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Eksipien Sediaan Farmasi

Steril
Untia Kartika Sari Ramadhani M,Farm Apt
POKOK BAHASAN
Eksipien
Karakteristik Eksipien
Tujuan Penggunaan Eksipien
Manfaat Penggunaan Eksipien
Jenis Sediaan Farmasi Steril
Karakteristik Sediaan Farmasi Steril
Tujuan Penggunaan Eksipien pada
Sediaan Farmasi Steril
Komponen Eksipien dalam Sediaan
Farmasi Steril
Eksipien
Eksipien adalah zat yang digunakan
sebagai bahan tambahan/ pendukung
suatu formula sediaan, berssifat inert dan
tidak memiliki efek farmakologi
Karakteristik Eksipien yang Baik
Inert
Stabil secara fisik dan kimia
Bebas mikroorganisme patogen
Dapat mendukung bioavaibilitas
Tersedia dalam perdagangan
Harganya terjangkau
Biokompatibel
Kompatibel dengan Obat dan Eksipien lainnya
Kompatibel dengan Pengemas
Tujuan Penggunaan Eksipien
Bahan pembantu selama proses
pembuatan sediaan berlangsung
Mencegah, mendukung atau
meningkatkan stabilitas dan bioavaibilitas
Membantu identifikasi produk
Meningkatkan keamanan, efektivitas
produk obat selama penyimpanan atau
penggunaan
Manfaat Penggunaan Eksipien
Dapat memberi nilai tambah pada sediaan
Lebih stabil secara fisik dan kimia
Memperbaiki tampilan fisik
Mempengaruhi sifat lepasnya obat
Oleh sebab itu mendesain suatu sediaan
perlu pengetahuan mengenai eksipien
yang digunakan dalam formula agar
dihasilkan produk yang bermutu, aman,
menarik dan memberikan efek terapi
yang diinginkan
Sediaan Farmasi Steril

Sediaan Sediaan
Parenteral Parenteral
Volume Besar Volume Kecil

Sediaan
Sediaan
Nasal dan
Oftalmik
Otik
Karakteristik
Sediaan Farmasi Steril

Penggunaan eksipien harus dapat mendukung pembuatan


sediaan farmasi steril yang memiliki 7 karakteristik dasar
sediaan farmasi steril
Eksipien Sediaan Farmasi Steril

Sediaan Sediaan
Parenteral Parenteral
Volume Besar Volume Kecil

Sediaan
Sediaan
Nasal dan
Oftalmik
Otik
Tujuan Penggunaan Eksipien
pada Sediaan Steril Farmasi
Menjaga (mempertahankan) kelarutan obat
Menjaga Stabilitas fisika dan kimia sediaan
Menjaga Sterilitas Sediaan
Memudahkan pemberian obat (misalnya
parenteral dengan cara mengurangi rasa nyeri
atau iritasi pada saat penyuntikan)
Sediaan Steril Oftalmik
Bentuk Sediaan
Tetes Mata
Larutan
Suspensi
Emulsi
Salep Mata (Semisolid)
Larutan Pencuci Mata (Kolirium)
Eksipien
Sediaan Steril Oftalmik
Agen Pengisotonis
Dapar (Buffering agents)
Pembawa (Vehicles)
Pengawet (Antimikrobia)
Antioksidan
Chelating Agent
Agen Pengental (Viscosity Agent)
Agen Pensuspensi (Suspending Agents)
Solubilizing and Wetting Agent
Eksipien
Sediaan Steril Oftalmik
Pengawet
Benzalkonium Klorida
70% digunakan untuk tetes mata
Jangan digunakan dengan lokal anastesi
Klorheksidin Asetat / Glukonat
Bakterisidal
Aktivitas meningkat dengan adanya aromatik
alkohol dan EDTA
Stabil pada pH 5-6, Kurang stabil pada proses
sterilasi dengan Autoklaf
Eksipien
Sediaan Steril Oftalmik
Pengawet
Thiomersal
Bakteriostatik dan Fungistatik
Klorbutol
Aktif membunuh bakteri dan fungi
Kompatibel dengan kebanyakan produk optalmik
Kekurangan: kurang stabil pada proses sterilisasi
dengan autoklav, volatilitas , mudah terabsorbi
dengan wadah plastik
Eksipien
Sediaan Steril Oftalmik
Dapar :
Buffer : Fosfat, Borat, Sitrat
Agen Pengental:
Metil selulosa
Polivinil Alkohol
Agen Pengisotonis
Dektrosa
NaCl
Eksipien
Sediaan Steril Oftalmik
Antioksidan :
Physostigmine
Na Metabisulfit , Na sulfit
Chelating Agents :
EDTA
Wetting Agent and Solubilizing Agents
Polysorbate 80
Gliserin
Propilen Glikol
Sediaan Steril Nasal dan Otik
Telinga
Tetes Telinga
Bentuk Sediaan: Larutan , Suspensi
Hidung
Tetes Hidung
Nasal Sprays
Eksipien
Sediaan Steril Nasal dan Otik
Dapar
Agen Pengisotonis
Pengawet
Pembawa
Agen Pengental
Chelating Agents
Solubilizing Agent
Suspending Agent
Eksipien
Sediaan Steril Nasal
Dapar
Asam Hidroklorat
Potasium Sorbat
Natrium Fosfat
Agen Pengisotonis
NaCl
Dextrose
Pembawa
WFI
Asam Oleat
Pengawet
Propyl dan Methyl Paraben
Eksipien
Sediaan Steril Nasal
Solubilizing Agent
Gliserin
PEG 400
Chelating Agents
EDTA
Eksipien
Sediaan Steril Otik
Agen Pengental
Solubilizing Agents
Agen Pengisotonis
Pengawet
Chelating Agents
Pembawa (Vehicle)
Dapar
Eksipien Sediaan Steril Otik
Agen Pengental
HEC ( Hydroxy Ethyl Cellulose)
Solubilizing Agents
Gliserin , Propylen Glycol
Polysorbate 20 dan 80 ( dapat juga sebagai suspending agent)
Pembawa (Vehicle)
Air ,Mineral Oil
Agen Pengisotonis
NaCl
Buffer
Kalsium Karbonat , Asam Sitrat , Asam Hidroklorat , Sodium Asetat
Pengawet
Methyl Paraben
Benzalkonium Klorida
Benzil Alkohol
Thimerosal
Eksipien Sediaan Steril Otik
Chelating Agents
EDTA , Potasium Metabisulfit , Na Bisulfit
Sediaan Parenteral
Sediaan Parenteral
Infus
Injeksi
Serbuk untuk Injeksi
Bentuk Sediaan Steril Parenteral
Larutan
Suspensi
Emulsi
Serbuk Kering (Dry Powder)
Eksipien Sediaan Steril
Parenteral
Bulking Agents (u/ sediaan parenteral serbuk injeksi)
Lyoprotectants (u/ Sediaan parenteral serbuk injeksi)
Dapar (Buffering Agents)
Agen Pengisotonis (Tonicity Adjusting Agents)
Pembawa (Vehicle)
Pelarut (Minyak dan Air)
Solubilizing agents
Pengawet
Agen Pengompleks dan Pendispersi (Complexing and
Dispersing Agents)
Eksipien Sediaan Steril
Parenteral
Agen Pensuspensi (Flocculating/suspending agents)
Antioksidan (Antioxidant And Reducing Agents)
Chelating agents
Wetting Agents
Surfaktan
Agen Pengental
Eksipien Sediaan Steril Parenteral
Bulking Agents
Bulking agents forms the bulk of the
lyophilized product and provide an adequate
structure to the cake. These are generally
used for low dose (high potency) drugs that do
not have the necessary bulk to support their
own structure
In such cases, a bulking agent is added to the
formulation matrix. The structure of the
lyophilized cake is important, since proper cake
formation leads to proper pore formation that
provides the means for vapor to escape from
the product during the drying cycle
Eksipien Sediaan Steril Parenteral
Bulking Agents
Eksipien Sediaan Steril Parenteral
Lyoprotectants
Lyoprotectant is defined as subtances used for the
stabilization and prevention of the degradation of a
molecule both during freeze-drying and afterwards,
during storage. Among disaccharides, sucrose and
trehalose appear to be the most commonly used.
In comparison to sucrose, trehalose seems to be a
preferable lyoprotectant, because it has a less
hygroscopicity, very low chemical reactivity and finally,
higher glass transition temperature (Tg) .
Critical temperature is the temperature above which the
freeze-dried product loses macroscopic structure and
collapses during freeze drying. Therefore, the excipients
which provide higher critical temperature are preferred
for lyophilization
Eksipien Sediaan Steril Parenteral
Lyoprotectants
Lyoprotectants And Bulking Agents Comments
Manitols Mannitol has a very high eutectic
melting temperature (-1.4C) after
crystallization and is processed well in
lyophilization. Crystallization of the
bulking agent, however, might
adversely affect the physical stability
of the product in certain
instances, for which, an amorphous
bulking agent is preferred
Lactose it is a good bulking agent but is a
reducing sugar and may undergo
Maillard reaction with proteins leading
to instabilityof the formulation(11). The
critical temperature of 1% lactose is
-32
Eksipien Sediaan Steril Parenteral
Lyoprotectants And Bulking Agents
Lyoprotectants And Bulking Agents Comments
Sucrose It is having similar collapse
temperature i.e -31C (2%)
as of lactose but it is not a reducing
sugar and does not undergo
Maillard reaction . Sucrose has a
higher density as compared to
lactose which can cause slight
collapse during drying.
PEG It provides good cake structure
and increases viscosity of water (13).
The 2% solution of PEG has
a critical temperature of -22C. Apart
from lyophilization it is also
used as a co-solvent and viscosity
modifier in parenteral including
ophthalmics.
Eksipien Sediaan Steril Parenteral
Lyoprotectants
Lyoprotectants Comments
Sucrose It is having similar collapse
temperature i.e -31C (2%)
as of lactose but it is not a reducing
sugar and does not undergo
Maillard reaction (12). Sucrose has a
higher density as compared to
lactose which can cause slight
collapse during drying.
Polyethylene glycol (PEG) It provides good cake structure
and increases viscosity of water (13).
The 2% solution of PEG has
a critical temperature of -22C. Apart
from lyophilization it is also
used as a co-solvent and viscosity
modifier in parenteral including
ophthalmics.
Eksipien Sediaan Steril Parenteral
Lyoprotectants And Bulking Agents
Lyoprotectants Comments
Polyvinyl pyrollidone (PVP) The low-molecular grades,
Povidone K 12 and K 17 are used as
solubilizing agents, dispersants
and crystallization inhibitors,
particularly for injectables. This
application is used in particular for
antibiotics in solution or in
lyophilized form.
The povidone grades K12 and K 17
are used as solubilizers in parenteral
applications. In addition Polyvinyl
pyrollidone also provides cryo-
protection to the product. The
C-grades are supplied with low
endotoxin levels (pyrogen-free)
Eksipien Sediaan Steril Parenteral
Pengawet
Pengawet Anti Mikrobial
Eksipien Sediaan Steril Parenteral
Dapar ( Buffering Agents)
Control of pH is critical to avoid degradation of drug during
processing, storage and reconstitution
The choice of buffer depends on the pH stability profile of
active ingredient as drug needs to be reconstituted and
stored for some time before it could be administered to the
patient. For this purpose, the pH of maximum stability of
drug should be known and maintained.
Selection of a suitable buffer and its concentration is
important for sensitive molecules.
Eksipien Sediaan Steril Parenteral
Dapar ( Buffering Agents)
The buffering agent should have a high collapse
temperature, be non-volatile and have a high glass
transition temperature (Tg).
A high collapse temperature would facilitate a faster primary
drying, and its non-volatile nature would prevent pH drift,
that might be detrimental to the product stability
Commonly used buffers in the parenteral formulations are
Acetate, Citrate, Tartrate, Phosphate,Triethanolamine
(TRIS).
Eksipien Sediaan Steril Parenteral
Dapar ( Buffering Agents)
Eksipien Sediaan Steril Parenteral
Dapar ( Buffering Agents)
Eksipien Sediaan Steril Parenteral
Agen Pengisotonis (Tonicity Adjusting Agents)

Parenteral formulations should be isotonic with human


plasma so as to avoid damage to the tissues. However, not
all drugs at their recommended dosage are isotonic with
blood, thus requiring the addition of a tonicity adjusting
agent to the formulation.
The most commonly used tonicity agent is dextrose, while
others such as glycerol and sodium chloride are less
commonly used. Other commonly used tonicity adjusting
agents are: Glycerin and Mannitol
Eksipien Sediaan Steril Parenteral
Pengawet
Pengawet Anti Mikrobial
Eksipien Sediaan Steril Parenteral
Pengawet Antimikobial

Antimicrobial agents are required for parenteral products that


are intended for multiple dosing, in order to protect the product from
accidental microbial contamination during clinical usage & maintain
sterility.
Some typical preservative used in parenteral suspensions
and their commonly used concentrations are as follows:
Benzyl alcohol (0.9% to 1.5%)
Methylparaben (0.18%to0.2%)
Propylparaben (0.02%)
Benzalkonium chloride (0.01% to 0.02%)
Thiomersal (0.001% to 0.01%)
Eksipien Sediaan Steril Parenteral
Agen Pengkhelat (Chelating Agents)
Chelating agents are used in formulations to aid in
inhibiting free radical formation and resultant oxidation of
active ingredients caused by trace metal ions such as
copper, iron, calcium, manganese, and zinc.
Ex: EDTA, Na Metabiulsfit
Antioksidan (Antioxidants and Reducing Agents)
The antioxidants and Reducing Agents are used to
prevent/minimize the oxidation reaction of the drug or
excipients over the shelf life of the product
The mechanisms:
Bind with free radical in the system
Bind with heavy metals that contain in formula
Prevent Reduction Oxidation Reaction
Eksipien Sediaan Steril Parenteral
Eksipien Sediaan Steril Parenteral
Eksipien Sediaan Steril Parenteral
VEHICLE
Solubilizing agents
The agents which help in dissolving or increase the
drug solubility into the formulation are known as
solubilizing agents, thesolubilising agents can be
broadly classified into :
surfactants : The surfactants increase the
dissolution by reducing the surface tension of the
drug substances
co-solvents.: are defined as a solvent that in
conjunction with another solvent can dissolve a
solute.
Eksipien Sediaan Steril Parenteral
VEHICLE
Solubilizing agents
Few examples of surfactants are:
Polyoxyethylene sorbitan monooleate (Tween
80), Sorbitan monooleate Polyoxyethylene
sorbitan monolaurate (Tween 20), Lecithin,
Polyoxyethylene polyoxypropylene copolymers
(Pluronics).
Examples of co-solvents are: Propylene glycol,
Glycerin, Ethanol, Polyethylene glycol (300 and
400), Sorbitol, Dimethylacetamide and
Cremophor EL etc.
Eksipien Sediaan Steril Parenteral
Eksipien Sediaan Steril Parenteral
VEHICLE
Air
Eksipien Sediaan Steril Parenteral
Air sbg Pembawa (VEHICLE)
Air Air
Air Steril Air Air Steril Air steril
Untuk Injeksi Bakteriostatik untuk Inhalasi untuk Irigasi
Untuk Injeksi
Disterilkan Ada 1 atau lebih Disterilkan Disterilkan
Dikemas dengan Agen Dimurnikan secara Dikemas dengan
bakteriostatika destilasi/ osmosis dosis tunggal
Kontener dosis tunggal (Benzil Alkohol , terbalik Tidak
kapasitas < 1000 ml Metil Paraben mengandung
dan Propil Dosis Tunggal antimikroba atau
Tidak Mengandung Paraben) zat lain
Zat Bakteriostatik Tidak mengandung Kapasitas < 1ltr
Kontener Takaran Antimikroba
Ganda Untuk
Untuk membersihkan
Dikemas dengan melembabkan luka
kapasitas < 30 ml udara atau alat
yang sama yang
mungkin
Eksipien Sediaan Steril Parenteral
Minyak sbg Pembawa (VEHICLE)
Minyak (Oil)
Persyaratan monografi minyak untuk sediaan
injeksi ( Farmakope Edisi III)
Minyak lemak nabati atau ester asam, lemak tinggi
alam atau sintetik dan harus jernih pada suhu 10C
Bilangan Asam: 0,2< X<0,9
Bilangan Yodium : 79 <X <128
Bilangan Penyabunan: 185 <X <200
Penyimpanan: Tertutup rapat, diisi penuh dan
terlindung dari cahaya
Eksipien Sediaan Steril Parenteral
Minyak sebagai Pembawa (VEHICLE)
Minyak (Oil)
Oily vehicles cannot be administered by the intravenous route
For some oil or lipid soluble drugs such as some vitamins (Vitamin
K, Vitamin E) hormons (e.g., progesterone, testosterone,
deoxycorticicosterone), oily vehicle can be used:
Soybean oil
Olive oil
Corn Oil
Cottonseed Oil
Sesame Oil
Peach Oil
Peanut Oil
Eksipien Sediaan Steril Parenteral
Wetting Agents
Various nonionic surfactants and non-aqueous
solvents like glycerin, alcohol & propylene glycol
are types of wetting agents commonly used in
injectable suspensions.
Wetting agents reduce the contact angle
between the surface of the particle & the wetting
liquid to obtain maximum wetting efficiency;
surfactants with hydrophilic lipophilic balance
(HLB) value in the range of 7to 9 should be
selected.
Eksipien Sediaan Steril Parenteral
Wetting Agents
The usual concentration of surfactants varies
from 0.05% to 0.5% depending on the solid
contents of the suspension.
Care should be taken in terms of the amount
used;excessive amounts may cause foaming or
caking or provide an undesirable taste/odor to
the product.
Surfactants (wetting agent)
Lecithin, Polysorbate 20, Polysorbate 80, Pluronic F-
68, Sorbitan
trioleate (span 85) are used, as surfactants in
injectable suspensions
Eksipien Sediaan Steril Parenteral
Wetting Agents
for e.g. in the preparation of a non-aqueous
suspension of Cefazolin
sodium in peanut oil, addition of polysorbate 80 at
concentration greater than 0.17% resulted in
deflocculated suspension which was difficult to
redisperse.
Microscopic examination revealed extensive
agglomeration and crystal growth of cefazolin sodium
in the presence of polysorbate 80
Eksipien Sediaan Steril Parenteral
Flocculating/suspending agents
The controlled flocculation approach uses a flocculating agent(s) to
from loosely bound aggregate or flocs in a controlled manner that
settles rapidly but redisperses easily upon agitation. An appropriate
amount or flocculating agent is added that result in maximum
sedimentation volume & prevents cake formation.
Electrolytes, surfactant and hydrophilic colloids have been typically
used as flocculating agents. Electrolytes & surfactants reduce
the electrical forces of repulsion between particles & allow the flocs
to form, which in turn is influenced by the surface charge on the
particles.
E.g. Electrolytes used in Parenteral Suspensions.
Potassium/sodium chloride
Potassium/sodium citrate
Potassium/sodium acetate
Eksipien Sediaan Steril Parenteral
Flocculating/suspending agents
The surface charge of the system can be measured by the zeta
potential. The zeta potential must be controlled so as to
lie within a range (generally less than 25 mV) to obtain a
flocculated,noncaking suspension with maximum
sedimentation.
Hydrophilic colloids (generally negatively charged) not
only affect the repulsive force but also provide
mechanical barrier to the particles.For e.g. a 25% PVP
solution is used in combination with polysorbate 80 (2%)
acts as a stabilizer to provide a stable injectable 30%
aqueous powder suspension.
Eksipien Sediaan Steril Parenteral
Viscosity Agents
Some viscosity building agents used in formulation of injectable
suspension are:
Sodium carboxymethyl cellulose
Acacia
Gelatin
Methyl cellulose
Polyvinyl pyrrolidone
Eksipien Sediaan Steril Parenteral
Complexing and Dispersing Agents
Complexation is sometimes used to improve the solubility of
drug in the solvent especially water.
Cyclodextrins have emerged as very effective additive compounds
for solubilizing hydrophobic drugs.
In the parenteral dosage form, modified cyclodextrins, such
as hydroxypropyl-b-cyclodextrin and sulfobutylether- b
cyclodextrin have been reported to solubilize and stabilize many
injectable drugs, including dexamethasone, estradiol, interleukin-
2, and other proteins and peptides without apparent compatibility
problems
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