TRABECTEDIN

Disusun Oleh :
Sundari
K11017R111

FAKULTAS FARMASI
UNIVERSITAS MUHAMMADIYAH SURAKARTA
SURAKARTA
 OUTLINE
 Structure
 Chemo-physico properties
 Pharmaceutical use
 Formulations
 Sources
 Manufacturing/extraction
 Quality control analytical methods (Physico-chemistry).
 TRABECTEDIN
• Trabectedin, also referred as ET-743 during its
development, is a marine derived antitumoral
agent discovered in the carribean tunicate
ecteinascidia turbinata and now produced
synthetically.
• It is approved for use in europe, russia and south
korea for the treatment of advanced soft tissue
sarcoma

• On october 23, 2015, the FDA approved

trabectedin, (as yondelis), for the treatment of
specific soft tissue sarcomas.
  Ecteinascidia turbinata, the mangrove tunicate, is a sea
squirt species in the genus ecteinascidia, which was
described to science in 1880 by William Abbott Herdman.

 Ecteinascidia turbinata is found all the year round in shallow

waters in the Caribbean Sea, the east coast of Florida,
Ecteinascidia Turbinata
Bermuda and the Gulf of Mexico. In the summer it is
occasionally found in Chesapeake Bay, off the coasts of
North and South Carolina and in the Mediterranean Sea.
STRUCTURE

• There are 3 subunits of the molecule labeled A,

B, and C important For how the drug works.
Subunits A and B are responsible for Binding
to DNA. The binding of ET‐743 to DNA
changes the normal Structure of the molecule,
causing it to bend.
• Subunit C interacts with other molecules, such
as transcription factors.ET‐743 also interferes
with the normal binding of proteins to DNA
function to activate genes

International Journal of Current Pharmaceutical Research

 CHEMO-PHYSICO PROPERTIES
Proper name : Trabectedin
Chemical name : (1'R,6R,6aR,7R,13S,14S,16R)-5-(acetyloxy)-
3',4',6,6a,7,13,14,16 octahydro-6',8,14-
trihydroxy-7',9-dimethoxy-4,10,23 trimethyl-
spiro[6,16 (epithiopropanoxymethano)-7,13-
imino-12H-1,3 dioxolo[7,8]isoquino[3,2
b][3]benzazocine-20,1'(2'H)-isoquinolin]-19-
one.
Molecular formula : C39H43N3O11S
Molecular mass : 761.84
Physicochemical
Properties : Trabectedin is hydrophobic, and has a low
solubility in water. Trabectedin solubility is
enhanced in acidic media.

International Journal of Current Pharmaceutical Research

 PHARMACEUTICAL USE

• Trabectedin in combination with CAELYX ® (pegylated liposomal doxorubicin hydrochloride [PLD])

is indicated for the treatment of patients with platinum-sensitive ovarian cancer for whom one first-line
platinum-based chemotherapy regimen, including adjuvant therapy, has failed, and who are not expected
to benefit, are ineligible or not willing to receive retreatment with platinum-based chemotherapy

• For the treatment of patients with metastatic liposarcoma or leiomyosarcoma after failure of
prior anthracycline and ifosfamide chemotherapy.
Formulations
Dosage form : powder for injection

(Pharmaceutical Formulations of ecteinascidin compounds, 2010 )

Bulk solutions were prepared and freeze-dried by a standardised
procedure.

A volume of 150 ml of each formulation was prepared

the amount of potassium phospathe was weighed and dissolved in

90% of final volume (135 ml) of water

Then, the pH was adjusted to pH 4.0 with 0.1 N phosphoric acid.

(Pharmaceutical Formulations of ecteinascidin compounds, 2010 )

ET-743 were added to compounding glass vessel and dissolved by
magnetical stirring in 2/3 volume (90 ml) of the potassium phosphate
solution for approximately 1 Hours (dissolution was checked visually)

the amount of bulking agent and surfactant were added

and dissolved in 1/3 volume of the potassium phosphate
solution

then, the solution was added to the Et-743 solution and

the agitation was maintained for 1 additional hour.

the solution was brought to final weight with water (a density of 1.019
g/cc) the solution was filtered through a 0.22 um cellulose filter.

(Pharmaceutical Formulations of ecteinascidin compounds, 2010 )

 The solution was filled into 25 ml glass vials at 5ml/vial and maintained at
20 C. until lyophilization was performed according to the following table 1 :

After Freeze-drying, the vials were sealed. The vials were transferred to a
refrigerated area (-200C)

(Pharmaceutical Formulations of ecteinascidin compounds, 2010 )

SOURCES
SOURCES
SOURCES
SOURCES
(United States Patent, 2009)
MANUFACTURING/EXTRACTION

(International Journal of Current Pharmaceutical Research, 2011)

 QUALITY CONTROL ANALYTICAL METHODS (PHYSICO-
CHEMISTRY).
Three commercial scale batches were stored at -20 o C ± 5 o C for 24 months (2 batches) and for 18
months (1 batch) in the proposed primary packaging. In addition, the effect of short term excursions outside
the storage conditions was evaluated on one batch at 25 o C/60% RH for 30 days and 5 o C for 6 months. All
the batches placed on stability studies complied with the requirements in the active substance specifications.
The results from the short excursions study showed no significant changes at the end of the study periods for
any parameter although there was a trend towards increased water content at higher temperature.
Phostostability and stress testing using thermal, oxidative, acidic and alkaline conditions was also carried out.
Stress conditions showed a slight increase in the impurities content and the photostability studies showed that
the active substance is not affected by exposure to light.