Lec 9- Microspheres and drug delivery Flashcards
(42 cards)
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
Ionotropic gelation
* 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
Microfluidics
* 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
Effect of processing parameters
Homogenisation time
28
The polymer concentration in the organic phase
29
Emulsifier concentration in external aqueous phase
30
Emulsifier type
31
Effect of processing parameters- spray drying
* Conditions
* Atomising air flow rate
* Inlet temperature
* Polymer type
* Liquid feed flow rate
* Impact
* Moisture content
* Yield
* Size
* Drug entrapment
* Release profile
32
Vaccine delivery
* Why microspheres
* Biodegradable
* Inherent immunogenicity
* Potential CR- single shot
* Versatility
* Materials
* Additional adjuvants
33
Sub-unit Antigens
* 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
Effect of additional adjuvants
Physico-chemical characteristics
35
Effect of additional adjuvants
* Different adjuvant combinations not only affect Physico-chemical, properties, but also immunological efficacy
* DDA potent Th1 adjuvant
36
Effect of location of Ag
Physico-chemical properties
37
Ab titres
38
Spleen cell proliferation
39
Cytokine secretion
40
Effect of antigen location
* 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
Key considerations
* 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
Case studies
1. TB vaccine Ag
2. Malarial vaccine Ag
3. Oral delivery of flucloxacillin (paediatrics)
4. Nasal delivery of RNA
5. Ophthalmic implant for macular degeneration
