Lec 9- Microspheres and drug delivery Flashcards
1
Q
Polymers
A
- Large macromolecule composed of several repeating monomer units
- Several arrangements of monomer units are feasible (e.g. linear, branched, grafted)
- We can attach various groups onto the polymer to change its pharmaceutical properties
- Can be naturally occurring, semi-synthetic or synthetic
- Present in all aspects of everyday life
2
Q
Types of commonly used polymer
A
- Suitability dependent on the application
- Natural
- Glass
- Silica
- Alginate
- Chitosan
- Synthetic
- Polyesters
- Methacrylates
- Cellulose derivatives
- Polyvinyl derivatives
3
Q
Time to think
A
- Why coat something in a polymer
- sustained release
- Gastro resistance
- Taste masking
- Excipient: viscosity modifier, flocculation
- Improve solubility
- Improve stability
- PEG to produce liposomes and increase F
4
Q
Pharmaceutical Uses
A
- Enteric coatings/ microencapsulation
- pH triggered release
- Enzyme triggered release
- Sustained release
- Controlled release
- Drug delivery systems (carriers)- if we need to drug to be present at a particular site
5
Q
Microencapsulation
A
- Enables liquids or solids to be surrounded by a coating of a synthetic, or natural polymer or lipid (compliance)
- The coating can be reactive- e.g. pH-sensitive, CR
- Can be employed for taste-masking
- Granulation or micropellets
6
Q
Reactive coating- pH
A
- Cellulose acetate phthalate
- 1/2 acid groups are phthalic acid
- A free carboxylic acid group can form a soluble salt form in weakly acidic, neutral and slightly alkaline, cation-containing environment
- Changes release profile in different pH’s
7
Q
Reactive coating- pH
A
- HPMCAP- Hypromellosephthalate
- pH value for rapid disintegration controlled by varying the amount of phthalic acid
- pH 5 => 24% phthalyl content
- pH 5.5 => 31% phthalyl content
8
Q
Reactive coatings- pH
A
- Polymethacrylates
- Co-polymer of methacrylates (Ester function) and methacrylic acid (carboxylic acid)
- Ratio 1:1 => pH 5.5-6 (Eudragit L)
- Ratio 2:1 => from pH 6.5 (Eudragit S)
9
Q
Reactive coatings- enzyme
A
- Azo-group containing polymers
- Concerns over toxicity
- Natural and semi-synthetic polysaccharides
- E.g. Chitosan, polysaccharides, pectin
- Degraded by microflora in the colon
- Potential problems arising from water solubility
- Can use cross-linking to avoid this
10
Q
Reservoir systems
A
- Drug is present in the core (reservoir)
- Surrounded by an inert polymer membrane (film)
- Release of drug-dependent on diffusion
- Rate dependent on the nature of the film (following Fick’s laws of diffusion)
- Commonly use ethylcellulose and poly(ethyl acrylate, methylmethacrylate)
- Eudragit RS and RL
11
Q
Matrix systems
A
- Drug is dispersed in a polymeric matrix
- Matrix is insoluble (e.g. Poly(ethylene), ethylcellulose)
- The drug is partly dissolved in the matrix
- Homogenous= evenly distributed (follow Higuchi equations)
- Porous= Additional soluble polymer (generally case II transport
12
Q
Bioerodible systems
A
- Matric systems
- Release not primarily governed by diffusion or dissolution
- Erosion of polymer the rate-limiting step
13
Q
Time-controlled release
A
- Can employ a combination of coatings to achieve site-specific targeting
- E.g. coating 1= sustained release polymer, Coating 2= pH responsive polymer
14
Q
Microspheres
History
A
- Been around since the 70s
- Several depot type formulations on the market (e.g. Zoladex, Nutropin)
- Renewed interest in their potential role for protein delivery => single-dose forms
15
Q
Why use them
A
- Variety of well known and characterised formulation techniques
- Exhibit prolonged, controlled release
- Can protect molecules from the harsh environment
- Due to particulate nature actively target APCs
- FDA approval
- Huge variety of materials => polymers
16
Q
Polyesters
A
17
Q
Biodegradable
A
- PLGA hydrolysis produces lactic and glycolic acids
- Scission of ester bonds generates oligomers and monomers and a general decrease in molecular weight
- Cleared through Kreb’s cycle to CO2 and H2O
18
Q
Applications
A
- Depot formulations
- Diagnostics => magnetic imaging etc
- Filler/ density modifiers => Paints
- Explosives
- Automotives
- Cosmetics => Biospheres
- Inks => Flexible display electronic inks
19
Q
Methods of manufacture
A
- Emulsion/ Solvent evaporation
- Spray drying
- Ionotropic gelation
- Microfluidics
- Nanoprecipitation
- Supercriticaal fluid mixing
20
Q
Methods of manufacture W1/o/W2
A
- Aqueous drug
- Put it in a (volatile) oil polymer
- Transfer primary emulsion into secondary aqueous phase usually with an emulsion stabiliser
- Allow volatile solvent to evaporate
- hardening on microspheres which has encapsulated the drug
21
Q
W/O/W microsphere
A
- Aqueous channels
- Polymer matrix
22
Q
Methods of manufacture O/W
A
- Organic phase which contains polymer (NO drug), put into an aqueous phase
- Allow evaporation of emulsion, hardened polymer microspheres
- Filter and wash
- Re-suspend in the drug solution
- The drug can then adsorb onto microspheres
- Useful for peptides and proteins with charges
23
Q
O/W
A
24
Q
Methods of manufacture (3)
Spray drying
A
25
Q
Ionotropic gelation
A
- Particularly useful for alginates
- Take alginate and add it to cationic solution
- because of the properties of alginate and cations (Ca)- cross-linking between calcium and alginates forms spheres
26
Q
Microfluidics
A
- Efficient mixing due to herringbone structure
- Continuous flow, high throughput
- Greater control over Physico-chemical characteristics
- With emulsion solvent evaporation and spray drying processes are
- Time consuming
- No tight control on microsphere size
- This method is rapid and has tight control of microsphere time
27
Q
Effect of processing parameters
Homogenisation time
A
28
Q
The polymer concentration in the organic phase
A
29
Q
Emulsifier concentration in external aqueous phase
A
30
Q
Emulsifier type
A
31
Q
Effect of processing parameters- spray drying
A
- Conditions
- Atomising air flow rate
- Inlet temperature
- Polymer type
- Liquid feed flow rate
- Impact
- Moisture content
- Yield
- Size
- Drug entrapment
- Release profile
32
Q
Vaccine delivery
A
- Why microspheres
- Biodegradable
- Inherent immunogenicity
- Potential CR- single shot
- Versatility
- Materials
- Additional adjuvants
33
Q
Sub-unit Antigens
A
- Derived from mycobacterial proteins or DNA
- Enhanced safety and side-effect profile
- Lack of immunostimulatory components of the whole-cell vaccines
- Require adjuvants and/or delivery systems
- Microspheres are one of several particulate delivery systems which have great potential
- Protect antigen
- Impart immunogenicity
- Potential for single shot
34
Q
Effect of additional adjuvants
Physico-chemical characteristics
A
35
Q
Effect of additional adjuvants
A
- Different adjuvant combinations not only affect Physico-chemical, properties, but also immunological efficacy
- DDA potent Th1 adjuvant
36
Q
Effect of location of Ag
Physico-chemical properties
A
37
Q
Ab titres
A
38
Q
Spleen cell proliferation
A
39
Q
Cytokine secretion
A
40
Q
Effect of antigen location
A
- Entrapped antigen appears to show a tendency for cellular immunity
- Absorbed Ag more likely to yield humoural immunity
- Both have advantages for particular application and diseases
41
Q
Key considerations
A
- Size
- limit of specific targeting
- Route of delivery
- Charge
- Interaction with cells/tissues
- Drug loading
- Polymer
- Release rate/ pH trigger/ taste masking
- Drug location
- Manufacturing process
42
Q
Case studies
A
- TB vaccine Ag
- Malarial vaccine Ag
- Oral delivery of flucloxacillin (paediatrics)
- Nasal delivery of RNA
- Ophthalmic implant for macular degeneration
