Suwaldi Martodihardjo
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Region of the Length, Internal Volume, Surface pH Average
GIT cm diameter, ml area, cm2 residence
cm time
Entire GIT 530-870 3-9 2 x 106 1.5-7 Up to 38 h
Mouth cavity 15-20 10 700
Esophagus 20 2-4 200
Stomach
Fasted state 25 15 25-50 1.4-2.1 0.5-1.5 h
Fed state 1000-1600 2-5 2-6 h
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Drug Delivery
Definition
– The appropriate administration of drugs through
various routes in the body for the purpose of
improving health
– It is highly interdisciplinary
– It is not a young field
– It has recently evolved to take into consideration
Drug physico-chemical properties
Body effects and interactions Controlled
Improvement of drug effect Drug Delivery
Patient comfort and well being
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Drug Delivery
Conventional Controlled
Enteral Sustained
Extended
Parenteral
Site-specific
Other
Pulsatile
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Oral Administration
Advantages Disadvantages
– Patient: Convenience, – Unconscious patients
not invasive, higher cannot take dose
compliance – Low solubility
– Manufacture: well – Low permeability
established processes, – Degradation by GI
available infrastructure enzymes or flora
– First pass metabolism
– Food interactions
– Irregular absorption
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Oral Administration
Traditional oral
delivery systems
– Tablets
– Capsules
– Soft gelatin capsules
– Suspensions
– Elixirs
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Buccal/Sublingual
Advantages Traditional delivery
– By-pass First pass system/devices
metabolism – Tablets
– Rapid absorption – Chewing gum
– Low enzymatic activity
Disadvantages
– Discomfort during
dissolution
– Probability of swallowing-
lost of effect
– Small doses
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SISTEM PENGHANTARAN OBAT
(DRUG DELIVERY SYSTEMS)
ASPEK TEMPORAL
ASPEK SPASIAL
•KOMPLEKSITAS PENGHANTARAN
•OPTIMASI OBAT SAMPAI LOKASI TARGET
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SOME EXAMPLES OF DRUG DELIVERY
SYSTEMS
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History of Controlled Drug
Delivery
Gas
Gas
Coacervation Technique
STEP #1:
Polymer/Oil
Drug/H20
Polymer dissolved in a solvent (or oil)
Drug dissolved in water
STEP #2:
2 liquids are rapidly mixed
water droplets form within the solvent
H20
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
Supercritical fluid precipitation
Solvent- polymer
solution f rom
pump
CO2
from
pump Flow straightener
He at e xchanger
Nozzle
Nozzle
contraction
Pr ecipitate
Back pressure
re gulator
Poly(l-lactide) ~1-mm diameter
particles formed by PCA processing
Gas outlet
0.2µm
filte r
Co-extrusion processing
• 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
Syringe pump
These concentric
Drug
cylinders then
breakup into
individual packets Polymer
Neg.
Bilayer
Liposome Formation
Liposome are typically formed by:
Fissure homogenization
High pressure homogenization
Extrusion through polycarbonate membranes
HO NH Organic Phase
CH3 [CH2]11CH
OSO 3 3 Na
3 CH [CH2]11 OSO3
Aqueous Phase • Complexes are prepared
OH Dodecyl Sodium Sulfate
by vigorously mixing
HO
NH
aqueous solutions of the
CH3 Cl CH3 [CH2]11 OSO3 Na
surfactant and drug.
• The complex either
Na Cl
l-PhenylephrineHydrochloride precipitates as a solid or
can be separated by
OH partitioning to an organic
HO NH Organic Phase
CH3 CH3 [CH2]11 OSO3
presents of salts
NH2
Na Cl Cl
CH3 CH2 OSO3
11 N
N CH3 CH 2 OSO 3
Na Cl 11 Na
S olid Tacrine-Surfactant (T• S) s
Na Cl F ree Tacrine (T•C l) aq
an d Su rfactant (N a• S)
More than protection and release:
targeting a site
The coating or matrix surrounding the
therapeutic molecule can also be used to
direct the particle to a targeted site.
Such systems include:
1. Liposomes
2. Surfactant
3. Nanoparticles
4. Antibodies, enzymes and other proteins
5. Viral vectors
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Factors Influencing the Selection of
the Delivery Route
Milling
Compression
Coating
Labeling
Packing
PENENTUAN BENTUK SEDIAAN
UNTUK SPO KONVENSIONAL
Contoh Obat:
PROGABIDA – suatu obat anti konvulsan
Progabide
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Systematic (IUPAC) name
4-[(4-chlorophenyl)-(5-fluoro-2-hydroxy-phenyl)-methylidene]aminobutanamide
Clinical data
Pregnancy cat. ?
Routes Oral
Pharmacokinetic data
Bioavailability 60%
Metabolism Hepatic
Half-life 4 hours
Excretion Renal
Chemical data
Formula C17H16ClFN2O2
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Profil Preformulasi Progabida pada suhu 37oC
pKa 3,41
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Bioavailabilitas Progabida setelah diberikan pada
manusia secara oral dengan dosis 600 mg, n=6
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Progabide is an analog and prodrug of gamma-aminobutyric acid.
It is commonly used in the treatment of epilepsy. It has agonistic
activity for both the GABAA and GABAB receptors.
Progabide has been investigated for many diseases besides epilepsy,
including Parkinson's disease, schizophrenia, clinical depression and
anxiety disorder with varying success.
Pharmacology:
Progabide, a fatty acid derivative, is a GABA receptor agonist used to
treat the symptoms of epilepsy.
Mechanism of action:
Progabide binds to both GABAA and GABAB receptors located on the
terminals of primary afferent fibers.
Binding to GABAA results in an increased affinity of the GABA
receptor for the amino acid, an augmented flux of chloride ions
across the terminal membrane, and an increase in the amount of
presynaptic inhibition.
Activation of the GABAB receptors retards the influx of calcium ions
into the terminals, thereby reducing the evoked release of excitatory
amino acids and possibly other transmitters.
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TERMINOLOGY OF MODIFIED RELEASE DDS
Sustained-release:
Any dosage form that provides medication over extended time
Controlled-release:
The system is able to provide some actual therapeutic control;
be of a temporal nature, spatial nature, or both.
The system attempts to control drug concentration in the
target tissue.
Delayed-release
Enteric coated tablets
Site-specific systems
Targeted-delivery systems
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Plasma concentration time profile
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Challenges in Oral
Drug Delivery
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Controlled Release Oral Drug
Delivery System
Advantages
Dose dumping.
Stability problem.
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Oral – controlled release
Formulation system:
Modification of delivery :
1. Multiple unit : e.g. coated pellets
2. Single unit: e.g. osmotic pump
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Materials Used as Components in
Controlled Release
Enteric coatings
Cellulosic
Noncellulosic
Methacrylic acid polymers
Shellac
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Materials Used as Components in
Controlled Release
Non-enteric coatings
Cellulosic
Ethylcellulose (EC)
Hydroxyethylcellulose (HEC)
Hydroxypropylmethylcellulose (HPMC)
Methylcellulose (MC)
Sodium carboxymethylcellulose (Na CMC)
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Materials Used as Components in
Controlled Release
Non-enteric coatings
Non-cellulosic
Carnauba wax
Castor oil
Cetyl alcohol
Ethylene vinyl acetate copolymer
Hydrogenated vegetable oils
Polyvinyl alcohol
Silicon-based polymers
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Mechanism aspects of Oral drug
delivery formulation
1.Dissolution : 1.Matrix
2.Encapsulation
2.Diffusion : 1.Matrix
2.Reservoir
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Several physicochemical factors controlling the
delivery of a bioactive agent to the host:
.
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POLYMER FOR CONTROLLED-
RELEASE DELIVERY
There are several important factors to consider in selecting or
developing a polymer for controlled delivery:
Biocompatibility and toxicology
Regulatory acceptance or concerns
Degradation rate and degradation products and their
biocompatibility and toxicology, if biodegradable
Cost
Chemical, physical, and mechanical properties
Suitable solvents
Processing requirements
Compatibility limits of the active agent with the polymer
Required sterilization methods
Thermal transition temperatures
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Dissolution Definition:
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Noyes Whitney Equation
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Matrix Type
Also called as Monolith dissolution
controlled system. Soluble drug
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Encapsulation
Called as Coating dissolution
controlled system. Soluble drug
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Diffusion
No energy required.
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Matrix Diffusion Types
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Matrix system
Rate controlling
step:
Diffusion of dissolved
drug in matrix.
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Higuchi Equation
Where ,
Q=amt of drug release per unit surface area at time t.
D=diffusion coefficient of drug in the release medium.
E=porosity of matrix.
Cs=solubility of drug in release medium.
T=tortuosity of matrix.
A=concentration of drug present in matrix per unit
volume.
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Reservoir System
Also called as Laminated matrix device.
Hollow system containing an inner core surrounded
in water insoluble membrane.
Polymer can be applied by coating or micro
encapsulation.
Rate controlling mechanism - partitioning into
membrane with subsequent release into surrounding
fluid by diffusion.
Commonly used polymers - HPC, ethyl cellulose &
polyvinyl acetate.
Examples: Nico-400, Nitro-Bid
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Reservoir System
Rate controlling
steps :
Polymeric content in
coating, thickness of
coating, hardness of
microcapsule.
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Dissolution & Diffusion
Controlled Release system
Drug encased in a partially soluble
membrane. Insoluble
membrane
Pores are created due to dissolution
of parts of membrane. Entry of
dissolution
fluid
It permits entry of aqueous medium
into core & drug dissolution. Drug
diffusion
Diffusion of dissolved drug out of
system. Pore created by
dissolution of
Ex- Ethyl cellulose & PVP mixture soluble fraction of
dissolves in water & create pores of membrane
insoluble ethyl cellulose membrane.
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METODE ION EXCHANGE
Resin yang tidak larut dalam air
Resin bermuatan positif atau negatif
.
Resin + obat ---agar terjadi kontak lama :
resin dan larutan obat dicampur
resin dalam kolom dan larutan obat dilewatkan resin secara berulang-ulang
obat-resin dicuci dan dikeringkan untuk membuat partikel atau butiran-butiran
(beads)
Pelepasan obat:
Resin-(NCH3) X + Z- Resin-(NCH3) Z + X-
Resin-(SO3) A + B+ Resin-(SO3) B + A+
X dan A adalah molekul obat
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ASPEK
FARMAKOKINETIKA
Agar konsentrasi obat dalam darah tetap, maka
Absorpsi:
Log (Ao – X) = Log Ao - Ka . t / 2,303
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ASPEK
FARMAKOKINETIKA
Eliminasi:
Log (Bo – E) = Log Bo - Kel.t / 2,303
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ABSORPSI = ELIMINASI
. RATE IN = RATE OUT
R = rate of delivery
Dalam proses absorpsi, kecepatan pembatas adalah
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SEDIAAN OBAT HIPOTETIS
R = Kel B*
R = (0,023)(80) mg/jam = 1,84 mg/jam
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Agar obat dalam darah konstan maka obat yang masuk
darah harus sama dengan kecepatan obat dieliminasi
.
R = Kel B* = Ka D ;
D = Jumlah obat dalam pool untuk diabsorpsi
Ka F D = Kel B*
Ka D = Kel B* / F
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Cp(steady state) = F D / V Kel Ƭ = F D / Cl Ƭ
.
D / Ƭ = Cp Cl / F
V = volume distribusi
Ƭ = interval pemberian obat
Cl = klirens
R = D/ Ƭ = 2,3 mg/jam
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Jika waktu yang diperlukan untuk pelepasan
terkontrol (sustaining time) = 10 jam, maka
dosis keseluruhan yang diperlukan selama 10
.
jam adalah:
Dm = R h ; Dm = maintaining dose;
h = sustaining time
Dt = D* + Dm ; Dt = total dose
Dt = 100 mg + 23 mg = 123 mg
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SOAL
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Osmotic Pressure Controlled
Drug Delivery System
Definition
Procedure
Diagram
Modifications
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Osmosis
- Movement of solvent from lower to higher concentration.
- The passage of solvent into a solution through
semipermeable membrane.
Semipermeable Membrane
Molecules are permitted only to one component
(Water).
Osmotic pressure
It is the hydrostatic pressure produced by a solution
in a space divided by a semipermeable membrane
due to difference in concentration of solutes.
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Osmotic Pressure Controlled
System
Provides zero order release
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Equation
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Osmotic Pressure Controlled
System
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Osmotic Pressure Controlled
System
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Modifications
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Immediate Release System
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Osmotically active system
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Some Popular Brand names used
for OCDDS
Spansule capsule ( SK & F )
Sequal capsule (Lederle )
Extentab tablets ( Robins )
Timespan tablet ( Roche )
Dospan tablet ( Merrell Dow )
Chronotab tablet ( Schering )
Plateau capsule ( Marion )
Tempule capsule ( Armour )
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Some Examples of OCDDS
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Recent Trends : Extended release
formulation of Bupropion
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Recent Trends: OROS Technology
(ALZA corporation)
ELEMENTARY OSMOTIC PUMP
Single layer tablet: Drug
core (water soluble drug
with or without excipients)
Semipermeable membrane
with a drilled orifice
Water imbibition by the core
because of osmotic action
results in drug dissolution,
which is released at a
controlled rate through the
orifice
Not suitable for water insoluble drugs.
Examples: Sudafed 24
hours (Pseudoephedrine); Volmax (Salbutamol)
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Recent trends: Geomatrix® (SKY Parma)
Products in market:
Cordicant -uno®
Madopar DR
SULAR ER
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References
Novel drug delivery system , volume 50,
Y.W.Chien
www.google.com
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Thank you
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