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SISTEM PENGHANTARAN OBAT

PARENTERAL
(Parenteral Drug Delivery System)

HENNI ROSAINI, S.Si,M.Farm.


Parenteral

The term parenteral derived from the Greek


words:
para (outside = disamping)
enteron, (intestine = usus)
sesuatu yang diberikan di luar usus dan tidak
melalui saluran cerna
denotes routes of administration other than oral
route.
refers to the injectable routes administration.
sterile
PENDAHULUAN
PENDAHULUAN
Efek terapi obat tergantung pada metoda /sistem
penghantarannya, salah satunya secara parenteral.

Ada beberapa cara penghantaran obat parenteral,


antara lain:
1. Intra vena
2. Intra muskular
3. Sub kutan
4. Intra dermal
5. Intra arteri
 Intra dermal
disebut juga intra kutan. Pemakaiannya dibawah
lapisan kulit.
Volume penyuntikkan yang diberikan sangat kecil,
yaitu 0,1 mL.
Absorbsi lambat. Biasanya hanya digunakan untuk
diagnosa dan sejumlah kecil vaksin.

 Sub kutan
pemakaiannya pada bagian hypodermis. Volume
penyuntikkan yang diberikan sangat kecil.
 Intra muskular
injeksi ke lapisan otot. Volume 2 mL, maks. 5 mL.
absorpsi lebih cepat daripada s.c
Absorpsi dapat diperlama dengan mengubah
bentuk sediaan dan pembawanya
 Intra vena
efek cepat, volume besar.
Sangat berbahaya karena obat yang sudah
diberikan tidak dapat ditarik kembali
 Intra arteri
rute ini tidak sering digunakan. Obat yang
diberikan akan langsung menuju organ tertentu.
Biasanya digunakan untuk diagnosa
Parenterals are Administered by:

• Physician
• Physician’s assistant
• Nurse

Parenterals are Administered at:

Hospitals
Clinics
Extended care facilities
Persyaratan sediaan parenteral :
steril dan bila disuntikkan dalam
jumlah lebih dari 5 atau 10 ml haruslah
bebas dari pirogen

Sediaan parenteral dapat berupa :


a. Larutan bekerja lebih cepat dari
bentuk suspensi
b. Suspensi
c. Serbuk
Jenis
Jenis sediaan
sediaan parenteral
parenteral ::
1.1. Larutan
Larutan :: -- air
air
-- air-pelarut
air-pelarut organik
organik
-- minyak
minyak
2.
2. Suspensi
Suspensi :: -- air
air
-- minyak
minyak
3.
3. Emulsi
Emulsi :: -- m/a
m/a
-- a/m
a/m
-- multiple
multiple (m/a/m,
(m/a/m, a/m/a)
a/m/a)
4.
4. Implants
Implants (pellet)
(pellet)
 Produk
Produk harus
harus memenuhi
memenuhi persyaratan
persyaratan secara
secara
farmasetika;
farmasetika; diterima
diterima oleh
oleh konsumen
konsumen
Solvents and Vehicles for Injections

1. Water for Injection, USP


• This water is purified by distillation or by reverse osmosis.

• Water for Injection is not required to be sterilized, it


must be pyrogen free.

2. Purified water, USP


• may not contain other substances and
• meets standard for the presence of total solids

3. Sterile Water for Injection, USP


• is water for injection which has been sterilized and
packaged in single-dose containers of not greater than 1 L
size.
• as water for Injection, it must be pyrogen free and may
Solvents and Vehicles for Injections

4. Bacteriostatic Water for Injection, USP


• is sterile water for injection containing one or
more suitable anti-microbial agents.
• it is packaged in pre-filled syringes or in vials
containing not more than 30 mL of the water.
Label must state, “Not for use in Newborns”.
Example: benzyl alcohol - not good for neonates and
the toxicity of the bacteriostat.
5. Sodium Chloride Injection, USP
a sterile isotonic solution of sodium chloride in Water
for Injection.
It contains no anti microbial agents
Solvents and Vehicles for Injections

6. Bacteriostatic Sodium Chloride Injection


– is a sterile isotonic solution of sodium chloride in Water for
Injection. It contains one or more suitable antimicrobial
agents which must be specified in the label.
– Sodium chloride concentration is 0.9% to render isotonic
solution. It is also used to flush a catheter or IV line to
maintain its patency.. “Not for use in Newborns”.

7. Ringer’s Injection, USP


– is a sterile solution of sodium chloride, potassium chloride,
and calcium chloride in water for injection.
– It is used as electrolyte replenisher and a systemic alkalizer.
– Lactated R = Na lactate
BACTERIOSTATIC WATER SODIUM
CHLORIDE INJECTION, USP;
POTASSIUM CHLORIDE

SODIUM CHLORIDE
INJECTION, USP STERILE WATER FOR
INJECTION, USP
BACTERIOSTATIC WATER FOR
INJECTION, USP
Examples of Nonaqueous Solvents

1. Fixed vegetable oils


2. Glycerin
3. Polyethylene glycols
4. Propylene glycol
5. Ethyl oleate
6. Isopropyl myristate
7. Methylacetamide
8. Alcohol
Examples of Nonaqueous Solvents

Examples of Fixed Oils Commonly Used in


Injections:
1. Corn Oil
2. Cottonseed seed Oil
3. Peanut Oil
4. Sesame Oil
5. Castor Oil and Olive Oil (occasion)
Such substances include:

1. Solubilizers
2. Chelating agents
3. Anti-microbial agents
4. Hydrolysis Inhibitors
5. Antioxidants
6. Buffers
7. Tonicity contributors
8. Antifoaming agents
Kelebihan Sistem Penghantaran Parenteral

1. Tidak melalui proses absorbsi


2. Tidak mengalami first pass effect
3. Onset sangat cepat, terutama pemberian iv
4. Obat tidak melalui Gastrointestinal, sehingga tidak
dirusak oleh asam lambung dan enzim
Kelemahan Sistem Penghantaran Parenteral

1. Efek kerja untuk waktu yang singkat


2. Diperlukan frekwensi pemakaian yang sering
3. Memerlukan alat khusus (injeksi)
4. Menimbulkan rasa sakit pada saat pemakaian,
sehingga menimbulkan rasa tidak nyaman pada pasien
5. Memerlukan bantuan tenaga medis
Kelebihan Sistem Penghantaran Parenteral

1. Tidak melalui proses absorbsi


2. Tidak mengalami first pass effect
3. Onset sangat cepat, terutama pemberian iv
4. Obat tidak melalui Gastrointestinal, sehingga tidak
dirusak oleh asam lambung dan enzim
Untuk mengurangi frekwensi pemakaian, digunakan
cara infus i.v , dimana
a. Konsentrasi obat dalam darah dapat
dipertahankan selama waktu yang diinginkan
b. Obat tidak melalui first pass metabolism
c. Obat tidak dirusak oleh asam lambung dan
enzym pencernaan

 Cara ini menyakitkan bagi pasien dan harus


dibawah pengawasan dokter (pasien rawat inap
di RS)

 Untuk mengatasi masalah ini, dibuat sistem


lepas lambat untuk rute parenteral
 pengembangan formula
(modifikasi sistem penghantaran)
sistem depo ; controled release
contoh: penisilin G-prokain (suspensi)
levonorgestrol (implant sub
dermal)
Intravenous Route (IV)
INTRAVENOUS
Intravenous Route (iv)
Intravenous Route (iv)

Advantage:
May be a life-saving procedure because of the placement
of the drug directly into the circulation and the prompt
actions which ensues.

Disadvantage:
• Once the drug administered, it cannot be retrieved.
• In the case of adverse reaction to the drug, for instance,
the drug cannot be easily removed from the circulation.

Precautions:
• Strict aseptic precautions must be taken at all times to
avoid risk of infection.
• The syringes and needles used must be sterilized and to
the point of entrance must be disinfected to reduce
chance of carrying bacteria from the skin into the blood
via the needle
Intravenous Route (IV)

Flow Rates:
• Generally, the flow rates of IV are expressed in mL/hour,
• Range from 42 to 150 mL/hour.
• Lower rates are used for keep-open (KO, KVO)
• Great care must be taken to prevent overdosing or
underdosing.

Example:
• Metoprolol (beta blocker)
– 3 bolus injections of 5 mg each at about 2-minute
intervals;
– oral dosing (100 mg/day)
Intravenous Route (IV)

• Not only are the injectable solutions sterile,


syringes, needles must also be disinfected to
reduce the chance of carrying bacteria
• A backflow of blood into the administration set or
syringe indicates proper placement of the needle
in the vein
• Intravenous drugs ordinarily must be aqueous
solution;
they must mix with the circulating blood and not
precipitate from solution. Such an event can lead
to pulmonary micropillary occlusion and blockage of
blood flow.
Intravenous Route (IV)

Intravenous fat emulsions


– Intralipid, 10,20,30%
– Clintec
– Liposyn 11,10, 20%
– Abott Liposyn 111, 10,20,30%

• as a source of calories and essential fatty acids


for patients requiring parenteral nutrition for
extended period, usually more than 5 days.

• The product contains up to:


30% soybean oil emulsified with eggyolk
phospholipids in a vehicle of glycerin in water
injection
Hazard Of Intravenous Injection

 The possibility of thrombus formation


– induced by the touching of the wall of the vein by
the catheter or needle.

 Thrombus
– is a blood clot formed within the blood vessel (or
heart) due usually to a slowing of the circulation or
to an alteration of the blood or vessel wall.

 Once such a blot circulates, it becomes an Embolus


– carried by the blood stream until it lodges in a
blood vessel, obstructing it, and resulting in
blockage or occlusion referred to as an Embolism.
Intramuscular (im)
Intramuscular (im)

• Intramuscular injections of drugs provide effects


that are less rapid, but generally of greater
duration than those obtained from intravenous
administration

• i.m are performed deep into the skeletal muscles.

• The point of injection should be as far as possible


from major nerves and blood vessels.

• Injuries to patients from i.m injection usually are


related to the point at which the needle entered
and where the medication was deposited.
Intramuscular (im)

Such injuries include:


1. Paralysis resulting from neural damage
2. Abscesses
3. Cysts
4. Embolism
5. Hematoma
6. Sloughing of the skin
7. Scar formation
Adult – upper outer quadrant of the gluteus maximus
Infants– gluteal area is small, composed primarily
fats not muscle, so not recommended
Infants and Young children
– deltoid, muscles of the upper arm or the
midlateral muscles of the thigh
Intramuscular (IM)

Volume of Administration:
• limited :
– 5 mL in the gluteal region
– 2 mL in the deltoid of the arm.
• Injection is 2 to 3 inches deep
• 20 to 22 gauge needle.
• To avoid staining: it must be injected only
into the muscle mass of the upper outer
quadrant of the buttock.
Intramuscular (IM)

a. The skin is displaced laterally, then needle


inserted and syringe aspirated, and injection
performed slowly and smoothly. The needle
is then withdrawn and the skin release. This
create a “Z” pattern that blocks infiltration of
medication into subcutaneous tissue.
b. The Z-Track Injection techniques is useful
for i.m injections of medications that stain
upper tissue.

Examples:
Iron dextran injection –irritate tissues
Diazepam (Valium) – by sealing in the lower
muscle
Subcutaneous delivery (sc)
Subcutaneous Route (sc)

• May be utilized for


the injection of small amounts of medication or of
drugs beneath the surface of the skin of the
1.upper arm,
2.the anterior surface of the thigh, and the
3.lower portion of the abdomen.
• The site of injection is usually rotated when
injections are frequently given, as with daily insulin
injection.
• The maximum amount of drug given sc is about 1.3mL
• Amounts greater than 2 mL will most likely cause
painful pressure.
Subcutaneous Route (SC)

• Syringes: up to 3 mL capacities
• Utilizing needles: 24 to 26 gauges
• SC insulin needles:
– gauge between 25 to 30
– needle length between 5-16 to 5-8 inch.
• Upon insertion, if blood appears in the syringe, a new
site should be selected.
• Irritating drugs and those in thick suspension may
produce
– induration, sloughing, or abscess and may be
painful. Such preparations are not suitable for
subcutaneous injection
Official Types of Injections

Insulin Injection, USP PROPOFOL

Methylprednisolone
Acetate Suspension
Biofarmasetika sediaan
Biofarmasetika sediaan

Pelepasan zat aktif


Pelepasan zat aktif

Transpor dari lokasi penyuntikan


Transpor dari lokasi penyuntikan

Sirkulasi sistemik
Sirkulasi sistemik

Penghantaran menuju jaringan sasaran


Penghantaran menuju jaringan sasaran
Kriteria yang harus diperhatikan pada pemberian
Kriteria yang harus diperhatikan pada pemberian
sediaan:
sediaan:
1. Laju dan kecepatan absorbsi
1. Laju dan kecepatan absorbsi
2. Volume total obat yang diberikan
2. Volume total obat yang diberikan
3. Frekuensi pemberian
3. Frekuensi pemberian
4. Kemungkinan iritasi, keasaman/basa dan
4. Kemungkinan iritasi, keasaman/basa dan
konsentrasi
konsentrasi
5. Iritasi lokal pada jaringan, kerusakan saraf
5. Iritasi lokal pada jaringan, kerusakan saraf
6. Usia dan kondisi fisiologi pasien
6. Usia dan kondisi fisiologi pasien
Kriteria minyak sebagai pembawa untuk formula sediaan
Kriteria minyak sebagai pembawa untuk formula sediaan
injeksi:
injeksi:
a. Komposisi minyak stabil dan netral secara kimia
a. Komposisi minyak stabil dan netral secara kimia
(mengandung minimal asam lemak). Tidak
(mengandung minimal asam lemak). Tidak
berinteraksi dengan obat
berinteraksi dengan obat
b. Secara fisika tidak terlalu kental, sehingga dapat
b. Secara fisika tidak terlalu kental, sehingga dapat
melalui jarum yang digunakan untuk mengaplikasikan
melalui jarum yang digunakan untuk mengaplikasikan
obat (stabil pada suhu tinggi & rendah)
obat (stabil pada suhu tinggi & rendah)
c. Inert dan tidak mengiritasi secara biologi. Cepat
c. Inert dan tidak mengiritasi secara biologi. Cepat
diabsorpsi dari tempat injeksi & tidak meninggalkan
diabsorpsi dari tempat injeksi & tidak meninggalkan
residu
residu
Sifat fisikokimia formula yang mempengaruhi
absorbsi obat:
1. Kelarutan obat dalam pembawa/pelarut
2. Ukuran partikel
3. Sifat kristal
4. pH formula
5. pKa obat
6. Lipofil / hidrofil
7. Koefisien partisi obat dalam pembawa dan dalam
jaringan
8. Interaksi obat dengan bahan tambahan
9. Kelarutan obat dalam cairan biologi di tempat
injeksi
10. Keadaan fisiologi di sekitar tempat injeksi
(misalnya aliran darah)
Ada beberapa teknik pembuatan sediaan lepas lambat
parenteral :
1. Membuat sediaan dengan viskositas tinggi
menggunakan pembawa yang dapat bercampur
dengan air, seperti gelatin dan PVP
2. Menggunakan pembawa yang tidak bercampur
dengan air (minyak sayur) dan bahan penolak air
(aluminium monostearat)
3. Suspensi tiksotropik
4. Pembuatan derivat obat yang tidak larut dalam air
(bentuk kompleks, bentuk ester)
5. Mendispersikan obat dalam polimer mikrosphere
dan mikrokapsulasi (pemilihan polimer)
6. Menambahkan vasokonstriktor
Depot obat dapat diklasifikasikan berdasarkan proses
Depot obat dapat diklasifikasikan berdasarkan proses
yang digunakan untuk mengatur proses pelepasan
yang digunakan untuk mengatur proses pelepasan
obat, yaitu:
obat, yaitu:
a. Dissolution-controlled depot formulations
a. Dissolution-controlled depot formulations
b. Adsorption-type depot preparations
b. Adsorption-type depot preparations
c. Encapsulation-type depot preparations
c. Encapsulation-type depot preparations
d. Esterification-type depot preparations
d. Esterification-type depot preparations
Dissolution-controlled depot formulation

Mengatur pelepasan obat dengan memperlambat


disolusi partikel obat (slow dissolution) dalam
sediaan atau cairan jaringan tempat obat
terlarut

Faktor yang mempengaruhi pelepasan obat yaitu:


a. Luas permukaan partikel,
b. Koefisien difusi obat dalam medium,
c. Kelarutan partikel dalam medium,
d. Ketebalan lapisan difusi hidrodinamik disekitar
partikel obat
Cara yang dapat dilakukan untuk memperlambat
disolusi obat:
1. Pembentukan garam atau senyawa kompleks yang
kelarutannya dalam air kecil (senyawa asam/basa
yang kelarutan tinggi dalam air dapat berperan
sebagai depot yang efektif apabila dirubah menjadi
bentuk garam yang kelarutannya lebih rendah).
Contoh: Penicillin G-procain; Penicillin G-benzathine;
Naloxone pamoat; Naltrexone-Zn-tannat
2. Pembentukan suspensi makrokristal;
bentuk kristal yang besar akan lebih lambat larut
dibanding kristal berukuran kecil (suspensi) →
kontrol disolusi.
Contoh: Suspensi Testosteron isobutyrat dalam air
(im), dietilstilbestrol monokristal (sc)
Adsorption-type depot preparations
a. Preparasi melalui pengikatan molekul obat pada
adsorben, dimana molekul yang diabsorbsi berada
dalam keadaan bebas (tidak terikat)
b. Sesaat setelah molekul obat bebas diserap, maka
fraksi yang terikat dilepaskan untuk mencapai
keseimbangan
c. Keadaan keseimbangan ditentukan oleh;
jumlah obat yang diabsorbsi (mg) dalam 1 g adsorben
jumlah maks obat yang diserap oleh adsorben (1 g)
contoh: preparasi sediaan vaksin (mengikatkan
antigen pada gel aluminium hidroksida untuk
mempertahankan pelepasan dan memperpanjang
stimulasi pembentukan antibodi)
Encapsulation-type depot preparations

a. Preparasi melalui pembentukan sistem enkapsulasi


sediaan padat dengan membran permeasi atau
dispersi partikel pada matriks difusi
b. Sistem permeasi membran maupun matriks difusi
tersusun atas senyawa makromolekul yang
biodegradable/bioabsorbable (gelatin, dekstran,
polilaktat, dll).
Contoh: naltrexone pamoate (microcapsulae),
liposome
c. Pelepasan molekul obat dikontrol oleh laju
permeasi pada perlintasan membran dan laju
biodegradasi membran makromolekul
Esterification-type depot preparations

a. Preparasi melalui proses esterifikasi obat dan


membentuk prodrug tipe ester yang
bioconvertible , kemudian diformulasikan dalam
formula injeksi
b. Laju absorbsi obat dikontrol oleh interfacial
partitioning molekul ester dari sediaan dengan
cairan jaringan dan laju bioconversion senyawa
ester untuk menghasilkan molekul obat yang aktif
Contoh: testosteron dalam pembawa minyak,
nandrolone decanoate
Injeksi lepas lambat sudah digunakan untuk
memformulasi:
1. Penicillin
2. Insulin
3. Vitamin B12
4. Steroid
5. Hormon adrenocorticotropik
6. Antipsychotic
7. Kontrasepsi
8. Antimalaria
9. Antinarkotik
CLASSIFICATION

IMPLANTS
INJECTABLES INFUSION DEVICES

Solutions Osmotic Pumps


Suspensions and Emulsions Vapor Pressure
Microspheres and Microcapsules Powered Pumps
Nanoparticles and Niosomes Intraspinal Infusion Pumps
Liposomes Intrathecal Infusion Pumps
Resealed
Erythrocytes
Injections

• Generally, if a drug is unstable in solution, it may be


prepared as a dry powder intended for reconstitution
with the proper solvent at the time of administration
• If the drug is unstable in water, the solvent may be
replaced in part or totally by a solvent in which the
drug is insoluble
• If the drug is insoluble in water, an injection may be
prepared as an aqueous suspension or as solution in a
suitable nonaqueous solvent, such as a vegetable oil
• If an aqueous solution is desired, a water soluble salt
form of the insoluble drug is frequently prepared
• Aqueous or blood miscible solutions may be injected
directly into the blood stream
Injections

• Blood immiscible liquids, such as oleaginous


injections and suspensions can interrupt
the normal flow of blood, and their use is
generally restricted to other than
intravenous administration
• Often times long action is desired to
reduce the frequency of injections.
• These long acting injections are called
respiratory or depot preparations
Advantages over conventional drug delivery
system

 Improved patient convenience and compliance.

 Reduction in fluctuation in steady-state levels.

 Increased safety margin of high potency drugs.

 Maximum utilization of drug.

 Reduction in health care costs through improved


therapy, shorter treatment period, less frequency
of dosing
Disadvantages of controlled release dosage
forms

 Decreased systemic availability

 Poor in vitro-in vivo correlation

 Possibility of dose dumping.

 Retrieval of drug is difficult in case of toxicity, poisoning or


hypersensitivity reactions.

 Reduced potential for dosage adjustments.

 Higher cost of formulations.


CHARACTERISTICS

• Free from living microbes


• Free from microbial products such as pyrogens
• Should match the osmotic nature of the blood
• Free from chemical contaminants
• Matching specefic gravity
Polymer membrane permeation controlled DDS

• Reservoir is solid drug or


dispersion of solid drug in
liquid or solid medium.

• Drug enclosed in reservoir and


reservoir is enclosed in rate
limiting polymeric membrane.
nonporous

Polymeric microporous
membrane
semipermeable
Polymer membrane permeation controlled DDS

• Encapsulation of drug in reservoir can be


done by encapsulation, microencapsulation,
extrusion, molding or any other technique.
Contoh: Norplant Subdermal Implant.
Polymer Matrix diffusion controlled DDS

• Drug is homogeneously
dispersed throughout
polymer matrix.
• Polymers used are :
– Lipophilic polymers
– Hydrophilipic polymers
– Porous
• Decreasing release with
time
Contoh: Compudose implant
Controlled drug delivery by activation process

• Osmotic pressure activated

• Vapor pressure activated

• Magnetically activated
Osmotic pressure activated

• Osmotic pressure is used as


energy source
• Drug reservoir is either a
solution or semisolid
formulation
• Cellulosic outer membrane
• Polyester internal membrane
Vapor pressure activated

• Vapor pressure is used as the power source.

• Drug reservoir is a solution formulation.

• Fluid which vaporizes at body temperature is used


such as fluorocarbon.

• E.g., Infusaid Pump for Heparin.


Vapor pressure activated
Magnetically activated
Magnet ring

1mm

Coated
Polymer
Magnet inside polymer
matrix
Magnetically activated

• Electromagnet is used as power source.

• Drug can be triggered to release at varying rates


depending upon the magnitude and the duration of
electromagnetic energy applied.

• A tiny donut shaped magnet at the centre of


medicated polymer matrix that contains a
homogeneous dispersion of drug

• It has low polymer permeability.


INSULIN
INJECTION
SITES
Infusaid Model 400
Implantable Pump
Water Implant
Gliadel Water Implant
Implant Inject
Infusate Implant
Biodegradable Implant
See you in the next
topic……………….
Ocular Drug Delivery
System