Advanced Drug Delivery Flashcards
1
Q
What does drug delivery/ targeting mean?
A
Delivery of a drug to its precise site of action at the right concentration for the right time
2
Q
What are conventional dosage forms?
A
Drug release/ drug plasma levels depend on the physicochemical properties of the active ingredient
3
Q
What are non-conventional dosage forms?
A
Drug release/ drug plasma levels are determined by the technological characteristics of the formulation (e.g. modified release)
4
Q
What type of dosage form is ‘modified-release’?
A
Non-conventional
5
Q
Can dopamine cross the blood brain barrier?
A
No
6
Q
In what terms can a drug be ‘modified’?
A
(1) Rate
(2) Time
(3) Space
7
Q
Why can L-DOPA cross the blood brain barrier where dopamine cannot?
A
Carboxylic acid group has been added
Is an amino acid
8
Q
What are some ways in which ‘rate’ of a drug release can be changed?
A
(1) Very fast release
(2) Sustained release
9
Q
How many ‘time’ of a drug release be changed?
A
When release starts after a certain time following administration
10
Q
How may ‘space’ of a drug release be changed?
A
Occurs in specific areas/ tissues
Targeting
11
Q
Who is Paul Ehrlich?
A
Nobel prize winner for medicine in 1908
Worked in field of immunity
12
Q
What is the objective of drug targeting?
A
Localise and concentrate drugs to the desired therapeutic site, avoiding all other tissues in the body
i.e. pharmacological response without the side-effects
13
Q
What is first order drug targeting?
A
Organ/ tissue specificity
14
Q
What is second order drug targeting?
A
Certain type of cell specificity
e.g. tumour cells
15
Q
What is third order drug targetting?
A
Intracellular compartment specificity
e.g. lysosomes
16
Q
What are three approaches to drug targeting?
A
(1) Magic bullet
(2) Prodrug
(3) Macromolecular carrier
17
Q
What is the ‘magic bullet’ approach to drug targeting?
A
API is potent + selective
18
Q
What is the ‘prodrug’ approach to drug targeting?
A
Inactive prodrug
Activated to drug in site of action
19
Q
What is the ‘macromolecular carrier’ approach to drug targeting?
A
Carrier transports the drug to desired site of action
20
Q
What drug targeting approach do monoclonal antibodies largely align with?
A
(1) Magic bullet
(2) Macromolecular carrier
21
Q
When were monoclonal antibodies first introduced?
A
1975
22
Q
What types of monoclonal antibody are commercially available?
A
(1) Diagnostic agents
(2) Therapeutic agents
23
Q
Why is drug targeting of bacterial cells easier than that of cancer cells?
A
Bacterial cells have many differences to human cells
Cancer cells are very similar
24
Q
Who coined the phrase ‘magic bullet’?
A
Paul Ehrlich
Medicine nobel prize winner
25
What is the difference between a polyclonal antibody and a monoclonal antibody?
Polyclonal: Multiple antigen targets
Monoclonal: Single antigen target
26
What was the first monoclonal antibody to reach the market?
OKT3
Anti-CD3 antibody
27
What is OKT3 used for?
Prevent rejection of kidney transplants
28
What is abciximab?
Monoclonal antibody
Used for prevention of cardiac ishaemic complications
29
What is trastuzumab?
Monoclonal antibody
HER-2 positive breast carcinoma
30
What is Herceptin?
Trastuzumab monoclonal antibody
31
What is ReoPro?
Abciximab monoclonal antibody
32
What is the principle of monoclonal antibodies as imaging agents?
mABs against tumour-associated antigens have been developed
mABs are conjugated with a diagnostic imaging agent
33
What are some available commercial products of monoclonal antibodies as imaging agents?
(1) Oncoscint
(2) Prostascint
(3) Myoscint
34
What is oncoscint?
Monoclonal antibody
For imaging of colon and ovarian cancer
35
What is prostascint?
Monoclonal antibody
For imaging of prostate cancer
36
What is myoscint?
Monoclonal antibody
Cardiac imaging
37
What is an antibody?
Protein
Produced by the body
As a result of exposure to an antigen
38
What is a prodrug?
Chemically/ pharmacologically inactive derivative of the drug
Undergo action at the target site
39
How many chains are there in an antibody?
4 chains
2 light
2 heavy
40
How are the chains of an antibody connected?
Disulfide bonds
41
What happens to a prodrug when it reaches the target site?
- Chemically activated
- Physically activated
- Enzymatically activated
42
Why are prodrugs used?
(1) Improve permeability through biological membranes
(2) Site-specific administration
(3) Increase duration of drug action
(4) Decrease toxicity and side-effects
(5) Improve the formulation
(6) Improve organoleptic properties
- Effects on organs
43
What does 'organoleptic' mean?
Action/ effects on organs
44
What are macromolecular carriers?
Biologically inert macromolecules
Used to deliver the drug to the site of action
45
What are macromolecular carriers generally composed of?
Polymers
46
What types of macromolecular carrier are there?
(1) Particulate carrier system
| (2) Soluble macromolecular carrier
47
How can a drug be in a macromolecular carrier?
(1) Entrapped in the carrier via physical bonds
| (2) Covalently conjugated via covalent bonds
48
In a macromolecular carrier, what does the distribution of the drug depend on?
The characteristics of the carrier
49
What are the types of targeting in macromolecular carriers?
(1) Active targeting
(2) Passive targeting
(3) Physical targeting
- Apply physical stimulus to promote API release in a certain area
50
How does 'passive targeting' work in macromolecular carriers?
Exploits the natural (passive) distribution pattern of a drug carrier
51
What type(s) of drug targeting technologies are associated with monoclonal antibodies?
(1) Magic bullet
| (2) Macromolecular carriers
52
What type(s) of drug targeting technologies are associated with liposomes?
Macromolecular carriers
53
What type(s) of drug targeting technologies are associated with microparticles?
Macromolecular carriers
54
What type(s) of drug targeting technologies are associated with nanoparticles?
Macromolecular carriers
55
What type(s) of drug targeting technologies are associated with micelles?
Macromolecular carriers
56
What type(s) of drug targeting technologies are associated with polymer therapeutics?
Macromolecular carriers
57
From smallest to largest, list the sizes of general drug delivery systems and carriers.
(1) Monoclonal antibodies
(2) Nanoparticles
(3) Microparticles
(4) Macrodevices
- e.g. implantable devices
58
What is needed for a drug to have a therapeutic effect?
(1) Pharmacologically active
| (2) To arrive at the right place at the right time
59
What is levodopa?
Modified dopamine, can cross BBB
Prodrug
60
How can drug release be modified?
(1) Rate
- very fast/ sustained release
(2) Time
- when release starts after a certain time following administration
(3) Space
- specific tissues (targeting)
61
What is 1st order targeting?
Organ/ tissue
e.g. liver
62
What is 2nd order targeting?
Certain type of cell
e.g. tumour cells
63
What is 3rd order targeting?
Intracellular compartment
e.g. lysosomes
64
What are some different targeting approaches?
(1) Magic bullet
(2) Prodrug
(3) Macromolecular carrier
65
What is magic bullet?
Targeting approach
Active ingredient is active and selective
66
What is prodrug targeting?
Targeting approach
Inactive prodrug - activated at site of action
67
What is macromolecular targeting?
Targeting approach
Carrier transports drug to site of action
68
What type(s) of activation can prodrugs undergo at the target site?
Chemical/ physical/ enzymatic activation
69
Why do we use prodrugs?
(1) Improve permeability through membranes
(2) Site-specific administration
(3) Increase duration of drug action
(4) Decrease toxicity + side effects
(5) Improve formulation
(7) Improve organoleptic properties
70
Define organoleptic properties.
Taste/ sight/ smell/ touch of drug
71
What are macromolecular carriers generally composed of?
Polymer
72
What are the two mechanisms by which a macromolecular carrier can deliver a drug?
(1) Entrapped in the carrier
- physical bonds
(2) Covalently conjugated
- covalent bonds
73
Which targeting approach is monoclonal antibodies and antibody-drug conjugates?
Magic bullet/ macromolecular carrier
74
Which targeting approach are liposomes?
Macromolecular carrier
75
Which targeting approach is micro/ nanoparticles?
Macromolecular carrier
76
Which targeting approach do micelles implement?
Macromolecular carrier
77
Which targeting approach are polymer therapeutics?
Macromolecular carrier
78
What are liposomes?
Microparticulated/ colloidal drug carriers
79
When were liposomes discovered and by whom?
1965
Bangham
80
Describe the structure of a liposome.
Vesicular structures
≥1 lipid bilayers
- normally phospholipids
Aqueous core
81
Describe structure of glycerol.
3 carbons
3 chains coming off each oxygen on each carbon
Fatty acid chains
82
Describe the structure of cholesterol.
Lipophilic (hydrophobic) region of rings
Hydrophilic hydroxyl group
83
What effect does cholesterol have on the phospholipid bilayer?
Tm = main transition temperature
Condensing effect (if above Tm)
Fluidising effect (if below Tm)
84
What is Tm?
Main transition temperature
Temperature above which are move fluid
85
When does addition of cholesterol into the phospholipid bilayer have a condensing effect?
If above Tm
86
When does addition of cholesterol into the phospholipid bilayer have a fluidising effect?
If below Tm
87
What type of lipid tends to form micelles?
Lisaphospholipids
88
What type of lipid tends to form bilayer vesicles?
Double chain phospholipids
Large head groups
89
What type of lipid tends to form planar bilayers?
Double chain phospholipids
Small head groups
90
What type of lipid tends to form inverted micelles?
Unsatured phosphadylethanol amine
91
What is an SUV?
Small unilamellar vesicles
92
What is an LUV?
Large unilamellar vesicles
93
What is an MLV?
Multilamellar vesicles
94
What is an MVV?
Multivesicular vesicles
95
How large are SUVs?
0.02-02 micrometres
96
How large are LUV?
0.2-10 micrometres
97
Where will a lipophilic drug reside in a liposome?
Inserted in the tails
98
Where will a hydrophilic drug reside in a liposome?
Inserted in aqueous core
99
How do you prepare liposomes?
Form spontaneously after addition of water to phospholipids
(1) Lipid hydration
(2) Selection of liposomes based on size
(3) Remove non-encapsulated drug
100
What is Thin Layer Evaporation?
(1) Phospholipids dissolved in organic solvent
(2) Phospholipid film
(3) Film hydration under stirring
(4) Sonication (ultrasound bath) OR extrusion (application of pressure through filters)
101
How are liposomes characterised?
- Lipid:drug ratio
- Encapsulation efficiency
- Size
- Lamellarity
102
What are the administration routes for liposomes?
- PARENTERALLY
- topically
- pulmonary
- orally
103
What are some issues with liposome stability, before administration?
- oxidation of lipophilic chains
| - hydrolysis + formation of lysophospholipids
104
What are some issues with liposome stability, after administration?
Can be captured by macrophages + carried to the liver
| - no longer bioavailable
105
What is STEALTH?
Sterically stabilised liposomes
Masks liposomes from macrophages
106
What are the different types of liposomes?
- conventional liposomes
- sterically stabilised (stealth) liposomes
- immunoliposomes (antibody targeted)
- cationic liposomes (gene delivery)
107
What is amphotericin B?
Antifungal
108
What are polymer-drug conjugates and polymer-protein conjugates, generally?
Systems with covalent conjugation between polymer and API
109
What are polymer-drug conjugates?
Many drugs
1 polymer
110
What is a polymer-protein conjugate?
Many polymers
1 protein
111
What does the term 'conjugation' indicate?
Covalent conjugation/ bonding
112
What are the following:
- asparaginase
- methioninase
- arginine deaminase
- uricase
Therapeutic enzymes
Proteins used for therapeutic applications
113
What are 3 types of protein used for therapeutic application?
(1) Therapeutic enzymes
(2) Signalling proteins
(3) Antibodies/ protein fragments/ peptides
114
What are some problems with proteins as therapeutic agents?
```
- rapid renal excretion
ø smaller than 40KDa
- proteolytic degradation
ø enzymes
- immunogenicity
- aggregation
- solubility
- difficulty in formulation
```
115
What size of protein will be excreted renally?
<40KDa
116
What effect does addition of polymers to a protein have, regarding renal excretion?
Increases hydrodynamic volume
Reduces renal clearance
Makes it too large
117
What effect does addition of polymers to a protein have, regarding aggregation?
Prevents/ reduces aggregation
HOWEVER, can reduce interaction with receptor
118
What relationship does PKa have on pH, with regard to a dynamic equilibrium?
PKa = pH when 2 components are at same concentration
119
What is PEG?
Best polymer for protein conjugation
Only has one potentially reactive group
120
What is an example of a PEGylated protein for cancer.
Oncaspar (Pegaspargase)
For acute lymphoblastic leukaemia
121
What effect does PEGylation have on half-life?
Increases half-life dramatically
122
Why did DIVEMA fail as an anticancer agent?
Toxicity
123
What is Copaxone used for?
SC administration in multiple sclerosis
Mimics myelin
124
Which are generally more cytotoxic, polycations or poylanions?
Polycations
125
How can polymeric drugs be broken down in the body?
(1) Biodegradable?
| (2) Is it > or < than 40KDa
126
What is a polymer-drug conjugate?
Drug delivery technology in which low MW drug molecules are covalently attached to a polymeric carrier
127
What is the Ringsdorf's model of polymer-drug conjugates?
- hydrophilic polymeric backbone
- biodegradable linker
- targeting group (binds to receptor)
128
What is HPMA?
First synthetic polymer-drug conjugate to undergo clinical evaluation
129
How does an angiogenic tumour vessel that is <1-2mm get nutrients?
Diffusion
No induction blood supply
130
How does an angiogenic tumour vessel that is >1-2mm get nutrients?
Induction of angiogenesis
131
How does an angiogenic tumour vessel that is >200mm^3 get nutrients?
Hypoxia + necrosis in ~20% of tumour
132
What is the enhanced permeability and retention (EPR) effect?
Polymeric therapeutic agents are retained better in tumour tissues than normal tissues, when compared with low MW drugs
133
How does a free drug (low MW) enter a cell, compared to polymer-drug conjugates?
Passive diffusion
134
How does a polymer-drug conjugate enter a cell, compared to a free (low MW) drug?
Endocytic capture
Endosome -> Lysosome -> Released intracellularly
135
What are some advantages/ rationale for polymer-drug conjugates?
- passive tumour targeting (EPR effect)
- decreased toxicity
- active tumour targeting (if targeting moiety present)
- solubilisation of active ingredient
- prolonged circulation time
ø extending half-life
- overcome some drug resistance mechanisms (MDR)
136
What are the requirements for polymer-drug conjugates?
(1) Drug
- potent, in relation to polymer carrying capacity
(2) Linker
- stable during transport
- degradable within target environment
(3) Polymer
- non-toxic + non-immunogenic
- suitable for industrial-scale manufacture
- biodegradable/ <40KDa
(4) Targeting group
- specific for a target
137
What is the only polymer-drug conjugate on the market?
Movantik
Carries naloxone
138
What is Movantik?
The only polymer-drug conjugate on the market
PEGylated naloxone
139
What is the polymer-drug conjugate carrying naloxone?
Movantik
140
What does Movantik deliver?
Naloxone
141
Where does naloxone initiate its effect?
Binds to mu-opioid receptors in GIT
142
What are the types of microparticles?
(1) Microcapsules
| (2) Microspheres
143
What is a microcapsule?
Type of microparticle
Outer shell + inner core (2 distinct regions)
144
What is a microsphere?
Type of microparticle
1 distinct region
Matrix style
145
How can the core of a microcapsule be referred to?
Nuclei OR core
146
How are microparticles administered?
(1) IV
(2) Directly to body compartment
- e.g. inhaled/ local injection/ SC injection
147
What are the requirements of the materials used for microparticles?
- chemically inert
- non-toxic
- biocompatible
- biodegradable
- easy to sterilise
148
What are some applications of microparticles?
- modified-release
- conversion of liquids into pseudo-solids
- protection from external environment
- mask flavour + odour
- reduce gastric irritation
149
What is a pseudo-solid?
Transferring a liquid into somewhat of a solid via binding
Solid, but act like liquid
150
What is a pseudo-solid?
Transferring a liquid into somewhat of a solid via binding
Solid, but act like liquid
151
How can microparticles be prepared?
(1) Dispersion of drug in polymer solution
(2) Coacervation (phase separation)
- changing temp of polymer solution
- salting out (add charged species)
- adding a non-solvent
- inducing a polymer-polymer reaction
(3) Hardening of coating
152
What is interfacial polymerisation?
Method of microparticle manufacture
(1) Aqueous phase + API
(2) Organic phase
153
What is coacervation?
Phase separation of a solvent and solute
154
State 2 methods for preparation of microspheres.
(1) Heat denaturation
| (2) Chemical denaturation
155
Describe the heat-denaturation method for preparation of microspheres.
(1) Oil + aqueous solution of protein + API
(2) Emulsion forms
(3) Heat at 100-170ºC
(4) Microspheres thermally stabilise
156
Describe the chemical-denaturation method for preparation of microspheres.
(1) Oil + aqueous solution of protein + API
(2) Emulsion forms
(3) Addition of glutharaldehyde/ butadiene
- cross-linking agents
(4) Microspheres chemically stabilise
157
What are some advantages of spray drying?
- quick + reproducible
- control on particle size
- low cost
- good yield
- applicable to heat sensitive materials
158
What are some disadvantages of spray drying?
- need polymers that make low-viscosity solutions
- need small droplets
- water-soluble compounds have poor encapsulation
159
How are drugs released from microspheres?
(1) Erosion
(2) Disintegration of microsphere
(3) Swelling
- API diffuses out
(4) Desorption + diffusion
(5) Ionic exchange
160
Which polymers are often used for nanoparticles?
- PLA
- PLGA
Esters with ester bonds
161
How can nanoparticles be prepared via solvent evaporation?
(1) Add aqueous solvent (polymer+drug) to water+emulsifying agent
(2) Forms droplets of solvent (in water phase) into water+emulsifying agent
(3) Evaporate solvent
(4) Nanoparticles containing API remain
162
What can cause longer term toxicity in nano/microparticles?
(1) Lack of biodegradation
| (2) Lack of bioerosion
163
What does toxicity of nano and microparticles depend on?
Size + number of particles injected
164
What is a problem with IV injections of nanoparticles?
Can be endocytose by macrophages
Causes problems to reach other tissues
BUT good for targeting liver/ spleen
165
How can endocytosis of nanoparticles by macrophages be prevented/ reduced?
PEGylation of nanoparticles
166
What is Abraxane?
PEGylated nanoparticle
Used in cancer therapy
167
What is an example of a PEGylated nanoparticle?
Abraxane
168
Define antibody-drug conjugates.
Monoclonal antibodies conjugated to cytotoxic agents
169
How can the anti-cancer activity of monoclonal antibodies be increased?
Conjugating them with effector molecules
Drug can be attached via a 'linker' molecule
170
What is a 'linker', with regard to advanced delivery methods?
Attaches the drug/ API to carrier (polymer/ antibody etc)
171
What is Neulasta?
PEGylated protein
Pegfilgrastim
172
What is Neulasta used for?
Reduction in duration of neutropenia + incidence of febrile neutropenia
In cytotoxic chemotherapy for malignancy
173
What is the rationale for using Neulasta?
42hr half-life compared to 3.5-3.8hrs
Due to MW being 39KDa vs 18.8KDa of Nupogen
174
How does the frequency of administration of Neulasta (Pegfilgrastim) compare to that of Neupogen (filgrastim)?
1 SC Neulasta 1x/cycle = OD SC Neupogen (filgrastim)
175
What is branded filgrastim called?
Neupogen
176
What is Neupogen?
Filgrastim branded
177
What is the administration route of Neulasta?
SC - 45º
178
What are some potential side effects of Neulasta use?
- spleen rupture
- Acute Respiratory Distress Syndrome
- anaphylaxis
179
What is Acute Respiratory Distress Syndrome?
- fever
- SOB
- trouble breathing
- fast breathing rate
180
What is the therapeutic application of Caelyx?
- metastatic breast cancer
| - advanced ovarian cancer when platinum drug has been tried already
181
What is the administration route of Caelyx?
IV infusion
