Development and assessment of an oxytocin parenteral dosage form prepared using pluronic ® F127
Abstract (Summary)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 . 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 . 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 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.
School Location:South Africa
Source Type:Master's Thesis
Keywords:faculty of pharmacy
Date of Publication:01/01/2007