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      Temperature stability of oxytocin ampoules labelled for storage at 2°C–8°C and below 25°C: an observational assessment under controlled accelerated and temperature cycling conditions

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          Abstract

          Introduction

          Oxytocin, administered via injection, is recommended by WHO for the prevention and treatment of postpartum haemorrhage. However, the susceptibility of oxytocin injection to thermal degradation has led WHO and UNICEF to recommend cold-chain storage of all oxytocin products. Nevertheless, some oxytocin products supplied to the global market are labelled for storage at ≤25°C, often with a shorter shelf-life relative to products labelled for refrigeration. Differences in labelled storage requirements can lead to uncertainties among stakeholders around the relative stability of oxytocin products and specifically whether ≤25°C products are more resistant to degradation. Such confusion can potentially influence policies associated with procurement, distribution, storage and the use of oxytocin in resource-poor settings.

          Objectives

          To compare the stability of oxytocin injection ampoules formulated for storage at ≤25°C with those labelled for refrigerated storage.

          Design

          Accelerated and temperature cycling stability studies were performed with oxytocin ampoules procured by the United Nations Population Fund (UNFPA) from four manufacturers.

          Method

          Using oxytocin ampoules procured by UNFPA, accelerated stability (up to 120 days) and temperature cycling (up to 135 days between elevated and refrigerated temperatures) studies were performed at 30°C, 40°C and 50°C. Oxytocin content was quantified using a validated HPLC-UV method.

          Results

          All ampoules evaluated exhibited similar stability profiles under accelerated degradation conditions with the exception of one product formulated for ≤25°C storage, where the rate of degradation increased at 50°C relative to other formulations. Similar degradation trends at elevated temperatures were observed during temperature cycling, while no significant degradation was observed during refrigerated periods of the study.

          Conclusion

          Oxytocin ampoules formulated for non-refrigerated storage demonstrated comparable stability to those labelled for refrigerated storage and should not be interpreted by stakeholders as offering a more stable alternative. Furthermore, these products should not be procured for use in territories with high ambient temperatures, where all oxytocin injection products should be supplied and stored under refrigerated conditions.

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          Most cited references10

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          Quality of oxytocin available in low- and middle-income countries: a systematic review of the literature.

          Oxytocin is the drug of choice for preventing and treating postpartum haemorrhage, an important cause of maternal death. Oxytocin is widely available in low and middle-income countries (LMIC) but there are concerns about its quality.
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            Towards Heat-stable Oxytocin Formulations: Analysis of Degradation Kinetics and Identification of Degradation Products

            Purpose To investigate degradation kinetics of oxytocin as a function of temperature and pH, and identify the degradation products. Materials and Methods Accelerated degradation of oxytocin formulated at pH 2.0, 4.5, 7.0 and 9.0 was performed at 40, 55, 70 and 80°C. Degradation rate constants were determined from RP-HPLC data. Formulations were characterized by HP-SEC, UV absorption and fluorescence spectroscopy. Degradation products were identified by ESI-MS/MS. Results The loss of intact oxytocin in RP-HPLC was pH- and temperature-dependent and followed (pseudo) first order kinetics. Degradation was fastest at pH 9.0, followed by pH 7.0, pH 2.0 and pH 4.5. The Arrhenius equation proved suitable to describe the kinetics, with the highest activation energy (116.3 kJ/mol) being found for pH 4.5 formulations. At pH 2.0 deamidation of Gln4, Asn5, and Gly9-NH2, as well as combinations thereof were found. At pH 4.5, 7.0 and 9.0, the formation of tri- and tetrasulfide-containing oxytocin as well as different types of disulfide and dityrosine-linked dimers were found to occur. Beta-elimination and larger aggregates were also observed. At pH 9.0, mono-deamidation of Gln4, Asn5, and Gly9-NH2 additionally occurred. Conclusions Multiple degradation products of oxytocin have been identified unequivocally, including various deamidated species, intramolecular oligosulfides and covalent aggregates. The strongly pH dependent degradation can be described by the Arrhenius equation.
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              Stability of essential drugs during shipment to the tropics.

              To determine whether present methods of international transport of essential drugs by sea adversely affect their quality. Controlled longitudinal study of drug shipments sent by sea from Unicef in Copenhagen to Lagos; to Mombasa and by land to Kampala; and to Bangkok. 11 essential drugs were stored in four locations on board the ships. Main shipping routes from Unicef, Copenhagen, to tropical countries. Temperature and relative humidity in the test packs during the journey. Amount of active ingredient in the drugs before and after shipment. Temperatures recorded within the test packs range from -3.5 degrees C to 42.4 degrees C and were 3-12 degrees C higher than the ambient temperature. Relative humidity within the packs ranged from 20% to 88%. Differences between the locations on board were negligible. Ergometrine injection, methylergometrine injection, and retinol capsules lost 1.5-5.8% of their activity. Ampoules of ergometrine showed a large variation in the amount of active ingredient after shipment, with three of 80 samples having concentrations 60% below those stated. Ampicillin, benzylpenicillin, phenoxymethylpenicillin, and tetracycline were not affected by transport. Drugs were exposed to a much higher temperature and humidity than is recommended by the manufacturer, especially in tropical harbours and during inland transport. Except for ergometrine and methylergometrine the transport would not affect clinical effectiveness.
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                Author and article information

                Journal
                BMJ Open
                BMJ Open
                bmjopen
                bmjopen
                BMJ Open
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2044-6055
                2019
                26 July 2019
                : 9
                : 7
                : e029083
                Affiliations
                [1 ] departmentDrug Delivery Disposition and Dynamics , Monash Institute of Pharmaceutical Sciences , Parkville, Victoria, Australia
                [2 ] departmentProcurement Services Branch , United Nations Population Fund , Copenhagen, Denmark
                Author notes
                [Correspondence to ] Dr Michelle P McIntosh; michelle.mcIntosh@ 123456monash.edu
                Author information
                http://orcid.org/0000-0003-4835-2833
                Article
                bmjopen-2019-029083
                10.1136/bmjopen-2019-029083
                6661635
                31350247
                014455f6-3b39-4631-a10e-3c3ad4cc65c6
                © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 11 January 2019
                : 1 July 2019
                Funding
                Funded by: McCall MacBain Foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/100006661, United Nations Population Fund;
                Funded by: Rotary Club of Balwyn;
                Categories
                Global Health
                Research
                1506
                1699
                Custom metadata
                unlocked

                Medicine
                maternal medicine,oxytocin,postpartum haemorrhage,temperature,stability,injection
                Medicine
                maternal medicine, oxytocin, postpartum haemorrhage, temperature, stability, injection

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