MIFEPRISTONE ORAL FORM FOR ITS USE IN CERVIX RIPENING AND LABOUR INDUCTION

Abstract

The invention relates to an oral dosage form of mifepristone of mifepristone oral formulation characterised in that said formulation comprises an amount selected from the group consisting of 75 mg, 150 mg or 300 mg mifepristone, and said formulation is for its use in the induction of labour and cervix ripening in a woman being at least 37 weeks pregnant.

Claims

1-10. (canceled)

11. A method of inducing labor in a pregnant woman with at least 37 weeks gestation and an unfavourable cervix with a Bishop score of between 0 to 6, the method comprising administering to the pregnant woman a mifepristone oral formulation comprising an amount of mifepristone selected from the group consisting of 75 mg, 150 mg, and 300 mg.

12. The method according to claim 11, wherein the pregnant woman is with at least 40 weeks gestation.

13. The method of claim 11, wherein the mifepristone oral formulation comprises 75 mg or 150 mg of mifepristone and the pregnant woman is multiparous.

14. The method of claim 11, wherein the pregnant woman has had a previous Caesarean section.

15. The method of claim 14, wherein the mifepristone oral formulation comprises 75 mg of mifepristone.

16. The method of claim 11, wherein the pregnant woman is multiparous and the mifepristone oral formulation comprises 150 mg or 300 mg of mifepristone.

17. The method of claim 11, wherein the pregnant woman is primiparous and the mifepristone oral formulation comprises 150 mg or 300 mg of mifepristone.

18. The method of claim 11, wherein the mifepristone oral formulation is administered in a single administration to the pregnant woman.

19. The method of claim 11, wherein the mifepristone oral formulation is further administered to the pregnant woman 24 hours±6 hours or 48 hours±6 hours after a first administration if her Bishop score is less than 6.

20. The method of claim 11, wherein the mifepristone oral formulation is administered in combination with a manual treatment selected from the group consisting of balloon catheter, manual dilatation, and combinations thereof, or with at least one further therapeutic agent selected from the group consisting of prostaglandins, prostaglandin analogues, and oxytocin.

21. The method of claim 11, wherein the induction of labour is carried out on an outpatient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0035] The present invention provides new dosages of a mifepristone oral formulation.

[0036] The first object of the invention is a mifepristone oral formulation comprising an amount of mifepristone selected from the group consisting of 75 mg, 150 mg or 300 mg, for use in the induction of labour in a pregnant woman with at least 37 weeks' gestation and an unfavourable cervix with a Bishop score of between 0 to 6.

[0037] Mifepristone (CAS number: 84371-65-3), also known as RU-486, is a steroidal antiprogestogen of the following formula:

##STR00001##

[0038] In the presence of progesterone, it acts as a competitive progesterone receptor antagonist. As a result of the withdrawal of the inhibitory effect of progesterone, there is an increase in the synthesis of prostaglandins. Sensitivity of the myometrium to the contraction inducing activity of prostaglandins markedly increased after mifepristone administration.

[0039] According to the present invention, the dosages of mifepristone are useful for inducing labour in a pregnant woman who is at term, i.e. a woman who is at least 37 weeks pregnant, preferably at least 40 weeks, more preferably 41 weeks. The dosages of mifepristone oral formulation according to the invention are specifically useful for ripening the cervix and thus inducing labour in full-term women when medically indicated.

[0040] Preferably, the Bishop score of the pregnant woman can be 6 or less than 6 more preferably 5 or less than 5 and even more preferably 4 or less than 4. The Bishop score, also known as Pelvic Score, is commonly used to rate the readiness of the cervix for induction of labour. The Bishop Score gives points to 5 measurements of the pelvic examination: dilation, effacement of the cervix, station of the foetus, consistency of the cervix, and position of the cervix. Each measurement is given a sub-score between 0 and 3 as follows:

TABLE-US-00001 TABLE 1 Cervical Exam 0 point 1 point 2 points 3 points Dilation Closed 1-2 cm 3-4 cm 5-6 cm Effacement (%) 0-30% 40-50% 60-70% 80% and more Station −3 −2 −1, 0 +1, +2 Consistency of the Firm medium soft cervix Position of cervix posterior Mid anterior

[0041] According to an embodiment of the invention, said pregnant woman is multiparous and had a previous Caesarean section, preferably said mifepristone oral formulation comprises 75 mg of mifepristone.

[0042] In a first embodiment, the mifepristone In a first embodiment, the mifepristone oral formulation for its use according the invention can comprise 75 mg or 150 mg of mifepristone when said pregnant woman is multiparous. Multiparous is the medical term for a woman having experienced one or more previous childbirths. However, within the context of the present invention, multiparous designates a woman having experienced two or more previous childbirths. According to the first embodiment, the mifepristone oral formulation for its use according the invention can comprise 75 mg or 150 mg of mifepristone when said pregnant woman has experienced 2 or more previous childbirths.

[0043] In a second embodiment, the mifepristone oral formulation for its use according the invention can comprise 150 mg or 300 mg of mifepristone when said pregnant woman is nulliparous. Nulliparous is the medical term for a female that has not borne offspring.

[0044] In a third embodiment, the mifepristone oral formulation for its use according to the invention can comprise 150 mg or 300 mg of mifepristone when said pregnant woman is a primiparous. Primiparous is the medical term for a female that has borne only one offspring. According to the third embodiment, the mifepristone oral formulation for its use according the invention can comprise 150 mg or 300 mg of mifepristone when said pregnant woman has experienced one previous childbirth.

[0045] The mifepristone oral formulation for its use according to the invention can be used for its single administration to the pregnant woman. The mifepristone oral formulation of the invention can be dosed only once to the pregnant woman the day of her arrival to labour induction. In this embodiment, the single administration is enough to induce cervix ripening and no further administration of said mifepristone oral formulation, therapeutic agent or manual treatment is required for labour induction.

[0046] The mifepristone oral formulation for its use according to the invention can be further administered to the pregnant woman 24 hours±6 hours or 48 hours±6 hours after the first administration if her Bishop score is still less than or 6.

[0047] Advantageously, the mifepristone oral formulation for its use according to the invention can increase the Bishop score at least 24 hours±6 hours after the first administration.

[0048] According to an aspect of the invention, the mifepristone oral formulation comprising an amount selected from the group consisting of 75 mg, 150 mg or 300 mg mifepristone, and said formulation is for use in the induction of labour in a pregnant woman with at least 37 weeks' gestation and an unfavourable cervix with a Bishop score of 6 or less than 6, and wherein: [0049] at Day 0: mifepristone is administered once to said pregnant woman, and if no signs of delivery [0050] optionally at Day 1: the Bishop score of said pregnant woman is determined, and/or [0051] optionally at Day 2: the Bishop score of said pregnant woman is determined,
and when a Bishop score of above 6 is observed, the pregnant woman will be treated with labour inducing compounds or methods according to a standard protocol. Standard protocols can be found in the WHO recommendations for induction of labour (ISBN: 978 92 4 150115 6) or adopted by the physician.

[0052] According to an embodiment, the mifepristone oral formulation comprising an amount selected from the group consisting of 75 mg, 150 mg or 300 mg mifepristone is for use in the induction of labour in a pregnant woman with at least 37 weeks gestation and an unfavourable cervix with a Bishop score of 6 or less than 6, and wherein said mifepristone oral formulation is administered only once to said pregnant woman on Day 0. Day 0 is the day of her arrival for the induction of the labour. In this embodiment, the mifepristone oral formulation is sufficient to induce and induce the labour in said pregnant woman within 1 or 2 days, without the further administration of therapeutic agents or manual treatment conventionally used for labour induction.

[0053] According to another embodiment, the mifepristone oral formulation comprising an amount selected from the group consisting of 75 mg, 150 mg or 300 mg mifepristone is for use in the induction of labour in a pregnant woman with at least 37 weeks gestation and an unfavourable cervix with a Bishop score of 6 or less than 6, and wherein said mifepristone oral formulation is administered a first time at Day 0, and if no sign of delivery, the Bishop score of said woman is determined at Day 1 and/or Day 2, and said mifepristone oral formulation can be further administered at Day 1 or Day 2. In this embodiment, the pregnant woman receives a first dose of the mifepristone oral formulation of the invention on Day 0. Then the Bishop score can be assessed on Day 1 and/or Day 2. According to the Bishop score of said pregnant woman, the mifepristone oral formulation according to the invention can be further administered either at Day 1, after the assessment of the Bishop score at Day 1 or before the assessment of the Bishop score at Day 2, or be further administered at Day 2, after the assessment of the Bishop score at Day 1 and/or Day 2. The skilled person is able to determine the moment to administer a second dose of the mifepristone oral formulation to said pregnant woman according to the Bishop score.

[0054] The mifepristone oral formulation according to the invention allows the ripening of the cervix and improves the Bishop score. Preferably, the mifepristone oral formulation for its use according to the invention can increase the Bishop score of the pregnant woman of 2 or at least 2.

[0055] In an embodiment of the invention, the induction of labour is outpatient. Indeed, the pregnant woman can receive the first dose, and possibly the second dose, and wait for the labour to start in the comfort of her home.

[0056] Advantageously, the mifepristone oral formulation for its use according to the invention can be used in combination with at least one further therapeutic agent or manual treatment chosen amongst prostaglandins, prostaglandins analogues, oxytocin, balloon catheter, manual dilatation, and their combination. The further therapeutic agent can be used at the usual dosage or carried out conventionally.

[0057] The mifepristone oral formulation for its use according to the invention can be a solid oral form chosen amongst a tablet, a capsule, an oral dispersible dosage form, a sachet, granules, a powder. In a preferred embodiment, the mifepristone oral form is a tablet, more preferably a breakable tablet.

[0058] The mifepristone oral formulation can further comprise at least one pharmaceutical acceptable excipient chosen amongst carriers, fillers, diluents, preservative, biding agents, wetting agent, dispersible agents, sweetener, flavouring agents, colouring agents, flow agents. The skilled person can use the appropriate pharmaceutical excipients to formulate the oral formulation according to the invention.

[0059] In the context of the invention, a “pharmaceutically acceptable” salt or excipient means any salt or excipient authorized by the European Pharmacopoeia (noted “Ph. Eur.”) and the United States Pharmacopoeia (noted “United States Pharmacopeia (USP)”).

[0060] In the most preferred embodiment, the mifepristone oral formulation of the invention is a tablet, preferably a breakable tablet, and further comprises corn starch, povidone, magnesium stearate, anhydrous colloidal silica and microcrystalline cellulose.

Example

[0061] A clinical trial is conducted on 150 pregnant women between 18 and 40 years old. The inclusion criteria were: [0062] full-term pregnancy women at week 40+5 days of gestation, [0063] Bishop score ≤5 at day 0 (baseline), [0064] intact membranes, [0065] primiparous women, [0066] BMI before pregnancy ≤30, [0067] singleton physiological pregnancy, and [0068] pregnancy without medical medication (no risk factors, no abnormalities in clinical and laboratory examinations during pregnancy).

[0069] The women either receive a 75 mg tablet, a 150 mg tablet or a 300 mg tablet of mifepristone at Day=0 of the trial or a placebo in the control group. The Bishop score is assessed 24 hours after the first administration of either mifepristone or placebo.

[0070] The primary endpoints of the study are a gain in Bishop score 48 hours from baseline and the presence or any adverse events. The secondary endpoints are the following: [0071] rate of subjects with Bishop score gain ≤2, [0072] change in Bishop Score after 24 hours, [0073] time to vaginal delivery, [0074] rate of spontaneous vaginal delivery (without any assistance other than mifepristone or placebo in the control group), and rate of Caesarean sections

[0075] Regarding the babies, a follow-up study is performed at the day of delivery, day of delivery +1 and day of delivery +2. The follow-up study comprises the assessment of the following measurements: [0076] Apgar Score (1, 5 and 10 minutes after the delivery) [0077] Vital signs [0078] Physical examination [0079] Newborn screening tests (day of delivery +1) [0080] Dosage of mifepristone and metabolites in umbilical cord blood (day of delivery) [0081] Dosage of ACTH, cortisol and aldosterone in umbilical cord blood (day of delivery) [0082] Concomitant medication, [0083] Adverse event recording.

[0084] The Apgar score is a method to quickly assess the health of new-born child. The Apgar score is determined by evaluating the new-born baby on five simple criteria on a scale from zero to two, then summing up the five values, as shown in Table 2. The resulting score thus ranges from zero to 10. The five criteria are summarized using words chosen to form a backronym (Appearance, Pulse, Grimace, Activity, Respiration).

TABLE-US-00002 TABLE 2 Parameter Score of 0 Score of 1 Score of 2 Skin color blue or pale blue at extremities, no cyanosis body (Appearance) all over body pink and extremities (acrocyanosis) pink Pulse rate Absent <100 beats per ≥100 beats per (Pulse) minute minute Reflex No response to grimace on suction cry on stimulation irritability stimulation or aggressive (Grimace) stimulation Muscle tone None Some flexion flexed arms and (Activity) legs that resist extension Respiratory absent weak, irregular, strong, robust cry effort gasping (respiration)

[0085] Another evaluation of the baby's health is carried out at the age of 5 months. Local paediatricians are asked to complete a questionnaire containing the information on psychomotor development, medication, any pathology in laboratory findings or any examinations, and adverse events.

[0086] Statistical analysis: a statistical analysis is done on the treatment difference for the gain in Bishop score at 48 hours from baseline The 2-sided 95% confidence interval is calculated and reported to detect a statistically significant and clinically relevant treatment effect.