Instability of misoprostol tablets outside the blister A serious concern for clinical routine in medical abortion M. Parachini,1 V.Berard, 2 Christian Fiala, 3,6 Sharon Cameron, 4 Teresa Bombas, 5 Kristina Gemzell-Danielsson 6  1 San Filippo Neri Hospital, Rome, Italy 2 ICB - CNRS, Division MaNaPI, Département Nanosciences, Université de Bourgogne, Dijon, France 3 Gynmed Clinic, Vienna, Austria 4 Chalmers Centre, NHS Lothian, Scotland 5 Obstetric Service, Centro Hospitalar e Universitário de Coimbra. Portugal 6 Department of Women’s and Children’s Health, Division of Obstetrics and Gynecology, Karolinska Institutet and Karolinska University Hospital, 171 76 Stockholm, Sweden 

Conflicts of interest: honoraria from Exelgyn for participating in an independent expert board

Context of the study: Misoprostol, a prostaglandin E1 analogue, marketed as Cytotec™ in tablet form, has been widely used in obstetric and gynaecological practice to enhance uterine tone and contractility (1), (2) and (3) despite only having approval to treat and prevent intestinal ulcers. Multiple trials have proved that misoprostol is an effective agent however, investigations continue regarding the optimal dose, dosing regimen, and route of administration. (1) D.A. Wing. Drug Safety, 25 (2002), p. 665 - (2) K.G. Perry Jr., W.E. Robert, R.W. Martine, E.F. Magann, D.L. Sullivan, J.C. MorrisonJ. Perinatol., 18 (1998), p. 24- (3)A.F. Borgida, J.F. Rodis, W. Hanlon, A. Craffey, L. Ciarleglio, W.A. CampbellObstet. Gynecol., 85 (1995), p. 697

Not resolute instability chemically Context of the study: Misoprostol, a PEG1 is chemically unstable except under very specific conditions. This is due to susceptibility to relative humidity and temperature factors. Misoprostol Not resolute instability chemically Galenical stabilization of misoprostol with hydroxypropyl methylcellulose (HPMC) against degradation by water

Context of the study: If these factors are not strictly respected until the moment of intake, misoprostol turns into 3 main degradation products: A-form and B-form prostaglandin and 8-epimer. Misoprostol isomérisation dehydratation isomérisation Type B misoprostol Type A misoprostol 8 épi misoprostol Non active products

Context of the study: The only solution to protect misoprostol tablets is their heat-sealed aluminium blister. Cytotec tablets are packaged in boxes of 50 or 60 tablets of 200 µg each. Each tablet is separately sealed in an alveoli and the blister is not pre-cut.

The problem? When used during medical abortions, the obstetrician gives the patient 2 or more 200 µg tablets of Cytotec® to take 24 to 48 hours after taking mifepristone. So they just have to cut the aluminium blister to deliver the rightnumber of tablets. Unfortunately the tablets are arranged in such a way that it is almost impossible to cut tablets from a blister without inadvertently damaging/opening one or more alveoli.

Objective of this study: The aim of this research was to study the effect on the stability of misoprostol of the exposure of Cytotec® tablets to European normal air/humidity conditions if the alveoli have inadvertently been opened. A possible instability would have a potential negative effect on the treatment of medical abortion. Cytotec® tablets were exposed outside their blister pack (worst case) in conditions of humidity and temperature equivalent to weather conditions in European zone, for a few hours to 1 month. Results were compared to tablets stored in blisters.

Materials and methods: 420 Cytotec® tablets from the same batch (B00460, PFIZER) have been taken out of their blister pack and were exposed for a few hours to 1 month at 25°C and 60% RH (WTB BINDER GmbH). Tablets stored in blisters are considered as reference = T0 The following data were assessed: Water content Karl Fisher Metrohm: 787 KF Titrino Analytical studies HPLC LaChrom Elite VWR 13 Pharmaco technical methods according European Pharmacopeia Mass uniformity Friability Hardness Diameter and thickness - Misoprostol dosage Decomposition products dosage : type A, type B and 8 epi misoprostol

Tablets water content results % At Day 2, 80% increase in the moisture content of exposed tablets in comparison with tablets stored in their blister.

Pharmaco-technical results These results show the penetration of the water in tablets which is the first stage of their modification. Misoprostol tablets uniformity weight Misoprostol tablets morphometrical measure % % Within 48 hours, in exposed tablets, there was penetration of the atmospheric water into tablets makes, with an inflate in Hydroxypropyl Methylcellulose (HPMC) which they contain. HPMC is present in order to protect the misoprostol and to slow down its degradation. 11

Misoprostol tablets friability Results: Pharmaco-technical results Friability test results : Misoprostol tablets friability % At 60% of relative humidity and 25°C, the penetration of water into the tablets is very fast and leads to their softening. Their mass loss during the friability test reached a maximum of 1300% in 48 hours compared to tablets kept in their blister 12

Analytical results: Misoprostol dosage Misoprostol tablets dosage in exposed tablets compared to the tablets stored inside blister % Within 48 hours, the quantity of misoprostol contained in exposed tablets fell by 5 % and the decrease continued over time. In higher-relative humidity conditions, the increased water content and plasticization of HPMC lead to an increased rate of misoprostol degradation1. 1T.T. Kararli et al, Int J Gynaecol Obstet, 1990 and 2004

Analytical results: degradation products dosage Type A and type B misoprostol are process impurities and are also degradation products. Their levels are restricted in misosprostol active substance. Type A misoprostol is obtained by dehydratation which is catalyzed by water. Type B misoprostol is the result of isomerisation of type A misoprostol to the more stable form. That is why it appears later. % % Change in the percentage of type A and B misoprostol in exposed tablets over time 14

Evolution of the percentage of 8 epi misoprostol in tablets in time Results: Analytical results: degradation products dosage 8 epi misoprostol is also a process and degradation impurity. It results from an isomerisation of the active substance. % Evolution of the percentage of 8 epi misoprostol in tablets in time After the 2nd day of storage outside the blister, the process of transformation is engaged and the speed of isomerisation is very fast because the quantity of 8 epi misoprostol doubles within 7 days. 15

Conclusions: If Cytotec® tablets came in contact with normal air only 2 days, the results of this research clearly showed: a rapid increase of water inside each tablet (+78,8%), an increase in the mass (+4,3%), the diameter (+1,2%), and the thickness (+4,8%) of the tablets, which is a sign of the swelling of the HPMC, a speed up of the transformation of misoprostol into decomposition compounds, a decrease in misoprostol content (- 5% in 2 days, -10% in 7 days). Misoprostol Type A misoprostol (+50%) 8 epi misoprostol (+60% in 7 days) Type B misoprostol (+25% in 7 days)

Conclusions: Under the current conditions of Cytotec® use for MToP, it is clear that cutting up the blister packs should not be recommended because the risk of damaging the heat formed alveoli around the tablets is too high. This drastic change observed in chemical composition appears after only 6 hours of exposure and reaches a maximum on the 2nd day, which is the day the patient normally takes the tablet.

Special caution must be taken in delivering Cytotec® tablets Conclusions: If a Cytotec® tablet is kept in a damaged blister (previously cut to deliver tablets to the previous patient) and stored in normal environmental conditions, its effectiveness may be likely seriously decreased for the next patient. This warning concerns all uses of Cytotec® for MToP and even when used as gastric protection, where the tablets, which can be divided into equal parts, can be taken by halves, the second half being stored in the open alveoli for an undetermined period. Special caution must be taken in delivering Cytotec® tablets 18