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CHEM426 > STEVE > Flashcards

STEVE Flashcards

1
Q

Which nanocarrier types rely on “attachment of drug

A

-Polymer therapeutics
(including denrimers, micelles, pegylation)
-Inorganics

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2
Q

Which nanocarrier types typically rely on matching drug ‘solubility’ within nanocarrier?

A
  • Micelles
  • Dendrimers
  • Nanoemulsions
  • Solid lipid nanoparticles
  • Liposomes
  • Polymer nanoprecipitates / particles
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3
Q

How have polymer therapeutics been used for aspririn? + What are the benefits?

A

Usin aspirin as a monomer - polymerising with diacid chloride - to form polyaspirin.

  • Polyaspirin eilminates the stomach irritation that is experienced with aspirin (gastric ulcers & bleeding)
  • Delayed release over long periods
  • Potential for better moulding and processing.
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4
Q

How have polymer therapeutics been used for morphine? + What are the benefits?

A

Morphine and glutaric anhydride used to synthesis polymorphine

  • polymorphine has ester and anyhdride weak links - good for biodegradation and drug release
  • Slow release of pain killers
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5
Q

What are the types of polymer therapeutics?

A
  • Polymers made from drugs (>50 wt% of the polymer is drug)
  • Polymer is the drug
  • Polymer drug conjugates
  • Polymer-drug micelles
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6
Q

Why is it an advantage to increase time to clear drug from the body?

A

Drugs that are rapidly eliminated have limited therapeutic value and require repeated dosing

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7
Q

What are some of the limitations of PEG conjugation?

A
  • PEG can accumulate and cause problems
  • No added stability to the protein outside the body
  • PEG is a ‘one-shot’ approach - not tailored to different proteins
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8
Q

What does PEG stand for

A

Polythylene glycol

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9
Q

What are the principle of PEG conjugation strategies?

A
  • Requires modification of the PEG-OH chain end

- Required a complementary functionality on the drug or protein

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10
Q

What effect do PEG groups have on proteins?

A

PEG groups are often degradable. - so don’t impact the behaviour of the protein, but impact the solubility.

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11
Q

Explain polymer-drug conjugation of the anti-cancer drug - doxorubicin?

A

Doxorubicin is highly toxic cytostatic drug with a large number of side effects.

Conjugation of polymers may leads to reduction in non-specific toxicity and better circulation lifetimes.

Conjugated doxorubicin - Passive targeting of tumours through enhanced permeation and retention effect.

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12
Q

What are the principles of polymer-drug micelles?

A

PEGylation of drug to make “drug surfactants”

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13
Q

How does PEGylation to form ‘drug surfactants’ then form polymer-drug micelles?

A

Can undergo self-assembly into micelles when

conc. > CMC (critical micelle conc.)

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14
Q

What are the advantages of drug conjugation?

A
  • Enhanced biostability
  • Increased drug loading
  • Extended circulation time
  • Selective recognition
  • Triggered drug release
  • Combination therapy
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15
Q

Why does polymer conjugation get more challenging to chaieve as the molecular weight of the polymer used increases?

A
  1. Chain ends decrease in concentration as the molecular weight (chain length) increases.
  2. Polymer chains coil and steric issues affect the backbone - also the chain ends may be ‘lost’ within the coils
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16
Q

How are gold nanoparticles used in nanomedicne?

A

Drug compounds e.g. doxorubicin - bind to gold surface

Gold coated silica particles are stabilised using thiol terminated PEG (stabiliser)

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17
Q

How are gold nano particles used for cancer treatment?

A

Localised heating via Au-nanoshells kills cancer selectively

Accumulation of Au-nanoshells at tumour, Near-infrared laser heats Au-nanoshells, kills cancer selectively

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18
Q

How are passive micelles used for nanomedicine?

A

Large polymeric micelle - inner core (hydrophobic) could be used to encapsulate poorly soluble hydrophobic drugs.

-Drug Stabilised within core - used for a nanocarrier

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19
Q

How are targeting MIXED micelles used for nanomedicine?

A

Combinations of 2 different types of A-B block copolymers - control number of targeting ligands by ration of two block copolymers

e.g, for Antibody targeting

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20
Q

How are polymer micelles self-assembled by dialysis?

A

Via solvent exchange:
Solvent environment within dialysis bag changes dramatically
- Switch from good solvent environment to not-so-good, to then really bad solvent environment.
-Changing solvent conditions force drug to interact with hydrophobic chains as they assemble

  • Hydrophobic chains start to aggregate together
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21
Q

How do dendrimers form unimolecular micelles?

A

If hydrophobic core & hydrophilic (charge stabilised) surface - acts as a unimolecular micelle

  • internal hydrophobic cavities
  • External hydrophilic functional groups

Drug loading by dissolving drug & dendrimer in MeOH, addition of water & slow evaporation of MeOH

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22
Q

What is a nanoemulsion?

A

Submicron stabilised emulsion droplets

-Surfactant stabilised

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23
Q

What are solid lipid nanoemulsions?

A

Submicron stabilised solid-oil droplets
-Substitution of the liquid oil phase within an emulsion, with a fatty acid (or derivative) that is solid at elevated temperatures

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24
Q

What are the advantages/disadvantages of solid lipid nanoparticles

A

Advantages:
• Improved drug stability
• Control over drug release
• Lipids are generally biodegradable
• Possibility to avoid organic solvents during preparation
• Relatively easy to scale-up and sterilize

Issues:
• Lipids crystallise and exclude “dissolved” drug
• Crystallised lipid leads to low loading of drug

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25
Q

How are solid lipid nanoparticles formed by emulsification/evaporation?

A

(Solid lipid + solvent + drug)
creates 2 phase system with water, add surfactant to create system which is emulsifiable
- solvent evaporation - to give nano-scale emulsion

-removal of solvent decreases the droplet size

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26
Q

What are the methods of forming solid lipid nanoparticles?

A
  • High shear homogenization
  • Ultrasonication/ high speed homogenization
  • Solvent emulsification/evaporation
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27
Q

How are polymer nanoprecipitates formed?

A
  • Organic solution (water miscible) of polymer and drug is rapidly added to water (anti-solvent)
  • Good solvent diffuses into poor solvent environment (water)
  • Decreasing solvent quality leads to aggregation (assembly into small structures)
  • Small structures aggregate
  • Aggregation is arrested by colloidal stability (steric/charge)
  • Final stable nanoprecipitate - Hydrophobic drug is encapsulated in core if initially present in good solvent.
28
Q

What factors control polymer nanoprecipitation?

A
  • Good solvent choice
  • Concentration in the good solvent
  • Dilution range
  • Drug/polymer miscibility
  • Viscosity
  • Temperature
  • Rate of addition to antisolvent
  • Possible by microfluidic approaches
29
Q

Define liposomes?

A

• Comprise assembled amphiphilic molecules
• Bilayer of surface active material
• Clear internal hydrophilic cavity surrounded by
hydrophilic stabilising groups (charge or steric) and
sandwiching a hydrophobic bilayer
• For small molecule liposomes, usually made from double
chain surfactants (or lipids)
• Hydrophilic drug encapsulation in the core plus
optional hydrophobic drug encapsulation in the bilayer

30
Q

What are the advantages of using liposomes as nanocarriers?

A
  • Very low toxicity
  • Often biodegradable
  • Low immunogenicity
  • Potential for targeted delivery
  • Protection of sensitive water soluble drugs
  • Enhanced drug solubility
  • Improvement of pharmacokinetics
31
Q

What are some disadvantages of using liposomes as nanocarriers?

A
  • Encapsulation into core often has low efficiency
  • Leakage of drug from bilayer and/or core during storage (Bilayer approx 5-6 nm thick)
  • Difficult to scale to large volumes
  • High batch to batch variation
  • High cost
32
Q

What is the differentce between unilamellar and multilamellar vesicales?

A

Unilamellar Vesicles - contain 1 bilayer

Miltilamellar vesicles - contain miltiple bilayers

33
Q

Describe the general production of liposomes

A

Lipids are generally used to produce liposomes. The following process is used to encapsulate a hydrophilic drug in a liposome:
• First the lipids are dissolved in an organic solvent.
• Rotary evaporation is then used to produce a dry lipid film.
• Water containing the hydrophilic drug is added to rehydrate the lipid film with gentle stirring to produce multilamellar vesicles.
• Processing techniques are required to achieve the desired liposome structure – i.e.
- Extrusion is used to produce large unilamellar vesicles
- Sonification /Homogenisation used to produce small unilamellar vesicles
• Purification techniques such as ultrafiltration or column chromatography are then completed to produce the final liposomal product

34
Q

What is the difference between liposomes produced by extrusion or sonification/ Homogenisation?

A

Extrusion - Large unilamellar vesicles

Sonification/ Homogenisation - Small unilamellar vesicles

35
Q

What are the issues with standard Doxorubicin drug?

A

Doxorubicin is highly toxic and targets DNA with proliferating cells.

Causes cardiomyopathy (heart disease and scarring) which may lead to congestive heart failure and death .

36
Q

What are the structural properties of doxorubicin?

A
  • Amphiphilic molecule
  • Well known to self-assemble in water at very low concentration (hydrophobic interaction and π-π stacking or aromatic groups)
37
Q

What are the benefits of putting doxorubicin in liposomes?

A

– Avoid non-specific organ toxicity
– Extend the circulation time after IV injection
– Targeting of solid tumour sites by the Enhanced Permeation and Retention (EPR) effect

38
Q

What are the differences between healthy tissue and tissue with tumour?

A

Healthy tissue: Endothelial cells packed close together, dissusion can happen through this into healthy tissue - active/highly controlled process.
-Also have a lymph system - removal of toxic material

Tumour :
Random/ Rapid growth
-Pulls open vascular system - causes stress/ strain on the blood vessel - leads to gaps in endothelial - nm size gaps

39
Q

How do nanocarriers target tumours?

A

Cytotoxic drug thats small enough to fit between the gaps between endothelial cells in blood vessels, by passive targeting - drug will filter into tumour tissue. Tumours don’t have a very strong lymphatic system - so anything that arrives at tumour stays there

40
Q

Explain the enhanced permeation retention (EPR) effect

A
  • Nanoparticles direct drug away from sites with tight epithelial junctions in the vasculature (blood vessels) such heart and muscle.
  • Accumulation in areas where fenestrations (gaps) exist eg liver, spleen, bone marrow, areas of inflammation, and neoplasms (new/abnormal tissue growth) – ENHANCED PERMEATION
  • Lack of lymphatic drainage from tumours also leads to poor removal of nanoparticles – ENHANCED RETENTION
41
Q

What issues with doxorubicin liposomes?

A

– Phagocytic cells (cells that “eat” foreign objects)
• The mononuclear phagocyte system (MPS) recognises particles as ‘‘foreign’’
• Leads to removal from the bloodstream
• Phagocytosis of Dox-liposomes releases doxorubicin and causes cell death which reduces the MPS capacity

42
Q

What are some requirements for Dox-liposome manufacture?

A

– Methodology must be straightforward, simple and use cheapest available materials.
– Liposome generation must be as uniform as possible (reproducible size distributions)
– Optimal loadings are 100% trapping efficiency at the desired drug-to-lipid ratio
• No need to remove un-encapsulated doxorubicin from the sample.
– Drug release rates need to be improve drug activity
• Decrease toxicity or increase efficacy
•Rapid (instantaneous) doxorubicin release after iv injection results in no benefit over free drug
• Complete drug retention (no drug release) may result in a therapy that is neither toxic nor efficacious. Possible substantial drug delivery to tumours and substantial reductions of delivery to cardiac tissue, BUT no therapeutic value

43
Q

How are Doxorubicin liposomes formed by passive encapsulation?

A

– Hydration of the dried lipid film with an aqueous solution of doxorubicin.
– Targets the aqueous volume trapped inside the liposome during formation.
– After rehydration drug/liposomes are co-dispersed and a fraction is entrapped directly
– Driven by a combination of hydrophilic, hydrophobic, and ionic interactions.
– Doxorubicin is amphiphilic so, depending on pH, may reside in the aqueous core and may partition into the lipid bilayer.
– Typically maximum efficiencies = 80%
– Drug-to-lipid ratio is low and dependent doxorubicin water solubility (<10 mM).
– Removal of unencapsulated drug is critical and difficult at production scale

44
Q

How are Doxorubicin liposomes formed by active encapsulation?

A

– Addition of doxorubicin to preformed liposomes
– Generation of a trans-bilayer ion (including pH) gradient needed
– Leads to a redistribution of drug occurs across the liposomal bilayer and trapping in the core: Mechanism of trapping - internal aqueous pH and induced drug precipitation.
– Drug-to-lipid ratios as high as 0.3:1 (wt:wt) = approx. 48,000 doxorubicin molecules per 100 nm diameter liposome.

45
Q

Explain the steps of active encapsulation dox-liposome manufacture using citrate

A

1- Rehydrate the liposome layer with an aqueous solution of citrate (acid buffer)
- pH gradient generated.

2- Base added or dialysis, column chromatography to modify external pH (increase)

  • Dox-HCl (Dox-hydrochloride salt) in equilibrium with Dox-NH2
  • Amine becomes deprotonated and is hydrophobic - so works way into core - where its protonated (core pH=3.5)

3- Doxorubicin citrate salt is formed

46
Q

Explain the steps of active encapsulation dox-liposome manufacture using ammonium sulphate

A

1- Add ammonium sulphate directly to generate an ammonium sulphate gradient - by hydration of dried lipid with (NH4)2SO4 solution.
2- External environment changed to NaCl at same pH (no base washing)
3- Ammonium counter ion within core of liposome will dissociate
- Ammonia (NH3) will permeate out of the liposome - rapid permeation

4- pH gradient established
Doxorubicin (Dox-NH2). will permeate in also.

5- Doxorubicin & acid environment within the core forms a sulphate salt

47
Q

What is the clinical benefit of Dox-liposome?

A

prevent MPS (mononuclear phagocyte system) activation and prolong circulation times

48
Q

What is the main requirement for drug delivery of doxorubicin by liposomes?

A

The doxorubicin must get out of the liposome

– move from the inside of the liposome to the outside
– must pass through the lipid bilayer
– drug must interact with the membrane interface (inside of the liposome), the lipid head-groups, the lipid acyl chains, and the membrane interface on the outside of the liposome.
– aqueous core pH and interfacial dictate the proportion of drug in the neutral and in the charged form.
– both neutral and charged drugs are believed to permeate the bilayer (neutral > charged)
– anionic lipids increases charged doxorubicin concentration at the interface resulting in an increased rate of drug release
– inclusion of PEG-modified phosphatidylethanolamine (anionic) increases doxorubicin release – potential increased hydration at the interface and anionic nature.

49
Q

What problems are addressed by solid drug nanoparticles

A
  • Oral dosing is the MAIN patient-acceptable route of drug administration
  • Many drug compounds have low water- solubility
  • Low bioavailability (% of drug that enters the systemic circulation after oral dose)
  • Low permeation across key barriers, eg: • Gut-blood
  • Blood-brain
  • Difficult to formulate
  • Difficult to dose
  • Poor distribution in target disease areas
50
Q

What is meant by intestinal permeability?

A

Intestinal permeability = how much drug goes through the gut after an oral dose

51
Q

How do drugs. permeate gut to absorb into the blood

A

Through the small intestine

  • has mucosa layer
  • Sub mucosa layer

Inside small intestine is actually a huge surface area - due to villi - direct route for exchange with the blood system

Structure of villus:

  • cells control what goes from gut into the blood
  • what comes from the blood to the gut

-Active transfort mechanism - taking nutrients from the gut & moving into the blood stream & also identifying species not beneficial to the body

52
Q

What are the routes of drug uptake?

A

Gut to blood: Passive and active process
• Absorption/permeation

Blood to gut: Active process
• Against concentration gradient
• “Efflux”

53
Q

What are the processes for making solid drug nanoparticles?

A

– Liquid processes (‘bottom-up’ techniques)
• Nanoprecipitation
• Emulsion manipulation

– Solid processing (‘top-down’ techniques; attrition)
• Homogenisation
• Nanomilling

54
Q

How are SDNs made by nanomilling?

A

A) Solid technique - take particle dispersion & smash it up - milling

Nanomilling - milling beads break particles into smaller pieces - must have stabilisers (polymers/surfactants)

  • Grinding of large particles using solid (metal or ceramic) beads and mechanical agitation
  • Plates and beads lead to impact on large drug particles and breaking up into smaller particles
  • Liquid MUST have stabilisers (polymers/surfactants) present to stabilise new active surfaces
55
Q

How are SDNs made by high pressure homogenisation?

A
  • Particle dispersion of bigger particles
  • move valve up - force liquid under high pressure though a tiny gap - smashes particles into smaller ones
  • Caviation forces are dramatic
  • Stabilisers required to protect particle
  • As previous for solid lipid nanoparticles
  • Solid slurry is forced through small gap between valve and seat
  • High pressure generated
  • Cavitation forces break apart large particles
  • Stabilisers required
56
Q

How are SDNs made by emulsion processing?

A

Emulsion processing:

  • Dissolved drug into an oil droplet & then evaporate solvent ot of emulsion after its made
  • when theres not solvent left - only drug - drug particle is made
  • As previous for solid lipid nanoparticles
  • Solution of drug in water immiscible solvent
  • High shear mixing and evaporation of solvent to precipitate or crystallise drug compound.
  • Stabilisers for emulsion used to stabilise final dispersion
57
Q

How are SDNs made by Nanoprecipitation?

A

Nanoprecipitation of Polymers/Drug

  • into aqueous solution of stabilisers
  • Ends p with particle dispersion
  • As previous for polymer nanoprecipitation
  • Drug dissolved in water miscible solvent
  • Added to water (anti solvent)
  • Stabilisers in water to prevent macrophase separation
58
Q

What is attrition?

A

Breaking material into pieces

59
Q

What are the problems with breaking large solid particles into smaller ones?

A

Surface tension between air & water - air is hydrophobic - surfaces interacting cohesive

  • Hydrophobic drug particles in water - similar solid-liquid interfacial tension - same tension observed
  • Particles of hydrophobic drug - with interfacial energy
60
Q

What happens during attrition methods if surfactants aren’t present?

A
  • when smashed into 2 bits - create more surface energy - put energy into the system
  • Increase in interfacial energy of system similar energy input to create new surface
  • Break again: generated even more surface, created more interfacial energy
  • If don’t stabilise the surfaces - the system will try and minimise the interfacial energy by reforming the starting materials - will aggregate
61
Q

What is the surface energy of a material?

A

Energy required to create a unit area of new surface

62
Q

What happens when surfactants are used in attrition methods?

A

The presence of surfactants and polymers in the aqueous phase minimises the interfacial energy to prevent aggregation

63
Q

What factors affect the selection of surfactants for attrition?

A

Stabiliser: needs to interact with particle and bind efficiently to prevent aggregation

  • Drug chemistry (surface interactions)
  • Concentrations of polymer and surfactant
  • Balance of entropy loss and total thermodynamic gain
64
Q

What components are in the final total drug formulation?

A
  • Drug
  • Surfactant
  • Polymer
  • Inorganic filler
  • Drying agent
  • Antimicrobial
65
Q

What are the advantages/ limitations of nanomilling?

A 
• Milling low melting point
materials not possible (energy
and forces involved) - because milling generates a lot of heat
-Need to have melting point >80-90 deg
• Must be very poorly soluble drug
• Many cycles may be needed
• Possible to mill the nano-mill so
potential for contamination from
metal or ceramic
• Drug cannot be water or heat
sensitive (hydrolytic stability) (if compound hydrolytically unstable - heat and presence of water leads to degradation of drug compound)

CHEM426 (4 decks)

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