Novel medical uses of tafoxiparin

Abstract

The present invention is directed to tapoxiparin for use in the spontaneous onset of labour in women at term, administered in a daily dose of 30-320 mg per day.

Description

[Technical field]

[0001] [Field of the Invention] The present invention is directed to the heparin derivative tafoxiparin for use in the spontaneous onset of labor in women at term.

[0002] During pregnancy, the uterus is primarily held in a quiescent state, and the cervix is ​​rigid and closed, designed to maintain the fetus within the uterus during pregnancy. Slowly during pregnancy, and more rapidly as term approaches, the uterine tissue undergoes structural changes in the extracellular matrix (ECM) and an increase in gap junctions, facilitating the initiation and progression of labor. Concurrently, remodeling of the cervix to a softer state occurs, a process commonly referred to as cervical ripening. This ripening process is essential for the induction of the latent phase of labor, and dysregulation in this process may result in the inability to spontaneously initiate the natural labor process in a timely manner. Failure to initiate the natural labor process may result in complications for both the mother and the fetus. This is especially true for nulliparous women, i.e., women who have not given birth before.

[0003] Standard methods used to induce labor are directed toward amniotomy, pharmaceutical intervention, 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 ​​deemed ripe, mechanical stimulation alone or in combination with an intravenous infusion of oxytocin may be sufficient to initiate labor within a short period of time, but if the cervix is ​​unfavorable, pharmacological 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; 567-582).

[0004] The use of topically administered prostaglandins E2 (PGE2) and E1 (PGE1) has been routine for many years, but due to side effects from excessive contractions that adversely affect umbilical blood flow, including threatening asphyxiation, oral low-dose PGE1 is being tested (Penfield CA et al. 2017; Obstet Gynecol Clin N Am 44; 567-582).

[0005] Oxytocin, the endogenous mediator of labor, is a potent inducer of uterine contractions. Intravenous administration of exogenous oxytocin is commonly used to induce labor, especially when used in combination with amniotomy (Mackenzie IZ 2006;Reproduction;131(6);pp.989-998).

[0006] WO 2003 / 055499 describes the use of certain sulfated glycosaminoglycans to prevent and treat slow progression of term labor. WO 2013 / 147689 describes the use of chemically modified heparin or heparan sulfate in labor induction. WO 2013 / 147690 describes the use of chemically modified heparin or heparan sulfate in labor arrest. WO 2013 / 169194 describes the use of chemically modified heparin or heparan sulfate in the treatment of postpartum hemorrhage (PPH). WO 2013 / 095279 describes novel chemically modified glycosaminoglycans that are described as useful in the prevention and treatment of prolonged labor (dystocia), protein leakage such as Gorham-Stout syndrome, sepsis, and protein-losing enteropathy. WO 2014 / 202982 describes a novel manufacturing method for preparing chemically modified glycosaminoglycans. WO 2021 / 165240 describes the use of tapoxiparin in the treatment of preeclampsia. Reproductive Sciences Volume 29, Supplement 1, March 2022, Abstract No. O-063, refers to a study investigating the effect of using tapoxiparin for up to 7 days on cervical ripening rates.

[0007] [Description of the Invention] The object of the present invention is a novel therapy for achieving spontaneous onset of labor in women at term.

[0008] More particularly, the present invention is directed to tapoxiparin for use in the spontaneous onset of labour in women at term, administered in a daily dose of 30-320 mg.

[0009] A further aspect of the invention is the use of tapoxiparin as a monotherapy. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows the proportion of women who achieved spontaneous onset of labor when treated with 300 mg tafoxiparin, 150 mg tafoxiparin, 75 mg tafoxiparin, and placebo, respectively. [Diagram 2] Figure 1 shows statistical analysis of time to delivery (Kaplan-Meier plot, vaginal birth population) for women in response group I. The figure shows time to delivery to time of vaginal delivery (delivery) for women with spontaneous onset of labour and which women were treated with 300 mg tafoxiparin, 150 mg tafoxiparin, 75 mg tafoxiparin, and placebo, respectively. [Diagram 3] FIG. 1 shows the change in Bishop score (cervical ripening) in women who had spontaneous onset of labour and were treated with 300 mg tapoxiparin, 150 mg tapoxiparin, 75 mg tapoxiparin and placebo, respectively. [Figure 4] FIG. 1 shows vaginal delivery patterns for women who had spontaneous onset of labor and were treated with 300 mg tapoxiparin, 150 mg tapoxiparin, 75 mg tapoxiparin, and placebo, respectively. [Diagram 5] FIG. 1 shows the mode of delivery for women who had spontaneous onset of labour and were treated with 300 mg tapoxiparin, 150 mg tapoxiparin, 75 mg tapoxiparin, and placebo, respectively. [Figure 6]FIG. 1 shows the rate of cervical ripening as measured by Bishop score during the first 7 days of treatment with 300 mg tapoxiparin, 150 mg tapoxiparin, 75 mg tapoxiparin, and placebo, respectively. Detailed Description of the Invention

[0011] One embodiment of the invention is a method for the onset of spontaneous labour in women at term, administered at a daily dose of 30 to 320 mg per day. (i) has anti-factor IIa activity of less than 10 IU / mg; (ii) has anti-factor Xa activity of less than 10 IU / mg; and (iii) having a weight average molecular weight (Mw) of 4.6 to 6.9 kDa; (iv) Predominantly occurring sugars of formula I: [ka] (In the formula, [ka] and n is an integer between 2 and 20, resulting in a polysaccharide chain having between 2 and 20 disaccharide units, corresponding to a molecular weight between 1.2 and 12 kDa. having; (v) the polysaccharide chain is essentially free of chemically intact non-sulfated iduronic acid and / or glucuronic acid from the pentasaccharide sequence that mediates the anticoagulant effect; and (vi) Chemically modified glycosaminoglycans are those listed in the following table: [Table 1] and their corresponding molecular weights, This is taphoxiparin.

[0012] A further aspect of the invention is tapoxiparin for use in the spontaneous onset of labour in women at term, administered as monotherapy in a daily dose of 30 to 320 mg per day.

[0013] In one aspect of the invention, the polysaccharide chains predominantly present in the tapoxiparin used according to the invention have between 6 and 12 disaccharide units with a molecular weight between 3.6 and 7.2 kDa.

[0014] In a further aspect of the present invention, the tafoxiparin described herein produces signals at 5.95 ppm and 6.15 ppm in the 1H-NMR spectrum.

[0015] In one embodiment of the invention, the tafoxiparin used according to the invention comprises a non-reducing terminal unsaturated glucosamine presented as a signal in the interval 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.

[0016] One aspect of the invention is tapoxiparin, as described herein, for use as a monotherapy.

[0017] One aspect of the invention is a method for spontaneous initiation of labor in a woman at term, comprising: (i) has anti-factor IIa activity of less than 10 IU / mg; (ii) has anti-factor Xa activity of less than 10 IU / mg; and (iii) having a weight average molecular weight (Mw) of 4.6 to 6.9 kDa; (iv) Predominantly occurring sugars of formula I: [ka] (In the formula, [ka] and n is an integer between 2 and 20, resulting in a polysaccharide chain having between 2 and 20 disaccharide units, corresponding to a molecular weight between 1.2 and 12 kDa. having; (v) the polysaccharide chain is essentially free of chemically intact non-sulfated iduronic acid and / or glucuronic acid from the pentasaccharide sequence that mediates the anticoagulant effect; and (vi) Chemically modified glycosaminoglycans are those listed in the following table: [Table 2] and their corresponding molecular weights, A therapeutically effective amount of tafoxiparin is administered to said full term pregnant female in a daily dose of 30-320 mg.

[0018] A further aspect of the invention is a method for spontaneous initiation of labour in a full term pregnant woman, wherein a therapeutically effective amount of tapoxiparin is administered to said full term pregnant woman as monotherapy.

[0019] One aspect of the invention relates to a method for the manufacture of a medicament for use in the onset of spontaneous labour in a woman at term, at a daily dose of 30 to 320 mg, (i) has anti-factor IIa activity of less than 10 IU / mg; (ii) has anti-factor Xa activity of less than 10 IU / mg; and (iii) having a weight average molecular weight (Mw) of 4.6 to 6.9 kDa; (iv) Predominantly occurring sugars of formula I: [ka] (In the formula, [ka] and n is an integer between 2 and 20, resulting in a polysaccharide chain having between 2 and 20 disaccharide units, corresponding to a molecular weight between 1.2 and 12 kDa. having; (v) the polysaccharide chain is essentially free of chemically intact non-sulfated iduronic acid and / or glucuronic acid from the pentasaccharide sequence that mediates the anticoagulant effect; and (vi) Chemically modified glycosaminoglycans are those listed in the following table: [Table 3] and their corresponding molecular weights, The use of tafoxiparin.

[0020] In one aspect of the invention, tafoxiparin is for use as a monotherapy.

[0021] In one embodiment of the invention, the daily dose of tafoxiparin used according to the invention is 50-320 mg.

[0022] In one embodiment of the invention, the daily dose of tafoxiparin used according to the invention is between 50 and 300 mg.

[0023] In a further embodiment of the invention the daily dose of tafoxiparin for use according to the invention is between 75 and 320 mg.

[0024] In a further embodiment of the invention the daily dose of tafoxiparin for use according to the invention is between 75 and 300 mg.

[0025] In a further embodiment of the invention the daily dose of tafoxiparin for use according to the invention is between 75 and 150 mg.

[0026] A further aspect of the invention is tapoxiparin for use in the spontaneous onset of labour in women at term, administered in a daily dose of 50 to 320 mg, such as 50 to 300 mg.

[0027] A further aspect of the invention is tapoxiparin for use in the spontaneous onset of labour in women at term, administered in a daily dose of 75 to 320 mg, such as 75 to 300 mg.

[0028] A further aspect of the invention is tapoxiparin for use in the spontaneous onset of labour in women at term, administered in a daily dose of 75 to 150 mg.

[0029] A further aspect of the invention is tapoxiparin for use in the spontaneous onset of labour in women at term, administered as monotherapy in a daily dose of 50 to 320 mg, such as 50 to 300 mg.

[0030] A further aspect of the invention is tapoxiparin for use in the spontaneous onset of labour in women at term, administered as monotherapy in a daily dose of 75 to 320 mg, such as 75 to 300 mg.

[0031] A further aspect of the invention is tapoxiparin for use in the spontaneous onset of labour in women at term, administered as monotherapy in a daily dose of 75 to 150 mg.

[0032] In one aspect of the invention, the daily dose of tafoxiparin used according to the invention is 30mg per day; or 40mg per day; or 50mg per day; or 60mg per day; or 70mg per day; or 80mg per day; or 90mg per day; or 100mg per day; or 110mg per day; or 120mg per day; or 130mg per day; or 140mg per day; or 150mg per day; or 160mg per day; or 170mg per day; or 180mg per day; or 190mg per day; or 200mg per day; or 210mg per day; or 220mg per day; or 230mg per day; or 240mg per day; or 250mg per day; or 260mg per day; or 270mg per day; or 280mg per day; or 290mg per day; or 300mg per day; or 310mg per day; or 320mg per day.

[0033] In one embodiment of the invention, the daily dose of tafoxiparin used according to the invention is from 30 to 320 mg, for example from 35 to 320 mg; 40 to 320 mg, for example from 45 to 320 mg; 50 to 320 mg, for example from 55 to 320 mg; 60 to 320 mg, for example from 65 to 320 mg; 70 to 320 mg, for example from 75 to 320 mg; 80 to 320 mg, for example from 85 to 320 mg; 90 to 320 mg, for example from 95 to 320 mg. 20mg;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;170-320mg, 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 g, for example, 255 to 320 mg; 260 to 320 mg, for example, 265 to 320 mg; 270 to 320 mg, for example, 275 to 320 mg; 280 to 320 mg, for example, 285 to 320 mg; and 290 to 320 mg, for example, 295 to 320 mg; 300 to 320 mg, for example, 305 to 320 mg; and 310 to 320 mg, for example, 315 to 320 mg.

[0034] In one aspect of the invention, the tapoxiparin and uses described herein are for once-daily use.

[0035] In a further aspect of the invention, the tapoxiparin and uses described herein are for twice daily use.

[0036] In a further aspect of the invention, the tapoxiparin and uses described herein are for use three times a day.

[0037] In one aspect of the invention, tapoxiparin and the uses described herein are for use for up to 14 days (including the 14th day).

[0038] In one aspect of the invention, the tapoxiparin and uses described herein are for use 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, or 12 days, or 13 days, or 14 days.

[0039] One aspect of the invention is tapoxiparin for use in the onset of spontaneous labour in women at term, wherein the daily dose is 30-320 mg of tapoxiparin administered as a double dose (i.e. 60-640 mg per day).

[0040] In a further aspect of the invention, the tafoxiparin is for use in the spontaneous onset of labour in a female at term of pregnancy, wherein said female subject is an obese female subject. By obese is meant a female subject having a BMI (Body Mass Index) of 30 or more, such as 35 or more, or 40 or more, or 45 or more, or 50 or more.

[0041] In one aspect of the invention, tapoxiparin and the uses described herein are in full-term pregnant women, between 36 and 42 weeks gestation.

[0042] In one aspect of the invention, tapoxiparin and the uses described herein are in full-term women between 37 and 42 weeks of gestation. In a further aspect of the invention, tapoxiparin and the uses described herein are in full-term women between 38 and 42 weeks of gestation. In a further aspect of the invention, tapoxiparin and the uses described herein are in full-term women between 39 and 42 weeks of gestation. In a further aspect of the invention, tapoxiparin and the uses described herein are in full-term women between 40 and 42 weeks of gestation. In a further aspect of the invention, tapoxiparin and the uses described herein are in full-term women between 41 and 42 weeks of gestation. In a further aspect of the invention, tapoxiparin and the uses described herein are in full-term women between 42 weeks of gestation.

[0043] In one aspect of the invention, tapoxiparin and the uses described herein are in women at term who have an unripe cervix.

[0044] In one aspect of the invention, a full term pregnant woman has a Bishop score of 6 or less. In one aspect of the invention, a full term pregnant woman has a Bishop score of 5 or less. In one aspect of the invention, a full term pregnant woman has a Bishop score of 4 or less. In one aspect of the invention, a full term pregnant woman has a Bishop score of 3 or less. In one aspect of the invention, a full term pregnant woman has a Bishop score of 2 or less. In one aspect of the invention, a woman at full term has a Bishop score of 1 or less. In one embodiment of the invention, a full term pregnant woman has a Bishop score of 0.

[0045] One aspect of the invention is tapoxiparin for use in the spontaneous onset of labour in nulliparous term pregnant women administered to said women in a daily dose of 30-320 mg.

[0046] One aspect of the invention is tapoxiparin for use in the spontaneous onset of labour in nulliparous term pregnant women administered as monotherapy at a daily dose of 30-320 mg to said women.

[0047] One aspect of the invention is tapoxiparin for use in the spontaneous onset of labour in a woman who is nulliparous and at term, having a Bishop score of 6 or less, administered to said woman in a daily dose of 30-320 mg.

[0048] One aspect of the invention is tapoxiparin for use in the spontaneous onset of labour in women who are nulliparous and at term, having a Bishop score of 6 or less, administered as monotherapy at a daily dose of 30 to 320 mg.

[0049] In one aspect of the invention, tafoxiparin is for use in full term pregnant women who have either previously borne a child or have not previously borne a child (nulliparous).

[0050] In one aspect of the invention, tafoxiparin is for use in labor priming of women at term as described herein.

[0051] In one aspect of the invention, tafoxiparin is for use in priming a woman at term to achieve spontaneous onset of labor, as described herein.

[0052] One aspect of the invention is tapoxiparin, as described herein, for use in relieving a woman of full term pregnancy to achieve natural onset of labor.

[0053] A further aspect of the invention is tapoxiparin, as described herein, for use in assisting a woman at term to achieve natural onset of labor.

[0054] A further aspect of the invention is tapoxiparin for use to initiate the spontaneous onset of labour in a woman at term as described herein.

[0055] A further aspect of the invention is tapoxiparin, as described herein, for use in remodeling the cervix and myometrium of a woman at term to achieve natural onset of labor.

[0056] In one aspect of the invention, the use of Tafoxiparin for uses described throughout this specification includes cervical ripening.

[0057] One aspect of the invention is tapoxiparin for use in cervical ripening in a female at term to be administered to said female in a daily dose of 30-320 mg.

[0058] One aspect of the invention is tapoxiparin for use in cervical ripening in a woman at term to be administered as monotherapy to said woman in a daily dose of 30 to 320 mg.

[0059] One aspect of the invention is tapoxiparin for use in cervical ripening in term pregnant women having a Bishop score of 6 or less administered as monotherapy at a daily dose of 30 to 320 mg to said women.

[0060] One aspect of the invention is tapoxiparin for use in cervical ripening in women who are nulliparous and at term with a Bishop score of 6 or less, administered at a daily dose of 30 to 320 mg to said women.

[0061] One aspect of the invention is tapoxiparin for use in cervical ripening in women who are nulliparous and at term with a Bishop score of 6 or less, administered as monotherapy at a daily dose of 30 to 320 mg.

[0062] One aspect of the invention is tapoxiparin for use in reducing fetal distress in a female fetus at term.

[0063] An aspect of the present invention is tapoxiparin for uses as described throughout the specification that further provide for an increased rate of vaginal delivery. The phrase "increased rate of vaginal delivery" means that treatment with tapoxiparin as described herein reduces the need for instrumental delivery.

[0064] An aspect of the invention is tapoxiparin for use as described throughout this specification for reducing the need for instrumental delivery. The phrase "reducing the need for instrumental delivery" means that the need for instrumental delivery is less frequent in women treated with tapoxiparin compared to the need for instrumental delivery required in women not treated with tapoxiparin.

[0065] One aspect of the invention is tapoxiparin for use in term pregnant women with an unfavorable cervix.

[0066] A further aspect of the invention is tapoxiparin for use in a woman at term to induce the onset of natural labour.

[0067] One aspect of the invention is tapoxiparin for use in a term pregnant woman having an unfavorable cervix, wherein said woman is subjected to induction therapy with tapoxiparin to achieve onset of labour.

[0068] One aspect of the invention is tapoxiparin for use as induction therapy in term pregnant women with an unfavorable cervix to reduce the need for standard of care (SOC) intervention to achieve onset of labor.

[0069] definition 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 RN1638190-65-4. DF01 is a depolymerized form of heparin that has essentially no anticoagulant activity.

[0070] More particularly, tafoxiparin is (i) has anti-factor IIa activity of less than 10 IU / mg; (ii) has anti-factor Xa activity of less than 10 IU / mg; and (iii) having a weight average molecular weight (Mw) of 4.6 to 6.9 kDa, for example 5.0 to 6.9 kDa; (iv) Predominantly occurring sugars of formula I: [ka] (In the formula, [ka] and n is an integer between 2 and 20, resulting in a polysaccharide chain having between 2 and 20 disaccharide units, corresponding to a molecular weight between 1.2 and 12 kDa. having; (v) the polysaccharide chain is essentially free of chemically intact non-sulfated iduronic acid and / or glucuronic acid from the pentasaccharide sequence that mediates the anticoagulant effect; and (vi) Chemically modified glycosaminoglycans are those listed in the following table: [Table 4] and their corresponding molecular weights, It is a heparin derivative.

[0071] The predominant polysaccharide chain of tafoxiparin has 6-12 disaccharide units with a molecular weight of 3.6-7.2 kDa.

[0072] Tafoxiparin may have a non-reducing terminal unsaturated glucosamine present as a signal in the 1H-NMR spectrum in the interval 5.0-6.5 ppm, with an intensity (% ratio) of less than 4% relative to the signal at 5.42 ppm from native heparin; 1 It is also possible to generate signals at 5.95 ppm and 6.15 ppm in the H-NMR spectrum.

[0073] Tafoxiparin is a glycol-split residue with the following chemical structure: [ka] may include.

[0074] As used herein, the term spontaneous onset of labor means labor that begins without any further standard of care (SOC) intervention, such as amniotomy, use of a balloon catheter, or use of pharmaceutical intervention, or any combination thereof.

[0075] As used herein, induction of labor, also known as induced labor, refers to both cervical ripening and myometrial stimulation to obtain established labor. As used throughout this specification, induction of labor or labor is induced means that a woman at full term does not achieve onset of labor without the use of standard treatment therapy.

[0076] As used herein, the expression spontaneous onset of labor in combination with SOC intervention refers to labor achieved in a full-term pregnant woman by treatment with tapoxiparin monotherapy as described herein, for example for up to 7 days, wherein said tapoxiparin monotherapy is combined with SOC therapy.

[0077] As used herein, the term IMP (investigational drug) refers to tapoxiparin.

[0078] The term LMWH means low molecular weight heparin.

[0079] As used herein, standard of care (SOC) therapy refers to the use of amniotomy, balloon catheters, or pharmaceutical intervention, or any combination thereof.

[0080] Oxytocin is a well-known pharmaceutical agent (a peptide hormone) for use as a standard therapeutic therapy to induce or increase uterine muscle contractions.

[0081] Prostaglandins such as PGE2 or PGE1 are well-known pharmaceuticals for use as standard treatment to promote cervical ripening and uterine muscle contraction in women with sub-ripening cervix. Examples of prostaglandins commonly used in labor induction are misoprostol (PGE1) and / or dinoprostone (PGE2).

[0082] Intervention for labor induction means that standard methods are used to induce labor. Such standard methods are amniotomy, pharmaceutical intervention, or a combination of both. The choice of which intervention to use is mainly based on the ripeness of the cervix. If the cervix is ​​considered ripe, mechanical stimulation alone or in combination with an intravenous infusion of oxytocin may be sufficient to initiate labor within a short period of time, but if the cervix is ​​unfavorable, pharmacological intervention in the form of prostaglandins such as PGE2 or PGE1, or a cervical balloon may be required.

[0083] A balloon catheter is a device used for cervical ripening to help dilate the cervix.

[0084] Amniotomy, also known as artificial rupture of membranes (AROM) or "rupture of the sac," is the intentional rupture of the amniotic sac by an obstetric care provider.

[0085] As used throughout the patent specification, the term pharmaceutical intervention refers to medications used as standard therapeutic therapy in the induction of labor.

[0086] As used herein, priming a woman for labor means that tapoxiparin is administered to a woman at term to provide for the onset of natural labor or to facilitate the process of birth of the baby.

[0087] As used herein, the expression induction therapy to achieve the onset of labour means that tapoxiparin is administered to a woman at term to provide a natural onset of labour in said woman or to facilitate the process of delivery of the baby.

[0088] A woman with a sub-ripening cervix is ​​one who is unable to naturally initiate the natural birth process. Women with a sub-ripening cervix usually 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.

[0089] The Bishop score is an assessment of the readiness of the cervix to deliver the baby vaginally. The Bishop score, also known as the cervical score, is a prepartum scoring system to assist physicians in predicting whether induction of labor will be necessary. A Bishop score of 8 or higher is in the realm of obstetrics considered favorable for spontaneous vaginal birth without the need for induction of labor. A Bishop score of 6 or lower may be considered an unfavorable cervix, possibly requiring induction of labor.

[0090] Cervical ripening is a remodeling process that results in softening of the cervix. The cervical ripening process is judged by assessing the change in Bishop score.

[0091] Cervical dilation refers to how many centimetres a woman's cervix has dilated. During vaginal birth, the cervix needs to dilate about 10 centimetres before a woman can start pushing.

[0092] As used herein, the onset of labor is defined as the last recorded cervical dilation of 4 cm visualized on the partogram and the progress of labor.

[0093] The term monotherapy as used herein refers to the treatment of women at term with tafoxiparin alone.

[0094] As used herein, a full-term pregnant woman is a woman who is 36 weeks pregnant or later, for example 37 weeks, or 38 weeks, or 39 weeks, or 40 weeks, or 41 weeks, or 42 weeks pregnant.

[0095] The terms post term pregnant or post term pregnancy refer to a pregnant woman who is past the 42nd week of pregnancy.

[0096] The term nulliparous woman means a pregnant woman who has not been previously pregnant or a woman who has not previously given birth.

[0097] The term fetal distress is defined as an abnormal fetal cardiotocogram and / or acidosis in the fetal scalp blood. The fetus usually responds to the onset of asphyxiation with a series of responses, primarily a complex regulated redistribution of blood flow that helps to limit the deleterious effects of oxygen restriction in vital organs. This allows the fetus to survive asphyxiation unharmed, unless the injury is severe and prolonged. The most common asphyxiation stress imposed on the fetus during labor is uterine or umbilical cord blood flow deficiency, and sometimes reduced uterine arterial blood oxygenation.

[0098] The term operative or operational delivery refers to Caesarean section (CS) and instrumental delivery.

[0099] The term instrumental delivery means forceps and vacuum extraction.

[0100] The term "operative delivery due to fetal distress (ODFD)" means cesarean section (CS) and / or assisted delivery, such as forceps and / or vacuum extraction, performed on a term pregnant subject to deliver the baby when there are indications that the fetus is not well (i.e., fetal distress).

[0101] The term childbirth refers to the culmination of a woman's pregnancy with the birth of a baby.

[0102] The expression uncomplicated birth means that a woman manages to deliver her baby without the need for interventions such as a caesarean section or the use of instrumental birth.

[0103] Response group I refers to subjects in clinical trial PPL17 disclosed herein who enter spontaneous onset of labor after being treated with 1 to 7 doses of tafoxiparin.

[0104] Responder Group II refers to subjects in the clinical trial PPL17 disclosed herein who are given 4-7 doses of tafoxiparin without going into spontaneous labor but who achieve a ripe cervix (defined as a Bishop score of 6 or greater). Subjects in responder Group II may have labor induced according to the usual standard of care, such as amniotomy and oxytocin treatment, but not before the 4 treatment doses of tafoxiparin have been given.

[0105] Responder group III refers to subjects in clinical trial PPL17 disclosed herein who have been treated with seven doses of tafoxiparin without going into spontaneous labor and have a subripe cervix. Subjects in responder group III must be treated with a cervical balloon catheter that remains in the cervix until expulsion or for a maximum of 24 hours. If the cervix is ​​still not ripe after 24 hours of balloon catheterization, the subject is treated with oral PGE-1 according to clinical routine. If the cervix is ​​ripe (Bishop score 6 or higher), the patient should be induced to labor with amniotomy and oxytocin. If the subject does not go into labor after PGE-1 and oxytocin treatment, the subject must be managed at the discretion of the treating physician.

[0106] Response group IV refers to subjects in the presently disclosed clinical trial PPL17 who, for medical reasons, need to have labor induced before being treated with the seven doses of tafoxiparin.

[0107] The term NICU as used in the clinical trial PPL17 disclosed herein means Neonatal Intensive Care Unit.

[0108] Throughout the patent specification and claims, the terms subject, patient and woman may be used interchangeably and refer to a woman of full term pregnancy as defined herein.

[0109] The singular forms "a," "an," and "the" can also refer to the plural.

[0110] The expression IUGR means intrauterine growth restriction and is the term used when a baby (fetus) in the womb does not grow as expected and is not as large as expected for the mother's gestational age (i.e., the gestational age of the unborn baby). The reason for IUGR can be insufficient nutrition, blood flow, and oxygen to the baby in the placenta.

[0111] The expression CTG recording means cardiotocography and is a technical method in obstetrics to record (-graphy) the fetal heartbeat during pregnancy using ultrasound (cardio-) and uterine contractions (-toco-). The machine used to perform the monitoring is called a cardiotocography and is commonly known as a fetal monitor.

[0112] Tocolytics are anticontractile or labor-inhibiting drugs used to inhibit premature labor. Commonly used tocolytics include β2 agonists, calcium channel blockers, NSAIDs, and magnesium sulfate. These can help delay premature labor by inhibiting uterine muscle contractions, and their use is intended to reduce fetal morbidity and mortality associated with premature labor.

[0113] The Apgar score is a scoring system commonly used by obstetricians to assess a newborn's oxygen levels and risk of asphyxiation. The assessment involves five parameters, each of which can be scored between 0 and 2 points (i.e., a maximum of 10 points at each time point of the Apgar assessment). Assessments are usually performed at 1, 5, and 10 minutes after delivery for all newborns, and then every 5 minutes if the newborn is continuously monitored.

[0114] Pharmaceutical Formulations and Routes of Administration Tafoxiparin used according to the present invention may be administered in a pharmaceutical composition suitable for systemic administration, such as parenteral administration, such as by subcutaneous administration, intravenous injection, or intramuscular administration.

[0115] Tafoxiparin used according to the present invention may also be administered by topical administration. Examples of topical administration that may be useful for administering Tafoxiparin according to the present invention include oral, vaginal, or rectal administration.

[0116] For parenteral administration, tafoxiparin may be incorporated into a solution or suspension that may also contain a sterile diluent, such as water for injection, physiological saline, fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents, one or more adjuvants, such as antibacterial agents, antioxidants, chelating agents, buffers, and agents for regulating osmotic pressure. Parenteral pharmaceutical preparations may be filled into ampoules, vials, disposable syringes, or as infusion arrangements, such as for self-administration.

[0117] In one aspect of the invention, the tafoxiparin described according to the invention is for use by self-administration by pregnant women in an outpatient setting. EXAMPLES

[0118] Manufacturing of Tafoxiparin The tafoxiparin as described and used according to the present invention may be prepared by following the synthetic procedures described in published patent applications WO 2013 / 095279, Examples 1-9 or WO 2014 / 202982, Examples 1-3. In the myograph experiments performed below, tafoxiparin was provided by Dilafor AB, Sweden, as a 150 mg / mL solution: [Table 5]

[0119] Phase II Clinical Trials A phase II clinical trial will be conducted as a randomized, double-blind, placebo-controlled, parallel group proof-of-concept study (Part A) and a conditional dose-ranging follow-up study (Part B) to evaluate the efficacy, safety, tolerability and dose-response of subcutaneously administered tafoxiparin as an adjunct to induction therapy in nulliparous women at term with an under-ripening cervix. The trial will be conducted in Sweden and Finland (PPL17) and the EMA description of the trial can be found on the EU Clinical Trials Register web (www.clinicaltrialsregister.eu / ctr-search / search?query=PPL17).

[0120] A total of 170 term pregnant women will be randomized to receive either 300 mg of tafoxiparin or matching placebo (vehicle) subcutaneously every 24±3 hours for up to a total of 7 doses or until delivery (Part A).

[0121] In the dose-ranging follow-up study (Part B), a total of 164 term pregnant women will be randomized to receive either 75 mg or 150 mg of tafoxiparin subcutaneously every 24 ± 3 hours from the start of induction of labor for up to a total of 7 doses or until delivery.

[0122] Subjects entering the 37th week of pregnancy or later may be subject to informed consent procedures.

[0123] Main purpose To evaluate the effectiveness of tafoxiparin on cervical ripening / cervical ripening rate during and up to the first 7 days of treatment, as measured by Bishop score. All women must be examined to confirm their cervical status prior to enrollment.

[0124] Secondary Objectives To assess the maternal and neonatal safety, tolerability, and dose-response of tafoxiparin as replacement therapy in term nulliparous women with a subripe cervix undergoing induction of labour.

[0125] The following endpoints are monitored: The time from the start of treatment to when Bishop score increases by 2 or more points or when natural labor begins, whichever comes first.The time from the start of treatment to when Bishop score increases by 3 or more points or when natural labor begins, whichever comes first.The time from the start of treatment to when Bishop score increases by 4 or more points or when natural labor begins, whichever comes first.

[0126] Cervical ripening measured by change in Bishop score from baseline to end of treatment.

[0127] Time from onset of labor to birth (onset of labor defined as the last recorded cervical dilatation of 4 cm visualized on a partograph and labor progression or the last recorded cervical dilatation of 4 cm combined with amniotomy and intravenous oxytocin). Percentage of women whose labour lasts 8 hours or less. Percentage of women in established labor ≥12 hours. Total dose of investigational medicinal product (IMP). Proportion of women who had spontaneous onset of labour (response group I). Proportion of women with a ripe cervix (response groups I+II+III). Proportion of women who have to induce labour for medical reasons according to clinical practice (response group IV).

[0128] Investigational Drug (Investigational Product, IMP) Part A of the exam: Tafoxiparin / placebo will be supplied to the site by Dilafor AB as a kit designed to constitute 300 mg of tafoxiparin or placebo for daily administration. Apart from the active substance, each ml of study drug constitutes 0.015 M phosphate buffer. Each patient's study drug kit will contain eight doses consisting of two vials containing 150 mg / ml tafoxiparin or placebo with a minimum draw volume of 1.6 ml. One dose is a reserve dose in case a dose becomes unavailable. Study drug should be administered subcutaneously by site staff every 24 ± 3 hours for a maximum of seven doses or until delivery. At each administration, 1.0 ml of drug will be drawn from each of the two vials and injected as separate sc injections in the abdominal or hip area.

[0129] Part B of the exam: Tafoxiparin / placebo will be supplied to the site by Dilafor AB in kits designed to constitute 75 mg or 150 mg of tafoxiparin for daily administration. Apart from the active substance, each ml of study drug constitutes 0.015 M phosphate buffer. Each patient's study drug kit will contain eight doses consisting of two vials for each injection occasion, containing 150 mg / ml tafoxiparin or placebo with a minimum collection volume of 1.6 ml. For subjects receiving 75 mg tafoxiparin, one vial contains the active substance and one vial contains the placebo. For subjects receiving 150 mg tafoxiparin, both vials contain the active substance. One dose is a reserve dose in case a dose becomes unavailable. Study drug must be administered subcutaneously by site staff every 24 ± 3 hours for a maximum of seven doses or until delivery. At each dose, 0.5 ml of drug is withdrawn from each of the two vials and injected as separate sc injections into the abdominal or hip area.

[0130] Study drug (placebo): The sites will be supplied with a matching placebo saline solution containing 9 mg / ml sodium chloride (NaCl) solution, which will be indistinguishable from the active solution in appearance, odor and packaging.

[0131] Non-investigational drugs: The status of the cervix is ​​checked, and in women with a Bishop score of less than 6 after 7 days, a balloon catheter is inserted, and the balloon catheter is expelled or retracted after a maximum of 24 hours. If the balloon catheter procedure is unsuccessful, treatment with oral PGE-1 may be administered according to clinical practice. Cervical balloon catheters and PGE-1 are provided by the hospital. If the cervix is ​​ripe (usually a Bishop score of 6 or more, scored by the attending physician) after 4 to 7 injections, amniotomy and oxytocin may be used to induce labor.

[0132] Study treatment and induction of labor If the subject is found eligible for the trial, he / she will be randomized to study treatment, i.e., 300 mg of tafoxiparin or matching placebo daily (Part A), or 75 mg or 150 mg daily (Part B). If baseline occurs within 24 hours after screening, do not repeat inclusion / exclusion criteria, vital signs, cervical palpation, and concomitant medications (mother) before treatment with IMP. Subjects will be included in the study if study treatment is initiated by the first injection of IMP. In Part A of the study, the daily dose of tafoxiparin will be 300 mg administered once daily. In Part B of the study, the daily dose of tafoxiparin will be 150 mg or 75 mg administered once daily. In the daily dosing example, subjects will receive SC injections.

[0133] The study drug is administered subcutaneously in the abdominal or hip area for up to a total of seven doses or until induction of labor or the onset of spontaneous labor. If the cervix is ​​still subripe after seven doses of IMP, the patient is given a cervical balloon catheter as a means of labor induction. Cervical palpation should be performed daily. Stripping of membranes to initiate labor should not be performed during the IMP procedure and prior to a ripe cervix.

[0134] Response Group I Subjects who enter spontaneous onset of labor after 1 to 7 doses of IMP should be managed according to clinical routine.

[0135] Response group II Subjects who have received 4 to 7 doses without going into spontaneous labor but who have a ripe cervix (Bishop score 6 or greater) should have labor induced by amniotomy and oxytocin treatment, but not before 4 treatment doses have been administered.

[0136] Response group III Subjects who receive seven IMPs without going into spontaneous labor and have an incompetent cervix must be treated with a hospital-provided cervical balloon catheter according to instructions provided by the sponsor. The balloon catheter must remain in the cervix until expelled or for a maximum of 24 hours. If the cervix is ​​still incompetent after 24 hours of balloon catheterization, the subject must be administered oral PGE-1 treatment according to clinical routine. If the cervix is ​​ripe (Bishop score ≥ 6), the patient should have labor induced by amniotomy and oxytocin. If the subject does not go into labor after PGE-1 and oxytocin treatment, the subject must be managed at the treating physician's discretion.

[0137] CTG recordings should be performed in conjunction with PGE-1 treatment, according to clinical practice. Abnormal CTGs with signs of hypercontractility should be treated according to clinical routine and, if necessary, with tocolytic drugs.

[0138] Response group IV For medical reasons or subject request, subjects must have labor induced before the seventh dose of IMP is administered. Subjects must be managed according to clinical practice.

[0139] Conducting clinical trials The following procedure is repeated every 24 hours or until a ripe cervix (Bishop score ≥ 6) is registered: Cervical palpation and Bishop score Vital signs (blood pressure (maternal), heart rate (maternal) Cardiotocography (fetal monitoring) Administration of investigational drug Injection site reactions Concomitant medications (maternal) Adverse events (maternal / fetal) If balloon catheterization is initiated after 7 days of IMP treatment, perform the following procedure upon drainage of the balloon catheter or 24 hours later: Vital signs (blood pressure, heart rate) Cervical palpation after 24 hours or when the balloon catheter is expelled Injection site reactions Concomitant medications (maternal) Adverse events (maternal / fetal)

[0140] If the cervix is ​​still subripened after 24 hours of balloon catheterization, oral PGE-1 treatment may be given according to clinical practice. CTG recordings should be performed 20-30 minutes before and 1 hour after every administration of PGE-1. Adverse events (maternal / fetal) should be recorded.

[0141] Secondary safety and tolerability endpoints included: 1. Proportion of patients who underwent cesarean section (CS). 2. Proportion of patients who underwent instrumental delivery (vacuum extraction (VE) / forceps delivery). 3. Fetal outcome as measured by birth weight, Apgar score, umbilical arterial or venous acidosis (pH less than 7.10) and / or basal excess less than 12 mmol / L. 4. Operational delivery instructions. 5. Rate of fetal distress. 6. Indication of referral to the Neonatal Intensive Care Unit (NICU). 7. Percentage of infants staying in the NICU for more than 48 hours. 8. Uterine hyperstimulation requiring tocolytic treatment. 9. Percentage of patients with postpartum hemorrhage (PPH) >2000ml.

[0142] Selection Criteria choice To participate in this study, subjects must meet all of the following inclusion criteria: Pregnant women aged ≥18 years and ≤64 years, who are nulliparous, have a subripe cervix with a score of 4 or less according to the Bishop score (0–10 point scale), and are planned for induction of labor after 4–7 days of IMP procedures.

[0143] Gestational age ≥ 37 weeks confirmed by ultrasound prior to 21 weeks of gestation. Singleton pregnancy. Subjects may, at the discretion of the investigator, comply with the requirements of the protocol, including the ability to be present for all necessary controls. Investigators are responsible for obtaining signed informed consent from all subjects prior to including them in any trial-related procedures.

[0144] Examples of diagnoses as a basis for induction are post-term pregnancy (40-41 weeks gestation), gestational diabetes, type 1 diabetes (well controlled), pre-eclampsia (BP < 100 diastolic, < 140 systolic), hypertension (well controlled), hepatitis (no clinically significant elevation of serum bile acids), maternal age > 40 years, humanitarian psychosocial reasons, and / or oligohydramnios.

[0145] exclusion 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 and other abnormal fetal presentations; previous uterine scarring; spontaneous rupture of membranes at selection; pathological CTG at selection; estimated fetal weight >2 SD above normal estimated fetal weight diagnosed early by ultrasound and recorded in the patient record; maternal BMI >35 in early pregnancy; known IUGR defined as 2 SD below normal; presence of eclampsia; severe preeclampsia; HELLP syndrome (hemolysis, elevated liver enzymes, and thrombocytopenia); clinically significant vaginal bleeding requiring hospitalization in the third trimester; placenta previa; previously known coagulopathy (Leiden, heterozygous-OK); heparin / LM in the past 6 months. Treatment with a WH product; current use of drugs that interfere with hemostasis, such as oral anticoagulants, nonsteroidal anti-inflammatory drug (NSAID) compounds, and vitamin K antagonists; current use or use within 1 week prior to inclusion of an acetylsalicylic acid (ASA) compound; 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 that, in the investigator's opinion, would prevent participation in the study; current participation in other interventional drug treatment trials; the subject has a fear of needles that the investigator believes would affect compliance with the investigational drug; any relevant conditions, laboratory values, or concomitant medications that, in the investigator's opinion, make the subject unsuitable for participation in the study.

[0146] delivery Onset of labor is defined as the last recorded cervical dilation of 4 cm visualized on a partogram and labor progression, or the last recorded cervical dilation of 4 cm combined with amniotomy and intravenous oxytocin. The CTG registry will be conducted continuously during established deliveries. In patients who have not already received oxytocin treatment, if labor progresses slowly (cervical dilation less than 1 cm / hour for 3 hours) or labor is stalled (no progression for 3 hours), subjects should be administered oxytocin treatment according to clinical practice. Assess and record neonatal characteristics. Arterial or venous cord blood will be collected for analysis of acidosis (pH less than 7.10) and / or base excess less than 12 mmol / L. After delivery, subjects will remain in the clinic according to clinical practice until discharge. The primary efficacy endpoint was "cervical ripening rate during the first 7 days of treatment as measured by Bishop score." Sixty-five percent of women who participated in part A of the clinical trial had a Bishop score of 0 to 2, and 35% of women who participated in part A of the trial had a Bishop score of 3 to 4.

[0147] result As shown in FIG. 1, 41.1% of women (37 of 90 women) treated with 300 mg of tafoxiparin achieved spontaneous onset of labor (p-value=0.089; p-value for Part A of the study was 0.080). 42.4% of women (36 of 85 women) treated with 150 mg of tafoxiparin achieved spontaneous onset of labor (p-value 0.039). 40.2% of women (33 of 82 women) treated with 75 mg of tafoxiparin achieved spontaneous onset of labor (p-value 0.102). Only 28.7% of women (25 of 87 women) treated with placebo achieved spontaneous onset of labor.

[0148] Thus, all three doses of tafoxiparin, 300 mg, 150 mg and 75 mg respectively, were effective in achieving spontaneous onset of labour.

[0149] Figure 2 shows the time to vaginal delivery (delivery) for women who had spontaneous onset of labour treated with 300 mg tapoxiparin (p value = 0.070), 150 mg tapoxiparin (p value 0.654) and 75 mg tapoxiparin (p value 0.114), respectively, compared to women treated with placebo. The data shows that women treated with tapoxiparin not only had spontaneous onset of labour, but also had a shorter time to vaginal delivery (delivery) compared to placebo.

[0150] Figure 3 shows the change in Bishop score (cervical ripening) in women treated with 300 mg, 150 mg and 75 mg of tapoxiparin, respectively, and placebo, who had spontaneous onset of labor. As shown in this figure, the data clearly show that women treated with 300 mg and 150 mg of tapoxiparin, respectively, achieved spontaneous onset of labor earlier than women treated with 75 mg of tapoxiparin and placebo, respectively. The data also support that both the 300 mg and 150 mg doses of tapoxiparin have a beneficial effect on cervical ripening.

[0151] Figure 4 shows the vaginal delivery pattern for women who were treated with 300 mg, 150 mg and 75 mg tafoxiparin, respectively, and placebo and had spontaneous onset of labor. As can be seen in the graph, of the women who achieved spontaneous onset of labor, only 18.2% (6 out of 33 women) of women treated with 300 mg tafoxiparin required instrumental delivery (p-value=0.048) (p-value for Part A of the study was 0.053). Of the women who were treated with 150 mg tafoxiparin and had spontaneous onset of labor, only 28.1% (9 out of 32 women) required instrumental delivery (p-value 0.422). Of the women who were treated with 75 mg tafoxiparin and had spontaneous onset of labor, only 24.1% (7 out of 29 women) required instrumental delivery (p-value=0.181). For women treated with placebo who had spontaneous onset of labour, 45.5% (10 of 22 women) required instrumental delivery.

[0152] This means that for women treated with 300 mg of tafoxiparin, 81.8% (27 of 33 women) achieved spontaneous onset of labor with uncomplicated delivery. For women treated with 150 mg of tafoxiparin, 71.9% (23 of 32 women) achieved spontaneous onset of labor with uncomplicated delivery, and for women treated with 75 mg of tafoxiparin, 75.9% (22 of 29 women) achieved spontaneous onset of labor with uncomplicated delivery. In the placebo group, only 54.5% (12 of 22 women) achieved spontaneous onset of labor and uncomplicated vaginal delivery.

[0153] In conclusion, all three doses of tafoxiparin (300 mg, 150 mg and 75 mg) were effective compared with placebo in reducing the need for instrumental delivery in women with spontaneous onset of labour.

[0154] Figure 5 shows the mode of delivery for women who had spontaneous onset of labour and were treated with 300 mg tafoxiparin, 150 mg tafoxiparin, 75 mg tafoxiparin and placebo, respectively. As can be seen in the graph, the following results were obtained for women who had spontaneous onset of labour: 73% (i.e., 27 of 37 women) treated with 300 mg of tapoxiparin achieved vaginal birth and did not require instrumental or cesarean section. 63.9% (23 of 36 women) treated with 150 mg of tapoxiparin achieved vaginal birth and did not require instrumental or cesarean section. 66.7% (22 of 33 women) treated with 75 mg of tapoxiparin achieved vaginal birth and did not require instrumental or cesarean section. For the group of women treated with placebo, only 48% (i.e., 12 of 25 women) achieved vaginal birth and did not require instrumental or cesarean section.

[0155] This graph also shows that of women with spontaneous onset of labor and treated with 300 mg of tafoxiparin, only 27% of women (i.e., 10 of 37 women) required an instrumental delivery or Caesarean section to reach birth. Of women with spontaneous onset of labor and treated with 150 mg of tafoxiparin, only 36.1% of women (13 of 36 women) required an instrumental delivery or Caesarean section to reach birth. Of women with spontaneous onset of labor and treated with 75 mg of tafoxiparin, only 33.3% of women (11 of 33 women) required an instrumental delivery or Caesarean section to reach birth. This should be compared to the placebo group, where 52% of women treated with placebo (i.e., 13 of 25 women) required an instrumental delivery or Caesarean section.

[0156] From this data it can be concluded that all three doses of tafoxiparin, 300 mg, 150 mg and 75 mg, were effective in helping women achieve vaginal birth with a reduced need for instrumental birth and caesarean section compared to placebo.

[0157] Effect of tapoxiparin on interventional onset of labour The effects of 300 mg, 150 mg and 75 mg of tafoxiparin were compared with placebo on the onset of interventional labour. The results are shown in Table 1 below.

[0158] [Table 6]

[0159] As shown in Table 1, the following surprising results were achieved: a. 70.5% of women treated with placebo required some type of intervention to induce labor, compared to only 58.2% of women treated with 300 mg tapoxiparin, 56.5% of women treated with 150 mg tapoxiparin, and 57.8% of women treated with 75 mg tapoxiparin. b. 58.0% of women in the placebo group were subjected to the use of a balloon catheter to induce labor, compared to only 46.2% of women treated with 300 mg tapoxiparin, 43.5% of women treated with 150 mg tapoxiparin, and 42.2% of women treated with 75 mg tapoxiparin. c. 54.5% of women in the placebo group were subjected to oxytocin treatment to induce labor, compared to 49.5% of women treated with 300 mg tapoxiparin, 44.7% of women treated with 150 mg tapoxiparin, and only 41.0% of women treated with 75 mg tapoxiparin. d. 56.8% of women in the placebo group underwent amniotomy to induce labor, compared to 54.9% of women treated with 300 mg tapoxiparin, 45.9% of women treated with 150 mg tapoxiparin, and only 55.4% of women treated with 75 mg tapoxiparin. e. 10.2% of women in the placebo group were subjected to PGE-1 treatment to induce labor, compared to only 5.5% of the group treated with 300 mg tafoxiparin, 8.2% of women treated with 150 mg tafoxiparin, and 8.4% of women treated with 75 mg tafoxiparin.

[0160] In conclusion, all three doses of tafoxiparin reduced the need for intervention to achieve onset of labour compared with placebo.

[0161] Fetal distress Fetal distress was assessed in women undergoing operative delivery (ie, Caesarean section or instrumental delivery) and treated with 300 mg tapoxiparin, 150 mg tapoxiparin, 75 mg tapoxiparin, and placebo, respectively. The results are shown in Table 2 below.

[0162] [Table 7]

[0163] As seen in Table 2, of the 91 women treated with 300 mg of tapoxiparin, 11 women (12.1%) required operative delivery due to fetal distress (ODFD). Of the 85 women treated with 150 mg of tapoxiparin, 20 women (23.5%) required operative delivery due to fetal distress (ODFD). Of the 83 women treated with 75 mg of tapoxiparin, 16 women (19.3%) required operative delivery due to fetal distress (ODFD).

[0164] In contrast, 20 of 88 women who received placebo required operative delivery due to fetal distress (22.7%).

[0165] Natural childbirth begins During this clinical trial, daily monitoring was also performed during the first 7 days of treatment with 300 mg, 150 mg and 75 mg tafoxiparin, and placebo to monitor the number of subjects (women) who achieved spontaneous onset of labor. The results are shown in Table 3 below.

[0166] [Table 8]

[0167] As can be seen in Table 3, the daily progression towards spontaneous onset of labor shows a dose-response relationship (i.e., response of efficacy as a function of exposure to the drug tafoxiparin). The term "N / A" in Table 3 means that on a particular study day, there were no remaining subjects (women) who had not reached spontaneous onset of labor.

[0168] Cervical ripening rate during the first 7 days of treatment Estimated cervical ripening rates were measured by Bishop score during the first 7 days of treatment with all three doses of tafoxiparin (300 mg, 150 mg and 75 mg) and with placebo. The expression "estimated cervical ripening rate" refers to an estimate of the magnitude of cervical ripening rate based on the observed value of the Bishop score.

[0169] As shown in Figure 6, cervical ripening rates were higher in women treated with all three doses of tafoxiparin (300 mg, 150 mg, and 75 mg) compared to women treated with placebo. These results also support a dose-response relationship (i.e., a response of efficacy as a function of exposure to the drug tafoxiparin).

[0170] conclusion The results of this clinical trial show that daily doses of 75 mg, 150 mg and 300 mg of tafoxiparin are effective in initiating spontaneous labor and, when used as monotherapy, prepare women for labor and delivery or reduce the need to use standard treatment therapy in women treated with any one of the three doses of 75 mg, 150 mg and 300 mg of tafoxiparin. Additionally, the results show a reduction in the need for operative delivery (i.e., Caesarean section and instrumental delivery) due to fetal distress. The results also show that women treated with any one of the three doses of 75 mg, 150 mg and 300 mg of tafoxiparin achieved a ripe cervix at an earlier time point than women treated with placebo, resulting in earlier onset of labor and uncomplicated delivery.

Claims

1. Tafoxiparin, administered at a daily dose of 75-320 mg per day, is intended for use as monotherapy at the onset of natural childbirth in women of full term.

2. The tafoxyparin for use according to claim 1, wherein the woman who is full-term pregnant is 36 to 42 weeks pregnant.

3. The tapoxyparin for use according to claim 1, wherein the woman who is pregnant is in the 37th to 42nd week of pregnancy, the 38th to 42nd week of pregnancy, the 39th to 42nd week of pregnancy, the 40th to 42nd week of pregnancy, the 41st to 42nd week of pregnancy, or the 42nd week of pregnancy.

4. The tafoxyparin for use according to claim 1, wherein the woman has a cervix that has not matured properly.

5. The tafoxyparin for use according to claim 1, 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.

6. Tafoxiparin for use according to claim 1, wherein the tafoxiparin is administered in a daily dose of 80-320 mg, 90-320 mg, 100-320 mg, 110-320 mg, 120-320 mg, 130-320 mg, 140-320 mg, 150-320 mg, 160-320 mg, 170-320 mg, 180-320 mg, 190-320 mg, 200-320 mg, 210-320 mg, 220-320 mg, 230-320 mg, 240-320 mg, 250-320 mg, 260-320 mg, 270-320 mg, 280-320 mg, 290-320 mg, or 300-320 mg per day.

7. The tafoxiparin for use according to claim 1, wherein the tafoxiparin is administered in a daily dose of 150-320 mg, 160-320 mg, 170-320 mg, 180-320 mg, 190-320 mg, 200-320 mg, 210-320 mg, 220-320 mg, 230-320 mg, 240-320 mg, 250-320 mg, 260-320 mg, 270-320 mg, 280-320 mg, 290-320 mg, or 300-320 mg per day.

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

9. Tafoxyparin for use according to any one of claims 1 to 7, wherein the use is for a maximum of 14 days.

10. Tapoxyparin for use according to claim 9, wherein the use is for one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, eleven days, twelve days, thirteen days, or fourteen days.

11. Tafoxiparin for use according to any one of claims 1 to 7, wherein the use is in nulliparous women.

12. Tafoxyparin for use according to any one of claims 1 to 7, wherein the use is for priming during childbirth.

13. Tafoxyparin for use according to any one of claims 1 to 7, wherein the use includes cervical ripening.

14. Tafoxyparin for use according to any one of claims 1 to 7, wherein the woman of full term pregnancy has an undesirable cervix.

15. Tafoxiparin for use according to any one of claims 1 to 7, wherein the tafoxyparin is administered by parenteral administration.

16. Tafoxiparin for use according to any one of claims 1 to 7, wherein the tafoxyparin is administered by local administration.

17. The use of tafoxyparin according to claim 15, wherein the parenteral administration is intravenous, intramuscular, or subcutaneous.

18. The use of tafoxyparin according to claim 16, wherein the local administration is oral, vaginal, or rectal administration.

19. The use of tafoxyparin according to any one of claims 1 to 7, wherein the use is self-administration by the pregnant woman in an outpatient setting.

20. Tafoxyparin for use according to any one of claims 1 to 7, wherein the use comprises reducing fetal distress in a fetus.

21. Tafoxyparin for use according to any one of claims 1 to 7, wherein the use further enables vaginal delivery of the child.

22. Tafoxyparin for use according to any one of claims 1 to 7, wherein the use reduces the need for surgical delivery of the child.

23. The tafoxyparin for use according to claim 22, wherein the surgical delivery is a cesarean section (CS).

24. The use of tafoxyparin according to claim 22, wherein the surgical delivery is an instrumental delivery.

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