ATOSIBAN ACETATE

PRODUCT IDENTIFICATION

CAS RN

90779-69-4

EINECS RN

FORMULA

MOLE WEIGHT

CLASSIFICATION

Hormone antagonist / Tocolytic agent / Polypeptide

PHYSICAL AND CHEMICAL PROPERTIES

PHYSICAL STATE

MELTING POINT

BOILING POINT

DENSITY

SOLUBILITY IN WATER

pH

VAPOR DENSITY

REFRACTIVE INDEX

FLASH POINT

INCOMPATIBLE MATERIALS

Strong oxidizing agents

Carbon monoxide, Carbon dioxide, Nitrogen oxides. Sulphur oxides

NFPA RATINGS

SAFETY

HAZARD NOTES

Target Organ Effect, Teratogen. Target Organs: Lungs, Heart, Nerves.

EYE

May cause eye irritation.

SKIN

May be harmful if absorbed through skin. May cause skin irritation.

INGESTION

May be harmful if swallowed.

INHALATION

Material may be irritating to mucous membranes and upper respiratory tract. May be harmful if inhaled.

CHRONIC

TRANSPORT & REGULATORY INFORMATION

UN NO.

HAZARD SYMBOL

RISK PHRASES

SAFETY PHRASES

Atosiban is a chemically-synthesised nonapeptide of the following formula [Mpa1,D-Tyr(Et)2,Thr4, Orn8] oxytocin. The active substance atosiban employed for the most of the batches used in preclinical and clinical studies was obtained by solid phase peptide synthesis (SPPS) and after 1994 by liquid phase peptide synthesis (LPPS) followed by a more efficient purification process. The impurity profiles obtained with the two methods have been shown to be similar. However, the impurity level obtained with the LPPS is lower. Thereby, the difference in manufacture of the active substance is considered of no clinical importance. The starting materials are amino-acid derivates, solvents and other reagents. Protected peptide fragments are synthesised by Boc-chemistry, to yield a linear nonapeptide, followed by deprotection by reduction with sodium in liquid ammonia and by disulphide formation by iodine oxidation. The final purification involves dilution in ethanol and purification by ion exchange chromatography (cation) and reverse phase chromatography. Finally the active substance is concentrated by reversed osmosis and thereafter lyophilised. The synthesis has been sufficiently validated with 4 batches of 2 kg atosiban acetate. The atosiban molecule contains nine chiral centres. The amino acid residues of tyrosine, aspargine, cyteine, proline and ornithine have one asymmetrical carbon each and the residues of isoleucine and threonine have two each. All of them are in the L-form, except for tyrosine, which is in the D-form. The D-form respectively the L-form have not been found in production batches in levels above 0.1%. Eleven diastereomers with one chiral centre can potentially be present in the raw material or formed during the synthesis of atosiban. However, neither of the epimers have been found in concentration above 0.1%. Cis-trans isomerisation occurs at the Ys-Pro bond. The trans form is the major form Atosiban is a white to off-white, very hygroscopic, freeze-dried amorphous powder, which is soluble in water, acetic acid, 0.1 M ammonium acetate, pH 6.0 and 6.8, methanol, ethanol and dimethylformamide. Atosiban, an oxytocin receptor antagonist, is no better than other drugs in delaying or preventing preterm birth but has fewer maternal side-effects. (http://www.emea.europa.eu/)

Tocolytic agents may postpone preterm delivery long enough to improve neonatal outcome, allow corticosteroids to be given to help the baby's lungs and other organs to mature and, if necessary, to allow transfer of the mother to a hospital that has facilities to provide neonatal intensive care. Tocolytic drugs called oxytocin receptor antagonists work by inhibiting the hormone oxytocin that stimulates labour. This review found that, although the oxytocin receptor antagonist atosiban resulted in fewer maternal side-effects than other tocolytic drugs (betamimetics), no benefit was shown in delaying or preventing preterm birth, and atosiban was associated with more infant deaths in one placebo controlled trial. Further well-designed trials are needed. (http://www.cochrane.org/)

Beta-sympathomimetics - salbutamol
These are the most widely used tocolytics and have been extensively studied in randomised controlled trials. Salbutamol has been the most widely used beta-sympathomimetic in Australia and was recommended by the NHMRC in its 1996 report1. It must be given intravenously, it has several maternal contraindications and significant maternal side effects. Recently more information has become available from trials comparing nifedipine (a calcium antagonist) atosiban (an oxytocin antagonist) and indomethacin (a prostaglandin antagonist) with beta-mimetics.
Calcium antagonists – nifedipine
Nifedipine is an equally effective tocolytic, as shown by a recent Cochrane Review 4. It is administered orally and has fewer maternal side effects. However, nifedipine is not approved for use in pregnancy and is classified as a risk Category C drug by the Australian Drug Evaluation Committee.
Oxytocin antagonists - atosiban
Atosiban appears to be as effective as beta-mimetics. It has fewer maternal side effects but is much more expensive than other options in preterm labour. However, it is not approved for use in Australia.
Prostaglandin antagonists – indomethacin
Indomethacin has been compared in small trials with beta-mimetics. These have suggested equal efficacy in delaying preterm birth but there are concerns about adverse affects on the fetal circulation.
Other agents – glyceryl trinitrate
Glyceryl trinitrate patches have been evaluated in a small number of women and there is insufficient evidence to support use in routine clinical practice. Clinicians should ensure their choice of agent is informed by the balance of evidence, as well as their experience in use of a given agent and in the light of advice from clinicians at the receiving hospital. Choice of tocolytic drug is also discussed in a recent RCOG draft evidence-based guideline for the use of tocolytics.(http://www.health.nsw.gov.au/)

SALES SPECIFICATION

APPEARANCE

IDENTIFICATION

pass

PEPTIDE PURITY

2.0% max

8.0% max

PACKING

PRICE INFORMATION