Drug delivery
-
Upload
mohammad-sedeigh-moeini -
Category
Health & Medicine
-
view
1.137 -
download
2
Transcript of Drug delivery
Introduction to Controlled Drug Deliveryمعینی صدیق محمد
1
Classical drug delivery
For most of the pharmaceutical industries existence, drug delivery induced simple, fast-acting responses via oral or injection delivery routes
Problems associated with this approach1. Reduced potencies because of partial degradation2. Toxic levels of administration3. Increase costs associated with excess dosing
2
Why control drug delivery?
Goal of more sophisticated drug delivery techniques
1. Deploy to a target site to limit side effects
2. Maintain a therapeutic drug level for prolonged periods of time
3. Predictable controllable release rates
4. Reduce dosing frequent and increase patient compliance
Toxicity level
Injection
Controlled release
Therapeutic Level
Time
As the cost and complexity of individual drug molecules has risen the problems with the classical delivery strategies over
took their benefits.
3
• Long delivery
• Place of delivery
• Delivery at the required time
• New patents and exclusive renewals period production
• Delivery of specific active ingredients (peptides and proteins)
• Eliminating the peaks and valleys of blood concentration and reduced side effects
Characteristics and Benefits
4
5
Drug levels in the blood with (a) traditional drug dosing and (b) controlled-delivery dosing
• Use Oily solvents
• Use sparingly soluble salts drug
• Use of pretreatment drugs (Prodrugs)
• Use of non-polymeric carriers (liposomes)
• Use mechanical drug delivery systems (pumps, drug delivery)
• Drug molecules bind to specific molecules (monoclonal antibodies, special proteins, PEG)
• The use of polymeric carriers
Methods of delivery:
6
7
Use Fick’s law to design drug release
8
Rate control
9
Polymers in drug delivery
• Matrix (Monolithic) devices- films with the drug in a polymer matrix
- Easy to fabricate, typically by simple mixing of polymer and drug
• Reservoir devices- Drug contained by the polymer
- Release is usually diffusion controlled (Fickian) i.e. J = -DC where J =flux, C = component of concentration across membrane of defined area, and is a differential vector operator
• Polymer drug conjugates- Polymer attached to drug by (covalent) sacrificial linker
10
• Controlled release implies controlled release of drugs from polymer drug delivery systems (DDS)
• Type of polymer– Non-degradable / Degradable
• Type of Design
Reservoir Matrix
Release mechanisms– Diffusion / polymer degradation / combination
11
Controlled Release Systems
Entrapment or Encapsulation• During the 1970, scientists first began to encapsulate and
entrap drugs within polymers
• Encapsulation involves surrounding drug molecules with a solid polymer shell
• Entrapment involves the suspension of drug molecules within a polymer matrix.
drugpolymer
DrugPolymer
12
Drug release by diffusion• Early encapsulation and entrapment systems released
the drug from within the polymer via molecular diffusion
– When the polymer absorbs water it swells in size different
– Swelling created voids throughout the interior polymer
– Smaller molecule drugs can escape via the voids at a known rate controlled by molecular diffusion (a function of temperature and drug size)
Addwater
Addtime
13
Drug release by erosion• Modern delivery systems employ biodegradable
polymers– When the polymer is exposed to water hydrolysis occurs– Hydrolysis degrades the large polymers into smaller
biocompatible compounds
– Bulk erosion process – Surface erosion process
mermer
Polymer
mermer mermer mermer mermer mermer mermer mermer mermer
Water attacks bond
mermer mermer mermer mermer mermer mermer mermer mermer mermer
mermer mermer mermer mermer mermer mermer mermer mermer mermer14
Bulk erosion:– These small compound diffuse out of the matrix through the
voids caused by swelling
– Loss of the small compounds accelerates the formation of voids thus the exit of drug molecules
– Polymers containing ester, ether, and amide groups, such as poly(lactic acid) (PLA), poly(glycolic acid), poly(ε-caprolactone), polyamide, proteins, and cellulose (and its derivatives), generally exhibit this type of erosion.
Addwater
Addtime
15
Surface erosion:
– hydrolysis mainly occurs in the region near the surface, whereas the bulk material is only slightly or not at all hydrolyzed. As the surface is eroded and removed.
– Polymers such as poly(ortho ester)s (POEs), PAHs, and some polycarbonates tend to undergo surface erosion.
Addwater
Addtime
16
How is entrapment or encapsulation obtained?
The physical entrapment and encapsulation of drugs within a polymer is complete via one of five techniques
1. Wurster
2. Coacervation
3. Spray drying (or precipitation)
4. Coextrustion
5. Self-assembly methods
17
Wurster processing (1949)
• The Wurstur process is essentially a coating process applied after a drug core is formed.
• The polymer shell is applied via spraying while the drug cores (liquid or solid) is suspended and recirculated in a gas stream.
Gas
DrugPolymer
Gas
DrugPolymer
18
Coacervation Technique• STEP #1:
– Polymer dissolved in a solvent (or oil)– Drug dissolved in water
• STEP #2:– 2 liquids are rapidly mixed – water droplets form within the solvent
• STEP # 3:– Emulsion from step #2 is mixed rapidly with fresh water – Oil droplets within the fresh water phase – Oil droplets contain original dispersed water/drug phase – Oil diffuses into the fresh water phase precipitating the
polymer & entrapping the drug
Drug/H
20
Polym
er/Oil
H20
19
Supercritical fluid precipitationSolvent-polymer
solution from pump
CO2 from pump Heat exchanger
Flow stra ightener
Nozzle
Nozzle contraction
Precipita te
0.2µm filter
Back pressure regula tor
Gas outle tPoly(l-lactide) ~1-m diameter
particles formed by PCA processing
Normal operating
conditions:8.5-MPa,
35°C
20
Co-extrusion processing
• These concentric cylinders then breakup into individual packets either driven by air flow, electrostatic or mechanical vibration
Syringe pump
HV supply
Neg.
Drug
Polymer
• There are numerous co-extrusion processes but they all share one feature – the polymer shell is flowed concentrically around a pipe containing the drug formulation
21
Self-assembling delivery systems
The next advance was to construct materials/polymers that would self assemble with drugs to create
controlled drug delivery vehicles
• Self assembly is typically approach via one of two methods:1. Using a molecule that has a hydrophilic head
and hydrophobic tail to form a shell, or2. Electrostatic interaction to entrap drug
molecules
22
Micelles & Bilayers• Entrapment by micelle or bilayer
formation can be obtained using lipids, surfactants and block copolymers
Polar Head Group(hydrophilic)
Fatty Tail(hydrophobic)
Bilayer
monlayer
micelle
23
Hydrogels(e.g. polyacrylic acids)
• Cross-linked, hydrophilic, 3-D polymer networks that are highly permeable• Do not swell in the presence of water unless activated• Swelling activate by pH, temperature, electric field• Drug release happens via void generated & diffusion (diffusion rate is regulated by cross-linking
ratio)
mermer mermer mermer mermer
mermer mermer mermer mermer
Add water+
activator
mermer mermer mermer mermer
mermer mermer mermer mermer24
Properties and Structures of Hydrogels
Rs = (Ws-Wd) / Wd
Rs = swelling ratio
Ws = weight of swollen hydrogels
Wd = weight of dried hydrogels
Swelling property is influenced by:•type and composition of monomers•other environmental factors such as :
temperature, pH, ionic strength•cross-linking
Cross-linking and/or copolymerization with hydrophobic comonomers density↑, mechanical strength↑, swelling property↓
25
Implantable pumpsThe pumps usually use polymer swelling to drive
drug formulations out of a reservoir
Polymer Drug/H20
Drug/H20
Water
Drug/H20
Water
Swell26
Alza – Duros pump
http://www.alza.com/alza/duros 27