GB2293101A - Butaprost compositions for preventing pre-term labour - Google Patents

Abstract

Compositions designed to achieve constant butaprost concentrations of less than 1 mu M at the myometrium surface inhibit uterine contractions while avoiding undesired side-effects and are useful in preventing preterm labour. The compositions are in the form of infusions, pessaries, gels or tablets and may further include anti-microbials, e.g. metronidazole or cefuroxime and/or inhibitors of bacterial prostaglandins, e.g. nabumetone, flosulide and SC 58125.

Description

COMPOUND FOR USE IN PRE-TERM LABOUR Background to the invention Field of the invention This invention concerns the prevention of pre-term labour and in particular a compound for use in the management of pre-term labour.

Description of the Related Art Pre-term delivery is a major cause of perinatal mortality and remains so, despite advances in obstetrics and neonatal care over the last decade. In any birth before 37 weeks of gestation, over 80% of neonatal deaths are due to early delivery rather than foetal abnormality. Aggressive treatment using existing tocolytic therapy may cause distress to the mother and foetus and many clinicians question the relevance of such therapy since there are few obvious benefits to the foetus and the possibility of risk to the patient is increased. The value of tocolytic therapy in pre-term labour thus remains doubtful since the incidence of pre-term delivery has not been reduced and prematurity is still the major contributing factor in neonatal mortality.The availability of modem technology allows the immature foetus to survive but the risk of permanent damage to the foetus and the cost of maintaining life are considerable. However, it is these advances in neonatal care, rather than improved tocolytic therapy, which have improved perinatal mortality rates in recent years.

Existing tocolytic therapies as reported in the literature include the use of ss-adrenoceptor mimetics such as ritodrine, salbutamol and terbutaline, magnesium sulphate and calcium channel antagonists. Other treatments under investigation include the use of oxytocin antagonists and prostaglandin synthesis inhibitors. However, these existing treatments for pre-term labour lack efficacy and no novel treatments have emerged to alter the overall perinatal mortality and morbidity rate in the last decade. Clearly there is an urgent need to find a safe and effective way of halting pre-term labour and prolonging gestation.

Present prostanoid receptor classification states that each of the natural prostanoids has its own receptor termed the P receptor where that particular prostanoid is at least ten times more potent than any of the other prostanoids. Thus the prostaglandin E2 (PGE2) sensitive receptor is termed the EP-receptor and likewise PGF2a the FP-receptor; PGD2 the DP-receptor; PGI2, the IP-receptor and thromboxane A2 (TXA2), the TP receptor. The EP receptor, according to this classification based on selective agonists and antagonists in both functional and binding studies, has been subdivided into at least 4 major subtypes, the EP" EP2 EP3 and EP4.Smooth muscle activation of the EP, and EP3 receptors usually results in stimulation of activity, whereas activation of EP2 receptors usually results in relaxation and EP4 activation results in dilation of certain vascular preparations.

Functional studies on human myometrium show the presence of EP" EP, and EP3 receptors on human myometrium. Selective prostaglandin agonists, antagonists and analogues as well as natural prostaglandins were used to characterise the receptors found on the human myometrium.

Senior et al. reports on the characterisation of receptors present on human myometrium in non-pregnant (Br J Pharmacol 1992 1Q2, 215-221 and Br J Pharmacol 1991 102 747-753) and term pregnant subjects (Br J Pharmacol 1993 108, 501-506). It was suggested that the potent inhibitory action of some synthetic prostaglandin analogues of these receptors could be useful in clinical hyperactivity states such as pre-term labour.

Butaprost was mentioned as the most selective EP2 receptor agonist used to date. Its use as a bronchodilator has been reported and it has been suggested for use in the treatment of bronchial asthma (Nials et al., Cardiovascular Drug Reviews 111993 165-179). It has also been shown that butaprost is dilator on human uterine artery in the micromolar concentration range (2-6) but was at least 100-fold weaker than PGE2 suggesting that EP2 receptors are not involved in this response (Baxter et al., 1995, Br J Pharmacol., 116 16921696).

The present inventor has surprisingly discovered that contrary to these reports butaprost is actually not a suitable compound for use in the management of pre-term labour as the literature articles would predict. Firstly, in vivo the half life of butaprost is very low and unpredictably, butaprost has a constrictor effect on the human umbilical artery.

Surprisingly since butaprost has a weak dilator effect on the human uterine artery, this was not predictable. Thus this constrictor affect seems specific to the umbilical artery and is unusual which has the undesirable and dangerous side effect of causing foetal distress.

Summarv of the invention It has surprisingly been found that butaprost when locally applied in a consistent dosage can be useful in the management of pre-term labour without the associated dangerous or undesirable side effects outlined above. Accordingly, the current invention is based on the observation that for butaprost to be a useful tool in the management of pre-term labour it must be at a concentration of less than 1 micromolar at the myometrium and present at a consistent level over a long period of time.

Thus according to a first aspect of the invention there is provided a pharmaceutical composition comprising butaprost for the treatment of pre-term labour wherein the composition is adapted to ensure that the concentration of butaprost at the myometrium surface is substantially constant and at a concentration of less than 1 micromolar.

Description of the Preferred Embodiments In the research directed towards the study of receptors on the human myometrium, many EP agonists have been employed but few show absolute selectivity for the individual EP" EP, and EP3 receptor types. Senior et al. (Br J Pharmacol 1993,108, 501-506) reports that butaprost is the most selective EP2 agonist used to date but, although inhibiting myometrial activity it was reported by Lawrence & Jones (Br J Pharmacol 1992, 105, 817-824) to have a constrictor effect on chick ileum and thus would not be indicative of any clinically useful role in pre-term labour management. This, coupled with the recent observations about a contractile effect on the umbilical artery effectively rule out butaprost as a serious approach to the management of pre-term labour. The full range of prostanoid receptors implicated in this response are not known but it is thought that thromboxane receptors account for at least 50%.

The observations that the concentrations of butaprost actually required for myometrial inhibition is less than the concentrations for toxicity and constrictor activity to become apparent lie at the heart of the invention. The problem is one of ensuring that the concentration of butaprost at the myometrium is correct to have advantageous and not disadvantageous effects.

The pharmaceutical composition of the present invention is adapted to achieve this aim. Thus, the concentration of butaprost at the myometrial surface is achieved over long periods of time by various methods. For example, a patient could be given a continuous infusion of butaprost. More preferable are controlled release formulation such as pessaries, gels and tablets. These have an added advantage of being locally (intravaginally) applied.

Most preferred are controlled release compositions comprising butaprost and a polymeric composition according to GB 2047094B, the contents of which are incorporated herein by reference.

Suitable dosages will depend on individual cases but generally will be in the range 1 0nM min-'. This dosage will maintain the necessary concentration of butaprost at the myometrial surface and can be maintained as long as necessary from hours to weeks depending upon the needs of the patient.. Preferably, retrieval devices are included if the composition takes the form of a pessary.

It has often been difficult to diagnose and manage pre-term labour which has led to inappropriate use of drugs. In some cases pre-term delivery is induced by pathogens present in the maternal reproductive tract. In such cases, appropriate antimicrobial therapy is provided. This is an area where treatment is promising in the management of pre-term labour. Conveniently then, the pharmaceutical composition of the present invention also includes an antimicrobial for the management of this infection. Currently used antimicrobials which may be applied topically for this condition and are thus suitable for inclusion in a controlled release locally applied formulation such as a pessary, include metronidazole and concentrations in the range of Img Kg-' bodyweight hour are desirable.It would also be useful to administer butaprost intravaginally as described hereinabove together with systemically administered antimicrobials e.g. cefuroxime either by infusion or orally.

Additionally, pre-term labour is often induced by bacterially induced prostaglandins. The enzyme prostaglandin GIH synthase-2 (PG HS-2) also named cyclo-oxygenase 2 is responsible for this synthesis and hence, the pharmaceutical composition of the invention together with or instead of the antibiotic also includes an inhibitor of this enzyme. Inhibitors include nabumetone, flosulide and SC 58125 and a concentration range of 0.01-0.1mM is preferable.

It will be appreciated by a person skilled in the art that a person in pre-term labour can be supplied with any combination of the above described pharmaceutical compositions depending upon whether or not there is an infection of the maternal reproductive tract when the patient presents herself.

The invention will now be illustrated by way of Example with reference to Figure 1 which shows the effect of various prostanoids on the human umbilical artery in vitro.

Example 1 Inhibitory activitv of butaprost on human mvometrium Method Samples of gestational human myometrium (term pregnancy) from the lower segment were removed at elective Caesarean section (non-labouring) and set up in a superfusion apparatus (n = 8). Tissues were tested for sensitivity by administering PGE, (5nM) as a bolus dose and only those strips which responded with a biphasic or inhibitory response were used. The concentration of butaprost was administered in the superfusate over a 15 min period and the number of tissues responding with complete inhibition of myogenic activity was recorded.

Results Butaprost at a concentration of 0.1 micromolar administered over a 15 min period caused complete inhibition of myogenic activity. The mean recovery time for the myogenic activity after cessation of superfusion of butaprost (0. micromolar) was 22 % 5 mins. No stimulation of uterine activity was noted at any dose of butaprost investigated.

The EP2 agonist, butaprost, is a potent inhibitor of human myometrial activity and is devoid of stimulant action.

The results are shown in Table 1 below.

TABLE 1 The % of samples of human myometrium from pregnant donors responding to the EP2 agonist, butaprost, at various concentrations.

Concentration of butaprost No response Complete inhibition InM 100 0 10nM 75 25 0.1 M 0 100 IpM 0 100 10 M 0 100 Example 2 Umbilical Arterv - effect of butaprost and other prostanoids Method The specimens of umbilical cord were set up in the laboratory within 120 mins of delivery of the foetus. The artery from the central section of the cord was dissected free of connective tissue and immersed in Krebs solution containing indomethacin 2.79 micromolar gassed with 2.5% 2 8% CO2 89.5% N2 at 370C. Cumulative dose-response curves were obtained from agonists.

Results and Conclusions Preliminary results using various prostanoid agonists are shown in Figure 1 (n = 4).

The ECs0 values for other agonists used are shown in Table 2. The thromboxane mimetic, U46619, is a potent constrictor of human umbilical artery in vitro, suggesting the presence of TP receptors on this tissue. The constrictor effects of PGF2a and PGE2 occur at much higher concentrations, suggesting that these compounds may be acting through the TP receptors rather than FP and EP receptors on this tissue. The constrictor effect of butaprost is surprising, since it is known to act selectively through EP2 receptors which normally show relaxant effects. As can clearly be seen this constrictor effect of butaprost is only apparent at concentrations greater than l,uM.

TABLE 2 The EC50 values for prostanoid agonists on human umbilical artery in vitro.

Prostanoid EC50 (AM) U46619 0.007 PGF2a 5 PGE2 20 Butaprost 60

Claims (7)

1. CLAIMS 1. A pharmaceutical composition for the treatment of pre-term labour comprising butaprost wherein the composition is adapted to ensure that the concentration of butaprost at the myometrium surface is substantially constant and at a concentration of less than 1 micromolar.
2. 2. A pharmaceutical composition according to claim 1 which is an infusion.
3. 3. A pharmaceutical composition according to claim 1 adapted for controlled release.
4. 4. A pharmaceutical composition according to claim 3 which is a pessary.
5. 5. A pharmaceutical composition according to claim 4 wherein the pessary includes a retrieval device.
6. 6. A pharmaceutical composition according to any preceding claim which further includes an antimicrobial.
7. 7. A pharmaceutical composition according to claim 6 wherein the antimicrobial is metronidazole.