Pengantaran Obat Terkontrol:

Dwi Lestari P.

Laboratorium Farmasi Fisik

Departemen Teknologi Farmasi
Fakultas Farmasi USU
Introduction:
• DDS: potensi dan tantangannya
• GI Tract: tantangan bagi pengembangan DDS
Colon DDS
• Introduction to Colon DDS
• Approaches and Development
• Oral Protein/Peptides Administering
• Natural Polysaccharide for Colon DDS
 ORAL DDS
Nano
Parentral
Technology
DDS
DDS

Buccal Topical
DDS DRUG DDS
DELIVERY
SYSTEMS

Pulmonary
Rectal DDS
DDS

MUCOSAL Vaginal
Nasal DDS
DDS

4
 ORAL
 Gastrik, enterik, kolonik
 INJEKSI DAN IMPLANT
 IV, SC, IM, intra-epidural, intra-kranial

 TRANSDERMAL
 Kulit

 MUKOSAL
 Oftalmik, nasal, vaginal, anal, bukal, sub-lingual

 INHALASI
 pulmonari
 Transdermal patches

Implanted, drug-loaded, degradable microparticles

Implanted, drug-loaded silicone rods

Soluble polymer-drug conjugates

Osmotic pressure-driven capsules for oral DD

Drug-loaded polymer coatings for stents

Special inhalers for pulmonary DD

“stealth” liposomes

Enteric coatings for oral tablets

COLON-SPECIFIC DDS
memastikan terapi langsung
pada lokasi penyakit,

menggunakan dosis yang

lebih rendah, dan

mengurangi efek samping

 WHERE
HOW
much
drug is
needed?

DDS
ORAL DELIVERY OF PROTEINS

EFFECTIVE DELIVERY OF LOW SOLUBILITY DRUGS

FEEDBACK DDS : using body signals to stimulate delivery of

specific amount of drug

CHRONO-DDS : delivery based on known circadian rhythms of

body organs (perhaps combined with feedback DDS)

PHARMACOGENOMICS : drug indications and prescriptions

based on one’s genetic makeup (many ethical issues)

A.S. Hoffman, UW, Seattle, WA)

 Fisiologi saluran cerna (GI tract)
 Sistem pengantaran di GI tract
 Window of absorption (jendela absorpsi:
 Pengantaran oral zat makromolekul
 Kelarutan obat vs. permeasi lipid
 Salut enterik
 Gastric retention foams and gels
 Swelling/gelling/dissolving “hydrogels
 Pelepasan ion-exchange
 Osmotic delivery devices
Gambar 2.5 Sistem Pencernaan Manusia

 BIAYA
 Waktu pengosongan lambung yang tidak
dapat diprediksi

 Variasi waktu pengosongan lambung yang

tinggi yang dipengaruhi oleh faktor usia, ras,
jenis kelamin, dan status penyakit

 Waktu kontak pada tapak absorpsi yang

terbatas
A. ORAL
 1/3 populasi mengalami masalah kesulitan menelan
 Tablet terdesintegrasi di mulut : solusi
 Tablet Bukal Bio-adesif: mencegah efek lintasan
pertama
 Formulasi In-situ gelling untuk terapi dental
B. LAMBUNG

Kebanyakan obat diabsorpsi

HANYA di usus halus bagian atas
Dirancang sebagai
once daily formulations

GI RETENTION platforms

Tantangan utama : mengatasi gerakan

peristaltik usus terutama saat puasa
C. USUS:
formulations for improved absorption of poorly soluble
drugs and high molecular weight drugs
 Lack of sufficient solubility : major problem in oral
drug delivery
 Delivering protein peptides : their instability in GI
environment
TECHNOLOGIES FOR IMPROVING DRUG SOLUBILITY
 Solid Dispersions
 Nanocrystals and nanoparticles
 Polymeric micelles
 Self-emulsifying systems
D. KOLON
Pengantaran enzim dan obat-obat yang tidak tahan
asam

Pengantaran sistemik obat-obat peptida dan

protein

Pengantaran lokal ke kolon : pada penyakit tertentu di

kolon
TEKNOLOGI:
 Salut enterik yang dimodifikasi
 Biodegradable swellable polymers
 pH-controlled systems
 Time delayed systems
A. ORAL: Easily Administered
Formulations
B. LAMBUNG: gastric
retention platforms
C. USUS HALUS: formulasi
yang meningkatkan
absorpsi obat2 sukar larut
dan BM tinggi
D. KOLON : Colon Targeted
Drug Delivery System
 LAMBUNG
 pH-sensitive polymers coating : ↗pelepasan obat di gastrik
 Mucoadhesive polymers coating : pelepasan dan dan retensi di lambung
 Incorporate gastric retention systems

 USUS HALUS
 pH-sensitive polymers coating : tahan di lambung dan larut di usus secara
perlahan
 Entrap drug in swelling/gelling polymers for controlled release
 Entrap drug in osmotic pressure-driven tablet for CR

 KOLON (USUS BESAR)

 Penggunaan carriers yang terdegradasi oleh bakteri spesifik
di kolon
 Desain sistem osmotik dan swelling systems yang melepaskan
obat setelah melewati lambung dan waktu transit di usus
Site specific drug delivery to colon : approaches and drug development
A. Oral : Rute Paling nyaman dan Paling
disukai; but
B. +C: Fisiologis GI tract : barier bagi
pengantaran obat (peptida dan obat
tak tahan asam, dosis obat terapi di
kolon >>>); meski kebanyakan obat
diabsorpsi di saluran cerna bagian atas
(upper GI tract)
D. Kolon : intensitas dan keragaman
aktivitas di kolon < B+C; wkt retensi di
kolon >>>, respon thd peningkat
absorpsi >>
1. Oral : paling nyaman dan disukai
2. Rektal : rute terpendek untuk tujuan
pengantaran ke kolon
 Tantangan:
▪ Mencapai bagian proksimal kolon melalui rute
rektal adalah cukup sulit
▪ Tidak nyaman bagi pasien
▪ Kepatuhan akan kurang optimal
 Bentuk sediaan : solusio, foam, supositoria
 Konsentrasi obat yang mencapai kolon
tergantung pada:
 Faktor Formulasi
 the extent of retrograde spreading, and
 Waktu retensi
Foam dan supositora: terutama tertahan di rektum
and kolon sigmoid
Enema solusio: have a great spreading capacity
 Kapasitas
absorpsi air
di kolon
cukup besar

Isi kolon cukup

kental dan
proses
pencampuran di Bioavailibilitas
kolon kurang kebanyakan obat
efisien di membran
absorptif
umumnya
RENDAH
 Eligen Technology (Ernisphere Technologies Ltd.)

 CLEC (Crosslinked Enzym Crystals)

(Altus Pharmaceuticals)

 Hydroance (Lipocence Inc.) (lipid base formulations)

 ORAL INSULIN DEVELOPMENT

» Ascending Colon
Mucosa
» Transverse colon
Submucosa

» Descending Colon

» Sigmoid Colon
Muscularis
externa

Serosa
 Relatif bebas dari enzim peptidase: untuk pengantaran obat peptida secara oral
untuk diabsorpsi secara sistemik

 Kaya akan Jaringan Limfoid: untuk Effective Vaccine Delivery

uptake antigen ke sel mast pada mukosa kolon akan mempercepat produksi antibodi
lokal

 Waktu Transit
 Lambung (< 3 jam); Usus halus (3-5 jam); Kolon (Usus Besar) (20 jam)
Faktor yang mempengaruhi waktu transit obat di bagian sal cerna yg berbeda:
makanan, motilitas sal cerna, aktivitas fisik pasien, kondisi puasa/makan
pasien

 Aktivitas Enzim dari Mikroba Kolon

 Misal:azoreductive (-N=N-) polymers dipecah oleh azoreduktase; sakarida dipecah
oleh sakaridase

 Respon yang baik terhadap

 Absorption enhancers
 Kolon manusia: >400 spesies bakteri sebagai resident flora,
populasi dapat mencapai 1010 bakteri per gram isi kolon
  untuk melindungi sal.cern dari bakteri patogen dg mereduksi azo dan
nitrogen dari lingkungan

 Mikroflora kolon menghasilkan banyak ENZIM HIDROLISIS DAN

REDUKSI :
 enzim azoreduktase (untuk prodrug dan salut berbasis polimer
azoaromatik dan matriks yg mengandung azoaromatic cross-
links)
 Glikosidase: degradasi polisakarida
 Proses metabolisme di kolon: bertanggung jawab pada
metabolisme kebanyakan obat  Untuk colon-targeted delivery
untuk makromolekul peptida seperti insulin untuk pemberian oral
 Colonic Microflora

Human intestinal microflora distribution in number

(Log 10 scale) per gram faeces.
 Terapi penyakit lokal di kolon
 Chronotherapy (asma, hipertensi, aritmia
jantung, artritis, inflamasi)
 Responsivitas thd peningkat absorpsi
 Aktivitas enzimatik <<<<
 Tapak bagi pengantaran obat yang sulit
(protein dan peptida)
 Pengantaran vaksin oral
 Terapi Penyakit-penyakit di Kolon
 ulcerative colitis, Chron’s disease, karsinoma dan
infeksi di kolon

 Absorpsi Sistemik (= memperbaiki absorpsi

obat-obat “rumit”)
 Obat-obat yang tidak stabil di upper GI tract
(peptida/protein: insulin, vaksin)
 Obat-obat yang kurang diabsorpsi di GI tract
 Obat yang ditarget
 Time Dependent System : waktu transit; time
delay
 pH dependent system: sediaan CDDS
terlindungi dengan baik di lambung, tidak
terjadi absorpsi sistemik yang tidak perlu
 Utilizing colonic microflora
 Inflammatory Bowel Disease

 Kanker Kolon
 PATOLOGI DI KOLON dan LOKASI PATOLOGI
Perubahan Morfologi Mukosa Kolon: Loosening
Perubahan produksi mukus kolon
tight junction, kerusakan dan inflamsi epitel

Mempengaruhi ABSORPSI obat di kolon

Permeabilitas mukosa usus↗

Meningkatkan Paparan isi lumen, obat, maupun zat patologi

Asma Artritis Hipertensi
 Dosis yang diberikan lebih rendah
 Efek samping lebih rendah
 Obat tersedia secara langsung di tapak target
 Memperbaiki penggunaan obat

Pemberian Glukokortikoid (deksametason, metil

prednisolon) oral dan iv efek samping sistemik
(adenosupresi, immunosuppresi, cushinoid
symptoms, dan resorpsi tulang)

Chronic colitis/ulcerative colitis, dan Crohn’s

disease diterapi dengan GLUKOKORTIKOID,
dan ANTIINFLAMASI lainnya
Kandidat terbaik CDDS:
 absorpsi buruk di lambung: peptides

 Obat yang digunakan untuk terapi patologi

di kolon (IBD, ulcerative colitis, diare, dan
kanker kolon) : CDDS lokal
 Sifat fisikokimia obat:
 Sifat kimia
 stabilitas
 Koefisien partisi

 Tipe peningkat absorpsi

 Gugus fungsi molekul obat

 Gugus anilin atau nitro: to link to gugus benzena lain group dengan
IKATAN AZO.  carriers, yang mengandung aditif seperti polimer (sbg
matrix dan hdrogel atau penyalut)  BERPENGARUH PADA SISTEM
PELEPASAN effksi sistem
 Jenis Penyakit
The simplest method for targeting of drugs to the
colon is to obtain slower release rates or
longer release periods by the application of
thicker layers of conventional enteric
coatings or extremely slow releasing
matrices.
Pendekatan Primer CDDS
• a. pH Sensitive Polymer Coated
• b. Delayed (Time Controlled Release System) Release
• c. MicrobiallyTriggered Drug Delivery to Colon
• i) Prodrug Approach for Drug Delivery to Colon
• (ii) Azo-Polymeric Prodrugs
• (iii) Polysaccharide Based Delivery Systems

Newly Developed Approaches for CDDS

• a. Pressure Controlled Drug-Delivery Systems
• b. Novel Colon Targeted Delivery System (CODESTM)
• c. Osmotic Controlled Drug Delivery (ORDS-CT)
 Pendekatan Fitur Dasar
1. Ikatan kovalen obat-carrier
1. Konyugat azo Obat dikonyugasi dengan ikatan azo
2. Konyugat siklodekstrin Obat dikonyugasi dengan siklodekstrin
3. Konyugat Glikosida Obat dikonyugasi dengan glikosida
4. Konyugat Glukuronat Obat dikonyugasi dengan glukoronat
5. Konyugat Dextran Obat dikonyugasi dengan dekstran
6. Konyugat Polipeptida Obat dikonyugasi dengan asam
poliaspartat
7. Prodrug polimerik Obat dikonyugasi dengan polimer

2. Pendekatan untuk pengantaran molekul yang melekat

di kolon (the intact molekul to colon)
 Pendekatan Fitur Dasar
2. Pendekatan untuk pengantaran molekul yang melekat di kolon (the intact molecule to colon)
1. Penyalutan dengan Polimer
1.Penyalutan denganpolimer yang sensitif pH salutpolimer enterikygmelepaskan obatsaatpH alkali
2.Penyalutan denganpolimer biodegradable obatdilepaskan setelah degradasi polimer oleh bakteri kolon
2. Embedding dalam matriks
1.Embedding dalam matriks /hidrogel yg biodegradable obat dilepaskan setelah polisakarida
mengembang dan dibiodegradasi
2.Embedding dalam matriks yang sensitif pH degradasi polimer yg sensitif pH akan
melepaskan obat
3. Time-release System setelah formulasi multisalut melewati lambung, obat dilepaskan
setelah lag time 3-5 jam yang ekivalen dengan waktu transit di
usushalus
4. Redox-sensitive Polymer Obat diformulasi dg polimer azo dan disulfida yang secara selektif
merespon potensial redoks kolon
5. Bioadhesive System obat disalut dg polimer bioadesif yg secara selektif menyediakan
daya adesi pada mukosa kolon yg dapat melepaskan obat di kolon
6. Penyalutan dengan mikropartikel obat diikat dengan mikropartikel
7. Osmotic-controlled drug delivery obat dilepaskan melalui membran semipemeabel akibat tekanan osmosis
Konsep Prodrug

Obat Carrier Molecule

Stimulus enzimatis dalam GI tract

memecah ikatan obat-carrier

 Mengatasi masalah STABILITAS obat pada upper GI tract ,

karena obat induk baru dilepaskan saat di kolon
 Memanfaatkan sifat khas kolon: pH yang meningkat ataupun
aktivitas enzim yg lebih tinggidaripada di tapak non-target
 Reducing enzymes Hydrolytic enzymes
» Nitroreductase » Esterases
» Azoreductase » Amidases
» N-oxide reductase » Glycosidases
» Sulphoxide reductase » Glucuronidase
» Hydrogenase » Sulfatase

» Azoreductases, which reduces azo-bonds selectively

and
» Polysaccharidases which degrades the polysaccharides.
Hidrolisis sulfasalazine (i)  asam 5aminosalisilat(ii) dan
sulfapiridin (iii)
 Sulfasalazin : terapi artritis rematoid dan
antiinflammasi .
 Sulfasalazin = salisilazosulfapiridin (SASP):
 Sulfapiridin berikatan dengan radikal salisilat
melalui ikatan azo
 Oral: sedikit dosis yang diabsorpsi di usus
halus  bulk sulfasalazin mencapai kolon
 Sulfapiridin : gugus yg bertanggung jawab
pada efek samping sulfasalazin  terapi IBD
mencari molekul carrier yg lebih aman
Struktur kimia SASP, balsalazide, ipsalazide dan OSZ yang menunujukkan
tempat pemutusan ikatan azo oleh bakteri yang melepaskan zat aktif 5-ASA
POLI ASA: based on the SASP carrier
concept: SP unit berikatan dengan
inert polymer backbone
Carrier –nya adalah
polisulfonamidoetilen yang berikatan
azo dengan 5-ASA
 Deksametason-21-ß-D-glukosida
(Tanda panah: tapak kerja glikosidase)
 Glikosidase utama yang ditemukan dalam
feses manusia: ßD-galaktosidase, ß-D-
glukosidase, -L-arabinofuranosidase, ß-D-
xylopiranosidase
 Lokasi enzim2 tsb : brush border  mudah
mencapai substrat
Deksametason-ß-D-glukuronida
 Cyclodextrins (CyDs): cyclic oligosaccharides of
six to eight glucose units through a-1,4
glucosidic bonds
 Improve solubility, stability and bioavailability
 interior :lipophilic, exterior: hydrophilic,
 form inclusion complexes with various drug
molecules
 being hydrolyzed and only slightly absorbed in
the stomach and small intestine;
 fermented by colonic microflora into small
saccharides and thus absorbed in the large
intestine
 ß CyDs digested in small intestin, completely
degraded by the microflora of the colon by most
bacterial strains that are isolated from human (as the
sole carbon source and by the stimulation of
cyclodextrinase activity by as low as 2-4 h of exposure
to cyclodextrins)
 Model drug: anti-inflammatory drug biphenylacetic
acid (BPAA) was selectively conjugated onto one of
the primary hydroxyl groups of a-, ß- and γ - CyDs
through an ester or amide linkage
 prednisolone succinate/alpha-cyclodextrin ester
conjugate after oral administration were studied using
IBD model rats.
 methyl prednisolone and dexamethasone
were covalently attached to dextran by the
use of a succinate linker.
 The kinetics of degradation of the hemiester
and corresponding dextran conjugates were
measured as a function of pH and
temperature.
Konyugat glisin dan asam
glutamat dari asam
salisilat:
(a) Konyugat Asam
Salicilurat
(b) Konyugat Asam Salisil
glutamat
1. Coating with pH-sensitive polymers
Sr. No. Polymer Threshold pH
1 Eudragit® L 100 6.0
Polymer of
2 Eudragit® S 100 7.0 methacrylic
acid are
3 Eudragit® L –30D 5.6 mostly used

4 Eudragit® FS 30D 6.8

5 Eudragit® FS 30D 5.5
6 Polyvinyl acetate phthalate 5.0
7 Hydroxy propyl methyl cellulose 4.5-4.8
phthalate
8 Cellulose acetate trimelliate 4.8 Threshold pH
of commonly
9 Cellulose acetate phthalate 5.0 used polymers.
 Drug Trade Name Coating Polymer / Formulation

Budesonide Entrocort® Eudragit® L 100-55, ethylcellulose

Budenofalk® Eudragit® S (Dissolution pH-7)
Targit® Coated Starch Capsule

Mesalazine Claversal® Eudragit® L100 (Dissolution pH-6)

Asacolitin® Eudragit® S (Dissolution pH-7)
Salofalk® Eudragit® S (Dissolution pH-6)
Pentasa® Ethyl cellulose coated pellets
Mesazal® Eudragit® L100 (Dissolution pH-6)
Calitofalk® Eudragit® L100 (Dissolution pH-6)
Asacol ® Eudragit® S (Dissolution pH-7)

Sulfasalazine Azulfidine® Cellulose acetate phthalate (Dissolution pH-

Colo-Pleon® 6.2-6.5)
Eudragit ® L100-55 (Dissolution pH-5.5)
 GI tract
segment PH
STOMACH 1-3
SMALL
(pH= 6,6)
INTESTINE
5 - 7.5
(proximal to
distal)
(pH= 7,0)
(pH= 5,7) LARGE
6.8-7.8
INTESTINE
(pH= 6,4) RECTUM 7.8-8
GI TRACT SEGMENT PH

STOMACH 1-3

SMALL INTESTINE
5 - 7.5
(proximal to distal)

LARGE INTESTINE 6.8-7.8

RECTUM 7.8-8
 pH sensitive polymer +
drug core Release of drug in Colon

DRUG Colonic pH
CORE

pH dependent polymer : insoluble at low pH levels but become increasingly

soluble as pH rises
 Although a pH dependent polymer can protect a formulation in the stomach,
and proximal small intestine, it may start to dissolve in the lower small intestine,
and the site-specificity of formulations can be poor.
The decline in pH from the end of the small intestine to the colon can also
result in problems, lengthy lag times at the ileo-cecal junction or rapid transit
through the ascending colon which can also result in poor site-specificity of
enteric-coated single-unit formulations
1. COATING WITH pH-SENSITIVE POLYMERS

Struktur kimia berbagai formulasi Eudragit®

2. COATING WITH BIODEGRADABLE POLYMERS
Tabel Azopolymer untuk Colon DDS
 Colonic
bacteria

Enteric coated Solublization of

Enteric coated enteric coat and Degradation of
matrix tablet
matrix tablet swelling of inner swelled matrix
in upper GI
matrix followed by tablet and drug
degradation by release
colonic bacteria
 Colonic
bacteria

Intact Swelling of coat Swelled coat

compression in upper GI Degraded by Degradation of
coated tablet Environment colonic bacterial coat and drug
enzymes release
 Colonic
bacteria

Mixed film Intact tablet in Swelled coat

coated tablet upper GI tract Degraded by Degradation of
colonic bacterial coat and drug
enzymes release
 Chitosan
 Pectin
 Guar gum
 Kondroitin sulfat
 Dekstran
 Almond gum
 Locust bean gum
 Siklodekstrin
 Inulin
 Boswellia gum
 Khaya gum
 to improve the effectiveness of medications for applications which target
large intestinal disease, supplements for improving intestinal flora and
other intestinal medicine.
 Characteristics:
 Solution and film coating method that use Chitosan as the main ingredient.
 Chitosan membrane can be formed on the surface of an object with s standard coater.
 Chitosan membranes dissolve in acid, are biodegradable but water-resistant.
 Colon-specific DDS can be achieved by coating with an enteric layer over the Chitosan
membrane.
 Can be applied to various shapes and sizes; such as pills, capsules, granules, etc.
1. Embedding in Biodegradable Matrices and Hydrogels
Tabel Karakteristik Polisakarida yang biodegradable untuk Colon DDS
Tabel Karakteristik Polisakarida yang biodegradable untuk Colon DDS
2. Embedding in pH-sensitive Matrices
 Releases the drug after a predetermined lag time
 The lag time usually starts after gastric emptying because
most of the time-controlled formulations are enteric
coated.
 Drug release from these systems is not pH dependent
the press coated swellable
hydrophobic polymer layer

DesainEnteric-coatedTimed-release Press –coatedTablet (ETPTablet)

The first formulation introduced

 main body: water insoluble (exposing

the body to formaldehyde vapour which
may be produced by the addition of
trioxymethylene tablets or potassium
permanganate to formalin or any other
method)
 The contents:contained within a body
by a hydrogel plug, which is covered by
a water-soluble cap
 The whole unit is coated with an enteric
polymer to avoid the problem of variable
gastric emptying.
 When the capsule enters the small
intestine the enteric coating dissolves
and the hydrogels plug starts to swell,
the amount of hydrogel is such adjusted
that it pops out only after the stipulated
period of time to the release the
contents.
Lag Phase
of 5 hrs.
obeserved
 Time Controlled Release System : sustained and
delayed release dosage form
 Fakta:
 Variasi waktu pengosongan lambung >>>  waktu
sediaan tiba di kolon tidak dapat diprediksi 
ketersediaan obat di kolon rendah
 Perpanjang lag time (no drug release period/waktu
transit yang dibutuhkan dari mulut sampai ke kolon)
sampai 5 – 6 jam
 Durasi lag time tergantung pada bobot dan komposisi
lapisan HPC
Kerugian Timed Release System:
1. Waktu pengosongan lambung bervariasi di antara individu atau
tergantung pada jumlah dan jenis makanan yang dikonsumsi
2. Gerakan saluran cerna, terutama peristaltik dan kontraksi
lambung, dapatmengubah waktu transit obat di saluran cerna
3. Waktu transit obat di sepanjang saluran cerna akan meningkat
pada pasien IBD, sindrom karsinoid, diare dan ulcerative colitis

Timed Released System TIDAK DAPAT diterapkan

untuk sediaan terapi lokal di Kolon

Integrasi sistem pH-dependent dengan time controlled

system
Teknologi Timed release lainnya:
 Sediaan multisalut yang terdiri dari inti yang disalut oleh tiga
jenis polimer
 Sistem dirancang untuk mengantisipasi waktu transit di usus halus yang
relatif singkat:
▪ Lapisan terluar larut pada pH > 5, lapisan tengah berupa lapisan yang mengembang
terbuat dari bahan enterik.

 Sediaan Pellet dengan penyalutan serbuk 5ASA pada nonpareil :

drug layered pellet disalut dengan lapisan dalam berupa
kombinasi 2 polimer yang tidak tergantung pH (Eudragit RL dan
RS) dan lapisan luar berupa polimer yang tergantung pH
(Eudragit FS).
 TimeClock®
 TIME-CLOCKTM
Salut Enterik
Lapisan surfaktan
hidrofobik (wax, Drug core
polysorbat 80, HPMC)

Membran polimer
CHRONOTROPICTM
tak larut air Salut Enterik (Eudragit®L)
Drug layer
Eudragit®S
(opsional)

Swelling agent layer (low Sucrose bead

substituted HPC) Salut HPMC
TIME-CONTROLLED EXPLOSION SYSTEM (TES) (viskositas tinggi) Drug core
 Mengendalikan kecepatan penetrasi air melalui
lapisan atau cangkang (pH induced)
 Mengendalikan kecepatan absorpsi cairan melalui
lapisan polimer (swelling induced)
 Mengendalikan aktivitas osmotik dari garam atau
senyawa polimer osmotik (pressure induced)
 Mengendalikan kecepatan erosi dan disolusi lapisan
polimer (erosion induced)
 Mengatur ketebalan lapisansalut
 Potensial redoks rata-rata di usus halus proksimal : -67 ±
90 mV, distal : -196 ± 97 mV, di kolon : -145 ± 72 mV
 Perubahan potensial redoks yang diinduksi oleh mikroflora
 sebagai highly selective mechanism for targeting to the
colon
 Noncrosslinked redox-sensitive polymers yang mengandung
ikatan azo dan/atau disulfida
 Analog dengan pemutusan ikatan azo oleh enzim di usus,
polimer baru yang dihidrolisis secara nonenzimatik oleh
flavin yang dihasilkan secara enzimatik  sedang
dikembangkan untuk CDDS
 Pemberian oral : membutuhkan konsentrasi obat
yang tinggi di kolon untuk efek terapi yang
optimal.
 Bioadesi : suatu proses yang mana suatu sediaan
tetap kontak pada organ tertentu untuk jangka
waktu yang yang lebih lama  memperbaiki
performa dan memperpanjang waktu tinggal obat
dalam CDDS
 Material untuk sistem bioadesif : polycarbophils,
polyurethanes and polyethylene oxide-polypropyline
oxide copolymers (sudah diteliti)
 Pada lingkungan
kolon, jaringan azo
terdegradasi
menghaslkan suatu
struktur yang dapat
membangun
interaksi mukoadesif
dengan mukosa
kolon
Mucoadhesive azo crosslinked acrylic acid
and predicted colonic degradation behaviour.
 Mirelman et al. prepared and evaluated a formulation : consisted
of small silica particles (5-10 µm in diameter) covalently linked
to a potent antiamoebic drug, 2-(4-aminophenoxymethyl)-5-
nitro-1-methylimidazole.
 Silica-drug particles were injected into mice, hamsters and guinea
pigs: found that trophozoites phagocytosed the particles in vivo
and in vitro, followed by rapid cell death due to the released drug.
 Analysis of mouse serum revealed that no drug was absorbed from
the intestine after placement of the drug-containing particles in
the intestine.
 The antiamoebic activity of particles recovered from the intestine
was almost fully retained.  useful for luminal therapy for
asymptomatic amebiasis and may minimize side effects and
frequency of administration.
 Depend upon the osmotic
pressure exerted by osmogen on
drug compartment with which
drug get released slowly though
the orifice
 to target the drug locally or to
achieve systemic absorption
 can be a single osmotic unit or may incorporate
as many as 5-6 push-pull units, each 4 mm in
diameter, encapsulated within a hard gelatin Irisan melintang sistem OROS CT
capsule
 Each bilayer push pull unit contains an osmotic push layer and a drug layer, both surrounded by
a semipermeable membrane
 orifice is drilled through the membrane next to the drug layer
 Immediately after the OROS-CT is swallowed, the gelatin capsule containing the push-pull units
dissolves. Because of its drug-impermeable enteric coating, each push-pull unit is prevented
from absorbing water in the acidic aqueous environment of the stomach, and hence no drug is
delivered
 As the unit enters the small intestine, the coating dissolves in this higher pH environment (pH
>7), water enters the unit, causing the osmotic push compartment to swell, and concomitantly
creates a flowable gel in the drug compartment. Swelling of the osmotic push compartment
forces drug gel out of the orifice at a rate precisely controlled by the rate of water transport
through the semipermeable membrane.
 For treating ulcerative colitis, each push pull unit is designed
with a 3-4 h post gastric delay to prevent drug delivery in the
small intestine. Drug release begins when the unit reaches the
colon.
 OROS-CT units can maintain a constant release rate for up to
24 hours in the colon or can deliver drug over a period as short
as four hours.
 Recently, new phase transited systems have come which
promise to be a good tool for targeting drugs to the colon.52-
55 Various in vitro / in vivo evaluation techniques have been

developed and proposed to test the performance and stability

of CDDS.
 Relies on the relatively strong peristaltic waves in the
colon that lead to an increased luminal pressure.
 In response to raised pressure of the colon, the dosage
form get ruptured and release the drug at desired site
 Takaya et al. developed pressure controlled colon-delivery capsules prepared
using ethylcellulose, which is insoluble in water.
 drug release occurs following the disintegration of a water-insoluble polymer capsule
because of pressure in the lumen of the colon.
 The thickness of the ethylcellulose membrane is the most important factor for the
disintegration of the formulation
 The system also appeared to depend on capsule size and density. Because of
reabsorption of water from the colon, the viscosity of luminal content is higher in the
colon than in the small intestine
 It has therefore been concluded that drug dissolution in the colon could present a
problem in relation to colon-specific oral drug delivery systems.
 In pressure controlled ethylcellulose single unit capsules the drug is in a liquid.
 Lag times of three to five hours in relation to drug absorption were noted when
pressure-controlled capsules were administered to humans.
» PULSINCAP
» OROS-CT
» CODESTM
» PORT® SYSTEM
» TIME CLOCK® SYSTEM
» CHRONOTROPIC® SYSTEM
» COLAL-PRED™
» TARGIT™ TECHNOLOGY
» ENTERIONTM CAPSULE
» TICKING CAPSULE
designed to avoid the inherent problems associated with pH or time
dependent systems
designed to avoid the inherent problems associated with pH or time
dependent systems
 CODESTM is a combined approach of pH dependent and microbially triggered CDDS
 utilizing a unique mechanism involving lactulose, which acts as a trigger for site specific
drug release in the colon,
 The system consists of a traditional tablet core containing lactulose, which is over coated
with and acid soluble material, Eudragit E, and then subsequently overcoated with an
enteric material, Eudragit L.
 The premise of the technology is that the enteric coating protects the tablet while it is
located in the stomach and then dissolves quickly following gastric emptying.
 The acid soluble material coating then protects the preparation as it passes through the
alkaline pH of the small intestine
 Once the tablet arrives in the colon, the bacteria enzymetically degrade the
polysaccharide (lactulose) into organic acid.
 This lowers the pH surrounding the system sufficient to effect the dissolution of the acid
soluble coating and subsequent drug release
 Sediaan solid disalut dengan barrier
lipida yang mengandung carnauba
Salut Enterik
wax dan bees wax dengan surfaktan
 Pada lapisan luar berikutnya,
sediaan disalut dengan salut polimer
untuk mencegah pelepasan obat
Drug core
Salut wax
yang prematur
dengan
 Pelepasan obat tergantung pada pH surfaktan
atau kondisi digestif saluran cerna
 Salut Enterik

Salut HPMC Drug core

 Sediaan pellet yang mengandung obat
prednisolon metasulfobenzoat yang disalut
dengan etilselulosa dan amilose khusus

 Sedang masuk uji klinik fase III untuk

memelihara remisi ulcerative colitis.
 TargitTM Technology(West Pharmaceutical
Services): salut yang sensitif terhadap pH
pada injection-moulded starch capsules

 Dari penelitian -scintigraphy: 90% Targit

Capsule (n=84) melepaskan zat aktifnya di
ileum terminal dan di kolon
 1 mL drug reservoir
 Bentuk sediaan yang umum:
 Solusio
 Suspensi
 API
 Formulated powder /granulate
 Pellet/minitablet
Chronotherapeutic device : menggunakan peraltan
elektrik untuk menkontrol pelepasan obat secara
pulsatile digabungkan dengan pengatur waktu
elektronik
For in vitro evaluation, not any standardized evaluation
technique is available for evaluation of CDDS because an ideal in
vitro model should posses the in-vivo conditions of GIT such as
pH, volume, stirring, bacteria, enzymes, enzyme activity, and
other components of food. Generally, these conditions are
influenced by the diet, physical stress, and these factors make it
difficult to design a slandered in-vitro model.

In vitro models used for CDDS are:

 a) In vitro dissolution test
 b) In vitro enzymatic tests
 c) In vivo evaluation
Drug Delivery Index (DDI) and Clinical Evaluation of Colon-
Specific Drug Delivery Systems
 Dissolution of controlled-release formulations used for colon-specific drug
delivery are usually complex, and the dissolution methods described in the
USP cannot fully mimic in vivo conditions such as those relating to pH,
bacterial environment and mixing forces.
 Dissolution tests relating to CDDS may be carried out using the
conventional basket method. Parallel dissolution studies in different buffers
may be undertaken to characterize the behavior of formulations at different
pH levels.
 Dissolution tests of a colon-specific formulation in various media simulating
pH conditions and times likely to be encountered at various locations in the
gastrointestinal tract have been studied.
 The media chosen were, for example, pH 1.2 to simulate gastric fluid, pH
6.8 to simulate the jejunal region of the small intestine, and pH 7.2 to
simulate the ileum segment.
 Enteric-coated capsules for CDDS have been investigated in a gradient
dissolution study in three buffers. The capsules were tested for two hours at
pH 1.2, then one hour at pH 6.8, and finally at pH 7.4
 Incubate carrier drug system in fermenter containing suitable
medium for bacteria (strectococcus faccium and B. Ovatus).
 The amount of drug released at different time intervals are
determined
 Drug release study is done in buffer medium containing
enzymes (ezypectinase, dextranase), or rat or guinea pig or
rabbit cecal contents.
 The amount of drug released in a particular time is determined,
which is directly proportional to the rate of degradation of
polymer carrier.
 dogs, guinea pigs, rats, and pigs : resemble the anatomic and
physiological conditions as well as the microflora of human GIT
 While choosing a model for testing a CDDS, relative model for
the colonic diseases should also be considered.
 Guinea pigs are commonly used for experimental IBD model.
 The distribution of azoreductase and glucouronidase activity in
the GIT of rat and rabbit is fairly comparable to that in the
human.
 Rapid evaluation of CDDS, a novel model has been proposed. In
this model, the human fetal bowel is transplanted into a
subcutaneous tullel on the back of thymic nude mice, which
bascularizes within four weeks, matures, and becomes capable
of developing of mucosal immune system from the host
 DDI is a calculated pharmacokinetic parameter, following single
or multiple dose of oral colonic prodrugs.
 DDI is the relative ratio of RCE (Relative colonic tissue exposure
to the drug) to RSC (Relative amount of drug in blood i.e. that is
relative systemic exposal to the drug).
 High drug DDI value indicates better colon drug delivery
 Absorption of drugs from the colon is monitored by colonoscopy
and intubation.
 Currently, gamma scintigraphy and high frequency capsules are
the most preferred techniques employed to evaluate colon drug
delivery systems.
 Bagian kolon dari saluran cerna telah menjadi tapak penting
bagi sistem pengantaran obat dan absorpsi obat
 CDDS menawarkan keuntungan bagi pasien baik untuk
terapilokal maupun sistemik
 Spesifisitas kolon dapat dicapai dengan sistem yang
menggunakan bahan alami yang dapatdidegradasi oleh enzim
bakteri kolon.
 Oleh karena kerumitan sistem CDDS dan ketidakpastian
metode disolusi yang sudah ada dalam menegakkan
hubungan invitro dan in vivo, maka hal ini masih menjadi
tantangan bagi para ahli farmasetika untuk mengembangkan
dan memvalidasi metode disolusi yang melibatkan sifat
fisiologis kolonyang dapat dipakai secara rutin di industri
untuk mengevaluasi sediaan CDDS
 Pengantaran Obat ke Kolon merupakan salah satu tantangan
besar
 Penanganan patologi lokal di kolon membutuhkan usaha
untuk mengurangi atau menghilangkan efek samping obat
 Sediaan konvensional sangat perlu untuk diperbaiki desain
sediaannya.
 Pengantaran obat ke tapak spesifik seperti kolon merupakan
alternatif yang potensial bagi perbaikan dalam pengobatan
 Kolon memiliki sifat-sifat khusus yang memungkinkannya
sebagai tapak absorpsi dalam merancang sistem
pengantaran
 Colon DDS memiliki nilai komersial yang tinggi.Tingginya
penelitian dalam bidang ini menunjukkan potensi pasar
farmasinya.
 Technology or design
alone do not make a
successful product.
 Technology needs to be Concorde : only 20 manufactured
implemented in an
appropriate design for a
successful product

Boeing 747: over 1300 manufactured

 Philip AK, et al. 2010. Colon Targeted Drug Delivery Systems:
A Review on Primary and Novel Approaches. OMJ. 25: 70-78.
 M. K. Chourasia, S. K. Jain. 2003. J Pharm Pharmaceut Sci.
6(1):33-66.
 Rajeev S. Raghuvanshi. 2007. Oral Controlled Release Drug
Delivery Systems (OCRDDS): Recent Trends & Future
Challenges
 Prof V. R. Sinha. Site Specific Drug Delivery to Colon:
Approaches and Recent Developments
METODE PENGANTARAN PRINSIP DICAPAI DENGAN CONTOH

1. PH-CONTROLLED Perbedaan Disolusi salut Salut enterik,

pH pada polimer yang pH- polimer basa
DRUG RELEASE usus halus dependent
dan kolon
Mengembangnya Polimer akrilat
polimer hidrogel
yang pH-
dependent

Pelepasan obat Insulin+gelatin B

yang pH- Olsalazine+anion
dependent dari ion exchange resin
exchange resin
complexes
 METODE PRINSIP DICAPAI DENGAN CONTOH
PENGANTARAN

2. ENZYME- Degradasi Degradasi Prodrug Mono-, oligo, atau

komponen polimer dengan
CONTROLLED sediaan oleh ikatan obat-carrier
DRUG RELEASE enzim bakteri
kolon Bahan penyalut Polimer azo, polimer
dengan ikatan yang dengan ikatan
dapat didegradasi + glikosida
cangkang kapsul

Hidrogel dan matrix Cross-linked guar,

yang terdiri dari pektin, dekstran,
polimer cross- inulin, polimer azo
lingked dan
biodegradabel

Salut sustaine Etilselulose atau

release dengan Eudragit®RS dg
domain terdegradasi galaktomanan, -
(pembentuk pori) siklodekstrin,
amilose glassy, inulin
 METODE PRINSIP DICAPAI DENGAN CONTOH
PENGANTARAN

3. TIME- Waktu transit Pengembangan Eter selulosa,

di usus halus polimer yang Eudragit®sustained
CONTROLLED yang relatif tergantung waktu -release coating
DRUG RELEASE konstan yaitu
sekitar 3 jam Tekanan osmotik COER-24 TM
yang muncul
perlahan dalam
sediaan

Lapisan polimer Eter selulosa,

yang tererosi atau Eudragit®E,
terdisolusi chitosan (dalam
tergantung waktu kombinasi dengan
asam)
 METODE PRINSIP DICAPAI DENGAN CONTOH
PENGANTARAN

4. PRESSURE- Desintegrasi Salut tebal yang Kapsul gelatin

sediaan di kolon terdiri dari polimer keras denga salut
CONTROLLED oleh adanya tak larut air, etilselulosa di
DRUG RELEASE tekanan polimer yang tidak bagian dalam
intraluminal mengembang
yang dihasilkan
dari gerakan
peristaltik yang
kuat
 Micropore Obat + Osmotic agent

Swelling agent
Salut enterik Membran semipermeabel
 Setelah disolusi lapisan enterik, sswelling polimer akan mendorong cairan pada
kompartemen osmotik keluar melalui micropore akibat adanya penetrasi air.
 Hal ini menyebabkan kombinasi pelepasan obat secara sustained release dan pH-
controlled.
 Micropore Kompartemen Obat

Kompartemen Osmotik
Membran semipermeabel
Polymer delay coat: berperan pada
delayed drug release
 Selama lag phase, kompartemen osmotik mengembang menyebabkan
peningkatan tekanan pada kompartemen obat
 Obat keluar secara sustained release via Micropore pada lapisan film
semipermeabel di bagian luar setelah disolusi dan ekstrusilap. delay di bawahnya.