British Journal of Obstetrics and Gynaecology November 1992, Vol. 99, pp. 877-880


The effect of pH on release of PGE, from vaginal and endocervical preparations for induction of labour: an in-vitro study T. A . J O H N S O N


Department of Obstetrics and Gynaecology

Objective To study the effect of pH and precoating with obstetric cream on the release of prostaglandin E, (PGE,) from commercially available triacetin and starch based gels, lactose based vaginal tablets and sustained release hydrogel polymer pessaries in-vitro. Design A prospective observational study. Methods PGE, preparations held in dialysis bags were placed in Ringers lactate buffer and release of PGE, into the buffer was measured over 8-12 h by radioimmunoassay. The hydrogel polymer pessary was also assessed after precoating with obstetric cream. Main outcome measures In-vitro PGE, release at pH 7.4, pH 5.4 and pH 3.4. Results The gel preparations provided rapid and reliable release, while the lactose based vaginal tablet provided much lower release of PGE, with sudden and variable release occurring after 5-8 h, an effect which was enhanced at low pH. With the triacetin gel preparation, release of PGE, was reduced at lower pH, while the starch based gel appeared to provide optimal release at pH 5.4. The hydrogel polymer pessaries provided linear release in-vitro and this was reduced at pH 3.4. In addition, precoating the sustained release hydrogel polymer pessaries with obstetric cream virtually abolished release of PGE,. Conclusions As the vagina is normally acid, these results suggest that vaginal pH could influence PGE, release and this may result in variable clinical responses. In view of this, pH should be taken into account in the development of preparations for clinical use. Furthermore, the use of obstetric cream should be avoided when administering PGE, preparations for induction of labour.

I. A . G R E E R R . W. K E L L Y MRC Reproductive Biology Unit A. A. C A L D E R Department of Obstetrics and G ynaecology University of Edinburgh, UK

Prostaglandin E, (PGE,) is widely employed for cervical ripening and induction of labour. A variety of routes of administration and vehicles exist. The vaginal and endocervical routes appear to be the most popular because of their efficacy combined with ease of administration and low incidence of side-effects. The most widely used commercially available preparations in Europe are the triacetin based gels administered either vaginally or endocervically (Prostin Gel and Prepidil respectively; Upjohn), the lactose based vaginal tablet (Prostin Tablet; Upjohn), and the starch based gel (Cerviprost; Organon). Recently a sustained release hydrogel polymer pessary (Controlled Therapeutics) has been assessed and was marketed as Propess (Roussel Laboratories Limited) in the UK. We have previously reported changes in plasma prostaglandin metabolites in-vivo following administration of 1 mg of PGE, triacetin-based vaginal gel (Upjohn) Correspondence: Professor I. A. Greer, Department of Obstetrics and Gynaecology, University of Glasgow, Royal Infirmary, 10 Alexandra Parade, Glasgow G312ER, UK.

and the 3 mg of PGE, lactose-based vaginal tablet (Greer et al. 1990), which suggested that both preparations released PGE, rapidly, but that the triacetin gel provided much greater bioavailability than the tablet. PGE, is an organic acid and is therefore less soluble in aqueous solution at low pH (Stehle 1982). As the vagina normally presents an acid environment with a mean pH of 4.09 (SD 0.52) at 3 7 4 2 weeks gestation (Gleeson et al. 1989) this could influence the availability of PGE, from vaginal preparations. The presence of factors such as vaginal infection will alter the normal pH of the vaginal environment being associated with a higher pH (Peeters et al. 1972). The aim of this study was to determine the PGE2 release characteristics of vaginal and endocervical PGE, preparations invitro and the effect thereon of pH. In addition, as obstetric cream is commonly used when women are examined before the induction of labour or during application of a prostaglandin preparation, we studied the effect on PGE, release of precoating one of these preparations, the hydrogel polymer pessary, with obstetric cream.



T. A . J O H N S O N E T A L .

Subjects and methods Four preparations were studied; 1 mg of PGE, triacetin gel (Prostin Gel; Upjohn, UK), 3 mg of PGE, lactose based vaginal tablet (Prostin Tablet; Upjohn, UK), 0.5 mg of PGE, starch-based gel (Cerviprost; Organon, UK) and the 10 mg of PGE, sustained release hydrogel polymer pessary (Controlled Therapeutics, UK). Each preparation was placed in a cellulose dialysis bag (Sigma, UK) and suspended in a flask containing 1000 ml of Ringers lactate solution maintained at 37°C in a shaking water bath (Gallenkamp, UK), kept at a constant 30 shakesimin. The experiment was performed at p H 7.4, p H 5.4 and pH 3.4 with the p H of the solution being adjusted by means of addition of hydrochloric acid and sodium hydroxide. The p H values were chosen to reflect (i) neutral pH (7.4); (ii) the p H just above which PGE, solubility changes abruptly (pH 5.4) (Stehle 1982); and (iii) a p H at the lower end of the range of vaginal p H (3.4). This covered a range of p H values from 3.4 to 7.4 spaced at equal intervals. A 5 ml aliquot of the Ringer lactate solution was taken at the following time intervals; 0 min (before the PGE, was inserted into the flask), and at 10,20,30,45,60,120,150,180,240,300, 360,420 and 480 min. The sustained release hydrogel preparation was sampled for a longer time period in view of its sustained release characteristics, and additional samples were taken at 540, 600, 660 and 720 min. In addition, the effect of precoating these pessaries with obstetric cream (Hibitane, ICI, LJK) was also assessed (the gels were not assessed with obstetric cream as it was impossible to coat them uniformly and as release from the lactose based tablet was found to be very poor, this preparation was also not assessed with obstetric cream). PGE, was measured by radioimmunoassay of the methyloxime derivative of PGE, as described previously (Kelly et aE. 1986,1989). The intra-assay coefficient of variation was 12.3% and interassay coefficient of variation 13.3%. The residual PGE, content of the hydrogel polymer pessaries was measured by high performance liquid chromatography (Barras et al. 1988) at the end of the experiment. Each preparation was studied three times at p H 3.4 and p H 5.4 and four times at neutral pH. The effect of p H on the release of PGE, over time was analysed for each preparation by means of a one factor analysis of covariance (Superanova programme; Abacus Concepts, California). In this analysis PGE, was the dependent variable, time was the regressor (covariate) and p H the factor studied in the statistical analysis. The interaction between time and p H was statistically significant for all preparations studied, therefore within each group the release of PGE, at each p H was compared with each of the other p H values in turn by further one factor analysis of covariance for the interaction of time and p H on PGE, concentration. The effect of precoating the hydrogel pessaries with obstetric cream was assessed by a two factor analysis of covariance to assess the interaction between precoating with obstetric cream, p H and time. In this analysis PGE, was the dependent variable, time the regressor and p H and obstetric cream the two factors studied.

Results The results are shown in Figs. 1and 2 and Tables 1 and 2. All

four preparations produced a significant increase in PGE, concentration in the bathing fluid over time and p H had a significant effect on prostaglandin concentrations obtained over time with all four preparations (ANCOVA for interaction of time and pH: F = 6.991, P

The effect of pH on release of PGE2 from vaginal and endocervical preparations for induction of labour: an in-vitro study.

To study the effect of pH and precoating with obstetric cream on the release of prostaglandin E2 (PGE2) from commercially available triacetin and star...
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