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PH4701- clinical pharmaceutics > Lec 8- Soluble drug carries and nanotechnology > Flashcards

Lec 8- Soluble drug carries and nanotechnology Flashcards

1
Q

Choice of a delivery system

A
  • The physicochemical characteristic of the drug
  • The physiology and location of the target site
  • The mechanism of targeting
  • The dose required
  • Route of administration
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2
Q

Soluble macromolecular drug carriers to promote targeting

A
  • What do we mean by this?
    • Antibodies
    • Polymers
    • Proteins
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3
Q

Advantages of soluble carriers

A
  • Vs pro-drug
    • Carriers can facilitate targeting through the Physico-chemical characteristics of the carrier rather than the drug
  • Vs larger carriers:
    • Easier for soluble carriers to escape from the systemic circulation as they are smaller
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4
Q

What is a polymer

A
  • Basically a large molecule composed of repeating units
  • PEG, PLGA
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5
Q

Polymeric conjugates

A
  • Synthetic polymers can be made to have defined characteristics
    • MW
    • Size
    • Charge
  • Easier to produce in large quantities than natural sources
  • Are generally less immunogenic than naturally derived macromolecules
  • Still use alginates (from seaweed)
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6
Q

Polymers

A
  • Also used in sustained release and controlled release systems
  • For drug-polymer conjugates, soluble polymers are used
  • There are 3 basic components to a polymer-drug conjugate
    • Water-soluble polymer
    • A linker
    • The drug
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7
Q

Schematic

A

*

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8
Q

Polymer clearance from the circulation

A
  • Rate is dictated by its molecular Wt
  • Clearance rate decreases with increased molecular weight up to the threshold of 45 kDa- if bigger cant be cleared by the kidneys
  • Non-biodegradable are limited to molecular masses of <40kDa, so they are cleared by the kidneys
  • Clearance via renal excretion if below these values
  • If above, clearance via MPS (Mononuclear phagocytic system)
  • Smaller the molecular weight the faster the excretion
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9
Q

Choice of polymer (as the carrier)

A
  • Conjugation of proteins to polymers can reduce protein immunogenicity and enhance the protein half-life in the circulation
  • How does it do this
    • Prevents renal elimination (must be bigger than 45kDa)
    • Avoids receptor-mediated protein uptake by MPS (Can attach PEG it to, no MPS degradation)
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10
Q

PEGylation of proteins

A
  • Generally, a 1:1 polymer-to-drug ratio is used
  • PEG molecular weights of 5000 to 40,000 used in clinical products
  • Disadvantages
    • PEGylation of proteins may also reduce their biological activity so the conjugation site of the PEG on the protein is important
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11
Q

Linkers

A
  • The drug can be
    • Directly covalently attached
    • Attached via a spacer/linker (more common)
  • The spacer linker overcomes the problem of the drug’s therapeutic action being blocked
  • It can also facilitate controlled release of the drug from the carrier (see prodrugs- for example, use of phosphate pro-drugs only present in cancer cells)
  • Targeting groups can also be attached to promote active targeting
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12
Q

Mechanism of linker cleavage (may require some directed reading)

A
  • Passive hydrolysis: linkers containing
    • e.g. esters are susceptible to hydrolysis
  • Enzymatic hydrolysis: Oligopeptide spacers can be degraded by lysosomal proteases and can aid the release of the drug from the carrier within the lysosomal compartment
  • pH-sensitive release: N-cis-aconityl spacers can trigger release when exposed to acidic pH conditions
    • pH of tumour site is often different to the rest of the body
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13
Q

Drug

A
  • Majority of polymer conjugates are for chemotherapy
  • Overall these polymer-drug conjugates are below 100nm in size and can also be seen as a new chemical entity in their own right, similar to pro-drugs
  • this is important to increasing patent, adding a carrier changes PD/PK parameters, have to go through the regulation all over again
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14
Q

Targeting of polymer-based carriers

A
  • In addition to improving the stability of proteins, polymer conjugates can enhance targeting of drugs and proteins
  • Passive targeting is via the EPR (Enhanced Permeation Retention) effect
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15
Q

What is EPR

A
  • Tumours have leaky vasculatures
  • Due to very rapid angiogenesis- not done properly, large gaps
  • Carrier system can easily pass into the tumour site= enhanced permeation
  • Lymphatic drainage is reduced for the same reason, so the drug is not cleared properly causing accumulation
  • Therefore the extent of EPR mediated targeting to tumour sites is depending on the plasma concentration of the polymer conjugates
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16
Q

Active targeting

A
  • None on the market yet
  • Can you provide some examples of targeting groups we could look to use
    • Abs
    • Folate
    • Galactose
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17
Q

Examples of polymer-drug conjugates

A
  • The linkers show that these are passive targeting drugs
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18
Q

Homework/CPD

A
  • Clinical: Be able to identify what each of the previous conjugates are used for clinically
  • Chemistry: Be sure you appreciate what each of the linkers are
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19
Q

Case studies

A
  • XYOTAX/OPAXIO: in this polymer-drug conjugate, paclitaxel is conjugated to poly-L-glutamic acid (PGA) via an ester linker. This conjugate has a high drug content (~37% w/w) and is stable in the circulation. The drug is released intracellularly via degradation of PGA by lysosomal proteases and the ester linker is degraded by esterases or acid hydrolysis. Xyotax is currently in clinical trials as a potential treatment for non-small cell lung cancer and ovarian cancer
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20
Q

Polymer-protein

A
  • Oncaspar®: In this conjugate L-asparaginase is bound to non-biodegradable monomethoxyl poly(ethylene glycol) (5000g/mol) via an amide linker. This conjugate is used for induction of remissions in acute lymphoblastic leukaemia. Asparaginase is an enzyme which breaks downs the amino acid L-asparagine. This interferes with the growth of malignant cells which, unlike most healthy cells, are unable to synthesise L-asparagine for their metabolism. Following IV injection the plasma half-life of the native enzyme is between 8 to 30 hours. Dosing regimens vary but generally requires daily administration for 10 days. PEGylation of the protein increases its half-life to 5.7 days markedly reducing the dosing regime. The PEGylated protein can also be used in patients that are hypersensitive to the native enzyme
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21
Q

Other soluble drug carriers

A
  • Protein- as drug carrier has also been investigated, but their delicate structures and potential immunogenicity have limited their application
  • Polysaccharides are generally degradable and therefore avoid accumulation within the body. Of particular interest is the use of dextrans which are colloidal, hydrophilic molecules which are inert in biological media but in vivo are slowly hydrolysed to soluble sugars by dextranase
22
Q

Particulate drug delivery

A
  • General described as constructs within the colloidal size range
    • Range of between 1nm to 1um in size
  • Here we include
    • Dendrimers
    • Nanoparticles
    • Micelles
    • Liposomes (liposomes) /Niosomes (non-ionic surfactants, more stable)
    • Microspheres
23
Q

Advantages of particulate delivery systems

A
  • Higher loading capacity- have more than one molecule of drug per carrier (multiple drugs in a liposome)
  • Can offer enhanced protection against drug degradation- increased stability
24
Q

Nanoparticles

A
  • Nanoparticles: defined as a particle with one or more of its dimensions in the nm range- around 100nm or less
  • There are a range of carrier systems that fit this definition
25
Q

Dendrimers

A
  • Dendrimers are highly branched, mono-dispersed macromolecules (polymers)
  • They have a regular and highly branched polymeric structure, they are exactly the same size- same PK profile
  • Can be between 1 and 100 nm in size
  • Can be considered as macromolecules or nanoparticles depending on MW
26
Q

Schematic representation of a dendrimer

A
  • Bulit by controlled chemical synthesis
  • Polymers
  • But unlike polymers, they can be prepared to be nearly monodisperse in size
  • You can have various end groups on them
  • Solubilising group- if a drug is hydrophilic
  • Targeting moiety- could be an antibody which will increase specificity
27
Q

Designing dendrimers

A
  • The versatility of dendrimers is immense- can attach lots of different aspects to one carrier system
  • Can be synthesised into a range of dimensions depending on the needs of the drug and the delivery site
  • Target groups can be added to the end for the active targeting
  • PEG groups can be added to modify PK to promote passive targeting via EPR
28
Q

PK and biodistribution of dendrimers

A
  • PK of these is the same as polymeric carriers and factors that control their biodistribution include
    • Liver accumulation increases with dendrimer size- bigger the size the more likely to go into the MPS
    • PEGylation increases the half-life and decreases liver accumulation
  • The polymer construct of the dendrimer will dictate if the system is biodegradable or not
    • E.g. poly-L-lysine dendrimers are biodegradable (any amino acid is biodegradable)
    • Polyaminoamine (PAMAM) dendrimers are not
29
Q

Solid nanoparticles

A
  • Should particulates in the nano range- the reduced size of the drug
  • Can be constructed in a variety of ways
    • Nanosizing of solid drug particles
    • Formulation of solid polymeric nanoparticles
    • Protein nanoparticles
    • Solid lipid nanoparticles
  • Prepared using a wide variety of either natural or synthetic polymers
  • Commonly studied biodegradable polymers: PGLA; PLA; PCL
30
Q

Polymeric nanoparticles

A
  • If prepared from a biodegradable polymer, after they are introduced into the body the breakdown of the polymer
  • Drugs can be released on this breakdown of the particles
  • Similar to polymer implants like Eligard
    • A PLGA polymeric matrix suspension that gives controlled release of leuprolide acetate over 1 to 6 months
    • After SC injection it forms a solid drug delivery depot (So not targeted delivery) so gives a controlled release, stays where it is injected
31
Q

Solid protein nanoparticles

A
  • Nanoparticles can be prepared from proteins and there is an albumin-based systems clinically available
  • Abraxane is the first commercial product based on protein nanotechnology
32
Q

Paclitaxel

A
  • Several anti-cancer agents are hydrophobic in nature and rely on drug delivery systems to improve their solubility
  • So many rings, not soluble has to be given as an emulsion
33
Q

Cremophor

A
  • Paclitaxel is available as taxol- A liquid formulation where paclitaxel is dissolved in polyethoxylated castor oil and ethanol emulsion
    • Putting emulsion into IV route (water) poor absorption
  • However, this formulation requires special infusion sets, prolonged infusion time (3h) and premedication with corticosteroids and antihistamine to reduce the risk of hypersensitivity reactions
  • Besides the toxicity, these delivery systems may reduce tumour penetration of the drug through the formulation of large polar micelles
34
Q

Role of albumin

A
  • Physicochemical: albumin functions to coat the paclitaxel and stabilises the drug
  • Albumin is able to do so due to it’s the ability to reversibly non-covalently bind hydrophobic substances
  • Do we have to learn paclitaxel + albumin?- yes re-write
    *
35
Q

Role (2)

A
  • Albumin may also play a role in supporting active targeting of the drug to tumour cells
  • Every time there is a receptor this is active targeting
  • Within the body, albumin is able to transport hydrophobic molecules such as vitamins, hormones and other plasma constituents and deliver these substances across the endothelial lining and out of the blood into the extravascular space via endothelial transcytosis
36
Q

Role (3)

A
  • This process is receptor mediated, with albumin binding to gp60 glycoprotein receptors on the cell surface
  • This albumin-gp60 mediated uptake may also play a role in preferential intratumour accumulation of paclitaxel
  • It is conceivable it may be applied to the delivery of other low solubility anti-cancer agents
37
Q

Solid lipid nanoparticles

A
  • Solid lipid nanoparticles are colloidal particles made of solid lipids- e.g. solid triglycerides and fatty acids dispersed in an aqueous phase
  • As they are solid (rather than liquid cores if used in low melting point lipids)
    • Avoids the potential for droplet coalescence
    • May provide better protection of the drug incorporated into the lipid particle against chemical and enzymatic degradation
    • As well as prolonged drug release]
  • Usually the size of the dispersed lipid particles is in the range of 50 to several hundreds of nanometers, making them suitable for intravenous application
  • No products have reached the market
38
Q

SLN application

A
  • Solid lipid nanoparticles dispersion have been developed for parenteral oral, ocular, dermal and cosmetic applications, but recently have also been investigated as a potential delivery system for targeted drug delivery
  • PEG coating of these systems have been shown to passively target tumour sites via the EPR effect
  • To actively target cancer cells, covalently coupling ferritin to the lipids used in the formulation of the solid lipid nanoparticles have been tested
  • Galactose has also been investigated to target liver carcinoma cells, which have increased levels of galactose receptor molecules
  • However, the development of solid lipid nanoparticles for targeted delivery is still at a very early stage (In vitro and animal experiments)
  • No products have reached the market
39
Q

Inorganic nanoparticles

A
  • There is a range of nanoparticles that have been fabricated from inorganic materials including
    • Nanotubes
    • Ceramics such as silica or alumnia
    • Metals (e.g. gold nanoparticles)
    • Metal oxides
    • And Metal sulfides
40
Q

Inorganic nanoparticles

A
  • Calcium phosphate-based nanoshells have also been prepared which have a hollow reservoir which can be loaded with drug
  • The inorganic systems are generally stable and can be used to entrap and protect drugs
  • However, generally they are not biodegradable so their application as potential pharmaceutical products is very limited
41
Q

Micelles for drug delivery

A
  • A wide range of molecules with surfactant properties are known to self assemble in an aqueous environment to form micelle structures
  • The driving force for micelle formation is through a combination of intermolecular forces, including hydrophobic, electrostatic and hydrogen bonding
  • Their small size and colloidal stability means that they are not subject to particle aggregation
42
Q

Surfactants ‘split-personality’

A

*

43
Q

Formation of micelles

A
  • When the interface is full the surfactant must enter the bulk phase
  • However, this results in the hydrophobic tail of the surfactant being in contact with the aqueous phase
  • At a certain concentration
    • The surfactant molecules aggregate into a structure which avoids the hydrophobic tail being in contact with the aq environment
44
Q

The critical micelle concentration (CMC)

A
45
Q

Products

A
  • A mixed micellar formulation of Amphotericin B deoxycholate is also available for parenteral administration
  • Amophotericin B is a potent anti-fungal agent used to treat invasive fungal infections such as systemic candidiasis and histoplasmosis
  • But Amphotericin B has very low oral absorption
  • However parenteral adminstration is associated with severe side effects including heamolysis and nephrotoxicity
46
Q

Amphotericin B

A
  • Amphotericin B has a broad spectrum of activity and is generally the drug of choice for life-threatening invasive fungal infections including disseminated candidiasis, aspergillosis and protozoal infections affecting the internal organs (visceral leishmaniasis)
  • However it’s use is compromised by assocaited adverse side effects
47
Q

fungizone

A
  • Each vial contains a sterile, non-pyrogenic, lyophilized cake (which may partially reduce to powder following manufacture) providing 50mg amphotericin B and 41mg sodium desoxycholate with 20.2 mg NaPO3 as a buffer
  • Crystalline Amphotericin B is insoluble in water, therefore, the antibiotic is solubilized by the addition of Na desoxycholate to form a mixture which provides a colloidal dispersion for IV infusion following reconstitution
48
Q

How do you design particulates for passive targeting

For example tumour

A
  • <100nm
  • No charge
  • Attach coating
  • EPR effect
  • Look back at this on replay
49
Q

Polymeric micelles

A
  • For the delivery and targeting of drugs block, copolymers with amphiphilic properties (due to large solubility differences between their hydrophilic and hydrophobic groups) have been widely investigated
  • Compared to surfactant micelles polymeric micelles are generally more stable and have a low critical micellar concentration
  • With these polymeric systems, a variety of hydrophilic components in particular PEG is used for the outer shell of the micelle
  • These hydrophobic polymer blocks not only provide the hydrophilic component of the molecule supporting the formation of micelles but they also provide steric stabilisation and stealth-coating to the constructs
50
Q

polymeric micelles continued

A
  • The hydrophobic component of these polymeric micelles can comprise of- Polylactide/aspartate
  • Polymeric micelles generally have sizes between 5nm upto as large as 100nm and have narrow particle size distribution
  • They are therefore sometimes referred to as nanoparticles
  • In terms of drug delivery, various types of drugs can be incorporated within the inner core of the micelles either by chemical conjugation or physical entrapment
  • Due to these attributes, polymeric micelles can be used as drug targeting systems as they can offer a high drug-loading capacity and are able to control the biodistribution of the drug through the control of size and surface characteristics
  • Due to there particle size, after IV injection, micelles are unable to pass through the epithelia of normal vessels but they are able to passively target tumour sites due to the EPR effect
  • Passive targeting of Paclitaxel, cisplatin via the EPR effect are underway

PH4701- clinical pharmaceutics (20 decks)

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