Postpartum haemorrhage is a leading cause of maternal death worldwide. Oxytocin, currently the drug of choice for prevention of PPH, requires constant refrigeration. In pursuit of an alternative medicine, Ferring Pharmaceuticals have developed a heat‐stable formulation of carbetocin, an oxytocin analogue. This study aimed to define that formulation, and to investigate its stability under ICH climate zone IV conditions (30°C/75% relative humidity) for at least 3 years and at extreme temperatures, such as 60°C, for shorter periods of time. The development resulted in a heat‐stable carbetocin formulation consisting of 0.1 mg/mL carbetocin in sodium succinate buffer, mannitol, and methionine. The optimum pH was determined to be pH 5.45 (5.25–5.65). The generated stability data of this formulation show that ≥95% purity of the peptide was maintained for a minimum of 3 years at 30°C, 6 months at 40°C, 3 months at 50°C and 1 month at 60°C. In addition, the heat‐stable carbetocin formulation was not sensitive to freezing or light. The reported highly stable peptide formulation facilitates the distribution in low and middle‐income countries, where maintaining cold chain distribution is difficult.Ferring Pharmaceuticals, the World Health Organization, and MSD# for Mothers have established a collaboration to develop this heat‐stable formulation of carbetocin for the prevention of post‐partum hemorrhage in women after vaginal childbirth, with the aim of making the medicine available in the public sector of developing countries that have a high burden of maternal mortality.

Reactions of cis-[Pt(NH(3))(NH(2)C(6)H(11))Cl(OH(2))](+) with d(Tp(S)T) and d(T(n)()p(S)T(16)(-)(n)()), n = 1, 4, 8, 12, and 15, were investigated by use of HPLC in an aqueous medium with pH 4.1 +/- 0.1 and sodium and magnesium ion concentrations varying between 1.5 mM and 0.50 M. Platination of the oligonucleotide fragments is favored over platination of d(Tp(S)T) in the whole salt concentration interval studied. The maximum rate enhancement after incorporation of the p(S)-site into the polymeric DNA environment is observed for d(T(8)p(S)T(8)), which reacts up to ca. 500 times faster than d(Tp(S)T), after suitable changes of the cation concentrations in the reaction medium. The platination rates of the oligonucleotide fragments d(T(n)()p(S)T(16)(-)(n)()) decrease with increasing salt concentration. For a given phosphorothioate position, the rate also decreases when the cations in the medium are changed from Na(+) or K(+) to Mg(2+), even at constant ionic strength. The reactions with embedded p(S)-sites in d(T(n)()p(S)T(16)(-)(n)()), n = 4, 8, and 12, were found to be kinetically favored over reactions with the 5'- and 3'-end positions. In a reaction medium containing monovalent cations there is a strong preference for platination of d(T(8)p(S)T(8)), whereas d(T(4)p(S)T(12)) and d(T(12)p(S)T(4)) show intermediate reactivity compared with fragments with n = 1 and 15. In contrast, no kinetic discrimination is found between the p(S)-sites in d(T(n)()p(S)T(16)(-)(n)()), n = 4, 8, and 12, in the presence of Mg(2+). The results are interpreted in terms of a general mechanism where preaccumulation of the cationic Pt(II) complex on the oligomers is required for product formation. The kinetics are consistent with a reaction model that includes release of cations from the DNA surface during the adduct formation process.

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† [HC 8 H 4 O 4 2 ] = 0.50 mm, pH = 4.2 adjusted with HClO 4 . ‡ Available upon request from the authors. § Obtained as k obs /[Pt II ] tot .

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