Sediaan Modified Release Compatibility Mode

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:





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)



(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,


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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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Sediaan Modified Release Compatibility Mode

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