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ORAL DELIVERY SYSTEM
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ABSORPSI PADA SALURAN CERNA :
MODIFIED RELEASE DOSAGE FORM
Delayed release :
the drug is not being released immediately following
administration but at a letter time
e.g: enteric coated tablets
 Repeat action:
an individual dose is released fairly soon after
administration, and second or third doses are
subsequently released at intermitten intervals
 Prolonged release:
the drug is provided for abs.over a longer period of
time than from a conventional dosage form. However,
there is an implication that onset is delayed because of
an overall slower release rate from the dosage form

LANJUTAN MR.....
Sustained release:
an initial release of drug sufficient to provide a
therapeutic dose soon after administration, and
then a gradual release over an extended period.
 Extended release :
dosage forms release drug slowly, so that plasma
concentrations are maintained at a therapeutic
level for a prolonged period of time (ussually
between 8 and 12 hours).
 Controlled release (CR):
dosage forms release at a constant rate and
provide plasma concentrations that remain
invariant with time.

RELEASE AND ABSORPTION OF INITIAL
PRIMING DOSE
Di
Dm
step 1
step 2
rapid rate
drug in sol
of release
in GI fluids
input
Drug in
body
output
drug in
urine
k’a
Dosage form
RELEASE AND ABSORPTION OF MAINTENANCE DOSE
step 3
step 4
Dm
Dosage form
Zero order
release
drug in sol
in GI fluids
input
k°m
Drug in
body
output
drug in
urine
GRDDS
COMPONENTS OF MR DELIVERY SYSTEM
These include:
 Active drug
 Release controlling agent(s) : matrix formers,
membrane formers
 Matrix or membrane modifier, such as channeling
agents for wax matrices and solubilizers, and
wicking agents for hydrophilic matrices
 Solubilizer, pH modifier and/or density modifiers
 Lubricant and flow aid, such as Mg Stearat, stearic
acid, talc, sod.stearyl fumarate, etc
 Supplementary coating to extend lag time further
reduce drug release
 Density modifiers
POLIMER YANG BIASA DIGUNAKAN
UNTUK CR....
1.
Nonbiodegradable Hydrophobic Polymer
Inert

Matriks dapat diambil setelah obat habis dalam
kondisi utuh (intact)

Sebagai rate-limitting step barrier terhadap
transport dan pelepasan obat dari sediaan.
Contoh:

Ethyl cellulose (EC)

Cellulose acetate (CA)

Polyethylene (PE)

Polyvinyl chloride (PVC)

Polyethylene vinil acetate (PVA)

LANJUTAN...
2. Hydrogel
Polimer ini mengembang tetapi tidak larut bila
kontak dengan air
 Bahan ini inert
 Matriks dapat diambil utuh dari tempat aplikasinya
 Fungsinya sebagai rate-limiting barrier terhadap
transport dan pelepasan obat dari sediaan.
Contoh:
 Polyhydroxyethyl methylacrylate (p-HEMA)
 Croos-linked polyvinyl alcohol (PVA)
 Croos-linked polyvinyl pyrrolidone (PVP)
 Polyacrylamide
 Dextrans

LANJUTAN...
3. Soluble polymer
Bahan ini mempunyai BM<75000 dalton
 Uncross-linked polymer
 Larut dalam air
 Kecepatan disolusi berkurang dengan naiknya BM
 Bahan ini dapat digunakan sendiri atau kombinasi
dengan polimer hidrofobik sehingga memberikan
pelepasan obat yang lebih lambat
Contoh:
 Polyethyleneglycol (PEG)
 Uncross-linked PVA/PVP
 HPMC, methocel
 Copolymers of methacrylic acid and acrylic acid
methyl ester (Eudragit L)

LANJUTAN...
4. Biodegradable polymers
 Bahan ini hilang secara lambat dari tempat
aplikasinya karena reaksi kimia, seperti
hidrolisis
 Pelepasan obat dari sediaan sebagai akibat
erosi permukaan
Contoh :
 Polylactic acid (PLA)
 Polyglycolic acid (PGA)
 Polycaprolactone (PCL)
 Polyanhydrides and polyorthoesters
CONTOH POLIMER ATAU MATRIKS YANG DIGUNAKAN
DALAM SEDIAAN CONTROLLED RELEASE
Enteric coatings
Cellulose
1.
2.
Non cellulose
1.
2.
3.
Non Enteric coatings
Cellulose
1.
2.
3.
4.
5.
Non cellulose
1.
2.
3.
4.
5.
6.
7.
Cellulose acetate phthalate (CAP)
Hydroxypropylmethylcellulose phthalate (HPMCP)
Methacrylic acid polymers
Polyvinylacetate phtalate (PVAP)
Shellac
Ethylcellulose (EC)
Hydroxyethylcellulose (HEC)
Hydroxypropylmethylcellulose (HPMC)
Methylcellulose (MC)
Sodium Carboxymethylcellulose (Na CMC)
Carnauba wax
Castor oil
Cetyl alcohol
Ethylene vinylacetate copolymer
Hydrogenated vegetable oils
Polivinyl alcohol
Silicon-based polimers
PROFIL SEDIAAN CR
THE THREE MAIN FUNCTIONS OF
MATERIALS USED AS CR COATING:
Provisions of the backbone structure of
the coating
 Facilitation or control over transport of
drug across the membrane
 Plasticization of the coating

THE MATERIAL USED
Cellulose Acetate Phthalate (CAP)
1. Cellulose eseter
2. It is soluble at pH values above about 6.0, and
thus will tend to release drug toward the distal
end of the small intestine
3. Compatible with plasticizers such us triacetin
or castor oil. Incompatible with ferrous sulfate,
ferrous chloride, silver nitrate, and other in
organic salt. Also, CAP incompatible with drugs
which is acid sensitive
LANJUTAN...
1.
2.
3.
4.
Hydroxypropylmethylcellulose phtalate
(HPMCP)
A monophtalic ester of hydroxy propylcellulose
It release drug at the pH about 5.0-5.5 (in the
proximal part of the small intestinal)
Plasticizers commonly used are castor oil,
diacetin, diethyl and dibuthyl phtalate, and
PEG
Incompatible include strong oxidizing agents,
more than 10% titanium dioxide (coloring
agent) may adversely effects physical stability
or gastric resistance of the film coat.
LANJUTAN.......
1.
2.
3.
4.
5.
Methacrylic acid polymer and other polymeric
methacrylates:
Often referred to as polymeric methacrylates or
Eudragit
Eudragit E is soluble below pH 5.0 is used as an
non enteric coating
Eudragit L 100-55 is used as an enteric coating for
drug release at a pH above 5.5
Eudragit NE 30D is used as a permeable, CR
coating, Eudragit RL 30 D is used in CR coating
Eudragit have been used in topikal, oral,
parenteral, ophthalmic, and other types of
pharmaceutical products.
LANJUTAN...
Polyvinylacetate phtalate (PVAP)
As enteric film coating it releases drug at pH
values above about 5.0 so that absorption
may occur throughout the small intestinal
LANJUTAN...
Shellac
1.
2.
3.
Is obtained from a gummy exudation produced
by female insect Laccifer Lacca Kerr. It is
available in several grades (bleached, orange,
white, etc)
The main component is resin; the pH at which
drug is release is about 7.0, which may well be
somewhat too high for most enteric coated
products.
This material is not recommended for anyone
developing a new product.
LANJUTAN...
Ethylcellulose (EC)
1. EC is a cellulose ether derivative with three
hydroxy groups available for substitution
2. It is insoluble in water, but it is freely soluble in
organic solvents; the permeability of EC films can
be increased by adding materials such as
hydroxypropyl cellulose, PEG, etc
3. Plasticizers used with EC include dibuthylphtalate,
dimethylphthalate, benzylbenzoate, cethyl alcohol,
castor oil, and corn oil
4. Stabilizers may be used for reducing oxidative
degradation (octylphenol or butylated
hydroxyphenol and also 2,4 dihydroxy
benzophenone)
LANJUTAN...
Hydroxyethylcellulose (HEC)
1. It is cellulose 2-hydroxyl ether
2. It is water soluble polymer (trade name:
celloside and natrosol)
Na. CMC
1. It is the sodium salt of cellulose
carboxycellulose ether
2. It is soluble in water and polar organic
solvents used for dental, oral, topikal, and
parenteral.
LANJUTAN...
Hydroxypropyl methylcellulose (HPMC)
1. It is cellulose 2-hydroxypropyl methyl ether
2. It is water soluble film former, low viscosity grades,
and used as an oral and topical application
3. It may be incompatible with oxidizing agents,
metallic salts, and ionic organics.
Methyl cellulose (MC)
1. It is cellulose methyl ether
2. It is soluble in water and organic solvents and used
in a number of CR, coated products, used in oral,
topical, buccal, vaginal, and parenteral pharm use
CONTROLLED RELEASE DESIGN
Monolithic matrix delivery system
Dalam sistem ini diklasifikasikan dalam 2
kelompok, yaitu :
Matrik koloid hidrofilik,
1.


partikel obat didispersikan dalam suatu matrik
yang larut (soluble matrix)
obat dilepaskan ketika matrik terlarut (erosi) atau
mengembang
....
CONTOH TERJADINYA EROSI
Matrik lipid atau polimer tidak larut
2.



partikel obat didispersikan dalam matrik yang
tidak larut (insoluble matrix)
obat dilepaskan ketika cairan/air masuk dalam
matrik dan melarutkan partikel obat.
Pelepasan obat tergantung kemampuan
medium air untuk melarutkan channeling
agent sehingga membentuk matrik yang
porous dan berkelok-kelok.
SISTEM TERKONTROL MEMBRAN ATAU
RESERVOIR
membran berfungsi sebagai pengatur
kecepatan pelepasan dari bentuk sediaan.
 membran harus permeable terhadap obat.
 polimer membran tidak mengalami erosi.

MEMBRAN......
Mekanisme terjadinya
difusi
Mekanisme sweeling
CONTOH BENTUK SUSTAINED RELEASE
(MIKROENKAPSULASI)
SISTEM POMPA OSMOTIK (OSMOTIC PUMP)
Pelepasan obat dikontrol oleh suatu
membran mempunyai satu lubang (hole).

 Obat
dimasukkan dalam suatu tablet inti
yang bersifat larut air serta disalut
dengan suatu membran
semipermeabel
 Ketika
obat dalam tablet inti terlarut
maka timbul tekanan hidrostatik dan
menekan larutan obat keluar melewati
lubang membran.
MEKANISME OSMOTIC PUMP
CONTOH KATEGORI OBAT PER ORAL SEDIAAN
RELEASE
Kategori
Produk
CONTROLLED
Zat aktif
Slow erosion with
initial fast release
dose
Tedral SA
Theophylline, ephedrin HCl,
Phenobarbital
Erosion core only
Tenuate
Dospan
Diethylpropion HCl
Repeat action tablets
Chlor-Trimeton
Pseudoephedrine sulfate
Chorpheniramine maleate
Pellets in tablets
Theo-dur
Retaphyl SR
Quibron SR
Glucovance
Theophylline
Glibenclamide + Metformin
HCl
LANJUTAN...
Microencapsulation
Osmotic delivery
Nitrospan
Nitroglycerin
Pulmo timelets
Teophyllin
Acutrim
Phenylpropanolami
ne HCl
Niphedipin
Adalat oros
Leaching
Desbutal
Gradumet
Enteric
Prohibit
Promezol
Methamphetamine
HCl
Pentobarbital
sodium
omeprazol
ASPEK FARMAKOKINETIKA SEDIAAN CR
Agar konsentrasi obat dalam darah tetap, maka
Rate in = rate out
absorpsi :
Log (Ao-X) = Log Ao-Ka.t/2,303
Ao
= obat mula-mula dalam saluran cerna
(telah mengalami disolusi)
X = obat yang telah diabsorpsi
Ka
= konstante kecepatan absorpsi
OBAT DIABSORPSI DENGAN KINETIKA ORDE I
Eliminasi :
Log (Bo-E) = Log Bo-Kel.t/2,303
Bo
E
Kel
= obat mula-mula dalam badan
= obat yang telah dieliminasi
= konstante eliminasi
Eliminasi obat mengikuti kinetika
orde I
ABSORPSI = ELIMINASI
Rate in = rate out
D(Ao-X)/dt = d (Bo-E)/dt
-Ka (Ao-X) = -Kel (Bo-E)
Untuk menjaga agar obat dalam darah konstan
maka sediaan harus memberikan obat dengan
kecepatan yang konstan pula
R = d (A0-X)/dt = Kel (Bo-E)
R= rate of delivery
Dalam proses absorpsi, kecepatan
pembatas adalah pelepasan obat dari
bentuk sediaan
SEDIAAN OBAT HIPOTESIS
D* = dosis diperlukan untuk mendapatkan
konsentrasi obat dalam darah pada konsentrasi
puncak.
B* = obat dalam badan waktu konsentrasi puncak
Contoh....
D* = 100 mg
B* = 80 mg
Kel = 0,023 jam-1
R = Kel B*
R = (0,023)(80) mg/jam = 1,84 mg/jam
PERHITUNGAN:
Jumlah obat dalam badan (A) = kadar x Vd
 Rate out = Kel x A
 Release rate = Rate out/F

Perhitungan MD:
MD = release rate x h
LD= A/F
DT = MD + LD
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
Biasanya, obat tidak diabsorpsi 100% tetapi obat
hanya sebagian yang diabsorpsi (F), misal F=0,6
Ka F D = Kel B*
Ka D = Kel B* / F
R = 1,84/0,6 mg/jam = 3,06 mg/jam
CP (STEADY STATE) = F.D/V.KEL.T = F.D/CL.T
D/T = Cp Cl/F
V = volume distribusi
T = interval pemberian obat
Cl = klirens
R = D/T = 3,06 mg/jam
Jika waktu yang diperlukan untuk
pelepasan terkontrol (sustaining time) =
10 jam, maka dosis keseluruhan selama
10 jam adalah :
Dm = R h
Dm = maintaining dose
h = sustaining time
Dm = (3,06 mg/jam)(10 jam) = 30,6 mg
Dt = D* + Dm ; Dt = total dose
Dt = 100 mg + 30,6 mg = 130,6 mg
SOAL....

Buatlah sediaan lepas terkontrol untuk
pemakaian oral suatu obat A !
Diketahui :
obat A mempunyai waktu paro eliminasi 4 jam,
sedangkan MEC = 5 µg/mL dan MTC = 10
µg/mL. Volume distribusi A=0,50 L/kg BB. Obat
A diabsorpsi dari saluran cerna dengan F = 0,9.
bagaimana anda mendesain sediaan itu?

Suatu obat B memiliki data farmakokinetika sbb:
Css = 5-10 µg/mL
Vd = 60 L
T ½ el = 4 jam
F = 0,85
h
= 12 jam
Desainlah bentuk sediaan CR dan jelaskan dengan
formula serta mekanisme pelepasan obat dari
sediaan!
DATA FARMAKOKINETIKA:
Desainlah sediaan dengan data berikut:
 BA immediate release = 45-75%
 BA sustained release = 65-89%
 T1/2 el = 2-6 jam
 VD = 0,8 L/kg
 CL = 7 mL/menit/kg
 Ikatan obat-protein plasma = 92-98%
 Log P = 2,2
 MEC 47±20 ng/mL
 pKa = 6,0