New medical use of tafaxiaparin

Abstract

The present invention relates to tafaxiparin for use in a natural delivery attack in a full-term pregnant woman, wherein tafaxiparin is administered in a daily dose of 30-320 mg per day.

Description

Technical Field

[0001] The present invention relates to a heparin derivative tafoxiparin for use in the onset of spontaneous labor in women with full-term pregnancy. Background Art

[0002] During pregnancy, the uterus is primarily quiescent, with a rigid and closed cervix designed to maintain the fetus within the uterus during pregnancy. Slowly during pregnancy and more rapidly as you approach term, uterine tissue undergoes structural changes in the extracellular matrix (ECM) and an increase in gap junctions, facilitating the onset and progression of labor. At the same time, the cervix remodels to a more supple state, a process often referred to as cervical ripening. This ripening process is critical for inducing the latent stages of labor, and dysregulation in this process may result in the failure of natural labor progression to initiate spontaneously at the appropriate time. Failure of the natural onset of labor may result in complications for both the mother and the unborn child. This is particularly true for nulliparous women, i.e. women who have never given birth before.

[0003] The standard approach used to induce labor involves amniocentesis, medical intervention, or a combination of both. The choice of which intervention to use is based primarily on the degree of cervical ripening. If the cervix is ​​considered ripe, mechanical stimulation alone or in combination with intravenous oxytocin is sufficient to initiate labor within a short period of time, but in the case of an unfavorable cervix, medical intervention in the form of prostaglandins (such as PGE2 or PGE1) or a cervical balloon may be required (Penfield CA et al 2017; Obstet Gynecol Clin N Am 44; pp. 567-582).

[0004] For many years, topical administration of prostaglandins E2 (PGE2) and E1 (PGE1) has been routine. However, due to the side effect of hyperconstriction, which can adversely affect umbilical cord blood flow and threaten asphyxia, lower doses of oral PGE1 have been tested (Penfield CA et al 2017; Obstet Gynecol Clin N Am 44; pp. 567-582).

[0005] Oxytocin is an endogenous mediator of labor and a potent inducer of uterine contractions. Exogenous intravenous oxytocin is often used to induce labor, especially when combined with amniocentesis (Mackenzie IZ 2006; Reproduction; 131(6); pp. 989-998).

[0006] WO 2003 / 055499 describes the use of certain sulfated glycosaminoglycans for the prevention and treatment of slow progress in term labor. WO 2013 / 147689 describes the use of chemically modified heparin or heparan sulfate in inducing labor. WO 2013 / 147690 describes the use of chemically modified heparin or heparan sulfate in the termination of labor. WO 2013 / 169194 describes the use of chemically modified heparin or heparan sulfate in the treatment of postpartum hemorrhage (PPH). WO 2013 / 095279 describes a novel chemically modified glycosaminoglycan that is described as being useful for the prevention and treatment of delayed labor (dystocia), protein leakage (such as Gorham Stout syndrome), sepsis, and protein-losing enteropathy. WO 2014 / 202982 describes a novel manufacturing process for preparing chemically modified glycosaminoglycans.

[0007] WO 2021 / 165240 describes the use of tafoxitin in the treatment of pre-eclampsia.

[0008] Abstract O-063 in Reproductive Sciences Vol. 29, Supplement 1, March 2022, mentions a study that examined the effects of using tafoxitin for up to 7 days on cervical ripening rates. Summary of the invention

[0009] The object of the present invention is a novel therapy for achieving the onset of spontaneous labor in women with term pregnancy.

[0010] More specifically, the present invention relates to tafoxitin for the onset of spontaneous labor in women at term pregnancy, wherein the tafoxitin is administered in a daily dose of 30-320 mg.

[0011] Yet another aspect of the invention is the use of tafoxitin as monotherapy.

[0012] BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The proportion of women achieving spontaneous onset of labor when treated with 300 mg tafoxiparin, 150 mg tafoxiparin, 75 mg tafoxiparin, and placebo, respectively, is shown.

[0014] Figure 2 is a statistical analysis (Kaplan-Meier curve, number of vaginal deliveries) of the time to delivery for women in response group I. The figure shows the time to delivery until vaginal delivery (delivery) for women with spontaneous onset of labor and for women who have been treated with 300 mg tafoxiparin, 150 mg tafoxiparin, 75 mg tafoxiparin and placebo, respectively.

[0015] Figure 3 Shown are the changes in Bishop score (cervical ripening) for women treated with 300 mg tafoxitin, 150 mg tafoxitin, 75 mg tafoxitin and placebo, respectively, and with spontaneous onset of labor.

[0016] Figure 4 The pattern of vaginal delivery for women treated with 300 mg tafoxiparin, 150 mg tafoxiparin, 75 mg tafoxiparin and placebo and with spontaneous onset of labor is shown.

[0017] Figure 5 The delivery pattern of women treated with 300 mg tafoxiparin, 150 mg tafoxiparin, 75 mg tafoxiparin and placebo and with spontaneous onset of labor are shown.

[0018] Figure 6 Shown are the cervical ripening rates measured by the Bishop score during the first 7 days of treatment with 300 mg tafoxiparin, 150 mg tafoxiparin, 75 mg tafoxiparin and placebo, respectively. DETAILED DESCRIPTION

[0019] Aspects of the invention are tafoxitin

[0020] (i) having an anti-factor IIa activity of less than 10 IU / mg;

[0021] (ii) having an anti-factor Xa activity of less than 10 IU / mg; and

[0022] (iii) having a weight average molecular weight (Mw) of 4.6 to 6.9 kDa;

[0023] (iv) having a predominantly present sugar of (Formula I):

[0024]

[0025] in

[0026]

[0027] n is an integer from 2 to 20, such that the polysaccharide chain has from 2 to 20 disaccharide units corresponding to a molecular weight between 1.2 and 12 kDa;

[0028] (v) wherein the polysaccharide chains are substantially free of chemically intact non-sulfated iduronic acid and / or glucuronic acid from a pentasaccharide sequence that mediates anticoagulant effects; and

[0029] (vi) wherein the chemically modified glycosaminoglycans have a distribution of polysaccharides and their corresponding molecular weights expressed as cumulative % by weight according to the following table:

[0030]

[0031] For the onset of spontaneous labor in women with full-term pregnancy, wherein the tafoxitin is administered at a daily dose of 30-320 mg per day.

[0032] Another aspect of the invention is tafoxitin for use in the onset of spontaneous labor in a term pregnant woman, wherein the tafoxitin is administered as a monotherapy in a daily dose of 30-320 mg per day.

[0033] In one aspect of the invention, the polysaccharide chains predominantly present in the tafoxitin used according to the invention have between 6 and 12 disaccharide units with a molecular weight of 3.6-7.2 kDa.

[0034] In another aspect of the invention, tafoxiparin as described herein produces signals at 5.95 ppm and 6.15 ppm in the 1H-NMR spectrum.

[0035] In one aspect of the invention, the tafoxitin used according to the invention contains a non-reducing terminal unsaturated glucosamine which appears as a signal in the interval of 5.0 to 6.5 ppm in the 1H-NMR spectrum with an intensity (% ratio) of less than 4% relative to the signal at 5.42 ppm from native heparin.

[0036] One aspect of the invention is tafoxitin as described herein, for use as a monotherapy.

[0037] One aspect of the invention is a method for the onset of spontaneous labor in a term pregnant woman, wherein a therapeutically effective amount of tafoxitin is:

[0038] (i) having an anti-factor IIa activity of less than 10 IU / mg;

[0039] (ii) having an anti-factor Xa activity of less than 10 IU / mg; and

[0040] (iii) having a weight average molecular weight (Mw) of 4.6 to 6.9 kDa;

[0041] (iv) having a predominantly present sugar of (Formula I):

[0042]

[0043] in

[0044]

[0045] n is an integer from 2 to 20, such that the polysaccharide chain has from 2 to 20 disaccharide units corresponding to a molecular weight between 1.2 and 12 kDa;

[0046] (v) wherein the polysaccharide chains are substantially free of chemically intact non-sulfated iduronic acid and / or glucuronic acid from the pentasaccharide sequence that mediates the anticoagulant effect; and

[0047] (vi) wherein the chemically modified glycosaminoglycans have a distribution of polysaccharides and their corresponding molecular weights expressed as cumulative % by weight according to the following table:

[0048]

[0049] A daily dose of 30-320 mg is administered to the full-term pregnant women.

[0050] Another aspect of the present invention is a method for the onset of spontaneous labor in a term pregnant woman, wherein a therapeutically effective amount of tafoxitin is administered to the term pregnant woman as a monotherapy.

[0051] One aspect of the present invention is the use of tafoxitin in the manufacture of a medicament, wherein:

[0052] (i) having an anti-factor IIa activity of less than 10 IU / mg;

[0053] (ii) having an anti-factor Xa activity of less than 10 IU / mg; and

[0054] (iii) having a weight average molecular weight (Mw) of 4.6 to 6.9 kDa;

[0055] (iv) having a predominantly present sugar of (Formula I):

[0056]

[0057] in

[0058]

[0059] n is an integer from 2 to 20, such that the polysaccharide chain has from 2 to 20 disaccharide units corresponding to a molecular weight between 1.2 kDa and 12 kDa;

[0060] (v) wherein the polysaccharide chains are substantially free of chemically intact non-sulfated iduronic acid and / or glucuronic acid from the pentasaccharide sequence that mediates the anticoagulant effect; and

[0061] (vi) wherein the chemically modified glycosaminoglycans have a distribution of polysaccharides and their corresponding molecular weights expressed as cumulative % by weight according to the following table:

[0062]

[0063] The drug is used in a daily dose of 30-320 mg for the onset of spontaneous labor in women with full-term pregnancy.

[0064] In one aspect of the invention, tafoxitin is used as a monotherapy.

[0065] In one aspect of the invention, the daily dose of tafoxitin for use according to the invention is 50-320 mg.

[0066] In one aspect of the invention, the daily dose of tafoxitin for use according to the invention is 50-300 mg.

[0067] In another aspect of the invention, the daily dose of tafoxitin for use according to the invention is 75-320 mg.

[0068] In another aspect of the invention, the daily dose of tafoxitin for use according to the invention is 75-300 mg.

[0069] In another aspect of the invention, the daily dose of tafoxitin for use according to the invention is 75-150 mg.

[0070] Another aspect of the invention is tafoxitin for use in the onset of spontaneous labor in a full-term pregnant woman, wherein the tafoxitin is administered in a daily dose of 50-320 mg (eg 50-300 mg).

[0071] Another aspect of the invention is tafoxitin for use in the onset of spontaneous labor in a full-term pregnant woman, wherein the tafoxitin is administered in a daily dose of 75-320 mg (eg 75-300 mg).

[0072] Another aspect of the invention is tafoxitin for use in the onset of spontaneous labor in a term pregnant woman, wherein the tafoxitin is administered in a daily dose of 75-150 mg.

[0073] Another aspect of the invention is tafoxitin for use in the onset of spontaneous labor in a term pregnant woman, wherein the tafoxitin is administered as a monotherapy in a daily dose of 50-320 mg (eg 50-300 mg).

[0074] Another aspect of the invention is tafoxitin for use in the onset of spontaneous labor in a term pregnant woman, wherein the tafoxitin is administered as a monotherapy in a daily dose of 75-320 mg (eg 75-300 mg).

[0075] Another aspect of the invention is tafoxitin for use in the onset of spontaneous labor in a term pregnant woman, wherein the tafoxitin is administered as a monotherapy in a daily dose of 75-150 mg.

[0076] In one aspect of the invention, the daily dose of tafoxitin used according to the invention is 30 mg per day; or 40 mg per day; or 50 mg per day; or 60 mg per day; or 70 mg per day; or 80 mg per day; or 90 mg per day; or 100 mg per day; or 110 mg per day; or 120 mg per day; or 130 mg per day; or 140 mg per day; or 150 mg per day; or 160 mg per day; or 170 mg per day; or 180 mg per day; or 190 mg per day; or 200 mg per day; or 210 mg per day; or 220 mg per day; or 230 mg per day; or 240 mg per day; or 250 mg per day; or 260 mg per day; or 270 mg per day; or 280 mg per day; or 290 mg per day; or 300 mg per day; or 310 mg per day; or 320 mg per day.

[0077] In one aspect of the invention, the daily dose of tafoxitin used according to the invention is selected from any daily dose: 30-320 mg, such as 35-320 mg; 40-320 mg, such as 45-320 mg; 50-320 mg, such as 55-320 mg; 60-320 mg, such as 65-320 mg; 70-320 mg, such as 75-320 mg; 80-320 mg, such as 85-320 mg; 90-320 mg, For example, 95-320mg; 100-320mg, for example, 105-320mg; 110-320mg, for example, 115-320mg; 120-320mg, for example, 125-320mg; 130-320mg, for example, 135-320mg; 140-320mg, for example, 145-320mg; 150-320mg, for example, 155-320mg; 160-320mg, for example, 165-320mg; 1 70-320mg, for example 175-320mg; 180-320mg, for example 185-320mg; 190-320mg, for example 195-320mg; 200-320mg, for example 205-320mg; 210-320mg, for example 215-320mg; 220-320mg, for example 225-320mg; 230-320mg, for example 235-320mg; 240-320mg, for example 245-320mg; 250-320mg, for example 255-320mg; 260-320mg, for example 265-320mg; 270-320mg, for example 275-320mg; 280-320mg, for example 285-320mg; and 290-320mg, for example 295-320mg; 300-320mg, for example 305-320mg; and 310-320mg, for example 315-320mg.

[0078] In one aspect of the invention, tafoxitin and the uses described herein are administered once daily.

[0079] In another aspect of the invention, tafoxitin and the uses described herein are administered twice daily.

[0080] In another aspect of the invention, tafoxitin and the uses described herein are administered three times daily.

[0081] In one aspect of the invention, tafoxitin and the uses described herein are for use for up to 14 days (inclusive).

[0082] In one aspect of the invention, tafoxitin and the uses described herein are used for 1 day, or 2 days, or 3 days, or 4 days, or 5 days, or 6 days, or 7 days, or 8 days, or 9 days, or 10 days, or 11 days, 12 days, 13 days or 14 days.

[0083] One aspect of the invention is tafoxitin for use in the onset of spontaneous labor in a term pregnant woman, wherein a daily dose of 30-320 mg of tafoxitin is administered as a double dose (ie 60-640 mg per day).

[0084] In another aspect of the present invention, tafoxitin is used for the onset of spontaneous labor in a full-term pregnant woman, wherein the subject (woman) is an obese subject (woman). The term "obese" means a subject (woman) with a BMI (body mass index) of 30 or more (e.g., 35 or more, or 40 or more, or 45 or more, or 50 or more).

[0085] In one aspect of the invention, tafoxitin and the uses described herein are for use in full-term pregnant women at 36-42 weeks of gestation.

[0086] In one aspect of the invention, tafoxiparin and the uses described herein are for full-term pregnant women at 37-42 weeks of gestation. In another aspect of the invention, tafoxiparin and the uses described herein are for full-term pregnant women at 38-42 weeks of gestation. In another aspect of the invention, tafoxiparin and the uses described herein are for full-term pregnant women at 39-42 weeks of gestation. In another aspect of the invention, tafoxiparin and the uses described herein are for full-term pregnant women at 40-42 weeks of gestation. In another aspect of the invention, tafoxiparin and the uses described herein are for full-term pregnant women at 41-42 weeks of gestation. In another aspect of the invention, tafoxiparin and the uses described herein are for full-term pregnant women at 42 weeks of gestation.

[0087] In one aspect of the invention, tafoxitin and the uses described herein are for use in term pregnant women with immature cervixes.

[0088] In one aspect of the invention, the Bishop score of the full-term pregnant woman is 6 or less.

[0089] In one aspect of the invention, the Bishop score of the full-term pregnant woman is 5 or less.

[0090] In one aspect of the invention, the Bishop score of the full-term pregnant woman is 4 or less.

[0091] In one aspect of the invention, the Bishop score of the full-term pregnant woman is 3 or less.

[0092] In one aspect of the invention, the Bishop score of the full-term pregnant woman is 2 or less.

[0093] In one aspect of the invention, the Bishop score of the full-term pregnant woman is 1 or less.

[0094] In one aspect of the invention, the Bishop score of a full-term pregnant woman is 0.

[0095] One aspect of the invention is tafoxitin for use in the onset of spontaneous labor in a nulliparous full-term pregnant woman, wherein tafoxitin is administered to said woman in a daily dose of 30-320 mg.

[0096] One aspect of the invention is tafoxitin for use in the onset of spontaneous labor in a nulliparous full-term pregnant woman, wherein tafoxitin is administered to said woman as a monotherapy in a daily dose of 30-320 mg.

[0097] One aspect of the invention is tafoxitin for use in the onset of spontaneous labor in a nulliparous, term pregnant woman with a Bishop score of 6 or less, wherein the tafoxitin is administered to the woman in a daily dose of 30-320 mg.

[0098] One aspect of the invention is tafoxitin for use in the onset of spontaneous labor in a nulliparous, term pregnant woman with a Bishop score of 6 or less, wherein tafoxitin is administered to said woman as a monotherapy at a daily dose of 30-320 mg.

[0099] In one aspect of the invention, tafoxitin is used in term pregnant women who have given birth previously or have not given birth previously (nulliated).

[0100] In one aspect of the invention, tafoxitin is used to induce labor in a woman who is pregnant at term, as described herein.

[0101] In one aspect of the invention, tafoxitin is used to induce labor in a term pregnant woman to achieve the onset of spontaneous labor, as described herein.

[0102] In one aspect of the invention, tafoxitin is used to promote the onset of spontaneous labor in a term pregnant woman, as described herein.

[0103] Another aspect of the invention is tafoxip for use in supporting a term pregnant woman to achieve the onset of spontaneous labour, as described herein.

[0104] Another aspect of the invention is tafoxip for use in initiating the onset of spontaneous labor in a term pregnant woman, as described herein.

[0105] Another aspect of the invention is the use of tafamidis for remodeling the cervix and myometrium of a term pregnant woman to achieve the onset of spontaneous labor, as described herein.

[0106] In one aspect of the invention, tafoxitin is used for the uses as described throughout this patent specification, including cervical ripening.

[0107] One aspect of the invention is tafoxitin for use in ripening the cervix of a pregnant woman at term, wherein tafoxitin is administered to said woman in a daily dose of 30-320 mg.

[0108] One aspect of the invention is tafoxitin for use in ripening the cervix of a pregnant woman at term, wherein tafoxitin is administered to said woman as a monotherapy at a daily dose of 30-320 mg.

[0109] One aspect of the invention is tafoxitin for use in ripening the cervix in a term pregnant woman with a Bishop score of 6 or less, wherein tafoxitin is administered to said woman as a monotherapy at a daily dose of 30-320 mg.

[0110] One aspect of the invention is tafoxitin for use in ripening the cervix in a nulliparous woman at term with a Bishop score of 6 or less, wherein tafoxitin is administered to said woman in a daily dose of 30-320 mg.

[0111] One aspect of the invention is tafoxitin for use in ripening the cervix in nulliparous women at term with a Bishop score of 6 or less, wherein tafoxitin is administered to said woman as monotherapy at a daily dose of 30-320 mg.

[0112] One aspect of the present invention is tafoxipin for use in alleviating fetal distress in a fetus of a woman who is pregnant at term.

[0113] One aspect of the invention is that tafoxitin for use as described throughout the patent specification further provides an increase in the rate of vaginal births. The phrase "increase in vaginal births" means that treatment with tafoxitin as described herein reduces the need for instrumental births.

[0114] One aspect of the invention is that tafoxitin is used for the purposes as described throughout the patent specification for providing a reduction in the need for instrumental delivery. The phrase "providing a reduction in the need for instrumental delivery" means that women who have been treated with tafoxitin require instrumental delivery less frequently than the need for instrumental delivery required by women who have not been treated with tafoxitin.

[0115] One aspect of the invention is the use of tafamidis for use in term pregnant women with an unfavorable cervix.

[0116] Another aspect of the invention is the use of tafoxitin for triggering the onset of spontaneous labor in a term pregnant woman.

[0117] One aspect of the invention is the use of tafoxitin in a term pregnant woman with an unfavorable cervix, wherein the woman undergoes triggered therapy with tafoxitin to achieve the onset of labor.

[0118] One aspect of the invention is the use of tafoxxiparin as a trigger therapy for term pregnant women with an unfavorable cervix to reduce the need for standard of care (SOC) interventions to achieve the onset of labor.

[0119] definition

[0120] Tafoxiparin is a heparin derivative with the company compound code DF01. The INN (International Nonproprietary Name) of DF01 is Tafoxiparin Sodium. The CAS Registry Number (CAS RN) of Tafoxiparin is RN 1638190-65-4. DF01 is a depolymerized form of heparin with essentially no anticoagulant activity.

[0121] More specifically, tafoxitin is a heparin derivative:

[0122] (i) having an anti-factor IIa activity of less than 10 IU / mg;

[0123] (ii) having an anti-factor Xa activity of less than 10 IU / mg; and

[0124] (iii) having a weight average molecular weight (Mw) of 4.6 to 6.9 kDa (e.g., 5.0-6.9 kDa);

[0125] (iv) having a predominantly present sugar of (Formula I):

[0126]

[0127] in

[0128]

[0129] n is an integer from 2 to 20, such that the polysaccharide chain has from 2 to 20 disaccharide units corresponding to a molecular weight between 1.2 kDa and 12 kDa;

[0130] (v) wherein the polysaccharide chains are substantially free of chemically intact non-sulfated iduronic acid and / or glucuronic acid from the pentasaccharide sequence that mediates the anticoagulant effect; and

[0131] (vi) wherein the chemically modified glycosaminoglycans have a distribution of polysaccharides and their corresponding molecular weights expressed as cumulative % by weight according to the following table:

[0132]

[0133] The polysaccharide chains predominantly present in tafoxitin have between 6 and 12 disaccharide units with a molecular weight of 3.6-7.2 kDa.

[0134] Tafoxitin may have a non-reducing terminal unsaturated glucosamine, which appears as a signal in the range of 5.0 to 6.5 ppm in the 1H-NMR spectrum, having an intensity (% ratio) of less than 4% relative to the signal at 5.42 ppm from natural heparin, and may also produce signals at 5.95 ppm and 6.15 ppm in the 1H-NMR spectrum.

[0135] Tafoxitin may contain an ethylene glycol cleavage residue according to the following chemical structure:

[0136]

[0137] The expression "spontaneous onset of labor" as used herein means that labor is initiated without any additional standard of care (SOC) intervention, such as amniocentesis, use of a balloon catheter, or use of medical intervention, or any combination of these.

[0138] As used herein, the phrase "induction of labor", also known as induction of labor, means ripening the cervix and stimulating the myometrium to achieve a given labor. As used throughout the patent specification, induction of labor or the phrase "induction of labor" means that a full-term pregnant woman is unable to achieve the onset of labor without the use of standard therapeutic treatments.

[0139] As used herein, the phrase "onset of spontaneous labor combined with SOC intervention" means labor achieved in a term pregnant woman by monotherapy with tafaximin (up to 7 days as described herein), wherein the tafaximin monotherapy is subsequently combined with SOC therapy.

[0140] As used herein, the expression "IMP (Investigational Medicinal Product)" refers to tafoxitin.

[0141] As used herein, the expression "LMWH" means low molecular weight heparin.

[0142] As used herein, "standard of care (SOC)" therapy means the use of amniocentesis, balloon catheters, or drug interventions, or any combination of these.

[0143] Oxytocin is a well-known drug (peptide hormone) used in standard therapeutic therapy to induce or increase contractions of the uterine myometrium.

[0144] Prostaglandins (such as PGE2 or PGE1) are well-known drugs used as standard treatment to promote cervical ripening and myometrial contraction in women with immature cervix. Examples of prostaglandins commonly used in induction of labor are misoprostol (PGE1) and / or dinoprostone (PGE2).

[0145] "Labor induction interventions" means standard methods used to induce labor. Such standard methods are amniocentesis, pharmacological interventions, or a combination of both. The choice of which intervention to use is based primarily on the ripeness of the cervix. If the cervix is ​​considered ripe, mechanical stimulation alone or in combination with intravenous oxytocin is sufficient to initiate labor within a short period of time, but in the case of an unfavorable cervix, pharmacological interventions in the form of prostaglandins (such as PGE2 or PGE1), or a cervical balloon may be required.

[0146] A balloon catheter is a device used in cervical ripening to help dilate the cervix.

[0147] Amniocentesis, also called artificial rupture of membranes (AROM) or "sac rupture," is the intentional disruption of the amniotic sac by an obstetrician.

[0148] The expression "drug intervention" as used throughout the patent specification means drugs used as standard therapeutic treatment in inducing labor.

[0149] As used herein, the expression "inducing labor in a woman" means that tafoxitin is administered to a full-term pregnant woman with the purpose of providing the onset of spontaneous labor in said woman, or promoting the progress of delivery of a baby.

[0150] As used herein, the expression "oxytocic therapy" means that tafoxitin is administered to a pregnant woman at term with the purpose of providing the onset of spontaneous labor in said woman, or promoting the progress of labor of a baby.

[0151] A woman with an immature cervix is ​​one who is unable to spontaneously initiate natural labor progression. Women with an immature cervix typically have a Bishop score of 6 or less, 5 or less, 4 or less, 3 or less, 2 or less, 1 or less, or 0.

[0152] The Bishop score is a rating of the cervix's readiness for vaginal delivery of a baby. The Bishop score, also known as the cervical score, is a prenatal scoring system that helps doctors predict whether an induction of labor will be necessary. In the field of obstetrics, a Bishop score of 8 or higher is considered favorable for a spontaneous vaginal birth without the need for induction of labor. A Bishop score of 6 or lower can be considered an unfavorable cervix, which may require induction of labor.

[0153] Cervical ripening is a remodeling process that results in a softening of the cervix. The progress of cervical ripening is assessed by estimating the change in the Bishop score.

[0154] Cervical dilation refers to how many centimeters a woman’s cervix has opened. During a vaginal birth, the cervix needs to be dilated about 10 centimeters before a woman can start pushing.

[0155] As used herein, "onset of labor" is defined as the last documentation of 4 cm cervical dilation visualized on the partograph and progress of labor.

[0156] As used herein, the expression "monotherapy" means the treatment of a term pregnant woman with tafoxitin alone.

[0157] As used herein, the phrase "full-term pregnant woman" refers to a woman who is 36 weeks pregnant or more, such as 37 weeks pregnant, or 38 weeks pregnant, or 39 weeks pregnant, or 40 weeks pregnant, or 41 weeks pregnant, or 42 weeks pregnant.

[0158] The term "post term pregnant" or ("post term pregnancy") refers to a pregnant woman after 42 weeks of pregnancy.

[0159] The term "nulliated woman" refers to a pregnant woman who has not been pregnant before, or a woman who has not given birth before.

[0160] The term "fetal distress" is defined as abnormalities in the fetal heart rate monitoring and / or fetal scalp blood acidosis. The fetus usually limits the deleterious effects of hypoxia in vital organs through a series of responses at the onset of asphyxia, primarily complex regulated redistribution of blood flow. This allows the fetus to survive asphyxia intact unless the damage is severe or prolonged. The most common asphyxiating stresses on the fetus during labor are inadequate uterine blood flow or umbilical cord blood flow and, occasionally, decreased uterine artery oxygenation.

[0161] The term "Operative delivery" or ("Operational Delivery") refers to both cesarean section (CS) and instrumental delivery.

[0162] The term "instrumental delivery" refers to both "forceps delivery" and "vacuum extraction."

[0163] The phrase "operative delivery for fetal distress (ODFD)" means a cesarean section (CS) and / or instrumental delivery, such as forceps delivery and / or vacuum extraction, performed on a full-term pregnant subject to deliver a baby in the presence of signs of fetal distress (i.e., fetal distress).

[0164] The term "labor" refers to the culmination of a woman's pregnancy, with the birth of the baby.

[0165] The wording "natural delivery (smooth delivery)" (" uncomplicated delivery(uncomplicatedpartus) ”) means a woman is able to give birth successfully without intervention such as a caesarean section or the use of an instrumental birth.

[0166] Responder Group I refers to the subjects in the clinical study PPL17 disclosed herein who entered spontaneous labor onset after treatment with 1-7 doses of tafoxitin.

[0167] Responder Group II refers to subjects in the clinical study PPL17 disclosed herein who were given 4-7 doses of tafoxitin and did not enter spontaneous labor onset, but these subjects achieved cervical ripening (defined as Bishop score ≥ 6). Subjects in Responder Group II can have labor induced according to normal standard treatment (such as amniocentesis and oxytocin management), but no earlier than after being given 4 therapeutic doses of tafoxitin.

[0168] Reaction group III means the subjects in the clinical study PPL17 disclosed herein, who have been treated with 7 doses of tafoxitin and have not entered the onset of spontaneous labor, and the cervix of these subjects is not mature. The subjects in reaction group III should be treated with a cervical balloon catheter, which should be left in the cervix until it is discharged, or up to 24 hours. If the cervix is ​​still not mature after 24 hours of balloon catheter treatment, the subject is treated with oral PGE-1 according to clinical routine. When the cervix is ​​ripe (Bishop score ≥ 6), the patient should be induced with amniocentesis and oxytocin. If the subject does not enter labor after PGE-1 and oxytocin treatment, the subject should be treated by the attending physician.

[0169] Responder Group IV refers to the subjects in the clinical study PPL17 disclosed herein who required induction of labor for medical reasons prior to treatment with 7 doses of tafoxitin.

[0170] The term NICU used in the clinical study PPL17 disclosed herein means neonatal intensive care unit.

[0171] Throughout the patent specification and claims, the terms subject, patient and woman are used interchangeably and refer to a full-term pregnant woman as defined herein.

[0172] The singular forms "a / an" and "this / that" can also be used in the plural.

[0173] The wording IUGR means intrauterine growth restriction, a term used when the baby (fetus) in the womb does not grow as expected and is not as large as expected for the stage of the mother's pregnancy (i.e. the gestational age of the unborn baby). The cause of IUGR may be insufficient nutrition, blood flow and oxygen to the placenta and fetus.

[0174] The term CTG recording means fetal cardiotocography recording, which in obstetrics is a technical method of recording (-graphy) the fetal heartbeat using ultrasound (cardio-) and uterine contractions (-toco-) during pregnancy. The machine used to perform the monitoring is called a fetal cardiotocography device, commonly referred to as a fetal monitor.

[0175] Tocolytics are anti-uterine contractile or labor-inhibiting drugs used to inhibit preterm labor. Commonly used tocolytics include beta-2 agonists, calcium channel blockers, NSAIDs, and magnesium sulfate. These drugs can help delay preterm labor by inhibiting uterine muscle contractions, and their use is intended to reduce fetal morbidity and mortality associated with preterm birth.

[0176] The Apgar score is a scoring system commonly used by obstetricians to assess the oxygen level and risk of asphyxia in newborns. The assessment includes 5 parameters, each of which can be given a score of 0 to 2 (i.e., a maximum of 10 points for each time point in the Apgar score). It is usually assessed at 1, 5, and 10 minutes after delivery of all newborns, and newborn monitoring is continued every 5 minutes thereafter.

[0177] Drug formulations and routes of administration

[0178] The tafoxitin used according to the present invention can be administered as a pharmaceutical composition suitable for systemic administration. Examples of systemic administration include parenteral administration, such as by subcutaneous administration, intravenous injection or intramuscular administration.

[0179] The tafoxitin used according to the present invention may also be administered by topical administration. Examples of topical administration that may be used to administer tafoxitin according to the present invention include oral administration, vaginal administration or rectal administration.

[0180] For parenteral administration, tafoxitin can be incorporated into a solution or suspension, which may also contain one or more adjuvants, such as a sterile diluent, such as water for injection, saline, fixed oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents, antibacterial agents, antioxidants, chelating agents, buffers and agents for regulating osmotic pressure. Parenteral pharmaceutical preparations can be filled into ampoules, vials, disposable syringes or as an infusion arrangement, for example for self-administration.

[0181] In one aspect of the invention, tafoxitin according to the invention is for self-administration by a pregnant woman in an outpatient setting.

[0182] Example

[0183] Manufacturing of Tafoxitin

[0184] Tafoxitin as described and used according to the present invention can be prepared according to the synthetic procedures described in Examples 1 to 9 of published patent applications WO 2013 / 095279 or Examples 1 to 3 of WO 2014 / 202982.

[0185] In the myograph experiments performed below, tafoxitin was provided by Dilafor AB, Sweden, as a 150 mg / mL solution:

[0186] Element concentration Function Tafoxitin (DF01) 150mg / mL API Sodium phosphate 15mM pH Buffers hydrochloric acid As needed pH Adjusters Sodium hydroxide As needed pH Adjusters Water for injection Add to 1ml Solvent / Thinner

[0187] Phase II clinical trial

[0188] The clinical phase II trial was conducted as a randomized, double-blind, placebo-controlled, parallel-group proof-of-concept study (Part A), with a conditional dose-finding follow-up study (Part B) to evaluate the efficacy, safety, tolerability and dose response of subcutaneous administration of tafoxitin as an addition to induction therapy for nulliparous women with term pregnancy and immature cervix. The study was conducted in Sweden and Finland (PPL17), and the EMA (European Medicines Agency) description of the study can be found on the EU Clinical Trials Register website (www.clinicaltrialsregister.eu / ctr-search / search?query=PPL17).

[0189] A total of 170 pregnant women at term were randomized to receive 300 mg of tafoxitin or matching placebo (vehicle) subcutaneously every 24±3 hours for a maximum of 7 doses or until delivery (Part A).

[0190] In the dose-finding follow-up study (Part B), a total of 164 pregnant women at term were randomized to receive 75 or 150 mg of tafoxitin subcutaneously every 24 ± 3 hours from the start of induction of labor for a maximum of 7 doses or until delivery.

[0191] Subjects entering ≥37 weeks of gestation may be subject to informed consent procedures.

[0192] Main Objectives

[0193] To evaluate the efficacy of tafoxitin on cervical ripening / cervical ripening rate during and during the first 7 days of treatment, as measured by the Bishop score. All women were required to be examined for cervical status prior to enrollment.

[0194] Secondary Objectives

[0195] To assess the maternal and neonatal safety, tolerability, and dose-response of tafoxitin as add-on therapy in nulliparous women at term with an unripe cervix undergoing induction of labor.

[0196] The following endpoints will be monitored:

[0197] Time from the start of treatment to an increase of ≥2 points in the Bishop score or the onset of spontaneous labor (whichever comes first). Time from the start of treatment to an increase of ≥3 points in the Bishop score or the onset of spontaneous labor (whichever comes first). Time from the start of treatment to an increase of ≥4 points in the Bishop score or the onset of spontaneous labor (whichever comes first).

[0198] Cervical ripening was measured by the change from baseline to end of treatment in the Bishop score.

[0199] The time from onset of labor to delivery was defined as the last documentation of 4 cm cervical dilation visualized on the partograph and labor progress, or the last documentation of 4 cm cervical dilation combined with amniocentesis and intravenous oxytocin administration.

[0200] Proportion of women whose labour lasted ≤8 hours.

[0201] The proportion of women whose labour lasted ≥12 hours was determined.

[0202] Total dose of study medication (IMP).

[0203] Proportion of women with spontaneous onset of labor (response group I).

[0204] Proportion of women with a ripe cervix (reaction groups I+II+III).

[0205] Proportion of women whose labour had to be induced for medical reasons according to clinical practice (response group IV).

[0206] Investigational Drugs (Investigational Medicinal Products, IMPs)

[0207] Part A of the study:

[0208] Tafoxiparin / placebo is provided to the research institution as a kit by Dilafor AB, which is designed to constitute a daily administration of 300mg tafoxiparin or placebo. In addition to the active substance, each ml of the study drug will constitute 0.015M phosphate buffer. The research drug kit for each patient will contain 8 doses, consisting of 2 vials, which contain a minimum extractable volume of 1.6ml 150mg / ml tafoxiparin or placebo. One dose is a reserve dose in case one dose cannot be used. The research product should be administered subcutaneously by research institution personnel every 24±3 hours, up to 7 doses, or until delivery. At each administration, 1.0ml of the drug will be extracted from each of the 2 vials and injected as a separate subcutaneous injection into the abdomen or buttocks area.

[0209] Part B of the study:

[0210] Tafoxi heparin / placebo is provided to the research institution by Dilafor AB as a kit designed to constitute a daily administration of 75 or 150 mg of tafoxi heparin. In addition to the active substance, each ml of the study drug will constitute 0.015M phosphate buffer. The research drug kit for each patient will contain 8 doses, consisting of 2 vials for each injection, which contain a minimum extractable volume of 1.6 ml 150mg / ml tafoxi heparin or placebo. For subjects receiving 75mg tafoxi heparin, one vial will contain the active substance and the other will contain the placebo. For subjects receiving 150mg tafoxi heparin, both vials contain the active substance. One dose is a reserve dose in case one dose cannot be used. The research product should be administered subcutaneously by research institution personnel every 24±3 hours, up to 7 doses, or until delivery. At each administration, 0.5ml of the drug will be extracted from each of the 2 vials and injected as a separate subcutaneous injection into the abdomen or buttocks area.

[0211] Study Product (Placebo):

[0212] A matching placebo saline solution containing 9 mg / ml sodium chloride (NaCl) solution will be supplied to the study site. The placebo saline solution will be indistinguishable from the active solution in appearance, odor, and packaging.

[0213] Non-research products:

[0214] The cervical status will be checked and for women with a Bishop score less than 6 days, a balloon catheter will be inserted after 7 days and expelled or retracted after a maximum of 24 hours. If balloon catheter management is unsuccessful, oral PGE-1 management may be administered according to clinical practice. Cervical balloon catheters and PGE-1 will be provided by the hospital.

[0215] If the cervix is ​​ripe (usually ≥ 6 as scored by the attending physician)

[0216] After 4-7 injections, amniocentesis and oxytocin may be used to induce labor.

[0217] Treatment research and induction of labor

[0218] If a subject is found eligible for the study, she will be randomized to study treatment, either 300 mg tafoxitin per day or matching placebo (Part A), or 75 or 150 mg per day (Part B).

[0219] If Baseline occurred ≤24 hours after Screening, inclusion / exclusion criteria, vital signs, cervical palpation, and concomitant medications (for mothers) were not repeated prior to treatment with IMP.

[0220] Subjects were enrolled in the study when study treatment was initiated with the first injection of IMP.

[0221] In part A of the study, the daily dose of tafoxitin was 300 mg once daily.

[0222] In Part B of the study, the daily dose of tafoxitin is 150 mg or 75 mg, administered once daily. In each daily administration scenario, subjects will receive a subcutaneous injection.

[0223] Study medication will be administered subcutaneously in the abdominal or gluteal region for up to 7 doses or until induction of labor or spontaneous onset of labor. If the cervix is ​​still not ripe after 7 doses of IMP, patients will be given a cervical balloon catheter as a means of inducing labor.

[0224] Cervical palpation should be performed daily. During treatment with IMP and before cervical ripening, membrane sweeps should not be performed to initiate labor.

[0225] Reaction Group I

[0226] Subjects who enter spontaneous labor onset after 1-7 doses of IMP should be managed according to clinical routine.

[0227] Reaction Group II

[0228] Subjects who do not enter spontaneous labor after 4-7 doses but have a ripe cervix (Bishop score ≥ 6) should undergo induction of labor via amniocentesis and oxytocin, but not before the 4th therapeutic dose.

[0229] Reaction Group III

[0230] Subjects who do not enter spontaneous labor after 7 doses of IMP and whose cervix is ​​not ripe should be managed with a hospital-provided cervical balloon catheter according to the instructions provided by the sponsor. The balloon catheter should remain in the cervix until expelled or up to 24 hours. If the cervix is ​​still not ripe after 24 hours of balloon catheter management, PGE-1 should be administered orally according to clinical routine. When the cervix is ​​ripe (Bishop score ≥6), patients should be induced with amniocentesis and oxytocin. If they do not enter labor after management with PGE-1 and oxytocin, they should be managed at the discretion of the attending physician.

[0231] CTG recordings related to PGE-1 disposition should be performed according to clinical practice. Abnormal CTGs with signs of hypercontraction will be treated according to clinical routine and with uterine tocolytics when indicated.

[0232] Reaction Group IV

[0233] Subjects must have labor induced before 7 doses of IMP for medical reasons or subject demand. They should be managed according to clinical practice.

[0234] Conduct of the trial

[0235] Repeat the following procedure every 24 hours or until a ripe cervix is ​​registered (Bishop score ≥ 6):

[0236] Cervical palpation and Bishop score

[0237] · Vital signs (blood pressure (maternal), heart rate (maternal)

[0238] Fetal heart rate monitoring (fetal monitoring)

[0239] Study drug administration

[0240] Injection site reactions

[0241] · Concomitant medication (maternal)

[0242] Adverse events (maternal / fetal)

[0243] If balloon catheter treatment is initiated 7 days after IMP treatment, the following procedure is performed when the balloon catheter is expelled or 24 hours later.

[0244] Vital signs (blood pressure, heart rate)

[0245] Palpate the cervix after 24 hours or when the balloon catheter is expelled

[0246] Injection site reactions

[0247] Concomitant medication (pregnant women)

[0248] Adverse events (maternal / fetal)

[0249] If the cervix is ​​still not ripe after 24 hours of balloon catheter treatment, oral PGE-1 treatment can be given according to clinical practice. CTG recordings should be performed 20-30 minutes before and 1 hour after each PGE-1 administration. Adverse events (maternal / fetal) should be recorded.

[0250] Secondary safety and tolerability endpoints included:

[0251] 1. Proportion of patients undergoing cesarean section (CS).

[0252] 2. Proportion of patients undergoing instrumental delivery (vacuum extraction (VE) / forceps delivery).

[0253] 3. Fetal outcome was measured by birth weight, Apgar score, arterial or venous cord blood acidosis (pH <7.10), and / or base excess <-12mmol / L.

[0254] 4. Indications for surgical delivery.

[0255] 5. The proportion of fetal distress.

[0256] 6. Indications for referral to the neonatal intensive care unit (NICU).

[0257] 7. Proportion of infants who stayed in the NICU for >48 hours.

[0258] 8. Uterine hyperstimulation requiring treatment with tocolytic agents.

[0259] 9. The proportion of patients with postpartum hemorrhage (PPH)>2000ml.

[0260] Selection criteria

[0261] Inclusion

[0262] To participate in this study, subjects must meet the following all Inclusion criteria:

[0263] Nulliparous women aged ≥18 to ≤64 years with an immature cervix ≤4 on the Bishop scale (0-10) and planned induction of labor 4-7 days after IMP.

[0264] Gestational age ≥ 37 weeks, confirmed by ultrasound before 21 weeks of gestation. Singleton pregnancy. Subjects are able to comply with the requirements of the protocol, including being able to attend all required examinations, as determined by the investigator. The investigator is responsible for obtaining signed informed consent from all subjects prior to enrolling them in any study-related procedures.

[0265] Examples of diagnoses that justify induction of labor include postterm pregnancy (40-41 weeks' gestation), gestational diabetes, type 1 diabetes (well controlled), preeclampsia (diastolic blood pressure <100, systolic blood pressure <140), hypertension (well controlled), liver disease (no clinically significant elevation of serum bile acids), maternal age ≥40, humanitarian psychosocial reasons, and / or oligohydramnios.

[0266] exclude

[0267] To participate in the study, subjects must not meet any of the following exclusion criteria: subjects unable to understand written and verbal instructions in the local language; breech presentation and other abnormal fetal presentations; previous uterine scarring; spontaneous rupture of membranes at inclusion; pathological CTG at inclusion; estimated fetal weight >2SD of normal estimated fetal weight, diagnosed earlier by ultrasound and recorded in the patient record; maternal BMI >35 in early pregnancy; known IUGR defined as ≤2SD of normal; presence of eclampsia; severe preeclampsia; HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets); clinically significant vaginal bleeding requiring hospitalization in late pregnancy; placenta previa; previously known coagulopathy (Leyden, heterozygous-OK); Treatment with heparin / LMWH products within six months; current use of any medication that interferes with hemostasis, such as oral anticoagulants, nonsteroidal anti-inflammatory drug (NSAID) compounds, and vitamin K antagonists; current use or use of acetylsalicylic acid (ASA) compounds within one week prior to inclusion; diagnosed with HIV or acute hepatitis; known history of allergy to standard heparin and / or LMWH heparin; history of heparin-induced thrombocytopenia; current drug or alcohol abuse, which the investigator believes should exclude participation in the study; current participation in other interventional drug treatment studies; the subject has a fear of needles, which the investigator believes will affect compliance with the study drug; any relevant conditions, laboratory values, or concomitant medications that the investigator believes make the subject unsuitable for participation in the study.

[0268] childbirth

[0269] The onset of labor was defined as the last documentation of 4 cm of cervical dilation visualized on the partograph and labor progress, or the last documentation of 4 cm of cervical dilation combined with amniocentesis and intravenous oxytocin administration.

[0270] CTG recordings will continue during confirmed labor.

[0271] If slow labor (cervical dilation <1 cm per hour over 3 hours) or arrested labor (no progress over 3 hours) develops in a patient who has not already received oxytocin, oxytocin should be administered according to clinical practice.

[0272] ·The characteristics of the newborn will be assessed and recorded.

[0273] Arterial or venous cord blood will be collected for analysis of acidosis (pH <7.10) and / or base excess <-12mmol / L

[0274] After delivery, subjects will remain in the clinic until discharge, as per clinical practice.

[0275] The primary efficacy endpoint was "cervical ripening rate during treatment up to the first 7 days, as measured by the Bishop score."

[0276] 65% of the women participating in Part A of this clinical study had a Bishop score of 0-2 and 35% of the women participating in Part A of the study had a Bishop score of 3-4.

[0277] result

[0278] like Figure 1 As shown, 41.1% (37 of 90 women) of women treated with 300 mg of tafoxitin achieved spontaneous onset of labor (p value = 0.089; p value for part A of the study was 0.080).

[0279] 42.4% (36 of 85) of women treated with 150 mg of tafoxitin achieved spontaneous onset of labor (p value 0.039). 40.2% (33 of 82) of women treated with 75 mg of tafoxitin achieved spontaneous onset of labor (p value 0.102). Only 28.7% (25 of 87) of women treated with placebo achieved spontaneous onset of labor.

[0280] Thus, all three doses of tafoxitin (300 mg, 150 mg, and 75 mg, respectively) were effective in achieving the onset of spontaneous labor.

[0281] Figure 2 The time to vaginal delivery (delivery) for women who had spontaneous onset of labor and were treated with 300 mg tafoxiparin (p value = 0.070), 150 mg tafoxiparin (p value 0.654) and 75 mg tafoxiparin (p value 0.114) respectively, compared to women treated with placebo are shown. The data showed that women treated with tafoxiparin not only had spontaneous onset of labor, but also had a shorter time to vaginal delivery (delivery) compared to placebo.

[0282] Figure 3 The changes in Bishop scores (cervical ripening) for women treated with 300 mg tafoxiparin, 150 mg tafoxiparin, and 75 mg tafoxiparin and placebo, respectively, and with the onset of spontaneous labor are shown. As shown in the figure, the data clearly show that women treated with 300 mg tafoxiparin and 150 mg tafoxiparin, respectively, achieved the onset of spontaneous labor at an earlier time point than women treated with 75 mg tafoxiparin and placebo, respectively. The data also supports that both 300 mg and 150 mg doses of tafoxiparin have a beneficial effect on cervical ripening.

[0283] Figure 4The vaginal pattern of delivery for women treated with 300 mg tafoxiparin, 150 mg tafoxiparin and 75 mg tafoxiparin and placebo and who had spontaneous onset of labor is shown. As shown in the figure, among women who achieved spontaneous onset of labor, only 18.2% of women treated with 300 mg tafoxiparin (6 of 33 women) required instrumental delivery (p value = 0.048) (p value for Part A of the study was 0.053). Among women treated with 150 mg tafoxiparin and who had spontaneous onset of labor, only 28.1% (9 of 32 women) required instrumental delivery (p value 0.422). Among women treated with 75 mg tafoxiparin and who had spontaneous onset of labor, only 24.1% (7 of 29 women) required instrumental delivery (p value = 0.181). For women treated with placebo and who had spontaneous onset of labor, 45.5% (10 of 22 women) required instrumental delivery.

[0284] This means that for women treated with 300 mg of tafoxiparin, 81.8% (27 of 33 women) achieved spontaneous onset of labor with an uneventful delivery. For women treated with 150 mg of tafoxiparin, 71.9% (23 of 32 women) achieved spontaneous onset of labor with an uneventful delivery, and for women treated with 75 mg of tafoxiparin, 75.9% (22 of 29 women) achieved spontaneous onset of labor with an uneventful delivery. In the placebo group, only 54.5% (12 of 22 women) achieved spontaneous onset of labor and an uneventful vaginal delivery.

[0285] In conclusion, all three doses of tafoxitin (300 mg, 150 mg, and 75 mg) were effective in reducing the need for instrumental delivery in women with spontaneous onset of labor compared with placebo.

[0286] Figure 5 The delivery pattern of women treated with 300 mg tafoxiparin, 150 mg tafoxiparin, 75 mg tafoxiparin and placebo and having spontaneous onset of labor is shown. As shown in the figure, for women having spontaneous onset of labor, the following results were obtained:

[0287] 73% (i.e., 27 of 37 women) treated with 300 mg of tafoxitin achieved delivery by vaginal delivery without instrumental delivery or cesarean section. 63.9% (23 of 36 women) treated with 150 mg of tafoxitin achieved delivery by vaginal delivery without instrumental delivery and cesarean section. 66.7% (22 of 33 women) treated with 75 mg of tafoxitin achieved delivery by vaginal delivery without instrumental delivery and cesarean section. For the group of women treated with placebo, only 48% (i.e., 12 of 25 women) achieved delivery by vaginal delivery without instrumental delivery and cesarean section.

[0288] The figure also shows that among women treated with 300 mg of tafoxiparin and who had spontaneous onset of labor, only 27% of women (i.e., 10 of 37 women) required instrumental delivery or cesarean section to achieve delivery. Among women treated with 150 mg of tafoxiparin and who had spontaneous onset of labor, only 36.1% of women (13 of 36 women) required instrumental delivery or cesarean section to achieve delivery. Among women treated with 75 mg of tafoxiparin and who had spontaneous onset of labor, only 33.3% of women (11 of 33 women) required instrumental delivery or cesarean section to achieve delivery. This should be compared to the placebo group, where 52% of women treated with placebo (i.e., 13 of 25 women) required instrumental delivery or cesarean section.

[0289] From this data, it can be concluded that all three doses of tafoxitin (300 mg, 150 mg, and 75 mg) were effective in enabling women to achieve birth via vaginal delivery and with a reduced need for instrumental delivery or cesarean section compared to placebo.

[0290] Effect of tafoxitin on the onset of labor intervention

[0291] The effects of 300 mg, 150 mg, and 75 mg of tafoxitin on the intervention-induced onset of labor were compared with placebo.

[0292] The results are shown in Table 1 below.

[0293] Table 1

[0294] Interventional labor episodes

[0295]

[0296] As shown in Table 1, the following surprising results were achieved:

[0297] a. 70.5% of women treated with placebo required some type of intervention for induction of labor, compared with 58.2% of women treated with 300 mg of tafoxitin, 56.5% of women treated with 150 mg of tafoxitin, and 57.8% of women treated with 75 mg of tafoxitin.

[0298] b. 58.0% of women in the placebo group experienced induction of labor with a balloon catheter, compared with only 46.2% of women treated with 300 mg of tafoxitin, 43.5% of women treated with 150 mg of tafoxitin, and 42.2% of women treated with 75 mg of tafoxitin.

[0299] c. 54.5% of women in the placebo group underwent oxytocin treatment to induce labor, compared with only 49.5% of women treated with 300 mg of tafoxitin, 44.7% of women treated with 150 mg of tafoxitin, and 41.0% of women treated with 75 mg of tafoxitin.

[0300] d. 56.8% of women in the placebo group underwent amniocentesis to induce labor, compared with only 54.9% of women treated with 300 mg of tafoxitin, 45.9% of women treated with 150 mg of tafoxitin, and 55.4% of women treated with 75 mg of tafoxitin.

[0301] e. 10.2% of women in the placebo group underwent PGE-1 treatment to induce labor, compared with only 5.5% of women treated with 300 mg of tafoxitin, 8.2% of women treated with 150 mg of tafoxitin, and 8.4% of women treated with 75 mg of tafoxitin.

[0302] In conclusion, all three doses of tafoxitin reduced the need for intervention to achieve onset of labor compared with placebo.

[0303] Fetal distress

[0304] Fetal distress was assessed in women undergoing operative delivery (ie, cesarean section or instrumental delivery) and treated with 300 mg tafoxitin, 150 mg tafoxitin, 75 mg tafoxitin, and placebo, respectively.

[0305] The results are shown in Table 2 below.

[0306] Table 2

[0307] Effect of tafoxitin on operative delivery for fetal distress (ODFD).

[0308]

[0309] As can be seen from Table 2, of the 91 women treated with 300 mg of tafoxitin, 11 women (12.1%) required surgical delivery due to fetal distress (ODFD). Of the 85 women treated with 150 mg of tafoxitin, 20 women (23.5%) required surgical delivery due to fetal distress (ODFD). Of the 83 women treated with 75 mg of tafoxitin, 16 women (19.3%) required surgical delivery due to fetal distress (ODFD).

[0310] In contrast, 20 of the 88 women (22.7%) who received the placebo required surgical delivery due to fetal distress.

[0311] Spontaneous labor onset

[0312] In this clinical study, daily monitoring was performed during the first 7 days of treatment with 300 mg tafoxitin, 150 mg tafoxitin and 75 mg tafoxitin and placebo to monitor the number of subjects (women) who achieved spontaneous onset of labor. The results are shown in Table 3 below:

[0313] Table 3

[0314] Summary of the number of subjects (women) who achieved spontaneous onset of labour.

[0315]

[0316] n = number of subjects (women)

[0317] As can be seen in Table 3, the daily progression toward spontaneous labor onset showed a dose-response relationship (i.e., the efficacy response as a function of the drug tafoxitin exposure). The wording "N / A" in Table 3 means that on a particular study day, no remaining subjects (women) did not achieve spontaneous labor onset.

[0318] Cervical ripening rate during the first 7 days of treatment

[0319] The estimated cervical ripening rate was determined by the Bishop score during treatment with all three doses of tafoxitin (300 mg, 150 mg and 75 mg) and during the first 7 days of treatment with placebo. The expression "estimated cervical ripening rate" means an estimate of the numerical value of the cervical ripening rate based on the observed value of the Bishop score.

[0320] like Figure 6 As shown, cervical ripening rates were higher in women treated with all three doses of tafoxitin (300 mg, 150 mg, and 75 mg) compared with women treated with placebo. These results also support a dose-response relationship (i.e., the efficacy response as a function of the amount of drug tafoxitin exposure).

[0321] in conclusion

[0322] The results of this clinical study showed that daily doses of 75 mg, 150 mg and 300 mg of tafoxitin were effective for the onset of spontaneous labor and, when used as a monotherapy, could keep women in the preparation stage of labor and parturition, or reduce the need for standard treatment in women treated with any of the three doses (75 mg, 150 mg and 300 mg) of tafoxitin. In addition, the results showed that the need for surgical delivery (i.e., cesarean section and instrumental delivery) due to fetal distress was reduced. The results also showed that women treated with any of the three doses (75 mg, 150 mg and 300 mg) of tafoxitin achieved cervical ripening at an earlier time point than women treated with placebo, which in turn provided an earlier onset of labor and a smooth delivery.

Claims

1. Tafoxitin for use in the onset of spontaneous labor in a pregnant woman at term, wherein the tafoxitin is administered in a daily dose of 30 to 320 mg per day.

2. Tafoxitin for use according to claim 1, wherein the use is a monotherapy.

3. Tafoxitin for use according to claim 1 or 2, wherein the full-term pregnant woman is at 36-42 weeks of pregnancy.

4. Tafoxitin for use according to claim 3, wherein the full-term pregnant woman is at 37-42 weeks of pregnancy, 38-42 weeks of pregnancy, 39-42 weeks of pregnancy, 40-42 weeks of pregnancy, 41-42 weeks of pregnancy or 42 weeks of pregnancy.

5. Tafoxitin for use according to any one of claims 1 to 4, wherein the woman has an unripe cervix.

6. Tafoxiparin for use according to any one of claims 1 to 5, wherein the woman has a Bishop score of 6 or less, 5 or less, 4 or less, 3 or less, 2 or less, or 1 or less.

7. Tafaxiparin for use according to any one of claims 1 to 6, wherein the dosage of said Tafaxiparin administered is 50-320 mg / day, 75-320 mg / day, or 75-150 mg / day.

8. Tafoxiparin for use according to any one of claims 1 to 7, wherein the daily dose is administered once a day, twice a day or three times a day.

9. Tafoxitin for use according to any one of claims 1 to 8, wherein the use lasts for a maximum of 14 days.

10. Tafoxiparin for use according to claim 9, wherein the use lasts for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days.

11. Tafoxiparin for use according to any one of the preceding claims, wherein the use is for nulliparous women.

12. Tafoxitin for use according to any one of the preceding claims, wherein The use is for inducing labor.

13. Tafoxitin for use according to any one of the preceding claims, wherein the use comprises cervical ripening.

14. Tafoxitin for use according to any one of claims 1 to 13, wherein the term pregnant woman has an unfavorable cervix.

15. Tafaxiparin for use according to any one of claims 1 to 14, wherein the tafaxiparin is administered by parenteral administration.

16. Tafaxiparin for use according to any one of claims 1 to 14, wherein the tafaxiparin is administered by topical administration.

17. Tafoxitin for use according to claim 15, wherein the parenteral administration is intravenous administration, intramuscular administration or subcutaneous administration.

18. Tafoxitin for use according to claim 16, wherein the topical administration is oral administration, vaginal administration or rectal administration.

19. Tafoxiparin for use according to any one of the preceding claims, wherein the use is self-administered by a pregnant woman in an outpatient setting.

20. Tafoxitin for use according to any one of the preceding claims, wherein the use comprises alleviating fetal distress in a fetus.

21. Tafoxitin for use according to any one of the preceding claims, wherein the use further provides for vaginal delivery of the infant.

22. Tafoxitin for use according to any one of the preceding claims, wherein said use reduces the need for surgical delivery of the baby.

23. Tafoxitin for use according to claim 22, wherein the surgical delivery is a caesarean section (CS).

24. Tafoxitin for use according to claim 22, wherein the surgical delivery is an instrumental delivery.

25. Use of tafoxitin for the preparation of a medicament for use in a daily dose of 30 to 320 mg in a woman at term during the onset of spontaneous labour.

26. A method for the onset of spontaneous labor in a full-term pregnant woman, wherein a therapeutically effective amount of tafoxitin is administered to the full-term pregnant woman at a daily dose of 30-320 mg.

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