Dwi Nurahmanto

INTRODUCTION
Drug delivery systems mengacu pada penggunaan teknologi untuk
memberikan obat pada daerah tubuh yang diinginkan sebagai tempat
pelepasan obat dan penyerapannya.
Penemuaan baru dan kemajuan teknologi telah mengakibatkan
berbagai teknik baru dalam memberikan obat untuk kepatuhan pasien
yang maksimum dengan dsois dan efek yang minimal

IDEAL DRUG DELIVERY SYSTEM

Pertama, harus memberikan obat pada level yang ditentukan oleh

kebutuhan tubuh selama masa pengobatan.
Kedua harus memberikan zat aktif semata mata pada lokasi tempat aksi
yang dibutuhkan
Hal ini dicapai dengan pengembangan berbagai bentuk pelepasan obat
sediaan baru yang dimodifikasi sediaan baru, seperti
Control release dosage forms
Time release dosage forms
Sustained release dosage forms
Site specific or targeted drug delivery systems etc

SUSTAINED RELEASE DRUG DELIVERY:Salah satu bentuk

sediaan yang mempertahankan tingkat terapetik obat pada darah
ataupun jaringan dengan pelepasan obat berkelanjutan, dalam
jangka waktu lama (8-12 jam) segera setelah pemberian dosis
tunggal.
SITE SPECIFIC AND RECEPTOR TARGETING :
Mentargetkan obat langsung menuju lokasi biologis tertentu.
Lokasi pelepasan berdekatan dengan organ atau jaringan yang
sakit. Targetnya adalah reseptor obat tertentu pada suatu organ
atau jaringan
CONTROLLED RELEASE DRUG DELIVERY :Pengiriman
obat pada tingkat yang telah ditentukan dan atau ke lokasi yang
dibutuhkan pada tubuh dari daerah yang sakit untuk jangka
waktu tertentu (24 jam atau lebih) mengikuti orde nol

Lanjutan..
TIMED RELEASE OR DELAYED RELEASE: Sistem yang
pelepasannya berulang ulang pada waktu tertentu, sediaan berisi satu
atau lebih unit yang langsung di rilis dalam bentuk sediaan tunggal.
Sistem pelepasan tertunda dalam bentuk salut enterik yang akan
melepas obat yang sengaja di tunda smapai mencapai lingkungan usus.
REPEAT ACTION DOSAGE FORM: Mengandung 2 atau 3 dosis penuh
yang didesain sedemikian rupa sehingga dosis yang dirilis secara
berurutan satu demi satu.
OTHER NOVEL(NEW) DOSAGE FORMS:
termasuk-Mikrosper, Nanopartikel,, sistem Trans-dermal
pemberian obat pada mata, pemberian obat hidung,
Implan dll

COMPARISION OF DRUG RELEASE

PROFILES

Differences between sustained and

controlled drug delivery system
Sustained release
dosage form
Merupakan bentuk dosis
yang menyediakan obat
selama jangka waktu
SRDF umumnya tidak
mencapai kinetika rilis orde
nol
Biasanya tidak
mengandung mekanisme
untuk melepas obat pada
lokasi pada situs aktif.

Controlled release
dosage form
Merupakan bentuk sediaan
yang mempertahankan tingkat
obat konstan dalam darah atau
jaringan
Menjaga tingkat obat konstan
dalam jaringan target darah
biasanya dengan melepaskan
obat dalam pola orde nol.
Bentuk sediaan Terkendali
berisi metode untuk melepas
obat pada situs aktif.

Manfaat SRDF
Pengurangan fluktuasi tingkat darah dari obat,
sehingga manajemen lebih baik pada penyakit.
Pengurangan frekuensi dosis.
Peningkatan kenyamanan pasien dan kepatuhan.
Pengurangan efek samping (baik sistemik dan
lokal), mis. Obat poten, pada pasien yang sensitif.
Pengurangan biaya perawatan kesehatan.
Peningkatan efisiensi pengobatan.
Mengurangi tugas keperawatan dan waktu rawat
inap.
Bioavailabilitas maksimum dengan dosis minimum.

Lanj..

Minimalkan akumulasi obat dengan dosis

kronis.
Menyembuhkan atau mengendalikan kondisi
yang lebih cepat.
Tingkat darah konstan saat mencapai efek
yang diinginkan dan efek ini dipertahankan
untuk jangka waktu yang dimaksudkan.
Obat rentan terhadap inaktivasi enzimatik atau
dengan bakteri pengurai dapat dilindungi
dengan enkapsulasi dalam sistem polimer yang
cocok untuk SR.

Keterbatasan SRDF
Pemberian dosis obat rilis berkelanjutan tidak
mengizinkan penghentian segera terapi.
Perubahan drastis dalam obat jika diperlukan
selama terapi ketika efek samping yang signifikan
ditemukan tidak dapat dilakukan.
Dokter tidak memiliki fleksibilitas dalam
menyesuaikan regimen dosis
Bentuk sediaan pelepasan berkelanjutan yang
dirancang untuk populasi normal yaitu atas dasar
rata-rata waktu paruh biologis .
Proses yang lebih mahal dan peralatan yang
terlibat dalam pembuatan berbagai bentuk
sediaan pelepasan berkelanjutan.

Lanj..
Pembuangan dosis sulit.
Unpredictable dan miskin hubungan in vitro dan
in vivo
Jangka waktu pelepasan obat yang efektif
dipengaruhi dan dibatasi oleh waktu tinggal GI
Perlu pendidikan pasien tambahan. (Seperti
tidak mengunyah atau menghancurkan sediaan
sebelum menelan)
Obat memiliki t1/2 sangat singkat atau t1/2
yang sangat panjang adalah kandidat yang jelek
untuk bentuk sediaan pelepasan berkelanjutan.
Ex: diazepam.
Onset tertunda, maka kadang-kadang tidak
berguna dalam kondisi akut

 Pada awalnya, pemberian obat dengan sistem

terkontrol sesuai kebutuhak terapeutik
Diberikan lewat infus dengan sejumlah dosis yang
dibutuhkan
Dalam perkembangannya, SPOT dicapai melalui sistem
polimer
Bahan aktif terlarut atau terdispersi dalam polimer
Dalam formulasi harus paham terhadap faktor faktor
yang mempengaruhi kinetika pelepasan obat

Sasaran pelepasan obat

Merancang pelepasan obat dari sediaan yang
merupakan faktor yang menentukan kecepatan
ketersediaan hayati obat
Ketersediaan hayati ditentukan oleh kinetika pelepasan
dan absorbsi obat
Kunci pengembangan sediaan SPOT adalah sintesis
molekul bahan aktif yang dapat ditranspor melalui
material polimer disamping memahami pula variabel
yang mempengaruhi proses trasnpor obat (dalam
polimer)

Faktor Faktor kritis yang

mempengaruhi pelepasan solut
Difusi
Parameter membran dan matrik
Lingkungan resipien
Koefisien partisi
Kelarutan obat dalam polimer
Viskositas dan konsentrasi

difusi
Proses perpindahan masa individual molekul zat
melalui suatu membran yang dibawa oleh
gerakan acak molekul yang berkaitan dengan
gradien konsentrasi
Membran adalah lapisan tipis yang memisahkan
fasa
Material dapat melewati baik secara pasif
maupun aktif maupun transpor terfasilitasi

 Transpor suatu obat melalui membran polimer melibatkan

disolusi obat dalam matrik membran dan merupakan
contoh sederhana difusi molekuler
Repersentasi membran pada skala molekuler adalah
untaian polimer yang tersusun seperti keset, dengan
cabang dan saluran saling berpotongan
Molekul dapat melewati pori yang terbentuk oleh susunan
polimer tergantung pada ukuran dan bentuk molekul yang
berdifusi
Jika ukuran solut terlalu besar untuk transport melalui
saluran, maka zat harus larut dalam matriks polimer dan
lewat secara difusi pasif sederhana

Hukum ficks pertama

Jumlah M bahan (material) yang mengalir
melalui suatu penghalang dengan diameter S
dalam waktu tertentu t dikenal dengan fluks J
J = dM/S.dt
Fluks berbanding lurus dengan gradien
konsentrasi dC/dx
J = -D dc/dx

 Proses difusi obat melalui matriks obat

sehingga obat tersebut dapat terabsorbsi
kedalam pembuluh darah manusia
Difusi berpengaruh pada proses pelepasan
obat serta ketersediaan hayati obat
tersebut

Parameter membran dan matrik

Sediaan SPOT terdiri dari dua komponen obat
dan matrik (membran)
Luas permukaan , geometri dan ketebalan
membran memegang peranan penting pada
kinetika pelepasan
Parameter parameter ini umumnya dapat
disesuaikan untuk mengatur kecepatan
pelepasan
Membran digunakan sebagai sistem reservoir
dengan larutan pekat obat didalamnya

Lingkungan resipien
Dalam keadaan mantap, kecepatan difusi dari
agen terapetik dalam sediaan berbentuk sistem
matrik dan membran secara porposional
berbanding terbalik dengan jumlah resistensi
difusi individual termasuk membran, matrik dan
lapisan perbatasan
Difusi lapisan perbatasan tidak dapat diabaikan
apabila besarnya sebanding dengan resistensi
difusi lain

 Untuk meneliti efek lingkungan

resipien terhadap kinetika sistem
matrik atau membran dapat dilakukan
secara kuantitatif menggunakan alat
permeasi 2 sel (horizontal)

Koefisien partisi
Permeasi bukan hanya karena difusifitas, tapi
juga karena distribusi solut antara polimer dan
cairan resipien di sekitarnya
Koefisien permeabilitas suatu obat dalam
polimer, secara konvensional didefinisikan
sebagai koefisien difusi obat dalam polimer dan
cairan resipien.
K = Cb*/Cb
Cb* dan Cb adalah kelarutan obat dalam
polimer dan dalam ruahan lariutan.

Kelarutan obat dalam polimer

Kelarutan obat dalam sistem polimer merupakan
pertimbangan penting dalam formulasi obat
Jika dua obat dengan dosis sama yang satu larut dan
yang lainnya tidak larut, kecepatan pelepasan obat
lebih baik bagi obat yang tidak larut

Viskositas dan konsentrasi

Ada hubungan fungsional antara viskositas dan
kecepatan disolusi tergantung pada
hidrodinamik sistem yang digunakan selama
eksperimen
Konsentrasi dan viskositas bervariasi pada
lapisan perbatasan
Variasi viskositas pada lapisan perbatasan sering
terjadi pada disolusi obat yang sangat larut dan
masalah yang terkait dengan difusi menjadi
sangat sulit

VARIOUS MECHANISMS OF
MEDICAMENT RELEASE
Diffusion is rate limiting
Diffusion is driving force where the movement of
drug molecules occurs from high concentration
in the tablet to lower concentration in gastro
intestinal fluids. This movement depends on
surface area exposed to gastric fluid, diffusion
pathway, drug concentration gradient and
diffusion coefficient of the system

 In practice, we can follow either of the two methods,

a) The drug is formulated in an insoluble matrix; the
gastric fluid penetrates the dosage form and dissolves
the medicament and release the drug through diffusion.
b) The drug particles are coated with polymer of defined
thickness so as the portion of drug slowly diffuse
through the polymer to maintain constant drug level in
blood

 Dissolution is rate limiting

The drugs with poor water solubility (BCS class 2 and 4) are
inherently sustained release forms. While for water soluble
drugs, its possible to incorporate a water insoluble carrier to
reduce dissolution of the drug particles are coated with this
type of materials e.g. Polyethylene Glycol. One may skip the
use of disintegrating agent to promote delayed release

 Osmotic pressure is rate limiting

Osmosis is a phenomenon in which the flow of liquid occurs from
lower concentration to higher concentration through a semi
permeable membrane which allows transfer of liquid only. The
whole drug is coated with a semi permeable membrane with a hole
on one end of tablet made by a laser beam. The gastric fluid
penetrates through the membrane, solubilizes the drug and increases
the internal pressure which pumps the drug solution out of the
aperture and releases the drug in gastric environment. The delivery
rate is constant provided that the excess of drug present inside the
tablet. But, it declines to zero once the concentration drops below
saturation

 Release is controlled by ion exchange

Ion exchangers are water insoluble resinous materials
containing salt forming anionic or cationic groups. While
manufacturing, the drug solution is mixed with resin and
dried to form beads which are tableted. The drug release
depends upon high concentration of charged ions in gastro
intestinal tract where, the drug molecules are exchanged
and diffused out of the resin into the surrounding fluid.
This mechanism relies upon the ionic environment of resin
and not pH or enzyme on absorption site

Drug properties relevant to sustained

release formulation
The design of sustained release delivery system is subjected to
several variables and each of variables are inter-related.
For the purpose of discussion it is convenient to describe the
properties of the drugs as being either physico-chemical or
biological ,these may be divided in two types.
1. Physicochemical properties
2. Biological properties

Factors to be considered In S.R.Dosage forms.

1.Biological Factors
1. Absorption.
2. Distribution.
3. Metabolism.

Physiological Factors:
1. Dosage size.
2. Partition coefficient and
molecular size.
3.

Aqueous Solubility.

4. Biological half life. 4. Drug stability.

(excreation)
5. Protein binding.
5. Margin of safety

6. Pka

Biological Factors
Absorption.
Absorption of drug need dissolution in fluid before it reaches to
systemic circulation. The rate, extent and uniformity in absorption
of drug are important factor when considering its formulation in to
controlled release system. Absorption= dissolution
The characteristics of absorption of a drug can be greatly effects
its suitability of sustained release product. The rate of release is
much slower than rate of absorption. The maximum half-life for
absorption should be approximately 3-4 hr otherwise, the device
will pass out of potential absorptive region before drug release is
complete.
Compounds that demonstrate true lower absorption rate constants
will probably be poor candidates for sustaining systems.

The rate, extent and uniformity of absorption of a drug are

important factors considered while formulation of sustained
release formulation. As the rate limiting step in drug delivery from a
sustained-release system is its release from a dosage form, rather
than absorption.
It we assume that transit time of drug must in the absorptive
areas of the GI tract is about 8-12 hrs.
If the rate of absorption is below 0.17/hr and above the
0.23/hr then it is difficult to prepare sustained release formulation.
an another important criteria is the through absorption of drug in
GIT tract, drug like Kanamycine and gentamycine shows absorption
are different sites, Riboflavin like drug absorbed effectively by
carrier transport and at upper part of GIT that make it preparation
in SRDF difficult.

As the rate limiting step in drug delivery from a

sustained-release system is its release from a dosage form,
rather than absorption. Rapid rate of absorption of drug,
relative to its release is essential if the system is to be
successful.

Distribution:
The distribution of drugs into tissues can be important factor in
the overall drug elimination kinetics.
Since it not only lowers the concentration of drug but it also can
be rate limiting in its equilibrium with blood and extra vascular
tissue, consequently apparent volume of distribution assumes
different values depending on time course of drug disposition.
For design of sustained/ controlled release products, one must
have information of disposition of drug.

Two parameters that are used to describe distribution

characteristics are its apperent volume of distribution and the ratio
of drug concentration in tissue that in plasma at the steady state the
so- colled T/P ratio.
The apparent volume of distribution Vd is nearly a proportional
constant that release drug concentration in the blood or plasma to
the amount of drug in the body. In case of one compartment model
Vd = dose/C0
Where:
C0= initial drug concentration immediately after an IV bolus
injection
In case of two compartment model.

Metabolism:
There are two areas of concern relative to metabolism that
significantly restrict sustained release formulation.
1.If drug upon chronic administration is capable of either inducing
or inhibition enzyme synthesis it will be poor candidate for
sustained release formulation because of difficulty of maintaining
uniform blood levels of drugs.
2. If there is a variable blood level of drug through a first-pass
effect, this also will make preparation of sustained release product
difficult.
Drug that are significantly metabolized before absorption, either in
lumen of intestine, can show decreased bio-availability from
slower-releasing dosage forms.

Most intestinal wall enzymes systems are saturable. As

drug is released at a slower rate to these regions less total
drug is presented to the enzymatic. Process device a
specific period, allowing more complete conversion of the
drug to its metabolite.

Biological half life.

The usual goal of sustained release product is to maintain
therapeutic blood level over an extended period, to this drug must
enter the circulation at approximately the same rate at which it is
eliminated. The elimination rate is quantitatively described by the
half-life (t1/2)
Therapeutic compounds with short half life are excellent
candidates for sustained release preparation since these can reduce
dosing frequency.

Drugs with half-life shorter than 2 hours. Such as e.g.:

Furosemide, levodopa are poor for sustained release
formulation because it requires large rates and large dose
compounds with long half-life. More than 8 hours are
also generally not used in sustaining forms, since their
effect is already sustained.
E.g.; Digoxin, Warfarin, Phenytoin etc.

e) Margin of safety:
In general the larger the volume of therapeutic index
safer the drug. Drug with very small values of therapeutic
index usually are poor candidates for SRDF due to
pharmacological limitation of control over release rate
.e.g.- induced digtoxin, Phenobarbital, phenotoin.

= TD50/ED50

Larger the TI ratio the safer is drug.

It is imperative that the drug release pattern is precise so
that the plasma drug concentration achieved in under
therapeutic range.

2. Physiological Factors:
a) Dosage size.
b) Partition coefficient and molecular size.
c) Aqueous Solubility.
d)Drug stability.
e) Protein binding.
f) Pka

1.Dosage size.
In general a single dose of 0.5 - 1.0 gm is considered for a
conventional dosage form this also holds for sustained release
dosage forms.
If an oral product has a dose size greater that 500mg it is a poor
candidate for sustained release system, Since addition of sustaining
dose and possibly the sustaining mechanism will, in most cases
generates a substantial volume product that unacceptably large.

2. Partition coefficient and molecular size.

When the drug is administered to the GIT ,it must cross a variety
of biological membranes to produce therapeutic effects in another
area of the body.
It is common to consider that these membranes are lipidic,
therefore the Partition coefficient of oil soluble drugs becomes
important in determining the effectiveness of membranes barrier
penetration.
Partition coefficient is the fraction of drug in an oil phase to that
of an adjacent aqueous phase.

High partition coefficient compound are predominantly lipid

soluble and have very low aqueous solubility and thus these
compound persist in the body for long periods.
Partition coefficient and molecular size influence not only the
penetration of drug across the membrane but also diffusion across
the rate limiting membrane
The ability of drug to diffuse through membranes its so called
diffusivity & diffusion coefficient is function of molecular size (or
molecular weight).
Generally, values of diffusion coefficient for intermediate
molecular weight drugs, through flexible polymer range from 10-8 to
10-9 cm2 / sec. with values on the order of 10-8 being most common
for drugs with molecular weight greater than 500.

Thus high molecular weight drugs or polymeric

drugs should be expected to display very slow
release kinetics in sustained release device using
diffusion through polymer membrane.
Phenothiazines are representative of this type of
compound

3.Aqueous Solubility.
Since drugs must be in solution before they can be absorbed,
compounds with very low aqueous solubility usually suffer oral
bioavailability Problems, because of limited GI transit time of
undissolved drug particles and limited solubility at the absorption
site.
E.g.: Tetracycline dissolves to greater extent in the stomach than in
the intestine, there fore it is best absorbed in the intestine.
Most of drugs are weak acids or bases, since the unchanged form
of a drug preferentially permeates across lipid membranes drugs
aqueous solubility will generally be decreased by conversion to an
unchanged form. for drugs with low water solubility will be
difficult to incorporate into sustained release mechanism.

Aqueous solubility and pKa

These are the most important to influence its absorptive behavior
and its aqueous solubility ( if its a weak acid or base) and its
pKa
The aqueous solubility of the drug influences its dissolution rate
which in turn establishes its concentration in solution and hence
the driving force for diffusion across the membranes as shown by
Noyes Whitneys equation which under sink condition that is
dc/dt= Kd.A.Cs
Where dc/dt = dissolution rate
Kd= dissolution rate constant
A = total surface area of the drug particles
Cs= aqueous solubility of the drug

Dissolution rate (dc/dt) is constant only when Surface Area A is

the initial rate is directly proportional to the Aqueous solubility
(Cs) hence Drug with low aqueous solubility have low dissolution
rate and its suffer low bioavailability problem.
The aqueous solubility of weak acid and bases are controlled by
pKa of the compound and pH the medium.
For weak acids
St= So(1+Ka/H+) = So (1+10pH-pKa )
Where St = total solubility of weak acid.
So = solubility of unionized form
Ka= Acid dissociation constant
H+= H ion concentration

Similarly for Weak Bases

St = So (1+H+/Ka) = So (1+10pKa-pH )
if a poorly soluble drug was consider as a suitable candidate for
formulation into sustained release system.
Since weakly acidic drugs will exist in the stomach pH 1-2 ,
primarily in the unionized form their absorption will be favored
from this acidic environment on the other hands weakly basic drugs
will be exist primarily in the ionized form (Conjugate Acids) at the
same site, their absorption will be poor.
in the upper portion of the small intestine the pH is more alkaline
pH 5-7 and the reverse will be expected for weak acids

4.Drug stability.
The stability of drug in environment to which it is exposed, is
another physico-chemical factor to be considered in design at
sustained/ controlled release systems, drugs that are unstable in
stomach can be placed in slowly soluble forms or have their release
delayed until they reach the small intestine.
Orally administered drugs can be subject to both acid, base
hydrolysis and enzymatic degradation. Degradation will proceed at
the reduced rate for drugs in the solid state, for drugs that are
unstable in stomach, systems that prolong delivery ever the entire
course of transit in GI tract are beneficial.

Compounds that are unstable in the small intestine may

demonstrate decreased bioavailability when administered form a
sustaining dosage from. This is because more drug is delivered in
small intestine and hence subject to degradation.
However for some drugs which are unstable in small intestine are
under go extensive Gut Wall metabolism have decreased the bio
availability .
When these drugs are administered from a sustained dosage form
to achieve better bio availability, at different routes of the drugs
administered should be chosen
Eg. Nitroglycerine
The presence of metabolizing enzymes at the site or pathway can
be utilized.

5.Protein binding.
It is well known that many drugs bind to plasma protein with the
influence on duration of action.
Drug-protein binding serve as a depot for drug producing a
prolonged release profile, especially it is high degree of drug
binding occurs.
Extensive binding to plasma proteins will be evidenced by a long
half life of elimination for drugs and such drugs generally most
require a sustained release dosage form. However drugs that exhibit
high degree of binding to plasma proteins also might bind to biopolymers in GI tract which could have influence on sustained drug
delivery. The presence of hydrophobic moiety on drug molecule
also increases the binding potential.

The binding of the drugs to plasma proteins(eg.Albumin) results

in retention of the drug into the vascular space the drug protein
complex can serves as reservoir in the vascular space for sustained
drug release to extra vascular tissue but only for those drugs that
exhibited a high degree of binding.
The main force of attraction are Wander-vals forces , hydrogen
binding, electrostatic binding.
In general charged compound have a greater tendency to bind a
protein then uncharged compound, due to electrostatic effect.
Eg amitryptline,
novobiocin.

cumarin,

diazepam,

digoxide,

dicaumarol,

6.Pka: (dissociation constant)

The relationship between Pka of compound and absorptive
environment, Presenting drug in an unchanged form is
adventitious for drug permeation but solubility decrease as the
drug is in unchanged form.
An important assumption of the there is that unionized form of the
drug is absorbed and permeation of ionized drug is negligible, since
its rate of absorption is 3-4 times lesser than the unionized form of
the drug.
The pka range for acidic drug whose ionization is PH sensitive and
around 3.0- 7.5 and pka range for basic drug whose ionization is ph
sensitive around 7.0- 11.0 are ideal for the optimum positive
absorption