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DELIVERY APPLICATIONS
• Definition :
Biodegradable polymers are defined as
polymers comprised of monomers linked to
one another through functional groups and
have unstable links in the backbone.
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Classification :
• Synthetic Polymers :
a) Aliphatic polyesters
b) Polyphospho-esters
c) Polyanhydrides
d) Polyorthoesters
• Natural Polymers :
a) Collagen
b) Albumin
c) Casein
d) gelatin
• Environment Responsive Polymers :
a) Thermo sensitive – Poly n-isopropyl acryl amide
b) pH sensitive – Poly acrylic acid
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Polymers used in controlled drug delivery
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Factors Affecting Biodegradation of Polymers
• Chemical structure.
• Chemical composition.
• Distribution of repeat units in multimers.
• Presents of ionic groups.
• Presence of unexpected units or chain defects.
• Configuration structure.
• Molecular weight.
• Molecular-weight distribution.
• Morphology (amorphous/semicrystalline, microstructures, residual
stresses).
• Presence of low-molecular-weight compounds.
• Processing conditions.
• Annealing.
• Sterilization process.
• Storage history.
• Shape.
• Site of implantation.
• Adsorbed and absorbed compounds (water, lipids, ions, etc.).
• Physicochemical factors (ion exchange, ionic strength, pH).
Physical factors (shape and size changes, variations of diffusion
coefficients,
Mechanical stresses, stress- and solvent-induced cracking, etc.).
• Mechanism of hydrolysis (enzymes versus water). 5
Biodegradable System
• Mainly used for parenteral controlled drug
delivery.
• Drug is encapsulated in biodegradable
microcapsules which are suspended in
aqueous medium and injected
subcutaneously or intra-muscularly.
• Polymers used for microcapsules are :
Gelatin, dextran, polylactate, lactide –
glycolide copolymer.
• The release of drug is controlled by the rate
of bio-degradation of polymer.
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Classical drug delivery
Injection
Goal of more sophisticated drug
delivery techniques Toxicity level
Deploy to a target site to limit side
effects
Shepard drugs through specific areas of Therapeutic Level
the body without degradation
Maintain a therapeutic drug level for Controlled release
prolonged periods of time
Predictable controllable release rates
Reduce dosing frequent and increase
patient compliance Time
History of Controlled Drug Delivery
Polymer
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
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)
Drug
Solvent
Add Add
water time
Drug release by erosion
Add Add
water time
Surface erosion
(e.g., polyanhydrides)
When the polymer is exposed to water hydrolysis occurs
Hydrolysis degrades the large polymers into smaller
biocompatible compounds
These small compound diffuse from the interface of the
polymer
Loss of the small compounds reveals drug trapped within
Note these polymer do not swell.
Add Add
water time
STIMULI RESPONSIVE HYDROGELS
Swellable polymer
Annular openings
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Osmotically Controlled Drug Delivery
System
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pH SENSITIVE HYDROGELS
• Poly(methacrylic acid-g-ethylene glycol), P(MAA-g-EG)
– MAA backbone grafted with terminally functional PEG chains
– Forms a water swollen, cross-linked polymer network
– Exhibits environmentally responsive pH dependent swelling
PMAA
CH3 CH3 H3C CH3
H3C CH3
O O O O
- -
O O O O
H H
H3C O O H
O O
PEG
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Controlled drug(FA) delivery
200 mg drug
90% drug/10% PVA
PVA or Polyimide
Silicone Tube PVA 25 gauge
seal
3.5 mm
OH
OD=0.37 mm O
HO O
H O
FA = fluocinolone acetonide
Solubility is a main driver for F H PD-0076535
release rate- most legacy VEGFR O
compounds ( free bases) •TD sol = 15 mg/mL (pH 7.4)
were not soluble enough •0.2 mg/day
•1000 day duration ~ 3 yr
•Phase III – 3 yr study 20
Drug Delivery to the Back of
the Eye
Intravitreal device delivery
• Subtenon
– Injection behind the eye in the
subtenon space
• Intravitreal ( IVT)
– Injection of a suspension or device
into the vitreous
• Topical
– Solution/Suspension dispensed to
front of the eye ( exploratory)
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Implantable pumps
The pumps usually use polymer swelling to
drive drug formulations out of a reservoir
Polymer Drug/H20
Water
Drug/H20
Water
Swell Drug/H20
Transdermal
•
patches
Topical skin application
• 3 layer design
– adhesive
– polymer/drug matrix Skin
– water proof backing
• Physical Barrier
– Acidic environment in
stomach
– Mucus layer on Stomach
Duodenum
intestines
Jejunum
– Tight, highly uniform Colon
Ileum
epithelial layer
Anus
Rectum
Complexation hydrogels
• Poly(methacrylic acid-g-ethylene glycol), P(MAA-g-EG)
– MAA backbone grafted with terminally functional PEG
chains
– Forms a water swollen, cross-linked polymer network
– Exhibits environmentally responsive pH dependent swelling
PMAA
CH3 CH3 H3C CH3
H3C CH3
O O O O
O
H
O
-
O
H
O
-
High pH pKa ~ 4.8 Low pH
H3C O
O
O
O
H Insulin
PEG
THERMORESPONSIVE HYDROGEL
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THERMORESPONSIVE POLYMERS
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Current Scenario in controlled Drug Delivery
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