CONTROLLED DRUG DELIVERY

BY BIODEGRADABLE
POLYMERS
BY- Ch.R.Naveen , P.Venkat Rao

Ch.R.Naveen,
3 year, B.Pharmacy,
rd

Raghu College of Pharmacy,

Dakamarri,
Bheemili,
Visakhapatnam – 531 162. ID-chinnuraghanaveen@yahoo.com
URL :http://www.pharmainfo.net/raghanaveen

P.Venkat Rao,
Assoc.Professor,
Raghu College of Pharmacy,
Dakamarri,
Bheemili,
Visakhapatnam – 531 162.
URL
:http://www.pharmainfo.net/venkatpasupuleti
CONTENTS
 Introduction
 Biomaterials For Delivery Systems

 Factors Affecting Biodegradation of Polymers

 Controlled-Release Mechanisms

 Factors Influencing Drug Release from Polymers

 Uses of biodegradable polymers in Parenteral Depot Systems

 Biodegradable polymeric microspheres

 Miscellaneous

 Recent advances

 Future opportunities in controlled drug delivery

 Conclusion
INTRODUCTION
Biodegradable polymeric drug delivery systems (DDS)
have been widely studied for several drug delivery systems
for human health purpose. During the last two decades,
advances in biodegradable materials have been made
significantly for the development in biomedical applications,
and in this category there are industrial applications as well.
Controlled and sustained drug delivery take place when a
polymer (natural or synthetic) will prudently combined with
a drug or other active substance in such a way that the
active substance is released from the material in a tailored
manner. The release of the active substance may be stable
over a long period, it may be repeated over a long period, or
it may be activated by the environment or other external
actions. In any situation, the purpose behind controlling the
drug delivery is to achieve more effective therapies while
eliminating the adverse effects of both under- and
overdosing.
BIOMATERIAL FOR DELIVERY SYSTEMS
 Poly(2-hydroxy ethyl methacrylate).
 Poly(N-vinyl pyrrolidone).
 Poly(methyl methacrylate).
 Poly(vinyl alcohol).
 Poly(acrylic acid).
 Poly(ethylene-co-vinyl acetate).
 Poly(ethylene glycol).
 Poly(methacrylic acid).
In recent years additional polymers designed primarily for medical applications have
entered the arena of controlled release .There are:-
 Polylactides (PLA).
 Polyglycolides (PGA).
 Poly(lactide-co-glycolides) (PLGA).
 Polyanhydrides.
 Polyorthoesters.
CLASSIFICATION OF
BIODEGRADABLE POLYMER

Biodegradable polymer may be classified based on the

mechanism of release of the drug entrapped in it:

 Natural - albumin starch, dextran, gelatin, fibrinogen,

hemoglobin.

 Synthetic - -cynoacrylates), poly ethylαpoly (alkyl

cynoacrylates, poly amides. Nylon 6-10 nylon − α-
cynoacrylates, poly butyl α- 6-6, poly acryl amides, poly
amino acid, poly urethane.
 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/semi crystalline, 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).
CONTROLLED-RELEASE MECHANISMS
There are three primary mechanisms by which active agents
can be released from a delivery system: diffusion, degradation, and
swelling followed by diffusion. Any or all of these mechanisms
may occur in a given release system. Diffusion occurs when a drug
or other active agent passes through the polymer that forms the
controlled-release device. The diffusion can occur on a macroscopic
scale—as through pores in the polymer matrix—or on a molecular
level, by passing between polymer chains. The mechanisms are
classified into two types i.e. Chemical and Physical types.
Classification based on Chemical mechanisms includes :
•Type-I

•Type-II

•Type-III
Biodegradable Polymers
Type I
x
x x
H2O soluble
x x Swelling
Dimensional stability

Type II

H2O insoluble
C C C C
Chemical change
O OR O OH O OR O O- No backbone cleavage

Type III
x x
x x x x H2O insoluble
Chemical cleavage
x x x x 30 MW↓
Classification based on Physical mechanisms includes :
.

Drug delivery from a typical matrix drug delivery

system

Drug delivery from typical reservoir devices

Delivery from release Environmentally Responsive

systems

Drug delivery from bulk-eroding and surface-eroding

biodegradable systems
DRUG DELIVERY FROM A TYPICAL
MATRIX DRUG DELIVERY SYSTEM
In Figure , a polymer and active
agent have been mixed to form a
homogeneous system, also referred to
as a matrix system. Diffusion occurs
when the drug passes from the
polymer matrix into the external
environment. As the release
continues, its rate normally decreases
with this type of system, since the
active agent has a progressively
longer distance to travel and therefore
requires a longer diffusion time to
release.
DRUG DELIVERY FROM TYPICAL
RESERVOIR DEVICES
In this design, a reservoir is surrounded
by a film or membrane of a rate-controlling
material whether solid drug, dilute solution, or
highly concentrated drug solution within a
polymer matrix. The only structure effectively
limiting the release of the drug is the polymer
layer surrounding the reservoir. Since this
polymer coating is essentially uniform and of a
non changing thickness, the diffusion rate of
the active agent can be kept fairly stable
throughout the lifetime of the delivery system.
 Figure a is representative of an implantable or
oral reservoir delivery system
 Figure b illustrates a transdermal drug delivery
system, in which only one side of the device
will actually be delivering the drug.
ENVIRONMENTALLY RESPONSIVE SYSTEMS

 It is also possible for a drug delivery

system to be designed so that it is
incapable of releasing its agent or agents
until it is placed in an appropriate
biological environment.
 Swelling-controlled release systems are
initially dry and, when placed in the
body, will absorb water or other body
fluids and swell.
 The swelling increases the aqueous
solvent content within the formulation as
well as the polymer mesh size, enabling
the drug to diffuse through the swollen
network into the external environment.
DELIVERY FROM ENVIRONMENTALLY
SENSITIVE RELEASE SYSTEMS
This picture illustrate the basic
changes in structure of these sensitive
systems. Once again, for this type of
system, the drug release is accomplished
only when the polymer swells. Because
many of the potentially most useful pH-
sensitive polymers swell at high pH
values and collapse at low pH values, the
triggered drug delivery occurs upon an
increase in the pH of the environment.
Such materials are ideal for systems such
as oral delivery, in which the drug is not
released at low pH values in the stomach
but rather at high pH values in the upper
small intestine.
DRUG DELIVERY FROM
BULK-ERODING AND
SURFACE-ERODING BIODEGRADABLE
SYSTEMS.
 Previously described systems are based on polymers that
do not change their chemical structure beyond what occurs
during swelling.
 However it is the not case happens in biodegradable
polymers.
 These materials degrade within the body as a result of
natural biological processes, eliminating the need to
remove a drug delivery system after release of the active
agent has been completed.
.

 Most biodegradable polymers are designed

to degrade as a result of hydrolysis of the
polymer chains into biologically acceptable,
and progressively smaller, compounds.
 Degradation may take place through bulk
hydrolysis, in which the polymer degrades
in a fairly uniform manner throughout the
matrix, as shown in Figure a.
 For some degradable polymers, most
notably the polyanhydrides and
polyorthoesters, the degradation occurs
only at the surface of the polymer, resulting
in a release rate that is proportional to the
surface area of the drug delivery system as
shown in Figure b.
USES OF BIODEGRADABLE POLYMERS IN
PARENTERAL DEPOT SYSTEM (PDS)
 Parenteral depot systems [PDS] ,these new drug delivery systems
are injected or implanted into the muscle or subcutaneous tissue and
release the incorporated drug in a controlled manner, allowing the
adjustment of release rates over extended periods of time, ranging
from several days up to one year.
 Parenteral products with a prolonged action have been known for
some time. In contrast to these formulations, PDS allow the control
and modulation of drug release using biodegradable polymers.
 The major advantage of the use of biodegradable polymers is that, it
does not required surgical removal even after complete drug
exhaustion. In addition the breakdown products are natural
biocompatible which overcome the problem of toxicity associated
with non-biodegradable implants .
.

 Another advantage of the biodegradable polymers in implants or drug

delivery devices is that it releases drug by diffusion controlled
mechanism hence predetermined drug delivery rate can be achieved
easily.

 Most of PDS developed so far are designed to deliver drugs to the

systemic compartment. Also local drug delivery is a possibility in this
case one attempts to achieve high drug concentration at the site of
implantation without exposing non affected tissue to the drug.

 Biodegradable materials, such as polylactic acid co-glycolic acid, are of

course preferred as this removes the need for surgical removal of the
implant after treatment has ended. However, non-biodegradable
materials do provide therapeutic levels of drug for up to one year in
vivo
Factors Influencing Drug Release from
Polymers
(a) Symmetrical model

polymer
chains

Diffusing
(b) Unsymmetrical model molecule

polymer
chains

8
Factors Influencing Drug Release
1. Molecular Weight
Avg. cumulative %age WR-7557 release in vitro

100 150 000 Molecualr Weight

210 000 Molecular Weight
80 450 000 Molecular Weight

60

40

20

0 10 20 30 40 50 60 70 80 90
Time (days)
10
2. Crystallinity

Change in the Crystallinity of

Poly(ε-Caprolactone) as a
Function of Molecular Weight

Molecular Crystallinity
Weight (Mw) (%)
59,300 47.5
53,000 50.6
46,400 50.5
37,100 52.5
30,600 57.0
26,800 58.6
23,400 58.4
21,700 59.5
11
Polymer %Crystallinity

Poly(L-lactic acid) 37%

Poly(DL-lactic acid) 0%
Poly(Glycolic acid) 50%

12
3. Glass Transition Temperature

0.85
V/(10-3 m3 kg-1)

0.84
h
0.02
h Tg(0.02)
100 Tg(100)
0.83
-25 0 25 50
T/°C

Polymer Tg (°C) SS Flux

(1011 g/cm/s)

Poly(ε-caprolactone) -65 6.1

Poly(DL-lactic acid) 57 0.00033
1:1 copolymer 27 5.8 13
4. Cross-Links Density
Dependence of in vitro and in vivo Release
Profiles of Norgestomet and Polymer
Diffusivities on Extent of Cross-Linkage
(XL) in Hydrogel Implants

XL Dp x 103 Q/t1/2 (mg cm-2 day -1/2)

(%) (cm2/day In vitro In vivoa

1.2 97.2 0.605 0.640

4.8 24.2 0.396 0.504
9.6 12.1 0.185 -----
12.0 9.7 0.133 -----
14.4 8.1 0.101 -----
16.8 6.9 0.074 -----
19.2 6.1 0.058 0.129
aResults from the subcutaneous implantation of Norgestomet-
releasing Hydrogen implants in 39 cows for 16 days
5. Biocompatibility
Healing
Acute Chronic

PMN’s
Fibroblasts

Fibrosis
INTENSITY

Mononuclear
Leukocytes

TIME
15
BIODEGRADABLE POLYMERIC
MICROSPHERES
 Biodegradable polymeric microspheres have been used to deliver a
variety of therapeutic substances such as proteins, peptides,
NSAIDs, antibiotics and anticancer drugs in recent years because of
their biocompatibility and degradation in vivo , to toxicologically
acceptable lactic and glycolic acids which are further eliminated by
the normal metabolic pathways and approved by US FDA

 Biodegradable polymeric drug delivery systems based on aliphatic

polyesters, polylactic acid (PLA), polyglycolic acid (PGA) and
poly(D,L-lactide-co-glycolide) (PLGA) microspheres have been
studied to protect encapsulated drugs from degradation, enhance
bioavailability and sustain drug release

 The objective of the present study was to prepare and characterize

protein loaded biodegradable polymeric microspheres
EXAMPLES OF BIODEGRADABLE
POLYMERIC MICROSPHERES

Biodegradable polymeric
Monodisperse PLGA microspheres
microspheres fabricated by
with encapsulated fluorescent
conventional technology (50 - 100
protein
μm)
.

 Hollow biodegradable capsules

after core-liquid removal
MISCELLANEOUS
 Sustained release medications
 Ethyl cellulose and methyl stearate mixtures
 Hydrated hydroxy alkyl cellulose
 Salts of polymeric carboxylates
 Chelated hydrogels
 Water-insoluble hydrophilic copolymers
 Cellulose ether compositions
 Partial esters o facrylate-unsaturated anhydride
copolymer
RECENT ADVANCES
 Medisorb
 Microencapsulation (50 µm) by PLA, PGA, PLGA
 Drug release : week to one year

 Polymeric prodrugs
 Cellulose and polyarabogalactants as drug carrier
 Naproxen with polyphosphazene : bioerodable implant
 Conjugate of poly(glutamic acid) and p-
phenylenediamine using immunoglobulin as a homing
device
 Immunogenicity, hemolytic activity, pyrogenicity,
osmotic property, interaction with plasma components
 Alzamer
 Bioerodible polymer : release at a controlled rate
 Chronic disease, contraception, topical therapy

 Sustained release tablet

 Compressed plastic matrix
 Diffuse through a network of channels
 Release controlled by altering the porosity or surface area of
the matrix, changing the solubility of drug, adding other
compounds that either speed up or delay the release
 Mixture of two or more substances : Polycaprolactone and
cellulose propionate
 Aqueous polymeric dispersion
 Safety hazards associated with use of organic solvent
 Water-based coating formulation

 Latex or pseudo-latex
 To coat pellets or tablets, film deposition on the substrate
 Tackiness or film rupturing

 Hydrogel
 Swelling and biocompatibility
 Multiblock copolymers
FUTURE OPPORTUNITIES IN
CONTROLLED DRUG DELIVERY
 Exciting opportunities in controlled drug
delivery lie in the field of responsive delivery
systems
 By this it will be possible to deliver drugs
through implantable devices in response to a
measured blood level or to deliver a drug
precisely to a targeted site
 Much of the development of novel materials
in controlled drug delivery is focusing on the
preparation and use of these responsive
polymers with specifically designed
macroscopic and microscopic structural and
chemical features.
.

Such systems include:

 Copolymers with desirable hydrophilic/hydrophobic interactions.

 Block or graft copolymers.

 Complexation networks responding via hydrogen or ionic bonding.

 Dendrimers or star polymers as nanoparticles for immobilization of

enzymes, drugs, peptides, or other biological agents.

 New biodegradable polymers.

 New blends of hydrocolloids and carbohydrate-based polymers.

CONCLUSION
• The main advantages in using biodegradable polymeric
substances are there is no possibility of toxicity problems,
their release rates can be customized and they degraded to
form biocompatible or non-toxic products in biological fluids,
which are removed from the body through normal metabolic
pathways and physiological mechanisms.

• However, biodegradable polymeric substances do produce

‘degradation by-products’ that must be tolerated with little or
no adverse reactions within the biological environment.

• Control and modulation of drug release is enhanced using

Parenteral Depot Systems [PDS] and microspheres.
ACKNOWLEDGMENT
Firstly I want to thank several colleagues who
shared their knowledge with me. I was lucky
once again to have all of my professors with me
especially our professor Venkat Rao garu for
giving his valuable suggestions and prodigious
support for us.
I also thank pharmainfo.net for
giving me an opportunity to participate in this
contest.
 THANK YOU
.