49
small unilamellar vesicles are used most commonly as there is less variation, what is the size range in nm?
30-100
50
What part of a phospholipid allows for the charge of a liposome to be altered?
R group attached to phosphate in hydrophilic head
can be +/-/neutral or combinations
51
why are SUVs most common type commercially?
easiest to make at reproducible size and lamellarity. Don’t want variation in medicines
52
What methods can be used to prepare liposomes?
- lipid film hydration
- solvent injection
- reverse phase evaporation
- microfluidic techniques
53
which prep method is very popular for lab scale production which is very popular and well established?
lipid film hydration
54
which 2 prep methods involve phospholipid sol in organic solvent and trading out solvent for aq medium, as they are not soluble arrange in bilayers?
solvent injection and reverse phase techniques
55
which prep method allows small scale production and large scale ?
microfluidic techniques
56
outline the steps involved in lipid film hydration?
diagram p54
- phospholipid dissolved organic solvent
- put on rotary evaporator
- solvent evaporates and removed by vaccum
- lipid deposit as a film around the side
- take aq medium such as buffer and water sol drug and add to film
- agitate
- dry lipid film swells as hydrated and arranges in liposome structure
- stir using rotary evaporator to hydrate
- size reduction
57
in lipid film hydration, why are component phospholipids first dissolved in an organic solvent in the round bottom flask?
as theyre NOT water soluble
58
which organic solvents may be used for lipid film hydration?
chloroform or methanol or combination
59
the solvents used in lipid film hydration are volatile. what happens to them once you start spinning the flask and hearing?
start to evaporate
60
in lipid film hydration you also have a vacuum on the system so what does this do to the solvent and whats left behind?
sucked out after evaporation, removed from phospholipids, then phospholipids deposit on wall of flask in a FILM
61
what do you add to lipid film to agitate?
buffer (aq medium)
62
how do you know the phospholipids in lipid film hydration wont dissolve and instead swell and arrange into liposomes at end?
as theyre amphiphilic
63
mlvs commonly produced for lipid film hydration with different sizes and lack of uniformity. After lipid film hydration what is needed?
size reduction
64
What are 3 different size reduction techniques? for MLVs??
- extrusion
- probe sonication
- bath sonication
65
which size reduction technique involves flushing heated water into a barrel and adding MLVs, membrane with defined hole sizes relate to desired membrane size, and pressure forces them through?
extrusion
66
which sonicator using high intensity and energy? and focussed
probe
67
which sonicator involves blasting sonic energy through water bath of liposomes to reduce size?
bath
68
What is the Tm or Tc of a phospholipid?
phase transition temperature: temp at which lipids undergo a change in physical state from ordered gel phase to disordered liquid crystalline phase
69
How will phospholipids be arranged if you're below the Tm?
gel phase - ordered and rigid
70
How will phospholipids be arranged if you're above the Tm?
liquid crystalline phase (disordered and fluid)
71
What properties of a phospholipid influence Tm?
- degree of saturation/unsaturation
- chain length
72
what effect does the fatty acid chain length of the phospholipid have on the Tm?
increased chain length,
more hydrophobic interactions
so higher Tm
73
do higher chain length phospholipids tend to have a higher or lower Tm?
higher - need more energy to break
74
what effect does the degree of saturation have on Tm?
more unsaturation, more kinks, disordered packing so lower Tm - need less energy to break
75
what type of phospholipids have LOWEST Tm?
low chain length
high degree of unsaturation (C=C)
76
what type of phospholipids have HIGHEST Tm?
high chain length
low degree of unsaturation (less C=C)
= tightly packed and happy
77
are liposomes more or less fluid in the liquid crystalline phase?
more
phospholipids in fluid, disordered state, hydrate better in this state 😊
78
which phase is more beneficial during lipid film hydration and other size reduction methods?
liquid crystalline
(but can be exploited to trigger drug release in vivo!)
79
why is liquid crystalline beneficial during lipid film hydrtaion and size reduction: extrusion?
extrusion: barrel heated to temp ABOVE Tm so in nice fluid state and pass through membrane easily, sonication etc
80
cons of liquid crystalline phase?
may lead to liposome instability and drug leakage during storage and use
81
gel phase liposomes are more rigid, when might this be more beneficial?
during storage to retain encapsulated drug
82
what can be used to reduce the Tm impact and improve drug retention?
cholesterol
83
how can cholesterol reduce bilayer permeability and increase drug retention?
reduces phospholipid mobility = more rigid and improves bilayer lipid packing
84
at certain concs, what can cholesterol do to Tm?
abolish it, as cholesterol has stabilising effect
85
liposome size is commonly measured using what technique?
dynamic light scattering (DLS machine)
86
What are properties we can characterise about liposomes?
- size
- size distribution
- particle surface charge
- entrapment efficiency
- drug loading
87
briefly outline how dynamic light scattering works?
- light focused on sample of suspended particles
- light scattered at all angles
- intensity of scattered light at given angle over time is measured
88
what does DLS actually measure?
Intensity of scattered light (at a given angle) over time is measured
89
intensity of scattered light at a given angle over time fluctuates due to what 2 things?
brownian motion and diffusion of particles
90
What is Brownian motion?
random movement of particles in a liquid or gas
91
How does Brownian motion change with the size of particles?
bigger particles move more slowly
92
PDI (polydispersity index) is a dimensionless number calc from light scattering and indicates size distribution of particles in a sample. What does a higher number (0-1) indicate?
polydisperse, broad size distribution
93
What technique is used to characterise the size distribution of liposomes?
polydispersity index (PDI)
94
What machine is used to measure PDI?
zeta sizer
95
what does a lower PDI number mean?
more monodisperse :)
96
difference in electrical potential between surface of a solid particle in a liquid, and the bulk liquid, determined by electrophoretic mobility =?
particle surface charge
97
What technique is used to characterise the particle surface charge of liposomes?
zeta potential
98
What is the size of the zeta potential indicative of about liposomes?
and what does a larger value over=/-30mV mean?
- the particle stability
- larger zeta potential - tend to repel each other preventing aggregation
99
term given to % of API successfully loaded into the delivery system?
i.e. how much drug is in the liposome compared to how much was loaded when making the system
entrapment efficiency
100
What is the formula for entrapment efficiency?
= (weight API in dleivery system/inintial API weight) x 100
101
term given to the amount of drug contained within a defined amount of delivery system?
i.e. if we want to give drug, how much liposome would I have to give?
drug loading
102
formula for drug loading?
= (weight API in delivery system/total weight of delivery ssytem) x 100
103
Advantages of liposomes as DDS?
biocompatible,
non toxic,
biodegradable,
tuneable composition and properties,
can be small or large scale manufacture,
104
what type of API molecule can be incorporated within aq core of liposomes or inter bilayer spaces if multiple bilayers?
hydrophilic (water soluble)
105
what type of API molecules can associate with the lipid tails of bilayers?
lipophilic/hydrophobic
106
what type of API molecules can incorporate BOTH in lipid bilayer snad aq spaces??
amphiphilic
as have hydrophilic and phobic parts in struc
107
how can liposome membrane structures be made more rigid?
use lipids with higher Tm thus increased chain length and saturation and addition of cholesterol
108
how can liposomes be made more stable?
add charged lipids to reduce vesicle aggregation and fusion
109
Alteration of liposome size, surface charge by choice of what?
component lipids
.... Potential for modification to create alternative lipid-based systems
110
disadvantages for liposomes as DDS?
physical instability = liposome fusion + premature leakage of drugs
111
what can liposomes alter/control regarding incorporated drug?
PK profile
112
how can liposomes change PK profile of the drug within?
* Protect against fast drug metabolism
* Prolong systemic drug circulation time
* sustained drug release
* Targeting drug delivery to specific cells/tissues
113
4 possible clinical applications of liposomes?
cancer therapy!!
anti-microbial
analgesia
vaccine delievry
114
caelyx is a liposomal formulation (SUV) of what drug for IV infusion in cancer therapy?
doxorubicin
115
PEG (polyethylene glycol) is a family of hydrophilic polymers that are used for caelyx and other systems for?
hydrophilic coating on liposome surface
116
name given to blood circulating components such as immunoglobulins etc?
opsonins
117
describe the role of opsonins (process)
bind to foreign particles in blood and tag for removal by phagocytic cells such as macrophages of MPS (mononuclear phagocyte system).
118
2 Consequence for DDS including liposomes
* Systemic circulation time is reduced
* Drug is prevented from reaching its target
119
liposomes subject to opsonisation by MPS system. How can this be avoided? 3
- smaller liposomes cleared more slowly so optimal size is less than or equal to 200 nm
- slower clearance with cholesterol rich and saturated phospholipids and neutral surface charge
- slower clearance with highly hydrophilic surface coating: PEGylation
120
3 things to change on liposomes to avoid opsonisation by MPS system?
size (smaller)
lipid composition (cholesterol,saturated, neutral)
surface character: PEGylate
121
what is the rationale behind PEGylation of liposome surfaces?
makes it hydrophilic
stealth tech, inhibits opsonisation and avoid MPS clearance
122
name another agent that can avoid opsoniation and avoid MPS clearance due to employing high Tm phospholipids and cholesterol?
daunoxome
123
how does pegylation facilitate liposome accumulation at the tumour site?
via EPR effect
124
what is the EPR effect?
how liposomes can alter PK of drug theyre associated with
Enhanced permeability and retention effect
125
healthy vasculature has tight endothelial cells therefore liposomes are not able to cross. How is this different in a diseased state such as tumour?
vasculature is damaged and leaky, meaning lipsomes less than or equal to 200 nm can escape through gaps, retained at tumour site longer as not cleared well
126
is selective accumulation of liposomes at tumour site an example or passive or active targeting?
passive as taking advantage of natural physiology to allow for liposome accumulation
127
how does amphotericin B cause nephrotox?
good potent antifungal BUT serious SEs:
binds to ergosterol (similar struc to cholesterol) in fungal cell membranes and exerts action but can bind to cholesterol in our membranes and causes damage, toxicity and infection
has low aq solubility
128
what effect does developing amphotericin B in liposomes (ambisome) have on the patient?
reduced side effects and improved tolerability
129
Doubling of serum creatinine = indicator of what SE caused by AmBisome potentially?
kidney damage and can check on nephrotoxicity mentioned before
130
ARIKAYCE ( liposome formulation of aminoglycoside antibiotic amikacin) is used to treat MAC lung infections. What is its route of delivery and why?
inhaled via nebuliser, targeted localised pulmonary delivery with low systemic exposure
131
nebulised aerosol droplets of liposomes in ARIKAYCE are between 4-5 um. Where are these distributed in the lung to target delivery?
central and peripheral lung
132
even though liposomes are 300 nm why are they still useful for local lung delivery?
nebulised as droplets as made to be 4-5 um
133
what category of liposomes do exparel (bupivacaine) and DepoDur (morphine sulphate) both fit into?
multivesicular liposomes (MVLs)
134
how can depofoam tech / MVLs be used for sustained drug release?
- micron sized lipid bilayer liposomes containing numerous internal aq compartments bound by lipid bilayers
- honeycomb structure
- release drug over hrs or weeks as lipid membranes erode / reorganise
135
name one example of a liposomal vaccine to provide protection against varicella zoster virus (shingles aka herpes zoster)?
shingrix
136
shingrix uses glycoprotein E (gE) which sits on surface of VZV. This is a subunit vaccine. What is gE mixed with?
AS01 liposome adjuvant system
137
what does shingrix contents: AS01 act as?
AS01 = liposomes containing two adjuvants (these don’t illicit an immune response themselves, so not antigens but more like catalysts. Act as danger signals to immune system, to alert system to act) the 2 adjuvants in AS01:
* QS-21: purified saponin extract from soap bark tree
* Monophosphoryl lipid A (MPL): detoxified form of lipopolysaccharide endotoxin
138
epaxal (hep A vaccine) and inflexal (influenza vaccine) use virosomes for enhanced antigen delivery to target immune cells. What are virosomes?
liposomal bilayers formed from phospholipids and viral antigen components
139
LNPs are used for moderna and pzifer bioNtech covid 19 vaccines. Why are rhey technically not liposomes?
may not have lipid bilayer structure
140
similarities of LNP: moderna and pfizer bioNtech vaccines?
both use DSPC standard phospholipid, + cholesterol + PEGylyated phospholipids + ionisable cationic lipids (different to liposomes. Really important structural component)
141
ionisable cationic lipids are used in both the moderna and pfizer covid 19 vaccines? true or false
true
142
outline LNP formation? p64
- lipids and cholesterol dissolved in ethanol
- rna dissolved in acidic buffer
- dilution, filtration or dialysis removes ethanol and adds more polar solvent to change mixture pH
- ionisable lipid is protonated and forms inverted micelles around mrna
- inverse micelles aggregate and vesicles form
- at neutral pH pegylated phospholipids coats vesicle
143
describe how microfluidic mixing works
2 inlet ports inside. 2 syringes, containing part of liposomes:
bring liposome components into chip + mix together inside to make liposomes
144
how is the mixing of aq medium and organic solution of phospholipids/lipid mixture controlled in case of microfluidic mixing?
Controlled mixing of liquid streams of very small (micron-sized) channels
145
what 2 things can we control with microfluidic mixing techniques?
* Total flow rate: rate of liquid flowing through chip
* Flow rate ratio: ratio of how quick aq stream flowing through chip compared to organic stream containing lipids
146
main benefit of microfluidic mixing vs thin film hydration?
no size reduction method needed 😊 as carefully control how meet and mix
147
2 ways to scale up microfluidic technique?
o Use multiple microfluidic chips in parallel (parallelisation or ‘numbering up’)
o Increase mixer scale, allowing larger volumes to pass through at faster rates
148
microfluidic aparatus?
staggered herringbone
troidal mixer
149
SHM or TrM has high throughput speeds and higher product volume possible?
TrM
150
microfluidic apparatus better for just lab scale and small batch production?
SHM
151
does method of liposome prep alter liposome properties
yes can do
152
how can liposomes undergo active targeting?
modifying surface of liposome by attaching molecule/ macromolecule to recognise specific receptor and go there to those cells
153
describe liposomes simply
They are vesicles with aq core of water or something inside.
154
how can you offer some protection against immune system of liposomes?
PEGylate
155
nanoemulsions meet the basic definition of an emulsion and are made up of what 2 phases, along with stabilisers?
lipid and aqueous
156
the particle diameter in nanoemulsions are often less than X nm?
500
157
How are nanoemulsions classified?
based on the nature of their lipid phase
158
is the lipid phase solid or liquid for these two types of delivery systems;
nanoemulsions (NEs)
lipid nanocapsules (LNCs)
liquid i.e. oil
159
is the lipid phase solid or liquid for solid lipid nanoparticles (SLNs)?
solid
160
the lipid phase is a mixture of solid and liquid lipids for which DDS?
nanostructured lipid carriers (NLCs)
161
What are the 2 types of emulsion?
oil-in-water (o/w) and water-in-oil (w/o)
162
What types of emulsion can be injected intravenously?
oil-in-water only
163
NEs can be oil in water or water in oil emulsions. What 3 high energy methods can be used to manufacture them?
ultrasound,
high shear homogenisation
high speed homogenisation
164
what low energy method can be used to manufacture NEs?
phase inversion method
165
the types of drugs delivered with NEs can vary with the type of emulsion produced. For o/w emulsions, do the drugs tend to be hydrophobic or hydrophilic?
hydrophobic
166
What is the size range in nm for nanoemulsions (NEs) ?
20-200
167
NEs usually have oil droplets dispersed in water or water droplets dispersed in oil and are a single layer membrane. Phospholipids will be used as a stabiliser. Name one suitable option?
lecithin
168
Describe the structural components of nanoemulsions.
- single layer phospholipid membrane (stabiliser)
- liquid oily core
169
How do phospholipids on nanoemulsion oil droplets orientate themselves?
- polar head facing outward aqueous medium
- apolar tails orientated towards oil droplet
170
name a suitable liquid oily core for NEs?
vegetable oil or medium chain triglyceride
171
What drugs are nanoemulsions used to encapsulate: hydrophilic or hydrophobic? How?
- hydrophobic
- suspended in oil phase
172
What can modify about a nanoemulsion to achieve active targeting?
- phospholipids
- functionalised PEG
173
do nanoemulsions have higher or lower visocosity compared to coarse emulsions (also better injectability)?
lower
174
nanoemulsions have less stability issues than coarse emulsions, true or false?
true
175
How can we modify the phospholipids of a nanoemulsion to achieve active targeting?
- attach molecules to phospholipids
- these can be e.g. fluorescent and used for imaging
176
What are the 2 types of processes we use to manufacture nanoemulsions?
- high-energy
- low-energy
177
high energy processes involve strong mechanical pressure that does what?
breaks particles down
178
why is destabilisation via sedimentation and creaming less likely with high energy processes: NEs
as size is small (compared to coarse emulsions)
179
What is the main mechanism via which nanoemulsions destabilise? Why?
- Ostwald ripening
- particle size is smaller
180
the dispersed phase of nanoemulsions are subject to brownian motion, true or false? and why
true bc smaller size
181
impact of Otswald ripening can be seen through the change of what 2 things?
size and size distribution
182
What is Ostwald ripening?
If we have particles of large size ranges, then:
At higher temperatures: Our smaller-size particles disappear and our particle size lowers
At lower temperatures: our particles precipitate on to the surface of other particles and you get bigger particles
183
How can we characterise the Ostwald ripening seen in nanoemulsions?
- by keeping track of particle size distribution over time
- polydispersity may indicate it has occurred
184
What type of emulsion delivers hydrophobic drugs?
o/w
185
What type of emulsion is used in vaccines? What is its role?
- water-in-oil
- as an adjuvant to potentiate the immune response = make it STRONG
186
NEs are mostly used to deliver hydrophobic drugs which are located inside the lipid phase. O/w emulsions are most commonly used. Give 1 use for w/o emulsions?
vaccine adjuvant ensuring immune response is strong and ensure immunity develops
187
TPN lipid name?
intralipid
188
What are emulsions used for with parenteral nutrition?
to deliver the lipids of the nutrition
189
why is it important that TPN is an oil in water emulsion and particle size is carefully controlled ?
IV route and prevent oil particles embolising
190
What routes of administration can nanoemulsions be used for?
- IV
- oral
- ocular
- transdermal
- intranasal
191
what type of emulsion are SLNs?
o/w
oil phase and stabiliser and this will be dispersed in biological fluids.
192
List some of the properties of lipids that make SLNs?
solid at room temp, melt at body temp, biocompatible, biodegradable
193
how are SLNs manufactured?
high pressure homogenisation at high or low temperature
194
how is the drug released from SLNs?
can provide sustained release depending on composition and manufacture method. However, burst release may occur - release of a given % of the drug in a very short period of time.
195
SLNs involve oily droplets stabilised with a monolayer of stabiliser dispersed in an X environment?
aq
196
size range of SLNs in nm?
50nm - 1000nm (1micron)
197
lipids are used for SLNs have to be GRAS, what does this mean?
generally recognised as safe
no issues w tox
198
NLCs are similar to SLNs as they are made using solid lipids. In what way are they different?
SLNs add a small amount of liquid lipids such as oil to the formulation
199
in the manufacture process of SLNs (high pressure hot/cold homogenisation) what is the first step ? This is also the stage where the drug is added for drug loaded particles?
melt the lipid
200
the second step of homogenisation for SLNs can be hot . What happens in this stage?
lipid phase that contains drug is emulsified into dispersing phase and homogenised at high temp
201
what considerations should be made if undergoing hot homogenisation to produce SLNs?
care for temperature labile drugs although exposure time is short
202
the solid matrix lipid NP s obtained at what point, during the high pressure homogenistaion method?
Solid matrix lipid NP obtained as the o/w nanoemulsions (as still have aq, phase, oil phase, and stabilser, and size in nano scale) cools down
203
for hot homogenisation for SLNs the why should the pre emulsion have micro sized droplets?
homogenisation not as effective if droplets are large
204
after homogenisation (SLN production) the temp is lowered from high temp to temp below MP of solid lipid phase. Why is this done?
allows lipid to solidify and isolate nanoparticles as oil in water nanoemulsions
205
the second step of cold homogenisation (SLN) involves cooling the drug lipid liquid prepartion is solidified using liquid nitrogen or dry ice. What is the temperature of this?
-80 and below
206
in cold homogenisation (SLN) after solidifying the lipid, what method is used for size reduction to target sizes between 50 to 100 microns?
milling
207
after milling (SLN cold homogenisation manufacture) the power is dispersed into what 2 things (and then known as pre suspension)?
aqueous phase with stabiliser and surfactant
208
after a pre suspension is obtained in the manufacture of SLNs via the cold homogenisation method, what happens next?
homogenisation at room temp or below
Sufficient difference between MP of lipid + homogenisation temp i.e. during homogenisation, ensure temp below MP of lipid phase… so no further cooling step. Can isolate SNPs straight away after this step.
209
SLNs are used mostly to deliver hydrophobic drugs, why?
high affinity for lipid phase
210
is it possible to deliver water soluble drugs or macromolecules via SLNs?
yes but affinity for aq phase must be reduced
211
give one way that affinity for the aq phase can be reduced so that water soluble drugs may be delivered via SLNs?
cold homogenisation
212
at high temps such as hot homogenisation for SLN manufacture the affinity of a drug for the aq phase is increased, true or false?
true
213
SLNs:
Transport of water-soluble low molecular weight drugs and macromolecules also reported
In this case, it will be crucial to minimise partition in water (affinity of drug for aq/dispersing phase) why?
as would then want to leave NP and go into dispersing phase
214
list some of factors that affect the amount of drug that can be loaded in SLN?
solubility of drug in the lipid melt,
miscibility of melted drug and lipid,
structure of solidified lipid matrix,
lipid polymorphism
215
miscibility of melted drug and lipid can affect amount of drug that can be loaded in SLN and NLC. when to be considered?
if when melting lipid, bring temp above MP of drug
And check melting drug not changed its structure
216
are NLC or SLN expected to allow more drug to be loaded?
NLC
217
SLN have an expected sustained release profile. What does this depend on?
composition such as nature of lipid phase, content of stabiliser and particle size and manufacturing method
218
hot homogenisation phase 1 melts the lipid and adds the drug in solution in the lipid phase which is then emulsified and dispersed in water. How does this affect burst release?
increasing temperature increases solubility of drug in water, some drug partitions out of lipid phase into aq phase.
When preparation is cooled solubility of drug in water is reduced. solidification happens from inside out of droplet with periphery being the last to solidify.
drug molecules close to surface travel short distance to be released after iv admin and responsible for burst release.
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problem with hot homogenistaion process- drug leaving lipid phase -> aq phase then wanting to go back?
as cooling preparation, triggered solidification (network forming) of lipid phase. Happens from inside out (form droplet)
Now space that was available when lipid in liquid form, no longer available. Space where drug can jump into becomes smaller
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in the hot homogenisation process, whats the last part to solidify?
Periphery last to solidify. As drug trying to come out of aq phase, only place it can fit is therefore in surface of NP. Drug mols close to surface.
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2 things which may affect burst release (SLNs)?
surfactant conc and temp
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why is surfactant concentration important for SLNs and burst release?
they can help increase solubility of drug in water so more likely will partition outside lipid phase into aq phase.
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high temp favours partition of drug from lipid phase to aq phase but once it goes down and lipid starts to solidify what happens?
no space for drug to go deep into nanoparticle so it stays on surface where it can diffuse out quickly and cause burst release
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below room temp conc of surfactant has little impact and low % of drug release as a burst, true or false?
true
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only way to avoid burst release when you reach a temperature above body temp for SLNs?
no surfactant/stabiliser
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Even low conc of stabiliser (0.5, 1, 2.5 %) can increase % of drug that will be ...
released as a burst.
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3 encapsulation models for drug loading- SLNs
solid solution
drug-enriched shell
lipid shell
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how is the drug encapsulated in solid solution SLNs?
uniform dispersion of drug throughout
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how is the drug encapsulated in drug enriched shell SLNs?
drug mostly in periphery of nanoparticle and almost none in lipid core
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how is the drug encapsulated in lipid shell?
drug enriched core- inside shell.
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drug enriched shells have been linked to burst release why?
drug close to surface and doesnt have to diffuse far to get out as with lipid shell (drug enriched core)
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why is burst release not very likely for lipid shell SLNs?
drug is concentrated inside nanoparticle and has to cross thick lipid shell before diffusing out and being released
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have lipid shell SLN encapsulation models been linked to cold or hot homogenisation?
cold
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which SLN encapsulation model has a nice sustained release profile and why?
lipid shell as it avoids burst and takes time for drug to diffuse across the shell
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For SLNs, working at high temperatures and/or with high concentrations of stabiliser make burst release more or least likely?
more likely
as both conditions will make the drug more likely to partition out of the lipid phase, into the aqueous phase.
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2 ways solubility of drug in water can indeed be improved? burst release, SLNs
temperature will increase the solubility of the drug in water AND
some stabilisers can also act as solubilisers
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p76: homogneisation process image !!!
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NLCs stand for...
nanostructured lipid carrier
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NLCs were suggested as a solution to issues associated with which other lipid based DDS?
SLN
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list 2 advantages of NLCs over SLNs?
SLNs have low drug loading and release of encapsulated drug during storage
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why are imperfections created through adding oil in SLNs?
(goal of NLCs)
so drug can be incorporated into solid lipid matrix
between fatty acid chains/ due to fact that crystalline structure is imperfect, so can load drug inside SLNs.
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during storage, crystalline network of SLN means that imperfections cease to exist that allow drug inside. As network changes what effect is seen on the drug?
premature release
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if we have an amorphous lipid this creates imperfections that allow drug incorporation. Little pockets of oil are created inside a lipid matrix to allow drug loading for which lipid based DDS?
NLCs
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why is premature drug release unlikely with NLCs?
Old SLN perfect crystal… brick wall. Not much space for drug
NLCs: imperfections cannot be corrected over time so perfect crystal structure will not form :)
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for NLCs drug will ideally be dissolved inside oil pockets and these pockets then exist inside?
solid lipid matrix
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lipid nanocapsules (LNCs) are what type of emulsion?
o/w
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do LNCs use long or medium chain triglycerides?
medium
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LNCs use two stabilisers. The first is phospholipid and makes up a small concentration. What is the majority stabiliser?
PEG C18
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when PEG is added to LNCs why does it face the external aqueous phase?
it is hydrophilic polymer
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In what way are LNCs similar to a nanoemulsion in terms if composition?
has oil and aqueous phases and surfactant
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in what ways are LNCs different to nanoemulsions?
uses PEG c18 that forms semi solid shell around lipid phase
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What is the oil phase of a LNC?
medium chain triglyceride
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What is the aqueous phase of a LNC?
saline solution (NaCl)
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What are the surfactants of a LNC?
- PEG660 hydroxysterate + free PEG
- phospholipid (69% phosphotidylcholine soya bean lecithin)
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the components used in nanocapsules are appropriate for which routes of admin as approved by the FDA?
oral, topical and parenteral
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What is the nature of the LNC shell? How is this achieved?
- semi-solid
- achieved by preparing at Temp less than the MP of the non-ionic surfactant
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are LNCs used mostly for the delivery of hydrophobic or hydrophilic drugs?
hydrophobic
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advantages of LNCs?
- no special equipment needed
- reproducible preparation
- stable over time
- useful for wide range of therapeutics
- low toxicity
- solvent-free preparation (no organic)
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What are the disadvantages of lipid nanocapsules?
- potential toxicity of excess surfactant (PEG-C18 can dissolve cell membranes)
- loading may still require solvents (not all drugs soluble enough)
- limited to ~100nm particles
- surface modification only through PEGylation
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LNCs are made using a high or low energy process?
low
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what are phase diagrams used for in terms of LNC production?
decide on composition of water, oil and surfactant phases to control properties of LNC
triangle - often stay within grey region
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What is the main post-manufacture modification that is done to LNCs? Why?
PEGylation:
- to maximise stealth properties, as PEG-C18 not long enough to fully mask hydrophobicity of LNC
- can also be used for active targeting
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PEG is quite short itself so not sufficient enough to cover hydrophilic phase of LNC and requires the insertion of PEG chains after the manufacture processes. What is used to do this, and how is this done?
phospholipid that is attached to PEG and then heat to soften shell to allow amphilic molecules to be integrated in the stabilising layer
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What do we PEGylate LNCs with?
a PEGylated phospholipid: PEG350-5000: HLB 5.44-17.14
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How do we PEGylate LNCs?
- incubate micellar solution of PEG-lipid at 60C
- requires presence of at least 2 aliphatic chains
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Give some LNC examples of drugs that have low water solubility and are dissolved in oil/ medium chain triglycerides are suitable solvents for these drugs?
- etoposide
- ibuprofen
- paclitaxel
- amiodarone
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what is the difference between drug loading and encapsulation efficiency?
loading is about the quantity of drug in the formulation and effciency is about the % of drug that has been loaded relative to the amount that was added to the formulation
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what is meant by a high encapsulation rate >90% ?
90% of drug that you added when making nanoparticle is actually encapsulated
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What oil are amiodarone and ibuprofen dissolved in within an LNC?
Labrafac CC
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What oil is etoposide dissolved in within an LNC?
Labrafac
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What oil is paclitaxel dissolved in within an LNC?
Captex 8000
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Through what process do drugs leave LNCs?
diffusion out of oil into dispersing phase
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What does drug diffusion out of the LNC shell depend on?
drug particle size, drug partition and solubility
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implications of pH (2 and 7.4) on drug release amiodarone?
Release will be faster at pH2 (almost 100% drug released by end. 1st graph) At pH7.4, more controlled release
At pH2: drug in ionised form and high affinity for aq and low for oil… meaning it will want to come out of NPs and go into aq dispersing phase.
At pH7.4: drug in neutral form… opposite: lower affinity for aq phase, higher for lipid phase. Takes more time for drug to come out of LNCs and be released
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amiodarone is a weak base pka 6.56.
At low pH it will exist mostly in its ionised form.
In which phase will the drug have higher affinity and preferentially partition?
higher affinity for aq phase and partition in water and be released quickly
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amiodarone is a weak base and has a pKa of 6.56.
at high PH, exists mostly in its unionised/ neutral form.
Which phase will it have higher affinity for and what will it therefore preferentially partition into?
higher affinity for lipid phase so drug will preferentially partition in the LNCs and be released slowly
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Explain how amiodarone's partition and solubility changes with increasing pH.
water solubility:
- decreases as pH increases
- due to it changing from ionised form (pKa means it's protonated) to neutral
partition:
- partitions preferentially into water as pH decreases
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larger liposomes have a higher capacity for drug loading than smaller ones. However, larger liposomes may be more prone to what?
aggregation and clearance by the immune system.
