07/09/2009

oleh

Eka Deddy Irawan,S.Si.,M.Sc.,Apt.

Bagian Farmasetika Fakultas Farmasi Universitas Jember

Mengingat

kembali Macam Bentuk Sediaan +

Formula Penyusunnya
Mekanisme Pelepasan Obat Sediaan
Faktor-2
Macam Rute Pemakaian
Proses Absorpsi Rute Pemakaian Faktor-2
Rute Pemakaian Bentuk Sediaan
Usaha untuk Meningkatkan Pelepasan
Absorpsi Obat
Keuntungan Kerugian Rute Tertentu

Shargel Applied Biopharmaceutics and

pharmacokinetics 5th Ed
pharmacokinetics,
Ed. Ch
Ch. 13,
13 14,
14 17
Ritchel Handbook of Basic Pharmacokinetic,
4th Ed.
Niazi Textbook of Biopharmaceutic s and
Clinical Pharmacokinetic, Ch 3,4
Gibaldi
Gibaldi Biopharmaceutics and Clinical
Pharmacokinetics Ch, 3, 4, 5, 6

Obat dengan sifat fisika kimia tertentu bentuk

sediaan/rute pemakaian manakah yang terpilih?
Faktor/hal-hal apakah yang harus diperhatikan ?
Mengapa diadakan berbagai bentuk sediaan/ rute
pemakaian?
Pada pemakaian peroral berapa % obat
diabsorpsi
di lambung/usus ?
Pada multi drug therapy- kapan obat digunakan?
- satu waktu ??
- berturutan ??

07/09/2009

Kapan / mengapa suatu obat digunakan

AC/DC/PC?
Bentuk sediaan manakah yang terpilih untuk
pasien dengan kondisi tertentu?
Rute pemakaian manakah yang terpilih untuk
pasien dengan kondisi tertentu

Sifat

Fisika-Kimia Bahan Obat

. Pka p
pH------ Pers. HH
. Ukuran Partikel Noyes Whitney
. Koefisien Partisi
. Poliformisme
. Solvat-Hidrat
. Garam Ester
Bentuk Sediaan
. Larutan . Suppositiria
. Suspensi . Kapsul/Tablet
. Emulsi . Controlled Release
. Salap/krem

Sediaan Padat
. Pengisi-laktosa,
g
, CaHPO4
. Disintegran starch, sellulosa
. Lubrikan Mg stearat, talk
. Bahan Granulasi- sukrosa, polivinil pirolidon
. Penyalut HPMC, CAP
. Fabrikasi

Pelepasan
Absorpsi

07/09/2009

Sediaan

Cair
. Bahan pens
pensuspensi
spensi / pengemulsi
pengem lsi
. Pemanis
. Pelarut
. Surfaktan
. Pengawet
g
Pelepasan
Absorpsi
Rute Pemakaian ---- Aspek Fisiologik

-Luas

tempat absorpsi
-Aliran
Aliran darah yg lewat tempat absorpsi
-First pass effect (FPE)
-Ada tidaknya ikatan protein thd obat

INTRAVASKULAR
- Intraarterial - Intravena
- Intrathecal - Intracardial
EKSTRAVASKULAR
- Peroral - Bukal , Sublingual
- Rektal - Inhalasi
- Intramuskular, Subkutan, Intraperitoneal
Enteral
Oral
Parenteral
Non Oral
Topikal, Transdermal

07/09/2009

RUTE PEMAKAIAN
OBAT
Lullman, Color Atlas
Pharmacology
TUJUAN RUTE
OBAT :
1 LOKAL
1.LOKAL
2.SISTEMIK
Lullman, Color Atllas Pharmacology, 2002

IDEALNYA DELIVERI OBAT

1 Mudah diterima pasien & n pasien komplians
1.Mudah
2.Reprodusibel
3.Mudah untuk diakhiri
4.Tidak ada / kecil ESO

Sediaan ditelan dan diabsorpsi dalam saluran cerna

Keuntungan :
- Pemakaian mudah, sendiri
- Ekonomis
- Aman
- Tidak sakit
Kerugian :
- Mual,
Mual muntah
-Tidak stabil dalam GIT
- Absorpsi Errartic
- Interaksi dengan makanan
- First Pass Metabolism

07/09/2009

Sebagian besar obat diabsorpsi difusi pasif

Terjadi
Terjadi sepanjang saluran cerna
Usus Halus >>>
Luas permukaan >>>(MIKROVILI)
Perfusi darah >>>
Mempertahankan
h k gradien
di k
konsentrasii obat
b
antara lumen usus - darah

Pengosongan isi lambung usus halus

Cairan dan Partikel < 1 mm tidak tertahan
dalam lambung
Feldman 1984
GET
Soft drink
30
Scrambled egg (digestible)
154
Radiopaque
p q ((undigestible)
g
)
3-4
jam
Partikel besar (tablet, kapsul)
3-6
jam
- ada makanan

PENGOSONGAN LAMBUNG
MOTILITAS
MOTILITAS USUS WAKTU TRANSIT
PERFUSI DARAH KE GIT
INTERAKSI OBAT, MAKANAN
METABOLISME FIRST PASS METABOLISM

07/09/2009

Laju absorpsi
jumlah terabsorpsi

Beberapa obat tidak stabil dalam suasana asam

Penundaan absorpsi
terjadi peruraian
contoh : Penisilin
Faktor pengosongan lambung
- makanan : karbohidrat,, p
protein,, lemak
- obat : antikholinergik
analgesik narkotik
- Emosi
- dll (lihat Shargel, Ritchel)

Aliran darah penting untuk membawa obat

Ke dalam sirkulasi sistemik
Pembuluh kapiler mesenterika
Aliran limfatik
Splanchnis Circulation 28% cardiac output
Meningkat setelah makan

Gerakan

peristaltik normal
- mencampur isi usus
- partikel obat kontak mukosa usus
ABSORPSI
Waktu tinggal (residence time) harus cukup
Small Intestine Transit Time (SITT) 3 4 jam
Puasa
P
lambung
l b
+ usus 4 8 jam
j
Keadaan makan SITT 6 12 jam
Faktor ??

Mengubah --- pH, motilitas, GET, kelarutan

obat
- absorpsi obat : Griseofulvin
- absorpsi obat : penisilin, tetrasiklin
Merangsang aliran empedu
- kelarutan lemak, obat larut lemak
Beberapa obat basa,
basa misal Cinnarizine
- kelarutan -- absorpsi
Keadaan puasa : absorpsi lebih baik

07/09/2009

Penyakit

dapat mengubah:
- pH
H lambung
l b
usus
- Pengosongan lambung
- Motilitas saluran cerna
- Aliran darah intestin
g usus
- Permeabilitas dinding
- Sekresi enzim pencernaan
- Sekresi empedu
- Flora normal saluran cerna
ABSORPSI OBAT

First Pass
Metabolism - FPE

Hepatic Portal Pain

07/09/2009

MULUT

VENA JUGULARIS INTERNA

PEMBULUH MESENTERIKA

LAMBUNG

USUS
REKTAL

- VENA H. SUPERIOR
- VENA H. MIDDLE
- VENA H. INFERIOR

oleh

Eka Deddy Irawan,S.Si.,M.Sc.,Apt.

B i F
tik Fakultas
F k lt F
i
it JJember
b
Bagian
Farmasetika
Farmasii U
Universitas

To

understand and describe the processes by

which drugs are distributed throughout the
body
To understand the effect of protein binding
on drug distribution and methods by which
protein binding is measured

Drug

distribution means the reversible

transfer of drug from one location to
another within the body
Once a drug has entered the vascular system
it becomes distributed throughout the
various tissues and body fluids in a pattern
that reflects the physiochemical nature of
the drug and the ease with which it
penetrates different membranes

07/09/2009

1) The drug may remain largely within the

vascular system,
system ex: Plasma substitutes such
as dextran and drugs which are strongly
bound to plasma protein

2) Some are uniformly distributed

throughout the body water,
water ex: low
molecular weight water soluble compounds
(ethanol) and a few sulfonamides

3) A few drugs are concentrated specifically

in one or more tissues that may or may not
be the site of action, ex: Iodine (in the
thyroid gland), chloroquine (in the liver even
at conc 1000 times those present in plasma),
tetracycline (irreversibly bound to bone and
developing teeth) and highly lipid soluble
compounds
d (distribute
(di t ib t into
i t fat
f t tissue)
ti
)

4) Most drugs exhibit a non-uniform

distribution in the body (largely determined
by the ability to pass through membranes
and their lipid/water solubility). The highest
concentrations are often present in the
kidney,
liver,
and
intestine.

07/09/2009

The

volume of plasma is approximately 3-4

L (in an adult), therefore a value of V in the
range of 3-5 L would be compatible with
pattern 1.
Pattern 2 would be expected to produce a V
value of 30 to 50 L, corresponding to total
body water.
Drugs exhibiting pattern 3 would exhibit very
large values of V. Chloroquine has a V value
of approximately 17,000 L.
Drugs following pattern 4 may have a V
value within a wide range of values.

Drug

Liters/Kg

Liter/70 Kg

Chloroquine

94 - 250

94 - 250

Nortriptyline

211

500

Digoxin

500

Lidocaine

1.7

120

Theophylline

0.5

35

Fluid
substances

Volume (liter)

Test

Extracellular
Fluid

13-16

Inulin, Na23, Br-,

I-

Plasma

3-4

Evans blue, I131

albumin,
dextrans

Interstitial fluids

10 13
10-13

Intracellular
fluids

25-28

Total body water

40-46

Antipyrine, D2O,
ethanol

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07/09/2009

Rate of distribution -

Membrane
permeability
Blood perfusion

Extent of Distribution
-

Lipid Solubility
pH - pKa
Plasma protein
binding
Intracellular binding

i) Permeability is greatly increased in the renal

capillaries by pores in the membrane of the
endothelial cells, and in specialized hepatic
capillaries, known as sinusoids which may
lack a complete lining. This results in more
extension distribution of many drugs out of
the capillary bed.
ii) On the other hand brain capillaries seem to
have impermeable
p
walls restricting
g the
transfer of molecules from blood to brain
tissue. Lipid soluble compounds can be
readily transferred but the transfer of polar
substances is severely restricted. This is the
basis of the "blood- brain" barrier.

A. Membrane permeability
The
capillaries are typically lined with
endothelium whose cells overlap,
overlap though to a
lesser degree than epithelial cells. Also, the
junctions between cells are discontinuous.
Capillary walls are quite permeable. Lipid
soluble drugs pass through very rapidly. Water
soluble compounds penetrate more slowly at a
rate more dependent on their size. Low
molecular weight drugs pass through by simple
diffusion. For compounds with molecular
di
diameter
t above
b
100 transfer
t
f is
i slow.
l
For drugs which can be ionized the drug's pKa
and the pH of the blood will have a large effect
on the transfer rate across the capillary
membrane.

B. Blood perfusion rate

: The rate at which blood perfuses to
different organs varies widely

11

07/09/2009

Organ

Bone
Brain
Fat
Heart
Kidneys
Liver
Muscle
Skin

Perfusion Rate
(ml/min/ml of
tissue)

% of cardiac
output

0.02
0.5
0.03
0.6
4.0
0.8
0.025
0.024

5
14
4
4
22
27
15
6

Total blood flow is greatest to brain, kidneys,

liver and muscle with highest perfusion rates
liver,
to brain, kidney, liver, and heart. It would be
expected that total drug concentration
would rise most rapidly in these organs.
Certain organs such as the adrenals
(1.2/0.2%) and thyroid (2.4/1%) also have
l g perfusion
large
f i rates.
t

Example :
thiopental gets into the brain faster than muscle, whereas,
penicillin g
p
gets into muscle more q
quickly
y than it g
gets into brain.
i) Thiopental is only partly ionized and passes into the brain or
muscle easily. Perfusion limits the transport. Since brain has a
higher perfusion rate the thiopental can transfer in and out more
quickly.
ii) Penicillin is quite polar and is thus slowly permeable.
Permeability limited transfer is faster in muscle as muscle
capillaries are less restrictive. Thus transfer of penicillin is faster
in muscle than brain.
I brain,
In
b i
perfusion
f i
or membrane
b
permeability
bili
li i
limits
d
drug
transport or distribution. Thiopental diffuses readily, thus
perfusion limits its distribution. Since perfusion is higher to the
brain than to muscle, transport to the brain is faster. Penicillin
less readily diffuses thus it is diffusion which limits penicillin
distribution. Muscle diffusion is easier thus distribution into
muscle is faster for penicillin than distribution into brain.

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07/09/2009

A. Plasma protein binding

Extensive plasma protein binding will cause more
drug to stay in the central blood compartment.
Therefore drugs which bind strongly to plasma
protein tend to have lower volumes of
distribution.
Of these plasma proteins, albumin, which
comprises 50 % of the total proteins binds the
widest range of drugs.
drugs Acidic drugs commonly
bind to albumin, while basic drugs often bind to
alpha1-acid glycoproteins and lipoproteins. Many
endogenous substances, steroids, vitamins, and
metal ions are bound to globulins.

electrostatic

interactions between groups

on the protein molecules with drugs i.e.
- the NH3+ of lysine and N- terminal
amino acids,
- the NH2+- of histidine,
- the - S- of cysteine
- the - COO- of aspartic and glutamic
acid residues.
residues
van der Waal's forces (dipole-dipole; dipoleinduced dipole; induced dipole-induced
dipole)
hydrogen bonding.

Drugs

Bilirubin, Bile acids, Fatty

Acids,Vitamin C, Salicylates,
Sulfonamides,Barbiturates,
Phenylbutazone,Penicillins,
Tetracyclines, Probenecid

Binding Sites for Acidic

Agents
Albumins

Binding
g Sites for Basic
Agents
Adenisine, Quinacrine,
Globulins, alpha1,
Quinine,Streptomycin,
alpha2, beta1, beta2,
Chloramphenicol,Digitoxin, Ouabain, gamma
Coumarin

Agents

which denature protein may cause

the release of bound drug.
drug
Often there may be competition between
drugs, in which agents that are bound very
tightly, such as coumarin anticoagulants, are
able to displace less tightly bound
compounds from their binding sites.

13

07/09/2009

Drug
Caffeine
Ca
e e
Digoxin
Gentamicin
Theophylline
Phenytoin
Diazepam
Warfarin
Phenylbutazone
Dicumarol

Percent Unbound (100 * fu)

90
77
50
85
13
4
0.8
5
3

Slight changes in the binding of highly bound

drugs can result in significant changes in clinical
response or cause a toxic response.
response Since it is
the free drug in plasma which equilibrates with
the site of pharmacological or toxic response, a
slight change in the extent of binding, such as 99
to 98 % bound, which can result in an almost 100
% change in free concentration, can cause very
significant alteration in response.
For a large number of drugs, including warfarin
and phenytoin, drug response will be dependent
on free
f
d g concentration.
drug
t ti
Alt ti
Alteration
off free
f
concentration by drug interaction or disease
state can alter the intensity of action of these
drugs. Examples include phenylbutazone and
salicylates displacing tolbutamide to give an
increased effect, hypoglycemia.

The

oleh

Eka Deddy Irawan,S.Si.,M.Sc.,Apt.

Bagian Farmasetika Fakultas Farmasi Universitas Jember

(BCS) has been developed to provide

a scientific approach to allow for the
prediction of in vivo pharmacokinetics of
oral immediate release (IR) drug products
by classifying drug compounds based on
their solubility related to dose and
permeabilityy in combination
intestinal p
with the dissolution properties of the
dosage form

14

07/09/2009

The

According to the BCS, drug substances are

classified as follows:
Class I
- High Permeability, High Solubility
Class II - High Permeability, Low Solubility
Class III - Low Permeability, High Solubility
Class IV - Low Permeability, Low Solubility

The

importance of drug dissolution in the

gastrointestinal tract and permeability across
the gut wall barrier in the oral absorption
process has been well known since the 1960s,
but the research carried out to constitute
the BCS has provided new quantitative data
of great importance for modern drug
d
development
l
t especially
i ll within
ithi the
th area off
drug permeability

BCS is a scientific framework for

classifying drug substances based on their
aqueous
solubility
and
intestinal
permeability. When combined with the
dissolution of the drug product, the BCS
takes into account three major factors that
govern the rate and extent of drug
absorption
b
ti
f
from
IR solid
lid orall dosage
d g forms:
f
dissolution,
solubility,
and
intestinal
permeability.

A drug substance is considered HIGHLY SOLUBLE

g
dose strength
g is soluble in <
when the highest
250 ml water over a pH range of 1 to 7.5.
A
drug substance is considered HIGHLY
PERMEABLE when the extent of absorption in
humans is determined to be > 90% of an
administered dose, based on mass-balance or in
comparison to an intravenous reference dose.
A drug product is considered to be RAPIDLY
DISSOLVING when > 85% of the labeled amount of
drug substance dissolves within 30 minutes using
USP apparatus I or II in a volume of < 900 ml
buffer solutions.

15

07/09/2009

It

can save both time and moneyif the

immediate -release,
release, orally administered drug
meets specific criteria, the FDA will grant a
waiver for expensive and time-consuming
bio-equivalence studies.
The aim of the BCS is to provide a regulatory
tool for the replacement of certain BE studies
g accurate in vitro dissolution
byy conducting
tests.

This

BCS

Combined

has been developed primarily for

regulatory applications,
applications but it has also
several other applications in both the preclinical and clinical drug development
processes and has gained wide recognition
within the research-based industry

step will certainly reduce timelines in the

drug development process, both directly and
indirectly, and reduce unnecessary drug
exposure in healthy volunteers, which is
normally the study population in BE studies.
It has also been reported that the application
of a BCS strategy in drug development will
g
direct and indirect savings
g
lead to significant
for pharmaceutical companies

with the dissolution, the BCS takes

into account the three major factors
governing bioavailability viz. dissolution,
solubility and permeability.
This classification is associated with drug
dissolution and absorption model, which
identifies the key parameters controlling
drug absorption as a set of dimensionless
numbers viz.

16

07/09/2009

Absorption number (An), defined as the ratio of

the mean residence time to mean absorption
time.
Dissolution number (Dn), defined as the ratio of
mean residence time to mean dissolution time.
Dose number (D0), defined as the mass (Dose)
divided by the product of (uptake volume (250
ml) and solubility of drug).
drug) D0 = Dose/(V.Cs)
Dose/(V Cs)

Class

Class II drugs have a high absorption number but

a low dissolution number. In vivo drug dissolution
is then a rate limiting step for absorption except
at a very high dose number. The absorption for
class II drugs is usually slower than class I and
occurs over a longer period of time.
In vitro- In vivo correlation (IVIVC) is usually
excepted for class I and class II drugs.
e.g.
Phenytoin,
Danazol,
Ketoconazole,
Mefenamic acid, Nifedinpine.

For

I drugs exhibit a high absorption

number and a high dissolution number.
number The
rate limiting step is drug dissolution.
If dissolution is very rapid, then gastric
emptying rate becomes the rate determining
step.
e.g.
g
Metoprolol,
p
Diltiazem, Verapamil,
p
Propranolol.

Class III drugs, permeability is rate

limiting step for drug absorption. These drugs
exhibit a high variation in the rate and
extent of drug absorption.
Since the dissolution is rapid, the variation is
attributable to alteration of physiology and
membrane permeability rather than the
g form factors.
dosage
e.g. Cimetidine, Acyclovir, Neomycin B,
Captopril.

17

07/09/2009

Class

IV drugs exhibit a lot of problems

for
effective
oral
administration
administration.
Fortunately, extreme examples of class IV
compounds are the exception rather than
the rule and are rarely developed and
reach the market. Nevertheless a number
g do exist. e.g.
g Taxol.
of class IV drugs

Once

the solubility and permeability

characteristics of the drug are known it
becomes an easy task for the research
scientist to decide upon which drug delivery
technology to follow or develop.

The major challenge in development of drug

delivery system for class I drugs is to achieve a
target release profile associated with a
particular
pharmcokinetic
and/or
pharmacodynamic profile.
Formulation approaches include both control of
release rate and certain physicochemical
properties of drugs like pH
pH-solubility
solubility profile of
drug.

18

07/09/2009

The

systems that are developed for class II

drugs
are
based
on
micronisation
micronisation,
lyophilization, addition of surfactants,
formulation as emulsions and microemulsions
systems, use of complexing agents like
cyclodextrins.

Class

III drugs require the technologies that

address to fundamental limitations of
absolute or regional permeability. Peptides
and proteins constitute the part of class III
and the technologies handling such materials
are on rise now days.

Class

IV drugs present a major challenge for

development of drug delivery system and the
route of choice for administering such drugs
is parenteral with the formulation containing
solubility enhancers

19