POLIMER 

DALAM KONTROL 
PELEPASAN OBAT
Teuku Nanda Saifullah Sulaiman
Laboratorium Teknologi Farmasi
Fakultas Farmasi UGM
 Tujuan penggunaan polimer dan
d d
dendrimer d l SPO untuk:
dalam k
• Prolong drug action by entrapping the drug 
g g y pp g g
within matrices
• Shift drug distribution in the direction of tumors
• Shunt therapeutic genes or oligonucleotides into 
cells
• Enable drug absorption at optimum 
Enable drug absorption at optimum
gastrointestinal tract absorptive sites
• Make the drug available only when there is a 
g y
defined change in temperature or when activated 
by an enzyme 
• In fact, recent reports show that polymers and 
, p p y
dendrimers themselves demonstrate intrinsic 
bioactivity. 
• The drug delivery macromolecule is alive and 
well, and now has both drug and drug carrier 
properties.
properties
• Simple manipulation of the water solubility of
polymers by increasing their chain length
polymers,
through cross‐linking or by hydrophobising or
y p
hydrophilizingg them with copolymers
p y and other
groups, yields a wealth of materials with a wide
spectrum of possible applications.
Micrograph of particles used to carry 
d
drugs to the lung
t th l
 Factors to consider in selecting or developing a 
polimer
li f
for controlled delivery
ll d d li
• Biocompatibility and toxicology
• Regulatory acceptance
R l t t
• Degradation rate and degradation product and their 
biocompatibility and toxicology, if biodegradable
p y gy, g
• Cost
• Chemical, physical and mechanical properties
• Suitable solvents
S i bl l
• Processing requirements
• Compatibility limits of the active agent with the 
Compatibility limits of the active agent with the
polimer
• Required sterilization methods
• Thermal transition temperature
h l
 Several physicochemical factors controlling the 
d li
delivery of a bioactive agent to the host
f bi i h h
• Local pH of the host site
oca p o t e ost s te
• Hydrophilic or hydrophobic nature of the active 
g
agent
• Solubility of the active in the delivery matrix
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• Permeability of the delivery matrix to water
• Solubility of the active in the local environment
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• Permeability of the delivery matrix to the active 
agent
• Bio‐stability of the delivery matrix
Polimer yg biasa digunakan dalam SPO
1.
1 Nonbiodegradable hydrophobic polimers
hydrophobic polimers
2. Hydrogels
3
3. S l bl
Soluble polimers
li
4. Biodegradable polimers
 Nonbiodegradable hydrophobic 
polimers
l
• Bahan ini inert
• Matrik dapat diambil setelah obat habis dalam
kondisi utuh
• Sebagai rate limiting barrier terhadap
transport dan pelepasan obat
transport dan
• Contoh: etil selulosa, selulosa asetat, 
polietilen, polivinil klorida, polietilen
polietilen, polivinil klorida, polietilen
vinilasetat, polidimetil siloksan dan polieter
uretan.
 Hydrogels
• inert
• Dapat mengembang tapi tidak larut bila
kontak dg air
dg air
• Matrik dapat diambil utuh dari tempat
aplikasinya
• Sebagai rate limiting barrier terhadap
transport dan pelepasan obat
transport dan
• Contoh: dextran, poliacrylamide, cross‐linked 
PVP, cross‐linked
PVP, cross linked polyvinyl alcohol
polyvinyl alcohol
 Soluble polimers
Soluble polimers
• BM kurang
BM kurang dari 75.000 dalton
75.000 dalton
• Larut dalam air
• Kecepatan disolusi berkurang dg naiknya
dg naiknya BM
• Dapat digunakan sendiri atau kombinasi dg 
polimer hidrofobik shg memberikan pelepasan
obat yg lebih lambat
• Contoh: PEG, uncross‐linked PVA/PVP, HPMC 
Contoh: PEG uncross‐linked PVA/PVP HPMC
(methocel), copolimers of methacrylic acid 
and acrylic acid methyl ester (Eudragit)
and acrylic acid methyl ester (Eudragit)
 Biodegradable polimers
Biodegradable polimers
• Dapat terdegradasi secara lambat dari tempat
aplikasi
• Pelepasan obat dari sediaan akibat erosi
permukaan
• Contoh: Polylactides
C h P l l id (PLA), Polyglycolides
(PLA) P l l lid
(PGA), Poly(lactide‐co‐glycolides) (PLGA), 
P l h d id P l
Polyanhydrides, Polyorthoesters.
h
• The greatest advantage of these degradable
polymers is that they are broken down into
biologically acceptable molecules that are
metabolized and removed from the body via
normal metabolic pathways.
• Biodegradable materials do produce
degradation by‐products that must be
tolerated
l d with
i h little
li l or no adverse
d reactions
i
within the biological environment.
Factors Affecting Biodegradation of Polymers
• Chemical structure and Chemical composition. 
Ch i l t t d Ch i l iti
• Distribution of repeat units in multimers. 
• Presents of ionic groups. 
• Presence of unexpected units or chain defects
Presence of unexpected units or chain defects. 
• Configuration structure. 
• Molecular weight and Molecular‐weight distribution. 
• Morphology (amorphous/semicrystalline, microstructures, residual stresses).
Morphology (amorphous/semicrystalline, microstructures, residual stresses). 
• Presence of low‐molecular‐weight compounds. 
• Processing conditions. 
• 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). 
mechanical stresses, stress‐ and solvent‐induced cracking)
• Mechanism of hydrolysis (enzymes versus water).
CONTROLLED‐RELEASE
CONTROLLED RELEASE MECHANISMS
MECHANISMS
• There
There are three primary mechanisms active 
are three primary mechanisms active
agents can be released from a delivery system:
– diffusion
– Degradation
– Swelling followed by diffusion
Swelling followed by diffusion
 Polymer
P l andd active
ti agentt have
h b
been
mixed to form a homogeneous system,
also referred to as a matrix system

Diffusion occurs when the drugg p

Drug delivery from a typical matrix drug delivery system.
 Figure b: illustrates a 
Figure a: is  transdermal drug 
representative of an
representative of an  delivery system, in which
delivery system, in which 
implantable or oral  only one side of the 
device will actually be 
reservoir delivery 
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delivering the drug
delivering the drug. 
system

Drug delivery from typical reservoir devices: (a) implantable or 
g yf yp ( ) p
oral systems, and (b) transdermal systems .
• In this design, a reservoir—whether solid 
drug dilute solution or highly concentrated
drug, dilute solution, or highly concentrated 
drug solution within a polymer matrix—is 
surrounded by a film or membrane of a rate
surrounded by a film or membrane of a rate‐
controlling material. 
• The only structure effectively limiting the 
Th l ff i l li i i h
release of the drug is the polymer layer 
surrounding the reservoir. Since this polymer 
di h i Si hi l
coating is essentially uniform and of a 
nonchanging
h i thickness, the diffusion rate of 
hi k h diff i f
the active agent can be kept fairly stable 
throughout the lifetime of the delivery system. 
h h h lif i f h d li
Environmentally sensitive polymers for drug delivery
 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 
p
placed in an appropriate biological environment. 
pp p g
• 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
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
the external environment. 
• Most of the materials used in swelling‐controlled release 
systems are based on hydrogels, which are polymers that will 
swell without dissolving when placed in water or other 
ll ith t di l i h l di t th
biological fluids. 
• These hydrogels can absorb a great deal of fluid and, at 
equilibrium, typically comprise 60–90% fluid and only 10–30% 
polymer
Drug delivery from (a) reservoir and (b) matrix 
g yf ( ) ( )
swelling‐controlled release systems
Drug delivery from environmentally 
Drug delivery from environmentally
sensitive release systems.
BIODEGRADABLE SYSTEMS
Drug delivery from :
(a) bulk‐eroding 
(b) (b) surface‐eroding biodegradable 
systems.
• The most common formulation for these
biodegradable materials is that of
p
microparticles,, which have been used in oral
delivery systems and in subcutaneously
j
injected deliveryy systems.
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Biodegradable microparticles of 60:40
lactide:glycolide PLGA. (Photo courtesy of T. Tice,
Southern Research Institute,
Institute Birmingham,
Birmingham AL.)
AL )
 Biodegradable microparticle of 75:25 
lactide:glycolide PLGA after 133 days of 
PLGA after 133 days of
degradation in water
Biodegradable polyorthoester rods after (left) 9 
and (right) 16 weeks of implantation in rabbits