POLYMERS IN DRUG

DELIVERY APPLICATIONS

Akhil Kumar Sen

Chemical Engineering and Technology
Birla Institute of Technology, Mesra
Ranchi 835215
Biodegradable Polymers

• Definition :
Biodegradable polymers are defined as
polymers comprised of monomers linked to
one another through functional groups and
have unstable links in the backbone.

• They slowly disappear from the site of

administration in response to a chemical
reaction such as hydrolysis.

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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

Poly(2-hydroxy ethyl methacrylate). Polylactides (PLA).

• Poly(N-vinyl pyrrolidone). • Polyglycolides (PGA).
• Poly(methyl methacrylate). • Poly(lactide-co-glycolides) (PLGA)
• Poly(vinyl alcohol). • Polyanhydrides.
• Poly(acrylic acid). • Polyorthoesters
• Polyacrylamide.
• Poly(ethylene-co-vinyl acetate).
• Poly(ethylene glycol).
• Poly(methacrylic acid).

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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

For most of the pharmaceutical industries

existence, drug delivery induced simple, fast-acting
responses via oral or injection delivery routes

Problems associated with this approach

 Reduced potencies because of partial degradation
 Toxic levels of administration
 Increase costs associated with excess dosing
 Compliance issue due to administration pain
 Why control drug delivery?
As the cost and complexity of individual drug molecules has
risen the problems with the classical delivery strategies over took
their benefits.

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

 Wurster technique 1949

 Coacervation (liquid encapsulation) 1953
 Mircroencapsulation 1960’s
65% of all current drugs use some form of micro-
encapsulation
 Implants 1970’s
 Transdermal 1980’s
 Site directed systems 1990’s
 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
polymer
drug

 Entrapment involves the suspension of drug molecules

within a polymer matrix.
Drug

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

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

Water attacks bond

Polymer

mer mer mer mer mer mer mer mer mer

mer mer mer mer mer mer mer mer mer

mer mer mer mer mer mer mer mer mer

Bulk erosion
(e.g. poly lactide, polyglycolic acid)

 When the polymer is exposed to water hydrolysis

occurs
 Hydrolysis degrades the large polymers into smaller
biocompatible compounds
 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

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

• 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, external
field
• Drug release happens via void generated &
diffusion (diffusion rate is regulated by cross-
linking ratio)
mer mer mer mer
Add water
mer mer mer mer
+
activator
mer mer mer mer mer mer mer mer
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 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)
Add water mer mer mer mer
mer mer mer mer +
activator

mer mer mer mer mer mer mer mer

 Polymer swells and generates hydrodynamic
pressure and induces the delivery of drug formulation
through the orifice.
Drug delivery orifice

Shape retaining housing

Collapsible drug container

Swellable polymer

Liquid drug formulation

Annular openings

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Osmotically Controlled Drug Delivery
System

• Drug is coated with semi-

permeable polymer
e.g. Cellulose acetate.
• Water generates osmotic
pressure gradient by
permeating through semi-
permeable membrane.
• Due to that drug pumps
out of delivery orifice over
a prolonged time at a
defined rate.

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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

• Drug is delivery to the skin up to saturation

• Blood via circulation removes drug locally and more

escapes the matrix to return levels to saturation
Challenges to oral insulin
delivery
• Enzymatic Barrier
– Majority of activity in the
stomach
– Some enzymes present
in the intestinal lumen Esophagus

• 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

• Class of stimuli responsive polymers.

• Hydrogels those are sensitive to changes in the
temperature
• Exhibit change in the properties as a function of
temperature.

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THERMORESPONSIVE POLYMERS

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Current Scenario in controlled Drug Delivery

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