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Faith Chaibva Msp Final Thesis 2006 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by SEALS Digital commons DEVELOPMENT AND ASSESSMENT OF AN OXYTOCIN PARENTERAL DOSAGE FORM PREPARED USING PLURONIC ® F127 By Faith Anesu Chaibva A Thesis Submitted to Rhodes University in Fulfilment of the Requirements for the Degree of MASTER OF SCIENCE (PHARMACY) December 2006 Faculty of Pharmacy RHODES UNIVERSITY Grahamstown South Africa ABSTRACT Post partum haemorrhage is one of the leading causes of maternal mortality in both the developed and developing world [1,2]. Post partum haemorrhage is caused by the loss of blood from the uterus following labour because of decreased uterine tone, retained placenta or placental fragments as well as lower genital tract trauma [3]. Routine management of post partum haemorrhage involves the use of parenteral oxytocin (OT) that is administered via the intramuscular or intravenous route to increase uterine tone and reduce bleeding. However, OT is rapidly metabolised in the liver and cleared from the body via the kidney [4]. The use of a long acting parenteral preparation of OT to maintain uterine tone is therefore proposed as a means of reducing maternal mortality by preventing post partum haemorrhage. A variety of alternatives were investigated for the development of an appropriate dosage form for OT delivery. The use of Pluronic ® F127 (PF-127) as a thermo-sensitive gel that exists as a viscous flowing liquid at low temperatures but forms a stiff gel on warming to body temperature is proposed. The properties of PF-127 allow for the administration of a cold liquid preparation via a syringe and needle into muscle tissue followed by the formation of a depot gel that has the potential for sustained delivery of OT in vivo. Aqueous solutions of PF-127 were prepared using the cold method. PF-127 solutions were characterised with respect to critical micelle concentration and gelation temperature for different concentrations of gel. The temperature at which gelation occurs was found to be concentration dependent. The rheological properties of solutions of PF-127 were also investigated and a dramatic change in viscosity was found to occur simultaneously with the visual onset of gelation. Due to the lack of compendial guidelines for in vitro release testing of controlled release parenteral preparations, different dissolution methods were evaluated for their potential to ii discriminate between formulations of different compositions. Tests that were used to assess discriminatory behaviour were ANOVA analysis, the f1 and f2 difference and similarity factors, and Gohel’s Similarity factor, Sd. The discriminatory behaviour was assessed by comparing the in vitro release of OT from 20%, 25%, and 30% w/w PF-127 containing preparations and it was observed that the USP Apparatus 3 showed the greatest potential to discriminate between all formulation compositions tested, compared to other test methods that were evaluated. The method was further optimised for OT per dose unit and to establish whether pH changes affected drug release from these systems. The Korsmeyer-Peppas power law was used to assess the primary mechanism of drug release from the extemporaneously prepared dosage forms tested using different dissolution methods. The values of the release exponent, n, revealed that the mechanism of release of OT from PF- 127 gels is generally a combination of diffusion and swelling controlled release or anomalous release. The extent to which diffusion or swelling impacts on the in vitro release of OT was dependent on the specific dissolution test that was used to evaluate the in vitro release of OT. iii ACKNOWLEDGEMENTS I would like to express my sincere gratitude and thankfulness to the following people and organisations: My supervisor, Prof. R.B. Walker, for his guidance and support and provision of laboratory facilities throughout the duration of my project. The Dean and Head, Prof I. Kanfer, and the staff of the Faculty of Pharmacy, for the use of the facilities in the Pharmacy Faculty at Rhodes University. Mr T. Samkange, for speedy technical support during my project and Mr. L. Purdon for assisting me in numerous ways. The Andrew Mellon Foundation and Joint Research Committee of Rhodes University for financial support. PolyPeptide Laboratories s.r.o. (Prague, Hostivar-Czech Republic) and BASF (Ludwigshafen, Germany) for their kind donations of oxytocin and Pluronic ® F127, respectively. Olarewaju Shaibu and Layla Cassim for assisting me with infrared and ultraviolet equipment, respectively. My colleagues in the Biopharmaceutics Research Laboratory for their academic assistance, objectiveness, honesty, and pleasant company for the duration of my project. My parents, Mr S. and Mrs J.M. Chaibva for their support of my dreams and hopes and always being objective and understanding as well as the financial support for my earlier studies. My siblings, Tendayi, Patience, and Tatenda and my sister-in-law, Rhoda, for always being there for me and pushing me to do better each time. Geoffrey Jjuko for listening to all my research woes and continuous support during this project. iv STUDY OBJECTIVES Post partum haemorrhage is one the primary causes of maternal morbidity and mortality [1,2]. The consequences of excessive haemorrhage following the delivery of a baby include hypo- volaemic shock and anaemia, which reduce the quality of life and care for both the mother and neonate. The incidence of post partum haemorrhage may be reduced by routine administration of oxytocin (OT) which maintains uterine tone and prevents bleeding. However, due to the short half-life of OT in vivo , the primary objective of the project was to develop and assess an alternate delivery system that would provide sustained and prolonged release of OT in vitro . The objectives of this study were: i. To develop and validate a suitable and sensitive High Performance Liquid Chromatographic (HPLC) method to accurately and precisely quantitate OT in pharmaceutical dosage forms and OT release from dosage forms during in vitro release testing, ii. To review current trends of protein and peptide delivery and objectively evaluate and propose an alternative sustained release OT dosage form, iii. To characterise a potential matrix for an OT dosage form for sustained delivery in order to understand factors that are likely to impact on the performance and integrity of the dosage form, iv. To develop a discriminatory in vitro dissolution method for assessing the release of OT from sustained release dosage forms of different formulation compositions and, v. To determine the mechanism/kinetics of OT release from the delivery matrix using model dependent approaches. v TABLE OF CONTENTS ABSTRACT .................................................................................................................................. II ACKNOWLEDGEMENTS........................................................................................................ IV STUDY OBJECTIVES .................................................................................................................V LIST OF FIGURES....................................................................................................................XII LIST OF TABLES.................................................................................................................... XIV CHAPTER 1 OXYTOCIN.............................................................................................................1 1.1 INTRODUCTION.................................................................................................................1 1.2 PHYSICO-CHEMICAL PROPERTIES ............................................................................1 1.2.1 DESCRIPTION ........................................................................................................................1 1.2.2 BIOLOGICAL ACTIVITY .........................................................................................................3 1.2.3 SYNTHESIS ............................................................................................................................3 1.2.4 SOLUBILITY ..........................................................................................................................6 1.2.5 ISOELECTRIC POINT ..............................................................................................................6 1.2.6 ULTRAVIOLET SPECTRUM ....................................................................................................6 1.2.7 INFRARED SPECTRUM ...........................................................................................................7 1.3 STABILITY...........................................................................................................................9 1.3.1 TEMPERATURE .....................................................................................................................9 1.3.2 PH.........................................................................................................................................9 1.3.3 OXIDATION .........................................................................................................................10 1.4 CLINICAL PHARMACOLOGY ......................................................................................10 1.4.1 PHYSIOLOGICAL ROLE OF OT IN THE UTERUS ...................................................................10 1.4.2 PHYSIOLOGICAL ROLE OF OT IN THE MAMMARY GLANDS
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