ETOMIDATE EMULSION AMPOULE

I. RANCANGAN FORMULA

Tiap ml mengandung

Etomidate 0.2% zat aktif

Soya oil 5% Fase minyak

Middle Chain Trigliserida (MCT) 10% fase minyak

Lesitin 1.2% emulsifier

Glyserol 2.5% peng-isotonis

Alfa tokoferol 0.05% antioksidan

Natrium Hidroksida pH adjustment

II.SPESIFIKASI FORMULA

Etomidate emulsion ampoule 10 ml, etomidate 2 mg/ml

Wadah : ampoule gelas tipe I

Volume wadah : 10 mL dengan kelebihan 0.7 mL

Spesifikasi Produk : pH 6-8

Dosis/ Aturan Pakai : Anestesia penginduksi 0.15-0.3 mg/kgBB

Geriartri 0.15-0.2 mg/kgBB (single dose)

III. DASAR FORMULASI

Etomidate adalah Etomidate is an ultrashort-acting non-barbiturate hypnotic

agent yang digunakan sebagai penginduksi anesthesia.

Etomidate dibuat dalam bentuk sediaan emulsi dengan wadah ampul sebab,

1. Etomidate sangat sukar larut dalam air, pada penelitian sebelumnya, dengan

menggunakan etomidate sulfat, telah diformulasi etomidate dengan pelarut

berupa phosfat Buffer dengang nilai Osmolality 270 mOsm/kg dengan Ph 3,3,

akan tetapi karena dapar posfat tidak stabil pada penyimpanan yang lama,

sehingga dicari modifikasi formula etomidate yang lain. Penelitian selanjutnya

mengembangkan etomidate dengan pelarut Propilenglikol 35%, akan tetapi

dengan nilai osmolaritas yang tinggi 4900 mOsm/kg, menyebabkan rasa nyeri

pada saat peng-injeksian.

(U.S. Pat. No.4,289,783 to mesens)

2. Sehingga salah satu cara mengatasinya adalah dengan cara pembuatan bentuk

sediaan dalam bentuk emulsi

“The first approach that is commonly used to increase the aqueous solubility of a drug

is to form water-soluble salts. Berge et al. (18) wrote what is now a near classic review of

salt form strategies acceptable for pharmaceuticals. If salt formation is not possible (e.g.,

the salt form is too unstable, or does not render the molecule sufficiently water-soluble),

a series of formulation approaches may be investigated. pH adjustment may be used to

increase the aqueous solubility of an ionizable drug. The next most frequently attempted

approach is the use of water-miscible cosolvents. Another approach is the use of

surfactants and complexing agents. The use of emulsions and other colloidal drug

delivery systems for intravenous administration is becoming widely and successfully

applicable (injectable dispersed system : 239)”

3. Penginjeksian Etomidate dalam bentuk larutan memberikan rasa nyeri

“Transient venous pain was observed immediately following intravenous injection of

etomidate in about 20% of the patients, with considerable difference in the reported

incidence (1.2% to 42%). This pain is usually described as mild to moderate in severity

but it is occasionally judged disturbing. The observation of venous pain is not associated

with a more than usual incidence of thrombosis of thrombophlebitis at the injection site.

Pain also appears to be less frequently noted when larger, more proximal arm veins are

employed and it appears to be more frequently noted when smaller more distal, hand or

wrist veins are employed.”

(http://dailymed.nlm.nih.gov/dailymed/)

Hal ini dapat diatasi, dengan modifikasi formula Etomidate injeksi menjadi

bentuk emulsi.

“Previous galenic preparations were associated with highly disturbing adverse effects.

These could be controlled only in a new formulation………..the water-insoluble active

ingredient etomidate is dissolved in an emulsion containing medium- and long-chain

triglycerides (MCT/LCT) which acts as the drug vehicle. The lipid emulsion has been in

clinical use for many years and has been shown to be efficacious and safe for parenteral

nutrition”

Oleh karena itu, sebagai pembawa digunakan kombinasi Trigliserida rantai

sedang (MCT) dan Trigliserida Rantai Panjang (LCT) yaitu soya oil. Sebagai

emulsifying agent digunakan lecithin (konsentrasi 0,3-2.3%)

“Lecithins are mainly used in pharmaceutical products as dispersing, emulsifying, and

stabilizing agents, and are included in intramuscular and intravenous injections,

parenteral nutrition formulations, and topical products such as creams and ointments.”

(Excipient : 386)”

Selain itu, lesitin juga merupakan emulsifying agent terbaik untuk sediaan

parenteral. Untuk sediaan emulsi parenteral, emulsyfyng yang dapat digunakan,

hanya dari golongan anionic. Dengan penggunaan Lesitin, maka akan dihasilkan

emulsi dengan globul berukuran 1 µm. (RPS :332-331))

Tidak digunakan pengawet karena dalam sediaan emulsi parenteral tidak

diperkenankan menggunakan pengawet.

“Since preservatives are not allowed as additives in parenteral emulsions [Ph.Eur.1997,

1997], even refrigerated storage of opened containers will not suffice to prevent

microbiological degradation. Only manufacture under aseptic conditions with terminal

steam-sterilisation can ensure the product’s sterility.”

Digunakan Gliserol sebagai peng-isotonis, sebab penggunaan NaCl, akan

menyebabkan perubahan warna pada sediaan emulsi dengan lesitin sebagai

emulsifying agent (perubahan jadi berwarna coklat) dan juga pemisahan fase

emulsi. (pdf dispersed system : 264). Sediaan dibuat isotonic dengan

penambahan Gliserin sebagai pengisotonis. Konsentrasi 2.5%, berdasarkan

penelitian sebelumnya yang menggunakan etomidate, soya bean oil, MCT, dan

lecithin sebagai emulsi parenteral.

“An ideal biocompatible emulsion is also isotonic, i.e., containing

280–300 mOsm=kg. In practice, there are few physiologically

acceptable tonicity agents, which may be incorporated into an

emulsion without causing disruption during thermal sterilization.

Isotonic saline is one such agent that does not cause emulsion

disruption.(Injectable Dispersed System).”

Penggunaan alfa tokoferol untuk mengatasi kemungkinan terjadinya

oksidasi pada bahan (emulsi).

IV. METODE STERILISASI

No Alat/bahan Metode Sterilisasi Pustaka

1. Etomidate Radiasi Gamma U.S. Paten

0055023

2. Tokoferol

3. Natrium Hidroksida Filtrasi Scoville

4 Lesitin

5. MCT Oven, 170ºC, 1 jam Excp : 430

6. WFI Autoklaf 115ºC-116ºC,

30 menit

FI III:97

7. Glycerin Pemanasan kering,

oven

Principle and

Practice of

disinfection,

preservation, and

sterilization : 386

8. Beker Autoklaf 121ºC, 15

menit

Scoville : 423

9. Erlenmeyer Autoklaf 121ºC, 30

menit

Scoville : 423

10. Gelas ukur Autoklaf 121ºC, 30

menit

Scoville : 423

11. Pipet tetes Oven 180 ºC Scoville : 406

12 Batang pengaduk Oven, 180 ºC,2 jam Lahman :1266

13. ampul Autoklaf 121ºC, 15

menit

Scoville:423

14. Sendok tanduk Autoklaf 121ºC, 30

menit

Lahman :1266

Sterilisasi akhir : autoklaf 121ºC, 15 menit.

“As other sterilisation techniques are not applicable to emulsions, steam-sterilisation is

favoured. Emulsions are sterilised according to pharmacopeial requirements (e.g. 121°C, 2 bar

for at least 15 min). Thermal stress might, however, change the physical and chemical stability

of the emulsions unfavourably. To minimise physical changes, rotating autoclaves are used to

avoid unequal heat-distribution in the emulsions. To prevent excess thermal stress and to avoid

refluxing on the upper surface of the bottles, readjustment to atmospheric conditions can be

accelerated by spraying iced water onto the bottles in the autoclave [Schurr, 1969]”

There is some evidence to suggest that relatively stable emulsion systems can be

obtained when the phase-inversion temperature of O=W emulsion is approximately 20–65_C

higher than the storage temperature (IDS :242))

V. PERHITUNGAN

Perwadah :

10 ml dilebihkan 0.7 ml (ketentuan di USP) = 10.7 ml. dicukupkan 12 ml

Etomidate 0.2% x 12 = 24 mg

Soya oil 5% x 12 = 0.6 g

Middle Chain Trigliserida (MCT) 10% x 12 = 1.2 g

Lesitin 1.2% x 12 = 144 mg

Glyserol 2.5% x 12 = 0.3 g

Alfa tokoferol 0.05% x 12 = 6 mg

Natrium Hidroksida qs

Aquades ad 12 mL

Perbatch : 10 vial @10 ml

Etomidate 24 mg x 10 = 240 mg

Soya oil 0.6 g x 10 = 6 g

Middle Chain Trigliserida (MCT) 1.2 g x 10 = 12 g

Lesitin 144 mgx 10 = 1440 mg = 1,44 g

Glyserol 0.3 g x 10 = 3 g

Alfa tokoferol 6 mg x 10 = 60 mg

Natrium Hidroksida qs

Aquades 12 mL x 10 = 120 ml

Pengenceran

α tokoferol dari Nature-E

1 kapsul @ 500 mg = 100 UI

1 mg α-tokoferol ~ 1,49 UI

Dibutuhkan 60 mg alfa-tokoferol = 60 x 1.49 UI = 89.4 UI

89.4 UI100 UI

× 500 mg=447 m g

VI. CARA KERJA

1. Lesitin, Gliserin dilarutkan dalam WFI

2. Dihomogenkan dengan homogenizer

3. Kemudian, difiltrasi dengan filter membrane (0.45 µm)

4. pH di-adjust dengan NaOH hingga Ph dalam range 6-8

5. fase air kemudian ditambahkan dengan fase minyak (MCT,Soya oil, dan alfa

tokoferol), dicampur dan dihomogenkan.

6. Emulsi akhir difiltrasi kembali dengan filter (0.8 µm)

7. pH di-adjust dengan NaOH hingga pH dalam range 6-8

8. emulsi yang terbentuk kembali di homogenkan dengan Homogenizer, kemudian

difilter dengan filter (5,0 µm)

9. emulsi dimasukkan dalam wadah ampoule

10.ampul di-vakumkan kemudian di-segel

11.sterilisasi akhir, autoklaf 121ºC, 15 menit

CATATAN:

UKURAN PARTIKEL EMULSI <1 MIKROMETER, >5 MIKROMETER

MENYEBABKAN EMBOLI DAN PENYUMBATAN KAPILER

Uses and Administration

Etomidate is an intravenous anaesthetic used for the induction of general anaesthesia (p.1780).

Anaesthesia is rapidly induced and may last for 6 to 10 minutes with a single usual dose.

Recovery is usually rapid without hangover effect. Etomidate has no analgesic activity. For the

induction of anaesthesia, etomidate is available as a conventional or an emulsion injection

formulation. The usual dose is 300 micrograms/kg of etomidate given slowly, preferably into a

large vein in the arm, although a lower dose of 150 micrograms/kg of the emulsion formulation

may be sufficient. An initial dose of 150 to 200 micrograms/kg is recommended in the elderly,

subsequently adjusted according to effects. Dosage should also be reduced in hepatic cirrhosis.

Children may require up to 30% more than the usual adult dose of the emulsion formulation.

Opioid analgesics or benzodiazepines as premedication reduce myoclonic muscle movements;

opioids also reduce injection site pain. A neuromuscular blocker is necessary if intubation is

required.

Administration in the elderly. A study1 in elderly patients has demonstrated that

although reducing the rate of intravenous injection of etomidate reduces the speed of induction,

the dosage

required is also reduced. Giving etomidate 0.2% solution at a rate of 10 mg/minute induced

anaesthesia in a mean of 89.6 seconds and required a mean dose of 0.11 mg/kg. Corresponding

values for a rate of 40 mg/minute were 47.7 seconds and 0.26 mg/kg, respectively. 1. Berthoud

MC, et al. Comparison of infusion rates of three i.v. anaesthetic agents for induction in elderly

patients. Br J Anaesth 1993; 70: 423–7.

Anaesthesia. Etomidate might be useful for induction if rapid tracheal intubation is

required with a competitive neuromuscular blocker as it has been shown to reduce the time to

onset of block with vecuronium.1,2 1. Gill RS, Scott RPF. Etomidate shortens the onset time of

neuromuscular block. Br J Anaesth 1992; 69: 444–6. 2. Bergen JM, Smith DC. A review of

etomidate for rapid sequence intubation in the (martindale : 1834)