Misoprostol is a prostaglandin E1 analogue used to prevent and treat gastric ulcers. It has been commonly used in gy necology and obstetrics, especially for the management of postpartum hemorrhage (PPH). For this purpose, 1000 μg intrarectal (insertion of five 200 μg tablets) has been recommended as the third line after injectable oxytocin and me thylergometrine. We proposed to manufacture a 1000 μg misoprostol suppository by determining formulation, release and stability. The administration facility was also evaluated. Several formulations of misoprostol suppositories were set up and evaluated. Misoprostol tablets and lipophilic bases (Hard fat — Adeps solidus Ph. Eur., Witepsol ? H15 and Suppocire ? AM and AS 2 X) were used to obtain suppositories. Surfactants were also tested (polysorbates Tween ? 20, Tween ? 80 and sodium lauryl sulfate (SLS)). The formula was monitored by the misoprostol release curve with an in vitro test and dosed by a HPLC method. Stability was determined by evaluating the percentage of misoprostol content remaining over the time in suppositories stored at 4℃ and 25℃. Facility of use versus tablets was evaluated by obste tricians of a Swiss regional hospital using a questionnaire. Misoprostol release was facilitated by adding surfactant to the lipophilic base. After 30 minutes, 59 % ± 1.4% and 57 % ± 8.2% of misoprostol was released with Adeps solidus + 1% SLS and Adeps solidus + 5% Tween 20 respectively. SLS was discarded to the final formula because of its irritating effect. After 7 months, suppositories still contained 94 % ± 3.7% misoprostol with storage at 4℃. The administration was considered easier and faster compared with intra rectal use of tablets. The formula, consisting of 5 crushed miso prostol tablets dispersed in a suppository base made of Adeps solidus + 5% Tween ? 20, is stable for at least 7 months at 4?C and facilitates the rectal administration of misoprostol in the treatment of PPH.
KeywordsPostpartum HemorrhageMisoprostolRectal
S. A. Pfizer, “Cytotec? (Misoprostol) Package Insert,” Zurich, 2010.
A. B. Goldberg, M. B. Greenberg and P. D. Darney, “Misoprostol and Pregnancy,” The New England Journal of Medicine, Vol. 344, No. 1, 2001, pp. 38-47. doi:10.1056/NEJM200101043440107
A. Elati and A. D. Weeks, “The Use of Misoprostol in Obstetrics and Gynaecology,” BJOG: An International Journal of Obstetrics and Gynaecology, Vol. 116, Suppl. 1, 2009, pp. 61-69. doi:10.1111/j.1471-0528.2009.02329.x
WHO, “WHO Model List of Essential Medicines,” 17th Edition, WHO, Geneva, 2011.
H. El-Refaey and C. Rodeck, “Post-Partum Haemorrhage: Definitions, Medical and Surgical Management. A Time for Change,” British Medical Bulletin, Vol. 67, No. 1, 2003, pp. 205-217. doi:10.1093/bmb/ldg016
O. Irion, S. Terraz, M. Boulvain, F. Boehlen and C. D. Becker, “Hémorragie de la Délivrance: Prévention, Embolisation Artérielle et Facteur VIIa Recombinant,” Revue Médicale Suisse, Vol. 4, No. 176, 2008, pp. 2269-2275.
P. V. Rajan and D. A. Wing, “Postpartum Hemorrhage: Evidence-Based Medical Interventions for Prevention and Treatment,” Clinical Obstetrics and Gynecology, Vol. 53, No. 1, 2010, pp. 165-181. doi:10.1097/GRF.0b013e3181ce0965
N. F. Zuberi, J. Durocher, R. Sikander, N. Baber, J. Blum and G. Walraven, “Misoprostol in Addition to Routine Treatment of Postpartum Hemorrhage: A Hospital-Based Randomized-Controlled Trial in Karachi, Pakistan,” BMC Pregnancy and Childbirth, Vol. 8, No. 40, 2008.
G. Walraven, Y. Dampha, B. Bittaye, M. Sowe and J. Hofmeyr, “Misoprostol in the Treatment of Postpartum Haemorrhage in Addition to Routine Management: A Placebo Randomised Controlled Trial,” BJOG: An International Journal of Obstetrics and Gynaecology, Vol. 111, No. 9, 2004, pp. 1014-1017. doi:10.1111/j.1471-0528.2004.00217.x
G. J. Hofmeyr, S. Ferreira, V. C. Nikodem, L. Mangesi, M. Singata, Z. Jafta, et al., “Misoprostol for Treating Postpartum Haemorrhage: A Randomized Controlled Trial,” BMC Pregnancy and Childbirth, Vol. 4, No. 16, 2004.
M. Baruah and G. M. Cohn, “Efficacy of Rectal Misoprostol as Second-Line Therapy for the Treatment of Primary Postpartum Hemorrhage,” The Journal of Reproductive Medicine, Vol. 53, No. 3, 2008, pp. 203-206.
R. Shojai, R. Desbrière, S. Dhifallah, B. Courbière, D. Ortega, C. d’Ercole, et al., “Le Misoprostol par voie Rectale dans l’Hémorragie de la Délivrance,” Gynécologie Obstetrique & Fertilité, Vol. 32, No. 9, 2004, pp. 703-707. doi:10.1016/j.gyobfe.2004.05.015
A. U. Lokugamage, K. R. Sullivan, I. Niculescu, P. Tigere, F. Onyangunga, H. El Refaey, et al., “A Randomized Study Comparing Rectally Administered Misoprostol versus Syntometrine Combined with an Oxytocin Infusion for the Cessation of Primary Post Partum Hemorrhage,” Acta Obstetricia Gynecologica Scandinavica, Vol. 80, No. 9, 2001, pp. 835-839. doi:10.1034/j.1600-0412.2001.080009835.x
H. Abdel-Aleem, I. El-Nashar and A. Abdel-Aleem, “Management of Severe Postpartum Hemorrhage with Misoprostol,” International Journal of Gynecology & Obstetrics, Vol. 72, No. 1, 2001, pp. 75-76. doi:10.1016/S0020-7292(00)00321-0
R. Shojai, L. Piéchon, C. d’Ercole, L. Boubli and J. E. Pontiès, “Le Misoprostol par Voie Rectale dans les Hémorragies de la Délivrance. Une étude Préliminaire,” Journal de Gynécologie Obstétrique et Biologie de la Reproduction, Vol. 30, No. 6, 2001, pp. 572-575.
P. O’Brien, H. El-Refaey, A. Gordon, M. Geary and C. H. Rodeck, “Rectally Administered Misoprostol for the Treatment of Postpartum Hemorrhage Unresponsive to Oxytocin and Ergometrine: A Descriptive Study,” Obstetrics and Gynecology, Vol. 92, No. 2, 1998, pp. 212-214. doi:10.1016/S0029-7844(98)00161-6
R. U. Khan, H. El-Refaey, S. Sharma, D. Sooranna and M. Stafford, “Oral, Rectal, and Vaginal Pharmacokinetics of Misoprostol,” Obstetrics and Gynecology, Vol. 103, No. 5, 2004, pp. 866-870. doi:10.1097/01.AOG.0000124783.38974.53
H. A. Mansouri and N. Alsahly, “Rectal versus Oral Misoprostol for Active Management of Third Stage of Labor: A Randomized Controlled Trial,” Archives of Gynecology and Obstetrics, Vol. 283, No. 5, 2011, pp. 935-939. doi:10.1007/s00404-010-1466-5
World Health Organization, “WHO Recommendations for the Prevention of Postpartum Haemorrhage,” WHO Press, Geneva, 2007.
International Confederation of Midwives/International Federation of Gynecology and Obstetrics. “Prevention and Treatment of Postpartum Haemorrhage: New Advances for Low Resource Settings,” 2012. http://www.pphprevention.org/toolkit.php
Pharmacopée Européenne. “Monographie du Misoprostol,” Addendum 5.3, 2006, pp. 3764-3765.
M. C. Williams, J. C. Tsibris, G. Davis, J. Baiano and W. F. O’Brien, “Dose Variation That Is Associated with Approximated One-Quarter Tablet Doses of Misoprostol,” American Journal of Obstetrics and Gynecology, Vol. 187, No. 3, 2002, pp. 615-619. doi:10.1067/mob.2002.124959
H. Hafirassou, F. Chiadmi, J. Schlatter, R. Ratiney and J. E. Fontan, “Stability of Misoprostol in Suppositories,” American Journal of Health-System and Pharmacy: Official Journal of the American Society of Health-System Pharmacists, Vol. 62, 2005, pp. 1192-1194.
N. Realdon, M. Dal Zotto, M. Morpurgo and E. Franceschinis, “Effects of Surfactant Characteristics on Drug Availability from Suppositories,” Die Pharmazie, Vol. 63, No. 6, 2008, pp. 459-463.
S. Azarmi, W. Roa and R. L?benberg, “Current Perspectives in Dissolution Testing of Conventional and Novel Dosage Forms,” International Journal of Pharmaceutics, Vol. 328, No. 1, 2007, pp. 12-21. doi:10.1016/j.ijpharm.2006.10.001
R. Dunn, H. Reimers, L. Ward and J. Chapman, “Suppository Dissolution Utilizing USP Apparatus 4,” Dissolution Technologies, Vol. 3, No. 1, 1996, pp. 18-19.
B. Patel, R. C. Campos and A. I. Fenandes, “Formulation and in Vitro Evaluation of Chloral Hydrate Rectal Suppositories for Paediatric Use,” 2nd Congress of the Portuguese Society of Pharmaceutical Sciences and 6th Congress of the Portuguese-Spanish Chapter of the Controlled Release Society, Lisbon, 2005.
M. Siewert, J. Dressman, C. K. Brown and V. Shah, “FIP/AAPS Guidelines to Dissolution/in Vitro Release Testing of Novel/Special Dosage Forms,” AAPS Pharm-SciTech, Vol. 4, No. 1, 2003, p. E7. doi:10.1208/pt040107
V. P. Shah, J. J. Konecny, R. L. Everett, B. McCullough, A. C. Noorizadeh and J. Skelly, “In Vitro Dissolution Profile of Water-Insoluble Drug Dosage Forms in the Presence of Surfactants,” Pharmaceutical Research, Vol. 6, No. 7, 1989, pp. 612-618. doi:10.1023/A:1015909716312
L. Tang, S. U. Khan and N. A. Muhammad, “Evaluation and Selection of Bio-Relevant Dissolution Media for a Poorly Water-Soluble New Chemical Entity,” Pharmaceutical Development and Technology, Vol. 6, No. 4, 2001, pp. 531-540. doi:10.1081/PDT-120000291
R. A. Tupker, K. Vermeulen, V. Fidler and P. J. Coenraads, “Irritancy Testing of Sodium Laurate and Other Anionic Detergents Using an Open Exposure Model,” Skin Research and Technology, Vol. 3, No. 2, 1997, pp. 133-136. doi:10.1111/j.1600-0846.1997.tb00175.x
G. J. Hofmeyr, A. M. Gülmezoglu, N. Novikova, V. Linder, S. Ferreira and G. Piaggio, “Misoprostol to Prevent and treat Postpartum Haemorrhage: A Systematic Review and Meta-Analysis of Maternal Deaths and Dose-Related Effects,” Bulletin of the World Health Organization, Vol. 87, No. 9, 2009, pp. 666-677. doi:10.2471/BLT.08.055715