SEDIAAN MODIFIED

RELEASE (MODIFIED
RELEASE DELIVERY SYSTEM)
DhadhangWahyu Kurniawan
@Dhadhang_WK
LABORATORIUM FARMASETIKA UNSOED
4/16/2013 1
Pendahuluan
Bentuk sediaan pelepasan dimodifikasi
adalah sistem penghantaran obat (DDS)
yang, berdasarkan formulasi dan desain
produk, memberikan pelepasan obat
dalam bentuk yang dimodifikasi berbeda dalam bentuk yang dimodifikasi berbeda
dari yang bentuk sediaan konvensional.
Pelepasan obat dapat ditunda atau
diperpanjang.
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Produk Obat Pelepasan-Dimodifikasi
Conventional drug products:
Tablets, capsules, etc to release the active drug
immediately after administration
Modified drug products
Drug products which release the active drug from the
product at a controlled rate product at a controlled rate
Controlled-release drug products
It is designed for different routes of administration
based on:
1. Physicochemical properties of drugs
2. Pharmacologic properties of drugs
3. Pharmacokinetic properties of drugs
4. Properties of materials used in the dosage form
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MODIFIED-RELEASE DOSAGE FORM
As one for which the drug-release
characteristics of time course and/or
locations are chosen to accomplish
therapeutic or convenience objectives not therapeutic or convenience objectives not
offered by conventional dosage forms
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Terminologi
The following terms have been applied to
extended or sustained drug delivery
systems:
Controlled-release
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Extended release (ER)
Sustained-release (SR)
Timed-release (TR)
Long-acting (LA)
Prolonged-action (PA), and
Sustained-action (SA)
Produk Produk Produk Produk Obat Obat Obat Obat Pelepasan Pelepasan Pelepasan Pelepasan- -- -Dimodifikasi Dimodifikasi Dimodifikasi Dimodifikasi
dan dan dan dan Rute Rute Rute Rute Pemberiannya Pemberiannya Pemberiannya Pemberiannya
Oral dosage forms
Extended release: controlled release, sustained
release, prolonged release
Delayed release: Enteric coated
Intramuscular dosage forms Intramuscular dosage forms
Depot injections
Water-immiscible injections (oil)
Subcutaneous dosage forms: Implants
Transdermal delivery systems: Patches,
Creams, Gel, etc.
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Delayed-release products
Biasanya tablet salut enterik atau
kapsul dirancang untuk melewati
lambung tanpa perubahan
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lambung tanpa perubahan
(unaltered) untuk melepaskan obat
mereka dalam saluran usus.
Extended-release products
Dirancang untuk melepaskan obat mereka
dalam cara yang terkendali, pada pre-
determined rate, durasi and lokasi dalam
tubuh untuk mencapai dan
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tubuh untuk mencapai dan
mempertahankan optimum therapeutic
blood levels of drug.
Rationale for extended release
pharmaceuticals
Obat yang tidak inheren tahan lama
memerlukan dosis harian ganda untuk
mencapai efek terapi yang diinginkan.
Beberapa dosis harian yang sering merepotkan
dan dapat mengakibatkan dosis yang
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dan dapat mengakibatkan dosis yang
terlewatkan, dibuat-up dosis dan pasien non-
compliant dengan regimen terapeutik.
Kadar obat dari bentuk sediaan konvensional
lepas-segera yang diambil lebih dari sekali
sehari jadwal pasti biasanya menunjukkan
puncak sekuensial dan palung (lembah) yang
berhubungan dengan dosis masing-masing.
Rationale for extended release
pharmaceuticals
Tablet atau kapsul yang pelepasannya diperpanjang
biasanya diambil hanya sekali atau dua kali sehari
dibandingkan dengan dosis konvensional yang
biasanya 2 sampai 4 kali sehari
Produk ini dirancang untuk memberikan pelepasan
segera obat yang akan segera menghasilkan terapi
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segera obat yang akan segera menghasilkan terapi
yang diinginkan, diikuti dengan pelepasan bertahap
dan berkesinambungan dari jumlah tambahan obat
untuk mempertahankan efek ini selama periode
waktu yang telah ditentukan.
Kebutuhan untuk dosis obat pada malam hari dapat
dihilangkan
Keuntungan Sediaan Lepas
Terkendali
1. Mengurangi frekuensi pemakaian obat
2. Menambah/lebih mengenakkan pasien
3. Menghindari/tidak perlu adanya
pemakaian obat pada malam hari pemakaian obat pada malam hari
4. Mengurangi fluktuasi kadar obat dalam
darah
5. Efek obat yang lebih uniform
6. Mengurangi iritasi saluran cerna
7. Mengurangi efek samping
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Kerugian Sediaan Lepas
Terkendali
1. Biaya
2. Korelasi in vitro-in vivo (sering jelek)
3. Dose dumping
4. Mengurangi fleksibilitas pemberian obat 4. Mengurangi fleksibilitas pemberian obat
5. Menaikkan kemungkinan first-pass
effect
6. Secara umum, bioavailabilitas kurang baik
7. Efektivitas pelepasan obat dipengaruhi
dan dibatasi oleh GI residence time
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Karakteristik Obat yang
Tidak Cocok Digunakan dalam
Sediaan Lepas Terkendali
1. Waktu paro eliminasi pendek
2. Waktu paro eliminasi panjang
3. IT kecil 3. IT kecil
4. Dosis besar
5. Absorpsi jelek
6. Absorpsi secara aktif
7. Kelarutan yang kecil
8. First-pass effect yang ekstensif
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MetodeFisikayang Potensial Digunakan
untukSediaanLepasTerkendali
1. Kapsul dengan bahan polimer
1. Dapat diisi bahan padat, cair, dan suspensi
2. Pelepasan dikontrol oleh difusi melalui dinding
kapsul
2. Dispersi heterogen partikel dalam matriks
1. Matriks biodegradable atau nonbiodegradabel
2. Pelepasan obat dikontrol oleh:
1. difusi melalui matriks
2. erosi matriks
3. kombinasi keduanya
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3. Pelapisan obat dengan bahan polimer
Obat dilapisi dengan film polimer yang biodegradable
atau nonbiodegradabel
Kontrol pelepasan oleh:
1. difusi melalui matriks
MetodeFisikayang Potensial Digunakan
untukSediaanLepasTerkendali
1. difusi melalui matriks
2. erosi bahan pelapis (film)
3. kombinasi keduanya
4. Dispersi heterogen atau pelarutan obat dalam
matriks hidrogel yang dapat mengembang
Kontrol pelepasan oleh: difusi obat melalui bagian
yang mengembang dari matriks
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5. Obat berada dalam larutan kental polimer
Kontrol pelepasan oleh: difusi perlahan-lahan
melalui polimer atau pengenceran oleh media
6. Ikatan kimia antara obat dengan polimer
(back-bone)
MetodeFisikayang Potensial Digunakan
untukSediaanLepasTerkendali
(back-bone)
Ikatan ester antara obat dengan polimer
Kontrol pelepasan oleh : hidrolisis ikatan ester
7. Pompa yang dapat melepaskan obat secara
mekanik atau kimiawi
Tekanan osmose menyebabkan air masuk ke dalam
depot obat dan obat dipompa keluar
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Metode Difusi
Metode ini menggantungkan penghantaran
obatnya dari kontrol difusi atau disolusi
Driving force perpindahan molekul obat Driving force perpindahan molekul obat
adalah gradien konsentrasi; obat bergerak
dari tempat yang berkonsentrasi tinggi ke
tempat yang berkonsentrasi rendah
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Diffusion
Major process for absorption.
No energy required.
Drug molecules diffuse from a region of higher
concentration to lower concentration until
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concentration to lower concentration until
equilibrium is attainded.
Directly proportional to the concentration gradient
across the membrane.
Polymer for Controlled-Release Delivery
There are several important factors to consider in
selecting or developing a polymer for controlled
delivery:
1. Biocompatibility and toxicology
2. Regulatory acceptance or concerns
3. Degradation rate and degradation products and their
biocompatibility and toxicology, if biodegradable biocompatibility and toxicology, if biodegradable
4. Cost
5. Chemical, physical, and mechanical properties
6. Suitable solvents
7. Processing requirements
8. Compatibility limits of the active agent with the polymer
9. Required sterilization methods
10. Thermal transition temperatures
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Matrix Type
Also called as Monolith
dissolution controlled
system.
Controlled dissolution by:
1.Altering porosity of tablet.
2.Decreasing its wettebility.
Soluble drug
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2.Decreasing its wettebility.
3.Dissolving at slower rate.
First order drug release.
Drug release determined by
dissolution rate of polymer.
Examples: Dimetane
extencaps, Dimetapp
extentabs.
Slowly
dissolving
matrix
Encapsulation
Called as Coating
dissolution controlled
system.
Dissolution rate of coat
depends upon stability &
thickness of coating.
Masks colour, odour, taste,
Soluble drug
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Masks colour, odour, taste,
minimising GI irritation.
One of the
microencapsulation method
is used.
Examples: Ornade spansules,
Chlortrimeton Repetabs
Slowly
dissolving
or erodible
coat
Matrix Diffusion Types
Rigid Matrix Diffusion: Materials used are
insoluble plastics such as PVP & fatty acids.
Swellable Matrix Diffusion
1. Also called as Glassy hydrogels.Popular for
sustaining the release of highly water soluble
drugs.
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sustaining the release of highly water soluble
drugs.
2. Materials used are hydrophilic gums.
Examples :
Natural- Guar gum,Tragacanth.
Semisynthetic -HPMC,CMC,Xanthum gum.
Synthetic -Polyacrilamides.
Examples: Glucotrol XL, Procardia XL
Matrix system
Rate controlling
step:
Diffusion of dissolved
drug in matrix.
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drug in matrix.
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.
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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
Reservoir System
Rate controlling
steps :
Polymeric content in
coating, thickness of
coating, hardness of
microcapsule.
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microcapsule.
Dissolution & Diffusion Controlled
Release system
Drug encased in a partially
soluble membrane.
Pores are created due to
dissolution of parts of
membrane.
Insoluble
membrane
Entry of
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It permits entry of aqueous
medium into core & drug
dissolution.
Diffusion of dissolved drug out
of system.
Ex- Ethyl cellulose & PVP
mixture dissolves in water &
create pores of insoluble ethyl
cellulose membrane.
Pore created by
dissolution of
soluble fraction of
membrane
dissolution
fluid
Drug
diffusion
Osmotic Pressure Controlled Drug
Delivery System
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Osmosis
- Movement of solvent from lower to higher concentration.
- The passage of solvent into a solution through
semipermeable membrane.
Osmotic Pressure Controlled Drug
Delivery System
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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.
Osmotic Pressure Controlled
System
Provides zero order release
Drug may be osmotically active, or
combined with an osmotically active
salt (e.g., NaCl).
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salt (e.g., NaCl).
Semipermeable membrane usually
made from cellulose acetate.
More suitable for hydrophilic drug.
Examples: Glucotrol XL, Procardia XL,
Osmotic Pressure Controlled
System
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Osmotic Pressure Controlled
System
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Recent Trends : Extended release
formulation of Bupropion
Bupropion is used in the treatment of
major depressive disorder.
Conventional formulation has to be
administered 3 times daily
Initially 150 mg ER formulation was
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Initially 150 mg ER formulation was
introduced for bid regimen
Later on 300 mg ER formulation was
introduced for once daily regimen
For ER formulation provide similar Cmax
and AUC values as compared to
immediate release formulation at steady
state.
Recent Trends: Extended release
formulation of Bupropion
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Recent Trends: OROS
Technology (ALZA corporation)
Single layer tablet: Drug
core (water soluble drug
with or without excipients)
Semipermeable membrane
with a drilled orifice
Water imbibition by the core
ELEMENTARY OSMOTIC PUMP
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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)
Recent trends: Geomatrix (SKY
Parma)
This technology Controls amount,
Products in market:
Cordicant -uno
Madopar DR
SULAR ER
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This technology Controls amount,
timing and location of release in
body.
-Formulation with predictable and
reproducible drug release profile.
-Controls rate of drug diffusion
throughout release process,
ensuring 100% release Products
thank you
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