sediaan modified release compatibility mode
TRANSCRIPT
SEDIAAN MODIFIED
RELEASE (MODIFIED
RELEASE DELIVERY SYSTEM)
Dhadhang Wahyu Kurniawan
@Dhadhang_WKLABORATORIUM FARMASETIKA UNSOED
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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 rateproduct 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 form4/16/2013 3
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)
ProdukProdukProdukProduk ObatObatObatObat PelepasanPelepasanPelepasanPelepasan----DimodifikasiDimodifikasiDimodifikasiDimodifikasi
dandandandan RuteRuteRuteRute PemberiannyaPemberiannyaPemberiannyaPemberiannya
� 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 haripemakaian 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
Terkendali1. Biaya
2. Korelasi in vitro-in vivo (sering jelek)
3. Dose dumping
4. Mengurangi fleksibilitas pemberian obat4. 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 Terkendali1. Waktu paro eliminasi pendek
2. Waktu paro eliminasi panjang
3. IT kecil3. IT kecil
4. Dosis besar
5. Absorpsi jelek
6. Absorpsi secara aktif
7. Kelarutan yang kecil
8. First-pass effect yang ekstensif4/16/2013 13
Metode Fisika yang Potensial Digunakan
untuk Sediaan LepasTerkendali
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
Metode Fisika yang Potensial Digunakan
untuk Sediaan LepasTerkendali
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)
Metode Fisika yang Potensial Digunakan
untuk Sediaan LepasTerkendali
(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 DeliveryThere 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 biodegradablebiocompatibility 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 temperatures4/16/2013 19
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 MembraneMolecules are permitted only to one component (Water).
Osmotic pressureIt 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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